KR20180051220A - Novel pyrrolopyrimidine derivatives and pharmaceutical composition comprising the same - Google Patents

Abstract

The present invention relates to a compound represented by chemical formula 1, or a pharmaceutically acceptable salt thereof. According to the present invention, the compound has effective inhibitory functions against Briton′s tyrosine kinase (BTK) and is able to be useful for preventing or treating diseases. In the chemical formula 1, X, L, and R are the same as defined in the present specification.

Description

TECHNICAL FIELD [0001] The present invention relates to novel pyrrolopyrimidine derivatives and pharmaceutical compositions containing the same. BACKGROUND OF THE INVENTION 1. Field of the Invention [0001] The present invention relates to pyrrolopyrimidine derivatives,

The present invention relates to novel pyrrolopyrimidine derivatives useful as BTK (Bruton's Tyrosine Kinase) inhibitors and pharmaceutical compositions containing them.

BTK (Bruton's Tyrosine Kinase) is a kind of TEC-type tyrosine kinase with ITK (Interleukin-2 Tyrosine Kinase), RLK (Resting Lymphocyte Kinase) and BMX (Bone-Marrow tyrosine kinase gene on chromosome X) But also function as modulators of mature B-cell activation, signal transduction and survival.

The B-cell is signaled by a B cell receptor (BCR) that recognizes an antigen attached to the surface of an antigen-presenting cell and is activated as a mature antibody-producing cell. However, abnormal signal transduction by BCR can lead to abnormal B-cell proliferation and the formation of pathologic autoantibodies, leading to cancer, autoimmune and / or inflammatory diseases.

Thus, in abnormal B-cell proliferation, signaling by the BCR may be blocked if BTK is deficient. Thus, inhibition of BTK can block B-cell mediated disease processes, so the use of BTK inhibitors may be a useful approach for the treatment of B-cell mediated diseases.

BTK can also be expressed by other cells that may be associated with disease besides B-cells. For example, BTK is an essential component of Fc-gamma signaling in bone marrow cells and is expressed by mast cells. Specifically, BTK-deficient bone marrow-derived mast cells exhibit damaged antigen-induced degranulation, and inhibition of BTK activity is known to be useful for treating pathological mast cell responses such as allergy and asthma (Iwaki et al. J. Biol Chem. 2005 280: 40261). It is also known that monocytes of patients with XKL without BTK activity are able to inhibit TNF alpha mediated inflammation by inhibiting BTF inhibitors by reducing TNF alpha production following stimulation (Horwood et al., J. Exp. Med. 197: 1603, 2003).

Accordingly, there is a need in the art to develop a BTK inhibitor capable of inhibiting the activity of BTK. At present, ibrutinib (PCI-32765) of Pharmacyclics has been released as a BTK inhibitor but it has been reported that side effects such as skin rash and diarrhea are reported in clinic. Therefore, development of a substance which inhibits BTK more stably and effectively (Drug Discov Today 2014 Aug 19 (8) 1200-4; WO2002 / 096909; WO2010-009342).

Accordingly, the present inventors have studied the novel compounds and found novel pyrrolopyrimidine derivative compounds having excellent low-performance as a BTK inhibitor, thereby completing the invention. Although the compounds belonging to the present invention have BTK inhibitory activity by themselves, they do not exclude the possibility that they are absorbed into the body and then exhibit a pharmacological action by a specific body environment or products of metabolic processes as agonists.

The present invention is to provide pyrrolopyrimidine derivatives useful as BTK inhibitors.

The present invention also provides a pharmaceutical composition comprising the pyrrolopyrimidine derivative as an active ingredient.

In order to solve the above-mentioned problems, the present invention provides a compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof:

[Chemical Formula 1]

In Formula 1,

X is NH, or O,

L is a bond, or CO,

R is C _3-10 heteroaryl containing 1 to 3 heteroatoms each independently selected from the group consisting of hydrogen, C _6-10 aryl, or N, O, and S,

Wherein R is unsubstituted or substituted with one or two R '

R 'is independently, halogen, C _1-4 alkyl, morpholino furnace substituted C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _6-10 Aryl, C _6-10 aryloxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, pyrazolyl, pyrazolyl substituted with one or two C _1-4 alkyl, piperazinyl, or Piperazinecarbonyl.

Preferably, R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl, wherein R is unsubstituted or substituted with one or two R '.

Preferably, each R 'is independently selected from the group consisting of fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, , Morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl.

Also preferably, L is a bond and R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl, wherein R is unsubstituted or substituted with one or two R '. Wherein R 'is selected from the group consisting of fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, Pyridinyl, methylpyrazolyl, or piperazinecarbonyl.

Also preferably, X is NH, L is CO, and R is phenyl or pyridinyl, wherein R is unsubstituted or substituted with one R '. At this time, it is preferable that R 'is phenoxy.

Also preferably, L is a bond and R is phenyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl, wherein R is unsubstituted or substituted with one R '. Wherein R 'is selected from the group consisting of methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, Nyl.

Also preferably, the compound represented by Formula 1 is represented by the following Formula 1-1:

[Formula 1-1]

In Formula 1-1,

X is NH, or O,

L is a bond, or CO,

R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl,

   Wherein R is unsubstituted or substituted with one or two R '

R 'is selected from the group consisting of fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, , Methyl pyrazolyl, or piperazinecarbonyl.

Also preferably, the compound represented by Formula 1 is represented by the following Formula 1-2:

[Formula 1-2]

In Formula 1-2,

X is NH,

L is a bond, or CO,

R is phenyl, or pyridinyl,

   Wherein R is unsubstituted or substituted with one R '

R 'is phenoxy, or pyridinyl.

The compound represented by the formula (1) is any one selected from the group consisting of:

One) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (4-phenoxyphenyl)

2) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (4-

3) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6-

4) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (4- (6- (4-phenoxyphenyl)

5) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3-

6) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3-

7) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6-

8) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (3-phenoxyphenyl)

9) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (4- (morpholine-

10) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (4- (tetrahydro-

11) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (4-cyclohexylphenyl)

12) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6-

13) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (naphthalen-

14) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (lH-

15) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) -phenyl] -N- (3- (6- (1- (2-morpholinoethyl) ) Acrylamide,

16) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (4- (morpholinomethyl)

17) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (lH-

18) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (benzofuran-5-

19) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (pyridin-

20) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (6-methylpyridin-

21) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (6- (trifluoromethyl)

22) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (6-morpholinopyridin-

23) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (6-methoxypyridin-

24) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6- (6-phenylpyridin-

25) Pyrrolo [2,3-d] pyrimidin-4-ylamino) -pyridin-2-yl] ) Phenyl) acrylamide,

26) Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide and N- (3- (6- (4- (piperazin- 1 -carbonyl)

27) N- (3- (6- (4- (morpholinomethyl) phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-yloxy) phenyl) acrylamide.

In addition, 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.

As the free acid, an organic acid and an inorganic acid can be used. As the inorganic acid, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like can be used. Examples of the organic acid 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, But are not limited thereto.

In addition, a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base. For example, a compound represented by the formula (1) is dissolved in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, the non-soluble compound salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt . At this time, it is preferable to prepare, as the metal salt, especially a sodium salt, a potassium salt or a calcium salt.

Other pharmaceutically acceptable salts or solvates of the compounds of formula (I) may be used as intermediates in the preparation of compounds of formula (I), their pharmaceutically acceptable salts or solvates.

In addition, the compounds represented by Formula 1 according to the present invention include, without limitation, pharmaceutically acceptable salts thereof, as well as solvates such as possible hydrates, which can be prepared therefrom, and all possible stereoisomers. The solvates and stereoisomers of the compounds represented by the formula (1) can be prepared from the compounds represented by the formula (1) using methods known in the art.

In addition, the compound represented by Formula 1 according to the present invention may be prepared in crystalline form or amorphous form, and may be optionally hydrated or solvated when prepared in crystalline form. In the present invention, compounds containing various amounts of water as well as stoichiometric hydrates of the compound represented by the formula (1) may be included. Solvates of the compounds of formula (I) according to the present invention include both stoichiometric solvates and non-stoichiometric solvates.

In addition, the present invention provides, for example, a compound represented by the above formula (1) through the following Reaction Scheme 1.

[Reaction Scheme 1]

In the above Reaction Scheme 1, X and R are the same as defined in Formula 1, X 'is amino or hydroxy, and Z is halogen.

Specifically, the compound represented by Formula 1 may be prepared in Step 1, 1-1, and 1-2 when L is CO, and may be prepared in Steps 1, 2, and 2 when L is a bond. -1 and 2-2.

Step 1 is a step for reacting a 6-chloro-7-desig purine compound represented by the formula A1 with benzenesulfonyl chloride to obtain 4-chloro-7- (phenylsulfonyl) -7H-pyrrolo [ , 3-d] pyrimidine compound. The reaction is preferably carried out in a tetrahydrofuran solvent.

Step 1-1 is a step of reacting a compound represented by the formula (A2) and a compound represented by the formula (A3) to prepare a compound represented by the formula (A4) wherein the R-CO group is introduced. The reaction is preferably carried out under lithium diisopropylamide, with tetrahydrofuran being preferred as the solvent.

Step 1-2 is a step of reacting a compound represented by the formula (A4) with a compound represented by the formula (A5) to prepare a compound represented by the formula (1) wherein L is CO. The reaction is preferably carried out at a temperature of 100 to 200 ° C, and the solvent is preferably an alcohol such as isopropyl.

Step 2 is a step of reacting a compound represented by the formula (A2) with a halogen to prepare a compound represented by the formula (A6). The reaction is preferably carried out under hydrochloric acid conditions, with tetrahydrofuran being preferred as the solvent.

Step 2-1 is a step of reacting a compound represented by the formula A6 with a boronic acid compound substituted with an R group represented by the formula A7 to prepare a compound represented by the formula A8 into which an R group has been introduced. The reaction is preferably carried out in the presence of a palladium catalyst and sodium carbonate, with 1,4-dioxane being preferred as the solvent.

Step 2-2 is a step of reacting a compound represented by the formula (A8) with a compound represented by the formula (A5) to prepare a compound represented by the formula (1) wherein L is a bond. The above reaction can be carried out in the same manner as in Step 1-2.

The present invention also relates to a method for preventing or treating an autoimmune disease or a cancerous disease, wherein the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof is effective as a BTK inhibitory action A pharmaceutical composition is provided.

Wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, childhood diabetes, psoriasis, aphthous stomatitis, chronic thyroiditis, some acquired acquired anemia, primary cirrhosis, ulcerative colitis, vesicular disease, Crohns disease, , Sjogren's syndrome, Gillian-Barre syndrome, dermatomyositis, multiple myositis, autoimmune hemolytic anemia, autoimmune encephalomyelitis, myasthenia gravis, Graves' thyroid hyperplasia, nodular polyarteritis, ankylosing spondylitis, temporal arteritis, Wilson's disease , Or Fanconi's syndrome,

Wherein the cancer is selected from the group consisting of blood cancer, extramedullary marginal B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myelogenous leukemia, macroglobulinemia, B cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-Hodgkin's lymphoma, Ovarian cancer, colon cancer, kidney cancer, gastric cancer, metastatic carcinoma, carcinoid, breast cancer, non-small cell lung cancer, or multiple myeloma.

The term "prophylactic" of the present invention means any action that inhibits or delays the occurrence, spread and recurrence of the disease upon administration of the composition of the present invention, and "treatment" Means any act that improves or is beneficially modified.

The pharmaceutical compositions of the present invention may be formulated into oral or parenteral administration forms according to standard pharmaceutical practice. These formulations may contain, in addition to the active ingredient, an additive such as a pharmaceutically acceptable carrier, adjuvant or diluent.

Suitable diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or lactose such as physiological saline, polyethylene glycol, ethanol, vegetable oil and isopropyl myristate. Or glycine, but are not limited thereto. In addition, the compounds of the present invention may be dissolved in oils, propylene glycol or other solvents commonly used in the preparation of injection solutions. The compounds of the invention may also be formulated in ointments or creams for topical application.

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.

Depending on the administration method, the pharmaceutical composition may contain 0.001 to 99% by weight, preferably 0.01 to 60% by weight, of the compound of the present invention.

The pharmaceutical composition according to 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.

The compound represented by the formula (1) of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof, may be usefully used for the prevention or treatment of diseases in which the BTK inhibitory action is beneficial.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example  1: N- (3 - ((6- (4- Phenoxyphenyl ) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

Step 1- 1: 4 - Chloro -7- ( Phenylsulfonyl ) -7H- Pyrrolo [2,3-d] pyrimidine  Produce

Chloro-7-desig purine (20 g, 1.0 eq) was dissolved in tetrahydrofuran (200 ml) at 0 ° C after dissolving 60% sodium hydride (7.8 g, 1.5 eq) in tetrahydrofuran . Was stirred at 0 < 0 > C for 10 min and benzenesulfonyl chloride (16.95 ml, 1.02 eq) was added dropwise. After the dropwise addition, the mixture was warmed to room temperature and stirred for 2 hours. Water was added and extracted with EA. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was slurried in acetonitrile (400 ml) and then filtered to give the title compound (29.7 g, yield 78%).

Step 1- 2: 4 - Chloro -6- Iodo -7- ( Phenylsulfonyl ) -7H- Pyrrolo [2,3-d] pyrimidine  Manufacturing

Pyrrolo [2,3-d] pyrimidine (5 g, 1.0 eq) obtained in Step 1-1 was dissolved in tetrahydrofuran (150 ml), followed by the addition of 4-chloro-7- (phenylsulfonyl) 1.5 M lithium diisopropylamide (17.02 ml, 1.5 eq) was added dropwise at -78 < 0 > C under nitrogen. After stirring at -78 ° C for 1 hour, iodine (5.62 g, 1.3 eq) was dissolved in tetrahydrofuran (30 ml) and added dropwise. After stirring at -78 ° C for 1 hour, 1N hydrochloric acid (90 ml) was added. The mixture was heated to room temperature and concentrated under reduced pressure. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was slurried in acetonitrile (50 ml) and then filtered to give the title compound (4.48 g, yield 63%).

Step 1- 3: 4 - Chloro -6- (4- Phenoxyphenyl ) -7- ( Phenylsulfonyl ) -7H- Pyrrolo [2,3-d] pyrimidine Manufacture of Middin

7-Pyrrolo [2,3-d] pyrimidine (100 mg, 1.0 eq) obtained in Step 1-2 was dissolved in 1,4-dioxane (51.4 mg, 1.0 eq), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (19.6 mg, 0.1 eq), sodium carbonate (76.3 mg, 3.0 eq). Followed by stirring at 100 DEG C for 12 hours. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate: hexane = 1: 4) to give the title compound (58.6 mg, yield 53%).

Step 1-4: N- (3- Nitrophenyl ) Acrylamide  Produce

3-Nitroaniline (500 mg, 1.0 eq) was dissolved in tetrahydrofuran (10 ml) and then triethylamine (0.76 ml, 1.5 eq) was added thereto and stirred for 10 minutes. Acryloyl chloride (0.59 ml, 2.0 eq) was added dropwise at 0 占 폚, followed by stirring at room temperature for 2 hours. The solid formed during the reaction was filtered, water was added to the filtrate and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was slurried in dichloromethane and then filtered to give the title compound (320 mg, yield 46%).

Step 1-5: N- (3- Aminophenyl ) Acrylamide  Produce

220 mg (1.0 eq) of N- (3-nitrophenyl) acrylamide obtained in Step 1-4 was dissolved in methanol (5 ml) and tetrahydrofuran (5 ml), and then tin chloride (1.29 g, 5.0 eq ). And the mixture was stirred at room temperature for 12 hours. Water was added and extracted with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain the title compound (145 mg, yield 78%).

Step 1-6: N- (3 - ((6- (4- Phenoxyphenyl ) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

Pyrrolo [2,3-d] pyrimidine (16.1 mg, 1.0 eq) obtained in Step 1-3 was added to a solution of 4-chloro-6- (4-phenoxyphenyl) After dissolving in isopropyl alcohol (2 ml), N- (3-aminophenyl) acrylamide (6.8 mg, 10 eq) obtained in Step 1-5 was added. And reacted in a microwave reactor at 150 ° C for 2 hours. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (dichloromethane: methanol = 9: 1) to obtain the title compound (1.3 mg, yield 18%).

^{1 H NMR (500 MHz, MeOD} ): 8.19-8.08 (m, 2H), 7.78 (d, 2H), 7.44-7.29 (m, 5H), 7.15 (t, 1H), 7.06 (t, 4H), 6.93 (d, IH), 6.48 (d, IH), 6.36 (d, IH), 5.76

Example  2: N- (3 - ((6- (4- (Pyridin-3-yl) phenyl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The same procedure as in Example 1 was performed except that (4- (pyridin-3-yl) phenyl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in Step 1-3 of Example 1 To give the title compound (4.2 mg, 24% yield).

¹ H NMR (500 MHz, DMSO): 12.37 (s, IH), 10.15 (s, IH), 9.47 2H), 7.86 (d, 1H), 7.51-7.48 (m, 1H), 7.33-7.25 (d, (m, 3H), 6.48 (d, IH), 6.25 (d, IH), 5.75

Example  3: N- (3 - ((6- (4- Molopolynophenyl ) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The procedure of Example 1 was repeated except for using (4-morpholinophenyl) boronic acid instead of (4-phenoxyphenyl) boronic acid in Step 1-3 of Example 1 to obtain the title compound 2.1 mg, yield: 12%).

^{1 H NMR (500 MHz, DMSO} ): 12.25 (s, 1H), 10.18 (s, 1H), 9.28 (s, 1H), 8.24 (d, 2H), 7.70-7.63 (m, 3H), 7.30-7.21 (m, 2H), 7.05-7.02 (m, 3H), 6.48 (d, IH), 6.23 (d, IH), 5.74 (d,

Example  4: N- (4 - ((6- (4- Phenoxyphenyl ) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The title compound (2.8 mg, yield 9%) was obtained by carrying out the same processes as in the above Example 1, except that 4-nitroaniline was used instead of 3-nitroaniline in the step 1-4 of Example 1 .

^{1 H NMR (500 MHz, MeOD} ): 8.20 (s, 1H), 7.77 (d, 2H), 7.70 (d, 2H), 7.64 (d, 2H), 7.38 (t, 2H), 7.14 (t, 1H ), 7.07-7.04 (m, 4H), 6.89 (s, IH), 6.45 (d, IH), 6.36

Example  5: N- (3 - ((6- Benzoyl -7H- Pyrrolo [2,3-d] pyrimidine 4-yl) amino) phenyl) Acrylamide  Produce

Step 5- 1: (4-Chloro-7- (phenylsulfonyl) -7H- Pyrrolo [2,3-d] pyrimidine -6-yl) (phenyl) methanone

Pyrrolo [2,3-d] pyrimidine (100 mg, 1.0 eq) obtained in Step 1-1 was dissolved in tetrahydrofuran (3.0 ml), followed by the addition of 4-chloro-7- (phenylsulfonyl) 1.5 M lithium diisopropylamide (0.3 ml, 1.2 eq) was added dropwise at -78 < 0 > C under nitrogen. After stirring at -78 ° C for 1 hour, benzoyl chloride (57.4 mg, 1.2 eq) was dissolved in tetrahydrofuran (1.0 ml) and added dropwise. After stirring at -78 ° C for 3 hours, ammonium chloride (1.0 ml) was added. The mixture was heated to room temperature and concentrated under reduced pressure. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was slurried in methanol (5.0 ml) and then filtered to give the title compound (30.0 mg, yield 63%).

Step 5-2: N- (3 - ((6- Benzoyl -7H- Pyrrolo [2,3-d] pyrimidine 4-yl) amino) phenyl) Ah Preparation of Crylamide

Pyrrolo [2,3-d] pyrimidin-6-yl) (phenyl) methanone (15.0 mg, 1.0 eq) obtained in Step 5-1, Was dissolved in isopropyl alcohol (2 ml), and then N- (3-aminophenyl) acrylamide (6.1 mg, 1.0 eq) obtained in Step 1-5 was added thereto. And reacted in a microwave reactor at 150 ° C for 2 hours. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 4: 1) to obtain the title compound (6.2 mg, yield 43%).

¹ H NMR (500 MHz, DMSO): 12.64 (s, IH), 10.16 (s, IH), 9.77 (s, IH), 8.39 ), 7.71-7.59 (m, 4H), 7.33-7.25 (m, 2H), 6.46 (d,

Example  6: N- (3 - ((6-Phenyl-7H- Pyrrolo [2,3-d] pyrimidine 4-yl) amino) phenyl) Arc Preparation of reamamide

The title compound (4.2 mg, yield: 24%) was prepared following the same procedure as in Example 1, except that phenylboronic acid was used instead of (4-phenoxyphenyl) boronic acid in Step 1-3 of Example 1 .

^{1 H NMR (500 MHz, MeOD} ): 8.23 (s, 1H), 8.20 (s, 1H), 7.79 (d, 2H), 7.63-7.40 (m, 4H), 7.34-7.30 (m, 2H), 7.02 (s, IH), 6.46 (d, IH), 6.37 (d, IH), 5.77

Example  7: N- (3 - ((6- (1- methyl -1H- Pyrazole Yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The same procedure as in Example 1 was performed except that (1-methyl-1H-pyrazol-4-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1 To give the title compound (7.4 mg, 34% yield).

^{1 H NMR (500 MHz, MeOD} ): 8.20 (s, 1H), 8.16 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.40 (t, 2H), 7.31 (t, 1H ), 6.71 (d, IH), 6.76 (d, IH)

Example  8: N- (3 - ((6- (3- Phenoxyphenyl ) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

Following the same procedure as in Example 1, except for using (3-phenoxyphenyl) boronic acid instead of (4-phenoxyphenyl) boronic acid in Step 1-3 of Example 1, the title compound (4.9 mg , Yield 16%).

^{1 H NMR (500 MHz, MeOD} ): 8.22 (s, 1H), 8.15 (s, 1H), 7.82 (d, 1H), 7.55 (d, 1H), 7.46-7.38 (m, 4H), 7.15 (t , 7.06 (d, 2H), 7.01 (s, IH), 6.98 (d, IH), 6.44

Example  9: N- (3 - ((6- (4- ( Morpholine -4- Carbonyl ) Phenyl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The same procedure as in Example 1 was performed except that (4- (morpholine-4-carbonyl) phenyl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1 To give the title compound (5.2 mg, 20% yield).

^{1 H NMR (500 MHz, MeOD} ): 8.27 (s, 1H), 8.21 (s, 1H), 7.89 (d, 2H), 7.53 (d, 2H), 7.46-7.31 (m, 3H), 7.12 (s (D, IH), 3.76 (m, 4H), 3.54 (m, 4H)

Example  10: N- (3 - ((6- (4- ( Tetrahydro -2H-pyran-4-yl) phenyl) -7H- Pyrrole 2,3-d] pyrimidin-4-yl) amino) phenyl) acrylamide

Example 1 was repeated except that (4- (tetrahydro-2H-pyran-4-yl) phenyl) boronic acid was used in place of (4-phenoxyphenyl) The same procedure was followed to give the title compound (4.7 mg, 23% yield).

^{1 H NMR (500 MHz, MeOD} ): 8.23 (s, 1H), 8.18 (s, 1H), 7.74 (d, 2H), 7.43-7.33 (m, 5H), 6.99 (s, 1H), 6.44 (d 1H), 1.82 (m, 4H), 2.45 (m, 2H)

Example  11: N- (3 - ((6- (4- Cyclohexylphenyl ) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The procedure of Example 1 was repeated except for using (4-cyclohexylphenyl) boronic acid instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1 to obtain the title compound (4.4 mg , Yield 19%).

^{1 H NMR (500 MHz, MeOD} ): 8.23 (s, 1H), 8.19 (s, 1H), 7.70 (d, 2H), 7.42 (t, 2H), 7.33-7.29 (m, 3H), 6.96 (s (M, 4H), 1.47 (m, 4H), 1.33 (m, 1H), 6.46 (d, 2H)

Example  12: N- (3 - ((6- (3- Molopolynophenyl ) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

(3-morpholinophenyl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1, the title compound (3.6 mg, yield 20%).

^{1 H NMR (500 MHz, MeOD} ): 8.24 (s, 1H), 8.19 (s, 1H), 7.43-7.24 (m, 6H), 6.99 (s, 1H), 6.96 (d, 1H), 6.46 (d (T, 1H), 6.36 (d, 1H), 5.77 (d,

Example  13: N- (3 - ((6- (Naphthalen-1-yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

Following the same procedure as in Example 1, except using (naphthalen-1-yl) boronic acid instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1, the title compound (4.6 mg , Yield: 24%).

^{1 H NMR (500 MHz, MeOD} ): 8.32 (m, 2H), 8.23 (s, 1H), 7.96-7.92 (m, 2H), 7.68 (d, 1H), 7.58-7.53 (m, 3H), 7.46 (M, 2H), 7.32 (t, IH), 6.47 (d, IH), 6.37

Example  14: N- (3 - ((6- (1H-Indol-4-yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The procedure of Example 1 was repeated except that (1H-indol-4-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1 to obtain the title compound 5.8 mg, yield 26%).

¹ H NMR (500 MHz, MeOD): 8.26 (s, IH), 8.21 (s, IH), 7.46-7.32 (m, 6H), 7.21 , 6.45 (d, IH), 6.36 (d, IH), 5.77 (d, IH)

Example  15: N- (3 - ((6- (1- (2- Molpolinoethyl ) -1H- Pyrazole Yl) -7H- Pyrrolo [2,3- d] pyrimidin-4-yl) amino) phenyl) acrylamide

Except that (1- (2-morpholinoethyl) -1H-pyrazol-4-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1, The title compound (1.0 mg, yield 4%) was obtained by carrying out the same procedure as in Example 1.

¹ H NMR (500 MHz, DMSO): 12.04 (s, IH), 10.13 (s, IH), 9.31 ), 7.62 (d, IH), 7.24 (d, IH), 7.24 (d, IH), 6.85 , 4.27 (m, 2H), 3.55 (m, 4H), 2.71 (m, 2H), 2.41

Example  16: N- (3 - ((6- (4- ( Molopolymomethyl ) Phenyl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The procedure of Example 1 was repeated except that (4- (morpholinomethyl) phenyl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in Step 1-3 of Example 1 to obtain (1.1 mg, yield 6%).

¹ H NMR (500 MHz, DMSO): 12.25 (s, 1 H), 10.17 (s, 1 H), 9.43 (M, 2H), 2.36 (d, IH), 5.73 (d, IH) m, 4H)

Example  17: N- (3 - ((6- (lH-indol-5-yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The procedure of Example 1 was repeated except for using (lH-indol-5-yl) boronic acid instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1 to obtain the title compound 2.1 mg, yield 15%).

^{1 H NMR (500 MHz, MeOD} ): 8.22 (s, 1H), 8.18 (s, 1H), 8.00 (s, 1H), 7.56 (d, 1H), 7.46-7.43 (m, 3H), 7.34-7.28 (m, 2H), 6.91 (s, IH), 6.52 (d, IH), 6.44

Example  18: N- (3 - ((6- ( Benzofuran -5-yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The same procedure as in Example 1 was conducted, except that (benzofuran-5-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1 to obtain the title compound 3.3 mg, yield 16%).

^{1 H NMR (500 MHz, MeOD} ): 8.23 (s, 1H), 8.18 (s, 1H), 8.04 (s, 1H), 7.84 (s, 1H), 7.75 (d, 1H), 7.60 (d, 1H ), 7.46-7.39 (m, 3H), 7.01 (s, IH), 6.92 (d, IH), 6.44

Example  19: N- (3 - ((6- (Pyridin-3-yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The same procedure as in Example 1 was performed, except that (pyridin-3-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in Step 1-3 of Example 1 to obtain the title compound (7.8 mg , Yield: 41%).

¹ H NMR (500 MHz, DMSO): 12.43 (s, IH), 10.15 (s, IH), 9.50 ), 8.26 (s, IH), 8.16 (d, IH), 7.66 (d, IH), 7.49 (d, IH), 7.33-7. 1H), < / RTI > 5.75 (d, 1H)

Example  20: N- (3 - ((6- (6- Methyl pyridine Yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The same procedure as in Example 1 was performed, except that (6-methylpyridin-3-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in the step 1-3 of Example 1 to obtain the title compound (1.3 mg, yield 8%).

¹ H NMR (500 MHz, MeOD): 8.85 (s, IH), 8.26 (s, IH), 8.21 (s, IH), 8.10 (d, IH), 7.46-7.39 , 7.09 (s, 1 H), 6.47 (d, 1 H), 6.38 (d,

Example  21: N- (3 - ((6- (6- ( Trifluoromethyl ) Pyridin-3-yl) -7H- Pyrrolo [2,3-d] pyrimidin- Pyrimidin-4-yl) amino) phenyl) acrylamide

Except that (6- (trifluoromethyl) pyridin-3-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1, To give the title compound (7.0 mg, 36% yield).

^{1 H NMR (500 MHz, MeOD} ): 9.13 (s, 1H), 8.35 (d, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.87 (d, 1H), 7.46 (d, 1H ), 7.39 (d, IH), 7.32 (t, IH), 7.27 (s, IH)

Example  22: N- (3 - ((6- (6- Molopolypyridine Yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The same procedure as in Example 1 was carried out except that (6-molopolypyridin-3-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1 The title compound (1.7 mg, yield 8%) was obtained.

¹ H NMR (500 MHz, MeOD): 8.58 (s, IH), 8.22 (s, IH), 8.19 (s, IH), 7.97 (d, IH), 7.44-7.30 (D, IH), 3.81 (t, 4H), 3.55 (t, 4H)

Example  23: N- (3 - ((6- (6- Methoxypyridine Yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The procedure of Example 1 was repeated except that (6-methoxypyridin-3-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in Step 1-3 of Example 1 to obtain Compound (4.2 mg, yield 18%).

^{1 H NMR (500 MHz, MeOD} ): 8.51 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 8.07 (d, 1H), 7.45-7.31 (m, 3H), 6.95 (s (D, IH), 6.76 (d, IH), 6.96 (d, IH)

Example  24: N- (3 - ((6- (6- Phenylpyridine Yl) -7H- Pyrrolo [2,3-d] pyrimidine Yl) amino) phenyl) acrylamide < / RTI >

The same procedure as in Example 1 was performed, except that (6-phenylpyridin-3-yl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1 to obtain the title compound (12.5 mg, yield 36%).

^{1 H NMR (500 MHz, MeOD} ): 9.07 (s, 1H), 8.29-8.24 (m, 3H), 8.03-7.96 (3H), 7.53-7.41 (m 5H), 7.33 (t, 1H), 7.19 ( s), 6.46 (d, IH), 6.37 (d, IH), 5.77

Example  25: N- (3 - ((6- (6- (1- methyl -1H- Pyrazole Yl) pyridin-3-yl) -7H- Pyrrole 2,3-d] pyrimidin-4-yl) amino) phenyl) acrylamide

Except that (6- (1-methyl-1H-pyrazol-3-yl) pyridin-3-yl) boronic acid was used in place of (4-phenoxyphenyl) boronic acid in step 1-3 of Example 1 , The same procedure as in Example 1 was conducted to give the title compound (9.4 mg, yield 27%).

^{1 H NMR (500 MHz, MeOD} ): 8.98 (s, 1H), 8.28 (s, 1H), 8.22 (d, 2H), 8.04 (d, 1H), 7.67 (s, 1H), 7.46 (d, 1H ), 7.42 (d, IH), 7.33 (t, IH), 7.17 (s, IH), 6.91 , 3.99 (s, 3H)

Example  26: N- (3 - ((6- (4- (Piperazin-1- Carbonyl ) Phenyl) -7H- Pyrrolo [2,3-d] pyrimidine 4-yl) amino) phenyl) acrylamide < / RTI >

The same procedure as in Example 1 was performed except that (4- (piperazine-1-carbonyl) phenyl) boronic acid was used instead of (4-phenoxyphenyl) boronic acid in Step 1-3 of Example 1 To give the title compound (1.2 mg, yield 8%).

^{1 H NMR (500 MHz, MeOD} ): 8.26 (d, 1H), 7.89 (d, 2H), 7.52 (d, 1H), 7.44-7.31 (m, 4H), 7.11 (d, 1H), 6.47 (d (T, 4H), 2.86 (t, 4H), 3.87 (d,

Example  27: N- (3- (6- (4- ( Molopolymomethyl ) Phenyl) -7H- Pyrrolo [2,3-d] pyrimidine -4- Work Oxy) phenyl) acrylamide

7H-pyrrolo [2,3-d] pyrimidine (50.0 mg, 0.15 mmol) obtained in the step 1-3 of Example 1 above was added to a solution of 4-chloro-6- (4-phenoxyphenyl) , 1.0 eq) was dissolved in dimethylformamide (2 ml), and then N- (3-hydroxyphenyl) acrylamide (17.4 mg, 1.0 eq) and potassium carbonate (29.6 mg, 2.0 eq) were added in this order. And reacted in a microwave reactor at 130 DEG C for 1 hour. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethyl acetate: hexane = 4: 1) to give the title compound (1.2 mg, yield 3%).

^{1 H NMR (500 MHz, MeOD} ): 8.28 (s, 1H), 7.78 (d, 2H), 7.72 (s, 1H), 7.53-7.41 (m, 4H), 7.02 (d, 1H), 6.74 (s 2H), 2.48 (m, 4H), 3.70 (d, IH)

Experimental Example  One: BTK  Inhibitory activity against

The inhibitory activity against BTK of the compounds prepared in Examples 1 to 27 was measured as follows.

Evaluation of inhibitory activity against BTK was evaluated using Promega's 'ADP-Glo ™ + BTK Kinase enzyme system' kit. If White 96-well plate to have a final concentration of 1 ng / μL one single concentration evaluation of BTK enzyme 10 μL and the compound prepared so that in the case where the final concentration of 1 μM, IC ₅₀ Rating Date 1000, 300, 100, 30, 10, 3 , 5 μL of compound at concentrations of 1, 0.3, 0.1, and 0.03 nM were mixed and reacted at room temperature for 15 minutes. 5 μL of the substrate and 5 μL of ATP prepared to give a final concentration of 10 μM were added to the plate after completion of the reaction, followed by reaction at 30 ° C. for 1 hour. All wells of the plate were reacted with 25 μL of ADP-Glo ™ reagent and reacted at 30 ° C for 40 minutes. After that, 50 μL of kinase detection buffer was added to all wells, and the reaction was stopped at 30 ° C. for 30 minutes. After all the reactions were completed, luminescence was measured and the results were calculated. Evaluation was carried out in duplicate. Negative control and positive control were calculated according to whether the enzyme was added or not, and the% inhibitory activity and IC ₅₀ were calculated based on the values.

% Inhibitory activity
(%, @ 1 [mu] M) IC ₅₀
(nM) % Inhibitory activity
(%, @ 1 [mu] M) IC ₅₀
(nM) Example 1 100 20.9 Example 15 94 1.8 Example 2 94 3.3 Example 16 95 1.3 Example 3 95 8.9 Example 17 98 5.9 Example 4 35 ~ 1000 Example 18 99 5.2 Example 5 89 138.6 Example 19 97 1.7 Example 6 97 3.6 Example 20 99 5.3 Example 7 97 1.1 Example 21 98 6.5 Example 8 94 67.2 Example 22 98 3.4 Example 9 98 1.1 Example 23 99 8.5 Example 10 94 5.8 Example 24 98 26.0 Example 11 93 20.1 Example 25 98 8.9 Example 12 96 6.1 Example 26 - 2.3 Example 13 96 42.3 Example 27 - 3.5 Example 14 90 2.8

From the results of Experimental Example 1, it can be seen that the compounds according to one embodiment of the present invention exhibit excellent BTK inhibitory activity.

Claims (10)

Claims 1. A compound represented by the following formula (1): < EMI ID =
[Chemical Formula 1]

In Formula 1,
X is NH, or O,
L is a bond, or CO,
R is C _3-10 heteroaryl containing 1 to 3 heteroatoms each independently selected from the group consisting of hydrogen, C _6-10 aryl, or N, O, and S,
Wherein R is unsubstituted or substituted with one or two R '
R 'is independently, halogen, C _1-4 alkyl, morpholino furnace substituted C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, C _3-6 cycloalkyl, C _6-10 Aryl, C _6-10 aryloxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, pyrazolyl, pyrazolyl substituted with one or two C _1-4 alkyl, piperazinyl, or Piperazinecarbonyl.
The method according to claim 1,
R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl,
Wherein R is unsubstituted or substituted with one or two R '
≪ / RTI > or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
R 'are each independently selected from the group consisting of fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, ≪ / RTI > pyridinyl, methylpyrazolyl, or piperazinecarbonyl,
≪ / RTI > or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
L is a bond,
R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl,
Wherein R is unsubstituted or substituted with one or two R '
R 'is selected from the group consisting of fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, , Methyl pyrazolyl, or piperazinecarbonyl,
≪ / RTI > or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
X is NH,
L is CO,
R is phenyl, or pyridinyl,
Wherein R is unsubstituted or substituted with one R '
R 'is phenoxy,
≪ / RTI > or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
L is a bond,
R is phenyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl,
Wherein R is unsubstituted or substituted with one R '
R 'is methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl ,
≪ / RTI > or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
The compound is represented by the following general formula (1-1)
A compound, or a pharmaceutically acceptable salt thereof:
[Formula 1-1]

In Formula 1-1,
X is NH, or O,
L is a bond, or CO,
R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl,
Wherein R is unsubstituted or substituted with one or two R '
R 'is selected from the group consisting of fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, , Methyl pyrazolyl, or piperazinecarbonyl.
The method according to claim 1,
The compound is represented by the following general formula (1-2)
A compound, or a pharmaceutically acceptable salt thereof:
[Formula 1-2]

In Formula 1-2,
X is NH,
L is a bond, or CO,
R is phenyl, or pyridinyl,
Wherein R is unsubstituted or substituted with one R '
R 'is phenoxy, or pyridinyl.
The method according to claim 1,
The compound represented by the general formula (1)
1) N- (3- (6- (4-phenoxyphenyl) -7H-pyrrolo [2,3- d] pyrimidin-4- ylamino) phenyl) acrylamide,
2) N- (3- (6- (4- (pyridin-3-yl) phenyl) -7H-pyrrolo [2,3- d] pyrimidin-
3) N- (3- (6- (4 -morpholinophenyl) -7H-pyrrolo [2,3-d] pyrimidin-
4) Synthesis of N- (4- (6- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-
5) N- (3- (6-Benzoyl-7H-pyrrolo [2,3-d] pyrimidin-4- ylamino) phenyl) acrylamide,
6) N- (3- (6-phenyl-7H-pyrrolo [2,3-d] pyrimidin-4- ylamino) phenyl) acrylamide,
7) N- (3- (6- (1 -methyl-1 H-pyrazol-4-yl) -7H-pyrrolo [2,3- d] pyrimidin-
8) N- (3- (6- (3-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-
9) N- (3- (6- (4- (morpholine-4-carbonyl) phenyl) -7H-pyrrolo [2,3- d] pyrimidin-
Yl) phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylic acid Amide,
11) N- (3- (6- (4-cyclohexylphenyl) -7H-pyrrolo [2,3-d] pyrimidin-
Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6-
13) N- (3- (6- (naphthalen-l-yl) -7H-pyrrolo [2,3- d] pyrimidin- 4- ylamino) phenyl) acrylamide,
Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3-
15) N- (3- (6- (1- (2-morpholinoethyl) -1H-pyrazol-4-yl) -7H- pyrrolo [2,3- d] pyrimidin- ) Phenyl) acrylamide,
16) N- (3- (6- (4- (morpholinomethyl) phenyl) -7H-pyrrolo [2,3- d] pyrimidin-
17) N- (3- (6- (lH-indol-5-yl) -7H-pyrrolo [2,3- d] pyrimidin-
18) N- (3- (6- (Benzofuran-5-yl) -7H-pyrrolo [2,3- d] pyrimidin- 4- ylamino) phenyl) acrylamide,
19) N- (3- (6- (pyridin-3-yl) -7H-pyrrolo [2,3- d] pyrimidin- 4- ylamino) phenyl) acrylamide,
Pyrrolo [2,3-d] pyrimidin-4-ylamino) phenyl) acrylamide, N- (3- (6-
21) N- (3- (6- (6- (trifluoromethyl) pyridin-3-yl)
22) N- (3- (6- (6-morpholinopyridin-3-yl) -7H-pyrrolo [2,3- d] pyrimidin-
23) N- (3- (6- (6-methoxypyridin-3- yl) -7H-pyrrolo [2,3- d] pyrimidin- 4- ylamino) phenyl) acrylamide,
24) N- (3- (6- (6-phenylpyridin-3- yl) -7H-pyrrolo [2,3- d] pyrimidin- 4- ylamino) phenyl) acrylamide,
Pyrrolo [2,3-d] pyrimidin-4-yloxy) -thiazol-4-yl] Amino) phenyl) acrylamide,
26) N- (3- (6- (4- (piperazine-1-carbonyl) phenyl) -7H-pyrrolo [2,3- d] pyrimidin-
27) N- (3- (6- (4- (morpholinomethyl) phenyl) -7H-pyrrolo [2,3- d] pyrimidin-4- yloxy) phenyl) acrylamide
≪ / RTI > is selected from the group consisting < RTI ID = 0.0 &
≪ / RTI > or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition for the prophylaxis or treatment of autoimmune diseases or cancer, comprising a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.