KR102297587B1 - A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient - Google Patents
A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient Download PDFInfo
- Publication number
- KR102297587B1 KR102297587B1 KR1020180091812A KR20180091812A KR102297587B1 KR 102297587 B1 KR102297587 B1 KR 102297587B1 KR 1020180091812 A KR1020180091812 A KR 1020180091812A KR 20180091812 A KR20180091812 A KR 20180091812A KR 102297587 B1 KR102297587 B1 KR 102297587B1
- Authority
- KR
- South Korea
- Prior art keywords
- pyrimidin
- amino
- pyridin
- amine
- indol
- Prior art date
Links
- CTVXPMSTJDDHHU-UHFFFAOYSA-N CC(C)(c1nc(Nc2nc(Nc(cc3OC)ccc3N(CC3)CCC3N(C)C)ncc2-c2c[o]cc2)ccc1)O Chemical compound CC(C)(c1nc(Nc2nc(Nc(cc3OC)ccc3N(CC3)CCC3N(C)C)ncc2-c2c[o]cc2)ccc1)O CTVXPMSTJDDHHU-UHFFFAOYSA-N 0.000 description 1
- NFGAAJWLYVNKBM-UHFFFAOYSA-N CC(C)(c1nc(Nc2nc(Nc(cc3OC)ccc3N(CC3)CCC3N(C)C)ncc2C(NC)=O)ccc1)O Chemical compound CC(C)(c1nc(Nc2nc(Nc(cc3OC)ccc3N(CC3)CCC3N(C)C)ncc2C(NC)=O)ccc1)O NFGAAJWLYVNKBM-UHFFFAOYSA-N 0.000 description 1
- DTEJWTUHMIGFHP-UHFFFAOYSA-N CC(C)(c1nc(Nc2nc(Nc3ccc(CCN(C)C4)c4c3)ncc2-c2cc(cccc3)c3[s]2)ccc1)O Chemical compound CC(C)(c1nc(Nc2nc(Nc3ccc(CCN(C)C4)c4c3)ncc2-c2cc(cccc3)c3[s]2)ccc1)O DTEJWTUHMIGFHP-UHFFFAOYSA-N 0.000 description 1
- PTHVCZJATZTMRF-UHFFFAOYSA-N CC(C)(c1nc(Nc2nc(Nc3ccc(CN(C)CC4)c4c3)ncc2-c(cc2)cnc2F)ccc1)O Chemical compound CC(C)(c1nc(Nc2nc(Nc3ccc(CN(C)CC4)c4c3)ncc2-c(cc2)cnc2F)ccc1)O PTHVCZJATZTMRF-UHFFFAOYSA-N 0.000 description 1
- FVNMBPXLQMGSLX-UHFFFAOYSA-N CC(C)(c1nc(Nc2nc(Nc3ccc(CNCC4)c4c3)ncc2-c2c[o]c3ccccc23)ccc1)O Chemical compound CC(C)(c1nc(Nc2nc(Nc3ccc(CNCC4)c4c3)ncc2-c2c[o]c3ccccc23)ccc1)O FVNMBPXLQMGSLX-UHFFFAOYSA-N 0.000 description 1
- BSKOOBWURXIUSU-UHFFFAOYSA-N CC(Nc1c(cc[n]2C)c2ccc1)=O Chemical compound CC(Nc1c(cc[n]2C)c2ccc1)=O BSKOOBWURXIUSU-UHFFFAOYSA-N 0.000 description 1
- VYASVFZBPISCCU-UHFFFAOYSA-N COc1ccc(c(-c2nc(Nc3ccc(CNCC4)c4c3)ncc2-c2c[o]cc2)c[nH]2)c2c1 Chemical compound COc1ccc(c(-c2nc(Nc3ccc(CNCC4)c4c3)ncc2-c2c[o]cc2)c[nH]2)c2c1 VYASVFZBPISCCU-UHFFFAOYSA-N 0.000 description 1
- STXQRMDBTWSUNF-IBGZPJMESA-N C[C@@H](C1)NCCN1c(c(OC)c1)ccc1Nc1ncc(-c(cc2)cnc2F)c(-c2c[n](C)c3c2cccc3)n1 Chemical compound C[C@@H](C1)NCCN1c(c(OC)c1)ccc1Nc1ncc(-c(cc2)cnc2F)c(-c2c[n](C)c3c2cccc3)n1 STXQRMDBTWSUNF-IBGZPJMESA-N 0.000 description 1
- LEQWZNSBXYEMEL-SFHVURJKSA-N C[C@@H](C1)NCCN1c(cc1)ccc1Nc1ncc(-c2cnc(C(F)(F)F)cc2)c(-c2c[nH]c3c2cccc3)n1 Chemical compound C[C@@H](C1)NCCN1c(cc1)ccc1Nc1ncc(-c2cnc(C(F)(F)F)cc2)c(-c2c[nH]c3c2cccc3)n1 LEQWZNSBXYEMEL-SFHVURJKSA-N 0.000 description 1
- ODOJPFQQFJVNMD-UHFFFAOYSA-N C[n](cc1)c2c1c(N)ccc2 Chemical compound C[n](cc1)c2c1c(N)ccc2 ODOJPFQQFJVNMD-UHFFFAOYSA-N 0.000 description 1
- NMFFZSXGKSRBDR-UHFFFAOYSA-N C[n]1c(cccc2)c2c(-c2nc(Nc3ccc(C4CCNCC4)cc3)ncc2-c(cc2)cnc2F)c1 Chemical compound C[n]1c(cccc2)c2c(-c2nc(Nc3ccc(C4CCNCC4)cc3)ncc2-c(cc2)cnc2F)c1 NMFFZSXGKSRBDR-UHFFFAOYSA-N 0.000 description 1
- PGDHJYFYDUZSLJ-UHFFFAOYSA-N C[n]1c2cc(OC)ccc2c(-c2nc(Nc(cc3)cc(OC)c3N3CCN(C)CC3)ncc2-c(cc2)cnc2F)c1 Chemical compound C[n]1c2cc(OC)ccc2c(-c2nc(Nc(cc3)cc(OC)c3N3CCN(C)CC3)ncc2-c(cc2)cnc2F)c1 PGDHJYFYDUZSLJ-UHFFFAOYSA-N 0.000 description 1
- BMZKMPVJXFHIES-UHFFFAOYSA-N C[n]1c2ccccc2c(-c2nc(Nc3ccc(CNCC4)c4c3)ncc2-c2c[nH]nc2)c1 Chemical compound C[n]1c2ccccc2c(-c2nc(Nc3ccc(CNCC4)c4c3)ncc2-c2c[nH]nc2)c1 BMZKMPVJXFHIES-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- 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
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
치환된 N-헤테로아릴 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물에 관한 것으로, 상기 유도체는 WEE1을 포함하는 다양한 단백질 키나아제에 대한 억제활성이 우수하므로, 이를 유효성분으로 함유하는 약학적 조성물은 단백질 키나아제 관련 질환, 특히 암의 치료 또는 예방에 유용하게 사용될 수 있으며, 간암, 폐암, 상피세포암, 대장암, 유방암, 백혈병 및 난소암에 대한 암세포증식 억제효과가 우수한 바, 특히, 간암, 폐암, 상피세포암, 대장암, 유방암, 백혈병 또는 난소암의 치료에 유용하게 사용될 수 있다. A substituted N-heteroaryl derivative, a method for preparing the same, and a pharmaceutical composition for the prevention or treatment of cancer comprising the same as an active ingredient, wherein the derivative has excellent inhibitory activity against various protein kinases including WEE1, A pharmaceutical composition containing as an active ingredient can be usefully used for the treatment or prevention of protein kinase-related diseases, particularly cancer, and has a cancer cell proliferation inhibitory effect on liver cancer, lung cancer, epithelial cell cancer, colorectal cancer, breast cancer, leukemia and ovarian cancer In particular, it can be usefully used in the treatment of liver cancer, lung cancer, epithelial cell cancer, colorectal cancer, breast cancer, leukemia or ovarian cancer.
Description
치환된 N-헤테로아릴 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.It relates to a substituted N-heteroaryl derivative, a method for preparing the same, and a pharmaceutical composition for preventing or treating cancer comprising the same as an active ingredient.
인간 간세포 암종(human hepatocellular carcinoma; HCC)은 장기간(long term) 간 염증에 의해 발병되는 질환이다. 비록 외과적 및 피부를 통한(percutaneous) 고주파(radiofrequency) 절제(ablation)술이 환자의 생존율을 개선시키지만, 진전된(advanced) 인간 간세포 암종(human hepatocellular carcinoma; HCC)에 대한 효과적인 치료를 얻기 위하여 새로운 치료 대안이 필요한 실정이다. 이에, 화학요법(chemotherapy) 및 저분자량 물질 운반에 의한 세포사멸 유도가 떠오르는 대안이다.Human hepatocellular carcinoma (HCC) is a disease caused by long-term liver inflammation. Although surgical and percutaneous radiofrequency ablation improves the survival rate of patients, new novel therapies are needed to obtain effective treatment for advanced human hepatocellular carcinoma (HCC). There is a need for treatment alternatives. Accordingly, induction of apoptosis by chemotherapy and delivery of low molecular weight substances is an emerging alternative.
전환성장인자 베타-1(Transforming growth factor-b1; TGF-β1)은 인간 간세포 암종(human hepatocellular carcinoma; HCC) 세포성장을 강력히 억제한다. 특히, 섬유모세포(fibroblasts) 및 성상(stellate) 세포와 같은 비-상피(non-epithelial) 세포에서 세포성장을 촉진하는 반면, 세포사멸 또는 세포주기 정지(cell cycle arrest)에 의해 설치류(rodent) 및 인간 간세포 암종(human hepatocellular carcinoma; HCC) 세포 모두에서 세포성장을 억제한다.Transforming growth factor beta-1 (Transforming growth factor-b1; TGF-β1) strongly inhibits human hepatocellular carcinoma (HCC) cell growth. In particular, it promotes cell growth in non-epithelial cells such as fibroblasts and stellate cells, whereas in rodents and rodents by apoptosis or cell cycle arrest. Inhibits cell growth in both human hepatocellular carcinoma (HCC) cells.
인간 간세포 암종(human hepatocellular carcinoma; HCC) 세포에서 TGF-β1에 의한 세포사멸의 유도는 cdc2 Tyr15의 탈인산화(dephosphorylation)(cdc2의 활성형태), 즉, cdc2 인산화 감소에 의해 매개된다. 상기 cdc2 활성은 Wee1 키나아제 하향조절로 유도되고, Tyr15 인산화 감소에 의한 cdc2 활성은 인간 간세포 암종(human hepatocellular carcinoma; HCC) 세포에서 TGF-β1-유도된 세포사멸에 매우 중요하다. TGF-β1 처리 후에 Wee1 키나아제 발현 감소가 관찰되고, cdc2 인산화는 Wee1 키나아제에 의해 조절된다. 이로부터, TGF-β1 매개된 세포사멸은 Wee1/cdc2 축에 유도된다고 할 수 있다.Induction of apoptosis by TGF-β1 in human hepatocellular carcinoma (HCC) cells is mediated by dephosphorylation of cdc2 Tyr15 (an active form of cdc2), that is, reduced phosphorylation of cdc2. The cdc2 activity is induced by Weel kinase downregulation, and the cdc2 activity by reducing Tyr15 phosphorylation is very important for TGF-β1-induced apoptosis in human hepatocellular carcinoma (HCC) cells. A decrease in Weel kinase expression was observed after TGF-β1 treatment, and cdc2 phosphorylation was regulated by Weel kinase. From this, it can be said that TGF-β1-mediated apoptosis is induced in the Wee1/cdc2 axis.
외과적으로 절제된 시료에서, 인간 간세포 암종(human hepatocellular carcinoma; HCC)에서 Wee1 키나아제는 과발현되어 있으나, 간경변(cirrhotic) 조직을 포함하는 비-암성(non-cancerous) 조직에서는 키나아제 발현이 관찰되지 않는다. Wee1 키나아제의 과발현은 뇌 종양 및 백혈병을 포함하는 다른 종양 유형에서 보고되어 있다(비특허문헌 1). 뇌 종양에서는 Wee1 키나아제의 발현이 단지 종양세포에서만 상승조절되고, 상승된 키나아제는 암세포 생존에 있어 중요한 역할을 한다.In surgically resected samples, Weel kinase is overexpressed in human hepatocellular carcinoma (HCC), but kinase expression is not observed in non-cancerous tissues, including cirrhotic tissues. Overexpression of Weel kinase has been reported in brain tumors and other tumor types including leukemia (Non-Patent Document 1). In brain tumors, the expression of Wee1 kinase is upregulated only in tumor cells, and the elevated kinase plays an important role in cancer cell survival.
Wee1 키나아제는 cdc2의 역조절인자(negative regulator)이다. TGF-β1은 다기능 사이토카인(multifunctional cytokine)이기 때문에, 실질적 치료 대안이 될 수는 없다. Wee1 키나아제는 DNA 손상이 회복되기 전에 마이토시스(mitosis)의 초기단계를 억제하여 G2/M 단계를 부정적으로(negatively) 조절하므로 조기 미토틱 진입(premature mitotic entry) 및 후속적 세포 사멸을 막는 것으로 여겨지고 있다. 특정 억제제 또는 siRNA를 사용하여 Wee1 키나아제를 억제하여 인간 간세포 암종(human hepatocellular carcinoma; HCC) 세포에서 세포사멸을 유도할 수 있다. 따라서, Wee1 키나아제 억제제는 인간 간세포 암종(human hepatocellular carcinoma; HCC)와 같은 Wee1 키나아제-과발현 암종에서 부각되는 새로운 치료전략 및 대안이 될 수 있고, 상기 유형의 억제제는 진전된 고형암에 대한 현실적 치료 대안이 될 수 있다.Wee1 kinase is a negative regulator of cdc2. Since TGF-β1 is a multifunctional cytokine, it cannot be a practical therapeutic alternative. Wee1 kinase negatively regulates the G2/M phase by inhibiting the early phase of mitosis before DNA damage is repaired, thus preventing premature mitotic entry and subsequent cell death. is considered Specific inhibitors or siRNAs can be used to inhibit Wee1 kinase to induce apoptosis in human hepatocellular carcinoma (HCC) cells. Therefore, Wee1 kinase inhibitors can be a new therapeutic strategy and alternative emerging in Wee1 kinase-overexpressing carcinomas such as human hepatocellular carcinoma (HCC), and this type of inhibitor is a realistic treatment alternative for advanced solid cancer. can be
본 발명의 일 목적은 치환된 N-헤테로아릴 유도체를 제공하는 것이다.One object of the present invention is to provide a substituted N-heteroaryl derivative.
본 발명의 다른 목적은 상기 치환된 N-헤테로아릴 유도체의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the substituted N-heteroaryl derivative.
본 발명의 다른 목적은 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating protein kinase-related diseases.
상기 목적을 달성하기 위하여,In order to achieve the above object,
본 발명의 일 측면에 따라, According to one aspect of the present invention,
하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염이 제공된다:A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof is provided:
[화학식 1][Formula 1]
(상기 화학식 1에 있어서,(In Formula 1,
A는 CH 또는 N이고;A is CH or N;
L은 NH 또는 부재이고;L is NH or absent;
R1 및 R2는 독립적으로 수소, 할로겐, 직쇄 또는 분지쇄의 C1-6알콕시 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 3 내지 8원자의 비치환 또는 치환된 헤테로사이클로알킬이거나, R1 및 R2는 이들이 결합된 탄소원자와 함께 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 3 내지 8원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고, R 1 and R 2 are independently hydrogen, halogen, straight or branched C 1-6 alkoxy or 3 to 8 membered unsubstituted or substituted including at least one heteroatom selected from the group consisting of N, O and S or R 1 and R 2 are 3 to 8 membered unsubstituted or substituted heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O and S together with the carbon atom to which they are attached can form,
이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 분지쇄의 C1-6알킬, 비치환 또는 직쇄 또는 분지쇄의 C1-6알킬로 하나이상 치환된 아민 및 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 비치환 또는 직쇄 또는 분지쇄의 C1-6알킬로 하나이상 치환된 3 내지 8원자의 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;In this case, the substituted heterocycloalkyl is selected from the group consisting of an amine, and N, O or S optionally substituted by one or more C 1-6 alkyl, unsubstituted or a straight-chain or branched-chain C 1-6 alkyl of straight or branched chain may be substituted with one or more substituents selected from the group consisting of 3 to 8 membered heterocycloalkyl substituted with at least one unsubstituted or straight or branched C 1-6 alkyl containing at least one heteroatom;
R3은 -(C=O)NR5R6, -(P=O)R7R8, -SO2R9, 비치환 또는 치환된 C6-10아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 5 내지 10 원자의 비치환 또는 치환된 헤테로아릴이고, R 3 is -(C=O)NR 5 R 6 , -(P=O)R 7 R 8 , -SO 2 R 9 , unsubstituted or substituted C 6-10 aryl and the group consisting of N, O and S 5 to 10 membered unsubstituted or substituted heteroaryl containing at least one heteroatom selected from;
이때, 상기 치환된 아릴 및 헤테로아릴은 각각 할로겐, 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-6알킬 및 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-6알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,In this case, the substituted aryl and heteroaryl C 1- each of halogen, unsubstituted or with one or more halogen-substituted straight chain or branched by one or more C 1-6 alkyl, unsubstituted or halogen-substituted straight-chain or branched-chain of 6 may be substituted with one or more substituents selected from the group consisting of alkoxy,
R5, R6, R7, R8 및 R9는 각각 수소 또는 직쇄 또는 분지쇄의 C1-6알킬이고;R 5 , R 6 , R 7 , R 8 and R 9 are each hydrogen or straight or branched C 1-6 alkyl;
R4는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 5 내지 10 원자의 비치환 또는 치환된 헤테로아릴이고,R 4 is an unsubstituted or substituted heteroaryl of 5 to 10 atoms including at least one heteroatom selected from the group consisting of N, O and S;
이때, 상기 치환된 헤테로아릴은 NO2, NH2, -NH(C=O)R10, -(C=O)NR11R12, -NHSO2R13, 할로겐, 비치환 또는 OH로 하나이상 치환된 직쇄 또는 분지쇄의 C1-6알킬 및 직쇄 또는 분지쇄의 C1-6알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,In this case, the substituted heteroaryl is NO 2 , NH 2 , -NH(C=O)R 10 , -(C=O)NR 11 R 12 , -NHSO 2 R 13 , at least one halogen, unsubstituted or OH One or more substituents may be substituted with a substituent selected from the group consisting of substituted straight-chain or branched C 1-6 alkyl and straight-chain or branched C 1-6 alkoxy,
R10, R11, R12 및 R13은 각각 수소 또는 직쇄 또는 분지쇄의 C1-6알킬이다).R 10 , R 11 , R 12 and R 13 are each hydrogen or linear or branched C 1-6 alkyl).
본 발명의 다른 측면에 따라,According to another aspect of the invention,
하기 반응식 1에 나타난 바와 같이,As shown in Scheme 1 below,
화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시키는 단계(단계 1); 및reacting the compound represented by Formula 4 with the compound represented by Formula 5 (step 1); and
화학식 2로 표시되는 화합물을 화학식 3으로 표시되는 화합물과 반응시키는 단계(단계 2)를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법이 제공된다:There is provided a method for preparing a compound represented by Formula 1, comprising reacting a compound represented by Formula 2 with a compound represented by Formula 3 (step 2):
[반응식 1][Scheme 1]
(상기 반응식 1에서, A, L, R1, R2, R3 및 R4는 상기 화학식 1에서 정의한 바와 같고;(In Scheme 1, A, L, R 1 , R 2 , R 3 and R 4 are as defined in Formula 1 above;
X1 및 X2는 각각 할로겐이고; 및X 1 and X 2 are each halogen; and
L1은 또는 다).L 1 is or all).
본 발명의 다른 측면에 따라,According to another aspect of the invention,
상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물이 제공된다.Provided is a pharmaceutical composition for preventing or treating a protein kinase-related disease comprising the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 개선용 건강기능식품이 제공된다.According to another aspect of the present invention, there is provided a health functional food for preventing or improving protein kinase-related diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능식품 조성물을 필요한 대상에게 투여하는 단계를 포함하는 단백질 키나아제 관련 질환의 예방 또는 치료 방법이 제공된다.According to another aspect of the present invention, protein kinase-related comprising the step of administering to a subject in need of a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient A method for preventing or treating a disease is provided.
본 발명의 다른 측면에 따라, 단백질 키나아제 관련 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능식품 조성물의 용도가 제공된다.According to another aspect of the present invention, there is provided the use of a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the prevention or treatment of protein kinase-related diseases do.
본 발명에 따른 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염은 WEE1을 포함하는 다양한 단백질 키나아제에 대한 억제활성이 우수하므로, 이를 유효성분으로 함유하는 약학적 조성물은 단백질 키나아제 관련 질환, 특히 암의 치료 또는 예방에 유용하게 사용될 수 있으며, 간암, 폐암, 상피세포암, 대장암, 유방암, 백혈병 및 난소암에 대한 암세포증식 억제효과가 우수한 바, 특히, 간암, 폐암, 상피세포암, 대장암, 유방암, 백혈병 또는 난소암의 치료에 유용하게 사용될 수 있다.Since the compound represented by Formula 1 according to the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof has excellent inhibitory activity against various protein kinases including WEE1, a pharmaceutical composition containing it as an active ingredient is a protein It can be usefully used for the treatment or prevention of kinase-related diseases, particularly cancer, and has excellent cancer cell proliferation inhibitory effects on liver cancer, lung cancer, epithelial cell cancer, colorectal cancer, breast cancer, leukemia and ovarian cancer, in particular, liver cancer, lung cancer, It can be usefully used for the treatment of epithelial cell cancer, colorectal cancer, breast cancer, leukemia or ovarian cancer.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일 측면은,One aspect of the present invention is
하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공한다.Provided are a compound represented by Formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에 있어서,In Formula 1,
A는 CH 또는 N이고;A is CH or N;
L은 NH 또는 부재이고;L is NH or absent;
R1 및 R2는 독립적으로 수소, 할로겐, 직쇄 또는 분지쇄의 C1-6알콕시 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 3 내지 8원자의 비치환 또는 치환된 헤테로사이클로알킬이거나, R1 및 R2는 이들이 결합된 탄소원자와 함께 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 3 내지 8원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고, R 1 and R 2 are independently hydrogen, halogen, straight or branched C 1-6 alkoxy or 3 to 8 membered unsubstituted or substituted including at least one heteroatom selected from the group consisting of N, O and S or R 1 and R 2 are 3 to 8 membered unsubstituted or substituted heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O and S together with the carbon atom to which they are attached can form,
이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 분지쇄의 C1-6알킬, 비치환 또는 직쇄 또는 분지쇄의 C1-6알킬로 하나이상 치환된 아민 및 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 비치환 또는 직쇄 또는 분지쇄의 C1-6알킬로 하나이상 치환된 3 내지 8원자의 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;In this case, the substituted heterocycloalkyl is selected from the group consisting of an amine, and N, O or S optionally substituted by one or more C 1-6 alkyl, unsubstituted or a straight-chain or branched-chain C 1-6 alkyl of straight or branched chain may be substituted with one or more substituents selected from the group consisting of 3 to 8 membered heterocycloalkyl substituted with at least one unsubstituted or straight or branched C 1-6 alkyl containing at least one heteroatom;
R3은 -(C=O)NR5R6, -(P=O)R7R8, -SO2R9, 비치환 또는 치환된 C6-10아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 5 내지 10 원자의 비치환 또는 치환된 헤테로아릴이고, R 3 is -(C=O)NR 5 R 6 , -(P=O)R 7 R 8 , -SO 2 R 9 , unsubstituted or substituted C 6-10 aryl and the group consisting of N, O and S 5 to 10 membered unsubstituted or substituted heteroaryl containing at least one heteroatom selected from;
이때, 상기 치환된 아릴 및 헤테로아릴은 각각 할로겐, 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-6알킬 및 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-6알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,In this case, the substituted aryl and heteroaryl C 1- each of halogen, unsubstituted or with one or more halogen-substituted straight chain or branched by one or more C 1-6 alkyl, unsubstituted or halogen-substituted straight-chain or branched-chain of 6 may be substituted with one or more substituents selected from the group consisting of alkoxy,
R5, R6, R7, R8 및 R9는 각각 수소 또는 직쇄 또는 분지쇄의 C1-6알킬이고;R 5 , R 6 , R 7 , R 8 and R 9 are each hydrogen or straight or branched C 1-6 alkyl;
R4는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 5 내지 10 원자의 비치환 또는 치환된 헤테로아릴이고,R 4 is an unsubstituted or substituted heteroaryl of 5 to 10 atoms including at least one heteroatom selected from the group consisting of N, O and S;
이때, 상기 치환된 헤테로아릴은 NO2, NH2, -NH(C=O)R10, -(C=O)NR11R12, -NHSO2R13, 할로겐, 비치환 또는 OH로 하나이상 치환된 직쇄 또는 분지쇄의 C1-6알킬 및 직쇄 또는 분지쇄의 C1-6알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,In this case, the substituted heteroaryl is NO 2 , NH 2 , -NH(C=O)R 10 , -(C=O)NR 11 R 12 , -NHSO 2 R 13 , at least one halogen, unsubstituted or OH One or more substituents may be substituted with a substituent selected from the group consisting of substituted straight-chain or branched C 1-6 alkyl and straight-chain or branched C 1-6 alkoxy,
R10, R11, R12 및 R13은 각각 수소 또는 직쇄 또는 분지쇄의 C1-6알킬이다.R 10 , R 11 , R 12 and R 13 are each hydrogen or linear or branched C 1-6 alkyl.
또한, 상기 화학식 1에서,In addition, in Formula 1,
상기 A는 CH 또는 N이고;wherein A is CH or N;
L은 NH 또는 부재이고;L is NH or absent;
R1 및 R2는 독립적으로 수소, 할로겐, 직쇄 또는 분지쇄의 C1-4알콕시 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 5 내지 7원자의 비치환 또는 치환된 헤테로사이클로알킬이거나, R1 및 R2는 이들이 결합된 탄소원자와 함께 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 5 내지 7원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고, R 1 and R 2 are independently hydrogen, halogen, straight or branched C 1-4 alkoxy, or 5 to 7 atoms including at least one heteroatom selected from the group consisting of N, O and S, unsubstituted or substituted or R 1 and R 2 are 5 to 7 membered unsubstituted or substituted heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O and S together with the carbon atom to which they are attached can form,
이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 분지쇄의 C1-4알킬, 비치환 또는 직쇄 또는 분지쇄의 C1-4알킬로 하나이상 치환된 아민 및 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 비치환 또는 직쇄 또는 분지쇄의 C1-4알킬로 하나이상 치환된 5 내지 7원자의 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;In this case, the substituted heterocycloalkyl is selected from the group consisting of an amine, and N, O or S optionally substituted by one or more C 1-4 alkyl, unsubstituted or C 1-4 straight or branched chain alkyl of straight or branched chain One or more substituents may be substituted with a substituent selected from the group consisting of 5 to 7 membered heterocycloalkyl substituted with one or more unsubstituted or straight or branched C 1-4 alkyl containing one or more heteroatoms;
R3은 -(C=O)NR5R6, -(P=O)R7R8, -SO2R9, 비치환 또는 치환된 C6-10아릴 및 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 5 내지 10 원자의 비치환 또는 치환된 헤테로아릴이고, R 3 is -(C=O)NR 5 R 6 , -(P=O)R 7 R 8 , -SO 2 R 9 , unsubstituted or substituted C 6-10 aryl and the group consisting of N, O and S 5 to 10 membered unsubstituted or substituted heteroaryl containing at least one heteroatom selected from;
이때, 상기 치환된 아릴 및 헤테로아릴은 각각 할로겐, 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-4알킬 및 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-4알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,In this case, the substituted aryl and heteroaryl are each halogen, unsubstituted or branched C 1-4 alkyl one or more substituted with halogen, and straight or branched chain C 1- substituted with one or more halogen, unsubstituted or halogen. 4 may be substituted with one or more substituents selected from the group consisting of alkoxy,
R5, R6, R7, R8 및 R9는 각각 수소 또는 직쇄 또는 분지쇄의 C1-4알킬이고;R 5 , R 6 , R 7 , R 8 and R 9 are each hydrogen or straight or branched C 1-4 alkyl;
R4는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상포함하는 5 내지 9 원자의 비치환 또는 치환된 헤테로아릴이고,R 4 is an unsubstituted or substituted heteroaryl of 5 to 9 atoms including at least one heteroatom selected from the group consisting of N, O and S;
이때, 상기 치환된 헤테로아릴은 NO2, NH2, -NH(C=O)R10, -(C=O)NR11R12, -NHSO2R13, 할로겐, 비치환 또는 OH로 하나이상 치환된 직쇄 또는 분지쇄의 C1-4알킬 및 직쇄 또는 분지쇄의 C1-4알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,In this case, the substituted heteroaryl is NO 2 , NH 2 , -NH(C=O)R 10 , -(C=O)NR 11 R 12 , -NHSO 2 R 13 , at least one halogen, unsubstituted or OH One or more substituents may be substituted with a substituent selected from the group consisting of substituted straight-chain or branched C 1-4 alkyl and straight-chain or branched C 1-4 alkoxy,
R10, R11, R12 및 R13은 각각 수소 또는 직쇄 또는 분지쇄의 C1-4알킬일 수 있다.R 10 , R 11 , R 12 and R 13 may each be hydrogen or a linear or branched C 1-4 alkyl.
또한, 상기 화학식 1에서,In addition, in Formula 1,
상기 A는 CH 또는 N이고;wherein A is CH or N;
L은 NH 또는 부재이고;L is NH or absent;
R1 및 R2는 독립적으로 수소, 할로겐, C1-2알콕시 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 6원자의 비치환 또는 치환된 헤테로사이클로알킬이거나, R1 및 R2는 이들이 결합된 탄소원자와 함께 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 6 또는 7원자의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고, R 1 and R 2 are independently hydrogen, halogen, C 1-2 alkoxy or 6-membered unsubstituted or substituted heterocycloalkyl containing at least one heteroatom selected from the group consisting of N, O and S, or R 1 and R 2 together with the carbon atom to which they are attached may form a 6 or 7 membered unsubstituted or substituted heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of N, O and S;
이때, 상기 치환된 헤테로사이클로알킬은 직쇄 또는 분지쇄의 C1-4알킬, 비치환 또는 C1-2알킬로 하나이상 치환된 아민 및 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 비치환 또는 C1-2알킬로 하나이상 치환된 6원자의 헤테로사이클로알킬로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;In this case, the substituted heterocycloalkyl is a straight or branched C 1-4 alkyl, an amine substituted with one or more unsubstituted or C 1-2 alkyl, and a heteroatom selected from the group consisting of N, O and S. may be substituted with one or more substituents selected from the group consisting of unsubstituted or 6-membered heterocycloalkyl substituted with one or more C 1-2 alkyl;
R3은 -(C=O)NR5R6, -(P=O)R7R8, -SO2R9, 비치환 또는 치환된 페닐 및 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 6 내지 9 원자의 비치환 또는 치환된 헤테로아릴이고, R 3 is -(C=O)NR 5 R 6 , -(P=O)R 7 R 8 , -SO 2 R 9 , unsubstituted or substituted phenyl and hetero selected from the group consisting of N, O and S 6 to 9 membered unsubstituted or substituted heteroaryl containing at least one atom,
이때, 상기 치환된 페닐 및 헤테로아릴은 각각 할로겐, 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-4알킬 및 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-4알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,In this case, the substituted phenyl and heteroaryl are each halogen, unsubstituted or branched C 1-4 alkyl one or more substituted with halogen, and straight or branched C 1 -chain substituted with one or more halogen unsubstituted or halogen. 4 may be substituted with one or more substituents selected from the group consisting of alkoxy,
R5, R6, R7, R8 및 R9는 각각 수소 또는 직쇄 또는 분지쇄의 C1-4알킬이고;R 5 , R 6 , R 7 , R 8 and R 9 are each hydrogen or straight or branched C 1-4 alkyl;
R4는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상포함하는 5 내지 9 원자의 비치환 또는 치환된 헤테로아릴이고,R 4 is an unsubstituted or substituted heteroaryl of 5 to 9 atoms including at least one heteroatom selected from the group consisting of N, O and S;
이때, 상기 치환된 헤테로아릴은 NO2, NH2, -NH(C=O)R10, -(C=O)NR11R12, -NHSO2R13, 할로겐, 비치환 또는 OH로 하나이상 치환된 직쇄 또는 분지쇄의 C1-4알킬 및 직쇄 또는 분지쇄의 C1-2알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,In this case, the substituted heteroaryl is NO 2 , NH 2 , -NH(C=O)R 10 , -(C=O)NR 11 R 12 , -NHSO 2 R 13 , at least one halogen, unsubstituted or OH One or more substituents may be substituted with a substituent selected from the group consisting of substituted straight-chain or branched C 1-4 alkyl and straight-chain or branched C 1-2 alkoxy,
R10, R11, R12 및 R13은 각각 수소 또는 직쇄 또는 분지쇄의 C1-2알킬일 수 있다.R 10 , R 11 , R 12 and R 13 may each be hydrogen or a linear or branched C 1-2 alkyl.
또한, 상기 화학식 1에서,In addition, in Formula 1,
상기 A는 CH 또는 N이고;wherein A is CH or N;
L은 NH 또는 부재이고;L is NH or absent;
R1 및 R2는 독립적으로 수소, F, 메톡시 또는 비치환 또는 치환된 피페리딘, 또는 피페라진이거나, R1 및 R2는 이들이 결합된 탄소원자와 함께 비치환 또는 치환된 피페리딘 또는 아제판을 형성할 수 있고, R 1 and R 2 are independently hydrogen, F, methoxy or unsubstituted or substituted piperidine, or piperazine, or R 1 and R 2 together with the carbon atom to which they are attached are unsubstituted or substituted piperidine or to form azepane,
이때, 상기 치환된 피페리딘, 피페라진 및 아제판은 각각 메틸, -N(CH3)2 및 비치환 또는 메틸로 하나이상 치환된 피페라진으로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;In this case, each of the substituted piperidine, piperazine and azepane may be substituted with one or more substituents selected from the group consisting of methyl, -N(CH 3 ) 2 and piperazine unsubstituted or one or more substituted with methyl. there is;
R3은 -(C=O)NR5R6, -(P=O)R7R8, -SO2R9, 비치환 또는 치환된 페닐, 피리디닐, 피라졸릴, 피롤릴, 티아졸릴, 이소옥사졸릴, 티오펜닐, 퓨라닐, 벤조퓨라닐, 벤조티오펜닐, 인돌리닐 또는 퀴놀리닐이고, R 3 is -(C=O)NR 5 R 6 , -(P=O)R 7 R 8 , -SO 2 R 9 , unsubstituted or substituted phenyl, pyridinyl, pyrazolyl, pyrrolyl, thiazolyl, isoxazolyl, thiophenyl, furanyl, benzofuranyl, benzothiophenyl, indolinyl or quinolinyl;
이때, 상기 치환된 페닐, 피리디닐, 피라졸릴, 피롤릴, 티아졸릴, 이소옥사졸릴, 티오펜닐, 퓨라닐, 벤조퓨라닐, 벤조티오펜닐, 인돌릴 및 퀴놀리닐은 각각 F, 메틸, CF3 및 메톡시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,In this case, the substituted phenyl, pyridinyl, pyrazolyl, pyrrolyl, thiazolyl, isoxazolyl, thiophenyl, furanyl, benzofuranyl, benzothiophenyl, indolyl and quinolinyl are each F, methyl , CF 3 And may be substituted with one or more substituents selected from the group consisting of methoxy,
R5, R6, R7, R8 및 R9는 각각 수소 또는 메틸이고;R 5 , R 6 , R 7 , R 8 and R 9 are each hydrogen or methyl;
R4는 비치환 또는 치환된 피리디닐 또는 인돌릴이고, R 4 is unsubstituted or substituted pyridinyl or indolyl,
이때, 상기 치환된 피리니딜 및 인돌릴은 각각 NO2, NH2, -NH(C=O)CH3, -(C=O)NH2, -NHSO2CH3, F, -C(CH2)2OH, 메틸 및 메톡시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있다.In this case, the substituted pyridyl and indolyl are each NO 2 , NH 2 , -NH(C=O)CH 3 , -(C=O)NH 2 , -NHSO 2 CH 3 , F, -C(CH 2 ) ) 2 OH, one or more may be substituted with a substituent selected from the group consisting of methyl and methoxy.
또한, 상기 화학식 1에서,In addition, in Formula 1,
상기 A는 CH 또는 N이고;wherein A is CH or N;
R1 및 R2는 독립적으로 수소, F, 메톡시, , , , 또는 이거나, R1 및 R2는 이들이 결합된 탄소원자와 함께 , 또는 을 형성할 수 있고;R 1 and R 2 are independently hydrogen, F, methoxy, , , , or or R 1 and R 2 together with the carbon atom to which they are attached , or can form;
R3은 -(C=O)NHCH3, -(C=O)N(CH3)2, -(P=O)(CH3)2, -SO2CH3, , , , , , , , , , , , , , , , , , , , , , , , , , 또는 이고;R 3 is -(C=O)NHCH 3 , -(C=O)N(CH 3 ) 2 , -(P=O)(CH 3 ) 2 , -SO 2 CH 3 , , , , , , , , , , , , , , , , , , , , , , , , , , or ego;
L-R4는 , , , , , , , , , , 또는 일 수 있다.LR 4 is , , , , , , , , , , or can be
본 발명에 따른 상기 화학식 1로 표시되는 화합물의 예로는 하기의 화합물들을 들 수 있다: Examples of the compound represented by Formula 1 according to the present invention include the following compounds:
<1> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노) -5-(1H-피라졸-4-일)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올;<1> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(1H-pyrazole-4- yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<2> 2-(6 -((2-(4-(4-(4- 메틸피페라진-1-일)피페리딘-1-일) 페닐)아미노)-5-(1H-피라졸-4-일)피리미딘-4-아미노)피리딘-2-일) 프로판-2-올;<2> 2-(6-((2-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(1H-pyrazole- 4-yl)pyrimidin-4-amino)pyridin-2-yl)propan-2-ol;
<3> 2-(6-(2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-5-(1H-피라졸-4-일)피리딘-4-일아미노)피리딘-2-일)프로판-2-올;<3> 2-(6-(2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-5-(1H-pyrazol-4-yl) pyridin-4-ylamino)pyridin-2-yl)propan-2-ol;
<4> 2-(6-((2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(1H-피라졸 -4-일)피리딘-4-일)아미노)피리딘-2-일)프로판-2-올;<4> 2-(6-((2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(1H- pyrazol-4-yl)pyridin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<5> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(6-플루오로피리딘-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<5> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(6-fluoropyridin-3 -yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<6> 2-(6-((5-(벤조퓨란 -2-일)-2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<6> 2-(6-((5-(benzofuran-2-yl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino )pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<7> 2-(6-(2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-5-(1-메틸-1H-인돌-5-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;<7> 2-(6-(2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-5-(1-methyl-1H-indole-5) -yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<8> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5- (퓨란-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<8> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(furan-3-yl)pyri midin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<9> 2-(6-(2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-5-(1-메틸-1H-피라졸-4-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;<9> 2-(6-(2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-5-(1-methyl-1H-pyrazole- 4-yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<10> 2-(6-(2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-5-(1-메틸-1H-피라졸-3-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;<10> 2-(6-(2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-5-(1-methyl-1H-pyrazole- 3-yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<11> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5- (티오펜-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<11> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(thiophen-3-yl) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<12> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5- (피리딘-3-일)피리미딘-4-일)아미노) 피리딘-2-일)프로판-2-올;<12> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(pyridin-3-yl)pyri midin-4-yl)amino) pyridin-2-yl)propan-2-ol;
<13> 2-(6-((5-(벤조퓨란-3-일)-2-((3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-아미노)아미노)피리딘-2-일)프로판-2-올;<13> 2-(6-((5-(benzofuran-3-yl)-2-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-amino)amino)pyridin-2-yl)propan-2-ol;
<14> 2-(6-(2-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐아미노)-5-(퀴놀린-6-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;<14> 2-(6-(2-(3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino)-5-(quinoline- 6-yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<15> 2-(6-((2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(1-메틸-1H- 피롤-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<15> 2-(6-((2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(1- methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<16> 2-(6-((5-(벤조퓨란 -2-일)-2-((3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-아미노)아미노)피리딘-2-일)프로판-2-올;<16> 2-(6-((5-(benzofuran-2-yl)-2-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-amino)amino)pyridin-2-yl)propan-2-ol;
<17> 2- (6 - ((2 - ((4- (4- 메틸피페라진 -1-일)피페리딘-1-일)페닐)아미노) -5-페닐피리미딘 -4-일)아미노)피리딘-2-일)프로판 -2-올;<17> 2- (6 - ((2- ((4- (4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-phenylpyrimidin-4-yl) amino)pyridin-2-yl)propan-2-ol;
<18> 2-(6 -((5-(벤조 [b]티오펜-3-일) -2 -((3-메톡시 -4-(4-메틸피페라진-1-일)피페리딘 -1-일)페닐)아미노)피리미딘 -4-일) 아미노) 피리딘 -2-일) 프로판 -2-올;<18> 2-(6-((5-(benzo [b]thiophen-3-yl) -2 -((3-methoxy-4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<19> 2- (6 - ((5- (1H- 인돌 -3-일) -2 - ((3- 메톡시 -4- (4- 메틸피페라진 -1-일) 피페리딘 -1-일) 페닐) 아미노 ) 피리미딘 -4-일) 아미노) 피리딘 -2-일) 프로판 -2-올;<19> 2- (6 - ((5- (1H-indol -3-yl) -2 - ((3- methoxy -4- (4-methylpiperazin-1-yl) piperidine -1- yl) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<20> 2-(6-((5-(벤조 [b]티오펜-2-일) -2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<20> 2-(6-((5-(benzo [b]thiophen-2-yl) -2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<21> 2-(6-((5-(5-플루오로피리딘-3-일)-2-((3-메톡시-4-(4- 메틸피페라진-1-일)피페리딘-1-일) 페닐)아미노)피리미딘-4-일)아미노) 피리딘-2-일)프로판-2-올;<21> 2-(6-((5-(5-fluoropyridin-3-yl)-2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-) 1-yl) phenyl)amino)pyrimidin-4-yl)amino) pyridin-2-yl)propan-2-ol;
<22> 2-(6-(2-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐아미노)-5-(티오펜-2-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;<22> 2-(6-(2-(3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino)-5-(thiophene) -2-yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<23> 2-(6-((2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(1H-피롤-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<23> 2-(6-((2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(1H- pyrrol-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<24> 2-(6-((5-(퓨란-2-일)-2-((3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-아미노)아미노)피리딘-2-일)프로판-2-올;<24> 2-(6-((5-(furan-2-yl)-2-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-amino)amino)pyridin-2-yl)propan-2-ol;
<25> 2-(6-((5-(벤조퓨란 -2-일)-2-((1,2,3,4- 테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘 -2-일)프로판-2-올;<25> 2-(6-((5-(benzofuran-2-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl )amino)pyridin-2-yl)propan-2-ol;
<26> 2-(6-((5-(퓨란-3-일)-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올;<26> 2-(6-((5-(furan-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) amino)pyridin-2-yl)propan-2-ol;
<27> 2-(6-((5-(벤조퓨란 -3-일)-2-((1,2,3,4- 테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘 -2-일)프로판-2-올;<27> 2-(6-((5-(benzofuran-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl )amino)pyridin-2-yl)propan-2-ol;
<28> 2-(6-((5-(6-플루오로피리딘-3-일)-2- ((1,2,3,4-테트라히드로이소퀴놀린 -6-일)아미노)피리미딘-4-일)아미노) 피리딘-2 -프로판-2-올;<28> 2-(6-((5-(6-fluoropyridin-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin- 4-yl)amino) pyridin-2-propan-2-ol;
<29> 2-(6-((5-(1-메틸-1H-피라졸-3-일)-2-((1,2,3,4-테트라 히드로이소퀴놀린-6-일)아미노) 피리미딘-4-일)아미노)피리딘-2-일) 프로판-2-올;<29> 2-(6-((5-(1-methyl-1H-pyrazol-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<30> 2-(6-((2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)-5-(티오펜-2-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<30> 2-(6-((2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(thiophen-2-yl)pyrimidin-4-yl )amino)pyridin-2-yl)propan-2-ol;
<31> 2-(6-((5-(벤조 [b]티오펜-2-일)-2-((1,2,3,4- 테트라히드로 이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<31> 2-(6-((5-(benzo [b]thiophen-2-yl)-2-((1,2,3,4-tetrahydro isoquinolin-6-yl)amino)pyrimidine -4-yl)amino)pyridin-2-yl)propan-2-ol;
<32> 2-(6-((5-(2-메톡시페닐)-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<32> 2-(6-((5-(2-methoxyphenyl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) amino)pyridin-2-yl)propan-2-ol;
<33> 2-(6-((5-(3-메톡시페닐)-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘 -2-일)프로판-2-올;<33> 2-(6-((5-(3-methoxyphenyl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) amino)pyridin-2-yl)propan-2-ol;
<34> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(티오펜-2-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<34> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(thiophen-2-yl) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<35> 2-(6-(5-(벤조[b]티오펜-2-일)-2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;<35> 2-(6-(5-(benzo[b]thiophen-2-yl)-2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl amino)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<36> 2-(6-((5-(벤조퓨란 -3-일)-2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<36> 2-(6-((5-(benzofuran-3-yl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino )pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<37> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5- (1H-피롤-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<37> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(1H-pyrrol-3-yl) )pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<38> 2-(6-((5-(1H-피롤-3-일)-2-((1,2,3,4-테트라 히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-프로판-2-올;<38> 2-(6-((5-(1H-pyrrol-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4- yl)amino)pyridin-2-propan-2-ol;
<39> 2-(6-(5-(벤조[b]티오펜-2-일)-2-(2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일아미노)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;<39> 2-(6-(5-(benzo[b]thiophen-2-yl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyri midin-4-ylamino)pyridin-2-yl)propan-2-ol;
<40> 2-(6-(5-(벤조[b]티오펜-2-일)-2-(1,2,3,4-테트라히드로이소퀴놀린-7-일아미노)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;<40> 2-(6-(5-(benzo[b]thiophen-2-yl)-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4- ylamino)pyridin-2-yl)propan-2-ol;
<41> 2-(6-((5-(벤조[b]티오펜-2-일)-2- ((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-7-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<41> 2-(6-((5-(benzo[b]thiophen-2-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<42> 2-(6-((5-(퓨란-3-일)-2-((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<42> 2-(6-((5-(furan-3-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine- 4-yl)amino)pyridin-2-yl)propan-2-ol;
<43> 2-(6-((5-(퓨란-3-일)-2-((1,2,3,4-테트라히드로이소퀴놀린-7-일)아미노) 피리미딘-4-일)아미노)피리딘-2-일) 프로판-2-올;<43> 2-(6-((5-(furan-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<44> 2-(6-((5-(퓨란-3-일)-2-((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-7-일)아미노)피리미딘-4-일)아미노) 피리딘-2-일)프로판-2-올;<44> 2-(6-((5-(furan-3-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidine- 4-yl)amino) pyridin-2-yl)propan-2-ol;
<45> 2-(6-((5-(6-플루오로피리딘-3-일)-2 -((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<45> 2-(6-((5-(6-fluoropyridin-3-yl)-2 -((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino )pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<46> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(티아졸-5-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<46> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(thiazol-5-yl) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<47> 2-(6-((2-((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)-5- (1H-피라졸-3-일) 피리미딘-4-일)아미노)피리딘-2-일) 프로판-2-올;<47> 2-(6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(1H-pyrazol-3-yl) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<48> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(퓨란-3-일) -4-(1-메틸-1H-인돌-3-일)2-아민;<48> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(furan-3-yl)-4-(1-methyl-1H- indol-3-yl)2-amine;
<49> N-(5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일)피리미딘 -2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<49> N-(5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso quinolin-6-amine;
<50> N-(5-(퓨란-3-일) -4-(1-메틸-1H-인돌-3-일)피리미딘 -2-일)-2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6 -아민;<50> N-(5-(furan-3-yl) -4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-methyl-1,2,3,4 -tetrahydroisoquinolin-6 -amine;
<51> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(1-메틸-1H- 인돌-3-일)-5-(티오펜-2-일)2-아민;<51> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)-5-( thiophen-2-yl)2-amine;
<52> N-(4-(1-메틸-1H-인돌-3-일)-5-(티오펜-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<52> N-(4-(1-methyl-1H-indol-3-yl)-5-(thiophen-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydro isoquinolin-6-amine;
<53> N-(5-(이소옥 사졸-4-일)-4-(1- 메틸-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<53> N-(5-(isoxazol-4-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydro isoquinolin-6-amine;
<54> N-(4-(1-메틸-1H-인돌-3-일)-5-(1H-피라졸-4-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<54> N-(4-(1-methyl-1H-indol-3-yl)-5-(1H-pyrazol-4-yl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-amine;
<55> N-(5-(퓨란-3-일)-4-(1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<55> N-(5-(furan-3-yl)-4-(1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-6- amines;
<56> N-(5-(6-플루오로 피리딘-3-일) -4- (1-메틸-1H-인돌 -3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<56> N-(5-(6-fluoro pyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4 -tetrahydroisoquinolin-6-amine;
<57> N-(5-(5-플루오로 피리딘-3-일)-4- (1-메틸-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<57> N-(5-(5-fluoro pyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4 -tetrahydroisoquinolin-6-amine;
<58> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(1-메틸-1H-인돌-3-일)-5-(티오펜-3-일)피리미딘-2-아민;<58> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)-5-( thiophen-3-yl)pyrimidin-2-amine;
<59> N-(5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일) 피리미딘-2-일) -1,2,3,4-테트라 히드로이소퀴놀린-7-아민;<59> N-(5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso quinolin-7-amine;
<60> N-(5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일) 피리미딘-2-일) -2,3,4,5-테트라히드로-1H-벤조[d]아제핀-7-아민;<60> N-(5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin-7-amine;
<61> 5-(퓨란-3-일)-4- (1-메틸-1H-인돌 -3-일)-N-(4-(4-메틸피페라진-1-일)페닐)피리미딘-2-아민;<61> 5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine- 2-amine;
<62> 5-(퓨란-3-일)-N-(3-메톡시-4-(4-메틸피페라진-1-일)페닐)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;<62> 5-(furan-3-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-4-(1-methyl-1H-indole-3- yl) pyrimidin-2-amine;
<63> (S)-5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일)-N-(4-(3-메틸피페라진-1-일)페닐)피리미딘-2-아민 ;<63> (S)-5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(3-methylpiperazin-1-yl)phenyl ) pyrimidin-2-amine;
<64> (S)-5-(퓨란-3-일)-N-(3-메톡시 -4-(3-메틸피페라진-1-일)페닐) -4-(1-메틸-1H- 인돌-3-일)피리미딘-2-아민;<64> (S)-5-(furan-3-yl)-N-(3-methoxy-4-(3-methylpiperazin-1-yl)phenyl)-4-(1-methyl-1H- indol-3-yl)pyrimidin-2-amine;
<65> N-(5-(퓨란-3-일)-4-(4-니트로-1H- 인돌-1-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<65> N-(5-(furan-3-yl)-4-(4-nitro-1H-indol-1-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso quinolin-6-amine;
<66> N-(1-(5-(퓨란-3-일)-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노) 피리미딘-4-일)-1H-인돌-4-일)메탄술폰아미드;<66> N-(1-(5-(furan-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)- 1H-indol-4-yl)methanesulfonamide;
<67> N-(4-(4-아미노-1H-인돌-1-일)-5- (퓨란-3-일)피리미딘-2-일)-1,2,3,4- 테트라히드로이소퀴놀린-6-아민;<67> N-(4-(4-amino-1H-indol-1-yl)-5-(furan-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso quinolin-6-amine;
<68> N-(1-(5-(퓨란-3-일)-2-((1,2,3,4-테트라히드로 이소퀴놀린-6-일)아미노)피리미딘-4-일)-1H-인돌-4-일)아세트아미드;<68> N-(1-(5-(furan-3-yl)-2-((1,2,3,4-tetrahydro isoquinolin-6-yl)amino)pyrimidin-4-yl)- 1H-indol-4-yl)acetamide;
<69> 5-(퓨란-3-일)-N-(3-메톡시-4- (4-메틸피페라진 -1-일)페닐)-4-(4-니트로-1H-인돌-1-일)피리미딘-2-아민;<69> 5-(furan-3-yl)-N-(3-methoxy-4- (4-methylpiperazin-1-yl)phenyl)-4-(4-nitro-1H-indole-1- yl) pyrimidin-2-amine;
<70> 1-(5-(퓨란-3-일) -2-((3-메톡시-4- (4-메틸피페라진 -1-일)페닐)아미노)피리미딘-4-일)-1H-인돌-4-아민;<70> 1-(5-(furan-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)- 1H-indol-4-amine;
<71> 5-(퓨란-3-일)-N- (4-(4-메틸피페라진-1-일)페닐)-4- (4-니트로-1H-인돌-1-일)피리미딘-2-아민;<71> 5-(furan-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(4-nitro-1H-indol-1-yl)pyrimidin- 2-amine;
<72> 1-(5-(퓨란-3-일)-2-((4-(4-메틸피페라진-1-일)페닐)아미노)피리미딘-4-일)-1H-인돌-4-아민;<72> 1-(5-(furan-3-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1H-indole-4 -amines;
<73> 5-(6-플루오로 피리딘-3-일)-4-(1-메틸-1H-인돌-3-일)-N-(4-(4-메틸피페라진-1-일)페닐)피리미딘-2-아민;<73> 5-(6-fluoro pyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl ) pyrimidin-2-amine;
<74> N-(3-플루오로-4-(4-메틸피페라진-1-일)페닐)-5-(6-플루오로피리딘-3-일)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;<74> N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-5-(6-fluoropyridin-3-yl)-4-(1-methyl-1H- indol-3-yl)pyrimidin-2-amine;
<75> 5-(6-플루오로 피리딘-3-일)-N- (3-메톡시-4-(4- 메틸피페라진-1-일)페닐)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;<75> 5-(6-fluoro pyridin-3-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-4-(1-methyl-1H- indol-3-yl)pyrimidin-2-amine;
<76> (S)-5-(6-플루오로피리딘-3-일)-4-(1-메틸-1H-인돌-3-일)-N-(4-(3-메틸피페라진 -1-일)페닐)피리미딘-2-아민;<76> (S)-5-(6-fluoropyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(3-methylpiperazine-1 -yl)phenyl)pyrimidin-2-amine;
<77> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(6-플루오로 피리딘-3-일)-4- (1-메틸-1H-인돌 -3-일)피리미딘-2- 아민;<77> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(6-fluoro pyridin-3-yl)-4-(1- methyl-1H-indol-3-yl)pyrimidin-2-amine;
<78> N-(3-플루오로-4-(4-메틸피페라진-1-일)페닐)-5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;<78> N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-5-(furan-3-yl)-4-(1-methyl-1H-indole-3- yl) pyrimidin-2-amine;
<79> N-(5-(퓨란-3-일)-4-(6-메톡시-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<79> N-(5-(furan-3-yl)-4-(6-methoxy-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydro isoquinolin-6-amine;
<80> N-(5-(퓨란-3-일)-4-(6-메톡시-1-메틸-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라 히드로이소퀴놀린-6-아민;<80> N-(5-(furan-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3, 4-tetrahydroisoquinolin-6-amine;
<81> N-(4-(1-메틸-1H- 인돌-3-일)-5-(6- (트리플루오로메틸)피리딘-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-4-일) 6-아민;<81> N-(4-(1-methyl-1H-indol-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)-1,2 ,3,4-tetrahydroisoquinolin-4-yl) 6-amine;
<82> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(6-메톡시-1-메틸-1H-인돌-3-일)-5-(6-(트리 플루오로메틸)피리딘-3-일)피리미딘-2-아민;<82> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(6-methoxy-1-methyl-1H-indol-3-yl )-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<83> 4-(6-메톡시-1-메틸-1H-인돌-3-일)-N-(3-메톡시-4-(4-메틸피페라진-1-일)페닐)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2-아민;<83> 4-(6-methoxy-1-methyl-1H-indol-3-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-5- (6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<84> N-(4-(6-메톡시-1-메틸-1H-인돌-3-일)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2-일)4-테트라히드로이소퀴놀린-6-아민;<84> N-(4-(6-methoxy-1-methyl-1H-indol-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl ) 4-tetrahydroisoquinolin-6-amine;
<85> N- (4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(6-플루오로 피리딘-3-일)-4-(6-메톡시-1-메틸-1H-인돌-3-일) 피리미딘-3-일)피리미딘-2-아민;<85> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(6-fluoro pyridin-3-yl)-4-(6- methoxy-1-methyl-1H-indol-3-yl) pyrimidin-3-yl)pyrimidin-2-amine;
<86> 5-(6-플루오로 피리딘-3-일)-4-(6-메톡시-1-메틸-1H-인돌-3-일)-N-(3-메톡시-4-(4-메틸피페라진-1-일) 페닐)피리미딘-2- 아민;<86> 5-(6-fluoro pyridin-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)-N-(3-methoxy-4-(4) -methylpiperazin-1-yl)phenyl)pyrimidin-2-amine;
<87> N-(5-(6-플루오로피리딘-3-일)-4-(6-메톡시-1-메틸-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<87> N-(5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1, 2,3,4-tetrahydroisoquinolin-6-amine;
<88> N-(4-(6-메톡시 -1H-인돌-3-일) -5-(6-(트리플루오로메틸)피리딘 -3-일)피리미딘 -2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<88> N-(4-(6-methoxy-1H-indol-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)-1, 2,3,4-tetrahydroisoquinolin-6-amine;
<89> N-(5-(6-플루오로피리딘-3-일)-4-(6-메톡시-1H- 인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라 히드로이소퀴놀린-6-아민;<89> N-(5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3, 4-tetrahydroisoquinolin-6-amine;
<90> N-(4-(4-(디메틸아미노)피페리딘 -1-일)-3-메톡시 페닐)-4-(6-메톡시-1H-인돌-3-일)-5-(6-(트리 플루오로메틸)피리딘-3-일)피리미딘-2-아민;<90> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(6-methoxy-1H-indol-3-yl)-5- (6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<91> 4-(6-메톡시-1H- 인돌-3-일)-N-(3-메톡시-4-(4- 메틸피페라진-1-일)페닐)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2-아민;<91> 4-(6-methoxy-1H-indol-3-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-5-(6-( trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<92> N-(4-(4-(디메틸아미노)피페리딘 -1-일)-3-메톡시 페닐)-5-(6-플루오로피리딘-3-일)-4-(6-메톡시 -1H-인돌-3-일) 피리미딘-2-아민;<92> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(6-fluoropyridin-3-yl)-4-(6- methoxy-1H-indol-3-yl) pyrimidin-2-amine;
<93> 5-(6-플루오로 피리딘-3-일)-4- (6-메톡시-1H-인돌-3-일)-N- (3- 메톡시-4-(4-메틸피페라진-1-일)페닐)피리미딘-2-아민;<93> 5-(6-fluoro pyridin-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(3-methoxy-4-(4-methylpiperazine) -1-yl)phenyl)pyrimidin-2-amine;
<94> N-(4-(6-플루오로-1H-인돌-3-일)-5- (6-플루오로피리딘-3-일)피리미딘 -2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<94> N-(4-(6-fluoro-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)pyrimidin-2-yl)-1,2,3, 4-tetrahydroisoquinolin-6-amine;
<95> N-(4-(6-플루오로-1-메틸-1H-인돌-3-일)-5-(6-플루오로피리딘-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;<95> N-(4-(6-fluoro-1-methyl-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)pyrimidin-2-yl)-1, 2,3,4-tetrahydroisoquinolin-6-amine;
<96> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(퓨란-3-일)-4-(6-메톡시-1H-인돌-3-일)피리미딘-2-아민;<96> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(furan-3-yl)-4-(6-methoxy-1H -indol-3-yl)pyrimidin-2-amine;
<97> 5-(퓨란-3-일)-4-(6-메톡시-1H-인돌-3-일)-N-(4-((S)-3-메틸피페라진-1-일)페닐)피리미딘-2-아민;<97> 5-(furan-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(4-((S)-3-methylpiperazin-1-yl) phenyl)pyrimidin-2-amine;
<98> (S)-5-(퓨란-3-일)-4-(6-메톡시-1H-인돌-3-일)-N-(3-메톡시-4- (3-메틸피페라진-1-일)페닐)피리미딘-2-아민;<98> (S)-5-(furan-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(3-methoxy-4- (3-methylpiperazine) -1-yl)phenyl)pyrimidin-2-amine;
<99> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(1H-인돌-3-일)-5-(6-(트리플루오로메틸)피리딘 -3-일)피리미딘-2-아민;<99> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(1H-indol-3-yl)-5-(6-(tri fluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<100> (S)-4-(1H-인돌-3-일)-N-(4-(3- 메틸피페라진-1-일)페닐)-5-(6-(트리플루오로메틸)피리딘-3-일) 피리미딘-2 -아민;<100> (S)-4-(1H-indol-3-yl)-N-(4-(3-methylpiperazin-1-yl)phenyl)-5-(6-(trifluoromethyl)pyridine -3-yl) pyrimidin-2-amine;
<101> (S)-5-(6-플루오로피리딘-3-일)-4-(6-메톡시-1H-인돌-3-일)-N-(4-(3-메틸피페라진-1-일)페닐) 2-피리미딘-아민;<101> (S)-5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(4-(3-methylpiperazine- 1-yl)phenyl) 2-pyrimidin-amine;
<102> (S)-5-(6-플루오로피리딘-3-일)-4-(6-메톡시-1H- 인돌-3-일)-N-(3-메톡시-4-(3- 메틸피페라진-1-일)페닐)피리미딘-2-아민;<102> (S)-5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(3-methoxy-4-(3) -methylpiperazin-1-yl)phenyl)pyrimidin-2-amine;
<103> N-(3-메톡시-4- (4-메틸피페라진-1-일)페닐)-4-(1- 메틸-1H-인돌-3-일)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2- 아민;<103> N-(3-methoxy-4- (4-methylpiperazin-1-yl)phenyl)-4-(1-methyl-1H-indol-3-yl)-5-(6-(tri fluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<104> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4 (1-메틸-1H- 인돌-3-일)-5-(6- (트리플루오로메틸)피리딘-3-피리미딘-2-아민;<104> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4 (1-methyl-1H-indol-3-yl)-5-(6 - (trifluoromethyl)pyridin-3-pyrimidin-2-amine;
<105> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(퓨란-3-일) -4-(6-메톡시-1- 메틸-1H-인돌-3-일)피리미딘-2-아민;<105> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(furan-3-yl)-4-(6-methoxy-1 -methyl-1H-indol-3-yl)pyrimidin-2-amine;
<106> 5-(퓨란-3-일)-4- (6-메톡시-1-메틸-1H-인돌-3-일)-N-(3-메톡시-4-(4-메틸피페라진-1-일)페닐)피리미딘 -2-아민;<106> 5-(furan-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)-N-(3-methoxy-4-(4-methylpiperazine) -1-yl)phenyl)pyrimidin-2-amine;
<107> (S)-4-(1-메틸-1H-인돌-3-일)-N- (4-(3-메틸피페라진-1-일)페닐) -5-(6-(트리 플루오로메틸) 피리딘-3-일)피리미딘-2-아민;<107> (S)-4-(1-methyl-1H-indol-3-yl)-N-(4-(3-methylpiperazin-1-yl)phenyl)-5-(6-(trifluoro romethyl) pyridin-3-yl)pyrimidin-2-amine;
<108> 4-(6-플루오로-1H-인돌-3-일)-5-(6-플루오로피리딘-3-일)-N-(4-((S)-3-메틸피페라진-1-일)페닐)피리미딘-2-아민;<108> 4-(6-fluoro-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)-N-(4-((S)-3-methylpiperazine- 1-yl)phenyl)pyrimidin-2-amine;
<109> (S)-4-(6-플루오로 -1H-인돌 -3-일)-5-(6-플루오로피리딘-3-일)-N-(3-메톡시-4-(3-메틸피페라진-1-일)페닐)피리미딘-2-아민;<109> (S)-4-(6-fluoro-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)-N-(3-methoxy-4-(3) -methylpiperazin-1-yl)phenyl)pyrimidin-2-amine;
<110> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(6- 플루오로-1H-인돌-3-일)-5-(6-플루오로피리딘-3-일)피리미딘-2-아민;<110> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(6-fluoro-1H-indol-3-yl)-5- (6-fluoropyridin-3-yl)pyrimidin-2-amine;
<111> N-(4-(6-플루오로-1H-인돌-3-일)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2-일)-1,2,3,4- 테트라히드로 이소퀴놀린-6-아민;<111> N-(4-(6-fluoro-1H-indol-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)-1, 2,3,4-tetrahydro isoquinolin-6-amine;
<112> (S)-5-(6-플루오로피리딘-3-일)-N-(3-메톡시-4-(3-메틸피페라진 -1-일)페닐)-4-(1-메틸-1H-인돌 -3-일)피리미딘-2-아민;<112> (S)-5-(6-fluoropyridin-3-yl)-N-(3-methoxy-4-(3-methylpiperazin-1-yl)phenyl)-4-(1- methyl-1H-indol-3-yl)pyrimidin-2-amine;
<113> 5-(6-플루오로 피리딘-3-일)-N- (3-메톡시-4-(피페리딘-4-일)페닐)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;<113> 5-(6-fluoro pyridin-3-yl)-N-(3-methoxy-4-(piperidin-4-yl)phenyl)-4-(1-methyl-1H-indole- 3-yl)pyrimidin-2-amine;
<114> 5-(6-플루오로 피리딘-3-일)-4- (1-메틸-1H-인돌 -3-일)-N-(4-(피페리딘-4-일)페닐)피리미딘-2-아민;<114> 5-(6-fluoro pyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(piperidin-4-yl)phenyl)pyri midin-2-amine;
<115> 5-(6-플루오로피리딘-3-일)-4-(6- 메톡시-1-메틸-1H-인돌-3-일)-N-(3-메톡시-4-(피페리딘-4-일) 페닐)피리미딘-2-아민;<115> 5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)-N-(3-methoxy-4-(p) peridin-4-yl) phenyl) pyrimidin-2-amine;
<116> 4-(6-플루오로-1H-인돌-3-일)-5-(6-플루오로피리딘-3-일)-N-(3-메톡시-4-(피페리딘-4-일)페닐)피리미딘-2-아민;<116> 4-(6-fluoro-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)-N-(3-methoxy-4-(piperidin-4) -yl)phenyl)pyrimidin-2-amine;
<117> 3-(5-(6-플루오로피리딘-3-일) -2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)-1H-인돌-1-카르복사미드;<117> 3-(5-(6-fluoropyridin-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) -1H-indole-1-carboxamide;
<118> 3-(5-(6-플루오로피리딘-3-일) -2-((3-메톡시-4-(피페리딘-4-일)페닐)아미노)피리미딘-4-일)-1H-인돌-1-카르복사미드;<118> 3-(5-(6-fluoropyridin-3-yl) -2-((3-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl )-1H-indole-1-carboxamide;
<119> 3-(2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(6-플루오로피리딘-3-일)피리미딘-4-일)-1-카르복사미드;<119> 3-(2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(6-fluoropyridin-3-yl) pyrimidin-4-yl)-1-carboxamide;
<120> (2-((4-(4-(디메틸아미노) 피페리딘-1-일)-3-메톡시페닐) 아미노)-4-((6- (2-히드록시프로판-2-일) 피리딘-2-일) 아미노)피리미딘 -5-일)디메틸포스핀옥사이드;<120> (2-((4-(4-(dimethylamino) piperidin-1-yl)-3-methoxyphenyl) amino)-4-((6- (2-hydroxypropane-2- yl) pyridin-2-yl) amino) pyrimidin-5-yl) dimethylphosphine oxide;
<121> (4-((6-(2-히드록시프로판-2-일) 피리딘-2-일) 아미노)-2-((3- 메톡시-4-(4-(4- 메틸피페라진-1-일)피페리딘-1 페닐)아미노) 피리미딘-5-일) 디메틸포스핀옥사이드;<121> (4-((6-(2-hydroxypropan-2-yl) pyridin-2-yl) amino)-2-((3- methoxy-4-(4-(4-methylpiperazine) -1-yl)piperidin-1 phenyl)amino)pyrimidin-5-yl)dimethylphosphine oxide;
<122> (4-((6-(2-히드록시프로판-2-일) 피리딘-2-일) 아미노)-2- ((1,2,3,4- 테트라히드로 이소퀴놀린-6-일)아미노)피리미딘-5-일) 디메틸포스핀옥사이드;<122> (4-((6-(2-hydroxypropan-2-yl) pyridin-2-yl) amino)-2- ((1,2,3,4-tetrahydro isoquinolin-6-yl) ) amino) pyrimidin-5-yl) dimethylphosphine oxide;
<123> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노) -5-(메틸술포닐) 피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<123> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(methylsulfonyl)pyrimidine- 4-yl)amino)pyridin-2-yl)propan-2-ol;
<124> 2-(6-((2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(메틸술포닐)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올;<124> 2-(6-((2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(methylsulfur) phonyl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<125> 2-(6-((5-(메틸술포닐)-2 ((1,2,3,4- 테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올;<125> 2-(6-((5-(methylsulfonyl)-2 ((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino)pyridine -2-yl) propan-2-ol;
<126> 2-(6-((2-(2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)-5- (메틸술포닐)피리미딘-4-일)아미노) 피리딘-2-일)프로판-2-올;<126> 2-(6-((2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(methylsulfonyl)pyrimidin-4-yl )amino) pyridin-2-yl)propan-2-ol;
<127> 2-(6-((5-(메틸술포닐)-2- ((1,2,3,4-테트라 히드로이소퀴놀린-7-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;<127> 2-(6-((5-(methylsulfonyl)-2-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl)amino) pyridin-2-yl)propan-2-ol;
<128> 2-(6-((2-((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-7-일)아미노)-5-(메틸술포닐)피리미딘-4-일)아미노)피리딘-2-일) 프로판-2-올;<128> 2-(6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(methylsulfonyl)pyrimidin-4- yl)amino)pyridin-2-yl)propan-2-ol;
<129> 2-(6-((2-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(메틸술포닐)피리미딘-4-일)(메틸)아미노)-2-일)프로판-2-올;<129> 2-(6-((2-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(methylsulfonyl)pyrimidin-4-yl )(methyl)amino)-2-yl)propan-2-ol;
<130> N-(4-(4-(디메틸아미노)피페리딘 -1-일)-3-메톡시페닐)-4-(1-메틸-1H- 인돌-3-일)-5-(메틸술포닐)피리미딘-2-아민;<130> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)-5-( methylsulfonyl)pyrimidin-2-amine;
<131> 2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-4-(6-(2-히드록시프로판-2-일)피리딘-2-일아미노)-N,N-디메틸피리미딘-5-카복스아마이드;<131> 2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-4-(6-(2-hydroxypropan-2-yl)pyridine- 2-ylamino)-N,N-dimethylpyrimidine-5-carboxamide;
<132> 4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N,N-디메틸-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-5-카복스아마이드;<132> 4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-((1,2,3,4-tetrahydroiso quinolin-6-yl)amino)pyrimidine-5-carboxamide;
<133> 4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N,N-디메틸-2-((2- 메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)피리딘-2-일)아미노)피리미딘-5-카복스아마이드;<133> 4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-((2-methyl-1,2,3,4 -tetrahydroisoquinolin-6-yl)pyridin-2-yl)amino)pyrimidine-5-carboxamide;
<134> (S)-4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N,N-디메틸-2 -((4-(3-메틸피페라진-1-일)페닐)아미노)피리미딘-5-카복스아마이드;<134> (S)-4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-((4-(3-methylpipe Razin-1-yl)phenyl)amino)pyrimidine-5-carboxamide;
<135> (R)-4-(6-(2-히드록시프로판-2-일)피리딘-2-일아미노)-2-(3-메톡시-4-(3-메틸피페라진-1-일)페닐아미노)-N,N-디메틸피리미딘-5-카복스아마이드;<135> (R)-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)-2-(3-methoxy-4-(3-methylpiperazine-1- yl)phenylamino)-N,N-dimethylpyrimidine-5-carboxamide;
<136> 2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-4-((6-(2-히드록시프로판-2-일)피리딘-2-일) 아미노)-N-메틸피리미딘-5-카복스아마이드;<136> 2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-4-((6-(2-hydroxypropan-2-yl) )pyridin-2-yl) amino)-N-methylpyrimidine-5-carboxamide;
<137> 4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N-메틸-2-((1,2,3,4-테트라 히드로이소퀴놀린-6-일)아미노) 피리미딘-5-카복스아마이드.<137> 4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N-methyl-2-((1,2,3,4-tetrahydroisoquinoline- 6-yl)amino) pyrimidine-5-carboxamide.
본 발명의 상기 화학식 1로 표시되는 화합물은 약학적으로 허용가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산, 아인산 등과 같은 무기산류, 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류 등과 같은 무독성 유기산, 트리플루오로아세트산, 아세테이트, 안식향산, 구연산, 젖산, 말레인산, 글루콘산, 메탄설폰산, 4-톨루엔설폰산, 주석산, 푸마르산 등과 같은 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염의 종류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트, 만델레이트 등을 포함한다.The compound represented by Formula 1 of the present invention may 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 inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, etc., aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. Non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids, etc., organic acids such as trifluoroacetic acid, acetate, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid, etc. get it from Examples of such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, and Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sube Late, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-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 결정화시켜서 제조할 수 있다. The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving the derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile, etc. and adding an organic or inorganic acid It can be prepared by filtration and drying, or by distilling the solvent and excess acid 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 prepare pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. The corresponding salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable negative salt (eg silver nitrate).
나아가, 본 발명은 상기 화학식 1로 표시되는 화합물 및 이의 약학적으로 허용가능한 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 광학 이성질체, 수화물 등을 모두 포함한다.Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like, which can be prepared therefrom.
본 발명의 다른 측면은,Another aspect of the present invention is
하기 반응식 1에 나타난 바와 같이,As shown in Scheme 1 below,
화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시키는 단계(단계 1); 및reacting the compound represented by Formula 4 with the compound represented by Formula 5 (step 1); and
화학식 2로 표시되는 화합물을 화학식 3으로 표시되는 화합물과 반응시키는 단계(단계 2)를 포함하는 상기 화학식 1로 표시되는 화합물의 제조방법을 제공한다.It provides a method for preparing a compound represented by the formula (1), comprising the step (step 2) of reacting the compound represented by the formula (2) with the compound represented by the formula (3).
[반응식 1][Scheme 1]
(상기 반응식 1에서, A, L, R1, R2, R3 및 R4는 상기 화학식 1에서 정의한 바와 같고;(In Scheme 1, A, L, R 1 , R 2 , R 3 and R 4 are as defined in Formula 1 above;
X1 및 X2는 각각 할로겐이고; 및X 1 and X 2 are each halogen; and
L1은 또는 다).L 1 is or all).
이하, 상기 반응식 1의 제조방법을 상세히 설명한다.Hereinafter, the preparation method of Scheme 1 will be described in detail.
상기 제조방법에 있어서, 단계 1은 화학식 4로 표시되는 화합물과 화학식 5로 표시되는 화합물을 반응시켜 화학식 2로 표시되는 화합물을 얻는 단계이며, 구체적으로, 화학식 4로 표시되는 화합물의 할로겐(X1)과 화학식 5로 표시되는 화합물의 1차아민이 염기 존재하여 반응하여 N-아릴화가 일어나 화학식 2로 표시되는 화합물을 얻는 단계이다.In the above preparation method, step 1 is a step of reacting a compound represented by Formula 4 with a compound represented by Formula 5 to obtain a compound represented by Formula 2, specifically, the halogen (X 1 ) of the compound represented by Formula 4 ) and the primary amine of the compound represented by Formula 5 are reacted in the presence of a base to undergo N-arylation to obtain a compound represented by Formula 2.
상기 염기는 N,N-다이메틸아미노피리딘 (DMAP), 피리딘, 트라이에틸아민, N,N-다이이소프로필에틸아민, 1,8-디아자비사이클로[5.4.0]-7-운데센 (DBU) 등의 유기염기 또는 소듐카보네이트, 소듐바이카보네이트, 소듐하이드록사이드, 리튬하이드록사이드, 포타슘하이드록사이드, 바륨하이드록사이드, NaH, 포타슘카보네이트 등의 무기염기를 단독 또는 혼합하여, 당량 또는 과량으로 사용할 수 있다.The base is N,N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) ) or an inorganic base such as sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, NaH, potassium carbonate, etc. can be used as
나아가, 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.Further, the solvents usable in the reaction include ether-based solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane; lower alcohols such as methanol, ethanol, propanol, butanol; dimethylformamide (DMF); dimethylsulfoxide (DMSO); Acetonitrile, water, etc. can be used individually or in mixture.
상기 제조방법에 있어서, 단계 2는 화학식 2으로 표시되는 화합물과 화학식 3으로 표시되는 화합물을 반응시켜 화학식 1로 표시되는 화합물을 얻는 단계이며, 구체적으로, 화학식 2으로 표시되는 화합물의 할로겐과 화학식 3로 표시되는 보론산 화합물을 금속리간드 및 염기 조건하에 반응시켜 화학식 1로 표시되는 화합물을 얻는 단계이다.In the above preparation method, step 2 is a step of reacting a compound represented by Formula 2 with a compound represented by Formula 3 to obtain a compound represented by Formula 1, specifically, the halogen of the compound represented by Formula 2 and Formula 3 This is a step to obtain a compound represented by Formula 1 by reacting the boronic acid compound represented by a metal ligand and a base condition.
이때, 상기 보론산 화합물은 상업적으로 시판되는 화합물들을 사용하거나, 대응되는 할라이드 화합물로부터 공지의 방법으로 제조하여 사용할 수 있으며, 상기 할라이드 화합물은 요오드화물 또는 브롬화물 등을 사용할 수 있다. In this case, as the boronic acid compound, commercially available compounds may be used or prepared from a corresponding halide compound by a known method, and the halide compound may be iodide or bromide.
또한, 상기 금속 리간드는, 구리, 팔라듐, 니켈, 주석 등을 사용할 수 있으며, 본 발명에서는 팔라듐 리간드로서 Pd(PPh3)4 를 사용하였으나, 이는 일례일 뿐, 이에 한정되는 것은 아니다.In addition, as the metal ligand, copper, palladium, nickel, tin, etc. may be used. In the present invention, Pd(PPh 3 ) 4 is used as the palladium ligand, but this is only an example and is not limited thereto.
또한, 상기 염기는 N,N-다이메틸아미노피리딘 (DMAP), 피리딘, 트라이에틸아민, N,N-다이이소프로필에틸아민, 1,8-디아자비사이클로[5.4.0]-7-운데센 (DBU) 등의 유기염기 또는 소듐카보네이트, 소듐바이카보네이트, 소듐하이드록사이드, 리튬하이드록사이드, 포타슘하이드록사이드, 바륨하이드록사이드, NaH, 포타슘카보네이트 등의 무기염기를 단독 또는 혼합하여, 당량 또는 과량으로 사용할 수 있다.In addition, the base is N,N-dimethylaminopyridine (DMAP), pyridine, triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) or an inorganic base such as sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, barium hydroxide, NaH, potassium carbonate alone or in mixture, equivalent to Or it can be used in excess.
나아가, 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.Further, the solvents usable in the reaction include ether-based solvents such as tetrahydrofuran, dioxane, dichloromethane, 1,2-dimethoxyethane; lower alcohols such as methanol, ethanol, propanol, butanol; dimethylformamide (DMF); dimethylsulfoxide (DMSO); Acetonitrile, water, etc. can be used individually or in mixture.
이때, 상기 반응식 1에서, 단계 1 및 단계 2는 순차적으로 진행할 수 있고, 단계 2 수행 후, 단계 1을 수행할 수도 있다.In this case, in Scheme 1, Step 1 and Step 2 may be sequentially performed, and after Step 2 is performed, Step 1 may be performed.
또한, 상기 반응식 1은 본 발명의 화학식 1로 표시되는 화합물을 제조하기 위한 일례일뿐, 이에 한정되는 것은 아니다.In addition, Scheme 1 is only an example for preparing the compound represented by Formula 1 of the present invention, and is not limited thereto.
또한, 구체적인 실험방법은 하기 실시예에 개시되어 있으며, 하기 실시예 또한 화학식 1로 표시되는 화합물을 제조하기 위한 일례일뿐, 이에 한정되는 것은 아니다.In addition, specific experimental methods are disclosed in the following examples, and the following examples are also only an example for preparing the compound represented by Formula 1, and are not limited thereto.
또한, 본 발명에 따른 화학식 1로 표시되는 화합물에서, R3가 아릴 또는 헤테로아릴이 아닌 -(C=O)NR5R6, -(P=O)R7R8, 또는 -SO2R9일 경우, 하기 실시예 120 내지 137에 개시된 방법을 수행하여 제조할 수도 있다. 이 또한, 일례일뿐, 이에 한정되는 것은 아니다.In addition, in the compound represented by Formula 1 according to the present invention, R 3 is not aryl or heteroaryl -(C=O)NR 5 R 6 , -(P=O)R 7 R 8 , or -SO 2 R In the case of 9, it may be prepared by performing the methods disclosed in Examples 120 to 137 below. Also, this is only an example, and is not limited thereto.
본 발명의 다른 측면은,Another aspect of the present invention is
상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 치료용 약학적 조성물을 제공한다.It provides a pharmaceutical composition for preventing or treating a protein kinase-related disease, comprising the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 단백질 키나아제는 AAK1, ABL1(E255K)-phosphorylated. ABL1(F317I)-nonphosphorylated, ABL1(F317I)-phosphorylated, ABL1(F317L)-nonphosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ACVR1, ACVR1B, ACVR2A, ACVR2B, ACVRL1, ADCK3, ADCK4, AKT1, AKT2, AKT3, ALK, ALK(C1156Y), ALK(L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, ARK5, ASK1, ASK2, AURKA, AURKB, AURKC, AXL, BIKE, BLK, BMPR1A, MPR1B, BMPR2, BMX, BRAF, BRAF(V600E), BRK, BRSK1, BRSK2, BTK, BUB1, CAMK1, CAMK1B, CAMK1D, CAMK1G, CAMK2A, CAMK2B, CAMK2D, CAMK2G, CAMK4, CAMKK1, CAMKK2, CASK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK2, CDK3, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK5, CDK7, CDK8, CDK9, CDKL1, CDKL2, CDKL3, CDKL5, CHEK1, CHEK2, CIT, CLK1, CLK2, CLK3, CLK4, CSF1R, CSF1R-autoinhibited, CSK, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E, CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CTK, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK, DMPK2, DRAK1, DRAK2, DYRK1A, DYRK1B, DYRK2, EGFR, EGFR(E746-A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EIF2AK1, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB4, EPHB6, ERBB2, ERBB3, ERBB4, ERK1, ERK2, ERK3, ERK4, ERK5, ERK8, ERN1, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3(G697C), FGFR4, FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2,S808G), GRK1, GRK2, GRK3, GRK4, GRK7, GSK3A, GSK3B, HASPIN, HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HUNK, ICK, IGF1R, IKK-alpha, IKK-beta, IKK-epsilon, INSR, INSRR, IRAK1, IRAK3, IRAK4, ITK, JAK1(JH1domain-catalytic), JAK1(JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), KIT-autoinhibited, LATS1, LATS2, LCK, LIMK1, LIMK2, LKB1, LOK, LRRK2, LRRK2(G2019S), LTK, LYN, LZK, MAK, MAP3K1, MAP3K15, MAP3K2, MAP3K3, MAP3K4, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAPKAPK2, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MAST1, MEK1, MEK2, MEK3, MEK4, MEK5, MEK6, MELK, MERTK, MET, MET(M1250T), MET(Y1235D), MINK, MKK7, MKNK1, MKNK2, MLCK, MLK1, MLK2, MLK3, MRCKA, MRCKB, MST1, MST1R, MST2, MST3, MST4, MTOR, MUSK, MYLK, MYLK2, MYLK4, MYO3A, MYO3B, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK9, NIK, NIM1, NLK, OSR1, p38-alpha, p38-beta, p38-delta, p38-gamma, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PCTK1, PCTK2, PCTK3, PDGFRA, PDGFRB, PDPK1, PFCDPK1(P.falciparum), PFPK5(P.falciparum), PFTAIRE2, PFTK1, PHKG1, PHKG2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA(C420R), PIK3CA(E542K), PIK3CA(E545A), PIK3CA(E545K), PIK3CA(H1047L), PIK3CA(H1047Y), PIK3CA(I800L), PIK3CA(M1043I), PIK3CA(Q546K), PIK3CB, PIK3CD, PIK3CG, PIK4CB, PIKFYVE, PIM1, PIM2, PIM3, PIP5K1A, PIP5K1C, PIP5K2B, PIP5K2C, PKAC-alpha, PKAC-beta, PKMYT1, PKN1, PKN2, PKNB(M.tuberculosis), PLK1, PLK2, PLK3, PLK4, PRKCD, PRKCE, PRKCH, PRKCI, PRKCQ, PRKD1, PRKD2, PRKD3, PRKG1, PRKG2, PRKR, PRKX, PRP4, PYK2, QSK, RAF1, RET, RET(M918T), RET(V804L), RET(V804M), RIOK1, RIOK2, RIOK3, RIPK1, RIPK2, RIPK4, RIPK5, ROCK1, ROCK2, ROS1, RPS6KA4(Kin.Dom.1-N-terminal), RPS6KA4(Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.1-N-terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK1(Kin.Dom.1, N-terminal), RSK1(Kin.Dom.2-C-terminal), RSK2(Kin.Dom.1-N-terminal), RSK2(Kin.Dom.2-C-terminal), RSK3(Kin.Dom.1-N-terminal), RSK3(Kin.Dom.2-C-terminal), RSK4(Kin.Dom.1-N-terminal), RSK4(Kin.Dom.2-C-terminal), S6K1, SBK1, SGK, SgK110, SGK2, SGK3, SIK, SIK2, SLK, SNARK, SNRK, SRC, SRMS, SRPK1, SRPK2, SRPK3, STK16, STK33, STK35, STK36, STK39, SYK, TAK1, TAOK1, TAOK2, TAOK3, TBK1, TEC, TESK1, TGFBR1, TGFBR2, TIE1, TIE2, TLK1, TLK2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKC, TRPM6, TSSK1B, TSSK3, TTK, TXK, TYK2(JH1domain-catalytic), TYK2(JH2domain-pseudokinase), TYRO3, ULK1, ULK2, ULK3, VEGFR2, VPS34, VRK2, WEE1, WEE2, WNK1, WNK2, WNK3, WNK4, YANK1, YANK2, YANK3, YES, YSK1, YSK4, ZAK 및 ZAP70으로 이루어진 군으로부터 선택되는 1종 이상일 수 있다.The protein kinase is AAK1, ABL1 (E255K)-phosphorylated. ABL1(F317I)-nonphosphorylated, ABL1(F317I)-phosphorylated, ABL1(F317L)-nonphosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(M351T) (Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ACVR1, ACVR1B, ACVR2A1B, ACVR2A ACVR2B, ACVRL1, ADCK3, ADCK4, AKT1, AKT2, AKT3, ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ANKK1, ARK5, ASK1, ASK2, AURKA, AURKB, AURKC, AURKB BIKE, BLK, BMPR1A, MPR1B, BMPR2, BMX, BRAF, BRAF(V600E), BRK, BRSK1, BRSK2, BTK, BUB1, CAMK1, CAMK1B, CAMK1D, CAMK1G, CAMK2A, CAMK2A, CAMK2A, CAMK2, CAMK2B, K CAMK2, CAMK2B, K CAMK2 , CASK, CDC2L1, CDC2L2, CDC2L5, CDK11, CDK2, CDK3, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK5, CDK7, CDK8, CDK9, CDKL1, CDKL2, CDKL3, CDKL5, CHEK1, CLK2, C , CLK3, CLK4, CSF1R, CSF1R-autoinhibited, CSK, CSNK1A1, CSNK1A1L, CSNK1D, CSNK1E , CSNK1G1, CSNK1G2, CSNK1G3, CSNK2A1, CSNK2A2, CTK, DAPK1, DAPK2, DAPK3, DCAMKL1, DCAMKL2, DCAMKL3, DDR1, DDR2, DLK, DMPK, DMPK2, FRRK2, DRAK1, DYK1 -A750del), EGFR(G719C), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R, T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EIF2AK1, EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHB1, EPHB2, EPHB3, EPHB2, EPHB3 ERBB3, ERBB4, ERK1, ERK2, ERK3, ERK4, ERK5, ERK8, ERN1, FAK, FER, FES, FGFR1, FGFR2, FGFR3, FGFR3 (G697C), FGFR4, FGR, FLT1, FLT3, FLT3 (D835H), FLT3 (D835H) D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FLT4, FRK, FYN, GAK, GCN2(Kin.Dom.2,S808G), GRK1, GRK2, GRK3, GRK4, GRK7, GSK3A, GSK3B, HASPIN, HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, HUNK, ICKK IGF1R -alpha, IKK-beta, IKK-epsilon, INSR, INSRR, IRAK1, IRAK3, IRAK4, ITK, JAK1 (JH1domain-c atalytic), JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P) ), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), KIT-autoinhibited, LATS1, LATS2, LCK, LIMK1, LIMK2, LKB1, LOK, LRRK2, LRRK2(G2019S), LTK, LYN, LZK, MAK, MAP3K1, MAP3K15, MAP3K2, MAP3K3, MAP3K4, MAP4K2, MAP4K3, MAP4K4, MAP4K5, MAPKAPK2, MAPKAPK5, MARK1, MARK2, MARK3, MARK4, MAST1, MEK5, MEK4, MAST1, MEK, MEK MERTK, MET, MET (M1250T), MET (Y1235D), MINK, MKK7, MKNK1, MKNK2, MLCK, MLK1, MLK2, MLK3, MRCKA, MRCKB, MST1, MST1R, MST2, MST3, MST4, MTOR, MUSK MYLK2, MYLK4, MYO3A, MYO3B, NDR1, NDR2, NEK1, NEK10, NEK11, NEK2, NEK3, NEK4, NEK5, NEK6, NEK7, NEK9, NIK, NIM1, NLK, OSR1, p38-alpha, p38-beta, p38-beta delta, p38-gamma, PAK1, PAK2, PAK3, PAK4, PAK6, PAK7, PCTK1, PCTK2, PCTK3, PDGFRA, PDGFRB, PDPK1, PFCDPK1 (P.falciparum), PFPK5 (P.falciparum), PFTAIRE2, PFTK1, PHKG1 PHKG2, PIK3C2B, PIK3C2G, PIK3CA, PIK3CA (C420R ), PIK3CA(E542K), PIK3CA(E545A), PIK3CA(E545K), PIK3CA(H1047L), PIK3CA(H1047Y), PIK3CA(I800L), PIK3CA(M1043I), PIK3CD PIKFYVE, PIM1, PIM2, PIM3, PIP5K1A, PIP5K1C, PIP5K2B, PIP5K2C, PKAC-alpha, PKAC-beta, PKMYT1, PKN1, PKN2, PKNB (M. , PRKCI, PRKCQ, PRKD1, PRKD2, PRKD3, PRKG1, PRKG2, PRKR, PRKX, PRP4, PYK2, QSK, RAF1, RET, RET(M918T), RET(V804L), RET(V804M), RIOK1, OKRIOK2, RIPK1, RIPK2, RIPK4, RIPK5, ROCK1, ROCK2, ROS1, RPS6KA4(Kin.Dom.1-N-terminal), RPS6KA4(Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.1-N- terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK1(Kin.Dom.1, N-terminal), RSK1(Kin.Dom.2-C-terminal), RSK2(Kin.Dom.1- N-terminal), RSK2 (Kin.Dom.2-C-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.2-C-terminal), RSK4 (Kin.Dom. 1-N-terminal), RSK4 (Kin.Dom.2-C-terminal), S6K1, SBK1, SGK, SgK110, SGK2, SGK3, SIK, SIK2, SLK, SNARK, SNRK, SRC, SRMS, SRPK1, SRPK2, SRPK3, STK16, STK33, STK35, STK36, STK39, SYK, TAK1, TAOK1, TAOK2, TAOK3, TBK1, TEC, TESK1, TGFBR1, TGFBR2, TIE1, TIE2, TLK1, TLK2, TNIK, TNK1, TNK2, TNNI3K, TRKA, TRKB, TRKB, TRKB, TRKB TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseudokinase), TYRO3, ULK1, ULK2, ULK3, VEGFR2, VPS34, VRK2, WEE1, WEE2, WNK1, WNK2, WNK3, WNK4, YANK3, WNK4, YANK It may be at least one selected from the group consisting of YES, YSK1, YSK4, ZAK and ZAP70.
또한, 상기 약학적 조성물에서, 상기 화합물은 AAK1, ABL1(E255K)-phosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ADCK4, AMPK-alpha1, AMPK-alpha2, ARK5, AURKB, BIKE, BLK, BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, CSNK2A1, CSNK2A2, DAPK1, DAPK3, DCAMKL1, DDR1, DDR2, DLK, DYRK1B, DYRK2, EGFR, EGFR(E746-A750del), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD, FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FRK, FYN, GAK, GCN2(Kin.Dom.2,S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK-epsilon, IRAK1, ITK, JAK1(JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2(G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4, MAP4K5, MARK1, MARK2, MARK3, MEK5, MELK, MERTK, MINK, MKNK2, MLK1, MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEK7, NEK9, PAK4, PAK7, PDGFRA, PDGFRB, PIK3CB, PIP5K1A, PIP5K2B, PKNB(M.tuberculosis), PLK1, PLK2, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK1, RIOK3, RIPK1, RPS6KA4(Kin.Dom.1-N-terminal), RSK1(Kin.Dom.1-N-terminal), RSK2(Kin.Dom.1-N-terminal), RSK3(Kin.Dom.1-N-terminal), RSK4(Kin.Dom.1-N-terminal), SBK1, SIK, SIK2, SLK, SNARK, SRC, SRPK1, SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, TRKA, TRKB, TRKC, TTK, TXK, TYK2(JH1domain-catalytic), TYK2(JH2domain-pseudokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, 및 YSK4로 이루어지는 군으로부터 선택되는 1종 이상의 키나아제에 대한 억제활성을 나타낼 수 있다.Further, in the pharmaceutical composition, the compound is AAK1, ABL1(E255K)-phosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1( Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ADCK4, AMPK-alpha1, AMPK-alpha1 -alpha2, ARK5, AURKB, BIKE, BLK, BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, DKL CSNK2A1, DDR2, CSNK2A2, DAPK3 , DLK, DYRK1B, DYRK2, EGFR, EGFR(E746-A750del), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L747-T751del,Sins), EGFR L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FGR, FLT1 , FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD, FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3(R834Q) -a utoinhibited, FRK, FYN, GAK, GCN2(Kin.Dom.2,S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK-epsilon, IRAK1, ITK, JAK1(JH2domain-pseudokinase), JAK2(JH2domain-pseudokinase) catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P), KIT (V559D), KIT (V559D, T670I), KIT(V559D,V654A), KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2(G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4, MAP4K5, MARK1, MARK2, MARK3, MEK5, MARK3, MINK, MKNK2, MLK1, MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEK7, NEK9, PAK4, PAK7, PDGFRA, PDGFRB, PIK3CB, PIP5K1A, PPLKNBK2B. , PLK2, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK1, RIOK3, RIPK1, RPS6KA4(Kin.Dom.1-N-terminal), RSK1(Kin.Dom.1-N) -terminal), RSK2 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK4 (Kin.Dom.1-N-terminal), SBK1, SIK, SIK2, SLK , SNARK, SRC, SRPK1, SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, TRKA, TRKB, TRKC, TTK, TXK, TYK2 (JH1domain-catal ytic), TYK2 (JH2domain-pseudokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, and YSK4 may exhibit inhibitory activity against one or more kinases selected from the group consisting of.
상기 단백질 키나아제 관련 질환은 암일 수 있다.The protein kinase-related disease may be cancer.
구체적으로 상기 암은 백혈병, 뇌암, 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강/부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 구강암, 흉부종양, 폐암, 상피세포암, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 직장암, 항문암, 방광암, 신장암, 남성 생식기종양, 음경암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암 또는 피부암일 수 있다.Specifically, the cancer is leukemia, brain cancer, brain tumor, benign astrocytoma, astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroglioma, intracranial race, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal/sinus Cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, lung cancer, epithelial cell cancer, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, Liver cancer, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colorectal cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterus sarcoma, vaginal cancer, female external genital cancer, female urethral cancer or skin cancer.
본 발명에 따른 화학식 1로 표시되는 화합물은 Wee1 키나아제 대하여 우수한 억제활성을 나타내고(실험예 1 참조), 다양한 키나아제에 대한 저해활성을 나타내므로(실험예 4 참조), 다양한 키나아제와 관련된 질환, 특히, Wee1 키나아제와 관련된 질환의 치료 또는 예방용 약학적 조성물로 유용하게 사용될 수 있다.Since the compound represented by Formula 1 according to the present invention exhibits excellent inhibitory activity against Wee1 kinase (see Experimental Example 1), and exhibits inhibitory activity against various kinases (see Experimental Example 4), various kinase-related diseases, in particular, It can be usefully used as a pharmaceutical composition for the treatment or prevention of diseases related to Weel kinase.
또한, 본 발명에 따른 화학식 1로 표시되는 화합물은 간암세포 증식 억제능을 나타내고(실험예 2 참조), 상피세포암, 폐암, 대장암, 유방암, 백혈병, 난소암의 암세포 증식 억제능을 나타내므로(실험예 3 참조), 암, 특히, 간암, 상피세포암, 폐암, 대장암, 유방암, 백혈병, 난소암의 치료 또는 예방용 약학적 조성물로 유용하게 사용될 수 있다.In addition, the compound represented by Formula 1 according to the present invention exhibits hepatocarcinoma cell proliferation inhibitory ability (see Experimental Example 2), and exhibits cancer cell proliferation inhibitory ability in epithelial cell carcinoma, lung cancer, colorectal cancer, breast cancer, leukemia, and ovarian cancer (experimental). See Example 3), cancer, in particular, liver cancer, epithelial cell cancer, lung cancer, colon cancer, breast cancer, leukemia, can be usefully used as a pharmaceutical composition for the prevention or treatment of ovarian cancer.
본 발명의 약학적 조성물은 암의 치료에 사용될 때, 개별 치료제로 투여하거나, 다른 사용중인 항암제와 병용투여하여 사용할 수 있다.When used for the treatment of cancer, the pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be used in combination with other anticancer agents in use.
본 발명의 다른 측면은, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing or treating cancer comprising the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 임상 투여시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등 이 포함되며, 이러한 고형제제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분, 탄산칼슘, 수크로오스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테로 등이 사용될 수 있다.The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be administered in various oral and parenteral formulations during clinical administration. In the case of formulation, it is prepared using diluents or excipients, such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in one or more compounds, for example, starch, calcium carbonate, sucrose or lactose ( lactose), gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, internal solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, and emulsions. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효 성분으로 하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. A pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient may be administered parenterally, and parenteral administration is administered by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection. depending on how
이때, 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 함유할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.At this time, in order to formulate a formulation for parenteral administration, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is mixed with water together with a stabilizer or buffer to prepare a solution or suspension, and this is an ampoule or vial unit dosage form. can be manufactured with The composition may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and mixing, granulation, in a conventional manner. It can be formulated according to the method of formulation or coating.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제, 트로키제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 함유하고 있다. 정제는 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘 등과 같은 결합제를 함유할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염 등과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 함유할 수 있다.Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, troches, and the like. , dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine and the like, and optionally boron such as starch, agar, alginic acid or its sodium salt, etc. It may contain releasing or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 단백질 키나아제 관련 질환의 예방 또는 개선용 건강기능식품이 제공된다.According to another aspect of the present invention, there is provided a health functional food for preventing or improving protein kinase-related diseases containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에 따른 상기 화학식 1로 표시되는 화합물은 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 건강식품 중의 상기 화합물의 양은 전체 식품 중량의 0.1 내지 90 중량부로 가할 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The compound represented by Formula 1 according to the present invention may be added to food as it is or used together with other food or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be suitably determined according to the purpose of its use (for prevention or improvement). In general, the amount of the compound in the health food may be added in an amount of 0.1 to 90 parts by weight based on the total weight of the food. However, in the case of long-term intake for health and hygiene or health control, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
또한, 본 발명의 건강 기능성 음료 조성물은 지시된 비율로 필수 성분으로서 상기 화합물을 함유하는 외에는 다른 성분에는 특별한 제한이 없으며 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어 레바우디오시드 A, 글리시르히진등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 조성물 100 g당 일반적으로 약 1 내지 20 g, 바람직하게는 약 5 내지 12 g이다.In addition, the health functional beverage composition of the present invention is not particularly limited in other ingredients except for containing the compound as an essential ingredient in the indicated ratio, and may contain various flavoring agents or natural carbohydrates as additional ingredients like a conventional beverage. 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. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (for example, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. The proportion 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), 합성 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. Furthermore, in addition to the above, the compound represented by Formula 1 according to the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pects acids and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonation 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, fruit juice, and pulp for the production of fruit juice beverages and vegetable beverages.
본 발명의 다른 측면에 따라, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 약학적 조성물 또는 건강기능식품 조성물을 필요한 대상에게 투여하는 단계를 포함하는 단백질 키나아제 관련 질환의 예방 또는 치료 방법이 제공된다.According to another aspect of the present invention, protein kinase-related comprising the step of administering to a subject in need of a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient A method for preventing or treating a disease is provided.
본 발명의 다른 측면에 따라, 단백질 키나아제 관련 질환의 예방 또는 치료에 있어서의, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 함유하는 약학적 조성물 또는 건강기능식품 조성물의 용도가 제공된다.According to another aspect of the present invention, there is provided the use of a pharmaceutical composition or a health functional food composition containing the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof in the prevention or treatment of protein kinase-related diseases do.
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by way of 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 content of the present invention is not limited to the following Examples and Experimental Examples.
<실시예 1> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노) -5-(1H-피라졸-4-일)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올의 제조<Example 1> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(1H-pyrazole- Preparation of 4-yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol
단계 1: 2-(6-((2-클로로-5-요오도피리딘-4-일)아미노)피리딘-2-일)프로판-2-올의 제조Step 1: Preparation of 2-(6-((2-chloro-5-iodopyridin-4-yl)amino)pyridin-2-yl)propan-2-ol
2,4-디클로로-5-요오도피리미딘 (1.0 당량)을 1,4-디옥산 (0.1 M)에 첨가하여 녹인 후, 2-(6-아미노피리딘-2-일)프로판-2-올 (1.0 당량)과 DIPEA (1.0 당량)를 상온에서 첨가하였고, 100 oC에서 72시간 동안 반응시켰다. 반응 혼합물을 실온으로 냉각시키고 물을 부은 후, EtOAc로 추출하였다. (x3) 모아진 유기층은 brine으로 씻어준 후, MgSO4로 물을 제거하였다. 이를 여과한 후, 농축하였고 화합물은 MPLC (MeOH/DCM)를 이용하여 정제하였다. 농축 후, 노란색 고체의 목적 화합물을 수득하였다. (수율: 99%)2,4-dichloro-5-iodopyrimidine (1.0 eq.) was dissolved in 1,4-dioxane (0.1 M), followed by 2-(6-aminopyridin-2-yl)propan-2-ol (1.0 equiv.) and DIPEA (1.0 equiv.) were added at room temperature, and reacted at 100 o C for 72 hours. The reaction mixture was cooled to room temperature, poured on water and extracted with EtOAc. (x3) The collected organic layer was washed with brine, and then water was removed with MgSO 4 . After filtration, it was concentrated and the compound was purified using MPLC (MeOH/DCM). After concentration, the title compound was obtained as a yellow solid. (Yield: 99%)
단계 2: 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-요오도피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올의 제조Step 2: 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-iodopyrimidin-4-yl ) Preparation of amino) pyridin-2-yl) propan-2-ol
상기 단계 1에서 제조한 화합물 (1.0 당량), 1-(4-아미노-2-메톡시페닐)-N, N-디메틸피페리딘-4-아민 (1.0 당량)과 K2CO3 (5.0 당량)를 sec-BuOH (0.1 M)에 첨가하여 녹인 후, 1분 동안 초음파 처리하여 가스를 제거하였다. 반응 혼합물에 Pd2(dba)3 (0.1 당량) 및 Xphos (0.1 당량)을 80 oC에서 첨가한 후, 16시간 동안 반응 시켰다. 반응 후, 반응 혼합물을 셀라이트로 여과하고, EtOAc와 MeOH로 씻어주었다. 얻어진 여과액을 농축한 후, MPLC (DCM:MeOH with 10% NH4OH)로 정제하여 짙은 갈색 고체의 목적화합물을 수득하였다. (수율: 97%)The compound prepared in step 1 (1.0 equiv.), 1-(4-amino-2-methoxyphenyl)-N, N-dimethylpiperidin-4-amine (1.0 equiv.) and K 2 CO 3 (5.0 equiv.) ) was dissolved in sec-BuOH (0.1 M) and then sonicated for 1 minute to remove gas. Pd 2 (dba) 3 (0.1 equiv.) and Xphos (0.1 equiv) were added to the reaction mixture at 80 o C, followed by reaction for 16 hours. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. The resulting filtrate was concentrated and purified by MPLC (DCM:MeOH with 10% NH 4 OH) to obtain the target compound as a dark brown solid. (Yield: 97%)
단계 3: 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노) -5-(1H-피라졸-4-일)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올의 제조Step 3: 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(1H-pyrazole-4- Preparation of yl) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol
상기 단계 2에서 제조한 화합물 (1.0 당량), 4-(4,4,5,5-테트라메틸-1,3,2-디옥사보롤란-2-일)-1H-피라졸 (1.0 당량)과 1M Na2CO3 (aq, 3.0 당량)를 1,4-dioxane (0.05 M)에 첨가하여 녹인 후, 1분 동안 초음파 처리하여 가스를 제거하였다. 반응 혼합물에 Pd(PPh3)4 (0.1 당량)을 100 oC에서 첨가한 후, 16시간 동안 반응 시켰다. 반응 후, 반응 혼합물을 셀라이트로 여과하고, EtOAc와 MeOH로 씻어주었다. 얻어진 여과액을 농축한 후, prep-HPLC로 정제하여 노란색 고체의 목적화합물을 수득하였다. (수율: 38%)The compound prepared in step 2 (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 equiv) and 1M Na 2 CO 3 (aq, 3.0 equivalents) were added to and dissolved in 1,4-dioxane (0.05 M), and then sonicated for 1 minute to remove gas. Pd(PPh 3 ) 4 (0.1 equivalent) was added to the reaction mixture at 100 o C, followed by reaction for 16 hours. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. The resulting filtrate was concentrated and purified by prep-HPLC to obtain the target compound as a yellow solid. (Yield: 38%)
상기 실시예 1과 유사한 방법으로 실시예 2 내지 47을 제조하였으며, 실시예 1 내지 47의 화학구조를 하기 표 1 및 2에, 화합물명과 1H NMR, mass, 수율 및 HPLC 분석 결과를 하기 표 3에 정리하여 나타내었다.Examples 2 to 47 were prepared in a manner similar to Example 1, and the chemical structures of Examples 1 to 47 are shown in Tables 1 and 2 below, and the compound name, 1 H NMR, mass, yield and HPLC analysis results are shown in Table 3 below. summarized in .
(%)transference number
(%)
r.t.(min)
PurityHPLC
rt(min)
Purity
<실시예 48> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일)2-아민의 제조 <Example 48> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(furan-3-yl)-4-(1-methyl- Preparation of 1H-indol-3-yl)2-amine
단계 1: 3-(2-클로로-5-요오도피리미딘-4-일)-1H-인돌의 제조Step 1: Preparation of 3-(2-chloro-5-iodopyrimidin-4-yl)-1H-indole
인돌 (2.0 당량)을 THF (0.3 M)에 첨가하여 녹인 후, 질소하에서 온도를 0 oC로 유지하면서 20분에 걸쳐 CH3MgBr (2.0 당량)를 천천히 첨가하였다. 상온에서 100분 동안 반응 시킨 후, 2,4-디클로로-5-요오도피리미딘 (1.0 당량)을 첨가하고 80 oC에서 1시간 동안 반응시켰다. 반응 혼합물을 실온으로 냉각시키고 메탄올로 금속 활성을 제거한 후, 농축하였다. 화합물은 CH2Cl2로 침전시킨 후, 용매를 제거하여 옅은 갈색 고체의 목적 화합물을 수득하였다. (수율: 95%)Indole (2.0 equiv.) was dissolved in THF (0.3 M), followed by slow addition of CH 3 MgBr (2.0 equiv) over 20 minutes while maintaining the temperature at 0 °C under nitrogen. After reacting at room temperature for 100 minutes, 2,4-dichloro-5-iodopyrimidine (1.0 equivalent) was added and reacted at 80 o C for 1 hour. The reaction mixture was cooled to room temperature, the metal activity was removed with methanol, and then concentrated. The compound was precipitated with CH 2 Cl 2 , and the solvent was removed to obtain the target compound as a pale brown solid. (Yield: 95%)
단계 2: 3-(2-클로로-5-요오도피리미딘-4-일)-1-메틸-1H-인돌의 제조Step 2: Preparation of 3-(2-chloro-5-iodopyrimidin-4-yl)-1-methyl-1H-indole
상기 단계 1에서 제조한 화합물 (1.0 당량)을 THF (0.5 M)에 첨가하여 녹인 후, 0 oC에서 NaH (1.2 당량)을 첨가하였다. 반응 혼합물을 0 oC에서 30분 동안 교반한 후, MeI (1.2 당량)을 첨가하고 상온에서 1 시간동안 반응시켰다. 반응 후, 반응 혼합물에 물을 넣고 형성된 침전물은 여과한 후, 건조시켜 갈색 고체의 목적화합물을 수득하였다. (수율: 95%)The compound prepared in step 1 (1.0 equiv.) was dissolved in THF (0.5 M), and then NaH (1.2 equiv.) was added at 0 o C. After the reaction mixture was stirred at 0 o C for 30 minutes, MeI (1.2 equivalents) was added and reacted at room temperature for 1 hour. After the reaction, water was added to the reaction mixture, and the formed precipitate was filtered and dried to obtain the target compound as a brown solid. (Yield: 95%)
단계 3: 3-(2-클로로-5-(퓨란-3-일)피리미딘-4-일)-1-메틸-1H-인돌의 제조Step 3: Preparation of 3-(2-chloro-5-(furan-3-yl)pyrimidin-4-yl)-1-methyl-1H-indole
상기 단계 2에서 제조한 화합물 (1.0 당량), 퓨란-3-일붕소산-피라졸 (1.0 당량)과 1M Na2CO3 (aq, 3.0 당량)를 1,4-dioxane (0.15 M)에 첨가하여 녹인 후, 1분 동안 초음파 처리하여 가스를 제거하였다. 반응 혼합물에 Pd(PPh3)4 (0.1 당량)을 100 oC에서 첨가한 후, 2시간 동안 반응 시켰다. 반응 후, 반응 혼합물을 상온으로 식힌 후, 물을 넣어 금속 활성을 제거하고 EtOAc로 추출하였다. 유기층은 MgSO4로 물을 제거/여과 후, 농축하였고, MPLC (EtOAc:Hex)로 정제하여 노란색 고체의 목적화합물을 수득하였다. (수율: 68%)The compound prepared in step 2 (1.0 equiv.), furan-3-ylboronic acid-pyrazole (1.0 equiv.) and 1M Na 2 CO 3 (aq, 3.0 equiv) were added to 1,4-dioxane (0.15 M) and then sonicated for 1 minute to remove gas. Pd(PPh 3 ) 4 (0.1 equivalent) was added to the reaction mixture at 100 o C, followed by reaction for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, water was added to remove metal activity, and extraction was performed with EtOAc. The organic layer was concentrated after removing/filtering water with MgSO 4 , and purified by MPLC (EtOAc:Hex) to obtain the target compound as a yellow solid. (Yield: 68%)
단계 4: N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일)2-아민의 제조 Step 4: N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(furan-3-yl)-4-(1-methyl-1H- Preparation of indol-3-yl) 2-amine
상기 단계 3에서 제조한 화합물 (1.0 당량), 1-(4-아미노-2-메톡시페닐)-N, N-디메틸피페리딘-4-아민 (1.0 당량)과 K2CO3 (5.0 당량)를 sec-BuOH (0.1 M)에 첨가하여 녹인 후, 1분 동안 초음파 처리하여 가스를 제거하였다. 반응 혼합물에 Pd2(dba)3 (0.1 당량) 및 Xphos (0.1 당량)을 80 oC에서 첨가한 후, 16시간 동안 반응 시켰다. 반응 후, 반응 혼합물을 셀라이트로 여과하고, EtOAc와 MeOH로 씻어주었다. 얻어진 여과액을 농축한 후, prep-HPLC로 정제하여 노란색 고체의 목적화합물을 수득하였다. (수율: 36%)The compound prepared in step 3 (1.0 equiv.), 1-(4-amino-2-methoxyphenyl)-N, N-dimethylpiperidin-4-amine (1.0 equiv.) and K 2 CO 3 (5.0 equiv.) ) was dissolved in sec-BuOH (0.1 M) and then sonicated for 1 minute to remove gas. Pd 2 (dba) 3 (0.1 equiv.) and Xphos (0.1 equiv) were added to the reaction mixture at 80 o C, followed by reaction for 16 hours. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. The resulting filtrate was concentrated and purified by prep-HPLC to obtain the target compound as a yellow solid. (Yield: 36%)
상기 실시예 48과 유사한 방법으로 실시예 49 내지 119를 제조하였으며, 실시예 48 내지 119의 화학구조를 하기 표 4 및 5에, 화합물명과 1H NMR, mass, 수율 및 HPLC 분석 결과를 하기 표 6에 정리하여 나타내었다.Examples 49 to 119 were prepared in a manner similar to Example 48, and the chemical structures of Examples 48 to 119 are shown in Tables 4 and 5 below, and the compound name, 1 H NMR, mass, yield and HPLC analysis results are shown in Table 6 summarized in .
(%)transference number
(%)
r.t.(min)
PurityHPLC
rt(min)
Purity
100%5.08
100%
100%4.65
100%
5.15100%
26
99 %4.79
99%
99 %
5.35
99%
29
100%4.89
100%
<실시예 120> (2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-4-((6-(2-히드록시프로판-2-일) 피리딘-2-일)아미노)피리미딘-5-일)디메틸포스핀옥사이드의 제조<Example 120> (2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-4-((6-(2-hydroxypropane- Preparation of 2-yl) pyridin-2-yl)amino)pyrimidin-5-yl)dimethylphosphine oxide
상기 실시예 1의 단계 2에서 제조한 화합물 (1.0 당량), 디메틸포스핀 옥사이트 (1.0 당량), K3PO4 (1.1 당량), Pd(OAc)2 (0.05 당량)과 Xantphos (0.05 당량)를 DMF (0.05 M)에 첨가하여 녹인 후, 마이크로웨이브를 이용하여 150 oC에서 1 시간 동안 반응 시켰다. 반응 후, 반응 혼합물은 그대로 prep-HPLC로 정제하여 붉은빛 액체의 목적화합물을 수득하였다. (수율: 11%)The compound prepared in step 2 of Example 1 (1.0 equivalent), dimethylphosphine oxide (1.0 equivalent), K 3 PO 4 (1.1 equivalent), Pd(OAc) 2 (0.05 equivalent) and Xantphos (0.05 equivalent) was dissolved in DMF (0.05 M), and then reacted at 150 o C for 1 hour using a microwave. After the reaction, the reaction mixture was purified by prep-HPLC as it was to obtain the target compound as a red liquid. (Yield: 11%)
<실시예 121> (4-((6-(2-히드록시프로판-2-일) 피리딘-2-일) 아미노)-2-((3- 메톡시-4-(4-(4- 메틸피페라진-1-일)피페리딘-1 페닐)아미노) 피리미딘-5-일) 디메틸포스핀옥사이드의 제조<Example 121> (4-((6-(2-hydroxypropan-2-yl) pyridin-2-yl) amino)-2-((3- methoxy-4-(4-(4-methyl) Preparation of piperazin-1-yl) piperidin-1 phenyl) amino) pyrimidin-5-yl) dimethylphosphine oxide
상기 실시예 120과 동일한 방법을 수행하여 (4-((6-(2-히드록시프로판-2-일) 피리딘-2-일) 아미노)-2-((3- 메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1 페닐)아미노) 피리미딘-5-일) 디메틸포스핀옥사이드를 제조하였다.In the same manner as in Example 120, (4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-2-((3-methoxy-4-(4 -(4-methylpiperazin-1-yl)piperidin-1 phenyl)amino)pyrimidin-5-yl)dimethylphosphine oxide was prepared.
<실시예 122> (4-((6-(2-히드록시프로판-2-일) 피리딘-2-일) 아미노)-2- ((1,2,3,4- 테트라히드로 이소퀴놀린-6-일)아미노)피리미딘-5-일) 디메틸포스핀옥사이드의 제조<Example 122> (4-((6-(2-hydroxypropan-2-yl) pyridin-2-yl) amino)-2-((1,2,3,4-tetrahydro isoquinoline-6 Preparation of -yl) amino) pyrimidin-5-yl) dimethylphosphine oxide
상기 실시예 120과 동일한 방법을 수행하여 (4-((6-(2-히드록시프로판-2-일) 피리딘-2-일) 아미노)-2- ((1,2,3,4- 테트라히드로 이소퀴놀린-6-일)아미노)피리미딘-5-일) 디메틸포스핀옥사이드를 제조하였다.In the same manner as in Example 120, (4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-2-((1,2,3,4-tetra Hydroisoquinolin-6-yl)amino)pyrimidin-5-yl)dimethylphosphine oxide was prepared.
<실시예 123> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(메틸술포닐)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올의 제조<Example 123> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(methylsulfonyl)pyri Preparation of midin-4-yl)amino)pyridin-2-yl)propan-2-ol
상기 실시예 1의 단계 2에서 제조한 화합물 (1.0 당량), 메탄술핀산 (1.2 당량), N,N'-디메틸에틸렌디아민 (0.2 당량)과 Cu(CF3SO3)2 (0.1 당량)를 DMSO (0.33 M)에 첨가하여 녹인 후, 110 oC에서 4 시간 동안 반응 시켰다. 반응 혼합물을 상온으로 식힌 후, EtOAc로 희석하고 그 혼합물을 셀라이트로 여과하였다. 여과된 용액은 물과 brine으로 순차적으로 씻어준 후, MgSO4로 물을 제거하였다. 이를 여과한 후, 농축하였고 화합물은 prep-HPLC 이용하여 정제하였다. 농축 후, 보라빛 액체의 목적 화합물을 수득하였다. (수율: 16%)The compound prepared in step 2 of Example 1 (1.0 equiv.), methanesulfinic acid (1.2 equiv.), N,N'-dimethylethylenediamine (0.2 equiv.) and Cu(CF 3 SO 3 ) 2 (0.1 equiv.) After being dissolved in DMSO (0.33 M), and reacted at 110 o C for 4 hours. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc and the mixture was filtered through Celite. The filtered solution was washed sequentially with water and brine, and then water was removed with MgSO 4 . After filtration, it was concentrated and the compound was purified using prep-HPLC. After concentration, the target compound as a purple liquid was obtained. (Yield: 16%)
<실시예 124> 2-(6-((2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(메틸술포닐)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올의 제조<Example 124> 2-(6-((2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-( Preparation of methylsulfonyl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol
상기 실시예 123과 동일한 방법을 수행하여 2-(6-((2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(메틸술포닐)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올을 제조하였다.In the same manner as in Example 123, 2-(6-((2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )-5-(methylsulfonyl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol was prepared.
<실시예 125> 2-(6-((5-(메틸술포닐)-2 ((1,2,3,4- 테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올의 제조<Example 125> 2-(6-((5-(methylsulfonyl)-2 ((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)amino ) Preparation of pyridin-2-yl) propan-2-ol
상기 실시예 123과 동일한 방법을 수행하여 2-(6-((5-(메틸술포닐)-2 ((1,2,3,4- 테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올을 제조하였다.In the same manner as in Example 123, 2-(6-((5-(methylsulfonyl)-2((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine- 4-yl) amino) pyridin-2-yl) propan-2-ol was prepared.
<실시예 126> 2-(6-((2-(2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)-5- (메틸술포닐)피리미딘-4-일)아미노) 피리딘-2-일)프로판-2-올의 제조<Example 126> 2-(6-((2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(methylsulfonyl)pyrimidine-4 Preparation of -yl)amino)pyridin-2-yl)propan-2-ol
상기 실시예 123과 동일한 방법을 수행하여 2-(6-((2-(2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)-5- (메틸술포닐)피리미딘-4-일)아미노) 피리딘-2-일)프로판-2-올을 제조하였다.In the same manner as in Example 123, 2-(6-((2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(methylsulfonyl) ) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol was prepared.
<실시예 127> 2-(6-((5-(메틸술포닐)-2- ((1,2,3,4-테트라 히드로이소퀴놀린-7-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올의 제조<Example 127> 2-(6-((5-(methylsulfonyl)-2-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl) Preparation of amino) pyridin-2-yl) propan-2-ol
상기 실시예 123과 동일한 방법을 수행하여 2-(6-((5-(메틸술포닐)-2- ((1,2,3,4-테트라 히드로이소퀴놀린-7-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올을 제조하였다.In the same manner as in Example 123, 2-(6-((5-(methylsulfonyl)-2-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidine -4-yl)amino)pyridin-2-yl)propan-2-ol was prepared.
<실시예 128> 2-(6-((2-((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-7-일)아미노)-5-(메틸술포닐)피리미딘-4-일)아미노)피리딘-2-일) 프로판-2-올의 제조<Example 128> 2-(6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(methylsulfonyl)pyrimidine- Preparation of 4-yl)amino)pyridin-2-yl)propan-2-ol
상기 실시예 123과 동일한 방법을 수행하여 2-(6-((2-((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-7-일)아미노)-5-(메틸술포닐)피리미딘-4-일)아미노)피리딘-2-일) 프로판-2-올을 제조하였다.In the same manner as in Example 123, 2-(6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(methylsulfonyl) Ponyl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol was prepared.
<실시예 129> 2-(6-((2-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(메틸술포닐)피리미딘-4-일)(메틸)아미노)-2-일)프로판-2-올의 제조<Example 129> 2-(6-((2-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(methylsulfonyl)pyrimidine-4 Preparation of -yl)(methyl)amino)-2-yl)propan-2-ol
상기 실시예 123과 동일한 방법을 수행하여 2-(6-((2-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(메틸술포닐)피리미딘-4-일)(메틸)아미노)-2-일)프로판-2-올을 제조하였다.In the same manner as in Example 123, 2-(6-((2-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(methylsulfonyl) )pyrimidin-4-yl)(methyl)amino)-2-yl)propan-2-ol was prepared.
<실시예 130> N-(4-(4-(디메틸아미노)피페리딘 -1-일)-3-메톡시페닐)-4-(1-메틸-1H- 인돌-3-일)-5-(메틸술포닐)피리미딘-2-아민의 제조<Example 130> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)-5 Preparation of -(methylsulfonyl)pyrimidin-2-amine
상기 실시예 123과 동일한 방법을 수행하여 N-(4-(4-(디메틸아미노)피페리딘 -1-일)-3-메톡시페닐)-4-(1-메틸-1H- 인돌-3-일)-5-(메틸술포닐)피리미딘-2-아민을 제조하였다.In the same manner as in Example 123, N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(1-methyl-1H-indole-3 -yl)-5-(methylsulfonyl)pyrimidin-2-amine was prepared.
<실시예 131> 2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-4-(6-(2-히드록시프로판-2-일)피리딘-2-일아미노)-N,N-디메틸피리미딘-5-카복스아마이드의 제조<Example 131> 2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-4-(6-(2-hydroxypropan-2-yl) Preparation of pyridin-2-ylamino)-N,N-dimethylpyrimidine-5-carboxamide
단계 1: 2,4-디클로로-N, N-디메틸피리미딘-5-카르복스아미드의 제조Step 1: Preparation of 2,4-dichloro-N,N-dimethylpyrimidine-5-carboxamide
2,4-디클로로피리미딘-5-카르보닐클로라이드 (1.0 당량)을 CH2Cl2 (0.1 M)에 첨가하여 녹인 후, 디메틸아민 (0.8 당량)과 TEA (0.8 당량)를 0 oC 에서 첨가한 후, 상온에서 3시간 동안 반응시켰다. 반응 혼합물에 물을 부은 후, CH2Cl2로 추출하였다.(x3) 모아진 유기층은 MgSO4로 물을 제거하였다. 이를 여과한 후, 농축하였고 화합물은 MPLC (EtOAc:Hex)를 통해 정제하였다. 농축 후, 밝은 노란색 액체의 목적 화합물을 수득하였다. (수율: 77%)2,4-dichloropyrimidine-5-carbonylchloride (1.0 equiv.) was dissolved in CH 2 Cl 2 (0.1 M), and then dimethylamine (0.8 equiv.) and TEA (0.8 equiv.) were added at 0 o C. After that, the reaction was carried out at room temperature for 3 hours. Water was poured into the reaction mixture, followed by extraction with CH 2 Cl 2 . (x3) The combined organic layers were removed with water using MgSO 4 . After filtration, it was concentrated and the compound was purified by MPLC (EtOAc:Hex). After concentration, the target compound was obtained as a light yellow liquid. (Yield: 77%)
단계 2: 2-클로로-4 -((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N, N-디메틸피리미딘-5-카르 복사미드의 제조Step 2: Preparation of 2-chloro-4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethylpyrimidine-5-carboxamide
상기 단계 1에서 제조한 화합물 (1.0 당량)을 1,4-디옥산 (0.1 M)에 첨가하여 녹인 후, 2-(6-아미노피리딘-2-일)프로판-2-올 (1.0 당량)와 DIPEA (1.0 당량)를 상온에서 첨가하였고, 110 oC에서 18시간 동안 반응시켰다. 반응 혼합물을 실온으로 냉각시키고 물을 부은 후, EtOAc로 추출하였다.(x3) 모아진 유기층은 brine으로 ??어준 후, MgSO4로 물을 제거하였다. 이를 여과한 후, 농축하였고 화합물은 MPLC (ETOAC:Hex)을 이용하여 정제하였다. 농축 후, 노란색 고체의 목적 화합물을 수득하였다. (수율: 52%)The compound prepared in step 1 (1.0 equiv.) was dissolved in 1,4-dioxane (0.1 M), followed by 2-(6-aminopyridin-2-yl)propan-2-ol (1.0 equiv.) and DIPEA (1.0 equiv.) was added at room temperature, and reacted at 110 o C for 18 hours. The reaction mixture was cooled to room temperature, poured with water, and extracted with EtOAc. (x3) The combined organic layers were washed with brine, and then water was removed with MgSO 4 . After filtration, it was concentrated and the compound was purified using MPLC (ETOAC:Hex). After concentration, the title compound was obtained as a yellow solid. (Yield: 52%)
단계 3: 2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-4-(6-(2-히드록시프로판-2-일)피리딘-2-일아미노)-N,N-디메틸피리미딘-5-카복스아마이드의 제조Step 3: 2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-4-(6-(2-hydroxypropan-2-yl)pyridin- Preparation of 2-ylamino)-N,N-dimethylpyrimidine-5-carboxamide
상기 단계 2에서 제조한 화합물 (1.0 당량), 1-(4-아미노-2-메톡시페닐)-N, N-디메틸피페리딘-4-아민 (1.0 당량)과 K2CO3 (5.0 당량)를 sec-BuOH (0.3 M)에 첨가하여 녹인 후, 1분 동안 초음파 처리하여 가스를 제거하였다. 반응 혼합물에 Pd2(dba)3 (0.1 당량) 및 Xphos (0.1 당량)을 100 oC에서 첨가한 후, 2시간 동안 반응 시켰다. 반응 후, 반응 혼합물을 셀라이트로 여과하고, EtOAc와 MeOH로 씻어주었다. 얻어진 여과액을 농축한 후, prep-HPLC로 정제하여 보랏빛 액체의 목적화합물을 수득하였다. (수율: 22%)The compound prepared in step 2 (1.0 equiv.), 1-(4-amino-2-methoxyphenyl)-N, N-dimethylpiperidin-4-amine (1.0 equiv.) and K 2 CO 3 (5.0 equiv.) ) was dissolved in sec-BuOH (0.3 M) and then sonicated for 1 minute to remove gas. Pd 2 (dba) 3 (0.1 equivalents) and Xphos (0.1 equivalents) were added to the reaction mixture at 100 o C, followed by reaction for 2 hours. After the reaction, the reaction mixture was filtered through celite and washed with EtOAc and MeOH. The obtained filtrate was concentrated and purified by prep-HPLC to obtain the target compound as a purple liquid. (Yield: 22%)
<실시예 132> 4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N,N-디메틸-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-5-카복스아마이드의 제조<Example 132> 4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-((1,2,3,4-tetra Preparation of hydroisoquinolin-6-yl)amino)pyrimidine-5-carboxamide
상기 실시예 131과 동일한 방법을 수행하여 4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N,N-디메틸-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-5-카복스아마이드를 제조하였다.4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-((1,2, 3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine-5-carboxamide was prepared.
<실시예 133> 4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N,N-디메틸-2-((2- 메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)피리딘-2-일)아미노)피리미딘-5-카복스아마이드의 제조<Example 133> 4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-((2-methyl-1,2,3 Preparation of ,4-tetrahydroisoquinolin-6-yl)pyridin-2-yl)amino)pyrimidine-5-carboxamide
상기 실시예 131과 동일한 방법을 수행하여 4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N,N-디메틸-2-((2- 메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)피리딘-2-일)아미노)피리미딘-5-카복스아마이드를 제조하였다.In the same manner as in Example 131, 4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-((2-methyl- 1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-2-yl)amino)pyrimidine-5-carboxamide was prepared.
<실시예 134> (S)-4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N,N-디메틸-2 -((4-(3-메틸피페라진-1-일)페닐)아미노)피리미딘-5-카복스아마이드의 제조<Example 134> (S)-4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-((4-(3- Preparation of methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide
상기 실시예 131과 동일한 방법을 수행하여 (S)-4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N,N-디메틸-2 -((4-(3-메틸피페라진-1-일)페닐)아미노)피리미딘-5-카복스아마이드를 제조하였다.(S)-4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-(((S)-4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N,N-dimethyl-2-(( Prepared 4-(3-methylpiperazin-1-yl)phenyl)amino)pyrimidine-5-carboxamide.
<실시예 135> (R)-4-(6-(2-히드록시프로판-2-일)피리딘-2-일아미노)-2-(3-메톡시-4-(3-메틸피페라진-1-일)페닐아미노)-N,N-디메틸피리미딘-5-카복스아마이드의 제조<Example 135> (R)-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)-2-(3-methoxy-4-(3-methylpiperazine- Preparation of 1-yl)phenylamino)-N,N-dimethylpyrimidine-5-carboxamide
상기 실시예 131과 동일한 방법을 수행하여 (R)-4-(6-(2-히드록시프로판-2-일)피리딘-2-일아미노)-2-(3-메톡시-4-(3-메틸피페라진-1-일)페닐아미노)-N,N-디메틸피리미딘-5-카복스아마이드를 제조하였다.In the same manner as in Example 131, (R)-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)-2-(3-methoxy-4-(3) -Methylpiperazin-1-yl)phenylamino)-N,N-dimethylpyrimidine-5-carboxamide was prepared.
<실시예 136> 2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-4-((6-(2-히드록시프로판-2-일)피리딘-2-일) 아미노)-N-메틸피리미딘-5-카복스아마이드의 제조<Example 136> 2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-4-((6-(2-hydroxypropane-2) Preparation of -yl)pyridin-2-yl)amino)-N-methylpyrimidine-5-carboxamide
상기 실시예 131과 동일한 방법을 수행하여 2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-4-((6-(2-히드록시프로판-2-일)피리딘-2-일) 아미노)-N-메틸피리미딘-5-카복스아마이드를 제조하였다.2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-4-((6-(2- Hydroxypropan-2-yl)pyridin-2-yl)amino)-N-methylpyrimidine-5-carboxamide was prepared.
<실시예 137> 4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N-메틸-2-((1,2,3,4-테트라 히드로이소퀴놀린-6-일)아미노) 피리미딘-5-카복스아마이드의 제조<Example 137> 4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N-methyl-2-((1,2,3,4-tetrahydroiso Preparation of quinolin-6-yl)amino) pyrimidine-5-carboxamide
상기 실시예 131과 동일한 방법을 수행하여 4-((6-(2-히드록시프로판-2-일)피리딘-2-일)아미노)-N-메틸-2-((1,2,3,4-테트라 히드로이소퀴놀린-6-일)아미노) 피리미딘-5-카복스아마이드를 제조하였다.4-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)amino)-N-methyl-2-((1,2,3, 4-tetrahydroisoquinolin-6-yl)amino)pyrimidine-5-carboxamide was prepared.
상기 실시예 120 내지 137에서 제조한 화합물의 화학구조를 하기 표 7에, 화합물명과 1H NMR, mass, 수율 및 HPLC 분석 결과를 하기 표 8에 정리하여 나타내었다.Chemical structures of the compounds prepared in Examples 120 to 137 are shown in Table 7 below, and the compound names, 1 H NMR, mass, yield and HPLC analysis results are summarized in Table 8 below.
(%)transference number
(%)
r.t.(min)
PurityHPLC
rt(min)
Purity
100 %4.34
100%
<실험예 1> Wee1 키나아제 억제활성 평가<Experimental Example 1> Wee1 kinase inhibitory activity evaluation
본 발명에 따른 화학식 1로 표시되는 화합물의 Wee1 키나아제에 대한 억제활성을 평가하기 위하여 하기와 같은 실험을 수행하였다.In order to evaluate the inhibitory activity of the compound represented by Formula 1 according to the present invention on Wee1 kinase, the following experiment was performed.
384-웰 플레이트에 재조합 Wee1 키나아제(Invitrogen, Carlsbad, CA), 3.4umol/l 폴리 G:T(4:1)(Signal Chem, Richmond, BC, Canada), 20μmol/L ATP (Invitrogen, Carlsbad, CA)를 키나아제 반응 버퍼 (40 mmol/L TrisHCl, 10 mmol/L MgCl2 및 0.1 μg/μL BSA(bovine serum albumin))에 첨가하여 혼합하였다. 본 발명에 따른 실시예 1-21 화합물을 각각 1μM 이하, 1μM 초과 내지 10μM 이하, 10μM 초과 내지 100μM 이하 및 100μM 초과 농도로 첨가한 후, 30℃ 인큐베이터에서 1시간 동안 반응시켰다. 반응이 종료된 후, 동량의 키나아제-글로(Kinase-Glo, Promega, Madison, WI) 용액을 첨가하여 1시간 동안 반응시키고, 탐지(detection) 용액을 첨가하여 상온에서 10분 동안 더 반응시킨 후, 마이크로플레이트 효소결합면역흡착검사 판독기(microplate ELISA reader; , Bio-Tek)를 이용하여 루시페라제(Luciferase)의 양을 측정하여 키나아제의 IC50 값을 산출하였다. 그 결과를 하기 표 9에 나타내었다.Recombinant Weel kinase (Invitrogen, Carlsbad, CA), 3.4 umol/l poly G:T(4:1) (Signal Chem, Richmond, BC, Canada), 20 μmol/L ATP (Invitrogen, Carlsbad, CA) in a 384-well plate in 384-well plates ) was added to kinase reaction buffer (40 mmol/L TrisHCl, 10 mmol/L MgCl2 and 0.1 μg/μL bovine serum albumin (BSA)) and mixed. After adding the compounds of Examples 1-21 according to the present invention at concentrations of 1 μM or less, more than 1 μM to 10 μM or less, 10 μM to 100 μM or less and more than 100 μM, respectively, they were reacted in an incubator at 30° C. for 1 hour. After completion of the reaction, the same amount of kinase-glo (Kinase-Glo, Promega, Madison, WI) solution was added to react for 1 hour, and a detection solution was added to further react for 10 minutes at room temperature, The IC 50 value of the kinase was calculated by measuring the amount of luciferase using a microplate enzyme-linked immunosorbent assay reader (microplate ELISA reader; Bio-Tek). The results are shown in Table 9 below.
측정된 키나아제의 IC50값을 10nM 미만인 경우 A등급, 10 ~ 100nM인 경우 B등급 100nM 초과인 경우 C등급으로 분류하여 하기 표 9에 정리하여 나타내었다. When the IC 50 value of the measured kinase is less than 10 nM, it is class A, when it is 10 to 100 nM, it is class B, when it exceeds 100 nM, it is classified as class C, and is summarized in Table 9 below.
Wee1Enzyme activity
Wee1
Wee1Enzyme activity
Wee1
상기 표 9에 나타난 바와 같이,As shown in Table 9 above,
본 발명의 실시예 화합물들은 Wee1 키나아제 대하여 우수한 억제활성을 나타냄을 확인하였다.It was confirmed that the Example compounds of the present invention exhibit excellent inhibitory activity against Weel kinase.
따라서, 본 발명에 따른 화학식 1로 표시되는 화합물은 Wee1 키나아제 활성과 관련된 질환의 치료에 유용하게 사용할 수 있다.Therefore, the compound represented by Formula 1 according to the present invention can be usefully used for the treatment of diseases related to Weel kinase activity.
<실험예 2> 간암 세포주의 세포증식 억제활성 평가<Experimental Example 2> Evaluation of cell proliferation inhibitory activity of liver cancer cell lines
본 발명에 따른 화학식 1로 표시되는 화합물의 간암 세포주에 대한 세포증식 억제 활성을 평가하기 위하여 하기와 같은 실험을 수행하였다.In order to evaluate the cell proliferation inhibitory activity of the compound represented by Formula 1 according to the present invention against a liver cancer cell line, the following experiment was performed.
간암 세포주인 Huh7 세포(제조사 : Rinken cell bank) 를 3000 세포/웰의 농도로 96-웰 플레이트에 넣고, 24시간 동안 배양하여 세포를 배양용기에 부착시켰다. 상기 배지에 실시에 1-14 화합물을 각각 1μM 이하, 1μM 초과 내지 10μM 이하, 10μM 초과 내지 100μM 이하 및 100μM 초과 농도로 녹인 후 세포가 들어있는 웰 플레이트로 교체하고 72시간 동안 배양하였다. 이후, MTS(3,-(4, 5-디메틸티아졸-2-일)-5-(3-카르복시메톡시페닐)-2-(4-설포페닐)-2H-테트라졸리움 염, Promega)용액 20μl을 각 웰에 첨가하고 1 시간 후, 마이크로플레이트 효소결합면역흡착검사 판독기 (microplate ELISA reader; , Bio-Tek)를 이용하여 490 nm의 파장에서 흡광도를 측정함으로써 EC50을 산출하였다. 그 결과를 하기 표 10에 나타내었다.Huh7 cells (manufacturer: Rinken cell bank), a liver cancer cell line, were placed in a 96-well plate at a concentration of 3000 cells/well, and cultured for 24 hours to attach the cells to the culture vessel. After dissolving the compounds of Example 1-14 in the above medium at concentrations of 1 μM or less, more than 1 μM to 10 μM or less, 10 μM to 100 μM or less and more than 100 μM, respectively, it was replaced with a well plate containing cells and cultured for 72 hours. Then, MTS (3,-(4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt, Promega) solution 20 μl was added to each well and after 1 hour, EC 50 was calculated by measuring absorbance at a wavelength of 490 nm using a microplate ELISA reader (, Bio-Tek). The results are shown in Table 10 below.
표 10에 있어서, A 는 0.1 μM 이하이고, B 는 0.1 μM 초과 내지 1 μM 이하이고, 및 C 는 1 μM 초과 내지 100μM 이하이다.In Table 10, A is 0.1 μM or less, B is more than 0.1 μM to 1 μM or less, and C is more than 1 μM to 100 μM or less.
Huh7Cellular activity
Huh7
Hep7Cellular activity
Hep7
상기 표 10에 나타난 바와 같이,As shown in Table 10 above,
본 발명에 따른 실시예 화합물들은 간암세포 증식 억제능을 나타냄을 알 수 있다.It can be seen that the example compounds according to the present invention exhibit the ability to inhibit the proliferation of liver cancer cells.
따라서, 본 발명에 따른 화학식 1로 표시되는 화합물은 암의 치료, 특히, 간암의 치료에 유용하게 사용할 수 있다.Therefore, the compound represented by Formula 1 according to the present invention can be usefully used for the treatment of cancer, in particular, the treatment of liver cancer.
<실험예 3> 간암 세포주 외 다른 암 세포주에서의 세포증식 억제활성 평가<Experimental Example 3> Evaluation of cell proliferation inhibitory activity in other cancer cell lines other than liver cancer cell lines
본 발명에 따른 화학식 1로 표시되는 화합물의 암세포 증식 억제(암세포 사멸) 효과를 평가하기 위하여 CCK 분석을 수행하였다. 구체적으로, 암 세포주인 A431 (상피세포암, epidermoid carcinoma), NCI-H23 (폐암, lung cancer), HT29 (대장암, colon cancer), T47D (유방암, mammary cancer), KG-1 (백혈병, leukemia) 및 UWB1.289 (난소암, ovarian cancer) 세포주를 대상으로 분석을 수행하였고, 각 세포에 적합한 배지를 이용하여 세포배양을 하였다.CCK analysis was performed in order to evaluate the cancer cell proliferation inhibitory (cancer cell death) effect of the compound represented by Formula 1 according to the present invention. Specifically, the cancer cell lines A431 (epidermoid carcinoma), NCI-H23 (lung cancer), HT29 (colon cancer), T47D (breast cancer, mammary cancer), KG-1 (leukemia) ) and UWB1.289 (ovarian cancer, ovarian cancer) cell lines were analyzed and cell culture was performed using a medium suitable for each cell.
보다 상세하게, A431(KCLB), NCI-H23(ATCC), HT29(ATCC), T47D(ATCC), KG-1(ATCC) 및 UWB1.289(ATCC) 는 96-웰 플레이트 (Corning)의 각 웰에, 각각 5 x 103/100 ㎕, 5 x 103/100 ㎕, 3 x 103/100 ㎕, 5 x 103/100 ㎕, 2 x 104/100 ㎕, 3 x 103/100 ㎕로 플레이팅하고하루 동안 부착시켰다. 배양액을 제거한 뒤, 3배수로 연속 희석된 9가지 농도(0.0015 - 10 μM)의 화합물 및 DMSO 대조군이 포함된 배양액으로 교체시킨 다음 37℃ CO2 배양기에서 72시간 동안 배양하였다. 72시간 후, 화합물을 처리한 플레이트를 꺼내어, Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc) 용액을 10μl/웰 처리 후, 잘 섞어 준다. 37℃ CO2 인큐베이터에서 2시간 동안 배양하여, 마이크로플레이트 판독기로 450nm에서의 흡광도를 측정한다. 데이터는 비히클 기준 처리된 세포에 비례하여 백분율로 나타내었고 GraphPad Prism 5.0(GraphPad software Inc., San Diego)을 이용하여 GI50 값을 산출하였다.More specifically, A431 (KCLB), NCI-H23 (ATCC), HT29 (ATCC), T47D (ATCC), KG-1 (ATCC) and UWB1.289 (ATCC) were mixed in each well of a 96-well plate (Corning). In, 5 x 10 3 /100 μl, 5 x 10 3 /100 μl, 3 x 10 3 /100 μl, 5 x 10 3 /100 μl, 2 x 10 4 /100 μl, 3 x 10 3 /100 μl, respectively plated and allowed to adhere for one day. After removing the culture medium, it was replaced with a culture medium containing 9 concentrations (0.0015 - 10 μM) of the compound and DMSO control serially diluted 3 times, and then cultured in a 37° C. CO 2 incubator for 72 hours. After 72 hours, the plate treated with the compound is taken out, and after treatment with 10 μl/well of Cell Counting Kit-8 (Dojindo Molecular Technologies, Inc) solution, mix well. Incubate for 2 hours in a 37° C. CO 2 incubator, and measure the absorbance at 450 nm with a microplate reader. The data were expressed as a percentage relative to the treated cells relative to the vehicle reference and GI 50 values were calculated using GraphPad Prism 5.0 (GraphPad software Inc., San Diego).
표 11에 있어서, A 는 1 μM 이하이고, B 는 1 μM 초과 내지 10 μM 이하이고, 및 C 는 10 μM 초과 내지 100μM 이하이다.In Table 11, A is 1 μM or less, B is more than 1 μM to 10 μM or less, and C is more than 10 μM to 100 μM or less.
상기 표 11에 나타난 바와 같이,As shown in Table 11 above,
본 발명의 실시예 화합물은 A431 (상피세포암, epidermoid carcinoma), NCI-H23 (폐암, lung cancer), HT29 (대장암, colon cancer), T47D (유방암, mammary cancer), KG-1 (백혈병, leukemia) 및 UWB1.289 (난소암, ovarian cancer) 세포주에 대하여 세포성장 억제능을 나타내었다.Example compounds of the present invention include A431 (epithelial cell carcinoma, epidermoid carcinoma), NCI-H23 (lung cancer), HT29 (colon cancer), T47D (breast cancer, mammary cancer), KG-1 (leukemia, leukemia) and UWB1.289 (ovarian cancer, ovarian cancer) cell lines were shown to inhibit cell growth.
따라서, 본 발명에 따른 화학식 1로 표시되는 화합물은, 암의 치료, 특히, 상피세포암, 폐암, 대장암, 유방암, 백혈병, 난소암의 치료에 유용하게 사용할 수 있다.Therefore, the compound represented by Formula 1 according to the present invention can be usefully used for the treatment of cancer, particularly, epithelial cell cancer, lung cancer, colorectal cancer, breast cancer, leukemia, and ovarian cancer.
<실험예 4> 키나아제 저해활성 평가 실험<Experimental Example 4> Kinase inhibitory activity evaluation experiment
본 발명에 따른 화학식 1로 표시되는 화합물의 보다 많은 효소에 대한 저해활성을 평가하기 위해 하기와 같은 실험을 수행하였다.In order to evaluate the inhibitory activity against more enzymes of the compound represented by Formula 1 according to the present invention, the following experiment was performed.
구체적으로, 본 별명의 실시예 화합물 중, 선별된 실시예 8, 실시예 49, 실시예 120에 대하여, DiscoverX 사에 의뢰하여 효소(kinase) 선택성을 측정하기로 하고, scanMAXTM Kinase 분석용 패널을 사용하여 실험을 진행하였다.Specifically, among the example compounds of this alias, selected Examples 8, 49, and 120 were requested to DiscoverX to measure the enzyme (kinase) selectivity, and scanMAX TM Kinase analysis panel The experiment was carried out using
이때, 효소에 처리되는 약물의 농도는 DMSO에 1 uM로 하였고, 다음 식 1과 같은 방법으로 조절 백분율(% control)을 정하였고, 그 결과를 하기 표 12-16에 나타내었다.At this time, the concentration of the drug treated with the enzyme was 1 uM in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below, and the results are shown in Tables 12-16 below.
[식 1][Equation 1]
(실시예 화합물 - 양성 대조군)/(음성 대조군 - 양성대조군) × 100(Example compound - positive control) / (negative control - positive control) × 100
여기서, 상기 양성 대조군은 0%의 조절 백분율을 나타내는 화합물을 말하며, 음성 대조군은 DMSO로 100%의 조절 백분율을 나타낸다. 또한, 본 발명의 효소 선택성은 각각의 효소에 대하여 조절 백분율이 < 35%(즉, 35% 미만)이면 해당 효소에 대하여 활성을 갖는 것으로 판단하였다.Here, the positive control refers to a compound showing a percentage control of 0%, and the negative control indicates a percentage control of 100% with DMSO. In addition, the enzyme selectivity of the present invention was determined to have activity for each enzyme if the control percentage was <35% (ie, less than 35%) for each enzyme.
AAK1, ABL1(E255K)-phosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ADCK4, AMPK-alpha1, AMPK-alpha2, ARK5, AURKB, BIKE, BLK, BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, CSNK2A1, CSNK2A2, DAPK1, DAPK3, DCAMKL1, DDR1, DDR2, DLK, DYRK1B, DYRK2, EGFR, EGFR(E746-A750del), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD, FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FRK, FYN, GAK, GCN2(Kin.Dom.2,S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK-epsilon, IRAK1, ITK, JAK1(JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2(G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4, MAP4K5, MARK1, MARK2, MARK3, MEK5, MELK, MERTK, MINK, MKNK2, MLK1, MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEK7, NEK9, PAK4, PAK7, PDGFRA, PDGFRB, PIK3CB, PIP5K1A, PIP5K2B, PKNB(M.tuberculosis), PLK1, PLK2, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK1, RIOK3, RIPK1, RPS6KA4(Kin.Dom.1-N-terminal), RSK1(Kin.Dom.1-N-terminal), RSK2(Kin.Dom.1-N-terminal), RSK3(Kin.Dom.1-N-terminal), RSK4(Kin.Dom.1-N-terminal), SBK1, SIK, SIK2, SLK, SNARK, SRC, SRPK1, SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, TRKA, TRKB, TRKC, TTK, TXK, TYK2(JH1domain-catalytic), TYK2(JH2domain-pseudokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, 및 YSK4 키나아제에 대하여 조절 백분율 35% 보다 작은 값을 가지는 것을 알 수 있다. AAK1, ABL1(E255K)-phosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated , ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ADCK4, AMPK-alpha1, AMPK-alpha2, ARK5, AURKB, BIKE, BLK, BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, CSNK2A1, CSNK2A2, DAPK1, DAPK3, DEGFR DY, DLRK DDR1, DDR2 ( E746-A750del), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR (L861Q), EGFR(S752-I759del), EGFR(T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FGR, FLT1, FLT3, FLT3 (D835H), FGFR1), (D835H) FLT3(D835Y), FLT3(ITD, FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FRK, FYN, GA K, GCN2 (Kin.Dom.2,S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK-epsilon, IRAK1, ITK, JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain) -catalytic), JNK1, JNK2, JNK3, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A) , KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2 (G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4, MAP4K5, MARK1, MARK2, MARK3, MEK5, MLK, K, MRKK MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEK7, NEK9, PAK4, PAK7, PDGFRA, PDGFRB, PIK3CB, PIP5K1A, PIP5K2B, PKNB (M.PLK1, RK2), PLK2 , RET(M918T), RET(V804L), RET(V804M), RIOK1, RIOK3, RIPK1, RPS6KA4(Kin.Dom.1-N-terminal), RSK1(Kin.Dom.1-N-terminal), RSK2( Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK4 (Kin.Dom.1-N-terminal), SBK1, SIK, SIK2, SLK, SNARK, SRC, SRPK1 , SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, TRKA, TRKB, TRKC, TTK, TXK, TYK2 (JH1domain-catalytic), TYK2 (JH2domain-pseu) dokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, and it can be seen that it has a value less than 35% of the control percentage for the YSK4 kinase.
이는 본 발명의 실시예 화합물이 상기 나열된 효소에 대하여 억제 활성을 갖고 있음을 나타내는 것이며, 이로부터 상기 나열된 효소와 관련된 질환에 사용시 유용한 효과가 있음을 암시하는 것이다.This indicates that the example compounds of the present invention have inhibitory activity against the enzymes listed above, suggesting that they have useful effects when used in diseases related to the enzymes listed above.
따라서, 본 발명에 따른 화학식 1로 표시되는 화합물은 AAK1, ABL1(E255K)-phosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ADCK4, AMPK-alpha1, AMPK-alpha2, ARK5, AURKB, BIKE, BLK, BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, CSNK2A1, CSNK2A2, DAPK1, DAPK3, DCAMKL1, DDR1, DDR2, DLK, DYRK1B, DYRK2, EGFR, EGFR(E746-A750del), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FGR, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD, FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT3-autoinhibited, FRK, FYN, GAK, GCN2(Kin.Dom.2,S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK-epsilon, IRAK1, ITK, JAK1(JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT(A829P), KIT(D816H), KIT(D816V), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2(G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4, MAP4K5, MARK1, MARK2, MARK3, MEK5, MELK, MERTK, MINK, MKNK2, MLK1, MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEK7, NEK9, PAK4, PAK7, PDGFRA, PDGFRB, PIK3CB, PIP5K1A, PIP5K2B, PKNB(M.tuberculosis), PLK1, PLK2, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK1, RIOK3, RIPK1, RPS6KA4(Kin.Dom.1-N-terminal), RSK1(Kin.Dom.1-N-terminal), RSK2(Kin.Dom.1-N-terminal), RSK3(Kin.Dom.1-N-terminal), RSK4(Kin.Dom.1-N-terminal), SBK1, SIK, SIK2, SLK, SNARK, SRC, SRPK1, SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, TRKA, TRKB, TRKC, TTK, TXK, TYK2(JH1domain-catalytic), TYK2(JH2domain-pseudokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, 및 YSK4 키나아제 관련 질환의 치료 또는 예방용 약학적 조성물로 유용하게 사용될 수 있다.Therefore, the compound represented by Formula 1 according to the present invention is AAK1, ABL1(E255K)-phosphorylated, ABL1(F317L)-phosphorylated, ABL1(H396P)-nonphosphorylated, ABL1(H396P)-phosphorylated, ABL1(M351T)-phosphorylated, ABL1(Q252H)-nonphosphorylated, ABL1(Q252H)-phosphorylated, ABL1(T315I)-nonphosphorylated, ABL1(T315I)-phosphorylated, ABL1(Y253F)-phosphorylated, ABL1-nonphosphorylated, ABL1-phosphorylated, ABL2, ADCK1, AMPK-alphaBL1 , AMPK-alpha2, ARK5, AURKB, BIKE, BLK, BMPR2, CDK4-cyclinD1, CDK7, CDKL2, CDKL3, CLK1, CLK2, CLK4, CSF1R, CSF1R-autoinhibited, CSNK1A1, CSNK2A1, KLAPK1 DDR2, DCAM2A1, DCSNK2 , DDR2, DLK, DYRK1B, DYRK2, EGFR, EGFR(E746-A750del), EGFR(G719S), EGFR(L747-E749del, A750P), EGFR(L747-S752del, P753S), EGFR(L747-T751del,Sins), EGFR(L858R), EGFR(L858R,T790M), EGFR(L861Q), EGFR(S752-I759del), EGFR(T790M), EPHA1, EPHB1, EPHB4, EPHB6, ERBB2, ERBB3, ERN1, FAK, FGFR1, FGR, FGFR1 , FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD, FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q) , F LT3-autoinhibited, FRK, FYN, GAK, GCN2 (Kin.Dom.2,S808G), HCK, HIPK1, HIPK2, HIPK3, HIPK4, HPK1, IKK-epsilon, IRAK1, ITK, JAK1 (JH2domain-pseudokinase), JAK2 (JH2domain-pseudokinase) JH1domain-catalytic), JAK3 (JH1domain-catalytic), JNK1, JNK2, JNK3, KIT, KIT (A829P), KIT (D816H), KIT (D816V), KIT (L576P), KIT (V559D), KIT (V559D, T670I) ), KIT(V559D,V654A), KIT-autoinhibited, LATS1, LCK, LOK, LRRK2, LRRK2(G2019S), LYN, LZK, MAP3K2, MAP3K3, MAP4K3, MAP4K4, MAP4K5, MARK3, MARK2, MARK3 MERTK, MINK, MKNK2, MLK1, MLK3, MST3, MST4, MUSK, MYLK4, NEK1, NEK11, NEK3, NEK6, NEK7, NEK9, PAK4, PAK7, PDGFRA, PDGFRB, PIK3CB, PIP5K1B, PIP5KNBM. , PLK1, PLK2, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK1, RIOK3, RIPK1, RPS6KA4(Kin.Dom.1-N-terminal), RSK1(Kin.Dom.1) -N-terminal), RSK2 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK4 (Kin.Dom.1-N-terminal), SBK1, SIK, SIK2 , SLK, SNARK, SRC, SRPK1, SRPK3, STK33, TAK1, TAOK1, TAOK2, TBK1, TNIK, TNK1, TNK2, TRKA, TRKB, TRKC, TTK, TXK, TYK2(JH1domain- catalytic), TYK2 (JH2domain-pseudokinase), ULK1, ULK2, ULK3, VEGFR2, WEE1, WEE2, YES, and YSK4 can be usefully used as a pharmaceutical composition for the treatment or prevention of kinase-related diseases.
따라서, 본 발명에 따른 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염은 WEE1을 포함하는 다양한 단백질 키나아제에 대한 억제활성이 우수하므로, 이를 유효성분으로 함유하는 약학적 조성물은 단백질 키나아제 관련 질환, 특히 암의 치료 또는 예방에 유용하게 사용될 수 있으며, 간암, 폐암, 상피세포암, 대장암, 유방암, 백혈병 및 난소암에 대한 암세포증식 억제효과가 우수한 바, 특히, 간암, 폐암, 상피세포암, 대장암, 유방암, 백혈병 또는 난소암의 치료에 유용하게 사용될 수 있다.Therefore, the compound represented by Formula 1 according to the present invention, its optical isomer, or a pharmaceutically acceptable salt thereof has excellent inhibitory activity against various protein kinases including WEE1, and thus a pharmaceutical composition containing it as an active ingredient can be usefully used for the treatment or prevention of protein kinase-related diseases, particularly cancer, and has excellent cancer cell proliferation inhibitory effects on liver cancer, lung cancer, epithelial cell cancer, colorectal cancer, breast cancer, leukemia and ovarian cancer, in particular, liver cancer, It can be usefully used for the treatment of lung cancer, epithelial cell cancer, colorectal cancer, breast cancer, leukemia or ovarian cancer.
Claims (12)
[화학식 1]
(상기 화학식 1에 있어서,
A는 CH 또는 N이고;
L은 NH 또는 부재이고;
R1 은 하나 이상의 N 원자를 포함하는 6원의 비치환 또는 치환된 헤테로사이클로알킬이고 및 R2는 수소, 할로겐 또는 메톡시이고, 또는
R1 및 R2는 이들이 결합된 탄소원자와 함께 N 원자를 포함하는 6 또는 7원의 비치환 또는 치환된 헤테로사이클로알킬을 형성할 수 있고,
이때, 상기 치환된 헤테로사이클로알킬은 각각 직쇄 또는 분지쇄의 C1-4알킬, 비치환 또는 C1-2알킬로 하나이상 치환된 아민 및 비치환 또는 메틸로 하나이상 치환된 피페라진으로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;
R3은 비치환 또는 치환된 페닐, 또는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 5 내지 10 원자의 비치환 또는 치환된 헤테로아릴이고,
이때, 상기 치환된 페닐 및 헤테로아릴은 각각 할로겐, 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-6알킬 및 비치환 또는 할로겐으로 하나이상 치환된 직쇄 또는 분지쇄의 C1-6알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;
R4는 N, O 및 S로 이루어지는 군으로부터 선택되는 헤테로원자를 하나이상 포함하는 5 내지 10 원자의 비치환 또는 치환된 헤테로아릴이고,
이때, 상기 치환된 헤테로아릴은 NO2, NH2, -NH(C=O)R10, -(C=O)NR11R12, -NHSO2R13, 할로겐, 비치환 또는 OH로 하나이상 치환된 직쇄 또는 분지쇄의 C1-6알킬 및 직쇄 또는 분지쇄의 C1-6알콕시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고,
R10, R11, R12 및 R13은 각각 수소 또는 직쇄 또는 분지쇄의 C1-6알킬이다).
A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
(In Formula 1,
A is CH or N;
L is NH or absent;
R 1 is a 6 membered unsubstituted or substituted heterocycloalkyl comprising one or more N atoms and R 2 is hydrogen, halogen or methoxy, or
R 1 and R 2 together with the carbon atom to which they are attached may form a 6 or 7 membered unsubstituted or substituted heterocycloalkyl comprising N atoms,
In this case, the substituted heterocycloalkyl is selected from the group consisting of straight-chain or branched C1-4 alkyl, amines unsubstituted or substituted at least one with C1-2 alkyl, and piperazine unsubstituted or substituted with at least one methyl group. may be substituted with one or more substituents;
R 3 is unsubstituted or substituted phenyl, or 5 to 10 membered unsubstituted or substituted heteroaryl containing at least one heteroatom selected from the group consisting of N, O and S;
In this case, the substituted phenyl and heteroaryl are halogen, unsubstituted or branched C 1-6 alkyl substituted at least one with halogen, and straight or branched chain C 1 substituted with at least one unsubstituted or halogen, respectively. 6 may be substituted with one or more substituents selected from the group consisting of alkoxy;
R 4 is an unsubstituted or substituted heteroaryl of 5 to 10 atoms including at least one heteroatom selected from the group consisting of N, O and S;
In this case, the substituted heteroaryl is NO 2 , NH 2 , -NH(C=O)R 10 , -(C=O)NR 11 R 12 , -NHSO 2 R 13 , at least one halogen, unsubstituted or OH One or more substituents may be substituted with a substituent selected from the group consisting of substituted straight-chain or branched C 1-6 alkyl and straight-chain or branched C 1-6 alkoxy,
R 10 , R 11 , R 12 and R 13 are each hydrogen or linear or branched C 1-6 alkyl).
상기 A는 CH 또는 N이고;
L은 NH 또는 부재이고;
R1은 비치환 또는 치환된 피페리딘 또는 피페라진이고, 및 R2는 수소, F, 또는 메톡시이고, 또는 R1 및 R2는 이들이 결합된 탄소원자와 함께 비치환 또는 치환된 피페리딘 또는 아제판을 형성할 수 있고,
이때, 상기 치환된 피페리딘, 피페라진 및 아제판은 각각 메틸, -N(CH3)2 및 비치환 또는 메틸로 하나이상 치환된 피페라진으로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;
R3은 비치환 또는 치환된 페닐, 피리디닐, 피라졸릴, 피롤릴, 티아졸릴, 이소옥사졸릴, 티오펜닐, 퓨라닐, 벤조퓨라닐, 벤조티오펜닐, 인돌리닐 또는 퀴놀리닐이고,
이때, 상기 치환된 페닐, 피리디닐, 피라졸릴, 피롤릴, 티아졸릴, 이소옥사졸릴, 티오펜닐, 퓨라닐, 벤조퓨라닐, 벤조티오펜닐, 인돌릴 및 퀴놀리닐은 각각 F, 메틸, CF3 및 메톡시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있고;
R4는 비치환 또는 치환된 피리디닐 또는 인돌릴이고,
이때, 상기 치환된 피리니딜 및 인돌릴은 각각 NO2, NH2, -NH(C=O)CH3, -(C=O)NH2, -NHSO2CH3, F, -C(CH2)2OH, 메틸 및 메톡시로 이루어지는 군으로부터 선택되는 치환기로 하나이상 치환될 수 있는 것을 특징으로 하는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
wherein A is CH or N;
L is NH or absent;
R 1 is unsubstituted or substituted piperidine or piperazine , and R 2 is hydrogen, F, or methoxy , or R 1 and R 2 together with the carbon atom to which they are attached are unsubstituted or substituted piperazine can form din or azepan,
In this case, each of the substituted piperidine, piperazine and azepane may be substituted with one or more substituents selected from the group consisting of methyl, -N(CH 3 ) 2 and piperazine unsubstituted or one or more substituted with methyl. there is;
R 3 is unsubstituted or substituted phenyl, pyridinyl, pyrazolyl, pyrrolyl, thiazolyl, isoxazolyl, thiophenyl, furanyl, benzofuranyl, benzothiophenyl, indolinyl or quinolinyl;
In this case, the substituted phenyl, pyridinyl, pyrazolyl, pyrrolyl, thiazolyl, isoxazolyl, thiophenyl, furanyl, benzofuranyl, benzothiophenyl, indolyl and quinolinyl are each F, methyl , CF 3 and may be substituted with one or more substituents selected from the group consisting of methoxy;
R 4 is unsubstituted or substituted pyridinyl or indolyl,
In this case, the substituted pyridyl and indolyl are each NO 2 , NH 2 , -NH(C=O)CH 3 , -(C=O)NH 2 , -NHSO 2 CH 3 , F, -C(CH 2 ) ) 2 OH, a compound characterized in that one or more may be substituted with a substituent selected from the group consisting of methyl and methoxy, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
상기 A는 CH 또는 N이고;
R1 은 , , , 또는 이고, 및 R2는 수소, F, 또는 메톡시이고,
또는 R1 및 R2는 이들이 결합된 탄소원자와 함께 , 또는 을 형성할 수 있고;
R3은 , , , , , , , , , , , , , , , , , , , , , , , , , 또는 이고;
L-R4는 , , , , , , , , , , 또는 인 것을 특징으로 하는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염.
According to claim 1,
wherein A is CH or N;
R 1 is , , , or , and R 2 is hydrogen, F, or methoxy,
or R 1 and R 2 together with the carbon atom to which they are attached , or can form;
R 3 is , , , , , , , , , , , , , , , , , , , , , , , , , or ego;
LR 4 is , , , , , , , , , , or A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that
상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염:
<1> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노) -5-(1H-피라졸-4-일)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올;
<2> 2-(6 -((2-(4-(4-(4- 메틸피페라진-1-일)피페리딘-1-일) 페닐)아미노)-5-(1H-피라졸-4-일)피리미딘-4-아미노)피리딘-2-일) 프로판-2-올;
<3> 2-(6-(2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-5-(1H-피라졸-4-일)피리딘-4-일아미노)피리딘-2-일)프로판-2-올;
<4> 2-(6-((2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(1H-피라졸 -4-일)피리딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<5> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(6-플루오로피리딘-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<6> 2-(6-((5-(벤조퓨란 -2-일)-2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<7> 2-(6-(2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-5-(1-메틸-1H-인돌-5-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;
<8> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5- (퓨란-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<9> 2-(6-(2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-5-(1-메틸-1H-피라졸-4-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;
<10> 2-(6-(2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)-5-(1-메틸-1H-피라졸-3-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;
<11> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5- (티오펜-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<12> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5- (피리딘-3-일)피리미딘-4-일)아미노) 피리딘-2-일)프로판-2-올;
<13> 2-(6-((5-(벤조퓨란-3-일)-2-((3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-아미노)아미노)피리딘-2-일)프로판-2-올;
<14> 2-(6-(2-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐아미노)-5-(퀴놀린-6-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;
<15> 2-(6-((2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(1-메틸-1H- 피롤-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<16> 2-(6-((5-(벤조퓨란 -2-일)-2-((3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-아미노)아미노)피리딘-2-일)프로판-2-올;
<17> 2- (6 - ((2 - ((4- (4- 메틸피페라진 -1-일)피페리딘-1-일)페닐)아미노) -5-페닐피리미딘 -4-일)아미노)피리딘-2-일)프로판 -2-올;
<18> 2-(6 -((5-(벤조 [b]티오펜-3-일) -2 -((3-메톡시 -4-(4-메틸피페라진-1-일)피페리딘 -1-일)페닐)아미노)피리미딘 -4-일) 아미노) 피리딘 -2-일) 프로판 -2-올;
<19> 2- (6 - ((5- (1H- 인돌 -3-일) -2 - ((3- 메톡시 -4- (4- 메틸피페라진 -1-일) 피페리딘 -1-일) 페닐) 아미노 ) 피리미딘 -4-일) 아미노) 피리딘 -2-일) 프로판 -2-올;
<20> 2-(6-((5-(벤조 [b]티오펜-2-일) -2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<21> 2-(6-((5-(5-플루오로피리딘-3-일)-2-((3-메톡시-4-(4- 메틸피페라진-1-일)피페리딘-1-일) 페닐)아미노)피리미딘-4-일)아미노) 피리딘-2-일)프로판-2-올;
<22> 2-(6-(2-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐아미노)-5-(티오펜-2-일)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;
<23> 2-(6-((2-((3-메톡시-4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(1H-피롤-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<24> 2-(6-((5-(퓨란-2-일)-2-((3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-아미노)아미노)피리딘-2-일)프로판-2-올;
<25> 2-(6-((5-(벤조퓨란 -2-일)-2-((1,2,3,4- 테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘 -2-일)프로판-2-올;
<26> 2-(6-((5-(퓨란-3-일)-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일) 아미노)피리딘-2-일)프로판-2-올;
<27> 2-(6-((5-(벤조퓨란 -3-일)-2-((1,2,3,4- 테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘 -2-일)프로판-2-올;
<28> 2-(6-((5-(6-플루오로피리딘-3-일)-2- ((1,2,3,4-테트라히드로이소퀴놀린 -6-일)아미노)피리미딘-4-일)아미노) 피리딘-2 -프로판-2-올;
<29> 2-(6-((5-(1-메틸-1H-피라졸-3-일)-2-((1,2,3,4-테트라 히드로이소퀴놀린-6-일)아미노) 피리미딘-4-일)아미노)피리딘-2-일) 프로판-2-올;
<30> 2-(6-((2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)-5-(티오펜-2-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<31> 2-(6-((5-(벤조 [b]티오펜-2-일)-2-((1,2,3,4- 테트라히드로 이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<32> 2-(6-((5-(2-메톡시페닐)-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<33> 2-(6-((5-(3-메톡시페닐)-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘 -2-일)프로판-2-올;
<34> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(티오펜-2-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<35> 2-(6-(5-(벤조[b]티오펜-2-일)-2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐아미노)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;
<36> 2-(6-((5-(벤조퓨란 -3-일)-2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<37> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5- (1H-피롤-3-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<38> 2-(6-((5-(1H-피롤-3-일)-2-((1,2,3,4-테트라 히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-프로판-2-올;
<39> 2-(6-(5-(벤조[b]티오펜-2-일)-2-(2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일아미노)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;
<40> 2-(6-(5-(벤조[b]티오펜-2-일)-2-(1,2,3,4-테트라히드로이소퀴놀린-7-일아미노)피리미딘-4-일아미노)피리딘-2-일)프로판-2-올;
<41> 2-(6-((5-(벤조[b]티오펜-2-일)-2- ((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-7-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<42> 2-(6-((5-(퓨란-3-일)-2-((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<43> 2-(6-((5-(퓨란-3-일)-2-((1,2,3,4-테트라히드로이소퀴놀린-7-일)아미노) 피리미딘-4-일)아미노)피리딘-2-일) 프로판-2-올;
<44> 2-(6-((5-(퓨란-3-일)-2-((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-7-일)아미노)피리미딘-4-일)아미노) 피리딘-2-일)프로판-2-올;
<45> 2-(6-((5-(6-플루오로피리딘-3-일)-2 -((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<46> 2-(6-((2-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(티아졸-5-일)피리미딘-4-일)아미노)피리딘-2-일)프로판-2-올;
<47> 2-(6-((2-((2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)-5- (1H-피라졸-3-일) 피리미딘-4-일)아미노)피리딘-2-일) 프로판-2-올;
<48> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(퓨란-3-일) -4-(1-메틸-1H-인돌-3-일)2-아민;
<49> N-(5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일)피리미딘 -2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<50> N-(5-(퓨란-3-일) -4-(1-메틸-1H-인돌-3-일)피리미딘 -2-일)-2-메틸-1,2,3,4-테트라히드로이소퀴놀린-6 -아민;
<51> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(1-메틸-1H- 인돌-3-일)-5-(티오펜-2-일)2-아민;
<52> N-(4-(1-메틸-1H-인돌-3-일)-5-(티오펜-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<53> N-(5-(이소옥 사졸-4-일)-4-(1- 메틸-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<54> N-(4-(1-메틸-1H-인돌-3-일)-5-(1H-피라졸-4-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<55> N-(5-(퓨란-3-일)-4-(1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<56> N-(5-(6-플루오로 피리딘-3-일) -4- (1-메틸-1H-인돌 -3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<57> N-(5-(5-플루오로 피리딘-3-일)-4- (1-메틸-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<58> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(1-메틸-1H-인돌-3-일)-5-(티오펜-3-일)피리미딘-2-아민;
<59> N-(5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일) 피리미딘-2-일) -1,2,3,4-테트라 히드로이소퀴놀린-7-아민;
<60> N-(5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일) 피리미딘-2-일) -2,3,4,5-테트라히드로-1H-벤조[d]아제핀-7-아민;
<61> 5-(퓨란-3-일)-4- (1-메틸-1H-인돌 -3-일)-N-(4-(4-메틸피페라진-1-일)페닐)피리미딘-2-아민;
<62> 5-(퓨란-3-일)-N-(3-메톡시-4-(4-메틸피페라진-1-일)페닐)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;
<63> (S)-5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일)-N-(4-(3-메틸피페라진-1-일)페닐)피리미딘-2-아민 ;
<64> (S)-5-(퓨란-3-일)-N-(3-메톡시 -4-(3-메틸피페라진-1-일)페닐) -4-(1-메틸-1H- 인돌-3-일)피리미딘-2-아민;
<65> N-(5-(퓨란-3-일)-4-(4-니트로-1H- 인돌-1-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<66> N-(1-(5-(퓨란-3-일)-2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노) 피리미딘-4-일)-1H-인돌-4-일)메탄술폰아미드;
<67> N-(4-(4-아미노-1H-인돌-1-일)-5- (퓨란-3-일)피리미딘-2-일)-1,2,3,4- 테트라히드로이소퀴놀린-6-아민;
<68> N-(1-(5-(퓨란-3-일)-2-((1,2,3,4-테트라히드로 이소퀴놀린-6-일)아미노)피리미딘-4-일)-1H-인돌-4-일)아세트아미드;
<69> 5-(퓨란-3-일)-N-(3-메톡시-4- (4-메틸피페라진 -1-일)페닐)-4-(4-니트로-1H-인돌-1-일)피리미딘-2-아민;
<70> 1-(5-(퓨란-3-일) -2-((3-메톡시-4- (4-메틸피페라진 -1-일)페닐)아미노)피리미딘-4-일)-1H-인돌-4-아민;
<71> 5-(퓨란-3-일)-N- (4-(4-메틸피페라진-1-일)페닐)-4- (4-니트로-1H-인돌-1-일)피리미딘-2-아민;
<72> 1-(5-(퓨란-3-일)-2-((4-(4-메틸피페라진-1-일)페닐)아미노)피리미딘-4-일)-1H-인돌-4-아민;
<73> 5-(6-플루오로 피리딘-3-일)-4-(1-메틸-1H-인돌-3-일)-N-(4-(4-메틸피페라진-1-일)페닐)피리미딘-2-아민;
<74> N-(3-플루오로-4-(4-메틸피페라진-1-일)페닐)-5-(6-플루오로피리딘-3-일)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;
<75> 5-(6-플루오로 피리딘-3-일)-N- (3-메톡시-4-(4- 메틸피페라진-1-일)페닐)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;
<76> (S)-5-(6-플루오로피리딘-3-일)-4-(1-메틸-1H-인돌-3-일)-N-(4-(3-메틸피페라진 -1-일)페닐)피리미딘-2-아민;
<77> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(6-플루오로 피리딘-3-일)-4- (1-메틸-1H-인돌 -3-일)피리미딘-2- 아민;
<78> N-(3-플루오로-4-(4-메틸피페라진-1-일)페닐)-5-(퓨란-3-일)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;
<79> N-(5-(퓨란-3-일)-4-(6-메톡시-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<80> N-(5-(퓨란-3-일)-4-(6-메톡시-1-메틸-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라 히드로이소퀴놀린-6-아민;
<81> N-(4-(1-메틸-1H- 인돌-3-일)-5-(6- (트리플루오로메틸)피리딘-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-4-일) 6-아민;
<82> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(6-메톡시-1-메틸-1H-인돌-3-일)-5-(6-(트리 플루오로메틸)피리딘-3-일)피리미딘-2-아민;
<83> 4-(6-메톡시-1-메틸-1H-인돌-3-일)-N-(3-메톡시-4-(4-메틸피페라진-1-일)페닐)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2-아민;
<84> N-(4-(6-메톡시-1-메틸-1H-인돌-3-일)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2-일)4-테트라히드로이소퀴놀린-6-아민;
<85> N- (4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(6-플루오로 피리딘-3-일)-4-(6-메톡시-1-메틸-1H-인돌-3-일) 피리미딘-3-일)피리미딘-2-아민;
<86> 5-(6-플루오로 피리딘-3-일)-4-(6-메톡시-1-메틸-1H-인돌-3-일)-N-(3-메톡시-4-(4-메틸피페라진-1-일) 페닐)피리미딘-2- 아민;
<87> N-(5-(6-플루오로피리딘-3-일)-4-(6-메톡시-1-메틸-1H-인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<88> N-(4-(6-메톡시 -1H-인돌-3-일) -5-(6-(트리플루오로메틸)피리딘 -3-일)피리미딘 -2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<89> N-(5-(6-플루오로피리딘-3-일)-4-(6-메톡시-1H- 인돌-3-일)피리미딘-2-일)-1,2,3,4-테트라 히드로이소퀴놀린-6-아민;
<90> N-(4-(4-(디메틸아미노)피페리딘 -1-일)-3-메톡시 페닐)-4-(6-메톡시-1H-인돌-3-일)-5-(6-(트리 플루오로메틸)피리딘-3-일)피리미딘-2-아민;
<91> 4-(6-메톡시-1H- 인돌-3-일)-N-(3-메톡시-4-(4- 메틸피페라진-1-일)페닐)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2-아민;
<92> N-(4-(4-(디메틸아미노)피페리딘 -1-일)-3-메톡시 페닐)-5-(6-플루오로피리딘-3-일)-4-(6-메톡시 -1H-인돌-3-일) 피리미딘-2-아민;
<93> 5-(6-플루오로 피리딘-3-일)-4- (6-메톡시-1H-인돌-3-일)-N- (3- 메톡시-4-(4-메틸피페라진-1-일)페닐)피리미딘-2-아민;
<94> N-(4-(6-플루오로-1H-인돌-3-일)-5- (6-플루오로피리딘-3-일)피리미딘 -2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<95> N-(4-(6-플루오로-1-메틸-1H-인돌-3-일)-5-(6-플루오로피리딘-3-일)피리미딘-2-일)-1,2,3,4-테트라히드로이소퀴놀린-6-아민;
<96> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(퓨란-3-일)-4-(6-메톡시-1H-인돌-3-일)피리미딘-2-아민;
<97> 5-(퓨란-3-일)-4-(6-메톡시-1H-인돌-3-일)-N-(4-((S)-3-메틸피페라진-1-일)페닐)피리미딘-2-아민;
<98> (S)-5-(퓨란-3-일)-4-(6-메톡시-1H-인돌-3-일)-N-(3-메톡시-4- (3-메틸피페라진-1-일)페닐)피리미딘-2-아민;
<99> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(1H-인돌-3-일)-5-(6-(트리플루오로메틸)피리딘 -3-일)피리미딘-2-아민;
<100> (S)-4-(1H-인돌-3-일)-N-(4-(3- 메틸피페라진-1-일)페닐)-5-(6-(트리플루오로메틸)피리딘-3-일) 피리미딘-2 -아민;
<101> (S)-5-(6-플루오로피리딘-3-일)-4-(6-메톡시-1H-인돌-3-일)-N-(4-(3-메틸피페라진-1-일)페닐) 2-피리미딘-아민;
<102> (S)-5-(6-플루오로피리딘-3-일)-4-(6-메톡시-1H- 인돌-3-일)-N-(3-메톡시-4-(3- 메틸피페라진-1-일)페닐)피리미딘-2-아민;
<103> N-(3-메톡시-4- (4-메틸피페라진-1-일)페닐)-4-(1- 메틸-1H-인돌-3-일)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2- 아민;
<104> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4 (1-메틸-1H- 인돌-3-일)-5-(6- (트리플루오로메틸)피리딘-3-피리미딘-2-아민;
<105> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-5-(퓨란-3-일) -4-(6-메톡시-1- 메틸-1H-인돌-3-일)피리미딘-2-아민;
<106> 5-(퓨란-3-일)-4- (6-메톡시-1-메틸-1H-인돌-3-일)-N-(3-메톡시-4-(4-메틸피페라진-1-일)페닐)피리미딘 -2-아민;
<107> (S)-4-(1-메틸-1H-인돌-3-일)-N- (4-(3-메틸피페라진-1-일)페닐) -5-(6-(트리 플루오로메틸) 피리딘-3-일)피리미딘-2-아민;
<108> 4-(6-플루오로-1H-인돌-3-일)-5-(6-플루오로피리딘-3-일)-N-(4-((S)-3-메틸피페라진-1-일)페닐)피리미딘-2-아민;
<109> (S)-4-(6-플루오로 -1H-인돌 -3-일)-5-(6-플루오로피리딘-3-일)-N-(3-메톡시-4-(3-메틸피페라진-1-일)페닐)피리미딘-2-아민;
<110> N-(4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)-4-(6- 플루오로-1H-인돌-3-일)-5-(6-플루오로피리딘-3-일)피리미딘-2-아민;
<111> N-(4-(6-플루오로-1H-인돌-3-일)-5-(6-(트리플루오로메틸)피리딘-3-일)피리미딘-2-일)-1,2,3,4- 테트라히드로 이소퀴놀린-6-아민;
<112> (S)-5-(6-플루오로피리딘-3-일)-N-(3-메톡시-4-(3-메틸피페라진 -1-일)페닐)-4-(1-메틸-1H-인돌 -3-일)피리미딘-2-아민;
<113> 5-(6-플루오로 피리딘-3-일)-N- (3-메톡시-4-(피페리딘-4-일)페닐)-4-(1-메틸-1H-인돌-3-일)피리미딘-2-아민;
<114> 5-(6-플루오로 피리딘-3-일)-4- (1-메틸-1H-인돌 -3-일)-N-(4-(피페리딘-4-일)페닐)피리미딘-2-아민;
<115> 5-(6-플루오로피리딘-3-일)-4-(6- 메톡시-1-메틸-1H-인돌-3-일)-N-(3-메톡시-4-(피페리딘-4-일) 페닐)피리미딘-2-아민;
<116> 4-(6-플루오로-1H-인돌-3-일)-5-(6-플루오로피리딘-3-일)-N-(3-메톡시-4-(피페리딘-4-일)페닐)피리미딘-2-아민;
<117> 3-(5-(6-플루오로피리딘-3-일) -2-((1,2,3,4-테트라히드로이소퀴놀린-6-일)아미노)피리미딘-4-일)-1H-인돌-1-카르복사미드;
<118> 3-(5-(6-플루오로피리딘-3-일) -2-((3-메톡시-4-(피페리딘-4-일)페닐)아미노)피리미딘-4-일)-1H-인돌-1-카르복사미드; 및
<119> 3-(2-((4-(4-(디메틸아미노)피페리딘-1-일)-3-메톡시페닐)아미노)-5-(6-플루오로피리딘-3-일)피리미딘-4-일)-1-카르복사미드.
According to claim 1,
The compound represented by Formula 1 is any one selected from the following compound group, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
<1> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(1H-pyrazole-4- yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<2> 2-(6-((2-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(1H-pyrazole- 4-yl)pyrimidin-4-amino)pyridin-2-yl)propan-2-ol;
<3> 2-(6-(2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-5-(1H-pyrazol-4-yl) pyridin-4-ylamino)pyridin-2-yl)propan-2-ol;
<4> 2-(6-((2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(1H- pyrazol-4-yl)pyridin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<5> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(6-fluoropyridin-3 -yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<6> 2-(6-((5-(benzofuran-2-yl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino )pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<7> 2-(6-(2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-5-(1-methyl-1H-indole-5) -yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<8> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(furan-3-yl)pyri midin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<9> 2-(6-(2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-5-(1-methyl-1H-pyrazole- 4-yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<10> 2-(6-(2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenylamino)-5-(1-methyl-1H-pyrazole- 3-yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<11> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(thiophen-3-yl) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<12> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(pyridin-3-yl)pyri midin-4-yl)amino) pyridin-2-yl)propan-2-ol;
<13> 2-(6-((5-(benzofuran-3-yl)-2-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-amino)amino)pyridin-2-yl)propan-2-ol;
<14> 2-(6-(2-(3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino)-5-(quinoline- 6-yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<15> 2-(6-((2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(1- methyl-1H-pyrrol-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<16> 2-(6-((5-(benzofuran-2-yl)-2-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-amino)amino)pyridin-2-yl)propan-2-ol;
<17> 2- (6 - ((2- ((4- (4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-phenylpyrimidin-4-yl) amino)pyridin-2-yl)propan-2-ol;
<18> 2-(6-((5-(benzo [b]thiophen-3-yl) -2 -((3-methoxy-4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<19> 2- (6 - ((5- (1H-indol -3-yl) -2 - ((3- methoxy -4- (4-methylpiperazin-1-yl) piperidine -1- yl) phenyl) amino) pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<20> 2-(6-((5-(benzo [b]thiophen-2-yl) -2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<21> 2-(6-((5-(5-fluoropyridin-3-yl)-2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-) 1-yl) phenyl)amino)pyrimidin-4-yl)amino) pyridin-2-yl)propan-2-ol;
<22> 2-(6-(2-(3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenylamino)-5-(thiophene) -2-yl)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<23> 2-(6-((2-((3-methoxy-4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-(1H- pyrrol-3-yl)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<24> 2-(6-((5-(furan-2-yl)-2-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-amino)amino)pyridin-2-yl)propan-2-ol;
<25> 2-(6-((5-(benzofuran-2-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl )amino)pyridin-2-yl)propan-2-ol;
<26> 2-(6-((5-(furan-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) amino)pyridin-2-yl)propan-2-ol;
<27> 2-(6-((5-(benzofuran-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl )amino)pyridin-2-yl)propan-2-ol;
<28> 2-(6-((5-(6-fluoropyridin-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin- 4-yl)amino) pyridin-2-propan-2-ol;
<29> 2-(6-((5-(1-methyl-1H-pyrazol-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<30> 2-(6-((2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(thiophen-2-yl)pyrimidin-4-yl )amino)pyridin-2-yl)propan-2-ol;
<31> 2-(6-((5-(benzo [b]thiophen-2-yl)-2-((1,2,3,4-tetrahydro isoquinolin-6-yl)amino)pyrimidine -4-yl)amino)pyridin-2-yl)propan-2-ol;
<32> 2-(6-((5-(2-methoxyphenyl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) amino)pyridin-2-yl)propan-2-ol;
<33> 2-(6-((5-(3-methoxyphenyl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) amino)pyridin-2-yl)propan-2-ol;
<34> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(thiophen-2-yl) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<35> 2-(6-(5-(benzo[b]thiophen-2-yl)-2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl amino)pyrimidin-4-ylamino)pyridin-2-yl)propan-2-ol;
<36> 2-(6-((5-(benzofuran-3-yl)-2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino )pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<37> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(1H-pyrrol-3-yl) )pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<38> 2-(6-((5-(1H-pyrrol-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4- yl)amino)pyridin-2-propan-2-ol;
<39> 2-(6-(5-(benzo[b]thiophen-2-yl)-2-(2-methyl-1,2,3,4-tetrahydroisoquinolin-6-ylamino)pyri midin-4-ylamino)pyridin-2-yl)propan-2-ol;
<40> 2-(6-(5-(benzo[b]thiophen-2-yl)-2-(1,2,3,4-tetrahydroisoquinolin-7-ylamino)pyrimidin-4- ylamino)pyridin-2-yl)propan-2-ol;
<41> 2-(6-((5-(benzo[b]thiophen-2-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino)pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<42> 2-(6-((5-(furan-3-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine- 4-yl)amino)pyridin-2-yl)propan-2-ol;
<43> 2-(6-((5-(furan-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidin-4-yl) amino) pyridin-2-yl) propan-2-ol;
<44> 2-(6-((5-(furan-3-yl)-2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)pyrimidine- 4-yl)amino) pyridin-2-yl)propan-2-ol;
<45> 2-(6-((5-(6-fluoropyridin-3-yl)-2 -((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino )pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<46> 2-(6-((2-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(thiazol-5-yl) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<47> 2-(6-((2-((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(1H-pyrazol-3-yl) pyrimidin-4-yl)amino)pyridin-2-yl)propan-2-ol;
<48> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(furan-3-yl)-4-(1-methyl-1H- indol-3-yl)2-amine;
<49> N-(5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso quinolin-6-amine;
<50> N-(5-(furan-3-yl) -4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2-methyl-1,2,3,4 -tetrahydroisoquinolin-6 -amine;
<51> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)-5-( thiophen-2-yl)2-amine;
<52> N-(4-(1-methyl-1H-indol-3-yl)-5-(thiophen-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydro isoquinolin-6-amine;
<53> N-(5-(isoxazol-4-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydro isoquinolin-6-amine;
<54> N-(4-(1-methyl-1H-indol-3-yl)-5-(1H-pyrazol-4-yl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-amine;
<55> N-(5-(furan-3-yl)-4-(1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline-6- amines;
<56> N-(5-(6-fluoro pyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4 -tetrahydroisoquinolin-6-amine;
<57> N-(5-(5-fluoro pyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4 -tetrahydroisoquinolin-6-amine;
<58> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(1-methyl-1H-indol-3-yl)-5-( thiophen-3-yl)pyrimidin-2-amine;
<59> N-(5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso quinolin-7-amine;
<60> N-(5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-2,3,4,5-tetrahydro- 1H-benzo[d]azepin-7-amine;
<61> 5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)pyrimidine- 2-amine;
<62> 5-(furan-3-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-4-(1-methyl-1H-indole-3- yl) pyrimidin-2-amine;
<63> (S)-5-(furan-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(3-methylpiperazin-1-yl)phenyl ) pyrimidin-2-amine;
<64> (S)-5-(furan-3-yl)-N-(3-methoxy-4-(3-methylpiperazin-1-yl)phenyl)-4-(1-methyl-1H- indol-3-yl)pyrimidin-2-amine;
<65> N-(5-(furan-3-yl)-4-(4-nitro-1H-indol-1-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso quinolin-6-amine;
<66> N-(1-(5-(furan-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl)- 1H-indol-4-yl)methanesulfonamide;
<67> N-(4-(4-amino-1H-indol-1-yl)-5-(furan-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroiso quinolin-6-amine;
<68> N-(1-(5-(furan-3-yl)-2-((1,2,3,4-tetrahydro isoquinolin-6-yl)amino)pyrimidin-4-yl)- 1H-indol-4-yl)acetamide;
<69> 5-(furan-3-yl)-N-(3-methoxy-4- (4-methylpiperazin-1-yl)phenyl)-4-(4-nitro-1H-indole-1- yl) pyrimidin-2-amine;
<70> 1-(5-(furan-3-yl) -2-((3-methoxy-4- (4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)- 1H-indol-4-amine;
<71> 5-(furan-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(4-nitro-1H-indol-1-yl)pyrimidin- 2-amine;
<72> 1-(5-(furan-3-yl)-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)-1H-indole-4 -amines;
<73> 5-(6-fluoro pyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl ) pyrimidin-2-amine;
<74> N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-5-(6-fluoropyridin-3-yl)-4-(1-methyl-1H- indol-3-yl)pyrimidin-2-amine;
<75> 5-(6-fluoro pyridin-3-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-4-(1-methyl-1H- indol-3-yl)pyrimidin-2-amine;
<76> (S)-5-(6-fluoropyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(3-methylpiperazine-1 -yl)phenyl)pyrimidin-2-amine;
<77> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(6-fluoro pyridin-3-yl)-4-(1- methyl-1H-indol-3-yl)pyrimidin-2-amine;
<78> N-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-5-(furan-3-yl)-4-(1-methyl-1H-indole-3- yl) pyrimidin-2-amine;
<79> N-(5-(furan-3-yl)-4-(6-methoxy-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydro isoquinolin-6-amine;
<80> N-(5-(furan-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3, 4-tetrahydroisoquinolin-6-amine;
<81> N-(4-(1-methyl-1H-indol-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)-1,2 ,3,4-tetrahydroisoquinolin-4-yl) 6-amine;
<82> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(6-methoxy-1-methyl-1H-indol-3-yl )-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<83> 4-(6-methoxy-1-methyl-1H-indol-3-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-5- (6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<84> N-(4-(6-methoxy-1-methyl-1H-indol-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl ) 4-tetrahydroisoquinolin-6-amine;
<85> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(6-fluoro pyridin-3-yl)-4-(6- methoxy-1-methyl-1H-indol-3-yl) pyrimidin-3-yl)pyrimidin-2-amine;
<86> 5-(6-fluoro pyridin-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)-N-(3-methoxy-4-(4) -methylpiperazin-1-yl)phenyl)pyrimidin-2-amine;
<87> N-(5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)pyrimidin-2-yl)-1, 2,3,4-tetrahydroisoquinolin-6-amine;
<88> N-(4-(6-methoxy-1H-indol-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)-1, 2,3,4-tetrahydroisoquinolin-6-amine;
<89> N-(5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1H-indol-3-yl)pyrimidin-2-yl)-1,2,3, 4-tetrahydroisoquinolin-6-amine;
<90> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(6-methoxy-1H-indol-3-yl)-5- (6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<91> 4-(6-methoxy-1H-indol-3-yl)-N-(3-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-5-(6-( trifluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<92> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(6-fluoropyridin-3-yl)-4-(6- methoxy-1H-indol-3-yl) pyrimidin-2-amine;
<93> 5-(6-fluoro pyridin-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(3-methoxy-4-(4-methylpiperazine) -1-yl)phenyl)pyrimidin-2-amine;
<94> N-(4-(6-fluoro-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)pyrimidin-2-yl)-1,2,3, 4-tetrahydroisoquinolin-6-amine;
<95> N-(4-(6-fluoro-1-methyl-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)pyrimidin-2-yl)-1, 2,3,4-tetrahydroisoquinolin-6-amine;
<96> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(furan-3-yl)-4-(6-methoxy-1H -indol-3-yl)pyrimidin-2-amine;
<97> 5-(furan-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(4-((S)-3-methylpiperazin-1-yl) phenyl)pyrimidin-2-amine;
<98> (S)-5-(furan-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(3-methoxy-4- (3-methylpiperazine) -1-yl)phenyl)pyrimidin-2-amine;
<99> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(1H-indol-3-yl)-5-(6-(tri fluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<100> (S)-4-(1H-indol-3-yl)-N-(4-(3-methylpiperazin-1-yl)phenyl)-5-(6-(trifluoromethyl)pyridine -3-yl) pyrimidin-2-amine;
<101> (S)-5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(4-(3-methylpiperazine- 1-yl)phenyl) 2-pyrimidin-amine;
<102> (S)-5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1H-indol-3-yl)-N-(3-methoxy-4-(3) -methylpiperazin-1-yl)phenyl)pyrimidin-2-amine;
<103> N-(3-methoxy-4- (4-methylpiperazin-1-yl)phenyl)-4-(1-methyl-1H-indol-3-yl)-5-(6-(tri fluoromethyl)pyridin-3-yl)pyrimidin-2-amine;
<104> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4 (1-methyl-1H-indol-3-yl)-5-(6 - (trifluoromethyl)pyridin-3-pyrimidin-2-amine;
<105> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-5-(furan-3-yl)-4-(6-methoxy-1 -methyl-1H-indol-3-yl)pyrimidin-2-amine;
<106> 5-(furan-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)-N-(3-methoxy-4-(4-methylpiperazine) -1-yl)phenyl)pyrimidin-2-amine;
<107> (S)-4-(1-methyl-1H-indol-3-yl)-N-(4-(3-methylpiperazin-1-yl)phenyl)-5-(6-(trifluoro romethyl) pyridin-3-yl)pyrimidin-2-amine;
<108> 4-(6-fluoro-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)-N-(4-((S)-3-methylpiperazine- 1-yl)phenyl)pyrimidin-2-amine;
<109> (S)-4-(6-fluoro-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)-N-(3-methoxy-4-(3) -methylpiperazin-1-yl)phenyl)pyrimidin-2-amine;
<110> N-(4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)-4-(6-fluoro-1H-indol-3-yl)-5- (6-fluoropyridin-3-yl)pyrimidin-2-amine;
<111> N-(4-(6-fluoro-1H-indol-3-yl)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidin-2-yl)-1, 2,3,4-tetrahydro isoquinolin-6-amine;
<112> (S)-5-(6-fluoropyridin-3-yl)-N-(3-methoxy-4-(3-methylpiperazin-1-yl)phenyl)-4-(1- methyl-1H-indol-3-yl)pyrimidin-2-amine;
<113> 5-(6-fluoro pyridin-3-yl)-N-(3-methoxy-4-(piperidin-4-yl)phenyl)-4-(1-methyl-1H-indole- 3-yl)pyrimidin-2-amine;
<114> 5-(6-fluoro pyridin-3-yl)-4-(1-methyl-1H-indol-3-yl)-N-(4-(piperidin-4-yl)phenyl)pyri midin-2-amine;
<115> 5-(6-fluoropyridin-3-yl)-4-(6-methoxy-1-methyl-1H-indol-3-yl)-N-(3-methoxy-4-(p) peridin-4-yl) phenyl) pyrimidin-2-amine;
<116> 4-(6-fluoro-1H-indol-3-yl)-5-(6-fluoropyridin-3-yl)-N-(3-methoxy-4-(piperidin-4) -yl)phenyl)pyrimidin-2-amine;
<117> 3-(5-(6-fluoropyridin-3-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidin-4-yl) -1H-indole-1-carboxamide;
<118> 3-(5-(6-fluoropyridin-3-yl) -2-((3-methoxy-4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl )-1H-indole-1-carboxamide; and
<119> 3-(2-((4-(4-(dimethylamino)piperidin-1-yl)-3-methoxyphenyl)amino)-5-(6-fluoropyridin-3-yl) pyrimidin-4-yl)-1-carboxamide.
A pharmaceutical composition for preventing or treating cancer comprising the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 암은 백혈병, 뇌암, 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 후두암, 구인두암, 비강/부비동암, 비인두암, 침샘암, 하인두암, 갑상선암, 구강암, 흉부종양, 폐암, 상피세포암, 소세포성 폐암, 비소세포성 폐암, 흉선암, 종격동 종양, 식도암, 유방암, 남성유방암, 복부종양, 위암, 간암, 담낭암, 담도암, 췌장암, 소장암, 대장암, 직장암, 항문암, 방광암, 신장암, 남성 생식기종양, 음경암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암 및 피부암으로 이루어진 군으로부터 선택되는 1종 이상인 것을 특징으로 하는 약학적 조성물.9. The method of claim 8,
The cancer is leukemia, brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroglioma, intracranioma, ependymoma, brainstem tumor, head and neck tumor, laryngeal cancer, oropharyngeal cancer, nasal/sinus cancer, Nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, thyroid cancer, oral cancer, chest tumor, lung cancer, epithelial cell cancer, small cell lung cancer, non-small cell lung cancer, thymus cancer, mediastinal tumor, esophageal cancer, breast cancer, male breast cancer, abdominal tumor, stomach cancer, liver cancer, Gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colorectal cancer, rectal cancer, anal cancer, bladder cancer, kidney cancer, male genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, A pharmaceutical composition, characterized in that at least one selected from the group consisting of vaginal cancer, female external genital cancer, female urethral cancer and skin cancer.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020180091812A KR102297587B1 (en) | 2018-08-07 | 2018-08-07 | A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020180091812A KR102297587B1 (en) | 2018-08-07 | 2018-08-07 | A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient |
Publications (2)
Publication Number | Publication Date |
---|---|
KR20200016567A KR20200016567A (en) | 2020-02-17 |
KR102297587B1 true KR102297587B1 (en) | 2021-09-06 |
Family
ID=69670756
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
KR1020180091812A KR102297587B1 (en) | 2018-08-07 | 2018-08-07 | A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient |
Country Status (1)
Country | Link |
---|---|
KR (1) | KR102297587B1 (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP4296268A1 (en) * | 2021-02-19 | 2023-12-27 | Wigen Biomedicine Technology (Shanghai) Co., Ltd. | Pyrimidine compound as wee-1 inhibitor |
CN116670127A (en) * | 2021-03-30 | 2023-08-29 | 贝达药业股份有限公司 | EGFR inhibitors and compositions and uses thereof |
CN113610808B (en) * | 2021-08-09 | 2023-11-03 | 中国科学院自动化研究所 | Group brain map individuation method, system and equipment based on individual brain connection diagram |
TW202328096A (en) | 2021-08-27 | 2023-07-16 | 南韓商柳韓洋行 | 5-membered heteroaryl-containing aminopyridine compounds as egfr inhibitors |
CN114105887B (en) * | 2021-09-16 | 2023-12-01 | 沈阳药科大学 | Aminopyrimidine derivative and preparation method and application thereof |
KR20230056331A (en) * | 2021-10-20 | 2023-04-27 | 한미약품 주식회사 | Therapeutically effective combination of a FLT3 inhibitor and a Bcl-2 inhibitor for the treatment of acute myeloid leukemia |
TW202400168A (en) * | 2022-05-04 | 2024-01-01 | 美商艾瑞斯卡公司 | Thiophene ulk1/2 inhibitors and their use thereof |
-
2018
- 2018-08-07 KR KR1020180091812A patent/KR102297587B1/en active IP Right Grant
Non-Patent Citations (1)
Title |
---|
European Journal of Medicinal Chemistry, 2017, Vol. 140, pp. 510-527* |
Also Published As
Publication number | Publication date |
---|---|
KR20200016567A (en) | 2020-02-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR102297587B1 (en) | A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient | |
KR102092812B1 (en) | Pyrolo-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient | |
KR101920456B1 (en) | Novel imidazopyridine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient | |
KR20190108079A (en) | 2,4,5-substituted pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient | |
CN111511748B (en) | Bcl-2 inhibitors | |
RU2655921C2 (en) | Polycyclic substituted pyrazole kinase activity inhibitors and use thereof | |
RU2730849C1 (en) | Pyrrolo-pyridine compound derivative, method for production thereof and pharmaceutical composition containing same as active ingredient for preventing and treating protein kinase related diseases | |
EP3246327B1 (en) | 3-acetylenyl-pyrazole-pyrimidine derivative, and preparation method therefor and uses thereof | |
CN111315727B (en) | Benzothiazole compounds and methods of treating neurodegenerative diseases using the same | |
ES2634014T3 (en) | Amino substituted isothiazoles | |
KR20190108080A (en) | 2,4,5-substituted pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating cancer or inflammatory disease in containing the same as an active ingredient | |
KR20200020622A (en) | A substituted heteroaryl derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient | |
US20110112091A1 (en) | Derivatives of tetrabromobenzimidazole, a process for the preparation thereof, a pharmaceutical composition comprising the same, a methof of using the same, a method for modulating or regulating serine/threonine kinases, and serine/threonine kinases modulating agent | |
KR102163494B1 (en) | heteroaromatic macrocyclic derivatives as protein kinase inhibitors | |
KR102293980B1 (en) | dihydropyrano[3,2-g]chromen-2-one derivatives and pharmaceutical composition for preventing or treating cancer | |
KR102328435B1 (en) | Novel pyrido-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease containing the same as an active ingredient | |
KR102286701B1 (en) | Pyrido[2,3-d]pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease as an active ingredient | |
RU2778370C2 (en) | Benzothiazole compounds and methods for their use for treatment of neurodegenerative disorders | |
KR20200105592A (en) | 4-((1H-pyrazol-3-yl)amino)phthalazin-1(2H)-one derivatives and pharmaceutical composition for use in preventing or treating cancer containing the same as an active ingredient | |
KR102328423B1 (en) | Novel triazolo-pyrimidine derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating protein kinase related disease containg the same as an active ingredient | |
KR20230113121A (en) | Heteroaryl derivatives and uses thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A201 | Request for examination | ||
E902 | Notification of reason for refusal | ||
E701 | Decision to grant or registration of patent right | ||
GRNT | Written decision to grant |