KR20150141275A - Novel pyrrolopyridine derivatives and its use as HIV inhibitor - Google Patents

Abstract

The present invention relates to a pyrrolopyridine derivative expressed as chemical formula 1, specifically a compound including a substituent group having an oxatane group in R1, its stereoisomer or racemic body, their pharmaceutically acceptable salts or their solvate, a manufacturing method thereof, and an antivirus composition containing the same as an active ingredient, wherein the compound expressed as chemical formula 1 has excellent selectivity and physiological activity with respect to wild type or resistant HIV-1 and therefore can be used as a remedy for AIDS.

Description

Novel pyrrolopyridine derivatives and their use as HIV inhibitors < RTI ID = 0.0 >

The present invention relates to a novel pyrrolopyridine derivative compound having a strong inhibitory activity against viruses, in particular, human immunodeficiency virus (HIV), exhibiting excellent activities in drug properties and cytotoxicity, will be.

Acquired immunodeficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV). There are two forms of HIV: HIV-1 and HIV-2. HIV-1 is prevalent worldwide. For the treatment of AIDS, enzyme inhibitors according to the functional group of HIV have been developed. Depending on the point of action, a nucleotide reverse transcriptase inhibitor (NRTI), a protease inhibitor (PI), a fusion inhibitor inhibitors, and integrase inhibitors. Recently, the most active research on integrase inhibitors has been carried out, and Raltegravir, developed in 2008, is a representative drug. The integrase inhibitor specifically identifies the point of action again as a catalytic site inhibitor and a non-catalytic site inhibitor. In order to effectively treat resistance-expressing viruses, It is actively proceeding. Such chemotherapy using drugs is called highly active anti-retroviral therapies (HAART), and drugs of different kinds of different targets are mixed to form two to four drugs as one pill And it has a great effect on the life extension. However, ultimately, AIDS is not cured, and the drug itself is toxic when taken over a long period of time, and resistance to currently used therapies is constantly emerging. Therefore, there is a continuing need to develop new therapeutic agents to overcome these problems.

In order to solve these problems, the present inventors have discovered novel pyrrolopyridine derivatives showing an activity of inhibiting the proliferation of HIV-1 as a new therapeutic agent for AIDS targeting non-catalytic point integrase, And reported through the international patent (WO 2013/073875). Furthermore, as a result of continuous research on the drug properties and toxicity of these substances, it was confirmed that further improvement is required to be developed as a therapeutic agent.

Therefore, the present inventors have intensively studied to modify the pyrrolopyridine derivative into a compound suitable for development as a therapeutic agent. As a result, the present inventors have found that pyrrolopyridine derivatives of the present invention can be obtained by reacting pyrrolopyridine derivatives with oxetane Derivatives of the present invention have excellent pharmacological effects and pharmacological actions, and show safe results in basic toxicity tests, and thus can be developed as a safe therapeutic agent.

One object of the present invention is to provide a novel pyrrolopyridine derivative having an activity of inhibiting the proliferation of HIV-1 by inhibiting the activity of integrase enzyme of HIV-1; Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof.

Another object of the present invention is to provide a process for producing the above compound.

It is still another object of the present invention to provide an antiviral composition comprising the compound as an active ingredient.

In one aspect of the present invention, the present invention provides a compound represented by the following general formula (1): Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof.

[Chemical Formula 1]

In this formula,

L ₁ is a direct bond or C _1-6 alkanediyl;

L ₂ is a direct bond or C _3-10 cycloalkanediyl;

R ₁ is oxetanyl, said oxetanyl being unsubstituted or substituted with 1 to 3 substituents each selected from the group consisting of C _1-6 alkyl, C _3-10 cycloalkyl or halogen;

R ₂ and R ₃ are each independently hydrogen, C _{3 -10} cycloalkyl, or C _{1 -6} alkyl;

R ₄ is selected from the group consisting of hydrogen, halogen, aryloxy, arylamino, thioaryl, aryl, chromanyl, 3,4-dihydro-2H- benzo [b] [1,4] oxazinyl, 4- (piperidin- Benzo [b] [1,4] thiophen-2-yl, phenyl or 2,3-dihydropyrano [4,3,2-de] quinolinyl, wherein the aryl, chromanyl, 3,4- ] Oxazinyl, 4- (piperidin-1-yl) phenyl or 2,3-dihydropyrano [4,3,2-de] quinolinyl is unsubstituted or substituted by amino, halogen, , CF _3, C _{1 -6} alkyl and C _1-6 alkoxy are optionally substituted with one to three substituents each selected from the group consisting of;

R ₅ is a substituted C ₁ to C _-6 alkoxy, unsubstituted or C _{1 -6} alkyl group _3-10 cycloalkoxy, or C _{1 - 6} alkyl;

R ₆ is C _{1 -6} alkyl, C _{3 -10} cycloalkyl, C _{1 -6} alkoxy, halogen atom, or CN.

Preferably,

If L ₂ is C _{3 -6} cycloalkyl alkanediyl yl, may be bonded to R ₁ and spiro form.

Preferably,

L ₁ is C _1-6 alkanediyl;

L ₂ is a direct bond or C _3-6 cycloalkanediyl;

R ₁ is oxetanyl wherein said oxetanyl is unsubstituted or substituted with 1 to 3 substituents each selected from the group consisting of C _1-6 alkyl or C _3-10 cycloalkyl;

R ₂ and R ₃ are each independently C _{1 -6} alkyl;

R ₄ is aryl, chromanyl, 3,4-dihydro-2H-benzo [b] [1,4] oxazinyl or 4- (piperidin- , 4-dihydro -2H- benzo [b] [1,4] oxazole or possess 4- (piperidin-1-yl) phenyl are each selected from the group consisting of unsubstituted or halogen or C _{1 -6} alkyl Beach ≪ / RTI >

R ₅ is C _{1 -6} alkoxy;

R ₆ can be C _{1 -6} alkyl.

Preferably,

L ₁ is methanediyl or ethanediyl;

L ₂ is a direct bond or cyclobutanediyl;

R ₁ is oxetanyl which is unsubstituted or substituted with one to three substituents each selected from the group consisting of methyl, cyclobutyl or cyclohexyl, said cyclobutyl or cyclohexyl being bonded in the spiro form;

R ₂ and R ₃ are each methyl;

R ₄ is phenyl, chromanyl, 3,4-dihydro-2H-benzo [b] [1,4] oxazinyl or 4- (piperidin- Benzo [b] [1,4] oxazinyl or 4- (piperidin-1-yl) phenyl is unsubstituted or substituted with at least one group selected from the group consisting of methyl, chloride or fluoride Substituted with one to two substituents;

R ₅ is a tert-butoxy;

R ₆ can be methyl.

Preferably,

R ₁ is selected from oxetan-2-yl, oxetan-3-yl, 2-methyl-oxetan-2-yl, 4-methyl- Oxaspiro [3,3] heptan-2-yl or 1-oxaspiro [3,5] nonan-2-yl.

Preferably, the compound represented by Formula 1 is a compound having the following structural formula, but is not limited thereto.

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The compound of the present invention contains the basic skeleton of pyrrolopyridine, but has excellent pharmacological and pharmacological action by binding oxetane derivatives directly to pyrrolo pyridine at the 1-position, that is, on the nitrogen atom on the pyrrole ring, or through a linker Lt; RTI ID = 0.0 > toxic < / RTI > The present inventors have confirmed through previous studies that pyrrolopyridine derivatives can exhibit antiviral activity. However, it has been confirmed that when these compounds are administered for a long period of time, they are likely to exhibit cytotoxicity, and thus they are insufficient to be developed as a therapeutic agent. Thus, it has been confirmed that the compound represented by the formula (1) newly synthesized in the present invention is a pyrrolopyridine derivative And exhibited antiviral activity and cytotoxicity, and thus had potential to be developed as a therapeutic agent.

The compounds of the present invention include all possible stereoisomers and racemates of the compounds of formula (1). In particular, all the (S) R _5, which occurs at a position substituted carbon-stereoisomers, (R) - may include stereoisomers and racemates. As well as their pharmaceutically acceptable salts and solvates thereof, without limitation.

The term "solvate" refers to any form of a compound according to the invention to which another molecule (most likely a polar solvent) is bound by noncovalent bonding. Examples of solvates include hydrates and alcoholates such as, for example, methanolate. The solvate is preferably a pharmaceutically acceptable solvate.

In another aspect, the present invention provides a process for preparing a compound represented by the following formula (4), comprising the steps of: reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) And a second step of hydrolyzing a compound represented by the following formula (4): < EMI ID = 6.1 >

[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

In this formula,

L ₁ , L ₂ and R ₁ to R ₆ are as defined in claim 1,

R ₇ is a C _{1 -6} alkyl,

X is halogen, methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl.

Preferably, R ₇ is methyl or ethyl, and X may be halogen.

Preferably, the reaction of the first step is carried out in a molar ratio of 1: 2 to 1: 3 in the compound represented by the formula (2) and the compound represented by the formula (3). Also, the reaction of the first step may be carried out by using dichloromethane, dimethylformamide, tetrahydrofuran or a combination thereof as a solvent, but is not limited thereto.

Preferably, the first step may be carried out in the presence of potassium hydroxide and a catalytic amount of tetrabutylammonium bromide, wherein dichloromethane may be used as the solvent.

Preferably, the first step may be carried out at 20 to 40 캜, more preferably at room temperature. In addition, the first step may be performed for 2 to 18 hours, but is not limited thereto.

Also, preferably, the first step may be carried out in the presence of cesium carbonate, and as the solvent, dimethylformamide may be used.

Preferably, the first step may be carried out at 50 to 100 DEG C for 4 to 18 hours, but is not limited thereto.

Preferably, the second step may use methanol, tetrahydrofuran, or a combination thereof as a solvent, but is not limited thereto.

Preferably, the hydrolysis reaction in the second step may be carried out using potassium hydroxide, lithium hydroxide or sodium hydroxide.

Preferably, the second step may be performed for 3 to 18 hours, but is not limited thereto.

In a specific example of the present invention, the hydrolysis reaction of the second stage was carried out using 4N-sodium hydroxide and methanol.

For example, the compound of formula (2) or its stereoisomer, which is used as a starting material in the preparation of the compound represented by formula (1) of the present invention, may be prepared according to the method described in the reference example of the present inventor's prior patent (WO 2013/073875) But is not limited thereto.

In another aspect, the present invention provides a compound represented by the above formula (1); Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof as an active ingredient.

Preferably, the antiviral composition inhibits a viral infection, and particularly, for an anti-HIV exhibiting excellent inhibitory activity against human immunodeficiency virus, the composition of the present invention can effectively inhibit infection by HIV, May be useful for the prevention or treatment of acquired immune dysficiency syndrome (AIDS) caused by HIV infection.

The compounds of the present invention may exist in the form of a salt, particularly a pharmaceutically acceptable salt. Salts include, without limitation, salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids. The term "pharmaceutically acceptable salt" of the present invention means a concentration that has a relatively non-toxic and harmless effective action in a patient, wherein the adverse effect due to the salt is an adverse effect of the compound &Quot; means all organic or inorganic addition salts.

The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration.

As the free acid, organic acids and inorganic acids can be used. As the inorganic acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acids include methanesulfonic acid, p- toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used , But are not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal salt or the alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the non-soluble salt salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically acceptable to produce sodium, potassium, or calcium salt, but not limited thereto. The corresponding silver salt can also be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

Pharmaceutically acceptable salts of the compounds of this invention include, unless otherwise indicated, salts of acidic or basic groups that may be present in the compounds of formula (I). For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and the other pharmaceutically acceptable salts of amino groups include hydrobromides, sulphates, sulphates, phosphates, hydrogen phosphates (Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts and the like, ≪ / RTI >

As the salt of the pyrrolopyridine derivative of the present invention, any salt of a pyrrolopyridine derivative which is equivalent to a pyrrolopyridine derivative compound and exhibits an inhibitory activity against HIV as a pharmaceutically acceptable salt can be used without limitation.

The term "prophylactic" of the present invention means any action that inhibits or delays the development, spread and recurrence of AIDS caused by HIV infection upon administration of the composition of the present invention, The administration of the composition means any action that alleviates or alleviates the symptoms of the disease.

The composition of the present invention can exhibit an effect of inhibiting the proliferation of HIV by inhibiting the integrase enzyme activity thereof, and thus can be usefully used for the prevention or treatment of a disease caused by HIV infection, such as AIDS.

The pharmaceutical composition of the present invention can be formulated into an oral or injection dosage form. Formulations for oral administration include, for example, tablets, capsules, etc. These formulations may contain, in addition to the active ingredient, a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, : Silica, talc, stearic acid and its magnesium or calcium salt and / or polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpicoloridine, optionally mixed with starch, agar, A disintegrating or boiling mixture such as a sodium salt and / or an absorbent, a colorant, an anti-agent, and a sweetening agent. As the formulations for injection, isotonic aqueous solutions or suspensions are preferred.

The composition may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wettable or emulsifying accelerators, salts for controlling osmotic pressure and / or buffers, and other therapeutically useful substances.

The formulations may be prepared by conventional mixing, granulating or coating methods and may contain the active ingredient in the range of about 0.1 to 75% by weight, preferably about 1 to 50% by weight. A unit dosage form for a mammal about 50-70 kg contains about 10-200 mg of active ingredient.

The preferred dosage of the compound of the present invention varies depending on the condition and the weight of the patient, the degree of the disease, the form of the drug, the administration route and the period of time, but can be appropriately selected by those skilled in the art. However, for the desired effect, the compound of the present invention is preferably administered at a daily dose of 0.0001 to 100 mg / kg (body weight), preferably 0.001 to 100 mg / kg (body weight). Administration may be by oral or parenteral route, once or divided once a day.

The pharmaceutical composition of the present invention can be administered to mammals including rats, mice, livestock, and humans in various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerbroventricular injections.

As described above, the compound represented by Formula 1 of the present invention; Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or their solvates are highly useful for the prevention and treatment of HIV infection because they have high selectivity and physiological activity as well as low toxicity for viruses, especially human immunodeficiency virus HIV-1.

Hereinafter, the present invention will be described in more detail with reference to the following Production Examples and Examples. However, the following Preparation Examples and Examples are for illustrating the present invention, but the scope of the present invention is not limited thereto.

Reference example  1: 2- ( Iodomethyl ) Oxetane  Produce

2-hydroxymethyloxetane was prepared by the method described in the literature through a three-step reaction represented by the above reaction using 2,3-epoxypropane as a starting material (Alan O Fitton et al . , Synthesis , 1987, 1140-1142).

Triphenylphosphine (10.36 g, 39.5 mmol) and imidazole (5.4 g, 79.3 mmol) were dissolved in dichloromethane (70 ml) and cooled to 0 ° C. To the mixture was added slowly iodine (10.36 g, 39.5 mmol) and stirred at the same temperature for 30 minutes. A solution of the above prepared 2-hydroxymethyloxetane (2.70 g, 30.68 mmol) dissolved in dichloromethane (30 ml) was added dropwise to the above solution, and the mixture was stirred at 0 ° C for 30 minutes and at 25 ° C for 18 hours The reaction was complete. The reaction solution was poured into ice water and the organic layer was separated, and the aqueous layer was extracted twice with dichloromethane (150 ml). The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain pure 2- (iodomethyl) oxetane (6.0 g, 100%).

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 2.37 (m, 1H), 2.74 (m, 1H), 3.38 (m, 2H), 4.52 (m, 2H), 4.79

LC-MS (ES, m / e) = 198 (M ^< ^{+ &} gt ^; ).

Reference example  2: 2- ( Iodoethyl ) Oxetane  Produce

Step 1: 2- (2- ( Benzyloxy )ethyl) Oxirane

Sodium hydride (60% oil dis. 7.72 g, 110 mmol) was added to tetrahydrofuran (60 ml) under nitrogen and the mixture was cooled to 0 C and then 2- (oxiran-2-yl) 55 mmol) was slowly added. Tetrabutylammonium iodide (14.7 mg, catalytic amount) and benzyl bromide (7.9 ml, 66 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. The reaction solution was cooled with ice water, and a saturated aqueous solution of sodium hydrogencarbonate (about 60 ml) was added slowly and extracted twice with ethyl acetate. The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain pure 2- (2- (benzyloxy) ethyl) oxirane (8.02 g, 82%).

^{1 H-NMR (500 MHz,} CDCl 3) δ ppm 1.81 (m, 1H), 1.94 (m, 1H), 2.55 (m, 1H), 2.81 (t, J = 4.3 Hz, 1H), 3.10 (m, 1H), 3.65 (m, IH), 4.56 (s, 2H), 7.32 (m, IH), 7.36 (m, 4H);

LC-MS (ES, m / e) = 178 (M ^< ^{+ &} gt ^; ).

Step 2: 2- (2- ( Benzyloxy )ethyl) Oxetane

To the mixture was added potassium tert-butoxide (4.77 g, 42.6 mmol) and trimethyloxysulfonyl iodide (9.37 g, 42.6 mmol) in tert-butanol (55 ml) and heated to 50 ° C. A solution prepared by dissolving 2- (2- (benzyloxy) ethyl) oxirane (3.73 g, 21.33 mmol) in tert-butanol (43 ml) was slowly added over 10 minutes. The reaction was completed by stirring at the same temperature for 3 days, and the solvent was removed with caution under reduced pressure and concentrated. To the residue was added water (120 ml) and extracted twice with ethyl acetate. The obtained organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1) to obtain pure 2- (2- (benzyloxy) ethyl) oxetane (2.67 g, 66%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 2.00 (m, 1H), 2.11 (m, 1H), 2.41 (m, 1H), 2.65 (m, 1H), 3.55 (m, 2H), 4.49 ( (m, 2H), 4.52 (m, 1H), 4.68 (m, 1H), 4.98 (m, 1H), 7.27

LC-MS (ES, m / e) = 192 (M ^< ^{+ &} gt ^; ).

Step 3: 2- ( Oxetane Yl) ethanol

2- (2- (Benzyloxy) ethyl) oxetane (2.67 g, 13.88 mmol) prepared in Step 2 was dissolved in methanol (50 ml) and 10% palladium carbon (370 mg) The reactor was reacted at a hydrogen pressure of 40 psi for 18 hours. The reaction solution was filtered through a pad of celite and washed with methanol three times. The filtrate was concentrated under reduced pressure to give 2- (oxetan-2-yl) ethanol (1.3 g, 91%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.90-2.04 (m, 2H), 2.08 (m, 1H), 2.51 (m, 1H), 2.74 (m, 1H), 3.76-3.93 (m, 2H ), 4.60 (m, 1 H), 4.71 (m, 1 H), 5.11 (m, 1 H);

LC-MS (ES, m / e) = 102 (M ^< ^{+ &} gt ^; ).

Step 4: 2- ( Iodoethyl ) Oxetane

Triphenylphosphine (2.80 g, 10.68 mmol) and imidazole (1.44 g, 21.2 mmol) were dissolved in methylene chloride (20 ml) and cooled to 0 占 폚. To this mixture was added slowly iodine (2.71 g, 10.68 mmol) in portions and stirred at the same temperature for 30 minutes. To this solution was added dropwise a solution of the above prepared 2- (oxetan-2-yl) ethanol (0.84 g, 8.5 mmol) in dichloromethane (9 ml) The reaction was completed by stirring for a period of time. The reaction solution was poured into ice water and the organic layer was separated, and the aqueous layer was extracted twice with dichloromethane (150 ml). The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1) to obtain pure 2- (iodoethyl) oxetane (1.38 g, 79%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 2.17 (m, 1H), 2.38 (m, 2H), 2.74 (m, 1H), 3.18 (m, 2H), 4.51 (m, 1H), 4.68 ( m, 1 H), 4.87 (m, 1 H);

LC-MS (ES, m / e) = 212 (M ^< ^{+ &} gt ^; ).

Reference example  3: 3- ( Iodomethyl ) Oxetane

Oxetan-3-ylmethanol was prepared from diethyl bis (hydroxymethyl) malonate according to the method described in the prior art (US Patent Publication 2008/0021032, Example 92).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 3.15 (m, 1H), 3.85 (d, J = 6.0 Hz, 2H), 4.48 (t, J = 6.75 Hz, 2H), 4.80 (t, J = 6.9 Hz, 2H);

LC-MS (ES, m / e) = 88 (M ^< ^{+ &} gt ^; ).

Except that oxetan-3-ylmethanol (1.0 g, 11.35 mmol) obtained above was used instead of 2- (oxetan-2-yl) ethanol in the same manner as in step 4 of Reference Example 2 To give 3- (2-iodomethyl) oxetane (1.42 g, 63%).

^{1 H-NMR (500 MHz,} CDCl 3) δ ppm 3.38 (m, 1H), 3.40 (s, 2H), 4.29 (t, J = 5.95 Hz, 2H), 4.70 (t, J = 6.87 Hz, 2H) ;

LC-MS (ES, m / e) = 198 (M ^< ^{+ &} gt ^; ).

Reference example  4: 3- ( Iodomethyl ) -3- Methyloxetane  Produce

Except that 3-methyl-3-oxetane methanol (1.27 g, 12.5 mmol) was used instead of 2- (oxetan-2-yl) ethanol, the reaction was carried out with the same reagents and conditions as in step 4 of Reference Example 2 To give 3- (iodomethyl) -3-methyloxetane (1.32 g, 87%).

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 1.49 (s, 3H), 3.49 (s, 2H), 4.37 (m, 4H);

LC-MS (ES, m / e) = 212 (M ^< ^{+ &} gt ^; ).

Reference example  5: 3- ( 2-iodoethyl ) Oxetane  Produce

Using diethyl malonate as a starting material, 2- (oxetan-3-yl) ethanol was prepared by the reaction of the first five steps shown in the above reaction scheme according to the method disclosed in the prior art (US Patent Publication 2007/0032433) Respectively.

Except that the above obtained 2- (oxetan-3-yl) ethanol (177 mg, 1.773 mmol) was used in place of 2- (oxetan-2-yl) ethanol, And the reaction was carried out under the same conditions to give 3- (2-iodoethyl) oxetane (337 mg, 92%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 2.29 (q, J = 10.62 Hz, 2H), 3.09 (t, J = 6.87 Hz, 2H), 3.07-3.12 (m, 1H), 4.40 (t, J = 6.21 Hz, 2H), 4.82 (q, J = 7.59 Hz, 2H);

LC-MS (ES, m / e) = 212 (M ^< ^{+ &} gt ^; ).

Reference example  6: 2- ( Iodomethyl )-4- Methyloxetane  Produce

Step 1: Preparation of pent-4-en-2-ol

(75.84 g, 400 mmol) and copper powder (25.41 g, 400 mmol) were mixed with water (300 ml), followed by the addition of tin (II) chloride mmol) were simultaneously added thereto, followed by vigorous stirring at room temperature for 18 hours. Insolubles were removed by filtration and extracted twice with dichloromethane (300 ml). The obtained organic layers were combined, dried over anhydrous magnesium sulfate and filtered, and the next step was immediately carried out using this solution.

A small amount was taken and concentrated under reduced pressure at a temperature of 10 ° C or lower.

^{1 H-NMR (500 MHz,} CDCl 3) δ ppm 1.24 (m, 3H), 2.23 (m, 2H), 3.84 (m, 1H), 5.13 (m, 2H), 5.82 (m, 1H);

LC-MS (ES, m / e) = 86 (M ^< ^{+ &} gt ^; ).

Step 2: 1- ( Oxirane Yl) propan-2-ol

The dichloromethane solution of pent-4-en-2-ol obtained from step 1 was cooled to 0 < 0 > C under nitrogen and to the solution was added metachloro and benzoic acid (26.9 g, 120 mmol) in dichloromethane The solution was slowly added. The reaction solution was warmed to room temperature, stirred for 18 hours, and washed with a 10% sodium sulfite aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a low temperature.

The obtained residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 6: 1) to obtain pure 1- (oxiran-2-yl) propan- ).

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 1.22-1.27 (m, 3H), 1.48-1.64 (m, 1H), 1.80-1.95 2.49-2.63 (m, 1H), 2.77-2.84 (m, 1H), 3.06-3.14 (m, 1H), 3.99-4.13 (m, 1H);

LC-MS (ES, m / e) = 102 (M ^< ^{+ &} gt ^; ).

Step 3: (4- Methyloxetane Yl) methanol

(8.5 g, 83.2 mmol) obtained in the above Step 2 and (normal-tributyl) tin methoxide (66.8 ml, 208.06 mmol) were mixed under nitrogen atmosphere . The mixture was heated to 120 DEG C and reacted for 3 hours, followed by stirring at 200 DEG C for 18 hours. The reaction solution was cooled to room temperature and purified by silica gel column chromatography (hexane: ethyl acetate and dichloromethane: ethyl acetate = 4/1 and 1/1 respectively) to collect the objective fraction, which was then concentrated under reduced pressure to obtain Cetane-2-yl) methanol (1.2 g, 14%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.27-1.38 (m, 3H), 1.50-1.66 (m, 1H), 2.03 and 2.40 (m, 1H), 2.70 (m, 1H), 3.86-3.98 (m, 1 H), 4.08 and 4.27 (m, 1 H), 4.47 - 4.53 (m, 1 H);

LC-MS (ES, m / e) = 102 (M ^< ^{+ &} gt ^; ).

Step 4: 2- ( Iodomethyl )-4- Methyloxetane

Triphenylphosphine (3.97 g, 15.15 mmol) and imidazole (2.06 g, 30.31 mmol) were dissolved in dichloromethane (36 ml) and cooled to 0 占 폚. To the mixture was added slowly iodine (3.84 g, 15.15 mmol) and stirred at the same temperature for 30 minutes. To the resulting solution was added dropwise a solution of (4-methyloxetan-2-yl) methanol (1.2 g, 11.75 mmol) obtained in the above step 3 in dichloromethane (10 ml) The reaction was completed by stirring at 25 DEG C for 18 hours. The reaction solution was poured into ice water, the organic layer was separated, and the aqueous layer was extracted twice with dichloromethane (30 ml). The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at reduced pressure.

The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to obtain pure 2- (Iodomethyl) -4-methyloxetane (1.07 g, 43%) as an isomer mixture.

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.39-1.58 (m, 3H), 1.92 and 2.37 (m, 1H), 2.42 and 2.79 (m, 1H), 3.21-3.37 (m, 1H), 3.39 (m, 2 H), 4.69 (m, 1 H), 4.82 (m, 1 H);

LC-MS (ES, m / e) = 212 (M ^< ^{+ &} gt ^; ).

Reference example  7: (4,4- Dimethyloxetane -2 days) methyl  4- Methylbenzenesulfonate  Produce

Step 1: 2- Methylpent -4-en-2-ol

A mixture of tin (II) chloride (37.92 g, 200 mmol) and copper powder (12.7 g, 200 mmol) was mixed with acetone (7.34 ml, 100 mmol) and allyl chloride (12.22 ml, ) Were simultaneously added thereto, followed by vigorous stirring at room temperature for 18 hours. Insolubles were removed by filtration and extracted twice with dichloromethane (200 ml). The obtained organic layers were combined, dried over anhydrous magnesium sulfate and filtered, and the next step was immediately carried out using this solution.

A small amount was taken and concentrated under reduced pressure at a temperature of 10 ° C or lower.

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 1.15 (m, 6H), 2.16 (d, J = 7.44 Hz, 2H), 5.07 (m, 2H), 5.80

LC-MS (ES, m / e) = 100 (M ^< ^{+ &} gt ^; ).

Step 2: 2- methyl -One-( Oxirane Yl) propan-2-ol

The dichloromethane solution of 2-methylpent-4-en-2-ol obtained from step 1 was cooled to 0 ° C under nitrogen and to this solution was added metachlorobenzoic acid (13.44 g, 60 mmol) in dichloromethane (100 ml) Was added slowly. The reaction solution was warmed to room temperature, stirred for 18 hours, and washed with a 10% sodium sulfite aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure at a low temperature.

The obtained residue was purified by silica gel column chromatography (dichloromethane: ethyl acetate = 6: 1 and 5: 1) to obtain pure 2-methyl-1- (oxiran- , 52.5% yield from step 1).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.32 (s, 3H), 1.34 (s, 3H), 1.56 (m, 1H, -OH), 1.81 (d, J = 4.17 Hz, 1H), 2.49 (m, 1 H), 2.89 (m, 1 H), 3.13 (m, 1 H);

LC-MS (ES, m / e) = 116 (M ^< ^{+ &} gt ^; ).

Step 3: (4,4- Dimethyloxetane Yl) methanol

(6.1 g, 52.5 mmol) and (normal-tributyl) tin methoxide (37.8 ml, 131.3 mmol) obtained from the above Step 2 under nitrogen at -78 & ) Were mixed. The mixture was heated to 120 DEG C and reacted for 3 hours, followed by stirring at 200 DEG C for 18 hours. The reaction solution was cooled to room temperature and purified by silica gel column chromatography (dichloromethane: ethyl acetate = 4/1 and 1/2). The objective fraction was collected and concentrated under reduced pressure at low temperature to give (4,4-dimethyloxetane- Yl) methanol (4.0 g, 65%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.39 (s, 3H), 1.49 (s, 3H), 1.99 (m, 1H), 2.28 (m, 1H), 2.41 (m, 1H), 3.57 ( m, 1 H), 3.37 (m, 1 H), 4.69 (m, 1 H);

LC-MS (ES, m / e) = 116 (M ^< ^{+ &} gt ^; ).

Step 4: (4,4- Dimethyloxetane -2 days) methyl  4- Methylbenzenesulfonate

(4,4-Dimethyloxetan-2-yl) methanol (1.17 g, 10 mmol) obtained from the above step 3 was dissolved in dichloromethane (60 ml) and cooled to 0 占 폚. Subsequently, triethylamine (2.79 ml, 20.1 mmol), dimethylaminopyridine (123 mg, 1.0 mmol) and para-toluenesulfonyl chloride (2.3 g, 12.08 mmol) were slowly added thereto and then stirred for 18 hours Respectively. The reaction solution was diluted with water / dichloromethane, adjusted to pH = 1.0 with 2N hydrochloric acid, and the organic layer was separated. The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain pure (4,4-dimethyloxetan-2-yl) methyl 4-methylbenzenesulfonate (2.21 g, 80% ≪ / RTI >

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.35 (s, 3H), 1.44 (s, 3H), 2.35 (m, 2H), 2.44 (s, 3H), 4.10 (s, 2H), 4.71 ( m, 1 H), 7.34 (d, J = 8.25 Hz, 2H), 7.81 (d, J = 8.22 Hz, 2H);

EI-MS (ES, m / e) = 270 (M ^< ^{+ &} gt ^; ).

Reference example  8: 2- ( Iodomethyl )-One- Oxaspiro [3,3] heptane  Produce

Step 1: 1- Allylcyclobutanol

1-allylcyclobutanol was obtained in the form of a solution in the same manner as in the step 1 of Reference Example 6 except that cyclobutanone (3.75 g, 53.52 mmol) was used instead of acetaldehyde to obtain the compound Respectively.

A small amount was taken and concentrated under reduced pressure at a temperature of 10 ° C or lower.

^{1 H-NMR (500 MHz,} CDCl 3) δ ppm 1.49-1.61 (m, 1H), 1.71-1.78 (m, 1H), 2.06 (m, 4H), 2.38 (d, J = 7.2 Hz, 2H), 5.15 (m, 2 H), 5.86 (m, 1 H).

Step 2: 1- ( Oxirane -2- Yl methyl ) Cyclobutanol

4-en-2-ol obtained in Step 1 was used instead of the dichloromethane solution of 1-allylcyclobutanol obtained in the above Step 1 to give 1- (oxy Ylmethyl) cyclobutanol (6.8 g, 98% yield from step 1).

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 1.56 (m, 1H), 1.68-1.79 (m, 2H), 2.05 ), 2.80 (m, 1 H), 3.15 (m, 1 H).

Step 3: 1- Oxaspiro [3,3] heptane -2- Diethanol

Step 3 of Reference Example 6 was repeated except that 1- (oxiran-2-ylmethyl) cyclobutanol obtained from the above Step 2 was used instead of 1- (oxiran-2-yl) The reaction was carried out in the same manner to obtain 1-oxaspiro [3,3] heptan-2-ylmethanol (450 mg, 11%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.50-1.59 (m, 1H), 1.67-1.76 (m, 2H), 1.97-2.32 (m, 6H), 3.73 and 3.76 (dd, J = 1.62, 1.65 Hz, 1H), 3.89 and 3.91 (dd, J = 4.56,4.59 Hz, 1H), 4.47 (m, 1H).

Step 4: 2- ( Iodomethyl )-One- Oxaspiro [3,3] heptane

(3,3] heptan-2-ylmethanol obtained from the above Step 3 was used in place of (4-methyloxetan-2-yl) methanol To obtain 2- (iodomethyl) -1-oxaspiro [3,3] heptane (198 mg, 21%).

^{1 H-NMR (500 MHz,} CDCl 3) δ ppm 1.49 (m, 1H), 1.69 (m, 1H), 2.19 (m, 1H), 2.26 (m, 1H), 2.34 (m, 3H), 2.79 ( m, 1 H), 3.27 (m, 1 H), 3.37 (m, 1 H), 4.62 (m,

Reference example  9: 1- Oxaspiro [3,5] nonane -2- Yl methyl  4- Methylbenzenesulfonate  Produce

Step 1: 1- Allylcyclohexanol

1-allylcyclohexanol was obtained in the form of a solution in the same manner as in step 1 of Reference Example 6, except that cyclohexanone (19.63 g, 200 mmol) was used instead of acetaldehyde to give Respectively.

A small amount was taken and concentrated under reduced pressure at a temperature of 10 ° C or lower.

^{1 H-NMR (500 MHz,} CDCl 3) δ ppm 1.29 (m, 10H), 1.42-1.80 (m, 1H, -OH), 2.24 (d, J = 9.9 Hz, 2H), 5.15 (m, 2H) , 5.89 (m, 1 H).

Step 2: 1- ( Oxirane -2- Yl methyl ) Cyclohexanol

Ol was obtained in the same manner as in Step 2 of Reference Example 6, except that a dichloromethane solution of 1-allylcyclohexanol obtained from the above Step 1 was used instead of the solution of 1- ( Ylmethyl) cyclohexanol (27.5 g, 88% yield from step 1).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.47-1.66 (m, 11H), 1.79 and 1.84 (dd, J = 4.29, 4.29 Hz, 1H), 2.48 (m, 1H), 2.79 (t, J = 4.51 Hz, 1 H), 3.15 (m, 1 H).

Step 3: 1- Oxaspiro [3,5] nonane -2- Diethanol

1- (Oxiran-2-ylmethyl) cyclohexanol (10 g, 64 mmol) obtained in the above Step 2 was dissolved in 75% dimethylsulfoxide aqueous solution (65 ml of water, 195 ml of dimethylsulfoxide) and 25.6 g, 640 mmol) under nitrogen and heated to 140-150 < 0 > C for 45 min. The reaction solution was cooled to room temperature, an excessive amount of ice water was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 5.8 g of crude product.

Step 4: 1- Oxaspiro [3,5] nonane -2- Yl methyl  4- Methylbenzenesulfonate

Oxaspiro [3,5] nonan-2-ylmethanol (5.81 g, 37.2 mmol) obtained from the above step 3 was dissolved in dichloromethane (300 ml) and cooled to 0 ° C. Then, triethylamine (10.36 ml, 74.3 mmol), dimethylaminopyridine (435 mg, 3.72 mmol) and para-toluenesulfonyl chloride (8.5 g, 44.6 mmol) were added thereto and slowly warmed to room temperature. Respectively. The reaction solution was diluted with water / dichloromethane, adjusted to pH = 1.0 with 2N hydrochloric acid, and the organic layer was separated. The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain pure 1-oxaspiro [3,5] Yield from step 3).

¹ H-NMR (500 MHz, CDCl ₃ )? Ppm 1.28-1.31 (m, 4H), 1.57-1.71 (m, 6H), 2.21 ), 4.12 (d, J = 4.5 Hz, 2H), 4.74 (m, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.25 Hz, 2H).

Reference example  10: 6- ( Iodomethyl )-2- Oxaspiro [3,3] heptane  Produce

Step 1: 3- Chloro -2,2- Bis (chloromethyl) propane -1-ol

Pentaerythritol (15 g, 0.11 mmol) was added to pyridine (27 ml) and heated to 65 ° C. Thionyl chloride (24.7 ml, 0.33 mol) was slowly added for 4 hours while maintaining the internal temperature at 65-95 ° C Respectively. The reaction solution was allowed to react for 18 hours while maintaining the temperature of the reaction solution at 120 to 130 캜 and then cooled to room temperature. The reaction solution was poured into ice water (75 ml) and stirred for 30 minutes. The resulting solid was filtered, washed thoroughly with water and dried to give 3-chloro-2,2-bis (chloromethyl) propan-1-ol (15.4 g, 73%).

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 1.73 (bs, 1H, -OH), 3.67 (s, 6H), 3.75 (s, 2H).

Step 2: 3,3- Bis (chloromethyl) oxetane

3-Chloro-2,2-bis (chloromethyl) propan-1-ol (15.4 g, 80.4 mmol) obtained in the above step 1 was dissolved in 98% ethanol (28 ml) and potassium hydroxide mmol) was added, and the mixture was heated and refluxed for 30 minutes. The reaction solution was cooled with ice water and stirred for 10 minutes. The resulting solid was filtered off and adjusted to pH = 7.5 with a 2N aqueous hydrochloric acid solution. After removing the solvent by distillation under reduced pressure, water (100 ml) was added to the residue and extracted twice with ethyl acetate (150 ml). The obtained organic layers were combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain pure 3,3-bis (chloromethyl) oxetane (9.2 g, 74%).

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 3.94 (s, 4H), 4.45 (s, 4H).

Step 3: Diethyl  2- Oxaspiro [3,3] heptane -6,6- Dicarboxylate

(7.59 g, 48.96 mmol) and tris (ethoxycarbonyl) methane (47.5 g, 205 mmol) obtained in the above Step 2 were added to ethanol (100 ml) And heated to reflux temperature. A 21% sodium ethoxide / ethanol solution (15 ml) was slowly added to the reaction solution. The reaction solution was heated to reflux for 18 hours and then cooled to room temperature. The resulting solid was filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. Water was added to the residue, and the mixture was extracted twice with diethyl ether. The resulting organic layer was combined, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 and 2: 1) to obtain pure diethyl 2-oxaspiro [3,3] heptane-6,6-dicarboxylate g, 15.4%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.27 (t, J = 7.5 Hz, 6H), 2.75 (s, 4H), 4.21 (q, J = 7.0 Hz, 1H), 4.69 (s, 4H) .

Step 4: Ethyl 2- Oxaspiro [3,3] heptane -6- Carboxylate

(1.83 g, 7.55 mmol), water (1.8 ml), dimethylsulfoxide (7.2 ml) and sodium diethyl 2-oxaspiro [3,3] heptane-6,6-dicarboxylate (0.44 g, 7.55 mmol) were successively added thereto, followed by mixing and reacting for 18 hours while heating to 180 ° C. The reaction mixture was cooled to room temperature, diluted with brine (40 ml), extracted twice with diethyl ether (30 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure at reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain pure ethyl 2-oxaspiro [3,3] heptane-6-carboxylate (804 mg, 62%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.2 (t, J = 7.0 Hz, 3H), 2.48 (d, J = 8.2 Hz, 4H), 4.14 (q, J = 6.9 Hz, 4H), 4.69 (d, J = 10.0 Hz, 4H).

Step 5: 2- Oxaspiro [3,3] heptane -6- Diethanol

Ethoxyl 2-oxaspiro [3,3] heptane-6-carboxylate (804 mg, 4.72 mmol) obtained from step 4 above under nitrogen was dissolved in anhydrous tetrahydrofuran (2.4 ml) , A solution of lithium aluminum hydride (123.8 mg, 6.12 mmol) suspended in tetrahydrofuran (2.4 ml) was slowly added. The solution was stirred at the same temperature for 20 minutes and further stirred at 25 < 0 > C for 2 hours to complete the reaction. Ethyl acetate (0.12 ml) and sodium sulfate decahydrate were added to the reaction solution with careful care and stirred for 1 hour. The solution was diluted with brine, extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 2-oxaspiro [3,3] heptan-6-ylmethanol (360 mg, 59% Respectively.

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.25 (brs, 1H, -OH), 1.97 (m, 2H), 2.33 (m, 3H), 3.53 (m, 2H), 4.06 (s, 2H) , ≪ / RTI > 4.69 (s, 2H).

Step 6: 6- ( Iodomethyl )-2- Oxaspiro [3,3] heptane

Except that 2-oxaspiro [3,3] heptan-6-ylmethanol (360 mg, 2.8 mmol) obtained from the step 5 was used instead of 2- (oxetan- 2-oxaspiro [3,3] heptane (219 mg, 33%) was obtained by carrying out the reaction under the same equivalent amount of reagents and conditions as in Step 4 of Example 1, Step 2.

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.87 (m, 2H), 2.40 (m, 3H), 3.16 (d, J = 6.93 Hz, 2H), 4.61 (s, 2H), 4.72 (s, 2H).

Example  1: (2S) -2- ( Rat - Butoxy ) -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -One-( jade Cetane-2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2-( Rat - Butoxy ) -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1- (ox Cetane -2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

(S) -methyl 2- (tert-butoxy) -2- (4- (4-chlorophenyl) -2,3,6-trimethyl- lH- pyrrolo [2,3- b] pyridin- ) Acetate (415 mg, 1 mmol) was dissolved in dimethylformamide (8 ml) and cesium carbonate (975 mg, 3 mmol) and 2- (iodomethyl) oxetane prepared by the method of Referential Example 1 mg, 3 mmol) was added thereto, followed by stirring at 80 ° C for 18 hours. Cooling water was added to the reaction, ethyl acetate (30 ml) was added, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was further extracted twice with ethyl acetate (30 ml). The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the desired compound (350 mg, 72%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.97 (s, 9H), 1.48 (s, 3H), 2.35 (s, 3H), 2.59 (m, 1H), 2.70 (s, 3H), 2.70 ( 1H), 7.22 (m, 1H), 7.41 (m, 2H), 5.07 (s, , 3H);

LC-MS (ES, m / e) = 485 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- ( Rat - Butoxy ) -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2- (tert-butoxy) -2- (4- (4-chlorophenyl) -2,3,6-trimethyl- 1- (oxetan- Yl) acetate (350 mg, 0.721 mmol) was dissolved in tetrahydrofuran (5.5 ml) and 4N sodium hydroxide / methanol solution (0.554 ml) Followed by stirring at 25 DEG C for 8 hours. The reaction solution was neutralized by the addition of the same amount of 4N-hydrochloric acid, and the solvent was concentrated under reduced pressure and dried in vacuo. An appropriate amount of dichloromethane was added to the product, followed by filtration to remove insolubles and concentration. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain pure target compound (less polar-212 mg, 62.5%, more polar-58 mg, 17%) as a white solid . Using a mixture of the unsubstituted R, S-stereoisomers and a polarity difference, into two stereoisomers.

^{Less polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 0.98 (s, 9H), 1.52 (s, 3H), 2.38 (s, 3H), 2.57 (m, 1H), 2.68 (s, 3H 1H), 5.16 (m, IH), 7.30 (m, IH), 4.50 (m, , 7.49 (m, 2 H), 7.58 (m, 1 H);

LC-MS (ES, m / e) = 470 (M ^< ^{+ &} gt ^; ).

^{More polar: 1 H-NMR (} 500 MHz, CD 3 OD) δ ppm 0.96 (s, 9H), 1.53 (s, 3H), 2.39 (s, 3H), 2.57 (m, 1H), 2.71 (s, 3H 1H), 5.13 (m, 1H), 7.43 (m, 1H), 4.73 (m, , 7.46 (m, 2 H), 7.50 (m, 1 H);

LC-MS (ES, m / e) = 470 (M ^< ^{+ &} gt ^; ).

Example  2: (2S) -2- Rat - Butoxy -2- (4- ( Croix -6-yl) -2,3,6- Trimethyl -One-( Oxse Tan-2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- ( Croix -6-yl) -2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-d] pyrimidin-2-ylmethyl) -lH-pyrrolo [2,3-b] pyridine- Yl) acetate was used in the place of (2S) -methyl 2-tert-butoxy-2- (4- (chroman- b] pyridin-5-yl) acetate (414 mg, 0.948 mmol) was used in the same manner as in Step 1 of Example 1, except that the same reagents were used. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the target compound (200 mg, 41%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.98 (s, 9H), 1.25 (s, 3H), 2.05 (m, 2H), 2.34 (s, 3H), 2.65 (s, 3H), 2.68 ( 2H), 2.80 (m, 2H), 3.66 (s, 3H), 4.25 (m, 2H), 4.45 , 6.80 (m, IH), 7.06 (m, IH)

MS (EI, m / e) = 506 (M ^< ^{+ &} gt ^; ).

Step 2: 2- (2S) -2- ( Rat - Butoxy ) -2- (4- ( Croix -6-yl) -2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(S) -methyl 2- (tert-butoxy) -2- (4- (4-chlorophenyl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,2,3,4-tetrahydroisoquinoline- Pyrrolidin-2-ylmethyl) -lH- pyrrolo [2,3-b] pyridin-5-yl) acetate (180 mg, 0.354 mmol) The same reagents as in step 2 of Example 1 were used in the same manner and reacted in the same manner. The resulting residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (130 mg, 74%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.86 (s, 9H), 1.46 (s, 3H), 1.95 (m, 2H), 2.26 (s, 3H), 2.42 (m, 1H), 2.54 (s, 3H), 2.59 (m, 1H), 2.73 (m, 2H), 4.14 (m, 2H), 4.38 (m, 1H), 6.73 (m, 1H), 6.84 (m, 1H), 7.15 (m, 1H);

MS (EI, m / e) = 492 (M ^< ^{+ &} gt ^; ).

Example  3: (2S) -2- ( Rat - Butoxy ) -2- (4- (5- Chlorochroman -6-yl) -2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (5- Chlorochroman -6-yl) -2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

(2S) -methyl 2-tert-butoxy-2- (4- (5-chlorochroman-6-yl) -2,3,6-trimethyl- lH- pyrrolo [2,3- b] (330 mg, 0.7 mmol) was dissolved in acetonitrile (30 ml), cesium carbonate (460 mg, 1.4 mmol) and 2- (iodomethyl) oxetane prepared by the method of Referential Example 1 (280 mg, 1.4 mmol) was added thereto, followed by stirring at 80 占 폚 for 18 hours. The reaction mixture was cooled to 5 캜, neutralized by adding 4N hydrochloric acid, concentrated under reduced pressure to remove acetonitrile, and water (20 ml) was added. The product was then extracted twice with dichloromethane (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give the desired compound (110 mg, 29%) as a pure, slightly solid solid.

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.10 (s, 9H), 1.49 (s, 3H), 2.12 (m, 2H), 2.34 (s, 3H), 2.60 (m, 2H), 2.80 ( 2H), 4.61 (m, 2H), 5.11 (s, 1H), 5.14 (m, 2H) 1H), 6.81 (m, 1H), 6.97 / 7.23 (dd, J = 8.3, 13.7 Hz, 1H);

MS (EI, m / e) = 541 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- ( Rat - Butoxy ) -2- (4- (5- Chlorochroman -6-yl) -2,3,6- Trimethyl -1- (Oxetan-2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (5-chlorochroman-6-yl) Pyrrolor2,3-blpyridin-5-yl) acetate (110 mg, 0.2 mmol) was used instead of 2-chloro- Were reacted in the same manner using the same reagents as in step 2 of Example 1. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain pure target compound (less polar-31 mg, 30%, more polar-24 mg, 23%) as a white solid . The objective compound was composed of two diastereoisomers, each of which was separated by a polarity difference.

^{Less polar: 1 H-NMR (} 500 MHz, CD 3 OD) δ ppm 1.13 (s, 9H), 1.15 (s, 3H), 2.13 (m, 2H), 2.38 (s, 3H), 2.55 (m, 1H ), 2.72 (m, 1H) , 2.78 (s, 3H), 2.85 (t, J = 6.5 Hz, 2H), 4.21 (m, 2H), 4.45 (m, 1H), 4.51 (m, 2H), 4.55 (m, IH), 5.17 (m, IH), 5.19 (s, IH), 6.80 (s, IH), 6.95 (m, IH);

MS (EI, m / e) = 527 (M ^< ^{+ &} gt ^; ).

^{More polar: 1 H-NMR (} 500 MHz, CD 3 OD) δ ppm 1.03 (s, 9H), 1.56 (s, 3H), 2.09 (m, 2H), 2.38 (s, 3H), 2.54 (m, 1H ), 2.69 (s, 3H) , 2.71 (m, 1H), 2.81 (t, J = 6.37 Hz, 2H), 4.22 (m, 2H), 4.51 (m, 1H), 4.52 (m, 2H), 4.54 (m, IH), 5.14 (s, IH), 5.19 (m, IH), 6.86 (s, IH), 7.36 (m, IH);

MS (EI, m / e) = 527 (M ^< ^{+ &} gt ^; ).

Example  4: (2S) -2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6-trimethyl-1- ( Oxetane -2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6-trimethyl-1- ( Oxetane -2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine -5-yl) acetate

2,3-d] pyrimidin-2-ylmethyl) -lH-pyrrolo [2,3-b] pyridine- (2S) -methyl 2-tert-butoxy-2- (4- (8-fluoro-5-methylchroman-6-yl) -2,3,6-trimethyl- Was reacted in the same manner using the same reagents as in step 1 of Example 1, except that 4-chloro-pyrrolor2,3-blpyridin-5-yl acetate (400 mg, 0.852 mmol) . The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (294 mg, 64%). The compound contained two stereoisomers but did not separate because of the large polarity difference.

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 1.00 and 1.11 (s, 9H), 1.41 and 1.45 (s, 3H), 1.72 and 1.78 2H), 2.32 and 2.34 (s, 3H), 2.65 (m, 2H), 2.69 and 2.74 (s, 3H), 3.57 and 3.63 ), 4.43 (m, 1H), 4.51 (m, 1H), 5.10 and 5.11 (s, 1H), 5.11 (m, 1H), 7.03 (d, J = 11.5 Hz, 1H);

MS (EI, m / e) = 538 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2- (tert-butoxy) -2- (4- (8-fluoro-5-methyl LH-pyrrolo [2,3-b] pyridin-5-yl) acetate (294 mg, 0.545 mmol) was used in the same manner as in Example 1, except that the same reagents as in Step 2 of Example 1 were used in the same ratio. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (less polar-34.6 mg, 12%, more polar-19 mg, 6.5%) as a white solid .

^{Less polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 1.13 (s, 9H), 1.46 (s, 3H), 1.83 (s, 3H), 2.05 (m, 2H), 2.13 (m, 2H ), 2.18 (s, 3H), 2.70 (m, 2H), 2.71 (s, 3H), 3.70 (m, 2H), 4.24 , 6.72 (d, J = 11.2 Hz, 1 H);

MS (EI, m / e) = 524 (M ^< ^{+ &} gt ^; ).

^{More polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 1.02 (s, 1H), 1.50 (s, 3H), 1.75 (s, 3H), 2.0 (m, 2H), 2.13 (m, 2H ), 2.34 (s, 3H), 2.70 (s, 3H), 2.70 (m, 2H), 3.70 (m, 2H), 4.24 , 7.11 (d, J = 11.4 Hz, 1 H);

MS (EI, m / e) = 524 (M ^< ^{+ &} gt ^; ).

Example  5: (2S) -2- Rat - Butoxy -2- (2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -4-p-tolyl-lH- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -4-p-tolyl-lH- Pyrrolo [2,3-b] pyridine -5 days) Acetate

2,3-d] pyrimidin-2-ylmethyl) -lH-pyrrolo [2,3-b] pyridine- (2S) -methyl 2-tert-butoxy-2- (2,3,6-trimethyl-4-p-tolyl-lH- pyrrolo [2,3- b] pyridin- - yl) acetate (755 mg, 1.91 mmol) was used in the same manner as in step 1 of Example 1, except that the same reagents were used. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired compound (100 mg, 11%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.96 (s. 9H), 1.47 (s, 3H), 2.34 (s, 3H), 2.44 (s, 3H), 2.61 (s, 3H), 2.61 ( (m, 2H), 4.66 (s, 3H), 4.63 (m, 2H) , 1H);

MS (EI, m / e) = 464 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -4-p-tolyl-lH- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (2,3,6-trimethyl-1- (oxetane Pyridin-2-ylmethyl) -4-p-tolyl-lH-pyrrolo [2,3- b] pyridin- 5-yl) acetate (100 mg, 0.215 mmol) The same reagents as in Step 2 were used in the same manner and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain the desired compound (68.5 mg, 71%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.95 (s, 9H), 1.51 (s, 3H), 2.37 (s, 3H), 2.46 (s, 3H), 2.48 (m, 1H), 2.67 (s, 3H), 2.69 (m, IH), 4.52 (m, 4H), 5.15 (m, IH), 5.21 m, 1 H);

MS (EI, m / e) = 450 (M ^< ^{+ &} gt ^; ).

Example  6: (2S) -2- Rat - Butoxy -2- (4- (3,4- Dimethylphenyl ) -2,3,6- Trimethyl -One-( Oxetane - 2-yl methyl ) -1H- Pyrrolo [2,3-b] pyridine -5-yl) acetic acid

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (3,4- Dimethylphenyl ) -2,3,6- Trimethyl -1- (ox Cetane - 2-yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-d] pyrimidin-2-ylmethyl) -lH-pyrrolo [2,3-b] pyridine- Yl) acetate was used in the place of (S) -methyl 2-tert-butoxy-2- (4- (3,4-dimethylphenyl) -2,3,6- b] pyridin-5-yl) acetate (400 mg, 0.978 mmol) was used in the same manner as in Step 1 of Example 1, except that the same reagents were used. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the target compound (175.6 mg, 37%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.95 (s. 9H), 1.49 (s, 3H), 1.50 (s. 3H), 2.40 (s, 6H), 2.59 (m, 2H), 2.69 ( (m, 2H), 5.17 (m, IH), 7.04 (m, IH) , ≪ / RTI > 1H), 7.18 (m, 2H), 7.42 (m, 1H);

MS (EI, m / e) = 478 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- (3,4- Dimethylphenyl ) -2,3,6- Trimethyl -One-( Oxetane - 2-yl methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2- (tert-butoxy) -2- (4- (3,4-dimethylphenyl) - [2,3-b] pyridin- 2, 3, 6-trimethyl-1- (oxetan -2-ylmethyl) -1 H - pyrrolo [2,3-b] pyridin-5-yl), except that the acetate (180 mg, 0.354 mmol) Were reacted in the same manner using the same reagents as in step 2 of Example 1 at the same ratio. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (136.8 mg, 82%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.96 (s, 9H), 1.51 (s, 3H), 2.38 (s, 6H), 2.60 (m, 1H), 2.66 (s, 3H), 2.69 (m, 1H), 3.32 (s, 3H), 4.48 (m, IH), 4.53 (s, 2H), 4.60 m, 1 H), 7.25 (m, 2 H), 7.61 (m, 1 H);

MS (EI, m / e) = 464 (M ^< ^{+ &} gt ^; ).

Example  7: (2S) -2- Rat - Butoxy -2- (4- (3,4- Dihydro -2H- Benzo [b] [1,4] oxazin-6-yl) -2,3,6- Trimethyl -One-( Oxetane - 2-yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (3,4- Dihydro -2H- Benzo [b] [l, 4] oxo 6-yl) -2,3,6- Trimethyl -One-( Oxetane - 2-yl methyl ) -1H- Pirolo  [2,3-b] pyridin-5-yl) acetate

2,3-d] pyrimidin-2-ylmethyl) -lH-pyrrolo [2,3-b] pyridine- (S) -methyl 2-tert-butoxy-2- (4- (3,4-dihydro-2H- benzo [b] [1,4] oxazin- (100 mg, 0.224 mmol) was used instead of (l, 2,3,6-trimethyl-l- (oxetan-2-ylmethyl) -lH- pyrrolo [2,3- b] pyridin- Were reacted in the same manner using the same reagents as in step 1 of Example 1. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain the desired compound (45 mg, 41%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.03 (s, 9H), 1.62 (s, 3H), 1.88 (m, 2H), 2.34 (s, 3H), 2.72 (s, 3H), 3.39 ( (m, 2H), 3.70 (s, 3H), 3.71 (m, 2H), 4.29 , ≪ / RTI > 1H), 6.79 (m, 1H), 6.92 (s, 1H);

MS (EI, m / e) = 507 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- (3,4- Dihydro -2H- Benzo [b] [1,4] oxazin-6-yl) -2,3,6- Trimethyl -One-( Oxetane - 2-yl methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (3,4-dihydro-2H-benzo 2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3- Yl) acetate (45 mg, 0.088 mmol) was used in the same manner as in Step 2 of Example 1, except that the same reagents were used. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (less polar-20 mg, 46%, more polar-8.7 mg, 20%) as a white solid . The objective compound was composed of two diastereoisomers, each of which was separated by a polarity difference.

^{Less polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 0.99 (s, 9H), 1.61 (s, 3H), 1.86 (m, 2H), 2.35 (s, 3H), 2.66 (s, 3H 2H), 4.37 (m, IH), 5.37 (s, IH), 6.51 (m, , 6.78 (m, 1 H), 6.88 (s, 1 H);

MS (EI, m / e) = 493 (M ^< ^{+ &} gt ^; ).

^{More polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 0.94 (s, 9H), 1.56 (s, 3H), 2.32 (s, 3H), 2.47 (m, 1H), 2.62 (s, 3H 1H), 6.43 (m, 2H), 4.40 (m, 2H), 4.65 (m, 1H), 6.69 - 6.79 (m, 2H);

MS (EI, m / e) = 493 (M ^< ^{+ &} gt ^; ).

Example  8: (2S) -2- Rat - Butoxy -2- (2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -4- (4- (piperidin-1-yl) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -4- (4- (piperidin-1-yl) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-d] pyrimidin-2-ylmethyl) -lH-pyrrolo [2,3-b] pyridine- Yl) acetate was used in the place of (S) -methyl 2-tert-butoxy-2- (2,3,6-trimethyl- 4- (4- (piperidin- Was reacted in the same manner using the same reagents as in Step 1 of Example 1, except that the above-mentioned starting materials were used in the same manner as in Step 1 of Example 1, except that thiophenol [2,3-b] pyridin-5-yl) acetate (109 mg, 0.249 mmol) The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (83 mg, 29%, starting material 35 mg).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.98 (s. 9H), 1.55 (s, 3H), 1.59 (s, 2H), 1.78 (bs. 4H), 2.37 (s, 3H), 2.63- 2H), 4.62 (m, 2H), 2.65 (s, 3H), 3.26 (bs, 4H) (m, IH), 5.28 (s, IH), 7.01 (m, 2H), 7.18 (m, IH), 7.35 (m, IH);

MS (EI, m / e) = 534 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (2,3,6- Trimethyl -One-( Oxetane -2- Yl methyl ) -4- (4- (piperidin-1-yl) Phenyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (2,3,6-trimethyl-1- (oxetane Pyridin-2-ylmethyl) -4- (4- (piperidin-l-yl) Except that the same reagents as in step 2 of Example 1 were used in the same proportions and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (21 mg, 33%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.96 (s, 9H), 1.59 (s, 3H), 1.66 (m, 2H), 1.83 (bs, 4H), 2.03 (m, 3H), 2.35 (s, 3H), 2.67 (s, 3H), 3.27 (bs, 4H), 3.73 (m, 2H), 4.21 m, 2 H), 7.18 (m, 1 H), 7.48 (m, 1 H);

MS (EI, m / e) = 519 (M ^< ^{+ &} gt ^; ).

Example  9: (S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -One-( Oxse Gt; Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (S) - methyl  2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -One-( Oxetane -3- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

(S) - methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,6- trimethyl -1 H-pyrrolo [2,3-b] pyridin-5-yl) Acetate (200 mg, 0.482 mmol) was dissolved in dichloromethane (6 ml) and potassium hydroxide (190 mg, 2.89 mmol) and tetrabutylammonium bromide (18 mg) Methyl) oxetane (382 mg, 1.92 mmol) was added thereto, followed by stirring at 40 ° C for 18 hours. Cooling water was added to the reaction mixture and the pH was adjusted to 6 to 7 with a 2N aqueous hydrochloric acid solution. The organic layer was separated and taken, and the aqueous layer was extracted twice more with dichloromethane (15 ml). The obtained organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain pure target compound (171 mg, 73%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.98 (s, 9H), 1.47 (s, 3H), 2.04 (s, 3H), 2.69 (s, 3H), 3.53 (m, 1H), 3.66 ( 1H, s, 3H), 4.51 (d, J = 7.11 Hz, 2H), 4.66 (m, 2H), 4.79 (t, J = 6.85Hz, 2H) 7.42 (m, 3 H);

LC-MS (ES, m / e) = 485 (M ^< ^{+ &} gt ^; ).

Step 2: (S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -One-( Oxetane -3 days Me Yl) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,3-trifluoroethoxy) (150 mg, 0.309 mmol) was used in place of the compound obtained in Step 2 of Example 1, except for using 6-trimethyl-1- (oxetan-3-ylmethyl) 1 were reacted in the same manner using the same reagents as in Step 2 of Step 1. The resulting residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain pure target compound (84 mg, 57%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 1.00 (s, 9H), 1.53 (s, 3H), 2.33 (s, 3H), 2.71 (s, 3H), 3.52 (m, 1H), 4.60 (d, J = 7.25 Hz, 2H), 4.68 (m, 2H), 4.75 (m, 2H), 5.10 (s, 1H), 7.32 (d, J = 6.55 Hz, 1H), 7.61 (t, J = 5.17 Hz, 2 H), 7.62 (m, 1 H);

LC-MS (ES, m / e) = 470 (M ^< ^{+ &} gt ^; ).

Example  10: (2S) -2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6-trimethyl-1- ( Oxetane -3- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6-trimethyl-1- ( Oxetane -3- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

(2S) -methyl 2-tert-butoxy-2- (4- (8-fluoro-5-methylchroman-6-yl) -2,3,6-trimethyl- 1 H- pyrrolo [2,3 -b] pyridin-5-yl) acetate (100 mg, 0.213 mmol) was dissolved in dimethylformamide (2 ml) and cesium carbonate (208.6 mg, 0.64 mmol) and 3- Iodomethyl) oxetane (84.3 mg, 0.426 mmol) was added thereto, followed by stirring at 60 ° C for 18 hours. Cooling water was added to the reaction mixture, and ethyl acetate (15 ml) was added thereto, followed by stirring for 10 minutes. The organic layer was separated and the aqueous layer was further extracted twice with ethyl acetate (15 ml), and the obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (71 mg, 62%). The compounds include two stereoisomers that appear in different NMR fields.

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.02 and 1.13 (s, 9H), 1.75 and 1.80 (s, 3H), 2.17 (m, 2H), 2.29 and 2.30 (s, 3H), 2.67 (m 2H), 2.73 and 2.77 (m, 2H), 3.56 (m, 1H), 3.57 and 3.66 (s, 3H), 4.31 , 2H), 4.71 (m, 2H), 5.12 and 5.13 (s, 1H), 6.75 and 7.04 (s, 1H);

LC-MS (ES, m / e) = 538 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6- Trimethyl -One-( Oxetane -3- Yl methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (8-fluoro-5-methylchroman LH-pyrrolo [2,3-b] pyridin-5-yl) acetate (66 mg, 0.122 mmol) ), The same reagents as in step 2 of Example 1 were used in the same proportions and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain pure target compound (less polar-14.4 mg, 11.8%, more polar-9.8 mg, 8%) as a white solid . The objective compound was composed of two diastereoisomers, each of which was separated by a polarity difference.

^{Less polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 1.00 (s, 9H), 1.32 (s, 3H), 1.70 (s, 3H), 2.00 (m, 2H), 2.18 (s, 3H ), 2.61 (s, 3H), 3.35 (m, 1H), 4.13 (m, 2H), 4.43-4.65 J = 6.55 Hz, 1 H);

LC-MS (ES, m / e) = 524 (M ^< ^{+ &} gt ^; ).

^{More polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 0.90 (s, 9H), 1.45 (s, 3H), 1.66 (s, 3H), 2.00 (m, 2H), 2.29 (s, 3H ), 2.56 (m, 2H), 2.63 (s, 3H), 3.40 (m, IH), 4.13 (m, 3H), 4.44-4.66 J = 6.55 Hz, 1 H);

LC-MS (ES, m / e) = 524 (M ^< ^{+ &} gt ^; ).

Example  11: (S) -2- Rat - Butoxy -2- (4- (3,4- Dimethylphenyl ) -2,3,6- Trimethyl -One-( jade The cetane- 3-yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (S) - methyl  2- Rat - Butoxy -2- (4- (3,4- Dimethylphenyl ) -2,3,6- Trimethyl -1- (ox Cetane - 3-yl methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

(2S) -methyl 2-tert-butoxy-2- (4- (8-fluoro-5-methylchroman-6-yl) -2,3,6-trimethyl- Methyl-2-tert-butoxy-2- (4- (3,4-dimethylphenyl) -2,3,6-trimethyl- 1 H The same reagents as in step 1 of Example 10 were used in the same proportions, except that the above-mentioned starting materials were used in the same manner as in Example 10, except that pyrrolo [2,3-b] pyridin-5-yl) acetate (200 mg, 0.489 mmol) . The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (203 mg, 85.8%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.99 (s. 9H), 1.49 (s, 3H), 2.29 (s. 6H), 2.30 (m, 1H), 2.37 (s, 3H), 2.70 ( (m, 2H), 4.79 (m, 2H), 5.18 (s, 1H), 7.04 (m, , ≪ / RTI > 1H), 7.18 (m, 2H), 7.44 (m, 1H);

MS (EI, m / e) = 478 (M ^< ^{+ &} gt ^; ).

Step 2: (S) -2- Rat - Butoxy -2- (4- (3,4- Dimethylphenyl ) -2,3,6- Trimethyl -One-( Oxetane - 3-yl methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (S) -methyl 2-tert-butoxy-2- (4- (3,4-dimethylphenyl) -2,2,3,4-tetrahydroisoquinolin- (4-fluorobenzyloxy) -lH-pyrrolo [2,3-b] pyridin-5-yl) acetate (180 mg, 0.376 mmol) The same reagents as in step 2 of Example 1 were used in the same manner and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (82 mg, 47%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.97 (s, 9H), 1.50 (s, 3H), 2.33 (s, 6H), 2.42 (s, 3H), 2.34-2.42 (m, 3H) 2H), 4.77 (m, 2H), 5.23 (s, IH), 7.05 (m, IH) 7.24 (m, 2 H), 7.49 (m, 1 H);

MS (EI, m / e) = 464 (M ^< ^{+ &} gt ^; ).

Example  12: (S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1 - ((3-methyloxetan-3-yl) methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (S) - methyl  2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1 - ((3- Heilk Cetane-3-yl) methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

(S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,6-trimethyl-lH- pyrrolo [2,3- b] pyridin- (400 mg, 0.964 mmol) was dissolved in dichloromethane (12 ml), potassium hydroxide (320 mg, 3.85 mmol) and tetrabutylammonium bromide (32 mg) were added and the mixture was stirred at room temperature for 3 - (Iodomethyl) -3-methyloxetane (0.525 mg, 8.435 mmol) was slowly added. The solution was stirred at 30 < 0 > C for 18 hours. Cooling water was added to the reaction solution and the pH was adjusted to 5 to 6 with a 2N aqueous hydrochloric acid solution. The organic layer was separated and taken, and the aqueous layer was extracted twice more with dichloromethane (60 ml). The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to obtain pure target compound (248 mg, 51%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.01 (s, 9H), 1.38 (s, 3H), 1.50 (s, 3H), 2.24 (s, 3H), 2.69 (s, 3H), 3.69 ( (m, 3H), 4.28 (m, 4H), 4.97 / 4.99 (dd, J = 6.0, 6.0 Hz, 2H), 5.09 (s, IH), 7.26

MS (EI, m / e) = 499 (M ^< ^{+ &} gt ^; ).

Step 2: (S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1 - ((3- Methyloxetane -3 days) methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,6-trimethyl- Yl) acetate (248 mg, 0.497 mmol) was dissolved in tetrahydrofuran (8.5 ml), water (4.2 ml) and methanol (8.5 ml) , And lithium hydroxide hydrate (59.5 mg, 2.48 mmol) was added thereto, followed by stirring at 50 ° C for 18 hours. To this solution was added an equal amount of 2N-hydrochloric acid aqueous solution to neutralize and the solvent was concentrated under reduced pressure and dried under high vacuum. An appropriate amount of dichloromethane was added to the product, followed by filtration to remove insolubles and concentrate.

The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 19: 1) to obtain pure target compound (58 mg, 24%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.98 (s, 9H), 1.31 (s, 3H), 1.54 (s, 3H), 2.27 (s, 3H), 2.67 (s, 3H), 4.29 (d, J = 8.4 Hz, 1H), 7.51 (m, 2H), 7.62 (d, J = 8.4 Hz, 1H);

MS (EI, m / e) = 485 (M ^< ^{+ &} gt ^; ).

Example  13: (2S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1- (2- (ox Cetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1- (2- (oxetan-2-yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

(2S) -methyl 2-tert-butoxy-2- (4- (8-fluoro-5-methylchroman-6-yl) -2,3,6-trimethyl- Methyl-2-tert-butoxy-2- (4- (4-chlorophenyl) -2,2,3,4-tetrahydropyridin-2- (165 mg, 0.4 mmol) and 3- (iodomethyl) -lH-pyrrolo [2,3-b] pyridin- The reaction was carried out in the same manner using the same reagents as in step 1 of Example 10, except that 3-methyloxetane (237 mg, 1.2 mmol) was used. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain pure target compound (162 mg, 81%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.97 (s, 9H), 1.48 (s, 3H), 2.22 (m, 2H), 2.29 (s, 3H), 2.36 (m, 1H), 2.64 ( 1H), 4.66 (m, 1H), 4.69 (s, 3H), 2.65 (s, 3H) , ≪ / RTI > 1H), 7.22 (m, 1H), 7.41 (m, 3H);

MS (EI, m / e) = 499 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,3a, (150 mg, 0.3 mmol) was used as the starting material instead of 2-ethynyl-pyridin-2-ylmethyl ester Were reacted in the same manner using the same reagents as in step 2 of Example 1 at the same ratio. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain the desired compound (124 mg, 85%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.99 (s, 9H), 1.31 (s, 3H), 2.20 (s, 2H), 2.34 (m, 3H), 2.38 (m, 1H), 2.64 (m, 1H), 2.70 (s, 3H), 4.33 (m, 2H), 4.55 s, 1 H), 7.51 (t, J = 7.8 Hz, 2 H), 7.62 (s, 1 H);

MS (EI, m / e) = 485 (M ^< ^{+ &} gt ^; ).

Example  14: (2S) -2- Rat - Butoxy -2- (4- ( Croix -6-yl) -2,3,6- Trimethyl -1- (2- (ox Cetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- ( Croix -6-yl) -2,3,6- Trimethyl -1- (2- (ox Cetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] Yl) -2,3,6-trimethyl-lH-pyrrolo [2,3-b] pyridine was used in the place of (S) -methyl 2- Pyridin-5-yl) acetate (400 mg, 0.91 mmol) was used in the same manner as in step 1 of Example 13. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain pure target compound (245 mg, 51%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.98 (s, 9H), 1.54 (s, 3H), 2.06 (m, 2H), 2.20 (m, 2H), 2.26 (s, 3H), 2.34 ( 2H), 2.68 (s, 3H), 2.74 (m, IH), 2.78 (m, IH), 3.66 (M, IH), 4.81 (m, IH), 5.23 (s, IH), 6.84 (m, IH), 6.95

MS (EI, m / e) = 520 (M < ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- ( Croix -6-yl) -2,3,6- Trimethyl -1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,2,3,4-tetrahydroisoquinoline- Yl) acetate (245 mg, 0.47 mmol) was used in place of the compound obtained in the step , The same reagents as in step 2 of Example 1 were used in the same manner and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain the desired compound (173 mg, 72%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.86 (s, 9H), 1.46 (s, 3H), 1.95 (m, 2H), 2.09 (m, 2H), 2.21 (m, 3H), 2.26 (m, IH), 2.49 (m, IH), 2.52 (s, 3H), 2.68 (m, 2H), 4.13 (m, 1H), 4.75 (m, 1H), 5.16 (s, 1H), 6.72 (t, J = 8.9 Hz, 1H), 6.85 (m, 1H), 7.17

MS (EI, m / e) = 506 (M ^< ^{+ &} gt ^; ).

Example  15: (2S) -2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6-trimethyl-1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6-trimethyl-1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] (2S) -methyl 2-tert-butoxy-2- (4- (8-fluoro-5-methylchroman-6-yl) -2,3,6-trimethyl- (3-fluorobenzyloxy) pyrrolo [2,3-b] pyridin-5-yl) acetate (200 mg, 0.426 mmol) was used in the same ratio. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain pure target compound (200 mg, 85%).

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 1.00 and 1.12 (s, 9H), 1.40 and 1.45 (s, 3H), 1.69 and 1.72 2H), 4.66 (m, 1H), 2.65 (m, 4H), 2.74 (m, 4.81 (m, 1 H), 5.11 (s, 1 H), 6.75 and 7.03 (m, 1 H);

MS (EI, m / e) = 552 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6- Trimethyl -1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (8-fluoro-5-methylchroman Pyrrolo [2,3-b] pyridin-5-yl) acetate (190 < mg, 0.343 mmol), the same reagents as in step 2 of Example 1 were used in the same manner and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 19: 1) to obtain pure target compound (less polar-96.2 mg, 46.8%, more polar-65.4 mg, 35.5%) as a white solid .

^{Less polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 1.13 (s, 9H), 1.45 (s, 3H), 1.82 (s, 3H), 2.18 (m, 4H), 2.32 (m, 1H 1H), 2.32 (s, 3H), 2.60 (m, 1H), 2.75 (m, 2H), 2.75 4.84 (m, 1 H), 5.12 (s, 1 H), 6.73 (d, J = 11.0 Hz, 1 H);

MS (EI, m / e) = 538 (M ^< ^{+ &} gt ^; ).

^{More polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 1.02 (s, 9H), 1.49 (s, 3H), 1.73 (s, 3H), 2.13 (m, 2H), 2.20 (m, 2H 2H), 2.71 (m, 2H), 2.71 (m, 2H), 2.31 (s, 3H) , 4.56 (m, 1H), 4.67 (m, 1H), 4.58 (m, 1H), 5.19 (s, 1H), 7.10 (d, J = 11.6 Hz, 1H);

MS (EI, m / e) = 538 (M ^< ^{+ &} gt ^; ).

Example  16: (S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1- (2- (ox Cetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (S) - methyl  2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1- (2- (ox Cetane Yl) ethyl-lH- Pyrrolo [2,3-b] pyridine Yl) acetate

(S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,6-trimethyl-lH- pyrrolo [2,3- b] pyridin- (165 mg, 0.396 mmol) was dissolved in dimethylformamide (3.3 ml) and cesium carbonate (387 mg, 1.188 mmol) and 3- (2-iodoethyl) oxetane prepared in Reference Example 5 mg, 0.792 mmol) were added thereto, followed by stirring at 60 DEG C for 18 hours. Cooling water was added to the reaction, ethyl acetate (30 ml) was added, and the mixture was stirred for 10 minutes. The organic layer was separated, and the aqueous layer was further extracted twice with ethyl acetate (30 ml). The obtained organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.

The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain the desired compound (189 mg, 96%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 1.00 (s, 9H), 1.50 (s, 3H), 2.16 (m, 2H), 2.31 (s, 3H), 2.36 (m, 1H), 2.71 ( 2H), 4.71 (m, 2H), 5.10 (s, 1H), 7.23 (m, 2H) , ≪ / RTI > 1H), 7.44 (m, 3H);

MS (EI, m / e) = 498 (M ^< ^{+ &} gt ^; ).

Step 2: (S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,3-trifluoroethoxy) Except that 178 mg (0.356 mmol) of 6-trimethyl-l- (2- (oxetan-3-yl) ethyl-lH- pyrrolo [2,3- b] pyridin- The reaction was carried out in the same manner using the same reagents as in step 2 of Example 1. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain the target compound (105 mg, 61%).

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.99 (s, 9H), 1.53 (s, 3H), 2.14 (m, 2H), 2.34 (s, 3H), 2.70 (s, 3H), 2.98 (m, 1H), 4.28 (m, 4H), 4.64 (m, 2H), 5.14 (s, IH), 7.32 (m, IH), 7.52 (m, 2H), 7.59

MS (EI, m / e) = 484 (M ^< ^{+ &} gt ^; ).

Example  17: (S) -2- Rat - Butoxy -2- (4- ( Croix -6-yl) -2,3,6- Trimethyl -1- (2- ( jade Cetane-3-yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (S) - methyl  2- Rat - Butoxy -2- (4- ( Croix -6-yl) -2,3,6- Trimethyl -1- (2- (ox Cetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] Yl) -2,3,6-trimethyl-lH-pyrrolo [2,3-b] pyridine was used in the place of (S) -methyl 2- Pyridin-5-yl) acetate (116 mg, 0.264 mmol) was used in the same manner as in Example 16, except that the same reagents were used. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain pure target compound (76 mg, 55%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.99 (s, 9H), 1.53 (s, 3H), 2.05 (m, 2H), 2.20 (m, 2H), 2.24 (s, 3H), 2.34 ( 2H), 2.64 (s, 3H), 2.74 (m, IH), 2.78 (m, IH), 3.63 1H), 4.81 (m, IH), 5.23 (s, IH), 6.84 (m, IH), 6.95 (m, IH), 7.17

MS (EI, m / e) = 520 (M < ^{+ &} gt ^; ).

Step 2: (S) -2- Rat - Butoxy -2- (4- ( Croix -6-yl) -2,3,6- Trimethyl -1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,2,3,4-tetrahydropyrimidin- 2,3-b] pyridin-5-yl) acetate (66 mg, 0.127 mmol) was used instead of 4- , The same reagents as in step 2 of Example 1 were used in the same manner and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 9: 1) to obtain pure desired compound (38 mg, 59%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.98 (s, 9H), 1.58 (s, 3H), 2.06 (m, 2H), 2.21 (m, 2H), 2.33 (s, 3H), 2.68 (s, 3H), 2.84 (m, 2H), 2.98 (m, 1H), 4.24-4.28 (m, 6H), 4.61-4.64 ), 6.82 (m, 1 H), 6.98 (m, 1 H), 7.28 (m, 1 H);

MS (EI, m / e) = 506 (M ^< ^{+ &} gt ^; ).

Example  18: (2S) -2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6-trimethyl-1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6-trimethyl-1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] (2S) -methyl 2-tert-butoxy-2- (4- (8-fluoro-5-methylchroman-6-yl) -2,3,6-trimethyl- Was reacted in the same manner using the same reagents as in step 1 of Example 16 except that the starting material was prepared by the same procedure as described in the preparation of Example 16, except that thiophenol [2,3-b] pyridin-5-yl) acetate (200 mg, 0.426 mmol) The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain pure target compound (224 mg, 95%). The compound contained two stereoisomers but did not separate because of the large polarity difference.

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 1.02 and 1.13 (s, 9H), 1.43 and 1.47 (s, 3H), 1.73 and 1.78 2H), 5.13 (s, 1 H), 6.84 (s, 3H), 2.63 (s, 3H) (d, J = 7.4 Hz, 1 H);

MS (EI, m / e) = 552 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- (8- Fluoro -5- Methyl chroman -6-yl) -2,3,6- Trimethyl -1- (2- ( Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (8-fluoro-5-methylchroman LH-pyrrolo [2,3-b] pyridin-5-yl) acetate (210 < mg, 0.38 mmol), the same reagents as in step 2 of Example 1 were used in the same manner and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 19: 1) to obtain pure target compound (less polar-81 mg, 40%, more polar-79 mg, 38.7%) as a white solid .

^{Less polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 1.01 (s, 9H), 1.33 (s, 3H), 1.69 (s, 3H), 2.02 (m, 4H), 2.20 (s, 3H 2H), 2.50 (s, 3H), 2.87 (m, 1H), 4.17 (m, 6H), 4.41-4.72 J = 11.0 Hz, 1H);

MS (EI, m / e) = 538 (M ^< ^{+ &} gt ^; ).

^{More polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 1.02 (s, 9H), 1.50 (s, 3H), 1.74 (s, 3H), 2.13 (m, 4H), 2.34 (s, 3H 2H), 2.72 (s, 3H), 3.01 (m, 1H), 4.19-4.29 (m, 6H), 4.56-4.63 d, J = 11.0 Hz, 1H);

MS (EI, m / e) = 538 (M ^< ^{+ &} gt ^; ).

Example  19: (S) -2- Rat - Butoxy -2- (4- (3,4- Dimethylphenyl ) -2,3,6- Trimethyl -1- (2-oxetan-3-yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (S) - methyl  2- Rat - Butoxy -2- (4- (3,4- Dimethylphenyl ) -2,3,6- Trimethyl -1- (2- (oxetan-3-yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] Pyrrolo [2,3-b] pyridin-2-ylmethyl) -1,2,3,4-tetrahydro- Pyridin-5-yl) acetate (200 mg, 0.482 mmol) was used in the same manner as in Example 16, except that the same reagents were used. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain pure target compound (206 mg, 85.8%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.96 (s. 9H), 1.48 (s, 3H), 2.22 (m. 2H), 2.28 (s, 6H), 2.35 (s, 3H), 2.39 ( 1H), 4.67 (m, 1H), 4.84 (m, 1H), 2.69 (s, 3H) , 5.18 (s, 1 H), 7.02 (m, 1 H), 7.18 (m, 2 H), 7.44 (m, 1H);

MS (EI, m / e) = 492 (M ^< ^{+ &} gt ^; ).

Step 2: (S) -2- Rat - Butoxy -2- (4- (3,4- Dimethylphenyl ) -2,3,6- Trimethyl -1- (2- Oxetane Yl) ethyl) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (S) -methyl 2-tert-butoxy-2- (4- (3,4-dimethylphenyl) -2,2,3,4-tetrahydroisoquinolin- 2,3-b] pyridin-5-yl) acetate (186 mg, 0.377 mmol) was used instead of 3,6-trimethyl- , The same reagents as in step 2 of Example 1 were used in the same manner and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (102 mg, 57%) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD)? Ppm 0.95 (s, 9H), 1.50 (s, 3H), 2.20 (m, 2H), 2.32 (s, 3H), 2.61 (m, 1H), 2.63 (s, 3H), 4.28 (m, 2H), 4.54 s, 1 H), 7.03 (m, 1 H), 7.24 (m, 1 H), 7.35 (m, 1 H);

MS (EI, m / e) = 478 (M ^< ^{+ &} gt ^; ).

Example  20: (2S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1 - ((4-methyloxetan-2-yl) methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1 - ((4- Heilk Cetane-2-yl) methyl ) -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] (S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,6-trimethyl-1H Yl) acetate (200 mg, 0.488 mmol) and 2- (iodomethyl) -4-methyloxetane (306 mg , 1.446 mmol), the same reagents as in step 1 of Example 16 were used in the same manner and reacted in the same manner. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to obtain the target compound (less polar-20 mg, more polar-19 mg) separated into two isomers.

^{Less polar: 1 H-NMR (} 300 MHz, CDCl 3) δ ppm 0.97 (. S 9H), 1.46 (s, 3H), 1.47 (. D J = 5.1 Hz, 3H), 2.04-2.14 (m, 1H) , 2.40 (s, 3H), 2.42 (s, 3H), 2.42-2.48 (m, (s, 1 H), 5.84-5.89 (m, 1 H), 7.23 (m, 1 H), 7.43 (m, 3 H);

MS (EI, m / e) = 499 (M ^< ^{+ &} gt ^; ).

^{More polar: 1 H-NMR (} 300 MHz, CDCl 3) δ ppm 0.97 (. S 9H), 1.28 (d, 3H), 1.48 (. S 3H), 2.11-2.14 (m, 1H), 2.35 (s, (M, 1H), 2.42-2.48 (m, 1H), 2.67 (s, 3H), 3.68-2.85 1H), 4.80 (m, IH), 5.00 (m, IH), 7.22 (m, IH), 7.43 (m, 3H);

MS (EI, m / e) = 499 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1 - ((4- Methyloxetane -2 days) methyl ) -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,3a, Two isomers (less polar-20 mg) of 6-trimethyl-l- ((4-methyloxetan- 2- yl) methyl) - lH- pyrrolo [2,3- b] pyridin- , 0.04 mmol, more polar-19 mg, 0.038 mmol) was used in the same manner as in Step 2 of Example 1, except that the same reagents were used. The obtained residue was purified by silica gel column chromatography (dichloromethane: acetone = 9: 1 and dichloromethane: methanol = 95: 5) to obtain the target compound (less polar-16.1 mg, 83% 17.5 mg, 95%).

Less polar: ¹ H-NMR (300 MHz, CD ₃ OD)? Ppm 0.92 (s, 9H), 1.41 (d, J = 6.0 Hz, 3H), 1.44 ), 2.35 (s, 3H), 2.36-2.42 (m, 1H), 2.64 (s, 3H), 3.97-4.18 (m, 2H), 4.22-4.27 5.67 - 5.73 (m, 1H), 7.23 (m, 1H), 7.41 - 7.52 (m, 3H);

MS (EI, m / e) = 485 (M ^< ^{+ &} gt ^; ).

^{More polar: 1 H-NMR (} 300 MHz, CD 3 OD) δ ppm 0.92 (s, 9H), 1.11 (d, J = 6.0 Hz, 3H), 1.49 (s, 3H), 1.99-2.02 (m, 1H 2H), 4.96 (m, 1H), 5.08 (s, 1H), 7.24 (m, 1H), < / RTI > 7.53 (m, 3H);

MS (EI, m / e) = 485 (M ^< ^{+ &} gt ^; ).

Example  21: (2S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -1 - ((4,4- Dimethyloxetane -2 days) methyl ) -2,3,6- Trimethyl -1H- Pyrrolo [2,3-b] pyridine Yl) acetic acid < / RTI >

Step 1: (2S) - methyl  2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -1 - ((4,4- Dimethyloxye Yl) methyl ) -2,3,6- Trimethyl -1H- Pyrrolo [2,3-b] pyridine Yl) acetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] (S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,6-trimethyl-1H Yl) acetate (200 mg, 0.488 mmol) and (4,4-dimethyloxetan-2-yl) methyl 4- Methylbenzenesulfonate (390 mg, 1.44 mmol) was used in the same manner as in Example 16, except that the same reagents were used in the same ratio. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (155 mg, 62%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.97 (s. 9H), 1.30 (s, 3H), 1.41 (s. 3H), 1.47 (s, 3H), 2.29-2.46 (m, 2H), (S, 3H), 3.66 (s, 3H), 4.32 (m, IH), 4.53 (m, 1 H), 7.41 (m, 3 H);

MS (EI, m / e) = 513 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- Rat - Butoxy -2- (4- (4- Chlorophenyl ) -1 - ((4,4- Dimethyloxetane -2 days) methyl ) -2,3,6- Trimethyl -1H- Pyrrolo [2,3-b] pyridine 5-yl) acetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -1 - (( 2,3-b] pyridin-5-yl) acetate (70 mg, 0.136 mmol) was used instead of 2-ethoxy- , The same reagents as in step 2 of Example 1 were used in the same manner and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 100: 1) to obtain pure target compound (44 mg, 65%) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD)? Ppm 0.93 (s, 9H), 1.22 (s, 3H), 1.36 (s, 3H), 2.40 (m, 1H), 2.62 (s, 3H), 4.43 (m, 2H), 4.88 m, 2 H), 7.53 (m, 1 H);

MS (EI, m / e) = 499 (M ^< ^{+ &} gt ^; ).

Example  22: (2S) -2- (1- (2- Oxaspiro [3,3] heptane -6- Yl methyl ) -4- (4- Chlorophenyl ) -2,3,6-trimethyl-1H- Pyrrolo [2,3-b] pyridine -5-yl) -2- Rat - Butoxyacetic acid  Produce

Step 1: (2S) - methyl  2- (1- (2- Oxaspiro [3,3] heptane -6- Yl methyl ) -4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1H- Pyrrolo [2,3-b] pyridine -5-yl) -2- Rat - Butoxy -acetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] (S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,6-trimethyl-1H (55.76 mg, 0.134 mmol) and 6- (iodomethyl) -2-oxaspiro [3,3-b] pyridine prepared by the method of Referential Example 10 ] Heptane (50.8 mg, 0.402 mmol) was used in the same manner as in Step 1 of Example 16, except that the same reagents were used. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (65.7 mg, 93%).

^{1 H-NMR (300 MHz,} CDCl 3) δ ppm 0.96 (s. 9H), 1.49 (s, 3H), 2.15 (m. 2H), 2.29 (s, 3H), 2.27-2.33 (m, 2H), 2H), 4.77 (s, 2H), 5.09 (s, 2H), 2.50 (s, 3H) 1H), 7.25 (m, 1H), 7.41-7.48 (m, 3H);

MS (EI, m / e) = 525 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- (1- (2- Oxaspiro [3,3] heptane -6- Yl methyl ) -4- (4- Chlorophenyl ) -2,3,6-trimethyl-1H- Pyrrolo [2,3-b] pyridine -5-yl) -2- Rat - Butoxyacetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2- (1- (2-oxaspiro [3,3] heptan-6-ylmethyl) - (65.7 mg, 0.125 mmol) was reacted with 4- (4-chlorophenyl) -2,3,6-trimethyl- lH- pyrrolo [2,3- b] pyridin- The same reagents as in step 2 of Example 1 were used in the same manner and reacted in the same manner. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (46 mg, 72%) as a white solid.

^{1 H-NMR (300 MHz,} CD 3 OD) δ ppm 0.94 (s, 9H), 1.46 (s, 3H), 2.02-2.09 (m, 2H), 2.19-2.29 (m, 2H), 2.23 (s, 2H), 4.63 (m, 4H), 5.45 (s, 1H), 7.26 (m, 1H), 7.43-7.54 (m, , 3H);

MS (EI, m / e) = 511 (M < ^{+ &} gt ^; ).

Example  23: (2S) -2- (1- (1- Oxaspiro [3,3] heptane -2- Yl methyl ) -4- (4- Chlorophenyl ) -2,3,6-trimethyl-1H- Pyrrolo [2,3-b] pyridine -5-yl) -2- Rat - Butoxyacetic acid  Produce

Step 1: (2S) - methyl  2- (1- (1- Oxaspiro [3,3] heptane -2- Yl methyl ) -4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1H- Pyrrolo [2,3-b] pyridine -5-yl) -2- Rat - Butoxyacetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] (S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,6-trimethyl-1H (29 mg, 0.070 mmol) and 2- (iodomethyl) -1-oxaspiro [3,3-b] pyridine prepared by the method of Referential Example 8 ] Heptane (50 mg, 0.21 mmol) was used in the same manner as in Example 16, except that the same reagents as in Step 1 of Example 16 were used in the same ratio. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (21.2 mg, 57%).

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 0.97 (s, 9H), 1.46 (s, 3H), 1.60 (m, 2H), 2.02 3H), 4.21-4.29 (m, 1 H), 4.53-3.52 (m, 3H) 4.59 (m, 2H), 4.90-4.94 (m, IH), 5.06 (s, IH), 7.21 (m, IH), 7.42 (m, 3H);

LC-MS (ES, m / e) = 525 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- (1- (1- Oxaspiro [3,3] heptane -2- Yl methyl ) -4- (4- Chlorophenyl ) -2,3,6-trimethyl-1H- Pyrrolo [2,3-b] pyridine -5-yl) -2- Rat - Butoxyacetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2- (1- (1-oxaspiro [3,3] heptan-2-ylmethyl) - (28 mg, 0.0533 mmol) was reacted with 4- (4-chlorophenyl) -2,3,6-trimethyl- lH-pyrrolo [2,3-b] pyridin- Except that the same reagents as in step 2 of Example 1 were used in the same ratio. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (21 mg, 77%) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD)? Ppm 0.95 (s, 9H), 1.49 (s, 3H), 1.50 (m, 2H), 2.32 (s, 3H), 2.40-2.43 (m, 1H), 2.61 (s, 3H), 2.68-2.71 (m, 1H), 4.37-4.42 , 2H), 4.84 (m, IH), 5.06 (s, IH), 7.23 (m, IH), 7.44 (m, 2H), 7.53 (m, IH);

MS (EI, m / e) = 511 (M < ^{+ &} gt ^; ).

Example  24: (2S) -2- (1- (1- Oxaspiro [3,5] nonane -2- Yl methyl ) -4- (4- Chlorophenyl ) -2,3,6-trimethyl-1H- Pyrrolo [2,3-b] pyridine -5-yl) -2- Rat - Butoxyacetic acid  Produce

Step 1: (2S) - methyl  2- (1- (1- Oxaspiro [3,5] nonane -2- Yl methyl ) -4- (4- Chlorophenyl ) -2,3,6- Trimethyl -1H- Pyrrolo [2,3-b] pyridine -5-yl) -2- Rat - Butoxyacetate

2,3-b] pyridin-5-ylmethyl) -lH-pyrrolo [2,3-b] (S) -methyl 2-tert-butoxy-2- (4- (4-chlorophenyl) -2,3,6-trimethyl-1H Yl] acetate (200 mg, 0.488 mmol) and 1-oxaspiro [3,5] nonan-2-ylmethyl 4 -Methylbenzenesulfonate (748 mg, 2.41 mmol) was used in the same manner as in step 1 of Example 16, except that the same reagents were used. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain the desired compound (260 mg, 97%).

¹ H-NMR (300 MHz, CDCl ₃ )? Ppm 1.00 (s, 9H), 1.27-1.40 (m, 4H), 1.49 (s, 3H), 1.59-1.81 1H), 4.58 (m, 1H), 2.37 (s, 3H), 2.69 (s, , 5.09 (s, IH), 7.25 (d, J = 8.1 Hz, IH), 7.43 (m, 3H);

MS (EI, m / e) = 553 (M ^< ^{+ &} gt ^; ).

Step 2: (2S) -2- (1- (1- Oxaspiro [3,5] nonane -2- Yl methyl ) -4- (4- Chlorophenyl ) -2,3,6-trimethyl-1H- Pyrrolo [2,3-b] pyridine -5-yl) -2- Rat - Butoxyacetic acid

(2S) -methyl 2-tert-butoxy-2- (4- (chroman-6-yl) -2,3,6-trimethyl- 1- (oxetan- (2S) -methyl 2- (1- (1-oxaspiro [3,5] nonan-2-ylmethyl) - (260 mg, 0.47 mmol) was reacted with 4- (4-chlorophenyl) -2,3,6-trimethyl- lH- pyrrolo [2,3- b] pyridin- Except that the same reagents as in step 2 of Example 1 were used in the same ratio. The obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1) to obtain pure target compound (112 mg, 44.2%) as a white solid.

¹ H-NMR (300 MHz, CD ₃ OD)? Ppm 0.99 (s, 9H), 1.31-1.37 (m, 4H), 1.47 2H), 4.94 (m, IH), 5.14 (s, IH), 7.53 (m, 2H), 2.37 ), 7.59 (m, 1 H);

MS (EI, m / e) = 539 (M ^< ^{+ &} gt ^; ).

Experimental Example  One: HIV -1 inhibitory effect and cytotoxicity test

In order to confirm the HIV-1 inhibitory effect of the compound of the present invention prepared from the above examples, a known method (H. Tanaka et al . , J. Med . Chem . , 1991, 34: 349), and the HIV-1 inhibitory effect in vitro was confirmed as described below. MT-4 cells were used as host cells. After the host cells were infected with HIV-1 and treated with the compound of the present invention, the decrease in cytotoxicity was confirmed.

First, MT-4 cells were dispersed at a concentration of 1 × 10 ⁴ cells / well in the culture medium and inoculated with HIV-1 so that 500 TCI ₅₀ (50% of the cells were infected) / well. Immediately after inoculation, 100 μl of the cell dispersion was dispensed into a flat microtiter plate containing the compound of the present invention, and cultured at 17 ° C for about 4 to 5 days. After that, the virus inhibition effect was confirmed by MTT method. In addition, the survival rate of cells infected with the virus was measured by MTT method to confirm cytotoxicity. As comparative compounds azidothymidine (AZT) and Raltegravir, which are known to inhibit HIV, were used. The results are shown in Table 1 below.

Example Wild type HIV-1 (IIIB) infected MT-4 cells EC ₅₀ (nM) ^* 1 (mixture) 6.31 1 (less polar) 6.37 1 (more polar) 7.00 2 5.68 3 (less polar) 36.0 3 (more polar) 6.07 4 (less polar) 4.57 4 (more polar) 105.8 5 29.3 6 25.83 7 (less polar) 141.9 7 (more polar) 34.4 8 47,972 9 (less polar) 115 10 (less polar) 137.2 10 (more polar) 672.8 11 206.1 12 660 13 30.9 14 6.11 15 (less polar) 7.61 15 (more polar) 501.2 16 24.74 17 5.92 18 (less polar) 5.75 18 (more polar) 130.0 19 28.73 20 (less polar) 22.67 20 (more polar) 5.97 21 56.1 22 5.87 23 136.97 24 109.43 Raltegravir 5.85 AZT 2.24

* EC ₅₀ : 50% inhibition of HIV infection

Experimental Example  2: Pharmacokinetics  exam( pharmacokinetics test )

Experiments were carried out to confirm the changes in the body dynamics such as in vivo absorption, distribution, metabolism and excretion of the compounds of the present invention prepared from the above Examples. A tube was inserted into the jugular vein and femoral vein of the rat. Blood was drawn from the jugular vein at a fixed time after intravenous administration of the femoral vein and oral administration via the oral cavity.

The dose of the drug was 5 mg / kg for intravenous administration and 10 mg / kg for oral administration. The collected blood was centrifuged to separate the plasma, plasma and urine samples were pretreated with appropriate organic solvent, and the concentration was analyzed by LC-MS / MS. Noncompartmental pharmacokinetic parameters were calculated from the blood concentration data of the drug for the time analyzed after oral and intravenous administration using WinNonlin (Pharsight, USA). The above experiment was carried out on the compound of Example 1 and the compound of Example 22, and the results are shown in Tables 2 and 3, respectively.

sample variable IV, 5 mg / kg PO, 10 mg / kg The compound of Example 1
(mixture) T _max - 1.33 C _max (nM) - 7,168 T _1/2 (hr) 6.53 9.84 AUC _t (nM · hr) 48,992 41,548 AUC _∞ (nM · hr) 50,665 48,957 CL (L / kg / hr) 0.107 - V _ss (L / kg) 0.227 - F (%) 42.4

sample variable IV, 5 mg / kg PO, 10 mg / kg The compound of Example 22 T _max - 3 C _max (nM) - 10,943 T _1/2 (hr) 7.93 7.2 AUC _t (nM · hr) 65,670 61,786 AUC _∞ (nM · hr) 69,395 66,745 CL (L / kg / hr) 0.143 - V _ss (L / kg) 0.685 - F (%) 47

Experimental Example  3: Metabolic stability test ( metabolic stability test )

The metabolic stability test for the compounds of the present invention prepared from the above examples was conducted. Metabolic stability was measured after 30 minutes in the lever microsomal. The remaining percentage was measured and reacted with NADPH using species-specific (rat, dog and human) lever microsomes containing various metabolic enzymes and analyzed by LC-MS / MS The stability of the drug was confirmed by quantitative analysis. The stability criterion according to the remaining% value of the test substance after 30 minutes of reaction can be judged as a stable compound having a half-life of 3 hours or more in the case of > 90% and a stable compound with a half life of 1 to 3 hours in the case of 70 to 90% have. The compound of Example 1 of the present invention showed a residual ratio of about 90%, confirming that it is a stable compound having a half-life of not less than 3 hours.

compound Rat (%) Dogs (%) human (%) The compound (mixture) of Example 1 86 ± 3.41 92.6 ± 3.17 89 ± 4.0 The compound of Example 22 83.4 ± 7.89 > 99 89.7 ± 1.12 The control (buspirone) 1.57 + - 0.277 5.27 ± 1.12 5.8 ± 1.94

Experimental Example  4: CYP450  Inhibition test

The CYP450 inhibition test on the compounds of the present invention prepared from the above examples was carried out. In general, inhibition of CYP450 by 50% or more at 10 μM can be considered to inhibit CYP. As shown in the following Table 5, it was confirmed that the compound of Example 1 did not inhibit the activity of the enzymes because the inhibitory concentrations of CYP1A2, CYP2C9, CYP2D6, CYP3A4 and CYP2C19 were less than 50% at 10 μM . CYP450 BACULOSOMES ^® samples were microsomes extracted from insect cells expressing human P450 isozyme and rabbit NADPH-P450 reductase. The water soluble fluorescent substance contained in the Vivid ^® substrate was added and the change by specific CYP enzymes was measured.

compound 1A2 2C9 2D6 3A4 2C19 The compound (mixture) of Example 1 0.9 36.9 33.0 0.0 0.0 Inhibitors ^* 92.4 99.0 98.4 81.6 94.2

* 1A2: alpha -naphthoflavone, 2C9: sulfaphenazole, 2D6: quinidine, 3A4: ketoconazole, 2C19: amitriptyline

Experimental Example  5: hERG  K ⁺  Channel activity test

The hERG K ⁺ channel activity test was performed to confirm the cardiac toxicity of the compounds of the present invention prepared from the above examples. The hERG activity of the compounds was measured with HERG-HEK293 using an automated planar patch clamp (PatchXpress 7000A). The method directly measures the flow of ions through the channel using voltage clamps as a representative ion channel study method. IC ₅₀ values of the measured hERG K ⁺ channel for the compounds of the invention was 82.80 μM, it is determined IC ₅₀ value of 10 μM or less as being potentially exhibit cardiac toxicity, the compounds of the invention exhibit cardiac toxicity But it is a safe compound.

compound IC ₅₀ ([mu] M) The compound (mixture) of Example 1 85.1 The control (astemizole) 0.079

Experimental Example  6: Solubility test

The solubilities of the compounds of the present invention prepared from the above examples were measured using UPLC (Waters). An excess amount of each sample was added to a buffer solution of pH 2 and pH 7.4 in a shaking-flask, followed by shaking for 24 hours, and quantitative solubility was calculated by plotting a calibration curve using UPLC.

compound pH 2.0 pH 7.4 The compound of Example 1
(mixture) 1,120 ± 51 μM
(304 ± 13.8 μg / ml) > 3,000 μM
(813 [mu] g / ml)

Claims (11)

A compound represented by Formula 1 below; Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof:
[Chemical Formula 1]

In this formula,
L ₁ is a direct bond or C _{1 -6} alkanediyl;
L ₂ is a bond or C _{3 -10} cycloalkyl alkanediyl gt;
R ₁ is oxetanyl, said oxetanyl being unsubstituted or substituted with 1 to 3 substituents each selected from the group consisting of C _{1 -6} alkyl, C _{3 -10} cycloalkyl or halogen;
R ₂ and R ₃ are each independently hydrogen, C _{3 -10} cycloalkyl, or C _{1 -6} alkyl;
R ₄ is selected from the group consisting of hydrogen, halogen, aryloxy, arylamino, thioaryl, aryl, chromanyl, 3,4-dihydro-2H- benzo [b] [1,4] oxazinyl, 4- (piperidin- Benzo [b] [1,4] thiophen-2-yl, phenyl or 2,3-dihydropyrano [4,3,2-de] quinolinyl, wherein the aryl, chromanyl, 3,4- ] Oxazinyl, 4- (piperidin-1-yl) phenyl or 2,3-dihydropyrano [4,3,2-de] quinolinyl is unsubstituted or substituted by amino, halogen, , CF _3, C _{1 -6} alkyl and C _{1 -6} alkoxy is substituted with 1 to 3 substituents each selected from the group consisting of;
R ₅ is a substituted C ₁ to C _-6 alkoxy, unsubstituted or C _{1 -6} alkyl group _3-10 cycloalkoxy, or C _{1 - 6} alkyl;
R ₆ is C _{1 -6} alkyl, C _{3 -10} cycloalkyl, C _{1 -6} alkoxy, halogen atom, or CN.
The method according to claim 1,
If L ₂ is C _{3 -6} cycloalkyl alkanediyl yl, the compound to bond to the R ₁ and spiro form; Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof.
The method according to claim 1,
L ₁ is C _{1 -6} alkanediyl;
L ₂ is a bond or C _{3 -6} cycloalkyl alkanediyl gt;
R ₁ is oxetanyl, said oxetanyl being unsubstituted or substituted with 1 to 3 substituents each selected from the group consisting of C _{1 -6} alkyl or C _{3 -10} cycloalkyl;
R ₂ and R ₃ are each independently C _{1 -6} alkyl;
R ₄ is aryl, chromanyl, 3,4-dihydro-2H-benzo [b] [1,4] oxazinyl or 4- (piperidin- , 4-dihydro -2H- benzo [b] [1,4] oxazole or possess 4- (piperidin-1-yl) phenyl are each selected from the group consisting of unsubstituted or halogen or C _{1 -6} alkyl Beach ≪ / RTI >
R ₅ is C _{1 -6} alkoxy;
The compound R ₆ is a C _{1 -6} alkyl; Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof.
The method according to claim 1,
L ₁ is methanediyl or ethanediyl;
L ₂ is a direct bond or cyclobutanediyl;
R ₁ is oxetanyl which is unsubstituted or substituted with one to three substituents each selected from the group consisting of methyl, cyclobutyl or cyclohexyl, said cyclobutyl or cyclohexyl being bonded in the spiro form;
R ₂ and R ₃ are each methyl;
R ₄ is phenyl, chromanyl, 3,4-dihydro-2H-benzo [b] [1,4] oxazinyl or 4- (piperidin- Benzo [b] [1,4] oxazinyl or 4- (piperidin-1-yl) phenyl is unsubstituted or substituted with at least one group selected from the group consisting of methyl, chloride or fluoride Substituted with one to two substituents;
R ₅ is a tert-butoxy;
R < ₆ > is methyl; Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof.
5. The method of claim 4,
R ₁ is selected from oxetan-2-yl, oxetan-3-yl, 2-methyl-oxetan-2-yl, 4-methyl- Yl, 1-oxaspiro [3,3] heptan-2-yl or 1-oxaspiro [3,5] nonan-2-yl; Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof.
The method according to claim 1,
The compound represented by the formula (1)

,

,

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Lt; / RTI > Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof.
Reacting a compound represented by the following formula (2) with a compound represented by the following formula (3) to prepare a compound represented by the following formula (4); And
And a second step of hydrolyzing a compound represented by the following formula (4): < EMI ID =
A process for producing a compound represented by the following formula (1)
[Chemical Formula 1]

(2)

(3)

[Chemical Formula 4]

In this formula,
L ₁ , L ₂ and R ₁ to R ₆ are as defined in claim 1,
R ₇ is a C _{1 -6} alkyl,
X is halogen, methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl.
8. The method of claim 7,
R < ₇ > is methyl or ethyl,
And X is halogen.
A compound represented by the general formula (1) of any one of claims 1 to 6; Stereoisomers or racemates thereof; A pharmaceutically acceptable salt thereof; Or a solvate thereof as an active ingredient.
10. The method of claim 9,
0.0 > viral < / RTI > infection.
11. The method of claim 10,
Wherein the virus is a human immunodeficiency virus.