Novel benzofuran, benzothiophene and indole analogs that inhibit the formation of tau oligomers and methods of using the same

Abstract

Novel benzofurans, benzothiophenes and indoles are provided that are useful as inhibitors of tau oligomerization, which are useful in the treatment of neurodegenerative diseases and related conditions. For example, a compound of the following formula is shown. TIFF2023052610000194.tif34166 The invention also relates to pharmaceutically acceptable salts of the compounds, processes for preparing the compounds, intermediates used in preparing the compounds, and pharmaceutical compositions containing the compounds. The invention further relates to methods of using the compounds, salts of the compounds, and compositions in the treatment of neurodegenerative diseases and related conditions.

Description

Technical Field

[0001] Description of Research with Federal Government Funds The United States Government has a paid-up license in this invention and has the right in limited circumstances to require the patent owner to license others under the terms of the grant numbers 5R44AG029777-05, 2R44AG029777-04, 5R44AG029777-03, 2R44AG029777-02A1, 1R43AG029777-01, 1R44AG053150-01 and 5R44AG053150-02, awarded by the National Institute On Aging of the National Institutes of Health, under reasonable conditions.

[0002] The present invention describes novel benzofurans, benzothiophenes and indoles useful as inhibitors of tau oligomer formation, which are useful in the treatment of neurodegenerative diseases and related conditions. The present invention also relates to pharmaceutically acceptable salts of said compounds, processes for the preparation of said compounds, intermediates used in the preparation of said compounds, and pharmaceutical compositions containing said compounds. The present invention further relates to methods of using said compounds, salts of said compounds, and said compositions in the treatment of neurodegenerative diseases and related conditions.

Background Art

[0003] There is a large and growing unmet need for disease-modifying drugs for Alzheimer's disease (AD). The prevalence of AD is increasing worldwide due to demographic changes resulting from an aging population, and ending AD would save the lives of 500,000 people a year. It is the most costly disease in the United States, with a financial burden exceeding $259 billion in direct costs in 2017 and projected to increase to $1.1 trillion / year by 2050. Women are far more likely to develop AD and bear the burden of caregiving (Non-Patent Document 1). Thus, a major goal of the National Alzheimer's Project is to prevent and effectively treat AD by 2025. Since all previous Phase 3 drug development programs based on the amyloid hypothesis have failed to meet their clinical endpoints, alternative approaches to AD therapy are needed, such as targeting tau. (Non-Patent Documents 2, 3)

[0004] Another approach to treating AD focuses on the development of disease-modifying therapeutics (DMTs) that inhibit tau self-association into oligomers and larger tau aggregates. Neurofibrillary tangles are pathological features associated with AD and related tauopathies, but their role in causing neurodegeneration is suspect; see Non-Patent Document 4. According to multiple studies, tau oligomers, which are neither fibrillar nor entangled, are closely correlated with neuronal deficits and memory impairment; see Non-Patent Documents 5 and 6. Significantly, Oligomerix has shown that tau oligomers disrupt neuronal signaling and inhibit memory formation in mice. Memory formation was impaired after administration of oligomeric tau to the hippocampus, a brain region involved in short-term memory formation. However, treatment with tau monomers (tau that did not self-associate) had no effect. This memory impairment was also found using oligomers formed from tau purified from human AD brain specimens by a method that preserves tau modifications associated with AD. Memory-specific mechanisms involved in gene regulation have been shown to be disrupted by these extracellular tau oligomers; see Non-Patent Documents 7 and 8. Subsequent studies have corroborated the inventors' findings, showing that tau oligomers impaired memory formation and induced synaptic and mitochondrial dysfunction in wild-type mice (Non-Patent Document 9) and a mouse model that recapitulates the spread of tau pathology in AD (Non-Patent Document 10). Oligomerix also found in a collaborative study with the laboratory of Dr. Michael Sierks at Arizona State University that a specific form of tau oligomer is toxic when applied to cultured neurons, whereas tau monomers are non-toxic at the same concentration; see Non-Patent Document 11. Tau oligomers targeted for therapeutic development have been validated in htau (human tau) by treatment with curcumin (Non-Patent Document 12) and a passive immunotherapy approach against tau oligomers (Non-Patent Document 13).

[0005] The spreading pattern of tau lesions in AD is highly consistent and can thus be used for disease staging (Non-Patent Document 14). The observation that tau lesions progress to synaptic connection regions of the brain led to the hypothesis that tau can transfer its own lesions from affected neurons to normal neurons. According to recent studies, tau aggregates, particularly tau oligomers isolated from AD brains, may act as templates for misfolding and aggregation of native tau, thereby promoting the spread of toxic forms of proteins. See Non-Patent Documents 15 and 16. Collectively, these studies strongly suggest that targeting tau oligomers should improve learning and memory and halt disease progression in AD, related tauopathies, and neurodegenerative diseases. Immunotherapeutic approaches targeting extracellular aggregated tau are in clinical development for AD and other tauopathies (Non-Patent Document 17). However, small molecule approaches may be more economical considering the chronic nature of the disease and the price difference between antibody injections and orally administrable drugs. Furthermore, small molecule drugs can more easily cross the plasma membrane and can thus directly target tau self-association intracellularly.

[0006] Currently, there is no disease-modifying therapy (DMT) for AD, and commercially available drugs for alleviating symptoms are not very effective. However, several strategies, including the mechanisms of hyperphosphorylation, protofibril aggregation, clearance of tau aggregates by macroautophagy, HSP90 inhibitors, and immunotherapeutic approaches, have been used in the development of drugs targeting tau (Non-Patent Documents 18 to 20). However, there is no clinically approved therapy that is useful for treating neurodegenerative diseases and related symptoms and is useful for inhibiting tau oligomer formation.

[0007] There has long been a need for new therapies that inhibit the formation of tau oligomers and are useful for the treatment of Alzheimer's disease (AD), which is disease-modifying. The present invention addresses the need for inhibiting the formation of tau oligomers that are useful for the treatment of Alzheimer's disease (AD). The present invention also addresses the long-standing need for new treatments for diseases caused by or associated with tau-based aggregates such as amyotrophic lateral sclerosis / Parkinsonism dementia complex, argyrophilic grain dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia / chronic traumatic encephalopathy, diffuse neurofibrillary tangles with calcification, Down syndrome, frontotemporal dementia linked to chromosome 17 with Parkinsonism, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guam type motor neuron disease with neurofibrillary changes, Pick's disease, postencephalitic Parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, neurofibrillary type dementia (tangle only dementia), etc., and means for preventing such diseases.

Prior Art Documents

Non-Patent Documents

[0008]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Non-Patent Document 14

Non-Patent Document 15

Non-Patent Document 16

Non-Patent Document 17

Non-Patent Document 18

Non-Patent Document 19

Non-Patent Document 20

Summary of the Invention

Means for Solving the Problems

[0009] The present invention relates to compounds of formula (I) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0010]

Chemical Formula

[0011] In the formula, R 1a and R 1d are each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, and C 1~6 haloalkoxy, R 1b and R 1c are selected from the group consisting of hydrogen, halogen, optionally substituted aryl, and optionally substituted heteroaryl, R 1b when it is hydrogen, R 1c is not hydrogen, R 1c when it is hydrogen, R 1b is not hydrogen, R 2 is selected from the group consisting of C 1~6 alkyl, C 3~7 branched alkyl, C 1~6 alkylaryl, optionally substituted aryl, and optionally substituted heteroaryl, X is selected from the group consisting of oxygen, sulfur, NH, and NR 5 and R 5is C 1~6 is alkyl, Y is

[0012]

Chemical formula

[0013] and optionally substituted 2-benzimidazole, and is selected from the group consisting of R 6 is hydrogen, OH, OR 7c , optionally substituted C 1~6 alkyl, NR 3a R 3b , optionally substituted aryl, and optionally substituted heteroaryl, and is selected from the group consisting of R 3a and R 3b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 3a and R 3b together with the atom to which they are attached, optionally including a member selected from the group consisting of O, NR 8 and S, form a 3- to 6-membered saturated ring optionally substituted with a group selected from OH, C 1~6 alkyl, NR 8a R 8b R 8 is hydrogen, C 1~6 alkyl and CO(C 1~6 alkyl), and is selected from the group consisting of R 8a and R 8b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 7a is selected from the group consisting of hydrogen and C 1~6 alkyl, R 7b is C 1~6 alkyl, aryl and heteroaryl, and is selected from the group consisting of R 7c is C 1~6 alkyl and C​3~7 It is selected from the group consisting of branched alkyls.

[0014] The compounds of the present invention include the compounds of formula (II) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0015]

Chemical formula

[0016] In the formula, R 1a , R 1b , R 1c , R 1d , R 2 and Y are as defined for formula I.

[0017] The compounds of the present invention include the compounds of formula (III) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0018]

Chemical formula

[0019] In the formula, R 1a , R 1b , R 1c , R 1d , R 2 and Y are as defined for formula I.

[0020] The compounds of the present invention include the compounds of formula (IV) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0021]

Chemical formula

[0022] In the formula, R 1a , R 1b , R1c , R 1d , R 2 and Y are as defined for formula I.

[0023] The compounds of the present invention include compounds of formula (V) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0024] [Chemical formula]

[0025] wherein R 1a , R 1b , R 1c , R 1d , R 2 , R 5 and Y are as defined for formula I.

[0026] The compounds of the present invention include compounds of formula (VI) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0027] [Chemical formula]

[0028] wherein R 1a , R 1b , R 1c , R 1d , R 2 , R 6 and X are as defined for formula I.

[0029] The compounds of the present invention include compounds of formula (VII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0030] [Chemical formula]

[0031] Wherein, R 1a , R 1b , R 1c , R 1d , R 2 , R 7a , R 7b and X are as defined for formula I.

[0032] The compounds of the present invention include the compounds of formula (VIII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0033]

Chemical formula

[0034] Wherein, R 1a , R 1b , R 1c , R 1d , R 2 and X are as defined for formula I.

[0035] The compounds of the present invention include the compounds of formula (IX) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0036]

Chemical formula

[0037] Wherein, R 1b , R 1c , R 2 , X and Y are as defined for formula I.

[0038] The compounds of the present invention include the compounds of formula (X) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0039]

Chemical formula

[0040] In the formula, R 1b and R 1c and R 2 and Y are as defined for formula I.

[0041] The compounds of the present invention include the compounds of formula (XI) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0042] [Chemical formula]

[0043] In the formula, R 1b and R 1c and R 2 and Y are as defined for formula I.

[0044] The compounds of the present invention include the compounds of formula (XII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0045] [Chemical formula]

[0046] In the formula, R 1b and R 1c and R 2 and Y are as defined for formula I.

[0047] The compounds of the present invention include the compounds of formula (XIII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0048] [Chemical formula]

[0049] In the formula, R1b , R 1c , X and Y are as defined for formula I, R 9a , R 9b and R 9c are independently selected from the group consisting of hydrogen, halogen and C 1~6 alkyl, X 1 is selected from the group consisting of oxygen and sulfur.

[0050] The compounds of the present invention include compounds of formula (XIV) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0051]

Chemical formula

[0052] wherein R 1c , R 2 , X and Y are as defined for formula I, A 1 , A 2 , A 3 , A 4 and A 5 are selected from the group consisting of nitrogen and CR 10 alkyl, A 1 , A 2 , A 3 , A 4 and A 5 No more than two of them can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 alkyl, R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0053] The compounds of the present invention include compounds of formula (XIVa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0054]

Chemical formula

[0055] In the formula, R 1b , R 2 , X and Y are as defined for formula I, A 6 , A 7 , A 8 , A 9 and A 10 are selected from the group consisting of nitrogen and CR 10 , A 6 , A 7 , A 8 , A 9 and A 10 Two or less of them can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 , R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0056] The compounds of the present invention include compounds of formula (XIVb) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0057]

Chemical formula

[0058] In the formula, R 2, X and Y are as defined for formula I, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 and A 10 is selected from the group consisting of nitrogen and CR 10 and A 1 , A 2 , A 3 , A 4 and A 5 Two or less of them can be nitrogen, A 6 , A 7 , A 8 , A 9 and A 10 Two or less of them can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 and R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0059] The compounds of the present invention include compounds of formula (XV) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0060] [Chemical formula]

[0061] wherein R 1c , R 2 and Y are as defined for formula I, A 1 , A2 and A 3 and A 4 and A 5 is selected from the group consisting of nitrogen and CR 10 and A 1 and A 2 and A 3 and A 4 and A 5 Two or less of them can be nitrogen R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 and is selected from the group consisting of R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl

[0062] The compounds of the present invention include compounds of formula (XV a) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes

[0063]

Chemical formula

[0064] wherein R 1b , R 2 and Y are as defined for formula I A 6 and A 7 and A 8 and A 9 and A 10 is selected from the group consisting of nitrogen and CR 10 and A 6 and A 7 and A 8 and A 9 and A 10 Two or less of them can be nitrogen R 10 is selected from the group consisting of hydrogen, C 1~6Alkyl, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, C 1~6 Alkoxy, halogen, hydroxy and NHSO 2 R 11 selected from the group consisting of: R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0065] The compounds of the present invention include the compounds of formula (XVb) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0066]

Chemical formula

[0067] wherein R 2 and Y are as defined for formula I, A 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 and A 10 are selected from the group consisting of nitrogen and CR 10 ; A 1 A 2 A 3 A 4 and A 5 No more than two of them can be nitrogen, A 6 A 7 A 8 A 9 and A 10 No more than two of them can be nitrogen, R 10 is hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6Alkoxy, halogen, hydroxy and NHSO 2 R 11 is selected from the group consisting of, R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0068] The compounds of the present invention include the compounds of formula (XVI) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0069]

Chemical formula

[0070] wherein R 1c , R 2 and Y are as defined for formula I, A 1 , A 2 , A 3 , A 4 and A 5 are selected from the group consisting of nitrogen and CR 10 , A 1 , A 2 , A 3 , A 4 and A 5 one or less of can be nitrogen, R 10 is hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 is selected from the group consisting of, R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0071] The compounds of the present invention include the compounds of formula (XVIa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0072] [Chemical formula]

[0073] wherein, R 1b , R 2 and Y are as defined for formula I, A 6 , A 7 , A 8 , A 9 and A 10 are selected from the group consisting of nitrogen and CR 10 , A 6 , A 7 , A 8 , A 9 and A 10 two or less of which can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 , R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0074] The compounds of the present invention include the compounds of formula (XVIb) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0075] [Chemical formula]

[0076] wherein, R 2 and Y are as defined for formula I, A 1 , A 2 , A 3 , A4 and A 5 and A 6 and A 7 and A 8 and A 9 and A 10 is selected from the group consisting of nitrogen and CR 10 and A 1 and A 2 and A 3 and A 4 and A 5 Two or less of them can be nitrogen A 6 and A 7 and A 8 and A 9 and A 10 Two or less of them can be nitrogen R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 and is selected from the group consisting of R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl

[0077] The compounds of the present invention include the compounds of formula (XVII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes

[0078]

Chemical formula

[0079] wherein, R 1c , R 2 and Y are as defined for formula I A 1 and A 2 and A 3 and A 4 and A 5 is nitrogen and CR 10selected from the group consisting of, A 1 , A 2 , A 3 , A 4 and A 5 one or less thereof can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 selected from the group consisting of, R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0080] The compounds of the present invention include compounds of formula (XVIIa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0081]

Chemical formula

[0082] wherein R 2 , R 1b and Y are as defined for formula I, A 6 , A 7 , A 8 , A 9 and A 10 is selected from the group consisting of nitrogen and CR 10 , A 6 , A 7 , A 8 , A 9 and A 10 two or less thereof can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6Alkoxy, halogen, hydroxy and NHSO 2 R 11 is selected from the group consisting of, R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0083] The compounds of the present invention include the compounds of formula (XVIIb) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0084]

Chemical formula

[0085] wherein R 2 and Y are as defined for formula I, A 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 and A 10 are selected from the group consisting of nitrogen and CR 10 and A 1 A 2 A 3 A 4 and A 5 two or less of them can be nitrogen, A 6 A 7 A 8 A 9 and A 10 two or less of them can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 and R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0086] The compounds of the present invention include the compounds of formula (XVIII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0087]

Chemical formula

[0088] wherein R 1c , R 2 , R 5 and Y are as defined for formula I, A 1 , A 2 , A 3 , A 4 and A 5 are selected from the group consisting of nitrogen and CR 10 . A 1 , A 2 , A 3 , A 4 and A 5 one or less of which can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 . R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0089] The compounds of the present invention include the compounds of formula (XVIIIa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0090]

Chemical formula

[0091] In the formula, R 1b and R 2 and R 5 and Y are as defined for formula I, A 6 and A 7 and A 8 and A 9 and A 10 are selected from the group consisting of nitrogen and CR 10 and, A 6 and A 7 and A 8 and A 9 and A 10 Two or less of them can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 and, R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0092] The compounds of the present invention include the compounds of formula (XVIIIb) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0093]

Chemical formula

[0094] In the formula, R 2 and R 5 and Y are as defined for formula I, A 1 and A 2 and A 3 and A 4 and A 5 and A6 , A 7 , A 8 , A 9 and A 10 is selected from the group consisting of nitrogen and CR 10 and A 1 , A 2 , A 3 , A 4 and A 5 Two or less of them can be nitrogen, A 6 , A 7 , A 8 , A 9 and A 10 Two or less of them can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 and is selected from the group consisting of R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl

[0095] The present invention further relates to a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0096] The present invention relates to a method for treating or preventing a disease involving the formation of tau oligomers, including, for example, Alzheimer's disease, amyotrophic lateral sclerosis / Parkinsonism dementia complex, argentophilic grain dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia / chronic traumatic encephalopathy, diffuse neurofibrillary tangles with calcification, Down syndrome, frontotemporal dementia linked to chromosome 17 with Parkinsonism, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guam type motor neuron disease with neurofibrillary changes, Pick's disease, postencephalitic Parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and neurofibrillary type dementia, which method comprises administering to a subject an effective amount of a compound or composition according to the present invention.

[0097] The present invention further relates to a method for treating or preventing a disease involving the formation of tau oligomers, including, for example, Alzheimer's disease, amyotrophic lateral sclerosis / Parkinsonism dementia complex, argentophilic grain dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia / chronic traumatic encephalopathy, diffuse neurofibrillary tangles with calcification, Down syndrome, frontotemporal dementia linked to chromosome 17 with Parkinsonism, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guam type motor neuron disease with neurofibrillary changes, Pick's disease, postencephalitic Parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and neurofibrillary type dementia, which method comprises administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0098] The present invention also relates to a method for treating or preventing a disease or a symptom associated with a disease including Alzheimer's disease, amyotrophic lateral sclerosis / dementia with Parkinsonism complex, argentophilic grain dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia / chronic traumatic encephalopathy, diffuse neurofibrillary tangles with calcification, Down syndrome, frontotemporal dementia linked to chromosome 17 with Parkinsonism, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guam type motor neuron disease with neurofibrillary changes, Pick's disease, postencephalitic Parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and diseases or symptoms related to neurofibrillary type dementia and the formation of tau oligomers. The method includes administering to a subject an effective amount of a compound or composition according to the present invention.

[0099] One embodiment of the present invention is also a method for treating or preventing a disease or a symptom associated with a disease including Alzheimer's disease, amyotrophic lateral sclerosis / dementia with Parkinsonism complex, argentophilic grain dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia / chronic traumatic encephalopathy, diffuse neurofibrillary tangles with calcification, Down syndrome, frontotemporal dementia linked to chromosome 17 with Parkinsonism, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guam type motor neuron disease with neurofibrillary changes, Pick's disease, postencephalitic Parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and diseases or symptoms related to neurofibrillary type dementia and the formation of tau oligomers, the method including administering to a subject a composition comprising an effective amount of one or more compounds according to the present invention and a pharmaceutically acceptable carrier.

[0100] The present invention also relates to a method for treating or preventing a disease or a symptom associated with the formation of tau oligomers. The method includes administering to a subject an effective amount of a compound or composition according to the present invention.

[0101] The present invention further relates to a method for treating or preventing a disease or condition associated with the formation of tau oligomers, the method comprising administering to a subject a pharmaceutical composition comprising an effective amount of one or more compounds according to the present invention and an excipient.

[0102] The present invention further relates to, for example, Alzheimer's disease, amyotrophic lateral sclerosis / Parkinsonism dementia complex, argyrophilic grain dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia / chronic traumatic encephalopathy, diffuse neurofibrillary tangles with calcification, Down syndrome, frontotemporal dementia linked to chromosome 17 with Parkinsonism, Gerstmann-Sträussler-Scheinker disease, Hallervorden-Spatz disease, myotonic dystrophy, NiemannA method for treating or preventing diseases including Pick's disease, non-Guam type motor neuron disease with neurofibrillary changes, Pick's disease, post-encephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and neurofibrillary type dementia, which method comprises administering to a subject an effective amount of a compound or composition according to the present invention, and an effective amount of another compound that is considered useful for the treatment of Alzheimer's disease when administered in combination with a compound of the present invention such as donepezil (Aricept®), galantamine (Razadyne®), memantine (Namenda®), rivastigmine (Exelon®), donepezil / memantine (Namzaric®), AC-1204 (triglyceride caprylate), ACI-35, AD-4833 / TOMM40, aducanumab (BIIB037), ALZ-801, ANAVEX2-73 / donepezil, AVN-101, AVN-322, AVP-786, AVP-923, AZD3293, azeliragon (TTP488), BAN2401, BI409306, bisnorcymserine, bryostatin-1, CAD106, CPC-201, crenezumab, E2609, ELND005, ensenicline, gantenerumab, GC021109, idalopirdine, immunoglobulin, JNJ-54861911, LMTX, Lu-AF20513, LY3002813 (N3pG-AβmAb), MEDI1814, mGlu2 agonist, MK-7622, MK-8931, MSDC-0160, NIC-515, PF-05212377, PF-06648671, Posiphen® (R-fenserine), PTI-80, RG1577, RG7345, rilapladib, RVT-101, RVX208, SAR228810, sGC1061 (nomethiazole), solanezumab, SUVN-502, SUVN-G3031, T-817MA, T3D-959, TPI287 (abiotaxel), UB-311, VX-745.

[0103] The present invention further relates to a method for diagnosing a disease involving the formation of tau oligomers using a positron emission technology (PET) or single photon emission computed tomography (SPECT) imaging probe. For example, Alzheimer's disease, amyotrophic lateral sclerosis / Parkinson's dementia complex, argentophilic grain dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia / chronic traumatic encephalopathy, diffuse neurofibrillary tangles disease with calcification, Down syndrome, frontotemporal dementia linked to chromosome 17 with Parkinsonism, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guam type motor neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic Parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and diseases including neurofibrillary type dementia, the method includes administering an effective amount of a PET or SPECT compound or composition according to the present invention to a subject, and scanning the patient with a (PET) or SPECT imaging system.

[0104] The present invention further relates to a process for preparing an inhibitor of tau oligomer formation of the present invention.

[0105] These and other objects, features, and effects should become apparent to those skilled in the art by reading the following detailed description and the appended claims. All percentages, ratios, and proportions herein are by weight unless otherwise specified. Unless otherwise specified, all temperatures are in degrees Celsius (°C). All cited references are relevant portions and are incorporated herein by reference, and no citation of any reference should be construed as an admission that it is prior art relevant to the present invention.

Mode for Carrying Out the Invention

[0106] The inhibitor of tau oligomer formation of the present invention can treat and prevent diseases associated with the formation of tau oligomers, such as Alzheimer's disease, amyotrophic lateral sclerosis / Parkinsonism dementia complex, argyrophilic grain dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia / chronic traumatic encephalopathy, diffuse neurofibrillary tangles disease with calcification, Down syndrome, frontotemporal dementia linked to chromosome 17 with Parkinsonism, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guam type motor neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic Parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and neurofibrillary type dementia. Furthermore, although not limited by theory, it is considered that the inhibitor of tau oligomer formation of the present disclosure can improve, alleviate, or otherwise control diseases associated with the formation of tau oligomers.

[0107] Throughout this text, when a composition is described as having or including (including or comprising) a particular component, or a process is described as having or including a particular process step, it is also contemplated that a composition of the present disclosure consists essentially of, or consists of, the recited components, and that a process of the present disclosure consists essentially of, or consists of, the recited processing steps.

[0108] In this application, when an element or component is described as being included in, and / or selected from, a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, and can also be selected from a group consisting of two or more of the recited elements or components.

[0109] The use of the singular form in this specification includes the plural form (and vice versa) unless otherwise stated. Further, when the term "about" is used before a quantitative value, the present teachings include the specific quantitative value itself unless otherwise stated.

[0110] It should be understood that the order of steps or the order in which an operation is performed is not important as long as the present teachings can be implemented. Further, two or more steps or operations can be performed simultaneously.

[0111] In this specification, the term "halogen" shall mean chlorine, bromine, fluorine and iodine. The term "halo" shall mean chloro, bromo, fluoro and iodo.

[0112] In this specification, unless otherwise stated, "alkyl" and / or "aliphatic", whether used alone or as part of a substituent, refer to straight-chain and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example 1 to 6 carbon atoms or 1 to 4 carbon atoms. The specified number of carbon atoms (e.g., C 1~6 ) shall independently refer to the number of carbon atoms in the alkyl component or the alkyl portion of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, etc. The alkyl group can optionally be substituted. Non-limiting examples of substituted alkyl groups include hydroxymethyl, chloromethyl, trifluoromethyl, aminomethyl, 1-chloroethyl, 2-hydroxyethyl, 1,2-difluoroethyl, 3-carboxypropyl, etc. (C 1~6 alkyl) 2 In substituents having multiple alkyl groups such as amino, the alkyl groups can be the same or different.

[0113] As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent, refer to straight-chain and branched carbon chains having from 2 to 20 carbon atoms, preferably from 2 to 20 carbon atoms. The alkenyl chain has at least one double bond in the chain, and the alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl groups may optionally be substituted. Non-limiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (or 2-methylethenyl), isopropenyl (or 2-methylethen-2-yl), buten-4-yl, and the like. Non-limiting examples of substituted alkenyl groups include 2-chloroethenyl (or 2-chlorovinyl), 4-hydroxybuten-1-yl, 7-hydroxy-7-methylocta-4-en-2-yl, 7-hydroxy-7-methylocta-3,5-dien-2-yl, and the like. Non-limiting examples of alkynyl groups include ethynyl, prop-2-ynyl (or propargyl), propyn-1-yl, and 2-methyl-hexa-4-yn-1-yl. Non-limiting examples of substituted alkynyl groups include 5-hydroxy-5-methylhexa-3-ynyl, 6-hydroxy-6-methylhepta-3-yn-2-yl, 5-hydroxy-5-ethylhepta-3-ynyl, and the like.

[0114] As used herein, "cycloalkyl", whether used alone or as part of another group, refers to, for example, a non-aromatic carbon-containing ring having 3 to 14 ring carbon atoms, preferably 3 to 7 or 3 to 6 ring carbon atoms, more preferably 3 to 4 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bonds, including cycloalkyl, alkenyl, and alkynyl groups. The cycloalkyl group can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., including fused, bridged, and / or spiro ring structures), and the carbon atoms can be located inside or outside the ring structure. Any suitable ring position of the cycloalkyl group can be covalently bonded to a defined chemical structure. The cycloalkyl ring can optionally be substituted. Non-limiting examples of cycloalkyl groups include cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, 2,3-dihydroxycyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, 2,5-dimethylcyclopentyl, 3,5-dichlorocyclohexyl, 4-hydroxycyclohexyl, 3,3,5-trimethylcyclohex-1-yl, octahydropentalenyl, octahydro-1H-indenyl, 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl, bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes carbocyclic rings that are bicyclic hydrocarbons, non-limiting examples of which include bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[3.1.1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and bicyclo[3.3.3]undecanyl.

[0115] "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with one or more halogens. The haloalkyl group includes perhaloalkyl groups in which all hydrogens of the alkyl group are substituted with halogens (e.g., -CF3 , -CF 2 CF 3 ). The haloalkyl group can optionally be substituted with one or more substituents in addition to the halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl groups.

[0116] The term "alkoxy" refers to the group -O-alkyl, where the alkyl group is as defined above. The alkoxy group can optionally be substituted. C 3 ~C 6 The term "cyclic alkoxy" refers to a ring containing 3 to 6 carbon atoms and at least one oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). C 3 ~C 6 The cyclic alkoxy group can optionally be substituted.

[0117] The term "aryl", used alone or as part of another group, is defined herein as an unsaturated aromatic monocyclic ring of 6 carbon members or an unsaturated aromatic polycyclic ring of 10 to 14 carbon members. The aryl ring can be, for example, a phenyl or naphthyl ring optionally substituted in each case by one or more moieties capable of substituting one or more hydrogen atoms. Non-limiting examples of aryl groups include phenyl, naphthalen-1-yl, naphthalen-2-yl, 4-fluorophenyl, 2-hydroxyphenyl, 3-methylphenyl, 2-amino-4-fluorophenyl, 2-(N,N-diethylamino)phenyl, 2-cyanophenyl, 2,6-di-tert-butylphenyl, 3-methoxyphenyl, 8-hydroxynaphthalen-2-yl, 4,5-dimethoxynaphthalen-1-yl and 6-cyano-naphthalen-1-yl. Aryl groups also include, for example, phenyl or naphthyl rings fused to one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5-trienyl, indanyl) which can be substituted at one or more carbon atoms of the aromatic and / or saturated or partially saturated ring.

[0118] The term "arylalkyl" or "aralkyl" refers to the group -alkyl-aryl, where the alkyl and aryl groups are as defined herein. The aralkyl groups of the present invention are optionally substituted. Examples of arylalkyl groups include, for example, benzyl (abbreviated as "Bn"), 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, fluorenylmethyl and the like.

[0119] The terms "heterocyclic", "heterocycle", and "heterocyclyl", whether used alone or as part of another group, refer to one or more rings having from 3 to 20 atoms, wherein at least one atom in at least one of the rings is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and further wherein the ring containing the heteroatom is non-aromatic, as defined herein as a ring. In a heterocyclic group containing two or more fused rings, a ring having no heteroatoms can be considered an aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclic groups have from 3 to 14 ring atoms, of which 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in the heterocyclic group can be oxidized. The heterocyclic group can optionally be substituted.

[0120] Non-limiting examples of heterocyclic units having a single ring include diazinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl, oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1H-indole, and 1,2,3,4-tetrahydro-quinoline. Non-limiting examples of heterocyclic units having two or more rings include hexahydro-1H-pyrrolidinyl, 3a,4,5,6,7,7a-hexahydro-1H-benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H-cycloocta[b]pyrrolyl.

[0121] The term "heteroaryl", whether used alone or as part of another group, is defined herein as one or more rings having from 5 to 20 atoms, wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and further, at least one of the rings containing a heteroatom is aromatic. In a heteroaryl group containing two or more fused rings, a ring having no heteroatoms can be a carbocyclic ring (e.g., 6,7-dihydro-5H-cyclopenta[4,5]pyrimidine) or an aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), oxygen (O), or sulfur (S). One or more N or S atoms in the heteroaryl group can be oxidized. The heteroaryl group can be substituted. Non-limiting examples of heteroaryl rings containing a single ring include 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H-imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, 2-phenylpyrimidinyl, pyridinyl, 3-methylpyridinyl, and 4-dimethylaminopyridinyl. Non-limiting examples of heteroaryl rings containing two or more fused rings include benzofuranyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 6-amino-9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzothiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxyquinolinyl, and isoquinolinyl.

[0122] One non-limiting example of the above-mentioned heteroaryl group is C having at least one additional ring atom (preferably 1 to 4 additional ring atoms which are heteroatoms) which is a heteroatom independently selected from 1 to 5 carbocyclic atoms and nitrogen (N), oxygen (O) or sulfur (S). 1 ~C 5 is heteroaryl. C 1 ~C 5 Examples of heteroaryl include, but are not limited to, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

[0123] Unless otherwise specified, when two substituents together form a ring having a specified number of ring atoms (e.g., R 2 and R 3 together with the nitrogen (N) to which they are attached form a ring having 3 to 7 ring members), the ring can have one or more (e.g., 1 to 3) additional heteroatoms independently selected from carbon atoms and optionally nitrogen (N), oxygen (O) or sulfur (S). The ring can be saturated or partially saturated and can optionally be substituted.

[0124] In the present invention, a fused ring unit and a spirocyclic ring, a bicyclic ring, etc. containing a single heteroatom are considered to belong to the cyclic family corresponding to the heteroatom-containing ring. For example, 1,2,3,4-tetrahydroquinoline having the following formula is considered a heterocyclic unit in the present invention.

[0125]

Chemical formula

[0126] In the present invention, the 6,7-dihydro-5H-cyclopenta-pyrimidine having the following formula is considered a heteroaryl unit.

[0127]

Chemical formula

[0128] When the fused ring unit contains heteroatoms in both a saturated ring and an aryl ring, the aryl ring predominates and determines the type of category to which the ring is assigned. For example, in the present invention, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the following formula is considered a heteroaryl unit.

[0129]

Chemical formula

[0130] Whenever any of the terms or their prefix roots appear in the name of a substituent, the name is to be interpreted as including the limitations described herein. For example, whenever any of the terms "alkyl" or "aryl" or their prefix roots appear in the name of a substituent (e.g., arylalkyl, alkylamino), the name is to be interpreted as including the above limitations for "alkyl" and "aryl".

[0131] The term "substituted" is used throughout the specification. The term "substituted" is defined herein as a moiety having one or more hydrogen atoms substituted with one substituent or several (e.g., 1 to 10) substituents as defined below, whether acyclic or cyclic. The substituents can replace one or two hydrogen atoms of a single moiety at a time. Further, these substituents can replace two hydrogen atoms on two adjacent carbons to form the substituent, new moiety or unit. For example, substitution units requiring a single hydrogen atom substitution include halogen, hydroxyl, etc. Substitution of two hydrogen atoms includes carbonyl, oxyimino, etc. Substitution of two hydrogen atoms from adjacent carbon atoms includes epoxy, etc. The term "substituted" is used throughout the specification to indicate that a moiety can have one or more hydrogen atoms substituted with substituents. When a moiety is described as "substituted", any number of hydrogen atoms can be substituted. For example, difluoromethyl is substituted C 1 alkyl, and trifluoromethyl is substituted C 1 alkyl, 4-hydroxyphenyl is a substituted aromatic ring, and (N,N-dimethyl-5-amino)octanyl is substituted C 8 alkyl, 3-guanidinopropyl is substituted C 3 alkyl, and 2-carboxypyridinyl is a substituted heteroaryl.

[0132] The variable groups defined herein, e.g., alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, aryloxy, aryl, heterocycle and heteroaryl groups as defined herein, can be used alone or as part of another group and can optionally be substituted. Optionally substituted groups are so indicated.

[0133] The following are non-limiting examples of substituents that can replace hydrogen atoms on a moiety: halogen (chlorine (Cl), bromine (Br), fluorine (F) and iodine (I)), -CN, -NO 2 , oxo (=O), -OR 12 , -SR 12, -N(R 12 ) 2 , -NR 12 C(O)R 12 , -SO 2 R 12 , -SO 2 OR 12 , -SO 2 N(R 12 ) 2 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 ) 2 , C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 2~8 alkenyl, C 2~8 alkynyl, C 3~14 cycloalkyl, aryl, heterocycle, or heteroaryl. Each of the alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, heterocycle and heteroaryl groups is optionally substituted with 1 to 10 (e.g., 1 to 6 or 1 to 4) groups independently selected from halogen, -CN, -NO 2 , oxo and R 12 , and R 12 is independently hydrogen, -OR 13 , -SR 13 , -C(O)R 13 , -C(O)OR 13 , -C(O)N(R 13 ) 2 , -SO 2 R 13 , -S(O) 2 OR 13 , -N(R 13 ) 2 , -NR 13 C(O)R 13 , C 1~6 alkyl, C 1~6 haloalkyl, C 2~8 alkenyl, C 2~8 alkynyl, cycloalkyl (e.g., C 3~6 cycloalkyl), aryl, heterocycle or heteroaryl, or two R 12The units, together with the atom(s) to which they are attached, optionally form a substituted carbocyclic or heterocyclic ring having 3 to 7 ring atoms, and the carbocyclic or heterocyclic ring is R 13 is independently hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 2~8 alkenyl, C 2~8 alkynyl, cycloalkyl (e.g., C 3~6 cycloalkyl), aryl, heterocyclic or heteroaryl, or two R 13 units, together with the atom(s) to which they are attached, optionally form a substituted carbocyclic or heterocyclic ring, and the carbocyclic or heterocyclic ring preferably has 3 to 7 ring atoms.

[0134] In some embodiments, the substituent is i) -OR 14 , for example, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , ii) -C(O)R 14 , for example, -COCH 3 , -COCH 2 CH 3 , -COCH 2 CH 2 CH 3 , iii) -C(O)OR 14 , for example, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 2 CH 2 CH 3 , iv) -C(O)N(R 14 ) 2 , for example, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , v) -N(R 14 ) 2 、 for example, -NH 2 、 -NHCH 3 、 -N(CH 3 ) 2 、 -NH(CH 2 CH 3 )、 vi) halogen: -F, -Cl, -Br and -I, vii) -CH e X g 、 wherein X is halogen, m is 0 to 2, and e + g = 3, for example, -CH 2 F, -CHF 2 、 -CF 3 、 -CCl 3 or -CBr 3 、 viii) -SO 2 R 14 、 for example, -SO 2 H, -SO 2 CH 3 、 -SO 2 C 6 H 5 、 ix) C 1 ~C 6 linear, branched or cyclic alkyl, x) cyano xi) nitro, xii) N(R 14 )C(O)R 14 、 xiii) oxo (=O), xiv) heterocyclic ring, and xv) heteroaryl selected from, each R 14 is independently hydrogen, optionally substituted C 1 ~C 6 linear or branched alkyl (for example, optionally substituted C 1 ~C 4 linear or branched alkyl), or optionally substituted C 3 ~C 6 cycloalkyl (for example, optionally substituted C 3 ~C 4 cycloalkyl), and two R14 The units can together form a ring containing 3 to 7 ring atoms. In certain embodiments, each R 14 is independently hydrogen, halogen, or C 1 -C 6 linear or branched alkyl or C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl.

[0135] Throughout this specification, substituents of compounds are shown in groups or ranges. The text is specifically intended to include each and every individual sub-combination of such groups and ranges. For example, the term "C 1~6 alkyl" is specifically intended to individually denote C 1 -, C 2 -, C 3 -, C 4 -, C 5 -, C 6 -, C 1 -C 6 -, C 1 -C 5 -, C 1 -C 4 -, C 1 -C 3 -, C 1 -C 2 -, C 2 -C 6 -, C 2 -C 5 -, C 2 -C 4 -, C 2 -C 3 -, C 3 -C 6 -, C 3 -C 5 -, C 3 -C 4 -, C 4 -C 6 -, C 4 -C 5 and C 5 -C 6 alkyl.

[0136] In the present invention, the terms "compound", "analog" and "composition" equally represent inhibitors of tau oligomer formation as defined herein, including all enantiomers, diastereomers, salts, etc., and the terms "compound", "analog" and "composition" are used interchangeably throughout this specification.

[0137] The compounds described herein can contain asymmetric atoms (also referred to as chiral centers), and some of the compounds can contain one or more asymmetric atoms or centers, and thus can give rise to optical isomers (enantiomers) and diastereomers. The compounds of the present teachings and disclosed herein include such enantiomers and diastereomers, as well as racemic and resolved enantiomerically pure R and S stereoisomers, and other mixtures of R and S stereoisomers, and pharmaceutically acceptable salts thereof. The optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, including but not limited to diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present teachings also encompass cis and trans isomers of compounds containing alkenyl moieties (e.g., alkenes and imines). The present teachings include all possible positional isomers and mixtures thereof that can be obtained in pure form by standard separation procedures known to those skilled in the art, including but not limited to column chromatography, thin layer chromatography, and high performance liquid chromatography. When the compounds described herein contain, for example, keto or oxime groups or aromatic moieties, tautomerism (tautomeric isomerism) can occur. Thus, a single compound may exhibit more than one type of isomerism.

[0138] All stereoisomers, geometric isomers, and tautomers of the compounds of the present disclosure, including compounds that exhibit more than one type of isomerism and mixtures of one or more of them, are included within the scope of the compounds of the present disclosure. Further included are acid addition or base salts where the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., DL-tartrate or DL-arginine.

[0139] Pharmaceutically acceptable salts of compounds of the present teachings that may have an acidic moiety can be formed with organic and inorganic bases. Depending on the number of acidic hydrogens available for deprotonation, both monoanionic and polyanionic salts are contemplated. Suitable salts formed with bases include metal salts such as alkali metal or alkaline earth metal salts, e.g., sodium, potassium, magnesium salts, ammonia salts and organic amine salts such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, mono-, di- or tri-lower alkylamines (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine) or mono-, di- or trihydroxy lower alkylamines (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO 3 , Na 2 CO 3 , K.H.C.O. 3 , K 2 CO 3 , Cs 2 CO 3 , LiOH, NaOH, KOH, NaH 2 PO 4 , Na 2 HPO 4 and Na 3 PO 4Examples include. Inner salts can also be formed. Similarly, when the compounds disclosed herein contain a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic acid, aspartic acid, boric acid, glucoheptonic acid, glucuronic acid, hexafluorophosphoric acid, 2-(4-hydroxybenzoyl)benzoic acid, hydroiodic acid, ethanedisulfonic acid, isethionic acid, nicotinic acid, orotic acid, palmitic acid, saccharic acid, stearic acid, trifluoroacetic acid, propionic acid, lactic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, tartaric acid, succinic acid, dichloroacetic acid, ethenesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phosphoric acid, phthalic acid, propionic acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, camphorsulfonic acid, and other known pharmaceutically acceptable acids. Further suitable base salts are formed from bases that form pharmaceutically acceptable salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts. For a general review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0140] Pharmaceutically acceptable salts of the compounds of formula (I) can be readily prepared by appropriately mixing solutions of the compounds of formula (I) and the desired acid or base together. The salt can precipitate from the solution and can be collected by filtration or recovered by evaporation of the solvent. The degree of ionization of the salt can vary from almost fully ionized to almost non-ionized.

[0141] The compounds of the present invention can exist in either non-solvated or solvated forms. The term "solvated compound" is used herein to describe a molecular complex comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" is used when the solvent is water. Pharmaceutically acceptable solvated compounds include hydrates and other solvated compounds, and the crystallization solvent can be isotopically substituted. For example, D 2 O, d 6 -acetone, d 6 -DMSO. The compounds of the present invention (including those in the form of salts, free bases, free acids and neutral compounds) can form hydrates and other solvated compounds.

[0142] The compounds of the present invention can exist as inclusion compounds such as drug-host inclusion compounds or other complexes. In contrast to the above solvated compounds, the drug and the host are present in stoichiometric or non-stoichiometric amounts. The compounds can also exist as complexes of drugs containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized or non-ionized. For a review of such complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975). The compounds of the present invention can also exist as their polymorphs and isomers (including optical, geometric and tautomeric isomers) and isotopically labeled compounds. In the solid state, the compounds of the present invention can exist in crystalline or amorphous forms.

[0143] The compounds of the present invention can be administered as prodrugs. Thus, certain derivatives of the compounds of the present disclosure, which may themselves have little or no pharmacological activity, can be converted, upon administration in or on the body, for example by hydrolysis, into a compound having the desired activity. Such derivatives are referred to as "prodrugs". Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems, Vol.14, ACS Symposium Series (T Higuchi and W Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (edited by E B Roche, American Pharmaceutical Association). Prodrugs can be prepared, for example, by substituting appropriate functional groups present in the compounds of the present disclosure with certain moieties known to those skilled in the art as "pro-moieties" as described in, for example, H Bundgaard "Design of Prodrugs" (Elsevier, 1985). Some examples of such prodrugs include (i) When the compound of formula (I) contains a carboxylic acid functional group (-COOH), its ester, for example, substitution of hydrogen by (C 1 ~C 8 ) alkyl, (ii) When the compound of formula (I) contains an alcohol functional group (-OH), its ether, for example, substitution of hydrogen by (C 1 ~C6) alkanoyloxymethyl, and (iii) When the compound of formula (I) contains a primary or secondary amino functional group (-NH 2 or -NHR, R≠H), its amide, for example, substitution of one or both hydrogens by (C 1 ~C 10 ) alkanoyl. [Further examples of substituents relating to the above examples and examples of other prodrug types can be found in the above references.] Finally, certain compounds of the present disclosure can themselves act as prodrugs of another compound of the present disclosure, respectively.

[0144] The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the disclosure in which one or more atoms are replaced with atoms having an atomic mass or mass number that is different from the atomic mass or mass number that is normally found in nature but has the same atomic number.

[0145] Examples of isotopes suitable for inclusion in the compounds of the present invention include 2 H, 3 isotopes of hydrogen such as 11 C, 13 C, 14 isotopes of carbon such as 36 isotopes of chlorine such as 18 isotopes of fluorine such as 123 I, 125 isotopes of iodine such as 13 N, 15 isotopes of nitrogen such as 15 O, 17 O, 18 isotopes of oxygen such as 32 isotopes of phosphorus such as 35 isotopes of sulfur such as

[0146] Certain isotopically labeled compounds of the disclosure, for example, isotopically labeled compounds incorporating a radioisotope, are useful in the study of drug and / or substrate tissue distribution. The radioisotopes tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in view of ease of incorporation and ready means of detection.

[0147] Replacement with a heavier isotope such as deuterium, i.e., 2 H, may result in certain therapeutic advantages due to increased metabolic stability, for example, an increase in in vivo half-life or a decrease in the required dose, and may therefore be preferred in certain situations.

[0148] 11 C, 18 F, 15 O, 13Substitution with a positron-emitting isotope such as N is useful in positron emission tomography (PET) studies for examining substrate receptor occupancy and may be useful as a diagnostic agent in patients and animals.

[0149] The isotope-labeled compounds of the present disclosure can generally be prepared by a process similar to those described in the appended examples and preparations using appropriate isotope-labeled reagents by conventional techniques known to those skilled in the art or in place of previously used unlabeled reagents.

[0150] When any component or any variable in any formula occurs more than once, its definition in each occurrence is independent of its definition in all other occurrences (e.g., in N(R x ) 2 each R x may be the same or different from the others). Combinations of substituents and / or variables are permitted only if such combinations result in a stable compound.

[0151] As used herein, the terms "treating", "treatment" and "treat" refer to partially or completely alleviating, inhibiting, ameliorating and / or palliating or preventing a suspected symptomatic condition with which a patient is afflicted.

[0152] As used herein, "therapeutically effective" and "effective amount" refer to a substance or amount that induces a desired biological activity or effect.

[0153] Unless otherwise indicated, the terms "subject" or "patient" are used interchangeably and refer to human patients, mammals such as non-human primates, as well as laboratory animals such as rabbits, rats, mice, and other animals. Thus, as used herein, the terms "subject" or "patient" mean any mammalian patient or subject to whom the compounds of the present invention can be administered. In one exemplary embodiment of the present invention, to identify a patient subject to treatment by the methods of the present invention, an accepted screening method is used to determine risk factors associated with a target or suspected disease or condition, or to determine the status of an existing disease or condition in the subject. These screening methods include, for example, conventional diagnostic tests that determine risk factors that may be associated with a target or suspected disease or condition. By these and other conventional methods, a clinician can select patients in need of therapy using the methods and compounds of the present invention.

[0154] One embodiment of the present invention includes compounds of formula (XIX) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0155]

Chemical formula

[0156] In the formula, R 1a and R 1d are each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, and C 1~6 haloalkoxy, R 1b and R 1c are selected from the group consisting of hydrogen, halogen, optionally substituted aryl, and optionally substituted heteroaryl, R 1b when is hydrogen, R 1c is not hydrogen, R 1c when is hydrogen, R1b is not hydrogen, R 2 is selected from the group consisting of C 1~6 alkyl, C 3~7 branched alkyl, C 1~6 alkylaryl, optionally substituted aryl and optionally substituted heteroaryl, X is selected from the group consisting of oxygen, sulfur, NH and NR 5 and, wherein R 5 is C 1~6 alkyl, Y is

[0157]

Chemical formula

[0158] and optionally substituted 2-benzimidazole, wherein R 6 is selected from the group consisting of hydrogen, OH, OR 7c , optionally substituted C 1~6 alkyl, NR 3a R 3b , optionally substituted aryl, and optionally substituted heteroaryl, R 3a and R 3b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 3a and R 3b together with the atom to which they are attached, optionally including a member selected from the group consisting of O, NR 8 and S, form a 3- to 6-membered saturated ring optionally substituted with a group selected from OH, C 1~6 alkyl, NR 8a R 8b and, R 8 is selected from the group consisting of hydrogen, C 1~6 alkyl and CO(C 1~6 alkyl), R8a and R 8b is independently selected from hydrogen and C 1~6 alkyl, respectively, R 7a is selected from the group consisting of hydrogen and C 1~6 alkyl, R 7b is C 1~6 selected from the group consisting of alkyl, aryl and heteroaryl, R 7c is C 1~6 alkyl and C 3~7 selected from the group consisting of branched alkyl.

[0159] Another embodiment of the present invention includes compounds of formula (XX), and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0160]

Chemical formula

[0161] wherein R 1a , R 1b , R 1c , R 1d , R 2 and Y are as defined for formula XIX.

[0162] Another embodiment of the present invention is a compound of formula (XXI)

[0163]

Chemical formula

[0164] and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes, wherein R 1a , R 1b , R 1c , R 1d , R 2 and Y are as defined for formula XIX, a compound of formula (XXII)

[0165]

Chem.

[0166] and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes, wherein R 1a , R 1b , R 1c , R 1d , R 2 , R 5 and Y are as defined for formula XIX. including.

[0167] Another embodiment of the present invention includes compounds of formula (XXIII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0168]

Chem.

[0169] wherein R 1a , R 1b , R 1c , R 1d , R 2 , R 6 and X are as defined for formula XIX.

[0170] Another embodiment of the present invention includes compounds of formula (XXIV) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0171]

Chem.

[0172] wherein R 1a , R 1b , R 1c , R 1d , R2 and R 7a and R 7b and X are as defined for formula XIX.

[0173] Another embodiment of the present invention includes compounds of formula (VII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0174]

Chemical formula

[0175] wherein R 1a and R 1b and R 1c and R 1d and R 2 and X are as defined for formula XIX.

[0176] Another embodiment of the present invention includes compounds of formula (XXVI) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0177]

Chemical formula

[0178] wherein R 1b and R 1c and R 2 and X and Y are as defined for formula XIX.

[0179] Another embodiment of the present invention includes compounds of formula (XXVII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0180]

Chemical formula

[0181] wherein R 1b, R 1c , R 2 and Y are as defined for formula I.

[0182] Another embodiment of the present invention includes compounds of formula (XXVIII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0183]

Chemical formula

[0184] wherein R 1b , R 1c , R 2 and Y are as defined for formula XIX.

[0185] Another embodiment of the present invention includes compounds of formula (XXIX) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0186]

Chemical formula

[0187] wherein R 1b , R 1c , R 2 and Y are as defined for formula XIX.

[0188] Another embodiment of the present invention includes compounds of formula (XXX) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0189]

Chemical formula

[0190] wherein R 1b , R 1c , X and Y are as defined for formula XIX, R 9a 、R 9b and R 9c are each independently selected from the group consisting of hydrogen, halogen, and C 1~6 alkyl, X 1 is selected from the group consisting of oxygen and sulfur.

[0191] Another embodiment of the present invention includes compounds of formula (XXXI) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0192]

Chemical formula

[0193] wherein R 1a and R 1d are each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl, and C 1~6 haloalkoxy, R 1b and R 1c are selected from the group consisting of hydrogen, halogen, optionally substituted aryl, and optionally substituted heteroaryl, R 1b when is hydrogen, R 1c is not hydrogen, R 1c when is hydrogen, R 1b is not hydrogen, R 2 is selected from the group consisting of C 1~6 alkyl, C 3~7 branched alkyl, C 1~6 alkylaryl, optionally substituted aryl, and optionally substituted heteroaryl, X is selected from the group consisting of oxygen, sulfur, NH, and NR 5 wherein R is C 5 alkyl, 1~6is alkyl, Y is

[0194]

Chemical formula

[0195] and optionally substituted 2-benzimidazole selected from the group consisting of In the formula, R 6 is hydrogen, OH, OR 7c , optionally substituted C 1~6 alkyl, NR 3a R 3b , optionally substituted aryl, and optionally substituted heteroaryl, selected from the group consisting of R 3a and R 3b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 3a and R 3b together with the atom to which they are attached, optionally including a member selected from the group consisting of O, NR 8 and S, form a 3- to 6-membered saturated ring optionally substituted with a group selected from OH, C 1~6 alkyl, NR 8a R 8b R 8 is hydrogen, C 1~6 alkyl and CO(C 1~6 alkyl), selected from the group consisting of R 8a and R 8b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 7a is hydrogen and C 1~6 alkyl, selected from the group consisting of R 7b is C 1~6 alkyl, aryl and heteroaryl, selected from the group consisting of R 7c is C 1~6 alkyl and C​3~7 It is selected from the group consisting of branched alkyls.

[0196] Another embodiment of the present invention is a compound of formula (XXXII)

[0197]

Chemical formula

[0198] and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes, wherein R 1b , R 1c , R 2 and Y are as defined for formula XXXI. A compound of formula (XXXIII),

[0199]

Chemical formula

[0200] and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes, wherein R 1b , R 1c , R 2 and Y are as defined for formula XXXI. includes.

[0201] Another embodiment of the present invention includes a compound of formula (XXXIV) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0202]

Chemical formula

[0203] wherein R 1b , R 1c , X and Y are as defined for formula XXXI, R 9a , R 9band R 9c is independently selected from the group consisting of hydrogen, halogen and C 1~6 alkyl, X 1 is selected from the group consisting of oxygen and sulfur.

[0204] Another embodiment of the present invention includes compounds of formula (XXXV) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0205]

Chemical formula

[0206] wherein R 1c , R 2 , X and Y are as defined for formula XXXI, A 1 , A 2 , A 3 , A 4 and A 5 are selected from the group consisting of nitrogen and CR 10 alkyl, A 1 , A 2 , A 3 , A 4 and A 5 Two or less of them can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 alkyl, R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0207] Another embodiment of the present invention includes compounds of formula (XXXVI) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0208]

Chem.

[0209] In the formula, R 1b and R 2 , X and Y are as defined for formula XXXI, A 6 , A 7 , A 8 , A 9 and A 10 are selected from the group consisting of nitrogen and CR 10 , A 6 , A 7 , A 8 , A 9 and A 10 Two or less of them can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 , R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0210] Another embodiment of the present invention includes compounds of formula (XXXVII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0211]

Chem.

[0212] In the formula, R 2 , X and Y are as defined for formula XXXI, A 1 , A 2 , A3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 and A 10 are selected from the group consisting of nitrogen and CR 10 and A 1 , A 2 , A 3 , A 4 and A 5 Two or less of them can be nitrogen A 6 , A 7 , A 8 , A 9 and A 10 Two or less of them can be nitrogen R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 and is selected from the group consisting of R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl

[0213] Another embodiment of the present invention includes compounds of formula (XXXVIII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0214] [Chemical formula]

[0215] wherein R 1c , R 2 and Y are as defined for formula XXXI A 1 , A 2 , A 3 , A 4 and A 5is selected from the group consisting of nitrogen and CR 10 and two or less of A 1 A 2 A 3 A 4 and A 5 can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 and two or less of R 11 are independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0216] Another embodiment of the present invention includes the compounds of formula (XXXIX) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0217]

Chemical formula

[0218] wherein R 1b R 2 and Y are as defined for formula XXXI, A 6 A 7 A 8 A 9 and A 10 is selected from the group consisting of nitrogen and CR 10 and two or less of A 6 A 7 A 8 A 9 and A 10 can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6Haloalkoxy, C 1~6 Alkoxy, halogen, hydroxy and NHSO 2 R 11 selected from the group consisting of, R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0219] Another embodiment of the present invention includes compounds of formula (XL) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0220]

Chemical formula

[0221] wherein R 2 and Y are as defined for formula XXXI, A 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 and A 10 are selected from the group consisting of nitrogen and CR 10 ; A 1 A 2 A 3 A 4 and A 5 two or less of which can be nitrogen, A 6 A 7 A 8 A 9 and A 10 two or less of which can be nitrogen, R 10 is hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R11 selected from the group consisting of R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0222] Another embodiment of the present invention includes compounds of formula (XLI) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0223]

Chemical formula

[0224] wherein R 1c , R 2 and Y are as defined for formula XXXI, A 1 , A 2 , A 3 , A 4 and A 5 are selected from the group consisting of nitrogen and CR 10 alkyl, A 1 , A 2 , A 3 , A 4 and A 5 one or less of which can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 alkyl, R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0225] Another embodiment of the present invention includes compounds of formula (XLII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0226] [Chemical formula]

[0227] In the formula, R 1b , R 2 and Y are as defined for formula XXXI, A 6 , A 7 , A 8 , A 9 and A 10 are selected from the group consisting of nitrogen and CR 10 , A 6 , A 7 , A 8 , A 9 and A 10 Two or less of them can be nitrogen, R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 , R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0228] Another embodiment of the present invention includes compounds of formula (XLIII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0229] [Chemical formula]

[0230] In the formula, R 2 and Y are as defined for formula XXXI, A 1 , A 2 , A 3 , A 4 , A5 , A 6 , A 7 , A 8 , A 9 and A 10 is selected from the group consisting of nitrogen and CR 10 and A 1 , A 2 , A 3 , A 4 and A 5 Two or less of them can be nitrogen A 6 , A 7 , A 8 , A 9 and A 10 Two or less of them can be nitrogen R 10 is selected from the group consisting of hydrogen, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 haloalkoxy, C 1~6 alkoxy, halogen, hydroxy and NHSO 2 R 11 and is selected from the group consisting of R 11 is independently selected from the group consisting of hydrogen and C 1~6 alkyl

[0231] Another embodiment of the present invention is a compound of formula (XLIV)

[0232] [Chemical formula]

[0233] and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes, wherein R 1a and R 1d are each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl and C 1~6 haloalkoxy R 1b and R 1cis selected from the group consisting of hydrogen, halogen, optionally substituted aryl, and optionally substituted heteroaryl, R 1b when R 1c is hydrogen, R 1c when R 1b is hydrogen, R 2 is C 1~6 alkyl, C 3~7 branched alkyl, C 1~6 alkylaryl, optionally substituted aryl, and optionally substituted heteroaryl, X is oxygen, wherein R 6 is hydrogen, OH, OR 7c optionally substituted C 1~6 alkyl, NR 3a R 3b optionally substituted aryl, and optionally substituted heteroaryl, R 3a and R 3b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 3a and R 3b together with the atom to which they are attached, optionally including a member selected from the group consisting of O, NR 8 and S, form a 3- to 6-membered saturated ring optionally substituted with a group selected from OH, C 1~6 alkyl, NR 8a R 8b and, R 8 is hydrogen, C 1~6 alkyl, and CO(C 1~6 alkyl), R 8a and R 8b are independently selected from hydrogen and C 1~6 alkyl, the compound of formula (XLV)

[0234] [Chemical formula]

[0235] and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes, wherein R 1a and R 1d are each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, C 1~6 haloalkyl and C 1~6 haloalkoxy, R 1b and R 1c are selected from the group consisting of hydrogen, halogen, optionally substituted aryl and optionally substituted heteroaryl, R 1b when is hydrogen, R 1c is not hydrogen, R 1c when is hydrogen, R 1b is not hydrogen, R 2 is selected from the group consisting of C 1~6 alkyl, C 3~7 branched alkyl, C 1~6 alkylaryl, optionally substituted aryl and optionally substituted heteroaryl, X is oxygen, wherein R 6 is selected from the group consisting of hydrogen, OH, OR 7c , optionally substituted C 1~6 alkyl, NR 3a R 3b , optionally substituted aryl, and optionally substituted heteroaryl, R 3a and R 3b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 3a and R 3bTogether with the atoms to which they are attached, optionally including members selected from the group consisting of O, NR 8 and S, form a 3- to 6-membered saturated ring optionally substituted with a group selected from OH, C 1~6 alkyl, NR 8a R 8b and form a 3- to 6-membered saturated ring optionally substituted with a group selected from the group consisting of R R 8 is selected from the group consisting of hydrogen, C 1~6 alkyl and CO(C 1~6 alkyl), R 8a and R 8b are independently selected from hydrogen and C 1~6 alkyl, R 7a is selected from the group consisting of hydrogen and C 1~6 alkyl, R 7b is selected from the group consisting of C 1~6 alkyl, aryl and heteroaryl, including.

[0236] Another embodiment of the present invention includes a compound selected from the following structures.

[0237]

Chemical formula

Chemical formula

[0238] Another embodiment of the present invention includes a compound selected from the following structures.

[0239]

Chemical formula

Chemical formula

[0240] Another embodiment of the present invention includes a compound selected from the following structures.

[0241]

Chem.

[0242] Another embodiment of the present invention includes a compound having the following structure.

[0243]

Chem.

[0244] Another embodiment of the present invention includes a compound having the following structure.

[0245]

Chem.

[0246] Another embodiment of the present invention includes a compound having the following structure.

[0247]

Chem.

[0248] Another embodiment of the present invention includes a compound having the following structure.

[0249]

Chem.

[0250] Another embodiment of the present invention includes a compound having the following structure.

[0251]

Chem.

[0252] Another embodiment of the present invention includes a compound having the following structure.

[0253] [Chemical formula]

[0254] Another embodiment of the present invention includes a compound having the following structure.

[0255] [Chemical formula]

[0256] In some embodiments, R 1a is hydrogen.

[0257] In some embodiments, R 1a is a halogen.

[0258] In some embodiments, R 1a is C 1~6 alkyl.

[0259] In some embodiments, R 1a is C 1~6 alkoxy.

[0260] In some embodiments, R 1a is C 1~6 haloalkyl.

[0261] In some embodiments, R 1a is C 1~6 haloalkoxy.

[0262] In some embodiments, R 1d is hydrogen.

[0263] In some embodiments, R 1d is a halogen.

[0264] In some embodiments, R 1d is C 1~6 alkyl.

[0265] In some embodiments, R 1d is C 1~6 alkoxy.

[0266] In some embodiments, R 1d is C 1~6 haloalkyl.

[0267] In some embodiments, R 1d is C 1~6 haloalkoxy.

[0268] In some embodiments, R 1b is hydrogen.

[0269] In some embodiments, R 1b is halogen.

[0270] In some embodiments, R 1b is optionally substituted aryl.

[0271] In some embodiments, R 1b is optionally substituted heteroaryl.

[0272] In some embodiments, R 1c is hydrogen.

[0273] In some embodiments, R 1c is halogen.

[0274] In some embodiments, R 1c is optionally substituted aryl.

[0275] In some embodiments, R 1c is optionally substituted heteroaryl.

[0276] In some embodiments, R 2 is C 1~6 alkyl.

[0277] In some embodiments, R 2 is C 3~7 branched alkyl.

[0278] In some embodiments, R 2 is C 1~6 alkylaryl.

[0279] In some embodiments, R 2 is optionally substituted aryl.

[0280] In some embodiments, R 2 is optionally substituted heteroaryl.

[0281] In some embodiments, X is oxygen.

[0282] In some embodiments, X is sulfur.

[0283] In some embodiments, X is NH.

[0284] In some embodiments, X is NR 5 wherein.

[0285] In some embodiments, R 2 is C 1~6 alkyl.

[0286] In some embodiments, Y is

[0287]

Chemical formula

[0288] as follows. In some embodiments, Y is

[0289]

Chemical formula

[0290] is. In some embodiments, Y is optionally substituted 2-benzimidazole.

[0291] In some embodiments, R 6 is hydrogen.

[0292] In some embodiments, R 6 is OH.

[0293] In some embodiments, R 6 is OR 7c is.

[0294] In some embodiments, R 6 is optionally substituted C 1~6 alkyl.

[0295] In some embodiments, R 6 is NR 3a R 3b is.

[0296] In some embodiments, R 6 is optionally substituted aryl.

[0297] In some embodiments, R 6 is optionally substituted heteroaryl.

[0298] In some embodiments, R 3a is hydrogen.

[0299] In some embodiments, R 3a is C 1~6 alkyl.

[0300] In some embodiments, R 3b is hydrogen.

[0301] In some embodiments, R 3b is C1~6 is alkyl.

[0302] In some embodiments, R 3a and R 3b together with the atoms to which they are attached, optionally including members selected from the group consisting of O, NR 8 and S, form a 3-membered saturated ring optionally substituted with a group selected from OH, C 1~6 alkyl, NR 8a R 8b

[0303] In some embodiments, R 3a and R 3b together with the atoms to which they are attached, optionally including members selected from the group consisting of O, NR 8 and S, form a 4-membered saturated ring optionally substituted with a group selected from OH, C 1~6 alkyl, NR 8a R 8b

[0304] In some embodiments, R 3a and R 3b together with the atoms to which they are attached, optionally including members selected from the group consisting of O, NR 8 and S, form a 5-membered saturated ring optionally substituted with a group selected from OH, C 1~6 alkyl, NR 8a R 8b

[0305] In some embodiments, R 3a and R 3b together with the atoms to which they are attached, optionally including members selected from the group consisting of O, NR 8 and S, form a 6-membered saturated ring optionally substituted with a group selected from OH, C 1~6 alkyl, NR 8a R 8b

[0306] In some embodiments, R​​​​8 is hydrogen.

[0307] In some embodiments, R 8 is C 1~6 alkyl.

[0308] In some embodiments, R 8 is CO(C 1~6 alkyl.

[0309] In some embodiments, R 8a is hydrogen.

[0310] In some embodiments, R 8a is C 1~6 alkyl.

[0311] In some embodiments, R 8b is hydrogen.

[0312] In some embodiments, R 8b is C 1~6 alkyl.

[0313] In some embodiments, R 7a is hydrogen.

[0314] In some embodiments, R 7a is C 1~6 alkyl.

[0315] In some embodiments, R 7b is C 1~6 alkyl.

[0316] In some embodiments, R 7b is aryl.

[0317] In some embodiments, R 7b is heteroaryl.

[0318] In some embodiments, R 7c is C1~6 is alkyl.

[0319] In some embodiments, R 7c is C 3~7 branched alkyl.

[0320] In some embodiments, R 9a is hydrogen.

[0321] In some embodiments, R 9a is halogen.

[0322] In some embodiments, R 9a is C 1~6 alkyl.

[0323] In some embodiments, R 9b is hydrogen.

[0324] In some embodiments, R 9b is halogen.

[0325] In some embodiments, R 9b is C 1~6 alkyl.

[0326] In some embodiments, R 9c is hydrogen.

[0327] In some embodiments, R 9c is halogen.

[0328] In some embodiments, R 9c is C 1~6 alkyl.

[0329] In some embodiments, X 1 is oxygen.

[0330] In some embodiments, X 1 is sulfur.

[0331] In some embodiments, A 1 is nitrogen.

[0332] In some embodiments, A 1 is CR 10 is.

[0333] In some embodiments, A 2 is nitrogen.

[0334] In some embodiments, A 2 is CR 10 is.

[0335] In some embodiments, A 3 is nitrogen.

[0336] In some embodiments, A 3 is CR 10 is.

[0337] In some embodiments, A 4 is nitrogen.

[0338] In some embodiments, A 4 is CR 10 is.

[0339] In some embodiments, A 5 is nitrogen.

[0340] In some embodiments, A 5 is CR 10 is.

[0341] In some embodiments, A 6 is nitrogen.

[0342] In some embodiments, A 6 is CR 10 is.

[0343] In some embodiments, A 7 is nitrogen.

[0344] In some embodiments, A 7 is CR 10 .

[0345] In some embodiments, A 8 is nitrogen.

[0346] In some embodiments, A 8 is CR 10 .

[0347] In some embodiments, A 9 is nitrogen.

[0348] In some embodiments, A 9 is CR 10 .

[0349] In some embodiments, A 10 is nitrogen.

[0350] In some embodiments, A 10 is CR 10 .

[0351] In some embodiments, R 10 is hydrogen.

[0352] In some embodiments, R 10 is C 1~6 alkyl.

[0353] In some embodiments, R 10 is C 1~6 haloalkyl.

[0354] In some embodiments, R 10 is C 1~6 haloalkoxy.

[0355] In some embodiments, R 10 is C 1~6 alkoxy.

[0356] In some embodiments, R 10 is a halogen.

[0357] In some embodiments, R 10 is a hydroxyl.

[0358] In some embodiments, R 10 is NHSO 2 R 11 wherein.

[0359] In some embodiments, R 11 is hydrogen.

[0360] In some embodiments, R 11 is C 1~6 alkyl.

[0361] Exemplary non - limiting embodiments of the present invention include the compounds in Tables 1, 2, and 3.

[0362]

Chemical formula

[0363] Table 1

Table 1

Table 2

[0364]

Chemical formula

[0365] Table 2

Table 3

[0366] For the purpose of showing the manner in which the compounds of the present invention are named and referred to herein, the compound having the following formula has the chemical name 4-(3-(5-methylfuran-2-yl)-6-(pyridin-3-yl)benzofuran-2-yl)butan-2-one.

[0367] [Chemical formula]

[0368] In the present invention, a compound represented in a racemic form equally represents either of two enantiomers or a mixture thereof, and when a second chiral center is present, equally represents all diastereomers.

[0369] In all of the embodiments described herein, examples of suitable optional substituents are not intended to limit the scope of the invention according to the claims. The compounds of the present invention can include any of the substituents or combinations of substituents described herein.

[0370] Process The compounds of the present teachings can be prepared from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, using standard synthetic methods and procedures known to those skilled in the art, according to the procedures outlined herein. Standard synthetic methods, procedures for the preparation of organic molecules, functional group transformations, and manipulations can be readily obtained from relevant scientific literature or standard textbooks in the field. It should be understood that when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions can also be used unless otherwise stated. The optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art by routine optimization procedures. Those skilled in the art of organic synthesis should recognize that the nature and order of the synthetic steps shown can be varied for the purpose of optimizing the formation of the compounds described herein.

[0371] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), mass spectrometry, or by chromatography such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), thin layer chromatography (TLC).

[0372] The preparation of compounds can include the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by one of ordinary skill in the art. The chemical nature of protecting groups can be found, for example, in Greene et al., Protective Groups in Organic Synthesis, 2nd Edition (Wiley & Sons, 1991), the entire disclosure of which is incorporated herein by reference.

[0373] The reactions or processes described herein can be carried out in a suitable solvent that can be readily selected by one of ordinary skill in organic synthesis. Suitable solvents are generally substantially non-reactive with respect to the reactants, intermediates, and / or products at the temperature at which the reaction is carried out, i.e., a temperature that can range from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, a solvent appropriate for the particular reaction step can be selected.

[0374] The compounds of these teachings can be prepared by methods known in the art of organic chemistry. The reagents used in the preparation of the compounds of these teachings are commercially available or can be prepared by standard procedures described in the literature. For example, the compounds of the present invention can be prepared according to the methods described in the following general synthetic schemes. General Synthetic Scheme for the Preparation of Compounds

[0375] The reagents used in the preparation of the compounds of the present invention are commercially available or can be prepared by standard procedures described in the literature. According to the present invention, compounds of a genus can be produced by one of the following reaction schemes.

[0376] The compounds of formula (I) can be prepared according to the processes outlined in Schemes 1-9 reported in the literature. Scheme 1

[0377]

Chemical Formula

[0378] Therefore, a properly substituted compound of formula (1), a known compound, or a compound prepared by known methods reacts with a properly substituted compound of formula (2) in the presence of an acid such as hydrochloric acid, phosphoric acid, sulfuric acid, etc. in a solvent such as water, acetic acid, ethanol, etc. to produce a compound of formula (3). Scheme 2

[0379]

Chemical Formula

[0380] Alternatively, a properly substituted compound of formula (4), a known compound, or a compound prepared by a known method reacts with a properly substituted compound of formula (5) in which X is halogen in the presence of a solvent such as ethyl ether, dioxane, tetrahydrofuran (THF), a known compound, or a compound prepared by a known method to produce a compound of formula (6). The compound of formula (6) reacts with a compound of formula (7), a known compound, or a compound prepared by a known method in a solvent such as water, acetic acid, ethanol in the presence of an acid such as hydrochloric acid, phosphoric acid, sulfuric acid to produce a compound of formula (8). Scheme 3

[0381]

Chemical formula

[0382] A properly substituted compound of formula (9), a known compound, or a compound prepared by a known method is in the presence of a palladium catalyst such as palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphosphine), bis(acetonitrile) dichloropalladium [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium, in the presence of a base such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, in a solvent such as methanol, ethanol, isopropanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, 1,2-dichloroethane, optionally in the presence of water, optionally heated, optionally by microwave irradiation, where Z in the formula is hydrogen, C 1 ~C 6 linear alkyl and C 3 ~C 6 reacts with a properly substituted compound of formula (10) selected from the group consisting of branched alkyl to produce a compound of formula (11). Scheme 4

[0383] [Chem.]

[0384] The properly substituted compound of formula (12) reacts with a properly substituted compound of formula (13) in which X is a halogen, a known compound, or a compound prepared by a known method in the presence of a solvent such as tetrahydrofuran, dioxane, ethyl ether, etc. to produce a compound of formula (14). Scheme 5

[0385] [Chem.]

[0386] The appropriately substituted compound of formula (15) is oxidized, optionally by heating or by microwave irradiation, with an alkaline hypohalite reagent such as sodium hypochlorite in an aqueous sodium hydroxide solution or with potassium permanganate in an aqueous sodium carbonate solution to produce the compound of formula (16). The compound of formula (16) is reacted, optionally by heating or by microwave irradiation, in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate, N,N-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, and optionally in the presence of a base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride, with a compound of formula (17), a known compound, or a compound prepared by a known method to produce the compound of formula (18). Alternatively, the compound of formula (16) is reacted, optionally by heating or by microwave irradiation, in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride, methanol, ethanol, with a compound of formula (17), a known compound, or a compound prepared by a known method to produce the compound of formula (18). Scheme 6

[0387] [Chemical formula]

[0388] The appropriately substituted compound of formula (19) reacts with a compound of formula (20), a known compound, or a compound prepared by a known method in the presence of a coupling agent such as O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, 1-hydroxy-7-azabenzotriazole, etc., and optionally in the presence of a base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, etc., in a solvent such as N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methylene chloride, etc., and optionally by heating and optionally by microwave irradiation to produce a compound of formula (21). Scheme 7

[0389] [Chemical formula]

[0390] The appropriately substituted compound of formula (22) condenses with a compound of formula (23), a known compound, or a compound prepared by a known method in the presence of an agent such as triphenyl phosphite, phosphorus oxychloride, etc., and in the presence of an acid such as pyridine, pure polyphosphoric acid, pure formic acid, etc., and optionally by heating and optionally by microwave irradiation to produce a compound of formula (24). Scheme 8

[0391] [Chemical formula]

[0392] The appropriately substituted compound of formula (25) reacts with the compound of formula (26), a known compound, or a compound prepared by a known method in the presence of an acid such as benzene, toluene, tetrahydrofuran, dioxane, ethyl ether, etc., optionally with heating and optionally with microwave irradiation to produce the compound of formula (28). Alternatively, the appropriately substituted compound of formula (25) reacts with the compound of formula (27), a known compound, or a compound prepared by a known method in the presence of a base such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, etc., in a solvent such as methanol, ethanol, isopropanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, 1,2-dichloroethane, etc., optionally in the presence of water, optionally with heating and optionally with microwave irradiation to produce the compound of formula (28). Alternatively, the appropriately substituted compound of formula (25) reacts with the compound of formula (27), a known compound, or a compound prepared by a known method in the presence of a base such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, etc., in the presence of lithium chloride, in a solvent such as methanol, ethanol, isopropanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, 1,2-dichloroethane, etc., optionally in the presence of water, optionally with heating and optionally with microwave irradiation to produce the compound of formula (28).The compound of formula (28) reacts with hydrogen in an organic solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, 1,4-dioxane, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, etc. in the presence of a palladium catalyst such as palladium on carbon, palladium on barium sulfate, palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), palladium on carbon, dichlorobis(acetonitrile)palladium(II), etc. to produce the compound of formula (29). Scheme 9

[0393]

Chemical formula

[0394] The appropriately substituted compound of formula (30) reacts with a halogenating reagent such as N-iodosuccimide, N-bromosuccinimide, iodine, bromine, etc. in the presence of an acid such as pyridine, dimethylformamide, tetrahydrofuran, acetic acid, etc., optionally with heating, and optionally with microwave irradiation, to produce the compound of formula (31). The compound of formula (31), a known compound, or a compound prepared by a known method, in the presence of a palladium catalyst such as palladium acetate, palladium bis(triphenylphosphine) dichloride, palladium tetrakis(triphenylphospine), bis(acetonitrile) dichloropalladium [1,1'-bis(diphenylphosphino) ferrocene] dichloropalladium, etc., in the presence of a base such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, etc., in a solvent such as methanol, ethanol, isopropanol, 1-butanol, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, 1,2-dichloroethane, etc., optionally in the presence of water, optionally with heating, and optionally with microwave irradiation, wherein Z is hydrogen, C 1~C 6 Linear alkyl and C 3 ~C 6 React with a suitably substituted compound of formula (32), a known compound, or a compound prepared by a known method selected from the group consisting of linear alkyl and branched alkyl to produce a compound of formula (33).

[0395] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0396] The prior art for the preparation / isolation of individual enantiomers involves chiral synthesis from a suitable optically pure precursor or resolution of a racemate (or a racemate of a salt or derivative), for example, using chiral high performance liquid chromatography (HPLC).

[0397] Alternatively, a racemate (or racemic precursor) can react with a suitable optically active compound, for example, an alcohol, and if the compound of formula (I) contains an acidic or basic moiety, it can react with an acid or base such as tartaric acid, 1-phenylethylamine, etc. The resulting mixture of diastereomers can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by means well known to those skilled in the art.

[0398] The chiral compounds of the present invention (and their chiral precursors) can be obtained in an enantiomerically enriched form by chromatography, generally by HPLC, on a resin, using a mobile phase consisting of an asymmetric stationary phase and a hydrocarbon containing 0 to 50%, generally 2 to 20% isopropanol and 0 to 5%, generally 0.1% diethylamine, generally heptane or hexane. The eluate is concentrated to obtain a concentrated mixture.

[0399] A mixture of stereoisomers can be separated by conventional techniques known to those skilled in the art. [See, for example, E L Eliel, "Stereochemistry of Organic Compounds" (Wiley, New York, 1994).]

[0400] The following non-limiting examples are representative methods for preparing the exemplary compounds of the present invention. To prepare the compounds of the present invention, those skilled in the art should know how to substitute appropriate reagents, starting materials and purification methods known to those skilled in the art.

[0401] 1 The 1H-NMR spectra were obtained by Varian Mercury 300MHz NMR. 1 The 1H nuclear magnetic resonance (NMR) spectra were in agreement with the proposed structures in all cases. The characteristic chemical shifts (δ) are given in parts per million in the downfield direction from tetramethylsilane using conventional abbreviations for the designation of the major peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Purity (%) and mass spectral data were measured by Waters Alliance 2695 HPLC / MS (Waters Symmetry C18, 4.6×75mm, 3.5μm) equipped with a 2996 diode array detector from 210 to 400 nm. The retention time (RT) is reported in minutes. The mass spectra (m / z) were recorded by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). When thin layer chromatography (TLC) was used, it refers to silica gel TLC using silica gel 60F 254 plates, and Rf is the distance traveled by the compound divided by the distance traveled by the solvent front on the TLC plate.

Example

[0402] Example 1: N-{3-[3-(5-Methyl-furan-2-yl)-2-(3-oxo-butyl)-benzofuran-5-yl]-phenyl}-methanesulfonamide

[0403]

Chem.

[0404] A mixture of the known compound 4-[5-bromo-3-(5-methyl-furan-2-yl)-benzofuran-2-yl]-butan-2-one (50 mg, 0.14 mmol), N-3-methanesulfonamidophenylboronic acid (31 mg, 0.14 mmol) and an aqueous solution of 2M potassium carbonate (216 μL, 0.43 mmol) in dioxane (1 mL) was degassed with nitrogen for 20 minutes, and then tetrakis(triphenylphosphine)palladium(0) (3.3 mg, 0.003 mmol) was added. The reaction mixture was heated at 80 °C overnight. The reaction was quenched with water, and the product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography (12 g silica cartridge, 0 - 65% ethyl acetate / hexane) gave the title compound ( 1 H NMR (300 MHz, CD 3 OD) δ 2.21 (s, 3H), 2.40 (s, 3H), 2.95 - 3.06 (m, 5H), 3.28 (m, 2H), 6.17 - 6.20 (m, 1H), 6.60 (d, J = 3.2 Hz, 1H), 7.21 - 7.29 (m, 1H), 7.39 - 7.59 (m, 5H), 7.97 (dd, J = 3 Hz, 1H). LCMS (ESI) m / z 438.2 (M+1) + .

[0405] Example 2. 4-(5-(6-Methoxypyridin-3-yl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one

[0406]

Chem.

[0407] 4-(5-(6-Methoxypyridin-3-yl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 1, except that 6-methoxypyridin-3-ylboronic acid was used instead of N-3-methanesulfonamidophenylboronic acid to obtain the product (53 mg, 71% yield). LC / MS: RT = 6.06 min, purity > 95%, (M + H) + = 374.01. 1 H NMR (300 MHz, CDCl 3 ) δ = 8.41 (br.s., 1H), 7.98~7.71 (m, 2H), 7.53~7.31 (m, 2H), 6.81 (d, J = 8.5 Hz, 1H), 6.49 (br.s., 1H), 6.25~5.98 (m, 1H), 4.07~3.86 (m, 3H), 3.32 (t, J = 7.3 Hz, 2H), 2.94 (t, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.20 (s, 3H).

[0408] Example 3. 4-(3-(5-Methylfuran-2-yl)-5-(pyridin-3-yl)benzofuran-2-yl)butan-2-one

[0409]

Chemical formula

[0410] 4-(3-(5-Methylfuran-2-yl)-5-(pyridin-3-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 1, except that pyridin-3-ylboronic acid was used instead of N-3-methanesulfonamidophenylboronic acid to obtain the product (120 mg, 57% yield). The product was converted to the HCl salt (112 mg). LC / MS: RT = 4.01 min, purity > 95%, (M + H) + = 343.94. 1 H NMR (300 MHz, CDCl 3) δ = 8.90 (br.s., 1H), 8.59 (br.s., 1H), 8.06 - 7.80 (m, 2H), 7.59 - 7.29 (m, 3H), 6.51 (br.s., 1H), 6.27 - 5.96 (m, 1H), 3.32 (d, J = 5.9 Hz, 2H), 2.98 (t, J = 6.7 Hz, 2H), 2.50 - 2.32 (s, 3H), 2.30 - 2.11 (s, 3H).

[0411] Example 4. 4-(5-(3-Hydroxyphenyl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one

[0412]

Chemical formula

[0413] 4-(5-(3-Hydroxyphenyl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 1, except that 3-hydroxyphenylboronic acid was used instead of N-3-methanesulfonamidophenylboronic acid to obtain the product (25 mg, 35% yield). LC / MS: RT = 6.67 min, purity > 95%, (M + H) + = 300.70 1 H NMR (300 MHz, CDCl 3 ) δ = 8.00 - 7.87 (m, 1H), 7.55 - 7.38 (m, 2H), 7.36 - 7.23 (m, 1H), 7.20 - 7.09 (m, 2H), 6.83 (dd, J = 2.5, 8.1 Hz, 1H), 6.51 (d, J = 3.2 Hz, 1H), 6.12 (d, J = 2.9 Hz, 1H), 3.33 (t, J = 7.5 Hz, 2H), 3.05 - 2.88 (m, 2H), 2.44 - 2.30 (m, 3H), 2.29 - 2.17 (m, 3H).

[0414] Example 5. 4-(5-(3-Methoxyphenyl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one

[0415]

Chemical formula

[0416] 4-(5-(3-Methoxyphenyl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 1, except that 3-methoxyphenylboronic acid was used instead of N-3-methanesulfonamidophenylboronic acid to obtain the product (51 mg, 68% yield). LC / MS: RT = 6.80 min, purity > 95%, (M+H) + = 314.75. 1 H NMR (300 MHz, CDCl 3 ) δ = 8.01 - 7.89 (m, 1H), 7.52 - 7.30 (m, 3H), 7.28 - 7.12 (m, 2H), 6.96 - 6.83 (m, 1H), 6.52 (d, J = 2.9 Hz, 1H), 6.18 - 6.03 (m, 1H), 3.93 - 3.81 (m, 3H), 3.42 - 3.19 (m, 2H), 3.02 - 2.83 (m, 2H), 2.44 - 2.31 (m, 3H), 2.26 - 2.16 (m, 3H).

[0417] Example 6. 4-(3-(5-Methylfuran-2-yl)-5-(pyridin-4-yl)benzofuran-2-yl)butan-2-one hydrochloride

[0418]

Chemical formula

[0419] 4-(3-(5-Methylfuran-2-yl)-5-(pyridin-4-yl)benzofuran-2-yl)butan-2-one hydrochloride was synthesized in the same procedure as in Example 1, except that 3-methoxyphenylboronic acid was used instead of N-3-methanesulfonamidophenylboronic acid to obtain the product (15 mg, 22% yield). LC / MS: RT = 3.99 min, purity > 95%, (M+H) + = 343.88. 1 H NMR (300 MHz, CDCl 3) δ = 8.61 (br.s., 2H), 8.03 (br.s., 1H), 7.69 - 7.44 (m, 4H), 6.71 - 6.41 (m, 1H), 6.16 (br.s., 1H), 3.54 - 3.22 (m, 2H), 3.13 - 2.87 (m, 3H), 2.58 - 2.38 (m, 3H), 2.33 - 2.13 (m, 3H).

[0420] Example 7. 4-(5-(2-Methoxypyridin-4-yl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one

[0421]

Chem.

[0422] 4-(5-(2-Methoxypyridin-4-yl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 1, except that 2-methoxypyridin-4-yl-4-boronic acid was used instead of N-3-methanesulfonamidophenylboronic acid to obtain the product (35 mg, 47% yield). LC / MS: RT = 5.42 min, purity > 95%, (M + H) + = 374.01. 1 H NMR (300 MHz, CDCl 3 ) δ = 8.37 - 8.13 (m, 2H), 7.99 (br.s., 1H), 7.63 - 7.37 (m, 2H), 7.19 - 7.05 (m, 1H), 7.00 (br.s, 1H), 6.62 - 6.42 (m, 1H), 6.26 - 6.01 (m, 1H), 4.00 (s, 3H), 3.33 (t, J == 7.2 Hz, 2H), 3.10 - 2.83 (m, 2H), 2.50 - 2.35 (m, 3H), 2.31 - 2.08 (m, 3H).

[0423] Example 8. 4-(3-(5-Methylfuran-2-yl)-5-(thiophen-2-yl)benzofuran-2-yl)butan-2-one

[0424]

Chem.

[0425] A mixture of 4-(5-bromo-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one (347 mg, 1.0 mmol), thiophene-2-boronic acid (210 mg, 1.5 mmol), palladium acetate (11 mg, 0.05 mmol), potassium phosphate (424 mg, 2.0 mmol), 2-dicyclohexylphosphinyl-2′4′6′-triisopropylbiphenyl (46 mg, 0.1 mmol) and n-butanol (2.0 mL) was heated at 100 °C for 10 h. The mixture was treated with water (30 mL) and extracted with ethyl acetate (3×). The combined extracts were washed with brine, dried, concentrated, and the residue was purified by flash column (24 g, 0–10% ethyl acetate / hexane) to give 4-(3-(5-methylfuran-2-yl)-5-(thiophen-2-yl)benzofuran-2-yl)butan-2-one (240 mg, 69% yield). LC / MS: RT = 5.82 min, purity >95%, 1 H NMR (300 MHz, CDCl 3 ) δ = 7.98 (br.s., 1H), 7.58–7.47 (m, 1H), 7.45–7.33 (m, 1H), 7.28 (d, J = 9 Hz, 2H), 7.09 (br.s., 1H), 6.51 (br.s., 1H), 6.14 (br.s., 1H), 3.40–3.21 (m, 2H), 2.96 (t, J = 6.9 Hz, 2H), 2.41 (s, 3H), 2.21 (s, 3H).

[0426] Example 9. 4-[5-Bromo-3-(3-methyl-butyl)-benzofuran-2-yl]-butan-2-one

[0427]

Chemical formula

[0428] 1-Bromo-3-methylbutane (1.56 mL, 12.4 mmol) was stirred with powdered magnesium turnings in diethyl ether for 15 minutes after the effervescence ceased. 5-Bromosalicylaldehyde (1.00 g, 4.98 mmol) in diethyl ether (10 mL) was added dropwise. The mixture was stirred for 5 minutes, then water (3 mL) was gradually added to decompose the excess magnesium. The insoluble material was filtered off and the filtrate was concentrated. Purification by flash chromatography (24 g silica, 0 - 35% EtOAc / hexane) gave 4-bromo-2-(1-hydroxy-4-methyl-pentyl)-phenol as a white solid (626 mg, 46% yield). 1 H NMR (300 MHz, CD 3 OD) δ 0.89 (d, J = 6 Hz, 6H), 1.10 - 1.40 (m, 2H), 1.49 - 1.78 (m, 3H), 4.90 (dd, J = 7.6, 5.3 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 7.15 (dd, J = 4.9 Hz, 1H), 7.38 (d, J = 2.6 Hz, 1H). LCMS (ESI) m / z 185 / 187 (M / M+2) + C 5 H 12 Fragment loss of O.

[0429] A mixture of 4-bromo-2-(1-hydroxy-4-methyl-pentyl)-phenol (620 mg, 2.27 mmol), 2-methylfuran (221 μL, 2.50 mmol) and p-toluenesulfonic acid (6 mg, 0.035 mmol) in toluene (2.3 mL) was heated to reflux for 15 minutes. The solvent was removed under reduced pressure and the residue was first purified by flash chromatography (12 g silica, 0 - 25% EtOAc / hexane) to give a mixture. A portion of the mixture (55 mg) was purified twice by preparative reverse-phase HPLC and freeze-dried to give pure 4-[5-bromo-3-(3-methyl-butyl)-benzofuran-2-yl]-butan-2-one as a white solid (40 mg, yield not measurable). 1 H NMR (300 MHz, CD 3OD) δ 0.97 - 1.00 (m, 6H), 1.45 - 1.67 (m, 3H), 2.15 - 2.17 (m, 3H), 2.59 - 2.67 (m, 2H), 2.87 - 3.02 (m, 4H), 7.28 - 7.30 (m, 2H), 7.57 (dd, J = 1.8, 0.9 Hz, 1H). LCMS (ESI) m / z 223 / 225 (M / M + 2) + C 7 H 14 Fragment loss of O.

[0430] Example 10. 4-(5-Bromo-3-phenylbenzofuran-2-yl)butan-2-one

[0431]

Chemical Structure

[0432] Phenylmagnesium bromide (1.25 mL, 3.75 mmol) was added to a solution of 5-bromo-2-hydroxybenzaldehyde (250 mg, 1.25 mmol) in tetrahydrofuran at 0 °C. The mixture was stirred for 2 hours and then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried, and concentrated. The residue was purified by flash column (10 - 40% ethyl acetate / hexane) to give 4-bromo-2-(hydroxy(phenyl)methyl)phenol (303 mg, 87% yield). LC / MS: RT = 4.61 min, purity > 95%, (M - 18) + = 260.92

[0433] A mixture of 4-bromo-2-(hydroxy(phenyl)methyl)phenol (84 mg, 0.3 mmol), 2-methylfuran (34 μL, 0.39 mmol), and 4-methylbenzenesulfonic acid (5 mg) in toluene (2 mL) was heated at 120 °C for 2 hours and then concentrated. The residue was purified by flash column to give the title compound (80 mg, 78% yield). LC / MS: RT = 6.64 min, purity > 95%, (M) + = 342.24 1 H NMR (300 MHz, CDCl 3) δ = 7.70~7.62 (m, 1H), 7.55 - 7.44 (m, 4H), 7.43 - 7.22 (m, 3H), 3.20 - 3.09 (m, 2H), 2.98 - 2.83 (m, 2H), 2.20~2.11 (m, 3H)

[0434] Example 11. 4-(5-Bromo-3-p-tolylbenzofuran-2-yl)butan-2-one

[0435]

Chemical formula

[0436] 4-(5-Bromo-3-p-tolylbenzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 11, except that phenylmagnesium bromide was used instead of 4-methylphenylmagnesium bromide to obtain the product (54 mg, 61% yield). LC / MS: RT = 6.78 min, purity > 95%, 1 H NMR (300 MHz, CDCl 3 ) δ = 7.64 (d, J = 1.5 Hz, 1H), 7.42 - 7.20 (m, 7H), 3.21 - 3.05 (m, 2H), 2.97 - 2.77 (m, 2H), 2.46 - 2.36 (m, 3H), 2.21 - 2.12 (m, 3H)

[0437] Example 12. 3-[5-Bromo-3-(5-methyl-furan-2-yl)-benzofuran-2-yl]-propionic acid

[0438]

Chemical formula

[0439] Bromine (1.15 mL, 22.5 mmol) was added dropwise to a solution of sodium hydroxide (3.80 g, 95.0 mmol) in water (8.65 mL) with stirring and cooling. A solution of the known compound 4-[5-bromo-3-(5-methyl-furan-2-yl)-benzofuran-2-yl]-butan-2-one (1.00 g, 2.88 mmol) in dioxane (4 mL) was added to the in-situ generated sodium hypobromite solution with stirring at room temperature. The reaction mixture was stirred for 5 h and then water (57 mL) was added. The water was extracted with diethyl ether (5×15 mL). Acetic acid (5.77 mL) was carefully added to the aqueous layer and the mixture was stirred over the weekend. The aqueous layer was then extracted with CH 2 Cl 2 (3×15 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by preparative reverse phase HPLC gave the title compound as a yellow solid (60 mg, 6% yield). 1 1H NMR (300 MHz, CD 3 OD) δ 2.40 (d, J = 0.9 Hz, 3H), 2.75 - 2.82 (m, 2H), 3.33 - 3.38 (m, 2H), 6.18 (d, J = 3.2 Hz, 1H), 6.58 (d, J = 3.2 Hz, 1H), 7.32 - 7.48 (m, 2H), 7.92 (s, 1H). LCMS (ESI) m / z 349 / 351 (M + 1) + 。

[0440] Example 13. 3-[5-Bromo-3-(5-methyl-furan-2-yl)-benzofuran-2-yl]-1-(4-hydroxy-piperidin-1-yl)-propan-1-one

[0441]

Chem.

[0442] A mixture of 3-[5-bromo-3-(5-methyl-furan-2-yl)-benzofuran-2-yl]-propionic acid (20 mg, 0.058 mmol), 4-hydroxypiperidine (13.8 mg, 0.136 mmol) and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (66 mg, 0.173 mmol) in dimethylformamide (288 μL) was stirred at room temperature for 1 hour. The reaction was purified by reverse phase HPLC and a yellow solid was obtained after lyophilization (21 mg, 84% yield). 1 H NMR (300 MHz, CD 3 OD) δ 1.28~1.51 (m, 2H), 1.60~1.85 (m, 2H), 2.38~2.41 (m, 3H), 2.84~2.95 (m, 2H), 3.08~3.29 (m, 2H), 3.33~3.39 (m, 2H), 3.79 (m, 2H), 4.01 (s, 1H), 6.18 (d, J = 3.2 Hz, 1H), 6.58 (d, J = 3.2 Hz, 1H), 7.36~7.44 (m, 2H), 7.92 (dd, J = 1.8, 0.9 Hz, 1H). LCMS (ESI) m / z 432 / 434 (M+1) + 。

[0443] Example 14. 2-{2-[5-Bromo-3-(5-methyl-furan-2-yl)-benzofuran-2-yl]-ethyl}-1H-benzimidazole

[0444]

Chemical formula

[0445] 3-[5-Bromo-3-(5-methyl-furan-2-yl)-benzofuran-2-yl]-propionic acid (16.5 mg, 0.048 mmol), o-phenylenediamine (5.1 mg, 0.048 mmol) and triphenyl phosphite (16 μL, 0.062 mmol) in anhydrous pyridine (700 μL) were heated in a microwave at 180 °C for 10 minutes. The reaction was directly purified by reverse phase HPLC and a pale yellow powder was obtained after lyophilization (19 mg, 75% yield, trifluoroacetic acid (TFA) salt).1 1H NMR (300 MHz, CD 3 OD) δ 2.22 (d, J = 0.9 Hz, 3H), 3.53 - 3.74 (m, 4H), 6.00 - 6.03 (m, 1H), 6.50 (d, J = 3.2 Hz, 1H), 7.31 - 7.39 (m, 1H), 7.43 - 7.56 (m, 3H), 7.62 - 7.68 (m, 2H), 7.87 (d, J = 1.8 Hz, 1H). LCMS (ESI) m / z 432 / 434 (M / M+2) + .

[0446] Example 15. 4-(5-Bromo-3-(5-methylfuran-2-yl)benzofuran-2-yl)-2-methylbutan-2-ol

[0447] [Chemical formula]

[0448] To a solution of 4-(5-bromo-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one (50 mg, 0.144 mmol) in tetrahydrofuran (2 mL) was added methylmagnesium bromide (0.1 mL, 0.3 mmol) at 0 °C. The mixture was stirred for 2 h and then treated with saturated ammonium chloride solution. The organic layer was separated, washed with brine, dried, and concentrated. The residue was purified by flash column (10 - 30% ethyl acetate / hexane) to give the desired compound (29 mg, 56% yield). LC / MS: RT = 6.50 min, purity > 95%, (M - 18) + = 344.89. 1 1H NMR (300 MHz, CDCl 3 ) δ = 7.97 - 7.82 (m, 1H), 7.41 - 7.21 (m, 2H), 6.51 - 6.38 (m, 1H), 6.19 - 6.06 (m, 1H), 3.20 - 2.98 (m, 2H), 2.40 (s, 3H), 2.06 - 1.88 (m, 2H), 1.35 - 1.24 (m, 7H)

[0449] Example 16. 4-(5-Bromo-3-(5-methylfuran-2-yl)benzofuran-2-yl)-2-p-tolylbutan-2-ol

[0450]

Chem.

[0451] 4-(5-Bromo-3-(5-methylfuran-2-yl)benzofuran-2-yl)-2-p-tolylbutan-2-ol was synthesized in the same procedure as in Example 15, except that 4-methylphenylmagnesium bromide (1.0 mL, 0.5 mmol) was used instead of methylmagnesium bromide to obtain the product (20 mg, 32% yield). LC / MS: RT f = 7.26 min, purity > 95%, (M - 18) + = 420.90. 1 H NMR (300 MHz, CDCl 3 ) δ = 7.87 (d, J = 1.5 Hz, 1H), 7.38 - 7.29 (m, 3H), 7.27 - 7.19 (m, 1H), 7.17 - 7.07 (m, 2H), 6.28 (d, J = 3.2 Hz, 1H), 6.09 - 6.01 (m, 1H), 3.10 - 2.96 (m, 2H), 2.95 - 2.76 (m, 2H), 2.35 (s, 6H), 1.67 - 1.56 (m, 3H).

[0452] Example 17. 4-(5-Bromo-3-(5-chlorothiophen-2-yl)benzofuran-2-yl)butan-2-one

[0453]

Chem.

[0454] 4-(5-Bromo-3-(5-chlorothiophen-2-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 10, except that 5-chloro-2-thienylmagnesium chloride was used instead of phenylmagnesium bromide to obtain the product (204 mg, 74% yield). LC / MS: RT = 6.95 min, purity > 95%, (M + 1) + = 382.88. 1 H NMR (300 MHz, CDCl 3) δ = 7.74 (d, J = 1.8 Hz, 1H), 7.43 - 7.24 (m, 2H), 7.03 - 6.86 (m, 2H), 3.25 - 3.14 (m, 2H), 3.01 - 2.87 (m, 2H), 2.24 - 2.14 (m, 3H)

[0455] Example 18. 4-(3-(5-Chlorothiophen-2-yl)-5-(pyridin-4-yl)benzofuran-2-yl)butan-2-one

[0456]

Chem.

[0457] To a mixture of the previously prepared 4-(5-bromo-3-(5-chlorothiophen-2-yl)benzofuran-2-yl)butan-2-one (70 mg, 0.183 mmol), 4-pyridylboronic acid (30 mg, 0.24 mmol) and tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.008 mmol) was added 2N potassium carbonate solution (0.5 mL) and dioxane (2 mL). The mixture was heated at 80 °C for 5 h. Ethyl acetate (10 mL) and water (10 mL) were added, filtered, and extracted with ethyl acetate (2×). The combined extracts were dried and concentrated. The residue was purified by flash column (12 g) to give the desired product (10 mg, 14% yield). LC / MS: RT = 4.39 min, purity >95%, (M + H) + = 381.85. 1 H NMR (300 MHz, CDCl 3 ) δ = 8.66 (br.s., 1H), 7.95 - 7.82 (m, 1H), 7.64 - 7.46 (m, 2H), 7.07 - 6.96 (m, 1H), 3.33 - 3.19 (m, 1H), 3.04 - 2.87 (m, 1H), 2.21 (s, 2H)

[0458] Example 19. 4-(3-(5-Chlorothiophen-2-yl)-5-(2-methoxypyridin-4-yl)benzofuran-2-yl)butan-2-one

[0459]

Chem.

[0460] 4-(3-(5-Chlorothiophen-2-yl)-5-(2-methoxypyridin-4-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 18, except that 2-methoxypyridin-4-yl-4-boronic acid was used instead of 4-pyridylboronic acid to obtain the product (48 mg, 64% yield). LC / MS: RT = 5.80 min, purity > 95%, (M + H) + = 411.88。 1 H NMR (300 MHz, CDCl 3 ) δ = 8.21 (d, J = 5.3 Hz, 1H), 7.86 (d, J = 0.9 Hz, 1H), 7.60 - 7.45 (m, 2H), 7.13 (d, J = 5.3 Hz, 4H), 3.99 (s, 3H), 3.30 - 3.14 (m, 2H), 3.03 - 2.86 (m, 2H), 2.21 (s, 3H)

[0461] Example 20. 4-(5-(6-Chloropyridin-3-yl)-3-(5-chlorothiophen-2-yl)benzofuran-2-yl)butan-2-one

[0462]

Chemical formula

[0463] 4-(5-(6-Chloropyridin-3-yl)-3-(5-chlorothiophen-2-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 18, except that 6-chloropyridyl-3-boronic acid was used instead of 4-pyridylboronic acid to obtain the product (23 mg, 30% yield). LC / MS: RT = 6.69 min, purity 95%, (M + H) + = 415.83。 1 H NMR (300 MHz, CDCl 3) δ = 8.69 - 8.53 (m, 1H), 7.94 - 7.70 (m, 2H), 7.61 - 7.34 (m, 3H), 7.09 - 6.93 (m, 2H), 3.33 - 3.16 (m, 2H), 3.05 - 2.89 (m, 2H), 2.27 - 2.14 (m, 3H)

[0464] Example 21. 4-(6-Bromo-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one

[0465] [Chemical formula]

[0466] To a mixture of 4-bromo-2-hydroxybenzaldehyde (1.0 g, 5.0 mmol) and 2-methylfuran (1.1 mL, 12.5 mmol) in ethanol (4 mL) was added saturated HCl in ethanol (4 mL). The mixture was stirred for 20 minutes, then 6 mL of saturated HCl in ethanol was added and the mixture was heated under reflux for 1 hour. The mixture was concentrated and purified by flash column (80 g) to give the desired product (997 mg, 57%). LC / MS: RT = 6.48 min, purity > 95%, (M + H) + = 346.83.

[0467] Example 22. 4-(3-(5-methylfuran-2-yl)-6-(pyridin-4-yl)benzofuran-2-yl)butan-2-one

[0468] [Chemical formula]

[0469] A mixture of 4-(6-bromo-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one (210 mg, 0.61 mmol), pyridin-4-ylboronic acid (97 mg, 0.8 mmol), tetrakis(triphenylphosphine)palladium(0) (35 mg, 0.03 mmol), 2N potassium carbonate (0.5 mL), and dioxane (1.0 mL) was stirred in a microwave apparatus at 110 °C for 20 minutes. The mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried, concentrated, and the residue was purified by flash column (20 g) to give the title compound (99 mg, 47% yield). LC / MS: RT = 4.16 min, purity >95%, (M+H) + = 345.98. 1 H NMR (300 MHz, CDCl 3 ) δ = 8.66 (d, J = 5.9 Hz, 1H), 7.97 - 7.81 (m, 1H), 7.68 (d, J = 1.2 Hz, 1H), 7.63~7.45 (m, 2H), 6.51 (d, J = 2.9 Hz, 1H), 6.14 (d, J = 23 Hz, 1H), 3.35 (t, J = 7.6 Hz, 1H), 3.04 - 2.89 (m, 1H), 2.48 - 2.34 (m, 1H), 2.30 - 2.15 (m, 1H)

[0470] Example 23. 4-(6-(2-Methoxypyridin-4-yl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one

[0471] [Chemical formula]

[0472] 4-(6-(2-Methoxypyridin-4-yl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 22, except that 2-methoxypyridyl-4-boronic acid was used instead of 4-pyridylboronic acid to obtain the product free base (109 mg, 47% yield). This product was dissolved in ethyl acetate (5 mL), and 75 μL of 4N HCl dioxane solution was added. The mixture was stirred for 20 minutes, filtered, washed with ethyl acetate, and dried to obtain 92 mg of the HCl salt. LC / MS: RT = 6.23 minutes, purity > 95%, (M + H) + = 374.01. 1 H NMR (300 MHz, CDCl 3 ) δ = 8.43 (br.S., 1H), 7.84 (t, / = 98.2 Hz, 2H), 7.56 (br.s., 1H), 7.44 (d, / = 8.5 Hz, 1H), 7.26 (br.S., 3H), 6.84 (d, / = 8.5 Hz, 1H), 6.51 (br.S., 1H), 6.13 (br.s., 1H), 4.00 (br.s., 3H), 3.33 (d, / = 8.2 Hz, 2H), 3.06 - 2.87 (m, 2H), 2.41 (s, 3H), 2.22 (br.s., 3H).

[0473] Example 24. 4-(3-(5-Methylfuran-2-yl)-6-(pyridin-3-yl)benzofuran-2-yl)butan-2-one

[0474]

Chemical Structure

[0475] 4-(3-(5-Methylfuran-2-yl)-6-(pyridin-3-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 22, except that 3-pyridylboronic acid was used instead of 4-pyridylboronic acid to obtain the product (140 mg, free base, 66% yield). LC / MS: RT = 4.14 minutes, purity > 95%, (M + H) + = 343.94. 1 H NMR (300 MHz, CDCl 3) δ = 8.91 (br.S., 1H), 8.60 (br.S., 1H), 7.90 (t, J = 9.8 Hz, 2H), 7.62 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.38 (br.S., 1H), 6.52 (br.S., 1H), 6.14 (br.S., 1H), 3.35 (t, J = 7.5 Hz, 2H), 3.06 - 2.85 (m, 2H), 2.41 (s, 3H), 2.30 - 2.15 (m, 3H).

[0476] Example 25. 4-(5-Bromo-3-(p-tolylmethyl)benzofuran-2-yl)butan-2-one

[0477] [Chemical formula]

[0478] To a solution of 5-bromo-2-hydroxybenzaldehyde (250 mg, 1.25 mmol) in tetrahydrofuran (5 mL) was added 4-methylbenzylmagnesium bromide (6.2 mL, 3.13 mmol, 0.5 N diethyl ether solution). The mixture was stirred for 1 hour, then treated with 1 N HCl solution (10 mL) and extracted with ethyl acetate (2 × 30 mL). The combined extracts were washed with brine, dried, and concentrated. The residue was purified by flash column (24 g silica: 5 - 15% ethyl acetate / hexane) to give 4-bromo-2-(1-hydroxy-2-p-tolylethyl)phenol (235 mg, 61%). LC / MS: RT = 5.42 min, purity > 95%. A mixture of 4-bromo-2-(1-hydroxy-2-p-tolylethyl)phenol (60 mg, 0.20 mmol), 2-methylfuran (23 uL, 0.26 mmol), and 4-methylbenzenesulfonic acid (5 mg) in toluene (2 mL) was heated to reflux for 0.5 hour. The mixture was cooled and concentrated. The residue was purified by flash column (12 g, 0 - 20% ethyl acetate / hexane) to give 4-(5-bromo-3-(p-tolylmethyl)benzofuran-2-yl)butan-2-one (40 mg, 54%). LC / MS: RT = 6.93 min, purity > 95%, (M + H) + = 371.45. 11H NMR (300 MHz, CDCl 3 ) δ = 7.47 - 7.33 (m, 1H), 7.31 - 7.14 (m, 2H), 7.14 - 6.94 (m, 4H), 4.03 - 3.77 (m, 2H), 3.10 - 2.92 (m, 2H), 2.91 - 2.77 (m, 2H), 2.38 - 2.21 (m, 3H), 2.21 - 2.00 (m, 3H)

[0479] Example 26. 4-(5-Bromo-3-(2-p-tolylethyl)benzofuran-2-yl)butan-2-one

[0480]

Chemical formula

[0481] 4-(5-Bromo-3-(2-p-tolylethyl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 25, except that 4-methylphenylethylmagnesium bromide was used instead of 4-methylbenzylmagnesium bromide to obtain the product (60 mg, 81%). LC / MS: RT = 7.17 min, purity > 95%, (M + H) + = 384.54 1 1H NMR (300 MHz, CDCl 3 ) δ = 7.59 - 7.41 (m, 1H), 7.37 - 7.16 (m, 2H), 7.12 - 6.84 (m, 4H), 2.95 - 2.77 (m, 4H), 2.75 - 2.63 (m, 2H), 2.51 - 2.36 (m, 2H), 2.37 - 2.22 (m, 3H), 2.13 - 1.96 (m, 3H).

[0482] Example 27. 4-(5-Bromo-3-(2-phenethyl)benzofuran-2-yl)butan-2-one

[0483]

Chemical formula

[0484] 4-(5-Bromo-3-(2-phenethyl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 25, except that phenylethylmagnesium bromide was used instead of 4-methylbenzylmagnesium bromide to obtain the product (30 mg, 40%). LC / MS: RT = 6.87 min, purity > 95%, (M+H) + = 370.45 1 H NMR (300 MHz, CDCl 3 ) δ = 7.61 - 7.48 (m, 1H), 7.37 - 7.14 (m, 5H), 7.12 - 7.00 (m, 2H), 3.02 - 2.81 (m, 4H), 2.76 - 2.58 (m, 2H), 2.49 - 2.30 (m, 2H), 2.18 - 1.97 (m, 3H).

[0485] Example 28: 4-(6-(6-Methoxypyridin-3-yl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one

[0486]

Chemical Structure

[0487] Example 28: 4-(6-(6-Methoxypyridin-3-yl)-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one was synthesized in the same procedure as in Example 22, except that 6-methoxypyridin-3-yl-3-boronic acid was used instead of 4-pyridylboronic acid to obtain the product (29 mg, free base, 48% yield). LC / MS: RT = 6.23 min, purity > 95%, (M) + = 375.04 1 H NMR (300 MHz, CDCl 3) δ = 8.43 (br.s., 1H), 7.84 (d, J = 8.2 Hz, 2H), 7.56 (br.s., 1H), 7.44 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 8.5 Hz, 1H), 6.51 (br.s., 1H), 6.13 (br.s, 1H), 4.00 (br.s., 3H), 3.33 (d, = 8.2 Hz, 2H), 3.01 - 2.93 (m, 2H), 2.41 (br.s., 3H), 2.22 (br.s., 3H).

[0488] Example 29: 4-(5-(Pyrimidin-5-yl)-3-p-tolylbenzofuran-2-yl)butan-2-one, diHCl salt

[0489]

Chemical formula

[0490] Example 29: The above 4-(5-(Pyrimidin-5-yl)-3-p-tolylbenzofuran-2-yl)butan-2-one, diHCl salt from 4-(5-Bromo-3-p-tolylbenzofuran-2-yl)butan-2-one (90 mg, 0.25 mmol) and pyrimidin-5-yl-5-boronic acid (63 mg, 0.5 mmol) which produced the title product (46 mg, 51% yield). The diHCl salt was subsequently prepared (44 mg). LC / MS: RT = 5.48 min, purity > 95%, 1 H NMR (300 MHz, CDCl 3 ) δ 9.08~9.25 (m, 1H), 8.78~9.02 (m, 2H), 7.70 (d, J = 1.76 Hz, 1H), 7.49~7.62 (m, 1H), 7.39~7.49 (m, 3H), 7.26~7.33 (m, 1H), 3.11~3.32 (m, 2H), 2.86~3.04 (m, 2H), 2.44 (s, 3H), 2.11~2.24 (m, 3H).

[0491] Example 30: 4-(3-(5-Methylfuran-2-yl)-6-(pyrimidin-5-yl)benzofuran-2-yl)butan-2-one, diHCl salt

[0492] [Chemistry]

[0493] Example 30: 4-(3-(5-Methylfuran-2-yl)-6-(pyrimidin-5-yl)benzofuran-2-yl)butan-2-one, dihydrochloride salt was synthesized from 4-(6-bromo-3-(5-methylfuran-2-yl)benzofuran-2-yl)butan-2-one (90 mg, 0.26 mmol) and pyrimidin-5-yl-5-boronic acid (64 mg, 0.52 mmol) as above to obtain the title product (31 mg, 34% yield). The dihydrochloride salt was subsequently prepared (30 mg). LC / MS: RT = 5.38 min, purity > 95%, (M + H) + = 347.17. 1 H NMR (300 MHz, CDCl 3 ) δ 9.16~9.35 (m, 1H), 9.02~9.16 (m, 2H), 7.80~8.03 (m, 1H), 7.64 (d, J = 0.88 Hz, 1H), 7.49 (dd, J = 1.17, 8.21 Hz, 1H), 6.42~6.58 (m, 1H), 6.04~6.20 (m, 1H), 3.20~3.43 (m, 2H), 2.86~3.14 (m, 2H), 2.41 (s, 3H), 2.15~2.32 (m, 3H).

[0494] Example 31: 4-(3-(4-Fluorophenyl)-6-(pyridin-3-yl)benzofuran-2-yl)butan-2-one hydrochloride salt

[0495] [Chemistry]

[0496] Example 31: 4-(3-(4-Fluorophenyl)-6-(pyridin-3-yl)benzofuran-2-yl)butan-2-one HCl salt was synthesized from 4-(6-bromo-3-(4-fluorophenyl)benzofuran-2-yl)butan-2-one (54 mg, 0.15 mmol) and 3-pyridyl-boronic acid (37 mg, 0.30 mmol) as described above to obtain the title product (39 mg, 72% yield). The HCl salt was subsequently prepared (32 mg). LC / MS: RT = 3.66 min, purity > 95%, (M + H) + = 360.08. 1 H NMR (300 MHz, CDCl 3 ) δ 8.78~8.97 (m, 1H), 8.51~8.64 (m, 1H), 7.91 (td, J = 1.91, 7.92 Hz, 1H), 7.66 (d, J = 0.88 Hz, 1H), 7.55~7.62 (m, 1H), 7.42~7.55 (m, 3H), 7.33~7.42 (m, 1H), 7.11~7.28 (m, 3H), 3.07~3.25 (m, 2H), 2.88~3.04 (m, 2H), 2.12~2.24 (m, 3H).

[0497] Formulation The present invention also relates to a composition or formulation comprising an inhibitor of tau oligomer formation according to the present invention. Generally, the composition of the present invention comprises an effective amount of one or more inhibitors of tau oligomer formation of the present disclosure and salts thereof according to the present invention and one or more excipients, which are effective in preventing tau oligomerization.

[0498] In the present invention, the terms "excipient" and "carrier" are used interchangeably throughout the description of the present invention, and the terms are defined herein as "components used in the formulation of a safe and effective pharmaceutical composition".

[0499] The formulator should understand that excipients are used not only to help the delivery vehicle as a whole to deliver the active pharmaceutical ingredient safely and stably, but also to serve as a means to achieve effective absorption of the active ingredient by the recipient. Excipients can play a simple and direct role as inert fillers, or the excipients used herein can be part of a pH stabilization system or coating to safely and surely deliver the ingredients to the stomach. The formulator can also utilize the fact that the compounds of the present invention improve the cellular potency, pharmacokinetic properties, and oral bioavailability.

[0500] The present teachings also provide pharmaceutical compositions comprising at least one compound described herein and one or more pharmaceutically acceptable carriers, excipients or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared according to recognized pharmaceutical procedures such as those described in Remingtons Pharmaceutical Sciences, 17th Edition, Alfonso R. Gennaro, ed., Mack Publishing Company, Easton, Pa (1985), which is incorporated herein by reference in its entirety. As used herein, "pharmaceutically acceptable" refers to substances that are acceptable for use in pharmaceutical applications from a toxicological perspective and do not have a harmful interaction with the active ingredient. Thus, a pharmaceutically acceptable carrier is compatible with the other ingredients in the formulation and is biologically acceptable. Supplementary active compounds can also be incorporated into the pharmaceutical composition.

[0501] The compounds of the present invention can be formulated into suitable dosage forms for oral administration, such as tablets, capsules, pills, powders, sustained-release formulations, solutions, suspensions; for parenteral injection, such as sterile solutions, suspensions or emulsions; for topical administration, such as ointments or creams; or for rectal administration, such as suppositories. The pharmaceutical composition can be in unit dosage forms suitable for precise dosage single administration.

[0502] The compounds of the present invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained, for example, as solid plugs, powders or films by methods such as precipitation, crystallization, freeze-drying, spray-drying, evaporation to dryness, etc. Microwave or radiofrequency drying can be used for this purpose.

[0503] The compounds of the present invention intended for pharmaceutical use can be administered alone, or in combination with one or more other compounds of the present invention, or in combination with one or more other drugs (or as any combination thereof). The pharmaceutical compositions contain a compound according to the present invention as an active ingredient together with conventional pharmaceutical carriers or excipients. Furthermore, it can contain other drugs or pharmaceuticals, carriers, adjuvants, etc. Generally, they are administered as formulations together with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any component other than the compound(s) of the present invention. The choice of excipient depends largely on factors such as the particular method of administration, the effect of the excipient on solubility and stability, the nature of the dosage form, etc. Descriptions of pharmaceutical compositions and methods for their preparation can be found, for example, in "Remington’s Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).

[0504] The compounds of the present disclosure can be administered orally or parenterally, either as such or in combination with conventional pharmaceutical carriers. Suitable solid carriers can include one or more substances that can also act as flavoring agents, lubricants, solubilizing agents, suspending agents, fillers, fluidizing agents, compression aids, binders or tablet disintegrants, or encapsulating materials. The compounds can be formulated in a conventional manner, for example, in a manner similar to those used in known treatment therapies for central nervous system disorders. Oral formulations containing the compounds disclosed herein can include tablets, capsule formulations containing particles, buccal tablets, troches, lozenges (including liquid-filled), gels, powders, solid solutions, multi- and nanoparticles, liposomes, films (including mucoadhesive), ova, sprays, as well as any conventionally used oral dosage forms including oral solutions, suspensions or solutions. In powders, the carrier can be a finely divided solid that is a mixture with the finely divided compound. In tablets, the compounds disclosed herein can be mixed with a carrier having the required compressibility in appropriate proportions and compressed into the desired shape and size. Powders and tablets can contain up to 99% of the compound.

[0505] Examples of solutions include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers in soft or hard capsules and generally contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, as well as one or more emulsifying and / or suspending agents. Solutions can also be prepared, for example, by reconstitution of a solid from a sachet. The compounds of the present invention can also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11(6), 981 - 986 (2001).

[0506] The capsule formulation can include a mixture of one or more compounds (singular or plural) disclosed herein and one or more inert fillers and / or diluents such as pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), flours, gelatin, gums, etc.

[0507] Useful tablet formulations can be manufactured by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents or stabilizers including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugar, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, microcrystalline cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, polyvinylpyrrolidine, alginic acid, gum arabic, xanthan gum, sodium citrate, complex silicate, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting wax and ion exchange resin. Surface modifiers include non-ionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, magnesium aluminum silicate and triethanolamine. The oral formulations herein can utilize standard delayed or sustained release formulations that alter the absorption of the compound(s). The oral formulation can also consist of administering the compounds disclosed herein in water or fruit juice, optionally containing suitable solubilizing or emulsifying agents.

[0508] The liquid carrier can be used for the preparation of solutions, suspensions, emulsions, syrups, elixirs, and inhalation delivery. The compounds of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent or a mixture of both, a pharmaceutically acceptable oil or fat. The liquid carrier can include other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmotic pressure regulators, etc. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water, alcohols (including monohydric and polyhydric alcohols such as glycols) and their derivatives, and oils (such as fractionated coconut oil and peanut oil), (especially including additives described herein, such as cellulose derivatives such as sodium carboxymethylcellulose solution). For parenteral administration, the carrier can be an oily ester such as ethyl oleate, isopropyl myristate. A sterile liquid carrier is used for a sterile liquid composition for parenteral administration. The liquid carrier for a pressurized composition can be a halogenated hydrocarbon or other pharmaceutically acceptable propellant.

[0509] A liquid pharmaceutical composition that is a sterile solution or suspension can be utilized, for example, by intramuscular, intraperitoneal or subcutaneous injection. A sterile solution can also be administered intravenously. A composition for oral administration can be liquid or solid.

[0510] Preferably, the pharmaceutical composition is in a unit dosage form, such as a tablet, capsule, powder, solution, suspension, emulsion, granule or suppository. In such dosage forms, the pharmaceutical composition can be subdivided into unit doses (single or plural) containing an appropriate amount of the compound. The unit dosage form can be a packaged composition, such as a packet powder, vial, ampoule, filled syringe or liquid-containing sachet. Alternatively, the unit dosage form can be the capsule or tablet itself, or an appropriate number of any such compositions in a packaged form. Such unit dosage forms can contain from about 1 mg / kg to about 500 mg / kg of the compound and can be administered in a single dose or in more than one dose. Such doses can be administered in any manner useful for delivering the compound(s) into the bloodstream of the recipient, including orally, by graft, parenterally (including intravenous, intraperitoneal and subcutaneous injection), rectally, vaginally and transdermally.

[0511] When administered for the treatment or prevention of a particular disease state or disorder, the effective dosage will be understood to vary according to the particular compound utilized, the mode of administration, and the severity of the symptoms being treated, as well as various physical factors associated with the individual being treated. In therapeutic applications, the compounds of the present teachings can be supplied to a patient already suffering from the disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a particular individual will generally have to be determined subjectively by the attending physician. Variables involved include the specific symptoms and their condition as well as the physical build, age and response pattern of the patient.

[0512] In some cases, it may be desirable to administer the compounds directly to the patient's airway using devices such as, but not limited to, metered dose inhalers, breath actuated inhalers, multiple dose dry powder inhalers, pumps, squeeze actuated nebulizing dispensers, aerosol dispensers, aerosol sprayers, etc. For administration by intranasal or intratracheal inhalation, the compounds of the present teachings can be formulated into liquid compositions, solid compositions or aerosol compositions. The liquid composition includes, for example, one or more compounds of the present teachings dissolved, partially dissolved or suspended in one or more pharmaceutically acceptable solvents and can be administered, for example, by a pump or a squeeze actuated nebulizing dispenser. The solvent can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, for example, a powder preparation including one or more compounds of the present teachings mixed with lactose or other inert powders acceptable for intratracheal use and can be administered, for example, by an aerosol dispenser, or by breaking or puncturing a capsule enclosing the solid composition and delivering the solid composition by a device for inhalation. The aerosol composition can include, for example, one or more compounds of the present teachings, a propellant, a surfactant, and a co-solvent and can be administered, for example, by a metering device. The propellant can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HFA), or other propellants acceptable physiologically and environmentally.

[0513] The compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or their pharmaceutically acceptable salts, hydrates or esters can be prepared in water appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersion agents can also be prepared in glycerol, liquid polyethylene glycol, and mixtures thereof in oil. Under normal storage and use conditions, these preparations generally include a preservative to inhibit the growth of microorganisms.

[0514] Suitable dosage forms for injection include sterile aqueous solutions or dispersions, and sterile powders for immediately preparing sterile injection solutions or dispersions. In some embodiments, the dosage form can be sterile and can flow through a syringe due to its viscosity. The dosage form is preferably stable under manufacturing and storage conditions and can protect against the contaminating effects of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium including, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0515] In the case of tablet dosage forms, depending on the dose, the drug can constitute 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets generally contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant constitutes 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0516] Binders are generally used to impart cohesiveness to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic rubbers, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets can also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0517] Tablets may optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and fluidizing agents such as silicon dioxide and talc. When present, the surfactant may constitute 0.2% to 5% by weight of the tablet, and the fluidizing agent may constitute 0.2% to 1% by weight of the tablet.

[0518] Tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant generally constitutes 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight. Other possible components include antioxidants, colorants, flavorants, preservatives, and taste modifiers.

[0519] Exemplary tablets contain up to about 80% drug, about 10% to about 90% by weight binder, about 0% to about 85% by weight diluent, about 2% to about 10% by weight disintegrant, and about 0.25% to about 10% by weight lubricant.

[0520] The tablet blend can be compressed directly or with rollers to form tablets. Alternatively, the tablet blend or a portion of the blend can be granulated wet, dry, or by melt granulation, melt solidification, or extrusion prior to tableting. The final formulation can contain one or more layers, can or cannot be coated, and can also be encapsulated. Tablet formulations are discussed in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X).

[0521] The above formulations for the various administrations can be formulated for immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0522] Suitable modified release formulations for the present invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies, such as high energy dispersive and osmotic coated particles, can be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in International Publication No. 00 / 35298.

[0523] The compounds described herein can be administered transdermally, i.e., across the inner wall of the body's ducts, including the body surface, as well as epithelial and mucosal tissues. Such administration can be carried out using the compounds of the present teachings and their pharmaceutically acceptable salts, hydrates or esters in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

[0524] The compounds of the present invention can also be administered directly into the bloodstream, muscle or viscera. Suitable means of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needleless syringes and infusion techniques.

[0525] Parenteral formulations are generally aqueous solutions that can contain excipients such as salts, carbohydrates, buffers (preferably pH 3-9), but for some applications, they are more appropriately formulated as sterile non-aqueous solutions or as dry bodies and used in combination with a suitable vehicle such as sterile water free of pyrogens.

[0526] The preparation of parenteral formulations under aseptic conditions, for example by lyophilization, can be readily carried out using standard pharmaceutical techniques well known to those skilled in the art. The solubility of the compounds of the present disclosure used in the preparation of parenteral solutions can be enhanced by the use of suitable formulation techniques such as the introduction of solubility enhancers.

[0527] The parenteral dosage forms can be formulated for immediate and / or modified release. That is, the compounds of the present invention can be formulated as solids, semi-solids or thixotropic liquids for administration as implantable depots that modify the release of the active compound. Examples of such dosage forms include polymeric polyglycolic acid-lactic acid (PGLA) microspheres.

[0528] Transdermal administration can be effected using a skin patch containing a compound such as a compound disclosed herein and a carrier that can be inert to the compound, can be non-toxic to the skin, and can enable the delivery of the compound for absorption into the bloodstream through the skin. The carrier can take any number of forms such as creams and ointments, pastes, gels, closure devices, etc. Creams and ointments can be water-in-oil or oil-in-water viscous liquids or semi-solid emulsions. Pastes containing absorbent powders dispersed in petrolatum or hydrophilic petrolatum containing the compound can also be suitable. The compound can be released into the bloodstream using various closure devices such as semi-permeable membranes covering reservoirs containing the compound with or without the carrier, matrices containing the compound, etc. Other closure devices are known in the literature. Liposomes can also be used. Typical carriers include alcohols, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol and propylene glycol. It can contain a penetration enhancer [see, for example, Finnin and Morgan, J Pharm Sci, 88(10), 955-958 (October 1999)]. Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and micro-needle or needleless (e.g., Powderject™, Bioject™, etc.) injection.

[0529] The compounds described herein can be administered rectally or vaginally in the form of conventional suppositories. Suppositories can be manufactured from conventional materials including cocoa butter, with or without the addition of waxes that change the melting point of the suppository, and glycerin. Water-soluble suppository bases such as polyethylene glycols of various molecular weights can also be used.

[0530] The compounds of the present teachings can be introduced into host cells in vitro or in vivo using lipid formulations or nanocapsules. Lipid formulations and nanocapsules can be prepared by methods known in the art.

[0531] The compounds of the invention can generally be administered nasally or by inhalation, in the form of dry powder (alone, as a mixture, for example, as a dry blend with lactose, or as mixed component particles mixed with a phospholipid such as phosphatidylcholine, for example) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that generates a fine mist by electrohydrodynamics) or nebulizer, using a suitable propellant such as 1,1,1,2 - tetrafluoroethane, 1,1,1,2,3,3,3 - heptafluoropropane, or without using a propellant. For nasal use, the powder can contain a bioadhesive agent, for example, chitosan or cyclodextrin.

[0532] The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of the compound(s) of the invention, for example, with ethanol, aqueous ethanol solution, or a suitable alternative agent that disperses, solubilizes, or extends the release of the active propellant(s) as a solvent, and an optional surfactant such as sorbitan trioleate, oleic acid, oligolactic acid, etc.

[0533] Before use in dry powder or suspension formulations, the formulation is micronized to a size suitable for inhalation delivery (generally less than 5 microns). [This can be done by any suitable milling method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing, high - pressure homogenization, spray drying, etc. that form nanoparticles.]

[0534] Capsules, blisters and cartridges for inhalers or injectors (e.g., made of gelatin or HPMC) can be formulated to contain a mixed powder of the compounds of the present invention, a suitable powder base such as lactose, starch, etc., and performance modifiers such as l-leucine, mannitol, magnesium stearate, etc. Lactose can be in the anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0535] Suitable solution agents for use in atomizers that generate fine mists by electrohydrodynamics can contain 1 μg to 20 mg of the compounds of the present invention per actuation, and the actuation volume can be 1 μl to 100 μl. Typical formulations can contain a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol. Suitable flavoring agents such as menthol, levomenthol, etc. or sweeteners such as saccharin, sodium saccharin, etc. can be added to the formulations of the present invention for inhalation / intranasal administration.

[0536] Formulations for inhalation / intranasal administration can be formulated to provide immediate and / or modified release, for example using poly(DL-lactic-co-glycolic acid (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release.

[0537] In the case of dry powder inhalers and aerosols, the unit dose is determined by a valve that delivers a fixed quantity. The units according to the present invention are generally prepared to administer a fixed dose that can be administered as a single dose, and more generally are prepared to be administered as divided doses throughout the day.

[0538] The compounds of the present invention can generally be administered directly to the eye or ear in the form of drops of a micronized suspension or solution in isotonic pH-adjusted sterile saline. Other formulations suitable for administration to the eye and ear include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses, and particulate or vesicular systems such as niosomes, liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers such as hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or heteropolysaccharide polymers such as gellan gum can be mixed together with preservatives such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0539] The compounds of the present invention can be combined with soluble macromolecular entities such as cyclodextrins and suitable derivatives thereof, polyethylene glycol-containing polymers, etc. in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the above administration methods.

[0540] For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion compounds can be used. As another method of leading to complex formation with a drug, cyclodextrin can be used as an adjuvant, i.e., a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in WO 91 / 11172, WO 94 / 02518 and WO 98 / 55148.

[0541] To enhance the effectiveness of the compounds of the present teachings, it may be desirable to combine the compounds with another agent effective in treating the target disease. For example, another active compound (i.e., another active ingredient or agent) effective in treating the target disease can be administered together with the compounds of the present teachings. The other agent can be administered simultaneously with, or at a different time than, the compounds disclosed herein.

[0542] The compounds of the present teachings may be useful in treating or preventing pathological conditions or disorders in mammals, such as human subjects. Accordingly, the present teachings provide a method of treating or preventing a pathological condition or disorder by supplying to a mammal a pharmaceutical composition comprising one or more compounds of the present teachings, including pharmaceutically acceptable salts thereof, in combination with or together with a pharmaceutically acceptable carrier. The compounds of the present teachings can be administered alone or in combination with another therapeutically effective compound or therapy for treating or preventing a pathological condition or disorder.

[0543] Non-limiting examples of the compositions according to the present invention include from about 0.001 mg to about 1000 mg of one or more compounds of the disclosure according to the present invention and one or more excipients, from about 0.01 mg to about 100 mg of one or more compounds of the disclosure according to the present invention and one or more excipients, and from about 0.1 mg to about 10 mg of one or more compounds of the disclosure according to the present invention, and one or more excipients.

[0544] In the case of administration to a human patient, for the above-mentioned treatment, the dosage will, of course, vary depending on the compound used, the method of administration, the desired treatment, and the disorder to be treated. For example, oral administration may require a higher total daily dose than intravenous administration. The total daily dose of the compound of formula I or the salt / solvate compound (active ingredient) of the compound of formula II is generally in the range of 1 mg to 1 gram, preferably 1 mg to 250 mg, more preferably 10 mg to 100 mg. The total daily dose can be administered as a single dose or divided doses. The present invention also encompasses sustained-release compositions. These dosages are based on an average human subject weighing approximately 65 kg to 70 kg. A physician can readily determine dosages for subjects outside this weight range, such as infants and the elderly.

[0545] The dosing schedule can be adjusted to obtain the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over a period of time, or the dosage can be increased or decreased proportionally to the urgency of the treatment situation. It is particularly advantageous to formulate parenteral compositions in unit dosage form to facilitate administration and to uniformize the dosage. As used herein, the term "unit dosage form" refers to physically discrete units suitable as unitary dosages for the mammalian subject to be treated, each unit containing a predetermined quantity of the active compound calculated to produce the desired therapeutic effect, together with the necessary pharmaceutical carrier. The specification of the unit dosage forms of the present invention is directly dependent on (a) the particular characteristics of the chemotherapeutic agent and the specific therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compounds to cope with the susceptibility in the individual.

[0546] Therefore, it should be appreciated by those skilled in the art that, based on the disclosure herein, the dosage and dosing schedule are adjusted according to methods well known in the art of therapy. That is, the maximum tolerated dose can be readily set, the effective amount that will give a detectable therapeutic effect to the patient can be determined, and the time requirements for administering each agent that will give a detectable therapeutic effect to the patient can be determined. Accordingly, certain dosages and dosing schedules are exemplified herein, but these examples in no way limit the dosages and dosing schedules that can be provided to a patient in the practice of the present invention.

[0547] It should be noted that the dosage may vary depending on the type and severity of the symptoms to be alleviated and may include single or multiple administrations. Furthermore, for any particular subject, the specific dosing regimen should be adjusted over time according to the individual needs and the professional judgment of the administrator or dispenser of the composition, and it should be understood that the dosage ranges described herein are merely illustrative and do not limit the scope or practice of the composition recited in the claims. For example, the dosage can be adjusted based on pharmacokinetic or pharmacodynamic parameters that may include clinical effects such as toxic effects and / or test values. Thus, the present invention encompasses increases in dosage within a patient determined by one of ordinary skill in the art. The determination of appropriate dosages and dosing regimens for the administration of chemotherapeutic agents is well known in the relevant art and will be achieved by one of ordinary skill in the art after the teachings disclosed herein are provided.

[0548] The pharmaceutical composition of the present invention can be prepared, packaged, or sold in bulk, as a single unit dose, or as multiple single unit doses. As used herein, a "unit dose" is an individual quantity of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient administered to the subject or, for example, to a convenient fraction of such a dosage, such as 1 / 2, 1 / 3, etc.

[0549] The relative amounts of the active ingredient, pharmaceutically acceptable carrier, and any additional active ingredients in the pharmaceutical composition of the present invention vary depending on the type of animal to be treated, the type of disease to be treated, the sex and age of the patient, the size and condition of the subject to be treated, and further depend on the route by which the composition is administered. By way of example, the composition can contain from 0.1% to 100% (w / w) of the active ingredient.

[0550] The compounds of the present disclosure and their isotope-labeled variants are useful, for example, in the diagnosis and / or treatment of diseases involving the formation of tau oligomers, including Alzheimer's disease, amyotrophic lateral sclerosis / Parkinsonism dementia complex, argyrophilic grain dementia, corticobasal degeneration, Creutzfeldt-Jakob disease, boxer dementia / chronic traumatic encephalopathy, diffuse neurofibrillary tangles with calcification, Down syndrome, frontotemporal dementia linked to chromosome 17 with Parkinsonism, Gerstmann-Straussler-Scheinker disease, Hallervorden-Spatz disease, myotonic dystrophy, Niemann-Pick disease type C, non-Guam type motor neuron disease with neurofibrillary tangles, Pick's disease, postencephalitic Parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, and neurofibrillary type dementia. Means for detecting the label are well known to those skilled in the art. For example, an isotope label can be detected using imaging techniques, photographic film, or a scintillation counter. In a preferred embodiment, the label is detected in vivo in the brain of a subject by imaging techniques, such as positron emission tomography (PET).

[0551] The labeled compounds of the present invention preferably contain at least one radionuclide as a label. Positron-emitting radionuclides are all candidates for use. In the context of the present invention, the radionuclide is preferably selected from 11 C,[[]] 13 C,[[]] 14 C,[[]] 18 F,[[]] 15 O,[[]] 13 N,[[]] 32 S,[[]] 2 H and 3 H, more preferably from 11 C and 18 F. The tracer can be selected according to the detection method chosen. Before implementing the method of the present invention, a diagnostically effective amount of the labeled or unlabeled compound of the present invention is administered to a living body including a human. The diagnostically effective amount of the labeled or unlabeled compound of the present invention administered before implementing the in vivo method for the present invention is 0.1 ng to 100 mg / kg body weight, preferably 1 ng to 10 mg / kg body weight.

[0552] Procedure The following procedure can be used to evaluate and select a compound as an inhibitor of tau oligomer formation.

[0553] In Vitro Assay Method A bacterial recombinant human tau 4R2N (the largest isoform of tau in the central nervous system, 441 amino acids in length, SEQ ID NO: 1) construct having a 6X-His or StrepII N-terminal epitope tag was purified from the lysate using denaturing conditions that prepare tau in its monomeric form.

[0554] ALA Assay: The AlphaLisa Assay (ALA) was used as a primary screen to identify compounds that inhibit tau oligomer formation. It is a bead-based assay that generates a signal only when the beads are in proximity to each other. Tau monomers (targets) form higher-order aggregates (dimers, trimers, tetramers, etc.) upon incubation, and when donor and acceptor beads bind to the epitope tag of tau, they come into proximity and generate a signal.

[0555] The tau target (equal mixture of each construct at 300 nM) was prepared in buffer (Tris-HCl pH 7.4) and incubated in a 96-well plate at room temperature for 4 hours with vehicle control (DMSO) and a dose range of the compounds of the present disclosure (0.098 uM to 50 uM). AlphaLisa acceptor beads & donor beads and the ligand of the epitope tag (Perkin Elmer) were diluted in bead buffer (25 mM HEPES pH 7.4, 100 mM NaCl, 0.1% Tween-20) (final 20 ug / mL / bead), added to the wells, and incubated for 1 hour at room temperature. Positive control (target not incubated) & blank (no tau) were prepared, mixed with the beads in bead buffer, and the plate was read immediately using an EnVision plate reader (Perkin Elmer).

[0556] CONFA assay: The Confirmatory Assay (CONFA) was used as a secondary screening to confirm the mechanism of action of the compounds identified as hits using the ALA assay. The assay is performed in a similar procedure as ALA, except that SDS-PAGE is utilized for the visualization and quantification of tau monomers and aggregated species (dimers, trimers, tetramers, pentamers, etc.). Only a single construct of tau without an epitope tag is required, but the assay can also use the same targets prepared in the ALA assay.

[0557] For the CONFA assay, the tau target (300 nM) was prepared in buffer (Tris-HCl pH 7.4) and incubated at room temperature for 3 hours with vehicle control (DMSO) and a range of doses of the compounds of the present disclosure (0.098 uM to 50 uM). Samples were mixed with an equal volume of 2× SDS sample buffer (4% SDS, 20% glycerol, 0.004% bromophenol blue, 125 mM Tris HCl, pH 7.0) and tau monomers and disulfide-bridged oligomers were separated on a 4-20% gradient polyacrylamide gel (Biorad) together with a positive control (tau target that does not form oligomers). The gel was stained with Oriole Fluorescent Gel Stain (BioRad) and imaged using a FluorChem R system (Protein Simple). AlphaView software (Protein Simple) was used for quantification of tau monomers and oligomers.

[0558] Data for compounds soluble in the test solutions described herein are shown in Table 3.

[0559] Table 3

Table 4

[0560] The appropriate daily dose of the compounds for the treatment of humans was about 0.01 to 100 mg / kg body weight for oral administration and 0.001 to 100 mg / kg body weight for parenteral administration. However, for any pharmaceutical composition used in the present invention, the therapeutically effective amount can first be estimated from animal models. Then, the dose-response curve derived from the animal system is used to determine the test doses for the initial clinical trials in humans. In the safety assessment of each composition, the dose and frequency of administration should match or exceed what is predicted for use in clinical trials.

[0561] Other factors to be considered are the conditions of the patient or subject animal, such as the administration procedure, age, weight, sex, sensitivity, diet, administration period, concomitant drugs, and severity of the disease. The appropriate dosage and administration time under certain conditions can be determined by tests based on the above indices, but can be refined and finally determined according to the judgment of the practitioner and the situation of each patient (age, general condition, severity of symptoms, sex, etc.) in accordance with standard clinical techniques.

[0562] The toxicity and therapeutic efficacy of the compositions of the present invention can be determined by standard pharmaceutical procedures in experimental animals, for example, by measuring the LD50 (the dose lethal to 50% of the population) and the ED50 (the therapeutically effective dose for 50% of the population). The dose ratio of the therapeutic effect to the toxic effect is the therapeutic index, which can be expressed as the ratio of ED50 / LD50. Compositions showing a high therapeutic index are preferred.

[0563] The treatment period can be short-term, for example, several weeks (e.g., 10 - 14 weeks), or long-term until the attending physician determines that further administration is no longer necessary to obtain benefits.

Claims

Claim 1 A compound selected from the group consisting of a compound of formula (I), 【Chemical 1】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein R １ａ is hydrogen, and R １ｂ is selected from the group consisting of hydrogen, methoxypyridine, chloropyridine, pyridine, hydroxyphenyl, methoxyphenyl, thiophene, and bromo, R １ｃ is selected from the group consisting of hydrogen, pyridine, methoxypyridine, pyrimidine and bromine, Halogen, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Haloalkyl and C １～６ each independently selected from the group consisting of haloalkoxy, R １ｄ is hydrogen, and R １ｂ When R is hydrogen, １ｃ R is not hydrogen, R １ｃ When R is hydrogen, １ｂ R is not hydrogen, R ２ is selected from the group consisting of methylfuran, chlorothiophene, trilethyl, tolyl, fluorophenyl, and C5 alkyl, X is oxygen, wherein, R ５ is C １～６ alkyl, Y is 【Chemical 2】 and optionally selected from the group consisting of substituted 2 - benzimidazole, wherein, R ６ is methyl or hydroxypiperidine, R ７ａ is hydrogen, and R ７ｂ is a trill A pharmaceutical composition for inhibiting the formation of tau oligomers containing the compound.

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