KR101956815B1 - Triazolo-pyridazine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient - Google Patents
Triazolo-pyridazine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating Bruton's tyrosine kinase activity related diseases containing the same as an active ingredient Download PDFInfo
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- KR101956815B1 KR101956815B1 KR1020170019931A KR20170019931A KR101956815B1 KR 101956815 B1 KR101956815 B1 KR 101956815B1 KR 1020170019931 A KR1020170019931 A KR 1020170019931A KR 20170019931 A KR20170019931 A KR 20170019931A KR 101956815 B1 KR101956815 B1 KR 101956815B1
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- KR
- South Korea
- Prior art keywords
- substituted
- branched
- triazolo
- pyridazin
- straight
- Prior art date
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Classifications
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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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
Abstract
본 발명은 트리아졸로피리다진 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 브루톤티로신 키나제 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명에 따른 트리아졸로피리다진 유도체는 브루톤 티로신 키나제를 우수하게 억제함으로써, 상기 브루톤 티로신 키나제 활성과 관련된 질환, 특히 암 또는 자가면역질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.The present invention relates to a triazolepyridazine derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating a disease associated with bruton tyrosine kinase containing the same as an active ingredient. The triazolopyridazine derivative according to the present invention can be effectively used for preventing or treating a disease associated with the above-mentioned bruton tyrosine kinase activity, particularly cancer or an autoimmune disease, by excellently suppressing brutonyl tyrosine kinase.
Description
본 발명은 트리아졸로피리다진 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 브루톤티로신 키나제 관련 질환의 예방 또는 치료용 약학적 조성물에 관한 것이다.The present invention relates to a triazolepyridazine derivative, a process for producing the same, and a pharmaceutical composition for preventing or treating a disease associated with bruton tyrosine kinase containing the same as an active ingredient.
암(cancer)은 유전자 발현의 다양한 변화에 의하여 세포의 사멸이 정상적으로 조절되지 않고 세포의 비성장적인 성장이 야기된 상태로, 암세포는 비정상적으로 분열하며, 분화하는 성질을 가지고 있다. 상기 암세포는 인접한 조직에 침투하여 조직을 파괴하고 다른 부위로 전이하여 결국 사람을 사망하게 한다. Cancer is a state in which cell death is not regulated normally by various changes of gene expression, and nonspecific growth of cells is caused. Cancer cells are abnormally divided and differentiated. The cancer cells penetrate adjacent tissues, destroying the tissues, and transferring them to other sites, eventually leading to death.
암은 신체의 어느 조직에서나 발생할 수 있고, 한가지 요인에 의해 유발되거나, 함께 작용하는 다양한 요인에 의해 유발된다고 알려져 있다. 상기 요인들로는 광범위하고 다양한 화학물질, 방사선 등의 환경적 요인, 바이러스감염 등의 감염성 질환 그리고 유전적 인자들을 들 수 있다. It is known that cancer can occur in any tissue of the body, caused by one factor, or caused by various factors acting together. These factors include a wide variety of chemicals, environmental factors such as radiation, infectious diseases such as viral infections, and genetic factors.
암의 2세대 치료방법으로 알려진 표적치료(targeted therapy)는 종양 생장 및 종양 생존에 필수적인 단백질 또는 유전자 등을 선택적으로 억제하는 것을 통해 특정 종양 세포의 생장 및 생존을 억제하여 항암효과를 유도하는 새로운 형태의 항암치료로서, 종래의 암세포를 직접적으로 공격하여 정상세포에도 공격 가능성이 커 부작용 발생 가능성이 큰 1세대 암 치료법인 화학항암제와 비교하여 암세포만 특이적으로 사멸이 가능하다. Targeted therapy, known as second-generation therapy for cancer, is a new form of cancer that inhibits the growth and survival of specific tumor cells by selectively inhibiting proteins or genes essential for tumor growth and tumor survival As cancer treatment, it is possible to specifically kill cancer cells only in comparison with chemotherapeutic drugs, which are first-generation cancer treatment methods, which are likely to attack normal cells by directly attacking conventional cancer cells and have a high possibility of side effects.
상기 표적치료제로는, 만성 골수성 백혈병(Chronic myeloid leukaemia, CML)에 널리 사용되는 imatinib(Gleevec)은 CML 환자에 많이 분포하는 Bcr-Abl 융합(fusion) 단백질의 활성을 억제하여, CML의 감소(regression)를 유도하게 된다. As the target therapeutic agent, imatinib (Gleevec) widely used for chronic myeloid leukemia (CML) inhibits the activity of Bcr-Abl fusion protein distributed widely in CML patients, .
뿐만 아니라, gefitinib 또는 erlotinib 과 같은 EGFR 억제제는 최근 비 소세포 폐암(Non-small-cell lung carcinoma, NSCLC), 췌장암 (pancreatic cancer), 뇌종양 (glioblastoma) 환자 중에서 EGFR 돌연변이(mutation)(L858R, exon19 deletion)로 인해서 EGFR의 활성이 높게 나타나는 종양에 선택적인 효과를 나타낸다고 보고되었다. 또한, 최근에 FDA에서 허가를 받은 crizotinib은 폐암환자중 EML4-ALK 융합 유전자(fusion gene)을 가진 환자에 대해서 선택적으로 높은 치료율을 보이고 있다. In addition, EGFR inhibitors such as gefitinib or erlotinib have recently been identified as EGFR mutations (L858R, exon19 deletion) in patients with non-small cell lung carcinoma (NSCLC), pancreatic cancer, and glioblastoma, And the EGFR activity is high in the tumors. In addition, recently, FDA-approved crizotinib has a high rate of treatment selectively for patients with the EML4-ALK fusion gene among lung cancer patients.
기존의 전통적인 항암치료에 사용되던 항암제 (Traditional antineoplastics:TANs)는 종양세포의 ‘빠른 세포 분열’ 특징을 표적으로 하여 제작되었으므로, ‘빠른 세포 분열’을 하는 종양세포 뿐만 아니라, 상대적으로 빠른 세포 분열을 하는 정상 세포(예, 모근세포, 위장관 세포, 골수세포, 생식세포)등을 손상시켜 극심한 부작용을 나타내는 문제가 있었다.Traditional antineoplastics (TANs), which have been used for conventional anticancer therapies, are designed to target the 'rapid cell division' characteristics of tumor cells. Therefore, not only tumor cells that undergo rapid cell division, but also relatively fast cell division (For example, hair follicle cells, gastrointestinal tract cells, bone marrow cells, reproductive cells) and the like, thereby causing severe side effects.
반면, 신개념 항암제(Novel antineoplastics: NANs)는 종양세포에만 특이적으로 작용하여, 종양세포의 생존에 필수적이나 정상세포에는 작용하지 않거나, 영향이 미비한 신호전달 물질들을 표적으로 하여 제작되어, 정상세포에 대한 선택성이 매우 높을 뿐 아니라, 또한, 암세포는 다양한 발암유전자 혹은 종양억제 유전자의 이상을 포함하지만 종양의 성장이나 발암과정은 흔히 하나 혹은 두 개의 신호전달경로의 지속적인 활성화에 의해 유지되므로 암세포의 성장이나 증식은 단 하나의 발암유전자를 불활성화시킴으로 해서 억제될 수 있다는 종양세포의 암유전자 중독(oncogene addiction)의 특징을 고려할 때 종양특이적인 신호전달 물질을 표적으로 하는 신개념 항암제의 종양선택성은 매우 우수한 것으로 나타났다. Novel antineoplastics (NANs), on the other hand, act specifically on tumor cells and are produced by targeting signal transduction substances essential for the survival of tumor cells but not acting on or affecting normal cells, In addition to being highly selective for cancer cells, cancer cells also contain a variety of oncogenes or tumor suppressor genes, but tumor growth or carcinogenesis is often sustained by the ongoing activation of one or two signaling pathways, Considering the characteristics of oncogene addiction of tumor cells that proliferation can be inhibited by inactivating only one oncogenic gene, the tumor selectivity of new-concept anticancer drugs that target tumor-specific signaling agents is very good appear.
한편, 브루톤 티로신 키나제(Bruton's tyrosine kinase, BTK)는 비 수용체 티로신 키나제(Non-receptor tyrosine kinases)이며, 염색체 Xq22에 위치하고 있다. 또한, BTK는 Tec 패밀리 키나제로서 BTK 외에도 TEC, ITK, TXK가 이 부류에 속한다. 다른 조직에서는 거의 발현하지 않으며, 혈액세포 중에서도 T 세포(T cell)에는 전혀 존재하지 않고 B 세포(B cell)에서만 존재하는 단백질이다.On the other hand, Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase and is located on chromosome Xq22. In addition, BTK belongs to this category as TEC family kinases, as well as BTK, TEC, ITK, and TXK. It is rarely expressed in other tissues, and it is a protein that exists only in B cells (B cells), not in T cells (T cells) among blood cells.
최근, 상기 B-세포 항원 수용체 신호전달 경로에서 중요한 말단 효소인 브루톤 티로신 키나제는 새로운 타겟으로 부상되고 있으며, 그 하위 신호전달 단백질은 정상 B-세포가 성장, 분화, 및 림프구로서 기능을 하는데 중요한 신호전달 역할을 하고 있다. 더욱이, 브루톤 티로신 키나제는 성숙 B-세포 림프증식성 질환들의 개시, 생존, 진행에 관련되어있는 것으로 알려져있어, 브루톤 티로신 키나제의 신호전달을 조절할 수 있는 치료제가 개발되면, 암종 및 브로톤 키나제와 관련된 다양한 면역관련 질환의 치료제로 개발될 가능성이 매우 크다. Recently, brutonyl tyrosine kinase, an important terminal enzyme in the B-cell antigen receptor signaling pathway, has emerged as a new target, and its downstream signaling proteins are important for normal B-cell function as growth, differentiation, and lymphocyte Signal transmission. Furthermore, it has been known that bruton tyrosine kinase is involved in the initiation, survival, and progression of mature B-cell lymphoproliferative diseases. When a therapeutic agent capable of regulating the signal transduction of bruton tyrosine kinase has been developed, Related diseases. ≪ / RTI >
특히, BTK는 성장인자, B-세포 항원, 케모카인의 수용체와 선천적 면역 수용체(innate immune receptor)의 하위신호 전달에 중요한 기능을 함으로써 세포성장, 생존, 분화, 병인, 신생혈관생성, 신호전달물질 생성, 항원제시와 같은 여러 세포활동에 중요하게 관여를 하고 있는 단백질로서 B-세포의 면역, 염증, 항암 등의 신호전달에 중요한 역할을 담당하고 있기 때문에, BTK 억제제(inhibitor)는 다른 조직은 공격하지 않고 오직 BTK의 활성이 있는 B 세포 종양만을 타겟으로 할 수 있으므로 암치료 과정에서 환자에게 일어나는 부작용을 최소화 할 수 있다는 장점이 있다. In particular, BTK plays a crucial role in the downstream signaling of growth factors, B-cell antigens, chemokine receptors and innate immune receptors, thereby inducing cell growth, survival, differentiation, pathogenesis, neovascularization, , And antigen presenting, BTK inhibitors play an important role in the immune, inflammation, and anti-cancer signaling of B-cells. Therefore, BTK inhibitors do not attack other tissues And only B-cell tumors with active BTK can be targeted, thereby minimizing adverse effects on patients during cancer treatment.
특히, BTK 억제제가 타겟으로 하는 백혈병(Leukemia)은 BTK의 기능이 중요한 역할을 하는 B 세포 수용체 신호전달(B cell receptor signaling, BCR signaling)이 만성적으로 활성화(chronic activation)되어 있으므로 BTK 억제제는 종양만을 선택적으로 타겟화 할 수 있다. In particular, the leukemia targeted by the BTK inhibitor is a chronic activation of B cell receptor signaling (BCR signaling), which plays an important role in the function of BTK. Therefore, And can be selectively targeted.
기존의 만성 림프모구 백혈병(Chronic lymphocytic leukemia, CLL) 치료를 위한 화합요법제들은 저연령의 어린 환자들에게서는 생존 기간을 증대시켰으나 고연령의 환자의 경우 골수억제 및 감염증가라는 심각한 부작용을 야기했으며, 이로인해서 CLL 치료제는 이제 표적치료를 추구하는 방향으로 연구되고 있다. Combination therapies for the treatment of chronic lymphocytic leukemia (CLL) have increased the survival period in younger patients, but have resulted in serious side effects of bone marrow suppression and infectious disease in older patients, CLL therapeutics are now being studied to pursue targeted therapies.
따라서, BTK를 억제하는 표적치료법을 통해 환자의 부작용을 최소화하면서 다양한 암종 및 면역에 관여하는 질병을 효과적으로 치료할 수 있다. Thus, target treatment that inhibits BTK can effectively treat various cancer and immune-related diseases while minimizing the side effects of the patients.
이에, 본 발명자들은 브루톤 티로신 키나제를 억제하는 효과를 나타내는 화합물을 개발하기 위해 노력하던 중, 본 발명에 따른 특정 구조의 트리아졸로피리다진 유도체가 브루톤 티로신 키나제를 우수하게 억제함으로써, 브루톤 티로신 키나제 활성 관련 질환의 예방 및 치료제로 사용될 수 있다는 것을 알아내고 본 발명을 완성하였다.Accordingly, the present inventors have made efforts to develop a compound exhibiting an effect of inhibiting brutonyl tyrosine kinase, wherein the triazolopyridazine derivative having a specific structure according to the present invention excellently inhibits the bruton tyrosine kinase, And can be used as a preventive and therapeutic agent for a kinase activity-related disease.
본 발명의 목적은 트리아졸로피리다진 유도체, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 제공하는 것이다.It is an object of the present invention to provide a triazolepyridazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 상기 트리아졸로피리다진 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a process for producing the triazolo pyridazine derivative.
본 발명의 또 다른 목적은 상기 트리아졸로피리다진 유도체, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 브루톤 티로신 키나제 활성 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Yet another object of the present invention is to provide a pharmaceutical composition for preventing or treating a Bruton tyrosine kinase activity-related disease containing the above-mentioned triazolopyridazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .
본 발명의 다른 목적은 상기 트리아졸로피리다진 유도체, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 브루톤 티로신 키나제 활성 관련 질환의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for preventing or ameliorating a disease associated with bruton tyrosine kinase activity comprising the above-mentioned triazolo pyridazine derivative, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 제공한다:The present invention provides a compound represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
[화학식 1][Chemical Formula 1]
(상기 화학식 1에서,(In the formula 1,
A는 단일 결합 또는 -NH-이고;A is a single bond or -NH-;
는 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로아릴 또는 비치환 또는 치환된 C6-10아릴이고, Is an unsubstituted or substituted heteroaryl or an unsubstituted or substituted C 6-10 aryl group containing from 5 to 7 atoms which comprises at least one heteroatom selected from the group consisting of N, O and S,
여기서, 상기 치환된 헤테로아릴은 직쇄 또는 측쇄의 C1- 5알킬; 직쇄 또는 측쇄의 C1- 5알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 5알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7원자의 비치환 또는 치환된 헤테로사이클로알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있으며, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1- 5알킬; 직쇄 또는 측쇄의 C1- 5알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 5알킬; 직쇄 또는 측쇄의 C1- 5알킬카보닐; 비치환된 C6- 10아릴카보닐; 비치환된 C6- 10아릴C0 - 2알킬; 및 아크릴로일;로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고,Here, the substituted heteroaryl C 1- 5 alkyl, straight or branched; A straight or branched C 1- 5 alkoxy; Hydroxyl C 1 of the straight-chain or branched-5 alkyl; And unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms containing at least one heteroatom selected from the group consisting of N, O and S; and at least one substituent selected from the group consisting of It may be, and wherein, the substituted heterocycloalkyl is a C 1- 5 alkyl, straight or branched; A straight or branched C 1- 5 alkoxy; Hydroxyl C 1 of the straight-chain or branched-5 alkyl; A straight or branched C 1- 5 alkyl-carbonyl; Unsubstituted C 6- 10 aryl-carbonyl; Unsubstituted C 6- 10 aryl C 0 - 2 alkyl; And acryloyl; and at least one substituent selected from the group consisting of
상기 치환된 C6-10아릴은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로사이클로알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로사이클로알킬-C1-3알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; 및 직쇄 또는 측쇄의 C1-5알킬카보닐;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고;Said substituted C 6-10 aryl is straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; An unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And unsubstituted or substituted heterocycloalkyl-C 1-3 alkyl of 5 to 7 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And wherein said substituted heterocycloalkyl is straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; And straight or branched C 1-5 alkylcarbonyl; and at least one substituent selected from the group consisting of:
R1는 수소 또는 비치환 또는 직쇄 또는 측쇄의 C1- 5알킬로 하나 이상 치환된 아민이고; 및R 1 is hydrogen or an unsubstituted or a straight-chain or one or more of the side chain to the C 1- 5 alkyl substituted amine; And
R2 및 R3는 각각 독립적으로 수소; 직쇄 또는 측쇄의 C1- 5알킬; 직쇄 또는 측쇄의 C1- 5알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 5알킬; 비치환된 C3- 7사이클로알킬; 비치환된 C6- 10아릴; 또는 비치환된 C6- 10아릴C1 - 2알킬;이거나, 이들이 결합한 N 원자와 함께 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고, 여기서, 상기 치환된 헤테로사이클로알킬은 -NH2 또는 직쇄 또는 측쇄의 C1- 5알킬; 직쇄 또는 측쇄의 C1- 5알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 5알킬; 비치환 또는 직쇄 또는 측쇄의 C1- 5알킬카보닐 및 아크릴로일로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환된 아민으로 치환될 수 있다).R 2 and R 3 are each independently hydrogen; C 1- 5 alkyl, straight or branched; A straight or branched C 1- 5 alkoxy; Hydroxyl C 1 of the straight-chain or branched-5 alkyl; Unsubstituted C 3- 7 cycloalkyl; Unsubstituted C 6- 10 aryl; Or unsubstituted C 6- 10 aryl C 1 - 2 alkyl, or, they beach of from 5 to 7 atoms containing, together with the N atom N, O, and one or more heteroatoms at least one selected from the group consisting of S bound ring or may form a substituted heterocycloalkyl, wherein, the substituted heterocycloalkyl is -NH 2 or a straight-chain or branched C 1- 5 alkyl; A straight or branched C 1- 5 alkoxy; Hydroxyl C 1 of the straight-chain or branched-5 alkyl; Unsubstituted or straight or branched C 1- 5 alkyl, carbonyl can be substituted with carbonyl, and with one or more substituents selected from the group consisting of acrylic days with one or more substituted amine).
또한, 본 발명은 하기 반응식 1에 나타낸 바와 같이,Also, as shown in the following Reaction Scheme 1,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1); 및Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And
상기 단계 1에서 얻은 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 얻는 단계(단계 2)를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다:There is provided a process for preparing a compound represented by the above formula (1), comprising the step of reacting a compound represented by the formula (4) and a compound represented by the formula (5) obtained in the above step 1 to obtain a compound represented by the formula :
[반응식 1][Reaction Scheme 1]
(상기 반응식 1에서,(In the above Reaction Scheme 1,
R1, R2, R3, A 및 는 상기 화학식 1에서 정의한 바와 같고;R 1 , R 2 , R 3 , A and Is as defined in Formula 1;
X1 및 X2는 각각 독립적으로 동일 또는 상이한 할로겐이고; 및X 1 and X 2 are each independently the same or different halogen; And
L1은 또는 다).L 1 is or All).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 브루톤 티로신 키나제 활성과 관련된 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Further, the present invention provides a pharmaceutical composition for preventing or treating diseases related to the brutonyl tyrosine kinase activity, which comprises the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 브루톤 티로신 키나제 활성과 관련된 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.The present invention also provides a health functional food composition for preventing or ameliorating diseases associated with the brutonyl tyrosine kinase activity, which comprises the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient .
본 발명에 따른 트리아졸로피리다진 유도체는 브루톤 티로신 키나제를 우수하게 억제함으로써, 상기 브루톤 티로신 키나제 활성과 관련된 질환, 특히 암 또는 자가면역질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.The triazolopyridazine derivative according to the present invention can be effectively used for preventing or treating a disease associated with the above-mentioned bruton tyrosine kinase activity, particularly cancer or an autoimmune disease, by excellently suppressing brutonyl tyrosine kinase.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by the following general formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof.
[화학식 1][Chemical Formula 1]
상기 화학식 1에서,In Formula 1,
A는 단일 결합 또는 -NH-이고;A is a single bond or -NH-;
는 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로아릴 또는 비치환 또는 치환된 C6-10아릴이고, Is an unsubstituted or substituted heteroaryl or an unsubstituted or substituted C 6-10 aryl group containing from 5 to 7 atoms which comprises at least one heteroatom selected from the group consisting of N, O and S,
여기서, 상기 치환된 헤테로아릴은 직쇄 또는 측쇄의 C1- 5알킬; 직쇄 또는 측쇄의 C1- 5알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 5알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7원자의 비치환 또는 치환된 헤테로사이클로알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있으며, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1- 5알킬; 직쇄 또는 측쇄의 C1- 5알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 5알킬; 직쇄 또는 측쇄의 C1- 5알킬카보닐; 비치환된 C6- 10아릴카보닐; 비치환된 C6- 10아릴C0 - 2알킬; 및 아크릴로일;로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고,Here, the substituted heteroaryl C 1- 5 alkyl, straight or branched; A straight or branched C 1- 5 alkoxy; Hydroxyl C 1 of the straight-chain or branched-5 alkyl; And unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms containing at least one heteroatom selected from the group consisting of N, O and S; and at least one substituent selected from the group consisting of It may be, and wherein, the substituted heterocycloalkyl is a C 1- 5 alkyl, straight or branched; A straight or branched C 1- 5 alkoxy; Hydroxyl C 1 of the straight-chain or branched-5 alkyl; A straight or branched C 1- 5 alkyl-carbonyl; Unsubstituted C 6- 10 aryl-carbonyl; Unsubstituted C 6- 10 aryl C 0 - 2 alkyl; And acryloyl; and at least one substituent selected from the group consisting of
상기 치환된 C6-10아릴은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로사이클로알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로사이클로알킬-C1-3알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; 및 직쇄 또는 측쇄의 C1-5알킬카보닐;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고;Said substituted C 6-10 aryl is straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; An unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And unsubstituted or substituted heterocycloalkyl-C 1-3 alkyl of 5 to 7 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And wherein said substituted heterocycloalkyl is straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; And straight or branched C 1-5 alkylcarbonyl; and at least one substituent selected from the group consisting of:
R1는 수소 또는 비치환 또는 직쇄 또는 측쇄의 C1- 5알킬로 하나 이상 치환된 아민이고; 및R 1 is hydrogen or an unsubstituted or a straight-chain or one or more of the side chain to the C 1- 5 alkyl substituted amine; And
R2 및 R3는 각각 독립적으로 수소; 직쇄 또는 측쇄의 C1- 5알킬; 직쇄 또는 측쇄의 C1- 5알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 5알킬; 비치환된 C3- 7사이클로알킬; 비치환된 C6- 10아릴; 또는 비치환된 C6- 10아릴C1 - 2알킬;이거나, 이들이 결합한 N 원자와 함께 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고, 여기서, 상기 치환된 헤테로사이클로알킬은 -NH2 또는 직쇄 또는 측쇄의 C1- 5알킬; 직쇄 또는 측쇄의 C1- 5알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 5알킬; 비치환 또는 직쇄 또는 측쇄의 C1- 5알킬카보닐 및 아크릴로일로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환된 아민으로 치환될 수 있다.R 2 and R 3 are each independently hydrogen; C 1- 5 alkyl, straight or branched; A straight or branched C 1- 5 alkoxy; Hydroxyl C 1 of the straight-chain or branched-5 alkyl; Unsubstituted C 3- 7 cycloalkyl; Unsubstituted C 6- 10 aryl; Or unsubstituted C 6- 10 aryl C 1 - 2 alkyl, or, they beach of from 5 to 7 atoms containing, together with the N atom N, O, and one or more heteroatoms at least one selected from the group consisting of S bound ring or may form a substituted heterocycloalkyl, wherein, the substituted heterocycloalkyl is -NH 2 or a straight-chain or branched C 1- 5 alkyl; A straight or branched C 1- 5 alkoxy; Hydroxyl C 1 of the straight-chain or branched-5 alkyl; With one or more substituents selected from the group consisting of days is unsubstituted or linear or branched C 1- 5 alkyl-carbonyl, and acrylic can be substituted with one or more substituted amines.
바람직하게는,Preferably,
상기 A는 단일 결합 또는 -NH-이고;A is a single bond or -NH-;
는 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로아릴 또는 비치환 또는 치환된 C6- 10아릴이고, A is N, O or 5-6 unsubstituted or substituted heteroaryl or unsubstituted of atoms including one or more heteroatoms at least one selected from the group consisting of S, or substituted C 6- 10 aryl,
여기서, 상기 치환된 헤테로아릴은 직쇄 또는 측쇄의 C1- 3알킬; 직쇄 또는 측쇄의 C1- 3알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 3알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6원자의 비치환 또는 치환된 헤테로사이클로알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있으며, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1- 3알킬; 직쇄 또는 측쇄의 C1- 3알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 3알킬; 직쇄 또는 측쇄의 C1- 3알킬카보닐; 벤조일; 페닐C0 - 2알킬; 및 아크릴로일;로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고,Here, the substituted heteroaryl C 1- 3 alkyl of straight or branched chain; A straight or branched C 1- 3 alkoxy; Hydroxyl C 1 of the straight-chain or branched-3 alkyl; And unsubstituted or substituted heterocycloalkyl of 5 to 6 atoms each containing at least one heteroatom selected from the group consisting of N, O and S, with one or more substituents selected from the group consisting of It may be, and wherein, the substituted heterocycloalkyl is a C 1- 3 alkyl of straight or branched chain; A straight or branched C 1- 3 alkoxy; Hydroxyl C 1 of the straight-chain or branched-3 alkyl; A straight or branched C 1- 3 alkyl-carbonyl; Benzoyl; Phenyl-C 0 - 2 alkyl; And acryloyl; and at least one substituent selected from the group consisting of
상기 치환된 C6-10아릴은 직쇄 또는 측쇄의 C1-3알킬; 직쇄 또는 측쇄의 C1-3알콕시; N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로사이클로알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로사이클로알킬-C1-2알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; 및 직쇄 또는 측쇄의 C1-5알킬카보닐;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고;Said substituted C 6-10 aryl is linear or branched C 1-3 alkyl; Straight or branched C 1-3 alkoxy; An unsubstituted or substituted heterocycloalkyl of 5 to 6 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And unsubstituted or substituted heterocycloalkyl-C 1-2 alkyl of 5 to 6 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And wherein said substituted heterocycloalkyl is straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; And straight or branched C 1-5 alkylcarbonyl; and at least one substituent selected from the group consisting of:
R1는 수소 또는 비치환 또는 직쇄 또는 측쇄의 C1- 3알킬로 하나 이상 치환된 아민이고; 및R 1 is hydrogen or an unsubstituted or a straight-chain or one or more of the side chain to the C 1- 3 alkyl-substituted amines; And
R2 및 R3는 각각 독립적으로 수소; 직쇄 또는 측쇄의 C1- 3알킬; 직쇄 또는 측쇄의 C1- 3알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 3알킬; 비치환된 C3- 6사이클로알킬; 비치환된 C6- 10아릴; 또는 비치환된 C6- 10아릴C1 - 2알킬;이거나, 이들이 결합한 N 원자와 함께 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고, 여기서, 상기 치환된 헤테로사이클로알킬은 -NH2 또는 직쇄 또는 측쇄의 C1- 3알킬; 직쇄 또는 측쇄의 C1- 3알콕시; 직쇄 또는 측쇄의 하이드록실C1 - 3알킬; 비치환 또는 직쇄 또는 측쇄의 C1- 3알킬카보닐 및 아크릴로일로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환된 아민으로 치환될 수 있다.R 2 and R 3 are each independently hydrogen; C 1- 3 alkyl of straight or branched chain; A straight or branched C 1- 3 alkoxy; Hydroxyl C 1 of the straight-chain or branched-3 alkyl; Unsubstituted C 3- 6 cycloalkyl; Unsubstituted C 6- 10 aryl; Or unsubstituted C 6- 10 aryl C 1 - 2 alkyl, or, they Beach a 5 to 6 atoms, including together with the N atom to which N, O and one or more heteroatoms at least one selected from the group consisting of S bound It may form a ring, or substituted heterocycloalkyl, and wherein, the substituted heterocycloalkyl is -NH 2 or a straight-chain or branched C 1- 3 alkyl; A straight or branched C 1- 3 alkoxy; Hydroxyl C 1 of the straight-chain or branched-3 alkyl; With one or more substituents selected from the group consisting of days is unsubstituted or linear or branched C 1- 3 alkyl carbonyl and acrylonitrile may be substituted with one or more substituted amine.
보다 바람직하게는,More preferably,
상기 A는 단일 결합 또는 -NH-이고;A is a single bond or -NH-;
는 N 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로아릴 또는 비치환 또는 치환된 페닐이고, Is an unsubstituted or substituted heteroaryl or unsubstituted or substituted phenyl of 5 to 6 atoms containing at least one N atom,
여기서, 상기 치환된 헤테로아릴은 메틸; 에틸; 메톡시; 에톡시; 하이드록실메틸; 하이드록시에틸; 및 비치환 또는 치환된 피롤리디닐, 피페리디닐, 피페라지닐 또는 모폴리닐;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있으며, 이때, 상기 치환된 피롤리디닐, 피페리디닐, 피페라지닐 및 모폴리닐은 메틸, 에틸, 메톡시, 에톡시, 하이드록실메틸, 하이드록시에틸, 아세틸, 에틸카보닐, 페닐, 벤질, 벤조일, 및 아크릴로일;로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고,Wherein said substituted heteroaryl is selected from the group consisting of methyl; ethyl; Methoxy; Ethoxy; Hydroxylmethyl; Hydroxyethyl; And unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; wherein the substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl may be substituted with one or more substituents selected from the group consisting of Riddinyl, piperazinyl and morpholinyl are each independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxylmethyl, hydroxyethyl, acetyl, ethylcarbonyl, phenyl, benzyl, benzoyl, Which may be substituted with one or more substituents,
상기 치환된 페닐은 메틸; 에틸; 메톡시; 에톡시; 하이드록실메틸; 하이드록시에틸; 비치환 또는 치환된 피롤리디닐, 피페리디닐, 피페라지닐 또는 모폴리닐; 및 비치환 또는 치환된 피롤리디닐메틸, 피페리디닐메틸, 피페라지닐메틸 또는 모폴리닐메틸;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고, 이때, 상기 치환된 피롤리디닐, 피페리디닐, 피페라지닐 및 모폴리닐은 메틸, 에틸, 메톡시, 에톡시, 아세틸 및 에틸카보닐으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고;Said substituted phenyl is methyl; ethyl; Methoxy; Ethoxy; Hydroxylmethyl; Hydroxyethyl; Unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; And unsubstituted or substituted pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, or morpholinylmethyl; and wherein the substituted piperidine ring may be substituted with one or more substituents selected from the group consisting of Pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl may be substituted one or more times with one or more substituents selected from the group consisting of methyl, ethyl, methoxy, ethoxy, acetyl and ethylcarbonyl;
R1는 수소, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3 또는 -N(CH2CH3)2이고; 및R 1 is hydrogen, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , -NHCH 2 CH 3 or -N (CH 2 CH 3 ) 2 ; And
R2 및 R3는 각각 독립적으로 수소, 메틸, 에틸, 이소프로필, 메톡시, 에톡시, 하이드록시메틸, 하이드록시에틸, 사이클로프로필, 사이클로펜틸, 사이클로헥실, 페닐 또는 벤질이거나, 이들이 결합한 N 원자와 함께 비치환 또는 치환된 피롤리디닐, 피페리디닐 또는 피페라지닐을 형성할 수 있고, 여기서, 상기 치환된 피롤리디닐, 피페리디닐 및 피페라지닐은 -NH2 또는 메틸, 에틸, 메톡시, 에톡시, 하이드록시메틸, 하이드록시에틸, 아세틸, 에틸카보닐 및 아크릴로일로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환된 아민으로 치환될 수 있다.R 2 and R 3 are each independently hydrogen, methyl, ethyl, isopropyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl or benzyl, To form unsubstituted or substituted pyrrolidinyl, piperidinyl or piperazinyl, wherein said substituted pyrrolidinyl, piperidinyl and piperazinyl is optionally substituted with one or more substituents selected from -NH 2 or methyl, ethyl, Substituted by one or more substituents selected from the group consisting of methoxy, ethoxy, hydroxymethyl, hydroxyethyl, acetyl, ethylcarbonyl and acryloyl.
가장 바람직하게는,Most preferably,
상기 A는 단일 결합 또는 -NH-이고;A is a single bond or -NH-;
는 비치환 또는 치환된 피라졸릴 또는 페닐이고, Is unsubstituted or substituted pyrazolyl or phenyl,
여기서, 상기 치환된 피라졸릴은 메틸, 하이드록시에틸, 및 비치환 또는 치환된 피페리디닐으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있으며, 이때, 상기 치환된 피페리디닐은 메틸, 하이드록시에틸, 아세틸, 벤질, 벤조일, 및 아크릴로일으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고,Wherein the substituted pyrazolyl may be substituted with one or more substituents selected from the group consisting of methyl, hydroxyethyl, and unsubstituted or substituted piperidinyl, wherein the substituted piperidinyl is substituted with at least one substituent selected from the group consisting of Which may be substituted with one or more substituents selected from the group consisting of methyl, hydroxyethyl, acetyl, benzyl, benzoyl, and acryloyl,
상기 치환된 페닐은 메톡시; 또는 비치환 또는 치환된 피페라지닐, 모폴리닐, 피페라지닐메틸 또는 모폴리닐메틸;로 하나 이상 치환될 수 있고, 상기 치환된 피페라지닐, 모폴리닐, 피페라지닐메틸 또는 모폴리닐메틸은 메틸 또는 아세틸로 하나 이상 치환될 수 있고;Wherein said substituted phenyl is methoxy; Or unsubstituted or substituted piperazinyl, morpholinyl, piperazinylmethyl or morpholinylmethyl; and the substituted piperazinyl, morpholinyl, piperazinylmethyl or morpholyl N-methyl may be substituted one or more times by methyl or acetyl;
R1는 수소 또는 -NH2이고; 및R 1 is hydrogen or -NH 2 ; And
R2 및 R3는 각각 독립적으로 수소, 메틸, 에틸, 이소프로필, 하이드록시에틸, 사이클로프로필, 사이클로펜틸, 사이클로헥실, 페닐 또는 벤질이거나, 이들이 결합한 N 원자와 함께 비치환 또는 치환된 피페리디닐을 형성할 수 있고, 여기서, 상기 치환된 피페리디닐은 -NH2 또는 아세틸, 에틸카보닐 및 아크릴로일로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환된 아민으로 치환될 수 있다.R 2 and R 3 are each independently hydrogen, methyl, ethyl, isopropyl, hydroxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl or benzyl or, together with the N atom to which they are attached, an unsubstituted or substituted piperidinyl , Wherein said substituted piperidinyl may be substituted with -NH 2 or an amine substituted by one or more substituents with one or more substituents selected from the group consisting of acetyl, ethylcarbonyl and acryloyl.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 바람직한 예로는 하기의 화합물들을 들 수 있다: Preferable examples of the compound represented by the formula (1) according to the present invention include the following compounds:
(1) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 비스트리플루오로아세테이트 염;(1) 3- (2-Amino-5- (1- (piperidin-4-yl) -1H-pyrazol- , 4] triazolo [4,3-b] pyridazine-6-amine bistrifluoroacetate salt;
(2) 1-(4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄온;(2) Synthesis of 1- (4- (4- (6-amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Pyridin-3-yl) -lH-pyrazol-l-yl) piperidin-l-yl) ethanone;
(3) (4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)(페닐)메탄온;(3) Synthesis of (4- (4- (6-amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- 3-yl) -lH-pyrazol-l-yl) piperidin-l-yl) (phenyl) methanone;
(4) 3-(2-아미노-5-(1-(1-벤질피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;(4) Synthesis of 3- (2-amino-5- (1- (1-benzylpiperidin-4-yl) -1H-pyrazol- 1,2,4] triazolo [4,3-b] pyridazin-6-amine;
(5) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 비스트리플루오로아세테이트 염;(5) 3- (2-Amino-5- (1- (piperidin-4-yl) -lH- pyrazol- 4] triazolo [4,3-b] pyridazin-6-amine bistrifluoroacetate salt;
(6) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(6) Synthesis of 3- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin- , 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(7) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(7) Synthesis of 3- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin- , 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(8) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로헥실-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(8) 3- (2-Amino-5- (1- (piperidin-4-yl) -lH- pyrazol-4- yl) pyridin- , 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(9) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-에틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(9) 3- (2-Amino-5- (1- (piperidin-4-yl) -1H-pyrazol- 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(10) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-벤질-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(10) 3- (2-Amino-5- (1- (piperidin-4-yl) -1H-pyrazol- 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(11) 2-((3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)아미노)에탄올 트리플루오로아세테이트 염;(11) 2- ((3- (2-Amino-5- (1- (piperidin- 4] triazolo [4,3-b] pyridazin-6-yl) amino) ethanol trifluoroacetate salt;
(12) N-이소프로필-3-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(12) Synthesis of N-isopropyl-3- (5- (1-methyl-1H-pyrazol-4-yl) pyridin- Pyridazin-6-amine trifluoroacetate salt;
(13) 2-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)에탄올 트리플루오로아세테이트 염;(13) Synthesis of 2- (4- (6-amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) ethanol trifluoroacetate salt;
(14) 1-(4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온 트리플루오로아세테이트 염;(14) 1- (4- (4- (6-Amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop-2-en-1-one trifluoroacetate salt;
(15) 3-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)-N5-(4-모폴리노페닐)피리딘-2,5-디아민 트리플루오로아세테이트 염;(15) Synthesis of 3- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin-3-yl) -N5- (4 -morpholinophenyl) 2,5-diamine trifluoroacetate salt;
(16) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-페닐-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(16) 3- (2-Amino-5- (1- (piperidin-4-yl) -1H-pyrazol- 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(17) 3-(6-(3-아미노피페리딘-1-일)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민;(17) Synthesis of 3- (6- (3-aminopiperidin-1-yl) - [1,2,4] triazolo [4,3- b] pyridazin- Methyl-lH-pyrazol-4-yl) pyridin-2-amine;
(18) N-((R)-1-(3-(2-아미노-5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)아크릴아마이드;(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) - [ Triazolo [4,3-b] pyridazin-6-yl) piperidin-3-yl) acrylamide;
(19) N-(1-(3-(2-아미노-5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)아세트아마이드;(19) Synthesis of N- (1- (3- (2-Amino-5- (1 -methyl-1 H- pyrazol-4-yl) pyridin- , 3-b] pyridazin-6-yl) piperidin-3-yl) acetamide;
(20) N-(1-(3-(2-아미노-5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)프로피온아마이드;(20) Synthesis of N- (1- (3- (2-Amino-5- (1 -methyl-1H-pyrazol-4-yl) pyridin- , 3-b] pyridazin-6-yl) piperidin-3-yl) propionamide;
(21) 1-(4-(4-((6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)아미노)-3-메톡시페닐)피페라진-1-일)에탄온 트리플루오로아세테이트 염;(21) 1- (4- (4 - ((6-Amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- ) Pyridin-3-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone trifluoroacetate salt;
(22) 2-(4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄올;(22) 2- (4- (4- (6-Amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Pyridin-3-yl) -lH-pyrazol-l-yl) piperidin-l-yl) ethanol;
(23) 3-(2-아미노-5-(4-((4-메틸피페라진-1-일)메틸)페닐)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;(23) 3- (2-Amino-5- (4 - ((4-methylpiperazin-1-yl) methyl) phenyl) pyridin- Triazolo [4,3-b] pyridazin-6-amine;
(24) 3-(2-아미노-5-(4-(모폴리노메틸)페닐)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;(24) Synthesis of 3- (2-amino-5- (4- (morpholinomethyl) phenyl) pyridin- ] Pyridazin-6-amine;
(25) 3-(2-아미노-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;(25) 3- (2-Amino-5- (1- (1- methylpiperidin-4-yl) 1,2,4] triazolo [4,3-b] pyridazin-6-amine;
(26) 3-(2-아미노-5-(4-((4-메틸피페라진-1-일)메틸)페닐)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(26) 3- (2-Amino-5- (4 - ((4-methylpiperazin-1-yl) methyl) phenyl) pyridin- Triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(27) 3-(2-아미노-5-(4-(모폴리노메틸)페닐)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(27) Synthesis of 3- (2-amino-5- (4- (morpholinomethyl) phenyl) pyridin- ] Pyridazin-6-amine trifluoroacetate salt;
(28) 1-(4-(4-(6-아미노-5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온;(28) 1- (4- (4- (6-Amino-5- (6- (cyclopentylamino) - [1,2,4] triazolo [ Pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop-2-en-1-one;
(29) 3-(2-아미노-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;(29) 3- (2-Amino-5- (1- (1- methylpiperidin-4-yl) 1,2,4] triazolo [4,3-b] pyridazin-6-amine;
(30) N-사이클로펜틸-3-(5-(1-(피페리딘 -4-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리프루오르아세테이트 염;(30) N-Cyclopentyl-3- (5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin- ≪ / RTI > zolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(31) N-사이클로펜틸-3-(5-(1-(피페리딘-3-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;(31) Synthesis of N-cyclopentyl-3- (5- (1- (piperidin-3-yl) -1H-pyrazol-4-yl) pyridin- ≪ / RTI > zolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(32) 1-(4-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온;(32) 1- (4- (4- (5- (6- (Cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop-2-en-1-one;
(33) 1-(3-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온;(33) 1- (3- (4- (5- (6- (Cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop-2-en-1-one;
(34) 2-(4-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄올.(34) 2- (4- (4- (5- (6- (Cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) piperidin-1-yl) ethanol.
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, 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 the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, And organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like are obtained from non-toxic organic acids such as dicarboxylic acids, Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene Sulfonates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, and the like, as well as sulfonates such as benzyl sulfonate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -Sulfonate, naphthalene-2-sulfonate, mandelate, 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 결정화시켜셔 제조할 수 있다. The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying. Alternatively, the solvent and excess acid may be distilled off under reduced pressure, followed by drying and crystallization 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, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as 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 encompasses the compounds represented by the formula (1) and pharmaceutically acceptable salts thereof as well as solvates, optical isomers and hydrates thereof which can be prepared therefrom.
또한, 본 발명은 하기 반응식 1에 나타낸 바와 같이,Also, as shown in the following Reaction Scheme 1,
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1); 및Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And
상기 단계 1에서 얻은 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 얻는 단계(단계 2)를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다.There is provided a process for preparing a compound represented by the above formula (1), comprising the step of reacting a compound represented by the formula (4) and a compound represented by the formula (5) obtained in the above step 1 to obtain a compound represented by the formula .
[반응식 1][Reaction Scheme 1]
상기 반응식 1에서,In the above Reaction Scheme 1,
R1, R2, R3, A 및 는 상기 화학식 1에서 정의한 바와 같고;R 1 , R 2 , R 3 , A and Is as defined in Formula 1;
X1 및 X2는 각각 독립적으로 동일 또는 상이한 할로겐이고; 및X 1 and X 2 are each independently the same or different halogen; And
L1은 또는 다.L 1 is or All.
이하, 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 대하여 상세히 설명한다.Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 1은 화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계이며, 구체적으로, 화학식 2로 표시되는 화합물의 할로겐과 화학식 3으로 표시되는 2차 아민이 아미네이션 반응하여 화학식 4로 표시되는 화합물을 얻는 단계이다.In the method for preparing the compound represented by the formula 1 according to the present invention, the step 1 is a step of reacting the compound represented by the formula 2 with the compound represented by the formula 3 to prepare the compound represented by the formula 4, , The halogen of the compound represented by the formula (2) and the secondary amine represented by the formula (3) are subjected to an amination reaction to obtain a compound represented by the formula (4).
상기 반응에서 사용가능한 용매는 테트라하이드로퓨란, 다이옥산, 디클로로메탄, 1,2-디메톡시에탄 등과 같은 에테르계 용매; 메탄올, 에탄올, 프로판올, 부탄올 등과 같은 저급알코올; 디메틸포름아미드(DMF); 디메틸설폭사이드(DMSO); 아세토나이트릴, 물 등을 단독 또는 혼합하여 사용할 수 있다.Solvents usable in the above reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane and the like; Lower alcohols such as methanol, ethanol, propanol, butanol and the like; Dimethylformamide (DMF); Dimethyl sulfoxide (DMSO); Acetonitrile, water, etc., may be used alone or in combination.
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 제조방법에 있어서, 상기 단계 2는 상기 단계 1에서 얻은 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 얻는 단계이며, 구체적으로, 화학식 4로 표시되는 할라이드 화합물과 화학식 5로 표시되는 보론산 화합물이 금속 촉매 및 염기 조건하에 반응시켜 화학식 1로 표시되는 화합물을 얻는 단계이다.In the method for preparing the compound represented by the formula 1 according to the present invention, the step 2 is a step of reacting the compound represented by the formula 4 and the compound represented by the formula 5 obtained in the step 1 to obtain the compound represented by the formula 1 Specifically, the halide compound represented by the formula (4) and the boronic acid compound represented by the formula (5) are reacted under a metal catalyst and a base to obtain a compound represented by the formula (1).
이때, 상기 보론산 화합물은 상업적으로 시판되는 화합물들을 사용하거나, 대응되는 할라이드 화합물로부터 공지의 방법으로 제조하여 사용할 수 있다.At this time, the boronic acid compound may be commercially available compounds or may be prepared from the corresponding halide compound by a known method.
또한, 상기 금속 촉매로는 팔라듐 촉매를 사용할 수 있으며, 사용가능한 팔라듐 촉매는 Pd/C, Pd(PPh3)4, PdCl2, Pd(OCOCH3)2, Pd(pph3)2Cl2 등을 사용할 수 있다. 바람직하게는 Pd(pph3)2Cl2을 사용할 수 있으나, 이에 한정하지는 않는다.Further, as the metal catalyst may be a palladium catalyst, usable palladium catalyst is a Pd / C, Pd (PPh 3 ) 4, PdCl 2, Pd (OCOCH 3) 2, Pd (pph 3) 2 Cl 2 , etc. Can be used. Preferably, Pd (pph 3 ) 2 Cl 2 can be used, but is not limited thereto.
나아가, 상기 염기로는 피리딘, 트리에틸아민, N,N-디이소프로필에틸아민, 1,8-디아자비사이클로[5.4.0]-7-운데센(DBU)등과 같은 유기염기 또는 수산화나트륨, 탄산나트륨, 탄산칼륨, 탄산세슘, 수산화바륨 등과 같은 무기염기를 단독 또는 혼합항, 당량 또는 과량으로 사용할 수 있다.Further, the base may be an organic base such as pyridine, triethylamine, N, N-diisopropylethylamine, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU) Inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, barium hydroxide and the like can be used singly or in admixture, in equivalent or in excess.
또한, 상기 반응에서 사용 가능한 용매로는 테트라하이드로퓨란, 다이옥산, 디클로로메탄, 1,2-디메톡시에탄 등의 에테르계 용매; 벤젠, 톨루엔, 자일렌 등의 아로마틱 하이드로카본용매; 메탄올, 에탄올 등의 알코올계 용매; 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴, 물 등이 있으며, 이를 단독 또는 혼합하여 사용할 수 있다.Examples of the solvent that can be used in the above reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane; Aromatic hydrocarbon solvents such as benzene, toluene and xylene; Alcohol solvents such as methanol and ethanol; Dimethylformamide (DMF), dimethylsulfoxide, acetonitrile, water and the like, which may be used alone or in combination.
또한, 본 발명에 따른 화학식 1로 표시되는 화합물은 치환기 R1이 -NH2일 경우, 하기 반응식 2에 나타난 바와 같이, In addition, when the substituent R 1 is -NH 2 , the compound represented by the formula (1)
화학식 6으로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계(단계 1);Reacting a compound represented by the formula (6) with a compound represented by the formula (3) to prepare a compound represented by the formula (7) (step 1);
상기 단계 1에서 얻은 화학식 7로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 8로 표시되는 화합물을 얻는 단계(단계 2); 및Reacting the compound represented by the formula (7) and the compound represented by the formula (5) obtained in the step 1 to obtain a compound represented by the formula (8) (step 2); And
상기 단계 2에서 얻은 화학식 8로 표시되는 화합물을 반응시켜 화학식 1a로 표시되는 화합물을 얻는 단계(단계 3)를 포함하는 제조방법으로 제조할 수도 있다.And a step of reacting the compound represented by the formula (8) obtained in the above step 2 to obtain the compound represented by the formula (1a) (step 3).
[반응식 2][Reaction Scheme 2]
상기 반응식 2에서,In the above Reaction Scheme 2,
R2, R3, A 및 는 상기 화학식 1에서 정의한 바와 같되, R1은 -NH2이고;R 2 , R 3 , A and Is as defined in Formula 1, R 1 is -NH 2 ;
X1 및 X2는 각각 독립적으로 동일 또는 상이한 할로겐이고;X 1 and X 2 are each independently the same or different halogen;
L1은 또는 이고; L 1 is or ego;
PG1은 t-부틸옥시카보닐(Boc), 카보벤질옥시(Cbz), 9-플루오레닐메틸옥시카보닐(Fmoc), 아세틸(Ac), 벤조일(Bz), 벤질(Bn), p-메톡시벤질(PMB), 3,4-다이메톡시벤질(DMPM), p-메톡시페닐(PMP), 토실(Ts), 2,2,2-트리클로로에톡시카보닐(Troc), 2-트리메틸실릴에톡시카보닐(Teoc) 및 아릴옥시카보닐(Alloc)로 이루어지는 군으로부터 선택되는 1종의 아민보호기이고; 및PG 1 is selected from the group consisting of t-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), acetyl (Ac), benzoyl (Bz) Methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), tosyl (Ts), 2,2,2- trichloroethoxycarbonyl - an amine protecting group selected from the group consisting of trimethylsilylethoxycarbonyl (Teoc) and aryloxycarbonyl (Alloc); And
상기 화학식 1a로 표시되는 화합물은 R1이 -NH2인 화학식 1로 표시되는 화합물의 유도체이다.The compound represented by the formula (1a) is a derivative of the compound represented by the formula (1) wherein R 1 is -NH 2 .
이하, 본 발명에 따른 상기 반응식 2의 제조방법에 대하여 상세히 설명한다.Hereinafter, the production method of Reaction Scheme 2 according to the present invention will be described in detail.
본 발명에 따른 상기 반응식 2의 제조방법에 있어서, 상기 단계 1은 화학식 6으로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 7로 표시되는 화합물을 제조하는 단계이며, 구체적으로, 화학식 6으로 표시되는 화합물의 할로겐과 화학식 3으로 표시되는 2차 아민이 아미네이션 반응하여 화학식 4로 표시되는 화합물을 얻는 단계이다.In the preparation of the reaction scheme 2 according to the present invention, the step 1 is a step of reacting a compound represented by the formula (6) with a compound represented by the formula (3) to prepare a compound represented by the formula (7) Is subjected to an amination reaction with a halogen of the compound represented by the general formula (3) and a secondary amine represented by the general formula (3) to obtain a compound represented by the general formula (4).
본 단계의 상세한 설명은 상기 화학식 1로 표시되는 화합물의 제조방법의 단계 1과 동일하다.The detailed description of this step is the same as the step 1 of the method for producing the compound represented by the above formula (1).
본 발명에 따른 상기 반응식 2의 제조방법에 있어서, 상기 단계 2는 상기 단계 1에서 얻은 화학식 7로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 8로 표시되는 화합물을 얻는 단계이며, 구체적으로, 화학식 7로 표시되는 할라이드 화합물과 화학식 5로 표시되는 보론산 화합물이 금속 촉매 및 염기 조건하에 반응시켜 화학식 8로 표시되는 화합물을 얻는 단계이다.In the method for preparing the reaction scheme 2 according to the present invention, the step 2 is a step of reacting the compound represented by the formula 7 and the compound represented by the formula 5 obtained in the step 1 to obtain the compound represented by the formula 8, Is a step of reacting a halide compound represented by the formula (7) and a boronic acid compound represented by the formula (5) under a metal catalyst and a base to obtain a compound represented by the formula (8).
본 단계의 상세한 설명은 상기 화학식 1로 표시되는 화합물의 제조방법의 단계 2와 동일하다.The detailed description of this step is the same as the step 2 of the process for producing the compound represented by the above formula (1).
본 발명에 따른 상기 반응식 2의 제조방법에 있어서, 상기 단계 3은 상기 단계 2에서 얻은 화학식 8로 표시되는 화합물을 반응시켜 화학식 1a로 표시되는 화합물을 얻는 단계이며, 구체적으로, 화학식 8로 표시되는 화합물을 반응ㅅ이켜 아민 보호기를 탈보호반응을 통해 제거하여 화학식 1a로 표시되는 화합물을 얻는 단계이다.In the preparation of the Reaction Scheme 2 according to the present invention, the above Step 3 is a step of reacting the compound represented by the general formula (8) obtained in the above Step 2 to obtain a compound represented by the general formula (1a) The compound is reacted to remove an amine protecting group through a deprotection reaction to obtain a compound represented by the formula (1a).
상기 탈보호 반응의 반응조건은 아민 보호기의 종류에 따라 상이하며, 통상적인 탈보호 반응 조건을 사용하여 수행할 수 있다.The reaction conditions for the deprotection reaction depend on the type of the amine protecting group, and can be performed using conventional deprotection reaction conditions.
본 발명에서는 산 조건을 사용하였으며, 상기 산으로는 염산, 황산, 메탄설폰산, 트리플루오로아세트산 등을 사용할 수 있다.In the present invention, an acid condition is used. As the acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and the like can be used.
또한, 상기 반응에서 사용 가능한 용매로는 테트라하이드로퓨란, 다이옥산, 디클로로메탄, 1,2-다이메톡시에탄 등의 에테르계 용매; 벤젠, 톨루엔, 자일렌 등의 아로마틱 하이드로카본용매; 메탄올, 에탄올 등의 알코올계 용매; 디메틸포름아미드(DMF), 디메틸설폭사이드, 아세토나이트릴, 물 등이 있으며, 이를 단독 또는 혼합하여 사용할 수 있다.Examples of the solvent usable in the reaction include ether solvents such as tetrahydrofuran, dioxane, dichloromethane and 1,2-dimethoxyethane; Aromatic hydrocarbon solvents such as benzene, toluene and xylene; Alcohol solvents such as methanol and ethanol; Dimethylformamide (DMF), dimethylsulfoxide, acetonitrile, water and the like, which may be used alone or in combination.
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 브루톤 티로신 키나제 활성과 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.Further, the present invention provides a pharmaceutical composition for preventing or treating Bruton tyrosine kinase activity and related diseases containing the compound represented by the above-mentioned formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
여기서, 상기 브루톤 티로신 키나제 활성과 관련 질환은 암, 자가면역질환 등을 포함할 수 있다.Herein, the Bruton tyrosine kinase activity-related diseases may include cancer, autoimmune diseases and the like.
이때, 상기 암은 혈액암, 난소암, 자궁경부암, 유방암, 대장암, 간암, 위암, 췌장암, 결장암, 복막 전이암, 피부암, 방광암, 전립선암, 갑상선암, 폐암, 골육종, 섬유성 종양 및 뇌종양으로 이루어지는 군으로부터 선택되는 어느 하나이며, 자가면역 질환은 류머티스성 관절염, 전신 홍반성 루푸스, 다발성 경화증, 제1형 당뇨병, 갑상선 기능 항진증, 근무력증, 크론병, 강직성 척추염, 건선, 자가면역성 악성빈혈 및 쇼그렌 증후군으로 이루어지는 군으로부터 선택되는 어느 하나이다.The cancer may be selected from the group consisting of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, Wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune malignant anemia, Syndrome, < / RTI >
본 발명에 따른 트리아졸로 피리다진 유도체의 브루톤 티로신 키나제 활성 억제 능력을 평가한 결과, 본 발명에 따른 모든 실시예 화합물이 마이크로몰 대의 농도에서 브루톤 티로신 키나제의 활성을 억제하고, 실시예 1-3, 5-14, 16, 22-30 화합물은 0.5 μM 이하의 낮은 IC50 값을 나타내어, 우수한 브루톤 티로신 키나제 활성 억제능을 나타냄을 알 수 있으며, 특히, 실시예 1, 2, 6, 7, 14 및 22 화합물은 0.1 μM, 즉, 100 nM 이하의 현저하게 낮은 농도에서도 브루톤 티로신 키나제 활성을 억제하는 것을 확인하였다(실험예 1 및 표 2 참조).As a result of evaluating the ability of the triazolo pyridazine derivatives according to the present invention to inhibit the bruton tyrosine kinase activity, all the compounds according to the present invention inhibited the activity of the bruton tyrosine kinase at the concentration of the micromolar band, 3, 5-14, 16, and 22-30 compounds exhibited low IC 50 values of 0.5 μM or less, indicating excellent inhibition of Bruton's tyrosine kinase activity. In particular, in Examples 1, 2, 6, 7, 14 and 22 compounds inhibited the bruton tyrosine kinase activity even at a significantly low concentration of 0.1 [mu] M, i.e., 100 nM or less (see Experimental Example 1 and Table 2).
따라서, 본 발명에 따른 트리아졸로 피리다진 유도체는 브루톤 티로신 키나제의 활성을 억제하는 능력이 우수하므로, 브루톤 티로신 키나제 활성과 관련된 질환, 특히 암 또는 자가면역질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.Therefore, the triazolo pyridazine derivative according to the present invention is excellent in the ability to inhibit the activity of the bruton tyrosine kinase, and thus can be usefully used for the prevention or treatment of diseases related to the bruton tyrosine kinase activity, particularly cancer or autoimmune diseases have.
본 발명에 따른 약학적 조성물에 있어서, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충전제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 제조될 수 있다.In the pharmaceutical composition according to the present invention, the compound represented by the formula (1), its optical isomer or pharmaceutically acceptable salt thereof may be administered in various formulations for oral administration and parenteral administration at the time of clinical administration. May be prepared by using diluents or excipients such as fillers, extenders, binders, humectants, disintegrants, surfactants, etc. which are usually used.
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.Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.
본 발명에 따른 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 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. The pharmaceutical composition comprising the compound of Formula 1, its optical isomer or its pharmaceutically acceptable salt as an active ingredient according to the present invention can be administered parenterally, and parenteral administration can be carried out by subcutaneous injection, intravenous injection, muscle Intravenous injection or intra-thoracic 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.In this case, in order to formulate the composition for parenteral administration, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, . The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.
또한, 본 발명의 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 바람직하게는 0.01 내지 200 mg/kg/일의 양으로 의사 또는 약사의 판단에 따라 일정시간 간격을 1일 수회, 바람직하게는 1일 1회 내지 3회로 분할하여 경구 또는 비경구적 경로를 통해 투여할 수 있다.The dose of the pharmaceutical composition containing the compound represented by the formula (1) of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient to the human body depends on the age, body weight, sex, May be varied depending on the health condition and the degree of disease, preferably 0.01 to 200 mg / kg / day, depending on the judgment of the physician or pharmacist, at intervals of several times a day, preferably once to three times a day May be administered by oral or parenteral route.
나아가, 본 발명의 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 브루톤티로신 키나제 활성 관련 질환의 예방 또는 치료를 위하여 단독으로, 또는 수술, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.Furthermore, the pharmaceutical composition comprising the compound represented by the formula (1) of the present invention, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient may be used alone or in combination with a pharmaceutically acceptable salt thereof for the prophylaxis or treatment of a glutathione kinase activity- Surgery, hormonal therapy, chemotherapy, and methods using biological response modifiers.
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 브루톤 티로신 키나제 활성과 관련 질환의 예방 또는 개선용 건강식품 조성물을 제공한다.In addition, the present invention provides a health food composition for preventing or ameliorating bruton tyrosine kinase activity and related diseases, which comprises the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
여기서, 상기 브루톤 티로신 키나제 활성과 관련 질환은 암 또는 자가면역질환 등을 포함할 수 있다.Herein, the disease associated with the Bruton tyrosine kinase activity may include cancer or autoimmune diseases and the like.
이때, 상기 암은 혈액암, 난소암, 자궁경부암, 유방암, 대장암, 간암, 위암, 췌장암, 결장암, 복막 전이암, 피부암, 방광암, 전립선암, 갑상선암, 폐암, 골육종, 섬유성 종양 및 뇌종양으로 이루어지는 군으로부터 선택되는 어느 하나이며, 자가면역 질환은 류머티스성 관절염, 전신 홍반성 루푸스, 다발성 경화증, 제1형 당뇨병, 갑상선 기능 항진증, 근무력증, 크론병, 강직성 척추염, 건선, 자가면역성 악성빈혈 및 쇼그렌 증후군으로 이루어지는 군으로부터 선택되는 어느 하나이다.The cancer may be selected from the group consisting of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, stomach cancer, pancreatic cancer, colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, Wherein the autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune malignant anemia, Syndrome, < / RTI >
상기 식품의 종류에는 특별한 제한은 없다. 상기 물질을 첨가할 수 있는 식품의 예로는 드링크제, 육류, 소시지, 빵, 비스킷, 떡, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 알코올 음료 및 비타민 복합제, 유제품 및 유가공 제품 등이 있으며, 통상적인 의미에서의 건강기능식품을 모두 포함한다.There is no particular limitation on the kind of the food. Examples of the foods to which the above substances can be added include dairy products including dairy products, meat, sausage, bread, biscuits, rice cakes, chocolate, candies, snacks, confectionery, pizza, ramen and other noodles, gums, ice cream, Beverages, alcoholic beverages and vitamin complexes, dairy products, and dairy products, all of which include health functional foods in a conventional sense.
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 the formula (1) according to the present invention can be added directly to food or used together with other food or food ingredients, and can be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (for prevention or improvement). Generally, the amount of the compound in the health food may be 0.1 to 90 parts by weight of the total food. However, in the case of long-term intake intended for health and hygiene purposes or for the purpose of controlling health, 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 exceeding 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, 사이클로덱스트린 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 제조 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 has no particular limitation on other components other than the above-mentioned compounds as essential components in the indicated ratios, and may contain various flavoring agents or natural carbohydrates as additional components such as ordinary beverages have. Examples of the above-mentioned natural carbohydrates include monosaccharides such as glucose, fructose and the like; Disaccharides such as maltose, sucrose and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavors (tau martin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.) and prepared flavors (saccharin, aspartame, etc.) can be advantageously used as flavors other than those described above The ratio of the natural carbohydrate 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 화합은 여러 가지 영양제, 비타민, 광물(전해질), 제조 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(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. 그 밖에 본 발명의 화학식 1로 표시되는 화합물은 천연 과일 쥬스 및 과일 쥬스 음료 및 야채 음료의 제조를 위한 과육을 함유할 수 있다. In addition, in addition to the above, the compound represented by formula (1) according to the present invention can be used as a flavoring agent such as various nutrients, vitamins, minerals (electrolytes), manufacturing flavorings and natural flavors, coloring agents and intermediates such as cheese and chocolate, Acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated beverages and the like. In addition, the compound represented by formula (1) of the present invention may contain natural fruit juice and pulp for the production of fruit juice drinks and vegetable drinks.
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다.However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the present invention is not limited to the following Examples and Experimental Examples.
<< 실시예Example 1> 3-(2-아미노-5-(1-(피페리딘-4-일)-1H- 1> 3- (2-Amino-5- (1- (piperidin-4-yl) 피라졸Pyrazole -4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Yl) pyridin-3-yl) -N-isopropyl- [1,2,4] triazolo [4,3- b] pyridazin- 비스트리플루오로아세Bistrifluoroacetic acid 테이트 염의 제조Preparation of Tate Salt
단계 1: 1-(6-클로로피리다진-3-일)히드라진의 제조Step 1: Preparation of 1- (6-chloropyridazin-3-yl) hydrazine
3,6-디클로로피리다진 (20 g, 134 mmol)을 에탄올 (175 mL)에 녹이고, 히드라진 수화물 (23 mL, 469 mmol)과 NH4OH (30 mL )를 가하여 80°C에서 30분동안 환류한 후, 반응 용액을 15시간 냉장 보관시켰다. 생성된 고체를 에테르로 결정화 및 여과하여 1-(6-클로로피리다진-3-일)히드라진(14 g, 100%)을 얻었다.Dissolve 3,6-dichloropyridazine (20 g, 134 mmol) in ethanol (175 mL), add hydrazine hydrate (23 mL, 469 mmol) and NH 4 OH (30 mL) and reflux at 80 ° C for 30 minutes After that, the reaction solution was stored in a refrigerator for 15 hours. The resulting solid was crystallized with ether and filtered to give 1- (6-chloropyridazin-3-yl) hydrazine (14 g, 100%).
1H-NMR (300 MHz, DMSO-d6) δ 8.19 (brs, 1H), 7.42 (d, J = 9.3Hz, 1H), 7.09 (d, J = 9.3 Hz, 1H), 4.34 (brs, 2H). 1 H-NMR (300 MHz, DMSO-d 6) δ 8.19 (brs, 1H), 7.42 (d, J = 9.3Hz, 1H), 7.09 (d, J = 9.3 Hz, 1H), 4.34 (brs, 2H ).
단계 2: 5-브로로-2-클로로-N'-(4-클로로피리다진-3-일)니코티노히드라지드의 제조Step 2: Preparation of 5-bromo-2-chloro-N '- (4-chloropyridazin-3-yl) nicotinohydrazide
1-(6-클로로피리다진-3-일)히드라진 (5.3 g, 21 mmol)과 5-브로모-2- 클로로피리딘 -3-카르보닐클로라이드 (3 g, 21 mmol)를 CH2Cl2 (50 mL) 에 녹이고, 상온에서 5분간 교반한 후, NEt3(3.1 mL, 22.6 mmol)을 가한 다음, 상온에서 13시간 동안 교반한다. 생성된 고체를 여과하여 제거하고, 얻어진 고체를 에틸아세테이트와 물에 녹여 생성된 고체를 여과하여 얻는다. 여액을 Na2SO4로 건조하고, 에틸아세테이트로 결정화하여 5-브로로-2-클로로-N'-(4-클로로피리다진-3-일)니코티노히드라지드(2.9 g, 39%)를 얻었다. (5.3 g, 21 mmol) and 5-bromo-2-chloropyridine-3-carbonyl chloride (3 g, 21 mmol) were dissolved in CH 2 Cl 2 50 mL). After stirring at room temperature for 5 minutes, NEt 3 (3.1 mL, 22.6 mmol) was added, and the mixture was stirred at room temperature for 13 hours. The resulting solid is removed by filtration, and the resulting solid is dissolved in ethyl acetate and water, and the resulting solid is filtered off. A (4-chloro-3-yl) nicotinoyl hydrazide (2.9 g, 39%) - Dry the filtrate with Na 2 SO 4, and crystallized with ethyl acetate-2-chloro -N '5-bromo .
1H-NMR (300 MHz, DMSO-d6) δ 10.78 (brs, 1H), 9.52 (s, 1H), 8.74 (s, 1H), 8.35 (s, 1H), 7.60 (d, J = 9.3Hz, 1H), 7.23(d, J = 9.3Hz, 1H); LCMS calculated for C12H8BrCl2N3O = 361.02, found: 363.94. 1 H-NMR (300 MHz, DMSO-d 6) δ 10.78 (brs, 1H), 9.52 (s, 1H), 8.74 (s, 1H), 8.35 (s, 1H), 7.60 (d, J = 9.3Hz , ≪ / RTI > 1H), 7.23 (d, J = 9.3 Hz, 1H); LCMS calculated for C 12 H 8 BrCl 2 N 3O = 361.02, found: 363.94.
단계 3: 3-(5-브로모-2-클로로피리딘-3-일)-6-클로로-[1,2,4]트리아졸로[4,3-b]피리다진의 제조Step 3: Preparation of 3- (5-bromo-2-chloropyridin-3- yl) -6-chloro- [1,2,4] triazolo [4,3-b] pyridazine
톨루엔 (70mL)에 5-브로모-2-클로로-N'-(4-클로로페닐)피리딘-3-카보하이드라지드 (2.91g, 8.01 mmol)와 p-톨루엔설포닉 애시드(1.9 g, 10 mmol)을 녹이고, 150°C에서 13시간동안 가열한다. 반응이 종결되면 톨루엔을 감압증류하여 제거하고, 농축액을 에틸아세테이트와 NaHCO3수용액으로 추출하였다. 유기층을 Na2SO4로 건조하고, 농축한 다음, 5% MeOH/MC로 컬럼크로마토그래피하여 3-(5-브로모-2-클로로피리딘-3-일)-6-클로로-[1,2,4]트리아졸로[4,3-b]피리다진(790 mg, 28%)을 얻엇다.To a solution of 5-bromo-2-chloro-N '- (4-chlorophenyl) pyridine-3-carbohydrazide (2.91 g, 8.01 mmol) and p- toluenesulfonic acid mmol) is dissolved and heated at 150 ° C for 13 hours. When the reaction was completed, the toluene was distilled off under reduced pressure, and the concentrate was extracted with ethyl acetate and an aqueous NaHCO 3 solution. The organic layer was dried over Na 2 SO 4 , concentrated and then column chromatographed with 5% MeOH / MC to give 3- (5-bromo-2-chloropyridin-3-yl) , 4] triazolo [4,3-b] pyridazine (790 mg, 28%).
1H-NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.66 (d, J = 9.6Hz, 1H), 8.56 (s, 1H), 7.6 6(d, J = 9.6Hz, 1H); LCMS calculated for C10H4BrCl2N5 = 344.98, found: 345.94. 1 H-NMR (300 MHz, DMSO-d 6) δ 8.88 (s, 1H), 8.66 (d, J = 9.6Hz, 1H), 8.56 (s, 1H), 7.6 6 (d, J = 9.6Hz, 1H); LCMS calculated for C 10 H 4 BrCl 2 N 5 = 344.98, found: 345.94.
단계 4: 3-(5- 브로모 -2- 클로로피리딘 -3- 일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민의 제조Step 4: Preparation of 3- (5-bromo-2-chloropyridin-3-yl) -N-isopropyl- [l, 2,4] triazolo [4,3-b] pyridazin-
3-(5-브로모-2-클로로피리딘-3-일)-6-클로로-[1,2,4]트리아졸로[4,3-b]피리다진(200 mg, 0.58 mmol)을 디메틸포름아미드 (10 mL)에 녹인 후, 프로판-2-아민 (0.5 mL, 8 mmol)을 가하고, 상온에서 15시간 동안 교반한다. 반응이 종결되면 에틸아세테이트/물로 반응 후 처리하여, 생성물을 유기층으로 추출하고, 유기층을 Na2SO4로 건조한 후, 농축한다. 5% MeOH/MC로 컬럼크로마토그래피하여 3-(5- 브로모 -2- 클로로피리딘 -3- 일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민(138 mg, 50%)을 얻었다.4,3-b] pyridazine (200 mg, 0.58 mmol) was dissolved in dimethylformamide (5 ml) Amide (10 mL), and then propan-2-amine (0.5 mL, 8 mmol) was added thereto, followed by stirring at room temperature for 15 hours. After the reaction is completed, the reaction is carried out with ethyl acetate / water, the product is extracted into an organic layer, and the organic layer is dried with Na 2 SO 4 and concentrated. Column chromatography with 5% MeOH / MC gave 3- (5-bromo-2-chloropyridin-3-yl) -N-isopropyl- [1,2,4] triazolo [ -6-amine (138 mg, 50%).
1H-NMR (300 MHz, CDCl3) δ 8.60 (d, J = 2.4Hz, 1H), 8.26 (d, J = 2.4Hz, 1H), 7.84 (d, J = 9.7Hz, 1H), 6.57 (d, J = 9.7Hz, 1H), 4.65 (d, J = 7.1Hz, 1H), 3.97 (m, 1H), 1.25 (d, J = 6.4Hz, 6H): LCMS calculated for C13H12BrClN6 = 367.63, found: 369.00. 1 H-NMR (300 MHz, CDCl 3) δ 8.60 (d, J = 2.4Hz, 1H), 8.26 (d, J = 2.4Hz, 1H), 7.84 (d, J = 9.7Hz, 1H), 6.57 ( d, J = 9.7Hz, 1H) , 4.65 (d, J = 7.1Hz, 1H), 3.97 (m, 1H), 1.25 (d, J = 6.4Hz, 6H): LCMS calculated for C 13 H 12 BrClN 6 = 367.63, found: 369.00.
단계 5: 3-(5-브로모-2-(2,4-디메톡시벤질아미노)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피라진-6-아민의 제조Step 5: Preparation of 3- (5-bromo-2- (2,4- dimethoxybenzylamino) pyridin-3-yl) -N-isopropyl- [1,2,4] triazolo [ ] Pyrazin-6-amine
압력반응기에 3-(5-브로모-2-클로로피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 (135 mg, 0.36 mmol)를 N-메틸-2-피롤리돈 (2 mL)에 용해시키고, (2,4-디메톡시페닐)메탄아민 (1M, 440 μL, 0.44 mmol)을 가한 다음, 100℃에서 15시간 동안 교반한다. 반응이 종결되면 에틸아세테이트/물로 반응 후 처리하여, 생성물을 유기층으로 추출하고, 유기층을 Na2SO4로 건조한 후, 농축한다. 컬럼크로마토그래피하여 3-(5-브로모-2-(2,4-디메톡시벤질아미노)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피라진-6-아민(150 mg, 82%)을 얻었다.To a pressure reactor was added 3- (5-bromo-2-chloropyridin-3-yl) -N-isopropyl- [1,2,4] triazolo [4,3- b] pyridazin- (2,4-dimethoxyphenyl) methanamine (1M, 440 [mu] L, 0.44 mmol) was added to the solution, which was then dissolved in N-methyl- Stir for 15 hours. After the reaction is completed, the reaction is carried out with ethyl acetate / water, the product is extracted into an organic layer, and the organic layer is dried with Na 2 SO 4 and concentrated. The resulting residue was purified by column chromatography to give 3- (5-bromo-2- (2,4-dimethoxybenzylamino) pyridin-3-yl) b] pyrazin-6-amine (150 mg, 82%).
1H-NMR (300 MHz, CDCl3) δ 9.31 (m, 2H), 8.21 (d, J = 2.4Hz, 1H), 7.81 (d, J = 9.8Hz, 1H), 7.27 (s, 1H), 6.52 (d, J = 9.8Hz, 1H), 6.46 (s, 1H), 6.40 (m, 1H), 4.76 (d, J = 5.6Hz, 2H), 4.54 (d, J = 6.8Hz, 1H), 4.11 (m, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 1.38 (d, J = 6.4Hz, 6H); LCMS calculated for C22H24BrN7O2 = 498.38, found : 499.99. 1 H-NMR (300 MHz, CDCl 3) δ 9.31 (m, 2H), 8.21 (d, J = 2.4Hz, 1H), 7.81 (d, J = 9.8Hz, 1H), 7.27 (s, 1H), J = 6.8 Hz, 1H), 6.54 (d, J = 9.8 Hz, 1H), 6.46 (s, 4.11 (m, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 1.38 (d, J = 6.4 Hz, 6H); LCMS calculated for C 22 H 24 BrN 7 O 2 = 498.38, found: 499.99.
단계 6: 4-(4-(6-(2,4-디메톡시벤질아미노)-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조Step 6: Preparation of 4- (4- (6- (2,4-dimethoxybenzylamino) -5- (6- (isopropylamino) - [1,2,4] triazolo [ Yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate
3-(5-브로모-2-(2,4-디메톡시벤질아미노)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 (100 mg, 0.20 mmol)과 t-부틸 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤레인-2-일)-1H-피라졸-1일)피페리딘-1-카르복실레이트 (151 mg, 0.40 mmol)을 1,4-디옥산(2 mL)에 가하고, 10분 동안 상온에서 교반한다. 후에 디클로로-비스(트리페닐포스핀) 팔라듐 (II) (84 mg, 0.12 mmol)룰 넣고 30분간 상온에서 교반한 후, Na2CO3 (1 M, 1.2mL)를 가한 후, 질소 충전하고, 110℃에서 15시간 동안 교반한다. 반응이 종결되면 에틸아세테이트/물로 반응후처리 하여, 생성물을 유기층으로 추출하고, 유기층을 Na2SO4로 건조한 후, 농축한다. 컬럼크로마토그래피하여 4-(4-(6-(2,4-디메톡시벤질아미노)-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(80 mg, 60%)를 얻었다.3-yl) -N-isopropyl- [1, 2,4] triazolo [4,3- b] pyridazine (prepared by reacting 3- (5-bromo- -6- amine (100 mg, 0.20 mmol) and t-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- Pyrazol-1-yl) piperidine-1-carboxylate (151 mg, 0.40 mmol) was added to 1,4-dioxane (2 mL) and stirred at room temperature for 10 minutes. Subsequently, dichloro-bis (triphenylphosphine) palladium (II) (84 mg, 0.12 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Na 2 CO 3 (1 M, 1.2 mL) Stir at 110 < 0 > C for 15 hours. After the reaction is completed, the reaction is carried out with ethyl acetate / water, the product is extracted into an organic layer, and the organic layer is dried with Na 2 SO 4 and concentrated. The resulting residue was purified by column chromatography to give 4- (4- (6- (2,4-dimethoxybenzylamino) -5- (6- (isopropylamino) - [1,2,4] triazolo [ Pyridazin-3-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (80 mg, 60%).
1H-NMR (300 MHz, CDCl3) δ 9.25 (m, 1H), 9.21 (d, J = 2.3Hz, 1H), 8.36 (d, J = 2.3Hz, 1H), 7.78 (d, J = 9.7Hz, 1H), 7.71 (s, 1H), 7.59 (s, 1H), 7.30 (d, J = 8.2Hz, 1H), 6.52 (d, J = 9.7Hz, 1H), 6.46 (d, J = 2.3Hz, 1H), 6.40 (dd, J = 8.2Hz, 2.4Hz, 1H), 4.81 (d, J = 5.5Hz, 2H), 4.68 (d, J = 7.0Hz, 1H), 4.32 (m, 2H), 4.02 (m, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 2.90 (m, 2H), 2.17 (m, 2H) 1.93 (m, 2H), 1.48 (s, 9H), 1.34 (d, J = 6.4Hz, 6H): LCMS calculated for C35H44N10O4 = 668.79, found: 669.27. 1 H-NMR (300 MHz, CDCl 3) δ 9.25 (m, 1H), 9.21 (d, J = 2.3Hz, 1H), 8.36 (d, J = 2.3Hz, 1H), 7.78 (d, J = 9.7 (D, J = 8.2 Hz, 1H), 6.52 (d, J = 9.7 Hz, 1H), 6.46 2H), 4.68 (d, J = 7.0 Hz, 1H), 4.32 (m, 2H), 6.40 (dd, J = 8.2 Hz, , 4.02 (m, 1H), 3.87 (s, 3H), 3.76 (s, 3H), 2.90 (m, 2H), 2.17 (d, J = 6.4Hz, 6H ): LCMS calculated for C 35 H 44 N 10 O 4 = 668.79, found: 669.27.
단계 7: 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 비스트리플루오로아세테이트 염의 제조Step 7: 3- (2-Amino-5- (1- (piperidin-4-yl) -lH-pyrazol-4-yl) pyridin- , 4] triazolo [4,3-b] pyridazine-6-amine bistrifluoroacetate salt
압력반응기에 t- 부틸 4-(4-(6-(2,4-디메톡시벤질아미노)-5-(6- (이소프로필아미노)-[1,2,4]트리아졸로 [4,3-b]피리다진-3-yl)피리딘-3-일)- 1H-피라졸-1-일)피페리딘1-카르복실레이트 (80 mg, 0.12 mmol)을 트리프로로아세테이트 (2 mL)에 녹이고, 60℃에서 15시간 동안 교반한다. 반응이 종결되면 트리프루오로아세테이트를 감압증류하여 제거하고, 에테르로 결정화하여 목적화합물(65 mg, 84%)을 얻었다.A pressure reactor was charged with t-butyl 4- (4- (6- (2,4-dimethoxybenzylamino) -5- (6- (isopropylamino) - [1,2,4] triazolo [ (80 mg, 0.12 mmol) was added to triproacetate (2 mL) and the mixture was stirred at room temperature for 1 hour. And the mixture was stirred at 60 ° C for 15 hours. When the reaction was completed, trifluoroacetate was distilled off under reduced pressure, and the residue was crystallized with ether to obtain the title compound (65 mg, 84%).
1H-NMR (300 MHz, CDCl3) δ 9.86 (d, J = 2.1Hz, 1H), 8.24 (d, J = 2.1Hz, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.93 (d, J = 2.1Hz, 1H), 6.97 (d, J = 9.9Hz, 1H), 4.79 (m, 1H), 4.13 (m, 1H), 3.62 (m, 2H), 3.28 (m, 2H), 2.36 (m, 4H), 1.35 (d, J = 6.4Hz, 6H): LCMS calculated for C21H26N10 = 418.50, found: 419.16. 1 H-NMR (300 MHz, CDCl 3) δ 9.86 (d, J = 2.1Hz, 1H), 8.24 (d, J = 2.1Hz, 1H), 8.18 (s, 1H), 7.97 (s, 1H), (M, 2H), 3.86 (m, 2H), 3.28 (m, 2H, ), 2.36 (m, 4H) , 1.35 (d, J = 6.4Hz, 6H): LCMS calculated for C 21 H 26 N 10 = 418.50, found: 419.16.
<< 실시예Example 2> 1-(4-(4-(6-아미노-5-(6-( 2> 1- (4- (4- (6-Amino-5- (6- 이소프로필아미노Isopropylamino )-) - [1,2,4]트리아졸[1,2,4] triazole 로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄온의 제조Pyridin-3-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin- 1 -yl) ethanone
상기 실시예 1에서 얻은 화합물(20 mg, 0.031 mmol)과 히드록시벤조트리아졸 (4.1 mg, 0.031 mmol), 1-에틸-3-(3-디메틸아미노프로필)카보디이미드 (5.9 mg, 0.031 mmol), 트리에틸아민 (1M 310 μL, 0.31 mmol)을 디메틸포름아미드 (1mL)에 녹인 후, 상온에서 10분 교반한다. 그 뒤 아세틸클로라이드 (1 M 31 μL, 0.031mmol)을 가하고, 상온에서 15시간 동안 교반한다. 반응이 종결되면 에틸아세테이트/물로 반응후처리 하여, 생성물을 Na2SO4로 건조 농축한다. 컬럼크로마토그래피하여 목적화합물(6 mg, 25%)을 얻었다.(20 mg, 0.031 mmol), hydroxybenzotriazole (4.1 mg, 0.031 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (5.9 mg, 0.031 mmol ) And triethylamine (310 μL, 0.31 mmol) were dissolved in dimethylformamide (1 mL), and the mixture was stirred at room temperature for 10 minutes. Acetyl chloride (1 M 31 L, 0.031 mmol) was then added and stirred at ambient temperature for 15 hours. After the reaction is completed, the reaction is worked up with ethyl acetate / water and the product is dried with Na 2 SO 4 and concentrated. The desired compound (6 mg, 25%) was obtained by column chromatography.
1H-NMR (300 MHz, CDCl3) δ 9.27 (d, J = 2.3Hz, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.85(d, J = 9.7Hz, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.14 (brs, 2H), 6.55 (d, J = 9.7Hz, 1H), 4.77 (d, J = 13.7Hz, 1H), 4.62 (d, J = 7.5Hz, 1H), 4.38 (m, 1H), 4.15 (m, 2H), 3.99 (d, J = 13.7Hz, 1H), 3.27 (t, J = 12.0Hz, 1H), 3.12 (m, 1H), 2.78 (t, J = 12.0Hz, 1H), 2.15 (s, 3H), 1.32 (s, 6H). 1 H-NMR (300 MHz, CDCl 3) δ 9.27 (d, J = 2.3Hz, 1H), 8.25 (d, J = 2.3Hz, 1H), 7.85 (d, J = 9.7Hz, 1H), 7.73 ( J = 7.7 Hz, 1 H), 4.77 (d, J = 13.7 Hz, 1 H), 4.62 (d, J = 7.5, 1H), 3.12 (m, 1H), 4.38 (m, 2H), 3.99 (d, J = 13.7 Hz, 2.78 (t, J = 12.0 Hz, 1H), 2.15 (s, 3H), 1.32 (s, 6H).
<< 실시예Example 3> (4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)(페닐)메탄온의 제조 3> b) pyridin-3-yl) pyridine-3 (2S) -Yl) -lH-pyrazol-l-yl) piperidin-l-yl) (phenyl) methanone
실시예 1에서 얻은 화합물(15 mg, 0.023 mmol)과 히드록시벤조트리아졸 (3.1 mg, 0.023 mmol), 1-에틸-3-(3-디메틸아미노프로필)카르보디이미드 (4.4 mg, 0.023 mmol), 트리에틸아민 (1M 230μL, 0.23mmol)을 디메틸포름아미드 (1 mL)에 녹인 후, 상온에서 10분 교반한다. 여기에 벤조일클로라이드 (1 M 23 μL, 0.023 mmol)을 가하고, 상온에서 15시간 교반한다. 반응이 종결되면 에틸아세테이트/물로 반응 후처리하고, 생성물을 유기층을 추출한 다음, Na2SO4로 건조 농축한다. 컬럼크로마토그래피하여 목적화합물(10 mg, 65%)을 얻었다.Hydroxybenzotriazole (3.1 mg, 0.023 mmol) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (4.4 mg, 0.023 mmol) were added to a solution of the compound obtained in Example 1 (15 mg, 0.023 mmol) , And triethylamine (1M, 230 μL, 0.23 mmol) were dissolved in dimethylformamide (1 mL), and the mixture was stirred at room temperature for 10 minutes. Benzoyl chloride (1 M 23 L, 0.023 mmol) was added thereto, followed by stirring at room temperature for 15 hours. After the reaction is completed, the reaction is carried out with ethyl acetate / water, and the product is extracted with an organic layer, followed by drying with Na 2 SO 4 . The desired compound (10 mg, 65%) was obtained by column chromatography.
1H-NMR (300 MHz, CDCl3) δ 9.23 (d, J = 2.3Hz, 1H), 8.35 (d, J = 2.3Hz, 1H), 8.16 (s, 1H), 8.03 (d, J = 10.4Hz, 1H), 7.76 (s, 1H), 7.48 (m, 7H), 6.88 (d, J = 10.4Hz, 1H), 4.50 (m, 2H), 4.03 (m, 2H), 2.09 (m, 2H), 1.89 (m, 2H), 1.27 (s, 6H): LCMS calculated for C28H30N10O = 522.60, found: 523.19. 1 H-NMR (300 MHz, CDCl 3) δ 9.23 (d, J = 2.3Hz, 1H), 8.35 (d, J = 2.3Hz, 1H), 8.16 (s, 1H), 8.03 (d, J = 10.4 2H), 4.03 (m, 2H), 2.09 (m, 2H), 7.76 (d, J = ), 1.89 (m, 2H) , 1.27 (s, 6H): LCMS calculated for C 28 H 30 N 10 O = 522.60, found: 523.19.
<< 실시예Example 4> 3-(2-아미노-5-(1-(1- 4> 3- (2-Amino-5- (1- (1- 벤질피페리딘Benzylpiperidine -4-일)-1H--4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민의 제조Yl) pyridin-3-yl) -N-isopropyl- [l, 2,4] triazolo [4,3-b] pyridazin-
실시예 1에서 얻은 화합물(15 mg, 0.023 mmol)과 (브로모메틸)벤젠 (1 M 23 μL, 0.023 mmol)을 디메틸포름아미드 (1 mL)에 녹인 후, K2CO3 (16 mg, 0.15 mmol)을 가하고, 상온에서 15시간 동안 교반한다. 반응이 종결되면, 에틸아세테이트/물로 반응후처리하고, 유기층을 추출하여 Na2SO4로 건조 농축한다. 컬럼크로마토그래피하여 목적화합물(1 mg, 8%)을 얻었다.The compound (15 mg, 0.023 mmol) obtained in Example 1 and (bromomethyl) benzene (1 M 23 L, 0.023 mmol) were dissolved in dimethylformamide (1 mL), K2CO3 (16 mg, 0.15 mmol) And the mixture is stirred at room temperature for 15 hours. When the reaction is completed, the reaction is carried out with ethyl acetate / water, and the organic layer is extracted and dried with Na 2 SO 4 . The desired compound (1 mg, 8%) was obtained by column chromatography.
1H-NMR (300 MHz, CDCl3) δ 9.26 (d, J = 2.3Hz, 1H), 8.16 (d, J =2.3Hz, 1H), 7.90 (s, 1H), 7.74 (d, J = 10.2Hz, 1H), 7.66 (s, 1H), 7.24 (m, 5H), 6.76 (d, J = 10.2Hz, 1H), 4.01 (m, 1H), 3.98 (m, 1H), 3.52 (s, 2H), 2.97 (m, 2H), 2.16 (m, 2H), 2.05 (m, 2H), 1.93 (m, 2H), 1.22 (s, 6H). 1 H-NMR (300 MHz, CDCl 3) δ 9.26 (d, J = 2.3Hz, 1H), 8.16 (d, J = 2.3Hz, 1H), 7.90 (s, 1H), 7.74 (d, J = 10.2 (M, 2H), 3.52 (s, 2H), 4.76 (s, 1H) ), 2.97 (m, 2H), 2.16 (m, 2H), 2.05 (m, 2H), 1.93 (m, 2H), 1.22
<< 실시예Example 5> 3-(2-아미노-5-(1-(피페리딘-4-일)-1H- 5> 3- (2-Amino-5- (1- (piperidin-4-yl) 피라졸Pyrazole -4-일)피리딘-3-일)-N-메틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Yl) pyridin-3-yl) -N-methyl- [1,2,4] triazolo [4,3- b] pyridazin- 비스트리플루오로아세테이트Bistrifluoroacetate 염의 제조 Manufacture of salt
3-(2-((2,4-디메톡시벤질)아미노)-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 (47 mg, 0.070 mmol)에 트리프루오르아세테이트(1 mL)을 가하고, 60 ℃ 에서 18시간 동안 반응한다. 반응 종료 후 트리프루오르아세테이트을 감압농축하여 제거하고 에테르로 필터하여 목적화합물(66 mg, 97%)을 얻었다.Yl) pyridin-3-yl) -N- (2-methoxybenzyl) amino] -5- (1- (piperidin- (47 mg, 0.070 mmol) was added triflouroacetate (1 mL), and the mixture was stirred at 60 占 폚 for 18 hours And reacts. After completion of the reaction, the trifluoroacetate was removed by concentrating under reduced pressure and then filtered with ether to obtain the desired compound (66 mg, 97%).
LCMS calculated for C19H22N10= 390.44, found: 391.27. LCMS calculated for C 19 H 22 N 10 = 390.44, found: 391.27.
<< 실시예Example 6> 3-(2-아미노-5-(1-(피페리딘-4-일)-1H- 6> 3- (2-Amino-5- (1- (piperidin-4-yl) 피라졸Pyrazole -4-일)피리딘-3-일)-N-사이클로프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Yl) pyridin-3-yl) -N-cyclopropyl- [1,2,4] triazolo [4,3- b] pyridazin- 트리플루오로아세Trifluoroacetic acid 테이트 염의 제조Preparation of Tate Salt
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염을 얻었다.(Piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N -Cyclopropyl- [l, 2,4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt.
LCMS calculated for C21H24N10= 416.48, found: 417.29 LCMS calculated for C 21 H 24 N 10 = 416.48, found: 417.29
<< 실시예Example 7> 3-(2-아미노-5-(1-(피페리딘-4-일)-1H- 7> 3- (2-Amino-5- (1- (piperidin-4-yl) 피라졸Pyrazole -4-일)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Yl) pyridin-3-yl) -N-cyclopentyl- [l, 2,4] triazolo [4,3- b] pyridazin- 트리플루오로아세테Trifluoroacetate 이트 염의 제조Preparation of yeast salts
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트염을 얻었다.(Piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N -Cyclopentyl- [l, 2,4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt.
LCMS calculated for C23H28N10= 444.54, found: 445.28.LCMS calculated for C 23 H 28 N 10 = 444.54, found: 445.28.
<< 실시예Example 8> 3-(2-아미노-5-(1-(피페리딘-4-일)-1H- 8> 3- (2-Amino-5- (1- (piperidin-4-yl) 피라졸Pyrazole -4-일)피리딘-3-일)-N-사이클로헥실-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Yl) pyridin-3-yl) -N-cyclohexyl- [1,2,4] triazolo [4,3- b] pyridazin- 트리플루오로아세테Trifluoroacetate 이트 염의 제조Preparation of yeast salts
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로헥실-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염을 얻었다.(Piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N -Cyclohexyl- [1,2,4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt.
LCMS calculated for C24H30N10= 458.27, found: 459.16.LCMS calculated for C 24 H 30 N 10 = 458.27, found: 459.16.
<< 실시예Example 9> 3-(2-아미노-5-(1-(피페리딘-4-일)-1H- 9> 3- (2-Amino-5- (1- (piperidin-4-yl) 피라졸Pyrazole -4-일)피리딘-3-일)-N-에틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Yl) pyridin-3-yl) -N-ethyl- [1,2,4] triazolo [4,3- b] pyridazin- 트리플루오로아세테이트Trifluoroacetate 염의 제조 Manufacture of salt
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-에틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염을 얻었다.(Piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N -Ethyl- [1,2,4] triazolo [4,3-b] pyridazine-6-amine trifluoroacetate salt.
LCMS calculated for C20H24N10= 404.22, found: 405.18.LCMS calculated for C 20 H 24 N 10 = 404.22, found: 405.18.
<< 실시예Example 10> 3-(2-아미노-5-(1-(피페리딘-4-일)-1H- 10> 3- (2-Amino-5- (1- (piperidin-4-yl) 피라졸Pyrazole -4-일)피리딘-3-일)-N-벤질-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Yl) pyridin-3-yl) -N-benzyl- [1,2,4] triazolo [4,3- b] pyridazin- 트리플루오로아세테이트Trifluoroacetate 염의 제조 Manufacture of salt
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-벤질-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염을 얻었다.(Piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N -Benzyl- [1,2,4] triazolo [4,3-b] pyridazine-6-amine trifluoroacetate salt.
LCMS calculated for C25H26N10= 466.23, found: 467.15.LCMS calculated for C 25 H 26 N 10 = 466.23, found: 467.15.
<< 실시예Example 11> 2-((3-(2-아미노-5-(1-(피페리딘-4-일)-1H- 11> 2 - ((3- (2-Amino-5- (1- (piperidin- 피라졸Pyrazole -4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)아미노)에탄올 Yl) - [1,2,4] triazolo [4,3-b] pyridazin-6- yl) amino) ethanol 트리플루오로아세테Trifluoroacetate 이트 염의 제조Preparation of yeast salts
실시예 1과 동일한 방법으로 진행하여 목적화합물 2-((3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)아미노)에탄올 트리플루오로아세테이트 염을 얻었다.1H-pyrazol-4-yl) pyridine-3-carbaldehyde in the same manner as in Example 1 to give the desired compound 2 - ((3- (2- Yl) - [1,2,4] triazolo [4,3-b] pyridazin-6-yl) amino) ethanol trifluoroacetate salt.
LCMS calculated for C20H24N10= 420.47, found: 421.27.LCMS calculated for C 20 H 24 N 10 = 420.47, found: 421.27.
<< 실시예Example 12> N-이소프로필-3-(5-(1- 12> N-Isopropyl-3- (5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염의 제조Yl) pyridin-3-yl) - [1,2,4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt
실시예 1과 동일한 방법으로 진행하여 목적화합물 N-이소프로필-3-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염을 얻었다.(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) - [1,2,4] triazole -Thiazol-4-yl] zolo [4,3-b] pyridazin-6-amine trifluoroacetate salt.
LCMS calculated for C17H19N9= 349.39, found: 350.28. LCMS calculated for C 17 H 19 N 9 = 349.39, found: 350.28.
<< 실시예Example 13> 2-(4-(6-아미노-5-(6-( 13> 2- (4- (6-Amino-5- (6- ( 이소프로필아미노Isopropylamino )-) - [1,2,4]트리아졸로[4,3-b]피리다진[1,2,4] triazolo [4,3-b] pyridazine -3-일)피리딘-3-일)-1H-피라졸-1-일)에탄올 Yl) pyridin-3-yl) -1H-pyrazol-1-yl) ethanol 트리플루오로아세테Trifluoroacetate 이트 염의 제조Preparation of yeast salts
실시예 1과 동일한 방법으로 진행하여 목적화합물 2-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)에탄올 트리플루오로아세테이트 염을 얻었다.The procedure of Example 1 was repeated to obtain the desired compound 2- (4- (6-Amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazine Yl) pyridin-3-yl) -1H-pyrazol-1-yl) ethanol trifluoroacetate salt.
LCMS calculated for C18H21N9O= 379.42, found: 380.28 LCMS calculated for C 18 H 21 N 9 O = 379.42, found: 380.28
<< 실시예Example 14> 1-(4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온 트리플루오로아세테이트 염의 제조 14> 1- (4- (4- (6-Amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) piperazin-1-yl) prop-2-en-1-one trifluoroacetate salt
실시예 1과 동일한 방법으로 진행하여 목적화합물 1-(4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온 트리플루오로아세테이트 염을 얻었다.The procedure of Example 1 was repeated to obtain the desired compound 1- (4- (4- (6-amino-5- (6- (isopropylamino) - [1,2,4] triazolo [ ] Pyridazin-3-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop- 2-en-1-one trifluoroacetate salt.
LCMS calculated for C24H28N10O= 472.55, found: 473.41.LCMS calculated for C 24 H 28 N 10 O = 472.55, found: 473.41.
<< 실시예Example 15> 3-(6-( 15> 3- (6- ( 이소프로필아미노Isopropylamino )-) - [1,2,4]트리아졸로[4,3-b]피리다진[1,2,4] triazolo [4,3-b] pyridazine -3-일)-N5-(4-모폴리노페닐)피리딘-2,5-디아민 Yl) -N5- (4-morpholinophenyl) pyridine-2,5-diamine 트리플루오로아세테이트Trifluoroacetate 염의 제조 Manufacture of salt
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)-N5-(4-모폴리노페닐)피리딘-2,5-디아민 트리플루오로아세테이트 염을 얻었다.(4,3-b] pyridazin-3-yl) -N5- (4-methylpiperazin-1- -Morpholinophenyl) pyridine-2,5-diamine trifluoroacetate salt.
LCMS calculated for C23H27N9O=445.52, found: 446.29.LCMS calculated for C 23 H 27 N 9 O = 445.52, found: 446.29.
<< 실시예Example 16> 3-(2-아미노-5-(1-(피페리딘-4-일)-1H- 16> 3- (2-Amino-5- (1- (piperidin-4-yl) 피라졸Pyrazole -4-일)피리딘-3-일)-N-페닐-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Yl) pyridin-3-yl) -N-phenyl- [1,2,4] triazolo [4,3- b] pyridazin- 트리플루오로아세테이트Trifluoroacetate 염의 제조 Manufacture of salt
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-페닐-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염을 얻었다.(Piperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl) -N -Phenyl- [l, 2,4] triazolo [4,3-b] pyridazine-6-amine trifluoroacetate salt.
LCMS calculated for C24H24N10 =452.22, found: 453.10.LCMS calculated for C 24 H 24 N 10 = 452.22, found: 453.10.
<< 실시예Example 17> 3-(6-(3- 17> 3- (6- (3- 아미노피페리딘Aminopiperidine -1-일)--1 day)- [1,2,4]트리아졸로[4,3-b]피리다진[1,2,4] triazolo [4,3-b] pyridazine -3-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민의 제조Yl) -5- (1-methyl-1H-pyrazol-4-yl) pyridin-
단계 1: tert-부틸 (1-(3-(2-(tert-부틸아미노)-5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)카바메이트Step 1: Preparation of tert- butyl (1- (3- (2- (tert-butylamino) -5- (1 -methyl-1H- pyrazol- 4] triazolo [4,3- b] pyridazin-6-yl) piperidin-3-yl) carbamate
1,4-디옥산(2ml)에 tert-부틸(1-(3-(5-브로모-2-(tert-부틸아미노)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)카바메이트(45mg, 0.0826mmol)을 녹이고, 1-메틸-4-(4,4,5,5-테트라메틸-1,3,2-디옥사보로란-2-일)-1H-피라졸 (61mg, 0.2931mmol)과 Pd2(pph3)2Cl2 (42 mg, 0.0598mmol), 1N Na2CO3 (0.494ml, 0.4956mmol)을 넣고 질소를 충전시킨 후 90oC에서 밤샘교반한다. 반응이 종결되면, 용액을 식힌 후 용매를 날리고, 농축액을 EA(에틸아세테이트)와 H2O로 추출하고 EA층을 MgSO4로 건조하고 농축하여 5% MeOH/DCM으로 관 컬럼크로마토그래피하여 tert-부틸 (1-(3-(2-(tert-부틸아미노)-5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)카바메이트(52 mg, 86%)를 얻었다. To a solution of tert-butyl (1- (3- (5-bromo-2- (tert-butylamino) pyridin-3- yl) - [l, 2,4] triazolo [ (4,4,5,5-tetramethyl-piperidin-3-yl) carbamate (45 mg, 0.0826 mmol) (61 mg, 0.2931 mmol), Pd 2 (pph 3 ) 2 Cl 2 (42 mg, 0.0598 mmol), 1N Na 2 CO 3 (0.494 ml, 0.4956 mmol), and the mixture is stirred at 90 ° C overnight. After the reaction was completed, the solution was cooled and the solvent was evaporated. The concentrate was extracted with EA (ethyl acetate) and H 2 O. The EA layer was dried with MgSO 4 , concentrated and subjected to column chromatography using 5% MeOH / DCM to obtain tert- Methyl-1H-pyrazol-4-yl) pyridin-3-yl) - [l, 2,4] triazolo [ 4,3-b] pyridazin-6-yl) piperidin-3-yl) carbamate (52 mg, 86%).
1H-NMR (500 MHz, CDCl3) δ 8.47(s, 1H), 7.93(s, 1H), 7.71(s, 1H), 7.57(s, 1H), 7.02(d, J=6Hz, 1H), 3.95(s, 3H), 3.95(d, J=6Hz, 1H), 3.70(s, 2H), 3.42-3.25(m, 2H), 2.85-2.76(m, 5H), 2.10-2.06(m, 2H), 1.65(s, 9H), 1.45(s, 9H), 1.27-1.13(m, 3H). 1 H-NMR (500 MHz, CDCl 3 )? 8.47 (s, IH), 7.93 (s, IH), 7.71 , 3.95 (s, 3H), 3.95 (d, J = 6 Hz, 1H), 3.70 (s, 2H), 3.42-3.25 (m, 2H), 2.85-2.76 2H), 1.65 (s, 9H), 1.45 (s, 9H), 1.27 - 1.13 (m, 3H).
단계 2: 3-(6-(3-아미노피페리딘-1-일)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민의 제조Step 2: 3- (6- (3-Aminopiperidin- l-yl) - [1,2,4] triazolo [4,3- b] pyridazin- Methyl-1H-pyrazol-4-yl) pyridin-2-amine
tert-부틸 (1-(3-(2-(tert-부틸아미노)-5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)카바메이트(52mg, 0.1331mmol)에 TFA 5ml을 넣고 녹여준 후 60 oC에서 18시간 교반한다. 반응이 종결되면 용매를 날리고, 에테르(ether)를 넣어서 녹는 부분을 제거해서 씻어내어(3회 반복) 목적 화합물(40mg, 82%)을 얻었다.(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) - [ (52 mg, 0.1331 mmol) was dissolved in 5 ml of TFA, followed by stirring at 60 ° C for 18 hours. When the reaction was completed, the solvent was blown off and the ether was added to remove the melting portion (washed three times) to obtain the aimed compound (40 mg, 82%).
1H-NMR (500 MHz, CDCl3) δ 8.52(s, 1H), 8.52-8.22(m, 1H), 8.19-8.05(m, 1H), 8.03-7.90(m, 1H), 7.82(s, 1H), 7.36-7.33(d, J=9Hz, 1H), 3.87(s, 3H), 3.72-3.55(m, 7H), 2.05-1.91(m, 1H), 1.80-1.72(m, 1H), 1.60-1.53(m, 1H), 1.19-1.17(m, 1H): LCMS calculated for C19H22N10 = 390.22, found : 390.44 1 H-NMR (500 MHz, CDCl 3) δ 8.52 (s, 1H), 8.52-8.22 (m, 1H), 8.19-8.05 (m, 1H), 8.03-7.90 (m, 1H), 7.82 (s, 1H), 7.36-7.33 (d, J = 9 Hz, 1H), 3.87 (s, 3H), 3.72-3.55 (m, 7H), 2.05-1.91 1.60-1.53 (m, 1H), 1.19-1.17 (m, 1H): LCMS calculated for C 19 H 22 N 10 = 390.22, found: 390.44
<< 실시예Example 18> N-((R)-1-(3-(2-아미노-5-(1- 18> N - ((R) -1- (3- (2-Amino-5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)아크릴아마이드의 제조Yl) pyridin-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) piperidin-
3-(6-(3-아미노피페리딘-1-일)-[1,2,4]트리아졸로[4,3-b]피리다진-3- 일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민 (15 mg, 0.038 mmol)을 디클로로메탄 (5 mL)에 녹이고, 아크릴산 (5.2 μL, 0.0768 mmol), EDCI(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide) (29 mg, 0.192 mmol), HOBt(Hydroxybenzotriazole) (26 mg, 0.1920 mmol), DIPEA(N,N-Diisopropylethylamine) (35 μl, 0.1920 mmol)을 가한 다음, 상온에서 15시간 동안 교반한다. 반응이 종결되면, 디클로로메탄과 물로 반응 후처리하고 유기층을 MgSO4로 건조하고, 농축하여 5% MeOH/DCM으로 관 컬럼크로마토그래피하여 목적화합물(5 mg, 29%)을 얻었다.- (l-methyl-lH-pyrrolo [2,3-d] pyrimidin- 3-yl) pyridin-2-amine (15 mg, 0.038 mmol) was dissolved in dichloromethane (5 mL), and acrylic acid (5.2 L, 0.0768 mmol) and EDCI (29 mg, 0.192 mmol), HOBt (Hydroxybenzotriazole) (26 mg, 0.1920 mmol) and DIPEA (N, N-Diisopropylethylamine) (35 μl, 0.1920 mmol) were added and stirred at room temperature for 15 hours . After the reaction was completed, the reaction mixture was treated with dichloromethane and water. The organic layer was dried over MgSO 4 , concentrated and subjected to column chromatography using 5% MeOH / DCM to obtain the target compound (5 mg, 29%).
1H-NMR (500 MHz, CDCl3) δ 8.43-8.40 (s, 1H), 7.92-7.87 (m, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 7.04-7.00 (m, 1H), 6.25-6.19 (m, 1H), 5.85-5.78 (m, 2H), 5.60 (d, J = 15, 1H), 4.90-4.82 (m, 1H), 4.02-4.01 (m, 1H), 3.82 (s, 3H), 3.61-3.52 (m, 1H), 3.35-3.25 (m, 1H), 2.91 (s, 3H), 2.78 (s, 3H): LCMS calculated for C26H26F6N10O5 = 444.21, found: 444.44. 1 H-NMR (500 MHz, CDCl 3) δ 8.43-8.40 (s, 1H), 7.92-7.87 (m, 1H), 7.67 (s, 1H), 7.52 (s, 1H), 7.04-7.00 (m, 1H), 6.25-6.19 (m, 1H), 5.85-5.78 (m, 2H), 5.60 (d, J = 15,1H), 4.90-4.82 3.82 (s, 3H): LCMS calculated for C 26 H 26 F 6 N 10 (m, 3H), 3.82 (s, 3H), 3.61-3.52 O 5 = 444.21, found: 444.44.
<< 실시예Example 19> N-(1-(3-(2-아미노-5-(1- 19> N- (1- (3- (2-Amino-5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)아세트아마이드의 제조Yl) pyridin-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) piperidin-
3-(6-(3-아미노피페리딘-1-일)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민 (20 mg, 0.051 mmol)을 디클로로메탄 (5 mL)에 가하고, 아크릴산 (5.71 μL, 0.10 mmol), EDCI (39 mg, 0.25 mmol), HOBt (34 mg, 0.25 mmol), 디이소프로필에틸아민 (47 μL, 0.25 mmol)을 추가로 가하고, 상온에서 15시간 동안 교반한다. 반응이 종결되면, 디클로로메탄과 물로 반응 후처리하고 유기층을 MgSO4로 건조하고, 농축하여 5% MeOH/CH2Cl2으로 관 컬럼크로마토그래피하여 목적화합물(7.5 mg, 54%)을 얻었다.- (l-methyl-lH-pyrrolo [2,3-d] pyrimidin- 2-amine (20 mg, 0.051 mmol) was added to dichloromethane (5 mL) and acrylic acid (5.71 L, 0.10 mmol), EDCI (39 mg, 0.25 mmol), HOBt 34 mg, 0.25 mmol) and diisopropylethylamine (47 L, 0.25 mmol) were further added, and the mixture was stirred at room temperature for 15 hours. After the reaction was completed, the reaction mixture was treated with dichloromethane and water, and the organic layer was dried over MgSO 4 , concentrated and subjected to column chromatography using 5% MeOH / CH 2 Cl 2 to obtain the desired compound (7.5 mg, 54%).
1H-NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 7.94 (s, 1H), 7.93( d, J = 3Hz, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.06 (d, J = 9Hz, 1H), 5.78-5.73 (m, 1H), 5.00-4.78 (m, 2H), 3.95 (s, 3H), 3.80-3.72 (m, 1H), 3.50-3.15 (m, 2H), 1.93 (s, 3H), 1.72-1.63 (m, 2H): LCMS calculated for C21H24N10O = 432.21, found: 432.48. 1 H-NMR (500 MHz, CDCl 3 )? 8.46 (s, IH), 7.94 (s, IH), 7.93 (d, J = 3 Hz, , 7.06 (d, J = 9 Hz, 1H), 5.78-5.73 (m, 1H), 5.00-4.78 (m, 2H), 3.95 (s, 3H), 3.80-3.72 m, 2H), 1.93 (s , 3H), 1.72-1.63 (m, 2H): LCMS calculated for C 21 H 24 N 10 O = 432.21, found: 432.48.
<< 실시예Example 20> N-(1-(3-(2-아미노-5-(1- 20> N- (1- (3- (2-Amino-5- (1- 메틸methyl -1H--1H- 피라졸Pyrazole -4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)프로피온아마이드의 제조Yl) pyridin-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin-6-yl) piperidin-3- yl) propionamide
3-(6-(3-아미노피페리딘-1-일)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민 (18 mg, 0.046 mmol)을 디클로로메탄 (5 mL)에 가하고, 아크릴산 (6.87 μL, 0.092 mmol), EDCI (36 mg, 0.23 mmol), HOBt (32 mg, 0.23 mmol), DIPEA (43 μL, 0.23 mmol)을 가한 다음, 상온에서 15시간 동안 교반한다. 반응이 종결되면, 디클로로메탄과 물로 반응 후처리 하고 유기층을 MgSO4로 건조하고, 농축하여 5% MeOH/CH2Cl2으로 관 컬럼크로마토그래피하여 목적화합물(6 mg, 47%)을 얻었다.- (l-methyl-lH-pyrrolo [2,3-d] pyrimidin- (6.87 μL, 0.092 mmol), EDCI (36 mg, 0.23 mmol), HOBt (0.25 mmol) and diisopropylethylamine were added to dichloromethane (5 mL) 32 mg, 0.23 mmol) and DIPEA (43 μL, 0.23 mmol) were added thereto, followed by stirring at room temperature for 15 hours. After the reaction was completed, the reaction mixture was treated with dichloromethane and water. The organic layer was dried over MgSO 4 , concentrated, and subjected to column chromatography using 5% MeOH / CH 2 Cl 2 to obtain the target compound (6 mg, 47%).
1H-NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 7.91 (s, 2H), 7.68 (s, 1H), 7.55 (s, 1H), 7.05 (d, J = 9Hz, 1H), 5.59-5.57 (m, 1H), 4.91-4.84 (m, 2H), 3.85 (s, 3H), 3.74-3.70 (m, 1H), 3.88-3.20 (m, 2H), 2.20-1.95 (m, 5H), 1.18-1.00 (m, 3H): LCMS calculated for C22H26N10O = 446.23, found : 446.51. 1 H-NMR (500 MHz, CDCl 3 )? 8.44 (s, IH), 7.91 (s, 2H), 7.68 2H), 2.20-1.95 (m, 2H), 3.85-3.52 (m, 5H), 1.18-1.00 (m, 3H ): LCMS calculated for C 22 H 26 N 10 O = 446.23, found: 446.51.
<< 실시예Example 21> 1-(4-(4-((6-아미노-5-(6-( 21> 1- (4- (4 - ((6-Amino-5- (6- 이소프로필아미노Isopropylamino )-) - [1,2,4]트리아졸로[4,3-b]피리다진[1,2,4] triazolo [4,3-b] pyridazine -3-일)피리딘-3-일)아미노)-3-메톡시페닐)피페라진-1-일)에탄온 트리플루오로아세테이트 염의 제조Yl) pyridin-3-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone trifluoroacetate salt
실시예 1과 동일한 방법으로 진행하여 목적화합물 1-(4-(4-((6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)아미노)-3-메톡시페닐)피페라진-1-일)에탄온 트리플루오로아세테이트 염을 얻었다.The procedure of Example 1 was repeated to obtain the desired compound 1- (4- (4 - ((6-Amino-5- (6- (isopropylamino) - [1,2,4] triazolo [ 3-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone trifluoroacetate salt.
LCMS calculated for C26H32N10O2=516.60, found: 517.32.LCMS calculated for C 26 H 32 N 10 O 2 = 516.60, found: 517.32.
<< 실시예Example 22> 2-(4-(4-(6-아미노-5-(6-( 22 2- (4- (4- (6-Amino-5- (6- ( 이소프로필아미노Isopropylamino )-) - [1,2,4]트리아졸[1,2,4] triazole 로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄올의 제조Pyridin-3-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) ethanol
실시예 1과 동일한 방법으로 진행하여 목적화합물 2-(4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄올을 얻었다.The procedure of Example 1 was repeated to obtain the desired compound 2- (4- (4- (6-amino-5- (6- (isopropylamino) - [1,2,4] triazolo [ ] Pyridazin-3-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) ethanol.
LCMS calculated for C21H26N10=418.23, found: 419.05. LCMS calculated for C 21 H 26 N 10 = 418.23, found: 419.05.
<< 실시예Example 23> 3-(2-아미노-5-(4-((4- 23> 3- (2-Amino-5- (4 - ((4- 메틸피페라진Methylpiperazine -1-일)-1 day) 메틸methyl )페닐)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민의 제조) Phenyl) pyridin-3-yl) -N-isopropyl- [1,2,4] triazolo [4,3-b] pyridazin-
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(4-((4-메틸피페라진-1-일)메틸)페닐)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민을 얻었다.(4-methylpiperazin-1-yl) methyl) phenyl) pyridin-3-yl) -N-isopropyl - [1,2,4] triazolo [4,3-b] pyridazin-6-amine.
LCMS calculated for C25H31N9=457.57, found: 458.23.LCMS calculated for C 25 H 31 N 9 = 457.57, found: 458.23.
<< 실시예Example 24> 3-(2-아미노-5-(4-( 24> 3- (2-Amino-5- (4- ( 모폴리노메틸Morpholinomethyl )페닐)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민의 제조) Phenyl) pyridin-3-yl) -N-isopropyl- [1,2,4] triazolo [4,3-b] pyridazin-
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(4-(모폴리노메틸)페닐)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민을 얻었다.(Morpholinomethyl) phenyl) pyridin-3-yl) -N-isopropyl- [1, 2,4] Triazolo [4,3-b] pyridazin-6-amine.
LCMS calculated for C24H28N8O=444.53, found: 445.15.LCMS calculated for C 24 H 28 N 8 O = 444.53, found: 445.15.
<< 실시예Example 25> 3-(2-아미노-5-(1-(1- 25> 3- (2-Amino-5- (1- (1- 메틸피페리딘Methylpiperidine -4-일)-1H--4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민의 제조Yl) pyridin-3-yl) -N-isopropyl- [l, 2,4] triazolo [4,3-b] pyridazin-
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민을 얻었다.(1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) pyridin-3-yl ) -N-isopropyl- [1,2,4] triazolo [4,3-b] pyridazin-6-amine.
LCMS calculated for C22H28N10=432.52, found: 433.21. LCMS calculated for C 22 H 28 N 10 = 432.52, found: 433.21.
<< 실시예Example 26> 3-(2-아미노-5-(4-((4- 26> 3- (2-Amino-5- (4 - ((4- 메틸피페라진Methylpiperazine -1-일)-1 day) 메틸methyl )페닐)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 ) Phenyl) pyridin-3-yl) -N-cyclopentyl- [l, 2,4] triazolo [4,3- b] pyridazin- 트리플루오로아세테Trifluoroacetate 이트 염의 제조Preparation of yeast salts
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(4-((4-메틸피페라진-1-일)메틸)페닐)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염을 얻었다.(4-methylpiperazin-1-yl) methyl) phenyl) pyridin-3-yl) -N-cyclopentyl - [1,2,4] triazolo [4,3-b] pyridazine-6-amine trifluoroacetate salt.
LCMS calculated for C27H33N9 = 483.29, found: 484.25.LCMS calculated for C 27 H 33 N 9 = 483.29, found: 484.25.
<< 실시예Example 27> 3-(2-아미노-5-(4-( 27> 3- (2-Amino-5- (4- ( 모폴리노메틸Morpholinomethyl )페닐)피리딘-3-일)-N-) Phenyl) pyridin-3-yl) -N- 사이클로Cyclo 펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염의 제조Pentyl- [l, 2,4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt
실시예 1과 동일한 방법으로 진행하여 목적화합물 3-(2-아미노-5-(4-(모폴리노메틸)페닐)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염을 얻었다.(Morpholinomethyl) phenyl) pyridin-3-yl) -N-cyclopentyl- [1, 2,4] Triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt.
LCMS calculated for C26H30N8O = 470.25, found: 471.14.LCMS calculated for C 26 H 30 N 8 O = 470.25, found: 471.14.
<< 실시예Example 28> 1-(4-(4-(6-아미노-5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온의 제조 28> 1- (4- (4- (6-Amino-5- (6- (cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop-2-en-
실시예 1과 동일한 방법으로 진행하여 목적화합물 1-(4-(4-(6-아미노-5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온을 얻었다.(4- (4- (6-Amino-5- (6- (cyclopentylamino) - [1,2,4] triazolo [4,3-b ] Pyridazin-3-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop- 2-en-1-one.
LCMS calculated for C26H30N10O = 498.27, found: 499.11.LCMS calculated for C 26 H 30 N 10 O = 498.27, found: 499.11.
<< 실시예Example 29> 3-(2-아미노-5-(1-(1- 29> 3- (2-Amino-5- (1- (1- 메틸피페리딘Methylpiperidine -4-일)-1H--4-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민의 제조Yl) pyridin-3-yl) -N-cyclopentyl- [1,2,4] triazolo [4,3- b] pyridazin-6-
실시예 4의 방법대로 시행하여, 목적화합물 3-(2-아미노-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민을 얻었다.The procedure of Example 4 was repeated to obtain the desired compound 3- (2-amino-5- (1- (1-methylpiperidin-4-yl) -1H-pyrazol- ) -N-cyclopentyl- [l, 2,4] triazolo [4,3-b] pyridazin-6-amine.
LCMS calculated for C24H30N10 = 458.27, found: 459.10.LCMS calculated for C 24 H 30 N 10 = 458.27, found: 459.10.
<< 실시예Example 30> N-사이클로펜틸-3-(5-(1-(피페리딘 -4-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Pyrazol-4-yl) pyridin-3-yl) - [l, 2,4] triazole [4,3-b] pyridazin-6-amine 트리프루오르아세테이트Trifluoroacetate 염의 제조 Manufacture of salt
단계 1: 5-브로모니코티노일클로라이드의 제조Step 1: Preparation of 5-bromonicotinoyl chloride
5-브로모니코티닉 애시드 (1 g, 4.9 mmol)를 티오닐클로라이드 (5 mL)에 가한 뒤, 디메틸포름아미드를 촉매로 (100 μL, 1.36 mmol) 가해준다. 반응 혼합물을 80 ℃ 에서 18시간 동안 반응시킨다. 반응 후 티오틸크로라이드를 감압 농축하여 제거하고, 농축된 수득물을 다음반응에 정제과정 없이 그대로 사용하였다.5-Bromonicotinic acid (1 g, 4.9 mmol) was added to thionyl chloride (5 mL) and then dimethylformamide (100 μL, 1.36 mmol) was added thereto. The reaction mixture is allowed to react at 80 DEG C for 18 hours. After the reaction, the thiotylchloride was removed by concentration under reduced pressure, and the concentrated product was used without purification in the next reaction.
단계 2: 5-브로모-N'-(6-클로로피리다진-3-일)니코티노히드라지드의 제조Step 2: Preparation of 5-bromo-N '- (6-chloropyridazin-3-yl) nicotinohydrazide
5-브로모니코티닐 클로라이드 (1 g, 4.9 mmol)을 디클로로메탄 (50 mL)에 녹인 후, 0 ℃에서 3-클로로-6-히드라지닐피리다진 (0.86 g, 5.9 mmol)과 트리에틸아민 (1 ml, 7.1 mmol)을 천천히 가한다. 질소 충전 뒤 상온에서 18 시간 동안 교반 반응한다. 반응 후 에틸아세테이트/물로 추출한 후, 유기층을 MgSO4로 건조 농축하였다. 에테르로 결정화하여 5-브로모-N'-(6-클로로피리다진-3-일)니코티노히드라지드를 얻었다.5-bromonicotinyl chloride (1 g, 4.9 mmol) was dissolved in dichloromethane (50 mL), and then 3-chloro-6-hydrazinylpyridazine (0.86 g, 5.9 mmol) and triethylamine 1 ml, 7.1 mmol) is added slowly. After charging with nitrogen, the mixture is stirred at room temperature for 18 hours. After the reaction, the reaction mixture was extracted with ethyl acetate / water, and the organic layer was dried over MgSO 4 . Crystallization with ether gave 5-bromo-N '- (6-chloropyridazin-3-yl) nicotinohydrazide.
LCMS calculated for C10H7BrClN5O = 328.55, found: 329.93. LCMS calculated for C 10 H 7 BrClN 5 O = 328.55, found: 329.93.
단계 3: 3-(5-브로모피리딘-3-일)-6-클로로-[1,2,4]트리아졸로[4,3-b]피리다진의 제조Step 3: Preparation of 3- (5-bromopyridin-3-yl) -6-chloro- [1,2,4] triazolo [4,3-b] pyridazine
5- 브로모-N'-(6- 클로로피리다진-3-일) 니코티노히드라지드 (230 mg, 0.70 mmol)을 톨루엔 (10 mL)에 녹인 후, p-톨루엔설폰산 (117 mg, 0.87 mmol)를 가하고, 110 ℃에서 18시간 동안 반응 한다. 반응 후 에틸아세테이트와 포화 NaHCO3 수용액으로 추출 한 후, 유기층을 MgSO4로 건조 농축하여 컬럼 크로마토그래피로 분리하여 3-(5-브로모피리딘-3-일)-6-클로로-[1,2,4]트리아졸로[4,3-b]피리다진(208 mg, 96%)을 얻었다.After dissolving 5-bromo-N '- (6-chloropyridazin-3-yl) nicotinohydrazide (230 mg, 0.70 mmol) in toluene (10 mL), p-toluenesulfonic acid (117 mg, mmol) is added, and the reaction is carried out at 110 DEG C for 18 hours. After the reaction, the reaction mixture was extracted with ethyl acetate and saturated aqueous NaHCO 3 , and the organic layer was dried over MgSO 4 and concentrated. The residue was purified by column chromatography to obtain 3- (5-bromopyridin-3-yl) , 4] triazolo [4,3-b] pyridazine (208 mg, 96%).
1H NMR (500 MHz, DMSO) δ 9.68 (s, 1H), 8.95 (s, 1H), 8.85 (s, 1H), 8.23 (d, J = 9.5 Hz, 2H), 7.28 (d, J = 5.0 Hz, 1H). 1 H NMR (500 MHz, DMSO ) δ 9.68 (s, 1H), 8.95 (s, 1H), 8.85 (s, 1H), 8.23 (d, J = 9.5 Hz, 2H), 7.28 (d, J = 5.0 Hz, 1H).
단계 4: 3-(5-브로모피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민의 제조Step 4: Preparation of 3- (5-bromopyridin-3-yl) -N-cyclopentyl- [l, 2,4] triazolo [4,3-b] pyridazin-
3-(5-브로모피리딘-3-일)-6-클로로-[1,2,4]트리아졸로[4,3-b]피리다진 (165 mg, 0.53 mmol)을 디메틸포름아미드 (5 mL)에 가하고, 사이클로펜틸아민 (79 μL, 0.79 mmol) 와 디이소프로필아민 (266 μL, 1.59 mmol)를 가하고, 질소 충전 후 상온에서 48시간 동안 반응한다. 반응 후 에틸아세테이트/물을 가하여 생성물을 유기층으로 추출하고, 유기층을 MgSO4로 건조 농축한다. 컬럼 크로마토그래피로 분리하여 3-(5-브로모피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민(68 mg, 27%)을 얻었다.(165 mg, 0.53 mmol) was dissolved in dimethylformamide (5 mL) at 0 < 0 > C, ), Cyclopentylamine (79 μL, 0.79 mmol) and diisopropylamine (266 μL, 1.59 mmol) were added. After charging with nitrogen, the mixture was reacted at room temperature for 48 hours. After the reaction, ethyl acetate / water was added to extract the product into an organic layer, and the organic layer was dried over MgSO4. Separation by column chromatography gave 3- (5-bromopyridin-3-yl) -N-cyclopentyl- [1,2,4] triazolo [4,3- b] pyridazin- , 27%).
1H-NMR (500 MHz, DMSO) δ 9.52 (s, 1H), 9.12 (s, 1H), 8.82 (s, 1H), 8.03 (d, J = 10.0Hz, 1H), 7.69 (d, J = 5.5Hz, 1H), 6.89 (d, J = 10.0Hz, 1H), 4.03 (m, 1H), 2.05 (s, 2H), 1.73 (s, 2H), 1.63 (s, 4H). 1 H-NMR (500 MHz, DMSO) δ 9.52 (s, 1H), 9.12 (s, 1H), 8.82 (s, 1H), 8.03 (d, J = 10.0Hz, 1H), 7.69 (d, J = 2H), 1.63 (s, 2H), 1.63 (s, 4H).
단계 5: tert-부틸 4-(4-(6-아미노-5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조Step 5: tert-Butyl 4- (4- (6- amino-5- (6- (cyclopentylamino) - [l, 2,4] triazolo [4,3- b] pyridazin- Pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate
3-(5-브로모피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 (50 mg, 0.14 mmol)을 1,4-디옥산 (5 mL)에 녹인 후, t-부틸 4-(4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤레인-2-일)-1H- 피라졸-1일)피페리딘-1-카르복실레이트 (78 mg, 0.21 mmol)과 1M Na2CO3 수용액 (0.834 mL, 0.83 mmol), Pd(pph3)2Cl2 (58 mg, 0.083 mmol)을 가하고, 질소 충전 후, 110 ℃ 에서 18시간 교반 한다. 반응 후 에틸아세테이트/물로 추출 한 후, 유기층을 MgSO4로 건조한다. 컬럼 크로마토그래피로 정제하여 tert-부틸 4-(4-(6-아미노-5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(23 mg, 32%)를 얻었다.Cyclopentyl- [l, 2,4] triazolo [4,3-b] pyridazin-6-amine (50 mg, 0.14 mmol) , 4-dioxane (5 mL), and then t-butyl 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- - pyrazol -1-yl) piperidine-1-carboxylate (78 mg, 0.21 mmol) and 1M aqueous Na2CO3 (0.834 mL, 0.83 mmol), Pd (pph 3) 2 Cl 2 (58 mg, 0.083 mmol) After charging with nitrogen, the mixture was stirred at 110 占 폚 for 18 hours. After the reaction, the mixture is extracted with ethyl acetate / water, and the organic layer is dried with MgSO 4 . The residue was purified by column chromatography to obtain tert-butyl 4- (4- (6-amino-5- (6- (cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazine- -Yl) -pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (23 mg, 32%).
LCMS calculated for C28H35N9O2 = 529.64, found: 530.21. LCMS calculated for C 28 H 35 N 9 O 2 = 529.64, found: 530.21.
단계 6: N-사이클로펜틸-3-(5-(1-(피페리딘 -4-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리프루오르아세테이트 염의 제조Step 6: N-Cyclopentyl-3- (5- (1- (piperidin-4-yl) -lH-pyrazol-4-yl) pyridin- Preparation of zolo [4,3-b] pyridazin-6-amine trifluoroacetate salt
실시예 17의 단계 2의 방법대로 시행하여 목적화합물 N- 사이클로펜틸 -3-(5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리프루오르아세테이트 염(20 mg, 87%)을 얻었다.The title compound was prepared by the same procedure as in the step 2 of Example 17 to give the desired compound N-cyclopentyl-3- (5- (1- (piperidin-4-yl) -1H-pyrazol- ) - [1,2,4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt (20 mg, 87%).
LCMS calculated for C23H27N9= 429.52, found: 430.04.LCMS calculated for C 23 H 27 N 9 = 429.52, found: 430.04.
<< 실시예Example 31> N- 31> N- 사이클로펜틸Cyclopentyl -3-(5-(1-(피페리딘-3-일)-1H--3- (5- (1- (piperidin-3-yl) -1H- 피라졸Pyrazole -4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 Yl) pyridin-3-yl) - [1,2,4] triazolo [4,3- b] pyridazin- 트리플루오로아세테이트Trifluoroacetate 염의 제조 Manufacture of salt
단계 1: t-부틸 3-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b] 피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트의 제조Step 1: tert -Butyl 3- (4- (5- (6- (cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate
실시예 30의 단계 5의 방법대로 시행하여 목적화합물 t-부틸 3-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘 -3-일)-1H-피라졸-1-일)피페리딘-1-카르복실레이트(52 mg, 34%)를 얻었다.The procedure of Step 5 of Example 30 was repeated to obtain the target compound t-butyl 3- (4- (5- (6- (cyclopentylamino) - [1,2,4] triazolo [4,3-b] Pyridin-3-yl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (52 mg, 34%).
LCMS calculated for C28H35N9O2= 529.64, found: 530.21. LCMS calculated for C 28 H 35 N 9 O 2 = 529.64, found: 530.21.
단계 2: N-사이클로펜틸-3-(5-(1-(피페리딘-3-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염의 제조Step 2: N-Cyclopentyl-3- (5- (1- (piperidin-3-yl) -1H-pyrazol-4- yl) pyridin- Preparation of zolo [4,3-b] pyridazin-6-amine trifluoroacetate salt
실시예 17의 단계 2의 방법대로 시행하여 목적화합물 N- 사이클로펜틸 -3-(5-(1-(피페리딘-3-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염(18 mg, 86%)을 얻었다.The procedure of Step 2 of Example 17 was repeated to obtain the desired compound N-cyclopentyl-3- (5- (1- (piperidin-3-yl) -1H-pyrazol- ) - [1,2,4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt (18 mg, 86%).
LCMS calculated for C23H27N9= 429.52, found: 430.11.LCMS calculated for C 23 H 27 N 9 = 429.52, found: 430.11.
<< 실시예Example 32> 1-(4-(4-(5-(6-( 32> 1- (4- (4- (5- (6- ( 사이클로펜틸아미노Cyclopentylamino )-) - [1,2,4]트리아졸로[4,3-b][1,2,4] triazolo [4,3-b] 피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온의 제조Pyridazin-3-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin- 1 -yl) prop-
실시예 18의 단계 2의 방법대로 시행하여 목적화합물 1-(4-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온(4 mg, 5%)을 얻었다.The procedure of Step 2 of Example 18 was repeated to obtain the desired compound 1- (4- (4- (5- (6- (cyclopentylamino) - [1,2,4] triazolo [4,3-b] 1-yl) prop-2-en-1-one (4 mg, 5%).
LCMS calculated for C26H29N9O= 483.57, found: 484.06.LCMS calculated for C 26 H 29 N 9 O = 483.57, found: 484.06.
<< 실시예Example 33> 1-(3-(4-(5-(6-( 33> 1- (3- (4- (5- (6- ( 사이클로펜틸아미노Cyclopentylamino )-) - [1,2,4]트리아졸로[4,3-b][1,2,4] triazolo [4,3-b] 피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온의 제조Pyridazin-3-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin- 1 -yl) prop-
실시예 18의 단계 2의 방법대로 시행하여 목적화합물 1-(3-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온(5 mg, 25%)을 얻었다.The procedure of Step 2 of Example 18 was repeated to obtain the desired compound 1- (3- (4- (5- (6- (cyclopentylamino) - [1,2,4] triazolo [4,3-b] 1-yl) prop-2-en-1-one (5 mg, 25%).
LCMS calculated for C26H29N9O= 483.57, found: 484.20.LCMS calculated for C 26 H 29 N 9 O = 483.57, found: 484.20.
<< 실시예Example 34> 2-(4-(4-(5-(6-( 34 2- (4- (4- (5- (6- ( 사이클로펜틸아미노Cyclopentylamino )-) - [1,2,4]트리아졸로[4,3-b][1,2,4] triazolo [4,3-b] 피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄올의 제조Pyridazin-3-yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin- 1 -yl) ethanol
실시예 4의 방법대로 시행하여 목적화합물 2-(4-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄올을 얻었다.The procedure of Example 4 was repeated to obtain the desired compound 2- (4- (4- (5- (6- (cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazine- Yl) pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) ethanol.
LCMS calculated for C25H31N9O= 473.57, found: 474.01.LCMS calculated for C 25 H 31 N 9 O = 473.57, found: 474.01.
하기 표 1에 상기 실시예 1 내지 34에서 제조한 화합물의 화학구조식을 정리하여 나타내었다.The chemical structures of the compounds prepared in Examples 1 to 34 are summarized in Table 1 below.
<< 실험예Experimental Example 1> 1> 트리아졸로Triazolo 피리다진Pyridazine 유도체의 Derivative 브루톤Bruton 티로신 Tyrosine 키나제Kinase (( Bruton'sBruton's tyrosine kinase, BTK) 활성 억제 평가 tyrosine kinase, BTK) activity inhibition assay
본 발명에 따른 트리아졸로 피리다진 유도체의 브루톤 티로신 키나제 활성 억제를 평가하기 위하여, 하기와 같은 실험을 수행하여 그 결과를 표 2에 나타내었다.In order to evaluate the inhibition of the brutonyl tyrosine kinase activity of the triazolo pyridazine derivative according to the present invention, the following experiment was carried out and the results are shown in Table 2.
BTK 효소 평가는 BTK 효소저해 진단키트 (시스바이오, Codolet, 프랑스)를 사용하여 평가하였다. ATP(adenosine triphosphate), BTK, 펩타이드(biotin-Aca-AAAEEIYGEI-NH2)와 본 발명에 따른 실시예 1-34 화합물을 가하고, 30분 동안 반응시키고, 여기에 EDTA(ethylenediaminetetraacetic acid)를 가하여 반응을 정지시켰다. 여기서 EDTA 용액은 유로피움을 함유하는 항체 (antiphosphoresidue antibody) 와 스트랩타비딘-XL665 (SA-XL665, cisbio)룰 함유하고 있으며, 1시간 동안 인큐베이션 하고 형광도 (fluorescence)를 측정하여, 엔비젼 (Envision)리더로 337 nm에서 여기 (excitation) 되는 665와 620 nm의 발광도 (emission)를 측정하여 값을 정하였다. IC50값은 그래패드 (GraphPad) 프리즘 (5 version)을 사용하여 구하였다. 여기서 커브는 간접적 (non-linear) 리그레션 모델로 로그함수와 반응값으로 구하였다. The BTK enzyme assay was evaluated using the BTK enzyme inhibition assay kit (Cibao, Codolet, France). ATP (adenosine triphosphate), BTK, peptide (biotin-Aca-AAAEEIYGEI-NH 2 ) and the compound of Example 1-34 according to the present invention were added and reacted for 30 minutes. EDTA (ethylenediaminetetraacetic acid) Stopped. The EDTA solution contained an antiphosphoresidue antibody and straptavidin-XL665 (SA-XL665, cisbio). The EDTA solution was incubated for 1 hour, and the fluorescence was measured. The Envision ) Was measured by measuring the emission of 665 and 620 nm excited at 337 nm by a reader. IC 50 values were determined using a GraphPad prism (version 5). Here, the curve is an indirect (non-linear) regression model with logarithmic functions and reaction values.
상기 표 2에 나타난 바와 같이, 본 발명에 따른 트리아졸로 피리다진 유도체는 μM 대의 농도에서 브루톤 티로신 키나제의 활성을 억제하고, 실시예 1-3, 5-14, 16, 22-30 화합물은 0.5 μM 이하의 낮은 IC50 값을 나타내어, 우수한 브루톤 티로신 키나제 활성 억제능을 나타냄을 알 수 있으며, 특히, 실시예 1, 2, 6, 7, 14 및 22 화합물은 0.1 μM, 즉, 100 nM 이하의 현저하게 낮은 농도에서도 브루톤 티로신 키나제 활성을 억제하는 것을 확인하였다.As shown in the above Table 2, the triazolo pyridazine derivatives according to the present invention inhibited the activity of bruton tyrosine kinase at a concentration of μM, and the compounds of Examples 1-3, 5-14, 16, and 22-30 inhibited the activity of 0.5 In particular, the compounds of Examples 1, 2, 6, 7, 14, and 22 exhibited a low IC 50 value of less than or equal to 0.1 μM, that is, less than or equal to 100 nM It was confirmed that the inhibition of the bruton tyrosine kinase activity even at a remarkably low concentration was confirmed.
따라서, 본 발명에 따른 트리아졸로 피리다진 유도체는 브루톤 티로신 키나제의 활성을 억제하는 능력이 우수하므로, 브루톤 티로신 키나제 활성과 관련된 질환, 특히 암 또는 자가면역질환을 예방 또는 치료하는데 유용하게 사용할 수 있다.Therefore, the triazolo pyridazine derivative according to the present invention is excellent in the ability to inhibit the activity of the bruton tyrosine kinase, and thus can be usefully used for the prevention or treatment of diseases related to the bruton tyrosine kinase activity, particularly cancer or autoimmune diseases have.
<제제예 1> 산제의 제조≪ Formulation Example 1 > Preparation of powders
화학식 1로 표시되는 화합물 2g2 g of the compound represented by the general formula (1)
유당 1gLactose 1g
상기의 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.The above components were mixed and packed in airtight bags to prepare powders.
<제제예 2> 정제의 제조≪ Formulation Example 2 > Preparation of tablet
화학식 1로 표시되는 화합물 100 ㎎100 mg of the compound represented by the formula (1)
옥수수전분 100 ㎎Corn starch 100 mg
유당 100 ㎎Lactose 100 mg
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
상기의 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.
<제제예 3> 캡슐제의 제조≪ Formulation Example 3 > Preparation of capsules
화학식 1로 표시되는 화합물 100 ㎎100 mg of the compound represented by the formula (1)
옥수수전분 100 ㎎Corn starch 100 mg
유당 100 ㎎Lactose 100 mg
스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate
상기의 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.
<제제예 4> 주사제의 제조≪ Formulation Example 4 > Preparation of injection
화학식 1로 표시되는 화합물 100 ㎎100 mg of the compound represented by the formula (1)
만니톨 180 ㎎180 mg mannitol
Na2HPO4ㆍ2H2O 26 ㎎Na 2 HPO 4 .2H 2 O 26 mg
증류수 2974 ㎎2974 mg of distilled water
통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.
<제제예 5> 건강식품의 제조≪ Formulation Example 5 > Preparation of health food
화학식 1로 표시되는 화합물 500ngThe compound represented by the formula (1)
비타민 혼합물 적량Vitamin mixture quantity
비타민 A 아세테이트 70mg Vitamin A acetate 70 mg
비타민 E 1.0mgVitamin E 1.0mg
비타민 0.13mg0.13mg of vitamin
비타민 B2 0.15mg0.15 mg of vitamin B2
비타민 B6 0.5mgVitamin B6 0.5mg
비타민 B12 0.2mgVitamin B12 0.2mg
비타민 C 10mgVitamin C 10mg
비오틴 10mgBiotin 10mg
니코틴산아미드 1.7mgNicotinic acid amide 1.7 mg
엽산 50mgFolic acid 50mg
판토텐산 칼슘 0.5mgCalcium pantothenate 0.5mg
무기질 혼합물 적량Mineral mixture quantity
황산제1철 1.75mg1.75 mg ferrous sulfate
산화아연 0.82mg0.82 mg of zinc oxide
탄산마그네슘 25.3mgMagnesium carbonate 25.3 mg
제1인산칼륨 15mg15 mg of potassium phosphate monobasic
제2인산칼슘 55mgCalcium phosphate diphosphate 55 mg
구연산칼륨 90mgPotassium citrate 90mg
탄산칼슘 100mgCalcium carbonate 100 mg
염화마그네슘 24.8mg24.8 mg of magnesium chloride
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
<제제예 6> 건강음료의 제조≪ Formulation Example 6 > Preparation of health drink
화학식 1로 표시되는 화합물 500ngThe compound represented by the formula (1)
구연산 1000mgCitric acid 1000mg
올리고당 100gOligosaccharide 100 g
매실농축액 2gPlum concentrate 2g
타우린 1gTaurine 1g
정제수를 가하여 전체 900mlPurified water was added to the entire 900 ml
통상의 건강 음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 건강 음료 조성물 제조에 사용하였다.The above components were mixed according to a conventional health drink manufacturing method, and the mixture was stirred and heated at 85 DEG C for about 1 hour. The resulting solution was filtered to obtain a sterilized container, which was sealed and sterilized, And used for manufacturing.
상기 조성비는 비교적 기호 음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호 도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.Although the composition ratio is relatively mixed with the ingredient suitable for the favorite drink, it is also possible to arbitrarily modify the blending ratio according to the regional or national preference such as the demand class, demand country, use purpose, and the like.
Claims (18)
[화학식 1]
(상기 화학식 1에서,
A는 단일 결합 또는 -NH-이고;
는 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로아릴 또는 비치환 또는 치환된 C6-10아릴이고,
여기서, 상기 치환된 헤테로아릴은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; 직쇄 또는 측쇄의 하이드록실C1-5알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7원자의 비치환 또는 치환된 헤테로사이클로알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있으며, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; 직쇄 또는 측쇄의 하이드록실C1-5알킬; 직쇄 또는 측쇄의 C1-5알킬카보닐; 비치환된 C6-10아릴카보닐; 비치환된 C6-10아릴C0-2알킬; 및 아크릴로일;로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고,
상기 치환된 C6-10아릴은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로사이클로알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로사이클로알킬-C1-3알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; 및 직쇄 또는 측쇄의 C1-5알킬카보닐;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고;
R1는 수소 또는 비치환 또는 직쇄 또는 측쇄의 C1-5알킬로 하나 이상 치환된 아민이고; 및
R2 및 R3는 각각 독립적으로 수소; 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; 직쇄 또는 측쇄의 하이드록실C1-5알킬; 비치환된 C3-7사이클로알킬; 비치환된 C6-10아릴; 또는 비치환된 C6-10아릴C1-2알킬;이거나, 이들이 결합한 N 원자와 함께 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 7 원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고, 여기서, 상기 치환된 헤테로사이클로알킬은 -NH2 또는 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; 직쇄 또는 측쇄의 하이드록실C1-5알킬; 비치환 또는 직쇄 또는 측쇄의 C1-5알킬카보닐 및 아크릴로일로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환된 아민으로 치환될 수 있다).
Claims 1. A compound represented by the following formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
(In the formula 1,
A is a single bond or -NH-;
Is an unsubstituted or substituted heteroaryl or an unsubstituted or substituted C 6-10 aryl group containing from 5 to 7 atoms which comprises at least one heteroatom selected from the group consisting of N, O and S,
Wherein said substituted heteroaryl is straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; Straight chain or branched hydroxyl C 1-5 alkyl; And unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms containing at least one heteroatom selected from the group consisting of N, O and S; and at least one substituent selected from the group consisting of Wherein said substituted heterocycloalkyl is a straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; Straight chain or branched hydroxyl C 1-5 alkyl; Straight or branched C 1-5 alkylcarbonyl; Unsubstituted C 6-10 arylcarbonyl; Unsubstituted C 6-10 aryl C 0-2 alkyl; And acryloyl; and at least one substituent selected from the group consisting of
Said substituted C 6-10 aryl is straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; An unsubstituted or substituted heterocycloalkyl of 5 to 7 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And unsubstituted or substituted heterocycloalkyl-C 1-3 alkyl of 5 to 7 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And wherein said substituted heterocycloalkyl is straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; And straight or branched C 1-5 alkylcarbonyl; and at least one substituent selected from the group consisting of:
R < 1 > is hydrogen or an amine that is unsubstituted or substituted one or more times with straight or branched C 1-5 alkyl; And
R 2 and R 3 are each independently hydrogen; Straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; Straight chain or branched hydroxyl C 1-5 alkyl; Unsubstituted C 3-7 cycloalkyl; Unsubstituted C 6-10 aryl; Or unsubstituted C 6-10 aryl C 1-2 alkyl, or a 5 to 7-membered ring containing at least one heteroatom selected from the group consisting of N, O and S, together with the N atom to which they are bonded, Substituted or substituted heterocycloalkyl, wherein said substituted heterocycloalkyl is -NH 2 or a straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; Straight chain or branched hydroxyl C 1-5 alkyl; Which may be unsubstituted or substituted by one or more substituents selected from the group consisting of straight or branched C 1-5 alkylcarbonyl and acryloyl.
상기 A는 단일 결합 또는 -NH-이고;
는 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로아릴 또는 비치환 또는 치환된 C6-10아릴이고,
여기서, 상기 치환된 헤테로아릴은 직쇄 또는 측쇄의 C1-3알킬; 직쇄 또는 측쇄의 C1-3알콕시; 직쇄 또는 측쇄의 하이드록실C1-3알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6원자의 비치환 또는 치환된 헤테로사이클로알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있으며, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1-3알킬; 직쇄 또는 측쇄의 C1-3알콕시; 직쇄 또는 측쇄의 하이드록실C1-3알킬; 직쇄 또는 측쇄의 C1-3알킬카보닐; 벤조일; 페닐C0-2알킬; 및 아크릴로일;로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고,
상기 치환된 C6-10아릴은 직쇄 또는 측쇄의 C1-3알킬; 직쇄 또는 측쇄의 C1-3알콕시; N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로사이클로알킬; 및 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로사이클로알킬-C1-2알킬;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고, 이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 측쇄의 C1-5알킬; 직쇄 또는 측쇄의 C1-5알콕시; 및 직쇄 또는 측쇄의 C1-5알킬카보닐;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고;
R1는 수소 또는 비치환 또는 직쇄 또는 측쇄의 C1-3알킬로 하나 이상 치환된 아민이고; 및
R2 및 R3는 각각 독립적으로 수소; 직쇄 또는 측쇄의 C1-3알킬; 직쇄 또는 측쇄의 C1-3알콕시; 직쇄 또는 측쇄의 하이드록실C1-3알킬; 비치환된 C3-6사이클로알킬; 비치환된 C6-10아릴; 또는 비치환된 C6-10아릴C1-2알킬;이거나, 이들이 결합한 N 원자와 함께 N, O 및 S로 이루어지는 군으로부터 선택되는 1종 이상의 헤테로 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고, 여기서, 상기 치환된 헤테로사이클로알킬은 -NH2 또는 직쇄 또는 측쇄의 C1-3알킬; 직쇄 또는 측쇄의 C1-3알콕시; 직쇄 또는 측쇄의 하이드록실C1-3알킬; 비치환 또는 직쇄 또는 측쇄의 C1-3알킬카보닐 및 아크릴로일로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환된 아민으로 치환될 수 있는 것을 특징으로 하는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염.
The method according to claim 1,
A is a single bond or -NH-;
Is an unsubstituted or substituted heteroaryl or an unsubstituted or substituted C 6-10 aryl group containing from 5 to 6 atoms which comprises at least one heteroatom selected from the group consisting of N, O and S,
Wherein said substituted heteroaryl is straight or branched C 1-3 alkyl; Straight or branched C 1-3 alkoxy; Straight chain or branched hydroxyl C 1-3 alkyl; And unsubstituted or substituted heterocycloalkyl of 5 to 6 atoms each containing at least one heteroatom selected from the group consisting of N, O and S, with one or more substituents selected from the group consisting of , Wherein said substituted heterocycloalkyl is a straight or branched C 1-3 alkyl; Straight or branched C 1-3 alkoxy; Straight chain or branched hydroxyl C 1-3 alkyl; Straight or branched C 1-3 alkylcarbonyl; Benzoyl; Phenyl C 0-2 alkyl; And acryloyl; and at least one substituent selected from the group consisting of
Said substituted C 6-10 aryl is linear or branched C 1-3 alkyl; Straight or branched C 1-3 alkoxy; An unsubstituted or substituted heterocycloalkyl of 5 to 6 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And unsubstituted or substituted heterocycloalkyl-C 1-2 alkyl of 5 to 6 atoms containing at least one heteroatom selected from the group consisting of N, O and S; And wherein said substituted heterocycloalkyl is straight or branched C 1-5 alkyl; Straight or branched C 1-5 alkoxy; And straight or branched C 1-5 alkylcarbonyl; and at least one substituent selected from the group consisting of:
R < 1 > is hydrogen or an amine that is unsubstituted or substituted one to three times with a linear or branched C 1-3 alkyl; And
R 2 and R 3 are each independently hydrogen; Linear or branched C 1-3 alkyl; Straight or branched C 1-3 alkoxy; Straight chain or branched hydroxyl C 1-3 alkyl; Unsubstituted C 3-6 cycloalkyl; Unsubstituted C 6-10 aryl; Or unsubstituted C 6-10 aryl C 1-2 alkyl; or a 5 to 6-membered ring containing at least one heteroatom selected from the group consisting of N, O and S, together with the N atom to which they are bonded, Substituted or substituted heterocycloalkyl, wherein said substituted heterocycloalkyl is -NH 2 or a straight or branched C 1-3 alkyl; Straight or branched C 1-3 alkoxy; Straight chain or branched hydroxyl C 1-3 alkyl; An unsubstituted or straight-chain or branched C 1-3 alkylcarbonyl, and an acyloyl, or an optical isomer thereof or a pharmacologically acceptable salt thereof. Acceptable salt.
상기 A는 단일 결합 또는 -NH-이고;
는 N 원자를 하나 이상 포함하는 5 내지 6 원자의 비치환 또는 치환된 헤테로아릴 또는 비치환 또는 치환된 페닐이고,
여기서, 상기 치환된 헤테로아릴은 메틸; 에틸; 메톡시; 에톡시; 하이드록실메틸; 하이드록시에틸; 및 비치환 또는 치환된 피롤리디닐, 피페리디닐, 피페라지닐 또는 모폴리닐;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있으며, 이때, 상기 치환된 피롤리디닐, 피페리디닐, 피페라지닐 및 모폴리닐은 메틸, 에틸, 메톡시, 에톡시, 하이드록실메틸, 하이드록시에틸, 아세틸, 에틸카보닐, 페닐, 벤질, 벤조일, 및 아크릴로일;로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고,
상기 치환된 페닐은 메틸; 에틸; 메톡시; 에톡시; 하이드록실메틸; 하이드록시에틸; 비치환 또는 치환된 피롤리디닐, 피페리디닐, 피페라지닐 또는 모폴리닐; 및 비치환 또는 치환된 피롤리디닐메틸, 피페리디닐메틸, 피페라지닐메틸 또는 모폴리닐메틸;으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고, 이때, 상기 치환된 피롤리디닐, 피페리디닐, 피페라지닐 및 모폴리닐은 메틸, 에틸, 메톡시, 에톡시, 아세틸 및 에틸카보닐으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고;
R1는 수소, -NH2, -NHCH3, -N(CH3)2, -NHCH2CH3 또는 -N(CH2CH3)2이고; 및
R2 및 R3는 각각 독립적으로 수소, 메틸, 에틸, 이소프로필, 메톡시, 에톡시, 하이드록시메틸, 하이드록시에틸, 사이클로프로필, 사이클로펜틸, 사이클로헥실, 페닐 또는 벤질이거나, 이들이 결합한 N 원자와 함께 비치환 또는 치환된 피롤리디닐, 피페리디닐 또는 피페라지닐을 형성할 수 있고, 여기서, 상기 치환된 피롤리디닐, 피페리디닐 및 피페라지닐은 -NH2 또는 메틸, 에틸, 메톡시, 에톡시, 하이드록시메틸, 하이드록시에틸, 아세틸, 에틸카보닐 및 아크릴로일로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환된 아민으로 치환될 수 있는 것을 특징으로 하는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염.
The method according to claim 1,
A is a single bond or -NH-;
Is an unsubstituted or substituted heteroaryl or unsubstituted or substituted phenyl of 5 to 6 atoms containing at least one N atom,
Wherein said substituted heteroaryl is selected from the group consisting of methyl; ethyl; Methoxy; Ethoxy; Hydroxylmethyl; Hydroxyethyl; And unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; wherein the substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl may be substituted with one or more substituents selected from the group consisting of Riddinyl, piperazinyl and morpholinyl are each independently selected from the group consisting of methyl, ethyl, methoxy, ethoxy, hydroxylmethyl, hydroxyethyl, acetyl, ethylcarbonyl, phenyl, benzyl, benzoyl, Which may be substituted with one or more substituents,
Said substituted phenyl is methyl; ethyl; Methoxy; Ethoxy; Hydroxylmethyl; Hydroxyethyl; Unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; And unsubstituted or substituted pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, or morpholinylmethyl; and wherein the substituted piperidine ring may be substituted with one or more substituents selected from the group consisting of Pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl may be substituted one or more times with one or more substituents selected from the group consisting of methyl, ethyl, methoxy, ethoxy, acetyl and ethylcarbonyl;
R 1 is hydrogen, -NH 2 , -NHCH 3 , -N (CH 3 ) 2 , -NHCH 2 CH 3 or -N (CH 2 CH 3 ) 2 ; And
R 2 and R 3 are each independently hydrogen, methyl, ethyl, isopropyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl or benzyl, To form unsubstituted or substituted pyrrolidinyl, piperidinyl or piperazinyl, wherein said substituted pyrrolidinyl, piperidinyl and piperazinyl is optionally substituted with one or more substituents selected from -NH 2 or methyl, ethyl, Which may be substituted with at least one amine substituted with at least one substituent selected from the group consisting of halogen, cyano, nitro, cyano, nitro, amino, methoxy, ethoxy, hydroxymethyl, hydroxyethyl, acetyl, ethylcarbonyl and acryloyl, Isomer or a pharmaceutically acceptable salt thereof.
상기 A는 단일 결합 또는 -NH-이고;
는 비치환 또는 치환된 피라졸릴 또는 페닐이고,
여기서, 상기 치환된 피라졸릴은 메틸, 하이드록시에틸, 및 비치환 또는 치환된 피페리디닐으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있으며, 이때, 상기 치환된 피페리디닐은 메틸, 하이드록시에틸, 아세틸, 벤질, 벤조일, 및 아크릴로일으로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환될 수 있고,
상기 치환된 페닐은 메톡시; 또는 비치환 또는 치환된 피페라지닐, 모폴리닐, 피페라지닐메틸 또는 모폴리닐메틸;로 하나 이상 치환될 수 있고, 상기 치환된 피페라지닐, 모폴리닐, 피페라지닐메틸 또는 모폴리닐메틸은 메틸 또는 아세틸로 하나 이상 치환될 수 있고;
R1는 수소 또는 -NH2이고; 및
R2 및 R3는 각각 독립적으로 수소, 메틸, 에틸, 이소프로필, 하이드록시에틸, 사이클로프로필, 사이클로펜틸, 사이클로헥실, 페닐 또는 벤질이거나, 이들이 결합한 N 원자와 함께 비치환 또는 치환된 피페리디닐을 형성할 수 있고, 여기서, 상기 치환된 피페리디닐은 -NH2 또는 아세틸, 에틸카보닐 및 아크릴로일로 이루어지는 군으로부터 선택되는 1종 이상의 치환기로 하나 이상 치환된 아민으로 치환될 수 있는 것을 특징으로 하는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염.
The method according to claim 1,
A is a single bond or -NH-;
Is unsubstituted or substituted pyrazolyl or phenyl,
Wherein the substituted pyrazolyl may be substituted with one or more substituents selected from the group consisting of methyl, hydroxyethyl, and unsubstituted or substituted piperidinyl, wherein the substituted piperidinyl is substituted with at least one substituent selected from the group consisting of Which may be substituted with one or more substituents selected from the group consisting of methyl, hydroxyethyl, acetyl, benzyl, benzoyl, and acryloyl,
Wherein said substituted phenyl is methoxy; Or unsubstituted or substituted piperazinyl, morpholinyl, piperazinylmethyl or morpholinylmethyl; and the substituted piperazinyl, morpholinyl, piperazinylmethyl or morpholyl N-methyl may be substituted one or more times by methyl or acetyl;
R 1 is hydrogen or -NH 2 ; And
R 2 and R 3 are each independently hydrogen, methyl, ethyl, isopropyl, hydroxyethyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl or benzyl or, together with the N atom to which they are attached, an unsubstituted or substituted piperidinyl , Wherein said substituted piperidinyl may be substituted with -NH 2 or an amine substituted with one or more substituents selected from the group consisting of acetyl, ethylcarbonyl and acryloyl , An optical isomer thereof or a pharmaceutically acceptable salt thereof.
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염:
(1) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 비스트리플루오로아세테이트 염;
(2) 1-(4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄온;
(3) (4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)(페닐)메탄온;
(4) 3-(2-아미노-5-(1-(1-벤질피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;
(5) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-메틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 비스트리플루오로아세테이트 염;
(6) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(7) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(8) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로헥실-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(9) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-에틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(10) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-벤질-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(11) 2-((3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)아미노)에탄올 트리플루오로아세테이트 염;
(12) N-이소프로필-3-(5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(13) 2-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)에탄올 트리플루오로아세테이트 염;
(14) 1-(4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온 트리플루오로아세테이트 염;
(15) 3-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)-N5-(4-모폴리노페닐)피리딘-2,5-디아민 트리플루오로아세테이트 염;
(16) 3-(2-아미노-5-(1-(피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-페닐-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(17) 3-(6-(3-아미노피페리딘-1-일)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)-5-(1-메틸-1H-피라졸-4-일)피리딘-2-아민;
(18) N-((R)-1-(3-(2-아미노-5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)아크릴아마이드;
(19) N-(1-(3-(2-아미노-5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)아세트아마이드;
(20) N-(1-(3-(2-아미노-5-(1-메틸-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-일)피페리딘-3-일)프로피온아마이드;
(21) 1-(4-(4-((6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)아미노)-3-메톡시페닐)피페라진-1-일)에탄온 트리플루오로아세테이트 염;
(22) 2-(4-(4-(6-아미노-5-(6-(이소프로필아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄올;
(23) 3-(2-아미노-5-(4-((4-메틸피페라진-1-일)메틸)페닐)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;
(24) 3-(2-아미노-5-(4-(모폴리노메틸)페닐)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;
(25) 3-(2-아미노-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-이소프로필-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;
(26) 3-(2-아미노-5-(4-((4-메틸피페라진-1-일)메틸)페닐)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(27) 3-(2-아미노-5-(4-(모폴리노메틸)페닐)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(28) 1-(4-(4-(6-아미노-5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온;
(29) 3-(2-아미노-5-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리딘-3-일)-N-사이클로펜틸-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민;
(30) N-사이클로펜틸-3-(5-(1-(피페리딘 -4-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리프루오르아세테이트 염;
(31) N-사이클로펜틸-3-(5-(1-(피페리딘-3-일)-1H-피라졸-4-일)피리딘-3-일)-[1,2,4]트리아졸로[4,3-b]피리다진-6-아민 트리플루오로아세테이트 염;
(32) 1-(4-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온;
(33) 1-(3-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)프로프-2-엔-1-온; 및
(34) 2-(4-(4-(5-(6-(사이클로펜틸아미노)-[1,2,4]트리아졸로[4,3-b]피리다진-3-일)피리딘-3-일)-1H-피라졸-1-일)피페리딘-1-일)에탄올.
The method according to claim 1,
The compound represented by the formula (1) is any one selected from the group consisting of the following compounds, an optical isomer thereof or a pharmaceutically acceptable salt thereof:
(1) 3- (2-Amino-5- (1- (piperidin-4-yl) -1H-pyrazol- , 4] triazolo [4,3-b] pyridazine-6-amine bistrifluoroacetate salt;
(2) Synthesis of 1- (4- (4- (6-amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Pyridin-3-yl) -lH-pyrazol-l-yl) piperidin-l-yl) ethanone;
(3) Synthesis of (4- (4- (6-amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- 3-yl) -lH-pyrazol-l-yl) piperidin-l-yl) (phenyl) methanone;
(4) Synthesis of 3- (2-amino-5- (1- (1-benzylpiperidin-4-yl) -1H-pyrazol- 1,2,4] triazolo [4,3-b] pyridazin-6-amine;
(5) 3- (2-Amino-5- (1- (piperidin-4-yl) -lH- pyrazol- 4] triazolo [4,3-b] pyridazin-6-amine bistrifluoroacetate salt;
(6) Synthesis of 3- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin- , 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(7) Synthesis of 3- (2-amino-5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin- , 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(8) 3- (2-Amino-5- (1- (piperidin-4-yl) -lH- pyrazol-4- yl) pyridin- , 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(9) 3- (2-Amino-5- (1- (piperidin-4-yl) -1H-pyrazol- 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(10) 3- (2-Amino-5- (1- (piperidin-4-yl) -1H-pyrazol- 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(11) 2- ((3- (2-Amino-5- (1- (piperidin- 4] triazolo [4,3-b] pyridazin-6-yl) amino) ethanol trifluoroacetate salt;
(12) Synthesis of N-isopropyl-3- (5- (1-methyl-1H-pyrazol-4-yl) pyridin- Pyridazin-6-amine trifluoroacetate salt;
(13) Synthesis of 2- (4- (6-amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) ethanol trifluoroacetate salt;
(14) 1- (4- (4- (6-Amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop-2-en-1-one trifluoroacetate salt;
(15) Synthesis of 3- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin-3-yl) -N5- (4 -morpholinophenyl) 2,5-diamine trifluoroacetate salt;
(16) 3- (2-Amino-5- (1- (piperidin-4-yl) -1H-pyrazol- 4] triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(17) Synthesis of 3- (6- (3-aminopiperidin-1-yl) - [1,2,4] triazolo [4,3- b] pyridazin- Methyl-lH-pyrazol-4-yl) pyridin-2-amine;
(1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) - [ Triazolo [4,3-b] pyridazin-6-yl) piperidin-3-yl) acrylamide;
(19) Synthesis of N- (1- (3- (2-Amino-5- (1 -methyl-1 H- pyrazol-4-yl) pyridin- , 3-b] pyridazin-6-yl) piperidin-3-yl) acetamide;
(20) Synthesis of N- (1- (3- (2-Amino-5- (1 -methyl-1H-pyrazol-4-yl) pyridin- , 3-b] pyridazin-6-yl) piperidin-3-yl) propionamide;
(21) 1- (4- (4 - ((6-Amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- ) Pyridin-3-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone trifluoroacetate salt;
(22) 2- (4- (4- (6-Amino-5- (6- (isopropylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Pyridin-3-yl) -lH-pyrazol-l-yl) piperidin-l-yl) ethanol;
(23) 3- (2-Amino-5- (4 - ((4-methylpiperazin-1-yl) methyl) phenyl) pyridin- Triazolo [4,3-b] pyridazin-6-amine;
(24) Synthesis of 3- (2-amino-5- (4- (morpholinomethyl) phenyl) pyridin- ] Pyridazin-6-amine;
(25) 3- (2-Amino-5- (1- (1- methylpiperidin-4-yl) 1,2,4] triazolo [4,3-b] pyridazin-6-amine;
(26) 3- (2-Amino-5- (4 - ((4-methylpiperazin-1-yl) methyl) phenyl) pyridin- Triazolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(27) Synthesis of 3- (2-amino-5- (4- (morpholinomethyl) phenyl) pyridin- ] Pyridazin-6-amine trifluoroacetate salt;
(28) 1- (4- (4- (6-Amino-5- (6- (cyclopentylamino) - [1,2,4] triazolo [ Pyridin-3-yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop-2-en-1-one;
(29) 3- (2-Amino-5- (1- (1- methylpiperidin-4-yl) 1,2,4] triazolo [4,3-b] pyridazin-6-amine;
(30) N-Cyclopentyl-3- (5- (1- (piperidin-4-yl) -1H-pyrazol-4-yl) pyridin- ≪ / RTI > zolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(31) Synthesis of N-cyclopentyl-3- (5- (1- (piperidin-3-yl) -1H-pyrazol-4-yl) pyridin- ≪ / RTI > zolo [4,3-b] pyridazin-6-amine trifluoroacetate salt;
(32) 1- (4- (4- (5- (6- (Cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop-2-en-1-one;
(33) 1- (3- (4- (5- (6- (Cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) piperidin-1-yl) prop-2-en-1-one; And
(34) 2- (4- (4- (5- (6- (Cyclopentylamino) - [1,2,4] triazolo [4,3- b] pyridazin- Yl) -1H-pyrazol-1-yl) piperidin-1-yl) ethanol.
화학식 2로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 4로 표시되는 화합물을 제조하는 단계(단계 1); 및
상기 단계 1에서 얻은 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 얻는 단계(단계 2)를 포함하는 제1항의 화학식 1로 표시되는 화합물의 제조방법:
[반응식 1]
(상기 반응식 1에서,
R1, R2, R3, A 및 는 제1항의 화학식 1에서 정의한 바와 같고;
X1 및 X2는 각각 독립적으로 동일 또는 상이한 할로겐이고; 및
L1은 또는 다).
As shown in Scheme 1 below,
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And
A process for producing a compound represented by formula (1) of claim 1, comprising the step of reacting a compound represented by formula (4) and a compound represented by formula (5) to obtain a compound represented by formula (1)
[Reaction Scheme 1]
(In the above Reaction Scheme 1,
R 1 , R 2 , R 3 , A and Is as defined in claim 1;
X 1 and X 2 are each independently the same or different halogen; And
L 1 is or All).
A pharmaceutical composition for preventing or treating cancer comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염은 브루톤 티로신 키나제(Bruton's tyrosine kinase, BTK)의 활성을 억제하는 것을 특징으로 하는 암의 예방 또는 치료용 약학적 조성물.
8. The method of claim 7,
The pharmaceutical composition for prevention or treatment of cancer, wherein the compound represented by the formula (1), its optical isomer or a pharmaceutically acceptable salt thereof inhibits the activity of Bruton's tyrosine kinase (BTK).
상기 암은 혈액암, 난소암, 자궁경부암, 유방암, 대장암, 간암, 위암, 췌장암, 결장암, 복막 전이암, 피부암, 방광암, 전립선암, 갑상선암, 폐암, 골육종, 섬유성 종양 및 뇌종양으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 암의 예방 또는 치료용 약학적 조성물.
8. The method of claim 7,
The cancer is selected from the group consisting of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, And a pharmaceutically acceptable carrier or excipient.
A pharmaceutical composition for preventing or treating an autoimmune disease, which comprises the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염은 브루톤 티로신 키나제(Bruton's tyrosine kinase, BTK)의 활성을 억제하는 것을 특징으로 하는 자가면역질환의 예방 또는 치료용 약학적 조성물.
11. The method of claim 10,
The compound represented by the above-mentioned formula (1), its optical isomer or its pharmaceutically acceptable salt is useful as a pharmaceutical for the prophylactic or therapeutic treatment of autoimmune diseases, which inhibits the activity of Bruton's tyrosine kinase (BTK) Composition.
상기 자가면역질환은 류머티스성 관절염, 전신 홍반성 루푸스, 다발성 경화증, 제1형 당뇨병, 갑상선 기능 항진증, 근무력증, 크론병, 강직성 척추염, 건선, 자가면역성 악성빈혈 및 쇼그렌 증후군으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 자가면역질환의 예방 또는 치료용 약학적 조성물.
11. The method of claim 10,
Wherein said autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune malignant anemia and Sjogren's syndrome Or a pharmaceutically acceptable salt thereof.
A health functional food composition for preventing or ameliorating cancer comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염은 브루톤 티로신 키나제(Bruton's tyrosine kinase, BTK)의 활성을 억제하는 것을 특징으로 하는 암의 예방 또는 개선용 건강기능식품 조성물.
14. The method of claim 13,
The compound represented by Formula 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof is characterized by inhibiting the activity of Bruton's tyrosine kinase (BTK), which is a health functional food composition for preventing or ameliorating cancer .
상기 암은 혈액암, 난소암, 자궁경부암, 유방암, 대장암, 간암, 위암, 췌장암, 결장암, 복막 전이암, 피부암, 방광암, 전립선암, 갑상선암, 폐암, 골육종, 섬유성 종양 및 뇌종양으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 암의 예방 또는 개선용 건강기능식품 조성물.
14. The method of claim 13,
The cancer is selected from the group consisting of blood cancer, ovarian cancer, cervical cancer, breast cancer, colon cancer, liver cancer, gastric cancer, pancreatic cancer, colon cancer, peritoneal metastasis cancer, skin cancer, bladder cancer, prostate cancer, thyroid cancer, lung cancer, osteosarcoma, Wherein the composition is one selected from the group consisting of:
A health functional food composition for preventing or ameliorating an autoimmune disease, which comprises the compound represented by the general formula (1) of claim 1, an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염은 브루톤 티로신 키나제(Bruton's tyrosine kinase, BTK)의 활성을 억제하는 것을 특징으로 하는 자가면역질환의 예방 또는 개선용 건강기능식품 조성물.
17. The method of claim 16,
The compound represented by the formula (1), its optical isomer or its pharmaceutically acceptable salt is useful as a health function for the prevention or amelioration of an autoimmune disease, characterized by inhibiting the activity of Bruton's tyrosine kinase (BTK) Food composition.
상기 자가면역질환은 류머티스성 관절염, 전신 홍반성 루푸스, 다발성 경화증, 제1형 당뇨병, 갑상선 기능 항진증, 근무력증, 크론병, 강직성 척추염, 건선, 자가면역성 악성빈혈 및 쇼그렌 증후군으로 이루어지는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 자가면역질환의 예방 또는 개선용 건강기능식품 조성물.17. The method of claim 16,
Wherein said autoimmune disease is selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, type 1 diabetes, hyperthyroidism, myasthenia, Crohn's disease, ankylosing spondylitis, psoriasis, autoimmune malignant anemia and Sjogren's syndrome Or a pharmaceutically acceptable salt thereof.
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