KR101068835B1 - Isoindolones with high binding affinity to ?-amyloid aggregates and fibrils, and preparation method thereof - Google Patents

Abstract

The present invention is beta-isoindole theory represented by the amyloid fibrils degenerative early diagnosis and, general formula (1) useful for the prevention and treatment of these diseases of the brain including Alzheimer's disease is also indicated a high binding affinity to the (beta -amyloid fibril) ( isoindolone) compounds, methods for their preparation, and pharmaceutical compositions comprising the same.

[Formula 1]

In the formula, A is a C═O or CH ₂ group, R ₁ is a halogen atom selected from H, OH, fluorine, chlorine, bromine and iodine, C _{1 to} C ₈ Alkyl group, C _{1 to} C ₈ Alkoxy group, a tosyloxy -C ₁ ~C ₈ Alkoxy group, a mesyl oxy -C ₁ ~C ₈ An alkoxy group, an aryloxy nosil -C ₁ ~C ₈ C ₁ to C ₈ substituted with halogen atoms selected from alkoxy groups, fluorine, chlorine, bromine and iodine Alkoxy group, or a C ₁ ~C ₈ Is an alkylamino group, R ₂ is a halogen atom selected from H, fluorine, chlorine, bromine and iodine or C _{1 to} C ₈ Alkyl group, R ₃ and R ₄ are each H, C _{1 to} C ₈ Alkoxy group or C _{1 to} C ₈ Alkylamino group.

Description

ISOINDOLONES WITH HIGH BINDING AFFINITY TO β-AMYLOID AGGREGATES AND FIBRILS, AND PREPARATION METHOD THEREOF}

The present invention is a beta-amyloid fibrils (beta -amyloid fibril) excellent coupling the represented and early diagnosis of degenerative cerebral diseases including dementia, and prevention and useful in the treatment isoindole Ron (isoindolone) compound, its production of these diseases affinity for It relates to a method and a pharmaceutical composition comprising the same.

The continuous improvement of living standards and the development of health and medical technology prolong the life expectancy of the people, resulting in the rapid growth of the elderly population. As a result of the aging of the population, aging dementia, a degenerative neurological disease commonly observed in the elderly, has emerged as a major social problem as one of the most serious diseases of the elderly.

Dementia is not a disease caused by one cause but a clinical syndrome caused by various causative diseases. There are more than 70 causative diseases known to date. Among them, the causative diseases known to cause senile dementia include Alzheimer's disease, cerebrovascular dementia, and Parkinson's disease.

Alzheimer's disease (AD), which accounts for the majority of dementia-caused diseases, was first discovered in 1907 by German doctor Alois Alzheimer. Alzheimer's disease is a neurodegenerative disease, and the incidence increases with age, according to the US statistics. One in ten people over 65 years old and four out of 10 people over 85 years old suffer from this disease.

Patients with Alzheimer's disease show decreased brain tissue volume, decreased brain activity metabolism, and the brain is only about one-fourth the size of normal people because of the decrease in the number of neurons in the brain. Symptoms include memory loss, loss of cognition, impairment of thinking and judgment, personality changes, and emotional disorders. Later, they become unable to care for themselves and die. The exact etiology and treatment of Alzheimer's disease is not yet known, but the brain of the patient shows that neurons secreting the neurotransmitter acetylcholine are selectively degraded.

Acetylcholine (acetylcoline) is an important substance used in the brain function of memory and learning, and in the past it has been believed that the decrease of acetylcholine is the cause of Alzheimer's disease. Accordingly, drugs with various mechanisms to solve the deficiency of acetylcholine have been developed. Typical drugs include Tacrine (trade name Cognex), Donepezil (product name Aricept), and Rivastigmine (product name Exelon) approved by the US Food and Drug Administration (FDA), and estrogen, vitamin C or E, which can inhibit or prevent neurodegeneration. Antioxidants, such as non-steroidal anti-inflammatory drugs (NSAIDs) And anti-inflammatory drugs. However, these drugs are acetylcholine degrading enzyme inhibitors and cannot be treated fundamentally, and are limited in that they only temporarily improve impaired cognitive function. Therefore, there is a need for the development of therapeutic drugs that enable the treatment of causes.

To date, pathological findings associated with Alzheimer's disease include senile plaques (SPs) and neuritic plaques, protein deposits observed outside neurons, as well as neurofibrillary bundles that look like tangled threads inside neurons. tangles, NFTs).

The senile plaque is composed of beta-amyloid protein, which is mostly composed of about 40-42 amino acids, and the bundle of cardiac fibers is a cell caused by hyperphosphorylation of tau, a microtubule-binding protein. It is made by my protein aggregation. It is estimated that abnormal protein aggregation, which is common in these two phenomena, is closely related to the pathogenesis of the disease. Therefore, the beta-amyloid hypothesis that beta-amyloid will be the cause of Alzheimer's disease is strongly accepted by various experimental evidences after the acetylcholine hypothesis, which was thought to be the cause of Alzheimer's disease in the early 1980s. .

The senile plaque is entangled with one or two kinds of proteins in the central part. This protein is composed of 40 or 42 amino acids. Aβ 40 is composed of 40 amino acids and Aβ 42 is composed of 42 amino acids. Aβ40 is the most common cause of Alzheimer's disease, while Aβ42 is highly virulent and Aβ42 is highly virulent and accounts for most of the amyloid deposits present in the central plaque.

Looking at the process of Aβ42 production, first, beta-amyloid protein is produced from amyloid precursor protein (APP). There are α, β, γ-secretases in the brain, among which ββ is produced by cleaving both ends of the Aβ42 amino acid sequence of APP. APP is a protein present in the brain of normal humans, and is usually metabolized by α-secretase and is present mostly in the secreted form of sAPPα. sAPPα acts like a growth factor in the brain, promotes the growth of brain cells, and plays an important role in memory and learning ability. In patients with Alzheimer's disease, abnormalities in these metabolisms occur, and a small amount of Aβ 42, which should be present, is generated in large quantities to form fibrils, and fibrils gather to form plaques.

Today, the share of medical imaging in clinical medicine has increased tremendously, and medical imaging tests such as X-rays, ultrasound, and computed tomography (CT) have contributed significantly to the development of 20th century medical science and to the diagnosis and treatment of patients. . However, since these anatomical imaging techniques have been aimed at early detection of pathological anatomical changes, there are limitations in detecting abnormalities at the molecular or cellular level and applying them to treatment. Recently, thanks to the development of molecular biology, gene therapy and gene duplication technology has been developed, and since 1990, reporter gene technology has been introduced to attract molecular images that can image molecular and cellular levels in vivo. It became.

Molecular imaging is a non-invasive method of imaging life phenomena in cells or molecular units of living organisms. It can help diagnose diseases by imaging microscopic functional differences in the initial state where anatomical changes do not occur. have. Molecular imaging therefore enables early detection and treatment of pre-disease conditions, new possibilities in the development of therapeutic agents, and early evaluation of post-treatment responses to minimize the toxicity associated with treatment and to tailor treatments to patients. . Inspection methods for obtaining such images include single photon emission computed tomography (SPECT) and positron emission tomography (PET). Imaging techniques using PET or SPECT are rapidly developing to evaluate the function of the central nervous system and are actually useful techniques for basic medical research and clinical practice. Both techniques are useful in distinguishing between steady state and disease information. In general, PET has better sensitivity and resolution, and can better reflect biochemical changes in quantitative analysis. More useful.

Recently, studies on brain imaging of dementia patients have been actively conducted. Among these, anatomical images such as CT and MRI can detect structural abnormalities of tumors and brains, but they are limited in that they do not detect typical degenerative changes early in the brain. Accordingly, molecular images using nuclear medicine techniques such as SPECT and PET are being actively researched as a tool for diagnosing Alzheimer's disease, and especially radioactive PET for imaging beta-amyloid accumulation which is considered as a causative agent of Alzheimer's disease. Research into the development of probes is actively conducted.

Compounds known to bind well with beta-amyloid fibril include Congo red (CR) derivatives, benzothiazole derivatives and naphthalene derivatives. Congo red (CR) derivatives are dyes that bind strongly to beta-amyloid fibrils, but have too polar and hydrophilic organic acid groups that do not cross the brain blood barrier (BBB). Thioflavin-T (Th-T), a benzothiazole derivative, is also difficult to develop as a radioactive probe because it is very difficult to cross the cerebrovascular barrier due to the charged and negative ions.

Recently, researches on derivatives of these compounds have been actively conducted to solve such problems. Among these, [ N -methyl- ¹¹ carbon] 2- (4'-methylaminophenyl) -6-hydroxybenzothiazole (Pittsburgh Compound-B, PIB compound) (Klunk, WE et al. Annals of Neurology, 55 , 306 (2004)), 2- (4'-dimethylaminophenyl) -6-iodoimidazo [1,2- α ] pyridine (IMPY compound) (Kung, HF et al. Brain Research , 956 , 202 (2002)), 2- (4'-dimethylaminophenyl) -6-iodobenzoxazole (IBOX compound) (Kung, HF et al. Nuclear) Medicine and Biology , 28 , 887 (2001)), ( E , E ) -1-iodo-2,5-bis (3-hydroxycarbonyl-4-methoxy) styrylbenzene (IMSB compound) (document Kung, HF et al. Journal of Medicinal Chemistry , 44 , 2270 (2001)], etc.) are typically reported to be able to bind beta-amyloid well, and also easy to cross the cerebrovascular barrier. Since these compounds specifically recognize beta-amyloid fibrils, many studies have been conducted as early diagnostic reagents for diagnosing dementia before senile plaques or beta-amyloid fibrils are formed in the brain.

The benzothiazole derivative, PIB, is a chemically altered Th-T that increases fat solubility and can be used as a diagnostic reagent because it can cross the cerebrovascular barrier and bind strongly to beta-amyloid. However, PIB is labeled with the radioactive isotope ¹¹ C, so its half-life is very short (20 minutes). The naphthalene derivative 2- (1- {6-[(2- [ ¹⁸ fluorine] fluoroethyl) (methyl) amino] -2-naphthyl} ethylidine} malononitrile (FDDNP) is a chemical agent of naproxen. Is the first hydrophobic molecular imager to be developed, which can cross the cerebrovascular barrier, has a high affinity for beta-amyloid fibrils, the amount of senile plaques (SPs) and neurofibrillary tangles (NFTs), and It is reported that the location is known, but FDDNP does not bind specifically to beta-amyloid, but has a disadvantage of nonspecific binding to other tissues.

The cause of Alzheimer's disease has not been clarified to date, but in view of the evidence, the accumulation of toxic protein beta-amyloid and its regression of neurons are known as the main symptoms or causes. Recent studies have shown that oligomers are five times more toxic than beta-amyloid fibrils, and that only Aβ42 forms this oligomer form.Along with the fibrils produced by Aβ42, oligomers are also known as Alzheimer's. It has emerged as a new target for the treatment of illness.

Accordingly, it is an object of the present invention to provide a compound or a pharmaceutically acceptable salt thereof, which exhibits excellent binding affinity to beta-amyloid fibril, and a method for preparing the same.

Another object of the present invention is to provide a pharmaceutical composition for early diagnosis, prevention or treatment of dementia containing the compound as an active ingredient.

Another object of the present invention is to provide an inhibitor of the formation of beta-amyloid fibrils containing the compound as an active ingredient.

The inventors of the present invention are isoindole-1,3-dione, a novel compound synthesized based on the skeletal structure of indoprofen, a non-steroidal anti-inflammatory drug. Isoindolone compounds, including isoindol-1-one and isoindol-1-one, have shown a particularly good binding ability to beta-amyloid and easy cerebrovascular barrier permeability. In addition, the inventors have found that these compounds can be useful for the prevention or treatment of diseases associated with beta-amyloid accumulation by inhibiting the formation of plaques as well as the formation of fibrils or oligomers, and radioactive isotopes such as ^The present invention was completed by confirming that labeling with ¹¹ C and ¹⁸ F can be used for early diagnosis of diseases associated with beta-amyloid accumulation.

Accordingly, the present invention relates to a compound of formula 1 or a pharmaceutically acceptable salt thereof.

In the formula,

A is a C═O or CH ₂ group,

R ₁ is a halogen atom selected from H, OH, fluorine, chlorine, bromine and iodine, C _{1 to} C ₈ Alkyl group, C _{1 to} C ₈ Alkoxy group, a tosyloxy -C ₁ ~C ₈ Alkoxy group, a mesyl oxy -C ₁ ~C ₈ An alkoxy group, an aryloxy nosil -C ₁ ~C ₈ C ₁ to C ₈ substituted with halogen atoms selected from alkoxy groups, fluorine, chlorine, bromine and iodine Alkoxy group, or a C ₁ ~C ₈ Alkylamino group,

R ₂ is a halogen atom selected from H, fluorine, chlorine, bromine and iodine or C _{1 to} C ₈ An alkyl group,

R ₃ and R ₄ are each H, C _{1 to} C ₈ Alkoxy group or C _{1 to} C ₈ Alkylamino group.

The compound of formula 1 includes a compound labeled with a radioactive element, such as a compound in which at least one halogen or carbon atom is a radioactive isotope, such as ¹⁸ F or ¹¹ C, in its molecular structure.

In addition, the present invention provides a method for preparing the compound of Formula 1, and a pharmaceutical composition for treating degenerative brain disease containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a pharmaceutical composition for the prevention, treatment and early diagnosis of a disease directly related to beta-amyloid fibrils containing the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

When such a pharmaceutical composition is used as a diagnostic reagent, the compound of formula 1 is a compound labeled with a radioactive element, such as one or more halogens or carbon atoms in its molecular structure, radioactive isotopes such as ¹⁸ F or ¹¹ C. Can be.

Hereinafter, the present invention will be described in more detail.

Formula 1a represents an isoindole-1,3-dione derivative in which A is a C═O group in Formula 1 compound.

In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as defined in Chemical Formula 1.

The following compounds 1a-1 to 1a-27 are preferable examples of the isoindole-1,3-dione derivative compound represented by the general formula (1a).

(1a-1) 5-dimethylamino-2- (4-dimethylaminophenyl) isoindole-1,3-dione;

(1a-2) 5-methoxy-2- (4-dimethylaminophenyl) isoindole-1,3-dione;

(1a-3) 5-hydroxy-2- (4-dimethylaminophenyl) isoindole-1,3-dione;

(1a-4) 5-methyl-2- (4-dimethylaminophenyl) isoindole-1,3-dione;

(1a-5) 2- (4-dimethylaminophenyl) isoindole-1,3-dione;

(1a-6) 5-fluoro-2- (4-dimethylaminophenyl) isoindole-1,3-dione;

(1a-7) 5-chloro-2- (4-dimethylaminophenyl) isoindole-1,3-dione;

(1a-8) 5-bromo-2- (4-dimethylaminophenyl) isoindole-1,3-dione;

(1a-9) 5-dimethylamino-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione;

(1a-10) 5-methoxy-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione;

(1a-11) 5-methyl-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione;

(1a-12) 2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione;

(1a-13) 5-fluoro-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione;

(1a-14) 5-chloro-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione;

(1a-15) 5-bromo-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione;

(1a-16) 2- (3-dimethylamino-4-methoxyphenyl) isoindole-1,3-dione;

(1a-17) 2- (3-dimethylaminophenyl) isoindole-1,3-dione;

(1a-18) 5-methoxy-2- (4-aminophenyl) isoindole-1,3-dione;

(1a-19) 5-methoxy-2- (4-methylaminophenyl) isoindole-1,3-dione;

(1a-20) 5-hydroxy-2- (4-aminophenyl) isoindole-1,3-dione;

(1a-21) 5-hydroxy-2- (4-methylaminophenyl) isoindole-1,3-dione;

(1a-22) 5- (2-fluoroethoxy) -2- (4-aminophenyl) isoindole-1,3-dione;

(1a-23) 5- (2-fluoroethoxy) -2- (4-methylaminophenyl) isoindole-1,3-dione;

(1a-24) 5- (2-fluoroethoxy) -2- (4-dimethylaminophenyl) isoindole-1,3-dione;

(1a-25) 5- (3-fluoropropoxy) -2- (4-aminophenyl) isoindole-1,3-dione;

(1a-26) 5- (3-fluoropropoxy) -2- (4-methylaminophenyl) isoindole-1,3-dione;

(1a-27) 5- (3-fluoropropoxy) -2- (4-dimethylaminophenyl) isoindole-1,3-dione.

Formula 1b represents an isoindol-1-one derivative in which A is a CH ₂ group in Formula 1 above.

In the formula, R ₁ , R ₂ , R ₃ and R ₄ are the same as defined in Chemical Formula 1.

The following compounds 1b-1 to 1b-33 are preferable examples of the isoindole-1-one derivative compound represented by the general formula (1b).

(1b-1) 5-methoxy-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-2) 5-hydroxy-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-3) 5-methyl-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-4) 2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-5) 5-fluoro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-6) 5-chloro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-7) 5-bromo-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-8) 6-methyl-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-9) 6-fluoro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-10) 6-chloro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-11) 5-methoxy-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-12) 5-methyl-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-13) 2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-14) 5-fluoro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-15) 5-chloro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-16) 5-bromo-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-17) 6-methyl-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-18) 6-fluoro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-19) 6-chloro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-20) 2- (3-dimethylamino-4-methoxyphenyl) -2,3-dihydroisoindol-1-one;

(1b-21) 2- (3-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-22) 5-methoxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one;

(1b-23) 5-methoxy-2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-24) 5-methoxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one;

(1b-25) 5-methoxy-2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-26) 5- (2-fluoroethoxy) -2- (4-aminophenyl) -2,3-dihydroisoindol-1-one;

(1b-27) 5- (2-fluoroethoxy) -2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-28) 5- (2-fluoroethoxy) -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-l-one;

(1b-29) 5- (3-fluoropropoxy) -2- (4-aminophenyl) -2,3-dihydroisoindol-1-one;

(1b-30) 5- (3-fluoropropoxy) -2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-31) 5- (3-fluoropropoxy) -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one;

(1b-32) 5-methoxy-2- (4- ¹¹ methylaminophenyl) -2,3-dihydroisoindol-1-one; And

(1b-33) 5- (2- to ¹⁸ in-trifluoroethoxy) -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one.

The compound of Formula 1 includes all forms of pharmaceutically acceptable salts derived from conventional inorganic or organic acids which are well known to those skilled in the art. Examples of inorganic or organic acids capable of forming pharmaceutically acceptable salts with compounds of Formula 1 include hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid , Fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc. Can be mentioned.

Hereinafter, a method for preparing the compound of Formula 1 according to the present invention will be described.

Method for producing a compound of formula (1) according to the present invention, for example, phthalic anhydride, for example, a compound represented by the formula (2a) or an ester of an alkylbenzoic acid having a suitable leaving group, for example, represented by the formula (2b) Reacting a compound with an aromatic amine compound represented by the formula (3).

In Formulas 2a, 2b, and 3, R ₁ , R ₂ , R _3, and R ₄ are the same as defined for Formula 1, respectively.

Scheme 1 is a schematic diagram of a method for preparing the compound of formula 1 according to the present invention by reacting the compound of formula 2a or 2b with formula 3.

In formula, A and R <_1> , R <_2> , R ₃ and R ₄ are the same as defined for Chemical Formula 1, respectively.

The reaction shown in Scheme 1 preferably proceeds by heating to reflux in an acidic solvent. At this time, acetic acid, hydrochloric acid or paratoluenesulfonic acid, preferably acetic acid may be used as the acidic solvent.

Compounds of formula (2a) or (2b) used as starting materials in the present invention are known from phthalic acid or 2-methylbenzoic acid, which are known compounds (Kazemi, F. et al, Phosphorus, Sulfur and Silicon, 2003 , 178 , 2287). -2291; Prasad, CSN et al, Heterocycl. Commun. 2002 , 8 , 281-286), respectively, by the methods illustrated in Schemes 2a and 2b.

In Schemes 2a and 2b, R ₁ And R ₂ are as defined for Formula 1, respectively.

As shown in Scheme 2a, phthalic acid is dissolved in a suitable solvent such as dichloromethane or chloroform with thionyl chloride, phosphorus oxychloride or phosphorus pentachloride, and 1,4-diazabicyclic [2.2.2]. In the presence of octane, the compound of formula 2a is obtained by cyclization reaction starting from 0 ° C to room temperature.

On the other hand, as shown in Scheme 2b, 2-methylbenzoic acid is heated to reflux with thionyl chloride, phosphorus oxychloride or phosphorus pentachloride in alcohol, preferably methanol or ethanol to give ethyl 2-methyl benzoic acid ester compound. The resulting mixture was heated and refluxed in the presence of N-bromosuccinimide and benzoyl peroxide in a suitable organic solvent to obtain ethyl 2-bromoethylbenzoic acid ester compound of Formula 2b.

Scheme 3 shows a process for preparing compounds 1a-18, 1a-20, 1b-22 and 1b-24, which are examples of compounds of formula 1, from compounds of formula 2a or 2b wherein R ₂ is hydrogen and R ₁ is a methoxy group It is shown.

In the formula, A and R ₄ are as defined in the formula (1), respectively.

As shown in Scheme 3, a compound of formula 2a or 2b is reacted with a compound of formula 3 to produce 5-methoxy-2- (4-nitrophenyl) isoindole-1,3-dione or 5-methoxy-2- ( 4-nitrophenyl) -2,3-dihydroisoindol-1-one compound was obtained, and these compounds were respectively prepared in an alcohol solvent such as methanol, ethanol, tin (Sn), zinc (Zn), iron ( Reaction with Fe), hydrazine (H ₂ N ₄ / FeCl ₃ ), copper sulfate (CuSO ₄ ) or tin chloride (SnCl ₂ ), preferably tin chloride (SnCl ₂ ) at 64 ° C to 78 ° C for 8 to 12 hours Compounds 1a-18 and 1b-22 are obtained.

In addition, compounds 1a-18 and 1b-22 were each added boron trichloride, boron trifluoride, boron tribromide, boron triiodide or iodotrimethylsilane, preferably boron tribromide, in dichloromethane or chloroform, Demethylation by stirring at from -70 [deg.] C. for 8-12 hours yields compounds 1a-20 and 1b-24.

Scheme 4 below illustrates a representative process for preparing compounds of Formula 1 wherein R ₃ is an alkylamino group, ie compounds 1a-19, 1a-21 and 1b-23, 1b-25. This reaction step is a reductive amination reaction of the amino compound obtained in the reduction reaction step of the nitro group of Scheme 3 with sodium methoxide, paraformaldehyde and sodium borohydride for 2 to 3 hours at 0 ℃ to 65 ℃ amination).

In the formulas, A and R ₄ are each as defined in the formula (1), and R ₅ is a methoxy or hydroxy group.

On the other hand, the compound of the formula (1) wherein R ₃ or R ₄ is a dialkylamino group, that is, compounds 1a-1 to 1a-17 and 1b-1 to 1b-21 can be prepared directly by Scheme 1.

Scheme 5 below illustrates the preparation of compounds 1a-22 to 1a-27 and 1b-26 to 1b-31 compounds of the present invention. This reaction is carried out using the 5-hydroxyisoindole-1,3-dione or 5-hydroxy-2,3-dihydroisoindol-1-one compound obtained by the method illustrated in Scheme 3 above in a dimethylformamide. For example, a compound represented by the general formula F (CH ₂ ) _n OR ₆ in the presence of potassium carbonate, wherein R ₆ is a tosyl (Ts), mesyl (Ms) or nosyl (Ns) group, and n is 2 or 3 And nucleophilic substitution reaction at 70 ° C. for 1 to 2 hours.

In the formulas, A, R ₃ and R ₄ are the same as defined in the general formula (1), R ₆ is a tosyl, mesyl or nosyl group, and n is 2 or 3. Here, the tosyl, mesyl and nosyl groups refer to p -toluenesulfonyl, methanesulfonyl and p -nitrobenzenesulfonyl groups as well known to those skilled in the art.

Radioactive by isotope of a compound labeled with ¹¹ C is generated the from the ^[11 C] carbon dioxide ^([11 C] CO ₂₎ gas generated in the cyclotron ^[11 C] methoxy-triflate _{^{([11 C] CH 3 OTf}} ) After reacting for 1 minute at 80 ℃, it can be obtained by the purification using high performance liquid chromatography. Schematic of this is shown in Scheme 6 below.

In formula, A and R <_1> , R <_2> , R <_4> are as having defined with respect to the said Formula (1), respectively.

Meanwhile, a compound labeled with ¹⁸ F, which is a radioisotope, can be prepared through two steps, Scheme 7 and Scheme 8. First, as shown in Scheme 7, a 5-hydroxyisoindole-1,3-dione or 5-hydroxy-2,3-dihydroisoindol-1-one compound was added as a base in dimethylformamide. For example, a compound represented by the general formula R ₆ O (CH ₂ ) _n OR ₆ in the presence of potassium carbonate, wherein R ₆ is a tosyl (Ts), mesyl (Ms) or nosyl (Ns) group, and n is 2 or 3 And nucleophilic substitution reaction at 70 ° C. for 1 to 2 hours to obtain a reaction intermediate.

In formula, A, R <_3> , R <_4> is as having respectively defined in General formula (1), R <_6> is a tosyl, mesyl, or nosyl group, n is 2 or 3.

Subsequently, the intermediate obtained by the reaction shown in Scheme 7 quaternary butylammonium ¹⁸ fluoride (TBAF ¹⁸⁾ and when purified using a reaction was then high performance liquid chromatography over at 120 ℃ 10 bun radioisotope is ¹⁸ F A compound labeled with is obtained. Schematic of this is shown in Scheme 8 below.

In the formulas, A, R ₃ and R ₄ are the same as defined in the general formula (1), R ₆ is a tosyl, mesyl or nosyl group, and n is 2 or 3.

Formulas 4 to 10 show specific examples of the compound of Formula 1, which may be synthesized by the method illustrated in Schemes 1 to 8.

[Formula 4]

[Chemical Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

In Formulas 4 to 10, A, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ and n are as defined above, and X is a halogen atom selected from fluorine, chlorine, bromine and iodine.

Example

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the examples presented below are only for illustrating the present invention, but the scope of the present invention is not limited thereto.

Example 1: Preparation of 4-methoxyphthalic anhydride (2a)

1,4-diazabicyclic [2.2.2] octane (336 mg, 3 mmol) was dissolved in anhydrous dichloromethane (3 mL), and distilled thionyl chloride (0.2 mL, 3 mmol) was slowly added at 0 ° C. Stir for 5 minutes with dropwise addition. Then 4-methoxyphthalic acid (200 mg, 1 mmol) was slowly added dropwise and stirred at room temperature for 50 minutes. 10% sodium bicarbonate was added to neutralize the reaction mixture solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure, separated and purified by column chromatography (silica gel, hexane / ethyl acetate = 3: 1) to obtain 139 mg (yield 78%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (d, J = 5.6 Hz, 1H) 7.43 (d, J = 2.9, 1H), 7.36 (dd, J = 11.2, 3.0 Hz, 1H), 3.99 (s , 1H).

¹³ C NMR (75 Hz, CDCl ₃ ) δ 166.17, 163.00, 162.43, 134.14, 127.28, 123.22, 123.98, 108.89, 56.44.

Example 2: Preparation of ethyl 2-bromomethyl-4-methoxybenzoic acid ester (2b)

Ethyl 2-methyl-4-methoxybenzoic acid ester (583 mg, 3 mmol) and N -bromosuccinimide (1335 mg, 7.5 mmol) were added to carbon tetrachloride (8 mL) and heated to reflux for 6 hours. After completion of the reaction, N -bromosuccinimide was removed by filtration, and carbon tetrachloride was distilled off under reduced pressure. Purification by column chromatography (silica gel, hexane / ethyl acetate = 40: 1) afforded 340 mg (yield 48%) of the title compound.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.99 (d, J = 2.6 Hz, 1H), 6.96 (d, J = 2.6 Hz, 1H), 6.85 (dd, J = 8.8, 2.6 Hz, 1H), 4.96 (s, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.86 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.15, 162.46, 141.56, 133.63, 121.33, 117.03, 113.56, 60.93, 55.50, 31.91, 14.29.

Example 3: Preparation of 5-methoxy-2- (4-nitrophenyl) isoindole-1,3-dione

1.1 g (6.2 mmol) of the 4-methoxyphthalic anhydride compound obtained in Example 1 was dissolved in 10 mL of acetic acid, and 856 mg (6.2 mmol) of 4-nitroaniline was added dropwise under a stream of nitrogen at 100 ° C., followed by 12 hours. Heated to reflux. At the end of the reaction, neutralized by addition of 10% NaHCO ₃ solution, extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 1.7 g (92%) of the title compound as a pale yellow solid.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.97 (s, 3H), 7.41 (dd, J = 2.2, 8.4 Hz, 1H), 7.53 (d, = 2.1 Hz, 1H), 7.78 (d, J = 9.0 Hz, 2H), 7.94 (d, J = 8.3 Hz, 1H), 8.40 (d, J = 9.0 Hz, 2H).

Example 4: Preparation of 5-methoxy-2- (4-nitrophenyl) -2,3-dihydroisoindol-1-one

1.72 g (6.3 mmol) of the ethyl 2-bromomethyl-4-methoxybenzoic acid ester compound obtained in Example 2 were dissolved in 20 mL of acetic acid, and 870 mg (6.3 mmol) of 4-nitroaniline under a stream of nitrogen at 100 ° C. After dropwise addition, the mixture was heated to reflux for 5 hours. At the end of the reaction, 10% NaHCO ₃ solution was added to neutralize, extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 900 mg (50%) of the title compound as a yellow solid.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.89 (s, 3H), 5.06 (s, 2H), 7.11 (d, J = 8.5 Hz, 1H), 7.23 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 9.4 Hz, 2H), 8.32 (d, J = 9.4 Hz, 2H).

Example 5: Preparation of 5-methoxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one (1b-22)

To 531 mg (1.86 mmol) of the 5-methoxy-2- (4-nitrophenyl) -2,3-dihydroisoindol-1-one compound obtained in Example 4 was added dropwise 25 mL of ethanol. After adding 2.1 g (9.3 mmol) of tin chloride, the mixture was heated to reflux for 24 hours. At the end of the reaction, 1 N sodium hydroxide solution was added to adjust pH to 10, distillation under reduced pressure to remove ethanol, and the residue was filtered using ethyl acetate and extracted with water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered to give 450 mg (95% yield) of the title compound as a yellow solid.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.85 (s, 3H), 5.02 (s, 2H), 5.33 (s, NH ₂ ), 6.60 (d, J = 8.6 Hz, 2H), 7.05 (d , J = 8.4 Hz, 1H), 7.16 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H).

Example 6: Preparation of 5-hydroxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one (1b-24)

50.8 mg (0.2 mmol) of the 5-methoxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one compound obtained in Example 5 was dissolved in 8 mL of anhydrous dichloromethane, and 0 2 mL (2 mmol) of boron tribromide (BBr ₃ ) was added under a nitrogen stream at 0 ° C., and the mixture was heated to reflux for 12 hours. When the reaction was terminated, neutralized with 1 N sodium hydroxide, extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 28 mg (yield 58%) of the title compound as a beige solid.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 4.75 (s, 2H), 5.00 (s, NH ₂ ), 6.59 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.5 Hz, 1H ), 6.91 (s, 1 H), 7.42 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 10.39 (bs, OH).

Example 7: Preparation of 5-hydroxy-2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one (1b-25)

50.8 mg (0.2 mmol) of the 5-hydroxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one compound obtained in Example 6 was dissolved in 8 mL of anhydrous dichloromethane, and 0 2 mL (2 mmol) of boron tribromide (BBr ₃ ) was added under a nitrogen stream at 0 ° C., and the mixture was heated to reflux for 12 hours. At the end of the reaction, the reaction was neutralized with 1 N sodium hydroxide, extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 28 mg (yield 58%) of the title compound as a beige solid.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 4.75 (s, 2H), 5.00 (s, NH ₂ ), 6.59 (d, J = 8.1 Hz, 2H), 6.86 (d, J = 8.5 Hz, 1H ), 6.91 (s, 1 H), 7.42 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.7 Hz, 1H), 10.39 (bs, OH).

Example 8: Preparation of 5-methoxy-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-1)

Acetic acid (1 mL) of ethyl 2-bromomethyl-4-methoxybenzoic acid ester compound (273 mg, 1 mmol) and N, N -dimethylbenzene-1,4-diamine (136 mg, ammol) obtained in Example 2 was obtained. ) Was heated to reflux at 120 ° C. for 4 hours. 10% sodium bicarbonate was added to neutralize the reaction mixture solution, and extracted with water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, hexane / ethyl acetate = 3: 1) to obtain 78 mg (yield 9%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82 (d, J = 11.1 Hz, 1H), 7.63 (d, J = 12.1 Hz, 2H), 7.00 (dd, J = 11.2, 2.8 Hz, 1H), 6.97 (s, 1 H), 6.79 (d, J = 12.2 Hz, 2H), 4.74 (s, 2H), 3.89 (s, 3H), 2.95 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.02, 162.84, 147.99, 142.51, 129.48, 126.20, 125.27, 121.50, 114.78, 113.13, 107.39, 55.67. 51.09, 40.88.

Example 9: Preparation of 5- (2-fluoroethoxy) -2- (4-aminophenyl) -2,3-dihydroisoindol-1-one (1b-26)

7.2 mg (30 mmol) of the 5-hydroxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one compound obtained in Example 6 were dissolved in 3 mL of anhydrous dimethylformamide, 6.2 mg (45 mmol) of potassium carbonate (K ₂ CO ₃ ) and 1-fluoro-2-tosyloxyethane under nitrogen stream at 0 ° C 9.8 mg (45 mmol) was added, followed by reaction at 70 ° C. for 2 hours. At the end of the reaction, the mixture was extracted with excess water and ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and filtered. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to give 5 mg (59%) of the title compound as a beige solid.

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 4.30 (m, 1H), 4.39 (m, 1H), 4.69 (m, 1H), 4.82 (s, 2H), 4.85 (m, 1H), 5.03 ( s, NH ₂ ), 6.50 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 7.19 (s, 1H), 7.44 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1H).

Example 10: 5-methoxy-2- (4- ¹¹ Preparation of Methylaminophenyl) -2,3-dihydroisoindol-1-one (1b-32)

[ ¹¹ C] CO ₂ gas was generated from nitrogen gas in cyclotron and the resulting [ ¹¹ C] CO ₂ gas was transferred from the target of cyclotron to the [ ¹¹ C] CH ₃ OTf production synthesis apparatus using helium gas. ^[11 C] CH ₃ OTf using the oven in the synthesizer ^[11 C] in which the CO ₂ gas into the ^[11 C] CH _4, and then reacted with I ₂ gas at 720 ℃ generate ^[11 C] CH ₃ I I was. The resulting [ ¹¹ C] CH ₃ I was reacted with silver triflate at 200 ° C. to produce [ ¹¹ C] CH ₃ OTf. 3.0 mg of 5-methoxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one compound obtained in Example 5 was dissolved in 400 uL of methylethylketone in a 2 mL quartz reactor. , [ ¹¹ C] CH ₃ OTf produced at 125 ° C. was collected. Upon completion of collection, the reaction was carried out at 80 ° C. for 1 minute, and then purified by high performance liquid chromatography to obtain the pure title compound.

Purification using high performance liquid chromatography A high performance liquid chromatography pump, UV detector and sodium iodide (NaI) pin detector system of [ ¹¹ C] CH ₃ OTf synthesizer were used. When injecting the sample, an automatic injection device in an automatic synthesis device was used and eluted at a rate of 4.0 mL / min with 50 mM TEAP: CH ₃ CN = 8: 2. Prodigy ODS-prep 10 mm (250 × 10 mm) was used as a column.

Example 11: Preparation of 5- (2-tosyloxyethoxy) -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one

Under nitrogen gas , anhydrous dimethylformamide (3 was dissolved in 5-hydroxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one compound (48 mg, 0.18 mmol) obtained in Example 6. mL) was added and stirred. Potassium carbonate (37 mg, 0.27 mmol) was added thereto, 1,2-bis (tosyloxy) ethane (100 mg, 0.27 mmol) was added, followed by heating to 80 ° C. After 2 hours when the reaction was complete, it was cooled and extracted with ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (33 mg, yield 40%).

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 7.80 (d, J = 8.1 Hz, 2H), 7.62 (m, 3H), 7.65 (d, J = 8.1 Hz, 2H), 7.07 (s, 1H) , 6.95 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 9.1 Hz, 2H), 4.84 (s, 2H), 4.37 (d, J = 3.1 Hz, 2H), 4.28 (d, J = 3.1 Hz, 2H), 2.89 (s, 6H), 2.40 (s, 3H).

Example 12: 5- (2- ¹⁸ Preparation of Fluoroethoxy) -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-33)

After the fluorine -18 (319.2 MBq) in water (0.5 mL) a quaternary bases in the support polymer cartridge (Chromafix ^ㄾ) ammonium salt, including a quaternary ammonium salt with the aqueous solution in butyl bicarbonate ions are dissolved in 20 mL Elution was carried out using 620 mL of a mixture of 300 mL of acetonitrile and 300 mL of water. The solution was azeotropically mixed distilled with nitrogen gas and acetonitrile (3 x 500 mL) at 100 ° C to completely remove moisture. The obtained quaternary butylammonium ¹⁸ fluoride (TBAF ¹⁸ ) was dissolved in 200 mL of acetonitrile and 500 mL of t -amyl alcohol, and 5- (2-tosyloxyethoxy) -2- (4- obtained in Example 11 4.0 mg (8.57 mmol) of dimethylaminophenyl) -2,3-dihydroisoindol-1-one were added. The reaction mixture was heated at 120 ℃ for 10 minutes and 5- (2-to ^{18-fluoro-ethoxy)} -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one to give the indole compound. The reaction yield (39.07%) was confirmed using thin membrane chromatography. The reaction solvent was removed by blowing nitrogen gas at 120 ° C., and the residue was dissolved in 1 mL of acetonitrile and then purified by high performance liquid chromatography. Injection with the 5- (2-fluoroethoxy) -2- (4-aminophenyl) -2,3-dihydroisoindol-1-one compound obtained in Example 9 confirmed that the title compound was synthesized. . Peaks with the same retention time were obtained in UV and radioactive chromatograms at around 9.5 minutes.

For purification using high performance liquid chromatography, a high performance liquid chromatography pump, UV detector (TSP, USA) and sodium iodide (NaI) pin detector system (Bioscan, Washington DC, USA) were used. 2 mL of high performance liquid chromatography loop and manual injector were used to inject the sample. Elution was performed at 4.0 mL / min with water: acetonitrile = 60: 40. Prodigy ODS-prep 10 mm C ₈ (250 × 10 mm) was used as a column.

Examples 13-65

The compounds of Examples 13-65 below were prepared in a similar manner to Examples 1-9 above. The structural confirmation data of these compounds is as follows.

Example 13: 5-dimethylamino-2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-1)

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 7.15 (s, 1H), 6.84 (d, J = 9.4 Hz , 1H) 6.80 (d, J = 8.6 Hz, 2H), 3.13 (s, 6H), 2.98 (s, 6H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 168.75, 168.37, 154.46, 150.06, 134.65, 127.62, 125.06, 120.86, 117.54, 114.86, 112.60, 105.85, 40.62, 40.52.

Example 14 5-methoxy-2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-2)

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.83 (d, J = 8.3 Hz, 1H), 7.41 (d, J = 2.2 Hz 1H), 7.27-7.19 (m, 3H), 6.80 (dd, J = 7.0 , 2.0 Hz), 3.95 (s, 3H), 3.00 (s, 6H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 167.74, 164.79, 150.21, 134.62, 127.54, 125.23, 123.88, 120.27, 120.11, 112.52, 108.06, 56.13, 40.55.

Example 15 5-hydroxy-2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-3)

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.0 (s, 1H), 7.75 (d, J = 10.7 Hz, 1H), 7.18-7.15 (m, 4H), 6.80 (d, J = 11.9 Hz, 2H), 2.94 (s, 6H).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 167.67, 163.81, 134.80, 128.54, 125.92, 122.17, 121.04, 113.57, 110.27, 41.25.

Example 16: 5-methyl-2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-4)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82 (d, J = 7.6 Hz, 1H), 7.75 (s, 1H), 7.56 (d, J = 10.2 Hz, 1H), 7.27-7.25 (m, 2H) , 6.85 (bs, 2H), 3.01 (s, 6H), 2.55 (s, 3H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 168.11, 168.00, 150.16, 145.41, 134.69, 132.35, 129.38, 127.52, 124.03, 123.44, 120.31, 112.55, 40.58, 22.05.

Example 17 2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-5)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97-7.92 (m, 2H), 7.80-7.76 (m, 2H), 7.26 (d, J = 7.1 Hz, 2H), 6.83 (d, J = 8.2 Hz, 2H), 3.02 (s, 6H).

¹³ C NMR δ (75 MHz, CDCl ₃ ) 167.95, 150.20, 134.16, 131.97, 127.54, 123.54, 120.10, 112.56, 40.60.

Example 18 5-fluoro-2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-6)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (dd, J = 8.2, 4.5 Hz, 1H), 7.62-7.59 (m, 1H), 7.47-7.40 (m, 1H), 7.24 (d, J = 8.9 Hz, 2H), 6.82 (d, J = 8.8 Hz, 2H), 3.01 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 168.19, 166.86, 166.54, 166.51, 164.79, 150.25, 134.88, 134.76, 127.76, 127.72, 127.43, 125.98, 125.85, 121.31, 121.00, 119.93, 112.53, 111.45, 111.12, 111.12 .

Example 19: 5-chloro-2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-7)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.90 (d, J = 1.1 Hz, 1H), 7.86 (d, J = 6.0 Hz, 1H), 7.73 (dd, J = 6.0, 1.3 Hz, 1H), 7.24 (d, J = 6.7 Hz, 2H), 6.84 (d, J = 5.0 Hz, 2H), 3.00 (s, 6H).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 167.00, 166.67, 150.34, 140.80, 134.19, 133.65, 130.03, 127.42, 124.80, 123.97, 119.65, 112.44, 40.51.

Example 20 5-bromo-2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-8)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.07 (d, J = 1.3 Hz, 1H), 7.91 (dd, J = 7.9, 1.6 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.25 -7.22 (m, 2H), 6.81 (d, J = 9.0 Hz, 2H), 3.01 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.09, 166.55, 150.35, 137.13, 133.63, 130.52, 129.00, 127.40, 126.86, 124.90, 119.72, 112.45,40.49.

Example 21 5-dimethylamino-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione (1a-9)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.74 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.95 (dd , J = 8.4, 2.1 Hz, 1H), 6.88 (d. J = 2.1 Hz, 1H), 6.85 (dd, J = 8.6, 2.4 Hz, 1H), 3.90 (s, 3H), 3.16 (s, 6H) , 2.82 (s, 6 H).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 168.51, 168.08, 154.59, 152.45, 134.50, 125.26, 119.18, 118.22, 117.26, 115.06, 109.96, 105.90, 55.57, 43.31, 40.56.

Example 22 5-methoxy-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione (1a-10)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.23 (dd, J = 8.3, 2.3 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.96 (dd, J = 8.4, 2.1 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H) , 2.83 (s, 6 H).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 167.50, 165.02, 152.51, 142.26, 134.51, 125.92, 125.47, 123.73, 120.38, 119.18, 118.25, 109.90, 108.25, 56.23, 55.64, 43.28.

Example 23 5-methyl-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione (1a-11)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82 (d, J = 7.6 Hz, 1H), 7.57 (d, J = 7.1 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.95 (dd , J = 8.4, 2.1 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 3.90 (s, 3H), 2.82 (s, 6H), 2.55 (s, 3H).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 167.81, 167.70, 152.43, 145.65, 134.87, 132.22, 129.25, 124.16, 123.57, 120.42, 119.12, 118.11, 109.88, 55.57, 43.20, 22.05.

Example 24 2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione (1a-12)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97-7.80 (m, 2H), 7.78-7.77 (m, 2H), 7.03 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.2 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 3.90 (s, 3H), 2.83 (s, 6H).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 167.64, 152.45, 142.46, 134.32, 131.84, 125.67, 123.67, 119.14, 118.11, 109.86, 55.58, 43.19.

Example 25: 2- (4-aminostillbene) -5- (3-fluoropropyloxy) benzoxazole (1a-13)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (dd, J = 8.2, 4.5 Hz, 1H), 7.63 (dd, J = 7.0, 2.1 Hz, 1H), 7.46 (dt, J = 8.5, 2.3 Hz, 1H), 6.98 (dd, J = 8.4, 2.1 Hz, 1H), 6.91 (d, J = 1.7 Hz, 1H), 3.92 (s, 3H), 2.88 (s, 6H).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 166.60, 166.05, 152.45, 142.63, 127.56, 126.14, 121.53, 121.29, 119.05, 118.13, 111.58, 111.33, 109.66, 55.59, 43.17.

Example 26 5-chloro-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione (1a-14)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, J = 1.4 Hz, 1H), 7.89 (d, J = 7.9 Hz, 1H), 7.76 (dd, J = 8.0, 1.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.2 Hz, 1H), 6.88 (d, J = 2.1 Hz, 1H), 3.91 (s, 3H), 2.84 (s, 6h) .

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 166.67, 166.17, 152.48, 141.10, 134.45, 133.46, 129.84, 124.95, 124.12, 119.08, 109.81, 55.65, 43.25.

Example 27 5-bromo-2- (4-dimethylamino-3-methoxyphenyl) isoindole-1,3-dione (1a-15)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, J = 1.2 Hz, 1H), 7.93 (dd, J = 7.9, 7.9 Hz, 1H), 7.82 (dd, J = 7.9, 0.3 Hz, 1H) , 7.03 (d, J = 8.4 Hz, 1H), 6.95 (dd, J = 8.4, 2.2 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 166.80, 166.26, 152.45, 137.36, 133.45, 130.42, 129.25, 127.01, 125.03, 119.06, 118.16, 109.77, 55.61, 43.15.

MS m / z 375 (M ⁺ ).

Example 28: 2- (3-dimethylamino-4-methoxyphenyl) isoindole-1,3-dione (1a-16)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97-7.94 (m, 2H), 7.81-7.78 (m, 2H), 7.02 (dd, J = 8.6, 2.2 Hz, 1H), 6.95 (d, J = 2.1 Hz, 1H), 3.94 (s, 3H), 2.83 (s, 6H).

¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 167.71, 152.16, 143.02, 134.26, 131.90, 124.42, 123.62, 120.65, 117.03, 111.14, 55.63, 43.15.

Example 29: 2- (3-dimethylaminophenyl) isoindole-1,3-dione (1a-17)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97-7.92 (m, 2H), 7.80-7.75 (m, 2H) 7.34 (t, J = 8.0 Hz, 1H), 6.78-6.70 (m, 3H), 2.98 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.52, 151.16, 134.24, 132.43, 131.94, 129.56, 123.64, 114.61, 114.40, 110.78, 40.46.

Example 30 5-methoxy-2- (4-aminophenyl) isoindole-1,3-dione (1a-18)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 3.94 (s, 3H), 5.33 (s, NH ₂ ), 6.62 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.6 Hz, 2H ), 7.35 (dd, J = 2.2, 8.3 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H).

Example 31 5-methoxy-2- (4-methylaminophenyl) isoindole-1,3-dione (1a-19)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.69 (d, J = 4.7 Hz, 3H), 3.69 (s, 3H) 5.91 (d, J = 4.5 Hz, NH), 6.60 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.2 Hz, 1H), 7.43 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H).

Example 32: 5-hydroxy-2- (4-aminophenyl) isoindole-1,3-dione (1a-20)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 5.31 (s, NH ₂ ), 6.61 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 7.13 (m, 2H ), 7.72 (d, J = 8.0 Hz, 1H), 11.24 (bs, OH).

Example 33: 5-hydroxy-2- (4-methylaminophenyl) isoindole-1,3-dione (1a-21)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.69 (d, J = 4.8 Hz, 3H), 5.90 (m, NH), 6.59 (d, J = 8.6 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 7.15 (m, 2H), 7.74 (d, J = 7.9 Hz, 1H), 10.97 (bs, OH).

Example 34: 5- (2-fluoroethoxy) -2- (4-aminophenyl) isoindole-1,3-dione (1a-22)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 4.42 (m, 1H), 4.51 (m, 1H), 4.71 (m, 1H), 4.87 (m, 1H), 5.33 (s, NH ₂ ), 6.62 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 8.5 Hz, 2H), 7.39 (dd, J = 2.0, 8.3 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H).

Example 35: 5- (2-fluoroethoxy) -2- (4-methylaminophenyl) isoindole-1,3-dione (1a-23)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.70 (d, J = 4.9 Hz, 3H), 4.42 (m, 1H), 4.52 (m, 1H), 4.71 (m, 1H), 4.87 (m, 1H), 5.91 (s, NH), 6.60 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 7.39 (dd, J = 2.1, 8.3 Hz, 1H), 7.48 ( d, J = 2.0 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H).

Example 36 5- (2-fluoroethoxy) -2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-24)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.94 (s, 6H), 4.43 (m, 1H), 4.52 (m, 1H), 4.71 (m, 1H), 4.88 (m, 1H), 6.79 ( d, J = 8.9 Hz, 2H), 7.18 (d, J = 8.9 Hz, 2H), 7.40 (dd, J = 2.1, 8.3 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.86 ( d, J = 8.3 Hz, 1H).

Example 37: 5- (3-fluoropropoxy) -2- (4-aminophenyl) isoindole-1,3-dione (1a-25)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.11 (t, J = 5.9 Hz, 1H), 2.19 (t, J = 5.9 Hz, 1H), 4.28 (t, J = 6.0 Hz, 2H), 4.55 (t, J = 5.6 Hz, 1H), 4.70 (t, J = 5.7 Hz, 1H), 5.31 (s, 2H), 6.62 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 8.4 Hz , 2H), 7.36 (d, J = 8.2 Hz, 1H), 7.43 (s, 1H), 7.83 (d, J = 8.3 Hz, 1H).

Example 38: 5- (3-fluoropropoxy) -2- (4-methylaminophenyl) isoindole-1,3-dione (1a-26)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.11 (t, J = 5.7, 6.1 Hz, 1H), 2.20 (t, J = 6.0, 6.1 Hz, 1H), 2.70 (d, J = 5.0 Hz, 3H), 4.28 (t, J = 6.2 Hz, 2H), 4.55 (t, J = 5.9 Hz, 1H), 4.71 (t, J = 5.9 Hz, 1H), 5.91 (m, NH), 6.60 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.36 (dd, J = 2.2, 8.3 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H).

Example 39: 5- (3-fluoropropoxy) -2- (4-dimethylaminophenyl) isoindole-1,3-dione (1a-27)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.11 (t, J = 5.7, 6.2 Hz, 1H), 2.20 (t, J = 5.7, 6.1 Hz, 1H), 2.94 (s, 6H), 4.28 ( t, J = 6.0, 6.2 Hz, 2H), 4.55 (t, J = 5.6 Hz, 1H), 4.71 (t, J = 5.5, 5.7 Hz, 1H), 6.79 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.45 (s, 1H), 7.84 (d, J = 8.3 Hz, 1H).

Example 40: 5-hydroxy-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-2)

¹ H NMR (400 MHz, CDCl ₃ ) δ 10.20, 7.60 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.3 Hz, 1H), 6.92 (s, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.76 (s, 2H), 4.78 (s, 2H), 2.86 (s, 6H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.53, 161.44, 147.67, 143.75, 130.07, 124.94, 124.31, 121.21, 116.22, 113.21, 109.73, 50.78, 40.91.

Example 41: 5-methyl-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-3)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.78 (d, J = 8.2 Hz, 1H), 7.66-7.64 (m, 2H), 7.36-7.28 (m, 2H), 6.80 (d, J = 8.9 Hz, 2H), 4.75 (s, 2H), 2.96 (s, 6H), 2.48 (s, 3H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.23, 148.05, 142.18, 140.65, 131.02, 129.23, 123.70, 122.97, 121.59, 113.10, 51.16, 40.89.

Example 42: 2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-4)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94-7.91 (m, 1H), 7.69 (d, J = 9.1 Hz, 2H), 7.58-7.56 (m, 1H), 7.53-7.49 (m, 2H), 6.85 (d, J = 7.8 Hz, 2H), 4.82 (s, 2H), 2.98 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.08, 148.16, 140.27, 133.58, 131.50, 129.19, 128.19, 123.90, 122.48, 121.66, 113.04, 51.33, 40.81.

Example 43 5-fluoro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-5)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88 (dd, J = 9.1, 5.1 Hz, 1H), 7.61 (dd, J = 6.9, 2.2 Hz, 2H), 7.21-7.16 (m, 2H), 6.78 ( dd, J = 6.9, 2.2 Hz, 2H), 4.78 (s, 2H), 2.96 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.83, 166.09, 163.50, 148.24, 142.64, 142.50, 129.59, 128.88, 126.00, 125.87, 121.70, 116.20, 115.89, 113.00, 110.08, 109.76, 51.01, 50.98, 40.80, 40.80

Example 44 5-chloro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-6)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82 (d, J = 8.6 Hz, 1H), 7.63 (d, J = 9.0 Hz, 2H), 7.46 (m, 2H), 6.79 (d, J = 8.6 Hz , 2H), 4.75 (s, 2H), 2.96 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.01, 148.26, 141.78, 137.80, 132.08, 128.86, 128.72, 125.10, 122.94, 121.66, 112.94, 50.87, 40.76.

Example 45 5-bromo-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-7)

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.87 (s, 1H), 7.61 (d, J = 8.9 Hz, 2H), 7.52 (dd, J = 8.0, 1.2 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 6.78 (d, J = 8.9 Hz, 2H), 4.77 (s, 2H), 2.96 (s, 6H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 165.74, 148.33, 138.36, 135.33, 134.54, 131.68, 128.68, 124.04, 123.78, 121.74, 112.94, 51.05, 40.76.

Example 46: 6-methyl-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-8)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.71-7.67 (m, 3H), 7.37 (s, 2H), 6.88 (bs, 2H), 4.75 (s, 2H), 2.97 (s, 6H), 2.46 ( s, 3H).

Example 47 6-fluoro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-9)

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67-7.63 (m, 2H), 7.58 (dd, J = 7.7, 2.4 Hz, 1H), 7.49-7.44 (m, 1H), 7.31-7.24 (m, 1H ), 6.83-6.79 (m, 2H), 4.79 (s, 2H), 2.98 (s, 6H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 166.06, 164.22, 161.77, 148.31, 135.68, 128.79, 124.05, 123.96, 121.74, 119.20, 118.96, 112.95, 110.75, 110.51, 50.98, 40.78.

Example 48 6-chloro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-10)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88 (d, J = 1.7 Hz, 1H), 7.65 (m, 2H), 7.53 (dd, J = 8.0, 1.7 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 6.81-6.78 (m, 2H), 4.78 (s, 2H), 2.98, (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 165.71, 148.29, 138.36, 135.33, 134.52, 131.67, 128.70, 124.02, 123.78, 121.69, 112.94, 51.02, 40.76.

Example 49: 5-methoxy-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-11)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.99 (s, 1H), 3.96 (s, 2H), 4.78 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 2.80 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.33, 163.23, 152.70, 142.34, 125.84, 125.38, 118.79, 115.10, 110.49, 107.36, 104.09, 55.70, 55.57, 50.77, 43.61.

Example 50: 5-methyl-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-12)

¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.2 Hz , 1H), 6.87-6.85 (m, 2H), 4.78 (s, 2H), 3.94 (s, 3H), 2.83 (s, 6H), 2.67 (s, 3H).

Example 51: 2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-13)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93-7.90 (m, 2H), 7.62-7.58 (m, 1H), 7.53-7.52 (m, 2H), 7.04-6.96 (m, 2H), 4.85 (s , 2H), 3.97 (s, 3H), 2.81 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.41, 152.64, 140.08, 134.79, 466.32, 131.94, 130.81, 128.38, 123.96, 122.56, 118.10, 110.98, 104.24, 55.53, 51.13, 43.45.

Example 52 5-Fluoro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-14)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.91-7.87 (m, 1H), 7.83 (s, 1H), 7.26-7.18 (m, 2H), 6.97 (s, 2H), 4.83 (s, 2H), 3.96 (s, 3 H), 2.80 (s, 6 H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.04, 166.33, 152.65, 142.47, 142.39, 139.54, 134.39, 129.40, 126.13, 126.00, 117.98, 116.44, 116.13, 110.98, 110.16, 109.84, 104.16, 55.42. .

Example 53: 5-chloro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-15)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.82 (m, 2H), 7.48 (m, 2H), 6.96 (m, 2H), 4..81 (s, 2H), 3.95 (s, 3H), 2.80 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.27, 152.63, 14.60, 139.65, 138.24, 134.23, 131.88, 129.05, 125.18, 123.01, 117.96, 111.05, 104.22, 55.54, 50.67, 43.39.

Example 54 5-bromo-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-16)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.86 (s, 2H), 7.23 (m, 2H), 7.00 (m, 2H), 4.82 (s, 2H), 3.96 (s, 3H), 2.82 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 166.36, 152.67, 129.34, 126.02, 118.30, 116.41, 116.19, 110.92, 110.13, 109.89, 104.21, 55.56, 50.74, 43.48.

Example 55 6-methyl-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-17)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.90 (s, 1H), 7.69 (s, 1H), 7.38 (s, 2H), 6.70 (s, 2H), 4.78 (s, 2H), 3.96 (s, 3H), 2.81 (s, 6H), 2.46 (s, 3H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.54, 152.64, 138.41, 137.30, 135.16, 133.44, 132.99, 124.12, 122.27, 118.25, 110.86, 104.19, 55.54, 50.90, 43.50, 21.40.

MS m / z 296 (M ⁺ ).

Example 56 6-fluoro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-18)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (s, 1H), 7.57 (dd, J = 7.6, 2.3 Hz, 1H), 7.51-7.47 (m, 1H), 7.31 (dd, J = 8.4, 2.3 Hz, 1H), 7.01 (s, 2H), 4.83 (s, 2H), 3.97 (s, 3H), 2.83 (s, 6H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 161.41, 152.66, 135.44, 124.17, 124.06, 119.72, 119.40, 111.06, 110.83, 104.35, 55.57, 50.73, 43.45.

Example 57 6-chloro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-19)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.88 (d, J = 1.5 Hz, 1H), 7.81 (d, J = 1.8 Hz, 1H), 7.56 (dd, J = 8.0, 1.7 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.03-6.95 (m, 2H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 165.94, 152.64, 139.74, 138.18, 135.16, 134.72, 134.19, 132.07, 124.10, 123.83, 117.97, 111.19, 104.34, 55.55, 50.83, 43.37.

Example 58: 2- (3-dimethylamino-4-methoxyphenyl) -2,3-dihydroisoindol-1-one (1b-20)

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 2.6 Hz, 1H), 7.59 (d, J = 6.8 Hz, 1H), 7.58-7.49 (m, 2H), 7.22 (dd, J = 8.7, 2.6 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 4.85 (s, 2H), 3.92 (s, 3H), 2.86 (s, 3H).

¹³ C NMR (75 MHz, CDCl ₃ ) δ 167.51, 149.62, 140.17, 134.15, 132.78, 131.89, 128.37, 124.00, 122.56, 114.30, 111.70, 111.27.

Example 59: 2- (3-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-21)

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.97 (d, J = 7.6 Hz, 1H), 7.72 (td, J = 7.5, 1.0 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.50 (dd, J = 7.0, 0.7 Hz, 1H), 6.68 (d, J = 8.3 Hz, 1H), 6.57 (s, 1H), 6.10 (d, J = 2.4 Hz, 1H), 6.07 (dd, J = 8.5, 2.5 Hz, 1H), 3.93 (s, 2H), 2.93 (s, 6H).

¹³ C NMR (100 MHz, CDCl ₃ ) δ 170.44, 152.41, 148.01, 147.48, 133.78, 129.21, 129.03, 127.16, 125.79, 123.86, 108.95, 103.32, 100.12, 80.79, 51.30, 40.29.

Example 60: 5-methoxy-2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one (1b-23)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.67 (s, 3H), 3.85 (s, 3H), 4.82 (s, 2H), 5.59 (s, NH), 6.57 (d, J = 8.3 Hz, 2H), 7.05 (d, J = 7.6 Hz, 1H), 7.16 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H).

Example 61 5- (2-fluoroethoxy) -2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one (1b-27)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.68 (d, J = 4.7 Hz, 3H), 4.30 (m, 1H), 4.40 (m, 1H), 4.70 (m, 1H), 4.83 (m, 3H), 5.59 (m, NH), 6.58 (d, J = 8.2 Hz, 2H), 7.09 (d, J = 8.4 Hz, 1H), 7.20 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.6 Hz, 1H).

Example 62: 5- (2-fluoroethoxy) -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-28)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.88 (s, 6H), 4.29 (m, 1H), 4.39 (m, 1H), 4.69 (m, 1H), 4.86 (m, 3H), 6.78 ( d, J = 8.9 Hz, 2H), 7.09 (dd, J = 1.9, 8.5 Hz, 1H), 7.20 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.68 ( d, J = 8.9 Hz, 1H).

Example 63: 5- (3-fluoropropoxy) -2- (4-aminophenyl) -2,3-dihydroisoindol-1-one (1b-29)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.10 (t, J = 5.6, 6.6 Hz, 1H), 2.19 (t, J = 5.5, 6.0 Hz, 1H), 4.17 (t, J = 6.0, 6.5 Hz, 2H), 4.55 (t, J = 5.3, 5.9 Hz, 1H), 4.71 (t, J = 5.3 Hz, 1H), 4.81 (s, 2H), 5.03 (s, NH ₂ ), 6.60 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.4 Hz, 1H), 7.18 (s, 1H), 7.43 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 8.6 Hz, 1H) .

Example 64 5- (3-fluoropropoxy) -2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one (1b-30)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.10 (t, J = 5.9 Hz, 1H), 2.19 (t, J = 6.0 Hz, 1H), 2.68 (s, 3H), 4.18 (t, J = 6.0 Hz, 2H), 4.55 (t, J = 5.7 Hz, 1H), 4.71 (t, J = 5.7 Hz, 1H), 4.82 (s, 2H), 5.59 (m, NH), 6.58 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.0 Hz, 1H), 7.18 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H).

Example 65 5- (3-fluoropropoxy) -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one (1b-31)

¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.09 (t, J = 6.1 Hz, 1H), 2.18 (t, J = 6.0 Hz, 1H), 2.88 (s, 6H), 4.17 (t, J = 6.2 Hz, 2H), 4.55 (t, J = 6.1 Hz, 1H), 4.70 (t, J = 6.2 Hz, 1H), 4.85 (s, 2H), 6.78 (d, J = 9.1 Hz, 2H), 7.07 (dd, J = 1.9, 8.4 Hz, 1H), 7.19 (d, J = 1.9 Hz, 1H), 7.61 (d, J = 9.0 Hz, 2H), 7.63 (d, J = 8.3 Hz, 1H).

Example 66 Pharmacological Activity Test—In Vitro ¹²⁵ Binding Affinity of I-TZDM with Beta-amyloid Fibrils Using Gamma Rays, IC ₅₀  And K _i Value analysis

1 mg of beta-amyloid peptide (Aβ _1-42 peptide, Bachem) was dissolved in 1 mL of dimethylsulfoxide (DMSO) and 9 mL of phosphate buffer (pH 7.4) was added. The resulting solution was incubated at 37 ° C. for 60 minutes to form beta-amyloid fibrils (Aβ _1-42 fibrils), which were dispensed in 500 μL into an e-tube and stored in a -80 ° C. freezer.

To determine whether the beta-amyloid fibrils formed well, 150 μL Thioflavin-T (Th-T) (5 μM) was added to 50 μL of the cultured beta-amyloid peptide, which was then combined with beta-amyloid fibrils. The fluorescence density of Th-T was measured with a multi label fluorescence counter (LS-55 Luminescence spectrometer: Perkin Elmer) at λex / λem (450/480 nm). As can be seen in FIG. 1, the beta-amyloid fibrils (Aβ _1- ) have a fluorescence density of 2,134 in the group in which the beta-amyloid protein (Aβ _1-40 ) of the monomer is bound to Th-T (control). ₄₂ fibrils) showed a very high fluorescence density of 176,619 ± 22,605, in combination with Th-T, thereby confirming the formation of beta-amyloid fibrils.

To obtain the dissociation constant (K _d ) of 2- (4'-dimethylaminophenyl) -6- [ ¹²⁵ iodo] iodobenzothiazole ( ¹²⁵ I-TZDM), a 12 mm x 75 mm borosilicate glass tube ( Beta-amyloid fibrils (Aβ _1-42 fibrils) were prepared in a borosilicate glass tube at a concentration of 10 nM (final reaction concentration), and 50 μL (0.046-5.9 pM) of TZDM labeled ¹²⁵ I was added thereto. Then, incubated for 3 hours at room temperature with a final volume of 1 mL with 10% ethanol. After incubation for 3 hours, ¹²⁵ I-TZDM that did not bind to ¹²⁵ I-TZDM bound to beta-amyloid fibrils was isolated using a cell harvester (Brandel M-24R). Nonspecific binding was performed using 2 μM Th-T, counted using gamma counter (Cobra-2), and then dissociation constant value (K _d ) using GraphPad Prism (GraphPad Software, San Diego, Calif.) Was determined. As can be seen in Figure 2, the dissociation constant value (K _d ) of TZDM obtained using beta-amyloid fibrils and ¹²⁵ I-TZDM was 0.13 nM.

As a binding affinity experiment with beta-amyloid fibrils, 850 μL of 10% ethanol was placed in a 12 mm × 75 mm borosilicate glass tube, and 50 μL of beta-amyloid fibrils (Aβ _1-42 fibrils) (final reaction). The concentration was 11.5 nM), and then 50 μL of the compound of the present invention (the concentration in the final reaction solution was 1 nM). 50 μL (final reaction concentration: 0.05 nM) of ¹²⁵ I-TZDM was added thereto and incubated at room temperature for 3 hours. To separate the ¹²⁵ I-TZDM is not combined with the amyloid fibrils and bound ¹²⁵ I-TZDM - 3 hours after the cultured cell harvester (Brandel M-24R) using a beta. Nonspecific binding was performed using 2 μM Th-T and counted using a gamma counter.

IC ₅₀ values for the binding affinity with beta-amyloid fibrils and the formation of beta-amyloid fibrils and ¹²⁵ I-TZDM for the compounds of the present invention were determined, and GraphPad Prism (GraphPad Software, San Diego, C) using the Cheng-Prusoff equation (K _i = IC ₅₀ / (1+ [L] / K _d ) (see Cheng, Y .; Prusoff, WH Biochem . Pharmacol , 22 , 3099 (1973))). Under inhibition Constant value (K _i ) was obtained. N -methyl- [ ¹¹ carbon] 2- (4'-methylaminophenyl) -6-hydroxybenzothiazole (Pittsburgh Compound-B, PIB) prepared directly by the inventor (Klunk, WE et al. Ann . Neurol. 55, was used as a control 306 (2004) reference) material.

Tables 1 to 3 below show the binding affinity and K _{i of the} compound of the present invention to beta-amyloid fibrils determined by the above method. It is a summary of the values.

a: The binding affinity at 10 nM was low, so no test at 1 nM was performed.

a: The binding affinity at 10 nM was low, so no test at 1 nM was performed.

As can be seen in Table 1 and Table 2, at the final concentration of 1 nM, three of the compounds of the examples of the present invention are commercially available material PIB (control material) showing excellent binding to beta-amyloid fibrils The binding affinity with beta-amyloid fibrils was shown to be better than), and the other three compounds were found to have a binding affinity with beta-amyloid fibrils that was almost equivalent to PIB.

On the other hand, as shown in Table 3, K _i for nine compounds of the compounds of the present invention The value was found to be better than the control PIB (K _i = 0.77 nM).

According to the present invention, a compound of Formula 1 having excellent binding affinity with beta-amyloid fibrils and inhibition of bond formation between beta-amyloid fibrils and ¹²⁵ I-TZDM has been provided. The compound of the present invention is excellent in binding affinity with beta-amyloid fibrils and inhibiting the formation of bond formation between beta-amyloid fibrils and ¹²⁵ I-TZDM, so that early diagnosis of diseases related to beta-amyloid fibrils, including dementia, It can be usefully used for prevention or treatment.

1 is a graph confirming beta-amyloid fibril formation using fluorescence of thioflavin-T (Th-T).

2 is a TZDM dissociation constant (K _d ) obtained using beta-amyloid fibrils and 2- (4'-dimethylaminophenyl) -6- [ ¹²⁵ iodo] iodobenzothiazole ( ¹²⁵ I-TZDM). Is a graph showing

Claims (19)

A compound represented by formula (1) or a pharmaceutically acceptable salt thereof: [Formula 1]

In the formula, A is a CH ₂ group, R ₁ is C substituted with halogen atom selected from H, OH, fluorine, chlorine, bromine and iodine, C ₁ -C ₈ alkyl group, C ₁ -C ₈ alkoxy group, fluorine, chlorine, bromine and iodine _{1 to} C ₈ alkoxy group or C _{1 to} C ₈ alkylamino group, R ₂ is a halogen atom or C ₁ -C ₈ alkyl group selected from H, fluorine, chlorine, bromine and iodine, R ₃ and R ₄ are each H, a C ₁ -C ₈ alkoxy group or a C ₁ -C ₈ alkylamino group, Provided that at least one of R ₁ to R ₄ contains one or more radioactive isotopes. delete The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the radioisotope is ¹¹ C or ¹⁸ F. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the methoxy or methyl has ¹¹ C or fluoro is ¹⁸ F, selected from the group consisting of the following compounds: 5-methoxy-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 5-hydroxy-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 5-methyl-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 5-fluoro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 5-chloro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 5-bromo-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 6-methyl-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 6-fluoro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 6-chloro-2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 5-methoxy-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one; 5-methyl-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one; 2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one; 5-fluoro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one; 5-chloro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one; 5-bromo-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one; 6-methyl-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one; 6-fluoro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one; 6-chloro-2- (4-dimethylamino-3-methoxyphenyl) -2,3-dihydroisoindol-1-one; 2- (3-dimethylamino-4-methoxyphenyl) -2,3-dihydroisoindol-1-one; 2- (3-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 5-methoxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one; 5-methoxy-2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one; 5-methoxy-2- (4-aminophenyl) -2,3-dihydroisoindol-1-one; 5-methoxy-2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one; 5- (2-fluoroethoxy) -2- (4-aminophenyl) -2,3-dihydroisoindol-1-one; 5- (2-fluoroethoxy) -2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one; 5- (2-fluoroethoxy) -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one; 5- (3-fluoropropoxy) -2- (4-aminophenyl) -2,3-dihydroisoindol-1-one; 5- (3-fluoropropoxy) -2- (4-methylaminophenyl) -2,3-dihydroisoindol-1-one; And 5- (3-fluoropropoxy) -2- (4-dimethylaminophenyl) -2,3-dihydroisoindol-1-one. The method of claim 1, wherein the pharmaceutically acceptable salt is hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid. Inorganic or organic acids selected from the group consisting of, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid A compound or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 and 3 to 5, or a pharmaceutically acceptable salt thereof, which is used for the diagnosis of degenerative brain disease. A pharmaceutical composition for diagnosing degenerative brain disease, comprising as an active ingredient a compound according to any one of claims 1 and 3 to 5 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 7, wherein the degenerative brain disease is Alzheimer's disease, cerebrovascular dementia or Parkinson's disease. (1) reacting a compound represented by the following Chemical Formula 2b with an aromatic amine compound represented by the following Chemical Formula 3, (2) The product of step (1) was subjected to tin (Sn), zinc (Zn), iron (Fe), hydrazine (H ₂ N ₄ / FeCl ₃ ), copper sulfate (CuSO ₄ ) or tin chloride (SnCl) under acidic conditions. ₂ ) reduction reaction and (3) subjecting the product of step (2) to a nucleophilic substitution reaction using [ ¹¹ C] alkoxytriplate Method for producing a compound represented by the formula (1) comprising: [Formula 1]

[Formula 2b]

(3)

In the formula, A is a CH ₂ group, R ₁ is a halogen atom selected from H, OH, fluorine, chlorine, bromine and iodine, a C ₁ -C ₈ alkyl group, a C ₁ -C ₈ alkoxy group, a tosyloxy-C ₁ -C ₈ alkoxy group, mesyloxy-C ₁ ~C ₈ alkoxy group, an aryloxy nosil -C ₁ ~C ₈ alkoxy group, a fluorine, chlorine, bromine and the halogen atom-substituted C ₁ ~C ₈ alkoxy group, or a C ₁ ~C ₈ alkyl group selected from iodine, R ₂ is a halogen atom or C ₁ -C ₈ alkyl group selected from H, fluorine, chlorine, bromine and iodine, R ₃ or R ₄ is a C ₁ -C ₈ [ ¹¹ C] alkylamino group. 10. The process according to claim 9, wherein the reaction of step (1) is carried out in an acidic solvent. The method of claim 10, wherein the acidic solvent is acetic acid, hydrochloric acid or paratoluenesulfonic acid. delete delete delete (1) reacting a compound represented by the following Chemical Formula 2b with an aromatic amine compound represented by the following Chemical Formula 3, (2) dealkylation of the product of step (1) with boron tribromide, (3) the product of step (2) is nucleophilic with a compound represented by the general formula R ₆ O (CH ₂ ) _n OR ₆ , wherein R ₆ is tosyl, mesyl or nosyl and n is 2 or 3 Substitution reaction and (4) nucleophilic substitution reaction of the product of step (3) with quaternary butylammonium ¹⁸ fluoride Method for producing a compound represented by the formula (1) comprising: [Formula 1]

[Formula 2b]

(3)

In the formula, A is a CH ₂ group, R ₁ is a C ₁ -C ₈ alkoxy group substituted with ¹⁸ F, R ₂ is a halogen atom or C ₁ -C ₈ alkyl group selected from H, fluorine, chlorine, bromine and iodine, R ₃ and R ₄ are each H, C ₁ ~C ₈ alkoxy group or a C ₁ ~C ₈ alkyl group. The process according to claim 15, wherein the reaction of step (1) is carried out in an acidic solvent. delete The method of claim 16, wherein the acidic solvent is acetic acid, hydrochloric acid or paratoluenesulfonic acid. delete

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