KR102560178B1 - Imidazo[1,5-a]pyrazine derivative compounds and pharmaceutical compositions for use in preventing or treating cancer or autoimmune disease containing the same as active ingredients - Google Patents

Imidazo[1,5-a]pyrazine derivative compounds and pharmaceutical compositions for use in preventing or treating cancer or autoimmune disease containing the same as active ingredients Download PDF

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KR102560178B1
KR102560178B1 KR1020210019275A KR20210019275A KR102560178B1 KR 102560178 B1 KR102560178 B1 KR 102560178B1 KR 1020210019275 A KR1020210019275 A KR 1020210019275A KR 20210019275 A KR20210019275 A KR 20210019275A KR 102560178 B1 KR102560178 B1 KR 102560178B1
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imidazo
pyrazin
cancer
phenyl
tolylamino
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KR20220115747A (en
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김경희
정경진
김진아
권수경
이선주
문희겸
주정민
박정은
김신애
진정욱
전용현
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재단법인 대구경북첨단의료산업진흥재단
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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
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/308—Foods, ingredients or supplements having a functional effect on health having an effect on cancer prevention
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/30—Other Organic compounds
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

본 발명은 신규한 이미다조[1,5-a]피라진 유도체 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염, 및 이를 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료를 위한 약학적 조성물에 관한 것으로, 상기 본 발명에서 제공하는 이미다조[1,5-a]피라진 유도체 화합물은 BTK(Bruton's tyrosine kinase)에 대하여 높은 선택성 및 억제능을 나타내므로 BTK 관련 질환의 예방 또는 치료에 유용하게 사용될 수 있다.The present invention relates to a novel imidazo[1,5-a]pyrazine derivative compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preventing or treating cancer or autoimmune disease containing the same as an active ingredient. It can be usefully used for the prevention or treatment of K-related diseases.

Description

이미다조[1,5-a]피라진 유도체 화합물 및 이를 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물{Imidazo[1,5-a]pyrazine derivative compounds and pharmaceutical compositions for use in preventing or treating cancer or autoimmune disease containing the same as active ingredients}Imidazo[1,5-a]pyrazine derivative compounds and pharmaceutical compositions for use in preventing or treating cancer or autoimmune disease containing the same as active ingredients}

이미다조[1,5-a]피라진 유도체 화합물 및 이를 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.It relates to an imidazo[1,5-a]pyrazine derivative compound and a pharmaceutical composition for preventing or treating cancer or autoimmune disease containing the compound as an active ingredient.

암의 발생은 화학물질, 방사선, 바이러스를 포함하는 여러 가지 환경적인 요인과 종양 유전자, 종양 억제 유전자, 세포사멸(apoptosis)과 DNA 복구에 관련된 유전자의 변화 등에 관련되어 있는데, 최근 이러한 암의 분자적 메커니즘을 이해함에 따라 새로운 치료법인 표적 항암치료가 가능하게 되었다. The occurrence of cancer is related to various environmental factors including chemicals, radiation, and viruses, as well as changes in oncogenes, tumor suppressor genes, and genes related to apoptosis and DNA repair. Recently, as the molecular mechanisms of these cancers are understood, targeted chemotherapy, a new treatment, has become possible.

표적 치료제들은 일반적으로 암세포가 특징적으로 가지고 있는 분자를 표적으로 하여 그 효과를 나타낼 수 있도록 만들어지며, 분자적 표적이 되는 것은 암세포의 신호전달경로(signal transduction pathway), 혈관신생(angiogenesis), 세포간질(matrix), 세포주기조절인자(cell cycle regulator), 세포사멸(apoptosis) 등에 관련된 유전자들이다. 현재 치료에서 중요한 표적 치료제로 사용되고 있는 것으로는 타이로신 키나아제(tyrosine kinase) 억제제를 비롯한 '신호전달경로 억제제'와 '신생혈관생성 억제제'들이 있다.Targeted therapies are generally made to show their effects by targeting molecules that are characteristic of cancer cells, and the molecular targets are genes related to signal transduction pathways, angiogenesis, cell matrix, cell cycle regulators, and apoptosis in cancer cells. Currently, there are 'signal transduction pathway inhibitors' and 'angiogenesis inhibitors', including tyrosine kinase inhibitors, that are used as important target therapeutics in the treatment.

타이로신 단백질 키나아제 Tec(Tyrosine protein kinase Tec, TEC) 중 하나인 BTK(Bruton's tyrosine kinase)은 B 세포, 골수세포(myeloid cells), 비만세포(mast cells), 대식세포(macrophages)에서 발현된다. BTK는 B 세포 성장 및 기능 조절에 중요한 역할을 하며, B 세포 수용체(B cell receptor, BCR)의 다운스트림(downstream)에서 활성화된다. BTK의 비정상적 기능은 B 세포 증식, 성장, 분화 및 세포 사멸의 여러 단계에서 중요한 역할을 하며, 이는 과민성 염증 및 혈액암(hematologic malignancy)을 유발한다(Buggy, J. J. et al., International reviews of immunology 2012, 31(2), 119-32).Bruton's tyrosine kinase (BTK), one of the tyrosine protein kinase Tec (TEC), is expressed in B cells, myeloid cells, mast cells, and macrophages. BTK plays an important role in regulating B cell growth and function, and is activated downstream of the B cell receptor (BCR). Abnormal function of BTK plays an important role in several stages of B cell proliferation, growth, differentiation and apoptosis, which leads to hyperinflammatory inflammation and hematologic malignancy (Buggy, J. J. et al., International reviews of immunology 2012, 31(2), 119-32).

암 및 자가면역질환에서 BTK의 역할에 대한 증거는, BTK-결핍성 마우스 모델에 의해 또한 제공되었다. 전신 홍반 루푸스 (systemic lupus erythematosus, SLE)의 임상 이전 쥐과 모델에서, BTK-결핍성 마우스는 질병 진행을 크게 완화하는 것을 나타낸다. 게다가, BTK-결핍성 마우스는 콜라겐-유도성 관절염에 저항적이다(Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459). 선택적 BTK 억제제는 마우스 관절염 모델 내에서 용량-종속효능을 나타내었다 (Z. Pan et al., Chem. Med Chem. 2007 2:58-61).Evidence for a role of BTK in cancer and autoimmune diseases has also been provided by a BTK-deficient mouse model. In a preclinical murine model of systemic lupus erythematosus (SLE), BTK-deficient mice show a significant remission of disease progression. Moreover, BTK-deficient mice are resistant to collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459). Selective BTK inhibitors showed dose-dependent efficacy in a mouse arthritis model (Z. Pan et al., Chem. Med Chem. 2007 2:58-61).

한편, 기존의 BTK 저해제는 EGFR(상피 성장 인자 수용체, epidermal growth factor receptor)에 대한 활성도 있어서 부작용이 우려되는 문제가 있었다. 이에, 본 발명자들은 EGFR에 대한 활성이 거의 없는 선택성이 높은 BTK 억제제를 개발하기 위해 이미다조[1,5-a]피라진 유도체가 BTK에 높은 선택성을 나타내는 것을 확인하여 본 발명을 완성하였다.On the other hand, existing BTK inhibitors also have activity for EGFR (epithelial growth factor receptor, epidermal growth factor receptor), so there is a problem of concern about side effects. Accordingly, the present inventors completed the present invention by confirming that imidazo[1,5-a]pyrazine derivatives show high selectivity to BTK in order to develop a BTK inhibitor with little activity to EGFR and high selectivity.

본 발명의 일 목적은 신규한 이미다조[1,5-a]피라진 유도체 화합물, 이의 입체 이성질체, 이의 수화물, 이의 약학적으로 허용 가능한 염을 제공하는 것이다.One object of the present invention is to provide a novel imidazo[1,5-a]pyrazine derivative compound, a stereoisomer thereof, a hydrate thereof, and a pharmaceutically acceptable salt thereof.

본 발명의 다른 일 목적은 상기 화합물, 이의 입체 이성질체, 이의 수화물, 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 BTK(Bruton's tyrosine kinase) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating BTK (Bruton's tyrosine kinase)-related diseases, containing the compound, its stereoisomer, its hydrate, and its pharmaceutically acceptable salt as an active ingredient.

본 발명의 다른 일 목적은 상기 화합물, 이의 입체 이성질체, 이의 수화물, 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer or autoimmune diseases containing the compound, its stereoisomer, its hydrate, or its pharmaceutically acceptable salt as an active ingredient.

본 발명의 또 다른 일 목적은 상기 화합물, 이의 입체 이성질체, 이의 수화물, 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for preventing or improving cancer or autoimmune diseases, containing the compound, its stereoisomer, its hydrate, or its pharmaceutically acceptable salt as an active ingredient.

본 발명의 다른 일 목적은 상기 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을, 이를 필요로 하는 개체나 대상에 투여하는 단계를 포함하는, 암 또는 자가면역질환의 치료방법을 제공하는 것이다.Another object of the present invention is to provide a method for treating cancer or autoimmune disease, comprising administering the compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to an individual or subject in need thereof.

본 발명의 또 다른 일 목적은 암 또는 자가면역질환의 치료에 사용하기 위한 상기 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.Another object of the present invention is to provide the compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of cancer or autoimmune disease.

본 발명의 다른 일 목적은 암 또는 자가면역질환의 치료용 약제의 제조에 사용하기 위한 상기 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공하는 것이다.Another object of the present invention is to provide a use of the compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the preparation of a drug for the treatment of cancer or autoimmune disease.

상기 목적을 달성하기 위하여,In order to achieve the above purpose,

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 제공한다.The present invention provides a compound represented by Formula 1 below, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

상기 화학식 1에서,In Formula 1,

상기 R1은 각각 독립적으로 -H, -CN, -OH, -NH2, 할로겐, 직쇄 또는 분지쇄 C1-5알킬, 또는 직쇄 또는 분지쇄 C1-5알콕시이고;each R 1 is independently -H, -CN, -OH, -NH 2 , halogen, straight or branched C 1-5 alkyl, or straight or branched C 1-5 alkoxy;

상기 R2는 각각 독립적으로 -H, -CN, 할로겐, 또는 -NR3R4이고,Wherein R 2 is each independently -H, -CN, halogen, or -NR 3 R 4 ;

상기 R3 및 R4는 각각 독립적으로 -H, -C(=O)R5, 또는 C1- 5알케닐설포닐이거나, 또는 상기 R3 및 R4는 이들이 결합된 N 원자와 함께 연결되어 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 10 원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성하고,R 3 and R 4 are each independently -H, -C(=O ) R 5 , or C 1-5 alkenylsulfonyl, or R 3 and R 4 are linked together with the N atom to which they are bonded to form a 3 to 10 membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S;

상기 R5는 치환 또는 비치환된 직쇄 또는 분지쇄 C1- 10알킬, 비치환 또는 치환된 C1- 10알케닐, 비치환 또는 치환된 C1- 10알카이닐이고,R 5 is substituted or unsubstituted straight-chain or branched-chain C 1-10 alkyl , unsubstituted or substituted C 1-10 alkenyl, or unsubstituted or substituted C 1-10 alkynyl ;

상기 치환된 직쇄 또는 분지쇄 C1- 10알킬, C1- 10알케닐, 및 C1- 10알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C1- 5알킬, 직쇄 또는 분지쇄 디C1 - 5알킬아미노, 직쇄 또는 분지쇄 C1- 5알킬아미노, 직쇄 또는 분지쇄의 C1- 5알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 10 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C1- 5알킬로 치환 또는 비치환된 3 내지 10원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C1- 10알킬, C1- 10알케닐, 및 C1- 10알카이닐이고; 및상기 치환된 직쇄 또는 분지쇄 C 1- 10 알킬, C 1- 10 알케닐, 및 C 1- 10 알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C 1- 5 알킬, 직쇄 또는 분지쇄 디C 1 - 5 알킬아미노, 직쇄 또는 분지쇄 C 1- 5 알킬아미노, 직쇄 또는 분지쇄의 C 1- 5 알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 10 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C 1- 5 알킬로 치환 또는 비치환된 3 내지 10원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C 1- 10 알킬, C 1- 10 알케닐, 및 C 1- 10 알카이닐이고; and

상기 n은 0 또는 1이고;wherein n is 0 or 1;

상기 x 및 y는 각각 독립적으로 1 내지 5의 정수이다.The x and y are each independently an integer of 1 to 5.

또한 본 발명은 상기 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 BTK(Bruton's tyrosine kinase) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating BTK (Bruton's tyrosine kinase) related diseases, containing the compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

또한 본 발명은 상기 화합물, 이의 입체 이성질체, 이의 수화물, 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating cancer or autoimmune disease, containing the compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

또한 본 발명은 상기 화합물, 이의 입체 이성질체, 이의 수화물, 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a health functional food composition for preventing or improving cancer or autoimmune diseases, containing the compound, its stereoisomer, its hydrate, and its pharmaceutically acceptable salt as an active ingredient.

또한 본 발명은 상기 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을, 이를 필요로 하는 개체나 대상에 투여하는 단계를 포함하는, 암 또는 자가면역질환의 치료방법을 제공한다.In addition, the present invention provides a method for treating cancer or autoimmune disease, comprising administering the compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof to a subject or subject in need thereof.

또한 본 발명은 암 또는 자가면역질환의 치료에 사용하기 위한 상기 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 제공한다.In addition, the present invention provides the compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the treatment of cancer or autoimmune disease.

또한 본 발명은 암 또는 자가면역질환의 치료용 약제의 제조에 사용하기 위한 상기 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공한다.In addition, the present invention provides a use of the compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof for use in the manufacture of a drug for the treatment of cancer or autoimmune disease.

본 발명에서 제공하는 이미다조[1,5-a]피라진 유도체 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염은 BTK(Bruton's tyrosine kinase)에 대하여 높은 선택성 및 억제능을 나타내므로 암 또는 자가 면역질환과 같은 BTK 관련 질환의 예방 또는 치료에 유용하게 사용될 수 있다.The imidazo[1,5-a]pyrazine derivative compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof provided in the present invention exhibits high selectivity and inhibitory activity against BTK (Bruton's tyrosine kinase), and thus can be usefully used for the prevention or treatment of BTK-related diseases such as cancer or autoimmune diseases.

이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.

한편, 본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.On the other hand, the embodiments of the present invention can be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. Furthermore, "include" a certain component throughout the specification means that other components may be further included without excluding other components unless otherwise stated.

본 발명의 일 실시예는 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 제공한다:An embodiment of the present invention provides a compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

상기 화학식 1에서,In Formula 1,

상기 R1은 각각 독립적으로 -H, -CN, -OH, -NH2, 할로겐, 직쇄 또는 분지쇄 C1-5알킬, 또는 직쇄 또는 분지쇄 C1- 5알콕시이고;each R 1 is independently -H, -CN, -OH, -NH 2 , halogen , straight or branched C 1-5 alkyl, or straight or branched C 1-5 alkoxy;

상기 R2는 각각 독립적으로 -H, -CN, 할로겐, 또는 -NR3R4이고,Wherein R 2 is each independently -H, -CN, halogen, or -NR 3 R 4 ;

상기 R3 및 R4는 각각 독립적으로 -H, -C(=O)R5, 또는 C1- 5알케닐설포닐이거나, 또는 상기 R3 및 R4는 이들이 결합된 N 원자와 함께 연결되어 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 10 원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성하고,R 3 and R 4 are each independently -H, -C(=O ) R 5 , or C 1-5 alkenylsulfonyl, or R 3 and R 4 are linked together with the N atom to which they are bonded to form a 3 to 10 membered unsubstituted or substituted heterocycloalkyl containing one or more heteroatoms selected from the group consisting of N, O and S;

상기 R5는 치환 또는 비치환된 직쇄 또는 분지쇄 C1- 10알킬, 비치환 또는 치환된 C1- 10알케닐, 비치환 또는 치환된 C1- 10알카이닐이고,R 5 is substituted or unsubstituted straight-chain or branched-chain C 1-10 alkyl , unsubstituted or substituted C 1-10 alkenyl, or unsubstituted or substituted C 1-10 alkynyl ;

상기 치환된 직쇄 또는 분지쇄 C1- 10알킬, C1- 10알케닐, 및 C1- 10알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C1- 5알킬, 직쇄 또는 분지쇄 디C1 - 5알킬아미노, 직쇄 또는 분지쇄 C1- 5알킬아미노, 직쇄 또는 분지쇄의 C1- 5알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 10 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C1- 5알킬로 치환 또는 비치환된 3 내지 10원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C1- 10알킬, C1- 10알케닐, 및 C1- 10알카이닐이고; 및상기 치환된 직쇄 또는 분지쇄 C 1- 10 알킬, C 1- 10 알케닐, 및 C 1- 10 알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C 1- 5 알킬, 직쇄 또는 분지쇄 디C 1 - 5 알킬아미노, 직쇄 또는 분지쇄 C 1- 5 알킬아미노, 직쇄 또는 분지쇄의 C 1- 5 알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 10 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C 1- 5 알킬로 치환 또는 비치환된 3 내지 10원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C 1- 10 알킬, C 1- 10 알케닐, 및 C 1- 10 알카이닐이고; and

상기 n은 0 또는 1이고;wherein n is 0 or 1;

상기 x 및 y는 각각 독립적으로 1 내지 5의 정수이다.The x and y are each independently an integer of 1 to 5.

이때, 상기 R5는 치환 또는 비치환된 직쇄 또는 분지쇄 C1- 8알킬, 비치환 또는 치환된 C1-8알케닐, 비치환 또는 치환된 C1-8알카이닐이고,In this case, R 5 is substituted or unsubstituted straight-chain or branched-chain C 1-8 alkyl, unsubstituted or substituted C 1-8 alkenyl, or unsubstituted or substituted C 1-8 alkynyl;

상기 치환된 직쇄 또는 분지쇄 C1- 8알킬, C1- 8알케닐, 및 C1- 8알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C1- 4알킬, 직쇄 또는 분지쇄 디C1 - 4알킬아미노, 직쇄 또는 분지쇄 C1- 4알킬아미노, 직쇄 또는 분지쇄의 C1- 4알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 8 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C1- 4알킬로 치환 또는 비치환된 3 내지 8원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C1- 8알킬, C1- 8알케닐, 및 C1- 8알카이닐일 수 있다.The substituted straight or branched chain COne- 8Alkyl, COne- 8alkenyl, and COne- 8Alkynyl is each independently -CN, -OH, halogen, COne- 4Alkyl, straight or branched chain diCOne - 4Alkylamino, straight or branched chain COne- 4C of alkylamino, straight or branched chainOne- 43 to 8 membered heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O and S, which is unsubstituted or substituted with alkyl, and straight-chain or branched-chain COne- 4Straight or branched chain C substituted with one or more substituents selected from the group consisting of cycloalkyl of 3 to 8 atoms unsubstituted or substituted with alkylOne- 8Alkyl, COne- 8alkenyl, and COne- 8may be alkynyl.

또는, 상기 R1은 각각 독립적으로 -H, -CN, -OH, -NH2, 할로겐, 직쇄 또는 분지쇄 C1-3알킬, 또는 직쇄 또는 분지쇄 C1-3알콕시이고;Alternatively, each R 1 is independently -H, -CN, -OH, -NH 2 , halogen, straight-chain or branched-chain C 1-3 alkyl, or straight-chain or branched-chain C 1-3 alkoxy;

상기 R5는 치환 또는 비치환된 직쇄 또는 분지쇄 C1- 5알킬, 비치환 또는 치환된 C1- 5알케닐, 비치환 또는 치환된 C1- 5알카이닐이고,R 5 is substituted or unsubstituted straight-chain or branched-chain C 1-5 alkyl , unsubstituted or substituted C 1-5 alkenyl, or unsubstituted or substituted C 1-5 alkynyl ;

상기 치환된 직쇄 또는 분지쇄 C1- 5알킬, C1- 5알케닐, 및 C1- 5알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C1- 3알킬, 직쇄 또는 분지쇄 디C1 - 3알킬아미노, 직쇄 또는 분지쇄 C1- 3알킬아미노, 직쇄 또는 분지쇄의 C1- 3알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 7 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C1- 3알킬로 치환 또는 비치환된 3 내지 7원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C1-5알킬, C1-5알케닐, 및 C1-5알카이닐이고; 및The substituted straight-chain or branched-chain C 1-5 alkyl, C 1-5 alkenyl , and C 1-5 alkynyl are each independently -CN , -OH, halogen, C 1-3 alkyl, straight - chain or branched -chain di One or more heteroatoms selected from the group consisting of N, O, and S unsubstituted or substituted with C 1-3 alkylamino , straight-chain or branched-chain C 1-3 alkylamino, or straight-chain or branched - chain C 1-3 alkyl ; Straight-chain or branched-chain substituted with one or more substituents selected from the group consisting of 3-7 membered heterocycloalkyl, and 3-7 membered cycloalkyl unsubstituted or substituted with straight - chain or branched C 1-3 alkyl. branched chain C 1-5 alkyl, C 1-5 alkenyl, and C 1-5 alkynyl; and

상기 x 및 y는 각각 독립적으로 1 내지 3의 정수일 수 있다.The x and y may each independently be an integer of 1 to 3.

또는, 상기 R1은 각각 독립적으로 -H, -CH3, 또는 할로겐이고;Alternatively, R 1 is each independently -H, -CH 3 , or halogen;

상기 R2는 각각 독립적으로 -H, -CN, -NH2, 할로겐, , , , , , , , , , , , , , , , , , , , , , , , , 또는이고;The R 2 are each independently -H, -CN, -NH 2 , halogen, , , , , , , , , , , , , , , , , , , , , , , , , or ego;

상기 x 및 y는 각각 독립적으로 1 또는 2일 수 있다.The x and y may each independently be 1 or 2.

또는 상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염일 수 있다:Alternatively, the compound represented by Formula 1 may be a compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is any one selected from the group of compounds below:

(1) 4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)벤조나이트릴;(1) 4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile;

(2) 3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)벤조나이트릴;(2) 3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile;

(3) 5-(3-아미노페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;(3) 5-(3-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;

(4) 5-(4-아미노페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;(4) 5-(4-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;

(5) 5-(3-(피페라진-1-일)페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;(5) 5-(3-(piperazin-1-yl)phenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;

(6) 5-(4-(피페라진-1-일)페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;(6) 5-(4-(piperazin-1-yl)phenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;

(7) N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)에텐설폰아마이드;(7) N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)ethenesulfonamide;

(8) 5-(5-아미노-2-클로로페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;(8) 5-(5-amino-2-chlorophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;

(9) 5-(3-아미노페녹시)-N-(4-플루오로-2-메틸페닐)이미다조[1,5-a]피라진-8-아민;(9) 5-(3-aminophenoxy)-N-(4-fluoro-2-methylphenyl)imidazo[1,5-a]pyrazin-8-amine;

(10) 2-플루오로-N-(4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;(10) 2-fluoro-N-(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;

(11) 2-사이아노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;(11) 2-cyano-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;

(12) N-(4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;(12) N-(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;

(13) N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;(13) N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;

(14) N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)프로피온아마이드;(14) N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)propionamide;

(15) 2-클로로-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;(15) 2-chloro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;

(16) N-(4-클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;(16) N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;

(17) 2-클로로-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;(17) 2-chloro-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;

(18) N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;(18) N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;

(19) 2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;(19) 2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;

(20) 2-플루오로-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;(20) 2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;

(21) N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰틴-2-아마이드;(21) N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butyn-2-amide;

(22) 2-브로모-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;(22) 2-bromo-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;

(23) 2-아이오도-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;(23) 2-iodo-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;

(24) (E)-4-하이드록시-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;(24) (E)-4-hydroxy-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide;

(25) (E)-4-(다이메틸아미노)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;(25) (E)-4-(dimethylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide;

(26) N-(4-클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-2-사이아노아세트아마이드;(26) N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyanoacetamide;

(27) 2-플루오로-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;(27) 2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;

(28) (E)-4-(메틸아미노)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;(28) (E)-4-(methylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;

(29) (E)-4-(4-아이소프로필피페라진-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;(29) (E)-4-(4-isopropylpiperazin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;

(30) (E)-4-(피페라진-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;(30) (E)-4-(piperazin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;

(31) (E)-4-(피롤리딘-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;(31) (E)-4-(pyrrolidin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;

(32) (E)-4-(사이클로프로필아미노)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;(32) (E)-4-(cyclopropylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide;

(33) (E)-4-몰폴리노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;(33) (E)-4-morpholino-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide;

(34) (E)-4-(4-메틸-1,4-다이아제판-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;(34) (E)-4-(4-methyl-1,4-diazepan-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;

(35) (E)-2-사이아노-3-사이클로프로필-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;(35) (E)-2-cyano-3-cyclopropyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;

(36) (E)-2-사이아노-4-메틸-4-몰폴리노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)펜텐-2-아마이드;(36) (E)-2-cyano-4-methyl-4-morpholino-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)penten-2-amide;

(37) (E)-2-사이아노-4-메틸-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)펜텐-2-아마이드;(37) (E)-2-cyano-4-methyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)penten-2-amide;

(38) (E)-2-사이아노-4,4-다이메틸-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)펜텐-2-아마이드;(38) (E)-2-cyano-4,4-dimethyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)penten-2-amide;

(39) (E)-N-(4-클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-2-사이아노-3-사이클로프로필아크릴아마이드;(39) (E)-N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyano-3-cyclopropylacrylamide;

(40) (E)-2-사이아노-3-사이클로프로필-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;(40) (E)-2-cyano-3-cyclopropyl-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;

(41) (E)-2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-4-메틸펜텐-2-아마이드;(41) (E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4-methylpenten-2-amide;

(42) (E)-2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-4,4-다이메틸펜텐-2-아마이드;(42) (E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4,4-dimethylpenten-2-amide;

(43) (E)-2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-4-메틸-4-몰폴리노펜텐-2-아마이드;(43) (E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4-methyl-4-morpholinopenten-2-amide;

(44) 3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)벤조나이트릴;(44) 3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)benzonitrile;

(45) 4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)벤조나이트릴;(45) 4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)benzonitrile;

(46) 5-(3-아미노페닐)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;(46) 5-(3-aminophenyl)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;

(47) N-(4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드;(47) N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide;

(48) N-(4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)프로피온아마이드;(48) N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propionamide;

(49) N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)프로피온아마이드;(49) N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propionamide;

(50) N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드;(50) N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide;

(51) (E)-4-브로모-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드;(51) (E)-4-bromo-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)buten-2-amide;

(52) (E)-4-하이드록시-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드;(52) (E)-4-hydroxy-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)buten-2-amide;

(53) 2-사이아노-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아세트아마이드;(53) 2-cyano-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acetamide;

(54) (E)-4-(다이메틸아미노)-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드;(54) (E)-4-(dimethylamino)-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)buten-2-amide;

(55) 2-플루오로-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드;(55) 2-fluoro-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide;

(56) 2-플루오로-N-(4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드; 및(56) 2-fluoro-N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide; and

(57) (E)-4-(메틸아미노)-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드.(57) (E)-4-(methylamino)-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)buten-2-amide.

본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc. It is obtained from organic acids such as acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulphate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, hep Thanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzene phonates, toluenesulfonates, chlorobenzenesulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, malates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and the like.

본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다.The acid addition salt according to the present invention can be prepared by a conventional method. For example, it can be prepared by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc., and adding an organic acid or inorganic acid. The resulting precipitate is filtered and dried, or the solvent and excess acid can be distilled off under reduced pressure, dried and crystallized in an organic solvent.

또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg, silver nitrate).

나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 광학 이성질체, 수화물 등을 모두 포함한다.Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like prepared therefrom.

본 발명의 다른 일 실시예는 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.Another embodiment of the present invention provides a pharmaceutical composition for preventing or treating cancer or autoimmune disease, containing the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

상기 화합물은 BTK(Bruton's tyrosine kinase)를 억제하여 암 또는 자가면역질환을 예방 또는 치료할 수 있다.The compound inhibits Bruton's tyrosine kinase (BTK) to prevent or treat cancer or autoimmune diseases.

이때, 상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 림프구성 백혈병(CLL), 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 미만성거대B-세포림프종, 맨틀세포림프종(MCL), 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 비호지킨림프종, 설암, 성상세포종, 소림프구성림프종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 재킷세포림프종, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 호지킨림프종, 횡문근육종, 후두암, 흉막암, 혈액암, 또는 흉선암일 수 있으나 이에 반드시 제한되는 것은 아니다.At this time, the cancer is pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract Cancer, colorectal cancer, lymphocytic leukemia (CLL), chronic myeloid leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), ampulla cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, rhinosinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small lymphocytic lymphoma, Small cell lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, primary site cancer, gastric lymphoma, stomach cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms' cancer, breast cancer, sarcoma , penile cancer, pharyngeal cancer, gestational choriocarcinoma, jacket cell lymphoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, tiger Hodgkin's lymphoma, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, or thymic cancer may be, but is not necessarily limited thereto.

상기 자가면역질환은 류마티스성 관절염, 건선 관절염, 골관절염, 스틸 질환, 연소성 관절염, 루푸스, 중증 근무력증, 하시모토 갑상선염, 요오드 갑상선염, 그레이브 질환 쇼그렌 증후군, 다발성 경화증, 길랑-바레 증후근, 급성 파종 뇌척수염, 애디슨 질환, 안구진탕-근간대성 증후군, 강직성 척수염, 항인지질 항체 증후군, 재생불량성 빈혈, 자가면역성 간염, 복강 질환, 구드패스츄어 증후군, 특발성 혈소판감소성 자반병, 시신경염, 공피증, 원발성 담즙성 간경변증, 라이터 증후군, 타카야스 동맥염, 측두 동맥염, 상온 자가면역성 용혈성 빈혈, 베게너 육아종증, 건선, 범발성 탈모증, 베체트 질환, 자율신경기능이상, 자궁내막증, 간질성 방광염, 신경 근육긴장증, 또는 외음통일 수 있으나 이에 반드시 제한되는 것은 아니다.The autoimmune diseases include rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodine thyroiditis, Grave's disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, nystagmus-myoclonic syndrome, ankylosing myelitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis , celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, normal temperature autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, generalized alopecia, Behçet's disease, autonomic dysfunction, endometriosis, interstitial cystitis, neuromuscular dystonia, or vulvodynia It can, but is not necessarily limited thereto.

또한, 본 발명의 일 실시예는 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 BTK(Bruton's tyrosine kinase) 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, one embodiment of the present invention provides a pharmaceutical composition for preventing or treating BTK (Bruton's tyrosine kinase)-related diseases containing the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

이때, 상기 BTK 관련 질환은, 예를 들면 상기 암 또는 자가면역질환이다.At this time, the BTK-related disease is, for example, the cancer or autoimmune disease.

또한, 상기 BTK 관련 질환은 혈액학적 악성종양(hematological malignancy), 혈액암, B-세포 만성림프성백혈병, 급성림프성백혈병, 비호지킨림프종, 호지킨림프종, 급성골수성백혈병, 미만성거대B-세포림프종, 다발성골수종, 재킷세포림프종, 소림프구성림프종, 맨틀세포림프종(MCL) 또는 림프구성 백혈병(CLL)일 수도 있고,In addition, the BTK-related disease may be hematological malignancy, hematological malignancy, B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, acute myelogenous leukemia, diffuse large B-cell lymphoma, multiple myeloma, jacket cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma (MCL) or lymphocytic leukemia (CLL) there is,

또는, BTK 관련 질환은 류마티스 관절염, 골관절염, 연소성관절염, 만성폐쇄성 폐질환, 다발성경화증, 천식, 전신성홍반성루푸스, 건선, 건선성관절염, 크론병, 궤양성대장염 또는 과민성대장증후군일 수도 있다.Alternatively, the BTK-related disease may be rheumatoid arthritis, osteoarthritis, juvenile arthritis, chronic obstructive pulmonary disease, multiple sclerosis, asthma, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis or irritable bowel syndrome.

상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral dosage forms during clinical administration. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing one or more compounds with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions for oral administration, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.

상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다.A pharmaceutical composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is performed by subcutaneous injection, intravenous injection, intramuscular injection or intrathoracic injection.

이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed in water together with a stabilizer or buffer to prepare a solution or suspension, which can be prepared in an ampoule or vial unit dosage form. The composition may be sterilized and/or contain preservatives, stabilizers, hydration agents or emulsification accelerators, adjuvants such as salts and/or buffers for osmotic pressure control, and other therapeutically useful substances, and may be formulated according to conventional mixing, granulation or coating methods.

경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and troches. Cole) is included. Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and the like, and optionally disintegrants or effervescent mixtures such as starch, agar, alginic acid or sodium salts thereof and/or absorbents, colorants, flavors, and sweeteners.

또한, 본 발명의 일 실시예는 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, one embodiment of the present invention provides a health functional food composition for preventing or improving cancer or autoimmune diseases containing the compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명에 따른 상기 화학식 1로 표시되는 화합물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The compound represented by Formula 1 according to the present invention may be added to food as it is or used together with other foods or food ingredients, and may be appropriately used according to conventional methods. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). Generally, the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for the purpose of health and hygiene or health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.

또한, 본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.In addition, the health functional beverage composition of the present invention is not particularly limited in other components except for containing the compound as an essential component in the indicated ratio, and may contain various flavors or natural carbohydrates as additional components like conventional beverages. Examples of the aforementioned natural carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrins, cyclodextrins, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those mentioned above, natural flavoring agents (thaumatin, stevia extract (e.g. rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion of the natural carbohydrates is generally about 1 to 20 g, preferably about 5 to 12 g, per 100 g of the composition of the present invention.

나아가, 상기 외에 본 발명에 따른 화학식 1로 표시되는 화합물은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. Furthermore, in addition to the above, the compound represented by Formula 1 according to the present invention may contain various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring agents and fillers (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH regulators, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, and the like.

이하, 본 발명의 실시예 및 실험예를 하기에 구체적으로 예시하여 설명한다. 다만, 후술하는 실시예 및 실험예는 본 발명의 일부를 예시하는 것일 뿐, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, examples and experimental examples of the present invention will be specifically illustrated and described. However, Examples and Experimental Examples to be described later are merely illustrative of a part of the present invention, and the present invention is not limited thereto.

[반응식 Ⅰ][Scheme Ⅰ]

단계 1-1step 1-1

5-브로모피라진-2-올 (3 g, 17.14 mmol)를 DMF-THF (65.4 mL; 1:1 비율)에 용해시킨 뒤 0 oC에서 NaH (0.686 g, 17.14 mmol)를 넣고 30분간 교반한다. 이후 1-(클로로메틸)-4-메톡시벤젠 (2.95 g, 18.86 mmol)를 THF (19.48 ml)에 녹여 적가하고 테트라뷰틸암모늄 아이오다이드 (0.633 g, 1.714 mmol)도 적가한 뒤 실온에서 12시간 동안 교반한다. 70 ℃에서 1시간 동안 추가로 교반하고 상온으로 냉각한 후 10% NH4Cl 수용액으로 반응을 종결시킨다. 반응액을 에틸아세테이트를 사용하여 추출하고 유기층을 소금물로 세척한 뒤, 유기층을 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류하여 얻은 잔사를 MPLC (Medium pressure liquid chromatography)로 분리, 정제하여 목적화합물 4.48 g (수율: 89%)을 얻었다.After dissolving 5-bromopyrazin-2-ol (3 g, 17.14 mmol) in DMF-THF (65.4 mL; 1:1 ratio), NaH (0.686 g, 17.14 mmol) was added at 0 ° C and stirred for 30 minutes. Thereafter, 1-(chloromethyl)-4-methoxybenzene (2.95 g, 18.86 mmol) was dissolved in THF (19.48 ml) and added dropwise, and tetrabutylammonium iodide (0.633 g, 1.714 mmol) was added dropwise, followed by stirring at room temperature for 12 hours. After further stirring at 70 °C for 1 hour and cooling to room temperature, the reaction was terminated with 10% NH 4 Cl aqueous solution. The reaction solution was extracted using ethyl acetate, the organic layer was washed with brine, the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and the solvent was distilled off under reduced pressure.

단계 1-2step 1-2

0 oC에서 NaH (0.686 g, 17.14 mmol)를 THF (18.39 mL)에 넣고 교반한다. 이후 5-브로모-1-(4-메톡시벤질)피라진-2(1H)-온 (3.68 g, 12.47 mmol)와 p-톨루엔설포닐메틸아이소사이아나이드 (2.68 g, 13.72 mmol)를 THF (40 ml)에 녹여 적가한 뒤 0 oC에서 30분간 교반하고 추가로 상온에서 1시간 동안 교반한다. 반응이 종결되면 반응액을 물을 이용하여 반응을 종료시키고, 에틸아세테이트를 부가하여 유기층을 추출하였다. 유기층을 물과 소금물로 세척한 뒤, 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류하여 얻은 잔사를 MPLC로 분리, 정제하여 목적화합물 3.71 g (수율: 89%)을 얻었다.Add NaH (0.686 g, 17.14 mmol) to THF (18.39 mL) at 0 o C and stir. After dissolving 5-bromo-1-(4-methoxybenzyl)pyrazin-2(1H)-one (3.68 g, 12.47 mmol) and p-toluenesulfonylmethylisocyanide (2.68 g, 13.72 mmol) in THF (40 ml), the mixture was added dropwise, stirred at 0 ° C for 30 minutes, and further stirred at room temperature for 1 hour. When the reaction was completed, the reaction was terminated using water, and the organic layer was extracted by adding ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and the solvent was distilled off under reduced pressure. The residue was separated and purified by MPLC to obtain 3.71 g of the target compound (yield: 89%).

단계 1-3Steps 1-3

5-브로모-7-(4-메톡시벤질)이미다조[1,5-a]피라진-8(7H)-온 (1.650 g, 4.94 mmol)와 아니솔 (9.66 ml, 89 mmol)를 0 oC에서 트라이플루오로아세트산 (0.378 ml, 4.94 mmol)에 용해시킨 뒤 트라이플루오로메테인설폰산 (5.41 ml, 61.2 mmol)를 천천히 적가한다. 반응액을 실온에서 30분 동안 교반한 뒤, 40 oC에서 1시간 동안 추가로 교반하고 트라이플루오로아세트산을 감압증류하여 제거한다. 남은 잔사에 다이에틸에테르를 부가하여 생성된 염을 여과하고 다이에틸에테르를 추가로 부가하여 세척한다. 염을 물에 용해시킨 뒤, 에틸아세테이트로 추출하고 NaHCO3 수용액으로 세척한다. 유기층을 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류하여 목적화합물 977.4 mg (수율: 92%)을 얻었다.5-Bromo-7-(4-methoxybenzyl)imidazo[1,5-a]pyrazin-8(7H)-one (1.650 g, 4.94 mmol) and anisole (9.66 ml, 89 mmol) were dissolved in trifluoroacetic acid (0.378 ml, 4.94 mmol) at 0 ° C, followed by trifluoromethanesulfonic acid (5.41 ml, 61.2 mmol). Add dropwise slowly. The reaction solution was stirred at room temperature for 30 minutes, further stirred at 40 ° C. for 1 hour, and trifluoroacetic acid was removed by distillation under reduced pressure. Diethyl ether was added to the remaining residue to filter the resulting salt, and diethyl ether was further added to wash. After dissolving the salt in water, extracting with ethyl acetate and NaHCO 3 Wash with aqueous solution. organic layer After drying with anhydrous Na 2 SO 4 and filtering, the solvent was distilled under reduced pressure to obtain 977.4 mg of the target compound (yield: 92%).

단계 1-4Steps 1-4

5-브로모이미다조[1,5-a]피라진-8-(7H)-온 (1.000 g, 4.67 mmol)를 포스포러스 옥시클로라이드 (25.0 ml, 267 mmol)에 용해시킨 뒤 트라이에틸아민 (1.302 ml, 9.34 mmol)를 적가한다. 온도를 서서히 올려서 reflux 조건에서 12시간 이상 반응한 뒤, 톨루엔과 함께 여러 차례 감압증류하여 포스포러스 옥시클로라이드를 제거한다. 남은 잔사를 디클로로메탄에 용해시킨 뒤 NaHCO3 수용액을 넣고 0 oC에서 10분간 교반한다. 수층을 추가로 디클로로메탄으로 추출하고 유기층을 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류하여 목적화합물 995.5 mg (수율: 92%)을 얻었다.After dissolving 5-bromoimidazo[1,5-a]pyrazin-8-(7H)-one (1.000 g, 4.67 mmol) in phosphorus oxychloride (25.0 ml, 267 mmol), triethylamine (1.302 ml, 9.34 mmol) is added dropwise. After reacting for more than 12 hours under reflux conditions by gradually raising the temperature, phosphorus oxychloride is removed by distillation under reduced pressure several times with toluene. After dissolving the remaining residue in dichloromethane, NaHCO 3 Add the aqueous solution and stir at 0 o C for 10 minutes. The aqueous layer was further extracted with dichloromethane, and the organic layer was dried over anhydrous Na 2 SO 4 , filtered, and the solvent was distilled under reduced pressure to obtain 995.5 mg of the target compound (yield: 92%).

단계 1-5Steps 1-5

5-브로모-8-클로로이미다조[1,5-a]피라진 (0.66 g, 2.84 mmol)와 o-톨리이딘 (0.456 g, 4.26 mmol)를 THF (28.4 ml)에 용해시키고 소듐 비스(트라이메틸실릴)아마이드 (18.45 ml, 18.45 mmol)를 천천히 적가한다. 반응액을 60 oC에서 1시간 동안 교반한다. 반응이 종결되면 상온으로 냉각한 뒤 NH4Cl 수용액으로 반응을 종료하고, 에틸아세테이트를 사용하여 추출한다. 유기층을 물과 소금물로 세척한 뒤, 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류하여 얻은 잔사를 MPLC(아닐린 실리카)로 분리, 정제하여 목적화합물 780 mg (수율: 91%)을 얻었다.5-Bromo-8-chloroimidazo[1,5-a]pyrazine (0.66 g, 2.84 mmol) and o-tolidine (0.456 g, 4.26 mmol) were dissolved in THF (28.4 ml), and sodium bis(trimethylsilyl)amide (18.45 ml, 18.45 mmol) was slowly added dropwise. The reaction solution is stirred at 60 ° C for 1 hour. Upon completion of the reaction, the reaction was cooled to room temperature, and the reaction was terminated with an aqueous solution of NH 4 Cl, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and the solvent was distilled off under reduced pressure. The residue was separated and purified by MPLC (aniline silica) to obtain 780 mg of the target compound (yield: 91%).

단계 1-6Steps 1-6

5-브로모-8-클로로이미다조[1,5-a]피라진 (30 mg, 0.13 mmol)와 4-플루오로-2-메틸아닐린 (24 mg, 0.19 mmol)를 THF (0.5 ml)에 용해시키고 소듐 비스(트라이메틸실릴)아마이드 (0.843 ml, 0.84 mmol)를 -50 oC에서 천천히 적가한다. 반응액을 상온에서 1시간 동안 교반한다. 반응이 종결되면 NH4Cl 수용액으로 반응을 종료하고, 에틸아세테이트를 사용하여 추출한다. 유기층을 물과 소금물로 세척한 뒤, 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류하여 얻은 잔사를 MPLC로 분리, 정제하여 목적화합물 41 mg (수율: 99%)을 얻었다.5-Bromo-8-chloroimidazo[1,5-a]pyrazine (30 mg, 0.13 mmol) and 4-fluoro-2-methylaniline (24 mg, 0.19 mmol) were dissolved in THF (0.5 ml) and sodium bis(trimethylsilyl)amide (0.843 ml, 0.84 mmol) was slowly added dropwise at -50 ° C. The reaction solution is stirred at room temperature for 1 hour. When the reaction is completed, the reaction is terminated with aqueous NH 4 Cl solution, and extraction is performed using ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous Na 2 SO 4 , filtered, and the solvent was distilled off under reduced pressure. The residue was separated and purified by MPLC to obtain 41 mg of the target compound (yield: 99%).

단계 1-7Steps 1-7

5-브로모-N-(4-플루오로-2-메틸페닐)이미다조[1,5-a]피라진-8-아민 (41 mg, 0.13 mmol), 다이-tert-뷰틸 다이카보네이트 (59 μL, 0.26 mmol), 4-(다이메틸아미노)피리딘 (1.6 mg, 0.013 mmol)을 THF (2 ml)에 용해시키고 트라이에틸아민 (36 μL, 0.26 mmol)를 적가한다. 반응액을 65 ℃에서 12시간 동안 교반한다. 반응이 종결되면, 에틸아세테이트를 첨가하고 물과 소금물로 세척한다. 유기층을 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류하여 얻은 잔사를 MPLC로 분리, 정제하여 목적화합물 36.9 mg (수율: 69%)을 얻었다.5-Bromo-N-(4-fluoro-2-methylphenyl)imidazo[1,5-a]pyrazin-8-amine (41 mg, 0.13 mmol), di-tert-butyl dicarbonate (59 μL, 0.26 mmol), 4-(dimethylamino)pyridine (1.6 mg, 0.013 mmol) were dissolved in THF (2 ml) and triethylamine (36 μL, 0.26 μL). mmol) is added dropwise. The reaction solution is stirred at 65 °C for 12 hours. When the reaction is complete, ethyl acetate is added and washed with water and brine. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and the solvent was distilled off under reduced pressure. The residue was separated and purified by MPLC to obtain 36.9 mg of the target compound (yield: 69%).

[반응식 Ⅱ][Scheme II]

<< 실시예Example 1> 4-((8- 1> 4-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)-5 days) 옥시oxy )) 벤조나이트릴의of benzonitrile 제조 manufacturing

5-브로모-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민 (20 mg, 0.066 mmol), 구리 419 mg, 6.60 μmol), 세슘 카보네이트 (64.5 mg, 0.198 mmol)와 4-하이드록시벤조나이트릴 (11.79 mg, 0.099 mmol)을 DMF (776 μl)에 용해시키고 100 °C에서 2시간 동안 교반한다. 반응이 종결되면 상온으로 냉각시킨 뒤, 에틸아세테이트를 사용하여 추출하고 유기층을 소금물과 물로 세척한다. 유기층을 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류하여 얻은 잔사를 MPLC로 분리, 정제하여 목적화합물 4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)벤조나이트릴(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile) 10 mg (수율: 42.3%)을 얻었다.5-Bromo-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (20 mg, 0.066 mmol), copper 419 mg, 6.60 μmol), cesium carbonate (64.5 mg, 0.198 mmol) and 4-hydroxybenzonitrile (11.79 mg, 0.099 mmol) were dissolved in DMF (776 μl) and 10 Stir for 2 h at 0 °C. After the reaction was completed, the mixture was cooled to room temperature, extracted using ethyl acetate, and the organic layer was washed with brine and water. The organic layer was dried over anhydrous Na 2 SO 4 , filtered, and the residue obtained by distilling the solvent under reduced pressure was separated and purified by MPLC to obtain the target compound 4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile (4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile) 10 mg rate: 42.3%) was obtained.

1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.68 (t, J = 7.4 Hz, 3H), 7.33 (s, 1H), 7.32 - 7.24 (m, 3H), 7.22 (d, J = 7.4 Hz, 1H), 7.17 (d, J = 7.7 Hz, 2H), 7.00 (s, 1H), 2.36 (s, 3H). LRMS (ESI), m/z = 342.2 [M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.97 (s, 1H), 7.68 (t, J = 7.4 Hz, 3H), 7.33 (s, 1H), 7.32 - 7.24 (m, 3H), 7.22 (d, J = 7.4 Hz, 1H), 7.17 (d, J = 7.7 Hz , 2H), 7.00 (s, 1H), 2.36 (s, 3H). LRMS (ESI), m/z = 342.2 [M+H] +

<< 실시예Example 2> 3-((8- 2> 3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)-5 days) 옥시oxy )) 벤조나이트릴의of benzonitrile 제조 manufacturing

상기 실시예 1과 같은 방법으로 제조하되, 3-하이드록시벤조나이트릴 (12.97 mg, 0.109 mmol) 시약을 사용하여 목적화합물 3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)벤조나이트릴(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile) 3 mg (수율: 11.6%)을 얻었다. It was prepared in the same manner as in Example 1, but using 3-hydroxybenzonitrile (12.97 mg, 0.109 mmol) reagent to obtain the desired compound 3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile ) 3 mg (yield: 11.6%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.69 (s, 1H), 8.37 (s, 1H), 7.79 (s, 1H), 7.68 (d, J = 1.5 Hz, 3H), 7.54 - 7.51 (m, 2H), 7.48 - 7.45 (m, 2H), 6.71 (s, 1H), 2.40 (s, 3H). LRMS (ESI), m/z = 342.04 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.69 (s, 1H), 8.37 (s, 1H), 7.79 (s, 1H), 7.68 (d, J = 1.5 Hz, 3H), 7.54 - 7.51 (m, 2H), 7.48 - 7.45 (m, 2H), 6.71 (s , 1H), 2.40 (s, 3H). LRMS (ESI), m/z = 342.04 [M+H] +

<< 실시예Example 3> 5-(3- 3 > 5-(3- 아미노페녹시aminophenoxy )-N-)-N- (o-톨릴)이미다조[1,5-a]피라진(o-tolyl)imidazo[1,5-a]pyrazine -8--8- 아민의amine 제조 manufacturing

상기 실시예 1과 같은 방법으로 제조하되, 3-아미노페놀 (7.20 mg, 0.066 mmol) 시약을 사용하여 목적화합물 5-(3-아미노페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민(5-(3-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine) 10 mg (수율: 45.7%)을 얻었다.It was prepared in the same manner as in Example 1, but using 3-aminophenol (7.20 mg, 0.066 mmol) reagent, 10 mg of target compound 5-(3-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (5-(3-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine) ( Yield: 45.7%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.66 (s, 1H), 8.36 (s, 1H), 7.53 - 7.46 (m, 4H), 7.27 (t, J = 8.4 Hz, 1H), 6.75 - 6.74 (m, 2H), 6.71 - 6.65 (m, 1H), 6.45 (s, 1H), 2.38 (s, 3H). LRMS (ESI), m/z = 332.09 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.66 (s, 1H), 8.36 (s, 1H), 7.53 - 7.46 (m, 4H), 7.27 (t, J = 8.4 Hz, 1H), 6.75 - 6.74 (m, 2H), 6.71 - 6.65 (m, 1H), 6.45 (s, 1H), 2.38 (s, 3H). LRMS (ESI), m/z = 332.09 [M+H] +

<< 실시예Example 4> 5-(4- 4 > 5-(4- 아미노페녹시aminophenoxy )-N-)-N- (o-톨릴)이미다조[1,5-a]피라진(o-tolyl)imidazo[1,5-a]pyrazine -8--8- 아민의amine 제조 manufacturing

상기 실시예 1과 같은 방법으로 제조하되, tert-뷰틸 (4-하이드록시페닐)카바메이트 (34.5 mg, 0.165 mmol) 시약을 사용하여 tert-뷰틸 (4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)카바메이트를 얻었다. 얻은 중간화합물을 디클로로메탄 (1 ml)에 녹이고 TFA(0.1 ml)를 넣고 상온에서 1시간 동안 교반하고, 반응이 종결되면 용매를 감압증류하여 얻은 잔사를 prep-HPLC로 분리, 정제하여 목적화합물 5-(4-아미노페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민(5-(4-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine) 6 mg (수율: 10.9%)을 얻었다.It was prepared in the same manner as in Example 1, but using tert-butyl (4-hydroxyphenyl) carbamate (34.5 mg, 0.165 mmol) reagent to obtain tert-butyl (4-((8- (o-tolylamino) imidazo [1,5-a] pyrazin-5-yl) oxy) phenyl) carbamate. The obtained intermediate compound was dissolved in dichloromethane (1 ml), TFA (0.1 ml) was added and stirred at room temperature for 1 hour. After the reaction was completed, the solvent was distilled under reduced pressure and the residue obtained was separated and purified by prep-HPLC to obtain the target compound 5-(4-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (5-(4-aminophenoxy)-N-(o-tolyl)im idazo[1,5-a]pyrazin-8-amine) 6 mg (yield: 10.9%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.28 (s, 1H), 7.52 - 7.39 (m, 4H), 7.34 - 7.27 (m, 2H), 7.22 - 7.16 (m, 2H), 6.42 (s, 1H), 2.37 (s, 3H). LRMS (ESI), m/z = 332.0 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.28 (s, 1H), 7.52 - 7.39 (m, 4H), 7.34 - 7.27 (m, 2H), 7.22 - 7.16 (m, 2H), 6.42 (s, 1H), 2.37 (s, 3H). LRMS (ESI), m/z = 332.0 [M+H] +

<< 실시예Example 5> 5-(3-(피페라진-1-일) 5> 5-(3-(piperazin-1-yl) 페녹시phenoxy )-N-)-N- (o-톨릴)이미다조[1,5-a]피라진(o-tolyl)imidazo[1,5-a]pyrazine -8-아민의 제조Preparation of 8-amine

상기 실시예 1과 같은 방법으로 제조하되, 3-(피페라진-1-일)페놀 (29.4 mg, 0.165 mmol) 시약을 사용하여 목적화합물 5-(3-(피페라진-1-일)페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민(5-(3-(piperazin-1-yl)phenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine) 1.1 mg (수율: 1.6%)을 얻었다.It was prepared in the same manner as in Example 1, but the target compound 5-(3-(piperazin-1-yl)phenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (5-(3-(piperazin-1-yl)phenoxy)-N-(o-to lyl)imidazo[1,5-a]pyrazin-8-amine) 1.1 mg (yield: 1.6%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.31 (s, 1H), 7.53 - 7.42 (m, 3H), 7.37 (t, J = 8.3 Hz, 1H), 7.03 -7.02 (m, 1H), 6.98 - 6.96 (m, 1H), 6.84 - 6.81 (m, 1H), 6.48 (s, 1H), 3.50 - 3.48 (m, 4H), 3.42 - 3.37 (m, 4H), 2.38 (s, 3H). LRMS (ESI), m/z = 401.21 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.31 (s, 1H), 7.53 - 7.42 (m, 3H), 7.37 (t, J = 8.3 Hz, 1H), 7.03 -7.02 (m, 1H), 6.98 - 6.96 (m, 1H), 6 .84 - 6.81 (m, 1H), 6.48 (s, 1H), 3.50 - 3.48 (m, 4H), 3.42 - 3.37 (m, 4H), 2.38 (s, 3H). LRMS (ESI), m/z = 401.21 [M+H] +

<< 실시예Example 6> 5-(4-(피페라진-1-일) 6> 5-(4-(piperazin-1-yl) 페녹시phenoxy )-N-)-N- (o-톨릴)이미다조[1,5-a]피라진(o-tolyl)imidazo[1,5-a]pyrazine -8-아민의 제조Preparation of 8-amine

상기 실시예 1과 같은 방법으로 제조하되, 4-(피페라진-1-일)페놀 (14.70 mg, 0.082 mmol) 시약을 사용하여 목적화합물 5-(4-(피페라진-1-일)페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민(5-(4-(piperazin-1-yl)phenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine) 1.5 mg (수율: 4.5%)을 얻었다.The target compound 5-(4-(piperazin-1-yl)phenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (5-(4-(piperazin-1-yl)phenoxy)-N-(o- tolyl)imidazo[1,5-a]pyrazin-8-amine) to obtain 1.5 mg (yield: 4.5%).

1H NMR (400 MHz, MeOD) δ 8.74 (s, 1H), 8.34 (s, 1H), 7.55 - 7.41 (m, 4H), 7.33 - 7.27 (m, 2H), 7.20 - 7.12 (m, 2H), 6.27 (s, 1H), 3.43 (s, 4H), 3.41 (s, 4H), 2.37 (s, 3H). LRMS (ESI), m/z = 401.29 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.74 (s, 1H), 8.34 (s, 1H), 7.55 - 7.41 (m, 4H), 7.33 - 7.27 (m, 2H), 7.20 - 7.12 (m, 2H), 6.27 (s, 1H), 3.43 (s, 4H), 3.41 (s, 4H), 2.37 (s, 3H). LRMS (ESI), m/z = 401.29 [M+H] +

<< 실시예Example 7> N-(3-((8- 7> N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)-5 days) 옥시oxy )페닐)에텐설폰아마이드의 제조) Preparation of phenyl) ethenesulfonamide

상기 실시예 1과 같은 방법으로 제조하되, N-(3-하이드록시페닐)에텐설폰아마이드 (16.43 mg, 0.082 mmol) 시약을 사용하여 목적화합물 N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)에텐설폰아마이드(N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)ethenesulfonamide) 0.7 mg (수율: 1.9%)을 얻었다.It was prepared in the same manner as in Example 1, but using N-(3-hydroxyphenyl)ethenesulfonamide (16.43 mg, 0.082 mmol) reagent as the target compound N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)ethenesulfonamide (N-(3-((8-(o-tolylamino)imidazo[1,5 -a]pyrazin-5-yl)oxy)phenyl)ethenesulfonamide) to obtain 0.7 mg (yield: 1.9%).

1H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.29 (s, 1H), 7.52 - 7.44 (m, 3H), 7.39 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.09 - 7.01 (m, 2H), 6.72 - 6.66 (m, 2H), 6.54 (s, 1H), 6.14 (d, J = 16.6 Hz, 1H), 5.99 (d, J = 10.0 Hz, 1H), 2.37 (s, 3H). LRMS (ESI), m/z = 422.13 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.29 (s, 1H), 7.52 - 7.44 (m, 3H), 7.39 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.09 - 7.01 (m, 2H) , 6.72 - 6.66 (m, 2H), 6.54 (s, 1H), 6.14 (d, J = 16.6 Hz, 1H), 5.99 (d, J = 10.0 Hz, 1H), 2.37 (s, 3H). LRMS (ESI), m/z = 422.13 [M+H] +

<< 실시예Example 8> 5-(5-아미노-2- 8> 5-(5-amino-2- 클로로페녹시Chlorophenoxy )-N-)-N- (o-톨릴)이미다조[1,5-a]피라진(o-tolyl)imidazo[1,5-a]pyrazine -8-아민의 제조Preparation of 8-amine

상기 실시예 1과 같은 방법으로 제조하되, 5-아미노-2-클로로페놀 (19.42 mg, 0.135 mmol) 시약을 사용하여 목적화합물 5-(5-아미노-2-클로로페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민(5-(5-amino-2-chlorophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine) 49 mg (수율: 97%)을 얻었다.It was prepared in the same manner as in Example 1, but using 5-amino-2-chlorophenol (19.42 mg, 0.135 mmol) as a reagent, the target compound 5-(5-amino-2-chlorophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine(5-(5-amino-2-chlorophenoxy)-N-(o-tolyl)imidazo[1,5-a] pyrazin-8-amine) to obtain 49 mg (yield: 97%).

1H NMR (400 MHz, MeOD) δ 8.81 (s, 1H), 8.37 (s, 1H), 7.54 - 7.43 (m, 4H), 7.27 (d, J = 8.7 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 8.7, 2.6 Hz, 1H), 6.23 (s, 1H), 2.37 (s, 3H). LRMS (ESI), m/z = 365.99 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.81 (s, 1H), 8.37 (s, 1H), 7.54 - 7.43 (m, 4H), 7.27 (d, J = 8.7 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 8.7, 2. 6 Hz, 1H), 6.23 (s, 1H), 2.37 (s, 3H). LRMS (ESI), m/z = 365.99 [M+H] +

<< 실시예Example 9> 5-(3- 9> 5-(3- 아미노페녹시aminophenoxy )-N-)-N- (4-플루오로-2-메틸페닐)이미다조(4-fluoro-2-methylphenyl) imidazo [1,5-a]피라진-8-아민의 제조Preparation of [1,5-a]pyrazin-8-amine

상기 실시예 1과 같은 방법으로 제조하되, 3-아미노페놀 (13 mg, 0.12 mmol) 시약을 사용하여 목적화합물 5-(3-아미노페녹시)-N-(4-플루오로-2-메틸페닐)이미다조[1,5-a]피라진-8-아민(5-(3-aminophenoxy)-N-(4-fluoro-2-methylphenyl)imidazo[1,5-a]pyrazin-8-amine) 25.9 mg (수율: 61.8%)을 얻었다.It was prepared in the same manner as in Example 1, but the target compound 5-(3-aminophenoxy)-N-(4-fluoro-2-methylphenyl)imidazo[1,5-a]pyrazin-8-amine was obtained using 3-aminophenol (13 mg, 0.12 mmol) reagent. 25.9 mg (yield: 61.8%) was obtained.

1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.57 (m, 1H), 7.29 - 7.24 (m, 1H), 7.11 (t, J = 8.1 Hz, 1H), 7.01 (dd, J = 9.2, 2.6 Hz, 1H), 6.95 (dt, J = 8.4, 4.2 Hz, 1H), 6.85 (s, 1H), 6.47 (m, 2H), 6.41 (s, 1H), 3.77 (s, 2H), 2.33 (s, 3H). LRMS (ESI), m/z = 349.94 [M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (s, 1H), 7.57 (m, 1H), 7.29 - 7.24 (m, 1H), 7.11 (t, J = 8.1 Hz, 1H), 7.01 (dd, J = 9.2, 2.6 Hz, 1H), 6.95 (dt, J = 8.4, 4.2 Hz, 1H), 6.85 (s, 1H), 6.47 (m, 2H), 6.41 (s, 1H), 3.77 (s, 2H), 2.33 (s, 3H). LRMS (ESI), m/z = 349.94 [M+H] +

<< 실시예Example 10> 2- 10> 2- 플루오로Fluoro -N-(4-((8--N-(4-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)아크릴아마이드의 제조Preparation of -5-yl) oxy) phenyl) acrylamide

상기 실시예 1과 같은 방법으로 제조하되, 2-플루오로-N-(4-하이드록시페닐)아크릴아마이드 (44.3 mg, 0.245 mmol) 시약을 사용하여 목적화합물 2-플루오로-N-(4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드(2-fluoro-N-(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) 13.8 mg (수율 20%)을 얻었다.It was prepared in the same manner as in Example 1, but the target compound 2-fluoro-N-(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide using 2-fluoro-N-(4-hydroxyphenyl)acrylamide (44.3 mg, 0.245 mmol) reagent (2-fluoro-N-(4-((8-(o-tolylamin) o)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) to obtain 13.8 mg (yield: 20%).

1H NMR (400 MHz, MeOD) δ 11.22 (s, 1H), 9.43 (s, 1H), 9.05 (s, 1H), 8.70 - 8.47 (m, 2H), 8.31 - 8.20 (m, 2H), 8.20 - 8.13 (m, 2H), 8.13 - 8.03 (m, 2H), 7.65 (s, 1H), 6.59 - 6.46 (m, 1H), 6.27 -6.22 (m, 1H), 3.11 (s, 3H). LRMS (ESI), m/z = 404.15 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 11.22 (s, 1H), 9.43 (s, 1H), 9.05 (s, 1H), 8.70 - 8.47 (m, 2H), 8.31 - 8.20 (m, 2H), 8.20 - 8.13 (m, 2H), 8.13 - 8 .03 (m, 2H), 7.65 (s, 1H), 6.59 - 6.46 (m, 1H), 6.27 -6.22 (m, 1H), 3.11 (s, 3H). LRMS (ESI), m/z = 404.15 [M+H] +

[반응식 Ⅲ][Scheme Ⅲ]

<< 실시예Example 11> 2- 11> 2- 사이아노Cyano -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)아세트아마이드의 제조Preparation of -5-yl) oxy) phenyl) acetamide

5-(3-아미노페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민 (20 mg, 0.060 mmol), 2-사이아노아세트산(5.65 mg, 0.066 mmol), HATU (22.95 mg, 0.060 mmol)와 N,N-다이아이소프로필에틸아민(10.51 μl, 0.060 mmol)을 디클로로메탄 (201 μl)에 용해시키고 25 ℃에서 2시간 동안 교반한다. 반응이 종결되면 에틸아세테이트를 사용하여 추출하고 유기층을 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류한다. 얻은 잔사를 MPLC로 분리, 정제하여 목적화합물 2-사이아노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드(2-cyano-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 17 mg (수율: 70%)을 얻었다. 5-(3-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (20 mg, 0.060 mmol), 2-cyanoacetic acid (5.65 mg, 0.066 mmol), HATU (22.95 mg, 0.060 mmol) and N,N-diisopropylethylamine (10.51 μl, 0.060 mmol) was dissolved in dichloromethane (201 μl) and stirred at 25° C. for 2 hours. When the reaction is complete, extraction is performed using ethyl acetate, and the organic layer is dried over anhydrous Na 2 SO 4 , filtered, and the solvent is distilled under reduced pressure. The obtained residue was separated and purified by MPLC to obtain the target compound 2-cyano-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide (2-cyano-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 17 mg (yield: 70%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.34 (s, 1H), 7.85 - 7.79 (m, 1H), 7.56 - 7.39 (m, 4H), 7.27 (d, J = 8.2 Hz, 1H), 7.12 - 7.09 (m, 1H), 6.53 (s, 1H), 3.78 (s, 2H), 2.39 (s, 3H). LRMS (ESI), m/z = 399.04 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.34 (s, 1H), 7.85 - 7.79 (m, 1H), 7.56 - 7.39 (m, 4H), 7.27 (d, J = 8.2 Hz, 1H), 7.12 - 7.09 (m, 1H), 6.53 (s, 1H), 3.78 (s, 2H), 2.39 (s, 3H). LRMS (ESI), m/z = 399.04 [M+H] +

<< 실시예Example 12> N-(4-((8- 12> N-(4-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)-5 days) 옥시oxy )페닐)아크릴아마이드의 제조) Preparation of phenyl) acrylamide

5-(4-아미노페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민 (4 mg, 0.012 mmol)을 디클로로메탄 (0.5 ml)에 용해시키고 -20 ℃에서 교반한 뒤, 아크릴로일 클로라이드 (1.073 μl, 0.013 mmol)을 천천히 가한다. 반응이 종결되면 용매를 감압증류하고 얻은 잔사를 prep-HPLC로 분리, 정제하여 목적화합물 N-(4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드(N-(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) 0.9 mg (수율: 19%)을 얻었다. 5-(4-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (4 mg, 0.012 mmol) was dissolved in dichloromethane (0.5 ml), stirred at -20 °C, and acryloyl chloride (1.073 μl, 0.013 mmol) was added slowly. After the reaction was completed, the solvent was distilled under reduced pressure and the obtained residue was separated and purified by prep-HPLC to obtain 0.9 mg of target compound N-(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide (N-(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) (yield: 19%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.75 (s, 1H), 8.36 (s, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.54 - 7.46 (m, 2H), 7.46 (s, 2H), 7.34 (d, J = 9.1 Hz, 2H), 6.44 (s, 1H), 6.42 - 6.38 (m, 1H), 6.36 (s, 1H), 5.83 - 5.80 (m, 1H), 2.38 (s, 3H). LRMS (ESI), m/z = 386.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.75 (s, 1H), 8.36 (s, 1H), 7.77 (d, J = 9.0 Hz, 2H), 7.54 - 7.46 (m, 2H), 7.46 (s, 2H), 7.34 (d, J = 9.1 Hz, 2H), 6.44 (s, 1H), 6.42 - 6.38 (m, 1H), 6.36 (s, 1H), 5.83 - 5.80 (m, 1H), 2.38 (s, 3H). LRMS (ESI), m/z = 386.0 [M+H] +

<< 실시예Example 13> N-(3-((8- 13> N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)-5 days) 옥시oxy )페닐)아크릴아마이드의 제조) Preparation of phenyl) acrylamide

상기 실시예 12과 같은 방법으로 제조하되, 아크릴로일 클로라이드 (2.68 μl, 0.033 mmol) 시약을 사용하여 목적화합물 N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드(N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) 1.5 mg (수율: 12.7%)을 얻었다.It was prepared in the same manner as in Example 12, but using acryloyl chloride (2.68 μl, 0.033 mmol) reagent to obtain the target compound N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide (N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy )phenyl)acrylamide) 1.5 mg (yield: 12.7%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.36 (s, 1H), 7.95 (t, J = 2.1 Hz, 1H), 7.49 - 7.44 (m, 5H), 7.34 (d, J = 9.2 Hz, 1H), 7.10 - 7.08 (m, 1H), 6.53 (s, 1H), 6.47 - 6.34 (m, 2H), 5.83 - 5.80 (m, 1H), 2.39 (s, 3H). LRMS (ESI), m/z = 386.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.36 (s, 1H), 7.95 (t, J = 2.1 Hz, 1H), 7.49 - 7.44 (m, 5H), 7.34 (d, J = 9.2 Hz, 1H), 7.10 - 7.08 (m, 1H) , 6.53 (s, 1H), 6.47 - 6.34 (m, 2H), 5.83 - 5.80 (m, 1H), 2.39 (s, 3H). LRMS (ESI), m/z = 386.0 [M+H] +

<< 실시예Example 14> N-(3-((8- 14> N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)-5 days) 옥시oxy )페닐)프로피온아마이드의 제조) Preparation of phenyl) propionamide

상기 실시예 12과 같은 방법으로 제조하되, 프로피오닐 클로라이드 (2.90 μl, 0.033 mmol) 시약을 사용하여 목적화합물 N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)프로피온아마이드(N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)propionamide) 6.5 mg (수율: 55.6%)을 얻었다.It was prepared in the same manner as in Example 12, but using propionyl chloride (2.90 μl, 0.033 mmol) reagent, the target compound N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)propionamide (N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5- yl)oxy)phenyl)propionamide) 6.5 mg (yield: 55.6%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.35 (s, 1H), 7.86 (t, J = 2.2 Hz, 1H), 7.57 - 7.44 (m, 4H), 7.42 (t, J = 8.2 Hz, 1H), 7.29 - 7.27 (m, 1H), 7.07 - 7.04 (m, 1H), 6.51 (s, 1H), 2.44 - 2.37 (m, 5H), 1.20 (t, J = 7.6 Hz, 3H). LRMS (ESI), m/z = 388.0 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.35 (s, 1H), 7.86 (t, J = 2.2 Hz, 1H), 7.57 - 7.44 (m, 4H), 7.42 (t, J = 8.2 Hz, 1H), 7.29 - 7.27 (m, 1H) , 7.07 - 7.04 (m, 1H), 6.51 (s, 1H), 2.44 - 2.37 (m, 5H), 1.20 (t, J = 7.6 Hz, 3H). LRMS (ESI), m/z = 388.0 [M+H] +

<< 실시예Example 15> 2- 15> 2- 클로로Chloro -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)아세트아마이드의 제조Preparation of -5-yl) oxy) phenyl) acetamide

상기 실시예 12과 같은 방법으로 제조하되, 2-클로로아세틸 클로라이드 (3.75 mg, 0.033 mmol) 시약을 사용하여 목적화합물 2-클로로-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드(2-chloro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 8.3 mg (수율: 67.4%)을 얻었다.It was prepared in the same manner as in Example 12, but the target compound 2-chloro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide (2-chloro-N-(3-((8-(o-tolylamino)imidazo[1,5- a]pyrazin-5-yl)oxy)phenyl)acetamide) to obtain 8.3 mg (yield: 67.4%).

1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.34 (s, 1H), 7.85 (t, J = 2.2 Hz, 1H), 7.55 - 7.42 (m, 5H), 7.36 -7.33 (m, 1H), 7.13 - 7.10 (m, 1H), 6.53 (s, 1H), 4.20 (s, 2H), 2.39 (s, 3H). LRMS (ESI), m/z = 408.0 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.34 (s, 1H), 7.85 (t, J = 2.2 Hz, 1H), 7.55 - 7.42 (m, 5H), 7.36 -7.33 (m, 1H), 7.13 - 7.10 (m, 1H), 6 .53 (s, 1H), 4.20 (s, 2H), 2.39 (s, 3H). LRMS (ESI), m/z = 408.0 [M+H] +

<< 실시예Example 16> N-(4- 16> N-(4- 클로로Chloro -3-((8--3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)아크릴아마이드의 제조Preparation of -5-yl) oxy) phenyl) acrylamide

상기 실시예 12과 같은 방법으로 제조하되, 5-(5-아미노-2-클로로페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민을 사용하고, 아크릴로일 클로라이드 (1.36 mg, 0.015 mmol) 시약을 사용하여 목적화합물 N-(4-클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드(N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) 1.6 mg (수율: 25.7%)을 얻었다.It was prepared in the same manner as in Example 12, but using 5-(5-amino-2-chlorophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine and using acryloyl chloride (1.36 mg, 0.015 mmol) as a reagent, the target compound N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazine 1.6 mg (yield: 25.7%) of -5-yl)oxy)phenyl)acrylamide (N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide was obtained.

1H NMR (400 MHz, MeOD) δ 8.82 (s, 1H), 8.39 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.54 - 7.42 (m, 4H), 7.38 (dd, J = 8.8, 2.4 Hz, 1H), 6.41 - 6.37 (m, 3H), 5.82 (dd, J = 8.1, 3.7 Hz, 1H), 2.38 (s, 3H). LRMS (ESI), m/z = 420.03 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.82 (s, 1H), 8.39 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.54 - 7.42 (m, 4H), 7.38 (dd, J = 8.8, 2. 4 Hz, 1H), 6.41 - 6.37 (m, 3H), 5.82 (dd, J = 8.1, 3.7 Hz, 1H), 2.38 (s, 3H). LRMS (ESI), m/z = 420.03 [M+H] +

<< 실시예Example 17> 2- 17> 2- 클로로Chloro -N-(3-((8--N-(3-((8- ((4-플루오로-2-메틸페닐)아미노)이미다((4-fluoro-2-methylphenyl)amino)imida 조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드의 제조 Preparation of crude [1,5-a] pyrazin-5-yl) oxy) phenyl) acetamide

상기 실시예 12와 같은 방법으로 제조하되, 2-클로로아세틸 클로라이드 (4.6 mg, 0.041 mmol) 시약을 사용하여 목적화합물 2-클로로-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드(2-chloro-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 4.1 mg (수율: 25.8%)을 얻었다.It was prepared in the same manner as in Example 12, but using 2-chloroacetyl chloride (4.6 mg, 0.041 mmol) reagent to obtain the target compound 2-chloro-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide (2-chloro-N-(3-((8-((4-fluoro-2-methylphenyl) )amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) to obtain 4.1 mg (yield: 25.8%).

1H NMR (400 MHz, MeOD) δ 8.12 (s, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.29 - 7.22 (m, 3H), 6.98 (dd, J = 9.4, 2.7 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz, 1H), 6.84 - 6.80 (m, 1H), 6.63 (s, 1H), 4.05 (s, 2H), 2.19 (s, 3H). LRMS (ESI), m/z = 425.96 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.12 (s, 1H), 7.80 (s, 1H), 7.45 (s, 1H), 7.29 - 7.22 (m, 3H), 6.98 (dd, J = 9.4, 2.7 Hz, 1H), 6.88 (td, J = 8.5, 2.9 Hz , 1H), 6.84 - 6.80 (m, 1H), 6.63 (s, 1H), 4.05 (s, 2H), 2.19 (s, 3H). LRMS (ESI), m/z = 425.96 [M+H] +

<< 실시예Example 18> N-(3-((8- 18> N-(3-((8- ((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]p 라진-5-일)옥시)페닐)아크릴아마이드의 제조Preparation of razin-5-yl)oxy)phenyl)acrylamide

tert-뷰틸 (5-(3-아미노페녹시)이미다조[1,5-a]피라진-8-일)(4-플루오로-2-메틸페닐)카바메이트 (18 mg, 0.040 mmol)을 디클로로메탄 (1 ml)에 용해시킨 뒤, -20 ℃에서 아크릴로일 클로라이드 (3.5 μl, 0.044 mmol)을 가한다. 상온에서 1시간 동안 교반한 뒤, 반응이 종결되면 에틸아세테이트와 물로 추출하고 유기층을 NaHCO3 수용액과 소금물을 사용하여 씻어준다. 추출한 유기층을 무수 Na2SO4으로 수분을 제거한 뒤, 감압증류하여 남은 잔사를 MPLC로 분리, 정제하여 중간체 20 mg (수율: 99%)을 얻었다. 얻어진 중간체 tert-뷰틸 (5-(3-아크릴아마이도페녹시)이미다조[1,5-a]피라진-8-일)(4-플루오로-2-메틸페닐)카바메이트 (20 mg, 0.04 mmol)를 THF (1 ml)에 용해시킨 뒤 -20 °C에서 4 M HCl in dioxane (30 μl, 0.119 mmol)을 넣고 65 °C에서 1시간 동안 가열하였다. 반응이 종결되면 NaHCO3 수용액으로 중화시킨 뒤 에틸아세테이트로 추출하였다. 유기층은 무수 Na2SO4으로 수분을 제거한 뒤, 감압증류하여 남은 잔사를 prep-HPLC로 분리, 정제하여 목적화합물 N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드(N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) 3.7 mg (수율: 22%)을 얻었다.tert-butyl (5-(3-aminophenoxy)imidazo[1,5-a]pyrazin-8-yl)(4-fluoro-2-methylphenyl)carbamate (18 mg, 0.040 mmol) is dissolved in dichloromethane (1 ml), then acryloyl chloride (3.5 μl, 0.044 mmol) is added at -20 °C. After stirring at room temperature for 1 hour, when the reaction is complete, extraction is performed with ethyl acetate and water, and the organic layer is washed with NaHCO 3 aqueous solution and brine. After removing moisture from the extracted organic layer with anhydrous Na 2 SO 4 , distillation under reduced pressure, and the remaining residue was separated and purified by MPLC to obtain 20 mg of an intermediate (yield: 99%). The obtained intermediate tert-butyl (5-(3-acrylamidophenoxy)imidazo[1,5-a]pyrazin-8-yl)(4-fluoro-2-methylphenyl)carbamate (20 mg, 0.04 mmol) was dissolved in THF (1 ml), and then 4 M HCl in dioxane (30 μl, 0.119 mmol) was added at -20 °C and heated at 65 °C for 1 hour. . Upon completion of the reaction, the mixture was neutralized with an aqueous solution of NaHCO 3 and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous Na 2 SO 4 and distilled under reduced pressure, and the remaining residue was separated and purified by prep-HPLC to obtain the target compound N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide (N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a] pyrazin-5-yl)oxy)phenyl)acrylamide) to obtain 3.7 mg (yield: 22%).

1H NMR (400 MHz, MeOD) δ 8.13 (s, 1H), 7.80 (s, 1H), 7.53 (s, 1H), 7.32 - 7.22 (m, 3H), 6.98 (dd, J = 9.5, 2.7 Hz, 1H), 6.89 (td, J = 8.5, 2.9 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.63 (s, 1H), 6.29 - 6.24 (m, 2H), 5.66 (dd, J = 9.0, 2.7 Hz, 1H), 2.19 (s, 3H). LRMS (ESI), m/z = 404.00 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.13 (s, 1H), 7.80 (s, 1H), 7.53 (s, 1H), 7.32 - 7.22 (m, 3H), 6.98 (dd, J = 9.5, 2.7 Hz, 1H), 6.89 (td, J = 8.5, 2.9 Hz , 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.63 (s, 1H), 6.29 - 6.24 (m, 2H), 5.66 (dd, J = 9.0, 2.7 Hz, 1H), 2.19 (s, 3H). LRMS (ESI), m/z = 404.00 [M+H]+

<< 실시예Example 19> 2- 19> 2- 사이아노Cyano -N-(3-((8--N-(3-((8- ((4-플루오로-2-메틸페닐)아미노)이미다((4-fluoro-2-methylphenyl)amino)imida 조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드의 제조Preparation of crude [1,5-a] pyrazin-5-yl) oxy) phenyl) acetamide

tert-뷰틸 (5-(3-아미노페녹시)이미다조[1,5-a]피라진-8-일)(4-플루오로-2-메틸)페닐)카바메이트 (10 mg, 0.022 mmol), 2-사이아노아세트산 (2.8 mg, 0.033 mmol), HATU (12.7 mg, 0.033 mmol)와 N,N-다이아이소프로필에틸아민 (5.8 μl, 0.033 mmol)을 디클로로메탄 (222 μl)에 용해시키고 25 ℃에서 2시간 동안 교반한다. 반응이 종결되면 에틸아세테이트를 사용하여 추출하고 유기층을 무수 Na2SO4으로 건조하여 여과 후 용매를 감압증류한다. 얻은 잔사를 MPLC로 분리, 정제하여 중간체 11 mg (수율: 99%)을 얻었다. 얻어진 중간체 tert-뷰틸 (5-(3-(2-사이아노아세트아미도)페녹시)이미다조[1,5-a]피라진-8-일)(4-플루오로-2-메틸페닐)카바메이트 (11 mg, 0.022 mmol)를 THF (1 ml)에 용해시킨 뒤 -20 °C에서 4 M HCl in dioxane (17 μl, 0.067 mmol)을 넣고 65 °C에서 1시간 동안 가열하였다. 반응이 종결되면 NaHCO3 수용액으로 중화시킨 뒤 에틸아세테이트로 추출하였다. 유기층은 무수 Na2SO4으로 수분을 제거한 뒤, 감압증류하여 남은 잔사를 prep-HPLC로 분리, 정제하여 목적화합물 2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드(2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 3 mg (수율: 32.4%)을 얻었다.tert-butyl (5-(3-aminophenoxy)imidazo[1,5-a]pyrazin-8-yl)(4-fluoro-2-methyl)phenyl)carbamate (10 mg, 0.022 mmol), 2-cyanoacetic acid (2.8 mg, 0.033 mmol), HATU (12.7 mg, 0.033 mmol) and N,N-diisopropylethylamine (5.8 μl , 0.033 mmol) in dichloromethane (222 μl) and stir at 25 °C for 2 h. When the reaction is complete, extraction is performed using ethyl acetate, and the organic layer is dried over anhydrous Na 2 SO 4 , filtered, and the solvent is distilled under reduced pressure. The obtained residue was separated and purified by MPLC to obtain 11 mg of the intermediate (yield: 99%). The obtained intermediate tert-butyl (5-(3-(2-cyanoacetamido)phenoxy)imidazo[1,5-a]pyrazin-8-yl)(4-fluoro-2-methylphenyl)carbamate (11 mg, 0.022 mmol) was dissolved in THF (1 ml), and then 4 M HCl in dioxane (17 μl, 0.067 mmol) was added at -20 °C to 65 Heated at °C for 1 hour. Upon completion of the reaction, the mixture was neutralized with an aqueous solution of NaHCO 3 and extracted with ethyl acetate. The organic layer was dehydrated with anhydrous Na 2 SO 4 and distilled under reduced pressure, and the remaining residue was separated and purified by prep-HPLC to obtain the target compound 2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide (2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl) )amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 3 mg (yield: 32.4%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.23 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.23 (dd, J = 9.3, 2.8 Hz, 1H), 7.13 (td, J = 8.4, 2.8 Hz, 1H), 7.04 (dd, J = 8.2, 2.3 Hz, 1H), 6.62 (s, 1H), 3.77 (s, 2H), 2.36 (s, 3H). LRMS (ESI), m/z = 417.11 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.55 (s, 1H), 8.23 (s, 1H), 7.74 (t, J = 2.0 Hz, 1H), 7.51 - 7.44 (m, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.23 (dd, J = 9.3, 2.8 Hz, 1H), 7.13 (td, J = 8.4, 2.8 Hz, 1H), 7.04 (dd, J = 8.2, 2.3 Hz, 1H), 6.62 (s, 1H), 3.77 (s, 2H), 2.36 (s, 3H). LRMS (ESI), m/z = 417.11 [M+H] +

<< 실시예Example 20> 2- 20> 2- 플루오로Fluoro -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)아세트아마이드의 제조Preparation of -5-yl) oxy) phenyl) acetamide

상기 실시예 11과 같은 방법으로 제조하되, 2-플루오로아세트산 (2.59 mg, 0.033 mmol) 시약을 사용하여 목적화합물 2-플루오로-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드(2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 11.4 mg (수율: 96%)을 얻었다.It was prepared in the same manner as in Example 11, but the target compound 2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide (2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5- a]pyrazin-5-yl)oxy)phenyl)acetamide) 11.4 mg (yield: 96%) was obtained.

1H NMR (400 MHz, CDCl3) δ 12.79 (s, 1H), 8.42 (s, 1H), 8.13 (d, J = 4.5 Hz, 1H), 7.92 (t, J = 2.2 Hz, 1H), 7.50 - 7.39 (m, 3H), 7.37 - 7.24 (m, 2H), 7.02 - 6.99 (m, 1H), 6.53 (s, 1H), 6.43 (s, 1H), 4.95 (d, J = 47.3 Hz, 2H), 2.32 (s, 3H). LRMS (ESI), m/z = 392.02 [M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 12.79 (s, 1H), 8.42 (s, 1H), 8.13 (d, J = 4.5 Hz, 1H), 7.92 (t, J = 2.2 Hz, 1H), 7.50 - 7.39 (m, 3H), 7.37 - 7.24 (m, 2H), 7.02 - 6.99 (m, 1H), 6.53 (s, 1H), 6.43 (s, 1H), 4.95 (d, J = 47.3 Hz, 2H), 2.32 (s, 3H). LRMS (ESI), m/z = 392.02 [M+H] +

<< 실시예Example 21> N-(3-((8- 21> N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)-5 days) 옥시oxy )페닐)뷰틴-2-아마이드의 제조) Preparation of phenyl) butyn-2-amide

상기 실시예 11과 같은 방법으로 제조하되, 2-뷰틴오익산 (5.58 mg, 0.066 mmol) 시약을 사용하여 목적화합물 N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰틴-2-아마이드(N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-ynamide) 2.7 mg (수율: 11%)을 얻었다.It was prepared in the same manner as in Example 11, but using 2-butinoic acid (5.58 mg, 0.066 mmol) reagent as the target compound N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butyn-2-amide (N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin -5-yl)oxy)phenyl)but-2-ynamide) 2.7 mg (yield: 11%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.36 (s, 1H), 7.81 (t, J = 2.1 Hz, 1H), 7.55 - 7.38 (m, 5H), 7.33 - 7.26 (m, 1H), 7.10 - 7.07 (m, 1H), 6.49 (s, 1H), 2.38 (s, 3H), 2.05 (s, 3H). LRMS (ESI), m/z = 398.11 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.36 (s, 1H), 7.81 (t, J = 2.1 Hz, 1H), 7.55 - 7.38 (m, 5H), 7.33 - 7.26 (m, 1H), 7.10 - 7.07 (m, 1H), 6.49 (s, 1H), 2.38 (s, 3H), 2.05 (s, 3H). LRMS (ESI), m/z = 398.11 [M+H] +

<< 실시예Example 22> 2- 22> 2- 브로모Bromo -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)아세트아마이드의 제조Preparation of -5-yl) oxy) phenyl) acetamide

상기 실시예 11과 같은 방법으로 제조하되, 2-브로모아세트산 (9.22 mg, 0.066 mmol) 시약을 사용하여 목적화합물 2-브로모-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드(2-bromo-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 1 mg (수율: 3.5%)을 얻었다.It was prepared in the same manner as in Example 11, but using 2-bromoacetic acid (9.22 mg, 0.066 mmol) reagent to obtain the target compound 2-bromo-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide (2-bromo-N-(3-((8-(o-tolylamino)imidazo[1,5 -a]pyrazin-5-yl)oxy)phenyl)acetamide) to obtain 1 mg (yield: 3.5%).

1H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.34 (s, 1H), 7.85 (t, J = 2.2 Hz, 1H), 7.53 - 7.43 (m, 5H), 7.32 - 7.26 (m, 1H), 7.11 - 7.08 (m, 1H), 6.53 (s, 1H), 3.98 (s, 2H), 2.39 (s, 3H). LRMS (ESI), m/z = 453.08 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.34 (s, 1H), 7.85 (t, J = 2.2 Hz, 1H), 7.53 - 7.43 (m, 5H), 7.32 - 7.26 (m, 1H), 7.11 - 7.08 (m, 1H), 6.53 (s, 1H), 3.98 (s, 2H), 2.39 (s, 3H). LRMS (ESI), m/z = 453.08 [M+H] +

<< 실시예Example 23> 2- 23> 2- 아이오도iodo -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)아세트아마이드의 제조Preparation of -5-yl) oxy) phenyl) acetamide

상기 실시예 11과 같은 방법으로 제조하되, 2-아이오도아세트산 (6.17 mg, 0.033 mmol) 시약을 사용하여 목적화합물 2-아이오도-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드(2-iodo-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 1.6 mg (수율: 10%)을 얻었다.It was prepared in the same manner as in Example 11, but using 2-iodoacetic acid (6.17 mg, 0.033 mmol) as a reagent, the target compound 2-iodo-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide (2-iodo-N-(3-((8-(o-tolylamino)imidazo[1 ,5-a]pyrazin-5-yl)oxy)phenyl)acetamide) 1.6 mg (yield: 10%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.37 (s, 1H), 7.86 (t, J = 2.2 Hz, 1H), 7.54 - 7.42 (m, 5H), 7.27 (d, J = 8.1 Hz, 1H), 7.11 - 7.08 (m, 1H), 6.51 (s, 1H), 3.87 (s, 2H), 2.39 (s, 3H). LRMS (ESI), m/z = 500.10 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.37 (s, 1H), 7.86 (t, J = 2.2 Hz, 1H), 7.54 - 7.42 (m, 5H), 7.27 (d, J = 8.1 Hz, 1H), 7.11 - 7.08 (m, 1H) , 6.51 (s, 1H), 3.87 (s, 2H), 2.39 (s, 3H). LRMS (ESI), m/z = 500.10 [M+H] +

<< 실시예Example 24> (E)-4- 24> (E)-4- 하이드록시hydroxy -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) butene-2-amide

상기 실시예 11과 같은 방법으로 제조하되, 2-아이오도아세트산 (6.17 mg, 0.033 mmol) 시약을 사용하여 목적화합물 (E)-4-하이드록시-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드((E)-4-hydroxy-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 1.1 mg (수율: 1.4%)을 얻었다.It was prepared in the same manner as in Example 11, but using 2-iodoacetic acid (6.17 mg, 0.033 mmol) reagent to obtain the target compound (E)-4-hydroxy-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide ((E)-4-hydroxy-N-(3-((8-(o-toly) lamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 1.1 mg (yield: 1.4%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 7.85 (s, 1H), 7.61 (s, 1H), 7.40 - 7.29 (m, 4H), 7.26 - 7.19 (m, 2H), 7.00 - 6.97 (m, 1H), 6.89 - 6.87 (m, 1H), 6.73 (s, 1H), 6.34 - 6.29 (m, 1H), 4.55 (s, 1H), 4.28 - 4.26 (m, 2H), 2.29 (s, 3H). LRMS (ESI), m/z = 416.15 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.20 (s, 1H), 7.85 (s, 1H), 7.61 (s, 1H), 7.40 - 7.29 (m, 4H), 7.26 - 7.19 (m, 2H), 7.00 - 6.97 (m, 1H), 6.89 - 6. 87 (m, 1H), 6.73 (s, 1H), 6.34 - 6.29 (m, 1H), 4.55 (s, 1H), 4.28 - 4.26 (m, 2H), 2.29 (s, 3H). LRMS (ESI), m/z = 416.15 [M+H] +

<< 실시예Example 25> (E)-4-( 25> (E)-4-( 다이메틸아미노dimethylamino )-N-(3-((8-)-N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)뷰텐-2-아마이드의 제조 Preparation of -5-yl) oxy) phenyl) butene-2-amide

상기 실시예 11과 같은 방법으로 제조하되, (E)-4-(다이메틸아미노)-2-뷰텐오익산 (12.86 mg, 0.100 mmol) 시약을 사용하여 목적화합물 (E)-4-(다이메틸아미노)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드((E)-4-(dimethylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 3.5 mg (수율: 8.6%)을 얻었다.It was prepared in the same manner as in Example 11, but using (E)-4-(dimethylamino)-2-butenoic acid (12.86 mg, 0.100 mmol) reagent to obtain the desired compound (E)-4-(dimethylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide ((E)- 3.5 mg (yield: 8.6%) of 4-(dimethylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) was obtained.

1H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 9.38 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.59 - 7.49 (m, 1H), 7.45 - 7.31 (m, 3H), 7.27 - 7.18 (m, 2H), 6.91 (s, 1H), 6.76 - 6.69 (m, 1H), 6.40 (d, J = 15.3 Hz, 1H), 3.93 (d, J = 6.9 Hz, 2H), 2.79 (s, 6H), 2.26 (s, 3H). LRMS (ESI), m/z = 443.17 [M+H]+ 1 H NMR (400 MHz, DMSO) δ 9.85 (s, 1H), 9.38 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.59 - 7.49 (m, 1H), 7.45 - 7.31 (m, 3H), 7.27 - 7.18 (m, 2H), 6.91 (s, 1H), 6.76 - 6.69 (m, 1H), 6.40 (d, J = 15.3 Hz, 1H), 3.93 (d, J = 6.9 Hz, 2H), 2.79 (s, 6H), 2.26 (s, 3H). LRMS (ESI), m/z = 443.17 [M+H] +

<< 실시예Example 26> N-(4- 26> N-(4- 클로로Chloro -3-((8--3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)-2-사이아노아세트아마이드의 제조Preparation of -5-yl) oxy) phenyl) -2-cyanoacetamide

상기 실시예 16과 같은 방법으로 제조하되, 아크릴로일 클로라이드 대신 2-사이아노아세트산 (10.23 mg, 0.120 mmol) 시약을 사용하여 목적화합물 N-(4-클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-2-사이아노아세트아마이드(N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyanoacetamide) 40.1 mg (수율: 84%)을 얻었다.It was prepared in the same manner as in Example 16, but using 2-cyanoacetic acid (10.23 mg, 0.120 mmol) reagent instead of acryloyl chloride to obtain the target compound N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyanoacetamide (N-(4-chloro-3-((8-(o-to) lylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyanoacetamide) 40.1 mg (yield: 84%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.81 (s, 1H), 8.37 (s, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.54 - 7.42 (m, 4H), 7.33 (dd, J = 8.8, 2.3 Hz, 1H), 6.38 (s, 1H), 3.78 (s, 2H), 2.38 (s, 3H). LRMS (ESI), m/z = 433.02 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.81 (s, 1H), 8.37 (s, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.54 - 7.42 (m, 4H), 7.33 (dd, J = 8.8, 2. 3 Hz, 1H), 6.38 (s, 1H), 3.78 (s, 2H), 2.38 (s, 3H). LRMS (ESI), m/z = 433.02 [M+H] +

<< 실시예Example 27> 2- 27> 2- 플루오로Fluoro -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)아크릴아마이드의 제조Preparation of -5-yl) oxy) phenyl) acrylamide

N-3-다이메틸아미노프로필-N'-에틸카르보다이이미드 하이드로클로라이드 EDCI (8.68 mg, 0.045 mmol), 4-다이메틸아미노피리딘, DMAP (0.737 mg, 6.04 μmol), 2-플루오로아크릴산 (2.72 mg, 0.030 mmol), 5-(3-아미노페닐)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민 (10 mg, 0.030 mmol)을 무수 디클로로메탄 (302 μl)에 용해시키고 12시간 동안 실온에서 반응한다. 반응종결 후 감압증류하여 얻은 잔사를 prep-HPLC로 분리, 정제하여 목적화합물 2-플루오로-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드(2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) 2 mg (수율: 16%)을 얻었다.N-3-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride EDCI (8.68 mg, 0.045 mmol), 4-dimethylaminopyridine, DMAP (0.737 mg, 6.04 μmol), 2-fluoroacrylic acid (2.72 mg, 0.030 mmol), 5-(3-aminophenyl)-N-(o-tolyl)imidazo[1,5-a ]Pyrazin-8-amine (10 mg, 0.030 mmol) was dissolved in anhydrous dichloromethane (302 μl) and reacted at room temperature for 12 hours. After completion of the reaction, the residue obtained by distillation under reduced pressure was separated and purified by prep-HPLC to obtain the target compound 2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide (2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) 2 mg (yield: 16%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.33 (s, 1H), 7.85 - 7.84 (m, 1H), 7.55 - 7.40 (m, 6H), 7.15 - 7.12 (m, 1H), 6.55 (s, 1H), 5.80 - 5.67 (m, 1H), 5.36 -5.32 (m, 1H), 2.39 (s, 3H). LRMS (ESI), m/z = 404.18 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.33 (s, 1H), 7.85 - 7.84 (m, 1H), 7.55 - 7.40 (m, 6H), 7.15 - 7.12 (m, 1H), 6.55 (s, 1H), 5.80 - 5. 67 (m, 1H), 5.36 -5.32 (m, 1H), 2.39 (s, 3H). LRMS (ESI), m/z = 404.18 [M+H] +

[반응식 Ⅳ][Scheme IV]

<< 실시예Example 28> (E)-4-( 28> (E)-4-( 메틸아미노methylamino )-N-(3-((8-)-N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) butene-2-amide

(E)-4-브로모-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-1-뷰텐아마이드 (23 mg, 0.048 mmol)을 DMF (0.5 ml)에 용해시킨 뒤, 0 ℃에서 메틸아민 (0.120 ml, 0.240 mmol)과 소듐 아이오다이드 (7.21 mg, 0.048 mmol)를 가한다. 상온에서 12시간 동안 교반한 뒤, 반응이 종결되면 에틸아세테이트와 물로 추출하고 유기층을 NaHCO3 수용액과 소금물을 사용하여 씻어준다. 추출한 유기층을 무수 Na2SO4으로 수분을 제거한 뒤, 감압증류하여 남은 잔사를 MPLC로 분리, 정제하여 목적화합물 (E)-4-(메틸아미노)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드((E)-4-(methylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 2.1 mg (수율: 10.1%)을 얻었다.(E)-4-bromo-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-1-butenamide (23 mg, 0.048 mmol) was dissolved in DMF (0.5 ml), followed by methylamine (0.120 ml, 0.240 mmol) and sodium iodide (7.21 mg, 0.048 mmol) at 0 °C. 048 mmol) was added. After stirring at room temperature for 12 hours, when the reaction is complete, extraction is performed with ethyl acetate and water, and the organic layer is washed with NaHCO 3 aqueous solution and brine. The extracted organic layer was dehydrated with anhydrous Na 2 SO 4 , distilled under reduced pressure, and the remaining residue was separated and purified by MPLC to obtain the target compound (E)-4-(methylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide ((E)-4-(methylamino)-N-(3-((8-(o-to) lylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 2.1 mg (yield: 10.1%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.53 - 7.38 (m, 6H), 7.11 - 7.08 (m, 1H), 6.91 - 6.84 (m, 1H), 6.55 (s, 1H), 6.50 (d, J = 15.4 Hz, 1H), 3.88 (d, J = 6.7 Hz, 2H), 2.76 (s, 3H), 2.39 (s, 3H). LRMS (ESI), m/z = 429.19 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.53 - 7.38 (m, 6H), 7.11 - 7.08 (m, 1H), 6.91 - 6.84 (m, 1H), 6.55 (s, 1H), 6.50 (d, J = 15.4 Hz, 1H), 3.88 (d, J = 6.7 Hz, 2H), 2.76 (s, 3H), 2.39 (s, 3H). LRMS (ESI), m/z = 429.19 [M+H] +

<< 실시예Example 29> (E)-4-(4- 29> (E)-4-(4- 아이소프로필피페라진isopropylpiperazine -1-일)-N-(3-((8--1-day)-N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) butene-2-amide

상기 실시예 28과 같은 방법으로 제조하되, 1-아이소프로필피페라진 (26.6 mg, 0.207 mmol) 시약을 사용하여 얻은 중간화합물을 디클로로메탄 (1 ml)에 녹이고 TFA (0.1 ml)를 넣고 상온에서 1시간 동안 교반한다. 반응이 종결되면 용매를 감압증류하여 얻은 잔사를 prep-HPLC로 분리, 정제하여 목적화합물 (E)-4-(4-아이소프로필피페라진-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드((E)-4-(4-isopropylpiperazin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 6.9 mg (수율: 17.5%)을 얻었다.It was prepared in the same manner as in Example 28, but the intermediate compound obtained using 1-isopropylpiperazine (26.6 mg, 0.207 mmol) reagent was dissolved in dichloromethane (1 ml), TFA (0.1 ml) was added, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the residue obtained by distillation of the solvent under reduced pressure was separated and purified by prep-HPLC to obtain the target compound (E)-4-(4-isopropylpiperazin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide ((E)-4-(4-isopropylpiperazin-1-yl)-N-(3-( (8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 6.9 mg (yield: 17.5%) was obtained.

1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.92 (s, 1H), 7.49 - 7.31 (m, 6H), 6.99 - 6.90 (m, 1H), 6.85 - 6.74 (m, 1H), 6.58 (s, 1H), 6.43 (d, J = 16.2 Hz, 2H), 3.69 (d, J = 6.7 Hz, 2H), 3.51 - 3.34 (m, 8H), 2.33 (s, 3H), 1.39 (d, J = 6.6 Hz, 6H). LRMS (ESI), m/z = 526.24 [M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.39 (s, 1H), 7.92 (s, 1H), 7.49 - 7.31 (m, 6H), 6.99 - 6.90 (m, 1H), 6.85 - 6.74 (m, 1H), 6.58 (s, 1H), 6.43 ( d, J = 16.2 Hz, 2H), 3.69 (d, J = 6.7 Hz, 2H), 3.51 - 3.34 (m, 8H), 2.33 (s, 3H), 1.39 (d, J = 6.6 Hz, 6H). LRMS (ESI), m/z = 526.24 [M+H] +

<< 실시예Example 30> (E)-4-(피페라진-1-일)-N-(3-((8- 30> (E)-4-(piperazin-1-yl)-N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) butene-2-amide

상기 실시예 29와 같은 방법으로 제조하되, tert-뷰틸 피페라진-1-카복실레이트 (38.6 mg, 0.207 mmol)시약을 사용하여 목적화합물 (E)-4-(피페라진-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드((E)-4-(piperazin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 1.2 mg (수율: 3.3%)을 얻었다.The target compound (E)-4-(piperazin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide ((E)- 1.2 mg (yield: 3.3%) of 4-(piperazin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) was obtained.

1H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.88 (s, 1H), 7.53 - 7.37 (m, 4H), 7.35 (d, J = 8.6 Hz, 1H), 7.07 - 7.04 (m, 1H), 6.93 - 6.86 (m, 1H), 6.57 (s, 1H), 6.34 (d, J = 15.4 Hz, 1H), 3.31 - 3.20 (m, 3H), 2.77 (s, 3H), 2.38 (s, 2H). LRMS (ESI), m/z = 484.12 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.88 (s, 1H), 7.53 - 7.37 (m, 4H), 7.35 (d, J = 8.6 Hz, 1H), 7.07 - 7.04 (m, 1H), 6.93 - 6.86 (m, 1H), 6.57 (s, 1H), 6.34 (d, J = 15.4 Hz, 1H), 3.31 - 3.20 ( m , 3H), 2.77 (s, 3H), 2.38 (s, 2H). LRMS (ESI), m/z = 484.12 [M+H]+

<< 실시예Example 31> (E)-4-( 31> (E)-4-( 피롤리딘pyrrolidine -1-일)-N-(3-((8--1-day)-N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) butene-2-amide

상기 실시예 29와 같은 방법으로 제조하되, 피롤리딘 (2.459 mg, 0.035 mmol)시약을 사용하여 목적화합물 (E)-4-(피롤리딘-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드((E)-4-(pyrrolidin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 7.9 mg (수율: 45.7%)을 얻었다.It was prepared in the same manner as in Example 29, but using pyrrolidine (2.459 mg, 0.035 mmol) reagent to obtain the target compound (E)-4-(pyrrolidin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide ((E)-4-(pyrrolidin-1-yl) -N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 7.9 mg (yield: 45.7%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.73 (s, 1H), 8.39 (s, 1H), 7.90 (s, 1H), 7.55 - 7.35 (m, 6H), 7.10 (d, J = 7.8 Hz, 1H), 6.96 - 6.80 (m, 1H), 6.55 (d, J = 12.8 Hz, 2H), 4.08 (d, J = 7.0 Hz, 2H), 3.67 (s, 2H), 3.16 (s, 2H), 2.39 (s, 3H), 2.19 (s, 2H), 2.06 (s, 2H). LRMS (ESI), m/z = 469.08 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.73 (s, 1H), 8.39 (s, 1H), 7.90 (s, 1H), 7.55 - 7.35 (m, 6H), 7.10 (d, J = 7.8 Hz, 1H), 6.96 - 6.80 (m, 1H), 6.55 (d , J = 12.8 Hz, 2H), 4.08 (d, J = 7.0 Hz, 2H), 3.67 (s, 2H), 3.16 (s, 2H), 2.39 (s, 3H), 2.19 (s, 2H), 2.06 (s, 2H). LRMS (ESI), m/z = 469.08 [M+H] +

<< 실시예Example 32> (E)-4-( 32> (E)-4-( 사이클로프로필아미노cyclopropylamino )-N-(3-((8-)-N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) butene-2-amide

상기 실시예 29와 같은 방법으로 제조하되, 사이클로프로필아민 (1.974 mg, 0.035 mmol) 시약을 사용하여 목적화합물 (E)-4-(사이클로프로필아미노)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드((E)-4-(cyclopropylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 5.2 mg (수율: 32.6%)을 얻었다.It was prepared in the same manner as in Example 29, but using cyclopropylamine (1.974 mg, 0.035 mmol) reagent to obtain the target compound (E)-4-(cyclopropylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide ((E)-4-(cyclopropylamino)-N-(3-((8 -(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 5.2 mg (yield: 32.6%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.37 (s, 1H), 7.90 (s, 1H), 7.56 - 7.35 (m, 6H), 7.11 - 7.09 (m, 1H), 6.94 - 6.85 (m, 1H), 6.55 (s, 1H), 6.52 (d, J = 15.4 Hz, 1H), 4.00 (d, J = 6.4 Hz, 2H), 2.85 - 2.79 (m, 1H), 2.39 (s, 3H), 1.01 - 0.87 (m, 4H). LRMS (ESI), m/z = 455.08 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.37 (s, 1H), 7.90 (s, 1H), 7.56 - 7.35 (m, 6H), 7.11 - 7.09 (m, 1H), 6.94 - 6.85 (m, 1H), 6.55 (s, 1H), 6.52 (d, J = 15.4 Hz, 1H), 4.00 (d, J = 6.4 Hz, 2H), 2.85 - 2.79 (m, 1H), 2.39 ( s , 3H), 1.01 - 0.87 (m, 4H). LRMS (ESI), m/z = 455.08 [M+H] +

<< 실시예Example 33> (E)-4- 33> (E)-4- 몰폴리노Morpholino -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) butene-2-amide

상기 실시예 29와 같은 방법으로 제조하되, 몰폴린 (8.95 μl, 0.104 mmol) 시약을 사용하여 목적화합물 (E)-4-몰폴리노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드((E)-4-morpholino-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 1.6 mg (수율: 9.2%)을 얻었다.It was prepared in the same manner as in Example 29, but using morpholine (8.95 μl, 0.104 mmol) reagent to obtain the target compound (E)-4-morpholino-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide ((E)-4-morpholino-N-(3-((8-(o-toly) lamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 1.6 mg (yield: 9.2%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 8.07 (s, 1H), 7.70 (s, 1H), 7.33 - 7.26 (m, 5H), 6.93 (d, J = 7.9 Hz, 1H), 6.80 - 6.72 (m, 2H), 6.51 (s, 1H), 6.43 (d, J = 15.2 Hz, 1H), 5.24 (t, J = 4.8 Hz, 2H), 3.90 (d, J = 7.3 Hz, 2H), 2.24 (s, 3H), 2.11 - 2.05 (m, 2H), 1.98 - 1.88 (m, 4H). LRMS (ESI), m/z = 485.05 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.40 (s, 1H), 8.07 (s, 1H), 7.70 (s, 1H), 7.33 - 7.26 (m, 5H), 6.93 (d, J = 7.9 Hz, 1H), 6.80 - 6.72 (m, 2H), 6.51 (s, 1H), 6.43 (d, J = 15.2 Hz, 1H), 5.24 (t, J = 4.8 Hz, 2H), 3.90 (d, J = 7.3 Hz, 2H), 2.24 (s, 3H), 2.11 - 2.05 (m, 2H), 1.98 - 1.88 (m, 4H). LRMS (ESI), m/z = 485.05 [M+H] +

<< 실시예Example 34> (E)-4-(4- 34> (E)-4-(4- 메틸methyl -1,4--1,4- 다이아제판Diazepan -1-일)-N-(3-((8--1-day)-N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) butene-2-amide

상기 실시예 29와 같은 방법으로 제조하되, 1-메틸-1,4-다이아제페인 (3.95 mg, 0.035 mmol) 시약을 사용하여 목적화합물 (E)-4-(4-메틸-1,4-다이아제판-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드((E)-4-(4-methyl-1,4-diazepan-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 2.9 mg (수율: 14.8%)을 얻었다.It was prepared in the same manner as in Example 29, but using 1-methyl-1,4-diazepane (3.95 mg, 0.035 mmol) reagent to obtain the target compound (E)-4-(4-methyl-1,4-diazepan-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide ((E)-4-(4-methyl-1,4-diazepan-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)but-2-enamide) 2.9 mg (yield: 14.8%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.36 (s, 1H), 7.91 (s, 1H), 7.54 - 7.38 (m, 6H), 7.11 - 7.09 (m, 1H), 6.94 - 6.87 (m, 1H), 6.57 - 6.49 (m, 2H), 3.96 (d, J = 6.9 Hz, 2H), 3.76 - 3.69 (m, 2H), 3.63 (s, 2H), 3.54 (s, 2H), 3.44 - 3.38 (m, 2H), 2.99 (s, 3H), 2.39 (s, 3H), 2.31 (d, J = 4.9 Hz, 2H). LRMS (ESI), m/z = 512.18 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.36 (s, 1H), 7.91 (s, 1H), 7.54 - 7.38 (m, 6H), 7.11 - 7.09 (m, 1H), 6.94 - 6.87 (m, 1H), 6.57 - 6.49 (m, 2H), 3.96 (d, J = 6.9 Hz, 2H), 3.76 - 3.69 (m, 2H), 3.63 (s, 2H), 3.54 (s, 2H), 3.44 - 3.38 (m, 2H), 2.99 (s, 3H), 2.39 (s, 3H), 2.31 (d, J = 4.9 Hz, 2H). LRMS (ESI), m/z = 512.18 [M+H]+

[반응식Ⅴ][Scheme V]

<< 실시예Example 35> (E)-2- 35> (E)-2- 사이아노Cyano -3--3- 사이클로프로필cyclopropyl -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)아크릴아마이드의 제조Preparation of -5-yl) oxy) phenyl) acrylamide

2-사이아노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드 (15 mg, 0.038 mmol), 피페리딘 (3.21 mg, 0.038 mmol)과 사이클로프로필카바알데하이드 (5.28 mg, 0.075 mmol)을 MeOH (1.3 ml)에 용해시키고 25 °C에서 12시간 동안 교반한다. 반응이 종결되면 용매를 감압증류하고 얻은 잔사를 에틸아세테이트와 2M HCl로 추출하고 물층을 NaHCO3 수용액을 사용하여 pH 8로 맞춘 뒤, 다시 에틸아세테이트로 추출한다. 추출한 유기층을 황산마그네슘으로 수분을 제거한 뒤 감압증류하여 남은 잔사를 MPLC로 분리, 정제하여 목적화합물 (E)-2-사이아노-3-사이클로프로필-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드((E)-2-cyano-3-cyclopropyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) 0.8 mg (수율: 4.5%)을 얻었다. 2-Cyano-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide (15 mg, 0.038 mmol), piperidine (3.21 mg, 0.038 mmol) and cyclopropylcarbaldehyde (5.28 mg, 0.075 mmol) were dissolved in MeOH (1.3 ml) and 25 Stir at °C for 12 hours. After the reaction was completed, the solvent was distilled under reduced pressure, the obtained residue was extracted with ethyl acetate and 2M HCl, and the aqueous layer was adjusted to pH 8 using NaHCO 3 aqueous solution, followed by extraction with ethyl acetate again. The extracted organic layer was dehydrated with magnesium sulfate, distilled under reduced pressure, and the remaining residue was separated and purified by MPLC to obtain the target compound (E)-2-cyano-3-cyclopropyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide ((E)-2-cyano-3-cyclopropyl-N-(3-((8-(o-toly) lamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) to obtain 0.8 mg (yield: 4.5%).

1H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.76 (s, 1H), 7.54 - 7.39 (m, 5H), 7.10 (d, J = 7.2 Hz, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.57 (s, 1H), 2.38 (s, 3H), 1.36 - 1.34 (m, 2H), 1.31 (s, 2H). LRMS (ESI), m/z = 450.93 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.76 (s, 1H), 7.54 - 7.39 (m, 5H), 7.10 (d, J = 7.2 Hz, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.57 (s, 1H), 2.38 (s, 3H), 1.36 - 1.34 (m, 2H), 1.31 (s, 2H). LRMS (ESI), m/z = 450.93 [M+H] +

<< 실시예Example 36> (E)-2- 36> (E)-2- 사이아노Cyano -4--4- 메틸methyl -4--4- 몰폴리노Morpholino -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)펜텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) penten-2-amide

상기 실시예 35와 같은 방법으로 제조하되, 2-메틸-2-몰폴리노프로판알 (5.52 mg, 0.035 mmol) 시약을 사용하여 목적화합물 (E)-2-사이아노-4-메틸-4-몰폴리노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)펜텐-2-아마이드((E)-2-cyano-4-methyl-4-morpholino-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)pent-2-enamide) 2.3 mg (수율: 11.5%)을 얻었다.It was prepared in the same manner as in Example 35, but using 2-methyl-2-morpholinopropanal (5.52 mg, 0.035 mmol) reagent to obtain the target compound (E)-2-cyano-4-methyl-4-morpholino-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)penten-2-amide ((E)-2 2.3 mg (yield: 11.5%) of -cyano-4-methyl-4-morpholino-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)pent-2-enamide) was obtained.

1H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.34 (s, 1H), 7.81 - 7.78 (m, 1H), 7.68 (s, 1H), 7.53 - 7.44 (m, 6H), 7.18 - 7.14 (m, 1H), 6.56 (s, 1H), 3.97 (s, 4H), 2.39 (s, 3H), 1.78 (s, 6H). LRMS (ESI), m/z = 538.1 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.34 (s, 1H), 7.81 - 7.78 (m, 1H), 7.68 (s, 1H), 7.53 - 7.44 (m, 6H), 7.18 - 7.14 (m, 1H), 6.56 (s, 1H), 3.97 (s, 4H), 2.39 (s, 3H), 1.78 (s, 6H). LRMS (ESI), m/z = 538.1 [M+H] +

<< 실시예Example 37> (E)-2- 37> (E)-2- 사이아노Cyano -4--4- 메틸methyl -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)펜텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) penten-2-amide

상기 실시예 35와 같은 방법으로 제조하되, 아이소뷰틸알데하이드 (3.62 mg, 0.050 mmol) 시약을 사용하여 목적화합물 (E)-2-사이아노-4-메틸-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)펜텐-2-아마이드((E)-2-cyano-4-methyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)pent-2-enamide) 1.9 mg (수율: 8.1%)을 얻었다.It was prepared in the same manner as in Example 35, but using isobutylaldehyde (3.62 mg, 0.050 mmol) reagent to obtain the target compound (E)-2-cyano-4-methyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)penten-2-amide ((E)-2-cyano-4-methyl-N-(3 -((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)pent-2-enamide) 1.9 mg (yield: 8.1%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.79 - 7.76 (m, 1H), 7.52 - 7.42 (m, 5H), 7.13 - 7.08 (m, 1H), 6.58 (s, 1H), 3.00 - 2.94 (m, 1H), 2.38 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H). LRMS (ESI), m/z = 453.06 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.29 (s, 1H), 7.79 - 7.76 (m, 1H), 7.52 - 7.42 (m, 5H), 7.13 - 7.08 (m, 1H), 6.58 (s, 1H), 3.00 - 2. 94 (m, 1H), 2.38 (s, 3H), 1.22 (s, 3H), 1.20 (s, 3H). LRMS (ESI), m/z = 453.06 [M+H] +

<< 실시예Example 38> (E)-2- 38> (E)-2- 사이아노Cyano -4,4--4,4- 다이메틸dimethyl -N-(3-((8--N-(3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)펜텐-2-아마이드의 제조Preparation of -5-yl) oxy) phenyl) penten-2-amide

상기 실시예 35와 같은 방법으로 제조하되, 피발알데하이드 (4.32 mg, 0.050 mmol) 시약을 사용하여 목적화합물 (E)-2-사이아노-4,4-다이메틸-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)펜텐-2-아마이드((E)-2-cyano-4,4-dimethyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)pent-2-enamide) 3.3 mg (수율: 13.6%)을 얻었다.It was prepared in the same manner as in Example 35, but using pivalaldehyde (4.32 mg, 0.050 mmol) as a reagent, the target compound (E)-2-cyano-4,4-dimethyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)penten-2-amide ((E)-2-cyano-4,4-dimethyl- 3.3 mg (yield: 13.6%) of N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)pent-2-enamide) was obtained.

1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.35 (s, 1H), 7.80 (t, J = 2.1 Hz, 1H), 7.54 - 7.41 (m, 7H), 7.15 - 7.12 (m, 1H), 6.54 (s, 1H), 2.39 (s, 3H), 1.36 (s, 9H). LRMS (ESI), m/z = 467.06 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.35 (s, 1H), 7.80 (t, J = 2.1 Hz, 1H), 7.54 - 7.41 (m, 7H), 7.15 - 7.12 (m, 1H), 6.54 (s, 1H), 2.39 (s , 3H), 1.36 (s, 9H). LRMS (ESI), m/z = 467.06 [M+H] +

<< 실시예Example 39> (E)-N-(4- 39> (E)-N-(4- 클로로Chloro -3-((8--3-((8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)옥시)페닐)-2-사이아노-3-사이클로프로필아크릴아마이드의 제조Preparation of -5-yl) oxy) phenyl) -2-cyano-3-cyclopropylacrylamide

N-(4- 클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-2-사이아노아세트아마이드 (5 mg, 0.012 mmol), 피페리딘 (1 mg, 0.012 mmol)과 사이클로프로필카바알데하이드 (1 mg, 0.012 mmol)을 아세트산 (0.5 ml)에 용해시키고 80 °C에서 1시간 동안 교반한다. 반응이 종결되면 용매를 감압증류하고 얻은 잔사를 preparative HPLC로 분리, 정제하여 목적화합물 (E)-N-(4-클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-2-사이아노-3-사이클로프로필아크릴아마이드((E)-N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyano-3-cyclopropylacrylamide) 1.5 mg (수율: 26.6%)을 얻었다.N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyanoacetamide (5 mg, 0.012 mmol), piperidine (1 mg, 0.012 mmol) and cyclopropylcarbaldehyde (1 mg, 0.012 mmol) were dissolved in acetic acid (0.5 ml) and stirred at 80 °C. Stir for 1 hour. After the reaction was completed, the solvent was distilled under reduced pressure and the obtained residue was separated and purified by preparative HPLC to obtain the target compound (E)-N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyano-3-cyclopropylacrylamide ((E)-N-(4-chloro-3-((8-(o-tolylamino)imidazo[1, 5-a]pyrazin-5-yl)oxy)phenyl)-2-cyano-3-cyclopropylacrylamide) 1.5 mg (yield: 26.6%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.80 (s, 1H), 8.38 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.54 - 7.41 (m, 5H), 7.04 (d, J = 11.1 Hz, 1H), 6.40 (s, 1H), 2.38 (s, 3H), 2.14 - 2.07 (m, 1H), 1.40 - 1.30 (m, 2H), 1.06 - 0.99 (m, 2H). LRMS (ESI), m/z = 485.06 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.80 (s, 1H), 8.38 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.62 - 7.58 (m, 1H), 7.54 - 7.41 (m, 5H), 7.04 (d, J = 11.1 Hz, 1H) ), 6.40 (s, 1H), 2.38 (s, 3H), 2.14 - 2.07 (m, 1H), 1.40 - 1.30 (m, 2H), 1.06 - 0.99 (m, 2H). LRMS (ESI), m/z = 485.06 [M+H] +

<< 실시예Example 40> (E)-2- 40> (E)-2- 사이아노Cyano -3--3- 사이클로프로필cyclopropyl -N-(3-((8--N-(3-((8- ((4-플루오로-2-메틸페닐)아미노)이미다((4-fluoro-2-methylphenyl)amino)imida 조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드의 제조Preparation of crude [1,5-a] pyrazin-5-yl) oxy) phenyl) acrylamide

상기 실시예 39와 같은 방법으로 제조하되, 사이클로프로필알데하이드 (0.5 mg, 7.7 μmol), 피페리딘 (0.8 μl, 7.7 μmol) 시약을 사용하여 목적화합물 (E)-2-사이아노-3-사이클로프로필-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드((E)-2-cyano-3-cyclopropyl-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) 1.8 mg (수율: 48.2%)을 얻었다.It was prepared in the same manner as in Example 39, but using cyclopropylaldehyde (0.5 mg, 7.7 μmol) and piperidine (0.8 μl, 7.7 μmol) reagents to obtain the target compound (E)-2-cyano-3-cyclopropyl-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl) 1.8 mg (yield: 48.2%) of acrylamide ((E)-2-cyano-3-cyclopropyl-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide) was obtained.

1H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.35 (s, 1H), 7.78 (t, J = 2.1 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.46 - 7.39 (m, 2H), 7.28 (dd, J = 9.2, 2.7 Hz, 1H), 7.18 (td, J = 8.4, 3.0 Hz, 1H), 7.11 (ddd, J = 7.8, 2.5, 1.4 Hz, 1H), 7.04 (d, J = 11.1 Hz, 1H), 6.57 (s, 1H), 2.38 (s, 3H), 2.15 - 2.04 (m, 2H), 1.40 - 1.32 (m, 3H), 1.07 - 1.00 (m, 2H). LRMS (ESI), m/z = 469.11 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.68 (s, 1H), 8.35 (s, 1H), 7.78 (t, J = 2.1 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.46 - 7.39 (m, 2H), 7.28 (dd, J = 9.2, 2.7 Hz, 1H), 7.18 (td, J = 8.4, 3.0 Hz, 1H), 7.11 (ddd, J = 7.8, 2.5, 1.4 Hz, 1H), 7.04 (d, J = 11.1 Hz, 1H), 6.57 (s, 1H), 2.38 (s, 3H), 2.15 - 2.04 (m, 2H), 1.40 - 1.32 (m, 3H), 1.07 - 1.00 (m, 2H). LRMS (ESI), m/z = 469.11 [M+H] +

<< 실시예Example 41> (E)-2- 41> (E)-2- 사이아노Cyano -N-(3-((8--N-(3-((8- ((4-플루오로-2-메틸페닐)아미노)이미다((4-fluoro-2-methylphenyl)amino)imida 조[1,5-a]피라진-5-일)옥시)페닐)-4-메틸펜텐-2-아마이드의 제조Preparation of crude [1,5-a] pyrazin-5-yl) oxy) phenyl) -4-methylpenten-2-amide

상기 실시예 39와 같은 방법으로 제조하되, 아이소뷰틸알데하이드 (0.6 mg, 7.7 μmol), 피페리딘 (0.8 μl, 7.7 μmol) 시약을 사용하여 목적화합물 (E)-2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-4-메틸펜텐-2-아마이드((E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4-methylpent-2-enamide) 0.4 mg (수율: 11%)을 얻었다.It was prepared in the same manner as in Example 39, but using isobutylaldehyde (0.6 mg, 7.7 μmol) and piperidine (0.8 μl, 7.7 μmol) reagents to obtain the target compound (E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4-methylphene 0.4 mg (yield: 11%) of ten-2-amide ((E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4-methylpent-2-enamide) was obtained.

1H NMR (400 MHz, MeOD) δ 8.67 (s, 1H), 8.35 (s, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.47 - 7.43 (m, 2H), 7.40 (d, J = 10.2 Hz, 1H), 7.28 (dd, J = 9.3, 2.7 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.12 (dd, J = 7.7, 1.5 Hz, 1H), 6.58 (s, 1H), 3.04 - 2.92 (m, 1H), 2.38 (s, 3H), 1.21 (d, J = 6.6 Hz, 6H). LRMS (ESI), m/z = 471.1 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.67 (s, 1H), 8.35 (s, 1H), 7.79 (d, J = 2.2 Hz, 1H), 7.53 - 7.47 (m, 1H), 7.47 - 7.43 (m, 2H), 7.40 (d, J = 10.2 Hz, 1H), 7.28 (dd, J = 9.3, 2.7 Hz, 1H), 7.21 - 7.15 (m, 1H), 7.12 (dd, J = 7.7, 1.5 Hz, 1H), 6.58 (s, 1H), 3.04 - 2.92 (m, 1H), 2.38 (s, 3H), 1.21 (d, J = 6.6 Hz, 6H). LRMS (ESI), m/z = 471.1 [M+H] +

<< 실시예Example 42> (E)-2- 42> (E)-2- 사이아노Cyano -N-(3-((8--N-(3-((8- ((4-플루오로-2-메틸페닐)아미노)이미다((4-fluoro-2-methylphenyl)amino)imida 조[1,5-a]피라진-5-일)옥시)페닐)-4,4-다이메틸펜텐-2-아마이드의 제조Preparation of crude [1,5-a] pyrazin-5-yl) oxy) phenyl) -4,4-dimethylpenten-2-amide

상기 실시예 39와 같은 방법으로 제조하되, 피발알데하이드 (0.8 mg, 9.7 μmol), 피페리딘 (0.9 μl, 9.7 μmol) 시약을 사용하여 목적화합물 (E)-2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-4,4-다이메틸펜텐-2-아마이드((E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4,4-dimethylpent-2-enamide) 0.5 mg (수율: 11%)을 얻었다.It was prepared in the same manner as in Example 39, but using pivalaldehyde (0.8 mg, 9.7 μmol) and piperidine (0.9 μl, 9.7 μmol) reagents to obtain the target compound (E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4,4-di Methylpenten-2-amide ((E) -2-cyano-N- (3 - ((8-((4-fluoro-2-methylphenyl) amino) imidazo [1,5-a] pyrazin-5-yl) oxy) phenyl) -4,4-dimethylpent-2-enamide) 0.5 mg (yield: 11%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.24 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.49 - 7.41 (m, 3H), 7.24 (dd, J = 9.2, 3.0 Hz, 1H), 7.13 (dd, J = 8.3, 2.6 Hz, 1H), 7.10 - 7.06 (m, 1H), 6.63 (s, 1H), 2.36 (s, 3H), 1.35 (s, 9H). LRMS (ESI), m/z = 485.1 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.24 (s, 1H), 7.73 (s, 1H), 7.51 (s, 1H), 7.49 - 7.41 (m, 3H), 7.24 (dd, J = 9.2, 3.0 Hz, 1H), 7.13 (dd, J = 8.3, 2.6 Hz, 1H), 7.10 - 7.06 (m, 1H), 6.63 (s, 1H), 2.36 (s, 3H), 1.35 (s, 9H). LRMS (ESI), m/z = 485.1 [M+H] +

<< 실시예Example 43> (E)-2- 43> (E)-2- 사이아노Cyano -N-(3-((8--N-(3-((8- ((4-플루오로-2-메틸페닐)아미노)이미다((4-fluoro-2-methylphenyl)amino)imida 조[1,5-a]피라진-5-일)옥시)페닐)-4-메틸-4-몰폴리노펜텐-2-아마이드의 제조Preparation of crude [1,5-a] pyrazin-5-yl) oxy) phenyl) -4-methyl-4-morpholinopenten-2-amide

상기 실시예 39와 같은 방법으로 제조하되, 2-메틸-2-몰폴리노프로판알 (1.5 mg, 9.7 μmol), 피페리딘 (0.9 μl, 9.7 μmol) 시약을 사용하여 목적화합물 (E)-2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-4-메틸-4-몰폴리노펜텐-2-아마이드((E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4-methyl-4-morpholinopent-2-enamide) 2 mg (수율: 37%)을 얻었다.It was prepared in the same manner as in Example 39, but using 2-methyl-2-morpholinopropanal (1.5 mg, 9.7 μmol) and piperidine (0.9 μl, 9.7 μmol) reagents to obtain the target compound (E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl ) -4-methyl-4-morpholinopenten-2-amide ((E) -2-cyano-N- (3 - ((8-((4-fluoro-2-methylphenyl) amino) imidazo [1,5-a] pyrazin-5-yl) oxy) phenyl) -4-methyl-4-morpholinopent-2-enamide) 2 mg (yield: 37%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.69 (s, 1H), 8.36 (s, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.54 - 7.45 (m, 3H), 7.29 (dd, J = 9.1, 3.0 Hz, 1H), 7.22 - 7.12 (m, 2H), 6.59 (s, 1H), 3.97 (s, 4H), 2.38 (s, 3H), 1.78 (s, 6H). LRMS (ESI), m/z = 556.14 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.69 (s, 1H), 8.36 (s, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.54 - 7.45 (m, 3H), 7.29 (dd, J = 9.1, 3.0 Hz, 1H), 7.22 - 7 .12 (m, 2H), 6.59 (s, 1H), 3.97 (s, 4H), 2.38 (s, 3H), 1.78 (s, 6H). LRMS (ESI), m/z = 556.14 [M+H] +

[반응식Ⅵ][Scheme VI]

Figure 112021017277461-pat00033
Figure 112021017277461-pat00033

<< 실시예Example 44> 3-(8- 44> 3-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)-5 days) 벤조나이트릴의of benzonitrile 제조 manufacturing

3-(4,4,5,5-테트라메틸-1,3,2-다이옥사보로레인-2-일)벤조나이트릴 (15.11 mg, 0.066 mmol), 세슘 카보네이트 (53.7 mg, 0.165 mmol), 5-브로모-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민 (20 mg, 0.066 mmol), PdCl2(dppf) (5.39 mg, 6.60 μmol)을 DMF (0.275 ml)와 물 (0.055 ml)에 용해시키고 120 °C에서 30분 동안 마이크로파를 조사하여 반응하였다. 반응종결 후 물과 에틸아세테이트로 추출하고 유기층을 황산마그네슘으로 건조하여 여과 후 감압증류하여 얻은 잔사를 prep-HPLC로 분리, 정제하여 목적화합물 3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)벤조나이트릴(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)benzonitrile) 8.1 mg (수율: 37.7%)을 얻었다. Pd Cl 2 (dppf) (5.39 mg, 6.60 μmol) was dissolved in DMF (0.275 ml) and water (0.055 ml) and reacted by microwave irradiation at 120 °C for 30 minutes. After completion of the reaction, extraction was performed with water and ethyl acetate, the organic layer was dried over magnesium sulfate, filtered, and the residue obtained by distillation under reduced pressure was separated and purified by prep-HPLC to obtain the target compound 3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)benzonitrile 8 .1 mg (yield: 37.7%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.61 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 8.07 - 7.96 (m, 2H), 7.82 (t, J = 7.8 Hz, 1H), 7.59 - 7.45 (m, 4H), 6.95 (s, 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 325.98 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.61 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 8.07 - 7.96 (m, 2H), 7.82 (t, J = 7.8 Hz, 1H), 7.59 - 7.45 (m, 4H), 6.95 (s , 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 325.98 [M+H] +

<< 실시예Example 45> 4-(8- 45 > 4-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)-5 days) 벤조나이트릴의of benzonitrile 제조 manufacturing

상기 실시예 44와 같은 방법으로 제조하되, 4-(4,4,5,5-테트라메틸-1,3,2-다이옥사보로레인-2-일)벤조나이트릴 (15.11 mg, 0.066 mmol) 시약을 사용하여 목적화합물 4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)벤조나이트릴(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)benzonitrile) 7.4 mg (수율: 34.5%)을 얻었다.It was prepared in the same manner as in Example 44, but using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile (15.11 mg, 0.066 mmol) reagent as the target compound 4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)benzonitrile (4-(8-(o-tolylamin o)imidazo[1,5-a]pyrazin-5-yl)benzonitrile) 7.4 mg (yield: 34.5%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.64 (s, 1H), 8.40 (s, 1H), 8.06 - 7.96 (m, 2H), 7.95 - 7.87 (m, 2H), 7.59 - 7.45 (m, 4H), 6.97 (s, 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 325.99 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.64 (s, 1H), 8.40 (s, 1H), 8.06 - 7.96 (m, 2H), 7.95 - 7.87 (m, 2H), 7.59 - 7.45 (m, 4H), 6.97 (s, 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 325.99 [M+H] +

<< 실시예Example 46> 5-(3- 46> 5-(3- 아미노페닐aminophenyl )-N-)-N- (o-톨릴)이미다조[1,5-a]피라진(o-tolyl)imidazo[1,5-a]pyrazine -8--8- 아민의amine 제조 manufacturing

실시예 44과 같은 방법으로 제조하되, 3-(4,4,5,5-테트라메틸-1,3,2-다이옥사보레인-2-일)아닐린) (217 mg, 0.990 mmol) 시약을 사용하여 목적화합물 5-(3-아미노페닐)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민(5-(3-aminophenyl)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine) 240 mg (수율: 76%)을 얻었다.It was prepared in the same manner as in Example 44, but using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)aniline) (217 mg, 0.990 mmol) reagent to obtain the target compound 5-(3-aminophenyl)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (5-(3-aminophenyl)-N-(o -tolyl)imidazo[1,5-a]pyrazin-8-amine) to obtain 240 mg (yield: 76%).

1H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 7.70 - 7.58 (m, 3H), 7.54 - 7.36 (m, 6H), 6.87 (s, 1H), 2.35 (s, 3H). LRMS (ESI), m/z = 316.06 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 7.70 - 7.58 (m, 3H), 7.54 - 7.36 (m, 6H), 6.87 (s, 1H), 2.35 (s, 3H). LRMS (ESI), m/z = 316.06 [M+H] +

[반응식Ⅶ][Scheme VII]

<< 실시예Example 47> N-(4-(8- 47> N-(4-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)-5-yl) phenyl) 아크릴아마이드의of acrylamide 제조 manufacturing

상기 실시예 12와 같은 방법으로 제조하되, 아크릴로일 클로라이드 (4.23 μl, 0.052 mmol) 시약을 사용하여 목적화합물 N-(4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드(N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide) 1.6 mg (수율: 8.9%)을 얻었다.It was prepared in the same manner as in Example 12, but using acryloyl chloride (4.23 μl, 0.052 mmol) reagent as the target compound N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide (N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide) 1.6 mg (yield: 8.9%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.59 (s, 1H), 8.42 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.73 - 7.66 (m, 2H), 7.59 - 7.46 (m, 4H), 6.81 (s, 1H), 6.47 - 6.45 (m, 2H), 5.87 - 5.84 (m, 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 369.9 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.59 (s, 1H), 8.42 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.73 - 7.66 (m, 2H), 7.59 - 7.46 (m, 4H), 6.81 (s, 1H), 6.47 - 6.45 (m, 2H), 5.87 - 5.84 (m, 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 369.9 [M+H] +

<< 실시예Example 48> N-(4-(8- 48> N-(4-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)-5-yl) phenyl) 프로피온아마이드의of propionamide 제조 manufacturing

상기 실시예 12와 같은 방법으로 제조하되, 프로피오닐 클로라이드 (4.84 mg, 0.052 mmol) 시약을 사용하여 목적화합물 N-(4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)프로피온아마이드(N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propionamide) 3.1 mg (수율: 17.2%)을 얻었다.It was prepared in the same manner as in Example 12, but using propionyl chloride (4.84 mg, 0.052 mmol) as a reagent, the target compound N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propionamide (N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propion ionamide) to obtain 3.1 mg (yield: 17.2%).

1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.47 - 7.43 (m, 2H), 7.39 - 7.31 (m, 2H), 6.94 (s, 1H), 6.54 (s, 1H), 2.51 - 2.45 (m, 2H), 2.35 (s, 3H), 1.30 (t, J = 6.2 Hz, 3H). LRMS (ESI), m/z = 372.04 [M+H]+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.30 (s, 1H), 7.77 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.47 - 7.43 (m, 2H), 7.39 - 7.31 (m, 2H), 6.94 (s, 1H), 6.54 (s, 1H), 2.51 - 2.45 (m, 2H), 2.35 (s, 3H), 1.30 (t, J = 6.2 Hz, 3H). LRMS (ESI), m/z = 372.04 [M+H] +

<< 실시예Example 49> N-(3-(8- 49> N-(3-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)-5-yl) phenyl) 프로피온아마이드의of propionamide 제조 manufacturing

상기 실시예 12와 같은 방법으로 제조하되, 프로피오닐 클로라이드 (6.78 mg, 0.073 mmol) 시약을 사용하여 목적화합물 N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)프로피온아마이드(N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propionamide) 12 mg (수율: 48.5%)을 얻었다.It was prepared in the same manner as in Example 12, but using propionyl chloride (6.78 mg, 0.073 mmol) reagent to obtain the target compound N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propionamide (N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propion ionamide) to obtain 12 mg (yield: 48.5%).

1H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.38 (s, 1H), 8.13 (t, J = 1.8 Hz, 1H), 7.65 - 7.62 (m, 1H), 7.60 - 7.49 (m, 5H), 7.44 - 7.41 (m, 1H), 6.86 (s, 1H), 2.48 - 2.42 (m, 2H), 2.41 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H). LRMS (ESI), m/z = 372.05 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.38 (s, 1H), 8.13 (t, J = 1.8 Hz, 1H), 7.65 - 7.62 (m, 1H), 7.60 - 7.49 (m, 5H), 7.44 - 7.41 (m, 1H), 6.86 (s, 1H), 2.48 - 2.42 (m, 2H), 2.41 (s, 3H), 1.23 (t, J = 7.6 Hz, 3H). LRMS (ESI), m/z = 372.05 [M+H] +

<< 실시예Example 50> N-(3-(8- 50> N-(3-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)-5-yl) phenyl) 아크릴아마이드의of acrylamide 제조 manufacturing

상기 실시예 12와 같은 방법으로 제조하되, 아크릴로일 클로라이드 (5.64 μl, 0.070 mmol) 시약을 사용하여 목적화합물 N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드(N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide) 2.7 mg (수율: 11.2%)을 얻었다.It was prepared in the same manner as in Example 12, but using acryloyl chloride (5.64 μl, 0.070 mmol) reagent as the target compound N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide (N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide) 2.7 mg (yield: 11.2%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.63 - 7.45 (m, 6H), 6.87 (s, 1H), 6.51 - 6.38 (m, 2H), 5.84 (d, J = 9.3 Hz, 1H), 2.42 (s, 3H). LRMS (ESI), m/z = 370.12 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.63 - 7.45 (m, 6H), 6.87 (s, 1H), 6.51 - 6.38 (m , 2H), 5.84 (d, J = 9.3 Hz, 1H), 2.42 (s, 3H). LRMS (ESI), m/z = 370.12 [M+H] +

<< 실시예Example 51> (E)-4- 51> (E)-4- 브로모Bromo -N-(3-(8--N-(3-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) phenyl) butene-2-amide

상기 실시예 12와 같은 방법으로 제조하되, (E)-4-브로모-1-뷰텐오일 클로라이드 (96 mg, 0.523 mmol) 시약을 사용하여 목적화합물 (E)-4-브로모-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드((E)-4-bromo-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)but-2-enamide) 10 mg (수율: 4.2%)을 얻었다.It was prepared in the same manner as in Example 12, but using (E)-4-bromo-1-butenoyl chloride (96 mg, 0.523 mmol) reagent to obtain the target compound (E)-4-bromo-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)buten-2-amide ((E)-4-bromo-N-(3-(8-( 10 mg (yield: 4.2%) of o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)but-2-enamide) was obtained.

1H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.61 - 7.47 (m, 5H), 7.45 (d, J = 7.5 Hz, 1H), 6.86 (s, 1H), 6.55 - 6.46 (m, 2H), 3.43 - 3.42 (m, 2H), 2.41 (s, 3H). LRMS (ESI), m/z = 462.99 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.61 - 7.47 (m, 5H), 7.45 (d, J = 7.5 Hz, 1H), 6.86 (s, 1H), 6.55 - 6.46 (m, 2H), 3.43 - 3.42 (m, 2H), 2.41 (s, 3H). LRMS (ESI), m/z = 462.99 [M+H] +

<< 실시예Example 52> (E)-4- 52> (E)-4- 하이드록시hydroxy -N-(3-(8--N-(3-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) phenyl) butene-2-amide

상기 실시예 11과 같은 방법으로 제조하되, (E)-4-하이드록시-2-뷰텐오익산 (10.68 mg, 0.105 mmol) 시약을 사용하여 목적화합물 (E)-4-하이드록시-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드((E)-4-hydroxy-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)but-2-enamide) 1.3 mg (수율: 3.34%)을 얻었다.It was prepared in the same manner as in Example 11, but using (E)-4-hydroxy-2-butenoic acid (10.68 mg, 0.105 mmol) as a reagent, the target compound (E)-4-hydroxy-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)butene-2-amide ((E)-4-hydroxy-N-(3-(8-) -(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)but-2-enamide) 1.3 mg (yield: 3.34%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 8.40 (s, 1H), 8.21 (s, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.57 - 7.48 (m, 3H), 7.45 (d, J = 7.6 Hz, 1H), 7.06 (dt, J = 15.3, 3.9 Hz, 1H), 6.87 (s, 1H), 6.41 (dt, J = 15.3, 2.1 Hz, 1H), 5.51 (s, 1H), 4.33 (dd, J = 3.9, 2.1 Hz, 2H), 2.41 (s, 3H). LRMS (ESI), m/z = 400.11 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 8.40 (s, 1H), 8.21 (s, 1H), 7.68 (d, J = 9.1 Hz, 1H), 7.60 (t, J = 7.9 Hz, 1H), 7.57 - 7.48 (m, 3H), 7.45 (d, J = 7.6 Hz, 1H), 7.06 (dt, J = 15.3, 3.9 Hz, 1H), 6.87 (s, 1H), 6.41 (dt, J = 15.3, 2.1 Hz, 1H), 5.51 (s, 1H), 4.33 (dd, J = 3.9, 2.1 Hz, 2H), 2.41 (s, 3H). LRMS (ESI), m/z = 400.11 [M+H] +

<< 실시예Example 53> 2- 53> 2- 사이아노Cyano -N-(3-(8--N-(3-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)아세트아마이드의 제조Preparation of -5-yl) phenyl) acetamide

상기 실시예 11과 같은 방법으로 제조하되, 2-사이아노아세트산 (0.030 g, 0.349 mmol) 시약을 사용하여 목적화합물 2-사이아노-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아세트아마이드(2-cyano-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acetamide) 80 mg (수율: 66%)을 얻었다.It was prepared in the same manner as in Example 11, but using 2-cyanoacetic acid (0.030 g, 0.349 mmol) reagent to obtain the target compound 2-cyano-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acetamide (2-cyano-N-(3-(8-(o-tolylamino)imidazo[1,5- a]pyrazin-5-yl)phenyl)acetamide) to obtain 80 mg (yield: 66%).

1H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.69 - 7.67 (m, 1H), 7.62 - 7.60 (m, 1H), 7.58 - 7.48 (m, 4H), 7.46 - 7.44 (m, 1H), 6.86 (s, 1H), 3.82 (s, 2H), 2.41 (s, 3H). LRMS (ESI), m/z = 382.98 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.69 - 7.67 (m, 1H), 7.62 - 7.60 (m, 1H), 7.58 - 7.48 (m, 4H), 7.46 - 7. 44 (m, 1H), 6.86 (s, 1H), 3.82 (s, 2H), 2.41 (s, 3H). LRMS (ESI), m/z = 382.98 [M+H] +

<< 실시예Example 54> (E)-4-( 54> (E)-4-( 다이메틸아미노dimethylamino )-N-(3-(8-)-N-(3-(8- (o-톨릴아미노)이미다조[1,5-(o-tolylamino)imidazo[1,5- a]피라진-5-일)페닐)뷰텐-2-아마이드의 제조Preparation of a] pyrazin-5-yl) phenyl) buten-2-amide

상기 실시예 11과 같은 방법으로 제조하되, (E)-4-(다이메틸아미노)-1-뷰텐오익산 (13.51 mg, 0.105 mmol) 시약을 사용하여 목적화합물 (E)-4-(다이메틸아미노)-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드((E)-4-(dimethylamino)-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)but-2-enamide) 1.8 mg (수율: 4.1%)을 얻었다.It was prepared in the same manner as in Example 11, but using (E)-4-(dimethylamino)-1-butenoic acid (13.51 mg, 0.105 mmol) reagent to obtain the target compound (E)-4-(dimethylamino)-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)butene-2-amide ((E)-4-( 1.8 mg (yield: 4.1%) of dimethylamino)-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)but-2-enamide) was obtained.

1H NMR (400 MHz, MeOD) δ 8.61 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 7.76 - 7.68 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.56 - 7.44 (m, 5H), 6.95 - 6.89 (m, 1H), 6.88 (s, 1H), 6.60 (d, J = 15.2 Hz, 1H), 4.04 - 4.01 (m, 2H), 2.95 (s, 6H), 2.41 (s, 3H). LRMS (ESI), m/z = 427.15 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.61 (s, 1H), 8.41 (s, 1H), 8.22 (s, 1H), 7.76 - 7.68 (m, 1H), 7.63 (t, J = 7.9 Hz, 1H), 7.56 - 7.44 (m, 5H), 6.95 - 6.89 (m, 1H), 6.88 (s, 1H), 6.60 (d, J = 15.2 Hz, 1H), 4.04 - 4.01 ( m , 2H), 2.95 (s, 6H), 2.41 (s, 3H). LRMS (ESI), m/z = 427.15 [M+H] +

<< 실시예Example 55> 2- 55> 2- 플루오로Fluoro -N-(3-(8--N-(3-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)아크릴아마이드의 제조Preparation of -5-yl) phenyl) acrylamide

상기 실시예 27과 같은 방법으로 제조하되, 5-(3-아미노페닐)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민 (10 mg, 0.032 mmol) 중간체를 사용하여 목적화합물 2-플루오로-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드(2-fluoro-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide) 2 mg (수율: 16%)을 얻었다.It was prepared in the same manner as in Example 27, but using 5-(3-aminophenyl)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (10 mg, 0.032 mmol) intermediate, the target compound 2-fluoro-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide (2-fluoro-N -(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide) 2 mg (yield: 16%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.64 (s, 1H), 8.41 (s, 1H), 8.17 - 8.16 (m, 1H), 7.83 - 7.80 (m, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.58 - 7.43 (m, 5H), 6.88 (s, 1H), 5.83 - 5.71 (m, 1H), 5.39 - 5.34 (m, 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 388.15 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.64 (s, 1H), 8.41 (s, 1H), 8.17 - 8.16 (m, 1H), 7.83 - 7.80 (m, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.58 - 7.43 (m, 5H), 6.88 (s, 1H), 5.83 - 5.71 (m, 1H), 5.39 - 5.34 (m, 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 388.15 [M+H] +

<< 실시예Example 56> 2- 56> 2- 플루오로Fluoro -N-(4-(8--N-(4-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)아크릴아마이드의 제조Preparation of -5-yl) phenyl) acrylamide

상기 실시예 27과 같은 방법으로 제조하되, 5-(4-아미노페닐)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민 (10 mg, 0.032 mmol) 중간체를 사용하여 목적화합물 2-플루오로-N-(4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드(2-fluoro-N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide) 4.5 mg (수율: 36%)을 얻었다. It was prepared in the same manner as in Example 27, but using 5-(4-aminophenyl)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine (10 mg, 0.032 mmol) intermediate, the target compound 2-fluoro-N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide (2-fluoro-N -(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide) 4.5 mg (yield: 36%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.38 (s, 1H), 8.02 - 7.92 (m, 2H), 7.76 - 7.67 (m, 2H), 7.58 - 7.43 (m, 4H), 6.83 (s, 1H), 5.85 - 5.72 (m, 1H), 5.39 - 5.35 (m, 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 388.15 [M+H]+ 1H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 8.38 (s, 1H), 8.02 - 7.92 (m, 2H), 7.76 - 7.67 (m, 2H), 7.58 - 7.43 (m, 4H), 6.83 (s, 1H), 5.85 - 5. 72 (m, 1H), 5.39 - 5.35 (m, 1H), 2.41 (s, 3H). LRMS (ESI), m/z = 388.15 [M+H] +

[반응식Ⅷ][Scheme VIII]

<< 실시예Example 57> (E)-4-( 57> (E)-4-( 메틸아미노methylamino )-N-(3-(8-)-N-(3-(8- (o-톨릴아미노)이미다조[1,5-a]피라진(o-tolylamino)imidazo[1,5-a]pyrazine -5-일)페닐)뷰텐-2-아마이드의 제조Preparation of -5-yl) phenyl) butene-2-amide

상기 실시예 25와 같은 방법으로 제조하되, 메틸아민 (81 μl, 0.162 mmol) 시약을 사용하여 목적화합물 (E)-4-(메틸아미노)-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드((E)-4-(methylamino)-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)but-2-enamide) 1 mg (수율: 7.3%)을 얻었다.It was prepared in the same manner as in Example 25, but using methylamine (81 μl, 0.162 mmol) reagent to obtain the target compound (E)-4-(methylamino)-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)butene-2-amide ((E)-4-(methylamino)-N-(3-(8-(o-tolylamino)im idazo[1,5-a]pyrazin-5-yl)phenyl)but-2-enamide) 1 mg (yield: 7.3%) was obtained.

1H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.56 - 7.47 (m, 4H), 6.94 - 6.86 (m, 2H), 6.54 (d, J = 15.3 Hz, 2H), 3.89 (d, J = 6.6 Hz, 2H), 2.77 (s, 3H), 2.41 (s, 3H). LRMS (ESI), m/z = 413.07 [M+H]+ 1 H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.56 - 7.47 (m, 4H), 6.94 - 6.86 (m, 2H), 6.54 (d, J = 15.3 Hz, 2H), 3.89 ( d , J = 6.6 Hz, 2H), 2.77 (s, 3H), 2.41 (s, 3H). LRMS (ESI), m/z = 413.07 [M+H] +

No.No. 화학구조chemical structure No.No. 화학구조chemical structure 1One 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717 1818 1919 2020 2121 2222 2323 2424 2525 2626 2727 2828 2929 3030 3131 3232 3333 3434 3535 3636 3737 3838 3939 4040 4141 4242 4343 4444 4545 4646 4747 4848 4949 5050 5151 5252 5353 5454 5555 5656 5757

<< 실험예Experimental example 1> 1> BTK에to BTK 대한 선택적 억제 활성 분석 Selective inhibitory activity assay for

1-1. BTK 억제 활성 분석1-1. BTK inhibitory activity assay

상기 실시예 화합물의 BTK 키나아제에 대한 억제활성을 평가하기 위하여 LanthaScreen Kinase assay 실험을 수행하였다. 보다 구체적으로 384-웰 플레이트에 최종농도 23 ng/ml 재조합 BTK 키나아제(Promega PV3363), 6 μmol/L ATP (Promega PV3227), 200 nM Fluorescein-Poly GT (Promega PV3610)를 키나아제 반응 버퍼 (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA)에 첨가하여 혼합하였다. 상기 실시예에 따른 각각의 화합물 최종 농도를 10 uM, 3.33 uM, 1.11 uM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.57 nM, 1.52 nM 그리고 0.5 nM로 첨가한 후, 23 ℃ 인큐베이터에서 1시간 동안 반응시켰다. 반응이 종료된 후, 동량의 4 nM LanthaScreenTM Tb-PY20 (Promega PV3552), 20 mm EDTA (Promega P2825)를 TR-FRET 용액에 첨가하여 30분 동안 반응시킨 후, 마이크로플레이트 효소결합면역흡착검사 판독기(microplate ELISA reader; Bio-Tek)를 이용하여 TRF/TR-FRET Dual PMT를 사용하여 TR-FRET 값을 측정하여 키나아제의 IC50 값을 산출하였다. 그 결과를 하기 표 2에 나타내었다.LanthaScreen Kinase assay was performed to evaluate the inhibitory activity of the compounds of the above examples on BTK kinase. More specifically, a final concentration of 23 ng/ml recombinant BTK kinase (Promega PV3363), 6 μmol/L ATP (Promega PV3227), and 200 nM Fluorescein-Poly GT (Promega PV3610) were added to a 384-well plate in a kinase reaction buffer (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl). 2 , 1 mM EGTA) and mixed. 10 uM, 3.33 uM, 1.11 uM, 370 nM, 123 nM, 41 nM, 13.7 nM, 4.57 nM, 1.52 nM and 0.5 nM were added to the final concentration of each compound according to the above example, and then reacted in a 23 ° C. incubator for 1 hour. After the reaction was completed, equal amounts of 4 nM LanthaScreen TM Tb-PY20 (Promega PV3552) and 20 mm EDTA (Promega P2825) were added to the TR-FRET solution and reacted for 30 minutes. The IC 50 value of was calculated. The results are shown in Table 2 below.

No.No. BTK IC50 (nM)BTK IC 50 (nM) No.No. BTK IC50 (nM)BTK IC 50 (nM) No.No. BTK IC50 (nM)BTK IC 50 (nM) 1One >1000>1000 2121 2.772.77 4141 29.429.4 22 >1000>1000 2222 8.0458.045 4242 88.9588.95 33 10031003 2323 5.7335.733 4343 38.3538.35 44 534534 2424 136.2136.2 4444 >1000>1000 55 763.5763.5 2525 22.8122.81 4545 >1000>1000 66 12541254 2626 71477147 4646 17081708 77 13.2213.22 2727 5.7345.734 4747 13.813.8 88 41674167 2828 20.920.9 4848 233.5233.5 99 231.1231.1 2929 103.7103.7 4949 635.8635.8 1010 215.3215.3 3030 112.3112.3 5050 0.440.44 1111 >1000>1000 3131 2.22.2 5151 19.6319.63 1212 29.729.7 3232 7.537.53 5252 14.7914.79 1313 1.151.15 3333 106.6106.6 5353 786786 1414 730730 3434 37.1637.16 5454 2.722.72 1515 0.190.19 3535 278278 5555 3.1283.128 1616 27.2127.21 3636 12.912.9 5656 79.1379.13 1717 0.26770.2677 3737 6.546.54 5757 4.0564.056 1818 1.7681.768 3838 9.719.71 1919 967.9967.9 3939 30083008 2020 468468 4040 337.4337.4

1-2. EGFR 억제 활성 분석1-2. EGFR inhibitory activity assay

본 발명에 따른 실시예 화합물이 BTK에 대한 선택적인 억제 활성을 보이는지 확인하기 위하여, 실시예 화합물의 EGFR (wild-type) 키나아제에 대한 억제활성을 나타내는지 여부를 확인하였다. 실험은 재조합 EGFR 키나아제 (Signalchem Inc), ADP-Glo kinase assay kit (Promega, USA)을 이용하여 다음과 같은 방법으로 수행하였다. 보다 구체적으로 384-웰 플레이트에 최종농도 1 ng 재조합 EGFR 키나아제, 5 μM ATP, 200 ng/μl Poly(4:1 Glu, Tyr) peptide (Signalchem Inc)를 키나아제 반응 버퍼 (40 mM Tris pH 7.5, 1 mM MgCl2, 1 mM MnCl2, 50 μM DTT )에 첨가하여 혼합하였다. 각각의 화합물 최종 농도를 50 μM, 10 μM, 2 μM, 0.4 μM, 0.08 μM, 0.016 μM, 3 nM, 0.64 nM, 0.12 nM, 0.026 nM 그리고 0.005 nM로 첨가한 후, 25 ℃ 인큐베이터에서 60분 동안 반응시켰다. 반응이 종료된 후, 동량의 ADP-Glo를 첨가하여 40분 동안 반응시키고, 탐지(detection) 용액을 첨가하여 상온에서 30분 동안 더 반응시킨 후, Synergy Neo2 (Biotek Instruments Incorporated, Winooski, VT, USA)를 이용하여 Luminescence 값을 측정하여 키나아제의 IC50 값을 산출하였다. 데이터는 비히클 기준 처리된 세포에 비례하여 백분율로 나타내었고 GraphPad Prism 7.0 (GraphPad software Inc., San Diego)을 이용하여 IC50 값을 산출하였다. 그 결과를 하기 표 3에 나타내었다.In order to confirm whether the example compounds according to the present invention show selective inhibitory activity against BTK, it was confirmed whether or not the example compounds exhibit inhibitory activity against EGFR (wild-type) kinase. Experiments were performed in the following manner using recombinant EGFR kinase (Signalchem Inc) and ADP-Glo kinase assay kit (Promega, USA). More specifically, kinase reaction buffer (40 mM Tris pH 7.5, 1 mM MgCl 2 , 1 mM MnCl 2 , 50 μM DTT) was added to a final concentration of 1 ng recombinant EGFR kinase, 5 μM ATP, and 200 ng/μl Poly(4:1 Glu, Tyr) peptide (Signalchem Inc) in a 384-well plate and mixed. 50 μM, 10 μM, 2 μM, 0.4 μM, 0.08 μM, 0.016 μM, 3 nM, 0.64 nM, 0.12 nM, 0.026 nM and 0.005 nM were added to the final concentration of each compound, and then reacted in a 25° C. incubator for 60 minutes. After the reaction was completed, the same amount of ADP-Glo was added and reacted for 40 minutes, and a detection solution was added and further reacted at room temperature for 30 minutes. Then, the Luminescence value was measured using Synergy Neo2 (Biotek Instruments Incorporated, Winooski, VT, USA) to calculate the IC 50 value of the kinase. Data were presented as percentages relative to treated cells relative to vehicle and IC 50 values were calculated using GraphPad Prism 7.0 (GraphPad software Inc., San Diego). The results are shown in Table 3 below.

No.No. EGFR IC50 (nM)EGFR IC 50 (nM) No.No. EGFR IC50 (nM)EGFR IC 50 (nM) No.No. EGFR IC50 (nM)EGFR IC 50 (nM) 1One -- 2121 13771377 4141 >50000>50000 22 -- 2222 -- 4242 -- 33 50355035 2323 -- 4343 -- 44 660660 2424 12531253 4444 -- 55 23002300 2525 247.6247.6 4545 -- 66 25572557 2626 -- 4646 -- 77 760.9760.9 2727 20812081 4747 21332133 88 2261022610 2828 186.2186.2 4848 -- 99 >50000>50000 2929 -- 4949 -- 1010 10881088 3030 -- 5050 30.930.9 1111 >50000>50000 3131 202.4202.4 5151 -- 1212 >50000>50000 3232 428428 5252 81.8781.87 1313 314.5314.5 3333 -- 5353 -- 1414 -- 3434 32003200 5454 12.9812.98 1515 -- 3535 >50000>50000 5555 639.6639.6 1616 530.6530.6 3636 >50000>50000 5656 15761576 1717 -- 3737 46904690 5757 13.4513.45 1818 696.8696.8 3838 1397013970 1919 -- 3939 -- 2020 -- 4040 >50000>50000

그 결과, 상기 실시예에 따른 대부분의 화합물은 EGFR 키나아제에 대해 억제 활성을 크게 보이지 않은 반면, BTK에 대해 높은 억제 활성을 보이는 것을 확인할 수 있었으며, 따라서 본 발명에 따른 화합물은 BTK에 대해 우수한 선택성을 보이므로 종래 EGFR에 대한 활성으로 부작용의 우려가 존재하던 BTK 저해제와 달리 BTK에 대한 단일 저해제로서 유용하게 사용될 수 있음을 알 수 있다.As a result, while most of the compounds according to the above examples did not show significant inhibitory activity against EGFR kinase, it was confirmed that they showed high inhibitory activity against BTK. Therefore, since the compound according to the present invention shows excellent selectivity for BTK, it can be seen that it can be usefully used as a single inhibitor for BTK, unlike BTK inhibitors, which have concerns about side effects due to activity against conventional EGFR.

한편, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명에 따른 상기 화학식 1로 표시되는 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로 본 발명이 이에 한정되는 것은 아니다.Meanwhile, the compound represented by Chemical Formula 1 according to the present invention can be formulated in various forms depending on the purpose. The following exemplifies some formulation methods containing the compound represented by Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

<제제예 1> 약학적 제제의 제조<Formulation Example 1> Preparation of pharmaceutical formulation

1-1. 산제의 제조1-1. manufacture of powders

화학식 1의 화합물 500 ㎎Compound of Formula 1 500 mg

유당 100 ㎎Lactose 100 mg

탈크 10 ㎎Talc 10 mg

상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.A powder is prepared by mixing the above ingredients and filling them in an airtight bag.

1-2. 정제의 제조1-2. manufacture of tablets

화학식 1의 화합물 500 ㎎Compound of Formula 1 500 mg

옥수수전분 100 ㎎Corn Starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎Magnesium stearate 2 mg

상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above ingredients, tablets are prepared by tableting according to a conventional tablet manufacturing method.

1-3. 캅셀제의 제조1-3. Manufacture of capsules

화학식 1의 화합물 500 ㎎Compound of Formula 1 500 mg

옥수수전분 100 ㎎Corn Starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎Magnesium stearate 2 mg

통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.Capsules are prepared by mixing the above ingredients and filling them into gelatin capsules according to a conventional capsule preparation method.

1-4. 주사제의 제조1-4. Manufacture of injectables

화학식 1의 화합물 500 ㎎Compound of Formula 1 500 mg

주사용 멸균 증류수 적량Appropriate amount of sterile distilled water for injection

pH 조절제 적량Appropriate amount of pH adjuster

통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조한다.It is prepared with the above component content per 1 ampoule (2 ml) according to the conventional method for preparing injections.

1-5. 액제의 제조1-5. Manufacture of Liquids

화학식 1의 화합물 100 ㎎100 mg of a compound of Formula 1

이성화당 10 gIsomerized sugar 10 g

만니톨 5 g5 g mannitol

정제수 적량Appropriate amount of purified water

통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색 병에 충진하여 멸균시켜 액체를 제조한다.According to the conventional method for preparing liquids, each component is dissolved in purified water, lemon flavor is added in an appropriate amount, the above components are mixed, and then purified water is added to adjust the total volume to 100 ml, and then filled into a brown bottle to sterilize to prepare a liquid.

이상, 본 발명을 바람직한 제조예, 실시예 및 실험예를 통해 상세히 설명하였으나, 본 발명의 범위는 특성 실시예에 한정되는 것은 아니며, 첨부된 특허청구범위에 의하여 해석되어야 할 것이다. 또한, 이 기술분야에서 통상의 지식을 습득한 자라면, 본 발명의 범위에서 벗어나지 않으면서도 많은 수정과 변형이 가능함을 이해하여야 할 것이다.In the above, the present invention has been described in detail through preferred manufacturing examples, examples and experimental examples, but the scope of the present invention is not limited to specific examples, and should be interpreted by the appended claims. In addition, those skilled in the art should understand that many modifications and variations are possible without departing from the scope of the present invention.

Claims (15)

하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염:
[화학식 1]

상기 화학식 1에서,
상기 R1은 각각 독립적으로 -H, -CN, -OH, -NH2, 할로겐, 직쇄 또는 분지쇄 C1-5알킬, 또는 직쇄 또는 분지쇄 C1-5알콕시이고;
상기 R2는 각각 독립적으로 -H, -CN, 할로겐, 또는 -NR3R4이고,
상기 R3 및 R4는 각각 독립적으로 -H, -C(=O)R5, 또는 C2-5알케닐설포닐이거나, 또는 상기 R3 및 R4는 이들이 결합된 N 원자와 함께 연결되어 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 10 원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성하고,
상기 R5는 치환 또는 비치환된 직쇄 또는 분지쇄 C1-10알킬, 비치환 또는 치환된 C2-10알케닐, 비치환 또는 치환된 C2-10알카이닐이고,
상기 치환된 직쇄 또는 분지쇄 C1-10알킬, C2-10알케닐, 및 C2-10알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C1-5알킬, 직쇄 또는 분지쇄 디C1-5알킬아미노, 직쇄 또는 분지쇄 C1-5알킬아미노, 직쇄 또는 분지쇄의 C1-5알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 10 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C1-5알킬로 치환 또는 비치환된 3 내지 10원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C1-10알킬, C2-10알케닐, 및 C2-10알카이닐이고; 및
상기 n은 1이고;
상기 x 및 y는 각각 독립적으로 1 내지 5의 정수이다.
A compound represented by Formula 1, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
each R 1 is independently -H, -CN, -OH, -NH 2 , halogen, straight or branched C 1-5 alkyl, or straight or branched C 1-5 alkoxy;
R 2 is each independently -H, -CN, halogen, or -NR 3 R 4 ;
R 3 and R 4 are each independently -H, -C(=O)R 5 , or C 2-5 alkenylsulfonyl, or R 3 and R 4 are linked together with the N atom to which they are attached to form a 3 to 10 membered unsubstituted or substituted heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O and S;
R 5 is substituted or unsubstituted straight-chain or branched-chain C 1-10 alkyl, unsubstituted or substituted C 2-10 alkenyl, or unsubstituted or substituted C 2-10 alkynyl;
상기 치환된 직쇄 또는 분지쇄 C 1-10 알킬, C 2-10 알케닐, 및 C 2-10 알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C 1-5 알킬, 직쇄 또는 분지쇄 디C 1-5 알킬아미노, 직쇄 또는 분지쇄 C 1-5 알킬아미노, 직쇄 또는 분지쇄의 C 1-5 알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 10 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C 1-5 알킬로 치환 또는 비치환된 3 내지 10원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C 1-10 알킬, C 2-10 알케닐, 및 C 2-10 알카이닐이고; and
wherein n is 1;
The x and y are each independently an integer of 1 to 5.
 제1항에 있어서,
상기 R5는 치환 또는 비치환된 직쇄 또는 분지쇄 C1-8알킬, 비치환 또는 치환된 C2-8알케닐, 비치환 또는 치환된 C2-8알카이닐이고,
상기 치환된 직쇄 또는 분지쇄 C1-8알킬, C2-8알케닐, 및 C2-8알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C1-4알킬, 직쇄 또는 분지쇄 디C1-4알킬아미노, 직쇄 또는 분지쇄 C1-4알킬아미노, 직쇄 또는 분지쇄의 C1-4알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 8 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C1-4알킬로 치환 또는 비치환된 3 내지 8원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C1-8알킬, C2-8알케닐, 및 C2-8알카이닐인 것을 특징으로 하는, 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
R 5 is substituted or unsubstituted straight-chain or branched-chain C 1-8 alkyl, unsubstituted or substituted C 2-8 alkenyl, or unsubstituted or substituted C 2-8 alkynyl;
상기 치환된 직쇄 또는 분지쇄 C 1-8 알킬, C 2-8 알케닐, 및 C 2-8 알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C 1-4 알킬, 직쇄 또는 분지쇄 디C 1-4 알킬아미노, 직쇄 또는 분지쇄 C 1-4 알킬아미노, 직쇄 또는 분지쇄의 C 1-4 알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 8 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C 1-4 알킬로 치환 또는 비치환된 3 내지 8원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C 1-8 알킬, C 2-8 알케닐, 및 C 2-8 알카이닐인 것을 특징으로 하는, 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염.
 제1항에 있어서,
상기 R1은 각각 독립적으로 -H, -CN, -OH, -NH2, 할로겐, 직쇄 또는 분지쇄 C1-3알킬, 또는 직쇄 또는 분지쇄 C1-3알콕시이고;
상기 R5는 치환 또는 비치환된 직쇄 또는 분지쇄 C1-5알킬, 비치환 또는 치환된 C2-5알케닐, 비치환 또는 치환된 C2-5알카이닐이고,
상기 치환된 직쇄 또는 분지쇄 C1-5알킬, C2-5알케닐, 및 C2-5알카이닐은 각각 독립적으로 -CN, -OH, 할로겐, C1-3알킬, 직쇄 또는 분지쇄 디C1-3알킬아미노, 직쇄 또는 분지쇄 C1-3알킬아미노, 직쇄 또는 분지쇄의 C1-3알킬로 치환 또는 비치환된 N, O 및 S로 이루어지는 군으로부터 선택되는 하나 이상의 헤테로원자를 포함하는 3 내지 7 원자의 헤테로사이클로알킬, 및 직쇄 또는 분지쇄의 C1-3알킬로 치환 또는 비치환된 3 내지 7원자의 사이클로알킬로 구성되는 군으로부터 선택되는 하나 이상의 치환기로 치환된 직쇄 또는 분지쇄 C1-5알킬, C2-5알케닐, 및 C2-5알카이닐이고; 및
상기 x 및 y는 각각 독립적으로 1 내지 3의 정수인 것을 특징으로 하는, 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
each R 1 is independently -H, -CN, -OH, -NH 2 , halogen, straight or branched C 1-3 alkyl, or straight or branched C 1-3 alkoxy;
R 5 is substituted or unsubstituted straight-chain or branched-chain C 1-5 alkyl, unsubstituted or substituted C 2-5 alkenyl, or unsubstituted or substituted C 2-5 alkynyl;
The substituted straight-chain or branched-chain C 1-5 alkyl, C 2-5 alkenyl, and C 2-5 alkynyl are each independently -CN, -OH, halogen, C 1-3 alkyl, straight-chain or branched-chain diC 1-3 alkylamino, straight-chain or branched-chain C 1-3 alkylamino, straight-chain or branched-chain C 1-3 alkyl, and 3 containing one or more heteroatoms selected from the group consisting of substituted or unsubstituted N , O and S straight or branched chain C 1-5 alkyl, C 2-5 alkenyl, and C 2-5 alkynyl; and
Wherein x and y are each independently an integer of 1 to 3, a compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
 제1항에 있어서,
상기 R1은 각각 독립적으로 -H, -CH3, 또는 할로겐이고;

상기 R2는 각각 독립적으로 -H, -CN, -NH2, 할로겐, , , , , , , , , , , , , , , , , , , , , , , , , 또는이고;

상기 x 및 y는 각각 독립적으로 1 또는 2인 것을 특징으로 하는, 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
R 1 is each independently -H, -CH 3 , or halogen;

The R 2 are each independently -H, -CN, -NH 2 , halogen, , , , , , , , , , , , , , , , , , , , , , , , , or ego;

Wherein x and y are each independently 1 or 2, a compound, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof.
 하기 화합물 군으로부터 선택되는 어느 하나의 화합물, 이의 입체 이성질체, 이의 수화물 또는 이의 약학적으로 허용 가능한 염:
(1) 4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)벤조나이트릴;
(2) 3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)벤조나이트릴;
(3) 5-(3-아미노페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;
(4) 5-(4-아미노페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;
(5) 5-(3-(피페라진-1-일)페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;
(6) 5-(4-(피페라진-1-일)페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;
(7) N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)에텐설폰아마이드;
(8) 5-(5-아미노-2-클로로페녹시)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;
(9) 5-(3-아미노페녹시)-N-(4-플루오로-2-메틸페닐)이미다조[1,5-a]피라진-8-아민;
(10) 2-플루오로-N-(4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;
(11) 2-사이아노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;
(12) N-(4-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;
(13) N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;
(14) N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)프로피온아마이드;
(15) 2-클로로-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;
(16) N-(4-클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;
(17) 2-클로로-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;
(18) N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;
(19) 2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;
(20) 2-플루오로-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;
(21) N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰틴-2-아마이드;
(22) 2-브로모-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;
(23) 2-아이오도-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아세트아마이드;
(24) (E)-4-하이드록시-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;
(25) (E)-4-(다이메틸아미노)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;
(26) N-(4-클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-2-사이아노아세트아마이드;
(27) 2-플루오로-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;
(28) (E)-4-(메틸아미노)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;
(29) (E)-4-(4-아이소프로필피페라진-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;
(30) (E)-4-(피페라진-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;
(31) (E)-4-(피롤리딘-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;
(32) (E)-4-(사이클로프로필아미노)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;
(33) (E)-4-몰폴리노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;
(34) (E)-4-(4-메틸-1,4-다이아제판-1-일)-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)뷰텐-2-아마이드;
(35) (E)-2-사이아노-3-사이클로프로필-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;
(36) (E)-2-사이아노-4-메틸-4-몰폴리노-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)펜텐-2-아마이드;
(37) (E)-2-사이아노-4-메틸-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)펜텐-2-아마이드;
(38) (E)-2-사이아노-4,4-다이메틸-N-(3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)펜텐-2-아마이드;
(39) (E)-N-(4-클로로-3-((8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-2-사이아노-3-사이클로프로필아크릴아마이드;
(40) (E)-2-사이아노-3-사이클로프로필-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)아크릴아마이드;
(41) (E)-2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-4-메틸펜텐-2-아마이드;
(42) (E)-2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-4,4-다이메틸펜텐-2-아마이드;
(43) (E)-2-사이아노-N-(3-((8-((4-플루오로-2-메틸페닐)아미노)이미다조[1,5-a]피라진-5-일)옥시)페닐)-4-메틸-4-몰폴리노펜텐-2-아마이드;
(44) 3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)벤조나이트릴;
(45) 4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)벤조나이트릴;
(46) 5-(3-아미노페닐)-N-(o-톨릴)이미다조[1,5-a]피라진-8-아민;
(47) N-(4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드;
(48) N-(4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)프로피온아마이드;
(49) N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)프로피온아마이드;
(50) N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드;
(51) (E)-4-브로모-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드;
(52) (E)-4-하이드록시-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드;
(53) 2-사이아노-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아세트아마이드;
(54) (E)-4-(다이메틸아미노)-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드;
(55) 2-플루오로-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드;
(56) 2-플루오로-N-(4-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)아크릴아마이드; 및
(57) (E)-4-(메틸아미노)-N-(3-(8-(o-톨릴아미노)이미다조[1,5-a]피라진-5-일)페닐)뷰텐-2-아마이드.
Any one compound selected from the following group of compounds, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof:
(1) 4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile;
(2) 3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)benzonitrile;
(3) 5-(3-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;
(4) 5-(4-aminophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;
(5) 5-(3-(piperazin-1-yl)phenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;
(6) 5-(4-(piperazin-1-yl)phenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;
(7) N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)ethenesulfonamide;
(8) 5-(5-amino-2-chlorophenoxy)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;
(9) 5-(3-aminophenoxy)-N-(4-fluoro-2-methylphenyl)imidazo[1,5-a]pyrazin-8-amine;
(10) 2-fluoro-N-(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;
(11) 2-cyano-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;
(12) N-(4-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;
(13) N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;
(14) N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)propionamide;
(15) 2-chloro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;
(16) N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;
(17) 2-chloro-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;
(18) N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;
(19) 2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;
(20) 2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;
(21) N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butyn-2-amide;
(22) 2-bromo-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;
(23) 2-iodo-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acetamide;
(24) (E)-4-hydroxy-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide;
(25) (E)-4-(dimethylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide;
(26) N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyanoacetamide;
(27) 2-fluoro-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;
(28) (E)-4-(methylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;
(29) (E)-4-(4-isopropylpiperazin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;
(30) (E)-4-(piperazin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;
(31) (E)-4-(pyrrolidin-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;
(32) (E)-4-(cyclopropylamino)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide;
(33) (E)-4-morpholino-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)buten-2-amide;
(34) (E)-4-(4-methyl-1,4-diazepan-1-yl)-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)butene-2-amide;
(35) (E)-2-cyano-3-cyclopropyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;
(36) (E)-2-cyano-4-methyl-4-morpholino-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)penten-2-amide;
(37) (E)-2-cyano-4-methyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)penten-2-amide;
(38) (E)-2-cyano-4,4-dimethyl-N-(3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)penten-2-amide;
(39) (E)-N-(4-chloro-3-((8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-2-cyano-3-cyclopropylacrylamide;
(40) (E)-2-cyano-3-cyclopropyl-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)acrylamide;
(41) (E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4-methylpenten-2-amide;
(42) (E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4,4-dimethylpenten-2-amide;
(43) (E)-2-cyano-N-(3-((8-((4-fluoro-2-methylphenyl)amino)imidazo[1,5-a]pyrazin-5-yl)oxy)phenyl)-4-methyl-4-morpholinopenten-2-amide;
(44) 3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)benzonitrile;
(45) 4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)benzonitrile;
(46) 5-(3-aminophenyl)-N-(o-tolyl)imidazo[1,5-a]pyrazin-8-amine;
(47) N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide;
(48) N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propionamide;
(49) N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)propionamide;
(50) N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide;
(51) (E)-4-bromo-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)buten-2-amide;
(52) (E)-4-hydroxy-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)buten-2-amide;
(53) 2-cyano-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acetamide;
(54) (E)-4-(dimethylamino)-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)buten-2-amide;
(55) 2-fluoro-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide;
(56) 2-fluoro-N-(4-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)acrylamide; and
(57) (E)-4-(methylamino)-N-(3-(8-(o-tolylamino)imidazo[1,5-a]pyrazin-5-yl)phenyl)buten-2-amide.
 제1항 또는 제5항의 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for preventing or treating cancer or autoimmune diseases, containing the compound of claim 1 or 5, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
 제6항에 있어서,
상기 화합물은 BTK(Bruton's tyrosine kinase)를 억제하는 것을 특징으로 하는, 약학적 조성물.
According to claim 6,
The pharmaceutical composition, characterized in that the compound inhibits BTK (Bruton's tyrosine kinase).
 제6항에 있어서,
상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 림프구성 백혈병(CLL), 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 미만성거대B-세포림프종, 맨틀세포림프종(MCL), 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 비호지킨림프종, 설암, 성상세포종, 소림프구성림프종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 재킷세포림프종, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 호지킨림프종, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 약학적 조성물.
According to claim 6,
The cancers include pseudomyxoma, intrahepatic cholangiocarcinoma, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, lip cancer, mycosis fungoides, acute myelogenous leukemia, acute lymphocytic leukemia, basal cell carcinoma, ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, bile duct cancer, Colorectal cancer, lymphocytic leukemia (CLL), chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, diffuse large B-cell lymphoma, mantle cell lymphoma (MCL), ampulla cancer, bladder cancer, peritoneal cancer, parathyroid cancer, adrenal cancer, rhinosinus cancer, non-small cell lung cancer, non-Hodgkin's lymphoma, tongue cancer, astrocytoma, small lymphocytic lymphoma, small cell Lung cancer, childhood brain cancer, childhood lymphoma, childhood leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenal cancer, malignant soft tissue cancer, bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureteral cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, stomach cancer, gastric carcinoma, gastrointestinal interstitial cancer, Wilms' cancer, breast cancer, sarcoma, penis Cancer, pharyngeal cancer, gestational trophoblastic disease, jacket cell lymphoma, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma, pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, Hodgkin's A pharmaceutical composition, characterized in that it is selected from the group consisting of lymphoma, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymus cancer.
 제6항에 있어서,
상기 자가면역질환은 류마티스성 관절염, 건선 관절염, 골관절염, 스틸 질환, 연소성 관절염, 루푸스, 중증 근무력증, 하시모토 갑상선염, 요오드 갑상선염, 그레이브 질환 쇼그렌 증후군, 다발성 경화증, 길랑-바레 증후근, 급성 파종 뇌척수염, 애디슨 질환, 안구진탕-근간대성 증후군, 강직성 척수염, 항인지질 항체 증후군, 재생불량성 빈혈, 자가면역성 간염, 복강 질환, 구드패스츄어 증후군, 특발성 혈소판감소성 자반병, 시신경염, 공피증, 원발성 담즙성 간경변증, 라이터 증후군, 타카야스 동맥염, 측두 동맥염, 상온 자가면역성 용혈성 빈혈, 베게너 육아종증, 건선, 범발성 탈모증, 베체트 질환, 자율신경기능이상, 자궁내막증, 간질성 방광염, 신경 근육긴장증, 및 외음통으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 약학적 조성물.
According to claim 6,
The autoimmune diseases include rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still disease, juvenile arthritis, lupus, myasthenia gravis, Hashimoto's thyroiditis, iodine thyroiditis, Grave's disease, Sjogren's syndrome, multiple sclerosis, Guillain-Barre syndrome, acute disseminated encephalomyelitis, Addison's disease, nystagmus-myoclonic syndrome, ankylosing myelitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis , celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, normal temperature autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, generalized alopecia, Behcet's disease, autonomic dysfunction, endometriosis, interstitial cystitis, neuromyotonia, and vulvodynia Characterized in that selected from the group consisting of, a pharmaceutical composition.
 제1항 또는 제5항의 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암 또는 자가면역질환의 예방 또는 개선용 건강기능식품 조성물.
A health functional food composition for preventing or improving cancer or autoimmune diseases, containing the compound of claim 1 or 5, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
 제1항 또는 제5항의 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 BTK(Bruton's tyrosine kinase) 관련 질환인 암 또는 자가면역질환의 예방 또는 치료용 약학적 조성물.
A pharmaceutical composition for preventing or treating cancer or autoimmune diseases, which are BTK (Bruton's tyrosine kinase)-related diseases, containing the compound of claim 1 or 5, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
 삭제delete 제11항에 있어서,
상기 BTK 관련 질환은 혈액학적 악성종양(hematological malignancy), 혈액암, B-세포 만성림프성백혈병, 급성림프성백혈병, 비호지킨림프종, 호지킨림프종, 급성골수성백혈병, 미만성거대B-세포림프종, 다발성골수종, 재킷세포림프종, 소림프구성림프종, 맨틀세포림프종(MCL) 및 림프구성 백혈병(CLL)으로 이루어진 군에서 선택되는 것을 특징으로 하는 약학적 조성물.
According to claim 11,
The BTK-related diseases are in the group consisting of hematological malignancy, hematological malignancy, B-cell chronic lymphocytic leukemia, acute lymphocytic leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma, acute myelogenous leukemia, diffuse large B-cell lymphoma, multiple myeloma, jacket cell lymphoma, small lymphocytic lymphoma, mantle cell lymphoma (MCL) and lymphocytic leukemia (CLL) A pharmaceutical composition, characterized in that selected.
 제11항에 있어서,
상기 BTK 관련 질환은 류마티스 관절염, 골관절염, 연소성관절염, 만성폐쇄성 폐질환, 다발성경화증, 천식, 전신성홍반성루푸스, 건선, 건선성관절염, 크론병, 궤양성대장염 및 과민성대장증후군으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 약학적 조성물.
According to claim 11,
The BTK-related disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, juvenile arthritis, chronic obstructive pulmonary disease, multiple sclerosis, asthma, systemic lupus erythematosus, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis and irritable bowel syndrome, characterized in that selected from the pharmaceutical composition.
 제1항 또는 제5항의 화합물, 이의 입체 이성질체, 이의 수화물, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 BTK(Bruton's tyrosine kinase) 관련 질환인 암 또는 자가면역질환의 예방 또는 개선용 건강기능식품 조성물.
A health functional food composition for preventing or improving cancer or autoimmune disease, which is a BTK (Bruton's tyrosine kinase) related disease, containing the compound of claim 1 or 5, a stereoisomer thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
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