2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine compounds

Abstract

Novel and useful compounds, such as 2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridines, are disclosed herein. Such compounds may be employed in various treatments, alleviation, or prevention of a group of disorders, such as disorders associated with Tau (tubulin associated unit) protein aggregates, such as neurofibrillary tangles (NFTs), such as Alzheimer's disease (AD).

Description

2,4-DIHYDROPYRAZOLO[3',4':4,5]PYRANO[2,3-B]PYRIDINE COMPOUNDSFIELD

[0001] This disclosure includes useful novel compounds that can be employed, for example, in the treatment, alleviation, or prevention of various disorders, such as those associated with Tau (Tubulin associated unit) protein aggregates. Such disorders may include Neurofibrillary Tangles (NFTs), such as Alzheimer’s disease (AD).BACKGROUND

[0002] Many aging diseases are based on or associated with extracellular or intracellular deposits of amyloid or amyloid-like proteins that contribute to the pathogenesis as well as to the progression of the disease. The best characterized amyloid protein that forms extracellular aggregates is amyloid beta (AP). Other examples of amyloid proteins that form extracellular aggregates are prion, ATTR (transthyretin), or ADan (ADanPP). Amyloid-like proteins, that form mainly intracellular aggregates, include, but are not limited to Tau, alpha-synuclein, TAR DNA-binding protein 43 (TDP-43), and huntingtin (htt). Diseases involving Tau aggregates are generally listed as tauopathies, such as AD.

[0003] Amyloid deposits result from misfolding of proteins followed by aggregation to give P-sheet assemblies in which multiple peptides or proteins are held together by inter-molecular hydrogenbonds. While amyloid or amyloid-like proteins have different primary amino acid sequences, their deposits often contain many shared molecular constituents, particularly the presence of P-sheet quaternary structures. The association between amyloid deposits and diseases remains largely unclear. A diverse range of protein aggregates, including both those associated and not associated with disease pathologies, have been found to be toxic, suggesting that the common molecular features of amyloid are implicated or responsible for disease on-set (Bucciantini et al., Nature, 2002, 416, 507-11). Various multimers of P-sheet aggregated peptides or proteins have also been associated with toxicity for different peptides or proteins ranging from dimers, through to soluble low molecular weight oligomers, protofibrils, or insoluble fibrillar deposits.

[0004] Disorders involving Tau aggregates are generally listed as tauopathies and they include, but are not limited to, Alzheimer’s disease (AD), familial AD, PART (primary age-related Tauopathy), Creutzfeldt- Jacob disease, dementia pugilistica, Down’s Syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, nonGuamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease,corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick’s disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD and Huntington's disease. (Williams et al., Intern. Med. J., 2006, 36, 652-60; Kovacs et al., J Neuropathol Exp Neurol. 2008; 67(10): 963-975; Higuchi et al., Neuropsychopharmacology - 5th Generation of Progress, 2002, Section 9, Chapter 94: 1339-1354; Hilton et al., Acta Neuropathol. 1995; 90(1): 101-6; Iqbal et al., Biochimica et Biophysica Acta 1739 (2005) 198- 210; McQuaid et al., Neuropathol Appl Neurobiol. 1994 Apr;20(2): 103-10; Vessel et al., Lancet Neurol 2017; 16: 311-22; Stephan et al., Molecular Psychiatry (2012) 17, 1056-1076; Anderson et al., Brain (2008), 131, 1736-1748; Savica et al., JAMA Neurol. 2013;70(7):859-866; Brown et al. Molecular Neurodegeneration 2014, 9:40; El Khoury et al., Front. Cell. Neurosci., 2014, Volume 8, Article22: 1-18; Tanskanen et al., Ann. Med. 2008;40(3):232-9; Gupta et al., CAN J OPHTHALMOL— VOL. 43, NO. 1, 2008: 53-60; Dickson et al., Int J Clin Exp Pathol2010;3(l): 1-23; Fernandez-Nogales et al., Nature Medicine, 20, 881-885 (2014); Bi et al., Nature Communications volume 8, Article number: 473 (2017); Murray et al., Biol Psychiatry. 2014 April 1; 75(7): 542-552).

[0005] A major neuropathological hallmark in AD is the intracellular neurofibrillary tangles (NFT) that originate by the aggregation of the hyperphosphorylated Tau protein, misfolded Tau or pathological Tau and its conformers. AD shares its etiopathology with many neurodegenerative tauopathies, in particular with specified types of frontotemporal dementia (FTD). The Tau protein is a freely soluble, "naturally unfolded" protein that binds avidly to microtubules (MT) to promote their assembly and stability. MT are of major importance for the cytoskeletal integrity of neurons - and thereby for the proper formation and functioning of neuronal circuits, hence for learning and memory.

[0006] Of all the agents in clinical trials for the treatment of AD in 2024, the ones targeting Tau are very scarce and represent only 7% of the Phase II clinical trials (Cummings et al., Alzheimer’s & Dementia: Translational Research & Clinical Interventions 10, 2 (2024) el2465). Current therapeutic approaches that target Tau protein comprise mainly antibody -based and active immunotherapies approaches with the main limitation of targeting only extracellular Tau. Among the approaches using small molecules, inhibitors of the glycoside hydrolase O-GlcNAcase (OGA), are the major representatives in clinical trials for intracellular aggregated Tau but are not Tau- specific. Lastly, among the Tau aggregation inhibitors only one, LMTX, is currently in clinical trials (Cummings et al., 2024). Although in recent years, Tau-based treatments have become a point of increasing focus, there is still a significant need for additional therapeutic agents that target the pathological Tau conformers that are known or presumed to cause tauopathies.SUMMARY

[0007] Provided herein are compounds that can be employed in the treatment, alleviation, or prevention of a group of disorders associated with Tau protein aggregates including, but not limited to, NFTs, such as Alzheimer’s disease (AD). Furthermore, there exists a need in the art for compounds which can be used as therapeutic agents for (a) decreasing Tau aggregates / NFTs, by preventing Tau aggregation, recognizing aggregated Tau, and / or disaggregating the aggregated Tau, for example by changing the Tau aggregate molecular conformation, and / or (b) preventing the formation of Tau aggregates, and / or (c) interfering intracellularly with Tau aggregates. This disclosure includes the surprising finding that these objects can be achieved by the compounds of Formula (I), including pharmaceutically acceptable salts thereof, as described hereinafter.

[0008] The compounds of Formula (I), including pharmaceutically acceptable salts thereof, display a high capability in decreasing Tau aggregates by, recognizing aggregated Tau and disaggregating Tau, for example by changing the Tau aggregate molecular conformation. Some compounds of Formula (I) prevent the formation of Tau aggregates, and / or interfere intracellularly with Tau aggregates. While not wishing to be bound by theory, it is theorized that the compounds of Formula (I) inhibit the Tau aggregation or disaggregate preformed Tau aggregates including when present intracellularly. Due to their unique design features, these compounds display properties such as appropriate lipophilicity and molecular weight, brain uptake and pharmacokinetics, cell permeability, solubility, and metabolic stability, to be a successful medicament for the treatment, alleviation, or prevention of tauopathies.

[0009] Ultrastructural analyses have shown that Tau inclusions are composed of paired helical filaments (PHF) or straight filaments (SF). High resolution structural analyses have shown that these filaments are composed of a core region comprising amino acids 306-378 of Tau which adapt a cross beta / beta-helix structure. The various compounds disclosed herein can recognize aggregated Tau and disaggregate Tau, for example by changing the Tau aggregate molecular conformation, and can therefore be expected to facilitate Tau clearance.

[0010] In addition, it has been shown that Tau is able to both propagate from cell-to-cell and that certain forms of Tau (acting as seeds) are able to induce the structural change of native Tau protein within the healthy cell to undergo misfolding and aggregation. It is considered that aggregated Tau is responsible for the seeding and thus of the Tau pathology spreading. The compounds of Formula (I) can interfere intracellularly with aggregated Tau and can therefore be expected to reduce Tau pathology spreading and finally prevent or reduce the associated cognitive deficits in AD.

[0011] The novel compounds of Formula (I), including pharmaceutically acceptable salts thereof, disclosed herein have the capabilities to decrease Tau aggregates, recognize aggregated Tau, and / or disaggregate Tau, for example by changing the Tau aggregate molecular conformation.

[0012] Also, various novel compounds of Formula (I), including pharmaceutically acceptable salts thereof, have the capability to prevent the formation of Tau aggregates, and / or to interfere intracellularly with Tau aggregates.

[0013] This disclosure also provides methods for the treatment of disorders associated with Tau protein aggregates including, but not limited to, NFTs, using a compound of Formula (I) or a pharmaceutical composition thereof. Further provides are pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable carrier or excipient.

[0014] As previously described, compounds disclosed herein include compounds of FormulaFormula (I) , whereinX1is a CR1or N, wherein R1is H or halogen;X2is a CR2or N, wherein R2is H or halogen;X3is a CR3or N, wherein R3is H or halogen;X4is a CH or a C-halogen;A is 4-10 membered saturated heterocyclyl with one ring atom which is N and optionally 1-2 ring atoms independently selected from N and O, wherein A is optionally substituted with 1-3 substituents selected from the group consisting of halogen, Ci-Ce alkyl, oxo, NR3R4, 4- to 6- membered heterocyclyl having one ring atom selected from N and O and optionally substituted with 1-2 halogen, and OR5;R3is selected from the group consisting of H, halogen, Ci-Ce alkyl, and C3-C6 cycloalkyl;R4is selected from the group consisting of Ci-Ce alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl with one ring atom selected from N and O; wherein R4is optionally substituted with 1-2 halogen, and wherein R5is selected from the group consisting of H and 4- to 6-membered heterocyclyl having one ring atom selected from N and O, wherein the heterocyclyl is optionally substituted with Ci-Ce alkyl; or a pharmaceutically acceptable salts thereof.

[0015] Exemplary compounds include compounds wherein X1is N. Such as where X2isCR2.

[0016] Exemplary compounds according to various aspects of Formula (I), or a pharmaceutically acceptable salts thereof, may include compounds having a formula according to Formula (II):Formula (II)

[0017] Further exemplary compounds according to various aspects of Formula (I), or a pharmaceutically acceptable salts thereof, may include compounds having the Formula (III):Formula (III)

[0018] According to various aspects, compounds may include compounds, and pharmaceutically acceptable salts, where A is selected from the group consisting of:

[0019] Additional aspects may include compounds, and pharmaceutically acceptable salts, where A is selected from the group consisting of:

[0020] Further aspects may include compounds, and pharmaceutically acceptable salts, where A is selected from the group consisting of:

[0021] More aspects may include compounds, and pharmaceutically acceptable salts, where A is selected from the group consisting of:

[0022] Some aspects may include compounds, and pharmaceutically acceptable salts, where A is selected from the group consisting of:

[0023] Exemplary compounds of Formula (I), according to various aspects, include compounds, and their pharmaceutically acceptable salts, selected from the group consisting of:1112131516171819

[0024] Also discloses herein are various methods of treating or alleviating a disorder associated with Tau protein aggregates, the method comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof as described herein to a subject in need thereof.

[0025] In various aspects, such methods may include methods where the disorder is selected from the group consisting of Alzheimer's disease (AD), familial AD, Primary Age-Related Tauopathy (PART), Creutzfeldt-Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Straussler- Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy,traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden- Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-associated neurocognitive disorder (HAND), adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD, Huntington’s disease, Aging related tau astrogliopathy (ARTAG), FTLD, FTLD with C9orf72 hexanucleotide repeat expansion, Neurofibrillary Tangle-Dominant Dementia (NFTD), Fahr’s Disease (idiopathic basal ganglia calcification), Primary Progressive Aphasia (PPA), Late-Onset Epilepsy of Unknown Etiology (LOEU), Kuf s Disease (adult-onset neuronal ceroid lipofuscinosis), Lafora Disease and Multiple system Tauopathy with dementia.

[0026] Also disclosed herein are, according to various aspects, methods of decreasing Tau aggregation comprising administering to a patient in need of decreasing Tau aggregation an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0027] Similarly, methods disclosed herein, according to various aspects, may include methods of promoting disaggregation of Tau aggregates comprising administering to a patient in need of promoting disaggregation of Tau aggregates an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0028] Various aspects disclosed herein also include methods of preventing the formation of Tau aggregates comprising administering to a patient in need of preventing the formation of Tau aggregates an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0029] Some aspects include methods of inhibiting the formation of Tau aggregates, such as methods comprising administering to a patient in need of inhibiting the formation of Tau aggregates an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0030] Also disclosed herein are pharmaceutical compositions, such as pharmaceutical compositions including a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and optionally at least one pharmaceutically acceptable excipient, carrier, diluent and / or adjuvant.

[0031] In various aspects, such pharmaceutical compositions may be used as a medicament. Various uses as a medicament may be for treatment for a disorder associated with Tau protein aggregates. As previously described, such disorders may include disorders selected from the group consisting of Alzheimer's disease (AD), familial AD, Primary Age-Related Tauopathy (PART), Creutzfeldt-Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corti cobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden- Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD and Huntington's disease.

[0032] Also disclosed herein are compounds for the manufacture of a medicament in the treatment of a disorder associated with Tau protein aggregates, which were previously described. For example, disorders, wherein the disorder is Alzheimer's disease.

[0033] Such compounds may also be used in therapy, such as, in various aspects, where the therapy is for treatment of a disorder associated with Tau protein aggregates.

[0034] Also, combinations including a therapeutically effective amount of such compounds disclosed herein, and their pharmaceutically acceptable salts, with one or more therapeutic agents different from the compound are also disclosed herein. Such therapeutic agents may include, for example, therapeutic agents selected from the group consisting of compounds against oxidative stress; anti-amyloid drug; anti-amyloid-beta antibody, anti-apoptotic compounds; metal chelators; inhibitors of DNA repair such as pirenzepine and metabolites; 3 -amino- 1 -propanesulfonic acid (3APS); 1,3-propanedisulfonate (1,3PDS); alpha-secretase activators; beta- and gamma-secretase inhibitors including BACE1; Tau proteins; neurotransmitters; beta-sheet breakers; attractants for amyloid beta clearing / depleting cellular components; inhibitors of N-terminal truncated amyloid beta including pyroglutamated amyloid beta 3-42; anti-inflammatory molecules; cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil, and / or galantamine; Ml agonists; amyloid-beta or Tau modifying drugs; nutritive supplements; neurological drugs; corticosteroids, antibiotics, or antiviral agents.

[0035] Also disclosed herein are use of the disclosed compounds for use as an analytical reference or an in vitro screening tool.DETAILED DESCRIPTION

[0036] As previously stated, this disclosure includes novel and useful compounds and methods. These compounds and methods may be employed in the treatment, alleviation, or prevention of a group of disorders associated with Tau protein aggregates including, but not limited to, NFTs, such as Alzheimer’s disease (AD).

[0037] As used interchangeably herein, “treatment” and / or “treating” and / or “treat” are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, stopping, or reversing of the progression of the disorders described herein, but does not necessarily indicate a total elimination of all disorder symptoms. Treatment includes administration of one of the compounds disclosed herein for treatment of a disease or condition in a human that would benefit from a reduction in the propagation of at least one of tau aggregate formation, NFT formation and neuronal loss, and includes: (a) inhibiting further progression of the disease, e.g., arresting its development; and (b) relieving the disease, e.g., causing regression of the disease or disorder or alleviating symptoms or complications thereof.

[0038] The various aspects disclosed below are not intended to be exhaustive or limit the disclosure to the precise form disclosed in the following detailed description. Rather, the aspects are chosen and described so that others skilled in the art may utilize their teachings.Definitions

[0039] Within the meaning of the present application the following definitions apply:

[0040] "Alkyl" refers to a saturated straight or branched organic moiety consisting of carbon and hydrogen atoms. Examples of suitable alkyl groups have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl and isobutyl.

[0041] " Hal" or "halogen" refers to F, Cl, Br, and I, preferably F.

[0042] "3- to 8-membered ring" refers to a three-, four-, five-, six-, seven- or eight-membered ring wherein none, one or more of the carbon atoms in the ring have been replaced by 1 or 2 (for the three-membered ring), 1, 2 or 3 (for the four-membered ring), 1, 2, 3, or 4 (for the five-membered ring) or 1, 2, 3, 4, or 5 (for the six-membered ring) 1, 2, 3, 4, 5 or 6 (for the seven-membered ring), or 1, 2, 3, 4, 5, 6 or 7 (for the eight-membered ring) of the same or different heteroatoms, whereby the heteroatoms are selected from O, N and S.

[0043] “Heterocycle” and “heterocyclyl” may be used interchangeably and refer to saturated or partially unsaturated monocyclic, bicyclic, or tricyclic groups having ring atoms including 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. Such monocyclic, bicyclic, and tricyclic groups have a total number of ring atoms regardless of the number of rings (e.g., 7-membered heterocyclyl may refer to a monocyclic heterocyclyl group, such as azepanyl, a spiro bicyclic group such as oxapspiroheptanyl or oxa- azospiroheptanyl, a bridged ring such as a diazabicycloheptanyl, or a fused bicyclic group such as an azabicycloheptanyl). Bicyclic and tricyclic heterocyclyl groups may include isolated rings, spiro rings, fused rings, and bridged rings. The heterocyclyl group may be attached through any ring atom, and where indicated, may optionally include one or more non-hydrogen substituents unless such attachment or substitution would violate valence requirements or result in a chemically unstable compound.

[0044] Compounds of Formula (I) having one or more optically active carbons can exist as racemates and racemic mixtures (including mixtures in all ratios), stereoisomers (including diastereomeric mixtures and individual diastereomers, enantiomeric mixtures and single enantiomers, mixtures of conformers and single conformers), tautomers, atropisomers, and rotamers.All isomeric forms are included in the present disclosure. Compounds described in this disclosure include compound containing olefinic double bonds include E and Z geometric isomers. Also included herein are all pharmaceutically acceptable salts, prodrugs, polymorphs, hydrates and solvates.

[0045] The term "polymorphs" refers to the various crystalline structures of the compounds of Formula (I). This may include, but is not limited to, crystal morphologies (and amorphous materials) and all crystal lattice forms. Various salts disclosed herein may be crystalline and may exist as more than one polymorph.

[0046] Solvates, hydrates as well as anhydrous forms of the salt are also encompassed by this disclosure. The solvent included in the solvates is not particularly limited and can be any pharmaceutically acceptable solvent. Examples include water and Ci 4 alcohols (such as methanol or ethanol).

[0047] "Pharmaceutically acceptable salts" are defined as derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric acid and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. The pharmaceutically acceptable salts disclosed herein may be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts can be found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, the disclosure of which is hereby incorporated by reference.

[0048] The compounds of Formula (I) can also be provided in the form of a prodrug, namely a compound which is metabolized in vivo to the active metabolite. As used herein, the term “prodrug” may be interpreted to include any covalently bonded compound which releases the active parent pharmaceutical due to in vivo biotransformation. The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8 ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated herein by reference.

[0049] "Pharmaceutically acceptable" is defined as those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0050] The patients or subjects are typically animals, particularly mammals, more particularly humans.

[0051] " Tau" as used herein refers to a highly soluble microtubule binding protein mostly found in neurons and includes the major 6 isoforms, cleaved or truncated forms, and other modified forms such as arising from phosphorylation, glycosylation, glycation, prolyl isomerization, nitration, acetylation, polyamination, ubiquitination, sumoylation and oxidation.

[0052] "Aggregated Tau" refers to aggregated monomers of Tau peptides or proteins which are folded into the oligomeric or polymeric structures.

[0053] "Neurofibrillary Tangles" (NFTs) as used herein refer to insoluble aggregates of the hyperphosphorylated Tau protein containing paired helical filaments (PHF) and straight filaments. Their presence is a hallmark of AD and other diseases known as tauopathies.

[0054] The definitions and preferred definitions given in the "Definition" -section apply to all of the embodiments described below unless stated otherwise.Pharmaceutical compositions

[0055] While it is possible for the compounds of Formula (I) to be administered alone, it is preferable to formulate them into a pharmaceutical composition in accordance with standard pharmaceutical practice. Thus, this disclosure also provides for pharmaceutical compositions which may include a therapeutically effective amount of a compound of Formula (I) optionally in admixture with a pharmaceutically acceptable carrier, diluent, adjuvant or excipient.

[0056] Pharmaceutically acceptable excipients are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publishing Co., New Jersey (1975). The pharmaceutical excipient can be selected with regard to the intended routeof administration and standard pharmaceutical practice. The excipient must be acceptable in the sense of being not deleterious to the recipient thereof.

[0057] Pharmaceutically useful excipients that may be used in the formulation of various pharmaceutical compositions disclosed herein, which may comprise, for example, carriers, vehicles, diluents, solvents such as monohydric alcohols such as ethanol, isopropanol and polyhydric alcohols such as glycols and edible oils such as soybean oil, coconut oil, olive oil, safflower oil cottonseed oil, oily esters such as ethyl oleate, isopropyl myristate, binders, adjuvants, solubilizers, thickening agents, stabilizers, disintegrants, glidants, lubricating agents, buffering agents, emulsifiers, wetting agents, suspending agents, sweetening agents, colorants, flavors, coating agents, preservatives, antioxidants, processing agents, drug delivery modifiers and enhancers such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, dextrose, hydroxypropyl-B-cyclodextrin, polyvinylpyrrolidone, low melting waxes, and ion exchange resins.

[0058] The routes for administration (delivery) of the various disclosed compounds include, but are not limited to, one or more of: oral (e.g., as a tablet, capsule, or as an ingestible solution), topical, mucosal (e.g., as a nasal spray or aerosol for inhalation), nasal, parenteral (e.g., by an injectable form), gastrointestinal, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, buccal, epidural, and sublingual.

[0059] For example, the compounds can be administered orally in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.

[0060] The tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.

[0061] Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the agent maybe combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and / or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

[0062] If the compounds of Formula (I), or pharmaceutically acceptable salts thereof, are administered parenterally, then examples of such administration include one or more of: intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously administering the compounds; and / or by using infusion techniques. For parenteral administration, the compounds are best used in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood. The aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary. The preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

[0063] As indicated, the compounds of Formula (I) can be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, spray or nebulizer with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA134AT) or 1, 1,1,2,3,3,3-heptafluoropropane (HFA 227EA), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container, pump, spray or nebulizer may contain a solution or suspension of the active compound, e.g., using a mixture of ethanol and the propellant as the solvent, which may additionally contain a lubricant, e.g., sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

[0064] Alternatively, the compounds of Formula (I) can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder. The compounds of Formula (I) may also be dermally or transdermally administered, for example, by the use of a skin patch.

[0065] They may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route. For ophthalmic use, the compounds can be formulated as micronized suspensions in isotonic, pH was adjusted, sterile saline, or, preferably, as solutions inisotonic, pH was adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride. Alternatively, they may be formulated in an ointment such as petrolatum.

[0066] For application topically to the skin, the compounds of Formula (I) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, they can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0067] Typically, a physician will determine the actual dosage most suitable for an individual subject. The specific dose level and frequency of dosage for any particular individual may be varied and may depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.

[0068] Proposed doses of the compounds for administration to a human (of approximately 70 kg body weight) may be from 0.1 mg to 1 g, preferably 1 mg to 500 mg of the active ingredient per unit dose. The unit dose may be administered one or multiple times per day, for example, 1 to 4 times per day. The dose may depend on the route of administration. It will be appreciated that it may be necessary to make routine variations to the dosage depending on the age and weight of the patient as well as the severity of the condition to be treated. The precise dose and route of administration will ultimately be at the discretion of the attendant physician or veterinarian.

[0069] The compounds disclosed herein may also be used in combination with other therapeutic agents. When compounds of this disclosure are used in combination with a second therapeutic agent active against the same disease, the dose of each compound may differ from that when the compound is used alone.

[0070] The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route. When administration is sequential, either a compound of this disclosure or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. Whencombined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

[0071] The pharmaceutical compositions disclosed herein may be produced in a manner known per se to the skilled person as described, for example, in Remington's Pharmaceutical Sciences, 15th Ed., Mack Publishing Co., New Jersey (1975).

[0072] The diseases or conditions that can be treated, alleviated, or prevented with the compounds of Formula (I) are disorders associated with Tau protein aggregates such as neurodegenerative disorders. Examples of diseases and conditions which can be treated, alleviated, or prevented are caused by or associated with the formation of neurofibrillary lesions. This is the predominant brain pathology in tauopathy. The diseases and conditions comprise a heterogeneous group of neurodegenerative diseases or conditions including diseases or conditions which show co-existence of Tau and amyloid pathologies.

[0073] Examples of the diseases and conditions which can be treated, alleviated or prevented include, but are not limited, to Alzheimer’s disease (AD), familial AD, PART (Primary Age-Related Tauopathy), Creutzfeldt-Jacob disease, dementia pugilistica, Down’s Syndrome, Gerstmann- Straussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonismdementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido- ponto-nigral degeneration, Pick’s disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD and Huntington'sdisease. Preferably the diseases and conditions which can be treated, alleviated or prevented include Alzheimer’s disease (AD), as well as other neurodegenerative tauopathies such as Creutzfeldt-Jacob disease, dementia pugilistica, amyotrophic lateral sclerosis (ALS), argyrophilic grain disease, corticobasal degeneration (CBD), frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Pick’s disease (PiD), progressive supranuclear palsy (PSP), tangle predominant dementia, Parkinson dementia complex of Guam, Hallervorden- Spatz disease, chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), and other frontotemporal lobar degeneration. More preferably Alzheimer’s disease (AD), corticobasal degeneration (CBD), Pick’s disease (PiD), and progressive supranuclear palsy (PSP).

[0074] The compounds of Formula (I) can also be employed to decrease protein aggregation, in particular Tau aggregation. The ability of a compound to decrease Tau aggregation can, for example, be determined using the ThT assay (Hudson et al., FEBS J., 2009, 5960-72).

[0075] The various compounds disclosed herein may be used in the treatment of a wide range of disorders in which the neuroinflammation process is associated with misfolding and / or pathologic aggregation of Tau protein.

[0076] The compounds of Formula (I) can be used as an analytical reference or an in vitro screening tool for characterization of tissue with Tau pathology and for testing of compounds targeting Tau pathology on such tissue.

[0077] The compounds of this disclosure may also be provided in the form of a mixture with at least one further biologically active compound and / or a pharmaceutically acceptable carrier and / or a diluent and / or an excipient. The compound and / or the further biologically active compound are preferably present in a therapeutically effective amount.

[0078] The nature of the further biologically active compound may depend on the intended use of the mixture. The further biologically active substance or compound may exert its biological effect by the same or a similar mechanism as the compound disclosed herein or by an unrelated mechanism of action or by a multiplicity of related and / or unrelated mechanisms of action.

[0079] Generally, the further biologically active compound may include neutron-transmission enhancers, psychotherapeutic drugs, acetylcholineesterase inhibitors, calcium -channel blockers, biogenic amines, benzodiazepine tranquillizers, acetylcholine synthesis, storage or release enhancers, acetylcholine postsynaptic receptor agonists, monoamine oxidase-A or -B inhibitors, N- methyl-D-aspartate glutamate receptor antagonists, non-steroidal anti-inflammatory drugs, antioxidants, and serotonergic receptor antagonists. In particular, the further biologically activecompound can be selected from the group consisting of a compound used in the treatment of amyloidosis, compounds against oxidative stress, anti-apoptotic compounds, metal chelators, inhibitors of DNA repair such as pirenzepine and metabolites, 3 -amino- 1 -propanesulfonic acid (3APS), 1,3 -propanedisulfonate (1,3PDS), a-secretase activators, P- and y-secretase inhibitors, Tau proteins, neurotransmitter, P-sheet breakers, attractants for amyloid beta clearing / depleting cellular components, inhibitors of N-terminal truncated amyloid beta including pyroglutamated amyloid beta 3-42, anti-inflammatory molecules, or cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil, and / or galantamine, Ml agonists, other drugs including any amyloid or Tau modifying drug and nutritive supplements, an antibody, including any functionally equivalent antibody or functional parts thereof, or a vaccine.

[0080] In further aspects, various mixtures comprise niacin or memantine together with a compound of the present disclosure and, optionally, a pharmaceutically acceptable carrier and / or a diluent and / or an excipient.

[0081] In some aspects, various mixtures are provided that may comprise as a further biologically active compound “atypical antipsychotics” such as, for example clozapine, ziprasidone, risperidone, aripiprazole or olanzapine for the treatment of positive and negative psychotic symptoms including hallucinations, delusions, thought disorders (manifested by marked incoherence, derailment, tangentiality), and bizarre or disorganized behavior, as well as anhedonia, flattened affect, apathy, and social withdrawal, together with a novel compound discloses herein and, optionally, a pharmaceutically acceptable carrier and / or a diluent and / or an excipient.

[0082] Other compounds that can be suitably used in mixtures in combination with the novel compounds disclosed herein may include, for example, those described in WO 2004 / 058258 (see especially pages 16 and 17) including therapeutic drug targets (pages 36 to 39), alkanesulfonic acids and alkanolsulfuric acids (pages 39 to 51), cholinesterase inhibitors (pages 51 to 56), NMDA receptor antagonists (pages 56 to 58), estrogens (pages 58 to 59), non-steroidal anti-inflammatory drugs (pages 60 and 61), antioxidants (pages 61 and 62), peroxisome proliferators-activated receptor (PPAR) agonists (pages 63 to 67), cholesterol-lowering agents (pages 68 to 75), amyloid inhibitors (pages 75 to 77), amyloid formation inhibitors (pages 77 to 78), metal chelators (pages 78 and 79), anti-psychotics and anti-depressants (pages 80 to 82), nutritional supplements (pages 83 to 89) and compounds increasing the availability of biologically active substances in the brain (see pages 89 to 93) and prodrugs (pages 93 and 94), which document is incorporated herein by reference.

[0083] This disclosure also includes all suitable isotopic alternatives of the various compounds disclosed herein. An isotopic variation of the compound may be understood as to include variations in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into some of the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine such as 2H, 3H, 13C, 14C, 15N, 170, 180, 35S, 18F and 36CI respectively. Certain isotopic variations of some of the compounds disclosed herein, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and / or substrate tissue distribution studies. Tritiated, (3H), and carbon-14 (14C), isotopes are particularly preferred for their ease of preparation and delectability. 18F -labeled compounds are particularly suitable for imaging applications such as PET. Further, substitution with isotopes such as deuterium,(2H), may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds of this disclosure may generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Preparations hereafter using appropriate isotopic variations of suitable reagents.Compounds

[0084] As previously described, the present disclosure includes various compounds of Formula (I), or pharmaceutically acceptable salts thereof:Formula<') , whereinX1is a CR1or N, wherein R1is H or halogen; X2is a CR2or N, wherein R2is H or halogen; X3is a CR3or N and R3is H or halogen; X4is a CH or a C-halogen; A is 4-10 membered saturated heterocyclyl with one ring atom which is N and optionally 1-2 ring atoms independently selected from N and O, wherein A is optionally substituted with 1-3 substituents selected from the group consisting of halogen, Ci-Ce alkyl, oxo, NR3R4, 4- to 6-membered heterocyclyl having one ring atom selected from N and O and optionally substituted with 1-2 halogen, and OR5; R3is selected from thegroup consisting of H, halogen, Ci-Ce alkyl, and C3-C6 cycloalkyl; R4is selected from the group consisting of Ci-Ce alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl with one ring atom selected from N and O; wherein R4is optionally substituted with 1-2 halogen, and wherein R5is selected from the group consisting of H and 4- to 6-membered heterocyclyl having one ring atom selected from N and O, wherein the heterocyclyl is optionally substituted with Ci-Ce alkyl.

[0085] In further aspects, compounds of Formula (II) and Formula (III) are also included:

[0086] Various aspects of Formula (I), Formula (II), and Formula (III) include compounds where A is selected from the group consisting of:

[0087] A is selected from the group consisting of:35

[0088] In further aspects, the following compounds of Formula (I) are exemplified in Table 1 :Table 1444546Certain abbreviations are as follows:General Synthetic Schemes for the preparation of building blocksScheme la."Lg" means a leaving group. Examples of suitable leaving groups include -F"Pg" means a protecting group. Examples of suitable protecting groups include -SEM

[0089] Commercially available ethyl 3-bromo-l / / -pyrazole-4-carboxylate can be protected with suitable protecting groups as 2-(trimethylsilyl)ethoxymethyl chloride (SEM-C1) to afford the SEM- protected product. Palladium catalyzed coupling of the SEM-protected compound with a suitable boronic acid or ester carrying a leaving group employing Suzuki coupling conditions (XPhos Pd G2, base, solvent) affords the desired coupling product after purification. Reduction of the ester moiety with a suitable reagent (DIBAL-H) in a suitable solvent affords the primary alcohol reduction product. Intramolecular cyclization via nucleophilic aromatic substitution employing a suitable base in a suitable solvent affords the tricyclic cyclization product after purification. Cleavage of the protecting group employing first acidic (TFA) and second basic (NaOH) conditions afford the desired tricyclic building block A containing aNH-moiety. Alternatively, commercially available 2-fhioronicotinaldehyde can be reacted with propargyl alcohol and a suitable base via nucleophilic aromatic substitution to afford the reaction product after purification. Reaction of the aldehyde moiety with p-toluenesulfonyl hydrazide affords the corresponding hydrazone. Treatment of the hydrazone with a suitable base (CS2CO3) at elevated temperature (hetero Diels-Alder reaction) affords the desired tricyclic building block A containing a NH-moiety after purification.Scheme lb."LG" means a leaving group. Examples of suitable leaving groups include -F, -Br, -I"Lg" means a leaving group. Examples of suitable leaving groups include -F"X1" is CR1or N, wherein R1is selected from H"X2" is CR2or N, wherein R2is selected from H

[0090] Commercially available ethyl 3-bromo-l / / -pyrazole-4-carboxylate can be treated with a suitable boronic acid or ester carrying a leaving group employing Chan-Lam coupling conditions (CU(OAC)2, air, base, solvent) to afford the coupling product after purification. Palladium catalyzedcoupling of the Cham-Lam coupling product with a suitable boronic acid or ester carrying a leaving group employing Suzuki coupling conditions (XPhos Pd G2, base, solvent) affords the desired coupling product after purification. Reduction of the ester moiety with a suitable reagent (DIBAL-H) in a suitable solvent affords the primary alcohol reduction product. Intramolecular cyclization via nucleophilic aromatic substitution employing a suitable base in a suitable solvent affords the desired tricyclic building blocks B carrying a leaving group after purification. Alternatively, the tricyclic building block A containing a NH-moiety can be treated with a suitable boronic acid or ester carrying a leaving group employing Chan-Lam coupling conditions (Cu(0Ac)2, air, base, solvent) to afford the desired tricyclic building blocks B carrying a leaving group after purification. Treatment of tricyclic building block A containing a NH-moiety with 2-fluoro-5 -iodo-pyridine employing nucleophilic aromatic substitution conditions (base, solvent) affords the desired tricyclic building blocks C carrying a leaving group after purification.Scheme 1c."Lg" means a leaving group. Examples of suitable leaving groups include -F"X2" is CR2wherein R2is selected from H"n" is 0, 2

[0091] Commercially available ethyl 3-bromo-l / / -pyrazole-4-carboxylate can be treated with 8-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-l,4-dioxa-8-azaspiro[4.5]decane, prepared in two steps from l-bromo-4-iodobenzene via Buchwald coupling (Pd2(dba)s, XantPhos, base, solvent) with l,4-dioxa-8-azaspiro[4.5]decane followed by boronic ester formation (bis(pinacolato)diboron, Pd(dppf)C12, KO Ac, solvent), employing Chan-Lam coupling conditions (Cu(OAc)2, air, base, solvent) to afford the coupling product after purification. Palladium catalyzed coupling of the Cham- Lam coupling product with a suitable boronic acid or ester carrying a leaving group employing Suzuki coupling conditions (Pd(dppf)C12, base, solvent) affords the desired coupling product after purification. Reduction of the ester moiety with a suitable reagent (DIBAL-H) in a suitable solventaffords the primary alcohol reduction product. Intramolecular cyclization via nucleophilic aromatic substitution employing a suitable base in a suitable solvent affords the desired tricyclic cyclization product. Cleavage of the acetal moiety with a suitable acid (HC1) affords the desired tricyclic building block D with n = 2 containing a ketone-moiety. Alternatively, tricyclic building block B with X2= CH can be coupled with 5,8-dioxa-2-azaspiro[3.4]octane employing Buchwald conditions (SPhos Pd G3, base, solvent) to afford the coupling product after purification. Cleavage of the acetal moiety with a suitable acid (H2SO4) affords the desired tricyclic building block D with n = 0 containing a ketone-moiety.Scheme Id.If "Y1" is NBoc then "Y2" is CH2, if "Y1" is CH2then "Y2" is NBocIf "Z1" is NH then "Z2" is CH2, if "Z1" is CH2then "Z2" is NH"n" is 0, 1, 2

[0092] Tricyclic building block B with X2= N can be coupled with l,4-dioxa-8-azaspiro[4.5]decane, l,4-dioxa-7-azaspiro[4.4]nonane, and 5,8-dioxa-2-azaspiro[3.4]octane employing nucleophilicaromatic substitution reactions (base, solvent) to afford the coupling products after purification. Cleavage of the acetal moiety with a suitable acid (HC1) affords the desired tricyclic building blocks E with n = 0, 1, 2 containing a ketone-moiety. Tricyclic building block B with X2= N can be coupled with tert-butyl octahydro- 17 / -pyrrolo[3,2-c]pyridine-l -carboxylate and tert-butyl octahydro- 2J7-pyrrolo[3,4-c]pyridine-2-carboxylate employing nucleophilic aromatic substitution reactions (base, solvent) to afford the coupling products after purification. Cleavage of the Boc-protecting groups with a suitable acid (TFA) affords the desired tricyclic building blocks I that contain a secondary amine-moiety. Tricyclic building block B with X2= N can be coupled with tert-butyl octahydro-5J / -pyrrolo[3,4-c]pyridine-5-carboxylate employing a nucleophilic aromatic substitution reaction (base, solvent) to afford the coupling product after purification. Cleavage of the Boc- protecting group with a suitable acid (TFA) affords the desired tricyclic building block J containing a secondary amine-moiety.Scheme le.

[0093] Tricyclic building block C with X1= N can be coupled with l,4-dioxa-8- azaspiro[4.5]decane, l,4-dioxa-7-azaspiro[4.4]nonane, and 5,8-dioxa-2-azaspiro[3.4]octane employing Buchwald conditions (SPhos Pd G3, base, solvent) to afford the coupling products after purification. Cleavage of the acetal moiety with a suitable acid (HC1, H2SO4) affords the desired tricyclic building blocks F with n = 0, 1, 2 containing a ketone-moiety.

[0094] Tricyclic building blocks B with X2= N and C with "X1" = N, CH can be coupled with 6- fluoro-l,4-dioxa-8-azaspiro[4.5]decane employing Buchwald conditions (SPhos Pd G3, base, solvent) to afford the coupling products after purification. Cleavage of the acetal moiety with a suitable acid (H2SO4) affords the desired tricyclic building blocks G containing a ketone-moiety. Tricyclic building block C with "X1" = CH can be coupled with tert-butyl piperidin-4-ylcarbamate employing Buchwald conditions (SPhos Pd G3, base, solvent) to afford the coupling product after purification. Cleavage of the acetal moiety with a suitable acid (HC1) affords the desired tricyclic building block H containing a primary amine moiety.

[0095] Protection of tert-butyl 3-hydroxypyrrolidine-l-carboxylate with 4-methylbenzenesulfonyl chloride (Tos-Cl) in a suitable solvent and employing a catalyst (DMAP) affords the tosyl -protected compound after purification. Nucleophilic displacement of the tosyl moiety with benzyl 3- hydroxyazetidine-1 -carboxylate employing a suitable base (NaH) and solvent affords the desired product after purification. Cleavage of the Boc-protecting group with a suitable acid (TFA) affords the desired building block K containing a free secondary amine and a secondary amine still protected by the benzyloxycarbonyl group.Scheme lh.

[0096] Commercially available 4-chloropyridine was treated with tert-butyl 3 -hy droxy azetidine- 1- carboxylate employing a nucleophilic aromatic substitution reaction (base, solvent) to afford thecoupling product after purification. Treating the coupling product with bromomethyl benzene affords the alkylation product. Reduction of the alkylation product with a suitable reagent (NaBTU) affords the reaction product after purification. Cleavage of the benzyl moiety and parallel reduction of the double bond employing a catalyst (Pd / C) in methanol affords the desired building block L.

[0097] Alternatively, pyridin-4-ol was treated with bromo-cyclopropane employing a nucleophilic aromatic substitution reaction (base, solvent) to afford the coupling product after purification.Treating the coupling product with bromomethyl benzene afforded the alkylation product. Reduction of the alkylation product with a suitable reagent (NaBTB) afforded the reaction product after purification. Cleavage of the benzyl moiety and parallel reduction of the double bond employing a catalyst (Pd / C) in methanol affords the desired building block L’.

[0098] Alternatively, pyridin-4-ol and 3-fluorocyclobutan-l-ol were reacted under Mitsunobu conditions (PPhs, DIAD) in a suitable solvent to afford the reaction product after purification. Treating the coupling product with bromomethyl benzene afforded the alkylation product. Reduction of the alkylation product with a suitable reagent (NaBTB) afforded the reaction product after purification. Cleavage of the benzyl moiety and parallel reduction of the double bond employing a catalyst (Pd / C) in methanol affords the desired building block L”.

[0099] Tricyclic building block B with X2= N can be coupled with 5-benzyloctahydro-l / Z- pyrrolo[3,2-c]pyridine, prepared in two steps from tert-butyl octahydro-l / / -pyrrolo[3,2-c]pyridine-l- carboxylate by reductive amination with benzaldehyde (NaBH(OAc)3, acetic acid) in a suitable solvent followed by Boc cleavage with acid (TFA), employing nucleophilic aromatic substitution reactions (base, solvent) to afford the coupling product after purification. Cleavage of the benzyl moiety by hydrogenation using a suitable catalyst (Pd / C) and solvent affords the desired tricyclic building block M after purification contain a secondary amine-moiety.Scheme lj.C Coupling Formula IAmines"LG" means a leaving group. Examples of suitable leaving groups include -I

[0100] Tricyclic building block C with "X1" = CH can be coupled with tert-butyl 3,6- diazabicyclo[3.1.1]heptane-6-carboxylate and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(177)- carboxylate employing Buchwald conditions (SPhos Pd G3, base, solvent) to afford the coupling products after purification. Cleavage of the Boc-protecting group with a suitable acid (TFA) affords compounds of Formula (I). Alternatively, tricyclic building block C with "X1" = N can be coupled with 3-fluoro-l,3'-biazetidine employing Buchwald conditions (SPhos Pd G3, base, solvent) to afford compounds of Formula (I) after purification.Scheme Ik,LG" means a leaving group. Examples of suitable leaving groups include -F

[0101] Tricyclic building block B with X2= N can be coupled with tert-butyl 5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylate, tert-butyl (5)-2-methylpiperazine-l -carboxylate, tert-butyl (A)-2-methylpiperazine-l -carboxylate, and building block L employing nucleophilic aromatic substitution reactions (base, solvent) to afford the coupling products after purification. Cleavage of the Boc-protecting group with a suitable acid (HC1, TFA) affords compounds of Formula (I).Alternatively, tricyclic building block B with X2= N can be coupled with 3-fluoro-l,3'-biazetidine, l-(azeti din-3 -yl)-3, 3 -difluoropyrrolidine, l-(azeti din-3 -yl)-3 -fluoropyrrolidine, 4-methoxypiperidine, 4-cyclopropoxypiperidine, and cz -4-(3-fluorocyclobutoxy)piperidine employing nucleophilic aromatic substitution reactions (base, solvent) to afford compounds of Formula (I) after purification. Compounds of Formula (I) containing a secondary amine moiety can be further modified by reductive amination (formaldehyde, NaBH(OAc)3, acetic acid) in a suitable solvent to obtain compounds of formula (I) after purification containing a tertiary amine moiety.Scheme 11.LG" means a leaving group. Examples of suitable leaving groups include -F

[0102] Tricyclic building block B with X2= N can be coupled with building block K employing nucleophilic aromatic substitution reaction (base, solvent) to afford the coupling product after purification. Cleavage of the Cbz-protecting followed by in situ reductive amination was achieved by employing a catalyst (Pd / C) in the presence of formaldehyde and hydrogen in a suitable solvent after purification. The mixture of enantiomers was separated by employing SFC chromatography to compounds of Formula (I). Alternatively, the Cbz-protecting group of the nucleophilic aromatic substitution product can be cleaved by hydrogenation employing a suitable catalyst (Pd / C) in a suitable solvent to afford compounds of Formula (I) after purification.Scheme Im,"n" is 0, 1, 2

[0103] Tricyclic building blocks E with X2= N and n = 0, 1, 2 can be coupled with A-methyloxetan-3-amine, 3 -fluoroazetidine, cyclobutylamine, oxetan-3 -amine, 3,3-difluorocyclobutan-l-amine, 3- fluorocyclobutan- 1 -amine, cis-3 -fluorocyclobutan- 1 -amine, trans-3 -fluorocyclobutan- 1 -amine, tetrahydrofuran-3 -amine, (A)-tetrahydrofuran-3 -amine, cyclopropylamine, 3,3-difluoroazetidine, 3,3- difluoropyrrolidine, (5)-tetrahydrofuran-3 -amine, A-methyl cyclobutyl amine, tetrahydro-2 / / -pyran-4- amine, and methylamine employing reductive amination conditions (NaBH(OAc)3, acetic acid;NaBFfCN, titanium(IV) isopropoxide, acetic acid)) in a suitable solvent to afford compounds ofFormula (I) after purification. In case compounds of Formula (I) are racemates, the enantiomers can be obtained by SFC chromatography. Compounds of Formula (I) containing a secondary amine moiety can be further modified by reductive amination (formaldehyde or oxetan-3-one, NaBH(OAc)3, acetic acid) in a suitable solvent to obtain compounds of formula (la) after purification containing a tertiary amine moiety. Alternatively, the tricyclic building block E with X2= N and n = 2 can be treated with Grignard reagents (CFFMgBr) to afford compounds of Formula (I) after purification. Alternatively, the tricyclic building block E with X2= N and n = 2 can be treated with a reducing agent (NaBFU) to afford compounds of Formula (I) after purification.Scheme In,Formula I"n" is 0, 1, 2

[0104] Tricyclic building blocks D with X2= CH and n = 0, 2 can be coupled with A-methyloxetan- 3-amine, ox etan-3 -amine, 3,3-difluorocyclobutan-l-amine, 3-fluorocyclobutanamine, and methylamine employing reductive amination conditions (NaBH(OAc)s, acetic acid; NaBHjCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification. In case compounds of Formula (I) are racemates, the enantiomers can be obtained by SFC chromatography. Compounds of Formula (I) containing a secondary amine moiety can be further modified by reductive amination (formaldehyde, NaBH(OAc)3, acetic acid) in a suitable solvent to obtain compounds of formula (la) after purification containing a tertiary amine moiety.

[0105] Tricyclic building blocks F with X1= N and n = 0, 1, 2 can be coupled with ox etan-3 -amine, A-m ethyl ox etan-3 -amine, 3,3-difhiorocyclobutan-l-amine, cyclobutylamine, 3-fhiorocyclobutanamine, trans-3-fluorocyclobutanamine, and 3,3 -difhiorocyclobutan-1 -amine employing reductive amination conditions (NaBH(0Ac)3, acetic acid; NaBHsCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification. In case compounds of Formula (I) are racemates, the enantiomers can be obtained by SFC chromatography. Compounds of Formula (I) containing a secondary amine moiety can be further modified by reductive amination (formaldehyde, NaBH(0Ac)3, acetic acid) in a suitable solvent to obtain compounds of Formula (I) after purification containing a tertiary amine moiety. Alternatively, the tricyclic building block F with X1= N and n = 2 can be treated with a reducing agent (NaBH4) to afford compounds of formula (I) after purification.Scheme lo.2. SFC separationFormula I Formula I

[0106] Tricyclic building block G with X2= CH and X1= CH can be coupled with oxetan-3 -amine employing reductive amination conditions (NaBH(OAc)s, acetic acid; NaBHsCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification. Alternatively, tricyclic building block G with X2= N and X1= CH can be coupled with oxetan-3- amine and fS')-tetrahydrofuran-3 -amine employing reductive amination conditions (NaBH(0Ac)3, acetic acid; NaBHjCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification. Tricyclic building block G with X2= CH and X1= N can be coupled with ox etan-3 -amine employing reductive amination conditions (NaBH(OAc)s, acetic acid; NaBHiCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification. In case compounds of Formula (I) are racemates, the enantiomers can be obtained by SFC chromatography. Compounds of Formula (I) containing a secondary amine moiety can be further modified by reductive amination (formaldehyde, NaBH(0Ac)3, acetic acid) in a suitable solvent to obtain compounds of formula (I) after purification containing a tertiary amine moiety.Scheme Ip.Reductive1 . ReductiveI amination2. SFC separation Formula I

[0107] Tricyclic building block I with X2= N, Z1= NH, Z2= CH2 and tricyclic building block I with X2= N, Z1= CH2, Z2= NH can be coupled with oxetan-3 -amine employing reductive amination conditions (NaBH(OAc)3, acetic acid; NaBHiCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification. In case compounds ofFormula (I) are racemates, the enantiomers can be obtained by SFC chromatography.Scheme Iq.Reductive amination2. SFC separationFormula I

[0108] Tricyclic building block J with X2= N can be coupled with oxetan-3 -amine employing reductive amination conditions (NaBH(OAc)s, acetic acid; NaBHiCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification. In case compounds of Formula (I) are racemates, the enantiomers can be obtained by SFC chromatography.Scheme lr.Reductive1. Reductive Formula Iamination2. SFC separation

[0109] Tricyclic building block M with X2= N can be coupled with oxetan-3 -amine employing reductive amination conditions (NaBH(OAc)s, acetic acid; NaBFfCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification. In case compounds of Formula (I) are racemates, the enantiomers can be obtained by SFC chromatography.Scheme Is.

[0110] Commercially available l-bromo-2-fluoro-4-iodobenzene can be treated with morpholine employing Buchwald conditions (Pd2(dba)s, XantPhos, base, solvent) to afford the coupling product after purification. The boronic ester moiety is introduced by employing suitable reaction conditions (bis(pinacolato)diboron, Pd(dppf)C12, KO Ac, solvent) to afford the boronic ester derivative. The boronic ester derivative can be coupled with tricyclic building block A employing Chan-Lam coupling conditions (Cu(0Ac)2, air, base, solvent) to afford compounds of Formula (I) after purification. Alternatively, tricyclic building block A can be coupled with (6-morpholinopyridin-3- yl)boronic acid employing Chan-Lam coupling conditions (Cu(0Ac)2, air, base, solvent) to afford compounds of Formula (I) after purification.Scheme It.

[0111] Tricyclic building block A can be coupled with (4-bromo-3-fluorophenyl)boronic acid employing Chan-Lam coupling conditions (Cu(OAc)2, air, base, solvent) to afford the coupling product after purification. Further reaction with l,4-dioxa-8-azaspiro[4.5]decane employing Buchwald conditions (Ruphos Pd G3, base, solvent) affords the reaction product after purification. Cleavage of the acetal moiety by acid (HC1) affords the ketone derivative. The ketone derivative is treated with oxetan-3 -amine and (5)-tetrahydrofuran-3 -amine employing reductive amination conditions (NaBH(OAc)3, acetic acid; NaBFLCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification.Scheme lu.

[0112] Tricyclic building block A can be coupled with 5 -bromo-2, 3 -difluoropyridine employing aromatic nucleophilic substitution conditions (base, solvent) to afford the coupling product after purification. Further reaction with l,4-dioxa-8-azaspiro[4.5]decane employing Buchwald conditions (Sphos Pd G3, base, solvent) affords the reaction product after purification. Cleavage of the acetal moiety by acid (HC1) affords the ketone derivative. The ketone derivative is treated with ox etan-3 - amine employing reductive amination conditions (NaBH(OAc)3, acetic acid; NaBHsCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford compounds of Formula (I) after purification containing a secondary amine moiety. An additional reductive amination (HCHO, NaBH(OAc)3, acetic acid) in a suitable solvent affords compounds of formula (I) after purification containing a tertiary amine moiety.Scheme Iv.

[0113] Commercially available 2,5-dibromo-3-fluoropyridine can be treated with l,4-dioxa-8- azaspiro[4.5]decane employing Buchwald conditions (Pd2(dba)s, XantPhos, base, solvent) to afford the coupling product after purification. Cleavage of the acetal moiety by acid (HC1) affords the ketone derivative. The ketone derivative is treated with / f-methyloxetan-3 -amine employing reductive amination conditions (NaBH(OAc)3, acetic acid; NaBFfCN, titanium(IV) isopropoxide, acetic acid) in a suitable solvent to afford the reaction product after purification. The treatment of the tertiary amine derivative with tricyclic building block A employing Ullmann coupling conditions (Cui, / ra / / .s- l,2-diaminocyclohexane, base) in a suitable solvent affords compounds of Formula (I) after purification.Scheme Iw.

[0114] Commercially available 2, 5 -dibromopyrazine and 2, 5 -dibromopyrimidine can be coupled with 4-methoxypiperidine employing aromatic nucleophilic substitution conditions (base, solvent) to afford the reaction products after purification. The treatment of the reaction products with tricyclic building block A employing Ullmann coupling conditions (Cui, traw -l,2-diaminocyclohexane, base) in a suitable solvent affords compounds of Formula (I) after purification.Scheme lx.LG" means a leaving group. Examples of suitable leaving groups include -Br

[0115] Commercially available tert-butyl 3,3-difluoro-4-oxo-piperidine-l-carboxylate ketone derivative is treated with / ra / / .s-3-fluorocyclobutan- l -amine and cv.s-3-fluorocyclobutan- l -amine employing reductive amination conditions (NaBH(OAc)3, molecular sieve, acetic acid) in a suitable solvent to afford the reaction products after purification. Cleavage of the Boc-protecting group by acid (HC1) affords the corresponding amine derivatives as salts. Coupling of the amine derivatives with tricyclic building block B (X2= N) employing Buchwald conditions (RuPhos Pd G4, base, solvent) affords compounds of Formula (I) after purification.

[0116] All reagents and solvents were obtained from commercial sources and used without further purification. 1H NMR spectra were recorded on Bruker AV 300 and 400 MHz spectrometers in deuterated solvents. Chemical shifts (5) are reported in parts per million and coupling constants (J values) in hertz. Spin multiplicities are indicated by the following symbols: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad singlet). Mass spectra were obtained on an Agilent 1290 Infinity II spectrometer with a 6130 Chemstation and an Agilent 1200 Infinity II spectrometer with a 6130 Chemstation. GC-MS data were collected using an Agilent 7890B gas chromatograph and 5977B mass spectrometer. Infrared spectra were obtained on a PerkinElmer spectrometer.Chromatography was performed using silica gel (Fluka: Silica gelOl 60, 0.063-0.2 mm) and suitable solvents as indicated in specific examples. Flash purification was conducted with a Biotage Isolera with HP-Sil or KP-NH SNAP cartridges (Biotage) and the solvent gradient indicated in specific examples. Thin layer chromatography (TLC) was carried out on silica gel plates with UV detection.Preparation 12,4-Dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridineMethod A Step AEthyl 3-bromo-l-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate

[0117] To a solution of ethyl 3-bromo-lH-pyrazole-4-carboxylate (100 g, 456.55 mmol) in THF(1000 ml) was added NaH (45.65 g, 1.14 mol, 60% purity) at 0 °C and stirred for 0.5 hr, then SEM-Cl (91.34 g, 547.86 mmol, 96.96 ml) was added. The mixture was stirred for 1 hr at 20 °C. The mixture was cooled to 20 °C and poured into ice-water (2000 ml). The aqueous phase was extracted with EtOAc (3 x 500 ml). The combined organic phase was washed with saturated aqueous NaCl (500 ml x 1), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography eluting with petroleum ether in EtOAc (50 / 1) to give the title compound (142.5 g, 89.36%) as a yellow oil. ES / MS: 350.1 (M+H)+'H-NMR (DMSO-tC) 8 = 8.00 - 8.09 (m, 1H), 5.39 - 5.44 (m, 2H), 4.18 - 4.29 (m, 4H), 3.50 - 3.62 (m, 5H), 1.24 - 1.31 (m, 7H), 0.79 - 0.87 (m, 5H), -0.07 - -0.05 (m, 9H).Step BEthyl 3-(2-fluoro-3-pyridyl)-l-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate

[0118] To a solution of ethyl 3-bromo-l-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate (80 g, 229.03 mmol) and (2-fluoro-3-pyridyl)boronic acid (129.09 g, 916.13 mmol) in the mixture of H2O (150 ml) and toluene (600 ml) and EtOH (300 ml) was added XPHOS-Pd-G? (9.01 g, 11.45 mmol) and K3PO4 (145.85 g, 687.10 mmol). The mixture was stirred at 70 °C for 1 hr. LCMS showed the reaction was completed. The mixture was cooled to 20 °C and poured into ice-water (1000 ml). The aqueous phase was extracted with EtOAc (3 x 500 ml). The combined organic phase was washed with saturated aqueous NaCl (500 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography eluting with petroleum ether in EtOAc (30 / 1) to give the title compound (21.5 g, 25.69%) as a yellow oil. ES / MS 336.3 (M+H)+. 'H-NMR (DMSO-t / 6) 5 ppm 8.38 - 8.43 (m, 1 H) 8.07 - 8.17 (m, 2 H) 7.58 - 7.50 (m, 1 H) 5.42 - 5.47 (m, 1 H) 5.33 - 5.38 (m, 2 H) 4.10 (br s, 2 H) 3.41 - 3.49 (m, 2 H) 1.03 - 1.09 (m, 3 H) 0.72 - 0.78 (m, 2 H) 0.08-0.10 (m, 9 H).Step C[3-(2-Fluoro-3-pyridyl)-l-(2-trimethylsilylethoxymethyl)pyrazol-4-yl]methanol

[0119] To a solution of ethyl 3-(2-fluoro-3-pyridyl)-l-(2-trimethylsilylethoxymethyl)pyrazole-4- carboxylate (14 g, 38.31 mmol) in THF (140 ml) was added DIBAL-H (1 M, 191.53 mL) at 0 °C .Then the mixture was stirred at 20 °C for 0.5 hr. The mixture was cooled to 20 °C and poured into saturated potassium sodium tartrate salt (1000 ml). The aqueous phase was extracted with EtOAc (3x 500 ml). The combined organic phase was washed with saturated aqueous NaCl (500 ml), dried with anhydrous ISfeSC , filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography eluting with petroleum ether / EtOAc (15 / 1,5 / 1) to give the title compound (9.33 g, 75.30%) as a yellow oil. ES / MS: 324.1 (M+H)+. 'H-NMR DMSO-tC) 58.24 - 8.28 (m, 1H), 8.04 - 8.16 (m, 2H), 7.63 (s, 1H), 7.42 - 7.48 (m, 1H), 5.29 (s, 2H), 4.25 (s, 2H), 3.36 - 3.43 (m, 2H), 0.69 - 0.79 (m, 2H), 0.09 (s, 8H).Step D Trimethyl-[2-(8-oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaen-4- y Imethoxy ) ethyl ] si lane

[0120] To a solution of [3-(2-fluoro-3-pyridyl)-l-(2-trimethylsilylethoxymethyl)pyrazol-4- yl]methanol (8.3 g, 25.66 mmol) in DMF (100 ml) was added CS2CO3 (41.81 g, 128.31 mmol). The mixture was stirred at 100 °C for 2 hr. LCMS showed the reaction was completed. The mixture was cooled to 20 °C and poured into ice-water (300 ml). The aqueous phase was extracted with EtOAc (3 x 80 ml). The combined organic phase was washed with saturated aqueous NaCl (80 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=8 / l) to give the title compound (5.1 g, 65.50%) as a brown oil. ES / MS: 304.1 (M+H)+. 'H-NMR (DMSO-t / e) 5 8.07 - 8.12 (m, 2H), 7.93 - 8.03 (m, 2H), 7.80 - 7.83 (m, 1H), 7.45 - 7.48 (m, 1H), 7.04 - 7.09 (m, 1H), 5.75 - 5.76 (m, 1H), 5.66 - 5.68 (m, 2H), 5.45 - 5.46 (m, 1H), 5.45 (d, J= 0.6 Hz, 1H), 5.43 - 5.43 (m, 1H), 3.53 - 3.57 (m, 2H), 3.31 - 3.33 (m, 1H), 0.81 - 0.85 (m, 2H), -0.08 - -0.10 (m, 9H).Step E 8-Oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-ylmethanol

[0121] To a mixture solution of TFA (90 ml) and DCM (10 ml) was added trimethyl-[2-(8-oxa- 3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaen-4-ylmethoxy)ethyl]silane (8 g, 26.37 mmol) . The mixture was stirred at 20 °C for 2 hrs. The mixture was cooled to 20 °C and poured into ice-water (300 ml) and neutralized by Na2CO3 and extracted with EtOAc (3 x 80 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give the title compound (15 g, crude) as a white solid.Step F2,4-Dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0122] To a solution of 8-oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaen-4- ylmethanol (10 g, 49.21 mmol) in THF (50 ml) was added aqueous NaOH (4 M, 50.00 ml). The mixture was stirred at 20 °C for 6 hrs. The mixture was cooled to 20 °C and poured into ice-water (500 ml). The aqueous phase was extracted with EtOAc (6 x 90 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml x 1), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by prep-HPLC (column: Welch Xtimate C18 250*70mm#10um; mobile phase: [water(NH4HCO3)-ACN];B%: 0%-30%,20min) to give the title compound (5 g, 58.67% ) as a white solid. ES / MS: 174.0 (M+H)+. ‘H-NMR (DMSO ) 5 = 8.47 (s, 1H), 7.77 - 7.90 (m, 1H), 7.70 - 7.76 (m, 1H), 7.06 - 7.14 (m, 1H), 6.73 - 6.95 (m, 1H), 5.40 - 5.44 (m, 2H).Alternatively, 2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine was prepared using method B below:Method B Step A 2-Prop-2-ynoxypyridine-3-carbaldehyde 2-(prop-2-yn-l-yloxy)ni cotinaldehyde

[0123] To a solution of 2-fluoropyridine-3-carbaldehyde 2-fluoronicotinaldehyde (50.00 g, 399.68 mmol) in DMF (500 ml) was added K2CO3 (165.71 g, 1.20 mol), then prop-2-yn-l-ol (67.22 g, 1.20 mol) was added. The reaction mixture was stirred at 50 °C for 16 hrs. The mixture was poured into H2O (1500 ml) and extracted with EtOAc (3 x 500 ml). The combined organic phase was washedwith saturated aqueous NaCl (3 x 300 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude was purified by silica gel column chromatography eluting with petroleum ether in EtOAc (5: 1) to give the title compound as a white solid. (38 g, 57.82%).ES / MS: 161.9 (M+H)+. 'H-NMR (DMSO-t / 6) 8 = 10.23 - 10.27 (m, 1H), 8.47 - 8.51 (m, 1H), 8.12 - 8.16 (m, 1H), 7.20 - 7.28 (m, 1H), 5.13 - 5.15 (m, 2H), 3.56 (t, J = 2.4 Hz, 1H).Step B(E)-4-Methyl-N'-((2-(prop-2-yn-l-yloxy)pyridin-3-yl)methylene)benzenesulfonohydrazide

[0124] To a solution of 2-prop-2-ynoxypyridine-3-carbaldehyde 2-(prop-2-yn-l- yloxy)nicotinaldehyde (9 g, 55.85 mmol) in EtOH (100 ml) was added 4- methylbenzenesulfonohydrazide (10.40 g, 55.85 mmol). The reaction mixture was stirred at 25°C for 1 hr. This reaction mixture was concentrated in vacuum to give the title compound as a white solid. (77.00 g). ES / MS: 330.1 (M+H)+.JH NMR (400 MHz, DMSO-d6) 511.52 - 11.68 (m, 1H), 8.19 - 8.23 (m, 1H), 8.07 - 8.10 (m, 1H), 7.96 - 8.02 (m, 1H), 7.72 - 7.78 (m, 2H), 7.37 - 7.44 (m, 2H), 7.05 - 7.12 (m, 1H), 5.01 (d, J = 2.4 Hz, 2H), 3.44 - 3.58 (m, 1H), 2.33 - 2.38 (m, 3H)Step C2,4-Dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0125] To a solution of (E)-4-methyl-N'-((2-(prop-2-yn-l-yloxy)pyridin-3- yl)methylene)benzenesulfonohydrazide (20.00 g, 60.72 mmol) in dioxane (2000 ml) was added CS2CO3 (29.68 g, 91.08 mmol). The mixture was stirred at 100 °C for 16 hrs. This reaction mixture was filtered, and the filtrate was concentrated in vacuum. The crude product was purified by reversed-phase HPLC (column: Welch Xtimate C18 250*70mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:15%-40% B over 18.0 min) to afford 2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine as a yellow solid (12.00 g, 24.25%). ES / MS: 174.1(M+H)+. 'H-NMR (DMSO-t / e) 8 7.88 (br d, J= 62 Hz, 1H), 7.71 (br s, 1H), 7.47 - 7.56 (m, 1H), 6.34 - 6.44 (m, 1H), 4.39 (s, 2H), 2.50 (s, 4H).Preparation 22-(6-Fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine2-(6-Fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine was prepared according to either method A or method B.Method A Step AEthyl 3-bromo-l-(6-fluoro-3-pyridyl)pyrazole-4-carboxylate

[0126] To a solution of 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (50.92 g, 228.27 mmol) and ethyl 5-bromo-lH-pyrazole-4-carboxylate (50 g, 228.27 mmol) in pyridine (500 ml) was added 4A MS (228.27 mmol) and Cu(OAc)2 (41.46 g, 228.27 mmol) in one portion at 25°C. The mixture was heated to 100 °C and stirred for 5 hrs under O2. The mixture was cooled to 20 °C and poured into ice-water (1000 ml). The aqueous phase was extracted with EtOAc (3 x 300 ml). The combined organic phase was washed with saturated aqueous NaCl (300 ml), dried with anhydrous ISfeSC , filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography eluting with petroleum ether in EtOAc (50 / 1) to give the title compound (200 g, 92.98% yield) as a white solid. ES / MS: 314.2 (M+H)+. 'H-NMR (DMSO-t / 6) 6 = 9.15 - 9.24 (m, 1H), 8.75 - 8.84 (m, 1H), 8.44 - 8.54 (m, 1H), 7.36 - 7.45 (m, 1H), 4.26 - 4.34 (m, 2H), 1.29 - 1.36 (m, 3H).Step BEthyl 3 -(2-fluoro-3 -pyridyl)- 1 -(6-fluoro-3 -pyridyl)pyrazole-4-carboxylate

[0127] To a solution of ethyl 3-bromo-l-(6-fluoro-3-pyridyl)pyrazole-4-carboxylate (100 g, 318.36 mmol) and (2-fluoro-3-pyridyl)boronic acid (89.72 g, 636.72 mmol) in a mixture of toluene (600 ml) and EtOH (300 ml) and H2O (150 ml) was added K3PO4 (202.73 g, 955.08 mmol) and XPhos-Pd G2 (10.02 g, 12.73 mmol) in one portion at 25 °C. The mixture was heated to 70 °C and stirred for 16 hrs under N2. The mixture was cooled to 20 °C and poured into ice-water (1000 ml). The aqueous phase was extracted with EtOAc (3 x 300 ml). The combined organic phase was washed with saturated aqueous NaCl (300 ml), dried with anhydrous ISfeSCU, filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography eluting with petroleum ether in EtOAc (30 / 1) to give the title compound (80 g, 76.08%) as a yellow solid. ES / MS: 331.5 (M+H)+. ’H-NMR (DMSO-t / e) 8 9.26 - 9.38 (m, 1H), 8.83 - 8.93 (m, 1H), 8.54 - 8.60 (m, 1H), 8.34 - 8.43 (m, 1H), 8.09 - 8.25 (m, 1H), 7.45 - 7.58 (m, 1H), 7.38 - 7.44 (m, 1H), 5.67 - 5.80 (m, 1H), 4.14 - 4.22 (m, 1H), 3.85 - 3.95 (m, 1H), 3.25 - 3.37 (m, 1H), 2.06 - 2.09 (m, 1H), 1.97 - 2.04 (m, 1H), 1.04 - 1.09 (m, 3H)Step C[3-(2-Fluoro-3-pyridyl)-l-(6-fluoro-3-pyridyl)pyrazol-4-yl]methanol

[0128] To a solution of ethyl 3 -(2-fluoro-3 -pyridyl)- l-(6-fluoro-3-pyridyl)pyrazole-4-carboxylate (20 g, 60.55 mmol) in THF (200 ml) was added DIBAL-H (1 M, 181.66 ml) at 0 °C .Then stirred at 25 °C for 0.5 hr. The mixture was poured into ice water (1000 ml). Then the precipitate was collected by filtration to give the title compound (19 g, crude, 80% purity) as a yellow solid.ES / MS: 289.2 (M+H)+'H NMR (400 MHz, DMSO-d6) 5 8.72 - 8.93 (m, 1 H) 8.60 - 8.70 (m, 1 H) 8.45 - 8.55 (m, 1 H) 8.21 - 8.37 (m, 2 H) 7.46 - 7.56 (m, 1 H) 7.33 - 7.43 (m, 1 H) 5.10 - 5.23 (m, 1 H) 4.53 (br s, 1 H)Step D2-(6-Fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0129] To a solution of [3-(2-fluoro-3-pyridyl)-l-(6-fluoro-3-pyridyl)pyrazol-4-yl]methanol (17 g,58.98 mmol) in THF (1000 ml) was added NaH (9.44 g, 235.90 mmol, 60% purity) at 0 °C, and stirred at 45 °C for 16 hrs. The mixture was cooled to 20 °C and poured into ice-water (2500 ml). The precipitate was collected by filtration to give the title compound (15 g, crude) as a yellow solid. ES / MS: 268.9 (M+H)+. 'H-NMR (DMSO-tfc) 5 = 8.71 - 8.82 (m, 1H), 8.41 - 8.57 (m, 2H), 8.09 - 8.21 (m, 2H), 7.34 - 7.45 (m, 1H), 7.08 - 7.20 (m, 1H), 5.48 - 5.61 (m, 2H).Method B2-(6-Fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0130] To a solution of 2-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (1.24 g, 5.54 mmol) and 2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (0.32 g, 1.85 mmol) in pyridine (20 ml) was added 4A MS (1.85 mmol) and Cu(OAc)2 (335.63 mg, 1.85 mmol) at 20 °C. The mixture was heated to 100 °C and stirred for 4 hrs under O2. The mixture was poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 50 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified on 230-400 silica gel cartridge using a Biotage purification system by employing a petroleum ether in EtOAc (50 / 1 / 5 / 1) to give the title compound (0.25 g, 50.43%) as a yellow solid.ES / MS: 268.9 (M+H)+. 'H-NMR (DMSO-t / e) 8 = 8.71 - 8.82 (m, 1H), 8.41 - 8.57 (m, 2H), 8.09 - 8.21 (m, 2H), 7.34 - 7.45 (m, 1H), 7.08 - 7.20 (m, 1H), 5.48 - 5.61 (m, 2H).

[0131] The compounds in Table 2 were prepared analogous to Method B of Preparation 2.Table 2Preparation 52-(5-Iodopyridin-2-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0132] To a solution of 2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (1 g, 5.77 mmol) and 2-fluoro-5-iodo-pyridine (1.29 g, 5.77 mmol) in DMF (10 ml) was added K2CO3 (2.39 g, 17.32 mmol). The mixture was stirred at 100 °C for 16 hrs. The mixture was cooled to 20 °C and pouredinto ice-water (200 ml). The precipitate was collected by filtration on a diatomaceous earth pad to give the title compound (2 g, 82.3%) as a white solid. ES / MS: 376.9 (M+H)+.Preparation 6 l-(4-(Pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)phenyl)piperidin-4-oneStep A8-(4-Bromophenyl)-l,4-dioxa-8-azaspiro[4.5]decane

[0133] To a solution of l-bromo-4-iodo-benzene (200 g, 706.95 mmol) and l,4-dioxa-8- azaspiro[4.5]decane (111.35 g, 777.65 mmol) in toluene (2000 ml) was added Xantphos (40.91 g, 70.70 mmol), Pd2(dba)s (9.71 g, 10.60 mmol) and CS2CO3 (460.68 g, 1.41 mol) and then the mixture was stirred at 100 °C for 12 hrs., under N2 atmosphere. The mixture was poured into water (1500 ml) and extracted with EtOAc (3 x 1000 ml), the organic layers were washed with saturated aqueous NaCl (2 x 800 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified on 230-400 silica gel cartridge using a Biotage purification system by employing a petroleum ether in EtOAc (10 / 1 : 1 / 1) to give the title compound (610 g, 71.55%) as a yellow solid.JH NMR (chloroform-d) 5 = 7.30 - 7.36 (m, 1H), 6.75 - 6.87 (m, 1H), 3.93 - 4.06 (m, 2H), 3.25 - 3.35 (m, 2H), 1.77 - 1.90 (m, 2H).Step B 8-[4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,4-dioxa-8-azaspiro[4.5]decane

[0134] A mixture of 8-(4-bromophenyl)-l,4-dioxa-8-azaspiro[4.5]decane (165 g, 553.37 mmol) ,4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (421.56 g, 1.66 mol), Pd(dppf)Cl2(8.10 g, 11.07 mmol) and KOAc (271.54 g, 2.77 mol) in DMSO (1000 ml) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 hrs.,under N2 atmosphere. The mixture was poured into water (400 ml) and extracted with EtOAc (2 x 400 ml), the organic layers were washed with saturated aqueous NaCl (5 x 50 ml), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified on 230-400 silica gel cartridge using a Biotage purification system by employing a petroleum ether in EtOAc (15 / 1 :5 / l) to give the title compound (415 g, 65.17%) as a yellow solid.'H NMR (chloroform-d) 5 = 7.62 - 7.78 (m, 1H), 6.85 - 6.95 (m, 1H), 3.92 - 4.05 (m, 3H), 3.34 - 3.47 (m, 4H), 1.76 - 1.86 (m, 4H), 1.29 - 1.40 (m, 9H).Step CEthyl 3-Bromo-l-[4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]pyrazole-4-carboxylate

[0135] A mixture of ethyl 3-bromo-lH-pyrazole-4-carboxylate (50 g, 228.27 mmol ), 8-[4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]-l,4-dioxa-8-azaspiro[4.5]decane (78.81 g, 228.27 mmol), CU(OAC)2 (62.19 g, 342.41 mmol), 4A MS (50 g) in pyridine (500 ml) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 100 °C for 16 hrs., under O2. The mixture was concentrated under vacuum to remove pyridine. The residue with was diluted with EtOAc (8000 ml) and washed with saturated EDTA (5 x 1000 ml) and saturated aqueous NaCl (1000 ml), the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified on 230-400 silica gel cartridge using a Biotage purification system by employing a petroleum ether in EtOAc (10 / 1 => 1 / 1) to give the title compound (85 g, 39.47%) as a yellow solid. 'H NMR (chloroform-d) 5 = 8.20 - 8.25 (m, 1H), 7.46 - 7.55 (m, 2H), 6.95 - 7.03 (m, 2H), 4.30 - 4.41 (m, 2H), 3.94 - 4.05 (m, 4H), 3.35 - 3.44 (m, 4H), 1.80 - 1.90 (m, 4H), 1.34 - 1.42 (m, 3H).Step DEthyl l-[4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]-3-(2-fluoro-3-pyridyl)pyrazole-4- carboxylate

[0136] To a solution of ethyl 3-bromo-l-[4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]pyrazole-4- carboxylate (35 g, 80.22 mmol) in dioxane (400 ml) and H2O (100 ml) was added (2-fluoro-3-pyridyl)boronic acid (22.61 g, 160.44 mmol), Na2COs (25.51 g, 240.66 mmol) and Pd(dppf)C12 (3.50 g, 4.78 mmol) and then degassed and purged with N2 for 3 times. The mixture was stirred at 100 °C for 16 hrs., under N2 atmosphere. LCMS showed the reaction was completed. The mixture was extracted with water (1600 ml) and EA (2 xl200 ml), the organic layers were washed with saturated aqueous NaCl (3x 300 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified on 230-400 silica gel cartridge using a Biotage purification system by employing a petroleum ether / EtOAc (10 / 1 => 1 / 1) to give the title compound (48 g, 65.79%) as a yellow solid.JH NMR (chloroform-d) 5 = 8.40 (s, 1H), 8.28 (br d, J= 4.0 Hz, 1H), 8.02 (br t, J= 8.2 Hz, 1H), 7.59 (d, J= 8.5 Hz, 2H), 7.27 - 7.31 (m, 1H), 7.01 (d, J= 8.8 Hz, 2H), 4.19 - 4.31 (m, 2H), 4.01 (s, 4H), 3.35 - 3.46 (m, 4H), 1.81 - 1.91 (m, 4H), 1.23 (t, J= 7.1 Hz, 3H).Step E (l-(4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-3-(2-fluoropyridin-3-yl)-lH-pyrazol-4- yl)methanol

[0137] To a solution of ethyl l-[4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]-3-(2-fluoro-3- pyridyl)pyrazole-4-carboxylate (48 g, 106.08 mmol) in THF (480 ml) was added DIBAL-H (1 M, 318.25 ml) at -15 °C slowly, and then the reaction mixture was stirred at 0 °C for 0.5 hr. The mixture was poured into saturated potassium sodium tartrate tetrahydrate salt (1500 ml) and EtOAc (1000 ml) was added. The mixture was stirred for 0.5 hr. Then the aqueous phase was extracted with EtOAc (2 x 600 ml), the organic layers washed with saturated aqueous NaCl (500 ml), dried over Na2SO4, filtered, and concentrated under vacuum to give the title compound (38 g, crude) as a yellow solid. 'H NMR (chloroform-d) 5 = 8.22 - 8.30 (m, 1H), 8.14 - 8.22 (m, 1H), 7.92 - 8.01 (m, 1H), 7.53 - 7.62 (m, 2H), 7.28 - 7.34 (m, 1H), 6.95 - 7.06 (m, 2H), 4.66 - 4.78 (m, 2H), 3.98 - 4.05 (m, 4H), 3.30 - 3.46 (m, 4H), 1.84 - 1.90 (m, 4H), 1.78 - 1.83 (m, 1H).Step F 2-(4-(l,4-Dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine

[0138] A mixture of [l-[4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl]-3-(2-fluoro-3- pyridyl)pyrazol-4-yl]methanol (17.5 g, 42.64 mmol), CS2CO3 (41.68 g, 127.91 mmol) in DMF (700 ml) was degassed and purged with N2 for 3 times, and then stirred at 100 °C for 10 hours under N2 atmosphere. LCMS showed the reaction was completed. The mixture was poured into water (2800 ml). The precipitate was collected by filtration and dried in vacuo. The crude product was triturated with EtOAc (400 ml) at 20 °C for 16 hrs., then filtered to give the title compound (28.5 g, 68.48%) as a yellow solid.Step G l-[4-(7-Oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)phenyl]piperidin-4- one

[0139] To a mixture of H2O (300 ml) and concentrated HC1 (300 ml) was added 2-(4-(l,4- dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (29.5 g, 75.56 mmol), and then the solution was stirred at 70 °C for 1 hr. The residue was poured into water (1000 ml), neutralized by Na2CO3.The aqueous phase was extracted with EtOAc (3 x 400 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 400 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give the title compound as a yellow solid which was used directly in the next step.

[0140] The following preparations on Table 3 were prepared analogous to preparation 6.Table 3Preparation 13 l-[5-(8-Oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaen-4-yl)-2- pyridyl]piperidin-4-oneES / MS 348.2 (M+H)+Step A2-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine

[0141] To a solution of 2-(6-Fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine (Preparation 2) (4.6 g, 17.15 mmol) and l,4-dioxa-8-azaspiro[4.5]decane (7.37 g, 51.45 mmol, 6.59 ml) in DMF (46 ml) was added Cs2CO3 (16.76 g, 51.45 mmol). The reaction mixture was stirred at 100 °C for 16 hrs. The mixture was poured into ice-water (300 ml). The aqueous phase was extracted with EtOAc (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (100 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the title compound (7 g, 85% purity) as a yellow solid. ES / MS: 392.2 (M+H)+.Step B l-[5-(8-Oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaen-4-yl)-2- pyridyl]piperidin-4-one

[0142] The solution of 2-(6-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-3-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (6.90 g, 17.63 mmol) in HC1 (6 M, 69 ml) was stirred at 25 °C for 2 hrs. The mixture was cooled to 20 °C and poured into ice-water (300 ml) and neutralized by ISfeCCh. The aqueous phase was extracted with EtOAc (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (100 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the title compound (5.5 g, 85% purity) as a white solid. ES / MS: 348.2 (M+H)+.

[0143] The following preparation on Table 3a was prepared analogous to preparation 13.Table 3aPreparation 14 l-(5-(Pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2-yl)pyrrolidin-3-oneES / MS: 334.2 (M+H)+.Step A 2-(6-(l,4-dioxa-7-azaspiro[4.4]nonan-7-yl)pyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine

[0144] To a solution of 2-(6-Fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine (Preparation 2) (1 g, 3.73 mmol) and l,4-dioxa-7-azaspiro[4.4]nonane (962.97 mg, 7.46 mmol) in DMF (10 ml) was added Cs2CO3 (3.64 g, 11.18 mmol). The mixture was stirred at 100 °C for 16 hrs. The mixture was cooled to 20 °C and poured into ice-water (200 ml). The aqueous phase was extracted with EtOAc (3 x 80 ml). The combined organic phase was washed with saturated aqueous NaCl (80 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude was washed with EtOAc (5 ml) to give the title compound (0.8 g) as a yellow solid. ES / MS: 378.3 (M+H)+.Step B l-(5-(Pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2-yl)pyrrolidin-3-one

[0145] 2-(6-(l,4-dioxa-7-azaspiro[4.4]nonan-7-yl)pyridin-3-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (0.8 g, 2.12 mmol) was added to H2SO4 (10 ml). The mixture was stirred at 25 °C for Ihr. The mixture was poured into ice-water (100 ml) and neutralized by ISfeCOs. The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give the title compound (0.6 g) as a yellow solid which was used for the next step directly without further purification. ES / MS: 334.2 (M+H)+.Preparation 15 l-[6-(8-Oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaen-4-yl)-3- pyridyl]piperidin-4-oneES / MS 348.2 (M+H)+Step A 2-(5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0146] To a solution of 2-(5-iodopyridin-2-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (1 g, 2.66 mmol) and l,4-dioxa-8-azaspiro[4.5]decane (Preparation 5)(1.14 g, 7.98 mmol, 1.02 ml) in 2-methylbutan-2-ol (10 ml) was added CS2CO3 (4.33 g, 13.29 mmol) and SPhos Pd G3 (207.43 mg, 265.85 pmol) in one portion at 25°C under N2. The mixture was stirred at 100 °C at for 16 hrs. The mixture was cooled to 20 °C and poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (1 x 50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was washed by EtOAc (10 ml) and dried in vacuum to give the title compound (0.9 g, 90% purity) as a yellow solid.Step B l-[6-(8-Oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaen-4-yl)-3- pyridyl]piperidin-4-one

[0147] To 10 ml 6M HC1 was added 2-(5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (0.9 g, 2.30 mmol). The mixture was stirred at 25 °C for 2 hrs. The mixture was poured into ice-water (100 ml) and neutralized by ISfeCOs. The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2sO4, filtered and concentrated in vacuum to give compound the title compound (1 g, 100%) as a yellow solid. ES / MS: 348.2 (M+H)+.Preparation 16 l-(6-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-3-yl)azetidin-3-oneES / MS 320.4 (M+H)Step A

[0148] To a solution of 2-(5-Iodopyridin-2-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (Preparation 5) (0.8 g, 2.13 mmol) and 5,8-dioxa-2-azaspiro[3.4]octane (489.72 mg, 4.25 mmol) in t-amylOH (10 ml) was added CS2CO3 (3.46 g, 10.63 mmol) and SPhos Pd G3 (165.95 mg, 212.68 pmol) in one portion at 25°C under N2. The mixture was stirred at 100°C for 16 hrs. The mixture was cooled to 20 °C and poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml) dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel chromatography eluting with petroleum ether in EtOAc (0: 1) to give the title compound (0.8 g, 95% purity) as a yellow solid. ES / MS: 364.1 (M+H)+.Step B l-(6-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-3-yl)azetidin-3-one

[0149] 2-(5-(5,8-dioxa-2-azaspiro[3.4]octan-2-yl)pyridin-2-yl)-2,4-dihydropyrazolo[3',4':4,5] pyrano[2,3-b]pyridine (0.8 g, 2.20 mmol) was added to H2SO4 (10 ml). The mixture was stirred at 25 °C for 16 hrs. The mixture was cooled to 20 °C and poured into ice-water (100 mL) and neutralized by Na2CO3. The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuum to give the title compound (0.45 g) as a yellow solid which was used for the next step directly without further purification. ES / MS: 320.3 (M+H)+Preparation 17 l-(4-(Pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)phenyl)piperidin-4-amineES / MS 348.2 (M+H)+Step Atert-butyl (l-(4-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)phenyl)piperidin-4-yl)carbamate

[0150] To a solution of 2-(4-iodophenyl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (0.5 g, 1.33 mmol) (Preparation 3) and tert-butyl piperidin-4-ylcarbamate (1.33 g, 6.66 mmol) in t-amylOH (20 ml) was added CS2CO3 (1.30 g, 4.00 mmol) and SPhos Pd G3 (103.99 mg, 133.28 mmol) in one portion at 25°C under N2. The mixture was stirred at 100 °C for 16 hrs. The mixture was cooled to 20 °C and poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel chromatography, eluting with DCM in MeOH (100:1) to give the title compound (0.43 g, 72.09%) as a yellow solid. ES / MS: 448.4 (M+H)+.Step B l-(4-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)phenyl)piperidin-4-amine

[0151] To 4M HClZEtOAc (10 ml) was added tert-butyl (l-(4-(pyrazolo[3',4':4,5]pyrano[2,3- b]pyridin-2(4H)-yl)phenyl)piperidin-4-yl)carbamate (0.43 g, 960.83 mmol). The reaction mixture was stirred at 25 °C for 2 hrs. The mixture was concentrated in vacuum to give the title compound (0.41 g, HC1 salt, crude) as a white solid. ES / MS: 348.2 (M+H)+.Preparation 184-[6-(l,2,3,3a,4,6,7,7a-Octahydropyrrolo[3,2-c]pyridin-5-yl)-3-pyridyl]-8-oxa-3,4,10- triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaneES / MS 375.3 (M+H)+Step A tert-Butyl (3aS,7aR)-5-(5-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2- yl)octahydro- lH-pyrrolo[3 ,2-c]pyridine- 1 -carboxylate

[0152] To a solution of 2-(6-fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (Preparation 2) (0.3 g, 1.12 mmol) and tert-butyl 2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridine- 1-carboxylate (506.21 mg, 2.24 mmol) in DMF (5 ml) was added CS2CO3 (1.09 g, 3.36 mmol). The reaction mixture was stirred at 100 °C for 2 hrs. The mixture was cooled to 20 °C and poured into ice-water (100 ml). The mixture was filtered to give the title compound (0.35 g, 90% purity) as a yellow solid. ES / MS: 475.4 (M+H)+.Step B 4-[6-(l,2,3,3a,4,6,7,7a-Octahydropyrrolo[3,2-c]pyridin-5-yl)-3-pyridyl]-8-oxa-3,4,10- triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentane

[0153] To a solution of tert-butyl (3aS,7aR)-5-(5-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)- yl)pyridin-2-yl)octahydro-lH-pyrrolo[3,2-c]pyridine-l-carboxylate (0.3 g, 632.17 pmol) in DCM (3 ml) was added TFA (3 ml). The reaction mixture was stirred at 25 °C for 1 hr. The mixture was cooled to 20 °C and poured into ice-water (100 ml), neutralized by Na2COs, The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give the title compound (0.3 g, crude, 80% purity) as a yellow solid. ES / MS: 375.3 (M+H)+.The following preparations on Table 4 were prepared analogous to Preparation 18.Preparation 214-cyclopropoxypyridine

[0154] To a solution of pyridin-4-ol (2.5 g, 26.29 mmol) and bromo-cyclopropane (6.36 g, 52.58 mmol, 4.21 ml) in NMP (25 ml) was added CS2CO3 (25.70 g, 78.87 mmol). The mixture was stirred at 150 °C for 1 h. The mixture was cooled to 20 °C and poured into ice-water (200 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (50 ml), dried with anhydrous ISfeSCU, filtered and concentrated in vacuum to give the crude product which was triturated with PE to give the title compound as a white solid (3.05 g, 86%).ES / MS: 136.1 (M+H)+.ExamplesExample 12-(4-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)phenyl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridineStep A tert-Butyl 3-(4-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)phenyl)-3,6- diazabicyclo[3.1.1 ]heptane-6-carboxylate

[0155] To a solution of 2-(4-iodophenyl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (0.5 g, 1.33 mmol) (Preparation 3) (0.5 g, 1.33 mmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6- carboxylate (1.32 g, 6.66 mmol) in t-amylOH (5 ml) was added CS2CO3 (1.30 g, 4.00 mmol) and SPhos Pd G3 (103.99 mg, 133.28 mmol) in one portion at 25°C under N2. The mixture was stirred at 100 °C for 4 hrs. The mixture was cooled to 20 °C and poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by silica gel chromatography eluting with petroleum ether in EtOAc (10:1) to give compound the title compound (0.5 g, 84.21%) as a yellow oil.Step B2-(4-(3,6-Diazabicyclo[3.1.1]heptan-3-yl)phenyl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine

[0156] To a solution of tert-butyl 3-(4-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)phenyl)- 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (0.5 g, 1.12 mmol) in DCM (6 ml) was added TFA (2 ml). The mixture was stirred at 25 °C for 4 hrs. The mixture was concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex luna Cl 8 80*40mm*3 mm; mobilephase: [water(HCl)-ACN];B%: 5%-35%,7min) to give the title compound (94.26 mg, 24.32%) as a yellow solid.ES / MS: 346.1 (M+H)+'H-NMR (DMSCM) 5 = 8.26 - 8.30 (m, 1H), 8.10 - 8.17 (m, 1H), 8.05 - 8.10 (m, 1H), 7.74 - 7.79 (m, 2H), 7.07 - 7.17 (m, 1H), 6.85 - 6.96 (m, 2H), 5.51 - 5.58 (m, 2H), 4.49 - 4.53 (m, 2H), 3.72 - 3.87 (m, 4H), 2.85 - 2.96 (m, 1H), 2.65 - 2.69 (m, 1H), 2.30 - 2.35 (m, 1H), 1.86 - 1.99 (m, 1H)

[0157] The following Example on Table 5 was prepared analogous to Example 1.Table 5Example 32-(6-(5-Oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridineter -Butyl 2-(5-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2-yl)-5-oxa-2,8- diazaspiro[3.5]nonane-8-carboxylate

[0158] To a solution of 2-(6-Fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine (Preparation 2) (470.01 mg, 1.75 mmol) and tert-butyl 5-oxa-2,8-diazaspiro[3.5]nonane- 8-carboxylate (0.4 g, 1.75 mmol) in DMF (5 ml) was added CS2CO3 (1.71 g, 5.26 mmol) at 20 °C. The mixture was stirred at 100 °C for 8 hrs. The mixture was poured into water (300 ml). The aqueous phase was extracted with EtOAc (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (100 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC eluting with DCM in MeOH (20:1) to give the title compound (0.4 g, 47.91%) as a colourless oilStep B2-(6-(5-Oxa-2,8-diazaspiro[3.5]nonan-2-yl)pyridin-3-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0159] The solution of tert-butyl 2-(5-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2- yl)-5-oxa-2,8-diazaspiro[3.5]nonane-8-carboxylate (0.2 g, 419.70 pmol) in 4 M HCl / EtOAc (3 ml) was stirred at 20 °C for 1 hr. The mixture was poured into water (200 ml), neutralized by ISfeCCh. The aqueous phase was extracted with EtOAc (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 100 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was triturated with petroleum ether at 20 °C for 5 min then filtered to give the title compound (0.06 g, 36.08%) as a white solid.‘HNMR (DMSO- e) 5 ppm 8.53 (d, J=2.50 Hz, 1 H) 8.24 (s, 1 H) 8.10 - 8.14 (m, 1 H) 8.05 (d, .7=7.38 Hz, 1 H) 7.97 (dd, J=8.94, 2.69 Hz, 1 H) 7.09 (dd, .7=7.25, 5.00 Hz, 1 H) 6.57 (d, J=8.88 Hz, 1 H) 5.52 (s, 2 H) 3.92 (d, J=8.63 Hz, 2 H) 3.78 (d, .7=8.76 Hz, 2 H) 3.53 - 3.59 (m, 2 H) 2.85 (s, 2 H) 2.66 (br d, J=4.13 Hz, 2 H)ES / MS: 377.1 (M+H)+

[0160] The following Examples on Table 6 were prepared analogous to Example 3.Table 6Example 62-(5-(3-Fluoro-[l,3'-biazetidin]-r-yl)pyridin-2-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine

[0161] To a solution of 2-(5-Iodopyridin-2-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (Preparation 5) (250 mg, 664.63 pmol) and l-(azetidin-3-yl)-3-fluoro-azetidine (243.44 mg, 996.94 pmol) in 2-methylbutan-2-ol (5 ml) was added CS2CO3 (1.08 g, 3.32 mmol) and SPhos Pd G3 (51.86 mg, 66.46 pmol). The mixture was stirred at 100 °C for 5 hrs. The mixture was poured into ice-water(100 ml) and extracted EtOAc (3 x 50 ml), The organic layers was washed with saturated aqueousNaCl (50 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC (neutral condition; column: Waters Xbridge C18 150*50mm* lOum; mobile phase:[H20(0.05%NH3H20+10mM NH4HCO3)-ACN]; gradient:30%-60% B over 8.0 min) to give the title compound (78 mg, 31.01%) as a white solid3. 'H NMR (DMSO-tC) 5 = 8.36 - 8.39 (m, 1H), 8.12 - 8.15 (m, 1H), 8.05 - 8.10 (m, 1H), 7.75 - 7.80 (m, 1H), 7.66 - 7.68 (m, 1H), 7.05 - 7.13 (m, 2H), 5.50 - 5.53 (m, 2H), 5.10 - 5.31 (m, 1H), 3.91 - 3.99 (m, 2H), 3.69 - 3.73 (m, 2H), 3.64 - 3.68 (m, 1H), 3.54 - 3.63 (m, 2H), 3.25 - 3.30 (m, 1H), 3.19 - 3.24 (m, 1H)4. 379.1Example 72-(6-(3-Fluoro-[l,3'-biazetidin]-r-yl)pyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine

[0162] To a solution of 2-(6-Fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine (Preparation 2) (0.2 g, 745.59 mmol) and l-(azeti din-3 -yl)-3-fluoro-azeti dine (291.14 mg, 2.24 mmol) in DMF (15 ml) was added CS2CO3 (2.43 g, 7.46 mmol). The mixture was stirred at 100 °C for 4 hrs. The reaction mixture poured into ice-water (100 ml) and extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (100 ml), dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep-TLC eluting with DCM in MeOH (20:1) to give the title compound (0.06 g, 21.05%) as a white solid.‘HNMR (400 MHz, DMSO-t / 6) 5 ppm 8.52 (d, J=2.63 Hz, 1 H) 8.24 (s, 1 H) 8.12 (dd, J=4.88, 1.88 Hz, 1 H) 8.05 (dd, J=7.38, 1.88 Hz, 1 H) 7.96 (dd, J=8.94, 2.69 Hz, 1 H) 7.09 (dd, J=7.38, 4.88 Hz, 1 H) 6.52 (d, J=8.88 Hz, 1 H) 5.52 (s, 2 H) 5.09 - 5.31 (m, 1 H) 3.98 - 4.04 (m, 2 H) 3.75 (dd, =8.63, 4.38 Hz, 2 H) 3.55 - 3.66 (m, 3 H) 3.26 (dd, J=9.38, 4.38 Hz, 1 H) 3.20 (dd, J=9.44, 4.31 Hz, 1 H).

[0163] The following Examples on Table 7 were prepared analogous to Example 7.Table 7Step ABenzyl 3-[l-[5-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)-2- pyridyl]pyrrolidin-3 -yl]oxy azetidine- 1 -carboxylate

[0164] To a solution of 2-(6-fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (445.16 mg, 1.66 mmol) and benzyl 3-pyrrolidin-3-yloxyazetidine-l-carboxylate (1.38 g, 4.99 mmol) in DMF (10 ml) was added CS2CO3 (1.62 g, 4.98 mmol). The mixture was stirred at 100°C for 16 hrs. The mixture was poured into water (200 ml). The aqueous phase was extracted with EtOAc(3 x 80 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 80 ml), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column 230-400 silica gel cartridge using a Biotage purification system eluting with DCM in MeOH (200 / 1 ~ 20 / 1) to give the title compound (0.68 g, 78.11%) as a yellow oil.Step B 2-(6-(3 -((1 -Methylazeti din-3 -y l)oxy)pyrrolidin- 1 -yl)pyri din-3 -yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0165] To a solution of benzyl 3-[l-[5-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12- pentaen-4-yl)-2-pyridyl]pyrrolidin-3-yl]oxyazetidine-l -carboxylate (0.3 g, 571.90 pmol) in MeOH (5 ml) was added Pd / C (121.72 mg, 114.38 pmol) and HCHO (109.00 mg, 1.34 mmol). The mixturewas stirred under H2 (15 psi) at 20 °C for 1 hr. The mixture was filtered and concentrated in vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*3 pm; mobile phase: [H2O(0.1% TFA)-ACN];gradient: 10%-45% B over 8.0 min) to give the title compound (0.0854 g, 28.23%) as a yellow solid. ES / MS: 405.1 (M+H)+.JH NMR (DMSO-de) 5 ppm 8.53 (d, J=2.75 Hz, 1 H) 8.22 (s, 1 H) 8.12 (dd, J=4.88, 1.88 Hz, 1 H) 8.05 (dd, .7=7.38, 2.00 Hz, 1 H) 7.94 (dd, J=9.13, 2.75 Hz, 1 H) 7.10 (dd, J=7.38, 4.88 Hz, 1 H) 6.59 (d, .7=9.01 Hz, 1 H) 5.53 (s, 2 H) 4.16 - 4.22 (m, 1 H) 4.13 (t, J=6.00 Hz, 1 H) 3.49 - 3.58 (m, 4 H) 3.41 - 3.46 (m, 2 H) 2.69 - 2.78 (m, 2 H) 2.21 (s, 3 H) 1.98 - 2.10 (m, 2 H).Step C

[0166] Racemic 2-(6-(3 -((1 -methylazeti din-3 -yl)oxy)pyrroli din- 1 -yl)pyri din-3 -y l)-2, 4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine was separated by SFC. column: column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [CO2-IPA:DCM=1 : 1 (0.1% NH3H2O)];B%:53%, isocratic elution mode to give:Enantiopure 1 (first eluting) 2-(6-(3-((l-methylazetidin-3-yl)oxy)pyrrolidin-l-yl)pyridin-3-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (21.18 mg, 6.59% ) as a white solid.ES / MS m / z: 405.2 (M+H)+1H NMR (DMSO-t / 6) 5 ppm 8.52 (d, J=2.75 Hz, 1 H), 8.22 (s, 1 H), 8.11 (dd, .7=4.88, 1.88 Hz, 1 H), 8.05 (dd, .7=7.38, 2.00 Hz, 1 H), 7.94 (dd, J=9.13, 2.75 Hz, 1 H), 7.09 (dd, J=7.38, 4.88 Hz, 1 H), 6.59 (d, .7=9.01 Hz, 1 H), 5.52 (s, 2 H), 4.08 - 4.21 (m, 2 H), 3.48 - 3.59 (m, 4 H), 3.39 - 3.46 (m, 2 H), 2.68 - 2.77 (m, 2 H), 2.21 (s, 3 H), 2.05 (br d, J=4.88 Hz, 2 H). andEnantiopure 2 (second eluting) 2-(6-(3-((l -methylazeti din-3 -yl)oxy)pyrrolidin-l-yl)pyri din-3 -yl)-2, 4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (22.11 mg, 6.88%) as a white solid.ES / MS m / z: 405.2 (M+H)+‘HNMR (DMSO- e) 5 ppm 8.52 (d, J=2.62 Hz, 1 H), 8.13 - 8.15 (m, 1 H), 8.12 (br s, 1 H), 8.05 (dd, .7=7.33, 1.85 Hz, 1 H), 7.92 (dd, J=8.94, 2.74 Hz, 1 H), 7.08 (dd, J=7.39, 4.89 Hz, 1 H), 6.59 (d, .7=9.18 Hz, 1 H), 5.53 (s, 2 H), 4.20 - 4.26 (m, 2 H), 3.56 - 3.74 (m, 4 H), 3.53 (br s, 2 H), 2.96 - 3.03 (m, 2 H), 2.35 (s, 3 H), 2.01 - 2.14 (m, 2 H).Example 142-(6-(3-(Azetidin-3-yloxy)pyrrolidin-l-yl)pyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine

[0167] To a solution of benzyl 3-[l-[5-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12- pentaen-4-yl)-2-pyridyl]pyrrolidin-3-yl]oxyazetidine-l -carboxylate (0.3 g, 571.90 pmol) in THF (3 ml) was added Pd / C (121.72 mg, 114.38 pmol). The mixture was stirred at 20 °C under H2 (15 psi) for 1 hr. The mixture was poured into 200 ml water and extracted with DCM (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 100 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by prep-HPLC. column: Phenomenex luna C18 100*40mm*3 pm; mobile phase: [H2O(0.1% TFA)- ACN];gradient:10%-30% B over 8.0 min to give the title compound (81.58 mg, 27.71%) as a yellow solid. ES / MS: 391.1 (M+H)+.‘HNMR (DMSO-t / 6) 5 ppm 8.53 (d, J=2.63 Hz, 1 H) 8.24 (s, 1 H) 8.12 (dd, J=4.94, 1.81 Hz, 1 H) 8.05 (dd, .7=7.38, 1.88 Hz, 1 H) 7.99 (dd, J=9.07, 2.69 Hz, 1 H) 7.10 (dd, J=7.38, 4.88 Hz, 1 H) 6.65 (d, .7=9.13 Hz, 1 H) 5.53 (s, 2 H) 4.53 (quin, .7=6.16 Hz, 1 H) 4.31 (br s, 1 H) 4.18 (br dd, J=6.75, 3.63 Hz, 2 H) 3.77 - 3.90 (m, 2 H) 3.42 - 3.60 (m, 4 H) 2.01 - 2.16 (m, 2 H).Example 152-(6-(4-(Azetidin-3-yloxy)piperidin-l-yl)pyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridineZc / V-Butyl 3-(4-pyridyloxy) azetidine- 1 -carboxylate

[0168] To a solution of NaH (4.76 g, 118.90 mmol, 60% purity) in DMSO (60 ml) was added 4- chloropyridine (4.5 g, 39.63 mmol). The reaction mixture was stirred at 20 °C for 1 hr., under N2atmosphere, tert- Butyl 3 -hydroxyazetidine-1 -carboxylate (6.86 g, 39.63 mmol) was then added. The mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition of H2O (300 ml) under N2, and then extracted with EtOAc (3 x 200 ml). The combined organic layers were washed with saturated aqueous NaCl (200 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by silica gel column chromatography eluting with petroleum ether / in EtOAc (10 / 1 to 3 / 1) to give the title compound (5 g, 48.89%) as a white solid. 'H-NMR (DMSO-t / 6) 8 = 8.37 - 8.44 (m, 2H), 6.84 - 6.90 (m, 2H), 5.05 - 5.13 (m, 1H), 4.27 - 4.39 (m, 2H), 3.80 (br dd, J = 2.6, 9.1 Hz, 2H), 1.38 (s, 9H)Step B tert-Butyl 3-(l-benzylpyridin-l-ium-4-yl)oxyazetidine-l -carboxylate

[0169] To a solution of tert-butyl 3 -(4-pyridyloxy)azetidine-l -carboxylate (4.8 g, 19.18 mmol) in DCM (50 ml) was added bromomethylbenzene (3.28 g, 19.18 mmol). The reaction mixture was stirred at 20 °C for 5 hrs. The reaction mixture was concentrated in vacuum to give the title compound (7.7 g, crude) as a white solid.Step C tert-Butyl 3-[(l-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]azetidine-l-carboxylate

[0170] To a solution of tert-butyl 3-(l-benzylpyridin-l-ium-4-yl)oxyazetidine-l-carboxylate (6.7 g, 19.62 mmol) in MeOH (70 ml) was added NaBH4 (2.93 g, 77.32 mmol) under N2 .The reaction mixture was stirred at 20 °C for 2 hrs., quenched by addition of H2O (300 ml) at 0 °C under N2., then extracted with DCM (3 x 100 ml). The organic phase was washed with water (3 x 100 ml), dried over anhydrous sodium sulfate, and concentrated in vacuum to give the title compound (5.2 g, crude) as a yellow oil.Step D tert-Butyl 3 -(4-piperidyloxy)azetidine-l -carboxylate

[0171] To a solution of tert-butyl 3-[(l-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxy]azetidine-l- carboxylate (2 g, 5.81 mmol) in MeOH (10 ml) was added Pd / C (1 g, 939.67 pmol, 10% purity). The reaction mixture was stirred at 20 °C for 5 hrs. Then the reaction was filtered and concentrated in vacuum to give the title compound (1.3 g, crude) as a yellow oil. ’H-NMR (DMSO- e) 5 4.27 - 4.43 (m, 1H), 3.91 - 4.08 (m, 2H), 3.51 - 3.67 (m, 2H), 3.32 (dtd, J = 4.6, 9.3, 13.8 Hz, 1H), 2.91 (td, J = 3.9, 12.4 Hz, 1H), 2.41 - 2.49 (m, 1H), 1.69 - 1.80 (m, 1H), 1.32 (br s, 9H), 1.31 (br s, 1H)Step E tert-Butyl 3-[[l-[5-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)-2- pyridyl]-4-piperidyl]oxy]azetidine-l -carboxylate

[0172] To a solution of 2-(6-fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (348.81 mg, 1.30 mmol) and tert-butyl 3-(4-piperidyloxy)azetidine-l-carboxylate (500 mg, 1.95 mmol) in DMSO (10 ml) was added DIPEA (504.19 mg, 3.90 mmol). The reaction mixture was stirred at 100 °C for 16 hrs. The reaction mixture was quenched by addition of H2O (100 ml), and then extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml), dried over Na2SC>4, filtered and concentrated in vacuum to give compound the title compound (500 mg, crude) as a yellow solid.Step F 2-(6-(4-(Azetidin-3-yloxy)piperidin-l-yl)pyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine

[0173] To a solution HClZEtOAc (1 ml) was added tert-butyl 3-[[l-[5-(8-oxa-3,4,10- triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)-2-pyridyl]-4-piperidyl]oxy]azetidine-l- carboxylate (100 mg, 198.18 pmol). The reaction mixture was stirred at 20 °C for 1 hr. The reaction mixture was filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10pm;mobile phase: [H2O(10mM NH4HC03)-ACN];gradient:10%-40% B over 6.0 min), to give the title compound (43 mg, 51.66%) as a white solid. ES / MS: 405.1 (M+H)+. 'H-NMR (DMSO-d6) 8 = 8.55 (d, J = 2.9 Hz, 1H), 8.25 (s, 1H), 8.12 (dd, J = 1.9, 4.9 Hz, 1H), 8.05 (dd, J = 2.0, 7.4 Hz, 1H), 7.95 (dd, J = 2.8, 9.2 Hz, 1H), 7.09 (dd, J = 4.9, 7.4 Hz, 1H), 6.99 (d, J = 9.1 Hz, 1H), 5.52 (s, 2H), 4.36 (t, J = 6.4 Hz, 1H), 4.02 (td, J = 4.3, 8.8 Hz, 2H), 3.45 - 3.58 (m, 3H), 3.38 (br t, J = 7.5 Hz, 2H), 3.12 - 3.19 (m, 2H), 1.79 - 1.88 (m, 2H), 1.36- 1.45 (m, 2H).Example 16N-Methyl-l-[5-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)-2- pyridyl]-N-(oxetan-3-yl)piperidin-4-amine

[0174] N-Methyl-l-[5-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)- 2-pyridyl]-N-(oxetan-3-yl)piperidin-4-amine was prepared in using Method A or alternatively Method B:Method A Step A 8-(5-Bromo-2-pyridyl)-l,4-dioxa-8-azaspiro[4.5]decane

[0175] To a solution of 5-bromo-2-fluoro-pyridine (10 g, 56.82 mmol) and l,4-dioxa-8- azaspiro[4.5]decane (8.14 g, 56.82 mmol) in DMF (100 ml) was added CS2CO3 (55.54 g, 170.47 mmol). The reaction mixture was stirred at 100 °C for 16 hrs. The reaction mixture was poured into H2O (250 ml), and then the mixture was filtered to give the title compound (14.5 g, crude) as a yellow solid.Step B l-(5-Bromo-2-pyridyl)piperidin-4-one

[0176] The solution of 8-(5-bromo-2-pyridyl)-l,4-dioxa-8-azaspiro[4.5]decane (7 g, 23.40 mmol) in HC1 (6 M, 70 ml) was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition of H2O (300 ml), and then neutralized with Na2COs and extracted with DCM (3 x 150 ml). The combined organic layers were washed with saturated aqueous NaCl (150 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give the title compound (5.5 g, crude) as a brown solid.Step C l-(5-Bromo-2-pyridyl)-N-methyl-N-(oxetan-3-yl)piperidin-4-amine

[0177] To a solution of l-(5-bromo-2-pyridyl)piperidin-4-one (400 mg, 1.57 mmol) and N- methylox etan-3 -amine (409.80 mg, 4.70 mmol) in DCM (7 ml) was added NaBH(OAc)3 (996.94 mg, 4.70 mmol), acetic acid (9.42 mg, 156.79 pmol) and 4A MS (400 mg). The reaction mixture was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition of H2O (100 ml), then neutralized with Na2COs, extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography eluting with DCM in MeOH (100 / 1 to 50 / 1) to give the title compound (400 mg, 78.20%) as a yellow oil. 'H-NMR (DMSO-d6) 5 = 8.13 (d, J = 2.5 Hz, 1H), 7.63 (dd, J = 2.6, 9.1 Hz, 1H), 6.82 (d, J = 9.3 Hz, 1H), 4.44- 4.50 (m, 4H), 4.29 (br d, J = 13.1 Hz, 2H), 3.88 (t, J = 6.9 Hz, 1H), 2.72 (dt, J = 2.0, 12.7 Hz, 2H), 2.45 - 2.49 (m, 1H), 2.07 (s, 3H), 1.59 (br d, J = 12.3 Hz, 2H), 1.25 - 1.37 (m, 2H)Step D

[0178] To a solution of l-(5-bromo-2-pyridyl)-N-methyl-N-(oxetan-3-yl)piperidin-4-amine (753.55 mg, 2.31 mmol) and 8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentane (200 mg,1.15 mmol) in dioxane (10 mL) was added (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine (492.84 mg, 3.46 mmol) and CS2CO3 (492.84 mg), then Cui (109.98 mg, 577.46 pmol) was added. The reaction mixture was stirred at 120 °C for 5 hrs. The reaction mixture was quenched by addition of H2O (200 ml) and extracted with DCM (3 x 60 ml). The combined organic layers were washed with saturated aqueous NaCl (60 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by silica gel column chromatography eluting with DCM in MeOH (100 / 1 to 30 / 1). The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* lOum; mobile phase: [H2O lOmM NH4HCO3)-ACN]; gradient: 10%-50% B over 8.0 min) to give the title compound (150 mg, 55.00%) as a white solid. ES / MS: 419.1 (M+H)+.JH NMR (DMSO-d6) 5 = 8.54 (d, J = 2.6 Hz, 1H), 8.24 (s, 1H), 8.12 (dd, J = 1.9, 4.9 Hz, 1H), 8.05 (dd, J = 1.9, 7.4 Hz, 1H), 7.94 (dd, J = 2.8, 9.1 Hz, 1H), 7.09 (dd, J = 4.9, 7.4 Hz, 1H), 6.98 (d, J = 9.3 Hz, 1H), 5.52 (s, 2H), 4.49 (d, J = 6.5 Hz, 4H), 4.39 (br d, J = 13.3 Hz, 2H), 3.90 (t, J = 6.9 Hz, 1H), 2.78 (br t, J = 11.9 Hz, 2H), 2.51 - 2.56 (m, 1 H), 2.09 (s, 3H), 1.64 (br d, J = 11.6 Hz, 2H), 1.37 (br dd, J = 3.8, 12.3 Hz, 2H).Method B

[0179] To N-methyloxetan-3-amine (1.00 g, 11.48 mmol) and l-[5-(8-oxa-3,4,10triazatricyclo [7.4.0.02,6]trideca-l(9), 2,5,10,12-pentaen-4-yl)-2-pyridyl]piperidin-4-one (1 g, 2.88 mmol) in DCM (10 mL) was added acetic acid (467.22 mg, 2.88 mmol) and NaBH(OAc)s (3.05 g, 14.39 mmol) under N2. The reaction mixture was stirred for 1 hr., at 20°C. The mixture was poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 330 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 30 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by silica gel chromatography eluting with petroleum ether in EtOAc (5 / 1, 1 / 1). The residue was then purified by prep-HPLC (column Waters Xbridge BEH C18 250*70mm*10um;mobile phase: [H2O(10mM NH4HCO3)- ACN];gradient:20%-50% B over 20.0 min) to give the title compound (650 mg, 53.48%) as a white solid. ES / MS: 419.2 (M+H)+‘H-NMR (DMSO-t / e): 8 ppm 8.54 (d, J=2.75 Hz, 1 H) 8.24 (s, 1 H) 8.12 (dd, J=4.94, 1.94 Hz, 1 H) 8.05 (dd, J=7.44, 1.94 Hz, 1 H) 7.94 (dd, J=9.19, 2.81 Hz, 1 H) 7.09 (dd, J=7.38, 5.00 Hz, 1 H) 6.98 (d, J=9.26 Hz, 1 H) 5.52 (s, 2 H) 4.45 - 4.55 (m, 4 H) 4.39 (br d, J=13.26 Hz, 2 H) 3.90 (t, J=6.88 Hz, 1 H) 2.71 - 2.87 (m, 2 H), 2.51 - 2.56 (m, 1 H) 2.09 (s, 3 H) 1.63 (br d, J=11.51 Hz, 2 H) 1.37 (br dd, J=12.07, 3.81 Hz, 2 H).

[0180] The following examples shown on Table 8 were prepared analogous to Method B of Example 16.Table 8

[0181] Chiral separation conditions:Conditions 1. The enantiopure Examples 23 and 24 above were obtained by prep-SFC separation starting from the corresponding racemic mixture (column: Phenomenex luna C18 100*40mm*5mm; mobile phase: [H2O(0.1%TFA)-ACN] ; gradient: l%-35% B over 8.0 min)Conditions 2. The enantiopure Examples 33, 34, 35, 36 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (column: DAICEL Chiralcel OD (250mm*30mm*10mm); mobile phase: [CO2-IPA(0.1%NH3H2O)]; 50% B, isocratic elution mode) Conditions 3 , The enantiopure Examples 37, 38 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (DAICEL ChiralPak AD (250mm*30mm*10mm)mobile phase: [CO2-IPA(0.1%NH3H2O)]; 56% B, isocratic elution mode)Conditions 4. The enantiopure Examples 39, 40, 41, 42 above were obtained by chiral SFC separation starting from the corresponding racemic mixtures (column: ChiralPak IH, 250*30mm*10mm; mobile phase: [CO2-EtOH(0.1%NH3H2O)]; 40% B, isocratic elution)Conditions 5. The enantiopure Examples 44, 45 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (column: ChiralPak IH, 250*30mm*10mm; mobile phase: [CO2-EtOH(0.1%NH3H2O)]; 56% B, isocratic elution)Example 492-(6-(4-(3 ,3 -Difluoroazetidin- 1 -yl)piperidin- 1 -yl)pyri din-3 -yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0182] To a mixture of l-(5-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2- yl)piperidin-4-one (0.2 g, 575.76 pmol) and 3,3-difluoroazetidine;hydrochloride (223.74 mg, 1.73 mmol) in DCM (10 ml) was added NaBH(OAc)3 (366.08 mg, 1.73 mmol) and acetic acid (34.57 mg, 575.76 pmol) and 4A MS (0.2 g) .The mixture was stirred at 20 °C for 2 hrs. The reaction mixture was poured into water (300 ml). The aqueous phase was extracted with DCM (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 100 ml), dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC (SiO2, DCM: MeOH = 20:1) then purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10pm; mobile phase: [H20(0.05% NH3H2O+10mM NH4HCO3)-ACN];gradient:25%- 65% B over 6.0 min) to give the title compound (0.063 g, 25.52% ) as a white solid. ES / MS m / z: 425.2 (M+H)+.JH NMR (DMSO-d6) 5 ppm 8.55 (d, J=2.75 Hz, 1 H) 8.25 (s, 1 H) 8.12 (dd, J=4.94, 1.94 Hz, 1 H) 8.05 (dd, J=7.38, 1.88 Hz, 1 H) 7.95 (dd, J=9.13, 2.88 Hz, 1 H) 7.09 (dd, J=7.44, 4.94 Hz, 1 H) 6.99 (d, J=9.13 Hz, 1 H) 5.52 (s, 2 H) 4.09 (br d, J=13.13 Hz, 2 H) 3.58 (t, J=12.44 Hz, 4 H) 3.07 (br t, J=10.32 Hz, 2 H) 2.39 - 2.45 (m, 1 H) 1.73 (br dd, J=12.63, 3.25 Hz, 2 H) 1.22 (br d, J=10.01 Hz, 2 H).

[0183] The compounds shown on Table 9 were prepared analogous to Example 49.Table 9Chiral separation conditions:

[0184] Conditions 4, The enantiopure Examples 52, 53 above were obtained by chiral SFC separation starting from the corresponding racemic mixtures (column: ChiralPak IH, 250*30mm*10mm; mobile phase: [CO2-EtOH(0.1%NH3H2O)]; 40% B, isocratic elution)

[0185] Conditions 6, The enantiopure Examples 55, 56 above were obtained by chiral SFC separation (DAICEL Chiralcel OJ (250mm*30mm* 10mm); mobile phase: [CO2- EtOH(0.1%NH3H2O)] ; 50% B, isocratic elution mode

[0186] Conditions 7. The enantiopure Examples 63, 64 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (column: ChiralPak H4, 250*30mm*10mm; mobile phase: [CO2-EtOH(0.1%NH3H2O)]; 50% B, isocratic elution)

[0187] Conditions 8. The enantiopure Examples 65, 66 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (column: ChiralPak H4, 250*30mm*10mm; mobile phase: [CO2-EtOH(0.1%NH3H2O)]; 80% B, isocratic elution)Example 74N-Cyclobutyl-N-methyl-l-(6-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-3-Step AN-Cyclobutyl-l-[6-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4- yl)-3-pyridyl]piperidin-4-amine

[0188] To a solution of l-[6-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen- 4-yl)-3-pyridyl]piperidin-4-one (180 mg, 518.18 pmol) and cyclobutanamine (110.56 mg, 1.55 mmol) in DCM (5 mL) was added 4A MS (150 mg) and acetic acid (3.11 mg, 51.82 pmol). The reaction mixture was stirred at 20 °C for 1 hr., and NaBH(OAc)3 (329.47 mg, 1.55 mmol) added. The mixture was stirred at 20 °C for 5 hrs. The reaction mixture was quenched by addition H2O (100 ml) and then extracted with DCM (3 x 30 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml), dried over Na2SO4, filtered, and concentrated under in vacuum togive a residue. The residue was purified by silica gel prep-TLC eluting with DCM in MeOH (20: 1) to give the title compound (80 mg, 37.21%) as a white solid.

[0189] To a solution of N-cyclobutyl-l-[6-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca- l(9),2,5,10,12-pentaen-4-yl)-3-pyridyl]piperidin-4-amine (60 mg, 149.07 pmol) and HCHO (13.43 mg, 447.21 pmol) in DCM (5 ml) was added acetic acid (895.18 pg, 14.91 pmol) and 4A MS (60 mg). The mixture was stirred at 20 °C for 1 hr. Then NaBH(OAc)3 (94.78 mg, 447.21 pmol) was added. The mixture was stirred at 20 °C for 5 hrs. The reaction mixture was quenched by addition of H2O (100 ml), extracted with DCM (3 x 30 ml). The combined organic layers were washed with saturated aqueous NaCl (20 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* lOum; mobile phase: [H2O (lOmM NH4HCO3)-ACN];gradient:15%-55% B over 8.0 min) to give the title compound (40 mg, 61.84%) as a yellow solid. ES / MS m / z: 417.1 (M+H)+.'H-NMR (DMSO-t / 6) 8 = 8.40 (s, 1H), 8.12 - 8.17 (m, 2H), 8.08 (dd, J = 2.0, 7.4 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.59 (dd, J = 3.0, 9.1 Hz, 1H), 7.11 (dd, J = 5.0, 7.4 Hz, 1H), 5.52 (s, 2H), 3.85 (br d, J = 12.3 Hz, 2H), 3.13 (br t, J = 7.3 Hz, 1H), 2.68 - 2.78 (m, 2H), 2.59 (br d, J = 3.3 Hz, 1H), 2.03 (s, 3H), 1.90 - 1.99 (m, 2H), 1.73 - 1.86 (m, 2H), 1.63 - 1.70 (m, 2H), 1.51 - 1.62 (m, 4H).The compounds shown on Table 10 were prepared analogous to Example 74.Table 10Chiral separation conditions:

[0190] Conditions 9. The enantiopure Examples 77, 78 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (column: Waters Xbridge C18 150*50mm*10mm; mobile phase: [EEO OmM NH4HCO3)-ACN] ; gradient:25%-65% B over 8.0 min)

[0191] Conditions 10. The enantiopure Examples 79, 80 above were obtained by chiral SFC separation starting from the corresponding racemic (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient: 15%-45% B over 8.0 min)

[0192] Conditions 11. The enantiopure Examples 81, 82 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (column: ChiralPak H4, 250*30mm*10 mm; mobile phase: [CO2-EtOH(0.1%NH3H2O)]; 54% B, isocratic elution)

[0193] Conditions 11. The enantiopure Examples 83, 84 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (column: ChiralPak H4, 250*30mm*10mm; mobile phase: [CO2-EtOH(0.1%NH3H2O)]; 50% B, isocratic elution).Example 85N-Methyl-N-(oxetan-3-yl)-l-(4-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)- yl)phenyl)piperidin-4-amine

[0194] To a solution of l-[4-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen- 4-yl)phenyl]piperidin-4-one (0.14 g, 404.18 pmol) and N-methyloxetan-3-amine (105.64 mg, 1.21 mmol) in DCM (12 ml) was added NaBH(OAc)3 (256.99 mg, 1.21 mmol) and 4A MS (0.12 g). The mixture was stirred at 20 °C for 1 hr. The residue was poured into water (50 ml). The aqueous phase was extracted with EtOAc (3 x 30 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 20 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. Theresidue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 pm; mobile phase: [H2O(TFA)-ACN];B%: l%-35%,8min) to give the title compound (0.05 g, 28.15%) as a yellow solid. ES / MS m / z: 418.2 (M+H)+.’H-NMR (DMSO-76) 5 8.25 (s, 1 H) 8.11 (dd, 7=4.96, 1.94 Hz, 1 H) 8.05 (dd, 7=7.34, 1.94 Hz, 1 H) 7.65 (d, 7=9.03 Hz, 2 H) 7.09 (dd, 7=7.40, 4.89 Hz, 1 H) 7.04 (d, 7=9.03 Hz, 2 H) 5.52 (s, 2 H) 4.50 (d, 7=6.90 Hz, 4 H) 3.91 (t, 7=6.90 Hz, 1 H) 3.79 (br d, 7=12.30 Hz, 2 H) 2.66 (br t, 7=11.42 Hz, 2 H) 2.37 - 2.46 (m, 1 H) 2.12 (s, 3 H) 1.65 (br d, 7=11.80 Hz, 2 H) 1.44 - 1.56 (m, 2 H).

[0195] The compounds shown on Table 11 were prepared analogous to Example 85.Table 11Chiral separation conditions:

[0196] Conditions 11. The enantiopure Examples 88, 89 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (column: ChiralPak H4, 250*30mm*10mm; mobile phase: [CO2-EtOH(0.1%NH3H2O)]; 50% B, isocratic elution)Examples 91 and 92N-(3-Fluorocyclobutyl)-l-[4-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen- 4-yl)phenyl] azeti din-3 -amine

[0197] To a solution of l-[4-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)phenyl]azetidin-3-one (500 mg, 1.57 mmol) and 3-fluorocyclobutanamine (591.71 mg, 4.71 mmol) in EtOH (5 ml) was added NaBEECN (148.06 mg, 2.36 mmol), acetic acid (94.32 mg, 1.57 mmol, 89.92 pL) and Ti(0i-Pr)4 (446.42 mg, 1.57 mmol). The reaction mixture was stirred at 60 °C for 6 hrs. The reaction mixture was quenched by addition of H2O (100 ml), and then extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purifiedby prep-HPLC (column: Waters Xbridge C18 150*50mm* 10pm; mobile phase: [EhOQOmM NH4HC03)-ACN];gradient:20%-40% B over 8.0 min) to give: cis-diastereoisomer (50 mg, 8.06%) as a white solid. ES / MS m / z: 392.2 (M+H)+‘HNMR (DMSO4) 8 = 8.21 (s, 1H), 8.00 - 8.13(m, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 5.0, 7.4 Hz, 1H), 6.47 - 6.57 (m, 2H), 5.51 (s, 2H), 5.05 - 5.28 (m, 1H), 4.06 (t, J = 7.1 Hz, 2H), 3.65 (td, J = 6.3, 10.0 Hz, 1H), 3.36 - 3.52 (m, 3H), 2.63 - 2.76 (m, 1H), 2.19 - 2.35 (m, 2H), 2.03 - 2.17 (m, 2H); and trans diastereoisomer (40 mg, 6.47%) as a white solid. ES / MS m / z: 392.2 (M+H)+.‘HNMR (DMSO4) 6 = 8.21 (s, 1H), 8.00 - 8.13 (m, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.08 (dd, J = 5.0, 7.4 Hz, 1H), 6.47 - 6.57 (m, 2H), 5.51 (s, 2H), 5.05 - 5.28 (m, 1H), 4.06 (t, J = 7.1 Hz, 2H), 3.65 (td, J = 6.3, 10.0 Hz, 1H), 3.36 - 3.52 (m, 3H), 2.63 - 2.76 (m, 1H), 2.19 - 2.35 (m, 2H), 2.03 - 2.17 (m, 2H).

[0198] The compounds shown on Table 12 were prepared analogous to Examples 91 and 92.Table 12Example 97N-Cyclopropyl-N-(oxetan-3-yl)-l-(5-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2- yl)piperidin-4-amine

[0199] To a solution of oxetan-3-one (278.26 mg, 3.86 mmol) and N-cyclopropyl-l-[5-(8-oxa- 3,4,10triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)-2-pyridyl]piperidin-4-amine) (300 mg, 772.27 pmol) in EtOH (5 ml) was added acetic acid (125.34 mg, 772.27 pmol) and NaBH3CN (242.66 mg, 3.86 mmol). The reaction mixture was stirred for 1 hr at 80°C. The mixture was poured into ice-water (100 ml). The aqueous phase was extracted with DCM (3 x 30ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 30ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by prep-TLC eluting with DCM in MeOH (20:1) then purified by prep-HPLC (column: Waters Xbridge C18 150*50mm*10pm; mobile phase: [H20(0.05% NH3H2O+10mM NH4HCO3)-ACN]; gradient:20%- 50% B over 8.0 min) to give the title compound as a white solid. ES / MS m / z: 445.2 (M+H)+'H-NMR (DMSO-t / e): 8 8.50 - 8.59 (m, 1 H) 8.22 - 8.28 (m, 1 H) 8.09 - 8.15 (m, 1 H) 8.02 - 8.08 (m,1 H) 7.90 - 7.98 (m, 1 H) 7.06 - 7.15 (m, 1 H) 6.94 - 7.03 (m, 1 H) 5.49 - 5.59 (m, 2 H) 4.66 - 4.75 (m,2 H) 4.37 - 4.50 (m, 4 H) 4.13 - 4.27 (m, 1 H) 2.70 - 2.86 (m, 3 H) 1.92 - 2.02 (m, 1 H) 1.66 - 1.77 (m, 2 H) 1.39 - 1.54 (m, 2 H) 0.45 - 0.53 (m, 2 H) 0.32 - 0.40 (m, 2 H).Example 98N-Methyl-l-(4-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)phenyl)piperidin-4-amine

[0200] To l-[4-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4- yl)phenyl]piperidin-4-one (200 mg, 577.40 pmol) was added MeNHVTHF (2 M, 16 ml) and stirred for 1 hr then NaBH(OAc)3 (611.87 mg, 2.89 mmol) was added. The reaction mixture was stirred for 15 hrs at 20 °C. The mixture was poured into ice- water (100 ml). The aqueous phase was extracted with EtOAc (3 x 30ml). The combined organic phase was washed with saturated aqueous NaCl (30 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 pm; mobile phase: [H2O(TFA)-ACN]; B%: l%-30%,8min) to give the title compound (80 mg, 37.57%) as a yellow solid. ES / MS: 362.3 (M+H)+.1H-NMR (DMSO-t / 6): 5 8.54 (br s, 2 H) 8.27 (s, 1 H) 8.12 (dd, J=4.88, 1.88 Hz, 1 H) 8.05 (dd, J=7.38, 2.00 Hz, 1 H) 7.69 (d, J=9.13 Hz, 2 H) 7.05 - 7.16 (m, 3 H) 5.52 (s, 2 H) 3.86 (br d, J=12.88 Hz, 2 H) 3.17 (br s, 1 H) 2.78 (br t, J=11.69 Hz, 2 H) 2.60 (br t, J=4.57 Hz, 3 H) 2.06 (br d, J=10.26 Hz, 2 H) 1.58 (br dd, J=12.01, 3.63 Hz, 2 H).Example 99N-Methyl-l-(5-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2-yl)piperidin-4-amine

[0201] A mixture of l-[5-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4- yl)-2-pyridyl]piperidin-4-one (180 mg, 518.18 pmol), methanamine;hydrochloride (349.86 mg, 5.18 mmol), DMAP (633.05 mg, 5.18 mmol) in DCM (3 ml) stirred at 20 °C for 1 hr., then was added NaBH(OAc)3 (549.12 mg, 2.59 mmol) and acetic acid (3.11 mg, 51.82 pmol, 2.97 pL). The reaction mixture was stirred at 20 °C for 1 hr. The mixture was extracted with water (200 ml) and EtOAc (3 x 100 ml), The organic layers were washed with saturated aqueous NaCl (100 ml), dried over Na2SO4, filtered, and concentrated in vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge C18 150*50mm* 10pm; mobile phase: [H20(10mM NH4HC03)-ACN];gradient: 10%-40%B over 8.0 min) to give the title compound (64 mg, 33.38%) as a white solid. ES / MS: 363.4 (M+H)+.'H-NMR (DMSO-t / e) 8 = 8.51 - 8.59 (m, 1H), 8.22 - 8.27 (m, 1H), 8.09 - 8.15 (m, 1H), 8.02 - 8.08 (m, 1H), 7.89 - 7.98 (m, 1H), 7.05 - 7.13 (m, 1H), 6.93 - 7.01 (m, 1H), 6.01 - 6.12 (m, 1H), 5.50 - 5.54 (m, 2H), 4.10 - 4.26 (m, 2H), 2.96 - 3.01 (m, 2H), 2.51 - 2.56 (m, 1H), 2.25 - 2.35 (m, 3H), 1.80 - 1.90 (m, 2H), 1.15 - 1.28 (m, 2H).Example 100 l-(3-Fluoro-5-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2-yl)-N-(oxetan-3- yl)piperidin-4-amineStep A8-(5-Bromo-3-fluoro-2-pyridyl)-l,4-dioxa-8-azaspiro[4.5]decane

[0202] To a solution of 2,5-dibromo-3-fluoro-pyridine (1 g, 3.92 mmol) and l,4-dioxa-8- azaspiro[4.5]decane (561.76 mg, 3.92 mmol) in toluene (30 ml) was added Xantphos (227.01 mg, 392.34 pmol) and Pd2(dba)s (359.27 mg, 392.34 pmol) and t-BuONa (1.13 g, 11.77 mmol). The reaction mixture was stirred at 20 °C for 1 hr. The residue was poured into water 500 (ml). The aqueous phase was extracted with EtOAc (3 x 200 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 200 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified on 230-400 silica gel cartridge using a Biotage purification system by eluting with petroleum ether in EtOAc (50 / 1 => 20 / 1) to give the title compound (0.5 g, 40.18%) as a yellow oil. ES / MS m / z: 318.9 (M+H)+.'H NMR (DMSO- e) 6 ppm 8.10 (s, 1 H) 7.86 (dd, 7=12.76, 1.88 Hz, 1 H) 3.91 (s, 4 H) 3.45 - 3.52 (m, 4 H) 1.66 - 1.73 (m, 4 H).Step B1 -(5 -Bromo-3 -fluoro-2-pyridyl)piperidin-4-one

[0203] The solution of 8-(5-bromo-3-fluoro-2-pyridyl)-l,4-dioxa-8-azaspiro[4.5]decane (0.5 g, 1.58 mmol) in HC1 (6 M, 20 ml) was stirred at 20 °C for 1 hr. The residue was poured into water (500 ml) and neutralized by Na2COs. The aqueous phase was extracted with EtOAc (3 x 200 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 200 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give the title compound (0.45 g, crude) as a yellow oil.Step C l-(5-Bromo-3-fluoro-2-pyridyl)-N-methyl-N-(oxetan-3-yl)piperidin-4-amine

[0204] To a solution of l-(5-bromo-3-fluoro-2-pyridyl)piperidin-4-one (0.4 g, 1.46 mmol) and N- methylox etan-3 -amine (382.80 mg, 4.39 mmol) in DCM (9 ml) was added NaBH(OAc)3 (931.26 mg, 4.39 mmol) and acetic acid (87.95 mg, 1.46 mmol) and 4A MS (0.5 g). The reaction mixture was stirred at 20 °C for 1 hr. The mixture was poured into water (200 ml). The aqueous phase was extracted with DCM (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 100 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel prep-TLC eluting with DCM in MeOH (20: 1) to give the title compound (0.4 g, 79.34%) as a yellow oil.Step D l-(3-Fluoro-5-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)pyridin-2-yl)-N-(oxetan-3- yl)piperidin-4-amine

[0205] To a solution of l-(5-bromo-3-fhioro-2-pyridyl)-N-methyl-N-(oxetan-3-yl)piperidin-4-amine (0.38 g, 1.10 mmol) and 8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentane (95.59 mg, 551.97 pmol) in dioxane (9 ml) was added Cui (105.12 mg, 551.97 pmol) and CS2CO3 (539.53 mg, 1.66 mmol) and (lR,2R)-Nl,N2-dimethylcyclohexane-l,2-diamine (157.03 mg, 1.10 mmol) at 20°C. The reaction mixture was stirred at 120°C for 16 hrs. The residue was poured into water (200 ml). The aqueous phase was extracted with EtOAc (3 x 80 ml). The combined organic phase waswashed with saturated aqueous NaCl (3 x 80 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified on column (Waters Xbridge C18 150*50mm* 10pm; mobile phase: [H2O (0.05% NH3H2O+10mMNH4HCO3)-ACN]; gradient:25%-55% B over 6.0 min.) to give the title compound (0.062 g, 24.96%) as a white solid. ES / MS m / z: 437.2 (M+H)+. 'H-NMR (DMSO-76) 5 8.53 (d, J=1.75 Hz, 1 H) 8.35 (s, 1 H) 8.14 (dd, 7=4.94, 1.94 Hz, 1 H) 8.01 - 8.09 (m, 2 H) 7.11 (dd, 7=7.38, 5.00 Hz, 1 H) 5.53 (s, 2 H) 4.49 (d, J=6.63 Hz, 4 H) 4.05 (br d, 7=13.01 Hz, 2 H) 3.91 (d, 7=6.88 Hz, 1 H) 2.84 (br t, 7=12.01 Hz, 2 H) 2.45 - 2.47 (m, 1 H) 2.11 (s, 3 H) 1.66 (br d, 7=11.13 Hz, 2 H) 1.44 - 1.55 (m, 2 H).Example 101 l-[5-Fluoro-6-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)-3- pyridyl]-N-methyl-N-(oxetan-3-yl)piperidin-4-amineStep A2-(5-Bromo-3-fluoropyridin-2-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0206] To a solution of 2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (1 g, 5.77 mmol) and 5- bromo-2,3-difluoro-pyridine (1.12 g, 5.77 mmol) in DMF (10 ml) was added CS2CO3 (5.64 g, 17.32 mmol). The reaction mixture was stirred at 100 °C for 16 hrs. The reaction mixture was quenched by addition of H2O (200 ml), then extracted with EtOAc (3 x 60 ml). The combined organic layers were washed with saturated aqueous NaCl (100 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by silica gel column chromatography eluting with petroleum ether in EtOAc (10 / 1 to 1 / 1) to give the title compound (800 mg, 35.92%) as a yellow solid.Step B 2-(3-Fluoro-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0207] To a solution of 2-(5-bromo-3-fluoropyridin-2-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine (370 mg, 1.07 mmol) and l,4-dioxa-8-azaspiro[4.5]decane (167.87 mg, 1.17 mmol) in 2- methylbutan-2-ol (6 ml) was added CS2CO3 (1.04 g, 3.20 mmol) and SPhos Pd G3 (83.16 mg, 106.58 pmol). The mixture was stirred at 100 °C for 16 hrs. The reaction mixture was quenched by addition of H2O (100 ml), and then extracted with EtOAc (3 x 30 ml). The combined organic layers were washed with saturated aqueous NaCl (30 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was washed by EtOAc (10 ml) to give the title compound (260 mg, 90% purity) as a yellow solid.Step C l-[5-Fluoro-6-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)-3- pyridyl]piperidin-4-one

[0208] The solution of 2-(3-fluoro-5-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)pyridin-2-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (250 mg, 610.63 pmol) in HC1 (6 M, 5 ml) was stirred at 20 °C for 1 hr. The reaction mixture was quenched by addition of H2O (100 ml), and then neutralized with Na2COs and extracted with DCM (3 x 50 ml). The combined organic layers were washed with saturated aqueous NaCl (50 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give the title compound (180 mg, crude) as a yellow solid which was used directly for the next step without further purification.Step D l-[5-Fluoro-6-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)-3- pyridyl]-N-(oxetan-3-yl)piperidin-4-amine

[0209] To a solution of l-[5-fluoro-6-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12- pentaen-4-yl)-3-pyridyl]piperidin-4-one (170 mg, 465.29 pmol) and oxetan-3 -amine (102.03 mg,1.40 mmol) in DCM (1 ml) was added 4A MS (170 mg) and acetic acid (2.79 mg, 46.53 pmol). The reaction mixture was stirred at 20 °C for 3 hrs. Then NaBH(OAc)3 (295.84 mg, 1.40 mmol) was added. The mixture was stirred at 20 °C for another 3 hr. The reaction mixture was quenched by addition of H2O (100 ml), and then extracted with DCM (3 x 50 ml). The combined organic layers were washed with saturated aqueous NaCl (50 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by prep-TLC eluting with DCM in MeOH (20: 1) to give the title compound (180 mg, 90% purity) as a yellow solid.Step E l-[5-Fluoro-6-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)-3- pyridyl]-N-methyl-N-(oxetan-3-yl)piperidin-4-amine

[0210] To a solution of l-[5-fluoro-6-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12- pentaen-4-yl)-3-pyridyl]-N-(oxetan-3-yl)piperidin-4-amine (170 mg, 426.08 pmol) and HCHO (38.38 mg, 1.28 mmol) in DCM (4 ml) was added 4A MS (170 mg) and acetic acid (2.56 mg, 42.61 pmol). The mixture was stirred at 20 °C for 3 hrs. Then NaBH(OAc)3 (270.91 mg, 1.28 mmol) was added. The mixture was stirred at 20 °C for 3 hrs. The reaction mixture was quenched by addition of H2O (100 ml), and then extracted with DCM (3 x 50 ml). The combined organic layers were washed with saturated aqueous NaCl (50 ml), dried over Na2SO4, filtered, and concentrated in vacuum to give a residue. The residue was purified by silica gel prep-TLC eluting with DCM in MeOH (20: 1) to give the title compound (98 mg, 51.64%) as a white solid. ES / MS: 437.2 (M+H)+.'H-NMR (DMSO-t / e) 8 = 8.09 - 8.17 (m, 2H), 8.00 - 8.07 (m, 2H), 7.53 (dd, J = 2.3, 14.0 Hz, 1H), 7.10 (dd, J = 5.0, 7.4 Hz, 1H), 5.53 (s, 2H), 4.47 - 4.53 (m, 4H), 3.87 - 4.00 (m, 3H), 2.80 (br t, J = 11.7 Hz, 2H), 2.46 (br s, 1H), 2.11 (s, 3H), 1.65 (br d, J = 12.0 Hz, 2H), 1.42 - 1.54 (m, 2H).Example 102 l-(2-Fluoro-4-(pyrazolo[3',4':4,5]pyrano[2,3-b]pyridin-2(4H)-yl)phenyl)-N-(oxetan-3-yl)piperidin- 4-amineStep A2-(4-Bromo-3-fluorophenyl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0211] To a solution of 8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentane (1 g, 5.77 mmol) and (4-bromo-3-fluoro-phenyl)boronic acid (3.79 g, 17.32 mmol) in pyridine (50 ml) was added Cu(OAc)2 (1.05 g, 5.77 mmol) and 4A MS (1 g) at 20 °C. The reaction mixture was stirred at 100 °C for 1 hr., under O2. The mixture was poured into water (300 ml). The aqueous phase was extracted with DCM (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 100 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified on 230-400 silica gel cartridge using a Biotage purification system by employing a petroleum ether in EtOAc (10 / 1 => 5 / 1) to give the title compound (1.5 g, 90% purity) as a blue solid.Step B 2-(3-Fluoro-4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0212] To a solution of 2-(4-bromo-3-fhiorophenyl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- b]pyridine (0.3 g, 866.67 pmol) and l,4-dioxa-8-azaspiro[4.5]decane (744.55 mg, 5.20 mmol) in dioxane (30 ml) was added sodium;2-methylpropan-2-olate (249.87 mg, 2.60 mmol) and dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphane;methanesulfonate;[2-[2- (methylamino)phenyl]phenyl]palladium(l+) (73.70 mg, 86.67 pmol) at 20°C. The mixture was stirred at 120 °C for 5 hrs. The residue was poured into water (300 ml). The aqueous phase was extracted with EtOAc (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 100 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified on prep-TLC eluting with petroleum ether in EtOAc (1 / 1) to give the title compound (0.2 g, 50.04%) as a yellow solid.Step C l-[2-Fluoro-4-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4- yl)phenyl]piperidin-4-one

[0213] The solution of raw material of 2-(3-fluoro-4-(l,4-dioxa-8-azaspiro[4.5]decan-8-yl)phenyl)- 2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine (0.3 g, 734.53 pmol) in HC1 (6 M, 5 ml) at 20 °C was stirred at 20 °C for 1 hr. The mixture was poured into water (200 ml), neutralized by Na2COs.The aqueous phase was extracted with EtOAc (3 x 80 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 80 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give the tile compound (0.3 g, crude) as a yellow solid.Step D l-[2-Fluoro-4-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12-pentaen-4-yl)phenyl]-N-(oxetan-3-yl)piperidin-4-amine

[0214] To a solution of l-[2-fluoro-4-(8-oxa-3,4,10-triazatricyclo[7.4.0.02,6]trideca-l(9),2,5,10,12- pentaen-4-yl)phenyl]piperidin-4-one (0.3 g, 823.33 pmol) and oxetan-3 -amine (300.90 mg, 4.12 mmol) in DCM (30 ml) was added 4A MS (0.3 g) and acetic acid (49.44 mg, 823.33 pmol) and NaBH(OAc)3 (523.49 mg, 2.47 mmol). The mixture was stirred at 20 °C for 1 hr. The reaction mixture was poured into water (300 ml). The aqueous phase was extracted with DCM (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (3 x 100 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by silica gel prep-TLC eluting with DCM in MeOH (20: 1) to give the title compound (0.07 g, 70.0%) as a yellow solid. ES / MS m / z: 422.2 (M+H)+.'H NMR (DMSO-76) 5 ppm 8.36 (s, 1 H) 8.14 (dd, 7=4.88, 1.88 Hz, 1 H) 8.08 (dd, 7=7.44, 1.94 Hz, 1 H) 7.68 (dd, 7=13.76, 2.50 Hz, 1 H) 7.60 (dd, 7=8.88, 2.25 Hz, 1 H) 7.07 - 7.19 (m, 2 H) 5.53 (s, 2 H) 4.65 (t, 7=6.50 Hz, 2 H) 4.34 (t, 7=6.25 Hz, 2 H) 3.94 - 4.03 (m, 1 H) 3.35 (br s, 2 H) 2.67 - 2.74 (m, 2 H) 2.43 - 2.47 (m, 1 H) 1.78 (br d, 7=11.63 Hz, 2 H) 1.37 - 1.46 (m, 2 H).Example 103Step A4-(4-Bromo-3-fluoro-phenyl)morpholine

[0215] To a solution of l-bromo-2-fluoro-4-iodo-benzene (2 g, 6.65 mmol) and morpholine (579.07 mg, 6.65 mmol, 584.92 pL) in toluene (20 ml) was added (5-diphenylphosphanyl-9,9-dimethyl- xanthen-4-yl)-diphenyl-phosphane (384.60 mg, 664.69 pmol), (lE,4E)-l,5-diphenylpenta-l,4-dien- 3-one;palladium (182.60 mg, 199.41 pmol) and CS2CO3 (4.33 g, 13.29 mmol). The mixture was stirred at 100 °C for 16 hrs. The mixture was cooled to 20 °C and poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography (1000 mesh silica gel) eluting with petroleum ether in EtOAc (80 / 1) to give the title compound (1.3 g, 75.19%) as a yellow oil. ES / MS m / z: 260.0 / 262.2 (M+H)+.Step B4-[3-Fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]morpholine

[0216] To a solution of 4-(4-bromo-3-fhioro-phenyl)morpholine (1.2 g, 4.61 mmol) and 4, 4, 5, 5- tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (4.10 g, 16.15 mmol) in dioxane (1 ml) was added Pd(dppf)C12 (337.58 mg, 461.36 pmol) and potassium acetate (1.36 g, 13.84 mmol). The mixture was stirred at 100 °C for 16 hrs. The mixture was concentrated in vacuum. The crude product was purified by silica gel chromatography (1000 mesh silica gel) eluting with petroleum etherin EtOAc (50 / 1) to give the title compound (1 g, 70.56%) as a yellow solid. ES / MS m / z: 308.2 (M+H)+.Step C4-(2-Fluoro-4-morpholino-phenyl)-8-oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12- pentaene

[0217] To a mixture of 8-oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaene (200 mg, 1.15 mmol) and 4-[3-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]morpholine (425.71 mg, 1.39 mmol) in pyridine (2 ml) was added Cu(OAc)2 (209.77 mg, 1.15 mmol) and 4A MS (1.15 mmol). The reaction mixture was heated to 100 °C and stirred for under O2 for 16 hrs. The mixture was cooled to 20 °C and poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by prep-TLC (DCM: MeOH=20:l) then prep-HPLC(column: Waters Xbridge Prep OBD C18 150*40mm*10um;mobile phase: [water(NH3H2O+NH4HCO3)-ACN];B%: 15%-45%,8min) to give the title compound (49.51 mg, 12.09%) as a white solid. ES / MS m / z: 353.2 (M+H)+.1H NMR (DMSO-76) 5 ppm 8.13 (dd, 7=4.89, 1.91 Hz, 1 H), 8.04 (dd, 7=7.39, 1.91 Hz, 1 H), 7.98 (d, 7=1.67 Hz, 1 H), 7.61 (t, 7=9.06 Hz, 1 H), 7.09 (dd, 7=7.39, 5.01 Hz, 1 H), 7.01 (dd, 7=14.90, 2.50 Hz, 1 H), 6.91 (dd, 7=9.06, 2.38 Hz, 1 H), 5.51 (s, 2 H), 3.73 - 3.76 (m, 4 H), 3.20 - 3.23 (m, 4 H).

[0218] The compound shown on Table 13 were prepared analogous to Example 103.Table 13Examples 105, 106 and 107Step Atert-Butyl 5-benzyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-l-carboxylate

[0219] To a solution of tert-butyl 2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridine-l-carboxylate(1.5 g, 6.63 mmol) and benzaldehyde (703.37 mg, 6.63 mmol, 669.88 pl) in DCM (15 ml) was added NaBH(OAc)3 (7.02 g, 33.14 mmol) and 4A MS (6.63 mmol) and acetic acid (39.80 mg, 662.79 pmol). The mixture was stirred at 25 °C for 1 hr. The mixture was poured into ice-water (500 ml). The aqueous phase was extracted with EtOAc (3 x 100 ml). The combined organic phase was washed with saturated aqueous NaCl (100 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by silica gel chromatography (1000 mesh silica gel) eluting with petroleum ether / in EtOAc (100 / 1) to give the title compound (2 g, 95.36%) as a colourless oil. ES / MS m / z: 317.3 (M+H)+.Step B5-Benzyl-l,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridine

[0220] To a solution of tert-butyl 5-benzyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridine-l- carboxylate (1.9 g, 6.00 mmol) in DCM (10 ml) was added TFA (10 ml). The mixture was stirred at 25 °C for Ihr. The mixture was cooled to 20 °C and poured into ice-water (200 ml) The aqueous phase was extracted with EtOAc (3 x 80 ml). The combined organic phase was washed with saturated aqueous NaCl (80 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give the title compound (1 g, crude) as a yellow oil. ES / MS m / z: 217.1 (M+H)+.Step C4-[6-(5-Benzyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-l-yl)-3-pyridyl]-8-oxa-3,4,10- triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaene

[0221] To a solution of 5-benzyl-l,2,3,3a,4,6,7,7a-octahydropyrrolo[3,2-c]pyridine (483.86 mg, 2.24 mmol) and 4-(6-fluoro-3-pyri dyl)-8-oxa-3, 4,10-triazatricyclo[7.4.0.02’6]trideca-l (9), 2,5,10,12-pentaene (0.3 g, 1.12 mmol) in DMF (5 ml) was added CS2CO3 (1.09 g, 3.36 mmol). The mixture was stirred at 100 °C for 16 hrs. The mixture was cooled to 20 °C and poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give the title compound (0.35 g, crude) as a yellow solid.ES / MS m / z: 465.2 (M+H)+.Step D4-[6-(2,3,3a,4,5,6,7,7a-Octahydropyrrolo[3,2-c]pyridin-l-yl)-3-pyridyl]-8-oxa-3,4,10- triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaene

[0222] To a solution of 4-[6-(5-benzyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-l-yl)-3- pyridyl]-8-oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaene (220 mg, 473.57 pmol) in THF (50 ml) was added 10% Pd / C (503.97 mg, 473.57 pmol, 10% purity). The mixture was stirred at 25 °C for Ihr. The mixture was filtered and concentrated in vacuum to give a crude product. The crude product was purified by prep-TLC (DCM: MeOH=20:l) to give the title compound (80 mg, 213.65 pmol, 45.12% yield) as a white solid. ES / MS: 375.3 (M+H)+.Step E2-(6-((3aS,7aS)-5-(Oxetan-3-yl)octahydro-lH-pyrrolo[3,2-c]pyridin-l-yl)pyridin-3-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-b]pyridine

[0223] To a solution of 4-[6-(2,3,3a,4,5,6,7,7a-octahydropyrrolo[3,2-c]pyridin-l-yl)-3-pyridyl]-8- oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaene (80 mg, 213.65 pmol) and oxetan-3-one (15.40 mg, 213.65 pmol) in DCM (2 ml) was added 4A MS (213.65 pmol) and NaBH(OAc)3 (226.41 mg, 1.07 mmol) and acetic acid (1.28 mg, 21.37 pmol, 1.22 pL). The mixture was stirred at 25 °C for 1 hr. The mixture was cooled to 20 °C and poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml*l), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by prep-TLC (DCM: MeOH =20:1) to give the title compound (23 mg, 23.92%) as a white solid. ES / MS m / z: 431.2 (M+H)+.'H NMR (400 MHz, DMSO-de) d ppm 8.48 (d, J=2.63 Hz, 1 H), 8.19 (s, 1 H), 8.10 - 8.13 (m, 1 H), 8.04 (dd, J=7.38, 1.88 Hz, 1 H), 7.87 - 7.91 (m, 1 H), 7.09 (dd, J=7.38, 5.00 Hz, 1 H), 6.55 - 6.59 (m, 1 H), 5.52 (s, 2 H), 4.53 - 4.57 (m, 2 H), 4.41 (dt, J=14.57, 5.72 Hz, 2 H), 4.00 - 4.06 (m, 1 H), 3.51 - 3.58 (m, 1 H), 3.37 - 3.41 (m, 2 H), 2.67 (br d, J=2.00 Hz, 1 H), 2.56 (br s, 1 H), 2.33 (br s, 2 H), 2.13 - 2.18 (m, 2 H), 1.96 (br dd, J=6.13, 4.00 Hz, 1 H), 1.78 - 1.85 (m, 1 H), 1.41 - 1.50 (m, 1 H). MS: 431.2 (M+H)+.Step F

[0224] The product from Step E was separated by SFC (column: ChiralPak IH, 250*30mm, 10pm; mobile phase: [CO2-EtOH(0.1%NH3H2O)];B%:50%, isocratic elution mode) to give:

[0225] Enantiopure isomer 1 (first eluting): 4-[6-[5-(oxetan-3-yl)-3,3a,4,6,7,7a-hexahydro-2H- pyrrolo[3,2-c]pyridin-l-yl]-3-pyridyl]-8-oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12- pentaene (5 mg, 26.32%) as a white solid. ES / MS: 431.2 (M+H)+.'HNMR (DMSO-de) d ppm 8.48 (d, J=2.63 Hz, 1 H), 8.19 (s, 1 H), 8.11 (dd, J=4.88, 1.88 Hz, 1 H), 8.04 (dd, J=7.38, 1.88 Hz, 1 H), 7.89 (dd, J=9.13, 2.75 Hz, 1 H), 7.09 (dd, J=7.38, 5.00 Hz, 1 H), 6.57 (d, J=9.13 Hz, 1 H), 5.52 (s, 2 H), 4.55 (td, J=6.41, 2.19 Hz, 2 H), 4.41 (dt, J=15.45, 6.03 Hz, 2 H), 3.99 - 4.06 (m, 1 H), 3.50 - 3.57 (m, 1 H), 3.38 (br dd, J=12.19, 5.94 Hz, 2 H), 2.67 - 2.71 (m, 1 H), 2.55 (br d, J=11.88 Hz, 1 H), 2.27 - 2.36 (m, 2 H), 2.11 - 2.18 (m, 2 H), 1.92 - 1.98 (m, 1 H), 1.77 - 1.85 (m, 1 H), 1.41 - 1.51 (m, 1 H);and

[0226] Enantiopure isomer 2 (second eluting): 4-[6-[5-(oxetan-3-yl)-3,3a,4,6,7,7a-hexahydro-2H- pyrrolo[3,2-c]pyridin-l-yl]-3-pyridyl]-8-oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12- pentaene (6 mg, 31.58%) as a white solid. ES / MS: 431.2 (M+H)+.'HNMR (DMSO-de) d ppm 8.48 (d, J=2.63 Hz, 1 H), 8.19 (s, 1 H), 8.11 (dd, J=4.88, 1.88 Hz, 1 H), 8.04 (dd, J=7.38, 1.88 Hz, 1 H), 7.89 (dd, J=9.13, 2.75 Hz, 1 H), 7.09 (dd, J=7.38, 4.88 Hz, 1 H), 6.57 (d, J=9.13 Hz, 1 H), 5.52 (s, 2 H), 4.55 (td, J=6.41, 2.19 Hz, 2 H), 4.41 (dt, J=15.42, 6.05 Hz, 2 H), 3.99 - 4.06 (m, 1 H), 3.50 - 3.57 (m, 1 H), 3.35 - 3.43 (m, 2 H), 2.69 (br d, J=12.01 Hz, 1 H), 2.54 - 2.57 (m, 1 H), 2.27 - 2.35 (m, 2 H), 2.10 - 2.19 (m, 2 H), 1.92 - 2.00 (m, 1 H), 1.77 - 1.85 (m, 1 H), 1.43 - 1.51 (m, 1 H). MS: 431.2 (M+H)+.Example 1084-Methyl-l-(5-(pyrazolo[3', 4':4,5]pyrano[2, 3-b]pyridin-2(4H)-yl)pyri din-2 -yl)piperidin-4-ol

[0227] To a solution of l-[5-(8-oxa-3,4,10-triazatricyclo[7.4.0.02’6]trideca-l(9),2,5,10,12-pentaen-4- yl)-2-pyridyl]piperidin-4-one (0.3 g, 863.63 pmol) in THF (5 ml) was added MeMgBr (3 M, 575.76 pl) at -70 °C. Then the mixture was warmed to 25 °C and stirred for 1 hr. The mixture was poured into ice-water (100 ml). The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum. The crude product was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*5pm; mobile phase: [H2O(0.1% TFA)-ACN];gradient: l%-20% B over 12.0 min). The combined fractions were neutralized by Na2COs. The aqueous phase was extracted with EtOAc (3 x 50 ml). The combined organic phase was washed with saturated aqueous NaCl (50 ml), dried with anhydrous Na2SO4, filtered, and concentrated in vacuum to give the title compound (61 mg, 19.20%) as a white solid. ES / MS m / z: 364.2 (M+H)+.JH NMR (DMSO- e) 5 ppm 8.53 (d, 7=2.63 Hz, 1 H), 8.24 (s, 1 H), 8.12 (dd, 7=4.94, 1.94 Hz, 1 H), 8.05 (dd, 7=7.38, 1.88 Hz, 1 H), 7.93 (dd, 7=9.19, 2.81 Hz, 1 H), 7.09 (dd, 7=7.38, 4.88 Hz, 1 H), 6.97 (d, 7=9.26 Hz, 1 H), 5.52 (s, 2 H), 4.37 (s, 1 H), 3.87 (dt, 7=12.91, 3.99 Hz, 2 H), 3.36 - 3.41 (m, 2 H), 1.46 - 1.53 (m, 4 H), 1.15 (s, 3 H).Example 1093,3-difluoro-7V-(-3-fluorocyclobutyl)-l-(5-(pyrazolo[3',4':4,5]pyrano[2,3-Z>]pyridin-2(477)-yl)pyridin- 2-yl)piperidin-4-amine (trans isomer)Step A tert-butyl 3,3-difluoro-4-[(-3-fluorocyclobutyl)amino]piperidine-l-carboxylate (trans isomer)Boc

[0228] To a solution of tert-butyl 3,3-difluoro-4-oxo-piperidine-l-carboxylate (1.87 g, 7.96 mmol) and (Ir, 3r)-3-fluorocyclobutan-l-amine hydrochloride (trans isomer) (2 g, 15.93 mmol) in DCM (10 ml) was added 4A MS (2 g), AcOH (478 mg, 7.96 mmol) and NaBH(OAc)3 (5.06 g, 23.89 mmol). The reaction mixture was stirred at 20 °C for 10 hr. The reaction mixture was poured into water (300 ml). The aqueous phase was extracted with DCM (3 x 100 ml). The combined organic phase was washed with brine (3 x 100 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge 150 x 25 mm 10 pm; mobile phase: [H2O (10 mM NH4HCO3)-ACN]; gradient: 35%-65% B over 9.0 min) to give the title compound as a white solid (0.44 g, 17%).JH NMR (DMSO-de) 5 = 5.03 - 5.24 (m, 1H), 3.84 - 3.98 (m, 1H), 3.69 (br d, J = 13.51 Hz, 1H), 3.52 - 3.62 (m, 1H), 3.20 - 3.31 (m, 1H), 2.97 - 3.10 (m, 1H), 2.82 - 2.95 (m, 1H), 2.03 - 2.35 (m, 6 H), 1.73 - 1.83 (m, 1H), 1.36 - 1.41 (m, 9H).Step B 3,3-difluoro-7V-(3-fluorocyclobutyl)piperidin-4-amine hydrochloride (trans isomer)

[0229] The solution of tert-butyl 3,3-difluoro-4-[((-3-fluorocyclobutyl)amino]piperidine-l- carboxylate (0.4 g, 1.30 mmol) in HCl / EtOAc (4 M, 4 ml) was stirred at 20 °C for 1 hr. The reaction mixture was concentrated in vacuum to give the title compound (0.3 g, crude) as a white solid.Step C3,3-difluoro-A-(-3-fluorocyclobutyl)-l-(5-(pyrazolo[3',4':4,5]pyrano[2,3-Z>]pyridin-2(4J7)- yl)pyri din-2 -yl)piperidin-4-amine (trans isomer)

[0230] To a solution of 2-(6-bromopyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- Z>]pyridine (0.134 g, 407.11 pmol) (Preparation 4) and 3,3-difluoro-7V-(3-fluorocyclobutyl)piperidin- 4-amine hydrochloride (299 mg, 1.22 mmol) in 1,4-dioxane (1.5 ml) was added RuPhos Pd G4 (35 mg, 40.71 pmol) and t-BuONa (391 mg, 4.07 mmol) at 20 °C. The reaction mixture was stirred at 100 °C for 7 hr. LCMS showed the reaction was completed. The reaction mixture was poured into aq. EDTA (300 ml) and stirred for 0.5 hr. The aqueous phase was extracted with DCM (3 x 100 ml). The combined organic phase was washed with brine (3 x 100 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD Cl 8 150 x 40 mm x 10 pm; mobile phase: [H2O (10 mM NEUE1CO3)-ACN]; gradient: 25%-55% B over 8.0 min) to give the title compound (61.9 mg, 31%) as a white solid. ES / MS: 457.2 (M+H)+.

[0231] 'H NMR (400 MHz, DMSO-de) 8 = 8.57 (d, J = 2.75 Hz, 1H), 8.28 (s, 1H), 8.12 (dd, J = 4.88, 1.88 Hz, 1H), 8.06 (dd, J = 7.44, 1.81 Hz, 1H), 7.99 (dd, J = 9.01, 2.75 Hz, 1H), 7.07 - 7.13 (m, 2H), 5.53 (s, 2H), 5.05 - 5.27 (m, 1H), 4.37 - 4.49 (m, 1H), 4.09 (br d, J = 13.26 Hz, 1H), 3.63 (br dd, J = 5.00, 3.13 Hz, 1H), 3.41 - 3.55 (m, 1H), 3.18 - 3.27 (m, 1H), 2.95 - 3.07 (m, 1H), 2.25 - 2.35 (m, 3H), 2.07 - 2.21 (m, 2H), 1.87 - 1.95 (m, 1H), 1.53 (br d, J = 10.88 Hz, 1H).

[0232] The compound shown on Table 14 was prepared analogous to Example 109.Table 14Example 1112-(6-(4-(3-fluorocyclobutoxy)piperidin-l-yl)pyridin-3-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-Z>]pyridine (cis isomer)Step A4-(-3-fluorocyclobutoxy)pyridine (cis isomer)

[0233] To a solution of pyridin-4-ol (1.06 g, 11.10 mmol) and 3-fluorocyclobutan-l-ol (1 g, 11.10 mmol) in THF (10 ml) was added PPh3 (4.37 g, 16.65 mmol) and DIAD (3.37 g, 16.65 mmol,) at 0 °C. The mixture was stirred at 50 °C for 2 hr under N2. The reaction mixture was cooled to 25 °C, then poured into water (100 ml). The aqueous phase was extracted with ethyl acetate (2 x 30 ml). The combined organic phase was washed with brine (30 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate= 1 : 1) followed by prep- HPLC (column: WePure Biotech XP tC18 250 x 70 mm x 10 pm; mobile phase: [1420(0.05% NH3H2O)-ACN]; gradient: 20%-50% B over 20.0 min) to give the title compound as a yellow solid (470 mg, 25%). ES / MS: 168.1 (M+H)+.Step B l-benzyl-4-(3-fluorocyclobutoxy)pyridin-l-ium (cis isomer)

[0234] To a solution of (bromomethyl)benzene (481 mg, 2.81 mmol) in DCM (5 ml) was added 4- (3-fluorocyclobutoxy)pyridine (470 mg, 2.81 mmol) at 20 °C. The reaction mixture was stirred for 16 hr at 20 °C. LCMS showed the reaction was completed. The reaction mixture was concentrated in vacuo to give the title compound (700 mg, crude) as a yellow oil. ES / MS: 258.1 (M+H)+ .Step C l-benzyl-4-(3-fluorocyclobutoxy)-l,2,3,6-tetrahydropyridine (cis isomer)

[0235] To l-benzyl-4-(3-fluorocyclobutoxy)pyridin-l-ium (500 mg, 1.94 mmol) in MeOH (5 ml) was added NaBTLj (217 mg, 5.81 mmol) at 0 °C under N2. The reaction mixture was stirred for 1 hr at 20 °C under N2. The reaction mixture was poured into ice-water (100 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (3 x 50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (500 mg, crude) as white solid. ES / MS: 262.1 (M+H)+ 1H NMR (DMSO-d6) 5 = 7.19 - 7.40 (m, 5H), 4.68 - 4.95 (m, 1H), 4.47 (t, J= 3.3 Hz, 1H), 3.93 - 4.07 (m, 1H), 3.52 (s, 2H), 2.78 - 3.00 (m, 4H), 2.54 (br s, 2H), 1.98 - 2.17 (m, 4H).Step D4-(3-fluorocyclobutoxy)piperidine (cis isomer)

[0236] To a solution of l-benzyl-4-(3-fluorocyclobutoxy)-l,2,3,6-tetrahydropyridine (500 mg, 1.91 mmol) in MeOH (8 ml) was added Pd / C (313 mg, 294 pmol, 10% purity) at 20 °C. The reaction mixture was stirred for 16 hrs at 50 °C under H2. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound (430 mg, crude) as a yellow oil which was used for the next step directly without further purification.Step E2-(6-(4-(3-fluorocyclobutoxy)piperidin-l-yl)pyridin-3-yl)-2,4- dihydropyrazolo[3',4':4,5]pyrano[2,3-Z>]pyridine (cis isomer)

[0237] To a solution of 2-(6-fluoropyridin-3-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-Z>]pyridine (Preparation 2) (100 mg, 372.79 pmol) and 4-(3-fluorocyclobutoxy)piperidine (320 mg, 1.85 mmol) in DMSO (1 ml) was added DIPEA (145 mg, 1.12 mmol, 195 pl) at 20 °C. The reaction mixture was heated to 100 °C and stirred for 16 hrs. The reaction mixture was poured into ice-water (100 ml).The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (3 x 50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuo.The crude product was purified by prep-TLC (DCM:MeOH=20: 1) followed by prep-HPLC (column: Waters Xbridge Prep OBD C18 150 x 40 mm x 10 pm; mobile phase: [EEO (0.05% NH3H2O+IO mM NH4HCO3)-ACN]; gradient: 30%-60% B over 8.0 min) to give the title compound (25.3 mg, 16%) as a white solid. ES / MS: 422.2 (M+H)+. Tl NMR (DMSO-de) 8 = 8.56 (d, J = 2.8 Hz, 1H), 8.26 (s, 1H), 8.10 - 8.19 (m, 1H), 8.03 - 8.10 (m, 1H), 7.91 - 8.00 (m, 1H), 7.07 - 7.16 (m, 1H), 7.00 (d, J = 9.1 Hz, 1H), 5.53 (s, 2H), 4.63 - 4.91 (m, 1H), 3.98 - 4.13 (m, 2H), 3.66 - 3.81 (m, 1H), 3.53 - 3.64 (m, 1H), 3.11 - 3.23 (m, 2H), 2.70 - 2.84 (m, 2H), 1.98 - 2.16 (m, 2H), 1.82 - 1.92 (m, 2H), 1.35 - 1.53 (m, 2H).

[0238] The compound shown on Table 15 was prepared analogous to Example 111 Step B to E.Table 15Example 1132-(5-(4-methoxypiperidin-l-yl)pyrazin-2-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- Z>]pyridine2-bromo-5-(4-methoxypiperidin-l-yl)pyrazine

[0239] To 2, 5 -dibromopyrazine (1 g, 4.20 mmol) and 4-methoxypiperidine (532.58 mg, 4.62 mmol) in DMSO (10 ml) was added DIPEA (1.63 g, 12.61 mmol). The mixture was stirred for 1 hr at 100 °C. The reaction mixture was poured into ice-water (200 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (3 x 50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give a residue. The residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate=10 / l, 5 / 1) to give the title compound (0.9 g, 79%) as a yellow solid. ES / MS: 272.0 / 274.0 (M+H)+. 'H NMR (DMSO-de) 5 = 8.19 (s, 1H), 8.15 (s, 1H), 3.84 - 3.95 (m, 2H), 3.40 - 3.47 (m, 1H), 3.20 - 3.31 (m, 5H), 1.82 - 1.93 (m, 2H), 1.36 - 1.51 (m, 2H).Step B2-(5-(4-methoxypiperidin-l-yl)pyrazin-2-yl)-2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3- Z>]pyridine

[0240] To a solution of 2-bromo-5-(4-methoxypiperidin-l-yl)pyrazine (565 mg, 2.08 mmol) and 2,4-dihydropyrazolo[3',4':4,5]pyrano[2,3-Z>]pyridine (Preparation 1) (300 mg, 1.73 mmol) in 1,4- dioxane (5 ml) was added CS2CO3 (1.69 g, 5.20 mmol), Cui (33 mg, 173.24 pmol) and 7V,7V- Dimethyl-(1 R, 27?)-l,2-cyclohexan ediamine (62 mg, 346.48 pmol) at 20 °C. The mixture was stirred for 16 hrs at 100 °C. The reaction mixture was poured into ice-water (100 ml). The aqueous phase was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was washed with brine (3 x 50 ml), dried with anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude. The crude was purified by prep-TLC (DCM:MeOH=20: 1 ) to give the title compound as a yellow solid (121.5 mg, 19%). ES / MS: 365.2 (M+H)+ XH NMR (DMSO-de) 5 = 8.67 (d, J = 1.1 Hz, 1H), 8.32 (s, 1H), 8.22 (d, J = 1.1 Hz, 1H), 8.13 - 8.18 (m, 1H), 8.05 - 8.12 (m, 1H), 7.07 - 7.21 (m, 1H), 5.53 (s, 2H), 3.91 - 4.07 (m, 2H), 3.42 - 3.53 (m, 1H), 3.26 - 3.32 (m, 5H), 1.86 - 2.00 (m, 2H), 1.40 - 1.58 (m, 2H).

[0241] The compound shown on Table 16 was prepared analogous to Example 113Table 16

[0242] The compounds shown on Table 17 were prepared analogous to Example 74.Table 17Chiral separation conditions:

[0243] Conditions 12. The enantiopure Examples 116, 117 above were obtained by chiral SFC separation starting from the corresponding racemic mixture (column: DAICEL CHIRALCEL OJ (250 mm x 30 mm x 10 pm); mobile phase: [CO2-EtOH:ACN=l : l (0.1% NH3H2O)]; B: 50%, isocratic elution mode)Biological Assay DescriptionThioflavin T (ThT)-based fluorescence assay to assess activity on aggregated recombinant human Tan (2N4R)

[0244] The longest isoform of human Tau (2N4R; 441 amino acids) was expressed in bacteria and purified (Boston Biochem). For the ThT-based assay assessing activity on aggregated Tau, recombinant 2N4R Tau at 35 pM in phosphate-buffered saline (PBS) was aggregated for 72 hours at 37 °C in the presence of 25 pM of heparin (Sigma- Aldrich) and 10 mM of DTT (Sigma-Aldrich) under shaking at 1000 RPM. Compounds were dissolved in anhydrous dimethyl sulfoxide (DMSO, Sigma-Aldrich) to reach a concentration of 2.5 mM. In a black 384-well assay plate (Perkin-Elmer), 2N4R Tau aggregates and serial dilutions of compounds were mixed together in PBS (volume 40 pL) in technical duplicate to a final concentration of 60 nM of 2N4R Tau and from 20 to 0.0048 pM of compound in 4% DMSO. The mixture was incubated for 30 minutes at room temperature (RT), then 10 pL of 5 pM ThT in 250 mM glycine (both from Sigma-Aldrich) in PBS were added. Fluorescence (relative fluorescence units; RFU) was measured on a TECAN SPARK® multimode microplate reader (excitation: 448 nm; emission: 485 nm; with automatic detection of optimal gain). Compound activity, expressed as ThT RFU percentage reduction, was calculated and the half maximal effective concentration was determined using GraphPad Prism (version 9.4 or higher, GraphPad Software) assuming an “[agonist] vs. response - Variable slope (four parameters)” model. The curves were constrained to 0 (bottom) and 100 (top). See Table 18Thioflavin T (ThT)-based fluorescence assay to assess activity on aggregated human Tau (PHF)

[0245] The Alzheimer’s disease brain samples used to isolate paired helical filaments (PHF) were purchased from the Banner Institute, Tissue solutions, and the Netherlands Brain Bank, and were characterized by immunohistochemistry to assess Tau burden. The PHF isolation protocol was modified from Jicha et al., 1997 and Rostagno and Ghiso, 2009. Compounds were dissolved in anhydrous dimethyl sulfoxide (DMSO, Sigma- Aldrich) to reach a concentration of 10 mM. PHF was sonicated at RT for 30 seconds and diluted in PBS. The final dilution of PHF was optimized for each PHF batch prior to the experiments and ranged between 1 :300 and 1 :800. Diluted PHF and serial dilutions of compounds were mixed together to a final concentration of compound from 100 to 0.1 pM in 1% DMSO. Each sample was then transferred to a black 384-well assay plate (Perkin-Elmer) in technical duplicate (volume 40 pL). The mixtures were incubated for 24 hours at 37 °C, then 10 pL of a 5 pM or 0.5 pM ThT solution in 250 mM glycine (both from Sigma- Aldrich) in PBS were added. ThT was used at 5 pM for PHF dilutions up to 1 :500, and at 0.5 pM for higher PHF dilutions. Fluorescence (relative fluorescence units; RFU) was measured on a Tecan Spark® multimode microplate reader (excitation: 448 nm; emission: 485 nm; with automatic detection of optimal gain). Compound activity for interfering with ThT binding, expressed as ThT RFU percentage reduction, was calculated and the half maximal effective concentration was determined using GraphPad Prism (version 9.4 or higher, GraphPad Software) assuming an “[agonist] vs. response - Variable slope (four parameters)” model. The curves were constrained to 0 (bottom) and 100 (top). See Table 18.

[0246] The following example compounds were measured:Table 18(1) Legend: +++ EC50 < 0.1 uM; ++ EC50 0.1<x<0.5 uM; + EC50 0.5<x<l uM.(2) Legend: +++ EC50 < 10 uM; ++ EC50 10<x<50 uM; + EC50 50<x<100 uM; nd : not determined;

[0247] As can be seen from Table 18above, the various compounds disclosed herein demonstrate activity on aggregated recombinant human Tau (2N4R) and demonstrate activity on aggregated human Tau (PHF).

[0248] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims.

[0249] Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while onlycertain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

[0250] The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various aspects, the terms “consisting essentially of’ and “consisting of’ can be used in place of “comprising” and “including” to provide for more specific aspects and are also disclosed.

[0251] Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood to be construed in light of the number of significant digits and ordinary rounding approaches, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims.

Claims

1. CLAIMSWe claim:

1. A compound of F ormula (I) :Formula0> , whereinX1is a CR1or N, wherein R1is H or halogen;X2is a CR2or N, wherein R2is H or halogen;X3is a CR3or N, wherein R3is H or halogen;X4is a CH or a C-halogen;A is 4-10 membered saturated heterocyclyl with one ring atom which is N and optionally 1-2 ring atoms independently selected from N and O, wherein A is optionally substituted with 1-3 substituents selected from the group consisting of halogen, Ci-Ce alkyl, oxo, NR3R4, 4- to 6- membered heterocyclyl having one ring atom selected from N and O and optionally substituted with 1-2 halogen, and OR5;R3is selected from the group consisting of H, halogen, Ci-Ce alkyl, and C3-C6 cycloalkyl;R4is selected from the group consisting of Ci-Ce alkyl, C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl with one ring atom selected from N and O; wherein R4is optionally substituted with 1-2 halogen, and wherein R5is selected from the group consisting of H and 4- to 6-membered heterocyclyl having one ring atom selected from N and O, wherein the heterocyclyl is optionally substituted with Ci-Ce alkyl; or a pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein X1is N.

3. The compound according to claim 1, wherein X2is N.

4. The compound according to claim 1 or 2, wherein X2is CR2.

5. The compound according to claim 4, wherein R2is H.

6. The compound according to claim 4, wherein R2is halogen.

7. The compound according to claim 6, wherein R2is fluorine.

8. The compound according to claim 1 or 3, wherein X1is CR1.

9. The compound according to claim 8, wherein R1is H.

10. The compound according to claim 8, wherein R1is halogen.

11. The compound according to claim 10, wherein R1is fluorine.

12. The compound according to any of the previous claims, wherein X3is CR3.

13. The compound according to any of the previous claims, wherein X4is CH.

14. The compound according to claims 1-12, wherein X4is C-halogen.

15. The compound according to claim 14, wherein X4is CF.

16. The compound according to claims 1-11, wherein X3is C-halogen.

17. The compound according to claim 16, wherein X3is CF.

18. The compound according to claims 1-10, wherein X3is N.

19. The compound according to claim 1, or a pharmaceutically salt thereof, having the Formula:Formula (II)20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the Formula:

21. The compound according to any of the previous claims, wherein A is selected from the group consisting of:17922. The compound according to claims 1-21, wherein A is selected from the group consisting of:

23. The compound according to claims 1-21, wherein A is selected from the group consisting of:

24. The compound according to claims 1-21, wherein A is selected from the group consisting of:

25. The compound according to claims 1-21, wherein A is selected from the group consisting of:

26. The compound of claim 1, wherein the compound is selected from the group consisting of the18418518618919019119227. A method of treating or alleviating a disorder associated with Tau protein aggregates, the method comprising administering an effective amount of a compound or a pharmaceutically acceptable salt thereof as defined in any of the proceeding claims to a subject in need thereof.

28. The method according to claim 26, wherein the disorder is selected from the group consisting of Alzheimer's disease (AD), familial AD, Primary Age-Related Tauopathy (PART), Creutzfeldt- Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, nonGuamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease,corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-associated neurocognitive disorder (HAND), adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD, Huntington's disease, Aging related tau astrogliopathy (ARTAG), FTLD, FTLD with C9orf72 hexanucleotide repeat expansion, Neurofibrillary Tangle-Dominant Dementia (NFTD), Fahr’s Disease (idiopathic basal ganglia calcification), Primary Progressive Aphasia (PPA), Late-Onset Epilepsy of Unknown Etiology (LOEU), Kufs Disease (adult-onset neuronal ceroid lipofuscinosis), Lafora Disease and Multiple system Tauopathy with dementia29. The method according to claim 27, wherein the disorder is Alzheimer's disease (AD).

30. A method of decreasing Tau aggregation comprising administering to a patient in need of decreasing Tau aggregation an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 25.

31. A method of promoting disaggregation of Tau aggregates comprising administering to a patient in need of promoting disaggregation of Tau aggregates an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 25.

32. A method of preventing the formation of Tau aggregates comprising administering to a patient in need of preventing the formation of Tau aggregates an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 25.

33. A method of inhibiting the formation of Tau aggregates comprising administering to a patient in need of inhibiting the formation of Tau aggregates an effective amount of a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 25.

34. A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 25, and optionally at least one pharmaceutically acceptable excipient, carrier, diluent and / or adjuvant.

35. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, for use as a medicament.

36. The compound according to claim 34, wherein the use as a medicament is for treatment for a disorder associated with Tau protein aggregates.

37. The use according to claim 35, wherein the disorder is selected from the group consisting of Alzheimer's disease (AD), familial AD, Primary Age-Related Tauopathy (PART), Creutzfeldt-Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corti cobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden- Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson'sdisease, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD and Huntington's disease.

38. The use according to claim 36, wherein the disorder is Alzheimer's disease.

39. Use of the compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament in the treatment of a disorder associated with Tau protein aggregates.

40. The use according to claim 38, wherein the disorder is selected from the group consisting of Alzheimer's disease (AD), familial AD, Primary Age-Related Tauopathy (PART), Creutzfeldt-Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, non-Guamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corti cobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden- Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD and Huntington's disease.

41. The use according to claim 39, wherein the disorder is Alzheimer's disease.

42. The compound according to any one of claims 1 to 25 for use in therapy.

43. The compound of claim 41, for use in therapy, wherein the therapy is for treatment of a disorder associated with Tau protein aggregates.

44. The compound for use in therapy claim 42, wherein the disorder is selected from the group consisting of Alzheimer's disease (AD), familial AD, Primary Age-Related Tauopathy (PART), Creutzfeldt- Jacob disease, dementia pugilistica, Down's Syndrome, Gerstmann-Straussler-Scheinker disease (GSS), inclusion-body myositis, prion protein cerebral amyloid angiopathy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), Parkinsonism-dementia complex of Guam, nonGuamanian motor neuron disease with neurofibrillary tangles, argyrophilic grain disease, corticobasal degeneration (CBD), diffuse neurofibrillary tangles with calcification, frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Hallervorden-Spatz disease, multiple system atrophy (MSA), Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Pick's disease (PiD), progressive subcortical gliosis, progressive supranuclear palsy (PSP), subacute sclerosing panencephalitis, tangle predominant dementia, postencephalitic Parkinsonism, myotonic dystrophy, subacute sclerosis panencephalopathy, mutations in LRRK2, chronic traumatic encephalopathy (CTE), familial British dementia, familial Danish dementia, other frontotemporal lobar degenerations, Guadeloupean Parkinsonism, neurodegeneration with brain iron accumulation, SLC9A6-related mental retardation, white matter tauopathy with globular glial inclusions, epilepsy, Lewy body dementia (LBD), mild cognitive impairment (MCI), multiple sclerosis, Parkinson's disease, HIV-related dementia, adult onset diabetes, senile cardiac amyloidosis, glaucoma, ischemic stroke, psychosis in AD and Huntington's disease.

45. The compound for use in therapy claim 43, wherein the disorder is Alzheimer's disease.

46. A combination comprising a therapeutically effective amount of a first compound according to claims 1 to 25, and one or more therapeutic agents different from the first compound.

47. The combination according to claim 45, wherein one or more therapeutic agents are selected from the group consisting of compounds against oxidative stress; anti-amyloid drug; anti-amyloid- beta antibody, anti-apoptotic compounds; metal chelators; inhibitors of DNA repair such as pirenzepine and metabolites; 3 -amino- 1 -propanesulfonic acid (3APS); 1,3 -propanedisulfonate (1,3PDS); alpha-secretase activators; beta- and gamma-secretase inhibitors including BACE1; Tau proteins; neurotransmitters; beta-sheet breakers; attractants for amyloid beta clearing / depletingcellular components; inhibitors of N-terminal truncated amyloid beta including pyroglutamated amyloid beta 3-42; anti-inflammatory molecules; cholinesterase inhibitors (ChEIs) such as tacrine, rivastigmine, donepezil, and / or galantamine; Ml agonists; amyloid-beta or Tau modifying drugs; nutritive supplements; neurological drugs; corticosteroids, antibiotics, or antiviral agents.

48. Use of a compound according to any one of claims 1 to 25, as an analytical reference or an in vitro screening tool.

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