KR20140100817A - 7H-Pyrrolo[2,3-d]pyrimidine-4-thiol derivatives using as JAK-3 inhibitors - Google Patents

Abstract

The present invention relates to a method for preparing a novel 7H-pyrrolo[2,3-d]pyrimidine-4-thiol derivative or a pharmaceutically acceptable salt thereof, and to a pharmaceutical composition containing the same as an active ingredient. The composition containing the novel 7H-pyrrolo[2,3-d]pyrimidine-4-thiol derivative according to the present invention can be useful for preventing or treating diseases caused by the overactivity of a Janus kinase (JAK).

Description

Pyrrolidine 2,3-d pyrimidine-4-thiol derivatives using as JAK-3 inhibitors useful as JAK-3 inhibitors.

The present invention relates to novel 7 H - relates to a pharmaceutical composition of pyrrolo [2,3- d] pyrimidin-4-thiol derivative, or a pharmaceutically acceptable salt thereof and a method for manufacturing this active ingredient.

Janus kinase (hereinafter referred to as 'JAK') is a cytoplasmic protein tyrosine kinase that plays a pivotal role in regulating cell function in the lympho-hematopoietic system. JAK activates STAT (signal transducer and activator of transcription, signal transduction and transcription factor activation) proteins through tyrosine phosphorylation to provide a rapid signaling pathway to cytokines. JAK / STAT signaling is known to be associated with allergies, asthma, autoimmune diseases (such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis, multiple sclerosis), solid tumors, blood cancers (e.g. leukemia, lymphoma etc.) .

The JAK (Janus kinase) family is classified into four types such as JAK1, JAK2, JAK3, and Tyk2. JAK1, JAK3, and Tyk2 are found throughout the expression, whereas JAK3 is found mainly in hematopoietic cells. JAK3 specifically binds to the gamma chain of interleukin receptors of IL-2, IL-4, IL-7, IL-9, IL-13 and IL-15 and is therefore important for the proliferation and differentiation of T lymphocytes. It plays a role.

JAK3 inhibitors have been shown to be effective in cancer (tumor), graft rejection, autoimmune and inflammatory diseases, proliferative diseases and the like, as revealed through animal experiments to date.

Diseases that can be treated and prevented by the JAK3 inhibitor are specifically selected from the group consisting of cancer, transplant rejection, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, psoriasis, asthma, allergic dermatitis, atopic dermatitis, eczema, type I diabetes, diabetic complications, Ulcerative colitis, Crohn's disease, and autoimmune thyroid disease. Currently, several pharmaceutical companies have made efforts to develop new drugs with selective inhibitory activity against JAK3, especially among JAK families.

Insight Corporation (INCYTE CORPORATION) by the International Patent Publication WO2007 / 070514 in the call to the 7 H- pyrrolo [2,3- d] pyrimidine compound 4-allyl-substituted heteroaromatic of the formula A which discloses the usefulness as JAK inhibitors There is a bar.

 (A)

(In the formula (A), Het represents a 5-membered heteroaromatic ring containing a nitrogen atom)

In addition, the Palau Pharma S. A. (PALAU PHARMA, SA) is to in International Publication Patent No. WO2008 / 119792 4- heterocyclic represented by the formula B substituted 7 H- pyrrolo [2,3- d] pyrimidine compounds JAK inhibitors. ≪ / RTI >

 [Chemical Formula B]

(In the above formula (B), Het represents a 6-membered heterocyclic ring containing a nitrogen atom)

Also, Pfizer, Inc. (PFIZER INC.) Is a substituted 4 represented by the following formula (C) in International Patent Publication WO 2010/020905 amino substituted 7 H- pyrrolo [2,3- d] pyrimidine compounds JAK Lt; RTI ID = 0.0 > inhibitor. ≪ / RTI >

 ≪ RTI ID = 0.0 &

As described above, in the prior art, a heteroaryl group containing a nitrogen (N) hetero atom at the C4 position of the 7 H -pyrrolo [2,3- d ] pyrimidine mother nucleus, a heterocyclic group, Lt; RTI ID = 0.0 > JAK < / RTI > inhibitor.

However, as characterized by the present invention, a compound in which a sulfide group (-SR) is introduced at the C4 position of the 7 H -pyrrolo [2,3- d ] pyrimidine mother nucleus corresponds to a novel compound which has not been reported in the literature And there is no example of confirming the activity as a JAK inhibitor against a 4-sulfide substituted 7H -pyrrolo [2,3- d ] pyrimidine compound.

It is an object of the present invention to provide novel compounds selected from 7H -pyrrolo [2,3- d ] pyrimidin-4-thiol derivatives and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a process for producing the novel compounds.

It is another object of the present invention to provide a pharmaceutical composition comprising said novel compound as a JAK3 inhibitor.

In order to achieve the above object, the present invention is characterized by a 7H -pyrrolo [2,3- d ] pyrimidine-4-thiol derivative represented by the following formula 1 or a pharmaceutically acceptable salt thereof .

[Chemical Formula 1]

In Formula 1,

;

; 또는

를 나타내고, R is-CH (Ar) ₂ ;

;

; or

Lt; / RTI >

R ¹ is mono (C ₁ -C ₁₀ Alkyl) amino group; Or di (C ₁ -C ₁₀ Alkyl) amino group,

R ² is C ₁ -C ₆ An alkyl group; Diphenylmethyl group; A C ₂ -C ₁₀ alkenyl group; C ₁ -C ₆ An alkylcarbonate group; A C ₃ -C ₁₅ cyclic alkyl group; A C ₃ -C ₁₂ heterocyclic alkyl group containing 1 to 2 nitrogen heteroatoms; C ₁ -C ₆ A benzyl group substituted or unsubstituted with 1 to 3 substituents selected from alkyl; Or halo, cyano, nitro, C ₁ -C ₆ Alkyl and C ₁ -C ₆ Alkoxy, < / RTI > and < RTI ID = 0.0 >

R ³ is a halogen atom; Halo, C ₁ -C ₆ A phenyl group substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of alkyl and C ₁ -C ₆ alkoxy; Or a C ₅ -C ₁₂ heteroaryl group containing 1 to 2 hetero atoms selected from O, S and N,

Het represents a C ₃ -C ₁₂ heterocyclic alkyl group containing 1 to 2 nitrogen atoms,

Ar is C ₆ -C ₁₅ An aryl group,

l represents an integer of 1 to 6,

m represents an integer of 0 to 6,

n represents an integer of 0 to 6,

q represents an integer of 0 to 6 as the number of substituents.

The present invention also relates to a 7H -pyrrolo [2,3- d ] pyrimidine-4-thiol derivative represented by the above formula (1) or a pharmaceutically acceptable salt thereof as a JAK3 inhibitor Characterized by a pharmaceutical composition.

The compound of the present invention shows inhibitory activity against Janus kinase (JAK), and is particularly useful for the treatment, prevention or alleviation of diseases and / or disorders caused by overactivity of JAK3, Do.

The diseases caused by overactivity of JAK3 may include cancer (tumor), graft rejection, autoimmune and inflammatory diseases, proliferative diseases, and the like. Specifically, cancer, transplant rejection, multiple sclerosis, rheumatoid arthritis, , Psoriasis, asthma, allergic dermatitis, atopic dermatitis, eczema, type I diabetes, diabetic complications, ulcerative colitis, Crohn's disease, autoimmune thyroid disorders and the like.

The present invention relates to a 7H -pyrrolo [2,3- d ] pyrimidine-4-thiol derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof or a process for producing these compounds, The present invention relates to a pharmaceutical composition containing as an active ingredient.

[Chemical Formula 1]

In Formula 1,

;

; 또는

를 나타내고, R is-CH (Ar) ₂ ;

;

; or

Lt; / RTI >

R ¹ is mono (C ₁ -C ₁₀ Alkyl) amino group; Or di (C ₁ -C ₁₀ Alkyl) amino group,

R ² is C ₁ -C ₆ An alkyl group; Diphenylmethyl group; A C ₂ -C ₁₀ alkenyl group; C ₁ -C ₆ An alkylcarbonate group; A C ₃ -C ₁₅ cyclic alkyl group; A C ₃ -C ₁₂ heterocyclic alkyl group containing 1 to 2 nitrogen heteroatoms; C ₁ -C ₆ A benzyl group substituted or unsubstituted with 1 to 3 substituents selected from alkyl; Or halo, cyano, nitro, C ₁ -C ₆ Alkyl and C ₁ -C ₆ Alkoxy, < / RTI > and < RTI ID = 0.0 >

R ³ is a halogen atom; Halo, C ₁ -C ₆ A phenyl group substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of alkyl and C ₁ -C ₆ alkoxy; Or a C ₅ -C ₁₂ heteroaryl group containing 1 to 2 hetero atoms selected from O, S and N,

Het represents a C ₃ -C ₁₂ heterocyclic alkyl group containing 1 to 2 nitrogen atoms,

Ar is C ₆ -C ₁₅ An aryl group,

l represents an integer of 1 to 6,

m represents an integer of 0 to 6,

n represents an integer of 0 to 6,

q represents an integer of 0 to 6 as the number of substituents.

The substituent used to define the compound represented by Formula 1 according to the present invention will be described in more detail as follows.

The 'halogen atom' in the present invention means a fluorine, chlorine, bromine, iodine atom.

"Alkyl" in the present invention is a group a straight chain, the carbon on the grinding chain having from one to ten carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert - butyl And the like.

The 'alkenyl group' in the present invention is a carbon chain group having 2 to 10 carbon atoms and containing at least one unsaturated bond, and examples thereof include an allyl group, a propenyl group, a butenyl group, a 1,3- Hexene diol, and the like.

The 'cyclic alkyl group' in the present invention is a carbon chain group having 3 to 12 carbon atoms and composed of a single ring, a naphtha ring or a three ring. Examples thereof include a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a bicyclo [ 2.2.1] heptan-2-yl group, bicyclo [3.2.0] octan-3-yl group, adamantyl group and the like.

The 'cyclic alkenyl group' in the present invention is a carbon chain group having 3 to 12 carbon atoms and composed of a single ring, a naphtha ring or a three ring containing at least one unsaturated bond. Examples thereof include a cyclohexene group, Dienes, cyclooctyl groups, and the like.

The 'heterocyclic alkyl group' in the present invention is a carbon chain group having 3 to 12 carbon atoms and containing from 1 to 4 hetero atoms selected from N, O and S, and consisting of a single ring, For example, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinonyl, piperidinoyl, isoindolidionyl, dioxanyl, dioxolanyl, benzo Diazinyl, chromanyl, azepanyl, diazepanyl, 8-azabicyclo [3.2.0] octan-3-yl, and the like.

The 'aryl group' in the present invention is an aromatic carbon chain group of a single ring, a bivalent or a triple ring including 6 to 15 carbon atoms, and examples thereof include a phenyl group, a biphenyl group, a naphthalene group, an anthracenyl group, Fluorenyl group, indanyl group, and the like.

The 'heteroaryl group' in the present invention is an aromatic heterocyclic group having 4 to 12 carbon atoms consisting of a single ring, a nugget or a three ring, containing 1 to 4 hetero atoms selected from N, O and S, Such as pyrrolyl, furyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl , Pyridinyl, pyrazinyl, triazinyl, pyridazinyl, pyrimidinyl, triazolyl, indolyl, indolizinyl, isoindolyl, benzofuryl, benzofurazanyl, dibenzofuryl, isobenzofuryl, Benzyloxazolyl, benzothiazolyl, dibenzothiophenyl, naphthyridyl, benzisothiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzothiazolyl, , The wheel Phenanthrenyl, phenanthridinyl, phenanthridinyl, phenanthrolinyl, phenanthrolinyl, phenanthrolinyl, phenanthrolinyl, phenanthrolinyl, phenanthrolinyl and the like.

In the compound represented by Formula 1 according to the present invention, Het as the heterocyclic alkyl group is preferably a piperidinyl group, a piperazinyl group, a 1,2-diazepanadiyl group, a 1,3-diazepanadiyl group, Diazepanyl group, or 8-azabicyclo [3.2.0] octan-3-yl group. As the aryl group, Ar preferably represents a phenyl group, a naphthalenyl group, or a fluorenyl group.

In the compound represented by Formula 1 according to the present invention, more preferably, R is a benzhydryl group, a 1- (dimethylamino) propyl group, a 3- (dimethylamino) propyl group, Cyclo [3.2.0] octane-3-yl group, 8-methyl-8-azabicyclo [3.2.0] Azabicyclo [3.2.0] octan-3-yl group, methyl 8-azabicyclo [3.2.0] octane-8-carboxylate group, ethyl 8-azabicyclo [3.2. Octa-8-carboxylate group, a tert -butyl 8-azabicyclo [3.2.0] octane-8-carboxylate group, a piperidin-1-yl group, a piperidin- Methyl-piperidin-4-yl group, a piperidin-1-ylbutyl group, a piperidine-4-yl group, (4-cyclohexylpiperazin-1-yl) butyl group, 4- [4- (diphenylmethyl) piperazine 1-yl] butyl group, 4- (4-benzylpiperazin-1-yl) 1-yl) butyl group, 4- (4- (4-nitrophenyl) piperazin-1-yl) 1-yl] butyl group, 4- [4- (2-tolyl) piperazin-1-yl] Yl] butyl group, 4- [4- (3-methoxyphenyl) piperazin-1-yl] Piperazin-1-yl] butyl group, 4- [4- (2-methylbenzyl) piperazin-1-yl] Butyl group, a 2-chlorophenyl group, a 2-fluorophenyl group, a 3-bromophenyl group, a 4-chlorophenyl group, a 4-chlorophenyl group, Fluorobenzyl group, 2-chlorobenzyl group, 2-fluorobenzyl group, 3-bromobenzyl group, 4-chlorobenzyl group, 2,6-difluorobenzyl group, 3- , 4- (2-fluorophenyl) benzyl group, 4- (3-fluoro Benzyl group, 4- (2-methoxyphenyl) benzyl group, 4- (2-tolyl) benzyl group, 4- 3-methoxyphenyl) benzyl group, a 4- (4-methoxyphenyl) benzyl group, a 4- (thiophen-2-yl) benzyl group, a naphthalenyl group, a naphthalenemethyl group and a fluorenyl group / RTI >

The compound represented by the formula (1) according to the present invention is specifically exemplified as follows:

1) 4- (Naphthalen-2-ylmethylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

2) 4- (3-Bromobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

3) 4- (4-Chlorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

4) 4- (2,6-Difluorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

5) 4- (2-fluorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

6) 4- (9 H - fluoren-9-yl thio) -7 H- pyrrolo [2,3- d] pyrimidine;

7) 4- (Benzhydrylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

8) 4- (Biphenyl-3-ylmethylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

9) 4- (2-chlorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

10) 4- ( 7H -Pyrrolo [2,3- d ] pyrimidin-4-ylthio) -N , N -dimethylpropan-1- amine;

11) 2- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -N , N -dimethylpropan-1- amine;

12) 4- (1-Methylpiperidin-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

13) 4 - ((3'-fluorobiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

14) 4 - ((2'-fluorobiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

15) 4 - ((3'-Methylbiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

16) 4 - ((4'-Methylbiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

17) 4- (4 '- (Thiophen-2-yl) benzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

18) 4 - ((2'-methoxybiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

19) 4- (4- (4-Cyclohexylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

20) 4- (4- (4-phenylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

21) 4- (4- (4-Benzhydrylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

22) 4- (4- (4-Benzylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

23) 4- (4- (4- (2-Methoxyphenyl) piperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

24) 4- (4- (4- m -Tolylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

25) 4- (4- (4- p -Tolylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

26) 4- (4- (4- (2,4,6-trimethylbenzylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

27) 2- (4- (4- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) butyl) piperazin-1-yl) benzonitrile;

28) 4- (4- (4- (2-fluorophenyl) piperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

29) 4- (4- (4-Benzyl-1,4-diazepan-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

30) 4- (4- (4- (4-Nitrophenyl) piperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

31) endo- tert -butyl-3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8- azabicyclo [3.2.1] octane- 8-carboxylate;

32) exo- tert -butyl-3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8- azabicyclo [3.2.1] octane-8-carboxylate;

33) Endo-4- (8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine dihydrochloride;

34) exo-4- (8-Azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine dihydrochloride;

35) Endo-4- (8-methyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

36) exo-4- (8-methyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine;

37) Endo-ethyl 3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8- azabicyclo [3.2.1] octane-8-carboxylate;

38) exo-ethyl 3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8- azabicyclo [3.2.1] octane-8-carboxylate;

39) Endo-4- (8-benzyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine; And

40) Endo-4- (8-allyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine.

The compound represented by Formula 1 according to the present invention may form a pharmaceutically acceptable salt by a conventional method in the art. Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The expression pharmaceutically acceptable salt means a salt which is relatively non-toxic to the patient and has a harmless effective action, and a side effect caused by this salt does not impair the beneficial effect of the base compound of the compound represented by the above formula (1) . As these salts, inorganic acids and organic acids can be used. Examples of the inorganic acid include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid, and phosphoric acid. Examples of the organic acid include citric acid, acetic acid, lactic acid, maleic acid, fumaric acid, gluconic acid, methanesulfonic acid, gluconic acid, succinic acid, tartaric acid, galacturonic acid, embic acid, glutamic acid, aspartic acid, oxalic acid, - or (L) -malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, 4-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid. These salts also include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, the acid addition salt may be an acid, an aspartate, a benzoate, a besylate, a bicarbonate or a carbonate, a bisulfate or a sulfate, a borate, a camylate, a citrate, an eddylate, an ethylate, a formate, Gluconate, gluconate, gluconate, gluconate, glucuronate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride or chloride, hydrobromide or bromide, hydroiodide or iodide, isethionate, lactate, Nitrates, oleates, oxalates, palmitates, pamoates, phosphates or hydrogen phosphates or dihydrophosphates, alkanes, such as methanesulfonate, methanesulfonate, Lactate, stearate, succinate, tartrate , Tosylate, trifluoroacetate, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, oleamine, potassium, sodium, tromethamine, zinc salts Etc., among which hydrochloride or trifluoroacetate is preferred.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound represented by Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile or the like, Or an acid aqueous solution of an inorganic acid, followed by precipitation or crystallization. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.

In addition, the compound represented by Formula 1 according to the present invention includes not only pharmaceutically acceptable salts, but also all salts, isomers, hydrates and solvates which can be prepared by conventional methods.

Meanwhile, the present invention encompasses a method of preparing the compound represented by Formula 1 as a scope of the present invention.

The production process according to the present invention can be carried out by including a two-step process as shown below.

Step 1: A process for preparing a thiol compound represented by the following formula (3) by reacting a chloro compound represented by the following formula (2) with thiourea; And

Step 2: reacting a thiol compound represented by the following formula (3) with a halide compound represented by RX (wherein R is as defined in the above formula (1) and X is a halogen atom) 7 H- pyrrolo [2,3- d] the process for producing a pyrimidin-4-thiol derivative.

(Wherein R is as defined in the above formula (1)

The manufacturing method according to the present invention will be described in detail as follows.

First step process

The first step according to the present invention is a step of preparing the thiol compound represented by Formula 3 by reacting the chloro compound represented by Formula 2 as the starting material with thiourea.

The chloro compound represented by the above formula (2) used as a starting material in the present invention can be obtained as a commercially available product or synthesized by a method known in the art.

The above-mentioned one-step reaction is generally well known in the field of organic chemistry, and the reaction conditions such as reaction solvent, reaction temperature, reaction time and the like can be appropriately selected in consideration of the reactant and the produced material. As the first-step reaction solvent, acetonitrile, N , N -dimethylformamide, and ethanol may be used. In the present invention, ethanol may be used. As the base catalyst, conventional inorganic or organic bases can be used. In the present invention, an alkali metal carbonate such as potassium carbonate can be used as an inorganic base, and a mono-, di- or tri-C ₁ -C ₆ alkylamine such as triethylamine can be used as an organic base. The reaction temperature may be maintained at a heating temperature of from 50 캜 to 90 캜.

The second stage process

The 2-step process according to the present invention comprises reacting the thiol compound represented by Formula 3 with a halide compound represented by RX to obtain 7H -pyrrolo [2,3- d ] pyrimidine represented by Formula 1 4-thiol derivative.

The above two-step reaction is generally well known in the field of organic chemistry, and the reaction conditions such as reaction solvent, reaction temperature, reaction time and the like can be appropriately selected in consideration of the reactant and the produced material. As the two-step reaction solvent, anhydrous acetonitrile, anhydrous N , N -dimethylformamide or anhydrous tetrahydrofuran can be used. In the present invention, anhydrous N , N -dimethylformamide can be used. As the base catalyst, conventional inorganic or organic bases can be used. In the present invention, an alkali metal carbonate such as potassium carbonate can be used as an inorganic base, and a mono-, di- or tri-C ₁ -C ₆ alkylamine such as triethylamine can be used as an organic base. The reaction temperature may be maintained at a heating temperature of from 50 캜 to 90 캜.

Meanwhile, the 7H -pyrrolo [2,3- d ] pyrimidine-4-thiol derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention is very effective as a JAK3 activity inhibitor. Accordingly, the present invention encompasses a pharmaceutical composition containing the novel compound represented by Formula 1 as an active ingredient, for the prophylaxis or treatment of diseases caused by hyperactivity of JAK3. The diseases caused by hyperactivity of JAK3 may include transplant rejection, autoimmune and inflammatory diseases, proliferative diseases and the like. Specific examples of the diseases caused by hyperactivity of JAK3 include transplant rejection, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, psoriasis, asthma, allergic dermatitis, atopic dermatitis, eczema, type I diabetes, diabetic complication, Chronic colitis, Crohn's disease, autoimmune thyroid disease, and the like.

The pharmaceutical composition of the present invention may be prepared by adding a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient to the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof to prepare pharmaceutical preparations such as tablets, Capsules, troches, liquids, suspensions, and the like, or parenterally administrable formulations.

Examples of the formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and the like. These formulations may contain, in addition to the active ingredient, a diluent such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, a lubricant such as silica, talc, stearic acid and its magnesium or calcium salt and / Or polyethylene glycol). The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine, optionally mixed with starch, agar, alginic acid or its sodium salt The same disintegrating or boiling mixture and / or absorbing agent, coloring agent, flavoring agent, and sweetening agent.

Examples of the formulations for parenteral administration include injections such as subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. In this case, in order to formulate the formulation for parenteral administration, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, .

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

The dose of the compound represented by Formula 1 may be varied depending on the patient's age, body weight, sex, dosage form, health condition, and disease severity. When the adult patient having a body weight of 70 kg is used , Generally 0.1 to 1,000 mg / day, preferably 1 to 500 mg / day, and may be administered once to several times a day at predetermined intervals according to the judgment of a doctor or pharmacist.

The present invention as described above will be described in more detail through the following Production Examples, Examples and Experimental Examples. However, the production examples, examples and experimental examples of the present invention exemplify the present invention, and the content of the present invention is not limited by the following production examples, examples and experimental examples.

[Manufacturing Example]

Production Example 1. Preparation of 7H -pyrrolo [2,3- d ] pyrimidin-4-thiol

6-Chloro-7-deazapurine (200 mg, 1.302 mmol) was added to ethanol (5 mL) and the mixture was stirred at 80 째 C and then thiourea (119 mg, 1.563 mmol) was added and reacted for 3 hours. The solvent was removed and the resulting mixture under reduced pressure, and then solidified using acetonitrile and filtered to 7 H- pyrrolo [2,3- d] pyrimidine to give a 4-thiol (92.4%).

^{1 H NMR (400 MHz, CDCl} 3) δ 6.59-6.61 (t, J = 3.3 Hz, 1H), 7.26-7.28 (t, J = 2.6 Hz, 1H), 8.02-8.06 (d, J = 3.7 Hz, 1H), 12.20 (s, 1H), 13.30 (s, 1H)

Preparation Example 2. Preparation of 4- (4-bromobutylthio) -7H -pyrrolo [2,3- d ] pyrimidine

Dimethylformamide was stirred at 7 H- pyrrolo [2,3- d] pyrimidin-4-put the thiol (300 mg, 1.984 mmol) 85 ℃ to (5 mL), triethylamine (1.66 mL , 11.91 mmol) and 1,4-dibromobutane (1.41 mL, 11.91 mmol) were added and reacted for 24 hours. The solvent was removed from the resulting mixture under reduced pressure, and the reaction mixture was extracted with dichloromethane (40 mL), dried using anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The obtained organic layer was purified by silica gel flash column chromatography (ethyl acetate: hexane = 1: 4) to give 4- (4-bromobutylthio) -7H -pyrrolo [2,3- d ] pyrimidine (88.5% ).

^{1 H NMR (400 MHz, CDCl} 3) δ 1.94-1.99 (m, 2H), 2.03-2.08 (m, 2H), 3.40-3.44 ( t, J = 6.9 Hz, 2H), 3.46-3.49 (t, J = 6.9 Hz, 2H), 6.55-6.56 (d, J = 6.5 Hz, 1H), 7.25- 7.26 (t, 1H), 8.67 (s, 1H), 10.54 (bs, 1H)

Preparation 3. Preparation of tert -butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate

After dissolving nortropinone hydrochloride (50 mg, 3.093 mmol) in dichloromethane (10 mL), triethylamine (1.08 mL, 7.734 mmol) was added and the mixture was reacted at 0 ° C. Then, di - tert - butyl dicarbonate (743 mg, 3.043 mmol) was added thereto, followed by reaction for 3 hours. The resulting mixture was extracted with dichloromethane (40 mL), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The obtained organic layer was purified by silica gel flash column chromatography (ethyl acetate: hexane = 1: 5) to obtain tert -butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (94.5% Respectively.

¹ H NMR (400 MHz, CDCl ₃ )? 1.50 (s, 9H), 1.67-1.68 (d, J = 7.8 Hz, 2H), 2.09-2.10 (m, 2H), 2.32-2.36 (d, J = 7.8 Hz, 2H), 2.51-2.82 (m, 2 H), 4.33 - 4.58 (m, 2H)

Preparation 4. Preparation of tert -butyl 3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate

To a solution of tert -butyl 3-oxo-8-azabicyclo [3.2.1] octane-8-carboxylate (700 mg, 3.107 mmol) in methanol (10 mL) 579 mg, 1.554 mmol) and sodium borohydride (58.1 mg, 1.554 mmol) were added and reacted for 12 hours. 5 mL of a saturated ammonium chloride solution was added thereto and reacted for 30 minutes. The solvent was removed from the resulting mixture under reduced pressure, and the reaction mixture was extracted with dichloromethane (40 mL), dried using anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The obtained organic layer was purified by silica gel flash column chromatography (ethyl acetate: hexane = 1: 4) to obtain tert -butyl 3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate.

^{1 H NMR (400 MHz, CDCl} 3, endo isomer) δ 1.46 (s, 9H), 1.55-1.63 (m, 2H), 1.66-1.75 (m, 2H), 1.89-2.21 (m, 5 H), 4.07 - 4.26 (m, 3H)

¹ H NMR (400 MHz, CDCl ₃ , exo isomer)? 1.42-1.43 (d, J = 5.8 Hz, 1H), 1.47 (s, 9H), 1.58-1.64 (m, 3H), 1.93-1.96 (m, 4H), 4.16-4.34 (m, 2H), 4.71-4.78 (m, 2H)

Preparation 5. Preparation of tert -butyl 3- (methylsulfonyloxy) -8-azabicyclo [3.2.1] octane-8-carboxylate

To a solution of tert -butyl 3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate (2 g, 8.80 mmol) and triethylamine (1.84 mL, 13.20 mmol) in dichloromethane (10 mL) Was added and stirred at 0 ° C, methanesulfonyl chloride (0.817 mL, 10.56 mmol) was added and reacted for 2 hours. The solvent was removed from the resulting mixture under reduced pressure, and the reaction mixture was extracted with dichloromethane (40 mL), dried using anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The obtained organic layer was purified by silica gel flash column chromatography (ethyl acetate: hexane = 1: 4) to obtain tert -butyl 3- (methylsulfonyloxy) -8-azabicyclo [3.2.1] octane-8-carboxylate 92.4%).

¹ H NMR (400 MHz, CDCl ₃ , endo isomer)? 1.46 (s, 9H), 1.57-1.62 (m, 2H), 1.95-2.05 (m, 4H), 2.10-2.30 (m, 2 H), 3.01 (s, 3 H), 4.12 - 4.32 (m, 2H), 5.01-5.06 (m, 1 H)

¹ H NMR (400 MHz, CDCl ₃ , exo isomer)? 1.48 (s, 9H), 1.53-1.62 (m, 2H), 1.64-1.72 (m, 2H), 1.78-2.18 (m, 5 H), 3.01 (s, 3 H), 4.18 - 4.37 (m, 1 H), 5.02 (m, 1 H)

[Example]

Example 1. Preparation of 4- (naphthalen-2-ylmethylthio) -7H -pyrrolo [2,3- d ] pyrimidine

Acetonitrile (3 mL) for 7 H- pyrrolo [2,3- d] pyrimidin-4-thiol (50 mg, 0.331 mmol) and put into a potassium carbonate (457 mg, 3.307 mmol) was stirred at 80 ℃ After the addition, 2-bromomethylnaphthalene (73.2 mg, 0.331 mmol) was added and reacted for 8 hours. The solvent was removed from the resulting mixture under reduced pressure. The reaction mixture was extracted with ethyl acetate (60 mL), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The obtained organic layer was purified by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) to obtain 4- (naphthalen-2-ylmethylthio) -7H -pyrrolo [2,3- d ] pyrimidine 91.3%).

¹ H NMR (400 MHz, CDCl ₃ )? 4.81 (s, 2H), 6.46-6.47 (d, J = 3.5 Hz, 1H), 7.46-7.48 (m, 3H), 7.49-7.50 (d, J = 3.6 Hz, 1H), 7.86-7.88 (dd, J = 5.4 Hz, 3H), 7.98 bs, 1H)

Example 2. Preparation of 4- (3-bromobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(59.1%) was obtained in the same manner as in Example 1, except that 3-bromobenzyl bromide was used instead of 2-bromomethylnaphthalene.

^{1 H NMR (400 MHz, CDCl} 3) δ 4.61 (s, 2H), 6.52-6.54 (dd, J = 3.6 Hz, 1H), 7.15-7.19 (t, J = 7.8 Hz, 1H), 7.22-7.24 ( dd, J = 3.6 Hz, 1H ), 7.36-7.41 (t, J = 8.2 Hz, 2H), 7.62-7.63 (t, J = 1.6 Hz, 1H), 8.70 (s, 1H), 9.62 (bs, 1H )

Example 3. Preparation of 4- (4-chlorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(88.4%) was obtained in the same manner as in Example 1, except that 4-chlorobenzyl bromide was used instead of 2-bromomethylnaphthalene.

^One≪ 1 > H NMR (400 MHz, CDCl3₃) [delta] 4.61 (s, 2H), 6.52-6.53 (dd,J= 3.6 Hz, 1 H), 7.23-7.24 (dd,J= 3.5 Hz, 1H), 7.27-7.28 (m, 2 H), 7.39-7.41 (m, 2 H), 8.70 (s, 1 H), 9.82 (bs, 1 H)

Example 4. Preparation of 4- (2,6-difluorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(68.9%) was obtained in the same manner as in Example 1, except that 2,6-difluorobenzyl bromide was used instead of 2-bromomethylnaphthalene.

^{1 H NMR (400 MHz, CDCl} 3) δ 4.77 (s, 2H), 6.52-6.53 (dd, J = 3.6 Hz, 1H), 6.90-6.93 (m, 2H), 7.20-7.24 (m, 2H), 8.73 (s, IH), 9.61 (bs, IH)

Example 5. Preparation of 4- (2-fluorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(91.8%) was obtained in the same manner as in Example 1, except that 2-fluorobenzyl bromide was used instead of 2-bromomethylnaphthalene.

^{1 H NMR (400 MHz, CDCl} 3) δ 4.70 (s, 1H), 6.52-6.53 (q, J = 3.6 Hz, 1H), 7.05-7.08 (m, 3 H), 7.20-7.24 (m, 1 H), 7.245-7.26 (m, 1 H), 7.55-7.56 (m, 1 H), 8.71 (s, 1 H), 9.37 (bs, 1 H)

Example 6. 4- (9 H - fluoren-9-yl thio) -7 H- pyrrolo [2,3- d] pyrimidine

(44.3%) was obtained by following the procedure of Example 1 while using 9-bromofluorene instead of 2-bromomethylnaphthalene.

^{1 H NMR (400 MHz, CDCl} 3) δ 6.43-6.44 (dd, J = 1.6 Hz, 1H), 6.79 (s, 1H), 7.27-7.31 (m, 2 H), 7.39-7.43 (m, 2H), 7.55-7.58 (m, 2H), 7.67-7.69 (d, J = 7.4 Hz, 1H), 7.76-7.78 (d, J = 7.6 Hz, 2H)

Example 7. Preparation of 4- (benzhydrylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(62.4%) was obtained in the same manner as in Example 1, except that bromodiphenylmethane was used instead of 2-bromomethylnaphthalene.

^{1 H NMR (400 MHz, CDCl} 3) δ 6.53-6.54 (dd, J = 3.5 Hz, 1H), 6.81 (s, 1H), 7.21-7.22 (m, 2H), 7.24-7.25 (m, 1 H), 7.29-7.33 (m, 4H), 7.49-7.51 (m, 4 H), 8.62 (s, 1 H), 10.76 (bs, 1 H)

Example 8. Preparation of 4- (biphenyl-3-ylmethylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(70.3%) was obtained in the same manner as in Example 1, except that 3-phenylbenzyl bromide was used instead of 2-bromomethylnaphthalene.

^{1 H NMR (400 MHz, CDCl} 3) δ 6.53-6.54 (t, J = 2.0 Hz, 1H), 7.21-7.22 (d, J = 2.6 Hz, 1H), 7.32-7.37 (m, 3H), 7.39-7.41 (m, 2H), 7.43-7.51 (m, 3H), 7.57-7.58 (d, J = 7.2 Hz, 2H), 7.71 (s,

Example 9. Preparation of 4- (2-chlorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(92.6%) was obtained in the same manner as in Example 1, except that 2-chlorobenzyl bromide was used instead of 2-bromomethylnaphthalene.

¹ H NMR (400 MHz, CDCl ₃ )? 4.79 (s, 2H), 7.18-7.21 (m, 2H), 7.23-7.25 (dd, J = 3.5 Hz, 1H) 7.38-7.48 (m, 2 H), 7.63-7.65 (m, 1 H), 8.72 (s, 1 H), 9.63 (bs, 1 H)

Example 10. Preparation of 3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -N , N -dimethylpropan-

(95.7%) was obtained in the same manner as in Example 1, except that 3-dimethylaminopropyl bromide was used instead of 2-bromomethylnaphthalene.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.95-2.03 (m, 2H), 2.28 ( s, 6H), 2.47-2.51 (t, J = 7.1 Hz, 2H), 3.38-3.42 (t, J = 7.2 Hz, 2H), 6.51-6.52 (d, J = 3.5 1H), 7.25-7.26 (d, J = 3.5 Hz, 1H), 8.64

Example 11. Preparation of 2- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -N , N -dimethylpropan-

(96.2%) was obtained by following the procedure of Example 1 while using 2-bromo-1- (dimethylamino) propane instead of 2-bromomethylnaphthalene.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.17-1.19 (d, J = 6.6 Hz, 3H), 2.39 (s, 6H), 2.97-3.02 (m, 1H), 3.40-3.44 ( q, J = 6.8 Hz, 1H), 3.59-3.64 (q, J = 6.7 Hz, 1H), 6.54-6.55 (d, J = 3.4 Hz, 1H), 7.25- 7.26 (d, J = 3.4 Hz, 1H), 8.65 (s, 1H), 12.03 (bs, 1H)

Example 12. Preparation of 4- (l-methylpiperidin-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(68.8%) was obtained in the same manner as in Example 1, except that 1-methylpiperidin-3-yl-4-bromide was used instead of 2-bromomethylnaphthalene.

^{1 H NMR (400 MHz, CDCl} 3) δ 0.86-0.88 (m, 2H), 1.25 (bs, 3H), 1.71 (bs, 2H), 2.44 (m, 1 H), 2.71 - 2.72 (d, J = 6.0 Hz, 3H), 6.56 - 6.57 (m, 1H), 7.24-7.26 (t, J = 2.4 Hz, 2H), 8.68

Example 13: Preparation of 4 - ((3'-fluorobiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(Dibenzylideneacetone) dipalladium (9.38 mg, 0.0091 mmol) and 1,1'-bis (diphenylphosphino) ferrocene (10 mg, 0.018 mmol) were added to toluene (2 mL) Lt; / RTI > In another reaction vessel, 4- (4-chlorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine (50 mg, 0.181 mmol) was dissolved in toluene (3 mL) and cesium carbonate 147.7 mg, 0.453 mmol) and 3-fluorophenylboronic acid were added and reacted at room temperature for 30 minutes. The two reaction solutions prepared above were mixed and reacted at 130 ° C for 24 hours. The solvent was removed from the resulting mixture under reduced pressure. The reaction mixture was extracted with ethyl acetate (10 mL), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The obtained organic layer was subjected to silica gel flash column chromatography (ethyl acetate: hexane = 1: 2) to give 4 as a - ((methylthio biphenyl-4-yl) 3'-fluoro-o) -7 H- pyrrolo [2, 3- d ] pyrimidine.

¹ H NMR (400 MHz, CDCl ₃ )? 4.62 (s, 2H), 6.54 (s, 1 H), 7.09-7.13 (m, 1H), 7.25-7.28 ( d, J = 9.2 Hz, 3H), 7.35-7.40 (d, J = 8.3 Hz, 3H), 7.63-7.65 (d, J = 7.5 Hz, 1H), 7.75- 7.77 (d, J = 7.2 Hz, 1H), 8.80 (s, 1H), 10.00 (bs, 1H)

Example 14: Preparation of 4 - ((2'-fluorobiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(89.0%) was obtained in the same manner as in Example 13, except that 2-fluorophenylboronic acid was used instead of 3-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 4.62 (s, 2H), 6.55 (s, 1H), 6.99-7.03 (t, J = 8.8 Hz, 2H), 7.17-7.19 (t, J = 6.6 Hz, 2H), 8.94 (s, 1H), 10.57 (bs, 1H), 7.26-7.28 (d, J = 8.5 Hz, 3H), 7.38-7.40

Example 15 Preparation of 4 - ((3'-methylbiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(86.7%) was obtained in the same manner as in Example 13, except that m -tolyl boronic acid was used in place of 3-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 2.38 (s, 3H), 4.61 (s, 2H), 6.52-6.54 (dd, J = 3.6 Hz, 1H), 7.23-7.25 (dd, J = 3.5 Hz, 2H), 7.28-7.29 (t, J = 2.4 Hz, 2H), 7.30-7.34 (m, 2H), 7.38-7.41 (m, 2H), 7.89-7.90 (d, J = 6.3 Hz, 1H), 8.76

Example 16. Preparation of 4 - ((4'-methylbiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(94.7%) was obtained in the same manner as in Example 13, except that p- tolylboronic acid was used instead of 3-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 2.38 (s, 3H), 4.61 (s, 2H), 6.52-6.53 (dd, J = 3.2 Hz, 1H), 7.23-7.25 (m, 4H), 7.27-7.28 (d, J = 2.8 Hz, 3H), 7.38-7.40 (d, J = 8.3 Hz, 2H), 8.80

Example 17. Preparation of 4- (4- (thiophen-2-yl) benzylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(85.5%) was obtained in the same manner as in Example 13, except that 2-thiopheneboronic acid was used instead of 3-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 4.62 (s, 2H), 6.52-6.54 (dd, J = 3.6 Hz, 1H), 7.14-7.15 (dd, J = 3.5 Hz, 1H), 7.23-7.24 ( t, J = 2.8 Hz, 1H), 7.35-7.40 (t, J = 6.4 Hz, 1H), 7.40-7.42 (m, 3 H), 7.69 - 7.71 (m, IH), 7.75-7.77 (d, J = 6.3 Hz, IH), 8.78

Example 18. Preparation of 4 - ((2'-methoxybiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(81.8%) was obtained by following the procedure of Example 13 while using 2-methoxyphenylboronic acid instead of 3-fluorophenylboronic acid.

^{1 H NMR (400 MHz, CDCl} 3) δ 3.03 (s, 3H), 4.65 (s, 2H), 6.52 (s, 1H), 6.97-7.01 (t, J = 3.6 Hz, 2H), 7.21-7.23 ( t, J = 3.5 Hz, 2H ), 7.27-7.29 (d, J = 2.8 Hz, 3H), 7.38-7.40 (d, J = 6.5 Hz, 2H), 8.86 (s, 1H), 10.48 (bs, 1H )

Example 19. Preparation of 4- (4- (4-cyclohexylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

Acetonitrile in 4 (3 mL) (4-bromo-butyl-thio) -7 H- pyrrolo [2,3- d] a and then stirring pyrimidine (50 mg, 0.175 mmol), 80 ℃ After heating, sodium carbonate (20 mg, 0.192 mmol) and 1-cyclohexylpiperazine (44 mg, 0.192 mmol) were added and reacted for 6 hours. The solvent was removed from the resulting mixture under reduced pressure, and the reaction mixture was extracted with dichloromethane (40 mL), dried using anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The obtained organic layer was subjected to silica gel flash column chromatography (dichloromethane: methanol = 10: 1) to give 4- (4- (4-cyclohexyl-1-silpi Blow-yl) butyl-thio) -7 H- pyrrolo [2,3- d ] pyrimidine (77.2%).

^{1 H NMR (400 MHz, CDCl} 3) δ 1.11-1.25 (m, 6H), 1.62-1.65 (m, 1 H), 1.68-1.73 (m, 2 H), 1.74-1.84 (t, J = 7.5 Hz, 3H), 2.64 (bs, 4H), 2.76 (bs, 3H), 3.37-3.40 (t, J = 6.9 Hz, 2H), 6.62-6.53 (d , J = 3.4 Hz, 1H), 7.25-7.28 (d, J = 3.4 Hz, 1H), 8.65 (s, 1H), 11.44 (bs, 1H)

Example 20: Preparation of 4- (4- (4-phenylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(93.7%) was obtained by following the procedure of Example 19 while using 1-phenylpiperazine instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.71-1.87 (m, 4H), 2.45-2.49 ( t, J = 7.5 Hz, 2H), 2.61-2.64 (t, J = 5.0 Hz, 4H), 3.19-3.22 (t, J = 4.9 Hz, 4H), 3.40- 3.44 (t, J = 7.0 Hz, 2H), 6.53 - 6.54 (m, 1H), 6.83-6.86 (t, J = 7.3 Hz, 1H), 6.91-6.93 (d, J = 7.9 Hz, 2H), 7.24-7.27 (m, 3 H), 8.66 (s, 1 H), 11.45 (bs, 1 H)

Example 21. Preparation of 4- (4- (4-benzhydrylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(91.8%) was obtained in the same manner as in the above Example 19, except that 1- (diphenylmethyl) piperazine was used instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.67-1.71 (m, 2H), 1.76-1.81 (m, 2 H), 2.41 - 2.57 (m, 10H), 3.36-3.39 ( t, J = 7.0 Hz, 2H), 4.20 (s, 1H), 6.51-6.52 (d, J = 3.4 Hz, 1H), 7.14-7.18 (m, 2H), 7.22-7.27 (m, 5H), 7.39-7.41 (m, 4H), 8.63 (s, IH), 11.31 (bs, IH)

Example 22: Preparation of 4- (4- (4-benzylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

The target compound (85.5%) was obtained by carrying out the same processes as in the Example 19, except that 1-benzylpiperazine was used instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.68-1.71 (m, 2H), 1.76-1.82 (m, 2H), 2.41 - 2.44 (t, J = 7.6 Hz, 3H), 2.46 - 2.61 (m, 6H), 3.36-3.40 ( t, J = 7.1 Hz, 2H), 3.51 (s, 2H), 6.51-6.52 (d, J = 3.5 Hz, 1H), 7.22-7.26 (m, 3H), 7.27-7.32 (m, 4H), 8.64 (s, IH), 11.68 (bs, IH)

Example 23. Preparation of 4- (4- (4- (2-methoxyphenyl) piperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(93.0%) was obtained in the same manner as in the above Example 19, except that 1- (2-methoxyphenyl) piperazine was used instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.73-1.77 (m, 2H), 1.83-1.87 (m, 2H), 2.48-2.52 ( t, J = 7.6 Hz, 2H), 2.67-2.71 (bs, 4H), 3.08-3.12 (bs, 4H), 3.40-3.44 (t, J = 7.1 Hz, 2H ), 3.86 (s, 3H), 6.53-6.54 (d, J = 3.2 Hz, 1H), 6.84-6.86 (dd, J = 7.9 Hz, 1H), 6.91-6.95 (m, 2 H), 6.97 - 6.99 (m, IH), 7.24-7.25 (d, J = 3.3 Hz, IH), 8.66

Example 24. Preparation of 4- (4- (4- m- tolylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(87.3%) was obtained by following the procedure of Example 19 while using 1- ( m- tolyl) piperazine instead of 1-cyclohexylpiperazine.

^One≪ 1 > H NMR (400 MHz, CDCl3₃) [delta] 1.72-1.78 (m, 2 H), 1.82-1.87 (m, 2H), 2.31 (s, 3H), 2.45-2. 49 (t,J= 7.5 Hz, 2H), 2.60-2.63 (t,J= 5.0 Hz, 4H), 3.18-3.21 (t,J= 4.9 Hz, 4H), 3.40-3.44 (t,J= 7.0 Hz, 2H), 6.53-6.54 (dd,J= 3.3 Hz, 1 H), 6.67-6.68 (d,J= 7.5 Hz, 1 H), 6.72-6.75 (m, 2H), 7.12-7.16 (t,J= 7.8 Hz, 1 H), 7.24-7.25 (t,J= 1.8 Hz, 1 H), 8.67 (s, 1 H), 11.48 (bs, 1 H)

Example 25. Preparation of 4- (4- (4- p- tolylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(86.4%) was obtained in the same manner as in the above Example 19, except that 1- ( p- tolyl) piperazine was used instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.72-1.78 (m, 2 H), 1.82-1.87 (m, 2H), 2.26 ( s, 3H), 2.45-2.49 (t, J = 7.5 Hz, 2H), 2.62-2.64 (t, J = 4.9 Hz, 4H), 3.15-3.17 (t, J = 4.9 Hz, 4H), 3.40-3.43 (t , J = 7.0 Hz, 2H), 6.54-6.56 (dd, J = 3.5 Hz, 1H), 6.81-6.86 (d, J = 8.4 Hz, 2H), 7.06-7.08 (d, J = 8.4 Hz, 2H), 7.23-7.24 (dd, J = 3.4 Hz, 1H)

Example 26. Preparation of 4- (4- (4- (2,4,6-trimethylbenzyl) piperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(94.2%) was obtained by following the procedure of Example 19 while using 1- (2,4,6-trimethylbenzyl) piperazine instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.67-1.71 (m, 2 H), 1.78-1.82 (m, 2H), 2.26 ( s, 9H), 2.37-2.40 (t, J = 7.6 Hz, 4H), 2.47-2.51 (bs, 5H), 3.36-3.40 (t, J = 7.1 Hz, 2H), 3.43 (s, 2H), 3.49 (s, 1H), 6.52-6.53 (d, J = 3.0 Hz, 1H), 6.82 (s, 2H), 7.23-7.24 (d, J = 2.3 Hz, 1H), 8.64 (s, 1 H), 10.80 (bs, 1 H)

Example 27. Preparation of 2- (4- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) butyl) piperazin-1-yl) benzonitrile

(82.6%) was obtained in the same manner as in the above Example 19, except that 1- (2-cyanophenyl) piperazine was used instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.74-1.78 (m, 2H), 1.80-1.84 (m, 2H), 2.44-2.47 (t, J = 7.5 Hz, 2H), 2.72-2.74 (m, 4H), 3.20-3.22 ( t, J = 7.6 Hz, 4H), 3.54-3.56 (t, J = 7.1 Hz, 2H), 6.55-6.56 (dd, J = 3.5 Hz, 1H), 6.94- 6.96 (m, 2H), 7.06-7.12 (m, 2H), 7.26-7.27 (m, 1 H), 8.65 (s, 1 H), 10.73 (bs, 1 H)

Example 28. Preparation of 4- (4- (4- (2-fluorophenyl) piperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(87.9%) was obtained in the same manner as in the above Example 19, except that 1- (2-fluorophenyl) piperazine was used instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.72-1.77 (m, 2 H), 1.82-1.87 (m, 2H), 2.46-2.50 ( t, J = 7.5 Hz, 2H), 2.65-2.67 (bs, 4H), 3.11-3.13 (t, J = 4.6 Hz, 4H), 3.40-3.44 (t, J = 7.1 Hz, 2H), 6.54-6.55 (dd, J = 3.5 Hz, 1H), 6.92-6.97 (m, 2H), 6.99-7.07 (m, 2H), 7.25-7.26 (dd, J = 3.5 Hz, 1H), 8.67

Example 29. Preparation of 4- (4- (4-benzyl-1,4-diazepan- 1 -yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

The objective compound (81.3%) was obtained by carrying out the same processes as in the Example 19, except that benzyl homopiperazine was used instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.60-1.63 (m, 2H), 1.67-1.70 (m, 2H), 1.75-1.79 (m, 2 H), 2.42 - 2.44 (m, 3H), 2.50-2.58 (m, 6H), 3.33-3.35 (m, 2H), 3.52-3.55 (m, 2H), 6.50-6.52 (dd, J = 3.5 Hz, 1H), 7.23-7.26 (m, 3H), 7.32-7.34 (m, 4 H), 8.63 (s, 1 H), 10.97 (bs, 1 H)

Example 30. Preparation of 4- (4- (4- (4-nitrophenyl) piperazin-l-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(85.0%) was obtained by following the procedure of Example 19 while using 1- (4-nitrophenyl) piperazine instead of 1-cyclohexylpiperazine.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.70-1.75 (m, 2H), 1.82-1.86 (m, 2H), 2.46-2.49 (t, J = 4.5 Hz, 2H), 2.53-2.58 (m, 5H), 2.61-2.64 (m, 3H), 3.44-3.46 (t, J = 7.1 Hz, 2H), 6.72-6.76 (m, 1H), 6.97-7.00 ( d, J = 3.5 Hz, 2H), 7.26-7.28 (d, J = 3.4 Hz, 2H), 7.36-7.38 (m, 1 H), 8.67 (s, 1 H), 10.68 (bs, 1 H)

Example 31 Synthesis of endo- tert -butyl 3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8-azabicyclo [3.2.1] octane- Manufacturing

To a solution of 7H -pyrrolo [2,3- d ] pyrimidin-4-thiol (417 mg, 1.365 mmol) and potassium carbonate (324 mg, 2.346 mmol) in N, N- dimethylformamide Insert after the reaction at 50 ℃, exo - tert - butyl-3 (methylsulfonyl-oxy) -8-azabicyclo [3.2.1] octane-8-carboxylate was added (284 mg, 1.878 mmol) and 18 Lt; / RTI > The solvent was removed from the resulting mixture under reduced pressure. The reaction mixture was extracted with dichloromethane (100 mL), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The obtained organic layer was subjected to silica gel flash column chromatography (dichloromethane: methanol = 10: 1) to give the endo - tert - butyl 3- (7 H- pyrrolo [2,3- d] pyrimidin-4-yl thio ) -8-azabicyclo [3.2.1] octane-8-carboxylate (76.6%).

^{1 H NMR (400 MHz, CDCl} 3) δ 1.20-1.22 (m, 2H), 1.45-1.50 (bs, 4H), 3.11 (s, 3H), 3.35-3.40 (q, J = 7.4 Hz, 3H) (m, 2H), 6.53-6.55 (t, J = 3.5 Hz, 1H), 7.20-7.22 (t, J = 2.3 Hz, 1H)

Example 32. Exo- tert -butyl 3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8-azabicyclo [3.2.1] octane- Manufacturing

Exo - tert - butyl-3 (methylsulfonyl-oxy) -8-azabicyclo [3.2.1] octane-8-carboxylate in place of the endo - tert - butyl-3- (methyl-sulfonyloxy) -8 The title compound (68.2%) was obtained by carrying out the same processes as in the Example 31, except using azabicyclo [3.2.1] octane-8-carboxylate.

¹ H NMR (400 MHz, CDCl ₃ )? 1.18-1.21 (bs, 2H), 1.53-1.57 (m, 2H), 1.62-1.66 (bs, 2H), 3.08 (s, 3H), 3.31-3.36 (m, 3H), 4.11-4.15 (m, 2H), 6.53-6.54 ( t, J = 3.5 Hz, 1H), 7.19-7.20 (t, J = 2.4 Hz, 1H), 8.37 (s, 1H), 10.33 (bs, 1H)

Example 33. Preparation of endo-4- (8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine

To a solution of exo- tert -butyl-3- (methylsulfonyloxy) -8-azabicyclo [3.2.1] octane-8-carboxylate (40 mg, 0.120 mmol) in ethyl acetate- ) Were added and reacted at 0 ° C for 3 hours. The solvent was removed from the resulting mixture under reduced pressure. The reaction mixture was solidified using ethyl acetate. Thereafter, filtration under reduced pressure gave the desired compound (88.5%).

^{1 H NMR (400 MHz, CDCl} 3) δ 1.24-1.26 (m, 2 H), 1.46 - 1.51 (m, 4H), 3.34-3.37 (m, 3H), 3.41-3.44 (m, 1 H), 4.06-4.11 (m, 2H), 6.52-6.55 ( t, J = 3.6 Hz, 1H), 7.23-7.25 (t, J = 2.4 Hz, 1H), 8.67 (s, 1H), 10.58 (s, 1H)

Example 34. Preparation of exo-4- (8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine

Exo-tert-butyl-3- (methyl sulfonyloxy), 8-azabicyclo [3.2.1] octane-8-carboxylate in place of endo-3-ethyl (methylsulfonyl hydroxyphenyl) -8-azabicyclo [3.2.1] octane-8-carboxylate was used in place of the target compound (90.7%).

^{1 H NMR (400 MHz, CDCl} 3) δ 1.21-1.24 (m, 2H), 1.54-1.56 (m, 2H), 1.63-1.65 (m, 2H), 3.05-3.08 (m, 1 H), 3.32-3.35 (m, 3H), 4.14-4.17 (m, 2H), 6.58-6.60 (t, J = 3.4 Hz, 1H), 7.24-7.26 (t, J = 3.4 Hz, 1H), 8.45 (bs, 1H)

Example 35. Preparation of endo-4- (8-methyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine

To a solution of exo-4- (8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine (50 mg, 0.166 mmol) were added and stirred. Potassium carbonate (44 mg, 0.285 mmol) and iodomethane (0.042 mL, 0.166 mmol) were added and reacted at 50 ° C for 12 hours. The solvent was removed from the resulting mixture under reduced pressure. The reaction mixture was extracted with dichloromethane (100 mL), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure. The resulting organic layer was purified by silica gel flash column chromatography (dichloromethane: methanol = 10: 1) to give endo-4- (8-methyl-8-azabicyclo [3.2.1] oct- 7H -pyrrolo [2,3- d ] pyrimidine (76.6%).

^{1 H NMR (400 MHz, CDCl} 3) δ 1.20-1.22 (m, 2H), 1.45-1.50 (bs, 4H), 3.11 (s, 3H), 3.35-3.40 (q, J = 7.4 Hz, 3H) (m, 2H), 6.53-6.55 (t, J = 3.5 Hz, 1H), 7.20-7.22 (t, J = 2.3 Hz, 1H)

Example 36. Preparation of exo-4- (8-methyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine

Instead of exo-4- (8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine, [3.2.1] octane-3-yl thio) -7 H- pyrrolo [2,3- d] pyrimidine, and a are the same in example 35 carried out in a manner desired compound (68.2%, and except for using) ≪ / RTI >

¹ H NMR (400 MHz, CDCl ₃ )? 1.18-1.21 (bs, 2H), 1.53-1.57 (m, 2H), 1.62-1.66 (bs, 2H), 3.08 (s, 3H), 3.31-3.36 (m, 3H), 4.11-4.15 (m, 2H), 6.53-6.54 ( t, J = 3.5 Hz, 1H), 7.19-7.20 (t, J = 2.4 Hz, 1H), 8.37 (s, 1H), 10.33 (bs, 1H)

Example 37. Preparation of endo-ethyl 3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8- azabicyclo [3.2.1] octane- 8-carboxylate

(88.5%) was obtained in the same manner as in Example 35, except that ethyl chloroformate was used in place of iodomethane.

^{1 H NMR (400 MHz, CDCl} 3) δ 0.94 (m, 1 H), 1.25 (m, 4H), 1.43-1.47 (t, J = 7.4 Hz, 4H), 1.86 (bs, (m, 1H), 2.18-2.21 (bs, 1H), 3.36-3.38 (q, J = 7.4 Hz, 2H), 4.10-4.12 (d, J = 3.6 Hz, 1H), 7.31-7.33 (d, J = 2.6 Hz, 1H), 8.64 10.87 (bs, 1 H)

Example 38. Preparation of exo-ethyl 3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8-azabicyclo [3.2.1] octane-8-

Instead of exo-4- (8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine, [3.2.1] octane-3-yl thio) -7 H- pyrrolo [2,3- d] and the above-described embodiment except using a pyrimidine, and iodo for using ethyl chloroformate in place of methane The procedure of Example 35 was repeated to obtain the target compound (80.8%).

^{1 H NMR (400 MHz, CDCl} 3) δ 0.87 (bs, 1H), 1.19-1.22 (m, 3H), 1.37-1.41 (t, J = 6.6 Hz, 3H), 1.72-1.78 (bs, 2H), 1.94-1.97 (m, 1 H), 2.92-2.94 (m, 2H), 3.28-3.34 (q, J = 7.4 Hz, 2H), 4.09-4.11 (m, 1 H), 4.21-4.24 (m, 1H), 6.47-6.48 (t, J = 1.8 Hz, 1H), 7.17-7.18 (d, J = 2.2 Hz, 1H), 8.58

Example 39. Preparation of endo-4- (8-benzyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine

(87.0%) was obtained in the same manner as in Example 35, except that benzyl bromide was used in place of iodomethane.

¹ H NMR (400 MHz, CDCl ₃ )? 1.25 (bs, 2H), 2.12-2.23 (m, 4H), 2.67 ( bs, 2H), 3.32 (bs, 2H), 3.67 (bs, 2H), 4.73-4.77 (t, J = 7.6 Hz, 1H), 6.52-6.53 (t, J = 2.0 Hz, 1H), 7.23-7.25 (m, 2H), 7.32-7.35 (t, J = 7.6 Hz, 2H), 7.44-7.45 (d, J = 7.2 Hz, 2H), 8.64

Example 40. Preparation of endo-4- (8-allyl-8-azabicyclo [3.2.1] octan-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine

The objective compound (66.2%) was obtained in the same manner as in Example 35, except that allyl bromide was used instead of iodomethane.

^{1 H NMR (400 MHz, CDCl} 3) δ 1.25-1.28 (bs, 2H), 2.19-2.21 (t, J = 5.8 Hz, 3H), 2.41-2.43 (m, 2H), 3.07-3.10 ( bs, 2H), 3.38-3.39 (d, J = 6.6 Hz, 2H), 3.70 (bs, 2H), 4.83-4.86 (t, J = 7.3 Hz, 1H), 5.34-5.38 (m, 2H), 6.49-6.50 (d, J = 3.5 Hz, 1H), 7.28-7.29 (d, J = 3.7 Hz, 1H)

Meanwhile, the novel compounds represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. Hereinafter, some formulation methods in which the compound represented by Formula 1 according to the present invention is contained as an active ingredient are illustrated, but the present invention is not limited thereto.

[Formulation Example]

Formulation 1: Tablets (direct pressurization)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

Formulation 2: Tablet (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

Formulation 3: Powder and Capsule

5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

Formulation 4: Injection

100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO ₄ .12H ₂ O and 2974 mg of distilled water were added to prepare an injection.

[Experimental Example]

Meanwhile, the novel compound represented by the formula (1) according to the present invention was confirmed as a JAK-3 inhibitor by the method shown in the following Experimental Examples.

Experimental example. Measurement of JAK-3 inhibitory activity

Kinase reactions were performed at various compound concentrations (10 nM, 100 nM, 1 μM, 10 μM, 100 μM). (50 mM Hepes, pH 7.5, 2 mM DTT, 1 mM EGTA, 10 mM Tris-HCl) supplemented with 20 μM ATP was added to each concentration of the test compound to give a concentration of 1 μM F-JAK peptide and 2.6 μg / mM mg, Cl ₂ , 0.01% Tween-20) was added thereto, followed by reaction at room temperature for 15 minutes. After the reaction, the reaction was terminated by heat treatment at 95 DEG C for 1 minute. For FP measurements, the reaction was diluted with EBC buffer (50 mM Tris, pH 8.0, 120 mM NaCl, 0.25% Nonidet P-40) containing 100 nM PY20 and the final peptide concentration in the buffer was 100 nM. The measurement results are shown in Table 1 below.

Experimental compound EC ₅₀ values (nM) Example 4 16 Example 5 58 Example 7 64 Example 17 75 Example 24 82 Example 25 99 Example 28 57 Example 29 62 Staurosporine 13.41

As shown in Table 1 above, the value of EC ₅₀ of the novel 7 H -pyrrolo [2,3- d ] pyrimidine-4-thiol derivative according to the present invention is 16 to 99 nM, The inhibitory activity of JAK-3 is comparable to that of staurosporine, which is used as an inhibitor of < RTI ID = 0.0 >

Accordingly, the composition according to the present invention is useful for the treatment and / or prophylaxis of diseases caused by hyperactivity of JAK, such as cancer, graft rejection, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, psoriasis, asthma, allergic dermatitis, Diabetic complications, ulcerative colitis, Crohn ' s disease, autoimmune thyroid disease, and the like.

Claims (9)

A compound selected from 7H -pyrrolo [2,3- d ] pyrimidine-4-thiol derivative represented by the following formula 1 and a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

In Formula 1,
R is-CH (Ar) ₂ ;

;

; or

Lt; / RTI >
R ¹ is mono (C ₁ -C ₁₀ Alkyl) amino group; Or di (C ₁ -C ₁₀ Alkyl) amino group,
R ² is C ₁ -C ₆ An alkyl group; Diphenylmethyl group; A C ₂ -C ₁₀ alkenyl group; C ₁ -C ₆ An alkylcarbonate group; A C ₃ -C ₁₅ cyclic alkyl group; A C ₃ -C ₁₂ heterocyclic alkyl group containing 1 to 2 nitrogen heteroatoms; C ₁ -C ₆ A benzyl group substituted or unsubstituted with 1 to 3 substituents selected from alkyl; Or halo, cyano, nitro, C ₁ -C ₆ Alkyl and C ₁ -C ₆ Alkoxy, < / RTI > and < RTI ID = 0.0 >
R ³ is a halogen atom; Halo, C ₁ -C ₆ A phenyl group substituted or unsubstituted with 1 to 3 substituents selected from the group consisting of alkyl and C ₁ -C ₆ alkoxy; Or a C ₅ -C ₁₂ heteroaryl group containing 1 to 2 hetero atoms selected from O, S and N,
Het represents a C ₃ -C ₁₂ heterocyclic alkyl group containing 1 to 2 nitrogen atoms,
Ar is C ₆ -C ₁₅ An aryl group,
l represents an integer of 1 to 6,
m represents an integer of 0 to 6,
n represents an integer of 0 to 6,
q represents an integer of 0 to 6 as the number of substituents.
The method according to claim 1,
The Het may be a piperidinyl group, a piperazinyl group, a 1,2-diazepanyl group, a 1,3-diazepanyl group, a 1,4-diazepan group or 8-azabicyclo [3.2.0] - Represents a diary,
And Ar represents a phenyl group, a naphthalenylene group, or a fluorenyl group.
The method according to claim 1,
The R may be a benzhydryl group, a 1- (dimethylamino) propyl group, a 3- (dimethylamino) propyl group, an 8-azabicyclo [3.2.0] Azabicyclo [3.2.0] octan-3-yl group, 8-allyl-8-azabicyclo [3.2.0] octan- 3 Weather, methyl 8-azabicyclo [3.2.0] octane-8-carboxylate group, ethyl 8-azabicyclo [3.2.0] octane-8-carboxylate group, tert - butyl-8-azabicyclo Yl group, a piperidin-4-yl group, a 1-methyl-piperazin-1-yl group, a piperazin- (Piperazin-1-yl) butyl, piperidin-4-yl, piperidin- (4-cyclohexylpiperazin-1-yl) butyl group, 4- [4- (diphenylmethyl) piperazin- (1) butyl group, 4- (4-phenylpiperazin-1-yl) butyl group, 4 (4- (4- (2-fluorophenyl) piperazin-1-yl) butyl group, 4- 1-yl) butyl group, 4- [4- (3-tolyl) piperazin-1-yl) Butyl group, 4- [4- (2-methoxyphenyl) piperazin-1-yl] (4-methoxyphenyl) piperazin-1-yl] butyl group, 4- [4- (2- ) Piperazin-1-yl] butyl group, 4- [4- (2,4,6-trimethylbenzyl) piperazin-1-yl] butyl group, 2- chlorophenyl group, Fluorophenyl group, 2-chlorobenzyl group, 2-fluorobenzyl group, 3-bromobenzyl group, 4-chlorobenzyl group, 2,6-difluorobenzyl group, Benzyl group, 4- (2-fluorophenyl) benzyl group, 4- (3-fluorophenyl) benzyl group, 4- Benzyl group, 4- (4-tolyl) benzyl group, 4- (2-methoxyphenyl ) Benzyl group, a 4- (3-methoxyphenyl) benzyl group, a 4- (4-methoxyphenyl) benzyl group, a 4- (thiophen- Lt; / RTI > is selected from the group consisting of diaryls.
The method according to claim 1,
1) 4- (Naphthalen-2-ylmethylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
2) 4- (3-Bromobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
3) 4- (4-Chlorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
4) 4- (2,6-Difluorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
5) 4- (2-fluorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
6) 4- (9 H - fluoren-9-yl thio) -7 H- pyrrolo [2,3- d] pyrimidine;
7) 4- (Benzhydrylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
8) 4- (Biphenyl-3-ylmethylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
9) 4- (2-chlorobenzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
10) 4- ( 7H -Pyrrolo [2,3- d ] pyrimidin-4-ylthio) -N , N -dimethylpropan-1- amine;
11) 2- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -N , N -dimethylpropan-1- amine;
12) 4- (1-Methylpiperidin-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
13) 4 - ((3'-fluorobiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
14) 4 - ((2'-fluorobiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
15) 4 - ((3'-Methylbiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
16) 4 - ((4'-Methylbiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
17) 4- (4 '- (Thiophen-2-yl) benzylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
18) 4 - ((2'-methoxybiphenyl-4-yl) methylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
19) 4- (4- (4-Cyclohexylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
20) 4- (4- (4-phenylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
21) 4- (4- (4-Benzhydrylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
22) 4- (4- (4-Benzylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
23) 4- (4- (4- (2-Methoxyphenyl) piperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
24) 4- (4- (4- m -Tolylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
25) 4- (4- (4- p -Tolylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
26) 4- (4- (4- (2,4,6-trimethylbenzylpiperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
27) 2- (4- (4- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) butyl) piperazin-1-yl) benzonitrile;
28) 4- (4- (4- (2-fluorophenyl) piperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
29) 4- (4- (4-Benzyl-1,4-diazepan-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
30) 4- (4- (4- (4-Nitrophenyl) piperazin-1-yl) butylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
31) endo- tert -butyl-3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8- azabicyclo [3.2.1] octane- 8-carboxylate;
32) exo- tert -butyl-3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8- azabicyclo [3.2.1] octane-8-carboxylate;
33) Endo-4- (8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine dihydrochloride;
34) exo-4- (8-Azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine dihydrochloride;
35) Endo-4- (8-methyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
36) exo-4- (8-methyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
37) Endo-ethyl 3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8- azabicyclo [3.2.1] octane-8-carboxylate;
38) exo-ethyl 3- ( 7H -pyrrolo [2,3- d ] pyrimidin-4-ylthio) -8- azabicyclo [3.2.1] octane-8-carboxylate;
39) Endo-4- (8-benzyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine; And
40) Endo-4- (8-allyl-8-azabicyclo [3.2.1] octane-3-ylthio) -7H -pyrrolo [2,3- d ] pyrimidine;
≪ / RTI >
Reacting a chloro compound represented by the following formula (2) with thiourea to prepare a thiol compound represented by the following formula (3); And

Reacting a thiol compound represented by the following formula (3) with a halide compound represented by RX (wherein R is as defined in claim 1 and X is a halogen atom) to obtain 7H -pyrrolo [2,3- d ] pyrimidine-4-thiol derivative;

(In the above scheme, R is the same as defined in claim 1)
The method of 7 H- pyrrolo [2,3- d] pyrimidin-4-thiol derivative, comprising a step of including.
6. The method of claim 5,
The method of 7 H- pyrrolo [2,3- d] pyrimidin-4-thiol derivative, characterized in that for performing the one-step process is ethanol solvent.
6. The method of claim 5,
The two-step process are acetonitrile or N, N - 7 H- pyrrolo characterized in that the die perform heating conditions by using dimethylformamide as a solvent, 50 ℃ to 90 ℃ [2,3- d] Pyrimidine-4-thiol derivative.
(JAK) selected from the group consisting of cancer or tumor, graft rejection, autoimmune and inflammatory diseases, and proliferative diseases, which comprises a compound of any one of claims 1 to 4 as an active ingredient. A pharmaceutical composition for the prevention or treatment of diseases caused by activity.
9. The method of claim 8,
The disease is selected from the group consisting of cancer, graft rejection, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, psoriasis, asthma, allergic dermatitis, atopic dermatitis, eczema, type I diabetes, diabetic complications, ulcerative colitis, Crohn's disease, ≪ RTI ID = 0.0 > disorder. ≪ / RTI >