WO2018088780A1 - Novel pyrrolopyrimidine derivatives and pharmaceutical composition comprising the same - Google Patents

Novel pyrrolopyrimidine derivatives and pharmaceutical composition comprising the same Download PDF

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Publication number
WO2018088780A1
WO2018088780A1 PCT/KR2017/012559 KR2017012559W WO2018088780A1 WO 2018088780 A1 WO2018088780 A1 WO 2018088780A1 KR 2017012559 W KR2017012559 W KR 2017012559W WO 2018088780 A1 WO2018088780 A1 WO 2018088780A1
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Prior art keywords
phenyl
pyrrolo
pyrimidin
ylamino
acrylamide
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PCT/KR2017/012559
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French (fr)
Inventor
Yun Soo Na
Keuk Chan Bang
Joon Seok Park
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Daewoong Pharmaceutical Co., Ltd.
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Publication of WO2018088780A1 publication Critical patent/WO2018088780A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to a novel pyrrolopyrimidine derivative useful as a BTK
  • BTK Bruton's Tyrosine Kinase
  • ITK Interleukin-2 Tyrosine Kinase
  • RLK Repsting Lymphocyte Kinase
  • BMX Benone- Marrow tyrosine kinase gene on chromosome X
  • BTK acts as a regulator of early B-cell development as well as of mature B-cell activation, signaling 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 into a mature antibody-producing cell.
  • BCR B cell receptor
  • aberrant signaling via BCR leads to abnormal B-cell proliferation and the formation of pathological autoantibodies, and thereby can induce cancer, autoimmune and/or inflammatory diseases.
  • BTK B-cell mediated diseases
  • BTK can be expressed by other cells that may be associated with disease besides B-cells.
  • BTK is important components for Fc-gamma signaling in bone marrow cells, and is expressed by mast cells.
  • BTK-deficient bone marrow-induced mast cells exhibit impaired 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).
  • monocytes from XLA patients in which BTK activity is absent, show decreased TNF alpha production following stimulation and thus TNF alpha-mediated inflammation could be inhibited by BTF inhibitors (see, Horwood et al, J. Exp. Med. 197: 1603, 2003).
  • BTK inhibitors capable of inhibiting the activity of BTK.
  • PCI-32765 PCI-32765, Pharmacyclics
  • side effects such as skin rash and diarrhea have been reported clinically, and thus there is a need to develop substances that can inhibit BTK more stably and effectively (see, Drug Discov Today 2014 Aug 19 (8) 1200-4; WO 2002/096909; WO 2010-009342).
  • the present inventors have found a novel pyrrolopyrimidine derivative having excellent inhibitory activity as a BTK inhibitor, thereby completing the present invention.
  • the compounds belonging to the present invention mainly have BTK inhibitory activity on their own, but do not exclude a possibility of exhibiting a pharmacological action as an efficacious agent by a special body environment or by products of metabolic process, after absorption into the body.
  • It is another object of the present invention to provide a pharmaceutical composition comprising the pyrrolopyrimidine derivative as an active ingredient.
  • the present invention provides a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
  • X is NH, or O
  • L is a bond, or CO
  • R is hydrogen, C 6 -io aryl, or C3.10 heteroaryl containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S,
  • R is unsubstituted or substituted with one or two R,
  • each R' is independently halogen, Cualkyl, Ci ⁇ alkyl substituted with morpholino, Q. 4 haloalkyl, Ci ⁇ alkoxy, C3 -6 cycloalkyl, C 6- ioaryl, C 6- io aryloxy, tetrahydropyranyl, mo ⁇ holino, mo ⁇ holinecarbonyl, pyridinyl, pyrazolyl, pyrazolyl substituted with one or two C alkyl, piperazinyl, or piperazinecarbonyl.
  • R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl, wherein the R is unsubstituted or substituted with one or two R'.
  • each R is independently fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl.
  • L is a bond
  • R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl, wherein the R is unsubstituted or substituted with one or two R.
  • R is preferably fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl.
  • X is NH
  • L is CO
  • R is phenyl or pyridinyl, wherein the R is unsubstituted or substituted with one R'.
  • R' is preferably phenoxy.
  • L is a bond and R is phenyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl, wherein the R is unsubstituted or substituted with one R'.
  • R' is preferably methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl .
  • the compound represented by Chemical Formula 1 is represented by the following Chem ical Formula 1 - 1 :
  • X is NH, or O
  • L is a bond, or CO
  • R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl,
  • R is substituted or is substituted with one or two R',
  • R is fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl.
  • Chemical Formula 1 is represented by the following Chemical Formula 1-2:
  • X is NH
  • L is a bond, or CO
  • R is phenyl or pyridinyl
  • R is unsubstituted or substituted with one R', and
  • R' is phenoxy, or pyridinyl.
  • the compound represented by Chemical Formula 1 is any one selected from the group consisting of:
  • the compounds of the present invention may exist in the form of salts, especially pharmaceutically acceptable salts.
  • salts salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids can be used without limitation.
  • pharmaceutically acceptable salt refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, whose concentration is relatively non-toxic and harmless to a patient and activates effectively and whose side effects do not degrade the beneficial efficacy of the above compound.
  • an organic acid and an inorganic acid can be used.
  • the inorganic acids include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like.
  • the organic acids include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like, but are not limited thereto.
  • a pharmaceutically acceptable metal salt can be obtained by a conventional method using a base.
  • a compound represented by Chemical Formula 1 is dissolved in an excessive amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, the non-soluble salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt.
  • a pharmaceutically unacceptable salt or solvate of the compound of Chemical Formula 1 may be used as an intermediate when preparing the compound of Chemical Formula 1 , or the pharmaceutically acceptable salt or the solvate thereof.
  • the compound of Chemical Formula 1 according to the present invention includes not only pharmaceutically acceptable salts thereof, but also solvates such as hydrates that can be prepared therefrom, and includes all possible stereoisomers, but are not limited thereto.
  • the solvate and the stereoisomer of the compound of Chemical Formula 1 may be prepared from the compound of Chemical Formula 1 using common methods known in the art.
  • the compound of Chemical Formula 1 according to the present invention may be prepared either in a crystalline form or in a non-crystalline form, and when the compound of Chemical Formula 1 is prepared in a crystalline form, it may be optionally hydrated or solvated.
  • the compound of Chemical Formula 1 may not only include a stoichiometric hydrate, but also include a compound containing various amounts of water.
  • the solvate of the compound of Chemical Formula 1 according to the present invention includes both stoichiometric solvates and non-stoichiometric solvates.
  • the present invention can produce the compound represented by Chemical Formula 1 through Reaction Scheme 1 below.
  • X and R are as previously defined in Chemical Fonnula 1
  • X' is amino or hydroxy
  • Z is halogen.
  • the compound represented by Chemical Formula 1 may be prepared though Step 1 , 1-1, and 1-2 when L is CO, and may be prepared through Steps 1, 2, 2-1 and 2-2 when L is a bond.
  • Step 1 is a step of reacting 6-chloro-7-daezapurine compound represented by Chemical Formula Al with benzenesulfonyl chloride to prepare 4-chloro-7-(phenylsulfonyl)-7H- pyrrolo[2,3-d]pyrimidine compound represented by Chemical Formula A2.
  • This reaction is preferably carried out in a solvent such as tetrahydrofuran.
  • Step l-l is a step of reacting a compound represented by Chemical Formula (A2) with a compound represented by Chemical Formula (A3) to prepare a compound represented by Chemical Formula (A4) in which an 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, with an alcohol such as isopropyl being preferred as the solvent.
  • Step 2 is a step of reacting a compound represented by Chemical Formula (A2) with a halogen to prepare a compound represented by Chemical 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 Chemical Formula (A 6) with a boronic acid compound substituted with an R group represented by Chemical Formula (A 7) to prepare a compound represented by Chemical Formula (A8) in which an R group is 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 Chemical Formula (A8) with a compound represented by Chemical Formula (A5) to prepare a compound represented by Chemical Formula 1 wherein L is a bond.
  • the reaction can be carried out in the same manner as in Step 1-2 described above.
  • the present invention provides a pharmaceutical composition for preventing or treating autoimmune diseases or cancers, which is effective for BTK inhibitory actions, comprising the compound represented by Chemical Formula 1 , or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient.
  • the autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, childhood diabetes, psoriasis, aphthous stomatitis, chronic thyroiditis, acquired aplastic anemia, primary cirrhosis, ulcerative colitis, Behcet's disease, Crohn's disease, Silicosis, asbestosis, Sjogren's syndrome, Guillain-Barre syndrome, dermatomyositis, polymyositis, multiple sclerosis, autoimmune hemolytic anemia, autoimmune encephalomyelitis, myasthenia gravis, Graves thyroid hyperplasia, nodular polyarteritis, ankylosing spondylitis, fibrositis, temporal arteritis, Wilson's disease, or Fanconi syndrome.
  • the cancer includes blood cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myelogenous leukemia, macroglobulinemia, B cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-hodgkin lymphoma, diffuse large B cell lymphoma, hariy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colorectal cancer, renal cancer, gastric cancer, transitional cell carcinoma, carcinoid tumor, breast cancer, non- small cell lung cancer, or multiple myeloma.
  • prevention refers to any act to delay or inhibit occurrence, spread or recurrence of the above-mentioned diseases by administration of the composition of the present invention, and “treatment” refrers to any act to improve or change the symptoms of the above diseases for the better by administration of the composition of the present invention.
  • compositions according to the present invention can be formulated in types for oral or parenteral administrations according to a standard pharmaceutical practice. These formulations may contain additives such as pharmaceutically acceptable carrier, adjuvant or diluent in addition to the active ingredient.
  • Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate and the like.
  • Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine and the like, but are not limited thereto.
  • the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents commonly used in the preparation of injection solutions.
  • the compounds of the present invention can be formulated in ointments or creams for topical application.
  • a preferred dose of the compound of the present invention may be varied according to the condition and weight of a patient, the severity of a disease, the type of a drug, and the route and duration of administration, but it may be suitably selected by those skilled in the art.
  • the compound of the present invention may be administrated daily at a dose of 0.0001 to 100 mg/kg (body weight), and preferably 0.001 to 100 mg/kg (body weight).
  • the administration may be performed once a day or in divided doses each day through an oral or parenteral route.
  • the Pharmaceutical composition may contain the compound of the present invention in an amount of 0.001 to 99% by weight, preferably 0.01 to 60% by weight.
  • the pharmaceutical composition according to the present invention may be administered to mammals such as a rat, a mouse, a domestic animal, a human, through various routes.
  • the administration may be carried out through all possible methods, for example, oral, rectal, intravenous, intramuscular, subcutaneous, intra-endometrial, intracerebroventricular injection.
  • the compound represented by Chemical Formula 1 according to the present invention or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof can be usefully used for the prevention or treatment of diseases in which the BTK inhibitory action is beneficial.
  • Step 1-1 Preparation of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2 y 3- d]pyrimidine
  • Step 1-2 Preparation of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2-3- d]pyriniidine
  • Step 1-3 Preparation of 4-chIoro-6-(4-phenoxyphenyl)-7-(phenyIsuIfonyI)-7H- pyrrolo
  • Step 1-6 Preparation of N-(3-(6-(4-phenoxyphenyl)-7H-pyrrolo[2 3-d]pyrimidin- 4-ylamino)phenyl)acrylaniide
  • Example 2 The title compound (2.8 mg, yield: 9%) was obtained in the same manner as in Example 1 , except that 4-nitroaniline was used instead of 3-nitroaniline in the step 1-4 of Example 1.
  • Step 5-2 Preparation of N-(3-((6-benzoyl-7H-pyrroIo[2 y 3-d]pyrimidin-4- yl)amino)phenyl)acryIamide
  • Step 5-1 After (4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6- yI)(phenyl)methanone (15 mg, 1.0 eq) obtained in Step 5-1 was dissolved in isopropyl alcohol (2 ml), N-(3-aminophenyl)acrylamide (6.1 ml, 1.0 eq) obtained in Step 1 -5 was added. The mixture was 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 then concentrated under reduced pressure.
  • Example 1 except that (lH-indol-4-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
  • Example 1 except that (6-methylpyridin-3-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
  • Inhibitory activities against BTK were measured for the compounds prepared in the above Examples 1 to 27 as follows.
  • the inhibitory activities against BTK were evaluated using 'ADP-Glo + BT Kinase enzyme system' kit (Promega Corporation).
  • 10 ⁇ of BTK enzyme prepared so as to have a final concentration of 1 ng/ ⁇ L was mixed with 5 ⁇ of compounds having a final concentration of 1 ⁇ in the case of evaluating a single concentration of compound and a concentration of 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1 and 0.03 nM in the case of IC50 evaluation, and then reacted at room temperature for 15 minutes.

Abstract

The present invention relates to a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof, and the compound according to the present invention can be usefully used for the prevention or treatment of diseases in which the BTK inhibitory action is beneficial.

Description

TITLE OF INVENTION
NOVEL PYRROLOPYRIMIDINE DERIVATIVES AND PHARMACEUTICAL COMPOSITION COMPRISING THE SAME TECHNICAL FIELD
The present invention relates to a novel pyrrolopyrimidine derivative useful as a BTK
(Bruton's Tyrosine Kinase) inhibitor and to a pharmaceutical composition comprising the same.
BACKGROUND OF ART
BTK (Bruton's Tyrosine Kinase) is a type of TEC -family tyrosine kinase together with ITK (Interleukin-2 Tyrosine Kinase), RLK (Resting Lymphocyte Kinase) and BMX (Bone- Marrow tyrosine kinase gene on chromosome X), and BTK acts as a regulator of early B-cell development as well as of mature B-cell activation, signaling 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 into a mature antibody-producing cell. However, aberrant signaling via BCR leads to abnormal B-cell proliferation and the formation of pathological autoantibodies, and thereby can induce cancer, autoimmune and/or inflammatory diseases.
Thus, in the abnormal B-cell proliferation, signaling via BCR may be blocked when BTK is deficient. Thus, inhibition of BTK can block B-cell mediated disease processes, and the use of BTK inhibitors may be a useful approach for the treatment of B-cell mediated diseases.
Furthermore, BTK can be expressed by other cells that may be associated with disease besides B-cells. For example, BTK is important components for Fc-gamma signaling in bone marrow cells, and is expressed by mast cells. Specifically, BTK-deficient bone marrow-induced mast cells exhibit impaired 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). In addition, it is known that monocytes from XLA patients, in which BTK activity is absent, show decreased TNF alpha production following stimulation and thus TNF alpha-mediated inflammation could be inhibited by BTF inhibitors (see, Horwood et al, J. Exp. Med. 197: 1603, 2003).
Thus, development of BTK inhibitors capable of inhibiting the activity of BTK is required in the industry. Currently, ibrutinib (PCI-32765, Pharmacyclics) has been introduced as a BTK inhibitor, but side effects such as skin rash and diarrhea have been reported clinically, and thus there is a need to develop substances that can inhibit BTK more stably and effectively (see, Drug Discov Today 2014 Aug 19 (8) 1200-4; WO 2002/096909; WO 2010-009342).
In view of the above, as a result of studying novel compounds, the present inventors have found a novel pyrrolopyrimidine derivative having excellent inhibitory activity as a BTK inhibitor, thereby completing the present invention. The compounds belonging to the present invention mainly have BTK inhibitory activity on their own, but do not exclude a possibility of exhibiting a pharmacological action as an efficacious agent by a special body environment or by products of metabolic process, after absorption into the body.
DETAILED DESCRIPTION OF THE INVENTION TECHNICAL PROBLEM
It is an object of the present invention to provide a pyrrolopyrimidine derivative useful as a BTK inhibitor.
It is another object of the present invention to provide a pharmaceutical composition comprising the pyrrolopyrimidine derivative as an active ingredient.
TECHNICAL SOLUTION
In order to solve the objects mentioned above, the present invention provides a compound represented by the following Chemical Formula 1, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure imgf000004_0001
in Chemical Formula 1,
X is NH, or O,
L is a bond, or CO,
R is hydrogen, C6-io aryl, or C3.10 heteroaryl containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S,
wherein R is unsubstituted or substituted with one or two R,
each R' is independently halogen, Cualkyl, Ci^ alkyl substituted with morpholino, Q. 4 haloalkyl, Ci^ alkoxy, C3-6 cycloalkyl, C6-ioaryl, C6-io aryloxy, tetrahydropyranyl, moφholino, moφholinecarbonyl, pyridinyl, pyrazolyl, pyrazolyl substituted with one or two C alkyl, piperazinyl, or piperazinecarbonyl.
Preferably, R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl, wherein the R is unsubstituted or substituted with one or two R'.
Preferably, each R is independently fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl.
Also preferably, L is a bond, and R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl, wherein the R is unsubstituted or substituted with one or two R. In this case, R is preferably fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl. Further, preferably, X is NH, L is CO, and R is phenyl or pyridinyl, wherein the R is unsubstituted or substituted with one R'. In this case, R' is preferably phenoxy.
Further, preferably, L is a bond and R is phenyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl, wherein the R is unsubstituted or substituted with one R'. In this case, R' is preferably methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl .
Further, preferably, the compound represented by Chemical Formula 1 is represented by the following Chem ical Formula 1 - 1 :
[Chemical Formula 1-1]
Figure imgf000005_0001
in Chemical 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 substituted or is substituted with one or two R',
R is fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl.
Further, preferably, the compound represented by Chemical Formula 1 is represented by the following Chemical Formula 1-2:
[Chemical Formula 1-2]
Figure imgf000006_0001
in Chemical Formula 1-2,
X is NH,
L is a bond, or CO, and
R is phenyl or pyridinyl,
wherein R is unsubstituted or substituted with one R', and
R' is phenoxy, or pyridinyl.
The compound represented by Chemical Formula 1 is any one selected from the group consisting of:
1) N-(3-(6-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acryIamide,
2) N-(3-(6-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylam ino)phenyl)acrylam ide,
3) N-(3-(6-(4-moφholinophenyl)-7H-pyrrolo[2,3-d]pyrimίdin-4- ylamino)phenyl)acrylamide,
4) N-(4-(6-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylam ide,
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-4- ylamino)phenyl)acrylamide,
8) N-(3-(6-(3-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-
>)phenyl)acrylamide,
9) N-(3-(6-(4-(mo holine-4-carbonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin■ ylam ino)phenyl)acrylam ide, 10) N-(3-(6 4-(tetrahydro-2H-pyran-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylam ide,
1 1) N-(3-(6-(4-cyclohexylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
12) N-(3-(6-(3-moφholinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
13) N-(3-(6-(naphthalen- 1 -yl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylam ide,
14) N-(3-(6-(l H-indol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
15) N-(3-(6-( 1 -(2-moφholinoethyl)- 1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-ylamino)phenyl)acrylamide,
, 16) N-(3-(6-(4-(mo holinomethyl)phenyl)-7H-pyπ·olo[2,3-d]pyrimidin-4- y lam i no)phenyl)acrylam ide,
17) N-(3-(6-(l H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
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- ylam ino)phenyl)acrylam ide,
20) N-(3-(6-(6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
21) N-(3-(6-(6-(trifluoromethyl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
22) N-(3-(6-(6-moφholinopyridin-3-yI)-7H-pyrrolo[2,3-d]pyrimidin-4- ylam ino)pheny l)acry lam ide,
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- ylam ino)phenyl)acrylam ide, 25) N-(3-(6-(6-( 1 -methyl- l H-pyrazol-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)phenyl)acrylamide,
26) N-(3-(6-(4-(piperazine-l-carbonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide, and
27) N-(3-(6-(4-(moφholinomethyl)phenyl)-7H-pyπΌlo[2,3-d]pyrimidin-4- yloxy)phenyl)acrylamide.
In addition, the compounds of the present invention may exist in the form of salts, especially pharmaceutically acceptable salts. As salts, salts commonly used in the art, such as acid addition salts formed by pharmaceutically acceptable free acids can be used without limitation. The term "pharmaceutically acceptable salt" as used herein refers to any organic or inorganic addition salt of the compound represented by Chemical Formula 1, whose concentration is relatively non-toxic and harmless to a patient and activates effectively and whose side effects do not degrade the beneficial efficacy of the above compound.
As the free acid, an organic acid and an inorganic acid can be used. Examples of the inorganic acids include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid and the like. Examples of the organic acids include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like, 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 Chemical Formula 1 is dissolved in an excessive amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, the non-soluble salt is filtered, and the filtrate is evaporated and dried to obtain a pharmaceutically acceptable metal salt. At this time, it is particularly preferable to prepare a sodium salt, a potassium salt or a calcium salt as the metal salt. A pharmaceutically unacceptable salt or solvate of the compound of Chemical Formula 1 may be used as an intermediate when preparing the compound of Chemical Formula 1 , or the pharmaceutically acceptable salt or the solvate thereof.
Also, the compound of Chemical Formula 1 according to the present invention includes not only pharmaceutically acceptable salts thereof, but also solvates such as hydrates that can be prepared therefrom, and includes all possible stereoisomers, but are not limited thereto. The solvate and the stereoisomer of the compound of Chemical Formula 1 may be prepared from the compound of Chemical Formula 1 using common methods known in the art.
In addition, the compound of Chemical Formula 1 according to the present invention may be prepared either in a crystalline form or in a non-crystalline form, and when the compound of Chemical Formula 1 is prepared in a crystalline form, it may be optionally hydrated or solvated. In the present invention, the compound of Chemical Formula 1 may not only include a stoichiometric hydrate, but also include a compound containing various amounts of water. The solvate of the compound of Chemical Formula 1 according to the present invention includes both stoichiometric solvates and non-stoichiometric solvates.
Furthermore, as an example, the present invention can produce the compound represented by Chemical Formula 1 through Reaction Scheme 1 below.
[Reaction Scheme 1 ]
Figure imgf000010_0001
in Reaction Scheme 1, X and R are as previously defined in Chemical Fonnula 1, X' is amino or hydroxy, and Z is halogen. Specifically, the compound represented by Chemical Formula 1 may be prepared though Step 1 , 1-1, and 1-2 when L is CO, and may be prepared through Steps 1, 2, 2-1 and 2-2 when L is a bond.
Step 1 is a step of reacting 6-chloro-7-daezapurine compound represented by Chemical Formula Al with benzenesulfonyl chloride to prepare 4-chloro-7-(phenylsulfonyl)-7H- pyrrolo[2,3-d]pyrimidine compound represented by Chemical Formula A2. This reaction is preferably carried out in a solvent such as tetrahydrofuran.
Step l-l is a step of reacting a compound represented by Chemical Formula (A2) with a compound represented by Chemical Formula (A3) to prepare a compound represented by Chemical Formula (A4) in which an 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, with an alcohol such as isopropyl being preferred as the solvent.
Step 2 is a step of reacting a compound represented by Chemical Formula (A2) with a halogen to prepare a compound represented by Chemical 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 Chemical Formula (A 6) with a boronic acid compound substituted with an R group represented by Chemical Formula (A 7) to prepare a compound represented by Chemical Formula (A8) in which an R group is 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 Chemical Formula (A8) with a compound represented by Chemical Formula (A5) to prepare a compound represented by Chemical Formula 1 wherein L is a bond. The reaction can be carried out in the same manner as in Step 1-2 described above.
Further, the present invention provides a pharmaceutical composition for preventing or treating autoimmune diseases or cancers, which is effective for BTK inhibitory actions, comprising the compound represented by Chemical Formula 1 , or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof as an active ingredient.
In this case, the autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, childhood diabetes, psoriasis, aphthous stomatitis, chronic thyroiditis, acquired aplastic anemia, primary cirrhosis, ulcerative colitis, Behcet's disease, Crohn's disease, Silicosis, asbestosis, Sjogren's syndrome, Guillain-Barre syndrome, dermatomyositis, polymyositis, multiple sclerosis, autoimmune hemolytic anemia, autoimmune encephalomyelitis, myasthenia gravis, Graves thyroid hyperplasia, nodular polyarteritis, ankylosing spondylitis, fibrositis, temporal arteritis, Wilson's disease, or Fanconi syndrome. The cancer includes blood cancer, extranodal marginal zone B-cell lymphoma, glioblastoma, lymphoplasmacytic lymphoma, acute myelogenous leukemia, macroglobulinemia, B cell lymphoma, chronic lymphocytic leukemia, follicular lymphoma, non-hodgkin lymphoma, diffuse large B cell lymphoma, hariy cell leukemia, mantle cell lymphoma, glioblastoma, bladder cancer, pancreatic cancer, ovarian cancer, colorectal cancer, renal cancer, gastric cancer, transitional cell carcinoma, carcinoid tumor, breast cancer, non- small cell lung cancer, or multiple myeloma.
As used herein, the term "prevention" refers to any act to delay or inhibit occurrence, spread or recurrence of the above-mentioned diseases by administration of the composition of the present invention, and "treatment" refrers to any act to improve or change the symptoms of the above diseases for the better by administration of the composition of the present invention.
The pharmaceutical composition according to the present invention can be formulated in types for oral or parenteral administrations according to a standard pharmaceutical practice. These formulations may contain additives such as pharmaceutically acceptable carrier, adjuvant or diluent in addition to the active ingredient.
Suitable carriers include, for example, physiological saline, polyethylene glycol, ethanol, vegetable oil, and isopropyl myristate and the like. Diluents include, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine and the like, but are not limited thereto. Further, the compounds of the present invention can be dissolved in oils, propylene glycol or other solvents commonly used in the preparation of injection solutions. Furthermore, the compounds of the present invention can be formulated in ointments or creams for topical application. A preferred dose of the compound of the present invention may be varied according to the condition and weight of a patient, the severity of a disease, the type of a drug, and the route and duration of administration, but it may be suitably selected by those skilled in the art. In order to achieve the desirable effects, however, the compound of the present invention may be administrated daily at a dose of 0.0001 to 100 mg/kg (body weight), and preferably 0.001 to 100 mg/kg (body weight). The administration may be performed once a day or in divided doses each day through an oral or parenteral route.
Depending on the method of administration, the Pharmaceutical composition may contain the compound of the present invention in an amount of 0.001 to 99% by weight, preferably 0.01 to 60% by weight.
The pharmaceutical composition according to the present invention may be administered to mammals such as a rat, a mouse, a domestic animal, a human, through various routes. The administration may be carried out through all possible methods, for example, oral, rectal, intravenous, intramuscular, subcutaneous, intra-endometrial, intracerebroventricular injection.
ADVANTAGEOUS EFFECTS
The compound represented by Chemical Formula 1 according to the present invention or a pharmaceutically acceptable salt, hydrate, solvate or isomer thereof can be usefully used for the prevention or treatment of diseases in which the BTK inhibitory action is beneficial.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Below, the present invention will be described in more detail by way of examples. However, these examples are provided for illustrative purposes only, and should not be construed as limiting the scope of the present invention to these examples.
Example 1: Preparation of N-(3-(6-(4-phenoxyphenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylainino)phenyl)acrylamide
Step 1-1: Preparation of 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2y3- d]pyrimidine
Figure imgf000014_0001
After 60% sodium hydride (7.8 g, 1.5 eq) was dissolved in tetrahydroiuran (300 ml), 6- chloro-7-deazapurine (20 g, 1.0 eq) was dissolved in tetrahydroiuran (200 ml) at 0°C and added dropwise. After stirring the mixture at 0°C for 10 minutes, benzenesulfonyl chloride (16.95 ml, 1.02 eq) was added dropwise. After dropwise addition, the temperature was raised to room temperature and the mixture was 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 obtain the title compound (29.7 g, yield: 78%).
Step 1-2: Preparation of 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2-3- d]pyriniidine
Figure imgf000014_0002
After 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (5 g, 1.0 eq) obtained in Step 1-1 was dissolved in tetrahydrofuran (150 ml), 1.5 M lithium diisopropylamide (17.02 ml, 1.5 eq) was added dropwise at -78°C under nitrogen. After stirring the mixture at -78°C for 1 hour, iodine (5.62 g, 1.3 eq) was dissolved in tetrahydrofuran (30 ml) and added dropwise. After stirring the mixture at -78°C for 1 hour, IN hydrochloric acid (90 ml) was added. The temperature was raised to room temperature and the mixture was concentrated under reduced pressure. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was slurried in acetonitrile (50 ml) and then filtered to obtain the title compound (4.48 g, yield: 63%).
Step 1-3: Preparation of 4-chIoro-6-(4-phenoxyphenyl)-7-(phenyIsuIfonyI)-7H- pyrrolo
Figure imgf000015_0001
After 4-chloro-6-iodo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 1.0 eq) obtained in Step 1-2 was dissolved in 1 ,4-dioxane, (4-phenoxyphenyl)boronic acid (51.4 mg, 1.0 eq), [l, l'-bis(diphenylphosphino)ferrocene]dichloro palladium(II) (19.6 mg, 0.1 eq), and sodium carbonate (76.3 mg, 3.0 eq) were sequentially added. The mixture was stirred at 100°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: hexsne = 1 : 4) to obtain the title compound (58.6 mg, yield: 53%).
Step 1-4: Preparation of N-(3-nitrophenyl)acrylamide
Figure imgf000015_0002
After 3-nitroaniline (500 mg, 1.0 eq) was dissolved in ietrahydrofuran (10 ml), 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°C and then stirred at room temperature for 2 hours. The solid formed during the reaction was filtered, water was added to the filtrate, and the mixture was extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was slurried in dichloromethane and then filtered to obtain the title compound (320 mg, yield
Step 1-5: Preparation of N-(3-aminophenyl)acrylamide
Figure imgf000015_0003
After N-(3-nitrophenyl)acrylamide (220 mg, 1.0 eq) obtained in Step 1 -4 was dissolved in ietrahydrofuran (5 ml), tin chloride (1.29 g, 5.0 eq ) was added. 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 then concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to obtain the title compound ( 145 mg, yield: 78%).
Step 1-6: Preparation of N-(3-(6-(4-phenoxyphenyl)-7H-pyrrolo[2 3-d]pyrimidin- 4-ylamino)phenyl)acrylaniide
Figure imgf000016_0001
After 4-chloro-6-(4-phenoxyphenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidirLe (1 6.1 mg, 1.0 eq) obtained in Step 1-3 was dissolved in isopropyl alcohol (2 ml), N-(3- aminophenyl)acrylamide (6.8 g, 10 eq) obtained in Step 1 -5 was added. The mixture was 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 then concentrated under reduced pressure. The resulting residue was purified by column chromatography (dichloromethane: methanol = 9: 1 ) to obtain the title compound (1.3 mg, yield: 18%).
' H NMR(500 MHZ, MeOD): 8.19-8.08(m, 2H), 7.78(d, 2H), 7.44-7.29(m, 5H), 7. l5(t, 1 H), 7.06(t, 4H), 6.93(d, 1 H), 6.48(d, 1 H), 6.36(d, 1 H), 5.76(d, 1 H) Example 2: Preparation of N-(3-(6-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylaniino)phenyl)acrylamide
Figure imgf000016_0002
The title compound (4.2 mg, yield: 24%) was obtained in the same manner as in Example 1 , except that (4-(pyridin-3-yl)phenyl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in Step 1-3 of Example 1. Ή NMR(500 MHz, DMSO): 12.37(s, I H), 10.15(s, I H), 9.47(s, I H), 8.97(s, I H), 8.57(d, I H), 8.31(s, I H), 8.26(s, I H), 8.14(d, I H), 7.95(d, 2H), 7.86(d, 2H), 7.66(d, I H), 7.51 - 7.48(m, 1 H), 7.33-7.25(m, 3H), 6.48(d, 1 H), 6.25(d, 1 H), 5.75(d, IH)
Example 3: Preparation of N-(3-(6-(4-morpholinophenyl)-7H-pyrrolo[2,3- d]pyrim de
Figure imgf000017_0001
The title compound (2.1 mg, yield: 12%) was obtained in the same manner as in Example 1, except that (4-morpholinophenyl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in Step 1-3 of Example 1.
Ή NMR(500 MHz, DMSO): 12.25(s, IH), 10.18(s, IH), 9.28(s, I H), 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, I H), 5.74(d, IH), 3.73(t, 4H), 3.16(t, 4H)
Example 4: Preparation of N-(4-(6-(4-phenoxyphenyl)-7H-pyrrolo[2 d]pyrim
Figure imgf000017_0002
The title compound (2.8 mg, yield: 9%) was obtained in the same manner as in Example 1 , except that 4-nitroaniline was used instead of 3-nitroaniline in the step 1-4 of Example 1.
Ή NMR(500 MHz, MeOD): 8.20(s, I H), 7.77(d, 2H), 7.70(d, 2H), 7.64(d, 2H), 7.38(t, 2H), 7.140, I H), 7.07-7.04(m, 4H), 6.89(s, I H), 6.45(d, I H), 6.36(d, I H), 5.76(d, I H)
Example 5: Preparation of N-(3-((6-benzoyl-7H-pyrroIo[2^-d]pyrimidin-4- yl)amino)phenyl)acrylamide Step 5-1: Preparation of (4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3- d]pyrimidin-6-yi)(phenyl)niethanone
Figure imgf000018_0001
After 4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (100 mg, 1.0 eq) obtained in Step 1-1 was dissolved in tetrahydrofiiran (3.0 ml), 1.5 M lithium diisopropylamide (0.3 ml, 1.2 eq) was added dropwise at -78°C under nitrogen. After stirring the mixture at -78°C for 1 hour, benzoyl chloride (57.4 mg, 1.2 eq) was dissolved in tetrahydrofiiran (1.0 ml) and added dropwise. After stirring the mixture at -78°C for 3 hours, ammonium chloride (1.0 ml) was added. The temperature was raised to room temperature and the mixture was concentrated under reduced pressure. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was slurried in methanol (5.0 ml) and then filtered to obtain the title compound (30.0 mg, yield: 63%). Step 5-2: Preparation of N-(3-((6-benzoyl-7H-pyrroIo[2y3-d]pyrimidin-4- yl)amino)phenyl)acryIamide
Figure imgf000018_0002
After (4-chloro-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6- yI)(phenyl)methanone (15 mg, 1.0 eq) obtained in Step 5-1 was dissolved in isopropyl alcohol (2 ml), N-(3-aminophenyl)acrylamide (6.1 ml, 1.0 eq) obtained in Step 1 -5 was added. The mixture was 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 then concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate: hexane = 4: 1 ) to obtain the title compound (6.2 mg, yield 43%). Ή NMR(500 MHz, DMSO): 12.64(s, I H), I0.16(s, IH), 9.77(s, I H), 8.39(s, IH), 8.26(s, IH), 7.88(d, 2H), 7.71-7.59(m, 4H), 7.33-7.25(m, 2H), 6.46(d, IH), 6.23(d, I H), 5.73(d, l H), 3.15(d, I H) Example 6: Preparation of N-(3-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide
Figure imgf000019_0001
The title compound (4.2 mg, yield: 24%) was obtained in the same manner as in Example 1, except that phenylboronic acid was used instead of (4-phenoxyphenyl)boronic acid in the step 1 -3 of Example 1.
Ή NMR(500 MHz, MeOD): 8.23(s, IH), 8.20(s, I H), 7.79(d, 2H), 7.63-7.40(m, 4H), 7.34-7.30(m, 2H), 7.02(s, I H), 6.46(d, I H), 6.37(d, IH), 5.77(d, IH)
Example 7: Preparation of N-(3-(6-(l-methyl-lH-pyrazol-4-yl)-7H-pyrrolo[2-3- dj yrimsdin-4~ylamino)phenyl)acrylainide
Figure imgf000019_0002
The title compound (7.4 mg, yield: 34%) was obtained in the same manner as in Example 1, except that (l-methyl-lH-pyrazol-4-yl)boronic acid was used , instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
. Ή NMR(500 MHz, MeOD): 8.20(s, 1 H), 8.16(s, 1 H), 7.97(s, I H), 7.86(s, I H), 7.40(t,
2H), 7.3 l(t, I H), 6.71 (s, I H), 6.46(d, I H), 6.36(d, I H), 5.76(d, I H), 3.95(s, 3H)
Example 8: Preparation of N-(3-(6-(3-phenoxyphenyl)-7H-pyrroIo[2,3- d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000020_0001
The title compound (4.9 mg, yield: 16%) was obtained in the same manner as in Example 1, except that (3-phenoxyphenyl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1 -3 of Example 1.
*H NMR(500 MHZ, MeOD): 8.22(s, I H), 8.15(s, 1 Η), 7.82(d, 1 H), 7.55(d, 1 Η), 7.46-
7.38(m, 4H), 7.15(t, I H), 7.06(d, 2H), 7.01(s, I H), 6.98(d, I H), 6.44(d, I H), 6.36(d, I H), 5.78(d, I H)
Example 9: Preparation of N-(3-(6-(4-(morpholine-4-carbonyI)phi pyrrolo[2 J-d]pyirimid ii-4-ylamino)phenyl)acrylamide
The title compound (5.2 mg, yield: 20%) was obtained in the same manner as in Example 1, except that (4- (morpholine-4-carbonyl)phenyl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, MeOD): 8.27(s, 1 H), 8.2 l(s, 1 H), 7.89(d, 2H), 7.53(d, 2H), 7.46-
7.31(m, 3H), 7.12(s, lH), 6.47(d, l H), 6.37(d, l H), 5.77(d, I H), 3.76(m, 4H), 3.54(m, 4H)
Example 10: Preparation of N-(3-(6-(4-(tetrahydro-2H-pyran-4-yI)phenyl)-7H- pyrrolo l)acrylamide
Figure imgf000020_0003
The title compound (4.7 mg, yield: 23%) was obtained in the same manner as in
Example 1, except that (4-(tetrahydro-2H-pyran-4-yl) phenyl)boronic acid was used instead of
(4-phenoxyphenyl)boronic acid in the step 1 -3 of Example 1 .
'H MR(500 MHZ, MeOD): 8.23(s, I H), 8.1 8(s, I H), 7.74(d, 2H), 7.43-7.33(m, 5H), 6.99(s, I H), 6.44(d, I H), 6.36(d, I H), 5.77(d, IH), 3.55(m, 4H), 2.85(m, I H), 1.82(m, 4H)
Example 11: Preparation of N-(3-(6-(4-cyclohexylphenyi)-7H-pyrrolo[2,3- d]pyriniidin-4-ylamino)phenyl)acrylamide
Figure imgf000021_0001
The title compound (4.4 mg, yield: 19%) was obtained in the same manner as in Example 1, except that (4-cyclohexylphenyl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1 -3 of Example 1.
'H NMR(500 MHZ, MeOD): 8.23(s, I H), 8.19(s, I H), 7.70(d, 2H), 7.42(t, 2H), 7.33- 7.29(m, 3H), 6.96(s, I H), 6.46(d, I H), 6.36(d, I H), 5.77(d, I H), 2.56(m, I H), 1.87(m, 4H), 1 .47(m, 4H), 1.33(m, 2H)
Example 12: Preparation of N-(3-(6-(3-morpholinophenyi)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000021_0002
The title compound (3.6 mg, yield: 20%) was obtained in the same manner as in Example 1, except that (3-morpholinophenyl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1 .
Ή NMR(500 MHz, MeOD): 8.24(s, I H), 8.19(s, I H), 7.43-7.24(m, 6H), 6.99(s, I H), 6.96(d, I H), 6.46(d, IH), 6.36(d, I H), 5.77(d, I H), 3.87(t, 4H), 3.22(t, 4H)
Example 13: Preparation of N-(3-(6-(naphthalen-l-yl)-7H-pyrrolo[2 5- d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000021_0003
The title compound (4.6 mg, yield: 24%) was obtained in the same manner as in Example 1, except that (naphthalen-l -yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, MeOD): 8.32(m, 2H), 8.23(s, I H), 7.96-7.92(m, 2H), 7.68(d, I H), 7.58-7.53(m, 3H), 7.46-7.4 l(m, 2 H), 7.32(t, IH), 6.47(d, 1 H), 6.37(d, 1 H), 5.77(d, IH)
Example 14: Preparation of N-(3-(6-(lH-indol-4-yl)-7H-pyrrolo[2^-d]pyrimidin- 4-ylamino)phenyl)acrylamide
Figure imgf000022_0001
The title compound (5.8 mg, yield: 26%) was obtained in the same manner as in
Example 1, except that (lH-indol-4-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
'H NMR(500 MHz, MeOD): 8.26(s, I H), 8.2 l(s, IH), 7.46-7.32(m, 6H), 7.2 l (t, I H), 7. ! 4(t, 1 H), 6.92(d, 1 H), 6.45(d, 1 H), 6.36(d, 1 H), 5.77(d, 1 H)
Example 15: Preparation of N-(3-(6-(l-(2-morpholinoethyl)-lH-pyrazol-4-yS)-7H- pyrrolo[2^-d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000022_0002
The title compound (1.0 mg, yield: 4%) was obtained in the same manner as in Example 1, except that (l-(2-morpholinoethyl)-l H-pyrazol-4-yl)boronic acid was used instead of (4-phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, DMSO): 12.04(s, IH), 10.13(s, I H), 9.3 l(s, IH), 8.22(s, 2H), 8.15(s, I H), 7.86(s, I H), 7.62(s, I H), 7.3 l(d, I H), 7.24(d, I H), 6.85(d, I H), 6.46(d, I H), 6.25(d, I H), 5.74(d, I H), 4.27(m, 2H), 3.55(m, 4H), 2.7 l(m, 2H), 2.4 l(m, 4H) Example 16: Preparation of N-(3-(6-(4-(morpholinomethyl)phenyl)-7H- pyrrolo[2 3-d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000023_0001
The title compound (1.1 mg, yield: 6%) was obtained in the same manner as in Example 1 , except that (4- (morpholinomethyl) phenyl) boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
'H NMR(500 MHZ, DMSO): 12.25(S, I H), 10.17(s, I H), 9.43(S, I H), 8.3 1 -8.25(m, 2H), 7.92(d, I H), 7.65(d, I H), 7.46-7.22(m, 3H), 6.48(d, I H), 6.25(d, I H), 5.73(d, I H), 3.57(m, 4H), 3.48(m, 2H), 2.36{m, 4H)
Example 17: Preparation of N-(3-(6-(lH-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-ylamino)phenyl)acrylamide
Figure imgf000023_0002
The title compound (2.1 mg, yield: 15%) was obtained in the same manner as in Example 1, except that (lH-indol-5-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
' H NMR(500 MHZ, MeOD): 8.22(s, I H), 8.18(s, IH), 8.00(s, IH), 7.56(d, I H), 7.46- 7.43(m, 3H), 7.34-7.28(m, 2H), 6.91(s, 1 H), 6.52(d, 1 H), 6.44(d, IH), 6.38(d, IH), 5.77(d, 1 H)
Example 18: Preparation of N-(3-(6-(benzofuran-5-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000023_0003
The title compound (3.3 mg, yield: 16%) was obtained in the same manner as in Example 1, except that (benzofuran-5-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, MeOD): 8.23(s, 1 H), 8.18(s, I H), 8.04(s, IH), 7.84(s, IH), 7.75(d, IH), 7.60(d, I H), 7.46-7.39(m, 3H), 7.01(s, I H), 6.92(d, I H), 6.44(d, I H), 6.37(d, IH), 5.78(d, IH)
Example 19: Preparation of N-(3-(6-(pyridin-3-yl)-7H-pyrrolo[2 3-d]pyrimidin-4- ylamino)phenyl)acrylamide
Figure imgf000024_0001
The title compound (7.8 mg, yield: 41%) was obtained in the same manner as in Example 1, except that (pyridin-3-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, DMSO): 12.43(s, I H), 10.15(s, I H), 9.50(s, I H), 9.03(s, IH), 8.50(d, I H), 8.31(s, I H), 8.26(s, I H), 8.16(d, I H), 7.66(d, I H), 7.49(d, I H), 7.33-7.25(m, 3H), 6.48(4 lH), 6.25(d, lH), 5.75(d, I H)
Example 20: Preparation of N-(3-(6-(6-methylpyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000024_0002
The title compound (1.3 mg, yield: 8%) was obtained in the same manner as in
Example 1 , except that (6-methylpyridin-3-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, MeOD): 8.85(s, I H), 8.26(s, I H), 8.2 l (s, I H), 8.10(d, I H), 7.46- 7.39(m, 3H), 7.32(t, I H), 7.09(s, I H), 6.47(d, I H), 6.38(d, I H), 5.77(d, I H)
Example 21: Preparation of N-(3-(6-(6-(trifluoromethyl)pyridin-3-yl)-7H- pyrrolo[2 5-d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000025_0001
The title compound (7.0 mg, yield: 36%) was obtained in the same manner as in Example 1, except that (6-(trifluoromethyl)pyridin-3-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, MeOD): 9.13(s, IH), 8.35(d, IH), 8.29(s, IH), 8.24(s, IH), 7.87(d, I H), 7.46(d, I H), 7.39(d, IH), 7.32(t, I H), 7.27(s, I H), 6.46(d, I H), 6.35(d, I H), 5.77(d, IH)
Example 22: Preparation of N-(3-(6-(6-morpholinopyridin-3-yl)-7H-pyrrolo[2-3- d]pyrimidin-4-yIamino)phenyl)acrylamide
Figure imgf000025_0002
The title compound (1.7 mg, yield: 8%) was obtained in the same manner as in Example 1, except that (6-mololenopyridin-3-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, MeOD): 8.58(s, IH), 8.22(s, IH), 8.19(s, I H), 7.97(d, I H), 7.44- 7.30(m, 3H), 6.92(d, IH), 6.89(s, IH), 6.46(d, IH), 6.36(d, I H), 5.77(d, IH), 3.81(t, 4H), 3.55(t, 41 1)
Example 23: Preparation of N-(3-(6-(6-methoxypyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000025_0003
The title compound (4.2 mg, yield: 18%) was obtained in the same manner as in Example 1, except that (6-methoxypyridin-3-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, MeOD): 8.51(s, IH), 8.25(s, IH), 8.20(s, I H), 8.07(d, I H), 7.45- 7.3 l(m, 3H), 6.95(s, IH), 6.88(d, I H), 6.46(d, I H), 6.36(d, IH), 5.76(d, IH), 3.96(s, 3H)
Example 24: Preparation of N-(3-(6-(6-phenylpyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000026_0001
The title compound (12.5 mg, yield: 36%) was obtained in the same manner as in Example 1, except that (6-phenylpyridin-3-yl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, MeOD): 9.07(s, IH), 8.29-8.24(m, 3H), 8.03-7.96(3 H), 7.53- 7.41(m 5H), 7.33(t, I H), 7.19(s, I H), 6.46(d, I H), 6.37(d, IH), 5.77(d, I H)
Example 25: Preparation of N-(3-(6-(6-(l-methyl-lH-pyrazol-3-yl)pyridin-3-yl)- 7H-pyrrolo[2 -d]pyriiBidin-4-ylamino)phenyl)acrylamide
Figure imgf000026_0002
The title compound (9.4 mg, yield: 27%) was obtained in the same manner as in Example 1 , except that (6-(l -methyl- l H-pyrazol-3-yI) pyridin-3-yl)boronic acid was used instead of (4-phenoxyphenyl)boronic acid in the step 1-3 of Example 1.
Ή NMR(500 MHz, MeOD): 8.98(s, I H), 8.28(s, IH), 8.22(d, 2H), 8.04(d, I H), 7.67(s, I H), 7.46(d, I H), 7.42(d, I H), 7.33(t, I H), 7.17(s, I H), 6.9 l(s, I H), 6.47(d, I H), 6.36(d, lH), 5.76(d, lH), 3.99(s, 3H)
Example 26: Preparation of N-(3-(6-(4-(piperazine-l-carbonyl)phenyl)-7H- pyrrolo[2 5-d]pyrimidin-4-ylamino)phenyl)acrylamide
Figure imgf000027_0001
The title compound (1.2 mg, yield: 8%) was obtained in the same manner as in Example 1, except that (4- (piperazine-l-carbonyl)phenyl)boronic acid was used instead of (4- phenoxyphenyl)boronic acid in the step 1-3 of Example I .
Ή NMR(500 MHz, MeOD): 8.26(d, 1H), 7.89(d, 2H), 7.52(d, 1 H), 7.44-7.3 l (m, 4H), 7.1 l(d, l H), 6.47(d, l H), 6.37(d, l H), 5.76(d, 1H), 3.87(t, 4H),'2.86(t, 4H)
Example 27: Preparation of N-(3-(6-(4-(morpholinomethyl)phenyl)-7H- pyrrolo[2 -d]pyr!midin-4-yloxy)phenyl)acrylamide
Figure imgf000027_0002
After 4-chloro-6-(4-phenoxyphenyl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (50.0 mg, 1.0 mmol) obtained in Step 1 -3 of Example 1 was dissolved in dimethylformamide (2. ml), N-(3-hydroxyphenyl)acrylamide (17.4 mg, 1.0 eq) and potassium carbonate (29.6 mg, 2.0 eq) were sequentially added. The mixture was reacted in a microwave reactor at 130°C for 1 hour. Water was added and extracted with dichloromethane. The separated organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate: hexane = 4: 1) to obtain the title compound (1.2 mg, yield 3%).
Ή NMR(500 MHz, MeOD): 8.28(s, 1 H), 7.78(d, 2H), 7.72(s, l H), 7.53-7.4 l(m, 4H), 7.02(d, 1 H), 6.74(s, 1 H), 6.4 l (d, 1 H), 6.37(d, 1 H), 5.76(d, 1 H), 3.70(m, 4H), 3.56(s, 2H), 2.48(m, 4H)
Experimental Example 1: Inhibitory activity against BTK
Inhibitory activities against BTK were measured for the compounds prepared in the above Examples 1 to 27 as follows. The inhibitory activities against BTK were evaluated using 'ADP-Glo + BT Kinase enzyme system' kit (Promega Corporation). In a white 96-well plate, 10 μΐ of BTK enzyme prepared so as to have a final concentration of 1 ng/^L was mixed with 5 μΐ of compounds having a final concentration of 1 μΜ in the case of evaluating a single concentration of compound and a concentration of 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1 and 0.03 nM in the case of IC50 evaluation, and then reacted at room temperature for 15 minutes. 5 μΐ^ of substrate and 5 pL of ATP prepared so as to have a final concentration of 10 μΜ were added to the plate on which reactions were completed, and then allowed to react at 30°C for 1 hour. All wells of the plate on which reactions were completed were treated with 25 μί of ADP-Glo™ reagent and allowed to react at 30°C for 40 minutes. After that, all wells were treated with 50 μΐ, of kinase detection buffer, and then reacted at 30°C for 30 minutes under Sight shielding conditions. For the plate on which all reactions were completed, luminescence was measured and the results were calculated. Evaluation was carried out in duplicate, and negative control and positive control were calculated depending on whether or not the enzyme was added without treatment of the compound. The % inhibitory activity and IC50 were calculated based on the calculated values.
[Table 1]
Figure imgf000028_0001
From the results of Experimental Example 1 , it could be seen that the compounds according to one embodiment of the present invention have excellent BTK inhibitory activity.

Claims

WHAT IS CLAIMED IS:
1. A compound represented by the following Chemical Formula larmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure imgf000029_0001
in Chemical Formula 1,
X is NH, or O,
L is a bond, or CO,
R is hydrogen, C6-io aryl, or C3-io heteroaryl containing 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S,
wherein R is unsubstituted or substituted with one or two R',
each R' is independently halogen, Ci^alkyl, C^ alkyl substituted with morpholino, Q. 4 haloalkyl, C^alkoxy, C3.6 cycloalkyl, C6-io aryl, C6-ioaryloxy, tetrahydropyranyl, morpholino, moφholinecarbonyl, pyridinyl, pyrazolyl, pyrazolyl substituted with one or two C M alkyl, piperazinyl, or piperazinecarbonyl.
2. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl,
wherein the R is unsubstituted or substituted with one or two R'.
3. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R' is independently fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, moφholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl.
4. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein
L is a bond,
R is hydrogen, phenyl, naphthyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl,
wherein the R is unsubstituted or substituted with one or two R', and
R is fluoro, methyl,
Figure imgf000030_0001
trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, ηιθφηοΐίηο, moφholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl.
5. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein
X is NH,
L is CO,
R is phenyl or pyridinyl,
wherein the R is unsubstituted or substituted with one R', and
R is phenoxy.
6. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein
L is a bond,
R is phenyl, pyridinyl, pyrazolyl, indolyl, or benzofuranyl,
wherein the R is unsubstituted or substituted with one R', and
R' is methyl, trifluoromethyl, methoxy, tetrahydropyranyl, ηιοφ
Figure imgf000030_0002
inyl, methylpyrazolyl, or piperazinecarbonyl.
7. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein
the compound is represented by the following Chemical Formula 1-1 :
[Chemical Formula 1-1]
Figure imgf000031_0001
in Chemical 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 substituted or is substituted with one or two R', and
R' is fluoro, methyl, morpholinomethyl, morpholinoethyl, trifluoromethyl, methoxy, cyclohexyl, phenyl, phenoxy, tetrahydropyranyl, morpholino, morpholinecarbonyl, pyridinyl, methylpyrazolyl, or piperazinecarbonyl.
8. The compound or a pharmaceutically acceptable salt thereof according to claim wherein
the compound is represented by the following Chemical Formula 1 -2:
[Chemical Formula 1 -2]
Figure imgf000031_0002
in Chemical 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', and
R is phenoxy, or pyridinyl.
9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein
the compound represented by Chemical Formula 1 is any one selected from the group consisting of:
1) N-(3-(6-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylam ino)phenyl)acrylam ide,
2) N-(3-(6-(4-(pyridin-3-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- y lam ino)phenyl)acrylam ide,
3) N-(3-(6-(4-moφholinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- y lam ino)phenyl)acry lam ide,
4) N-(4-(6-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
5) N-(3-(6-beiTzoyi-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenyl)acrylamide,
6) N-(3-(6-phenyI-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenyl)acrylamide,
7) N-(3-(6-(l-methyl-l H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- y lam ino)pheny l)acrylam ide,
8) N-(3-(6-(3-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylam ide,
9) -(3-(6-(4-(moφholine-4-carbonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
10) N-(3-(6-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
1 1) N-(3-(6-(4-cyclohexylphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
12) N-(3-(6-(3-moφholinophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide, 13) N-(3-(6-(naphthalen- 1 -yl)-7H-pyrrolo[2,3-d]pyrimidin-4- y lam ino)pheny l)acry lam ide,
14) N-(3-(6-(l H-indol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- y lam ino)pheny l)acrylam ide,
15) Ν-(3-(6-(1 -(2ΜΉθφηο1ϊηοεΐ1ψ1)-1 H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin- 4-y lam ino)pheny l)acry lam ide,
16) N-(3-(6-(4-(moφholinomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- y lam ino)phenyl)acrylam ide,
17) N-(3-(6-(l H-indol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
18) N-(3-(6-(benzofijran-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylam ino)pheny!)acrylam ide,
59) N-(3-(6-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide,
20) N-(3-(6-(6-methylpyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- y lam ino)pheny l)acry lam ide,
21 ) N-(3-(6-(6-(trifluoromethyl)pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidjn ylamino)phenyl)acrylamide,
22) N-(3-(6-(6-moφholinopyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4- y lam ino)pheny l)acry lam ide,
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)actylamide,
25) N-(3-(6-(6-(l -methyl- l H-pyrazol-3-yl)pyridin-3-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-ylamino)phenyl)acrylamide,
26) N-(3-(6-(4-(piperazine- 1 -carbonyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- ylamino)phenyl)acrylamide, and
27) N-(3-(6-(4-(moφ^^olinomethyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4- yloxy)phenyl)acrylamide.
10. A pharmaceutical composition for preventing or treating autoimmune diseases or cancers, comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
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