Description

NEW DIAZA-BRIDGED HETEROCYCLE DERIVATIVES AND SOLID-PHASE PREPARATION METHOD THEREOF

Technical Field

[1] The present invention relates to a new diaza-bridged heterocycle derivative and a solid-phase preparation method thereof, and more specifically the present invention is characterized by using a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof, and then subjecting the product to solid-phase cleavage in a one -pot reaction by means of the Pictet-Spengler mechanism under acidic conditions to obtain the objective compound. Background Art

[2] Generally, the libraries in the combinatorial chemistry are simply a collection of the molecules. These libraries vary depending on the method for generating the members of the libraries, or the method used to identify the member which reacts with a biological target of interest, as well as the chemical species in the libraries. The methods for generating the libraries and screening them in this field have been already diversified and complicated. For example, the articles published in recent years, relating to various libraries in the combinatorial chemistry, disclose a number of technologies (Dolle, J. Com. Chem., 2(3): 383-433, 2000), including the use of all the labeled or unlabeled members of the libraries (Janda, Proc. Natl. Acad. Sci. USA 91: 10779-10785, 1994).

[3] The combinatorial chemistry is permitted in both the solution phase and the solid phase. However, development of a new chemistry, which is completely different from that which have performed the reaction only in the classical solution phase since the use of a Merrifield Resin in 1963, has become a basis of rapid development of the combinatorial chemistry. Thereafter, as many researchers including Wang, et al. have prepared new resins, the solid-phase chemical reaction has been further developed. The solid-phase synthesis in initial stages certainly has focused on the synthesis of a peptide and an oligonucleotide, but the solid-phase synthesis method has been gradually used as a general and most efficient means for generating the combinatorial library. When the synthesis is effected in the solid phase, simultaneous synthesis of many materials can be promoted, as well as the solvents and the reagents used in excess can be easily washed out merely by filtration. Thus, it was possible to prepare many materials even more easily and rapidly, as compared with the conventional reactions in the solution phase.

[4] Based on such historical circumstances, the combinatorial chemistry has been

rapidly developed.

[5] The compound library is a basic element for rapidly exploring the lead materials in the initial step of drug discovery, as well as for HTS (high throughput screening). Accordingly, the researches for the construction of the unique compound libraries having drug properties by means of a combinatorial chemistry technology, which is a highly efficient synthesis method, can be said to a basic research field which is critical to the improvement of the probability of exploration of the lead materials for new drugs.

[6] In summary, the combinatorial chemistry synthesis belongs to a new technical field involving the synthesis for discovering new substances and new materials. It can be said that it is a high-efficiency method for the synthesis of the chemical products, allowing a wide variety of many compounds to be synthesized at the same time and also allowing automation of a multi-step synthesis process, while the conventional organic synthesis allows only one compound to be synthesized. Also, the synthesis technology in the combinatorial chemistry has advantages that since the reaction process is largely maintained in the solid support, continuous multi-step reactions and automated reaction processes can be allowed, and that since the process for separating and purifying the products is very simple, high-efficiency, massive assays can be allowed.

[7] As such, the synthesis technology in the combinatorial chemistry is a new synthesis method which overcame the problems such as poor economy and efficiency in the conventional synthesis technologies, however this could not be easily applied to the organic synthesis field. One of the reasons therefore is that since the chemical reaction on the solid support requires that most of the reaction reagents should be used in excessive amounts, and thus, in some cases, undesired side reactions occur and the range for the selection of the reaction conditions is extremely narrow due to the limitation of the solvent which can be used according to the physical properties of the selectively used solid support. Accordingly, it can be said that in the synthesis of the compound library employing the solid-phase synthesis, the selection of proper solid- phase supporters and the establishment of proper reaction conditions which can minimize the chemical reactions and side reactions applicable in the solid phase are important elements.

[8] On the other hand, the bromoacetal polystyrene resin is generally not a frequently used solid support, but can serve as an important element for generating cleavage in the solid phase under acidic conditions as a feature of the solid support, and the intramolecular cyclization reaction by the reaction of the active aldehyde generated during said cleavage with amide and amine. USA Molecumetics demonstrated the usefulness of a bromoacetal polystyrene resin by employing the bromoacetal polystyrene resin in the production of a double-ring peptidomimetic compound library

as a beta-turn analogues (J. Med. Chem. 2002, 45. 7. 1395-1398, PCT WO 01/00210). Further, in Korea, Choongwae Pharma Corporation demonstrated advantages of the commercial use of the bromoacetal polystyrene resin in the solid-phase synthesis by using said bromoacetal polystyrene resin for the construction of a peptidomimetic compound library.

[9] As such, in spite of the important advantages offered by the combinatorial chemistry, the issue concerning the selection of the structure of a compound library is a very important element in the viewpoints of drug discovery. Furthermore, in the organic chemical views, the biological activity of the objective compounds is even more important than the structural or chemical interest thereof because many of the drugs distributed in the market, which are largely derived from the natural products, can sufficiently meet the needs as above. It is widely well known that these natural product mimetic compounds may basically contribute the development of the chemical biology in the views of basic science, as well as for the purpose of drug discovery (Boldi, A. M. Curr. Opin. Chem. Biol. 2004, 8, 281), and thus it is thought that in the practical views, the construction of a compound library is sufficiently reasonable.

[10] ,

[H] The compounds as illustrated above exhibit the anti-cancer effect and the activity on the nervous system, and ET-743 as one example thereof is a drug which is approved as an anti-cancer drug in the market. On reviewing said compounds, the compounds have the structure which can be commonly shown in alkaloids which are frequently

found in natural products, and the substances having biological activity. Accordingly, many researchers have tried to synthesize the natural product mimetics having the biological activity as described above. However, the methods for synthesizing the natural product mimetics, which are largely classical organic synthesis methods, required considerable amount of labors and presented difficulties in preparing the derivatives other than the objective compounds.

[12] Therefore, the synthesis of a library of various compounds in the art for the synthesis of peptides, natural products, natural product mimetics, or the like has been tried, and since in earlier 1990's, Ellman group developed the solid-phase synthesis of

1,4-benzodiazepine, a number of peptides, natural products and natural product mimetics libraries have been synthesized, however the range thereof was significantly limited.

Disclosure of Invention

Technical Problem

[13] Therefore, the present inventors have investigated the efficient and massive synthesis methods of the natural product mimetics having the biological activity for the treatment of diseases in the human bodies, in particular the anti-cancer effect and the activity on the nervous system, and during the investigation, have analyzed the structure as illustrated above, which can be commonly seen in the alkaloid often found in the natural products and the materials having biological activity, to obtain a clue for configuring its key structure, and thus have prepared a library of various compounds by using a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof. Thus, they confirmed that this synthesis method allows more rapid and massive production of a variety of lead compounds for drug discovery, thus completing the present invention. Technical Solution

[14] The present invention aims to provide a new diaza-bridged heterocycle derivative.

[15] Further, the present invention aims to provide a solid-phase preparation method of the above-described diaza-bridged heterocycle derivative. Best Mode for Carrying Out the Invention

[16] The present invention provides a diaza-bridged heterocycle derivative represented by the following chemical formula 1 :

[17] [Chemical formula 1]

[18]

[19] wherein

[20] R is hydrogen;

[21] a C -C linear or branched alkyl which is unsubstituted or substituted with at least

1 8 ^J one group selected from the group consisting of halogen, hydroxy, mercapto, amino, C

1 -C4 alkylamino, C 1 -C4 dialkylamino, C 1 -C4 alkylthio, C 1 -C4 alkylsulfinyl, C 1 -C4 alkylsulfonyl, C -C alkoxy, C -C cycloalkyl, C -C aryl, C -C cycloheterocycle, and C -C aryl substituted with halogen, CF or C -C alkoxy;

6 20 ^{J &} 3 1 4 ^J

[22] C -C alkenyl which is unsubstituted or substituted with at least one group selected from the group consisting of halogen, hydroxy, mercapto, amino, C -C alkylamino, C -C dialkylamino, C -C alkylthio, C -C alkylsulfinyl, C -C alkylsulfonyl, C -C alkoxy, C -C cycloalkyl, C -C aryl, C -C cycloheterocycle, and C -C aryl

^J 3 8 ^{J J} 6 20 ^J 5 20 ^{J J} 6 20 ^ substituted with halogen, CF or C -C alkoxy; or

[23] C -C alkynyl which is unsubstituted or substituted with at least one group selected from the group consisting of halogen, hydroxy, mercapto, amino, C -C alkylamino, C -C dialkylamino, C -C alkylthio, C -C alkylsulfinyl, C -C alkylsulfonyl, C -C alkoxy, C -C cycloalkyl, C -C aryl, C -C cycloheterocycle, and C -C aryl

^ 3 8 ^ ^J 6 20 ^J 5 20 ^{J J} 6 2O ^-7 substituted with halogen, CF or C -C alkoxy, [24] R is hydrogen or -(X)-R ,

[25] wherein X is NH, NH(CO), CO, (CO) 2 , SO, SO 2 or (CH 2 ) n (wherein n is an integer of 1 to 4), [26] R is C -C linear or branched alkyl; C -C alkenyl; C -C alkynyl; C -C cycloalkyl;

3 1 8 2 8 2 8 3 8

C -C aryl; C -C cycloheterocycle; C -C aryl substituted with halogen; C -C linear

6 20 ^J 5 20 ^{J J} 6 20 ^{J to} 1 8 or branched alkyl substituted with C -C aryl, or C -C aryl substituted with halogen;

^J 6 20 ^J 6 20 ^{J to}

C -C alkenyl substituted with C -C aryl, or C -C aryl substituted with halogen; C -

2 8 ^J 6 20 ^J 6 20 ^{J to} 2

C alkynyl substituted with C -C aryl, or C -C aryl substituted with halogen; or NA

8 ^{J J} 6 20 ^J 6 20 ^{J to} 1

[27] wherein A and A may each be independently same or different, and represent hydrogen; C -C linear or branched alkyl which is unsubstituted or substituted with phenyl; C -C alkenyl; or C -C aryl which is unsubstituted or substituted with ^{r J} 2 8 ^J 6 20 ^J halogen, C -C alkyl or C -C alkoxy, and [28] Ar is C -C aryl which is unsubstituted or substituted with halogen, hydroxy,

6 20 amino, C -C cycloalkyl or C -C alkoxy; or

3 8 1 4

[29] C -C cycloheterocycle which is unsubstituted or substituted with halogen,

20 hydroxy, amino, C -C cycloalkyl or C -C alkoxy,

[30] provided that in the case where Ar is phenyl, it contains at least one substituent.

[31] Preferably, in the above-described chemical formula 1,

[32] R is hydrogen;

[33] C -C linear or branched alkyl which is unsubstituted or substituted with at least one

1 8 ^J group selected from the group consisting of methoxy, tetrahydrofuran, phenyl, and phenyl substituted with F, Cl, Br, CF or methoxy; [34] C -C alkenyl which is unsubstituted or substituted with at least one group selected from the group consisting of methoxy, tetrahydrofuran, phenyl, and phenyl substituted with F, Cl, Br, CF or methoxy; or [35] C -C alkynyl which is unsubstituted or substituted with at least one group selected from the group consisting of methoxy, tetrahydrofuran, phenyl, and phenyl substituted with F, Cl, Br, CF or methoxy; [36] X is CO, SO ₂ or CH ₂ ,

[37] R is C -C linear or branched alkyl; C -C cycloheterocycle; phenyl substituted with F, Cl or Br; C 1 -C 8 linear or branched alkyl substituted with at least one group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; C 2 -C 8 alkenyl substituted with at least one group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; C -C alkynyl substituted with at least one group selected from the group consisting of phenyl, naphthyl, and phenyl substituted with F, Cl or Br; or NA A ,

[38] wherein A and A may each be independently same or different, and represent hydrogen; C -C linear or branched alkyl which is unsubstituted or substituted with

1 8 phenyl; C -C alkenyl; or phenyl which is substituted with F, Cl, Br, C -C alkyl or C -

2 8 1 4 1

C alkoxy, and

[39] Ar is indole or dihydroxyphenyl.

[40] Further, the present invention provides a solid-phase preparation method of the diaza-bridged heterocycle derivative represented by the above chemical formula 1. [41] The solid-phase preparation method of the diaza-bridged heterocycle derivative according to the present invention comprises: [42] 1) a step for preparing a secondary amine compound (3) by reacting a bromoacetal resin (2) with a primary amine compound, [43] 2) a step for preparing a compound (4) by subjecting the secondary amine compound (3) and an amino acid derivative having a protecting group to condensation reaction, [44] 3) a step for removing a protecting group by reacting the compound (4) prepared in the 2) step with piperidine, and preparing a compound (5) by reacting the compound

(4) with a R compound, and [45] 4) a step for intramolecular cyclization by reacting the compound (5) with formic acid,

[46] and is shown in the following reaction scheme 1.

[47] [Reaction scheme 1]

[48]

nDiI FEAή _ _E . _t . ₀ „ / ^{' 1} V ^> _N N_ _R]

Ar

1 ⁾ 25% pιperιλne

G ^{" " '} 1

[49] wherein R , R , and Ar are as defined in the chemical formula 1.

[50] A stepwise preparation method of the solid-phase of a diaza-bridged heterocycle derivative according to the present invention will be described in detail as follows.

[51] The bromoacetal resin (2) used as a starting material is commercially available or directly synthesized for use.

[52] In the above step 1), a bromoacetal resin is put into a Robbins 96-well reactor and

12 different primary amines are distributed into the previously designated wells. The reaction mixture is heated by shaking in a rotating oven at 6O ⁰ C for 12 hours. The resulting resins are washed sequentially three times each with dimethylformamide (DMF), methanol (MeOH) and dichloromethane (DCM), and then vacuum-dried. The formation of a secondary amine compound is confirmed by conducting a chloranil test.

[53] In the above step 2), amino acids with Fmoc (9-fluorenylmethylchloroformate),

HATU (2-(7-aza- lH-benzotriazol- 1-yl)- 1 , 1 ,3,3-tetramethyluronium hexafluo- rophosphate) and DIPEA (N,N'-diisopropylethanolamine) are dissolved in DMF, and after 30 minutes, the reaction mixture is distributed into the reaction vessel, followed by loading it into each of 96 wells. The reaction mixture is subjected to reaction in a rotating oven at room temperature for 12 hours. The resulting resins are washed sequentially three times each with DMF, MeOH and DCM, and then vacuum-dried. HATU is the most effective reagent in terms of yield and purity. The completion of the reaction is confirmed by conducting a chloranil test, which is progressed to the next step.

[54] In the above step 3), the compound (4) prepared in the step 2) is reacted with piperidine in DMF to remove a protecting group (Fmoc functional group) and is condensed with a R compound (carboxylic acid, isocyanate, sulfonamide or aldehyde). The reaction conditions can be varied depending on the kind of the R compound.

[55] a) Carboxylic acid condensation

[56] A mixed solvent of 25% piperidine/DMF is distributed into the reaction vessel, and the reaction mixture is reacted with shaking at room temperature for 1 hour to remove an Fmoc functional group. The resulting resins are then washed in the same manner as described above. 3 equivalents of each of 8 carboxylic acids are added to each well, DIC (diisopropylcarbodiimide, 3 equivalents) and HOBt (N-hydroxybenzotriazole, 3 equivalents) are added thereto. The resulting mixture is dissolved in DMF to react with each other and then is distributed into a 96-well reactor. The reaction mixture is shaken in a rotating oven at room temperature for 12 hours. The resulting resins are washed sequentially three times each with DMF, MeOH and DCM, and then vacuum-dried.

[57] b) Isocyanate condensation

[58] This step is conducted in the same manner as in the above 3a), except that isocyanate (3 equivalents) and DIPEA (3 equivalents) are dissolved in a dichloroethane solvent.

[59] c) Sulfonamide condensation

[60] This step is conducted in the same manner as in the above 3a), except that sulfonamide (3 equivalents) and DIPEA (3 equivalents) are dissolved in a dichloroethane solvent.

[61] d) Aldehyde condensation

[62] Aldehyde (3 equivalents) and sodium borohydride (3 equivalents) are dissolved in

DMF, followed by adding the solution to the resin, and the reaction mixture is reacted with shaking at room temperature for 5 hours. The resulting resins are washed sequentially three times each with DMF, MeOH and DCM, and then vacuum-dried.

[63] In the above step 4), the solid-phase cleavage/cyclization reaction is performed using the Pictet-Spengler mechanism in a one-pot reaction under acidic conditions.

[64] The resins are put into the 96-well reaction vessel which had been sufficiently vacuum-dried and 100% formic acid is distributed into 96 wells to react the resins with shaking at room temperature for 18 hours. After the completion of the reaction, the resins are removed by filtration, the compound obtained is concentrated and freeze- dried using a parallel evaporation device (SpeedVac) to obtain solid-phase products. The products are isolated, and the purity thereof and whether or not the desired products are present by LC/MS are observed.

[65] In order to more specifically describe the method for preparing the diaza-bridged

heterocycle derivative according to the present invention, a Pictet-Spengler reaction wherein Ar is indole or dihydroxyphenyl will be explained by way of an example. [66] The Pictet-Spengler-type carbon nucleophiles in indole and dihydroxyphenyl can easily attack the activated acyliminium intermediates in the presence of acid catalysts. [67] The Pictet-Spengler mechanism wherein Ar is indole is shown in the reaction scheme 2 and the Pictet-Spengler mechanism wherein Ar is dihydroxyphenyl is shown in the reaction scheme 3.

[68] [Reaction scheme 2]

[69]

[70] As shown in the above reaction scheme 2, in the case where Ar is indole, when indole is subjected to Pictet-Spengler reaction and cyclization with iminium moieties that are generated in a one-pot from aldehyde and amide protected under the acidic condition, a attacking carbons at the two nucleophilic locations, C2 and C3, in indole become possible.

[71] C2 attack can provide 3,9-diazabicyclo[3.3.1]non-6-en-2-one derivative (Ia) as a single diastereomer. [72] In the case of C3 attack, it is speculated that a spiro-five-membered intermediate is generated, followed by cationic migration and hydride elimination, because the compound (Ia) is a single regioisomer and diastereomer in this reaction.

[73] The use of neat formic acid can lead to the formation of the desired scaffold in nearly quantitative yields as a single diastereomer.

[74] [Reaction scheme 3] [75]

[76] As shown in the above reaction scheme 3, when Ar is dihydroxyphenyl, there are two possible modes of nucleophilic attack on one-pot generated cyclic iminium (si face and re face). The predefined stereochemistry of the alpha-carbons of L-amino acids significantly influenced the stereochemical outcome of diaza-bridged heterocycles, which favors an re face attack because of the distance between the nucleophilic carbon and the cyclic iminium. Therefore, when Ar is dihydroxyphenyl, it is present only as a single diastereomer (Ib).

[77] In the solid-phase preparation method of the diaza-bridged heterocycle derivative according to the present invention, a reaction scheme shown by selecting a representative compound is represented by the following reaction scheme 4.

[78] [Reaction scheme 4] [79]

[80] •X Reaction condition : (i) R ¹ NH , DMSO, 6O ⁰ C; (ii) Fmoc(N-Boc)TrpOH, HATU, DIPEA, DMF, room temperature); (iii) Fmoc(O-DiTBS)DOPA, HATU, DIPEA, DMF, room temperature; (iv) a) 25% piperidine, room temperature, b) R CO H, DIC, HOBt, DIPEA, room temperature; (v) R ³ NCO, DIPEA, DCE, room temperature; (vi) neat HCO H, room temperature; (vii) neat HCO H, 6O ⁰ C.

[81] All reactions proceed using a high performance synthesizer consisting of 96 units to prepare 96 compounds per one series. [82] The diaza-bridged heterocycle derivative according to the present invention comprises a structure which is commonly shown in alkaloids which are frequently discovered in natural products, and the substances having biological activity, and thus

it is expected that it has anti-cancer effect, anti- virus effect, anti-inflammatory effect, or pharmacological activity in heart circulating system disease, immune system disease, central nervous system disease or the like.

[83] Further, the solid-phase preparation method of the diaza-bridged heterocycle derivative according to the present invention comprises using a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof, and then subjecting the product to solid-phase cleavage and intramolecular cyclization reaction in a one-pot reaction by means of the Pictet-Spengler mechanism under acidic conditions to obtain the objective compound. Therefore, a library of various compounds can be prepared at the same time, and this preparation method allows more rapid and massive production of a variety of lead compounds for drug discovery. Mode for the Invention

[84] Hereinbelow, the preferred Examples of the present invention will be presented for further understanding of the present invention. However, the following Examples are presented merely for illustrative purpose, and thus do not limit the scope of the present invention.

[85] The starting materials, the reactants and the solvents were purchased from Aldrich

Chemical Co. (Milwaukee, WI), respectively, and used without further purification. A bromoacetal solid-phase support was purchased from Advanced ChemTech. H NMR spectra were recorded on a Bruker Avance 300 MHz and Varian 500 MHz, Chemical shifts (δ) were recorded in ppm relative to TMS as an internal standard. All specimens were dissolved in DMSO and CDCl 3 unless otherwise mentioned. LC-MS data were recorded on a platform from Micromass. In the parallel solid-phase synthesis, FlexChem Synthesis System was purchased from SciGene (Sunnyvale, CA) and used.

[86] Example 1 : Solid-phase preparation method of diaza-bridged heterocycle derivative according to the present invention

[87] 1. Amine Substitution

[88] A bromoacetal resin (40 mg, 1.6 mmol/g, 0.064 mmol) was loaded into each well of a Robbins 96-well reactor, and 12 different primary amines (20 equivalents in DMSO 1.2 mL) were distributed into the previously designated wells. The reaction mixture was heated with shaking in a rotating oven at 6O ⁰ C for 12 hours. The resins were washed sequentially three times each with DMF, MeOH and DCM, and then vacuum- dried.

[89] 2. Amino acid condensation

[90] Fmoc-Trp(Boc)-OH or Fmoc-L-DOPA(DiTBS)-OH (3 equivalents), HATU (3 equivalents), and DIPEA (6 equivalents) were dissolved in DMF (1.2 mL/well), and

after 30 minutes, the reaction mixture was distributed into the reaction vessel, followed by loading it into each of 96 wells. The reaction mixture was subjected to reaction in a rotating oven at room temperature for 12 hours. The resins were washed sequentially three times each with DMF, MeOH and DCM, and then vacuum-dried.

[91] 3. Carboxylic acid, isocyanate, sulfonamide or aldehyde condensation

[92] a) Carboxylic acid condensation

[93] A mixed solvent of 25% piperidine/DMF was distributed into the reaction vessel, and the reaction mixture was reacted with shaking at room temperature for 1 hour. The resins were washed sequentially three times each with DMF, MeOH and DCM and then again with DMF. 3 equivalents of each of 8 carboxylic acids were added to each reaction well, DIC (3 equivalents) and HOBt (3 equivalents) were dissolved in DMF to react with each other for 30 minutes. The reaction mixture was distributed into the 96-well reactor, and the reaction mixture was shaken in a rotating oven at room temperature for 12 hours. The resins were washed sequentially three times each with DMF, MeOH and DCM, and then vacuum-dried.

[94] b) Isocyanate condensation

[95] This step was conducted in the same manner as in the above 3a), except that isocyanate (3 equivalents) and DIPEA (3 equivalents) were dissolved in a dichloroethane solvent instead of carboxylic acid in the above a).

[96] c) Sulfonamide condensation

[97] This step was conducted in the same manner as in the above 3a), except that sulfonamide (3 equivalents) and DIPEA (3 equivalents) were dissolved in a dichloroethane solvent instead of carboxylic acid in the above a).

[98] d) Aldehyde condensation

[99] This step was conducted in the same manner as in the above 3a), except that aldehyde (3 equivalents) and sodium borohydride (3 equivalents) were dissolved in DMF instead of carboxylic acid in the above 3 a), followed by adding the solution to the resin, and the reaction mixture was reacted with shaking at room temperature for 5 hours.

[100] 4. Solid-phase cleavage reaction and cyclization reaction

[101] The resins were put into the 96-well reaction vessel which had been sufficiently vacuum-dried, and 100% formic acid (1.2 mL) was distributed into 96 wells to react the resins with shaking at room temperature for 18 hours. After the completion of the reaction, the resins were removed by filtration in the 96-well reaction vessel, the compound obtained was concentrated and freeze-dried using a parallel evaporation device (SpeedVac) to obtain solid-phase products. The resulting products were diluted with 50% water/acetonitrile and freeze-dried, which yielded a pale powder. The products were isolated, and the purity thereof and whether or not the desired products

are present by LC/MS were observed. [102] Hereinafter, the structures and the analysis data of the diaza-bridged heterocycle derivative prepared by the preparation method of the Example 1 are shown in Table 1. [103] [Table 1]

[104]

[105]

7.75 (s, 4H), 6.00 IH), 14.9, 3 45 3H),

8 16 (s, /= (d, 4.86 2, IH), (m, IH),

[107]

[108]

8.21 (s, 40 (d, /= IH), 15.2, (dd, / 3H);

[109]

[HO]

[111]

[113]

8 04 (bs, 5H), 8 O, 3.4,

(s,

[115]

8 43 (bs, 07 36 (d, J (d, /=

4 00

3H) 6= 6.8Kt, IH), 6 2H) 3 8,

[117]

[121]

[127]

713 (ra

6 51

(s

4 20

42

[133]

7.26 (ra, (d, /= IH), 4.74 2H), (m,

7.26 (m, 6.61 5.26 (d,

(m,

[141]

[142]

[144]

[149]

[150]

[152] The purity and the molecular weight of the representative compound among the compounds shown in Table 1, were measured and shown in Table 2. [153] Table 2

[154] Example 2 : Preparation of 4,5-dihydroxy-l l,13-diaza-tricyclo[7.3.1.0 ] trideca-

2(7),3,5-trien-10-one: Preparation by general organic synthesis method [155]

[156] Boc-L-DOPA-OH (3.5 g, 11.78 mmol) was dissolved in dichloromethane (250 rnL), diisopropylcarbodiimide (1.9 mL, 11.78 mmol), hydroxybenzotriazole (1.8 g, 11.78 mmol) and diisopropylethylamine (4 mL, 23.56 mmol) were added thereto, and the resulting mixture was stirred at room temperature for 30 minutes. Aminoacetaldehyde (1.71 mL, 11.78 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, the organic layer was washed with a 10% aqueous citric acid solution, and then organic layer was dehydrated over sodium sulfate. After the mixed solvent was concentrated, the compound was added to neat formic acid, and then the mixture was stirred for 15 hours to complete the reaction. Then, formic acid was removed by concentration. The resulting compound was purified with silica gel to obtain 1.1 g of the objective compound as a solid.

[157] ¹ U NMR (300 MHz, DMSO-d ) δ 7.35 (d, J= 3.5, IH), 6.49 (s, IH), 6.40 (s, IH), 5.35 (s, IH), 5.34 (s, IH), 4.00 (d, J = 3.4, IH), 3.6 (m, 3H), 3.05 (dd, J = 11.8, 3.8, IH), 2.95 (dd, J= 16.0, 6.1, IH) 2.62 (d, J= 17.4, IH);

[158] MS(ESI ⁺ ) m/z 220.90 [M + H] ⁺ . Industrial Applicability

[159] The diaza-bridged heterocycle derivative according to the present invention can be

obtained as the objective compound by using a solid-phase bromoacetal resin as a starting material to react with amino acids and various derivatives thereof, and then subjecting the product to solid-phase cleavage and intramolecular cyclization reaction in a one -pot reaction by means of the Pictet-Spengler mechanism under acidic conditions. Therefore, the effect that a library of various compounds can be prepared at the same time is obtained, and this preparation method allows more rapid and massive production of a variety of lead compounds for drug discovery.