KR100769732B1 - 2,2'-alkyisubstituted-3,4-dehydro-6-alkylamino benzopyran derivatives as protection agents for cerebral cell death - Google Patents

Abstract

A 2,2'-alkylsubstitued-3,4-dehydro-6-alkylamino benzopyran derivative is provided to secure the activity of controlling neuronal death by controlling the activity of a glutamate receptor, thereby being useful as a prophylactic and therapeutic agent of stroke, epilepsy, amyotrophic lateral sclerosis, Parkinson's diseases, Huntington's disease and Alzheimer's disease. A pharmaceutical composition comprises a 2,2'-double substituted-7,8-double substituted-6-alkylamino benzopyran derivative represented by the formula(1) or a pharmaceutically acceptable salt thereof. In the formula(1), R^1 is C1-10 alkyl, benzyl, or substituted benzyl, phenethyl, 2-pyrimidylmethyl, thiophene, 2-methylthiophenemethyl, 5-methyl-2-thiophenemethyl, 3-thiophenemethyl, indolylmethyl, benzo dioxiranylmethyl, naphthalenylmethyl, or furanylmethyl, each R^2 and R^3 is H, C1-6 alkyl, halogen, or phenyl and substituted phenyl, R^4 is C1-10 alkyl, phenyl or substituted phenyl, or a hetero-cyclic group selected from the group consisting of thiophene and furan(wherein the benzyl, phenyl or the heterocyclic group is able to be substituted by 1-4 substituents selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, nitro, cyano and C1-6 alkoxy), and n is an integer from 1 to 5.

Description

2,2'-Alkyisubstituted-3,4-dehydro-6-alkylamino benzopyran derivatives as protection agents for cerebral cell death}

1 is a graph showing the protective effect of the drug against the death of mouse hippocampal neuronal cell line (HT22) by glutamate treatment.

Figures 2a and 2b is a graph showing the effect of inhibiting cell death from the toxicity of each compound glutamate in cerebral cortical neurons.

Figure 3 is a graph showing the behavioral test results of the animal model of the stroke, (a) is the mNSS test results, (b) is the rotarod test results, (c) is the adhesion removal test results.

The present invention provides a 6-alkylamino-2,2'-disubstituted-benzopyran derivative represented by the following formula (1) with excellent activity of inhibiting neuronal cell death by controlling the activity of glutamate receptors, It relates to the use for the prevention and treatment of stroke, epilepsy, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease.

In the formula (1), R ¹ is a C ₁ -C ₁₀ alkyl group, benzyl or substituted benzyl group, phenethyl group, 2-pyrimidylmethyl group, thiophene group, 2-methylthiophenmethyl group, 5-methyl-2 -Thiophenmethyl group, 3-thiophenmethyl group, indolylmethyl group, benzodioxoranylmethyl group, naphthalenylmethyl group, or furanylmethyl group; R ² and R ³ each represent a hydrogen atom, an alkyl group of C _{1 to} C ₅ , a halogen, or a phenyl and substituted phenyl group; R ⁴ represents a C ₁ to C ₁₀ alkyl group, phenyl or substituted phenyl group, or a heterocyclic group selected from thiophene and furan; And the benzyl group, the phenyl group or the heterocyclic group is a substituent selected from C _{1 to} C ₆ alkyl group, C _{1 to} C ₆ haloalkyl group, halogen, nitro group, cyano group and C _{1 to} C ₆ alkoxy group. Four may be substituted, n represents an integer of 1 to 5.

Glutamate is neurotransmitted through the activity of glutamate receptors such as N -methyl- D -aspartate (NMDA), kainate, alpha-amino-3-hydroxy-4-isoxazole propionic acid (AMPA) It is an excitatory neurotransmitter of the central nervous system. The properties of these biological activities of glutamate receptors play an important role in learning, memory, and plasticity of the nervous system (Siegel, GJ et al., Basic Neurochemistry , 6 ^th edition, Lippincott Williams & Wilkins: 315-333 (1999)). Another characteristic of glutamate receptors is that excessive excitement leads to neuronal cell death.

Glutamate receptors are blocked by Mg ²⁺ when neurons are at rest, but when neurons undergo external stimulation, Mg ²⁺ is released from the receptors and Ca ²⁺ and Na ⁺ are introduced into the cells. Fall into depolarization. When neurons reach the depolarized state, the release of glutamate-containing neurotransmitters increases at the nerve endings, and glutamate reuptake by glia decreases, resulting in the excitatory neurotransmitter glutamate at the nerve junctions. Stacked [Choi, DW and Rothman, SM, Annu. Rev. Neurosci., 13: 171-182 (1990); Benveniste, H. et al., J. Neurochem., 43 (5): 1369-1374 (1984). This excessive accumulation of glutamate causes neuronal cell death, mainly due to the excessive activity of NMDA glutamate receptors.

Recently, many studies have been conducted on cell death due to excitatory toxicity of glutamate receptors, and specific research results related to cerebral nervous system diseases are as follows.

1) cerebral apoplexy

When stroke occurs, the excitatory neurotransmitter glutamate accumulates at the neuronal junction, and neuronal cell death proceeds rapidly due to the transient activity of Ca ²⁺ -permeable glutamate receptors. Indeed, administration of antagonists of NMDA glutamate receptors is known to significantly reduce brain cell death by ischemic stroke, which accounts for 80% of strokes [Goldberg, MP et al. , J. Pharmac. Exp. Ther., 243: 784-791 (1987); Simon, RP et al., Science, 226: 850-852 (1984); Sheardown, MJ et al., Science, 247: 571-574 (1990); Simon et al., Science, 226: 850-852 (1984); Park et al. , Ann Neurol. , 24: 543-551 (1988); Wieloch, Science, 230: 681-683 (1985); Kass et al. , Exp. Neurol., 103: 116-122 (1989); Weiss et al. , Brain Res., 380: 186-190 (1986).

2) epilepsy

Administration of ionic glutamate receptor agonist kainate induces epileptic seizures, and NMDA receptor antagonists have been reported to have an effect of inhibiting convulsions and epileptic seizures in animal models of various epileptic seizures [Anderson et al. , J. Neurophysiol , 57: 1-21 (1987); Wong et al., Neurosci Lett. 85: 261-266 (1988); Mc Namara et al. , Neuropharmacology , 27: 563-568 (1988). Olney et al also found that oral administration of mono glutamate caused neuronal cell death in the brains of infants and monkeys [Olney, JW and Sharpe, LG, Science, 166: 386. -388 (1969); Olney, JW and Ho, OL, Nature, 227 (258): 609-611 (1970)], Glutamate is an excitatory neurotransmitter and has been shown to cause neuronal death by epilepsy [Olney, JW , Int. Rev. Neurobiol., 27: 337-362 (1985). In addition, administration of glutamate to cultured neurons induces neuronal death, Ca ²⁺ is required for the process of excitatory toxicity, and NMDA glutamate receptors have been reported to play an important role [Choi, DW, J. Neurosci., 7 (2): 369-379 (1987)].

3) Amyotrophic lateral sclerosis (ALS)

Excitotoxicity is also known to be involved in the death of neurons in amyotrophic lateral sclerosis (ALS). Patients with ALS have decreased glutamate transport proteins in glial cells, and it has been reported that the injection of ionic glutamate receptor agonists into the spine of rats shows similar pathological changes as those with patients with ALS [Rothstein et al. , Clin Neurosci. 3: 348-359 (1995); Ikonomidou et al. , J Neuropathol Exp Neurol, 55: 211-224 (1996)].

Parkinson's Disease (PD)

Parkinson's disease is a degenerative brain disease that indicates impairment of motor function by selective death of melanoma dopaminergic neurons. The death of dopaminergic neurons after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which induces symptoms of Parkinson's disease, is known to be reduced by administration of NMDA receptor antagonists. Lang et al. , Arch Phamacol. 348: 586-592 (1993); Brouillet and Beal, Neuroreport. , 4: 387-390 (1993). Moreover, NMDA receptor antagonists have been reported to improve the therapeutic effect of levodopa, a treatment for Parkinson's disease [Papa and Chase, Ann. Neurol. 39: 574-578 (1996); Marin et al. , Brain Res. 736: 202-205 (1996).

Huntington's Disease (HD)

Huntington's disease, a degenerative nervous system disease, involves the death of interneurons in the brain's striatum. Since the pathological characteristics of Huntington's disease are similarly reproduced by treatment with NMDA receptor agonists, selective neuronal cell death in HD is known to be mediated by NMDA receptors [Koh et al. , Science, 234: 73-76 (1986); Beal et al. , Nature, 321: 168-171 (1986); Beal et al. , J. Neurosci ., 11: 1649-1659 (1991).

6) Alzheimer's disease (AD)

Alzheimer's disease involves the death of glutamate neurons in the cerebral cortex and hippocampus and acetylcholine neurons in the basal brain, and amyloid plaque outside the neurons and neurofibrillary tangles in the neurons. tangles are found to be common.

As described above, the development of new antagonists for glutamate receptors is essential in the development of new drugs for preventing and treating cerebral nervous system diseases.

The inventors of the present invention have been studying to develop a new drug that can prevent and treat cerebral nervous system diseases by an action mechanism that inhibits the death of brain cells, the 6-alkylamino-2,2'-double represented by the formula (1) The present invention has been completed by confirming that substituted-benzopyran derivatives exhibit excellent activity as glutamate receptor antagonists.

Accordingly, an object of the present invention is to provide a use of the 6-alkylamino-2,2'-disubstituted-benzopyran derivative represented by the above formula (1) as an agent for preventing and treating cerebral neurological diseases.

The present invention relates to the prevention of cerebral neurological diseases containing 6-alkylamino-2,2'-disubstituted-benzopyran derivatives represented by the following formula (1), isomers thereof or pharmaceutically acceptable salts thereof as an active ingredient, and The therapeutic agent is characterized by that.

[Formula 1]

In the above formula (1),

R ¹ is a C ₁ -C ₁₀ alkyl group, benzyl or substituted benzyl group, phenethyl group, 2-pyrimidylmethyl group, thiophene group, 2-methylthiophenmethyl group, 5-methyl-2-thiophenmethyl group, 3- Thiophenmethyl group, indolylmethyl group, benzodioxoranylmethyl group, naphthalenylmethyl group, or furanylmethyl group; R ² and R ³ each represent a hydrogen atom, an alkyl group of C _{1 to} C ₅ , a halogen, or a phenyl and substituted phenyl group; R ⁴ represents a 5 to 7 membered hetero ring containing a hetero atom selected from a C ₁ to C ₁₀ alkyl group, a phenyl or substituted phenyl group, or an oxygen or sulfur atom; And groups wherein a phenyl group or a heterocyclic substituent selected from an alkoxy group of C ₁ ~C ₆ alkyl group, C ₁ ~C ₆ haloalkyl group, a halogen, a nitro group, a cyano group and a C ₁ ~C ₆ of the 1-4-substituted N may represent an integer of 1 to 5.

On the other hand, the 2,2'-alkyl-substituted-3,4-dihydro-6-alkylamino benzopyran derivative represented by the formula (1) is present in the chiral carbon, therefore the present invention is a racemic compound or conventional separation Each of the isomeric compounds separated by the method and all of these isomeric mixtures are included.

The 6-alkylamino-2,2'-disubstituted-benzopyran derivatives represented by the formula (1), which is used as an active ingredient in the prophylactic and therapeutic agent for cerebral nervous system diseases, are first synthesized by the present inventors in Korea. It is a compound disclosed by Unexamined-Japanese-Patent No. 2005-91124. Korean Patent Publication No. 2005-91124 (US Patent Publication No. 2005-203145, Japanese Patent Publication No. 2005-255666) discloses the compound represented by the formula (1), its preparation method, and the compound as an agent for preventing and treating inflammatory diseases. Uses for use are disclosed. In addition, the present inventors have filed a patent application of the compound represented by the formula (1) as an anticancer agent in Korean Patent Application No. 2005-22826.

However, the literature suggesting the availability of the 6-alkylamino-2,2'-disubstituted-benzopyran derivatives represented by the formula (1) as glutamate receptor antagonists or exemplifying specific biological activities has not been reported to date. none.

Examples of specific compounds for the 6-alkylamino-2,2'-disubstituted-benzopyran derivative represented by the formula (1) used as an active ingredient in the prophylactic and therapeutic agent for cerebral nervous system diseases Combinatorial chemical synthesis techniques for the synthesis of these compounds are described in detail in Korean Patent Publication No. 2005-91124.

A method for preparing a 2,2'-alkyl substituted 6-alkylamino benzopyran derivative represented by the general formula (1) described in Korean Patent Publication No. 2005-91124 is shown in Scheme 1 below.

In Scheme 1, R ¹ , R ² , R ³ , R ⁴ And n are each as defined above; Ⓟ represents a solid support in the form of a high molecular polymer selected from polystyrene-divinylbenzene, methacrylic acid-dimethylacrylamide and hydroxyl methacrylic acid.

The pharmaceutical agent of the present invention may be used in the form of a free base in the use of the 6-alkylamino-2,2'-disubstituted-benzopyran derivative represented by the above formula (1) as an active ingredient, but in the form of free base It is also within the scope of the present invention to convert to the form of acceptable salts. Pharmaceutically acceptable salts can be prepared by conventional methods in the art, for example salts with inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, carbonic acid, formic acid, acetic acid Salts of pharmaceutically acceptable salts of these acids together with organic acids such as oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gesty acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin) Can be formed. It is also possible to react with alkali metal ions such as sodium and potassium to form their metal salts, or to react with ammonium ions to form another form of a pharmaceutically acceptable salt.

In addition, the pharmaceutical composition of the present invention is a non-toxic pharmaceutically acceptable carrier which is conventional in 2,2'-disubstituted-7,8-disubstituted-6-alkylamino benzopyran derivatives or pharmaceutically acceptable salts thereof, It may be made by adding a reinforcing agent, excipient, and the like. In addition, the pharmaceutical composition of the present invention can be formulated into a conventional formulation in the pharmaceutical field, for example, oral administration or parenteral administration such as tablets, capsules, troches, solutions, suspensions. In addition, the dosage of the compound according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and degree of disease of the patient, and generally based on an adult patient having a weight of 70 kg. It is 0.01-1000 mg / day, and it can also divide and administer once a day to several times at fixed time intervals according to the judgment of a doctor or a pharmacist.

As described above, the present invention will confirm the usefulness of the 6-alkylamino-2,2'-disubstituted-benzopyran derivative represented by Formula 1 as a prophylactic and therapeutic agent for cerebral neurological diseases through the following examples. However, specific examples of the preparation method of the compound represented by Formula 1 and its synthesis method are to be replaced by Korean Patent Publication No. 2005-91124 (US Patent Publication No. 2005-203145, Japanese Patent Publication No. 2005-255666). do.

Example.

The structures of representative compounds applied in this example are shown in Table 1 below.

Compound number R ¹ R ² R ³ n R ⁴ Analytical Data (NMR & Mass) 1-1 Bn H H 0 Me ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.39-7.26 (m, 5H), 6.64 (d, 1H, J = 8.5 Hz), 6.45 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.33 (d, 1H, J = 2.8 Hz), 6.24 (d, 1H, J = 9.7 Hz), 5.60 (d, 1H, J = 9.7 Hz), 4.27 (s, 2H), 1.39 (s, 6H) 13C NMR (75 MHz, CDCl ₃ ): 145.17, 142.19, 139.52, 131.59, 128.55, 127.62, 127.17, 122.58, 121.90, 116.80, 113.88, 111.00, 75.46, 49.34, 27.5; m / z: 256.20 1-2 2-MeO-Bn H H 0 Me m / z: 295.35 1-3 3-MeO-Bn H H 0 Me m / z: 295.23

1-4 4-MeO-Bn H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.27 (d, 2H, J = 8.6 Hz), 6.86 (d, 2H, J = 8.6 Hz), 6.64 (d, 1H, J = 8.5 Hz), 6.44 (dd , 1H, J = 8.5 Hz, J = 2.8 Hz, 6.33 (d, 1H, J = 2.8 Hz), 6.23 (d, 1H, J = 9.8 Hz), 5.59 (d, 1H, J = 9.8 Hz), 4.17 (s, 2H), 3.79 (s, 3H), 1.39 (s, 6H) m / s: 295.35 1-5 4-t-Bu-Bn H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.39-7.24 (m, 4H), 6.64 (d, 1H, J = 8.6 Hz), 6.45 (dd, 1H, J = 8.6 Hz, J = 2.6 Hz), 6.34 (d, 1H, J = 2.6 Hz), 6.24 (d, 1H, J = 9.8 Hz), 5.60 (d, 1H, J = 9.8 Hz), 4.21 (s, 2H), 1.39 (s, 6H), 1.32 (s, 9H) m / z: 321.40 1-6 2-Me-Bn H H 0 Me _{1 H NMR (} 300 MHz, CDCl ₃ ) δ 7.26 (m, 1H), 7.19 (m, 3H), 6.66 (d, 1H, J = 8.5 Hz), 6.47 (dd, 1H, J = 8.5 Hz, J = 2.7 Hz), 6.34 (d, 1H, J = 2.7 Hz), 6.25 (d, 1H, J = 9.8 Hz), 5.61 (d, 1H, J = 9.8 Hz), 4.21 (s, 2H), 2.37 (s, 3H), 1.40 (s, 6H) m / z: 279.41 1-7 3-Me-Bn H H 0 Me m / z: 279.35 1-8 4-Me-Bn H H 0 Me ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.25 (d, 1H, J = 7.9 Hz), 7.14 (d, 2H, J = 7.92 Hz), 6.64 (d, 1H, J = 8.1 Hz), 6.47 (dd , 1H, J = 8.1 Hz, J = 2.7 Hz, 6.36 (d, 1H, J = 2.7 Hz), 6.24 (d, 1H, J = 9.6 Hz), 5.60 (d, 1H, J = 9.6 Hz), 4.22 (s, 2H), 2.34 (s, 3H), 1.39 (s, 6H) m / z: 279.36 1-9 2-F-Bn H H 0 Me ¹ H NMR ₍ 200 MHz, CDCl ₃ ) δ 7.44-7.36 (m, 1H), 7.29-7.21 (m, 1H), 7.15-6.70 (m, 2H), 6.68 (d, 1H, J = 8.3 Hz), 6.48 (dd, 1H, J = 8.3 Hz, J = 2.6 Hz), 6.36 (d, 1H, J = 2.6 Hz), 6.27 (d, 1H, J = 9.8 Hz), 5.63 (d, 1H, J = 9.8 Hz), 4.40 (s, 2 H), 3.61 (br, 1 H), 1.42 (s, 6 H); m / z: 283.37 1-10 3-F-Bn H H 0 Me ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.28 (m, 1H), 7.12 (m, 2H), 6.93 (m, 1H), 6.64 (d, 1H, J = 8.5 Hz), 6.42 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz, 6.30 (d, 1H, J = 2.8 Hz), 6.23 (d, 1H, J = 9.7 Hz), 5.60 (d, 1H, J = 9.7 Hz), 4.28 (s , 2H), 1.39 (s, 6H) m / z: 283.45 1-11 4-F-Bn H H 0 Me ¹ H NMR (500 MHz, CDCl ₃ ): δ 7.33-7.30 (m, 2H), 7.02-6.99 (m, 2H), 6.64 (d, 1H, J = 8.5 Hz), 6.45 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz, 6.34 (d, 1H, J = 2.8 Hz), 6.23 (d, 1H, J = 9.7 Hz), 5.61 (d, 1H, J = 9.7 Hz), 4.22 (s, 2H ), 1.39 (s, 6H) m / z: 283.25

1-12 3-Cl-Bn H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.37 (s, 1H), 7.25 (m, 3H), 6.64 (d, 1H, J = 8.6 Hz), 6.42 (dd, 1H, J = 8.6 Hz, J = 2.8 Hz), 6.31 (d, 1H, J = 2.8 Hz), 6.23 (d, 1H, J = 9.8 Hz), 5.61 (d, 1H, J = 9.8 Hz), 4.25 (s, 2H), 1.39 (s , 6H) m / z: 299.84 1-13 2-CN-Bn H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.96 (d, 1H, J = 6.7 Hz), 7.56-7.27 (m, 3H), 7.20 (dd, 1H, J = 8.5 Hz, J = 2.4 Hz), 7.09 (d, 1H, J = 2.4 Hz), 6.78 (d, 1H, J = 8.5 Hz), 6.35 (d, 1H, J = 9.7 Hz), 5.62 (d, 1H, J = 9. 7 Hz), 5.43 (s, 2H), 1.50 (s, 6H) m / z: 290.35 1-14 4-CN-Bn H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.63 (d, 2H, J = 8.0 Hz), 7.49 (d, 2H, J = 8.0 Hz), 6.64 (d, 1H, J = 8.7 Hz), 6.41 (m , 1H), 6.27 (d, 1H, J = 2.6 Hz), 6.21 (d, 1H, J = 9.8 Hz), 5.61 (d, 1H, J = 9.8 Hz), 4.37 (s, 2H), 1.40 (s , 6H) m / z: 290.34 1-15 4-NO ₂ -Bn H H 0 Me ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.09 (d, 2H, J = 9.0 Hz), 7.46 (d, 2H, J = 9.0 Hz), 6.95 (dd, 1H, J = 9.0 Hz, J = 3.0 Hz ), 6.90 (d, 1H, J = 3.0 Hz), 6.69 (d, 1H, J = 9.0 Hz), 6.19 (d, 1H, J = 9.0 Hz), 5.69 (d, 1H, J = 9.0 Hz), 4.38 (s, 2H), 1.42 (s, 6H) m / z: 310.31 1-16 2-CF ₃ -Bn H H 0 Me m / z: 333.26 1-17 3-CF ₃ -Bn H H 0 Me m / z: 333.24 1-18 4-CF ₃ -Bn H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.59 (d, 2H, J = 8.2 Hz), 7.48 (d, 2H, J = 8.2 Hz), 6.65 (d, 1H, J = 8.4 Hz), 6.42 (dd , 1H, J = 8.4 Hz, J = 2.8 Hz, 6.30 (d, 1H, J = 2.8 Hz), 6.23 (d, 1H, J = 9.9 Hz), 5.61 (d, 1H, J = 9.9 Hz), 4.35 (s, 2H), 1.40 (s, 6H) m / z: 333.35 1-19 4-EtO-Bn H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.30 (d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.4 Hz), 6.68 (d, 1H, J = 8.6 Hz), 6.49 (m , 1H), 6.35 (d, 1H, J = 2.8 Hz), 6.27 (d, 1H, J = 9.7 Hz), 5.63 (d, 1H, J = 9.7 Hz), 4.20 (s, 2H), 4.05 (q , 2H, J = 6.9 Hz), 3.57 (br, 1H), 1.48-1.40 (m, 9H) m / z: 309.31

1-20 2,5-Di-Me-Bn H H 0 Me ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.10 (s, 1H), 6.97 (s, 2H), 6.86 (dd, 1H, J = 8.6 Hz, J = 2.5 Hz), 6.79 (d, 1H, J = 2.5 Hz), 6.67 (d, 1H, J = 8.6 Hz), 6.22 (d, 1H, J = 9.8 Hz), 5.64 (d, 1H, J = 9.8 Hz), 4.21 (s, 2H), 2.22 (s , 3H), 2.11 (s, 3H), 1.40 (s, 6H) m / z: 293.31 1-21 2,6-Di-Me-Bn H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) 7.07-6.93 (m, 5H), 6.68 (d, 1H, J = 8.6 Hz), 6.21 (d, 1H, J = 9.8 Hz), 5.61 (d, 1H, J = 9.8 Hz), 4.20 (s, 2H), 2.18 (s, 3H), 2.04 (s, 3H), 1.40 (s, 6H) m / z: 293.40 1-22 4-Br-2-F-Bn H H 0 Me ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.23 (m, 3H), 6.63 (d, 1H, J = 9.3 Hz), 6.46 (dd, 1H, J = 9.3 Hz, J = 3.0 Hz), 6.34 (d , 1H, J = 3.0 Hz), 6.22 (d, 1H, J = 9.6 Hz), 5.61 (d, 1H, J = 9.8 Hz), 4.29 (s, 2H), 1.39 (s, 6H) m / z: 362.14 1-23

H H 0 Me m / z: 266.26 1-24

H H 0 Me m / z: 266.27 1-25

H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.55 (d, 2H, J = 5.2 Hz), 7.30 (d, 2H, J = 5.2 Hz), 6.63 (d, 1H, J = 8.2 Hz), 6.38 (dd , 1H, J = 8.2 Hz, J = 2.6 Hz, 6.25 (d, 1H, J = 2.6 Hz), 6.25 (d, 1H, J = 2.5 Hz), 6.20 (d, 1H, J = 10.0 Hz), 5.60 (d, 1H, J = 10.0 Hz), 4.32 (s, 2H), 1.39 (s, 6H) m / z: 266.31 1-26

H H 0 Me m / z: 271.17 1-27

H H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.34-7.30 (m, 1H), 7.20 (m, 1H), 7.12-7.08 (m, 1H), 6.69 (d, 1H, J = 8.5 Hz), 6.498 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.37 (d, 1H, J = 2.8 Hz), 6.28 (d, 1H, J = 9.8 Hz), 5.64 (d, 1H, J = 9.8 Hz ), 4.29 (s, 2H), 3.58 (br, 1H), 1.44 (s, 6H) m / z: 271.14 1-28

H H 0 Me m / z: 285.36 1-29

H H 0 Me ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.81 (m, 4H), 7.47 (m, 3H), 6.66 (d, 1H, J = 8.6 Hz), 6.57 (d, 1H, J = 2.8 Hz), 6.46 (d, 1H, J = 2.78 Hz), 6.23 (d, 1H, J = 9.8 Hz), 5.61 (d, 1H, J = 9.8 Hz), 4.41 (s, 2H), 1.41 (s, 6H) m / z: 315.32 1-30

H H 0 Me ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.65 (d, 1H, J = 7.7 Hz), 7.31 (d, 1H, J = 8.0 Hz), 7.21-7.06 (m, 3H), 6.68 (d, 1H, J = 8.50 Hz), 6.49 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.37 (d, 1H, J = 2.8 Hz), 6.25 (d, 1H, J = 9.7 Hz), 5.60 (d , 1H, J = 9.7 Hz), 4.39 (s, 2H), 1.40 (s, 6H) m / z: 304.26

1-31 PhEt H H 0 Me ¹ H NMR (300 MHz, CDCl ₃ ) 7.25 (m, 5H), 6.68-6.23 (m, 4H), 3.35 (t, 2H), 2.91 (t, 2H), 1.40 (s, 6H) m / z: 279.35 1-32 Bn H H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.30-7.19 (m, 5H), 6.57 (d, 1H, J = 8.6 Hz), 6.38 (dd, 1H, J = 8.6 Hz, J = 2.6 Hz), 6.26 (d, 1H, J = 2.6 Hz), 6.21 (d, 1H, J = 10.0 Hz), 5.50 (d, 1H, J = 10.0 Hz), 4.20 (s, 2H), 1.62 (q, 2H,, J = 7.5 Hz), 1.27 (s, 3H), 0.88 (t, 3H, J = 7.5 Hz) m / z: 279.34 1-33

H H One Me m / z: 285.31 1-34

H H One Me m / z: 285.21 1-35

H H One Me m / z: 299.40 1-36

H H One Me m / z: 314.30 1-37 Bn H H 2 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.28-7.23 (m, 5H), 7.02-6.92 (m, 2H), 6.66 (d, 1H, J = 8.5 Hz), 6.23 (d, 1H, J = 10.0 Hz), 5.59 (d, 1H, J = 10.0 Hz), 4.22 (s, 2H), 1.70-1.57 (m, 2H), 1.50-1.26 (m, 2H), 1.36 (s, 3H), 0.90 (t , 3H, J = 7.0 Hz) m / z: 293.43 1-38 2-MeO-Bn H H 2 Me m / z: 323.42 1-39 3-MeO-Bn H H 2 Me m / z: 323.42 1-40 4-MeO-Bn H H 2 Me m / z: 323.41 1-41 4-t-Bu-Bn H H 2 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.39-7.27 (m, 4H), 6.65 (d, 1H, J = 8.5 Hz), 6.58-6.53 (m, 1H), 6.44 (m, 1H), 6.27 ( d, 1H, J = 10.0 Hz, 5.57 (d, 1H, J = 10.0 Hz), 4.80 (br, 1H), 4.22 (s, 2H), 1.71-1.60 (m, 2H), 1.54-1.23 (m , 2H), 1.32 (s, 3H), 1.31 (s, 3H), 0.92 (t, 3H, J = 7.1 Hz) m / z: 349.57 1-42 2-Me-Bn H H 2 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.33-7.26 (m, 1H), 7.20-7.14 (m, 3H), 6.65 (s, 2H), 6.55 (s, 1H), 6.26 (d, 1H, J = 9.8 Hz), 5.59 (d, 1H, J = 9.8 Hz), 4.25 (s, 2H), 2.29 (s, 3H), 1.71-1.59 (m, 2H), 1.51-1.27 (m, 2H), 1.36 (s, 3H), 0.92 (t, 3H, J = 7.1 Hz); m / z: 307.41 1-43 3-Me-Bn H H 2 Me m / z: 307.24 1-44 4-Me-Bn H H 2 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.16 (d, 2H, J = 6.5 Hz), 7.06 (d, 2H, J = 6.5 Hz), 6.88-6.78 (m, 2H), 6.65 (d, 1H, J = 8.3 Hz), 6.25 (d, 1H, J = 9.8 Hz), 5.59 (d, 1H, J = 9.8 Hz), 4.17 (s, 2H), 2.26 (s, 3H), 1.70-1.58 (m, 2H), 1.51-1.27 (m, 2H), 1.35 (s, 3H), 0.96-0.87 (m, 3H) m / z: 307.40

1-45 2-F-Bn H H 2 Me m / z: 311.44 1-46 3-F-Bn H H 2 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.35-7.25 (m, 1H), 7.17-7.07 (m, 2H), 7.00-6.91 (m, 1H), 6.63 (d, 1H, J = 8.5 Hz), 6.46-6.40 (m, 1H), 6.31 (d, 1H, J = 8.5 Hz), 6.46-6.40 (m, 1H), 6.31 (d, 1H, J = 2.8 Hz), 6.25 (d, 1H, J = 9.9 Hz), 5.57 (d, 1H, J = 9.9 Hz), 4.28 (s, 2H), 3.38 (br, 1H), 1.70-1.59 (m, 2H), 1.53-1.40 (m, 2H), 1.35 ( s, 3H), 0.91 (t, 3H, J = 7.1 Hz) m / z: 311.30 1-47 4-F-Bn H H 2 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.37-7.30 (m, 2H), 7.06-6.97 (m, 2H), 6.63 (d, 1H, J = 8.5 Hz), 6.46 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz, 6.35 (d, 1H, J = 2.8 Hz), 6.26 (d, 1H, J = 9.9 Hz), 5.57 (d, 1H, J = 9.9 Hz), 4.24 (s, 2H) , 3.6 (br, 1H), 1.70-1.59 (m, 2H), 1.53-1.26 (m, 2H), 1.35 (s, 3H), 0.91 (t, 3H, J = 7.1 Hz) m / z: 311.43 1-48 3-Cl-Bn H H 2 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.42-7.34 (m, 1H), 7.27-7.23 (m, 3H), 6.64 (d, 1H, J = 8.5 Hz), 6.57-6.51 (m, 1H), 6.44-6.42 (m, 1H), 6.26 (d, 1H, J = 10.0 Hz), 5.57 (d, 1H, J = 10.0 Hz), 4.25 (s, 2H), 1.71-1.59 (m, 2H), 1.50 -1.27 (m, 2H), 1.36 (s, 3H), 0.97-0.94 (m, 3H) m / z: 327.76 1-49 4-CF ₃ -Bn H H 2 Me m / z: 361.61 1-50

H H 2 Me m / z: 294.50 1-51

H H 2 Me m / z: 294.44 1-52

H H 2 Me m / z: 294.41 1-53

H H 2 Me m / z: 299.24 1-54

H H 2 Me m / z: 299.14 1-55

H H 2 Me m / z: 313.37 1-56

H H 2 Me m / z: 328.25 1-57 Bn H H 2 Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.07 (m, 2H), 7.18 (m, 8H), 6.86 (dd, 1H, J = 8.6 Hz, J = 2.8 Hz), 6.77 (d, 1H, J = 2.8 Hz), 6.67 (d, 1H, J = 8.6 Hz), 6.28 (d, 1H, J = 10.0 Hz), 5.62 (d, 1H, J = 10.0 Hz), 4.21 (s, 2H), 2.72 (m , 2H), 1.95 (m, 2H), 1.40 (s, 3H) m / z: 355.41 1-58 4-MeO-Bn H H 2 Ph ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.30-7.22 (m, 5H), 7.15 (d, 2H), 6.87 (m, 2H), 6.66 (d, 1H), 6.45 (dd, 1H), 6.32 ( d, 1H), 6.30 (d, 1H), 5.59 (d, 1H,, J = 9.8 Hz), 4.17 (s, 2H), 3.78 (s, 3H), 2.74 (m, 2H),), 1.94 ( m, 2H), 1.40 (s, 3H) m / z: 385.34

1-59 2-F-Bn H H 2 Ph ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35 (m, 1H), 7.26-7.05 (m, 8H), 6.65 (d, 1H, J = 8.5 Hz), 6.43 (dd, 1H, J = 8.50 Hz, J = 2.8 Hz), 6.30 (d, 1H, J = 2.8 Hz), 6.28 (d, 1H, J = 9.8 Hz), 5.57 (d, 1H, J = 9.8 Hz), 4.30 (s, 2H), 2.73 (m, 2H), 1.97 (m, 2H), 1.38 (s, 3H) m / z: 373.47 1-60 3-F-Bn H H 2 Ph m / z: 373.58 1-61 4-F-Bn H H 2 Ph m / z: 373.55 1-62 2-CN-Bn H H 2 Ph ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.95 (d, 1H, J = 7.5 Hz), 7.50 (m, 2H), 7.38 (d, 1H, J = 7.5 Hz), 7.25-7.15 (m, 6H) , 7.09 (d, 1H, J = 2.4 Hz), 6.79 (d, 1H, J = 8.4 Hz), 6.40 (d, 1H, J = 9.6 Hz), 5.60 (d, 1H, J = 9.6 Hz), 5.40 (s, 2H), 2.82-2.73 (m, 2H), 2.08-1.89 (m, 2H), 1.44 (s, 3H) m / z: 380.26 1-63 4-CN-Bn H H 2 Ph ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.60 (d, 2H, J = 8.0 Hz), 7.47 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 6.6 Hz), 7.15 (m , 3H), 6.65 (d, 1H, J = 8.4 Hz), 6.38 (dd, 1H, J = 8.4 Hz, J = 2.7 Hz), 6.27 (d, 1H, J = 9.9 Hz), 6.25 (d, 1H) , J = 2.7 Hz), 5.61 (d, 1H, J = 9.9 Hz), 4.35 (s, 2H), 3.87 (br-s, 1H), 2.78-2.67 (m, 2H), 2.00- 1.90 (m, 2H), 1.40 (s, 3H) m / z: 380.87 1-64 4-NO ₂ -Bn H H 2 Ph ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.15 (m, 2H, J = 8.6 Hz), 7.50 (d, 2H, J = 8.6 Hz), 7.24 (m, 2H), 7.14 (m, 3H), 6.64 (d, 1H, J = 8.5 Hz), 6.37 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.26 (d, 1H, J = 9.8 Hz), 6.24 (d, 1H, J = 2.8 Hz ), 5.60 (d, 1H, J = 9.8 Hz), 4.37 (s, 2H), 2.72 (m, 2H), 1.96 (m, 2H), 1.39 (s, 3H) m / z: 400.40 1-65 2-CF ₃ -Bn H H 2 Ph m / z: 423.28 1-66 3-CF ₃ -Bn H H 2 Ph m / z: 423.48 1-67 4-CF ₃ -Bn H H 2 Ph m / z: 423.58 1-68 4-EtO-Bn H H 2 Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.32-7.08 (m, 7H), 6.84 (d, 2H, J = 8.6 Hz), 6.65 (d, 1H, J = 8.5 Hz), 6.42 (dd, 1H, J = 8.50 Hz, J = 2.6 Hz), 6.31 (d, 1H, J = 2.6 Hz,), 6.28 (d, 1H, J = 9.8 Hz), 5.57 (d, 1H, J = 9.8 Hz), 4.14 ( s, 2H), 3.98 (q, 2H, J = 7.1 Hz), 2.73 (m, 2H), 1.94 (m, 2H), 1.38 (s, 3H), 1.38 (t, 3H, J = 7.1 Hz) m / z: 399.74

1-69 2,5-Di-Me-Bn H H 2 Ph m / z: 383.24 1-70 2,6-Di-Me-Bn H H 2 Ph m / z: 383.24 1-71 4-Br-2-F-Bn H H 2 Ph m / z: 452.54 1-72

H H 2 Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.29-7.22 (m, 6H), 7.19-6.90 (m, 2H), 6.70 (d, 1H, J = 9.7 Hz), 6.58-6.40 (m, 1H), 6.40-6.32 (m, 2H), 6.64 (d, 1H, J = 9.8 Hz), 4.47 (s, 2H), 3.60-3.20 (br, 1H), 2.80-2.60 (m, 2H), 2.10-1.80 ( m, 2H), 1.44 (s, 3H) m / z: 361.52 1-73

H H 2 Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.28-7.10 (m, 7H), 7.04 (dd, 1H, J = 4.8 Hz, J = 1.2 Hz), 6.67 (d, 1H, J = 8.6 Hz), 6.44 (dd, 1H, J = 8.6 Hz, J = 2.8 Hz), 6.30 (m, 2H), 5.59 (d, 1H, J = 9.6 Hz), 4.23 (s, 2H), 3.53 (br, 1H), 2.80 -2.69 (m, 2H), 2.06-1.89 (m, 2H), 1.39 (s, 3H) m / z: 361.27 1-74

H H 2 Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.27-7.16 (m, 5H), 6.77-6.60 (m, 1H), 6.60-6.40 (m, 1H), 6.38-6.31 (m, 2H), 5.61 (d , 1H, J = 10.2 Hz, 5.17 (s, 1H), 4.37 (s, 2H), 2.90-2.80 (m, 2H), 2.45 (s, 3H), 2.07-1.80 (m, 2H), 1.42 ( s, 3 H) m / z: 375.77 1-75

H H 2 Ph m / z: 390.21 1-76 Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.40-7.25 (m, 5H), 7.08 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 6.67 (d, 1H, J = 8.5 Hz), 6.46 (dd, 1H, J = 8.5 Hz, J = 2.5 Hz), 6.35-6.28 (m, 2H), 5.60 (d, 1H, J = 9.8 Hz), 4.28 (s, 2H) , 3.78 (s, 3H), 2.72-2.61 (m, 2H), 1.99-1.87 (m, 2H), 1.40 (s, 3H); m / z: 385.27 1-77 2-MeO-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.34-7.21 (m, 2H), 7.09 (d, 2H, J = 8.6 Hz), 7.05-6.88 (m, 2H), 6.81 (d, 2H, J = 8.7 Hz), 6.66 (d, 1H, J = 8.5 Hz), 6.49 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.37-6.29 (m, 2H), 5.59 (d, 1H, J = 9.7 Hz), 4.28 (s, 2H), 3.87 (s, 3H), 3.78 (s, 3H), 2.76-2.61 (m, 2H), 1.99-1.88 (m, 2H), 1.40 (s, 3H); m / z: 415.82 1-78 3-MeO-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.31-7.23 (m, 1H), 7.09 (d, 2H, J = 8.5 Hz), 7.06-6.94 (m, 2H), 6.85-6.77 (m, 3H), 6.67 (d, 1H, J = 8.5 Hz), 6.46 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.35-6.28 (m, 2H), 5.61 (d, 1H, J = 9.8 Hz), 4.26 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H), 2.76-2.61 (m, 2H), 2.00-1.88 (m, 2H), 1.41 (s, 3H); m / z: 415.74

1-79 4-MeO-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.29 (d, 2H, J = 8.5 Hz), 7.08 (d, 2H, J = 8.5 Hz), 6.88 (d, 2H, J = 8.5 Hz), 6.80 (d , 2H, J = 8.5 Hz, 6.66 (d, 1H, J = 8.5 Hz), 6.46 (dd, 1H, J = 8.5 Hz, J = 2.5 Hz), 6.35-6.29 (m, 2H), 5.60 (d , 1H, J = 9.8 Hz, 4.20 (s, 2H), 3.81 (s, 3H), 3.78 (s, 3H), 2.75-2.61 (m, 2H), 1.99-1.87 (m, 2H), 1.40 ( s, 3H); m / z: 415.04 1-80 4-t-Bu-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.40-7.26 (m, 4H), 7.08 (d, 2H, J = 8.7 Hz), 6.80 (d, 2H, J = 8.7 Hz), 6.67 (d, 1H, J = 8.5 Hz), 6.47 (dd, 1H, J = 8.5 Hz, J = 2.7 Hz), 6.36-6.29 (m, 2H), 5.60 (d, 1H, J = 9.8 Hz), 4.23 (s, 2H) , 3.78 (s, 3H), 2.75-2.62 (m, 2H), 1.99-1.87 (m, 2H), 1.40 (s, 3H), 1.32 (s, 9H); m / z: 441.47 1-81 4-Me-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.29-7.25 (m, 2H), 7.15 (d, 2H, J = 8.1 Hz), 7.08 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 6.66 (d, 1H, J = 8.5 Hz), 6.46 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.35-6.28 (m, 2H), 5.60 (d, 1H, J = 9.8 Hz), 4.23 (s, 2H), 3.78 (s, 3H), 2.75-2.61 (m, 2H), 2.35 (s, 3H), 1.99-1.87 (m, 2H), 1.40 (s, 3H) ); m / z: 399.40 1-82 2-F-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.43-7.35 (m, 1H), 7.30-7.20 (m, 1H), 7.13-7.01 (m, 4H), 6.80 (d, 2H, J = 8.9 Hz), 6.66 (d, 1H, J = 8.5 Hz), 6.47 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.35-6.28 (m, 2H), 5.60 (d, 1H, J = 9.8 Hz), 4.35 (s, 2H), 3.78 (s, 3H), 2.75-2.01 (m, 2H), 1.99-1.87 (m, 2H), 1.40 (s, 3H); m / z: 403.77 1-83 3-F-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.33-7.26 (m, 1H), 7.25-7.06 (m, 4H), 7.05-6.96 (m, 1H), 6.83-6.78 (m, 2), 6.65 (d , 1H, J = 8.5 Hz), 6.43 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.32-6.27 (m, 2H), 5.60 (d, 1H, J = 10.1 Hz), 4.28 (s , 2H), 3.78 (s, 3H), 2.75-2.61 (m, 2H), 1.99-1.87 (m, 2H), 1.40 (s, 3H); m / z: 403.52 1-84 4-F-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.37-7.26 (m, 2H), 7.10-6.98 (m, 4H), 6.80 (d, 2H, J = 8.7 Hz), 6.66 (d, 1H, J = 8.5 Hz), 6.45 (dd, 1H, J = 8.5 Hz, J = 2.5 Hz), 6.33-6.27 (m, 2H), 560 (d, 1H, J = 9.8 Hz), 4.24 (s, 2H), 3.78 ( s, 3H), 2.75-2.61 (m, 2H), 1.99-1.87 (m, 2H), 1.40 (s, 3H); m / z: 403.04

1-85 2-Cl-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.45-7.36 (m, 2H), 7.24-7.19 (m, 2H), 7.08 (d, 2H, J = 8.8 Hz), 6.80 (d, 2H, J = 8.8 Hz), 6.66 (d, 1H, J = 8.6 Hz), 6.44 (dd, 1H, J = 8.6 Hz, J = 2.9 Hz), 6.32-6.28 (m, 2H), 5.60 (d, 1H, J = 9.8 Hz), 4.38 (s, 2H), 3.78 (s, 3H), 2.75-2.61 (m, 2H), 1.99-1.87 (m, 2H), 1.40 (s, 3H); m / z: 419.71 1-86 3-Cl-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.37 (s, 1H), 7.26 (s, 3H), 7.08 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 6.66 (d, 1H, J = 8.5 Hz), 6.43 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.32-6.27 (m, 2H), 5.60 (d, 1H, J = 9.8 Hz), 4.26 (s, 2H), 3.78 (s, 3H), 2.75-2.61 (m, 2H), 1.99-1.87 (m, 2H), 1.40 (s, 3H); m / z: 419.52 1-87 4-Cl-Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.30 (s, 4H), 7.08 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 6.65 (d, 1H, J = 8.5 Hz), 6.46 (dd, 1H, J = 8.3 Hz, J = 2.7 Hz), 6.33 (d, 1H, J = 2.7 Hz), 6.29 (d, 1H, J = 9.8 Hz), 5.60 (d, 1H , J = 9.8 Hz, 4.25 (s, 2H), 3.77 (s, 3H), 2.71-2.62 (m, 2H), 1.98-1.90 (m, 2H), 1.39 (s, 3H); m / z: 419.94 1-88 2-NO ₂ -Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.08-8.02 (m, 1H), 7.70-7.61 (m, 1H), 7.60-7.52 (m, 1H), 7.45-7.41 (m, 1H), 7.07 (d , 2H, J = 8.7 Hz, 6.79 (d, 2H, J = 8.7 Hz), 6.63 (d, 1H, J = 8.5 Hz), 6.38 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.29-6.24 (m, 2H), 5.59 (d, 1H, J = 10.2 Hz), 4.65 (s. 2H), 3.77 (s, 3H), 2.73-2.61 (m, 2H), 1.98-1.86 (m, 2H), 1.39 (s, 3H); m / z: 430.21 1-89 3-NO ₂ -Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.25 (s, 1H), 8.12 (d, 1H, J = 8.5 Hz), 7.71 (d, 1H, J = 7.7 Hz), 7.50 (t, 1H, J = 7.7 Hz), 7.07 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 6.65 (d, 1H, J = 8.5 Hz), 6.1 (dd, 1H, J = 8.5 Hz , J = 2.8 Hz), 6.31-6.26 (m, 2H), 5.61 (d, 1H, J = 9.8 Hz), 4.40 (s, 2H), 3.77 (s, 3H), 2.74-2.61 (m, 2H) , 1.99-1.87 (m, 2H), 1.40 (s, 3H); m / z: 430.24 1-90 4-NO ₂ -Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.19 (d, 2H, J = 9.0 Hz), 7.53 (d, 2H, J = 9.0 Hz), 7.07 (d, 2H, J = 8.5 Hz), 6.80 (d , 2H, J = 8.5 Hz, 6.65 (d, 1H, J = 8.5 Hz), 6.39 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.30-6.24 (m, 2H), 5.61 (d , 1H, J = 9.8 Hz, 4.41 (s, 2H), 3.77 (s, 3H), 2.74-2.05 (m, 2H), 1.99-1.87 (m, 2H), 1.40 (s, 3H); m / z: 430.71

1-91 4-CF ₃ -Bn H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.59 (d, 2H, J = 8.3 Hz), 7.48 (d, 2H, J = 8.3 Hz), 7.07 (d, 2H, J = 8.5 Hz), 6.79 (d , 2H, J = 8.5 Hz, 6.65 (d, 1H, J = 8.5 Hz), 6.42 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.30-6.26 (m, 2H), 5.60 (d , 1H, J = 9.8 Hz, 4.35 (s, 2H), 3.77 (s, 3H), 2.74-2.61 (m, 2H), 1.98-1.86 (m, 2H), 1.39 (s, 3H); m / z: 453.24 1-92

H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.58 (m, 1H), 7.65 (m, 1H), 7.34 (d, 1H, J = 6.7 Hz), 7.21-7.14 (m, 1H), 7.07 (d, 2H, J = 8.5 Hz, 6.79 (d, 2H, J = 8.5 Hz), 6.66 (d, 1H, J = 8.5 Hz), 6.48 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.35 (d, 1H, J = 2.8 Hz), 6.30 (d, 1H, J = 9.8 Hz), 5.59 (d, 1H, J = 9.8 Hz), 4.41 (s, 2H), 3.77 (s, 3H), 2.74 -2.61 (m, 2H), 1.98-1.86 (m, 2H), 1.39 (s, 3H); m / z: 386.85 1-93

H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.24-7.22 (m, 1H), 7.21-7.07 (m, 2H), 7.06-6.94 (m, 2H), 6.80 (d, 2H, J = 8.5 Hz), 6.68 (d, 1H, J = 8.5 Hz), 6.50 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.38 (d, 1H, J = 2.8 Hz), 6.31 (d, 1H, J = 10.2 Hz), 5.60 (d, 1H, J = 10.2 Hz), 4.46 (s, 2H), 3.78 (s, 3H), 2.76-2.61 (m, 2H), 2.02-1.87 (m, 2H), 1.41 (s , 3H); m / z: 391.47 1-94

H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.33-7.26 (m, 1H), 7.21-7.18 (m, 1H), 7.11-7.07 (m, 3H), 6.81 (d, 2H, J = 8.5 Hz), 6.68 (d, 1H, J = 8.5 Hz), 6.48 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.36-6.29 (m, 2H), 5.61 (d, 1H, J = 10.2 Hz), 4.28 (s, 2H), 3.78 (s, 3H), 2.76-2.61 (m, 2H), 1.99-1.40 (m, 2H), 1.41 (s, 3H); m / z: 391.95 1-95

H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.09 (d, 2H, J = 8.5 Hz), 6.83-6.77 (m, 4H), 6.68 (d, 1H, J = 8.6 Hz), 6.61-6.59 (m, 1H), 6.49 (dd, 1H, J = 8.6 Hz, J = 2.8 Hz), 6.37-6.29 (m, 2H), 5.60 (d, 1H, J = 9.7 Hz), 4.36 (s, 2H), 3.78 ( s, 3H), 2.76-2.65 (m, 2H), 2.45 (s, 3H), 2.00-1.88 (m, 2H), 1.41 (s, 3H); m / z: 405.47

1-96

H H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.85-7.79 (m, 4H), 7.52-7.27 (m, 3H), 7.08 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 6.67 (d, 1H, J = 8.5 Hz), 6.50 (dd, 1H, J = 8.5 Hz, J = 2.7 Hz), 6.38 (d, 1H, J = 2.7 Hz), 6.30 (d, 1H, J = 9.8 Hz), 5.60 (d, 1H, J = 9.8 Hz), 4.44 (s, 2H), 3.77 (s, 3H), 2.75-2.61 (m, 2H), 1.999-1.87 (m, 2H), 1.40 (s, 3 H); m / z: 435.95 1-97 PhEt Me H 2 4-MeO-Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.37-7.13 (m, 5H), 7.08 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.5 Hz), 6.66 (d, 1H, J = 8.5 Hz), 6.44 (dd, 1H, J = 8.5 Hz, J = 2.8 Hz), 6.34-6.29 (m, 2H), 5.60 (d, 1H, J = 9.8 Hz), 3.77 (s, 3H) , 3.36 (t, 2H, J = 6.9 Hz), 2.91 (t, 2H, J = 6.9 Hz), 2.75-2.61 (m, 2H), 1.99-1.87 (m, 2H), 1.40 (s, 3H); m / z: 399.74 1-98 Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.41-7.32 (m, 5H), 6.61 (s, 1H), 6.32 (s, 1H), 6.26 (d, 1H, J = 9.8 Hz), 5.55 (d, 1H, J = 9.8 Hz, 4.32 (s, 2H), 2.13 (s, 3H), 1.41 (s, 6H); m / z: 279.65 1-99 4-MeO-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.32 (d, 2H, J = 8.8 Hz), 6.90 (d, 2H, J = 8.8 Hz), 6.59 (s, 1H), 6.32 (s, 1H), 6.26 (d, 1H, J = 9.7 Hz), 5.54 (d, 1H, J = 9.7 Hz), 4.23 (s, 2H), 3.82 (s, 3H), 2.11 (s, 3H), 1.40 (s, 6H) ; m / z: 309.35 1-100 4-t-Bu-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.43-7.27 (m, 4H), 6.61 (s, 1H), 6.37 (s, 1H), 6.29 (d, 1H, J = 9.8 Hz), 5.56 (d, 1H, J = 9.8 Hz), 4.28 (s, 2H), 2.13 (s, 3H), 1.41 (s, 6H), 1.35 (s, 9H) m / z: 335.01 1-101 2-Me-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.37-7.33 (m, 1H), 7.25-7.18 (m, 3H), 6.61 (s, 1H), 6.34 (s, 1H), 6.29 (d, 1H, J = 9.8 Hz), 5.56 (d, 1H, J = 9.8 Hz), 4.26 (s, 2H), 2.40 (s, 3H), 2.11 (s, 3H), 1.42 (s, 6H) m / z: 293.74 1-102 4-Me-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.30 (d, 2H, J = 7.9 Hz), 7.18 (d, 2H, J = 7.9 Hz), 6.60 (s, 1H), 6.34 (s, 1H), 6.27 (d, 1H, J = 9.7 Hz), 5.55 (d, 1H, J = 9.7 Hz), 4.27 (s, 2H), 2.37 (s, 3H), 2.12 (s, 3H), 1.41 (s, 6H) m / z: 293.65

1-103 2-F-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.38 (m, 1H), 7.13-7.01 (m, 3H), 6.58 (s, 1H), 6.32 (s, 1H), 6.23 (d, 1H, J = 9.8 Hz), 5.53 (d, 1H, J = 9.8 Hz), 4.38 (s, 2H), 2.13 (s, 3H), 1.39 (s, 6H) m / z: 297.17 1-104 3-F-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.37-7.29 (m, 1H), 7.19-7.09 (m, 2H), 7.02-6.94 (m, 1H), 6.61 (s, 1H), 6.24 (s, 1H ), 6.23 (d, 1H, J = 9.7 Hz), 5.54 (d, 1H, J = 9.7 Hz), 4.33 (s, 2), 2.15 (s, 3H), 1.40 (s, 6H) m / z: 297.31 1-105 4-F-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.40-7.32 (m, 2H), 7.09-7.00 (m, 2H), 6.60 (s, 1H), 6.28 (s, 1H), 6.24 (d, 1H, J = 9.6 Hz), 5.55 (d, 1H, J = 9.6 Hz), 4.28 (s, 2H), 2.13 (s, 3H), 1.40 (s, 6H) m / z: 297.37 1-106 2-Cl-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.42-7.37 (m, 2H), 7.2-7.20 (m, 2H), 6.60 (s, 1H), 6.23 (m, 2H), 5.53 (d, 1H, J = 9.8 Hz), 4.43 (s, 3H), 2.16 (s, 3H), 1.40 (s, 6H) m / z: 313.78 1-107 3-Cl-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.40 (s, 1H), 7.28 (m, 3H), 6.61 (s, 1H), 6.26-6.21 (m, 2H), 5.59-5.52 (m, 1H), 4.31 (s, 2H), 2.15 (s, 3H), 1.41 (s, 6H) m / z: 313.28 1-108 4-CN-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.63 (d, 2H,, J = 8.4 Hz), 7.48 (d, 2H, J = 8.4 Hz), 6.60 (s, 1H), 6.16 (d, 1H, J = 9.8 Hz), 6.12 (s, 1H), 5.52 (d, 1H, J = 9.8 Hz), 4.41 (s, 2H), 2.15 (s, 3H), 1.38 (s, 6H) m / z: 304.74 1-109 4-NO ₂ -Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.19 (d, 2H, J = 8.8 Hz), 7.54 (d, 2H, J = 8.8 Hz), 6.60 (s, 1H), 6.18 (s, 1H), 6.12 (d, 1H, J = 9.8 Hz), 5.52 (d, 1H, J = 9.8 Hz), 4.45 (s, 2H), 2.17 (s, 3H), 1.38 (s, 6H); m / z: 324.77 1-110 4-CF ₃ -Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.60 (d, 2H, J = 8.2H), 7.50 (d, 2H, J = 8.2 Hz), 6.61 (s, 1H), 6.21 (m, 2H), 5.53 (d, 1H, J = 9.6 Hz), 4.40 (s, 2H), 2.15 (s, 3H), 1.39 (s, 6H) m / z: 347.59

1-111 4-EtO-Bn Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.32-7.26 (m, 2H), 6.88 (d, 2H, J = 8.7 Hz), 6.58 (s, 1H), 6.33 (s, 1H), 6.26 (d, 1H, J = 9.7 Hz, 5.53 (d, 1H, J = 9.7 Hz), 4.22 (s, 2H), 4.05 (q, 2H, J = 7.0 Hz), 2.10 (s, 3H), 1.45-1.26 ( m, 9H) m / z: 323.35 1-112

Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.48-7.41 (m, 1H), 7.26-7.21 (m, 1H), 7.04-6.96 (m, 1H), 6.68 (s, 1H), 6.37 (s, 1H ), 6.26 (d, 1H, J = 9.6 Hz), 5.55 (d, 1H, J = 9.6 Hz), 4.49 (s, 2H), 2.12 (s, 3H), 1.40 (s, 6H) m / z: 285.54 1-113

Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.33 (dd, 1H, J = 4.8 Hz, J = 3.0 Hz), 7.23 (dd, 1H, J = 3.0 Hz, J = 1.0 Hz), 7.12 (dd, 1H) , J = 4.8 Hz, J = 1.0 Hz, 6.62 (s, 1H), 6.36 (s, 1H), 6.29 (d, 1H, J = 9.8 Hz), 5.56 (d, 1H, J = 9.8 Hz), 4.33 (s, 2H), 2.13 (s, 3H), 1.42 (s, 6H) m / z: 285.74 1-114

Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) 6.80-6.66 (m, 1H), 6.64-6.58 (m, 2H), 6.37 (s, 1H), 6.27 (d, 1H, J = 9.7 Hz), 5.55 (d , 1H, J = 9.8 Hz, 4.40 (s, 2H), 2.46 (s, 3H), 2.10 (s, 3H), 1.39 (s, 6H) m / z: 299.47 1-115

Me H 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.88-7.82 (m, 4H), 7.56-7.47 (m, 3H), 6.63 (s, 1H), 6.36 (s, 1H), 6.24 (d, 1H, J = 9.8 Hz), 5.53 (d, 1H, J = 9.8 Hz), 4.49 (s, 2H), 2.16 (s, 3H), 1.41 (s, 6H) m / z: 329.74 1-116 4-MeO-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.34 (d, 2H,, J = 8.8 Hz), 6.92 (d, 2H, J = 8.8 Hz), 6.62 (s, 1H), 6.34 (s, 1H), 6.32 (d, 1H, J = 9.8 Hz), 5.52 (d, 1H, J = 9.8 Hz), 4.25 (s, 2H), 3.83 (s, 3H), 2.12 (s, 3H), 1.71 (q, 2H ,, J = 7.4 Hz), 1.36 (s, 3H), 0.98 (t, 3H,, J = 7.4 Hz) m / z: 323.47 1-117 4-t-Bu-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.41 (d, 2H, J = 8.6 Hz), 7.34 (d, 2H, J = 8.6 Hz), 6.60 (s, 1H), 6.35 (s, 1H), 6.33 (d, 1H, J = 9.8 Hz), 5.51 (d, 1H, J = 9.8 Hz), 4.28 (s, 2H), 2.12 (s, 3H), 1.70 (q, 2H, J = 7.6 Hz), 1.35 (s, 12H), 0.97 (t, 3H, J = 7.6 Hz) m / z: 349.57

1-118 2-Me-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.35 (m, 1H), 7.25-7.20 (m, 3H), 6.61 (s, 1H), 6.33 (m, 2H), 5.52 (d, 1H, J = 9.8 Hz), 4.26 (s, 2H), 2.40 (s, 3H), 2.11 (s, 3H), 1.71 (q, 2H, J = 7.6 Hz), 1.36 (s, 3H), 0.97 (t, 3H, J = 7.6 Hz) m / z: 307.65 1-119 4-Me-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.30 (d, 2H, J = 7.8 Hz), 7.17 (d, 2H, J = 7.8 Hz), 6.59 (s, 1H), 6.32 (s, 1H), 6.30 (d, 1H, J = 9.8 Hz), 5.50 (d, 1H, J = 9.8 Hz), 4.27 (s, 2H), 2.37 (s, 3H), 2.12 (s, 3H), 1.70 (q, 2H, , J = 7.4 Hz), 1.35 (s, 3H), 0.96 (t, 3H, J = 7.4 Hz) m / z: 307.58 1-120 3-F-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.32 (m, 1H), 7.15 (m, 2H), 6.68 (m, 1H), 6.61 (s, 1H), 6.27 (d, 1H, J = 10.0 Hz) , 6.23 (s, 1H), 5.50 (d, 1H, J = 10.0 Hz), 4.33 (s, 2H), 2.15 (s, 3H), 1.70 (q, 2H, J = 7.6 Hz), 1.35 (s, 3H), 0.96 (t, 3H, J = 7.6 Hz) m / z: 311.17 1-121 4-F-Bn Me H One Me ₁ ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.40-7.33 (m, 2H), 7.09-7.00 (m, 2H), 6.60 (s, 1H), 6.28 (d, 1H, J = 9.9 Hz), 6.27 (s, 1H), 5.50 (d, 1H, J = 9.9 Hz), 4.28 (s, 2H), 2.13 (s, 3H), 1.70 (q, 2H, J = 7.5 Hz), 1.35 (s, 3H) , 0.96 (t, 3H, J = 7.5 Hz); m / z: 311.47 1-122 2-Cl-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.44-7.37 (m, 2H), 7.25-7.20 (m, 2H), 6.59 (s, 1H), 6.27 (d, 1H, J = 9.8 Hz), 6.22 ( s, 1H), 5.49 (d, 1H, J = 9.8 Hz), 4.42 (s, 2H), 2.16 (s, 3H), 1.69 (q, 2H,, J = 7.5 Hz), 1.34 (s, 3H) , 0.95 (t, 3H, J = 7.5 Hz) m / z: 327.52 1-123 3-Cl-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.40 (s, 1H), 7.28 (m, 3H), 6.60 (s, 1H), 6.27 (d, 1H, J = 9.8 Hz), 6.22 (s, 1H) , 5.50 (d, 1H, J = 9.8 Hz), 4.30 (s, 2H), 2.15 (s, 3H), 1.69 (q, 2H,, J = 7.4 Hz), 1.34 (s, 3H), 0.96 (t , 3H, J = 7.4 Hz) m / z: 327.74 1-124 4-CN-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.62 (d, 2H, J = 8.2 Hz), 7.48 (d, 2H, J = 8.2 Hz), 6.59 (s, 1H), 6.20 (d, 1H, J = 9.8 Hz), 6.09 (s, 1H), 5.47 (d, 1H, J = 9.8 Hz), 4.40 (s, 2H), 3.32 (br-s, 1H), 2.15 (s, 3H), 1.67 (q, 2H,, J = 7.6 Hz), 1.32 (s, 3H), 0.93 (t, 3H,, J = 7.6 Hz) m / z: 318.74

1-125 4-CF ₃ -Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.62 (d, 2H, J = 8.4 Hz), 7.51 (d, 2H, J = 8.4 Hz), 6.61 (s, 1H), 6.25 (d, 1H, J = 9.8 Hz), 6.20 (s, 1H), 5.50 (d, 1H, J = 9.8 Hz), 4.40 (s, 2H), 2.16 (s, 3H), 1.70 (q, 2H, J = 7.4 Hz), 1.34 (s, 3H), 0.96 (t, 3H,, J = 7.4 Hz) m / z: 361.95 1-126 4-EtO-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.32-7.26 (m, 2H), 6.87 (d, 2H, J = 8.7 Hz), 6.85 (s, 1H), 6.57 (s, 1H), 6.28 (d, 1H, J = 9.9 Hz, 5.49 (d, 1H, J = 9.9 Hz), 4.22 (s, 2H), 4.03 (t, 2H, J = 6.9 Hz), 2.09 (s, 3H), 1.70-1.66 ( m, 2H), 1.45-1.23 (m, 5H), 0.94 (m, 3H) m / z: 337.74 1-127 4-Br-2-F-Bn Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.28-7.24 (m, 3H), 6.58 (s, 1H), 6.25 (d, 1H, J = 9.9 Hz), 6.20 (s, 1H), 5.49 (d, 1H, J = 9.9 Hz), 4.34 (s, 2H), 2.13 (s, 2H), 1.68 (q, 2H, J = 7.5 Hz), 1.33 (s, 3H), 0.96 (t, 3H,, J = 7.5 Hz) m / z: 390.57 1-128

Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.33 (dd, 1H,, J = 4.8 Hz, J = 3.2 Hz), 7.23 (dd, 1H, J = 3.2 Hz, J = 1.2 Hz), 7.14 (dd, 1H, J = 4.8 Hz, J = 1.2 Hz, 6.62 (s, 1H), 6.35 (s, 1H), 6.33 (d, 1H, J = 9.8 Hz), 5.53 (d, 1H,, J = 9.8 Hz ), 4.33 (s, 2H), 2.13 (s, 3H), 1.71 (q, 2H,, J = 7.6 Hz), 1.37 (s, 3H), 0.98 (t, 3H,, J = 7.6 Hz) m / z: 299.77 1-129

Me H One Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.88-7.82 (m, 4H), 7.56-7.46 (m, 3H), 6.62 (s, 1H), 6.35 (s, 1H), 6.28 (d, 1H, J = 9.8 Hz), 5.49 (d, 1H, J = 9.8 Hz), 4.48 (s, 2H), 2.16 (s, 3H), 1.70 (q, 2H, J = 7.6 Hz), 1.35 (s, 3H), 0.96 (t, 3H,, J = 7.6 Hz) m / z: 343.44

1-130 2-F-Bn Me H 2 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.50-7.30 (m, 1H), 7.30-7.20 (m, 1H), 7.20-7.00 (m, 2H), 6.58 (s, 1H), 6.58-6.25 (m , 2H), 5.49 (d, 1H, J = 9.8 Hz), 2.13 (s, 3H), 1.73-1.62 (m, 2H), 1.39-1.22 (m, 5H), 1.01-0.91 (m, 3H) m / z: 325.78 1-131

Me H 2 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.36-7.32 (m, 1H), 7.27-7.23 (m, 1H), 7.16-7.12 (m, 1H), 6.61 (s, 1H), 6.36 (s, 1H ), 6.32 (d, 1H, J = 9.7 Hz), 5.53 (d, 1H, J = 9.7 Hz), 4.34 (s, 2H), 3.36 (br, 1H), 2.14 (s, 3H), 1.74-1.66 (m, 2H), 1.64-1.41 (m, 2H), 1.38 (s, 3H), 0.95 (m, 3H) m / z: 313.14 1-132

Me H 2 Ph ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.39-7.16 (m, 7H), 6.69 (s, 1H), 6.41 (d, 1H, J = 9.8 Hz), 6.41 (s, 1H), 5.61 (d, 1H, J = 9.8 Hz, 4.37 (s, 2H), 3.39 (br, 1H), 2.89-2.78 (m, 2H), 2.18 (s, 6H), 2.14-2.00 (m, 2H), 1.48 (s , 3H) m / z: 389.41 1-133 4-MeO-Bn Me Br 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.30 (d, 2H, J = 8.6 Hz), 6.89 (d, 2H, J = 8.6 Hz), 6.30 (s, 1H), 6.23 (d, 1H, J = 8.6 Hz, J = 2.8 Hz, 5.59 (d, 1H, J = 9.8 Hz), 4.22 (s, 2H), 3.81 (s, 3H), 2.28 (s, 3H), 1.44 (s, 6H) m / z: 388.71 1-134 Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 6.8 (d, 2H, J = 7.55 Hz), 7.53-.26 (m, 8H), 6.57 (d, 1H, J = 2.8 Hz), 6.36 (d, 1H , J = 2.8 Hz, 6.30 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.31 (s, 2H), 1.41 (s, 6H) m / z: 341.57 1-135 4-MeO-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.58-7.53 (m, 2H), 7.42-7.26 (m, 5H), 6.89 (d, 2H, J = 8.9 Hz), 6.56 (d, 1H, J = 2.8 Hz), 6.35 (d, 1H, J = 2.8 Hz), 6.30 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.23 (s, 2H), 3.81 (s, 3H), 1.40 (s, 6H) m / z: 371.17 1-136 4-t-Bu-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.58-7.53 (m, 2H), 7.43-7.29 (m, 7H), 6.57 (d, 1H, J = 2.8 Hz), 6.38 (d, 2H, J = 2.8 Hz), 6.31 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.27 (s, 2H), 1.41 (s, 6H), 1.34 (s, 9H) m / z : 397.54 1-137 2-Me-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.60-7.55 (m, 2H), 7.44-7.20 (m, 7H), 6.57 (d, 1H, J = 2.8 Hz), 6.37 (d, 1H, J = 2.8 Hz), 6.31 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.26 (s, 2H), 2.39 (s, 3H), 1.42 (s, 6H) m / z : 355.77

1-138 4-Me-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.58-7.53 (m, 2H), 7.43-7.26 (m, 5H), 7.16 (d, 2H, J = 7.7 Hz), 6.57 (d, 1H, J = 2.8 Hz), 6.36 (d, 1H, J = 2.8 Hz), 6.31 (d, 1H, J = 9.8 Hz), 5.64 (d, 1H, J = 9.8 Hz), 4.62 (s, 2H), 2.36 (s, 3H), 1.451 (s, 6H) m / z: 355.57 1-139 3-F-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.57-7.51 (m, 2H), 7.43-7.26 (m, 4H), 7.18-7.09 (m, 2H), 7.01-6.93 (m, 1H), 6.53 (d , 1H, J = 2.8 Hz, 6.32 (d, 1H, J = 2.8 Hz), 6.28 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.32 (s, 2H ), 1.41 (s, 6H) m / z: 359.55 1-140 4-F-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.57-7.52 (m, 2H), 7.43-7.26 (m, 5H), 7.08-6.99 (m, 2H), 6.54 (d, 1H, J = 2.8 Hz), 6.34 (d, 1H, J = 2.8 Hz), 6.29 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.27 (d, 2H), 1.40 (s, 6H); m / z: 359.25 1-141 2-Cl-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.56-7.52 (m, 2H), 7.48-7.29 (m, 5H), 7.26-7.20 (m, 2H), 6.55 (d, 1H, J = 2.8 Hz), 6.33 (d, 1H, J = 2.8 Hz), 6.29 (d, 1H, J = 9.8 Hz), 5.63 (d, 1H, J = 9.8 Hz), 4.41 (s, 2H), 1.40 (s, 6H) m / z: 375.04 1-142 3-Cl-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.57 (m, 2H), 7.43-7.26 (m, 7H), 6.53 (d, 1H, J = 2.9 Hz), 6.32 (d, 1H, J = 2.9 Hz) , 5.29 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.29 (s, 6H) m / z: 375.97 1-143 4-CN-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.64 (d, 2H, J = 8.5 Hz), 7.54-7.42 (m, 4H), 7.41-7.26 (m, 3H), 6.50 (d, 1H, J = 2.9 Hz), 6.29-6.45 (m, 2H), 5.66 (d, 1H, J = 9.4 Hz), 4.40 (s, 2H), 1.41 (s, 6H) m / z: 366.54 1-144 4-CF ₃ -Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.63-7.48 (m, 6H), 7.43-7.26 (m, 3H), 6.53 (d, 1H, J = 2.8 Hz), 6.31 (d, 1H, J = 2.8 Hz), 6.28 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.38 (s, 2H), 1.40 (s, 6H) m / z: 409.12 1-145 2,6-Di-Me-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) 7.60-7.56 (m, 2H), 7.44-7.26 (m, 4H), 7.12-7.01 (m, 2H), 6.57 (d, 1H, J = 2.4 Hz), 6.37 (d, 1H, J = 2.8 Hz), 6.31 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.21 (s, 2H), 2.34 (s, 3H), 2.33 (s, 3H), 1.41 (s, 6H) m / z: 369.65

1-146 3,5-Di-MeO-Bn H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.55-7.42 (m, 2H), 7.41-7.26 (m, 5H), 6.60-6.56 (m, 3H), 6.40-6.37 (m, 2H), 6.29 (d , 1H, J = 9.8 Hz, 5.64 (d, 1H, J = 9.8 Hz), 4.24 (s, 2H), 3.78 (s, 6H), 1.40 (s, 6H) m / z: 401.98 1-147

H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 8.59-8.56 (m, 2H), 7.53-7.48 (m, 2H), 7.41-7.26 (m, 5H), 6.47 (d, 1H, J = 1.6 Hz), 6.28-6.23 (m, 2H), 5.64 (d, 1H, J = 9.7 Hz), 4.37 (s, 2H), 1.40 (s, 6H) m / z: 342.64 1-148

H Ph 0 Me m / z: 347.55 1-149

H Ph 0 Me m / z: 347.24 1-150

H Ph 0 Me m / z: 361.01 1-151

H Ph 0 Me 1 H NMR (200 MHz, CDCl ₃ ) δ 7.52 (d, 2H, J = 6.5 Hz), 7.43-7.24 (m, 5H), 6.53 (d, 1H, J = 2.8 Hz), 6.47 (d, 1H, J) = 3.7 Hz), 6.32 (d, 1H, J = 2.8 Hz), 6.28 (d, 1H, J = 9.8 Hz), 5.66 (d, 1H, J = 9.8 Hz), 4.41 (s, 2H), 4.40- 3.80 (br, 1H), 1.39 (s, 6H) m / z: 376.41 1-152

H Ph 0 Me ¹ H NMR (200 MHz, CDCl ₃ ) δ 7.85-7.82 (m, 4H), 7.56-7.26 (m, 8H), 6.63-6.60 (m, 1H), 6.40-6.31 (m, 1H), 6.28-6.27 (d, 1H, J = 9.8 Hz), 5.65 (d, 1H, J = 9.8 Hz), 4.47 (s, 2H), 1.41 (s, 6H) m / z: 391.77

Example 1 Experiment for Measuring Apoptosis Using Neuronal Cell Lines

In acute ischemia, brain cells are widely known to induce apoptosis due to overexposure to glutamate, a neurotransmitter. The death of mouse hippocampus-derived neuronal cell line (HT22) by glutamate treatment depends on the concentration of glutamate, treatment time and inoculation concentration of cells. In this example, apoptosis inhibitory efficacy was determined by referring to a previously reported study on HT22 cell line (Tan et al., J Cell Biol ., 141: 1423-1432, 1998).

Cell line 3 days with DMEM (Invitrogen Life Technologies) containing 10% Fetal Bovine Serum (FBS) and Antibiotic-Antimycotic Solution (Invitrogen Life Technologies) in a 5% CO ₂ incubator at 37 ° C Once, incubated in a 100 mm dish while passaged at an inoculation concentration of 1 × 10 ⁵ . In order to measure the inhibition of apoptosis, the cells were cultured in a 96 well plate at a concentration of 5 × 10 ³ for 24 hours, treated with 5 mM glutamate and the test compound, and treated with MTT (3 -[4,5-dimethylthiazol-2-yl] -2,5-diphenyl tetrazolium bromid) analysis was performed. 20 μL MTT (5 mg / mL) solution was added to each well and reacted at 37 ° C. for 4 hours. Then, the solution was removed and 200 μL of dimethylsulfoxide (DMSO) was added to the cells for 10 minutes at room temperature. Formazan crystals were dissolved and the absorbance was measured at 550 nm using an E ^max microplate reader (Molecular Devices). The degree of cell death was calculated as% of the comparison group not treated with glutamate and test compound and the comparison group treated with glutamate only. The results are shown in FIG. 1 and Table 2 below.

Inhibitory effect of each compound on neurotoxicity (IC ₅₀ ) Experimental Compound IC ₅₀ [nM] 1-53 40.5 1-55 35.4 1-59 10.0 1-94 26.0 1-126 33.9 1-128 12.1 1-131 20.3 1-138 20.3 1-147 46.6

As shown in FIG. 1, it showed a weak survival effect against 5 mM glutamate at 50 nM, showed a survival effect of IC ₅₀ at 100 nM, and protection against cell death up to 90% at 500 nM. The effect was shown. In case of compound Nos. 1-59, cell death was most effectively inhibited at 100 nM.

Example 2 Experiment for Measuring Apoptosis Using Cerebral Cortical Neurons

Primary cortical neurons were used to measure the ability of the compounds of the present invention to inhibit toxicity by glutamate.

Brains are taken from ICR mice at 14-15 gestation periods and crushed into dissection media (including HBSS, Invitrogen Life Technologies, 5 mg / mL glucose, 7 mg / mL sucrose, 0.35 mg / mL NaHCO ₃ ), The cells were separated by pipetting and the number of viable cells was counted. 10% Fetal Bovine Serum (FBS, Invitrogen Life Technologies) and Antibiotic-Antimycotic Solution (Invitrogen Life Technologies) were added to a 96 well plate at a concentration of 1 × 10 ⁵ using Invitrogen Life Technologies (DMEM). Let go. Incubate for 2 days at 37 ℃, 5% CO ₂ incubator, and treated with 5 μM cytosine arabinoside (Sigma) for 48 hours to inhibit the growth of cells except the nerve, and then 5 mM glutamate and various concentrations After treatment with a mixture of experimental compounds and cultured for 24 hours and neuronal cell death was measured by the MTT method. The degree of cell death was calculated as% of the comparison group not treated with glutamate and derivatives and the comparison group treated with glutamate only.

As shown in Figures 2a and 2b compounds of the present invention showed an effect of inhibiting cell death from toxicity to glutamate with increasing concentration. The test compound showed more than 50% of apoptosis inhibitory effect at 30 nM or less, and the IC ₅₀ of the compound Nos. 1-59 was the lowest as in the cell line experiment.

Example 3 Bioassay Experiments Using Animal Models In vivo  assay; Mouse ear edema model)

1) Brain ischemic model production

Sprague-Dawley male rats (Samtaco Co., Ltd., 250-300 g) weigh 75 mg / kg ketamine and 5 mg / Kg Rumpun After anesthesia using Xylazine hydrochloride (Bayer Korea), the neck muscles were excised to the right common carotid artery (CCA), right external carotid artery (ECA), right internal carotid artery , ICA). Puncture the CCA, insert a 5-0 nylon suture and push it 20-22 mm into the ICA, fix the nylon thread by ligation of the right middle cerebral artery (MCA), 120 min. The nylon thread was then removed. The body temperature of the rats was kept constant at 37.8 ° C. during the surgery period and all surgical instruments were used sterilized.

2) Drug Administration to Stroke Animals

From the first day after analyzing the behavioral pattern for each stroke induction item, the test compounds were dissolved in dimethyl sulfoxide (DMSO) stock solution and injected intraperitoneally once a day in the amount of 10 mg / Kg for 28 days. Dimethyl sulfoxide was injected into the negative control group by 0.1 mL each in the same manner.

3) Behavioral test of stroke animal model

Before inducing the stroke, the subjects were trained for items related to behavioral pattern analysis to be verified for 7 days, and only the rats without birth defects were selected to perform the stroke. Behavioral tests were performed on each item 1 day, 7, 14 and 28 days after stroke induction. Behavioral tests include the Adhesive removal test, which is a sensory and motor function test item, the Rotarod test, which is a motor control function test item, and the complex functions such as sensory function, motor function, and balance function. The test item mNSS test (Modified neurological severity scoring test) was performed. The deposit removal test is a measure of the time it takes to attach a tape of 10 mm each to each forefoot before removing it. The Rotarod test measures the time remaining on a cylinder when the 55 mm diameter cylinder (UGO Basile Co.) spins while accelerating at 4 to 40 rpm for 5 minutes. The mNSS test was scored according to the indicators in Table 3 below and was calculated based on a total score of 12.

MNSS testing on rats score Lift the rat by its tail Foreleg flexion One Hind leg flexion One Head moved more than 10 ° about vertical axis within 30 seconds One Rat placed on the ground Fail to walk straight One Drawing a circle towards the numb One Falling to the Paralyzed One Sensory test Responsive to self-sensation (stimulates leg muscles by pushing towards the edge of the table) One Beam balance test Noisy beam One Hugging the beam and one leg falls off the beam One Cuddle the beam and both legs fall off the beam, or fall off the beam spin (over 60 seconds) One Attempt equilibrium at the beam but fall off (20 seconds or more) One Falling (no attempt to balance or hang on the beam (20 seconds or less) One  12 points: Deemed incompetent to perform the task or not suitable for the test, 8-11 points: Severe damage, 4-7 points: Normal damage, 1-3 points: Minor damage

As a result of the bioassay experiment using the animal model as described above, it was found that the behavioral test could not be performed regardless of the administration of the test compound on the first day immediately after the stroke induction. However, the behavioral tests conducted on days 7, 14 and 28 showed that the recovery rate was faster in all items of the attachment removal test, the rotarod test, and the mNSS test when the test compound was administered compared to the negative control DMSO. 3]. In particular, the rotarod test, a test item for motor coordination function, showed a tendency to recover for 28 days compared to the control group.

The following are some examples of formulation methods containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.

Formulation 1 : tablet (direct pressure)

After sifting 5.0 mg of active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressed to form a tablet.

Formulation 2 : Tablet (Wet Granulation)

After sifting 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of polysorbate 80 was dissolved in pure water and then an appropriate amount of this solution was added and then atomized. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressed into tablets.

Formulation 3 : Powders and Capsules

5.0 mg of the active ingredient was sieved, followed by mixing with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. No. solid the mixture using a suitable device. Filled in 5 gelatin capsules.

Formulation 4 : Injection

Injectables were prepared by containing 100 mg as active ingredient, as well as 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water.

As described above, the 2,2'-alkyl-substituted-3,4-dihydro-6-alkylamino benzopyran derivative represented by Formula 1 has an activity of inhibiting neuronal cell death by controlling the activity of glutamate receptors. Since it is excellent, it is particularly useful as a preventive and therapeutic agent for cerebral nervous system diseases, such as stroke, epilepsy, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease, and Alzheimer's disease.

Claims (2)

It is characterized by comprising a 2,2'-disubstituted-7,8-disubstituted-6-alkylamino benzopyran derivative or a pharmaceutically acceptable salt thereof, characterized in that represented by the following formula (1) Pharmaceutical compositions for the prevention and treatment of stroke, epilepsy, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease or Alzheimer's disease: [Formula (1)]

In the formula (1), R ¹ is a C ₁ -C ₁₀ alkyl group, benzyl or substituted benzyl group, phenethyl group, 2-pyrimidylmethyl group, thiophene group, 2-methylthiophenmethyl group, 5-methyl-2 -Thiophenmethyl group, 3-thiophenmethyl group, indolylmethyl group, benzodioxoranylmethyl group, naphthalenylmethyl group, or furanylmethyl group; R ² and R ³ each represent a hydrogen atom, an alkyl group of C _{1 to} C ₅ , a halogen, or a phenyl and substituted phenyl group; R ⁴ represents a C ₁ to C ₁₀ alkyl group, phenyl or substituted phenyl group, or a heterocyclic group selected from thiophene and furan; And the benzyl group, the phenyl group or the heterocyclic group is a substituent selected from C _{1 to} C ₆ alkyl group, C _{1 to} C ₆ haloalkyl group, halogen, nitro group, cyano group and C _{1 to} C ₆ alkoxy group. Four may be substituted, n represents an integer of 1 to 5. To 2,2'-disubstituted-7,8-disubstituted-6-alkylamino benzopyran derivatives or pharmaceutically acceptable salts thereof, which are represented by the following formula (1) Drugs for the prevention and treatment of stroke, epilepsy, amyotrophic lateral sclerosis, Parkinson's disease, Huntington's disease or Alzheimer's disease [Formula (1)]

In the formula (1), R ¹ is a C ₁ -C ₁₀ alkyl group, benzyl or substituted benzyl group, phenethyl group, 2-pyrimidylmethyl group, thiophene group, 2-methylthiophenmethyl group, 5-methyl-2 -Thiophenmethyl group, 3-thiophenmethyl group, indolylmethyl group, benzodioxoranylmethyl group, naphthalenylmethyl group, or furanylmethyl group; R ² and R ³ each represent a hydrogen atom, an alkyl group of C _{1 to} C ₅ , a halogen, or a phenyl and substituted phenyl group; R ⁴ represents a C ₁ to C ₁₀ alkyl group, phenyl or substituted phenyl group, or a heterocyclic group selected from thiophene and furan; And the benzyl group, the phenyl group or the heterocyclic group is a substituent selected from a C _{1 to} C ₆ alkyl group, a C _{1 to} C ₆ haloalkyl group, a halogen, a nitro group, a cyano group and a C _{1 to} C ₆ alkoxy group. 4 may be substituted, n represents an integer of 1 to 5.

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