Novel quinazolinones that inhibit the formation of tau oligomers and methods of using the same

Abstract

Compounds are provided for treating or preventing diseases or conditions involving the formation of tau oligomers, such as Alzheimer's disease, amyotrophic lateral sclerosis / parkinsonism dementia complex, and the like. For example, compounds of formula (II) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes. TIFF2023055767000192.tif28169 [In the formula, R 1 is hydrogen, C 1~6 Alkyl, branched C 3~7 is selected from the group consisting of alkyl, aryl, and heteroaryl; R 2 is selected from the group consisting of aryl and heteroaryl; R 3a , R 3b , R 3c and R 3d is hydrogen, halogen, C 1~6 Alkyl, C 1~6 and the like.]

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 appropriate conditions defined by 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.

[0002] The present invention relates to novel quinazolinones useful as inhibitors of tau oligomer formation, which are useful for the treatment of neurodegenerative diseases and related symptoms. 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 comprising 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 symptoms.

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 the aging population, and ending AD would save an estimated 500,000 lives 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. To date, most late-stage drug development activities in Alzheimer's disease have focused on targeting the amyloid cascade hypothesis. The main premise of this hypothesis is that it is the pathological accumulation of amyloid-β, a peptide fragment of a membrane protein called amyloid precursor protein, which acts as the underlying cause of AD and triggers its lesion formation. Recent data do not support this mechanism. It is clear that another approach is needed for the development of AD therapies, as all previous phase 3 drug development programs based on the amyloid hypothesis have failed to meet their clinical endpoints. (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 loss 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 in a mouse model that recapitulates the spread of tau pathology in AD (Non-Patent Document 10). Oligomerix has 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 verified in htau by treatment with curcumin (Non-Patent Document 12) and by a passive immunotherapy approach against tau oligomers (Non-Patent Document 13).

[0005] The diffusion 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 research, tau aggregates, especially 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 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 available for inhibiting tau oligomer formation or useful for treating neurodegenerative diseases and related symptoms.

[0007] There has been a long-standing need for new therapies that are disease-modifying and useful for treating Alzheimer's disease (AD) symptoms and that inhibit the formation of tau oligomers. The present invention addresses the need for inhibiting the formation of tau oligomers, which is useful for treating 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, 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-Sträussler-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, 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, A is

[0012]

Chemical Formula

[0013] selected from the group consisting of R 1 is hydrogen, optionally substituted C 1~6 alkyl, optionally substituted branched C 3~7 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, selected from the group consisting of R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, R 3a , R 3b , R 3c and R 3d are hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, -C(O)NR 4a R 4b , -NR 5 COR 6, each independently selected from the group consisting of aryl and heteroaryl, R 4a and R 4ab are each independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 5 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 6 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[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] wherein R 1 , R 2 , R 3a , R 3b , R 3c and R 3d are as defined for the compounds of formula (I).

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

[0018]

Chemical formula

[0019] wherein R 1 , R 2 , R 3a , R 3b , R 3c and R 3d are as defined for the compounds of formula (I), X is selected from the group consisting of CH and N, R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 ; R 8 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0020]

Chemical formula

[0021] , (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 1~6 alkyl, and (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 3~7 cycloalkyl, independently selected from the group consisting of; R 9 is hydrogen, C 1~6 alkyl and COR 10 ; R 10 is selected from the group consisting of hydrogen and C 1~6 alkyl; R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1~6 alkyl; n is 1, 2 or 3; m is 1 or 2.

[0022] The compounds of the present invention include the compounds of formula (III) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0023]

Chemical formula

[0024] Wherein, R 1 , R 2 , R 3a , R 3b and R 3c are as defined for the compounds of formula (I).

[0025] The compounds of the present invention include the compounds of formula (IIIa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0026]

Chemical formula

[0027] Wherein X is selected from the group consisting of CH and N, R 1 , R 3a , R 3b , R 3c and R 3d are as defined for the compounds of formula (I), R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 , R 8 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0028]

Chemical formula

[0029] , (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 1~6 alkyl, and (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 3~7Independently selected from the group consisting of cycloalkyl, R 9 is hydrogen, C 1~6 alkyl and COR 10 selected from the group consisting of, R 10 is hydrogen and C 1~6 selected from the group consisting of alkyl, R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, n is 1, 2 or 3, m is 1 or 2.

[0030] The compounds of the present invention include the compounds of formula (IV) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0031]

Chemical formula

[0032] wherein R 1 , R 2 , R 3a , R 3b and R 3c are as defined for the compounds of formula (I).

[0033] The compounds of the present invention include the compounds of formula (IVa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0034]

Chemical formula

[0035] wherein, X is selected from the group consisting of CH and N, R 1 , R 3a , R 3b and R 3cis as defined for the compound of formula (I), R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 and, R 8 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0036]

Chemical formula

[0037] , (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 1~6 alkyl, and (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 3~7 cycloalkyl, independently selected from the group consisting of, R 9 is hydrogen, C 1~6 alkyl and COR 10 selected from the group consisting of, R 10 is hydrogen and C 1~6 alkyl selected from the group consisting of, R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, n is 1, 2 or 3, m is 1 or 2.

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

[0039]

Chemical formula

[0040] The compounds of the present invention include compounds of formula (Va) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0041]

Chemical formula

[0042] wherein X is selected from the group consisting of CH and N, R 1 、R 2 、R 3a 、R 3b and R 3c are as defined for the compounds of formula (I), R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 ; R 8 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0043]

Chemical formula

[0044] 、(OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 1~6 alkyl, and (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 3~7 cycloalkyl, independently selected from the group consisting of; R 9 is selected from the group consisting of hydrogen, C 1~6 alkyl and COR 10 ; R 10 is hydrogen and C1~6 selected from the group consisting of alkyl, R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, n is 1, 2 or 3, m is 1 or 2.

[0045] The compounds of the present invention include the compounds of formula (VI) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0046]

Chemical formula

[0047] wherein, R 1 , R 2 , R 3a , R 3b and R 3c are as defined for the compounds of formula (I).

[0048] The compounds of the present invention include the compounds of formula (VIa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0049]

Chemical formula

[0050] wherein, X is selected from the group consisting of CH and N, R 1 , R 3a , R 3b and R 3c are as defined for the compounds of formula (I), R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 , R 8is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0051]

Chemical formula

[0052] , (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 1~6 alkyl, and (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 3~7 cycloalkyl, independently selected from the group consisting of, R 9 is hydrogen, C 1~6 alkyl and COR 10 selected from the group consisting of, R 10 is hydrogen and C 1~6 alkyl selected from the group consisting of, R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, n is 1, 2 or 3, m is 1 or 2.

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

[0054]

Chemical formula

[0055] wherein, R 1 , R 2 , R 3a and R 3bis as defined for the compound of formula (I).

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

[0057] [Chemical formula]

[0058] wherein X is selected from the group consisting of CH and N, R 1 , R 3a and R 3b are as defined for the compound of formula (I), R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 , R 8 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0059] [Chemical formula]

[0060] , (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 1~6 alkyl, and (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 3~7 cycloalkyl, independently selected from the group consisting of R 9 is hydrogen, C 1~6 alkyl and COR 10 , selected from the group consisting of R 10 is hydrogen and C1~6 selected from the group consisting of alkyl, R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, n is 1, 2 or 3, m is 1 or 2.

[0061] The compounds of the present invention include compounds of formula (VIII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0062]

Chemical formula

[0063] wherein, R 1 , R 2 , R 3a and R 3b are as defined for the compounds of formula (I).

[0064] The compounds of the present invention include compounds of formula (VIIIa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0065]

Chemical formula

[0066] wherein, X is selected from the group consisting of CH and N, R 1 , R 3a and R 3b are as defined for the compounds of formula (I), R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 , R 8is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0067]

Chemical formula

[0068] , (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 1~6 alkyl, and (OH, C 1~6 alkoxy and NR 11a R 11b )-optionally substituted C 3~7 cycloalkyl, independently selected from the group consisting of, R 9 is hydrogen, C 1~6 alkyl and COR 10 selected from the group consisting of, R 10 is hydrogen and C 1~6 alkyl selected from the group consisting of, R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, n is 1, 2 or 3, m is 1 or 2.

[0069] The present invention also relates to a pharmaceutical composition comprising an effective amount of one or more compounds according to the present invention and a pharmaceutically acceptable carrier.

[0070] The present invention also relates to a method for treating or preventing diseases including the formation of tau oligomers, such as 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, the method comprising administering an effective amount of a compound or composition according to the present invention to a subject in need of such treatment or prevention.

[0071] The present invention also relates to a method for treating or preventing diseases including the formation of tau oligomers, such as 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, the method comprising administering a composition comprising an effective amount of one or more compounds according to the present invention and a pharmaceutically acceptable carrier to a subject.

[0072] The present invention also relates to a method for treating or preventing a disease or condition associated with 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 diseases or conditions related to neurofibrillary type dementia and the formation of tau oligomers. The method includes administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition according to the present invention.

[0073] The present invention further relates to a method for treating or preventing a disease or condition associated with 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 diseases or conditions related to neurofibrillary type dementia and the formation of tau oligomers, the method including administering to a subject in need of such treatment or prevention a pharmaceutical composition comprising an effective amount of one or more compounds according to the present invention and a pharmaceutically acceptable carrier.

[0074] The present invention also relates to a method for treating or preventing a disease or condition associated with the formation of tau oligomers. The method comprises administering to a subject in need of such treatment or prevention an effective amount of a compound or composition according to the present invention.

[0075] 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 in need of such treatment or prevention a composition comprising an effective amount of one or more compounds according to the present invention and a pharmaceutically acceptable carrier.

[0076] The present invention relates to, 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 type CA method for treating or preventing diseases including the formation of tau oligomers, 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, the method comprising administering an effective amount of a compound or composition according to the present invention, and 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-phenserine), 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, and other compounds known to be clinically relevant to Alzheimer's disease.

[0077] 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, post-encephalitic 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.

[0078] The present invention further relates to a process for preparing an inhibitor of tau oligomer formation according to the present invention.

[0079] These and other objects, features, and advantages should become apparent to those skilled in the art by reading the following detailed description and the appended claims. All percentages, ratios, and proportions in this specification 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 document should be construed as an admission that it is prior art relevant to the present invention.

Brief Description of the Drawings

[0080]

Figure 1

Mode for Carrying Out the Invention

[0081] The inhibitor of tau oligomer formation of the present invention can treat and prevent diseases related to 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, reduce, or otherwise control diseases related to the formation of tau oligomers.

[0082] Throughout the 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 the composition of the present disclosure consists essentially of, or consists of, the recited components, and it is also contemplated that the process of the present disclosure consists essentially of, or consists of, the recited processing steps.

[0083] 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.

[0084] The use of the singular form in this specification includes the plural (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.

[0085] It should be understood that the order of steps or the order of performing an operation is not important as long as the present teachings can be implemented. Further, two or more steps or operations can be executed simultaneously.

[0086] In this specification, the term "halogen" shall mean chlorine, bromine, fluorine and iodine. The term "halo" shall mean the substituents chloro, bromo, fluoro and iodo.

[0087] 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 ) independently refers 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 the case of a substituent having a plurality of alkyl groups such as amino, the alkyl groups may be the same or different.

[0088] 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 2 to 20 carbon atoms. An alkenyl chain has at least one double bond in the chain, and an alkynyl chain has at least one triple bond in the chain. Alkenyl and alkynyl groups can be optionally 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.

[0089] As used herein, "cycloalkyl", whether used alone or as part of another group, refers to, for example, a non-aromatic carbon-containing ring including cycloalkyl, alkenyl and alkynyl groups 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 including one or more (e.g., 1, 2 or 3) double or triple bonds. 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.

[0090] "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.

[0091] 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 1 oxygen atom (e.g., tetrahydrofuran, tetrahydro-2H-pyran). C 3 ~C 6 The cyclic alkoxy group can optionally be substituted.

[0092] 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.

[0093] 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.

[0094] 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, 1 to 5 of which 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.

[0095] 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.

[0096] The term "heteroaryl", whether used alone or as part of another group, is defined herein as one or more rings having 5 to 20 atoms, with at least one atom in at least one of the rings being a heteroatom selected from nitrogen (N), oxygen (O), or sulfur (S), and further, at least one of the rings containing the heteroatom is aromatic. In a heteroaryl group containing two or more fused rings, a ring having no heteroatom 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 5 to 14 ring atoms and contain 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-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7-tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, 8-hydroxy-quinolinyl, and isoquinolinyl.

[0097] One non-limiting example of the above-mentioned heteroaryl group is a 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.

[0098] 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.

[0099] In the present invention, a fused ring unit, 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.

[0100]

Chemical formula

[0101] In the present invention, the 6,7-dihydro-5H-cyclopenta[4,5]pyrimidine having the following formula is considered a heteroaryl unit.

[0102] [Chemical formula]

[0103] When the fused ring unit contains heteroatoms in both the saturated ring and the 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.

[0104] [Chemical formula]

[0105] 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".

[0106] 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. A substituent 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 replacement include halogen, hydroxyl, etc. Substitutions of two hydrogen atoms include carbonyl, oxyimino, etc. Substitutions of two hydrogen atoms from adjacent carbon atoms include epoxy, etc. The term "substituted" is used throughout the specification to indicate that a moiety can have one or more hydrogen atoms replaced with a substituent. When a moiety is described as "substituted", any number of hydrogen atoms can be replaced. 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.

[0107] 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.

[0108] 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 11 , -SR 11, -N(R 11 ) 2 , -NR 11 C(O)R 11 , -SO 2 R 11 , -SO 2 OR 11 , -SO 2 N(R 11 ) 2 , -C(O)R 11 , -C(O)OR 11 , -C(O)N(R 11 ) 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 11 , and R 11 is, independently of each other, hydrogen, -OR 12 , -SR 12 , -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 ) 2 , -SO 2 R 12 , -S(O) 2 OR 12 , -N(R 12 ) 2 , -NR 12 C(O)R 12 , 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 11The 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 12 each, independently, is 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 12 units, together with the atom(s) to which they are attached, optionally form a substituted carbocyclic or heterocyclic ring, preferably having 3 to 7 ring atoms.

[0109] In some embodiments, the substituent is i) -OR 13 such as, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , ii) -C(O)R 13 such as, -COCH 3 , -COCH 2 CH 3 , -COCH 2 CH 2 CH 3 , iii) -C(O)OR 13 such as, -CO 2 CH 3 , -CO 2 CH 2 CH 3 , -CO 2 CH 2 CH 2 CH 3 , iv) -C(O)N(R 13 ) 2 such as, -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , v) -N(R 13 ) 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 , where 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 13 , 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 13 )C(O)R 13 , xiii) oxo (=O), xiv) heterocyclic ring, and xv) heteroaryl selected from, each R 13 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 R13 The units can together form a ring containing 3 to 7 ring atoms. In certain embodiments, each R 13 is independently hydrogen, halogen, or optionally substituted C 1 -C 6 linear or branched alkyl or C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkyl.

[0110] At various places in this specification, substituents of compounds are shown in groups or ranges. It is specifically intended that the text include each and every individual subcombination 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.

[0111] 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.

[0112] 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. 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, tautomeric isomerism ("tautomerism") can occur. Thus, a single compound may exhibit more than one type of isomerism.

[0113] 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 thereof, are included within the scope of the compounds of the present disclosure. Further included are acid addition or base salts in which the counterion is optically active, e.g., D-lactate or L-lysine, or racemic, e.g., DL-tartrate or DL-arginine.

[0114] 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, borneol sulfonic 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, borneol sulfonic 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).

[0115] Pharmaceutically acceptable salts of the compounds of formula (I) can be readily prepared by appropriately mixing a solution of the compound 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.

[0116] The compounds of the present invention can exist in either a non-solvated form or a solvated form. 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.

[0117] 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 compound can also exist as a complex of a drug containing two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complex 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.

[0118] 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, e.g., by hydrolysis, into compounds 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, e.g., 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) or 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) or 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) or its amide, for example, substitution of one or both hydrogens by (C 1 ~C 10 )alkanoyl. [Further examples of substituents related to the above examples and 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.

[0119] The present invention includes all pharmaceutically acceptable isotope-labeled compounds of the present 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.

[0120] 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 and isotopes of sulfur such as

[0121] Certain isotope-labeled compounds of the present disclosure, for example, isotope-labeled compounds incorporating a radioisotope, are useful in the study of drug and / or substrate tissue distribution. The radioisotope 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.

[0122] 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.

[0123] 11 C, 18 F, 15 O, 13Substitution with a positron-emitting isotope such as N is useful for positron emission tomography (PET) studies to examine substrate receptor occupancy and may be useful as a diagnostic agent in patients and animals.

[0124] The isotope-labeled compounds of the present disclosure can generally be prepared by a process similar to that 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.

[0125] 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.

[0126] As used herein, the terms "treating," "treatment," and "treat" refer to partially or completely alleviating, preventing, ameliorating, and / or relieving a suspected symptomatic condition with which a patient is afflicted.

[0127] As used herein, "therapeutically effective" and "effective amount" refer to a substance or amount that induces a desired biological activity or effect.

[0128] Unless otherwise stated, the term "subject" or "patient" is used interchangeably and refers to human patients, mammals such as non-human primates, and experimental animals such as rabbits, rats, mice, and other animals. Thus, as used herein, the term "subject" or "patient" refers to any mammalian patient or subject to which the compounds of the present invention can be administered. In an exemplary embodiment of the present invention, to identify patients for treatment with the methods of the present invention, accepted screening methods are used to determine risk factors associated with the 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 workups to determine risk factors that may be associated with the target or suspected disease or condition. These and other routine methods allow the clinician to select patients who require therapy with the methods and compounds of the present invention.

[0129] One embodiment of the present invention includes compounds of formula (IX) and their enantiomers, diastereomers, hydrates, solvates, pharma- ceutically acceptable salts, and complexes.

[0130] [ka]

[0131] During the ceremony, R 1 , R 2 , R 3a , R 3b , R 3c and R 3d is hydrogen, optionally substituted C 1~6 Alkyl, optionally substituted branched C 3~7 selected from the group consisting of alkyl, optionally substituted aryl, and optionally substituted heteroaryl; R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R 3a , R 3b , R3c and R 3d is each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, -C(O)NR 4a R 4b , -NR 5 COR 6 , aryl and heteroaryl, R 4a and R 4ab is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 5 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 6 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0132] Another embodiment of the present invention includes compounds of formula (IXa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0133]

Chemical formula

[0134] Wherein, X is selected from the group consisting of CH and N, R 1 is selected from the group consisting of hydrogen, optionally substituted C 1~6 alkyl, optionally substituted branched C 3~7 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, R 3a , R 3b , R 3c and R 3d is hydrogen, halogen, C 1~6 alkyl, C1~6 Alkoxy, -C(O)NR 4a R 4b , -NR 5 COR 6 each independently selected from the group consisting of aryl and heteroaryl, R 4a and R 4ab are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 5 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 6 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 from the group consisting of, R 8 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0135]

Chemical formula

[0136] , (OH, C 1~6 alkoxy and NR 11a R 11b ) optionally substituted C 1~6 alkyl, and (OH, C 1~6 alkoxy and NR 11a R 11b ) optionally substituted C 3~7 cycloalkyl independently selected from the group consisting of, R 9 is selected from the group consisting of hydrogen, C 1~6 alkyl and COR 10 from the group consisting of, R 10 is selected from the group consisting of hydrogen and C 1~6 alkyl, R 11a and R11b is independently selected from the group consisting of hydrogen and C 1~6 alkyl, n is 1, 2 or 3, and m is 1 or 2.

[0137] Another embodiment of the present invention includes compounds of formula (X) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0138]

Chemical formula

[0139] wherein R 1 is hydrogen, optionally substituted C 1~6 alkyl, optionally substituted branched C 3~7 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, R 3a and R 3b are each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, -C(O)NR 4a R 4b -, -NR 5 COR 6 -, aryl and heteroaryl, R 4a and R 4b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 5 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 6 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0140] Another embodiment of the present invention includes compounds of formula (Xa) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0141]

Chemical formula

[0142] wherein X is selected from the group consisting of CH and N, R 1 is selected from the group consisting of hydrogen, optionally substituted C 1~6 alkyl, optionally substituted branched C 3~7 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, and R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, R 3a , R 3b are each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, -C(O)NR 4a R 4b , -NR 5 COR 6 , aryl, and heteroaryl, R 4a and R 4ab are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 5 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 6 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 , R 8is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0143]

Chemical formula

[0144] , OH, C 1~6 alkoxy and NR 11a R 11b- optionally substituted with a group selected from C 1~6 alkyl, and OH, C 1~6 alkoxy and NR 11a R 11b optionally substituted with a group selected from C 3~7 cycloalkyl, independently selected from the group consisting of, R 9 is hydrogen, C 1~6 alkyl and COR 10 selected from the group consisting of, R 10 is hydrogen and C 1~6 alkyl selected from the group consisting of, R 11a and R 11b are independently selected from the group consisting of hydrogen and C 1~6 alkyl, n is 1, 2 or 3, and m is 1 or 2.

[0145] Another embodiment of the present invention includes compounds of formula (XI) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0146]

Chemical formula

[0147] wherein, X is selected from the group consisting of CH and N, R 1 is hydrogen, optionally substituted C 1~6 alkyl, optionally substituted branched C 3~7Selected from the group consisting of alkyl, optionally substituted aryl, and optionally substituted heteroaryl, R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, R 3a , R 3b , R 3c and R 3d are each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, -C(O)NR 4a R 4b , -NR 5 COR 6 , aryl and heteroaryl, R 4a and R 4ab are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 5 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 6 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 7 is independently selected from the group consisting of hydrogen and NR 5 COR 8 , R 8 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0148]

Chemical Formula

[0149] , (OH, C 1~6 alkoxy and NR 11a R 11b )-substituted C 1~6 alkyl, and (OH, C 1~6 alkoxy and NR 11a R 11bC optionally substituted with a group selected from 3~7 independently selected from the group consisting of cycloalkyl, R 9 is hydrogen, C 1~6 alkyl and COR 10 selected from the group consisting of R 10 is hydrogen and C 1~6 alkyl selected from the group consisting of R 11a and R 11b are each independently selected from hydrogen and C 1~6 alkyl, n is 1, 2 or 3, and m is 1 or 2.

[0150] Another embodiment of the present invention includes compounds of formula (XII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0151]

Chemical formula

[0152] wherein R 1 is hydrogen, optionally substituted C 1~6 alkyl, optionally substituted branched C 3~7 alkyl, optionally substituted aryl, and optionally substituted heteroaryl selected from the group consisting of R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, R 3a , R 3b is each independently selected from hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, -C(O)NR 4a R 4b , -NR 5 COR 6 , aryl and heteroaryl, R 4a and R4ab is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 5 is independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 6 is independently selected from the group consisting of hydrogen and C 1~6 alkyl.

[0153] Another embodiment of the present invention includes compounds of formula (XIII) and their enantiomers, diastereomers, hydrates, solvates, pharmaceutically acceptable salts, and complexes.

[0154]

Chemical formula

[0155] wherein X is selected from the group consisting of CH and N, R 1 is hydrogen, optionally substituted C 1~6 alkyl, optionally substituted branched C 3~7 alkyl, optionally substituted aryl, and optionally substituted heteroaryl, R 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, R 3a and R 3b are each independently selected from the group consisting of hydrogen, halogen, C 1~6 alkyl, C 1~6 alkoxy, -C(O)NR 4a R 4b -, -NR 5 COR 6 -, aryl, and heteroaryl, R 4a and R 4ab are independently selected from the group consisting of hydrogen and C 1~6 alkyl, R 5 is hydrogen and C 1~6Independently selected from the group consisting of alkyl, R 6 is hydrogen and C 1~6 Independently selected from the group consisting of alkyl, R 7 is hydrogen and NR 5 COR 8 Independently selected from the group consisting of, R 8 is hydrogen, optionally substituted aryl, optionally substituted heteroaryl,

[0156]

Chemical formula

[0157] , OH, C 1~6 alkoxy and NR 11a R 11b- Optionally substituted C with a group selected from 1~6 alkyl, and OH, C 1~6 alkoxy and NR 11a R 11b Optionally substituted C with a group selected from 3~7 cycloalkyl, independently selected from the group consisting of, R 9 is hydrogen, C 1~6 alkyl and COR 10 Selected from the group consisting of, R 10 is hydrogen and C 1~6 alkyl selected from the group consisting of, R 11a and R 11b is hydrogen and C 1~6 alkyl independently selected from the group consisting of, n is 1, 2 or 3, and m is 1 or 2.

[0158] In some embodiments, A is

[0159]

Chemical formula

[0160] It is. In some embodiments, A is

[0161]

Chemical formula

[0162] It is. In some embodiments, A is

[0163]

Chemical formula

[0164] It is. In some embodiments, A is

[0165]

Chemical formula

[0166] It is. In some embodiments, A is

[0167]

Chemical formula

[0168] It is. In some embodiments, A is

[0169]

Chemical formula

[0170] It is. In some embodiments, A is

[0171]

Chemical formula

[0172] It is. In some embodiments, R 1 is hydrogen.

[0173] In some embodiments, R 1 is optionally substituted C 1~6 alkyl.

[0174] In some embodiments, R 1 is optionally substituted C 3~7 branched alkyl.

[0175] In some embodiments, R 1 is optionally substituted aryl.

[0176] In some embodiments, R 1 is optionally substituted heteroaryl.

[0177] In some embodiments, R 2 is optionally substituted aryl.

[0178] In some embodiments, R 2 is optionally substituted heteroaryl.

[0179] In some embodiments, R 3a is hydrogen.

[0180] In some embodiments, R 3a is halogen.

[0181] In some embodiments, R 3a is C 1~6 alkyl.

[0182] In some embodiments, R 3a is C 1~6 alkoxy.

[0183] In some embodiments, R3a is -C(O)NR 4a R 4b is.

[0184] In some embodiments, R 3a is -NR 5 COR 6 is.

[0185] In some embodiments, R 3a is aryl.

[0186] In some embodiments, R 3a is heteroaryl.

[0187] In some embodiments, R 3b is hydrogen.

[0188] In some embodiments, R 3b is halogen.

[0189] In some embodiments, R 3b is C 1~6 alkyl.

[0190] In some embodiments, R 3b is C 1~6 alkoxy.

[0191] In some embodiments, R 3b is -C(O)NR 4a R 4b is.

[0192] In some embodiments, R 3b is -NR 5 COR 6 is.

[0193] In some embodiments, R 3b is aryl.

[0194] In some embodiments, R 3b is heteroaryl.

[0195] In some embodiments, R 3c is hydrogen.

[0196] In some embodiments, R 3c is halogen.

[0197] In some embodiments, R 3c is C 1~6 alkyl.

[0198] In some embodiments, R 3c is C 1~6 alkoxy.

[0199] In some embodiments, R 3c is -C(O)NR 4a R 4b wherein.

[0200] In some embodiments, R 3c is -NR 5 COR 6 wherein.

[0201] In some embodiments, R 3c is aryl.

[0202] In some embodiments, R 3c is heteroaryl.

[0203] In some embodiments, R 3d is hydrogen.

[0204] In some embodiments, R 3d is halogen.

[0205] In some embodiments, R 3d is C 1~6 alkyl.

[0206] In some embodiments, R 3d is C1~6 is an alkoxy group.

[0207] In some embodiments, R 3d is -C(O)NR 4a R 4b wherein.

[0208] In some embodiments, R 3d is -NR 5 COR 6 wherein.

[0209] In some embodiments, R 3d is aryl.

[0210] In some embodiments, R 3d is heteroaryl.

[0211] In some embodiments, R 4a is hydrogen.

[0212] In some embodiments, R 4a is C 1~6 alkyl.

[0213] In some embodiments, R 4b is hydrogen.

[0214] In some embodiments, R 4b is C 1~6 alkyl.

[0215] In some embodiments, R 5 is hydrogen.

[0216] In some embodiments, R 5 is C 1~6 alkyl.

[0217] In some embodiments, R 6 is hydrogen.

[0218] In some embodiments, R6 is C 1~6 alkyl.

[0219] In some embodiments, X is CH.

[0220] In some embodiments, X is N.

[0221] In some embodiments, R 7 is hydrogen.

[0222] In some embodiments, R 7 is NR 5 COR 8 wherein.

[0223] In some embodiments, R 8 is hydrogen.

[0224] In some embodiments, R 8 is optionally substituted aryl.

[0225] In some embodiments, R 8 is optionally substituted heteroaryl.

[0226] In some embodiments, R 8 is

[0227]

Chemical formula

[0228] wherein. In some embodiments, R 8 is C optionally substituted with a group selected from OH, C 1~6 alkoxy and NR 11a R 11b alkyl. 1~6 In some embodiments, R

[0229] is C optionally substituted with a group selected from OH, C 8 is OH, C1~6 Alkoxy and NR 11a R 11b is C optionally substituted with a group selected from 3~7 cycloalkyl.

[0230] In some embodiments, R 9 is hydrogen.

[0231] In some embodiments, R 9 is C 1~6 alkyl.

[0232] In some embodiments, R 9 is COR 10 .

[0233] In some embodiments, R 10 is hydrogen.

[0234] In some embodiments, R 10 is C 1~6 alkyl.

[0235] In some embodiments, R 11a is hydrogen.

[0236] In some embodiments, R 11a is C 1~6 alkyl.

[0237] In some embodiments, R 11b is hydrogen.

[0238] In some embodiments, R 11b is C 1~6 alkyl.

[0239] In some embodiments, n is 1.

[0240] In some embodiments, n is 2.

[0241] In some embodiments, n is 3.

[0242] In some embodiments, m is 1.

[0243] In some embodiments, m is 2.

[0244] Exemplary non-limiting embodiments of the present invention include the compounds of Tables 1, 2, and 3.

[0245]

Chemical formula

[0246]

Table 1

[0247]

Chemical formula

[0248]

Table 2

[0249]

Chemical formula

[0250]

Table 3

[0251] 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 3-(2-ethylnaphthalen-6-yl)-2-(pyridin-3-yl)quinazolin-4(3H)-one.

[0252]

Chemical formula

[0253] In the present invention, a compound represented in a racemic form equally represents either two enantiomers or a mixture thereof, and in the case where a second chiral center exists, equally represents all diastereomers.

[0254] 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.

[0255] Process The compounds of the present teachings can be prepared from commercially available starting materials, compounds known from 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 is to 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 be used unless otherwise stated. Optimal reaction conditions can vary depending on the particular 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.

[0256] The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be by nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), spectroscopic means such as infrared spectroscopy, spectrophotometry (e.g., ultraviolet-visible), mass spectrometry, or chromatography such as high pressure liquid chromatography (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), thin layer chromatography (TLC), etc. can be used for monitoring.

[0257] The preparation of the 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 those skilled in the art. The chemical properties of the 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.

[0258] The reactions or processes described herein can be carried out in a suitable solvent that can be readily selected by those skilled in the art of organic synthesis. A suitable solvent is 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 be in the range of 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 stage, a solvent appropriate for the particular reaction stage can be selected.

[0259] 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.

[0260] General Synthetic Scheme for the Preparation of Compounds 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 the genus can be prepared by one of the following reaction schemes.

[0261] Compounds of formula (I) can be prepared according to the process outlined in Scheme 1-x.

[0262]

Chemical formula

[0263] Thus, an appropriately substituted compound of formula (1), a known compound, or a compound prepared by a known method, either as such or in the presence of sodium bisulfite, N-ethyl-pyridinium tetrafluoroborate, copper chloride or sodium bisulfite, in the presence of a solvent such as N,N-dimethylacetamide, ethanol, water, nitrobenzene, dioxane, tetrahydrofuran, etc., optionally heated and optionally by microwave irradiation, reacts with an appropriately substituted compound of formula (2), a known compound, or a compound prepared by a known method to produce a compound of formula (3).

[0264]

Chemical formula

[0265] The appropriately substituted compound of formula (4), a known compound, or a compound prepared by a known method reacts, 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, and optionally with heating and optionally by microwave irradiation, with the compound of formula (5), a known compound, or a compound prepared by a known method to produce the compound of formula (6). The compound of formula (6) reacts in a solvent such as trifluoroacetic acid (abbreviated as TFA), hydrochloric acid (abbreviated as HCl), methylene chloride (CH 2 Cl 2 ), 1,2-dichloroethane, tetrahydrofuran, 1,4-dioxane to produce the compound of formula (7). The compound of formula (7) reacts, as it is or in the presence of sodium bisulfite, N-ethyl-pyridinium tetrafluoroborate, copper chloride or sodium bisulfite, in the presence of a solvent such as N,N-dimethylacetamide, ethanol, water, nitrobenzene, dioxane, tetrahydrofuran, and optionally with heating and optionally by microwave irradiation, with the appropriately substituted compound of formula (2), a known compound, or a compound prepared by a known method to produce the compound of formula (9).

[0266] [Chemical formula]

[0267] The compound appropriately substituted in formula (10), a known compound, or a compound prepared by a known method reacts with an acid such as hydrochloric acid, hydrobromic acid, trifluoroacetic acid, etc. in the presence of a solvent such as dichloromethane, isopropanol, tetrahydrofuran, water, etc., optionally with heating, and optionally with microwave irradiation to produce the compound of formula (11). The compound of formula (11) reacts with a compound of formula (12), 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., 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., optionally with heating, and optionally with microwave irradiation to produce the compound of formula (13).

[0268] The compound appropriately substituted in formula (14), a known compound, or a compound prepared by a known method reacts with the compound appropriately substituted in formula (15), a known compound, or a compound prepared by a known method in the presence of sodium toluenesulfonate sodium bisulfite, in a solvent such as N,N-dimethylacetamide, or in an alcohol solvent such as methanol, ethanol, etc. in the presence of a base such as sodium methoxide, sodium ethoxide, etc. Alternatively, the compound of formula (15) can be pretreated with hydrochloric acid in an alcohol solvent, and the imidate generated in situ can then be treated with the compound of formula (14) sodium bisulfite to produce the compound of formula (16) in the presence of a solvent such as ethanol, methanol, etc., optionally with heating, and optionally with microwave irradiation.

[0269] Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

[0270] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor, or resolution of a racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC).

[0271] 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.

[0272] The chiral compounds of the present invention (and their chiral precursors) can be obtained in enantiomerically enriched form by chromatography, generally 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.

[0273] Mixtures 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).]

[0274] 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.

[0275] 1 The 1H-NMR spectrum was obtained by Varian Mercury 300 MHz NMR. 1 The 1H nuclear magnetic resonance (NMR) spectra were in agreement with the proposed structures in all cases. Characteristic chemical shifts (δ) are given in parts per million from tetramethylsilane in the downfield direction using conventional abbreviations for the designation of the major peaks: e.g., 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, 4.6×75 mm, 3.5 μm) equipped with a 2996 diode array detector at 210 - 400 nm. Retention times (RT) are reported in minutes. 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

[0276] Example 1: 3-(4-Ethyl-3-hydroxyphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one

[0277]

Chem.

[0278] Step 1: 5-Nitro-2-vinylphenol. To a mixture of 5-nitro-2-bromophenol (109 mg, 0.5 mmol) and tributyl(vinyl)stannane (206 mg, 0.65 mmol) in degassed dimethylformamide (2 mL) for 5 minutes was added tetrakis(triphenylphosphine)palladium(0) (116 mg, 0.1 mmol). The mixture was heated at 90 °C for 4 hours. The mixture was filtered, poured into water (25 mL), and extracted with ethyl acetate (3 × 40 mL). The organic layer was washed with brine (20 mL), dried, and concentrated. The residue was purified by flash column (20 g, 30% ethyl acetate / hexane). The solvent was removed under reduced pressure to isolate the product (66 mg, 80%). LC / MS: RT = 4.41 min, purity > 95%.

[0279] Step 2: 5-Amino-2-ethylphenol. A mixture of 5-nitro-2-vinylphenol (60 mg, 0.36 mmol) and 20% palladium hydroxide on carbon (60 mg) in methanol (1 mL) was held in a hydrogen atmosphere using a balloon for 18 hours. The mixture was filtered and concentrated to obtain the desired product (36 mg, 72% yield). LC / MS: RT = 2.26 min, purity > 95%.

[0280] Step 3: 2-Amino-N-(4-ethyl-3-hydroxyphenyl)benzamide. A mixture of 5-amino-2-ethylphenol (78 mg, 0.60 mmol), N-t-butyloxycarbonyl 2-aminobenzoic acid (175 mg, 0.78 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (342 mg, 0.90 mmol), and triethylamine (0.5 mL) in dimethylformamide (3 mL) was stirred for 18 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 30 mL). The combined extracts were washed with brine (50 mL), dried, and concentrated. The residue was purified by reverse phase HPLC. (31 mg, 15%). LC / MS: RT = 5.84 min, purity > 95%, (M - 100 + H) += 257.41. The t-butyloxycarbonyl protected intermediate was treated with a dichloromethane solution of trifluoroacetic acid (1 mL each) for 4 hours. The solvent was removed under reduced pressure to obtain the deprotected amine intermediate (28 mg, 94%). LC / MS: RT = 3.66 min, purity > 95%, (M + H) + = 257.35.

[0281] Step 4: 3-(4-Ethyl-3-hydroxyphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one. 2-Amino-N-(4-ethyl-3-hydroxyphenyl)benzamide (28 mg, 0.11 mmol) and 3-pyridinecarboxaldehyde (14 μL, 0.14 mmol) were mixed with sodium bisulfite in dimethylacetamide and heated to 150 °C. After the reaction mixture was cooled to room temperature, it was poured into water (20 mL) and then extracted with ethyl acetate (3 × 20 mL). The combined extracts were washed with brine (20 mL), dried, and concentrated. The residue was purified by flash column (12 g, 0 - 10% ethyl acetate / hexane) to obtain the title compound (10 mg, TFA salt, 20%). LC / MS: RT = 3.51 min, purity > 95%, (M + H) + = 344.43. 1 H NMR (300 MHz, CD 3 OD) δ = 9.01 (s, 1H), 8.82 (d, J = 5.6 Hz, 1H), 8.63 (d, J = 8.2 Hz, 1H), 8.43 - 8.24 (m, 1H), 8.09 - 7.90 (m, 2H), 7.90 - 7.79 (m, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.19 - 6.99 (m, 1H), 6.87 - 6.60 (m, 2H), 2.70 - 2.42 (m, 2H), 1.22 - 1.01 (m, 3H)

[0282] According to the procedure of Example 1 above and substituting appropriate reagents, starting materials, and purification methods known to those skilled in the art, Examples 2 - 5 of the present invention were prepared.

[0283] Example 2: 3-(4-Chloro-3-hydroxyphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride

[0284] [Chemistry]

[0285] 3-(4-Chloro-3-hydroxyphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride was synthesized from 2-amino-N-(4-chloro-3-hydroxyphenyl)benzamide (67 mg, 0.26 mmol) and 3-pyridinecarboxaldehyde (32 μL, 0.33 mmol). Product (44 mg, 49% yield). LC / MS: RT = 3.27 min, purity >95%, (M+1) + = 349.98. 1 H NMR (300 MHz, CD 3 OD) δ = 8.30 (dd, J = 1.5, 7.9 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.97~7.88 (m, 1H), 7.85~7.78 (m, 1H), 7.69~7.60 (m, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.93~6.87 (m, 1H), 6.80~6.71 (m, 1H)

[0286] Example 3: 3-(4-Hydroxybutyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride

[0287] [Chemistry]

[0288] 3-(4-Hydroxybutyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride was synthesized from 2-amino-N-(4-hydroxybutyl)benzamide (87 mg, 0.42 mmol) and 3-pyridinecarboxaldehyde (51 μL, 0.55 mmol). Product (55 mg, 44% yield). LC / MS: RT = 2.63 min, purity >95%, (M+1) + = 296.07. 1 H NMR (300 MHz, CD 3OD) δ = 9.00 (d, J = 7.9 Hz, 1H), 8.35 (dd, J = 1.3, 8.1 Hz, 1H), 8.02 - 7.87 (m, 1H), 7.83 - 7.62 (m, 2H), 4.35 (t, J = 5.7 Hz, 1H), 4.19 - 3.97 (m, 2H), 3.46 (t, J = 6.2 Hz, 1H), 1.85 - 1.65 (m, 3H), 1.52 - 1.33 (m, 1H).

[0289] Example 4: 3-(3-(Benzyloxy)phenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride

[0290]

Chemical formula

[0291] 3-(3-(Benzyloxy)phenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride was synthesized from 2-amino-N-(3-(benzyloxy)phenyl)benzamide (115 mg, 0.36 mmol) and 3-pyridinecarboxaldehyde (46 μL, 0.47 mmol). Product (91 mg, 62% yield). LC / MS: RT = 4.46 min, purity > 95%, (M + 1) + = 406.04. 1 H NMR (300 MHz, CD 3 OD) δ = 9.04 (br.s., 1H), 8.82 (br.s., 1H), 8.57 - 8.48 (m, 1H), 8.35 (dd, J = 1.5, 8.2 Hz, 1H), 8.02 - 7.90 (m, 2H), 7.90 - 7.82 (m, 1H), 7.76 - 7.65 (m, 1H), 7.42 - 7.27 (m, 6H), 7.11 - 7.03 (m, 2H), 7.00 - 6.92 (m, 1H), 5.07 (d, J = 4.4 Hz, 2H).

[0292] Example 5: 3-(Naphthalen-2-yl)-2-(pyridin-3-yl)quinazolin-4(3H)-one

[0293]

Chemical formula

[0294] Step 1: N-t-Butyloxycarbonyl-2-amino-N-(naphthalen-2-yl)benzamide was synthesized from N-t-butyloxycarbonyl 2-aminobenzoic acid (462 mg, 1.95 mmol) and naphthalene-2-amine (214 mg, 1.5 mmol). t-Butyloxycarbonyl protected intermediate (418 mg, 77% yield). LC / MS: RT = 6.66 min, purity > 95%, (M+H) + = 363.40

[0295] Step 2: 2-Amino-N-(naphthalen-2-yl)benzamide was synthesized from N-t-butyloxycarbonyl 2-amino-N-(naphthalen-2-yl)benzamide (176 mg, 0.49 mmol) and 4N HCl dioxane solution (2 mL). Product (115 mg, 90%). LC / MS: RT = 4.57 min, purity > 95%, (M+H) + = 263.46

[0296] Step 3: 3-(Naphthalen-2-yl)-2-(pyridin-3-yl)quinazolin-4(3H)-one was synthesized from 2-amino-N-(naphthalen-2-yl)benzamide (111 mg, 0.42 mmol) and 3-pyridinecarboxaldehyde (52 uL, 0.55 mmol). Temperature: 150 °C. Product: (33 mg TFA salt: 16% yield). LC / MS: RT = 3.97 min, purity > 95%, (M+H) + = 350.48. 1 H NMR (300 MHz, CD 3 OD) δ = 8.99 (s, 1H), 8.64 (d, J = 4.7 Hz, 1H), 8.52 (td, J = 1.6, 8.1 Hz, 1H), 8.37 (dd, J = 1.6, 8.1 Hz, 1H), 8.07~7.65 (m, 8H), 7.65~7.41 (m, 3H)

[0297] Example 6: 2-(Pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one dihydrochloride

[0298] [Chemistry]

[0299] A mixture of 3-aminopyridine-4-carboxylic acid (137 mg, 1.0 mmol), nicotinonitrile (125 mg, 1.2 mmol), and sodium methoxide (54 mg, 0.25 mmol) in methanol (6 mL) was heated to reflux for 3 days. The mixture was concentrated, dissolved in dimethylformamide, and purified by reverse-phase HPLC to obtain the desired product. This was converted to the HCl salt (57 mg) using 4N HCl dioxane solution. LC / MS: RT = 1.86 min, purity > 95%, (M+1) + = 224.98.

[0300] Example 7: N-(4-(3,4-Dihydro-4-oxo-3-(pyridin-3-yl)quinazolin-2-yl)phenyl)-1-methylazetidine-3-carboxamide dihydrochloride

[0301] [Chemistry]

[0302] Step 1: 2-(4-Aminophenyl)-3-(pyridin-3-yl)quinazolin-4(3H)-one dihydrochloride 4N HCl dioxane solution (2 mL) was added to N-(4-(3,4-dihydro-4-oxo-3-(pyridin-3-yl)quinazolin-2-yl)phenyl)acetamide (70 mg, 0.20 mmol) in methanol (3 mL). The mixture was heated at 80 °C for 7 hours. After cooling, the solid was collected by filtration, washed with ethyl acetate, and dried to obtain the title compound (50 mg, 65% yield). LC / MS: RT = 2.63 min, purity > 95%, (M+1) + = 315.01.

[0303] Step 2: N-(4-(3,4-Dihydro-4-oxo-3-(pyridin-3-yl)quinazolin-2-yl)phenyl)-1-methylazetidine-3-carboxamide dihydrochloride. A mixture of 2-(4-aminophenyl)-3-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride (50 mg, 0.13 mmol), 1-methylazetidine-3-carboxylic acid (41 μL, 0.33 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (162 mg, 0.42 mmol), and diisopropylethylamine (0.15 mL, 0.7 mmol) in dimethylformamide (1 mL) was stirred for 18 h. The reaction mixture was filtered and then purified by reverse-phase HPLC (3 - 35% acetonitrile / water) to afford the title compound (23 mg). The sample was converted to the HCl salt using 4N HCl dioxane solution (10 mg). LC / MS: RT = 2.76 min, purity >95%, (M + 1) + = 412.02. 1 H NMR (300 MHz, CD 3 OD) δ = 8.53 (d, J = 8.2 Hz, 1H), 8.46 - 8.30 (m, 1H), 8.17 - 7.92 (m, 3H), 7.92 - 7.81 (m, 1H), 7.81 - 7.65 (m, 3H), 7.58 - 7.42 (m, 2H), 4.62 - 4.39 (m, 2H), 4.30 - 4.05 (m, 2H), 3.92 - 3.69 (m, 1H), 3.02 - 2.85 (m, 4H), 1.41 - 1.21 (m, 1H)

[0304] Example 8: N-(4-(3,4-Dihydro-4-oxothieno[3,2-d]pyrimidin-2-yl)phenyl)nicotinamide hydrochloride

[0305]

Chemical formula

[0306] Step 1: 2-(4-Aminophenyl)thieno[3,2-d]pyrimidin-4(3H)-one hydrochloride. A mixture of N-(4-(3,4-dihydro-4-oxothieno[3,2-d]pyrimidin-2-yl)phenyl)acetamide (180 mg, 0.63 mmol) and 4N HCl dioxane solution (3 mL) in methanol (2 mL) was heated at 80 °C for 7 hours. After cooling to room temperature, the solid was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to obtain the desired product (131 mg, 74% yield). LC / MS: RT = 2.38 min, purity > 95%, (M+1) + = 243.97.

[0307] Step 2: N-(4-(3,4-Dihydro-4-oxothieno[3,2-d]pyrimidin-2-yl)phenyl)nicotinamide hydrochloride. To a mixture of 2-(4-aminophenyl)thieno[3,2-d]pyrimidin-4(3H)-one hydrochloride (43 mg, 0.15 mmol), diisopropylethylamine (0.15 mL), and dimethylformamide (1 mL) was added nicotinoyl chloride hydrochloride (55 mg, 0.31 mmol). The mixture was stirred for 2 hours. The mixture was filtered. The solid was washed with ethyl acetate and dried (30 mg, 56% yield). To the product (23 mg) in methanol was added 4N HCl dioxane solution (0.2 mL). The mixture was stirred for 30 minutes. The solid was collected, washed with ethyl acetate, and dried to obtain the HCl salt (21 mg). LC / MS: RT = 2.89 min, purity > 95%, (M+1) + = 348.90.

[0308] Example 9: N-(4-(3,4-Dihydro-4-oxothieno[3,2-d]pyrimidin-2-yl)phenyl)-1-methylazetidine-3-carboxamide hydrochloride

[0309]

Chemical Structure

[0310] A mixture of 2-(4-aminophenyl)thieno[3,2-d]pyrimidin-4(3H)-one hydrochloride (43 mg, 0.15 mmol), diisopropylethylamine (0.15 mL), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate) (134 mg, 0.35 mmol), 1-methylazetidine-3-carboxylic acid (36 mg, 0.31 mmol) and dimethylformamide (2 mL) was stirred for 18 h. The reaction mixture was filtered and then purified by reverse phase HPLC (3 - 35% acetonitrile / water). To the product (26 mg) in ethyl acetate / methanol was added 4N HCl dioxane solution. The mixture was stirred for 30 min. The solid was collected by filtration, washed with ethyl acetate and dried to give the desired HCl salt (12 mg). LC / MS: RT = 2.59 min, purity >95%, (M+1) + = 341.02.)

[0311] Example 10: 2,3-Di(pyridin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one

[0312] [Chemical formula]

[0313] Step 1: 3-Amino-N-(pyridin-3-yl)thiophene-2-carboxamide. A mixture of 3-t-butyloxycarbonylaminothiophene-2-carboxylic acid (486 mg, 2.0 mmol), 3-aminopyridine (244 mg, 2.6 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (1.0 g, 2.6 mmol) and diisopropylethylamine (1.0 mL, 5.48 mmol) in dimethylformamide (10 mL) was stirred for 18 h. The mixture was diluted with ethyl acetate (60 mL), washed with water, brine, dried and concentrated. The residue was purified by flash column (30 - 50% ethyl acetate / hexane) to give the t-butyloxycarbonyl protected intermediate (500 mg, 78% yield). The product was deprotected by reacting with 4N HCl dioxane solution overnight. The solvent was removed under reduced pressure and the residue was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was separated, dried (magnesium sulfate), filtered and the solvent was removed under reduced pressure to give the amine product (264 mg, 77% yield).

[0314] Step 2: 2,3-Di(pyridin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one. A mixture of 3-amino-N-(pyridin-3-yl)thiophene-2-carboxamide (35 mg, 0.16 mmol), 3-pyridinecarboxaldehyde (23 uL, 0.24 mmol), copper(II) chloride (45 mg, 0.34 mmol) in dimethylacetamide (1.0 mL) was heated at 120 °C for 4 h. After cooling, the mixture was diluted with ethyl acetate (30 mL), then washed with water (2×30 mL), saturated aqueous sodium bicarbonate, brine (30 mL), dried and concentrated again. The residue was purified by reverse phase HPLC to give the title compound (6 mg, 12%). LC / MS: RT = 2.40 min, purity >95%, (M+1) + = 307.00, 1 H NMR (300 MHz, CD 3 OD) δ = 8.88 - 8.38 (m, 4H), 8.28 - 8.16 (m, 1H), 8.08 - 7.90 (m, 2H), 7.63 - 7.42 (m, 3H)

[0315] According to the above procedure of Example 10, Examples 11 to 16 of the present invention were further prepared by substituting appropriate reagents, starting materials and purification methods known to those skilled in the art.

[0316] Example 11: 3-(3-Hydroxy-4-methylphenyl)-2-(pyridin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one

[0317]

Chemical formula

[0318] Step 1: 3-t-Butyloxycarbonyl-amino-N-(3-hydroxy-4-methylphenyl)thiophene-2-carboxamide was synthesized from 3-t-butyloxycarbonylamino-thiophene-2-carboxylic acid (123 mg, 1.0 mmol) and 5-amino-2-methylphenol (243 mg, 1.0 mmol) to obtain a t-butyloxycarbonyl protected intermediate (250 mg, 72% yield). LC / MS: RT = 5.49 minutes, purity > 95%, (M - 100)+ = 249.39.

[0319] Step 2: 3-Amino-N-(3-hydroxy-4-methylphenyl)thiophene-2-carboxamide. 2 mL of 4N HCl dioxane solution was added to 3-t-butyloxycarbonyl-amino-N-(3-hydroxy-4-methylphenyl)thiophene-2-carboxamide (250 mg, 0.72 mmol) in dichloromethane / methanol (5 / 3 mL). The mixture was stirred for 18 hours and concentrated. The residue was stirred in ethyl acetate (50 mL), washed with saturated aqueous sodium bicarbonate solution and brine, and concentrated again to obtain the title compound (166 mg, 93% yield). LC / MS: RT = 3.49 minutes, purity > 95%, (M + 1) + = 249.26.

[0320] Step 3: 3-(3-Hydroxy-4-methylphenyl)-2-(pyridin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one was synthesized from 3-amino-N-(3-hydroxy-4-methylphenyl)thiophene-2-carboxamide (84 mg, 0.34 mmol) and 3-pyridinecarboxaldehyde (41 μL, 0.44 mmol). The title compound (32 mg, 30% yield). LC / MS: RT = 2.88 min, purity >95%, (M+1) + = 336.41 1 H NMR (300 MHz, CD 3 OD) δ = 8.90~8.51 (m, 2H), 8.29~8.03 (m, 2H), 7.75~7.53 (m, 1H), 7.52~7.37 (m, 1H), 7.14~6.96 (m, 1H), 6.77~6.54 (m, 2H), 2.13 (s, 3H)

[0321] Example 12: N-(4-(3,4-Dihydro-4-oxo-3-(pyridin-3-yl)thieno[3,2-d]pyrimidin-2-yl)phenyl)acetamide hydrochloride

[0322]

Chemical Structure

[0323] N-(4-(3,4-Dihydro-4-oxo-3-(pyridin-3-yl)thieno[3,2-d]pyrimidin-2-yl)phenyl)acetamide hydrochloride was synthesized from 3-amino-N-(pyridin-3-yl)thiophene-2-carboxamide (70 mg, 0.32 mmol) and N-(4-formylphenyl)acetamide (78 mg, 0.32 mmol). The product (60 mg, 52% yield). LC / MS: RT = 2.87 min, purity >95%, (M+1) + = 362.96 1 H NMR (300 MHz, DMSO) δ = 10.07 (br.s., 1H), 8.68~8.43 (m, 2H), 8.31 (br.s., 1H), 8.05~7.85 (m, 1H), 7.60~7.36 (m, 4H), 7.26 (d, J = 7.6 Hz, 2H), 2.07~1.89 (m, 3H)

[0324] Example 13: N-(4-(3,4-Dihydro-3-(6-methoxypyridin-3-yl)-4-oxothieno[3,2-d]pyrimidin-2-yl)phenyl)acetamide

[0325]

Chemical formula

[0326] N-(4-(3,4-Dihydro-3-(6-methoxypyridin-3-yl)-4-oxothieno[3,2-d]pyrimidin-2-yl)phenyl)acetamide was synthesized from 3-amino-N-(6-methoxypyridin-3-yl)thiophene-2-carboxamide (75 mg, 0.3 mmol) and N-(4-formylphenyl)acetamide (73 mg, 0.45 mmol). Product (80 mg, 68% yield). LC / MS: RT = 3.59 min, purity > 95%, (M+1) + = 392.92 1 H NMR (300 MHz, DMSO) δ = 10.14~9.98 (m, 1H), 8.35~8.21 (m, 1H), 8.11~7.97 (m, 1H), 7.81~7.63 (m, 1H), 7.55~7.37 (m, 3H), 7.36~7.22 (m, 2H), 6.90~6.69 (m, 2H), 3.88~3.68 (m, 3H), 2.00 (s, 3H)

[0327] Example 14: 3-(6-Methoxypyridin-3-yl)-2-(pyridin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride

[0328]

Chemical formula

[0329] 3-(6-Methoxypyridin-3-yl)-2-(pyridin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one dihydrochloride was synthesized from 3-amino-N-(6-methoxypyridin-3-yl)thiophene-2-carboxamide (75 mg, 0.3 mmol) and 3-pyridinecarboxaldehyde (43 μL, 0.45 mmol). At 120 °C for 2 hours. The product (103 mg, 100% yield). LC / MS: RT = 2.94 min, purity > 95%, (M+1) + = 336.94

[0330] N-(4-(3-(4-Ethyl-3-hydroxyphenyl)-3,4-dihydro-4-oxothieno[3,2-d]pyrimidin-2-yl)phenyl)acetamide was synthesized from 3-amino-N-(4-ethyl-3-hydroxyphenyl)thiophene-2-carboxamide (78 mg, 0.30 mmol) and 3-pyridinecarboxaldehyde (64 μL, 0.39 mmol). The product (38 mg, 31% yield). LC / MS: RT = 3.97 min, purity > 95%, (M+1) + = 405.97 1 H NMR (300 MHz, CD 3 OD) δ = 8.16~8.10 (m, 1H), 7.52~7.45 (m, 2H), 7.43~7.38 (m, 1H), 7.38~7.32 (m, 2H), 7.03 (d, J = 7.6 Hz, 1H), 6.65~6.58 (m, 2H), 2.68~2.43 (m, 2H), 2.12~2.07 (m, 3H), 1.18~1.09 (m, 3H)

[0331] Example 15: 2-(Pyridin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one

[0332]

Chemical Structure

[0333] 2-(Pyridin-3-yl)thieno[3,2-d]pyrimidin-4(3H)-one was synthesized from commercially available 3-aminothiophene-2-carboxamide (142 mg, 1.0 mmol) and 3-pyridinecarboxaldehyde (160 μL, 1.3 mmol). Product (36 mg). LC / MS: RT = 2.17 min, purity > 95%, (M + 1) + = 230.07 1 H NMR (300 MHz, CDCl 3 ) δ = 8.78 (br.s., 1H), 8.63 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 5.3 Hz, 1H), 7.59 (dd, J = 5.0, 7.9 Hz, 1H), 7.44 (d, J = 5.3 Hz, 1H), 1.99 (s, 3H)

[0334] Example 16: N-(4-(3-(4-Ethyl-3-hydroxyphenyl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)phenyl)acetamide

[0335]

Chemical Structure

[0336] Step 1: 5-Nitro-2-vinylphenol. Tetrakis(triphenylphosphine)palladium(0) (636 mg, 0.55 mmol) was added to a mixture of 5-nitro-2-bromophenol (2.0 g, 9.17 mmol) and tributyl(vinyl)stannane (3.5 g, 11 mmol) in degassed dimethylformamide (12 mL) for 5 minutes. The mixture was heated at 115 °C for 20 minutes (MV). The mixture was filtered, poured into water (250 mL), and extracted with ethyl acetate (3 × 100 mL). The ethyl acetate layer was washed with brine (50 mL), dried, and concentrated. The residue was purified by flash column (120 g, 30% ethyl acetate / hexane). Product (1.13 g, 75%). LC / MS: RT = 4.41 min, purity > 95%.

[0337] Step 2: 5-Amino-2-ethylphenol. A mixture of 5-nitro-2-vinylphenol (1.13 g, 6.85 mmol) and Pd on carbon (10%, 200 mg) in methanol (15 mL) was hydrogenated using a balloon for 4 hours. The mixture was filtered and concentrated to give the desired product (910 mg, 97% yield). LC / MS: RT = 2.26 min, purity > 95%.

[0338] Step 3: 3-Amino-N-(4-ethyl-3-hydroxyphenyl)thiophene-2-carboxamide. A mixture of 5-amino-2-ethylphenol (500 mg, 3.65 mmol), N-t-butyloxycarbonyl 3-aminothiophene-2-carboxylic acid (931 mg, 3.83 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (1.8 g, 4.75 mmol), and Et 3 N (2.0 mL) in dimethylformamide (20 mL) was stirred for 18 hours. The mixture was poured into water (250 mL) and extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with brine (50 mL), dried, and concentrated. The residue was purified by flash column (40 g) to give the t-butyloxycarbonyl protected intermediate (773 mg, 60%). LC / MS: RT = 5.78 min, purity > 95%, (M - 100 + H) + = 262.96. The de-t-butyloxycarbonyl product (677 mg, 80% purity). LC / MS: RT = 4.02 min, purity > 95%, (M + H) + = 262.96.

[0339] Step 4: N-(4-(3-(4-Ethyl-3-hydroxyphenyl)-3,4-dihydro-4-oxothieno[3,2-d]pyrimidin-2-yl)phenyl)acetamide. From 3-amino-N-(4-ethyl-3-hydroxyphenyl)thiophene-2-carboxamide (300 mg, 1.14 mmol, 80% purity) and N-(4-formylphenyl)acetamide (242 mg, 1.5 mmol). Prepared in the same manner as in Step 4 of Example 1. At 80 °C for 3 hours. Product (125 mg, 34% yield). LC / MS: RT = 3.97 min, purity > 95%, (M+H) + = 405.97.

[0340] According to the above procedure of Example 16, Examples 17 to 21 of the present invention were further prepared by substituting appropriate reagents, starting materials and purification methods known to those skilled in the art.

[0341] Example 17: 3-(3-Fluoro-4-ethylphenyl)-2-(pyrimidin-3-yl)quinazolin-4(3H)-one

[0342]

Chemical formula

[0343] Step 1: N-tert-butyloxycarbonyl 2-amino-N-(4-ethyl-3-fluorophenyl)benzamide was synthesized from N-tert-butyloxycarbonyl-2-aminobenzoic acid (385 mg, 1.63 mmol) and 4-ethyl-3-fluorophenylamine (175 mg, 1.25 mmol). Isolated product: tert-butyloxycarbonyl protected amide intermediate (275 mg, 61% yield). LC / MS: R f = 6.85 min, purity > 95%, (M+Na) + = 381.48

[0344] Step 2: 2-Amino-N-(4-ethyl-3-fluorophenyl)benzamide was synthesized from N-t-butyloxycarbonyl-2-amino-N-(4-ethyl-3-fluorophenyl)benzamide (275 mg, 0.77 mmol) and 4N HCl dioxane solution (2 mL). Product (180 mg, 91%). LC / MS: RT = 4.86 min, purity >95%, (M+H) + =259.45

[0345] Step 3: 3-(3-Fluoro-4-ethylphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one was synthesized from 2-amino-N-(4-ethyl-3-fluorophenyl)benzamide (77 mg, 0.3 mmol) and 3-pyridinecarboxaldehyde (37 μL, 0.39 mmol). Temperature: 150 °C. Product: (30 mg TFA salt: 22% yield). LC / MS: RT = 4.15 min, purity >95%, (M+H) + =346.47 1 H NMR (300 MHz, DMSO) δ = 8.70 (d, J = 1.8 Hz, 1H), 8.56 (dd, J = 1.5, 5.0 Hz, 1H), 8.21 (dd, J = 1.3, 8.1 Hz, 1H), 8.06 - 7.86 (m, 2H), 7.84 - 7.73 (m, 1H), 7.70 - 7.59 (m, 1H), 7.48 (dd, J = 5.3, 7.9 Hz, 1H), 7.40 - 7.20 (m, 2H), 7.18 - 7.11 (m, 1H), 2.67 - 2.53 (m, 2H), 1.21 - 1.04 (m, 3H)

[0346] Example 18: 3-(3-Bromo-4-ethylphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one

[0347]

Chem.

[0348] Step 1: N-t-Butyloxycarbonyl-2-amino-N-(4-ethyl-3-bromophenyl)benzamide was synthesized from N-t-butyloxycarbonyl 2-aminobenzoic acid (270 mg, 1.14 mmol) and 4-ethyl-3-bromophenylamine (175 mg, 0.875 mmol). t-Butyloxycarbonyl protected intermediate (182 mg, 50% yield).

[0349] Step 2: 2-Amino-N-(4-ethyl-3-bromophenyl)benzamide was synthesized from N-t-butyloxycarbonyl 2-amino-N-(4-ethyl-3-bromophenyl)benzamide (182 mg, 0.43 mmol) and 4N HCl dioxane solution (2 mL). Product (34 mg, 25%). LC / MS: RT = 5.32 min, purity > 95%, (M + H) + = 319.39

[0350] Step 3: 3-(3-Bromo-4-ethylphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one was synthesized from 2-amino-N-(4-ethyl-3-bromophenyl)benzamide (34 mg, 0.11 mmol) and 3-pyridinecarboxaldehyde (12 uL, 0.14 mmol). Temperature: 150 °C. Product: (17 mg TFA salt: 39% yield). LC / MS: RT = 4.55 min, purity > 95%, (M + H) + = 406.43. 1 H NMR (300 MHz, CD 3 OD) δ = 8.95 (s, 1H), 8.75 (d, J = 5.6 Hz, 1H), 8.43 (d, J = 8.2 Hz, 1H), 8.38 - 8.29 (m, 1H), 8.03 - 7.90 (m, 1H), 7.90 - 7.79 (m, 2H), 7.90 - 7.79 (m, 2H), 7.75 - 7.62 (m, 2H), 7.41 - 7.23 (m, 2H), 2.85 - 2.57 (m, 2H), 1.25 - 1.13 (m, 3H).

[0351] Example 19: 3-(2-Ethylnaphthalen-6-yl)-2-(pyridin-3-yl)quinazolin-4(3H)-one

[0352]

Chem.

[0353] Step 1: 6-Vinylnaphthalen-2-amine. Tetrakis(triphenylphosphine)palladium(0) (462 mg, 0.4 mmol) was added to a mixture of 6-bromonaphthalen-2-amine (650 mg, 2 mmol) and tributyl(vinyl)stannane (827 mg, 2.6 mmol) in degassed dimethylformamide (10 mL) for 5 minutes. The mixture was heated at 90 °C for 4 hours. The mixture was filtered, poured into water (100 mL), and extracted with ethyl acetate (3 × 50 mL). The combined extracts were washed with brine (50 mL), dried, and concentrated. The residue was purified by flash column (40 g, 10 - 30% ethyl acetate / hexane). Product (220 mg, 65%). LC / MS: RT = 3.28 min, purity > 95%, (M + H) + = 170.26

[0354] Step 2: 6-Ethylnaphthalen-2-amine. A mixture of 6-vinylnaphthalen-2-amine (144 mg, 0.85 mmol) and 5% palladium hydroxide on carbon (144 mg) in methanol (4 mL) was maintained in a hydrogen atmosphere using a balloon for 5 hours. The reaction mixture was filtered and concentrated to give the desired product (132 mg, 91% yield). LC / MS: RT = 3.38 min, purity > 95%, (M + H) + = 172.23.

[0355] Step 3: 2-Amino-N-(2-ethylnaphthalen-6-yl)benzamide. A mixture of 6-ethylnaphthalen-2-amine (70 mg, 0.41 mmol), n-t-butyloxycarbonylaminobenzoic acid (126 mg, 0.53 mmol), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (233 mg, 0.61 mmol), and triethylamine (0.5 mL) in dimethylformamide (2 mL) was stirred for 18 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined extracts were washed with brine (50 mL), dried, and concentrated. The residue was purified by flash column (12 g, 0-10% ethyl acetate / hexane). t-Butyloxycarbonyl protected intermediate (36 mg, 23% yield). LC / MS: RT = 5.30 min, purity >95%, (M - 100 + H) + = 291.47. Deprotected product (25 mg, 94%). LC / MS: RT = 7.15 min, purity >95%, (M + H) + = 291.41.

[0356] Step 4: 3-(2-Ethylnaphthalen-6-yl)-2-(pyridin-3-yl)quinazolin-4(3H)-one was synthesized from 2-amino-N-(2-ethylnaphthalen-6-yl)benzamide (25 mg, 0.086 mmol) and 3-pyridinecarboxaldehyde (11 uL, 0.11 mL). Temperature: 150 °C. Product (11 mg, 34% yield). LC / MS: RT = 4.65 min, purity >95%, (M + H) + = 378.49. 1 H NMR (300 MHz, DMSO) δ = 8.60 (d, J = 2.1 Hz, 1H), 8.41 - 8.15 (m, 2H), 8.02 - 7.87 (m, 1H), 7.88 - 7.74 (m, 4H), 7.74 - 7.56 (m, 3H), 7.56 - 7.34 (m, 2H), 7.19 (dd, J = 4.8, 7.8 Hz, 1H), 2.89 - 2.62 (m, 2H), 1.39 - 1.06 (m, 3H).

[0357] Example 20: 3-(4-Methyl-3-hydroxyphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride

[0358]

Chem.

[0359] 3-(4-Methyl-3-hydroxyphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride was synthesized from 2-amino-N-(4-methyl-3-hydroxyphenyl)benzamide (62 mg, 0.25 mmol) and 3-pyridinecarboxaldehyde (34 μL, 0.32 mmol). Product (43 mg, 52% yield). LC / MS: RT = 3.07 min, purity 95%, (M - 35)+ = 330.02. 1 H NMR (300 MHz, CD 3 OD) δ 9.01 (d, J = 1.76 Hz, 1H) 8.83 (d, J = 5.86 Hz, 1H) 8.66 (dt, 7 = 8.21, 1.76 Hz, 1H) 8.34 (dd, J = 8.06, 1.61 Hz, 1H) 7.81 - 8.18 (m, 3H) 7.39 - 7.77 (m, 1H) 7.00 - 7.38 (m, 1H) 6.91 (br d, J = 6.74 Hz, 1H) 6.79 (d, J = 2.05 Hz, 1H) 6.68 (dd, J = 7.92, 2.05 2.07 - 2.23 (m, 3H)

[0360] Example 21: 3-(3-Hydroxyphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride

[0361]

Chem.

[0362] 3-(3-Hydroxyphenyl)-2-(pyridin-3-yl)quinazolin-4(3H)-one hydrochloride was synthesized from 2-amino-N-(3-hydroxyphenyl)benzamide (80 mg, 0.35 mmol) and 3-pyridinecarboxaldehyde (47 μL, 0.44 mmol). Product (43 mg, 60% yield). LC / MS: RT = 2.78 min, purity 95%, (M - 35)+ = 316.03. 1 H NMR (300 MHz, CD 3 OD) δ 9.02 (br s, 1H) 8.84 (br s, 1H) 8.66 (dt, 7 = 8.21, 1.47 Hz, 1H) 8.34 (dd, J = 7.92, 1.47 Hz, 1H) 7.80~8.16 (m, 3H) 7.70 (ddd, 7 = 8.14, 7.11, 1.17 Hz, 2H) 6.93~7.24 (m, 1H) 6.79 (d, J = 2.05 Hz, 1H) 6.68 (dd, J = 7.92, 2.35 Hz, 1H)

[0363] 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, which are effective in preventing tau oligomerization, and one or more excipients.

[0364] 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".

[0365] The formulator should understand that the excipient serves mainly to deliver a safe and stable functional pharmaceutical, not only as part of the delivery vehicle in its entirety, but also as a means to achieve effective absorption of the active ingredient by the recipient. The excipient can serve the simple and direct role of being an inert filler, or the excipient used herein can be part of a pH stabilization system or coating to safely and surely deliver the ingredient 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.

[0366] The present teachings also provide pharmaceutical compositions comprising at least one compound and one or more pharmaceutically acceptable carriers, excipients, or diluents described herein. 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 Remington’s 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 an adverse 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.

[0367] 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 a unit dosage form suitable for administration of an exact dosage singly.

[0368] The compounds of the present invention intended for use in pharmaceuticals 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 radio frequency drying can be used for this purpose.

[0369] The compounds of the present invention intended for use in pharmaceuticals 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).

[0370] 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), ovules, sprays, and 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 compression molded into the desired shape and size. Powders and tablets can contain up to 99% of the compound.

[0371] 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, and 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).

[0372] The capsule agent can contain a mixture of one or more compounds (singular or plural) disclosed in this specification and pharmaceutically acceptable starches (e.g., corn, potato or tapioca starch), sugars, artificial sweeteners, powdered cellulose (e.g., crystalline and microcrystalline cellulose), flours, gelatin, rubbers and other inert fillers (singular or plural) and / or diluents (singular or plural).

[0373] Useful tablet formulations can be manufactured by conventional compression, wet granulation or dry granulation methods, and include, but are 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 point wax and ion exchange resin, pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surfactants), suspending agents or stabilizers can be utilized. Surface modifiers include nonionic 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 ester, 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.

[0374] 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 materials, viscosity regulators, stabilizers, osmotic pressure regulators, and the like. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water, alcohols (including monohydric alcohols 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 or 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.

[0375] 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.

[0376] 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 implant, parenterally (including intravenous, intraperitoneal and subcutaneous injection), rectally, vaginally and transdermally.

[0377] When administered for the treatment or prevention of a particular condition or disorder, the effective dosage will be understood to vary depending on the particular compound utilized, the method 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.

[0378] In some cases, it may be desirable to administer the compounds directly to the patient's airway using a device such as, but not limited to, a metered dose inhaler, a breath-actuated inhaler, a multiple-dose dry powder inhaler, a pump, a squeeze-actuated nebulizer dispenser, an aerosol dispenser, an aerosol sprayer, etc. For administration by intranasal or intratracheal inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. 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 nebulizer 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 punching a hole in 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.

[0379] 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 in oil, liquid polyethylene glycol, and mixtures thereof. Under normal storage and use conditions, these preparations generally contain a preservative to inhibit the growth of microorganisms.

[0380] Suitable dosage forms for injection include sterile aqueous solutions or dispersions, and sterile powders for immediate preparation of 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.

[0381] In the case of tablet dosage forms, depending on the dosage, 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.

[0382] 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 (HPMC). Tablets can also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, calcium hydrogen phosphate dihydrate and the like.

[0383] 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 can constitute 0.2% to 5% by weight of the tablet, and the fluidizing agent can constitute 0.2% to 1% by weight of the tablet.

[0384] Tablets generally also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, a mixture of magnesium stearate and sodium lauryl sulfate, etc. 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, flavoring agents, preservatives, and taste-masking agents.

[0385] 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.

[0386] 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 wet granulated, dry granulated, melt granulated, melt solidified, or extruded 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).

[0387] The above formulations for the various administrations can be formulated to provide immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0388] 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 dispersions 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.

[0389] The compounds described herein can be administered transdermally, i.e., across the inner walls 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).

[0390] The compounds of the present invention can also be administered directly to 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 needles (including microneedles) syringes, needleless syringes and infusion techniques.

[0391] 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 solids and used in combination with a suitable vehicle such as sterile water free of pyrogens.

[0392] For example, the preparation of parenteral formulations under aseptic conditions, such as by freeze-drying, 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.

[0393] 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.

[0394] Transdermal administration can be carried out using a skin patch containing a compound such as the compounds disclosed herein and a carrier that can be inert to the compound, can be non-toxic to the skin, and enables 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 petroleum or hydrophilic petroleum 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.

[0395] 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.

[0396] 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.

[0397] The compounds of the present 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), 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, with or without using a suitable propellant such as 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane. For nasal use, the powder can contain a bioadhesive agent such as chitosan or cyclodextrin.

[0398] The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of the compound(s) of the present invention, for example, with ethanol, an aqueous ethanol solution, or a suitable alternative agent that disperses, solubilizes or extends the release of the active propellant(s) as a solvent, and optionally a surfactant such as sorbitan trioleate, oleic acid, oligolactic acid.

[0399] 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.]

[0400] 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.

[0401] Suitable solutions for use in atomizers that generate fine mists by electrohydrodynamics can contain from 1 μg to 20 mg of the compounds of the present invention per actuation, and the actuation volume can be from 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 in place of propylene glycol include glycerol and polyethylene glycol. Suitable flavoring agents such as menthol, levomenthol, etc. or sweeteners such as saccharin, sodium saccharinate, etc. can be added to the formulations of the present invention for inhalation / intranasal administration.

[0402] 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.

[0403] 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 quantity that can be administered as a single dose, and more generally are prepared to be administered as divided doses throughout the day.

[0404] 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 a preservative such as benzalkonium chloride. Such formulations can also be delivered by iontophoresis.

[0405] 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.

[0406] 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.

[0407] 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.

[0408] The compounds of the present teachings may be useful in treating or preventing pathological symptoms or disorders in mammals, such as human subjects. Accordingly, the present teachings provide a method of treating or preventing pathological symptoms or disorders by supplying to a mammal a pharmaceutical composition comprising one or more compounds of the present teachings, including the 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 the pathological symptoms or disorders.

[0409] 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.

[0410] In the case of administration to a human patient, for the above-mentioned treatment, the dosage will, of course, vary depending on the compound to be 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 in 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.

[0411] 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 make the dosage uniform. As used herein, 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 specifications for the unit dosage forms of the present invention are directly dependent on (a) the particular characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compounds to address the susceptibility in the individual.

[0412] Accordingly, 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 tolerance can be readily set, the effective amount that gives a detectable therapeutic effect to the patient can be determined, and the time requirements for administering each agent that gives 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.

[0413] 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 increased dosages 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.

[0414] 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, "unit dose" is an individual quantity of the 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.

[0415] The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional active ingredients in the pharmaceutical composition of the present invention vary depending on the type of animal being treated, the type of disease being treated, the gender and age of the patient, the size and condition of the subject being 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.

[0416] The compounds of the present disclosure and their isotope-labeled variants are useful, for example, for the diagnosis and / or treatment of diseases involving the formation of tau oligomers, including 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 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, isotope labels can be detected using imaging techniques, photographic film, or scintillation counters. In a preferred embodiment, the label is detected in vivo in the subject's brain by imaging techniques, such as positron emission technology (PET) or single photon emission computed tomography (SPECT) imaging probes.

[0417] The labeled compounds of the present invention preferably contain at least one radionuclide as a label. All positron-emitting radionuclides are 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 selected from 11C and 18F. The tracer can be selected according to the detection method chosen.

[0418] Before carrying out 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 carrying out 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.

[0419] Procedure The following procedure can be used to evaluate and select a compound as an inhibitor of tau oligomer formation.

[0420] 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 for preparing tau in its monomeric form.

[0421] 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 close proximity to each other. Tau monomers (targets) form higher-order aggregates (dimers, trimers, tetramers, etc.) when incubated, and when donor and acceptor beads bind to the epitope tag of tau, they come into close proximity and generate a signal.

[0422] The tau target (equal mixture of each construct at 300 nM) was prepared in buffer (Tris-HCl pH 7.4) and incubated at room temperature for 4 hours in a 96-well plate 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).

[0423] CONFA Assay: Confirmatory Assay (CONFA) used as a secondary screening to confirm the mechanism of action of compounds identified as hits using the ALA assay. The assay is performed in a similar procedure to 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.

[0424] For the CONFA assay, the tau target (300 nM) was prepared in buffer (Tris-HCl pH 7.4) and incubated with vehicle control (DMSO) and a dose range of the compounds of the present disclosure (0.098 μM to 50 μM) for 3 hours at room temperature. The 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 separated for tau monomers and disulfide-bridged oligomers 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.

[0425] Data for compounds soluble in the test solutions described herein are shown in Table 4.

[0426]

Table 4

[0427] Four groups of htau mice (n = 25 / group) at 2.5 - 6.5 months of age were treated with 0, 10, 40, and 100 mg / kg of the compound TO-0582, which was pulverized in the diet. The study was conducted independently and blindly. The primary endpoint of the study was a statistically significant decrease in insoluble tau aggregates in the brains of the mice. Treatment with the compound decreased insoluble tau at all doses, and the decrease in insoluble tau was statistically significant at the 40 mg / kg and 100 mg / kg doses in male mice (female htau mice in this study did not develop lesions until 6 months of age). The biochemical analysis method for tau used in this study has been described previously (Acker CM et al., Sensitive quantitative assays for tau and phospho-tau in transgenic mouse models. Neurobiol Aging. 2013. 34:338). The results in Figure 1 show the in vivo efficacy of the compound in reducing tau lesions. The insoluble tau levels in the cortex of htau mice treated with compound TO-0582 (Example 21) were measured using the pan-tau monoclonal antibody (mAb) DA31. These values were normalized to total tau in the lysates of the cortex of each mouse. Error bars indicate the standard error of the mean. The P values for the comparison of the groups treated with 10, 40, or 100 mg / kg TO-0582 to the control group (white bar, 0 mg / kg) were 0.0503 (horizontal bar, 10 mg / kg), 0.0154 (diagonal bar, 40 mg / kg), and 0.0488 (vertical bar, 100 mg / kg). * indicates a P value < 0.05. The test compound had good tolerance over the study period at all doses and did not produce toxic effects on body weight, behavior, or disease status.

[0428] The appropriate daily dose of the compound 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 dose for the initial clinical trials in humans. In the safety determination of each composition, the dose and frequency of administration should match or exceed what is predicted for use in clinical trials.

[0429] Other factors to be considered are the conditions of the patient or subject animal such as the administration procedure, age, body weight, sex, sensitivity, diet, administration period, concomitant drugs, and severity of the disease. The appropriate dose 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 practicing physician and the situation of each patient (age, general condition, severity of symptoms, sex, etc.) in accordance with standard clinical techniques.

[0430] 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 dose therapeutically effective 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 large therapeutic index are preferred.

[0431] The treatment period can be short-term, for example, several weeks (e.g., 10 to 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 A is 【Chemical 2】 selected from the group consisting of R １ is selected from the group consisting of hydrogen, optionally substituted C １～６ alkyl, optionally substituted branched C ３～７ alkyl, optionally substituted aryl, and optionally substituted heteroaryl R ２ is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl, R ３ａ 、R ３ｂ 、R ３ｃ and R ３ｄ are hydrogen, a compound of formula (II): 【Chemical 3】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein R １ 、 R ２ 、 R ３ａ 、 R ３ｂ 、 R ３ｃ and R ３ｄ are as defined for the compound of formula (I), a compound of formula (IIa): 【Chemical 4】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein X is selected from the group consisting of CH and N, R １ 、 R ３ａ 、 R ３ｂ 、 R ３ｃ and R ３ｄ are as defined for the compound of formula (I), R ７ is independently selected from the group consisting of hydrogen and NR ５ COR ８ and is independently selected from the group consisting of, R5 is selected from the group consisting of hydrogen and C1-6 alkyl, R ８ is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, 【Chemical Formula 5】 , (OH, C １～６ alkoxy and NR １１ａ R １１ｂ )-optionally substituted C １～６ alkyl, and (OH, C １～６ alkoxy and NR １１ａ R １１ｂ )-optionally substituted C ３～７ independently selected from the group consisting of cycloalkyl, R ９ is selected from the group consisting of hydrogen, C １～６ alkyl and COR １０ and is selected from the group consisting of R １０ is selected from the group consisting of hydrogen and C １～６ alkyl, R １１ａ and R １１ｂ are independently selected from the group consisting of hydrogen and C １～６ alkyl, n is 1, 2 or 3, m is 1 or 2, a compound of formula (III): [[Chemical Formula 6]] and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein R １ 、R ２ 、R ３ａ 、R ３ｂ and R ３ｃ are as defined for the compound of formula (I), a compound of formula (IIIa): 【Chemical Formula 7】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein X is selected from the group consisting of CH and N, R １ , R ３ａ , R ３ｂ and R ３ｃ are as defined for the compound of formula (I), R ７ is independently selected from the group consisting of hydrogen and NR ５ COR ８ and is independently selected from the group consisting of; R5 is selected from the group consisting of hydrogen and C1-6 alkyl, R ８ is hydrogen, optionally substituted aryl, or optionally substituted heteroaryl, 【Chemical 8】 , (OH, C １～６ alkoxy and NR １１ａ R １１ｂ )-optionally substituted C １～６ alkyl, and OH, C １～６ alkoxy and NR １１ａ R １１ｂ )-optionally substituted C ３～７ independently selected from the group consisting of cycloalkyl, R ９ is selected from the group consisting of hydrogen, C １～６ alkyl and COR １０ and is selected from the group consisting of R １０ is selected from the group consisting of hydrogen and C １～６ alkyl, R １１ａ and R １１ｂ are each independently selected from the group consisting of hydrogen and C １～６ alkyl, n is 1, 2 or 3, m is 1 or 2, a compound of formula (IV), 【Chemical Formula 9】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein, R １ , R ２ , R ３ａ , R ３ｂ and R ３ｃ are as defined for the compound of formula (I), a compound of formula (IVa): 【Chemical Formula 10】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein X is selected from the group consisting of CH and N, R １ 、R ３ａ 、R ３ｂ and R ３ｃ are as defined for the compound of formula (I), R ７ is independently selected from the group consisting of hydrogen and NR ５ COR ８ and is selected independently from the group consisting of, R5 is selected from the group consisting of hydrogen and C1-6 alkyl, R ８ is hydrogen, optionally substituted aryl, or optionally substituted heteroaryl, 【Chemical 11】 , (OH, C １～６ alkoxy and NR １１ａ R １１ｂ )-optionally substituted C １～６ alkyl, and (OH, C １～６ alkoxy and NR １１ａ R １１ｂ )-optionally substituted C ３～７ cycloalkyl, independently selected from the group consisting of, R ９ is selected from the group consisting of hydrogen, C １～６ alkyl and COR １０ and is selected from the group consisting of; R １０ is selected from the group consisting of hydrogen and C １～６ alkyl, R １１ａ and R １１ｂ are independently selected from the group consisting of hydrogen and C １～６ alkyl, n is 1, 2 or 3, m is 1 or 2, a compound of formula (V): 【Chemical 12】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein R １ 、 R ２ 、 R ３ａ 、 R ３ｂ and R ３ｃ are as defined for the compound of formula (I), a compound of formula (Va): 【Chemical 13】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein X is selected from the group consisting of CH and N, R １ 、 R ３ａ 、 R ３ｂ and R ３ｃ are as defined for the compound of formula (I), R ７ is independently selected from the group consisting of hydrogen and NR ５ COR ８ and is selected independently from the group consisting of, R5 is selected from the group consisting of hydrogen and C1-6 alkyl, R ８ is hydrogen, optionally substituted aryl, or optionally substituted heteroaryl, 【Chemical 14】 , (OH, C １～６ alkoxy and NR １１ａ R １１ｂ )-optionally substituted C １～６ alkyl, and (OH, C １～６ alkoxy and NR １１ａ R １１ｂ )-optionally substituted C ３～７ cycloalkyl, independently selected from the group consisting of, R ９ is selected from the group consisting of hydrogen, C １～６ alkyl and COR １０ and is selected from the group consisting of R １０ is selected from the group consisting of hydrogen and C １～６ alkyl, R １１ａ and R １１ｂ are independently selected from the group consisting of hydrogen and C １～６ alkyl, n is 1, 2 or 3, m is 1 or 2, a compound of formula (VI): 【Chemical Formula 15】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein R １ 、R ２ 、R ３ａ 、R ３ｂ and R ３ｃ are as defined for the compound of formula (I), a compound of formula (VIa): 【Chemical 16】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein X is selected from the group consisting of CH and N, R １ 、R ３ａ 、R ３ｂ and R ３ｃ are as defined for the compound of formula (I), R ７ is independently selected from the group consisting of hydrogen and NR ５ COR ８ and is selected independently from the group consisting of, R5 is selected from the group consisting of hydrogen and C1-6 alkyl, R ８ is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, 【Chemical 17】 , (OH, C １～６ alkoxy and NR １１ａ R １１ｂ ), optionally substituted with a group selected from the group consisting of C １～６ alkyl, and (OH, C １～６ alkoxy and NR １１ａ R １１ｂ ), optionally substituted with a group selected from the group consisting of C ３～７ cycloalkyl, independently selected from the group consisting of: R ９ is selected from the group consisting of hydrogen, C １～６ alkyl and COR １０ and is selected from the group consisting of R １０ is selected from the group consisting of hydrogen and C １～６ alkyl, R １１ａ and R １１ｂ are independently selected from the group consisting of hydrogen and C １～６ alkyl, n is 1, 2 or 3, m is 1 or 2, a compound of formula (VII): 【Chemical Formula 18】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein, R １ 、 R ２ 、 R ３ａ and R ３ｂ are as defined for the compound of formula (I), a compound of formula (VIIa) [[0304]] 【Chemical Formula 19】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein, X is selected from the group consisting of CH and N, R １ , R ３ａ and R ３ｂ are as defined for the compound of formula (I), R ７ is independently selected from the group consisting of hydrogen and NR ５ COR ８ and is independently selected from the group consisting of; R5 is selected from the group consisting of hydrogen and C1-6 alkyl, R ８ is hydrogen, optionally substituted aryl, optionally substituted heteroaryl, 【Chemical 20】 , OH, C １～６ alkoxy and NR １１ａ R １１ｂ optionally substituted C with a group selected from １～６ alkyl, as well as OH, C １～６ alkoxy and NR １１ａ R １１ｂ optionally substituted C with a group selected from ３～７ cycloalkyl, independently selected from the group consisting of R ９ is selected from the group consisting of hydrogen, C １～６ alkyl and COR １０ and is selected from the group consisting of R １０ is selected from the group consisting of hydrogen and C １～６ alkyl, R １１ａ and R １１ｂ are independently selected from the group consisting of hydrogen and C １～６ alkyl, n is 1, 2 or 3, m is 1 or 2, a compound of formula (VIII): 【Chemical 21】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, wherein, R １ 、 R ２ 、 R ３ａ and R ３ｂ are as defined for the compound of formula (I), a compound of formula (VIIIa): 【Chemical 22】 and their enantiomers, diastereomers, hydrates, solvates, and pharmaceutically acceptable salts, X is selected from the group consisting of CH and N, R １ , R ３ａ and R ３ｂ are as defined for the compound of formula (I), R ７ is independently selected from the group consisting of hydrogen and NR ５ COR ８ and is independently selected from the group consisting of; R5 is selected from the group consisting of hydrogen and C1-6 alkyl, R ８ is hydrogen, optionally substituted aryl, or optionally substituted heteroaryl, 【Chemical 23】 , (OH, C １～６ alkoxy and NR １１ａ R １１ｂ－ )-optionally substituted C １～６ alkyl, and (OH, C １～６ alkoxy and NR １１ａ R １１ｂ－ )-optionally substituted C ３～７ independently selected from the group consisting of cycloalkyl, R ９ is selected from the group consisting of hydrogen, C １～６ alkyl and COR １０ and is selected from the group consisting of R １０ is selected from the group consisting of hydrogen and C １～６ alkyl, and R １１ａ and R １１ｂ are independently selected from the group consisting of hydrogen and C １～６ alkyl, n is 1, 2 or 3, m is 1 or 2, a pharmaceutical composition for inhibiting the formation of tau oligomers containing the compound.

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