KR20220136931A - Pyrimidin derivatives as protein kinase inhibitors and pharmaceutical compositions for treating disease containing the same - Google Patents

Pyrimidin derivatives as protein kinase inhibitors and pharmaceutical compositions for treating disease containing the same Download PDF

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KR20220136931A
KR20220136931A KR1020220039968A KR20220039968A KR20220136931A KR 20220136931 A KR20220136931 A KR 20220136931A KR 1020220039968 A KR1020220039968 A KR 1020220039968A KR 20220039968 A KR20220039968 A KR 20220039968A KR 20220136931 A KR20220136931 A KR 20220136931A
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amino
chloro
compound
phenyl
pyrimidin
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심태보
조병철
조한나
센굽타 산딥
말라 레디 가나라푸
김영훈
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주식회사 테라펙스
연세대학교 산학협력단
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Priority to BR112023019370A priority Critical patent/BR112023019370A2/en
Priority to IL307327A priority patent/IL307327A/en
Priority to US18/279,348 priority patent/US20240228458A1/en
Priority to AU2022250976A priority patent/AU2022250976A1/en
Priority to MX2023010016A priority patent/MX2023010016A/en
Priority to CA3207015A priority patent/CA3207015A1/en
Priority to JP2023559714A priority patent/JP2024511514A/en
Priority to EP22781692.3A priority patent/EP4286376A1/en
Priority to CN202280025860.3A priority patent/CN117120424A/en
Priority to PCT/KR2022/004702 priority patent/WO2022211573A1/en
Publication of KR20220136931A publication Critical patent/KR20220136931A/en

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Abstract

The present invention relates to a pharmaceutical composition for preventing and treating cancers, including lung cancer, caused by abnormal cell growth, wherein the pharmaceutical composition contains, as active ingredients, a novel trisubstituted pyrimidine derivative having an inhibitory activity against protein kinases including EGFR, and a pharmaceutically acceptable salt thereof. The novel compound of the present invention has an excellent inhibitory activity against protein kinases. Particularly, the novel compound of the present invention has an excellent inhibitory effect on various EGFR mutant species having drug resistance (EGFR mutant species including exon 19 deletion-T790M-C797S-EGFR, L858R-T790M-C797S-EGFR, exon 19 deletion-T790M-EGFR, and L858R-T790M-EGFR), and is useful as an agent for preventing and treating cancers caused by the EGFR mutant species.

Description

단백질 키나아제 저해 활성을 갖는 피리미딘 유도체 및 이를 포함하는 치료용 약학 조성물{PYRIMIDIN DERIVATIVES AS PROTEIN KINASE INHIBITORS AND PHARMACEUTICAL COMPOSITIONS FOR TREATING DISEASE CONTAINING THE SAME}Pyrimidine derivatives having protein kinase inhibitory activity and therapeutic pharmaceutical compositions comprising the same

본 발명은 단백질 키나아제 저해활성을 갖는 신규한 삼치환된 피리미딘 유도체, 이의 약학적으로 허용 가능한 염, 이의 수화물 또는 이의 입체 이성질체로부터 선택된 화합물, 및 상기 화합물의 제조방법, 상기 화합물을 포함하는 유효성분으로 포함하는 비정상 세포 성장으로 유발되는 암 질환의 예방 , 경감 또는 치료용 약학 조성물에 관한 것이다.The present invention provides a compound selected from novel trisubstituted pyrimidine derivatives having protein kinase inhibitory activity, a pharmaceutically acceptable salt thereof, a hydrate thereof or a stereoisomer thereof, a method for preparing the compound, and an active ingredient comprising the compound It relates to a pharmaceutical composition for preventing, alleviating or treating cancer diseases caused by abnormal cell growth comprising

단백질 키나아제는 ATP의 감마-인산기를 단백질의 타이로신, 세린 및 트레오닌의 히드록시 그룹에 전달하는 인산화 반응을 촉매하는 효소로서, 세포의 대사, 유전자 발현, 세포 성장, 분화 및 세포 분열 작용을 담당하며 세포 신호 전달에 중요한 역할을 하고 있다. 단백질 키나아제는 진핵 생물 유전체의 약 2% 정도 되며, 사람 유전체에는 약 518 종이 존재한다. 단백질 키나아제는 타이로신을 인산화하는 타이로신 단백질 키나아제와 세린, 트레오닌을 인산화하는 세린/트레오닌 키나아제로 분류된다. 그 중 약 90 종 이상은 타이로신 키나아제이며, 수용체 타이로신 키나아제 (RTK)와 비수용체 타이로신 키나아제 (NRTK)로 나뉜다. 수용체 타이로신 키나아제는 세포 표면에 성장 인자를 수용할 수 있는 도메인을 가지고 있고, 세포질에 타이로신 잔기를 인산화할 수 있는 활성부위를 갖고 있는 막단백질이다. 단백질 키나아제는 분자 스위치로 세포 내에서 활성과 비활성 상태 사이의 전이가 원활하게 조절되어야 한다. 비정상적으로 조절되면 세포 내 신호 전달을 과도하게 활성화시켜 통제불능의 세포 분열 및 증식을 유도하게 된다. 또한, 단밴질 키나아제의 유전자 변이, 증폭 및 과발현에 의한 비정상적인 활성화는 다양한 종양의 발생 및 진행과 관련이 있어 암세포의 성장과 전이에 결정적인 역할을 하게 된다.Protein kinase is an enzyme that catalyzes the phosphorylation reaction that transfers the gamma-phosphate group of ATP to the hydroxyl groups of tyrosine, serine and threonine of proteins, and is responsible for cell metabolism, gene expression, cell growth, differentiation, and cell division. It plays an important role in signal transmission. Protein kinases make up about 2% of the eukaryotic genome, and there are about 518 species in the human genome. Protein kinases are classified into tyrosine protein kinases that phosphorylate tyrosine and serine/threonine kinases that phosphorylate serine and threonine. More than about 90 of them are tyrosine kinases, and are divided into receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (NRTKs). Receptor tyrosine kinase is a membrane protein having a domain that can accommodate growth factors on the cell surface and an active site capable of phosphorylating tyrosine residues in the cytoplasm. Protein kinases are molecular switches, and the transition between active and inactive states in cells must be smoothly regulated. Abnormal regulation leads to excessive activation of intracellular signaling, leading to out-of-control cell division and proliferation. In addition, abnormal activation by gene mutation, amplification and overexpression of protein kinase is associated with the development and progression of various tumors, and thus plays a decisive role in the growth and metastasis of cancer cells.

페암은 호흡기관인 폐에 생긴 악성 종양으로 암세포의 크기와 형태에 따라 비소세포폐암과 소세포 폐암으로 구분되며 비소세포폐암은 전체 폐암의 80%를 차지한다. 비소세포폐암은 조기 발견하면 수술로 완치가 가능하지만, 수술 받은 환자의 20~ 50%가 재발을 보이며, 뇌, 뼈, 간과 다른 쪽 폐 등으로 전이가 다른 암보다 많다. Lung cancer is a malignant tumor that occurs in the lungs, the respiratory tract, and is divided into non-small cell lung cancer and small cell lung cancer depending on the size and shape of cancer cells. Non-small cell lung cancer accounts for 80% of all lung cancers. Non-small cell lung cancer can be cured with surgery if detected early, but 20-50% of patients undergoing surgery have recurrence, and metastases to the brain, bone, liver and other lung are more common than other cancers.

비소세포성폐암의 가장 큰 원인은 상피세포성장인자수용체 (EGFR) 티로신키나제 유전자의 돌연변이다. 아시아의 비소세포성폐암 환자 30 ~ 40%, 미국과 유럽의 10 ~ 15%가 EGFR 유전자에 돌연변이를 가지고 있고, 아시아 비흡연 여성 환자의 경우 40 ~ 50%가 EGFR 돌연변이를 가지고 있다. EGFR 유전자에 돌연변이는 흡연 여부와 상관 없이 폐암의 원인이 된다. 전체 EGFR 돌연변이 중 90%는 상피세포성장인자 없이도 EGFR의 활성화가 가능한 activating 돌연변이 (19번 엑손 결손 돌연변이 43%, L858R 점돌연변이 41%)다.The most common cause of non-small cell lung cancer is a mutation in the epidermal growth factor receptor (EGFR) tyrosine kinase gene. 30-40% of non-small cell lung cancer patients in Asia and 10-15% in the United States and Europe have EGFR mutations, and 40-50% of Asian non-smokers have EGFR mutations. Mutations in the EGFR gene cause lung cancer regardless of whether or not you smoke. Of all EGFR mutations, 90% are activating mutations that can activate EGFR without epidermal growth factor (exon 19 deletion mutation 43%, L858R point mutation 41%).

막 관통 티로신키나제인 EGFR은 상피세포성장인자와 같은 리간드가 결합하면 이합체를 형성하고, 티로신 잔기가 인산화되면서 활성화 된다. 활성화된 EGFR은 하위 분자들과 결합하기 쉬운 조건이 형성되고 이들을 인산화 시키면서 하위 경로(RAS-mitogen-activated protein kinase(MAPK), phosphotidylinosititol 3-kinase(PI3-K)-Akt, phospholipase-Cγ(PLCγ)/protein kinase-C(PKC), signal transducer and activator of transcription(STAT) 등)를 활성화 시켜 세포사멸을 억제, 세포 성장 및 증식 촉진, 유전자의 발현 등을 조절한다. 19번 엑손 결손 돌연변이나 L858R 점돌연변이와 같은 activating 돌연변이가 발생하면, 리간드 없이도 항상 활성화 구조를 유지하기 때문에 세포의 무한 증식을 야기하며 암을 형성한다. EGFR, a transmembrane tyrosine kinase, forms a dimer when a ligand such as epidermal growth factor binds, and is activated by phosphorylation of tyrosine residues. Activated EGFR forms a condition for easy binding to sub-molecules and phosphorylates them in lower pathways (RAS-mitogen-activated protein kinase (MAPK), phosphotidylinosititol 3-kinase (PI3-K)-Akt, phospholipase-Cγ (PLCγ) / It activates protein kinase-C (PKC), signal transducer and activator of transcription (STAT), etc.) to inhibit apoptosis, promote cell growth and proliferation, and regulate gene expression. When an activating mutation such as exon 19 deletion mutation or L858R point mutation occurs, the activating structure is always maintained even without a ligand, leading to indefinite proliferation of cells and formation of cancer.

경구 투여가 가능한 1세대 EGFR 티로신키나제 억제제인 이레사 (gefitinib, lressa®, 아스트라제네카)와 타쎄바 (erlotinib, Tarceva®, 로슈)는 기존의 항암 표준요법인 세포독성 항암제 대비 10개월 생존기간을 연장하며 우월성이 입증되었으나, 1세대 저해제 내성으로 60%의 환자에게서 T790M 돌연변이가 발생한다. T790M 돌연변이를 억제할 수 있는 2세대 EGFR 티로신키나제 억제제인 질로트리프 (afatinib, Gilotrif®, 베링거인겔하임)가 출시되어 임상에서 좋은 효과를 증명하였지만, therapeutic window를 확보하지 못하였다. 2세대 저해제는 EGFR 돌연변이가 있는 국소 진행성 또는 전이성 비소세포폐암에 대한 1차 치료제로만 승인을 받아 적응증이 비교적 좁다. 3세대 EGFR 티로신키나제 억제제인 타그리소 (osimertinib, Targrisso®, 아스트라제네카)는 cysteine과 공유결합이 가능한 michael acceptor를 도입하여 3세대 EGFR 표적 항암제로는 최초로 FDA승인을 받고 출시되었으나, 약 10개월간 투약한 환자에게서 C797S 돌연변이 획득 내성이 발생하였다. C797S 돌연변이는 타그리소 결합 부위의 cysteine 잔기가 serine으로 변형된 돌연변이로 타그리소의 공유결합을 무력화시킨다. 타그리소는 1세대, 2세대 EGFR저해제로 치료 후 T790M 변이가 발생하였을 때 사용이 가능하기 때문에, 타그리소에 내성이 생기는 환자들은 EGFR activating 돌연변이 (엑손 19 결손 또는 L858R), T790M 및 C797S 세 개의 돌연변이를 모두 가지고 있다. 따라서 4세대 EGFR 저해제는 삼중 돌연변이 (엑손 19 결손/T790M/C797S 또는 L858R/T790M/C797S)는 물론, 이중 돌연변이 (엑손 19 결손/T790M 또는 L858R/T790M) 와 activating 돌연변이 (엑손 19 결손 또는 L858R) 각각에도 적당한 효능을 가지고 있어야 한다. Iressa (gefitinib, lressa®, AstraZeneca) and Tarceva (erlotinib, Tarceva®, Roche), the first-generation EGFR tyrosine kinase inhibitors that can be administered orally, extend the survival period by 10 months compared to cytotoxic anticancer drugs, which are the existing standard anticancer drugs. Although superiority has been demonstrated, first-generation inhibitor resistance results in T790M mutations in 60% of patients. Jilotrif (afatinib, Gilotrif®, Boehringer Ingelheim), a second-generation EGFR tyrosine kinase inhibitor capable of inhibiting the T790M mutation, was released and demonstrated good efficacy in clinical practice, but did not secure a therapeutic window. Second-generation inhibitors have relatively narrow indications as they are only approved as first-line treatment for locally advanced or metastatic non-small cell lung cancer with EGFR mutations. Tagrisso (osimertinib, Targrisso®, AstraZeneca), a third-generation EGFR tyrosine kinase inhibitor, introduced a michael acceptor that can covalently bind to cysteine and was the first third-generation EGFR-targeted anticancer drug to be released after receiving FDA approval. The patient developed C797S mutation acquired resistance. The C797S mutation is a mutation in which the cysteine residue of the tagrisso binding site is changed to serine, and it disables the covalent binding of tagrisso. Because Tagrisso can be used when a T790M mutation occurs after treatment with first- and second-generation EGFR inhibitors, patients who develop resistance to Tagrisso have an EGFR activating mutation (exon 19 deletion or L858R), and three mutations T790M and C797S. have all Thus, fourth-generation EGFR inhibitors have triple mutations (exon 19 deletion/T790M/C797S or L858R/T790M/C797S) as well as double mutations (exon 19 deletion/T790M or L858R/T790M) and activating mutations (exon 19 deletion or L858R), respectively. should also have a suitable effect.

타그리소와 같이 Michael acceptor를 보유하고 있는 3세대 저해제들은 심각한 부작용 (Stevens-Johnson Syndrome, 표피 발진, 심장 질환 유발 등)을 이유로 임상에서 중단되었다. 3세대 저해제 내성을 극복하면서도 부작용이 경감된 4세대 EGFR 저해제 개발이 필요하다. 부작용 경감을 위해서는 EGFR 야생형과 돌연변이의 구별이 가능해야 한다. 현재까지 개발된 약물은 EGFR 야생형과 돌연변이간의 window가 크지 않아 효능이 있는 만큼 독성도 높은 한계점이 있다.Third-generation inhibitors with Michael acceptors, such as Tagrisso, were discontinued from clinical trials due to serious side effects (Stevens-Johnson Syndrome, epidermal rash, heart disease, etc.). It is necessary to develop a fourth-generation EGFR inhibitor with reduced side effects while overcoming third-generation inhibitor resistance. For the mitigation of side effects, it should be possible to distinguish between EGFR wild-type and mutant EGFR. Drugs developed so far have a high toxicity limit as they have efficacy because the window between wild-type and mutant EGFR is not large.

폐암은 연간 2만명 이상 발생하며 국내 사망률 1위로 매우 치명적인 암이다. 특히 다른 장기로 전이될 경우 5년 생존률이 8.9%로 매우 낮다. 2021년 국내 폐암 환자수는 약 3만명으로 이 가운데 30~40%가 EGFR 돌연변이 양성이다. 폐암 이외에도 교모세포종 (50%), 삼중음성유방암 (13% - 30%), 대장암 (25% -77%) 등 여러 암종에서도 EGFR 돌연변이가 발견되고, EGFR 저해제는 폐암, 두경부암을 비롯한 광범위한 암종에 대해 임상시험이 진행되고 있다. Lung cancer is one of the most lethal cancers, with more than 20,000 occurrences per year and the highest mortality rate in Korea. In particular, when it metastasizes to other organs, the 5-year survival rate is very low at 8.9%. In 2021, the number of lung cancer patients in Korea will be about 30,000, of which 30-40% are EGFR mutation-positive. In addition to lung cancer, EGFR mutations are also found in several carcinomas including glioblastoma (50%), triple-negative breast cancer (13% - 30%), and colorectal cancer (25% -77%). Clinical trials are in progress.

이에, 본 발명자들은 3세대 EGFR 저해제의 한계를 극복 할수있는 신규 물질을 개발하기 위한 연구를 수행하여 본 발명을 완성하였다.Accordingly, the present inventors completed the present invention by conducting research to develop a novel material that can overcome the limitations of the third-generation EGFR inhibitor.

PCT 특허공개공보 WO/2018/230934/AlPCT Patent Publication WO/2018/230934/Al US/2020/0207768/AlUS/2020/0207768/Al 한국공개특허 10-2019-0114910Korean Patent Laid-Open Patent No. 10-2019-0114910 PCT 특허공개공보 WO/2019/112344/A1PCT Patent Publication No. WO/2019/112344/A1 PCT 특허공개공보 WO/2020/147702/A1PCT Patent Publication No. WO/2020/147702/A1

J. Med. Chem. 2018, 61, 4290-4300 J. Med. Chem. 2018, 61, 4290-4300 J. Med. Chem. 2019, 62, 10272-10293 J. Med. Chem. 2019, 62, 10272-10293

따라서 본 발명의 목적은 단백질 키나아제의 저해활성을 가지는 신규의 피리미딘 유도체 화합물을 제공하는데 있다.Accordingly, it is an object of the present invention to provide a novel pyrimidine derivative compound having an inhibitory activity of protein kinase.

또한, 본 발명의 다른 목적은 신규 피리미딘 유도체 화합물, 약학적으로 허용가능한 이의 염, 이의 수화물, 이의 용매화물 또는 이의 입체 이성질체가 유효성분으로 함유되는 암질환의 치료, 예방 및 경감에 유용한 약학조성물을 제공하는 것을 그 목적으로 한다.In addition, another object of the present invention is a novel pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, or a pharmaceutical composition useful for the treatment, prevention and alleviation of cancer diseases containing a stereoisomer thereof as an active ingredient. Its purpose is to provide

또한, 본 발명의 다른 목적은 신규의 피리미딘 유도체 화합물, 이의 약학적으로 허용되는 염, 이의 수화물, 이의 용매화물 또는 이의 이성질체가 유효성분으로 함유하는 EGFR 돌연변이로 유발되는 암 질환의 치료제를 제공하는 것을 그 목적으로 한다.In addition, another object of the present invention is to provide a therapeutic agent for cancer diseases caused by EGFR mutation containing a novel pyrimidine derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof or an isomer thereof as an active ingredient. for that purpose

또한, 본 발명의 일측면은 상기한 신규 화합물의 제조방법을 제공하고자 한다.In addition, one aspect of the present invention is to provide a method for preparing the above-described novel compound.

또한, 본 발명의 일측면은 상기한 제조방법을 수행하는 과정에서 합성된 신규의 중간체 화합물을 제공하고자 한다.In addition, one aspect of the present invention is to provide a novel intermediate compound synthesized in the process of performing the above-described preparation method.

상기한 과제 해결을 위하여, 본 발명의 일측면은 하기 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In order to solve the above problems, one aspect of the present invention provides a compound selected from a pyrimidine derivative compound represented by the following Chemical Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[화학식 10][Formula 10]

Figure pat00001
Figure pat00001

[화학식 11][Formula 11]

Figure pat00002
Figure pat00002

[화학식 12][Formula 12]

Figure pat00003
Figure pat00003

상기 화학식 10 내지 12에서,In Formulas 10 to 12,

R1는 수소; 히드록시기; 할로겐기; C1-C13 알킬기; 또는 C1-C6 알콕시기;이고,R 1 is hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; Or a C 1 -C 6 alkoxy group;

R2는 수소; 할로겐기; C1-C13 알킬기; C3-C10 사이클릴기; 아미노기(-NR8R9); 또는 니트로기(-N(O)2);이고,R 2 is hydrogen; halogen group; C 1 -C 13 alkyl group; C 3 -C 10 cyclyl group; an amino group (-NR 8 R 9 ); or a nitro group (—N(O) 2 );

R3는 및 R4는 각각 독립적으로 수소; C1-C13 알킬기; C3-C10 사이클릴기; 설피드기(-SR8); 술폰기(-S(O)2R8);또는 포스피릴기(-P(O)R8R9)이고;R 3 and R 4 are each independently hydrogen; C 1 -C 13 alkyl group; C 3 -C 10 cyclyl group; sulfide group (-SR 8 ); a sulfone group (-S(O) 2 R 8 ); or a phospyryl group (-P(O)R 8 R 9 );

R5, R6 및 R7는 각각 독립적으로 수소; 히드록시기; 할로겐기; C1-C13 알킬기; C1-C6 알콕시기; C3-C10 사이클릴기; C3-C10 헤테로사이클릴기; -C(O)-(C1-C13 알킬); 아미노기(-NR8R9); 니트로기(-N(O)2); 아마이드기(-(C=O)NR8R9); 카르복실산기(-C(O)OH); 니트릴기(-CN); 유레아기(-NR8(C=O)NR9-); 술폰아미드기(-NHS(O)2R8); 설피드기(-SR8); 술폰기(-S(O)2R8);또는 포스피릴기(-P(O)R8R9)이고;R 5 , R 6 and R 7 are each independently hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; C 1 -C 6 alkoxy group; C 3 -C 10 cyclyl group; C 3 -C 10 heterocyclyl group; -C(O)-(C 1 -C 13 alkyl); an amino group (-NR 8 R 9 ); nitro group (-N(O) 2 ); an amide group (-(C=O)NR 8 R 9 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 8 (C=O)NR 9 -); a sulfonamide group (—NHS(O) 2 R 8 ); sulfide group (-SR 8 ); a sulfone group (-S(O) 2 R 8 ); or a phospyryl group (-P(O)R 8 R 9 );

X1, X2 및 X3 은 각각 독립적으로 탄소 또는 질소이고,X 1 , X 2 and X 3 are each independently carbon or nitrogen,

A는 C1-C13 알킬기; 아미노기(-NR8R9); C6-C10 아릴기; C3-C10 사이클릴기; C3-C10 헤테로아릴기; C3-C10 헤테로사이클릴기; 또는 A는 R6과 연결된 탄소 원자와 함께 N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, 또는 SO2 중 적어도 1종을 임의로 포함할 수 있고, 수소, C1-C13 알킬기, C6-C10 아릴기, C3-C10 헤테로아릴기, 히드록실기, 할라이드기 및 시아노기 중 적어도 1종으로 임의로 치환될 수 있는 3 내지 7원(membered) 포화 고리를 형성하고;A is a C 1 -C 13 alkyl group; an amino group (-NR 8 R 9 ); C 6 -C 10 aryl group; C 3 -C 10 cyclyl group; C 3 -C 10 heteroaryl group; C 3 -C 10 heterocyclyl group; or A together with the carbon atom connected to R 6 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 -, or SO 2 , which may optionally include at least one of hydrogen, a C 1 -C 13 alkyl group, a C 6 -C 10 aryl group, a C 3 -C 10 heteroaryl group, a hydroxyl group, a halide group, and a cyano group. form a 3 to 7 membered saturated ring which may be optionally substituted with at least one;

B는 C6-C10 아릴기; C3-C10 사이클릴기; C3-C10 헤테로아릴기; 또는 C3-C10 헤테로사이클릴기; 이고,B is a C 6 -C 10 aryl group; C 3 -C 10 cyclyl group; C 3 -C 10 heteroaryl group; or a C 3 -C 10 heterocyclyl group; ego,

X1 또는 X3가 각각 독립적으로 질소일 때, R2 또는 R7은 치환되지 않으며,When X 1 or X 3 is each independently nitrogen, R 2 or R 7 is unsubstituted,

상기 C1-C6 알콕시기, C1-C13 알킬기 또는 C3-C10 사이클릴기는, 수소; 히드록시기; 할로겐기; C1-C13 알킬기; C1-C6 알콕시기; 아미노기(-NR8R9); 니트로기(-N(O)2); 아마이드기(-(C=O)NR8R9); 카르복실산기(-C(O)OH); 니트릴기(-CN); 유레아기(-NR8(C=O)NR9-); 술폰아미드기(-NHS(O)2-); 설피드기(-S-); 술폰기(-S(O)2-); 포스피릴기(-P(O)R8R9); C6-C10 아릴기; C3-C10 헤테로아릴기; 및 C3-C10 헤테로사이클릴기로 이루어진 군으로부터 선택되는 1 이상의 치환기를 포함하며,The C 1 -C 6 alkoxy group, C 1 -C 13 alkyl group, or C 3 -C 10 cyclyl group may include hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; C 1 -C 6 alkoxy group; an amino group (-NR 8 R 9 ); nitro group (-N(O) 2 ); an amide group (-(C=O)NR 8 R 9 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 8 (C=O)NR 9 -); sulfonamide group (-NHS(O) 2 -); sulfide group (-S-); sulfonic group (-S(O) 2 -); a phospyryl group (-P(O)R 8 R 9 ); C 6 -C 10 aryl group; C 3 -C 10 heteroaryl group; and one or more substituents selected from the group consisting of a C 3 -C 10 heterocyclyl group,

상기 C6-C10 아릴기, C3-C10 헤테로아릴기 또는 C3-C10 헤테로사이클릴기는, 수소; 히드록시기; 할로겐기; 카보닐기(-(C=O)R8R9); 할로겐 또는 C3-C10 헤테로사이클릴기로 치환 또는 비치환된 C1-C3 알킬기; 할로겐 또는 C3-C10 헤테로사이클릴기로 치환 또는 비치환된 C1-C3 알콕시기; C6-C10 페녹시; 아미노기(-NR8R9); 니트로기(-N(O)2); 아마이드기(-(C=O)NR8R9); 카르복실산기(-C(O)OH); 니트릴기(-CN); 유레아기(-NR8(C=O)NR9-); 술폰아미드기(-NHS(O)2-); 설피드기(-S-); 술폰기(-S(O)2-); 포스피릴기(-P(O)R8R9); C6-C10 아릴기; C3-C10 헤테로아릴기 및 C3-C10 헤테로사이클릴기로 이루어진 군에서 선택되는 1 이상의 치환기를 포함하고,The C 6 -C 10 aryl group, C 3 -C 10 heteroaryl group, or C 3 -C 10 heterocyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R 8 R 9 ); a C 1 -C 3 alkyl group unsubstituted or substituted with a halogen or C 3 -C 10 heterocyclyl group; a C 1 -C 3 alkoxy group unsubstituted or substituted with a halogen or C 3 -C 10 heterocyclyl group; C 6 -C 10 phenoxy; an amino group (-NR 8 R 9 ); nitro group (-N(O) 2 ); an amide group (-(C=O)NR 8 R 9 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 8 (C=O)NR 9 -); sulfonamide group (-NHS(O) 2 -); sulfide group (-S-); sulfonic group (-S(O) 2 -); a phospyryl group (-P(O)R 8 R 9 ); C 6 -C 10 aryl group; Containing one or more substituents selected from the group consisting of a C 3 -C 10 heteroaryl group and a C 3 -C 10 heterocyclyl group,

상기 R8 및 R9은 각각 독립적으로 수소; C1-C6 알킬기; C1-C6 알케닐기; C1-C6 알키닐기; C6-C10 아릴기; C3-C10 헤테로아릴기; C3-C10 헤테로사이클릴기; 또는 R8는 R9과 연결된 질소 또는 탄소 원자와 함께 N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, 또는 SO2 중 적어도 1종을 임의로 포함할 수 있고, 수소, C1-C13 알킬기, C6-C10 아릴기, C3-C10 헤테로아릴기, 히드록실기, 할라이드기 및 시아노기 중 적어도 1종으로 임의로 치환될 수 있는 3 내지 7원(membered) 포화 고리를 형성하고,wherein R 8 and R 9 are each independently hydrogen; C 1 -C 6 alkyl group; C 1 -C 6 alkenyl group; C 1 -C 6 alkynyl group; C 6 -C 10 aryl group; C 3 -C 10 heteroaryl group; C 3 -C 10 heterocyclyl group; or R 8 together with the nitrogen or carbon atom connected to R 9 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 - or SO 2 may optionally include at least one of hydrogen, C 1 -C 13 alkyl group, C 6 -C 10 aryl group, C 3 -C 10 heteroaryl group, hydroxyl group, halide group, and Forms a 3 to 7 membered saturated ring that may be optionally substituted with at least one of a cyano group,

상기 C3-C10 헤테로아릴기 및 C3-C10 헤테로사이클릴기는 N, O, 및 S로 이루어지는 군에서 선택된 1종 이상의 헤테로원자를 포함한다.The C 3 -C 10 heteroaryl group and the C 3 -C 10 heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.

본 발명의 다른 측면은 상기의 화합물이 유효성분으로 포함된 EGFR 단백질 키나아제에 의해 유발되는 질환의 예방, 개선 또는 치료용 약학 조성물을 제공한다.Another aspect of the present invention provides a pharmaceutical composition for preventing, improving or treating diseases caused by EGFR protein kinase containing the compound as an active ingredient.

본 발명의 다른 측면에서, 상기 EGFR 단백질 키나아제에 의해 유발되는 질환은 EGFR 단백질 키나아제에 의해 유발되는 대사성 질환; 또는 EGFR 단백질 키나아제에 의해 유발되는 비정상적 세포 서장에 의한 종양 질환; 인, 약학 조성물을 제공한다.In another aspect of the present invention, the disease induced by the EGFR protein kinase is a metabolic disease induced by EGFR protein kinase; or tumor diseases caused by abnormal cell proliferation caused by EGFR protein kinase; Phosphorus, provides a pharmaceutical composition.

본 발명의 다른 측면에서, 상기 질환은 폐암, 간암, 식도암, 위암, 대장암, 소장암, 췌장암, 흑색종, 유방암, 구강암, 뇌종양, 갑상선암, 부갑상선암, 신장암, 자궁경부암, 육종, 전립선암, 요도암, 방광암, 고환암, 혈액암, 림프종, 피부암, 건선 및 섬유선종으로 이루어진 군으로부터 선택되는 질환일 수 있다.In another aspect of the present invention, the disease is lung cancer, liver cancer, esophageal cancer, stomach cancer, colorectal cancer, small intestine cancer, pancreatic cancer, melanoma, breast cancer, oral cancer, brain tumor, thyroid cancer, parathyroid cancer, kidney cancer, cervical cancer, sarcoma, prostate cancer , urethral cancer, bladder cancer, testicular cancer, blood cancer, lymphoma, skin cancer, may be a disease selected from the group consisting of psoriasis and fibroadenoma.

본 발명의 다른 측면에서, 상기 유효성분은 EGFR 키나아제 또는 EGFR 돌연변이의 활성 저해를 통해 상기 질환을 예방, 개선 또는 치료하는, 약학 조성물을 제공한다.In another aspect of the present invention, the active ingredient provides a pharmaceutical composition for preventing, improving or treating the disease through inhibition of the activity of EGFR kinase or EGFR mutation.

본 발명의 다른 측면에서, 상기 EGFR 돌연변이는, del19, L858R, T790M, C797S 의 활성 또는 이들의 조합일 수 있다.In another aspect of the present invention, the EGFR mutation may be the activity of del19, L858R, T790M, C797S, or a combination thereof.

본 발명의 다른 측면에서, 상기 유효성분은 세포독성치료제와 병용 투여할 수 있는, 약학 조성물을 제공한다.In another aspect of the present invention, the active ingredient provides a pharmaceutical composition that can be administered in combination with a cytotoxic therapeutic agent.

본 발명의 다른 측면에서, 상기 유효성분과 세포독성치료제는 유효성분 100 중량부에 대하여 세포독성치료제 10 내지 1000 중량부로 병용 투여할 수 있는, 약학 조성물을 제공한다.In another aspect of the present invention, the active ingredient and the cytotoxic agent provide a pharmaceutical composition that can be administered in combination in an amount of 10 to 1000 parts by weight of the cytotoxic agent based on 100 parts by weight of the active ingredient.

본 발명의 화합물은 EGFR 단백질 키나아제의 활성을 저해하는 능력이 우수하므로 비정상적인 세포 성장 및 대사로 인해 유발되는 질환의 예방 및 치료를 위한 약제조성물의 유효성분으로 사용될 수 있다.Since the compound of the present invention has excellent ability to inhibit the activity of EGFR protein kinase, it can be used as an active ingredient in a pharmaceutical composition for the prevention and treatment of diseases caused by abnormal cell growth and metabolism.

따라서 본 발명에 따른 화합물은 비정상적인 세포 성장 및 대사로 인해 유발되는 질환으로서 예를 들면 당뇨, 비만 등의 대사성질환 및 자궁내막암, 방광암, 위암, 폐암, 간암, 대장암, 소장암, 췌장암, 뇌암, 뼈암, 흑색종, 유방암, 경화성선종, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 백혈병, 다발성골수종, 골수이형성증후군과 같은 혈액암, 호치킨병과 비호치킨림프종과 같은 림프종, 또는 섬유선종 등으로부터 선택된 각종 종양 질환의 예방 및 치료제로 사용될 수 있다.Therefore, the compound according to the present invention is a disease caused by abnormal cell growth and metabolism, for example, metabolic diseases such as diabetes and obesity, endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer , bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, blood cancer such as myelodysplastic syndrome, Hodgkin's disease and non-Hodgkin's disease It can be used as a prophylactic and therapeutic agent for various tumor diseases selected from lymphoma, such as lymphoma, or fibroadenoma.

정의Justice

달리 명시되지 않는 한, 본 명세서에서 사용된 성분, 반응 조건, 성분의 함량을 표현하는 모든 숫자, 값 및/또는 표현은, 이러한 숫자들이 본질적으로 다른 것들 중에서 이러한 값을 얻는 데 발생하는 측정의 다양한 불확실성이 반영된 근사치들이므로, 모든 경우 "약"이라는 용어에 의해 수식되는 것으로 이해되어야 한다. 또한, 본 기재에서 수치범위가 개시되는 경우, 이러한 범위는 연속적이며, 달리 지적되지 않는 한 이러한 범 위의 최소값으로부터 최대값이 포함된 상기 최대값까지의 모든 값을 포함한다. 더 나아가, 이러한 범위가 정수를 지칭하는 경우, 달리 지적되지 않는 한 최소값으로부터 최대값이 포함된 상기 최대값까지를 포함하는 모든 정수가 포함된다.Unless otherwise specified, all numbers, values, and/or expressions expressing ingredients, reaction conditions, and amounts of ingredients used herein refer to a variety of measures that may occur in obtaining such values, among others, in which such numbers are inherently different. Since they are approximations reflecting uncertainty, it should be understood as being modified by the term "about" in all cases. Also, where the disclosure discloses numerical ranges, such ranges are continuous and inclusive of all values from the minimum to the maximum inclusive of the range, unless otherwise indicated. Furthermore, when such ranges refer to integers, all integers inclusive from the minimum to the maximum inclusive are included, unless otherwise indicated.

본 명세서에 있어서, 범위가 변수에 대해 기재되는 경우, 상기 변수는 상기 범위의 기재된 종료점들을 포함하는 기재된 범위 내의 모든 값들을 포함하는 것으로 이해될 것이다. 예를 들면, "5 내지 10"의 범위는 5, 6, 7, 8, 9, 및 10의 값들뿐만 아니라 6 내지 10, 7 내지 10, 6 내지 9, 7 내지 9 등의 임의의 하위 범위를 포함하고, 5.5, 6.5, 7.5, 5.5 내지 8.5 및 6.5 내지 9 등과 같은 기재된 범위의 범주에 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다. 또한 예를 들면, "10% 내지 30%"의 범위는 10%, 11%, 12%, 13% 등의 값들과 30%까지를 포함하는 모든 정수들뿐만 아니라 10% 내지 15%, 12% 내지 18%, 20% 내지 30% 등의 임의의 하위 범위를 포함하고, 10.5%, 15.5%, 25.5% 등과 같이 기재된 범위의 범주 내의 타당한 정수들 사이의 임의의 값도 포함하는 것으로 이해될 것이다.In this specification, when a range is described for a variable, the variable will be understood to include all values within the stated range including the stated endpoints of the range. For example, a range of “5 to 10” includes the values of 5, 6, 7, 8, 9, and 10, as well as any subranges such as 6 to 10, 7 to 10, 6 to 9, 7 to 9, etc. It will be understood to include any value between integers that are appropriate for the scope of the recited range, such as 5.5, 6.5, 7.5, 5.5 to 8.5 and 6.5 to 9, and the like. Also for example, a range of “10% to 30%” includes values such as 10%, 11%, 12%, 13%, and all integers up to and including 30%, as well as 10% to 15%, 12% to It will be understood to include any subrange, such as 18%, 20% to 30%, etc., as well as any value between reasonable integers within the scope of the recited range, such as 10.5%, 15.5%, 25.5%, and the like.

본원에 사용된 바의, 용어 "개체(들)", "대상(들)"및 "환자(들)"는 임의의 포유동물을 의미한다. 일부 실시 양태에서, 포유동물은 인간이다. 일부 실시 양태에서, 포유동물은 인간이 아니다. 어떤 용어도 건강 관리 종사자(예컨대, 의사, 정규 간호사, 견습 간호사, 의사 보조원, 잡역 또는 호스피스 작업자)의 감독(예컨대, 상시 또는 간헐적)에 의해 특징 지어지는 상황을 필요로하지 않고, 또는 그것으로 한정되지 않는다. As used herein, the terms “individual(s),” “subject(s),” and “patient(s)” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is not a human. Neither term requires, or is limited to, a situation characterized by the supervision (e.g., regular or intermittent) of a health care practitioner (e.g., physician, regular nurse, apprentice nurse, physician's assistant, handyman or hospice worker) doesn't happen

"치료"는 한 질환의 병변이 발전되거나 변경되는 것을 예방하는 의도로 수행되는 시도이다. 따라서, "치료"는　치료법적　치료　및 예방적인 차원의 것들 모두를 가리킨다.　 치료할 필요가 있는 것들은 이미 질환을 가지고 있는 상태뿐만 아니라 질환이 예방되어야 할 상태를 포함한다. 종양 치료에 있어서, 치료제는 종양 세포의 병리를 직접적으로 감소시키거나 종양 세포를 다른 치료제, 예를 들어 방사선 및/또는 화학 요법 및/또는 면역 요법에 의한 치료에 더욱 민감하게 하는 것을 의미할 수 있다. 본 명세서에 사용되는 용어인 "경감" 또는 "치료됨"은 통상적인 통계 테스트로 측정된 정규화된 값에 접근하는 징후를 의미한다. 여기서 정규화된 값에 접근하는 징후는, 예를 들어, 건강한 환자 또는 개체에게서 수득된 값으로 정규화된 값과 50% 미만으로 차이를 보이는 값, 바람직하게 25% 미만으로 차이를 보이는 값, 더 바람직하게 10% 미만으로 차이를 보이는 값, 더욱 더 바람직하게 정규화된 값과 크게 차이를 보이지 않는 값일 수 있다. "Treatment" is an attempt made with the intention of preventing the development or alteration of a lesion of a disease. Accordingly, "treatment" refers to both therapeutic, therapeutic and prophylactic dimensions. Those that need to be treated include those already having the disease as well as those in which the disease is to be prevented. In the treatment of tumors, a therapeutic agent may mean directly reducing the pathology of the tumor cells or making the tumor cells more susceptible to treatment by other therapeutic agents, for example radiation and/or chemotherapy and/or immunotherapy. . As used herein, the term “relief” or “treated” refers to a symptom approaching normalized values measured by conventional statistical tests. A sign approaching a normalized value here is, for example, a value obtained from a healthy patient or individual, a value which differs from the normalized value by less than 50%, preferably a value which differs by less than 25%, more preferably It may be a value showing a difference of less than 10%, and more preferably a value not significantly different from a normalized value.

"암의 치료"는 하기 효과들 중 어느 하나 이상을 의미한다; 1) i) 둔화 또는 ii) 완전한 성장 정지를 포함하는 종양 성장의 억제; 2) 종양 세포 수의 감소; 3) 종양 크기의 유지; 4) 종양 크기의 감소; 5) i) 감소 또는 ii) 둔화 또는 iii) 완전한 예방을 포함하는 말초 기관으로의 종양 세포 침윤 억제; 6) i) 감소 또는 ii) 둔화 또는 iii) 완전한 예방을 포함한 전이의 억제; 7) 항 종양 면역 반응의 향상으로, i) 종양 크기 유지 또는 ii) 종양 크기 감소 또는 iii) 종양의 성장 둔화 또는 iv) 침습의 감소, 둔화 또는 예방을 야기할 수 있는, 항-종양 면역반응의 증진."Treatment of cancer" means any one or more of the following effects; 1) i) inhibition of tumor growth, including slowing or ii) complete growth arrest; 2) reduction in the number of tumor cells; 3) maintenance of tumor size; 4) reduction in tumor size; 5) inhibition of tumor cell infiltration into peripheral organs comprising i) reduction or ii) blunting or iii) complete prophylaxis; 6) i) reduction or ii) slowing or iii) inhibition of metastasis, including complete prevention; 7) enhancement of the anti-tumor immune response, which may result in i) maintenance of tumor size or ii) reduction in tumor size or iii) slowing of growth of a tumor or iv) reduction, slowing or prevention of invasion. increase.

본 명세서에서 사용된 "유효량" 또는 "치료학적 유효량"은 치료해야할 질환 또는 상태(예를 들어, 암 또는 염증성 질환, 치주 질환 또는 연조직 석회화 )의 증상을 어느 정도 경감시키는, 본 명세서에 개시된 화합물의 충분한 양을 의미한다. 일부 구현예에 있어서, 상기 결과는 1) 질환의 징후, 증상 또는 원인의 감소 및/또는 완화, 또는 2) 임상 환경에서 생물학적 시스템의 임의의 다른 바람직한 변경이다. 일부 구현예에 있어서, 어떤 개별 사례에 있어서 적절한 "유효"량은 용량 증가 연구와 같은 기술을 사용하여 결정된다.As used herein, "effective amount" or "therapeutically effective amount" refers to a compound disclosed herein that relieves to some extent the symptoms of a disease or condition to be treated (eg, cancer or inflammatory disease, periodontal disease, or soft tissue calcification). means a sufficient amount. In some embodiments, the outcome is 1) reduction and/or alleviation of the signs, symptoms or causes of a disease, or 2) any other desirable alteration of a biological system in a clinical setting. In some embodiments, an appropriate "effective" amount for any individual case is determined using techniques such as dose escalation studies.

일부 구현예에서, "유효량"은 단일요법 또는 조합 요법에서 개시된 화합물의 양, 즉, 하나 이상의 용량으로 투여 될 때, 화합물로 처리하지 않은 개체에서 EGFR 활성과 비교하거나, 또는 화합물로 처리하기 전 또는 후에 개체에서 EGFR 활성과 비교하였을때, EGFR을 약 20 % (20 % 억제), 적어도 약 30 % (30 % 억제), 적어도 약 40 % (40 % 억제), 적어도 약 50 % (50 % 억제), 약 60 % 이상 (60 % 억제), 약 70 % 이상 (70 % 억제), 약 80 % 이상 (80 % 억제), 약 90 % 이상 (90 % 억제) 만큼 억제하는 데 효과적인 양이다.In some embodiments, an "effective amount" is an amount of a disclosed compound in monotherapy or combination therapy, i.e., when administered in one or more doses, compared to EGFR activity in an individual not treated with the compound, or prior to treatment with the compound, or EGFR by about 20% (20% inhibition), at least about 30% (30% inhibition), at least about 40% (40% inhibition), at least about 50% (50% inhibition) when compared to EGFR activity in the subject later. , about 60% or more (60% inhibition), about 70% or more (70% inhibition), about 80% or more (80% inhibition), about 90% or more (90% inhibition).

일부 구현예에서, "치료학적 유효량"은 단일요법 또는 조합 요법에서 개시된 화합물의 양, 즉, 하나 이상의 용량으로 투여 될 때, 화합물로 치료하지 않은 객체의 종양 부담과 비교하거나, 또는 화합물로 처리하기 전 또는 후에 객체의 종양 부담과 비교하였을 때, 객체의 종양 부담을 약 20 %, 약 30 % 이상, 약 40 % 이상, 약 50 % 이상, 약 60 % 이상, 약 70 % 이상, 약 80 % 이상, 약 90 % 이상의 양만큼 감소시키기에 효과적인 양이다. 본 명세서에서 사용된 용어 "종양 부담"은 암을 가진 객체가 지니고 있는 종양 조직의 총 질량이다. In some embodiments, a “therapeutically effective amount” is an amount of a compound disclosed in monotherapy or combination therapy, i.e., when administered in one or more doses, compared to the tumor burden of a subject not treated with the compound, or to be treated with the compound. about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, when compared to the subject's tumor burden before or after , an amount effective to reduce by an amount greater than or equal to about 90%. As used herein, the term “tumor burden” is the total mass of tumor tissue carried by a subject with cancer.

일부 구현예에서, "치료학적 유효량"은 단일요법 또는 조합 요법에서 개시된 화합물의 양, 즉, 하나 이상의 용량으로 투여 될 때, 화합물로 치료하지 않은 객체에서 종양 수축을 관찰하기 위해 필요한 방사선 요법의 용량과 비교하여, 객체에서 종양 수축을 관찰하기 위해 필요한 방사선요법의 양을 약 20 %, 약 30 % 이상, 약 40 % 이상, 약 50 % 이상, 약 60 % 이상, 약 70 % 이상, 약 80 % 이상, 약 90 % 이상 줄이기에 효과적인 양이다.In some embodiments, a "therapeutically effective amount" is an amount of a compound disclosed in monotherapy or combination therapy, i.e., the dose of radiation therapy required to observe tumor shrinkage in subjects not treated with the compound when administered in one or more doses. compared to about 20%, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% of the amount of radiotherapy required to observe tumor shrinkage in a subject. It is an effective amount to reduce more than, about 90% or more.

약학 조성물pharmaceutical composition

비히클, 보조제, 담체 또는 희석제와 같은 약제학적으로 허용되는 부형제는 통상의 기술자가 쉽게 이용 가능하다. pH 조절제 및 완충제, 등장성 조절제, 안정제, 습윤제 등과 같은 약제학적으로 허용되는 보조 물질은 통상의 기술자가 쉽게 이용 가능하다.Pharmaceutically acceptable excipients such as vehicles, adjuvants, carriers or diluents are readily available to those skilled in the art. Pharmaceutically acceptable auxiliary substances such as pH adjusting agents and buffers, isotonicity adjusting agents, stabilizers, wetting agents and the like are readily available to those skilled in the art.

일부 구현예에서, 본원발명의 화합물은 수성 완충제로 제형화된다. 적합한 수성 완충제는 5mM 내지 1000mM의 강도가 다양한 아세테이트, 숙시네이트, 시트레이트 및 포스페이트 완충제를 포함하지만 이에 제한되지는 않는다. 일부 구현예에서, 수성 완충제는 등장 용액을 제공하는 시약을 포함한다. 이러한 시약은 염화나트륨, 당, 예를 들어 만니톨, 덱스트로스, 수크로스 등을 포함하지만, 이에 제한되지는 않는다. 일부 구현예에서, 수성 완충제는 폴리소르 베이트 20 또는 80과 같은 비이온성계면활성제를 추가로 포함한다. 임의로, 제제는 보존제를 추가로 포함할 수 있다. 적합한 보존제는 벤질알코올, 페놀, 클로로부탄올, 벤즈알코늄클로라이드 등을 포함하지만 이에 제한되지는 않는다. 다른 구체 예에서, 제형은 약 4 ℃로 저장된다. 제제는 또한 동결 건조될 수 있으며, 이들은 일반적으로 자당, 트레할로스, 락토스, 말토오스, 만니톨 등과 같은 동결 방지제를 포함한다. 동결 건조 제제는 상온도에서도 장기간에 걸쳐 저장될 수있다.In some embodiments, a compound of the invention is formulated in an aqueous buffer. Suitable aqueous buffers include, but are not limited to, acetate, succinate, citrate and phosphate buffers of varying strengths from 5 mM to 1000 mM. In some embodiments, aqueous buffers include reagents that provide isotonic solutions. Such reagents include, but are not limited to, sodium chloride, sugars such as mannitol, dextrose, sucrose, and the like. In some embodiments, the aqueous buffer further comprises a nonionic surfactant such as polysorbate 20 or 80. Optionally, the formulation may further comprise a preservative. Suitable preservatives include, but are not limited to, benzyl alcohol, phenol, chlorobutanol, benzalkonium chloride, and the like. In another embodiment, the formulation is stored at about 4°C. The formulations may also be lyophilized, which generally contain a cryoprotectant such as sucrose, trehalose, lactose, maltose, mannitol, and the like. Freeze-dried preparations can be stored for a long period of time even at room temperature.

본 명세서에서, 약학조성물은 본원 발명에 개시된 화합물, 또는 그의 약학적으로 허용되는 염, 그의 이성질체, 그의 호변 이성질체를 포함하거나, 필수적으로 구성될 수 있으며, 추가적으로 약학조성물은 하나 이상의 추가의 관심있는 활성제를 포함하거나 필수적으로 구성될 수 있는 약학 조성물을 제공한다. 임의의 편리한 활성제가 본원발명 화합물과 함께 본 방법에 사용될 수있다. 일 구현예에서, 병용 요법에 대해 본원발명에 기재된 바와 같은 추가의 치료제뿐만 아니라 본원발명의 화합물 및 면역관문억제제는 경구, 피하, 근육내, 비강내, 비경구 또는 다른 경로로 투여될 수 있다. 다른 구체예에서, 본원발명의 화합물 및 화학요법제제 (특히 생체 내에서 cGAMP의 생성을 유도할 수 있는 화학요법제제), 및 병용요법을 위한 본원발명에 기재된 추가의 치료제는 경구, 피하, 근육내, 비강내, 비경구 또는 기타 경로로 투여될 수 있다. 본원발명의 화합물 및 제 2 활성제 (존재하는 경우)는 동일한 투여 경로 또는 상이한 투여 경로에 의해 투여될 수 있다. 치료제는 영향을 받는 기관으로 경구, 직장, 코, 국소, 질, 비경구, 정맥내, 비강내, 종양 내 주사를 포함하지만 이에 제한되지 않는 임의의 적합한 수단에 의해 투여될 수있다. In the present specification, a pharmaceutical composition may comprise, or consist essentially of, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an isomer thereof, a tautomer thereof, and additionally the pharmaceutical composition comprises one or more additional active agents of interest. It provides a pharmaceutical composition comprising or consisting essentially of. Any convenient active agent may be used in the present methods with the compounds of the present invention. In one embodiment, the compound of the invention and the checkpoint inhibitor, as well as the additional therapeutic agent as described herein for combination therapy, may be administered orally, subcutaneously, intramuscularly, intranasally, parenterally or by other routes. In another embodiment, a compound of the present invention and a chemotherapeutic agent (especially a chemotherapeutic agent capable of inducing cGAMP production in vivo), and an additional therapeutic agent described herein for combination therapy are oral, subcutaneous, intramuscular , intranasal, parenteral or other routes. The compound of the invention and the second active agent, if present, may be administered by the same route of administration or by different routes of administration. The therapeutic agent may be administered by any suitable means including, but not limited to, oral, rectal, nasal, topical, vaginal, parenteral, intravenous, intranasal, intratumoral injection into the organ affected.

본원발명 화합물은 단위 투여 형태로 투여될 수 있고 당 업계에 잘 알려진 임의의 방법에 의해 제조될 수있다. 이러한 방법은 본원발명 화합물을 하나 이상의 보조 성분 중 하나를 구성하는 약학적으로 허용되는 담체 또는 희석제와 조합하는 단계를 포함한다. 약학적으로 허용되는 담체는 선택된 투여 경로 및 표준 약학적 관행에 기초하여 선택된다. 각각의 담체는 제제의 다른 성분과 상용성이고 객체 또는 환자에 해를 끼치지 않는다는 점에서 "약학적으로 허용 가능" 해야한다. 이 담체는 고체 또는 액체 일 수 있으며, 유형은 일반적으로 사용되는 투여 유형에 따라 선택된다.The compounds of the present invention may be administered in unit dosage form and may be prepared by any method well known in the art. Such methods include the step of combining a compound of the present invention with a pharmaceutically acceptable carrier or diluent which constitutes one of one or more accessory ingredients. Pharmaceutically acceptable carriers are selected based on the chosen route of administration and standard pharmaceutical practice. Each carrier must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the formulation and not harming the subject or patient. This carrier may be solid or liquid, the type of which is generally selected according to the type of administration used.

적합한 고체 담체의 예는 락토스, 슈크로스, 젤라틴, 한천 및 벌크 분말을 포함한다. 적합한 액체 담체의 예는 물, 약학적으로 허용되는 지방 및 오일, 알코올 또는 기타 유기 용매, 예를 들어 에스테르, 에멀젼, 시럽 또는 엘릭시르 제(elixirs), 현탁액 및 비발포성과립으로부터 재구성된 용액 및/또는 현탁액을 포함한다. 이러한 액체 담체는 예를 들어 적합한 용매, 보존제, 유화제, 현탁제, 희석제, 감미제, 증점제 및 용융제를 함유할 수있다.Examples of suitable solid carriers include lactose, sucrose, gelatin, agar and bulk powder. Examples of suitable liquid carriers include water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents such as esters, emulsions, syrups or elixirs, suspensions and solutions reconstituted from non-foaming granules and/or including suspensions. Such liquid carriers may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweetening, thickening and melting agents.

이하, 본 발명에 대하여 상세히 설명한다.Hereinafter, the present invention will be described in detail.

본 발명의 일측면은 하기 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.One aspect of the present invention provides a compound selected from a pyrimidine derivative compound represented by the following Chemical Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

[화학식 10][Formula 10]

Figure pat00004
Figure pat00004

[화학식 11][Formula 11]

Figure pat00005
Figure pat00005

[화학식 12][Formula 12]

Figure pat00006
Figure pat00006

상기 화학식 10 내지 12에서,In Formulas 10 to 12,

R1는 수소; 히드록시기; 할로겐기; C1-C13 알킬기; 또는 C1-C6 알콕시기;이고,R 1 is hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; Or a C 1 -C 6 alkoxy group;

R2는 수소; 할로겐기; C1-C13 알킬기; C3-C10 사이클릴기; 아미노기(-NR8R9); 또는 니트로기(-N(O)2);이고,R 2 is hydrogen; halogen group; C 1 -C 13 alkyl group; C 3 -C 10 cyclyl group; an amino group (-NR 8 R 9 ); or a nitro group (—N(O) 2 );

R3는 및 R4는 각각 독립적으로 수소; C1-C13 알킬기; C3-C10 사이클릴기; 설피드기(-SR8); 술폰기(-S(O)2R8);또는 포스피릴기(-P(O)R8R9)이고;R 3 and R 4 are each independently hydrogen; C 1 -C 13 alkyl group; C 3 -C 10 cyclyl group; sulfide group (-SR 8 ); a sulfone group (-S(O) 2 R 8 ); or a phospyryl group (-P(O)R 8 R 9 );

R5, R6 및 R7는 각각 독립적으로 수소; 히드록시기; 할로겐기; C1-C13 알킬기; C1-C6 알콕시기; C3-C10 사이클릴기; C3-C10 헤테로사이클릴기; -C(O)-(C1-C13 알킬); 아미노기(-NR8R9); 니트로기(-N(O)2); 아마이드기(-(C=O)NR8R9); 카르복실산기(-C(O)OH); 니트릴기(-CN); 유레아기(-NR8(C=O)NR9-); 술폰아미드기(-NHS(O)2R8); 설피드기(-SR8); 술폰기(-S(O)2R8);또는 포스피릴기(-P(O)R8R9)이고;R 5 , R 6 and R 7 are each independently hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; C 1 -C 6 alkoxy group; C 3 -C 10 cyclyl group; C 3 -C 10 heterocyclyl group; -C(O)-(C 1 -C 13 alkyl); an amino group (-NR 8 R 9 ); nitro group (-N(O) 2 ); an amide group (-(C=O)NR 8 R 9 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 8 (C=O)NR 9 -); a sulfonamide group (—NHS(O) 2 R 8 ); sulfide group (-SR 8 ); a sulfone group (-S(O) 2 R 8 ); or a phospyryl group (-P(O)R 8 R 9 );

X1, X2 및 X3 은 각각 독립적으로 탄소 또는 질소이고,X 1 , X 2 and X 3 are each independently carbon or nitrogen,

A는 C1-C13 알킬기; 아미노기(-NR8R9); C6-C10 아릴기; C3-C10 사이클릴기; C3-C10 헤테로아릴기; C3-C10 헤테로사이클릴기; 또는 A는 R6과 연결된 탄소 원자와 함께 N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, 또는 SO2 중 적어도 1종을 임의로 포함할 수 있고, 수소, C1-C13 알킬기, C6-C10 아릴기, C3-C10 헤테로아릴기, 히드록실기, 할라이드기 및 시아노기 중 적어도 1종으로 임의로 치환될 수 있는 3 내지 7원(membered) 포화 고리를 형성하고;A is a C 1 -C 13 alkyl group; an amino group (-NR 8 R 9 ); C 6 -C 10 aryl group; C 3 -C 10 cyclyl group; C 3 -C 10 heteroaryl group; C 3 -C 10 heterocyclyl group; or A together with the carbon atom connected to R 6 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 -, or SO 2 , which may optionally include at least one of hydrogen, a C 1 -C 13 alkyl group, a C 6 -C 10 aryl group, a C 3 -C 10 heteroaryl group, a hydroxyl group, a halide group, and a cyano group. form a 3 to 7 membered saturated ring which may be optionally substituted with at least one;

B는 C6-C10 아릴기; C3-C10 사이클릴기; C3-C10 헤테로아릴기; 또는 C3-C10 헤테로사이클릴기; 이고,B is a C 6 -C 10 aryl group; C 3 -C 10 cyclyl group; C 3 -C 10 heteroaryl group; or a C 3 -C 10 heterocyclyl group; ego,

X1 또는 X3가 각각 독립적으로 질소일 때, R2 또는 R7은 치환되지 않으며,When X 1 or X 3 is each independently nitrogen, R 2 or R 7 is unsubstituted,

상기 C1-C6 알콕시기, C1-C13 알킬기 또는 C3-C10 사이클릴기는, 수소; 히드록시기; 할로겐기; C1-C13 알킬기; C1-C6 알콕시기; 아미노기(-NR8R9); 니트로기(-N(O)2); 아마이드기(-(C=O)NR8R9); 카르복실산기(-C(O)OH); 니트릴기(-CN); 유레아기(-NR8(C=O)NR9-); 술폰아미드기(-NHS(O)2-); 설피드기(-S-); 술폰기(-S(O)2-); 포스피릴기(-P(O)R8R9); C6-C10 아릴기; C3-C10 헤테로아릴기; 및 C3-C10 헤테로사이클릴기로 이루어진 군으로부터 선택되는 1 이상의 치환기를 포함하며,The C 1 -C 6 alkoxy group, C 1 -C 13 alkyl group, or C 3 -C 10 cyclyl group may include hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; C 1 -C 6 alkoxy group; an amino group (-NR 8 R 9 ); nitro group (-N(O) 2 ); an amide group (-(C=O)NR 8 R 9 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 8 (C=O)NR 9 -); sulfonamide group (-NHS(O) 2 -); sulfide group (-S-); sulfonic group (-S(O) 2 -); a phospyryl group (-P(O)R 8 R 9 ); C 6 -C 10 aryl group; C 3 -C 10 heteroaryl group; and one or more substituents selected from the group consisting of a C 3 -C 10 heterocyclyl group,

상기 C6-C10 아릴기, C3-C10 헤테로아릴기 또는 C3-C10 헤테로사이클릴기는, 수소; 히드록시기; 할로겐기; 카보닐기(-(C=O)R8R9); 할로겐 또는 C3-C10 헤테로사이클릴기로 치환 또는 비치환된 C1-C3 알킬기; 할로겐 또는 C3-C10 헤테로사이클릴기로 치환 또는 비치환된 C1-C3 알콕시기; C6-C10 페녹시; 아미노기(-NR8R9); 니트로기(-N(O)2); 아마이드기(-(C=O)NR8R9); 카르복실산기(-C(O)OH); 니트릴기(-CN); 유레아기(-NR8(C=O)NR9-); 술폰아미드기(-NHS(O)2-); 설피드기(-S-); 술폰기(-S(O)2-); 포스피릴기(-P(O)R8R9); C6-C10 아릴기; C3-C10 헤테로아릴기 및 C3-C10 헤테로사이클릴기로 이루어진 군에서 선택되는 1 이상의 치환기를 포함하고,The C 6 -C 10 aryl group, C 3 -C 10 heteroaryl group, or C 3 -C 10 heterocyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R 8 R 9 ); a C 1 -C 3 alkyl group unsubstituted or substituted with a halogen or C 3 -C 10 heterocyclyl group; a C 1 -C 3 alkoxy group unsubstituted or substituted with a halogen or C 3 -C 10 heterocyclyl group; C 6 -C 10 phenoxy; an amino group (-NR 8 R 9 ); nitro group (-N(O) 2 ); an amide group (-(C=O)NR 8 R 9 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 8 (C=O)NR 9 -); sulfonamide group (-NHS(O) 2 -); sulfide group (-S-); sulfonic group (-S(O) 2 -); a phospyryl group (-P(O)R 8 R 9 ); C 6 -C 10 aryl group; Containing one or more substituents selected from the group consisting of a C 3 -C 10 heteroaryl group and a C 3 -C 10 heterocyclyl group,

상기 R8 및 R9은 각각 독립적으로 수소; C1-C6 알킬기; C1-C6 알케닐기; C1-C6 알키닐기; C6-C10 아릴기; C3-C10 헤테로아릴기; C3-C10 헤테로사이클릴기; 또는 R8는 R9과 연결된 질소 또는 탄소 원자와 함께 N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, 또는 SO2 중 적어도 1종을 임의로 포함할 수 있고, 수소, C1-C13 알킬기, C6-C10 아릴기, C3-C10 헤테로아릴기, 히드록실기, 할라이드기 및 시아노기 중 적어도 1종으로 임의로 치환될 수 있는 3 내지 7원(membered) 포화 고리를 형성하고,wherein R 8 and R 9 are each independently hydrogen; C 1 -C 6 alkyl group; C 1 -C 6 alkenyl group; C 1 -C 6 alkynyl group; C 6 -C 10 aryl group; C 3 -C 10 heteroaryl group; C 3 -C 10 heterocyclyl group; or R 8 together with the nitrogen or carbon atom connected to R 9 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 - or SO 2 may optionally include at least one of hydrogen, C 1 -C 13 alkyl group, C 6 -C 10 aryl group, C 3 -C 10 heteroaryl group, hydroxyl group, halide group, and Forms a 3 to 7 membered saturated ring that may be optionally substituted with at least one of a cyano group,

상기 C3-C10 헤테로아릴기 및 C3-C10 헤테로사이클릴기는 N, O, 및 S로 이루어지는 군에서 선택된 1종 이상의 헤테로원자를 포함한다.The C 3 -C 10 heteroaryl group and the C 3 -C 10 heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.

본 발명에 따른 상기 화학식 10, 11 또는 12로 표시되는 피리미딘 화합물의 약학적으로 허용 가능한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있다. 약학적으로 허용된 염은 인체에 독성이 낮고 모화합물의 생물학적 활성과 물리화학적 성질에 악영향을 주지 않아야 한다. 약학적으로 허용된 염 제조에 사용될 수 있는 유리산은 무기산과 유기산으로 나눌 수 있다. 무기산은 염산, 황산, 질산, 인산, 과염소산, 브롬산 등이 사용될 수 있다. 유기산은 초산, 메탄설폰산, 에탄설폰산, p-톨루엔설폰산, 푸마린산, 말레산, 말론산, 프탈산, 숙신산, 젖산, 구연산, 시트르산, 글루콘산, 타타르산, 살리실산, 말산, 옥살산, 벤조산, 엠본산, 아스파르트산, 글루탐산 등이 사용될 수 있다. 유기염기부가염 제조에 사용될 수 있는 유기염기는 트리스(히드록시메틸)메틸아민, 디시클로헥실아민 등이다. 아미노산부가염기 제조에 사용될 수 있는 아미노산은 알라닌, 글라이신 등의 천연아미노산이다. A pharmaceutically acceptable salt of the pyrimidine compound represented by Formula 10, 11 or 12 according to the present invention may be prepared by a conventional method in the art. Pharmaceutically acceptable salts should have low toxicity to the human body and should not adversely affect the biological activity and physicochemical properties of the parent compound. Free acids that can be used to prepare pharmaceutically acceptable salts can be divided into inorganic acids and organic acids. The inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, hydrobromic acid, and the like. Organic acids include acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Organic bases that can be used in the preparation of organic base addition salts are tris(hydroxymethyl)methylamine, dicyclohexylamine, and the like. Amino acids that can be used to prepare the amino acid addition base are natural amino acids such as alanine and glycine.

본 발명에 따른 상기 화학식 10, 11 또는 12로 표시되는 피리미딘 화합물은 상기한 약학적으로 허용된 염과 더불어 모든 수화물 그리고 용매화물도 포함한다. 수화물 및 용매화물은 상기 화학식 10, 11 또는 12로 표시되는 화합물을 메탄올, 에탄올, 아세톤, 1,4-디옥산과 같은 물과 섞일 수 있는 용매에 녹인 다음에 유리산 또는 유리염기를 가한 후에 결정화되거나 또는 재결정화될 수 있다. 그러한 경우, 용매화물(특히 수화물)이 형성될 수 있다. 따라서, 본 발명의 화합물로서 동결건조와 같은 방법으로 제조 가능한 다양한 양의 물 함유 화합물 이외에 수화물을 비롯한 화학 양론적 용매화물도 포함한다.The pyrimidine compound represented by Formula 10, 11 or 12 according to the present invention includes all hydrates and solvates in addition to the pharmaceutically acceptable salts described above. Hydrates and solvates are crystallized after the compound represented by Formula 10, 11 or 12 is dissolved in a water-miscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane, and then a free acid or a free base is added. or recrystallize. In such cases, solvates (especially hydrates) may be formed. Accordingly, the compounds of the present invention include stoichiometric solvates including hydrates in addition to various amounts of water-containing compounds that can be prepared by methods such as freeze-drying.

본 발명에 따른 화합물을 정의하기 위해 사용된 치환기에 대해 보다 상세히 설명하면 다음과 같다.The substituents used to define the compounds according to the present invention will be described in more detail as follows.

본 발명에서 치환기에 대한 정의에서, 용어 '알킬'은 지방족 탄화수소 래디칼을 의미한다. 알킬은 알케닐이나 알키닐 부위를 포함하지 않는 "포화 알킬 (saturated alkyl)" 이거나, 적어도 하나의 알케닐 또는 알키닐 부위를 포함하는 "불포화 알킬 (unsaturated alkyl)" 일 수 있다. "알케닐 (alkenyl)"은 적어도 하나의 탄소-탄소 이중결합을 포함하는 그룹을 의미하며, "알키닐 (alkynyl)"은 적어도 하나의 탄소-탄소 삼중 결합을 포함하는 그룹을 의미한다. 알킬은 단독으로 또는 조합하여 사용되는 경우에 각각 고리형, 분지형 또는 직쇄형일 수 있다.In the definition of a substituent in the present invention, the term 'alkyl' means an aliphatic hydrocarbon radical. Alkyl may be "saturated alkyl" containing no alkenyl or alkynyl moieties, or "unsaturated alkyl" containing at least one alkenyl or alkynyl moiety. "Alkenyl" means a group comprising at least one carbon-carbon double bond, and "alkynyl" means a group comprising at least one carbon-carbon triple bond. Alkyl, when used alone or in combination, may each be cyclic, branched or straight-chain.

용어 '아릴'은 단독으로 또는 다른 래디칼과 조합하여, 방향족, 포화 또는 불포화될 수 있는 제2의 5 또는 6원성 카보사이클릭기와 추가로 융합된 수 있는, 탄소 원자 6개를 포함하는 카보사이클릭 방향족 단환식 기를 의미한다. 아릴의 예로는 페닐, 인다닐, 1-나프틸, 2-나프틸, 테프라히아드로나프틸 등을 포함할 수 있으나 이에 한정되지 않는다. 아릴은 방향족 고리 상의 적정 위치에서 다른 기와 연결될 수 있다. The term 'aryl', alone or in combination with other radicals, refers to a carbocyclic containing 6 carbon atoms which may be further fused with a second 5 or 6 membered carbocyclic group which may be aromatic, saturated or unsaturated. aromatic monocyclic group. Examples of aryl may include, but are not limited to, phenyl, indanyl, 1-naphthyl, 2-naphthyl, teprahyadronaphthyl, and the like. Aryl may be linked with other groups at appropriate positions on the aromatic ring.

용어 '알콕시'는 산소 원자를 통해 다른 기에 연결된 알킬기 (즉, -O-알킬)를 의미한다. 알콕시기는 치환되지 않거나 하나 이상의 적절한 치환기로 치환될 수 있다. 알콕시기의 예로는 (C1-C6)알콕시기, 예컨대 -O-메틸, -O-에틸, -O-프로필, -O-이소프로필, -O-2-메틸-1-프로필, -O―2-메틸-2-프로필, -O―2-메틸-1-뷰틸, -O-3-메틸-1-뷰틸, -O-2-메틸-3-뷰틸, -O-2,2-디메틸-1-프로필, -O―2-메틸-1-펜틸, 3-O-메틸-1-펜틸, -O-4-메틸-1-펜틸, -O-2-메틸-2-펜틸, -O-3-메틸-2-펜틸, -O-4-메틸-2-펜틸, -O-2,2-디메틸-1-뷰틸, -O-3,3-디메틸-뷰틸, -O-2-에틸-1-뷰틸, -O-뷰틸, -O-이소뷰틸, -O-t-뷰틸, -O-펜틸, -O-이소펜틸, -O-네오펜틸 및 -O-헥실을 포함하나, 이에 제한되지 않는다.The term 'alkoxy' refers to an alkyl group linked to another group through an oxygen atom (ie, -O-alkyl). Alkoxy groups may be unsubstituted or substituted with one or more suitable substituents. Examples of the alkoxy group include a (C1-C6)alkoxy group such as -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-2-methyl-1-propyl, -O-2 -Methyl-2-propyl, -O-2-methyl-1-butyl, -O-3-methyl-1-butyl, -O-2-methyl-3-butyl, -O-2,2-dimethyl-1 -Propyl, -O-2-methyl-1-pentyl, 3-O-methyl-1-pentyl, -O-4-methyl-1-pentyl, -O-2-methyl-2-pentyl, -O-3 -Methyl-2-pentyl, -O-4-methyl-2-pentyl, -O-2,2-dimethyl-1-butyl, -O-3,3-dimethyl-butyl, -O-2-ethyl-1 -butyl, -O-butyl, -O-isobutyl, -O-t-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl and -O-hexyl.

용어 '페녹시'는 산소 원자를 통해 다른 기에 연결된 페닐기 (즉, -O-아릴)를 의미한다. 페녹시기는 치환되지 않거나 하나 이상의 할로젠; 알킬기; 아릴기 및 헤테로 아릴기로 치환될 수 있으나 이에 한정되지 않는다. The term 'phenoxy' refers to a phenyl group linked to another group through an oxygen atom (ie, -O-aryl). The phenoxy group is unsubstituted or one or more halogen; an alkyl group; It may be substituted with an aryl group and a hetero aryl group, but is not limited thereto.

용어 '아미노기'는 질소 원자를 통해 다른 기에 연결된 알킬기 (즉, -NH- 또는 -N-알킬)를 의미한다. 아미노기는 치환되지 않거나 하나 이상의 적절한 치환기로 치환될 수 있다. 아미노기의 예로는 (C1-C6)아미노기, 예컨대 -NH-메틸, -NH-에틸, -NH-프로필, -NH-이소프로필, -NH-2-메틸-1-프로필, -NH―2-메틸-2-프로필, -NH―2-메틸-1-뷰틸, -NH-3-메틸-1-뷰틸, -NH-2-메틸-3-뷰틸, -NH-2,2-디메틸-1-프로필, -NH―2-메틸-1-펜틸, 3-NH-메틸-1-펜틸, -NH-4-메틸-1-펜틸, -NH-2-메틸-2-펜틸, -NH-3-메틸-2-펜틸, -NH-4-메틸-2-펜틸, -NH-2,2-디메틸-1-뷰틸, -NH-3,3-디메틸-뷰틸, -NH-2-에틸-1-뷰틸, -NH-뷰틸, -NH-이소뷰틸, -NH-t-뷰틸, -NH-펜틸, -NH-이소펜틸, -NH-네오펜틸, -NH-헥실, -N,N-디메틸, -N-메틸-N-에틸, -N-메틸-N-프로필, -N-메틸-이소프로필, -N-메틸-N-뷰틸, -N-메틸-N-이소뷰틸, -N-메틸-N-펜틸, -N-메틸-N-이소펜틸, N-메틸-N-헥실, N-메틸-N-이소헥실, -N,N-디에틸, -N-에틸-N-프로필, -N-에틸-N-이소프로필, -N-에틸-N-뷰틸, -N-에틸-N-이소뷰틸, -N-에틸-N-펜틸, -N-에틸-N-이소펜틸, -N-에틸-N-헥실, , -N-에틸-N-이소헥실, -N,N-디프로필, -N-프로필-N-이소프로필, -N-프로필-N-뷰틸, -N-프로필-N-이소뷰틸, -N-프로필-N-펜틸, -N-프로필-N-이소펜틸, -N-프로필-N-헥실, -N-프로필-N-이소헥실, -N,N-디뷰틸, -N-뷰틸-N-이소뷰틸, -N-뷰틸-N-펜틸, -N-뷰틸-N-이소펜틸, -N-뷰틸-N-헥실, -N-뷰틸-N-이소헥실, -N,N-디펜틸, -N-펜틸-N-헥실, -N-펜틸-N-이소헥실, -N,N-디헥실을 포함하나, 이에 제한되지 않는다. The term 'amino group' refers to an alkyl group linked to another group through a nitrogen atom (ie -NH- or -N-alkyl). The amino group may be unsubstituted or substituted with one or more suitable substituents. Examples of the amino group include a (C1-C6)amino group such as -NH-methyl, -NH-ethyl, -NH-propyl, -NH-isopropyl, -NH-2-methyl-1-propyl, -NH-2-methyl -2-propyl, -NH-2-methyl-1-butyl, -NH-3-methyl-1-butyl, -NH-2-methyl-3-butyl, -NH-2,2-dimethyl-1-propyl , -NH-2-methyl-1-pentyl, 3-NH-methyl-1-pentyl, -NH-4-methyl-1-pentyl, -NH-2-methyl-2-pentyl, -NH-3-methyl -2-pentyl, -NH-4-methyl-2-pentyl, -NH-2,2-dimethyl-1-butyl, -NH-3,3-dimethyl-butyl, -NH-2-ethyl-1-butyl , -NH-butyl, -NH-isobutyl, -NH-t-butyl, -NH-pentyl, -NH-isopentyl, -NH-neopentyl, -NH-hexyl, -N,N-dimethyl, -N -Methyl-N-ethyl, -N-methyl-N-propyl, -N-methyl-isopropyl, -N-methyl-N-butyl, -N-methyl-N-isobutyl, -N-methyl-N- pentyl, -N-methyl-N-isopentyl, N-methyl-N-hexyl, N-methyl-N-isohexyl, -N,N-diethyl, -N-ethyl-N-propyl, -N-ethyl -N-isopropyl, -N-ethyl-N-butyl, -N-ethyl-N-isobutyl, -N-ethyl-N-pentyl, -N-ethyl-N-isopentyl, -N-ethyl-N -Hexyl, -N-ethyl-N-isohexyl, -N,N-dipropyl, -N-propyl-N-isopropyl, -N-propyl-N-butyl, -N-propyl-N-isobutyl , -N-propyl-N-pentyl, -N-propyl-N-isopentyl, -N-propyl-N-hexyl, -N-propyl-N-isohexyl, -N,N-dibutyl, -N- Butyl-N-isobutyl, -N-butyl-N-pentyl, -N-butyl-N-isopentyl, -N-butyl-N-hexyl, -N-butyl-N-isohexyl, -N,N- dipentyl, -N-pentyl-N-hexyl, -N-pentyl-N-isohexyl, -N,N-dihexyl.

용어 '할로겐기'는 불소, 염소, 브롬 또는 요오드를 의미한다.The term 'halogen group' means fluorine, chlorine, bromine or iodine.

용어 '헤테로사이클기'는 다른 언급이 없으면, N, O, 및 S로 구성된 군으로부터 선택된 1 종 이상의 헤테로 원자를 포함하는 헤테로방향족 화합물을 의미한다. 바람직하게는, 상기 헤테로사이클릴기는 피롤리딘, 퓨란기, 몰폴린기, 피페라진 및 피페리딘기를 포함할 수 있고, 더욱 바람직하게는 피롤리딘기, 피페리딘기, 피페라진기, 및 몰포린기를 포함할수 있으나 이에 한정되지 않는다. The term 'heterocycle group' refers to a heteroaromatic compound including at least one hetero atom selected from the group consisting of N, O, and S, unless otherwise stated. Preferably, the heterocyclyl group may include a pyrrolidine group, a furan group, a morpholine group, a piperazine and a piperidine group, more preferably a pyrrolidine group, a piperidine group, a piperazine group, and a mol It may include a porine group, but is not limited thereto.

용어 '헤테로아릴기'은 다른 언급이 없으면, N, O, 및 S로 구성된 군으로부터 선택된 1 종 이상의 헤테로 원자를 포함하는 헤테로방향족 화합물을 의미한다. 바람직하게는 상기 헤테로아릴기는, 피리딘기, 피라진기, 피리미딘기, 피리다진기, 피라졸기, 이미다졸기, 트리아졸기, 인돌기, 옥사디아졸기, 싸이아디아졸기, 퀴놀린, 이소퀴놀린기, 아이속사졸기, 옥사졸기, 싸이아졸기롤기, 피롤기를 포함할 수 있으나 이에 한정되지 않는다.The term 'heteroaryl group' refers to a heteroaromatic compound including at least one hetero atom selected from the group consisting of N, O, and S, unless otherwise stated. Preferably, the heteroaryl group is a pyridine group, a pyrazine group, a pyrimidine group, a pyridazine group, a pyrazole group, an imidazole group, a triazole group, an indole group, an oxadiazole group, a thiadiazole group, a quinoline, an isoquinoline group, It may include, but is not limited to, an isoxazole group, an oxazole group, a thiazole group, and a pyrrole group.

본 발명의 일측면에서, R1는 수소; 또는 할로겐기; 또는 C1-C3 알킬기; 이고, R2는 수소; C1-C3 알킬기; 또는 아미노기(-NR8R9); 이며, R3는 수소; C1-C3 알킬기; 설피드기(-SR8); 또는 술폰기(-S(O)2R8); 이고, R4는 수소; 또는 C1-C3 알킬기;이며, R5 는 수소; 히드록시기; 할로겐기; C1-C3 알킬기; 또는 C1-C6 알콕시기; 이고, R6 는 수소; 할로겐기; 또는 C1-C3 알킬기; 이며, R7는 수소; 또는 C1-C3 알킬기;인, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, R 1 Is hydrogen; or a halogen group; or a C 1 -C 3 alkyl group; and R 2 is hydrogen; C 1 -C 3 alkyl group; or an amino group (-NR 8 R 9 ); and R 3 is hydrogen; C 1 -C 3 alkyl group; sulfide group (-SR 8 ); or a sulfone group (—S(O) 2 R 8 ); and R 4 is hydrogen; Or a C 1 -C 3 alkyl group; and R 5 is hydrogen; hydroxyl group; halogen group; C 1 -C 3 alkyl group; or a C 1 -C 6 alkoxy group; and R 6 is hydrogen; halogen group; or a C 1 -C 3 alkyl group; and R 7 is hydrogen; or a C 1 -C 3 alkyl group; phosphorus, a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

본 발명의 일측면에서, 상기 A는 아미노기(-NR8R9); C3-C10 헤테로아릴기; C3-C10 헤테로사이클릴기; 또는 A는 R6과 연결된 탄소 원자와 함께 N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, 또는 SO2 중 적어도 1종을 임의로 포함할 수 있고, 수소, C1-C13 알킬기, C6-C10 아릴기, C3-C10 헤테로아릴기, 히드록실기, 할라이드기 및 시아노기 중 적어도 1종으로 임의로 치환될 수 있는 3 내지 7원(membered) 포화 고리를 형성하고; 상기 B는 C6-C10 아릴기; 또는 C3-C10 헤테로아릴기; 인, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, A is an amino group (-NR 8 R 9 ); C 3 -C 10 heteroaryl group; C 3 -C 10 heterocyclyl group; or A together with the carbon atom connected to R 6 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 -, or SO 2 , which may optionally include at least one of hydrogen, a C 1 -C 13 alkyl group, a C 6 -C 10 aryl group, a C 3 -C 10 heteroaryl group, a hydroxyl group, a halide group, and a cyano group. form a 3 to 7 membered saturated ring which may be optionally substituted with at least one; The B is a C 6 -C 10 aryl group; or a C 3 -C 10 heteroaryl group; Provided is a compound selected from phosphorus, a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

본 발명의 일측면에서, R1는 할로겐기; 이고, R2는 수소; 또는 아미노기(-NR8R9); 이며, R3는 수소; C1-C3 알킬기; 또는 술폰기(-S(O)2R8); 이고, R4는 수소; 이며, R5 는 수소; 할로겐기; 또는 C1-C6 알콕시기; 이고, R6 는 수소; 할로겐기; 또는 C1-C3 알킬기; 이며, R7는 수소; 이며, A는 피페라진, 피페리딘, 모르포린, 피롤리딘 및 이미다졸로 이루어준 군에서 선택된 어느 하나이며, B는 벤젠, 사이아졸, 사이오펜, 피라졸, 벤조사이오펜, 피리다진, 피라진, 이미다졸, 옥사디아졸, 트리아졸, 퓨란, 피리미딘, 옥사졸, 피롤, 피리딘, 옥사디아졸, 트리아진, 시아디아졸, 이속사졸, 및 테트라졸로 이루어진 군에서 선택된 어느 하나인, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, R 1 Is a halogen group; and R 2 is hydrogen; or an amino group (-NR 8 R 9 ); and R 3 is hydrogen; C 1 -C 3 alkyl group; or a sulfone group (—S(O) 2 R 8 ); and R 4 is hydrogen; and R 5 is hydrogen; halogen group; or a C 1 -C 6 alkoxy group; and R 6 is hydrogen; halogen group; or a C 1 -C 3 alkyl group; and R 7 is hydrogen; A is any one selected from the group consisting of piperazine, piperidine, morpholine, pyrrolidine and imidazole, B is benzene, cyazole, thiophene, pyrazole, benzothiophene, pyridazine, Any one selected from the group consisting of pyrazine, imidazole, oxadiazole, triazole, furan, pyrimidine, oxazole, pyrrole, pyridine, oxadiazole, triazine, cyadiazole, isoxazole, and tetrazole, the formula Provided is a compound selected from the pyrimidine derivative compound represented by 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

본 발명의 일측면에서, R1는 Cl 또는 Br 이고, R2는 수소 또는 -NH2 이며, R3는 수소; -CH3; 또는 -S(O)2CH3; 이고, R4는 수소; 이며, R5 는 수소; Cl; Br; -OCH3; -OCH2CH3 또는 -OCH2CF3 이고, R6 는 수소; Cl; Br; F; -CH3; 또는 -CF3; 이며, R7는 수소; 이며, A는 피페라진, 피페리딘, 모르포린 및 피롤리딘로 이루어진 군에서 선택된 어느 하나이며, B는 벤젠, 벤조사이아졸, 퀴놀린 및 퀴녹살린으로 이루어진 군에서 선택된 어느 하나인, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, R 1 is Cl or Br, R 2 is hydrogen or —NH 2 , R 3 is hydrogen; -CH 3 ; or —S(O) 2 CH 3 ; and R 4 is hydrogen; and R 5 is hydrogen; Cl; Br; -OCH 3 ; -OCH 2 CH 3 or -OCH 2 CF 3 and R 6 is hydrogen; Cl; Br; F; -CH 3 ; or -CF 3 ; and R 7 is hydrogen; wherein A is any one selected from the group consisting of piperazine, piperidine, morpholine and pyrrolidine, and B is any one selected from the group consisting of benzene, benzocyazole, quinoline and quinoxaline, Formula 10, Provided is a compound selected from the pyrimidine derivative compound represented by 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

본 발명의 일측면에서, 상기 A는In one aspect of the present invention, A is

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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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및
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중에서 선택된 어느 하나인, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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,
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and
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Provided is a compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, which is any one selected from among, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

본 발명의 일측면에서, 상기 B는In one aspect of the present invention, B is

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,
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,
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,
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,
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,
Figure pat00047
,
Figure pat00048
,
Figure pat00049
,
Figure pat00050
,
Figure pat00051
,
Figure pat00052
,
Figure pat00053
,
Figure pat00054
,
Figure pat00055
,
Figure pat00056
,
Figure pat00057
,
Figure pat00058
,
Figure pat00059
,
Figure pat00060
,
Figure pat00061
,
Figure pat00062
,
Figure pat00063
,
Figure pat00064
,
Figure pat00065
,
Figure pat00066
,
Figure pat00067
,
Figure pat00068
,
Figure pat00069
,
Figure pat00070
및
Figure pat00071
중에서 선택된 어느 하나인, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.
Figure pat00036
,
Figure pat00037
,
Figure pat00038
,
Figure pat00039
,
Figure pat00040
,
Figure pat00041
,
Figure pat00042
,
Figure pat00043
,
Figure pat00044
,
Figure pat00045
,
Figure pat00046
,
Figure pat00047
,
Figure pat00048
,
Figure pat00049
,
Figure pat00050
,
Figure pat00051
,
Figure pat00052
,
Figure pat00053
,
Figure pat00054
,
Figure pat00055
,
Figure pat00056
,
Figure pat00057
,
Figure pat00058
,
Figure pat00059
,
Figure pat00060
,
Figure pat00061
,
Figure pat00062
,
Figure pat00063
,
Figure pat00064
,
Figure pat00065
,
Figure pat00066
,
Figure pat00067
,
Figure pat00068
,
Figure pat00069
,
Figure pat00070
and
Figure pat00071
Provided is a compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, which is any one selected from among, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

본 발명의 일측면에서, R1는 Cl 또는 Br 이고, R2는 수소 또는 -NH2 이며, R3는 수소; -CH3; 또는 -S(O)2CH3; 이고, R4는 수소; 이며, R5 는 수소; Cl; Br; -OCH3; -OCH2CH3 또는 -OCH2CF3 이고, R6 는 수소; Cl; Br; F; -CH3; 또는 -CF3; 이며, R7는 수소; 이며, A는

Figure pat00072
,
Figure pat00073
,
Figure pat00074
,
Figure pat00075
및
Figure pat00076
으로 이루어진 군에서 선택된 어느 하나이며, B는
Figure pat00077
,
Figure pat00078
,
Figure pat00079
,
Figure pat00080
,
Figure pat00081
및
Figure pat00082
으로 이루어진 군에서 선택된 어느 하나인, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, R 1 is Cl or Br, R 2 is hydrogen or —NH 2 , R 3 is hydrogen; -CH 3 ; or —S(O) 2 CH 3 ; and R 4 is hydrogen; and R 5 is hydrogen; Cl; Br; -OCH 3 ; -OCH 2 CH 3 or -OCH 2 CF 3 and R 6 is hydrogen; Cl; Br; F; -CH 3 ; or -CF 3 ; and R 7 is hydrogen; and A is
Figure pat00072
,
Figure pat00073
,
Figure pat00074
,
Figure pat00075
and
Figure pat00076
Any one selected from the group consisting of, B is
Figure pat00077
,
Figure pat00078
,
Figure pat00079
,
Figure pat00080
,
Figure pat00081
and
Figure pat00082
Provided is a compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, which is any one selected from the group consisting of, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

본 발명의 일측면에서, 상기 화합물은 하기 화합물번호 1 내지 283로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다:In one aspect of the present invention, the compound is a pyrimidine derivative compound represented by Formula 10, 11 or 12, characterized in that any one selected from the group consisting of the following compound numbers 1 to 283, a pharmaceutically acceptable A compound selected from salts, hydrates thereof and stereoisomers thereof is provided:

화합물번호 1: N-(2-((5-클로로-2-((6-(4-에틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 1: N -(2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-4-yl) amino)phenyl)methanesulfonamide;

화합물번호 2: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 2: N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 3: N-(2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 3: N -(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino )pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 4: N-(2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)-2-(2,2,2-트라이플루오로에톡시)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 4: N -(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2) ,2-trifluoroethoxy)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 5: N-(2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 5: N- (2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 6: N-(2-((5-클로로-2-((6-(1,1-다이옥시싸이오몰폴리노)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 6: N -(2-((5-chloro-2-((6-(1,1-dioxythiomorpholino)-2-methoxypyridin-3-yl)amino)pyrimidine-4 -yl)amino)phenyl)methanesulfonamide;

화합물번호 7: N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메설폰아마이드;Compound No. 7: N -(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)mesulphonamide;

화합물번호 8: N-(5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)-N-(2-(메틸설폰아마이도)페닐)메탄설폰아마이드;Compound No. 8: N- (5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine-4 -yl) -N- (2-(methylsulfonamido)phenyl)methanesulfonamide;

화합물번호 9: N-(5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)-N-(2-(메틸설폰아마이도)페닐)메탄설폰아마이드;Compound No. 9: N -(5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)-N- ( 2-(methylsulfonamido)phenyl)methanesulfonamide;

화합물번호 10: N-(5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)-N-(2-(메틸설폰아마이도)페닐)메탄설폰아마이드;Compound No. 10: N- (5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) amino)pyrimidin-4-yl)-N- ( 2-(methylsulfonamido)phenyl)methanesulfonamide;

화합물번호 11: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리디니-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)-N-메틸설폰아마이드;Compound No. 11: N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidini-1-yl)piperidini-1-yl) yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl) -N -methylsulfonamide;

화합물번호 12: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드;Compound No. 12: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide;

화합물번호 13: N-(2-((5-클로로-2-((6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드; Compound No. 13: N- (2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methane sulfonamides;

화합물번호 14: N-(2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-yl)피페리딘-1-일)피리딘-3-일)아마이도)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 14: N- (2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amai Figure) pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 15: N-(2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 15: N- (2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 16: N-(2-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 16: N- (2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 17: N-(2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 17: N- (2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 18: N-(2-((5-클로로-2-((6-(4-(2-하이드록시메틸)피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 18: N- (2-((5-chloro-2-((6-(4-(2-hydroxymethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino )pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 19: N-(2-((2-((6-(4-아세틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)-5-클로로피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 19: N- (2-((2-((6-(4-acetylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-5-chloropyrimidine-4- yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 20: N-(2-((5-클로로-2-((2-메톡시-6-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 20: N- (2-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 21: N-(2-((5-클로로-((6-(4-하이드록시피페리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 21: N- (2-((5-chloro-((6-(4-hydroxypiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4- yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 22: N-(2-((5-클로로-2-((2-메톡시-6-(4-(옥세탄-3-일)피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 22: N- (2-((5-chloro-2-((2-methoxy-6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl) amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 23: N-(2-((5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 23: N- (2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino) pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 24: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드; Compound No. 24: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide;

화합물번호 25: N-(2-((5-브로모-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 25: N- (2-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 26: N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 26: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 27: N-(2-((5-브로모-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 27: N- (2-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 28: N-(2-((5-브로모-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 28: N- (2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 29: N-(2-((5-브로모-2-((2-메톡시-6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 29: N- (2-((5-bromo-2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)-5- fluorophenyl)methanesulfonamide;

화합물번호 30: N-(2-((5-브로모-2-((6-(4-사이클로프로필피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 30: N- (2-((5-bromo-2-((6-(4-cyclopropylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine- 4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 31: N-(2-((5-브로모-2-((2-메톡시-6-(4-몰폴리노피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 31: N- (2-((5-bromo-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidine -4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 32: N-(2-((5-브로모-2-((6-(4,4-다이메틸피페리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드 ;Compound No. 32: N- (2-((5-bromo-2-((6-(4,4-dimethylpiperidin-1-yl)-2-methoxypyridin-3-yl)amino) pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 33: N-(2-((5-브로모-2-((6-(4,4-다이플루오로피페리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 33: N- (2-((5-bromo-2-((6-(4,4-difluoropiperidin-1-yl)-2-methoxypyridin-3-yl)amino) )pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 34: N-(2-((5-브로모-2-((2-클로로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)-5-(트라이플루오로메틸)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 34: N- (2-((5-bromo-2-((2-chloro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5) -(trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 35: N-(2-((5-브로모-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드 ;Compound No. 35: N- (2-((5-bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl) amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 36: N-(2-((5-브로모-2-((2-메톡시-6-(4-(1-메틸피페리딘-4-일)피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 36: N- (2-((5-bromo-2-((2-methoxy-6-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 37: N-(2-((5-브로모-2-((2-메톡시-6-(4-(1-메틸-4-일)피페라진-1-일)-5-(트라이플루오로메틸)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 37: N -(2-((5-bromo-2-((2-methoxy-6-(4-(1-methyl-4-yl)piperazin-1-yl)-5-( trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 38: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 38: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 39: N-(2-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 39: N- (2-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 40: N-(2-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 40: N- (2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-) 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 41: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-((1-메틸-1H-피라졸-5-일)아미노)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 41: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1H-pyrazol-5-yl)amino) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 42: N-(2-((5-브로모-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 42: N- (2-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy -5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 43: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페리딘-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 43: N- (2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperidin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 44: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 44: N- (2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 45: N-(2-((5-브로모-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)플루오로페닐)메탄설폰아마이드; Compound No. 45: N- (2-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)fluorophenyl)methanesulfonamide;

화합물번호 46: 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민;Compound No. 46: 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine;

화합물번호 47: 5-클로로-N 2-(2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민; Compound No. 47: 5-chloro- N 2 -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(2- (trifluoromethyl)phenyl)pyrimidine-2,4-diamine;

화합물번호 48: 5-클로로-N 2-(4-(4-에틸피페라진-1-일)페닐)-N 4-(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민; Compound No. 48: 5-chloro- N 2 -(4-(4-ethylpiperazin-1-yl)phenyl) -N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-dia min;

화합물번호 49: 5-클로로-N 2-(6-몰폴리노피리딘-3-일)-N 4-(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민;Compound No. 49: 5-Chloro- N 2 -(6-morpholinopyridin-3-yl) -N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine;

화합물번호 50: 2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드; Compound No. 50: 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino) -N -methylbenzenesulfonamide;

화합물번호 51: 2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;Compound No. 51: 2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri midin-4-yl)amino) -N -methylbenzenesulfonamide;

화합물번호 52: 2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;Compound No. 52: 2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidine -4-yl)amino) -N -methylbenzenesulfonamide;

화합물번호 53: 2-((5-클로로-2-((6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드; Compound No. 53: 2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino) -N -methylbenzenesulfonamide;

화합물번호 54: 2-((5-클로로-2-((6-(4-에틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;Compound No. 54: 2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino ) -N -methylbenzenesulfonamide;

화합물번호 55: 2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;Compound No. 55: 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) )amino)pyrimidin-4-yl)amino) -N -methylbenzenesulfonamide;

화합물번호 56: 2-((5-클로로-2-((6-(4-(2-하이드록시에틸)피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;Compound No. 56: 2-((5-chloro-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine -4-yl)amino) -N -methylbenzenesulfonamide;

화합물번호 57: 2-((5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;Compound No. 57: 2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine- 4-yl)amino) -N -methylbenzenesulfonamide;

화합물번호 58: 2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;Compound No. 58: 2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine -3-yl)amino)pyrimidin-4-yl)amino) -N -methylbenzenesulfonamide;

화합물번호 59: 2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-사이클로프로필벤젠설폰아마이드;Compound No. 59: 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino) -N -cyclopropylbenzenesulfonamide;

화합물번호 60: 2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-사이클로프로필벤젠설폰아마이드;Compound No. 60: 2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri midin-4-yl)amino) -N -cyclopropylbenzenesulfonamide;

화합물번호 61: 2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페라딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-사이클로프로필벤젠설폰아마이드;Compound No. 61: 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperadin-1-yl)pyridin-3-yl) )amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide;

화합물번호 62: 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민;Compound No. 62: 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine;

화합물번호 63: 5-클로로-N 2-(3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민;Compound No. 63: 5-chloro- N 2 -(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(2- ((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine;

화합물번호 64: 5-클로로-N 2-(2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)-N 4-(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민;Compound No. 64: 5-chloro- N 2 -(2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) -N 4 -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine;

화합물번호 65: N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;Compound No. 65: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 66: N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드; Compound No. 66: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 67: N-(4-클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드; Compound No. 67: N- (4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 68: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;Compound No. 68: N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 69: N-(2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;Compound No. 69: N- (2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 70: N-(2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;Compound No. 70: N- (2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 71: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드; Compound No. 71: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 72: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;Compound No. 72: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 73: N-(4,5-다이클로로-2-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;Compound No. 73: N- (4,5-dichloro-2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 74: N-(4,5-다이클로로-2-((5-클로로-2-((6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;Compound No. 74: N- (4,5-dichloro-2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl) acetamide;

화합물번호 75: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드; Compound No. 75: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 76: N-(4,5-다이클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;Compound No. 76: N- (4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 77: N-(4,5-다이클로로-2-((5-클로로-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;Compound No. 77: N- (4,5-dichloro-2-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;

화합물번호 78: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)-N-메틸아세타마이드;Compound No. 78: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl) -N -methylacetamide;

화합물번호 79: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)(메틸)아미노)페닐)-N-메틸아세타마이드;Compound No. 79: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl) -N -methylacetamide;

화합물번호 80: N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 80: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 81: N-(4-클로로-2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노페닐)메탄설폰아마이드;Compound No. 81: N- (4-chloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide;

화합물번호 82: N-(4-클로로-2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; Compound No. 82: N- (4-chloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 83: N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 83: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 84: N-(4-클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 84: N- (4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 85: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노-4-클로로페닐)메탄설폰아마이드; Compound No. 85: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino-4-chlorophenyl)methanesulfonamide;

화합물번호 86: N-(2-((5-브로모-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 86: N- (2-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 87: N-(2-((5-브로모-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드; Compound No. 87: N- (2-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 88: N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 88: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 89: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설포닐아마이드; Compound No. 89: N -(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonylamide;

화합물번호 90: N-(2-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 90: N- (2-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 91: N-(2-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 91: N- (2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-) 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 92: N-(2-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드; Compound No. 92: N- (2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 93: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드; Compound No. 93: N -(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 94: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 94: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 95: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 95: N -(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 96: N-(2-((5-브로모-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 96: N- (2-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1) -yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 97: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드; Compound No. 97: N -(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 98: N-(2-((5-브로모-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 98: N- (2-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 99: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 99: N -(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 100: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐메탄설폰아마이드; Compound No. 100: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenylmethanesulfonamide;

화합물번호 101: N-(4,5-다이클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 101: N- (4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 102: N-(4,5-다이클로로-2-((5-클로로-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아민노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 102: N- (4,5-dichloro-2-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) quinolin-6-yl)amineno)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 103: N-(4,5-다이클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노페닐)메탄설폰아마이드;Compound No. 103: N- (4,5-dichloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide;

화합물번호 104: N-(4,5-다이클로로-2-((5-클로로-2-((4-(4-((2-(다이메틸아미노)에틸)(메틸)아미노)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 104: N- (4,5-dichloro-2-((5-chloro-2-((4-(4-((2-(dimethylamino)ethyl)(methyl)amino)piperidine -1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 105: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(메틸(3-(4-메틸피페라진-1-일)프로필)아미노)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설포나마이드;Compound No. 105: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(methyl(3-(4-methylpiperazine-1) -yl)propyl)amino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 106: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드; Compound No. 106: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;

화합물번호 107: N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드;Compound No. 107: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;

화합물번호 108: N-(2-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메톡시-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드;Compound No. 108: N- (2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methoxy-1-yl)piperidine-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;

화합물번호 109: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드; Compound No. 109: N- (2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;

화합물번호 110: N-(5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드; Compound No. 110: N- (5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)-N- ( 4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

화합물번호 111: N-(5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드;Compound No. 111: N- (5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) amino)pyrimidin-4-yl)-N- ( 4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

화합물번호 112: N-(5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드; Compound No. 112: N- (5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine -4-yl) -N- (4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

화합물번호 113: N-(5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드; Compound No. 113: N- (5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) amino)pyrimidin-4-yl)-N- ( 4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

화합물번호 114: N-(5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드;Compound No. 114: N- (5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)-N- ( 4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;

화합물번호 115: N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드;Compound No. 115: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;

화합물번호 116: N-(6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드;Compound No. 116: N -(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;

화합물번호 117: N-(6-((5-클로로-2-((2-메톡시-6-(4-몰폴리노피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드; Compound No. 117: N- (6-((5-chloro-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidine- 4-yl)amino)quinolin-5-yl)methanesulfonamide;

화합물번호 118: N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메톡시피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드; Compound No. 118: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methoxypiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;

화합물번호 119: N-(6-((5-클로로-2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드; Compound No. 119: N- (6-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino) quinolin-5-yl)methanesulfonamide;

화합물번호 120: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)메탄설폰아마이드;Compound No. 120: N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide;

화합물번호 121: N-(2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)(메틸)아미노)페닐)메탄설폰아마이드; Compound No. 121: N -(2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide;

화합물번호 122: (6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드; Compound No. 122: (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 123: (6-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;Compound No. 123: (6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3- yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 124: (6-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;Compound No. 124: (6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3- yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 125: (6-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드; Compound No. 125: (6-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 126: (6-((5-클로로-2-((2-메톡시-6-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;Compound No. 126: (6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3- yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 127: (6-((5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;Compound No. 127: (6-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 128: (6-((5-클로로-2-((2-메톡시-6-(피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;Compound No. 128: (6-((5-chloro-2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoc salin-5-yl)dimethylphosphine oxide;

화합물번호 129: 4-(5-((5-클로로-4-((5-(다이메틸포스포릴)퀴녹살린-6-일)아미노)피리미딘-2-일)아미노)-6-메톡시피리딘-2-일)싸이오몰폴린 1,1-다이옥사이드;Compound No. 129: 4-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-6-methoxy pyridin-2-yl)thiomorpholine 1,1-dioxide;

화합물번호 130: (6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드; Compound No. 130: (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 131: N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드; Compound No. 131: N -(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

화합물번호 132: N-(6-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드; Compound No. 132: N- (6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

화합물번호 133: N-(6-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드;Compound No. 133: N- (6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

화합물번호 134: N-(6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드; Compound No. 134: N- (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

화합물번호 135: N-(6-((5-클로로-2-((2-메톡시-6-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드;Compound No. 135: N- (6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;

화합물번호 136: N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-y일)아미노)퀴녹살린-5-일)메탄설폰아마이드;Compound No. 136: N -(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yyl)amino)quinoxalin-5-yl)methanesulfonamide;

화합물번호 137: N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-(트라이플루오로메틸)페닐)메탄설폰아마이드;Compound No. 137: N- (2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide;

화합물번호 138: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-(트라이플루오로메틸)페닐)메탄설폰아마이드;Compound No. 138: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide;

화합물번호 139: N-(2-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-(트라이플루오로메틸)페닐)메탄설폰아마이드;Compound No. 139: N -(2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide;

화합물번호 140: N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 140: N -(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 141: N-(2-((6-아미노-5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 141: N- (2-((6-amino-5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperid) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 142: ((2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸- λ 6-설파논; Compound No. 142: ((2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl- λ 6 -sulfanone;

화합물번호 143: ((2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸- λ 6-설파논;Compound No. 143: ((2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl- λ 6 -sulfanone;

화합물번호 144: ((2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸-λ 6-설파논;Compound No. 144: ((2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl- λ 6 -sulfanone;

화합물번호 145: N-(2-((5-브로모-2-((2-메톡시-6-(1-메틸아제판-4-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 145: N- (2-((5-bromo-2-((2-methoxy-6-(1-methylazepan-4-yl)pyridin-3-yl)amino)pyrimidine-4 -yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 146: N-(2-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 146: N- (2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 147: N-(2-((5-브로모-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 147: N- (2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 148: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 148: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperi) diin]-1′-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 149: N-(2-((5-브로모-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 149: N- (2-((5-bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 150: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 150: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperi) diin]-1′-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 151: N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드; Compound No. 151: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperid) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 152: N-(4-클로로-2-((6-클로로-3-(( -2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-1,2,4-트리아진-5-일)아미노)페닐)메탄설폰아마이드;Compound No. 152: N -(4-chloro-2-((6-chloro-3-((-2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)pi) peridin-1-yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)phenyl)methanesulfonamide;

화합물번호 153 : (4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)다이메틸포스핀 옥사이드;Compound No. 153: (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;

화합물번호 154 : (4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)다이메틸포스핀 옥사이드;Compound No. 154: (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;

화합물번호 155 : N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드;Compound No. 155: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide;

화합물번호 156 : N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드;Compound No. 156: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide;

화합물번호 157 : N-(4-클로로-2-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 157: N- (4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperi) din-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 158 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 158: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 159 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 159: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 159 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 159: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 160 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-아이소프로필페닐)메탄설폰아마이드;Compound No. 160: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide;

화합물번호 161 : N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-아이소프로필페닐)메탄설폰아마이드;Compound No. 161: N- (2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide;

화합물번호 162 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 162: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepane-1-) yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 163 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 163: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1) -yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 164 : N-(2-((6-클로로-3-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-1,2,4-트리아진-5-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 164: N- (2-((6-chloro-3-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 165 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 165: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 166 : 5-클로로-N4-(5-클로로-2-(1H-1,2,3-트리아졸-4-일)페닐)-N2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;Compound No. 166: 5-chloro- N 4-(5-chloro-2-(1 H -1,2,3-triazol-4-yl)phenyl) -N 2-(2-methoxy-5-methyl -4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

화합물번호 167 : N-(4-클로로-2-((5-클로로-2-((1-(3-(다이메틸아미노)프로필)-1H-피라졸-4-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 167: N- (4-chloro-2-((5-chloro-2-((1-(3-(dimethylamino)propyl) -1H -pyrazol-4-yl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide;

화합물번호 168 : N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 168: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 169 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 169: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 170 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;Compound No. 170: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide;

화합물번호 171 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;Compound No. 171: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;

화합물번호 172 : N-(6-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 172: N- (6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperid) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 173 : N-(6-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 173: N- (6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 174 : N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 174: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 175 : N-(6-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 175: N- (6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 176 : N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 176: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 177 : N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로-5-플루오로페닐)메탄설폰아마이드;Compound No. 177: N- (2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide;

화합물번호 178 : N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로-5-플루오로페닐)메탄설폰아마이드;Compound No. 178: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide;

화합물번호 179 : N-(4-클로로-2-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;Compound No. 179: N- (4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperi) din-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide;

화합물번호 180 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;Compound No. 180: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepane-1-) yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide;

화합물번호 181 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 181: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 182 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;Compound No. 182: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;

화합물번호 183 : N-(6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드.Compound No. 183: N- (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide.

화합물번호 184 : N-(6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 184: N- (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 185 : 5-클로로-N4-(5-클로로-2-(1H-1,2,3-트라이졸-5-일)페닐)-N2-(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;Compound No. 185: 5-chloro- N 4-(5-chloro-2-( 1H -1,2,3-trizol-5-yl)phenyl) -N2- (2-chloro-5-methyl- 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

화합물번호 186 : 5-클로로-N 4-(5-클로로-2-(1H-1,2,3-트리아졸-5-일)페닐)-N 2-(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;Compound No. 186: 5-chloro- N 4 -(5-chloro-2-(1 H -1,2,3-triazol-5-yl)phenyl) -N 2 -(5-chloro-2-methoxy -4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

화합물번호 187 : 5-브로모-N 4-(5-클로로-2-(1H-1,2,3-트리아졸-5-일)페닐)-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;Compound No. 187: 5-bromo- N 4 -(5-chloro-2-(1 H -1,2,3-triazol-5-yl)phenyl) -N 2 -(2-methoxy-5- methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

화합물번호 188 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 188: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 189 : N-(6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 189: N- (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 190 : (6-((5-클로로-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;Compound No. 190: (6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 191 : N-(2-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;Compound No. 191: N- (2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;

화합물번호 192 : (6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드.Compound No. 192: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide.

화합물번호 193 : (6-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;Compound No. 193: (6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 194 : (6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;Compound No. 194: (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;

화합물번호 195 : 5-브로모-N 4-(5-클로로-2-(1H-1,2,3-트리아졸-5-일)페닐)-N 2-(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;Compound No. 195: 5-bromo- N 4 -(5-chloro-2-(1 H -1,2,3-triazol-5-yl)phenyl) -N 2 -(5-chloro-2-methyl oxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;

화합물번호 196 : N-(6-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 196: N- (6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 197 : N-(6-((5-클로로-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 197: N- (6-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl) )-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 198 : N-(4-클로로-2-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;Compound No. 198: N- (4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;

화합물번호 199 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 199: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 200 : N-(2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 200: N- (2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 201 : N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드.Compound No. 201: N- (2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide.

화합물번호 202 : N-(2-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 202: N- (2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 203 : N-(2-((5-클로로-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 203: N- (2-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 204 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 204: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 205 : N-(6-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 205: N- (6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 206 : N-(6-((5-클로로-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 206: N- (6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 207 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 207: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 208 : N-(6-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 208: N- (6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 209 : N-(6-((5-클로로-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 209: N- (6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 210 : N-(6-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 210: N- (6-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 211 : N-(6-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 211: N- (6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-) 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 212 : N-(6-((5-브로모-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 212: N- (6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy -5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 213 : N-(6-((5-브로모-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 213: N- (6-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1) -yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 214 : N-(6-((5-브로모-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 214: N- (6-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 215 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 215: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 216 : N-(6-((5-브로모-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 216: N- (6-((5-bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 217 : N-(6-((5-브로모-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 217: N- (6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 218 : N-(6-((5-클로로-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 218: N- (6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 219 : N-(6-((5-클로로-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 219: N- (6-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl) )-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 220 : N-(6-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 220: N- (6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 221 : N-(6-((5-클로로-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 221: N- (6-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 222 : N-(6-((5-클로로-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 222: N- (6-((5-chloro-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 223 : N-(6-((5-클로로-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 223: N- (6-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 224 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-((1-메틸-1H-피라졸-5-일)아미노)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 224: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1 H -pyrazol-5-yl)amino) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 225 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-(트라이플루오로메틸)피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 225: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)pi) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 226 : N-(4-클로로-2-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;Compound No. 226: N- (4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide;

화합물번호 227 : N-(2-((5-브로모-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드;Compound No. 227: N- (2-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1) -yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide;

화합물번호 228 : N-(2-((5-브로모-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드;Compound No. 228: N- (2-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide;

화합물번호 229 : N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 229: N- (2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 230 : N-(2-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 230: N- (2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 231 : N-(2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 231: N- (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 232 : N-(2-((5-클로로-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 232: N- (2-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 233 : N-(2-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 233: N- (2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 234 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 234: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine) ]-1′-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 235 : N-(2-((5-클로로-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 235: N- (2-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 236 : N-(2-((5-클로로-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 236: N- (2-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl) )-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 237 : N-(2-((5-클로로-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;Compound No. 237: N- (2-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl) )-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;

화합물번호 238 : N-(6-((5-브로모-2-((2-메톡시-6-(4-메틸-1,4-다이아제판-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 238: N- (6-((5-bromo-2-((2-methoxy-6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)amino) )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 239 : N-(6-((5-브로모-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 239: N- (6-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 240 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 240: N- (6-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 241 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 241: N- (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 242 : N-(6-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 242: N- (6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 243 : N-(6-((5-브로모-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 243: N- (6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 244 : N-(6-((5-브로모-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 244: N- (6-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 245 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 245: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperi) din]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 246 : N-(6-((5-브로모-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설포닐아마이드;Compound No. 246: N- (6-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonylamide;

화합물번호 247 : N-(6-((5-브로모-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 247: N- (6-((5-bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)) amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 248 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 248: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 249 : N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 249: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 250 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 250: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 251 : N-(6-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 251: N- (6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 252 : N-(6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 252: N- (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 253 : N-(6-((5-브로모-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 253: N- (6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 254 : N-(6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 254: N- (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 255 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-(트라이플루오로메틸)피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 255: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 256 : N-(6-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 256: N- (6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 257 : N-(6-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 257: N- (6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 258 : N-(6-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 258: N- (6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -Methoxy-5-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 259 : N-(6-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 259: N- (6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 260 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)-N-메틸메탄설폰아마이드;Compound No. 260: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl) -N -methylmethanesulfonamide;

화합물번호 261 : N-(6-((5-브로모-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 261: N- (6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy) -5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 262 : N-(6-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 262: N- (6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-) 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 263 : N-(6-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 263: N- (6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 264 : N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 264: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 265 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 265: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 266 : N-(6-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 266: N- (6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 267 : N-(6-((5-클로로-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;Compound No. 267: N- (6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;

화합물번호 268 : N-(6-((5-클로로-2-((2,5-다이플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 268: N- (6-((5-chloro-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 269 : N-(5-((5-브로모-2-((2,5-다이플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-4-일)메탄설폰아마이드;Compound No. 269: N- (5-((5-bromo-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanesulfonamide;

화합물번호 270 : N-(6-((2-((5-브로모-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 270: N- (6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 271 : N-(6-((2-((5-브로모-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 271: N- (6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 272 : 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(1-메틸인돌린-6-일)피리미딘-2,4-다이아민;Compound No. 272: 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;

화합물번호 273 : 5-클로로-N 2-(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(1-메틸인돌린-6-일)피리미딘-2,4-다이아민;Compound No. 273: 5-chloro- N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;

화합물번호 274 : 5-클로로-N 2-(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(1-메틸인돌린-6-일)피리미딘-2,4-다이아민;Compound No. 274: 5-chloro- N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 - (1-methylindolin-6-yl)pyrimidine-2,4-diamine;

화합물번호 275 : 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)-N 4-(1-메틸인돌린-6-일)피리미딘-2,4-다이아민;Compound No. 275: 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl) phenyl) -N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;

화합물번호 276 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-1-메틸인돌린-5-일)메탄설폰아마이드;Compound No. 276: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide;

화합물번호 277 : 5-클로로-N 2-(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(인돌린-6-일)피리미딘-2,4-다이아민;Compound No. 277: 5-chloro- N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 - (indolin-6-yl)pyrimidine-2,4-diamine;

화합물번호 278 : 5-클로로-N 2-(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(인돌린-6-일)피리미딘-2,4-다이아민;Compound No. 278: 5-chloro- N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(indolin-6-yl)pyrimidine-2,4-diamine;

화합물번호 279 : 5-클로로-N 4-(인돌린-6-일)-N 2-(2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;Compound No. 279: 5-chloro- N 4 -(indolin-6-yl) -N 2 -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1 -yl)phenyl)pyrimidine-2,4-diamine;

화합물번호 280 : N-(6-((2-((5-브로모-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 280: N- (6-((2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 281 : N-(6-((5-브로모-2-((5-브로모-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;Compound No. 281: N- (6-((5-bromo-2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1') -yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;

화합물번호 282 : N-(6-((2-((5-브로모-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드; 및Compound No. 282: N- (6-((2-((5-bromo-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine-) 1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; and

화합물번호 283 : N-(6-((2-((5-브로모-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드.Compound No. 283: N- (6-((2-((5-bromo-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)- 2-Methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide.

본 발명의 일측면에서, 상기 약학적으로 허용 가능한 염은 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타타르산, 시트르산, 아스코빈산, 팔미트산, 말레인산, 하이드록시말레인산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 벤젠설폰산 및 톨루엔설폰산으로 구성된 군에서 선택되는 무기산 또는 유기산의 염인, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물을 제공한다.In one aspect of the present invention, the pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, but Delic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid selected from the group consisting of Provided is a compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, which is a salt of an inorganic acid or an organic acid, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.

본 발명의 다른 측면은 사익 본 발명의 일측면 중 어느 하나의 측면에 따른 화합물이 유효성분으로 포함되어 있는 암 예방, 경감 또는 치료용 약학 조성물을 제공한다. Another aspect of the present invention provides a pharmaceutical composition for preventing, alleviating or treating cancer, wherein the compound according to any one of the aspects of the present invention is included as an active ingredient.

본 발명의 다른 측면에서, 상기 암이 EGFR 돌연변이로 유발되는 것을 특징으로 하는, 암 예방, 경감 또는 치료용 약학 조성물을 제공한다.In another aspect of the present invention, it provides a pharmaceutical composition for preventing, alleviating or treating cancer, characterized in that the cancer is caused by EGFR mutation.

본 발명의 다른 측면에서, 상기 약학 조성물은 EGFR 돌연변이를 갖는 환자에 적용되는, 암 예방, 경감 또는 치료용 약학 조성물을 제공한다.In another aspect of the present invention, the pharmaceutical composition provides a pharmaceutical composition for preventing, alleviating or treating cancer, which is applied to a patient having an EGFR mutation.

본 발명의 다른 측면에서, 상기 암은 교모세포종, 삼중음성 유방암, 대장암, 폐암 및 두경부암으로 이루어진 군으로부터 선택되는 1 이상인, 암 예방, 경감 또는 치료용 약학 조성물을 제공한다.In another aspect of the present invention, the cancer is at least one selected from the group consisting of glioblastoma, triple-negative breast cancer, colorectal cancer, lung cancer and head and neck cancer, and provides a pharmaceutical composition for preventing, alleviating or treating cancer.

본 발명의 다른 측면에서, 상기 암은 폐암인, 암 예방, 경감 또는 치료용 약학 조성물을 제공한다.In another aspect of the present invention, the cancer is lung cancer, it provides a pharmaceutical composition for preventing, alleviating or treating cancer.

본 발명의 다른 측면에서, 상기 약학 조성물은 EGFR 관련 돌연변이인 엑손19결손/T790M/C797S 의 삼중 돌연변이 또는 L858R/T790M/C797S 의 삼중 돌연변이를 보유한 환자에게 투여되는 것을 특징으로 하는, 암의 예방, 경감 또는 치료용 약학 조성물을 제공한다.In another aspect of the present invention, the pharmaceutical composition is an EGFR-related mutation, exon 19 deletion / T790M / C797S triple mutation or L858R / T790M / C797S triple mutation of L858R / T790M / C797S It is characterized in that administered to a patient, prevention, alleviation of cancer Or it provides a pharmaceutical composition for treatment.

본 발명의 다른 측면에서, 상기 약학 조성물은 EGFR 관련 돌연변이인 엑손19결손/T790M 의 이중 돌연변이 또는 L858R/T790M 의 이중 돌연변이를 보유한 환자에게 투여되는 것을 특징으로 하는, 암의 예방, 경감 또는 치료용 약학 조성물을 제공한다.In another aspect of the present invention, the pharmaceutical composition is an EGFR-related mutation, exon 19 deletion / T790M double mutation or L858R / T790M double mutation, characterized in that administered to a patient carrying a, cancer prevention, alleviation or treatment pharmaceuticals A composition is provided.

본 발명의 다른 측면에서, 상기 약학 조성물은 EGFR 관련 돌연변이인 엑손19결손 돌연변이 또는 L858R 돌연변이를 보유한 환자에게 투여되는 것을 특징으로 하는, 암의 예방, 경감 또는 치료용 약학 조성물을 제공한다.In another aspect of the present invention, the pharmaceutical composition provides a pharmaceutical composition for preventing, alleviating or treating cancer, characterized in that it is administered to a patient having an exon 19 deletion mutation or L858R mutation, which is an EGFR-related mutation.

상기 약학 조성물은 마우스, 토끼, 랫트, 기니피그, 또는 햄스터와 같은 실험 동물 또는 인간을 포함한 영장류 등에 적용될 수 있으나 이에 제한되지 않으며, 바람직하게는 인간을 포함한 영장류, 더욱 바람직하게는 인간에 적용될 수 있다.The pharmaceutical composition may be applied to, but not limited to, experimental animals such as mice, rabbits, rats, guinea pigs, or hamsters, or primates including humans, preferably, primates including humans, more preferably humans.

본 명세서에서, '치료'는 증상의 경감 또는 개선, 질환의 범위의 감소, 질환 진행의 지연 또는 완화, 질환 상태의 개선, 경감 또는 안정화, 부분적 또는 완전한 회복, 생존의 연장 기타 다른 이로운 치료 결과 등을 모두 포함하는 의미로 사용될 수 있다. As used herein, 'treatment' refers to alleviation or amelioration of symptoms, reduction of the scope of disease, delay or alleviation of disease progression, improvement, alleviation or stabilization of disease state, partial or complete recovery, prolongation of survival and other beneficial therapeutic results, etc. may be used in the meaning of including all of them.

또한 본 명세서에서 암의 치료는 모든 암세포에 대한 치료를 의미하며, 암이란, 내피 세포의 혈관신생 및 이의 유사분열 (고형 종양, 종양 전이 및 양성 종양)도 포함한다. 예를 들어, 암이란 유방암, 난소암, 자궁경부암, 전립선암, 정소암, 비뇨생긱기관 암, 식도암, 후두암, 교모세포종, 위암, 피부암, 각질극세포종, 폐암, 편평세포암종, 대세포 암종, 소세포 암종, 폐선암, 골암, 결장암, 선종, 췌장암, 선암종, 갑산성암, 여포상선암, 미분화암, 유두암, 정상피종, 흑색종, 육종, 방광암, 간암 및 담즙관암, 신장암, 골수성 질환, 림프성 질환, 호지킨병, 모발세포암, 구강암, 인두(구두)암, 구순암, 설암, 소장암, 결장-직장암, 대장암, 직장암, 뇌암, 중추신경계암, 백혈병, 혈관종, 트라코마 또는 화농성 육가종을 포함할 수 있으나, 이에 제한되지 않는다.In addition, as used herein, the treatment of cancer refers to treatment of all cancer cells, and cancer includes angiogenesis of endothelial cells and mitosis (solid tumors, tumor metastases and benign tumors). For example, cancer is breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, urogenital organ cancer, esophageal cancer, laryngeal cancer, glioblastoma, gastric cancer, skin cancer, keratoacytoma, lung cancer, squamous cell carcinoma, large cell carcinoma, Small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, undifferentiated cancer, papillary cancer, seminomas, melanoma, sarcoma, bladder cancer, liver and bile duct cancer, kidney cancer, myeloid disease, lymphoid Disease, Hodgkin's disease, hair cell cancer, oral cancer, pharyngeal (oral) cancer, labial cancer, tongue cancer, small intestine cancer, colon-rectal cancer, colorectal cancer, rectal cancer, brain cancer, central nervous system cancer, leukemia, hemangioma, trachoma or sarcoidosis suppurativa may include, but is not limited thereto.

본 발명의 약학 조성물의 사용태양 및 사용방법에 따라 유효성분인 상기 화학식 10, 11 또는 12로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 또는 수화물의 함량은 당업자의 선택에 따라 적절히 조절하여 사용될 수 있다. The content of the compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient according to the mode and method of use of the pharmaceutical composition of the present invention may be appropriately adjusted according to the selection of those skilled in the art. can

일예로, 상기 약학 조성물은 상기 화학식 10, 11 또는 12로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 또는 수화물을 전체 조성물의 총 중량에 대하여 0.1 내지 10 중량％, 더욱 바람직하게는 0.5 내지 5 중량％의 양으로 포함할 수 있다.For example, the pharmaceutical composition may contain the compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt, or hydrate thereof in an amount of 0.1 to 10% by weight, more preferably 0.5 to 5% by weight, based on the total weight of the total composition. It may be included in an amount by weight %.

상기 화학식 10, 11 또는 12로 표시되는 화합물 이의 약학적으로 허용 가능한 염, 또는 수화물은 상기 약학 조성물 내에 단독으로 포함될 수 있으며, 또는 그 외 약리학적으로 허용 가능한 담체, 부형제, 희석제 또는 부성분과 함께 포함될 수도 있다. A pharmaceutically acceptable salt or hydrate thereof of the compound represented by Formula 10, 11 or 12 may be included alone in the pharmaceutical composition, or may be included together with other pharmaceutically acceptable carriers, excipients, diluents or subcomponents. may be

상기 약학적으로 허용되는 담체, 부형제 또는 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유, 덱스트린, 칼슘카보네이트, 프로필렌글리콜, 리퀴드 파라핀 및 생리식염수로 이루어진 군에서 선택된 1종 이상을 들 수 있으나, 이에 한정되는 것은 아니며 통상의 담체, 부형제 또는 희석제 모두 사용 가능하다. 또한, 상기 약학 조성물은 통상의 충진제, 증량제, 결합제, 붕해제, 항응집제, 윤활제, 습윤제, pH 조절제, 영양제, 비타민, 전해질, 알긴산 및 그의 염, 펙트산 및 그의 염, 보호성 콜로라이드, 글리세린, 향료, 유화제 또는 방부제 등을 추가로 포함할 수 있다. Examples of the pharmaceutically acceptable carrier, excipient or diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, propylhydroxybenzoate, talc, magnesium stearate and mineral oil , dextrin, calcium carbonate, propylene glycol, liquid paraffin, and at least one selected from the group consisting of physiological saline, but is not limited thereto, and all conventional carriers, excipients or diluents may be used. In addition, the pharmaceutical composition may contain conventional fillers, extenders, binders, disintegrants, anti-aggregating agents, lubricants, wetting agents, pH adjusting agents, nutrients, vitamins, electrolytes, alginic acid and salts thereof, pectic acid and salts thereof, protective colors, glycerin , a fragrance, emulsifier or preservative may be further included.

본 발명에 따른 화학식 10, 11 또는 12의 화합물 또는 이의 약학적으로 허용 가능한 염은, 암 또는 종양을 치료하기 위한 다른 항암제와 함께 병용 투여함으로써 항암제의 치료효과를 강화시킬 수 있다.The compound of Formula 10, 11 or 12 or a pharmaceutically acceptable salt thereof according to the present invention may be administered in combination with other anticancer agents for treating cancer or tumors to enhance the therapeutic effect of the anticancer agent.

상기 약학 조성물의 투여방법은 경구 또는 비경구 모두 가능하며, 일 예로는 경구, 경피, 피하, 정맥 또는 근육을 포함한 여러 경로를 통해 투여될 수 있다. 또한, 상기 조성물의 제형은 사용방법에 따라 달라질 수 있으며, 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 본 발명이 속하는 기술분야에 잘 알려진 방법을 사용하여 제형화될 수 있다. 일반적으로는, 경구 투여를 위한 고형제제에는 정제(TABLETS), 알약, 연질 또는 경질 캅셀제(CAPSULES), 환제(PILLS), 산제(POWDERS) 및 과립제(GRANULES) 등이 포함되고, 이러한 제제는 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제(SUSTESIONS), 내용액제, 유제(EMULSIONS) 및 시럽제(SYRUPS) 등이 해당되는데, 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제 예를 들면, 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구투여를 위한 형태는 크림(CREAM), 로션제(LOTIONS), 연고제(ONITMENTS), 경고제(PLASTERS), 액제(LIQUIDS AND SOULTIONS), 에어로솔제(AEROSOLS), 유동엑스제(FRUIDEXTRACTS), 엘릭서(ELIXIR), 침제(INFUSIONS), 향낭(SACHET), 패취제(PATCH) 또는 주사제(INJECTIONS) 등의 형태일 수 있으며, 주사용 제형이 될 경우 바람직하게는 등장성 수용액 또는 현탁액의 형태가 될 수 있다. The method of administering the pharmaceutical composition may be oral or parenteral. For example, it may be administered through several routes including oral, transdermal, subcutaneous, intravenous or intramuscular. In addition, the formulation of the composition may vary depending on the method of use, and is formulated using a method well known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. can be In general, solid preparations for oral administration include tablets (TABLETS), pills, soft or hard capsules (CAPSULES), pills (PILLS), powders (POWDERS), and granules (GRANULES), and such preparations include one or more An excipient, for example, may be prepared by mixing starch, calcium carbonate, sucrose or lactose, gelatin, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid formulations for oral use include suspensions (SUSTESIONS), internal solutions, emulsions (EMULSIONS), and syrups (SYRUPS). Sweetening agents, flavoring agents, preservatives, and the like may be included. Forms for parenteral administration are creams, lotions, ointments, ONITMENTS, PLASTERS, LIQUIDS AND SOULTIONS, aerosols, FRUIDEXTRACTS, and elixirs. (ELIXIR), infusions (INFUSIONS), sachets (SACHET), patches (PATCH) or injections (INJECTIONS) may be in the form of, etc., and preferably in the form of an isotonic aqueous solution or suspension in the case of an injection formulation. .

상기 약학 조성물은 멸균제, 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제와, 기타 치료학적으로 유용한 물질을 더 함유할 수 있으며, 통상적인 혼합, 과립화 또는 코팅방법에 따라 제제화할 수 있으며, 이외에도 당해 기술 분야의 공지된 적절한 방법을 사용하여 제형화할 수 있다.The pharmaceutical composition may further contain adjuvants such as sterilizing agents, preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for regulating osmotic pressure, and other therapeutically useful substances, and conventional mixing, granulation Alternatively, it may be formulated according to a coating method, and in addition, it may be formulated using an appropriate method known in the art.

또한, 상기 약학 조성물의 투여량은 투여방법, 복용자의 연령, 성별, 환자의 중증도, 상태, 체내에서 활성 성분의 흡수도, 불활성율 및 병용되는 약물을 고려하여 결정할 수 있으며, 1회 또는 수회로 나누어 투여할 수 있다. 약학 조성물의 유효성분으로서 바람직하게는 사람을 비롯한 포유류에게 1일 기준으로 0.001 내지 100 ㎎/㎏ 체중, 바람직하게는 0.01 내지 35 ㎎/㎏ 체중의 양으로, 1일 1회 또는 분할하여 경구 또는 비경구 경로로 투여될 수 있다. In addition, the dosage of the pharmaceutical composition can be determined in consideration of the administration method, the age, sex, severity, condition of the patient, the absorption of the active ingredient in the body, the inactivation rate, and the drug to be used in combination, once or several times. It can be administered in divided doses. As an active ingredient of the pharmaceutical composition, preferably in an amount of 0.001 to 100 mg/kg body weight, preferably 0.01 to 35 mg/kg body weight, per day to mammals including humans, once a day or divided into oral or parenteral It may be administered by the oral route.

본 발명의 또 다른 일 구현예는, 하기 화학식 10, 11 또는 12로 표시되는 화합물, 이의 약학적으로 허용 가능한 염, 또는 수화물을 치료학적 유효량으로 투여하는 단계를 포함하는, 암의 치료방법을 제공한다. Another embodiment of the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound represented by the following Chemical Formulas 10, 11 or 12, a pharmaceutically acceptable salt thereof, or a hydrate thereof do.

바람직하게는 상기 치료방법은 상기 투여 단계 이전에 상기 암의 예방 또는 치료를 필요로 하는 환자를 확인하는 단계를 추가로 포함할 수 있다. Preferably, the treatment method may further include the step of identifying a patient in need of prevention or treatment of the cancer before the administering step.

본 발명의“치료학적 유효량"은 암의 예방 또는 치료에 효과적인, 포유류에 대한 유효 성분의 양을 의미하며, 상기 치료학적 유효량은 질환의 종류, 질환의 중증도, 조성물에 함유된 유효 성분 및 다른 성분의 종류 및 함량, 제형의 종류 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 혈중 청소율, 치료 기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있으나, 바람직하게는 상술한 바와 같이, 1일 기준으로 0.001 내지 100 ㎎/㎏ 체중, 바람직하게는 0.01 내지 35 ㎎/㎏ 체중의 양으로, 1일 1회 또는 분할하여 경구 또는 비경구 경로로 투여할 수 있다.The "therapeutically effective amount" of the present invention means an amount of an active ingredient for a mammal that is effective for the prevention or treatment of cancer, and the therapeutically effective amount includes the type of disease, the severity of the disease, the active ingredient and other ingredients contained in the composition. It can be adjusted according to various factors including the type and content of the drug, the type of dosage form, and the patient's age, weight, general health, sex and diet, administration time, administration route and blood clearance of the composition, treatment period, and concurrently used drugs. However, preferably, as described above, in an amount of 0.001 to 100 mg/kg body weight, preferably 0.01 to 35 mg/kg body weight, once a day or divided into oral or parenteral routes. can do.

한편, 본 발명은 하기 화학식 1로 표시되는 화합물의 제조방법을 그 특징으로 한다. Meanwhile, the present invention is characterized by a method for preparing a compound represented by the following formula (1).

[화학식 1][Formula 1]

Figure pat00083
Figure pat00083

상기 화학식 1에서,In Formula 1,

R1은 수소원자, -Cl, -Br, 이고;R 1 is a hydrogen atom, -Cl, -Br, and;

R2는 수소원자, C-1-C5 알킬기, -SO2CH3, 또는 -SO2CF3 이며; R 2 is a hydrogen atom, a C- 1 -C 5 alkyl group, —SO 2 CH 3 , or —SO 2 CF 3 ;

R3, R4, R8 , 및 R9 는 서로 독립적으로 수소원자, 할로겐, 아미노기, C-1-C5 할로알킬기, 알콕시기, C-1-C5 알킬기, 중 선택되는 것이며, R 3 , R 4 , R 8 , and R 9 is each independently selected from a hydrogen atom, a halogen, an amino group, a C- 1 -C 5 haloalkyl group, an alkoxy group, a C- 1 -C 5 alkyl group,

R5 및 R6 은 서로 독립적으로 수소원자, 할로겐, -CF3, C-1-C5 할로알킬기, C-1-C5 알킬기, 중 선택되는 것이고; R 5 and R 6 are each independently a hydrogen atom, halogen, -CF 3, C- 1 -C 5 haloalkyl group, C- 1 -C 5 alkyl group, is selected from;

R7 은 -CF3, C-1-C5 할로알킬기, C-1-C5 알킬기, 중 선택되는 것이고; R 7 is -CF 3, C- 1 -C 5 haloalkyl group, C- 1 -C 5 alkyl group, is selected from;

상기 A는 C3-C10 헤테로사이클로알킬기; 또는 C6-C13 헤테로바이사이클로알킬기; 또는 C3-C15 선형 또는 분지형 헤테로알킬기이며, 상기 헤테로사이클로알킬기 또는 헤테로바이사이클로알킬기, 및 선형 또는 분지형 헤테로알킬기는 할로겐; 히드록시기; 알킬알코올기; C1-5 알킬기 중 선택되는 1개 이상의 치환기를 가질 수 있으며;Wherein A is a C 3 -C 10 heterocycloalkyl group; or a C 6 -C 13 heterobicycloalkyl group; or a C 3 -C 15 linear or branched heteroalkyl group, wherein the heterocycloalkyl group or heterobicycloalkyl group, and the linear or branched heteroalkyl group are halogen; hydroxyl group; an alkyl alcohol group; It may have one or more substituents selected from a C 1-5 alkyl group;

상기 X는 탄소, 또는 질소이고,X is carbon or nitrogen,

상기 Y는 -N-, -NH-, -CH2-, -CO-, 중 선택되는 것이며;Y is -N-, -NH-, -CH 2 -, -CO-, is selected from;

상기 Z는 -NH-, -SO-2-, -SO-(CH3)--2, 중 선택되는 것이고;wherein Z is -NH-, -SO- 2 -, -SO-(CH 3 )-- 2 , is selected from;

상기 B는 C6 아릴기, 헤테로아릴기, 또는 C3-C10 -헤테로바이사이클로아릴기이다. Wherein B is a C 6 aryl group, a heteroaryl group, or a C 3 -C 10 -heterobicycloaryl group.

본 발명의 일측면에서, B는 모노사이클릭 아릴기 또는 N, S, 및 O로부터 선택된 하나 이상의 헤테로원자를 포함하는 바이사이클릭의, 치환 또는 비치환될 수 있는, 방향족 그룹을 의미한다. 바이사이클릭 헤테로아릴의 예로는 인돌일, 벤조티오펜일, 벤조퓨란일, 벤즈이미다졸릴, 벤즈옥사졸릴, 벤즈이속사졸릴, 벤즈티아졸릴, 벤즈티아디아졸릴, 벤즈트리아졸릴, 퀴놀린일, 이소퀴놀린일, 퓨린일, 퓨로피리딘일, 옥소크로멘, 디옥소이소인돌린, 피라졸로피리디닐, 피라졸로[1,5-a]피리디닐, 이소퀴녹살린 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는것은 아니다.In one aspect of the present invention, B refers to a monocyclic aryl group or a bicyclic, substituted or unsubstituted, aromatic group containing one or more heteroatoms selected from N, S, and O. Examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolinyl, iso quinolinyl, purinyl, puropyridinyl, oxochromene, dioxoisoindoline, pyrazolopyridinyl, pyrazolo[1,5-a]pyridinyl, isoquinoxaline, and the like; it's not going to be

하기 반응식 1에 나타낸 제조방법에 의하면, 본 발명은 하기 화학식 2로 표시되는 상업적으로 입수 가능한 피리미딘 화합물과 상기 화학식 3으로 표시되는 아민을 결합반응시켜, 하기 화학식 1로 표시되는 피리미딘 화합물을 제조하는 과정을 포함한다.According to the preparation method shown in Scheme 1, the present invention combines a commercially available pyrimidine compound represented by Formula 2 with an amine represented by Formula 3 to prepare a pyrimidine compound represented by Formula 1 below. includes the process of

[반응식 1][Scheme 1]

Figure pat00084
Figure pat00084

상기 반응식 1에서 R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y, Z, A 및 B는 상기 화학식 I에서 정의한 바와 같다. In Scheme 1, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , X, Y, Z, A and B are as defined in Formula I above.

상기 반응식 1에 따른 제조방법은 상업적으로 입수 가능한 피리미딘 화합물 (화학식 2)로부터 상업적으로 입수 가능한 화학식 3을 결합시키는 반응으로 화학식 4를 얻을 수 있다. 60 ℃ 온도에서 교반하는 것을 수반하며, 이때 반응용매로서는 테트라하이드로퓨란, 디옥산, N,N-디메틸포름아마이드, N,N-디메틸설폭사이드, 2-부탄올, 2-펜탄올 등이 포함되는 통상의 유기용매를 사용할 수 있다. The preparation method according to Scheme 1 can obtain Chemical Formula 4 by combining commercially available Chemical Formula 3 from a commercially available pyrimidine compound (Formula 2). It entails stirring at a temperature of 60 ° C. In this case, the reaction solvent is usually tetrahydrofuran, dioxane, N,N -dimethylformamide, N,N -dimethylsulfoxide, 2-butanol, 2-pentanol, etc. of organic solvents can be used.

또는 이어서 제조된 화학식 4를 상업적으로 입수 가능한 설포닐 클로라이드 또는 요오드화 메테인을 이용하여 수소화나트륨과 같은 염기조건으로 N,N-다이메틸포름아마이드와 같은 용매 중에서 상온에서 반응시켜 설폰기 또는 메틸기가 치환된 화학식 6을 얻을 수 있다. Alternatively, a sulfone group or a methyl group is substituted by reacting the prepared formula (4) at room temperature in a solvent such as N,N -dimethylformamide under basic conditions such as sodium hydride using commercially available sulfonyl chloride or methane iodide. Formula 6 can be obtained.

제조된 화학식 4 또는 화학식 6과 화학식 5로 표기된 아민을 1.25 M 염산 메탄올 용액과 아세트산 존재하에 120 ℃ 에서 교반하여 화학식 1을 얻을 수 있다. Formula 1 can be obtained by stirring the prepared amines represented by Formula 4 or Formula 6 and Formula 5 at 120° C. in the presence of 1.25 M hydrochloric acid methanol solution and acetic acid.

[반응식 2][Scheme 2]

Figure pat00085
Figure pat00085

상기 반응식 2은 화학식 5 아민 중간체를 제조하기 위한 반응식이며, Scheme 2 is a reaction scheme for preparing an amine intermediate of Formula 5,

상기 반응식 2에서, R3, R4, R8, X, 및 A는 상기 화학식 1에서 정의한 바와 같고, R8 은 플루오로기 또는 클로로기이다. In Scheme 2, R 3 , R 4 , R 8 , X, and A are as defined in Formula 1 above, and R 8 is a fluoro group or a chloro group.

상기 반응식 2에 따른 제조방법에 의하면, 상업적으로 입수 가능한 화학식7로 표기되는 나이트로 화합물을 A와 결합반응을 통해 화학식 8을 얻을 수 있다. According to the preparation method according to Scheme 2, Chemical Formula 8 can be obtained by combining a commercially available nitro compound represented by Chemical Formula 7 with A.

또한 이어서 제조된 화학식 8을 철과 염화 암모니아를 테트라하이드로퓨란, 메탄올, 물의 혼합 용매 하에서 85 ℃로 교반하여 나이트로기를 아미노기로 환원하여 화학식 5를 얻을 수 있다.In addition, in Formula 8, iron and ammonia chloride are stirred at 85° C. in a mixed solvent of tetrahydrofuran, methanol, and water to reduce the nitro group to an amino group to obtain Formula 5.

한편, 본 발명은 상기 화학식 1, 화학식 10, 화학식 11 또는 화학식 12로 표시되는 피리미딘 화합물, 약학적으로 허용되는 이의 염, 이의 용매화물, 이의 수화물 또는 이의 광학 이성질체가 유효성분으로 포함된 약학 조성물을 제공한다. Meanwhile, the present invention relates to a pharmaceutical composition comprising the pyrimidine compound represented by Formula 1, Formula 10, Formula 11 or Formula 12, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, or an optical isomer thereof as an active ingredient. provides

본 발명의 화합물은 EGFR 단백질 키나아제의 활성을 저해하는 능력이 우수하므로 비정상적인 세포 대사 및 당 대사로 유발되는 질환의 예방 및 치료를 위한 약제조성물의 유효성분으로 사용될 수 있다. 따라서 본 발명에 따른 화합물은 비정상적인 세포 대사 및 당 대사로 유발되는 질환으로서 예를 들면 당뇨, 비만 등의 대사성질환 및 자궁내막암, 방광암, 위암, 폐암, 간암, 대장암, 소장암, 췌장암, 뇌암, 뼈암, 흑색종, 유방암, 경화성선종, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 백혈병, 다발성골수종, 골수이형성증후군과 같은 혈액암, 호치킨병과 비호치킨림프종과 같은 림프종, 또는 섬유선종 등으로부터 선택된 각종 종양 질환의 예방 및 치료제로 사용될 수 있다.Since the compound of the present invention has excellent ability to inhibit the activity of EGFR protein kinase, it can be used as an active ingredient in a pharmaceutical composition for the prevention and treatment of diseases caused by abnormal cell metabolism and sugar metabolism. Therefore, the compound according to the present invention is a disease caused by abnormal cell metabolism and glucose metabolism, for example, metabolic diseases such as diabetes and obesity, endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colon cancer, small intestine cancer, pancreatic cancer, brain cancer , bone cancer, melanoma, breast cancer, sclerosing adenoma, head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, blood cancer such as myelodysplastic syndrome, Hodgkin's disease and non-Hodgkin's disease It can be used as a prophylactic and therapeutic agent for various tumor diseases selected from lymphoma, such as lymphoma, or fibroadenoma.

따라서, 본 발명은 상기 화학식 1, 화학식 10, 화학식 11 또는 화학식 12로 표시되는 피리미딘 화합물, 약학적으로 허용되는 이의 염, 이의 용매화물, 이의 수화물을 유효성분으로 포함하는 약제조성물과, 비정상적인 세포 대사 및 당 대사로 유발되는 질환의 예방 및 치료제를 특징으로 한다. Accordingly, the present invention provides a pharmaceutical composition comprising the pyrimidine compound represented by Formula 1, Formula 10, Formula 11 or Formula 12, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as an active ingredient, and abnormal cells It is characterized as a preventive and therapeutic agent for diseases caused by metabolism and sugar metabolism.

본 발명의 약제조성물은 상기 화학식 1, 화학식 10, 화학식 11 또는 화학식 12로 표시되는 피리미딘 화합물, 약학적으로 허용되는 이의 염, 이의 용매화물, 및 이의 수화물로부터 선택된 1종 이상을 유효성분으로 함유하고, 여기에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구투여용 제제 또는 비경구투여용 제제로 제제화할 수 있다. The pharmaceutical composition of the present invention contains at least one selected from the pyrimidine compound represented by Formula 1, Formula 10, Formula 11 or Formula 12, pharmaceutically acceptable salts thereof, solvates thereof, and hydrates thereof as an active ingredient. and a conventional non-toxic pharmaceutically acceptable carrier, adjuvant and excipient added thereto, for example, a formulation for oral administration such as tablets, capsules, troches, solutions, suspensions, etc. It can be formulated as a preparation for parenteral administration.

본 발명의 약제 조성물에 사용될 수 있는 부형제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활탁제, 충진제, 방향제 등이 포함될 수 있다. 예를 들면 락토스, 덱스트로스, 슈크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소디움 알진산염, 메틸셀룰로오스, 소디움 카르복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다. Excipients that can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, and the like. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterine, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, arginic acid, sodium Alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.

또한, 본 발명에 따른 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환정도에 따라 달라질 수 있으며, 몸무게가 70kg인 성인환자를 기준으로 할 때 일반적으로 0.01 내지 1,000 mg/일이며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.In addition, the dosage of the compound according to the present invention to the human body may vary depending on the patient's age, weight, sex, dosage form, health status and disease level, and is generally 0.01 based on an adult patient weighing 70 kg. to 1,000 mg/day, and may be administered in divided doses once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist.

이상에서 설명한 바와 같은 본 발명은 하기 실시예, 제제예, 및 실험예에 의거하여 더욱 상세히 설명하겠는 바, 하기의 실시예, 제제예, 및 실험예는 본 발명을 예시하는 것일 뿐 본 발명의 범위가 이들에 의해 한정되는 것은 아니다.The present invention as described above will be described in more detail based on the following Examples, Formulation Examples, and Experimental Examples, and the following Examples, Formulation Examples, and Experimental Examples are merely illustrative of the present invention. is not limited by these.

[실시예][Example]

실시예 1: Example 1: NN -(2-((5-클로로-2-((6-(4-에틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)-4-일)아미노)페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-4-yl)amino)phenyl)methane Preparation of sulfonamides

Figure pat00086
Figure pat00086

단계 1) N-(2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide

N-(2-아미노페닐)메탄설폰아마이드 5.0 g (26.9 mmol)과 2,4,5-트라이클로로피리미딘 3.37 ml (35.0 mmol)을 아이소프로필알코올 54 ml에 묽히고 N,N-다이아이소프로필에틸아민 9.3 ㎖ (53.8 mmol)을 가한 후, 60℃ 에서 12 시간 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 에틸 아세테이트로 묽힌 후 증류수 세척하였다. 얻어진 잔사를 컬럼 크로마토그래피 (50% 에틸 아세테이트 / 헥산)으로 분리하여 표제화합물 4.66 g (수율: 52 %)을 얻었다.Dilute 5.0 g (26.9 mmol) of N- (2-aminophenyl)methanesulfonamide and 3.37 ml (35.0 mmol) of 2,4,5-trichloropyrimidine in 54 ml of isopropyl alcohol, and then dilute N,N -diisopropyl After adding 9.3 ml (53.8 mmol) of ethylamine, the mixture was stirred at 60° C. for 12 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The obtained residue was separated by column chromatography (50% ethyl acetate / hexane) to obtain 4.66 g (yield: 52 %) of the title compound.

단계 2) 6-(4-에틸피페라진-1-일)-2-메톡시피리딘-3-아민의 제조Step 2) Preparation of 6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-amine

6-클로로-2-메톡시-3-나이트로피리딘 1.0 g (5.38 mmol)과 1-에틸피페라진 0.82 ml (5.38 mmol)을 DMSO 10 ml에 묽히고 탄산칼륨 1.48g (10.8 mmol)을 가한 후 85 ℃에서 5시간 동안 교반시키고 반응 혼합물을 다이클로로메탄과 증류수를 이용하여 추출 후 얻은 유기층을 황상 마그네슘으로 건조시키고 별도의 정제 없이 얻어진 잔사를 10 ml 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말 0.3 g (2.7 mmol)와 염화 암모늄 0.16 g (2.7 mmol)를 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 1.2 g (수율: 94%)를 얻었다. After diluting 1.0 g (5.38 mmol) of 6-chloro-2-methoxy-3-nitropyridine and 0.82 ml (5.38 mmol) of 1-ethylpiperazine in 10 ml of DMSO, 1.48 g (10.8 mmol) of potassium carbonate was added thereto. After stirring at 85° C. for 5 hours, the reaction mixture was extracted with dichloromethane and distilled water, and the obtained organic layer was dried over magnesium sulfate. After dissolving in 1 (volume ratio), 0.3 g (2.7 mmol) of iron powder and 0.16 g (2.7 mmol) of ammonium chloride were added, followed by stirring at 85 °C for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain 1.2 g (yield: 94%) of the title compound.

단계 3) N-(2-((5-클로로-2-((6-(4-에틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)-4-일)아미노)페닐)메탄설폰아마이드의 제조Step 3) N- (2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-4-yl)amino ) Preparation of phenyl) methanesulfonamide

상기 단계 1)에서 제조된 화합물 100 mg (0.3 mmol)과 상기 단계 3)에서 제조된 화합물 57 mg (0.24 mmol)을 1.5 ㎖ 아세트산 : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 30 mg (수율: 20%)을 얻었다. [M+H]+ = 534 .100 mg (0.3 mmol) of the compound prepared in step 1) and 57 mg (0.24 mmol) of the compound prepared in step 3) were dissolved in 1.5 ml of acetic acid: 1.25 M HCl/methanol solution = 1: 1 (volume ratio) It was sealed and stirred at 120 °C for 3 hours. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain 30 mg of the title compound (yield: 20%). [M+H] + = 534 .

실시예 2: N -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조 Example 2 : N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00087
Figure pat00087

상기 실시예 1의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 614.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 1 and the corresponding aniline. [M+H] + = 614.

실시예 3: Example 3: NN -(2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidine-4 Preparation of -yl)amino)phenyl)methanesulfonamide

Figure pat00088
Figure pat00088

상기 실시예 1의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 571.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 1 and the corresponding aniline. [M+H] + = 571.

실시예 4: Example 4: NN -(2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)-2-(2,2,2-트라이플루오로에톡시)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(2-((5-Chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2,2-trifluoro) Preparation of roethoxy)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00089
Figure pat00089

상기 실시예 1의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 669.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 1 and the corresponding aniline. [M+H] + = 669.

실시예 5: Example 5: NN -(2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- Preparation of 4-yl)amino)phenyl)methanesulfonamide

Figure pat00090
Figure pat00090

상기 실시예 1의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 558.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 1 and the corresponding aniline. [M+H] + = 558.

실시예 6: Example 6: NN -(2-((5-클로로-2-((6-(1,1-다이옥시싸이오몰폴리노)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((6-(1,1-dioxythiomorpholino)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino) Preparation of phenyl) methanesulfonamide

Figure pat00091
Figure pat00091

상기 실시예 1의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 553. The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 1 and the corresponding aniline. [M+H] + = 553.

실시에 7: Implementation 7: NN -(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메설폰아마이드의 제조-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl) amino) phenyl) mesulfonamide

Figure pat00092
Figure pat00092

상기 실시예 1의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 634.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 1 and the corresponding aniline. [M+H] + = 634.

실시예 8: Example 8: NN -(5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)--(5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)- NN -(2-(메틸설폰아마이도)페닐)메탄설폰아마이드의 제조Preparation of -(2-(methylsulfonamido)phenyl)methanesulfonamide

Figure pat00093
Figure pat00093

단계1) N-(2,5-다이클로로피리미딘-4-일)-N-(2-(메틸설폰아마이도)페닐)메탄설폰마아이드의 제조Step 1) Preparation of N- (2,5-dichloropyrimidin-4-yl ) -N-(2-(methylsulfonamido)phenyl)methanesulfonamide

상기 실시예 1의 단계 1)에서 제조된 화합물 1.0 g (3.0 mmol)을 N,N-다이메틸포름아마이드 6 ㎖에 묽히고 60 % 수소화나트륨 138 mg (6.0 mmol)을 0 ℃에서 천천히 가한 후 상온에서 30 분 교반시켰다. 여기에 메탄설포닐 클로라이드 0.27 ㎖ (3.6 mmol)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (50% 에틸 아세테이트/헥산) 정제하여 표제화합물 1.95 g (수율: 65%)을 얻었다.1.0 g (3.0 mmol) of the compound prepared in step 1) of Example 1 was diluted in 6 ml of N,N-dimethylformamide, and 138 mg (6.0 mmol) of 60% sodium hydride was slowly added at 0° C. at room temperature. was stirred for 30 min. To this, 0.27 ml (3.6 mmol) of methanesulfonyl chloride was slowly added at 0° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate/hexane) to obtain 1.95 g (yield: 65%) of the title compound.

단계 2) N-(5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)-N-(2-(메틸설폰아마이도)페닐)메탄설폰아마이드의 제조Step 2) N- (5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4- Preparation of yl) -N- (2-(methylsulfonamido)phenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 N,N-다이메틸피롤리딘-3-아민을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정을 수행하여 표제화합물을 얻었다. [M+H]+ = 610.The same process as in Example 1 was performed, except that the compound prepared in step 1) and N , N -dimethylpyrrolidin-3-amine in step 2) of Example 1 were used. The compound was obtained. [M+H] + = 610.

실시예 9:Example 9: NN -(5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)--(5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- 4-day)- NN -(2-(메틸설폰아마이도)페닐)메탄설폰아마이드의 제조Preparation of -(2-(methylsulfonamido)phenyl)methanesulfonamide

Figure pat00094
Figure pat00094

상기 실시예 8의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 692.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 8 and the corresponding aniline. [M+H] + = 692.

실시예 10: Example 10: NN -(5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)--(5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidine- 4-day)- NN -(2-(메틸설폰아마이도)페닐)메탄설폰아마이드의 제조Preparation of -(2-(methylsulfonamido)phenyl)methanesulfonamide

Figure pat00095
Figure pat00095

상기 실시예 8의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 679.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 8 and the corresponding aniline. [M+H] + = 679.

실시예 11: Example 11: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리디니-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)--(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)(methyl)amino)phenyl)- NN -메틸설폰아마이드의 제조-Preparation of methylsulfonamide

Figure pat00096
Figure pat00096

단계 1) N-(2-((2,5-다이클로로피리미딘-4-일)(메틸)아미노)페닐)-N-메틸메탄설폰아마이드의 제조Step 1) Preparation of N- (2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)phenyl) -N -methylmethanesulfonamide

상기 실시예 1의 단계 1)에서 제조된 화합물 1.0 g (3.0 mmol)을 N,N-다이메틸포름아마이드 6 ㎖에 묽히고 60 % 수소화나트륨 138 mg (6.0 mmol)을 0 ℃에서 천천히 가한 후 상온에서 30 분 교반시켰다. 여기에 메틸아이오다이드 0.22 ㎖ (3.6 mmol)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (50% 에틸 아세테이트/헥산) 정제하여 표제화합물 600 mg (수율: 53%)을 얻었다.1.0 g (3.0 mmol) of the compound prepared in step 1) of Example 1 was diluted in 6 ml of N,N-dimethylformamide, and 138 mg (6.0 mmol) of 60% sodium hydride was slowly added at 0° C. at room temperature. was stirred for 30 min. 0.22 ml (3.6 mmol) of methyl iodide was slowly added thereto at 0° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate/hexane) to obtain 600 mg of the title compound (Yield: 53%).

단계 2) N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리디니-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)-N-메틸설폰아마이드의 제조Step 2) N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl) -N -methylsulfonamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정을 수행하여 표제화합물을 얻었다. [M+H]+ = 679.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used. [M+H] + = 679.

실시예 12: Example 12: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide

Figure pat00097
Figure pat00097

단계 1) N-(2-((2,5-다이클로로피리미딘-4-일)아미노)-5-플루오로페닐)메탄설포닐아마이드의 제조Step 1) Preparation of N- (2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonylamide

상기 실시예 1의 단계 1)에서 N-(2-아미노-5-플루오로페닐)메탄설폰아마이드를 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다.The title compound was obtained in the same manner as in Step 1) of Example 1 using N -(2-amino-5-fluorophenyl)methanesulfonamide in Step 1) of Example 1.

단계 2) N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드의 제조Step 2) N-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide

상기 단계 1)에서 상기 실시예 1의 단계 2)에서 제조된 화합물과 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.In step 1), the compound prepared in step 2) of Example 1, 1-chloro-5-methoxy-2-methyl-4-nitrobenzene, and 1-methyl-4-piperidin-4-yl - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 13: Example 13: NN -(2-((5-클로로-2-((6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드의 제조Preparation of -(2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide

Figure pat00098
Figure pat00098

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 493.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 493.

실시예 14: Example 14: NN -(2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-yl)피페리딘-1-일)피리딘-3-일)아마이도)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amido)pyrimidine- Preparation of 4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00099
Figure pat00099

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 589.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 589.

실시예 15: Example 15: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3) Preparation of -yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00100
Figure pat00100

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 633.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 633.

실시예 16: Example 16: NN -(2-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino Preparation of )pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00101
Figure pat00101

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 607.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 607.

실시예 17: Example 17: NN -(2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino Preparation of )pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00102
Figure pat00102

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 619.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 619.

실시예 18: Example 18: NN -(2-((5-클로로-2-((6-(4-(2-하이드록시메틸)피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((6-(4-(2-hydroxymethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine-4 Preparation of -yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00103
Figure pat00103

상기 실시예 13의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 566.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 13 and the corresponding aniline. [M+H] + = 566.

실시예 19: Example 19: NN -(2-((2-((6-(4-아세틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)-5-클로로피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((2-((6-(4-acetylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-5-chloropyrimidin-4-yl)amino)- Preparation of 5-fluorophenyl)methanesulfonamide

Figure pat00104
Figure pat00104

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 565.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 565.

실시예 20: Example 20: NN -(2-((5-클로로-2-((2-메톡시-6-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3-yl)amino Preparation of )pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00105
Figure pat00105

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 565.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 565.

실시예 21: Example 21: NN -(2-((5-클로로-((6-(4-하이드록시피페리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-chloro-((6-(4-hydroxypiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino)- Preparation of 5-fluorophenyl)methanesulfonamide

Figure pat00106
Figure pat00106

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 538.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 538.

실시예 22: Example 22: NN -(2-((5-클로로-2-((2-메톡시-6-(4-(옥세탄-3-일)피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드 의 제조-(2-((5-chloro-2-((2-methoxy-6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl)amino)pyrimidine- Preparation of 4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00107
Figure pat00107

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 578.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 578.

실시예 23: Example 23: NN -(2-((5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4- Preparation of yl) amino)-5-fluorophenyl) methanesulfonamide

Figure pat00108
Figure pat00108

상기 실시예 12의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 550.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 12 and the corresponding aniline. [M+H] + = 550.

실시예 24: Example 24: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amido)-5-fluorophenyl) methanesulfonamide

Figure pat00109
Figure pat00109

단계 1) N-(2-((5-브로모-2-클로로피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드를 의 제조Step 1) Preparation of N- (2-((5-bromo-2-chloropyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

상기 실시예 1의 단계 1)에서 5-브로모-2,4-다이클로로피리미딘과 N-(2-아미노-5-플루오로페닐)메탄설폰아마이드를 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다.Step 1) of Example 1 using 5-bromo-2,4-dichloropyrimidine and N- (2-amino-5-fluorophenyl)methanesulfonamide in Step 1) of Example 1) The title compound was obtained in the same manner as described above.

단계 2) N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드의 제조Step 2) N-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

1H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.12 (s, 1H), 7.93-7.73 (m, 2H), 7.43 (s, 1H), 7.14 (dd, J = 10.9, 2.8 Hz, 1H), 6.79-6.58 (m, 2H), 3.76 (s, 3H), 3.06 (d, J = 11.1 Hz, 2H), 2.84 (s, 3H), 2.78-2.26 (m, 14H), 2.04 (s, 3H), 1.93-1.80 (m, 2H), 1.68-1.50 (m, 2H). [M+H]+ = 677. 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.12 (s, 1H), 7.93-7.73 (m, 2H), 7.43 (s, 1H), 7.14 (dd, J = 10.9, 2.8 Hz, 1H), 6.79-6.58 (m, 2H), 3.76 (s, 3H), 3.06 (d, J = 11.1 Hz, 2H), 2.84 (s, 3H), 2.78-2.26 (m, 14H), 2.04 (s, 3H), 1.93-1.80 (m, 2H), 1.68-1.50 (m, 2H). [M+H] + = 677.

실시예 25: Example 25: NN -(2-((5-브로모-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) Preparation of amino) pyrimidin-4-yl) amino)-5-fluorophenyl) methanesulfonamide

Figure pat00110
Figure pat00110

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 652.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 652.

실시예 26: Example 26: NN -(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino)-5-fluorophenyl) methanesulfonamide

Figure pat00111
Figure pat00111

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 697.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 697.

실시예 27: Example 27: NN -(2-((5-브로모-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- Preparation of 4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00112
Figure pat00112

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 667.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 667.

실시예 28: Example 28: NN -(2-((5-브로모-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) Preparation of amino) pyrimidin-4-yl) amino)-5-fluorophenyl) methanesulfonamide

Figure pat00113
Figure pat00113

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 664.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 664.

실시예 29: Example 29: NN -(2-((5-브로모-2-((2-메톡시-6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methane Preparation of sulfonamides

Figure pat00114
Figure pat00114

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 568.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 568.

실시예 30: Example 30: NN -(2-((5-브로모-2-((6-(4-사이클로프로필피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((6-(4-cyclopropylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino Preparation of )-5-fluorophenyl)methanesulfonamide

Figure pat00115
Figure pat00115

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 607.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 607.

실시예 31: Example 31: NN -(2-((5-브로모-2-((2-메톡시-6-(4-몰폴리노피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl) Preparation of amino)-5-fluorophenyl)methanesulfonamide

Figure pat00116
Figure pat00116

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 651.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 651.

실시예 32: Example 32: NN -(2-((5-브로모-2-((6-(4,4-다이메틸피페리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드 의 제조-(2-((5-bromo-2-((6-(4,4-dimethylpiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4- Preparation of yl) amino)-5-fluorophenyl) methanesulfonamide

Figure pat00117
Figure pat00117

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 594.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 594.

실시예 33: Example 33: NN -(2-((5-브로모-2-((6-(4,4-다이플루오로피페리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((6-(4,4-difluoropiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine-4 Preparation of -yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00118
Figure pat00118

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 602.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 602.

실시예 34: Example 34: NN -(2-((5-브로모-2-((2-클로로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)-5-(트라이플루오로메틸)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((2-chloro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(trifluoro) Preparation of methyl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00119
Figure pat00119

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 736.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 736.

실시예 35: Example 35: NN -(2-((5-브로모-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드 의 제조-(2-((5-Bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidine- Preparation of 4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00120
Figure pat00120

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 684.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 684.

실시예 36: Example 36: NN -(2-((5-브로모-2-((2-메톡시-6-(4-(1-메틸피페리딘-4-일)피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-6-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-3-yl) Preparation of amino) pyrimidin-4-yl) amino)-5-fluorophenyl) methanesulfonamide

Figure pat00121
Figure pat00121

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 664.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 664.

실시예 37: Example 37: NN -(2-((5-브로모-2-((2-메톡시-6-(4-(1-메틸-4-일)피페라진-1-일)-5-(트라이플루오로메틸)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((2-methoxy-6-(4-(1-methyl-4-yl)piperazin-1-yl)-5-(trifluoromethyl) Preparation of pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00122
Figure pat00122

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 732.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 732.

실시예 38: Example 38: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1) Preparation of -yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00123
Figure pat00123

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 690.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 690.

실시예 39: Example 39: NN -(2-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5) Preparation of -methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00124
Figure pat00124

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 705.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 705.

실시예 40: Example 40: NN -(2-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00125
Figure pat00125

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 691.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 691.

실시예 41: Example 41: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-((1-메틸-1H-피라졸-5-일)아미노)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1H-pyrazol-5-yl)amino)piperidin- Preparation of 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00126
Figure pat00126

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 691.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 691.

실시예 42: Example 42: NN -(2-((5-브로모-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl) Preparation of amino) pyrimidin-4-yl) amino)-5-fluorophenyl) methanesulfonamide

Figure pat00127
Figure pat00127

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 703.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 703.

실시예 43: Example 43: NN -(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페리딘-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperidin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino)-5-fluorophenyl) methanesulfonamide

Figure pat00128
Figure pat00128

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 681.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 681.

실시예 44: Example 44: NN -(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00129
Figure pat00129

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 696.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 696.

실시예 45: Example 45: NN -(2-((5-브로모-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)플루오로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5- Preparation of methylphenyl)amino)pyrimidin-4-yl)amino)fluorophenyl)methanesulfonamide

Figure pat00130
Figure pat00130

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 710.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 710.

실시예 46: 5-클로로-Example 46: 5-Chloro- NN 22 -(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)--(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)- NN 44 -(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine

Figure pat00131
Figure pat00131

단계 1) 2,5-다이클로로-N-(2-(트라이플루오로메틸)페닐)피리미딘-4-아민의 제조Step 1) Preparation of 2,5-dichloro- N- (2-(trifluoromethyl)phenyl)pyrimidin-4-amine

상기 실시예 1의 단계 1)에서 2-(트라이플루오로메틸)아닐린을 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다.Step 1) of Example 1 was carried out in the same manner as in Step 1) of Example 1 using 2-(trifluoromethyl)aniline to obtain the title compound.

단계 2) 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민의 제조Step 2) 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 - Preparation of (2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 47: 5-클로로-Example 47: 5-Chloro- NN 22 -(2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)--(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)- NN 44 -(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine

Figure pat00132
Figure pat00132

상기 실시예 46의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 576.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 46 and the corresponding aniline. [M+H] + = 576.

실시예 48: 5-클로로-Example 48: 5-Chloro- NN 22 -(4-(4-에틸피페라진-1-일)페닐)--(4-(4-ethylpiperazin-1-yl)phenyl)- NN 44 -(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine

Figure pat00133
Figure pat00133

상기 실시예 46의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 477.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 46 and the corresponding aniline. [M+H] + = 477.

실시예 49: 5-클로로-Example 49: 5-Chloro- NN 22 -(6-몰폴리노피리딘-3-일)--(6-morpholinopyridin-3-yl)- NN 44 -(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine

Figure pat00134
Figure pat00134

상기 실시예 46의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 46 and the corresponding aniline.

1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 2.6 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.78 (dd, J = 9.0, 2.5 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.30 - 7.24 (m, 6H), 6.86 (s, 1H), 6.59 (d, J = 9.0 Hz, 1H), 3.89 - 3.77 (m, 4H), 3.52 - 3.28 (m, 4H). [M+H]+ = 451. 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 2.6 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.07 (s, 1H), 7.78 (dd, J = 9.0, 2.5) Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.30 - 7.24 (m, 6H), 6.86 (s, 1H), 6.59 (d, J = 9.0 Hz) , 1H), 3.89 - 3.77 (m, 4H), 3.52 - 3.28 (m, 4H). [M+H] + = 451.

실시예 50: 2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-Example 50: 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)- NN -메틸벤젠설폰아마이드의 제조-Preparation of methylbenzenesulfonamide

Figure pat00135
Figure pat00135

단계 1) 2-((2,5-다이클로로피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드의제조Step 1) Preparation of 2-((2,5-dichloropyrimidin-4-yl)amino) -N -methylbenzenesulfonamide

상기 실시예 1의 단계 1)에서 2-아미노-N-메틸벤젠설폰아마이드를 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다.In step 1) of Example 1, the title compound was obtained in the same manner as in step 1) of Example 1 using 2-amino- N -methylbenzenesulfonamide.

단계 2) 2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드의 제조Step 2) 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino)pyrimidin-4-yl)amino) -N -methylbenzenesulfonamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 51: 2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-Example 51: 2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri midin-4-yl)amino)- NN -메틸벤젠설폰아마이드의 제조-Preparation of methylbenzenesulfonamide

Figure pat00136
Figure pat00136

상기 실시예 50의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 601.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 50 and the corresponding aniline. [M+H] + = 601.

실시예 52: 2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-Example 52: 2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidine -4-yl)amino)- NN -메틸벤젠설폰아마이드의 제조-Preparation of methylbenzenesulfonamide

Figure pat00137
Figure pat00137

상기 실시예 50의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 572.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 50 and the corresponding aniline. [M+H] + = 572.

실시예 53: 2-((5-클로로-2-((6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아미노)-Example 53: 2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)- NN -메틸벤젠설폰아마이드의 제조-Preparation of methylbenzenesulfonamide

Figure pat00138
Figure pat00138

상기 실시예 50의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 50 and the corresponding aniline.

1H NMR (400 MHz, DMSO) δ 9.28 (s, 2H), 8.52 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.81 (dd, J = 12.1, 5.4 Hz, 3H), 7.60 (t, J = 7.4 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 9.1 Hz, 1H), 3.83 - 3.47 (m, 4H), 3.43 - 3.18 (m, 4H), 2.44 (s, 3H). [M+H]+ = 476. 1 H NMR (400 MHz, DMSO) δ 9.28 (s, 2H), 8.52 (s, 1H), 8.30 (s, 1H), 8.22 (s, 1H), 7.81 (dd, J = 12.1, 5.4 Hz, 3H ), 7.60 (t, J = 7.4 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 6.81 (d, J = 9.1 Hz, 1H), 3.83 - 3.47 (m, 4H), 3.43 - 3.18 (m, 4H), 2.44 (s, 3H). [M+H] + = 476.

실시예 54: 2-((5-클로로-2-((6-(4-에틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-Example 54: 2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino )- NN -메틸벤젠설폰아마이드의 제조-Preparation of methylbenzenesulfonamide

Figure pat00139
Figure pat00139

상기 실시예 50의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 533.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 50 and the corresponding aniline. [M+H] + = 533.

실시예 55: 2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-Example 55: 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) )amino)pyrimidin-4-yl)amino)- NN -메틸벤젠설폰아마이드 의 제조-Preparation of methylbenzenesulfonamide

Figure pat00140
Figure pat00140

상기 실시예 50의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 602.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 50 and the corresponding aniline. [M+H] + = 602.

실시예 56: 2-((5-클로로-2-((6-(4-(2-하이드록시에틸)피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-Example 56: 2-((5-chloro-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine -4-yl)amino)- NN -메틸벤젠설폰아마이드 의 제조-Preparation of methylbenzenesulfonamide

Figure pat00141
Figure pat00141

상기 실시예 50의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 549.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 50 and the corresponding aniline. [M+H] + = 549.

실시예 57: 2-((5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-Example 57: 2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine- 4-yl)amino)- NN -메틸벤젠설폰아마이드의 제조-Preparation of methylbenzenesulfonamide

Figure pat00142
Figure pat00142

상기 실시예 50의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 533.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 50 and the corresponding aniline. [M+H] + = 533.

실시예 58: 2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-Example 58: 2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine -3-yl)amino)pyrimidin-4-yl)amino)- NN -메틸벤젠설폰아마이드의 제조-Preparation of methylbenzenesulfonamide

Figure pat00143
Figure pat00143

상기 실시예 50의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 616.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 50 and the corresponding aniline. [M+H] + = 616.

실시예 59: 2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-Example 59: 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)- NN -사이클로프로필벤젠설폰아마이드의 제조-Preparation of cyclopropylbenzenesulfonamide

Figure pat00144
Figure pat00144

단계 1) N-사이클로프로필-2-((2,5-다이클로로피리미딘-4-일)아미노)벤젠설폰아마이드의 제조Step 1) Preparation of N -cyclopropyl-2-((2,5-dichloropyrimidin-4-yl)amino)benzenesulfonamide

상기 실시예 1의 단계 1)에서 2-아미노-N-사이클로프로필벤젠설폰아마이드를 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다.In step 1) of Example 1, the title compound was obtained in the same manner as in step 1) of Example 1 using 2-amino- N -cyclopropylbenzenesulfonamide.

단계 2) 2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-사이클로프로필벤젠설폰아마이드의 제조Step 2) 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino)pyrimidin-4-yl)amino) -N -cyclopropylbenzenesulfonamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 60: 2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-Example 60: 2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri midin-4-yl)amino)- NN -사이클로프로필벤젠설폰아마이드의 제조-Preparation of cyclopropylbenzenesulfonamide

Figure pat00145
Figure pat00145

상기 실시예 59의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 615.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 59 and the corresponding aniline. [M+H] + = 615.

실시예 61: 2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페라딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-사이클로프로필벤젠설폰아마이드의 제조Example 61: 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperadin-1-yl)pyridin-3-yl Preparation of )amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide

Figure pat00146
Figure pat00146

상기 실시예 59의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 628.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 59 and the corresponding aniline. [M+H] + = 628.

실시예 62: 5-클로로-Example 62: 5-Chloro- NN 22 -(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)--(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)- NN 44 -(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine

Figure pat00147
Figure pat00147

단계 1) 2,5-다이클로로-N-(2-((메틸설포닐)메틸)페닐)피리미딘-4-아민Step 1) 2,5-dichloro- N- (2-((methylsulfonyl)methyl)phenyl)pyrimidin-4-amine

상기 실시예 1의 단계 1)에서 2-((메틸설포닐)메틸)아닐린을 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다.The title compound was obtained in the same manner as in Step 1) of Example 1 using 2-((methylsulfonyl)methyl)aniline in Step 1) of Example 1.

단계 2) 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민의 제조Step 2) 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 - Preparation of (2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 63: 5-클로로-Example 63: 5-Chloro- NN 22 -(3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)--(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)- NN 44 -(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine

Figure pat00148
Figure pat00148

상기 실시예 62의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 588.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 62. [M+H] + = 588.

실시예 64: 5-클로로-Example 64: 5-Chloro- NN 22 -(2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)--(2-Methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)- NN 44 -(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine

Figure pat00149
Figure pat00149

상기 실시예 62의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 601.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 62. [M+H] + = 601.

실시예 65: Example 65: NN -(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

Figure pat00150
Figure pat00150

단계 1) N-(4-클로로-2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)아세타마이드의 제조Step 1) Preparation of N- (4-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)acetamide

상기 실시예 1의 단계 1)에서 N-(2-아미노-4-클로로페닐)아세타마이드를 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다.In Step 1) of Example 1, the title compound was obtained in the same manner as in Step 1) of Example 1 using N- (2-amino-4-chlorophenyl)acetamide.

단계 2) N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조Step 2) N -(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine) Preparation of -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 66: Example 66: NN -(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

Figure pat00151
Figure pat00151

상기 실시예 65의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 614.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 65 and the corresponding aniline. [M+H] + = 614.

실시예 67: Example 67: NN -(4-클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드 의 제조-(4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl) amino) phenyl) acetamide

Figure pat00152
Figure pat00152

상기 실시예 65의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 587.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 65 and the corresponding aniline. [M+H] + = 587.

실시예 68: Example 68: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl) amino) phenyl) acetamide

Figure pat00153
Figure pat00153

단계 1) N-(2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)아세타마이드의 제조Step 1) Preparation of N- (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)acetamide

상기 실시예 1의 단계 1)에서 N-(2-아미노페닐)아세타마이드를 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다.In Step 1) of Example 1, the title compound was obtained in the same manner as in Step 1) of Example 1 using N- (2-aminophenyl)acetamide.

단계 2) N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조Step 2) N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 69: Example 69: NN -(2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드-(2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- 4-yl)amino)phenyl)acetamide

Figure pat00154
Figure pat00154

상기 실시예 68의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 553.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 68 and the corresponding aniline. [M+H] + = 553.

실시예 70: Example 70: NN -(2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- Preparation of 4-yl)amino)phenyl)acetamide

Figure pat00155
Figure pat00155

상기 실시예 68의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 554.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 68 and the corresponding aniline. [M+H] + = 554.

실시예 71: Example 71: NN -(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-) Preparation of 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

Figure pat00156
Figure pat00156

단계 1) N-(2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)아세타마이드의 제조Step 1) Preparation of N- (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)acetamide

N-(2-아미노-4,5-다이클로로페닐)아세타마이드 5.0 g (22.8 mmol)과 2,4,5-트라이클로로피리미딘 3.37 ml (35.0 mmol)을 다이메틸설폭사이드 54 ml에 묽히고 트라이에틸아민 7.54 ml (53.8 mmol)와 테트라뷰틸암모늄 아오다이드 841 mg (2.28 mmol)을 가한 후, 상온에서 24 시간 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 에틸 아세테이트로 묽힌 후 증류수 세척하였다. 얻어진 잔사를 컬럼 크로마토그래피 (50% 에틸 아세테이트 / 헥산)으로 분리하여 표제화합물 5.01 g (수율: 60 %)을 얻었다.Dilute 5.0 g (22.8 mmol) of N- (2-amino-4,5-dichlorophenyl)acetamide and 3.37 ml (35.0 mmol) of 2,4,5-trichloropyrimidine in 54 ml of dimethyl sulfoxide. After adding 7.54 ml (53.8 mmol) of higo triethylamine and 841 mg (2.28 mmol) of tetrabutylammonium iodide, the mixture was stirred at room temperature for 24 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The obtained residue was separated by column chromatography (50% ethyl acetate / hexane) to obtain 5.01 g (yield: 60%) of the title compound.

단계 2) N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이의 제조Step 2) N -(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)) Preparation of piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetami

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 72: Example 72: NN -(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

Figure pat00157
Figure pat00157

상기 실시예 71의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 71.

1H NMR (400 MHz, DMSO-d6) δ 9.97 (brs, 1H), 8.37 (s, 1H), 8.10-7.88 (m, 3H), 7.69 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.21 (d, J = 8.5 Hz, 1H), 4.19 (d, J = 12.7 Hz, 2H), 3.76 (s, 3H), 2.75 (t, J = 11.6 Hz, 3H), 2.64-2.30 (m, 11H), 2.09 (s, 3H), 1.87-1.75 (m, 2H), 1.46-1.32 (m, 2H). [M+H]+ = 639. 1 H NMR (400 MHz, DMSO-d6) δ 9.97 (brs, 1H), 8.37 (s, 1H), 8.10-7.88 (m, 3H), 7.69 (s, 1H), 7.51 (d, J = 8.5 Hz) , 1H), 6.21 (d, J = 8.5 Hz, 1H), 4.19 (d, J = 12.7 Hz, 2H), 3.76 (s, 3H), 2.75 (t, J = 11.6 Hz, 3H), 2.64-2.30 (m, 11H), 2.09 (s, 3H), 1.87-1.75 (m, 2H), 1.46-1.32 (m, 2H). [M+H] + = 639.

실시예 73: Example 73: NN -(4,5-다이클로로-2-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

Figure pat00158
Figure pat00158

상기 실시예 71의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 622.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 71. [M+H] + = 622.

실시예 74: Example 74: NN -(4,5-다이클로로-2-((5-클로로-2-((6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조Preparation of -(4,5-dichloro-2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

Figure pat00159
Figure pat00159

상기 실시예 71의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 508.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 71. [M+H] + = 508.

실시예 75: Example 75: NN -(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

Figure pat00160
Figure pat00160

상기 실시예 71의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 634.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 71. [M+H] + = 634.

실시예 76: Example 76: NN -(4,5-다이클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide

Figure pat00161
Figure pat00161

상기 실시예 71의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 621.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 71. [M+H] + = 621.

실시예 77: Example 77: NN -(4,5-다이클로로-2-((5-클로로-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of )amino)pyrimidin-4-yl)amino)phenyl)acetamide

Figure pat00162
Figure pat00162

상기 실시예 71의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 621.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 71. [M+H] + = 621.

실시예 78: Example 78: NN -(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)--(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)- NN -메틸아세타마이드-Methylacetamide

Figure pat00163
Figure pat00163

단계 1) N-(4,5-다이클로로-2-((2,5-다이클로로피리미딘-4-일)(메틸)아미노)페닐)-N-메틸아세타마이드의 제조Step 1) Preparation of N- (4,5-dichloro-2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)phenyl) -N -methylacetamide

상기 실시예 22의 단계 1)에서 제조된 화합물 1.0 g (2.73 mmol)을 N,N-다이메틸포름아마이드 6 ㎖에 묽히고 60 % 수소화나트륨 138 mg (6.0 mmol)을 0 ℃에서 천천히 가한 후 상온에서 30 분 교반시켰다. 여기에 메틸아이오다이드 0.22 ㎖ (3.6 mmol)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (50% 에틸 아세테이트/헥산) 정제하여 표제화합물 720 mg (수율: 66%)을 얻었다1.0 g (2.73 mmol) of the compound prepared in step 1) of Example 22 was diluted in 6 ml of N,N-dimethylformamide, 138 mg (6.0 mmol) of 60% sodium hydride was slowly added at 0° C., and then at room temperature was stirred for 30 min. 0.22 ml (3.6 mmol) of methyl iodide was slowly added thereto at 0° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate/hexane) to obtain 720 mg (yield: 66%) of the title compound.

단계 2) N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)-N-메틸아세타마이드의 제조Step 2) N -(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)) Preparation of piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl) -N -methylacetamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 79: Example 79: NN -(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)(메틸)아미노)페닐)--(4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)- NN -메틸아세타마이드의 제조-Preparation of methylacetamide

Figure pat00164
Figure pat00164

상기 실시예 78의 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 6-클로로-2-메톡시-3-나이트로피리딘과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The compound prepared in step 1) of Example 78 and 6-chloro-2-methoxy-3-nitropyridine and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 80: Example 80: NN -(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00165
Figure pat00165

단계 1) N-(4-클로로-2-나이트로페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (4-chloro-2-nitrophenyl)methanesulfonamide

4-클로로-2-나이트로아닐린 5.0 g (29.0 mmol)을 N,N-다이메틸포름아마이드 60 ml에 묽히고 60 % 수소화나트륨 1.33 g (58.0 mmol)을 0 ℃에서 천천히 가한 후 상온에서 30 분 교반시켰다. 여기에 메탄설포닐 클로라이드 2.68 ml (34.8 mmol)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (20% 에틸 아세테이트/헥산) 정제하여 표제화합물 5.1 g (수율: 70%)을 얻었다.5.0 g (29.0 mmol) of 4-chloro-2-nitroaniline was diluted in 60 ml of N,N-dimethylformamide, 1.33 g (58.0 mmol) of 60% sodium hydride was slowly added at 0 ° C., and then at room temperature for 30 minutes. stirred. To this, 2.68 ml (34.8 mmol) of methanesulfonyl chloride was slowly added at 0° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (20% ethyl acetate/hexane) to obtain 5.1 g (yield: 70%) of the title compound.

단계 2) N-(2-아미노-4-클로로페닐)메탄설폰아마이드의 제조Step 2) Preparation of N- (2-amino-4-chlorophenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물 5.1 g (20.0 mmol) 을 100 ml 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말 11.2 g (200 mmol)와 염화 암모늄 10.8 g (200 mmol)를 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 3.96 g (수율: 90%)를 얻었다5.1 g (20.0 mmol) of the compound prepared in step 1) was dissolved in 100 ml tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), and then 11.2 g (200 mmol) of iron powder and 10.8 g of ammonium chloride ( 200 mmol) was added and stirred at 85 °C for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain 3.96 g (yield: 90%) of the title compound.

단계 3) N-(4-클로로-2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)메탄설폰아마아이드의 제조Step 3) Preparation of N- (4-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide

상기 실시예 21의 단계 2)에서 상기 단계 2)에서 제조된 화합물을 사용하는 것을 제외하고는, 상기 실시예 21와 동일한 공정을 수행하여 표제화합물을 얻었다.The title compound was obtained in the same manner as in Example 21, except that the compound prepared in step 2) was used in step 2) of Example 21.

단계 4) N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조Step 4) N -(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine) Preparation of -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

상기 단계 3)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The compound prepared in step 3) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

1H NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.13-8.07 (m, 2H), 8.04 (brs, 1H), 7.36-7.26 (m, 2H), 7.09 (dd, J = 8.6, 2.4 Hz, 1H), 6.68 (s, 1H), 3.76 (s, 3H), 3.14-3.02 (m, 2H), 2.88 (s, 3H), 2.77-2.24 (m, 14H), 2.06 (s, 3H), 1.94-1.80 (m, 2H), 1.64-1.48 (m, 2H). 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (brs, 1H), 8.13-8.07 (m, 2H), 8.04 (brs, 1H), 7.36-7.26 (m, 2H), 7.09 (dd, J = 8.6, 2.4 Hz, 1H), 6.68 (s, 1H), 3.76 (s, 3H), 3.14-3.02 (m, 2H), 2.88 (s, 3H), 2.77-2.24 (m, 14H), 2.06 (s) , 3H), 1.94-1.80 (m, 2H), 1.64-1.48 (m, 2H).

실시예 81: Example 81: NN -(4-클로로-2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3) Preparation of -yl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide

Figure pat00166
Figure pat00166

상기 실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline.

1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.23 (brs, 1H), 8.17-8.04 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 6.9 Hz, 1H), 6.31 (d, J = 8.5 Hz, 1H), 4.25 (d, J = 13.0 Hz, 2H), 3.78 (s, 3H), 2.94 (d, J = 19.2 Hz, 3H), 2.76 (t, J = 11.8 Hz, 3H), 2.68-2.42 (m, 8H), 2.32 (s, 3H), 1.90-1.79 (m, 2H), 1.48-1.33 (m, 2H). [M+H]+ = 636. 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.23 (brs, 1H), 8.17-8.04 (m, 2H), 7.52 (d, J = 8.4 Hz, 1H), 7.28 (d , J = 8.5 Hz, 1H), 7.05 (d, J = 6.9 Hz, 1H), 6.31 (d, J = 8.5 Hz, 1H), 4.25 (d, J = 13.0 Hz, 2H), 3.78 (s, 3H) ), 2.94 (d, J = 19.2 Hz, 3H), 2.76 (t, J = 11.8 Hz, 3H), 2.68-2.42 (m, 8H), 2.32 (s, 3H), 1.90-1.79 (m, 2H) , 1.48-1.33 (m, 2H). [M+H] + = 636.

실시예 82: Example 82: NN -(4-클로로-2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl) amino) phenyl) methanesulfonamide

Figure pat00167
Figure pat00167

상기 실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline.

1H NMR (400 MHz, DMSO-d6) δ 8.73 (brs, 1H), 8.14 (brs, 1H), 8.12-8.02 (m, 2H), 7.38 (d, J = 8.6 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.06 (dd, J = 8.5, 2.3 Hz, 1H), 6.61 (d, J = 1.9 Hz, 1H), 6.50-6.41 (m, 1H), 3.83-3.63 (m, 5H), 2.89 (s, 3H), 2.76-2.20 (m, 14H), 1.92-1.80 (m, 2H), 1.60-1.44 (m, 2H). [M+H]+ = 635. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (brs, 1H), 8.14 (brs, 1H), 8.12-8.02 (m, 2H), 7.38 (d, J = 8.6 Hz, 1H), 7.29 (d , J = 8.5 Hz, 1H), 7.06 (dd, J = 8.5, 2.3 Hz, 1H), 6.61 (d, J = 1.9 Hz, 1H), 6.50-6.41 (m, 1H), 3.83-3.63 (m, 5H), 2.89 (s, 3H), 2.76-2.20 (m, 14H), 1.92-1.80 (m, 2H), 1.60-1.44 (m, 2H). [M+H] + = 635.

실시예 83: Example 83: NN -(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00168
Figure pat00168

상기 실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 650.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 650.

실시예 84: Example 84: NN -(4-클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드 의 제조-(4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl) amino) phenyl) methanesulfonamide

상기 실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 623.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 623.

Figure pat00169
Figure pat00169

실시예 85: Example 85: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino-4-chlorophenyl) methanesulfonamide

Figure pat00170
Figure pat00170

단계 1) N-(2-((5-브로모-2-클로로-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (2-((5-bromo-2-chloro-4-yl)amino)-4-chlorophenyl)methanesulfonamide

상기 실시예 80의 단계 3)에서 5-브로모-2,4-다이클로로피리미딘을 사용하는 것을 제외하고는, 상기 실시예 25의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. The title compound was obtained in the same manner as in step 3) of Example 25, except that 5-bromo-2,4-dichloropyrimidine was used in step 3) of Example 80.

단계 2)Step 2)

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

1H NMR (400 MHz, DMSO-d6) δ 8.67 (brs, 1H), 8.19-8.11 (m, 2H), 8.07 (brs, 1H), 7.33-7.26 (m, 2H), 7.07 (dd, J = 8.5, 2.4 Hz, 1H), 6.69 (s, 1H), 3.76 (s, 3H), 3.14-3.03 (m, 2H), 2.90 (s, 3H), 2.78-2.24 (m, 14H), 2.09 (s, 3H), 1.92-1.81 (m, 2H), 1.64-1.49 (m, 2H). 1 H NMR (400 MHz, DMSO-d6) δ 8.67 (brs, 1H), 8.19-8.11 (m, 2H), 8.07 (brs, 1H), 7.33-7.26 (m, 2H), 7.07 (dd, J = 8.5, 2.4 Hz, 1H), 6.69 (s, 1H), 3.76 (s, 3H), 3.14-3.03 (m, 2H), 2.90 (s, 3H), 2.78-2.24 (m, 14H), 2.09 (s) , 3H), 1.92-1.81 (m, 2H), 1.64-1.49 (m, 2H).

실시예 86: Example 86: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- Preparation of 3-yl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00171
Figure pat00171

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 694.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 694.

실시예 87: Example 87: NN -(2-((5-브로모-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine Preparation of -4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00172
Figure pat00172

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 667.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 667.

실시예 88: Example 88: NN -(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -4-chlorophenyl) methanesulfonamide

Figure pat00173
Figure pat00173

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline.

1H NMR (400 MHz, DMSO-d6) δ 8.68 (brs, 1H), 8.25-8.20 (m, 2H), 8.04 (brs, 1H), 7.58 (s, 1H), 7.30 (t, J = 8.7 Hz, 1H), 7.10 (dd, J = 8.5, 2.4 Hz, 1H), 6.78 (s, 1H), 3.80 (s, 3H), 3.36-3.25 (m, 2H), 2.92 (s, 3H), 2.80-2.27 (m, 14H), 1.94-1.80 (m, 2H), 1.66-1.52 (m, 2H). [M+H]+ = 713. 1 H NMR (400 MHz, DMSO-d6) δ 8.68 (brs, 1H), 8.25-8.20 (m, 2H), 8.04 (brs, 1H), 7.58 (s, 1H), 7.30 (t, J = 8.7 Hz) , 1H), 7.10 (dd, J = 8.5, 2.4 Hz, 1H), 6.78 (s, 1H), 3.80 (s, 3H), 3.36-3.25 (m, 2H), 2.92 (s, 3H), 2.80- 2.27 (m, 14H), 1.94-1.80 (m, 2H), 1.66-1.52 (m, 2H). [M+H] + = 713.

실시예 89: Example 89: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설포닐아마이드의 제조-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1) Preparation of -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonylamide

Figure pat00174
Figure pat00174

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 707.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 707.

실시예 90: Example 90: NN -(2-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5) Preparation of -methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00175
Figure pat00175

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 721.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 721.

실시예 91: Example 91: NN -(2-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00176
Figure pat00176

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 707.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 707.

실시예 92: Example 92: NN -(2-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of )amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00177
Figure pat00177

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 696.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 696.

실시예 93: Example 93: NN -(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl) amino) -4-chlorophenyl) methanesulfonamide

Figure pat00178
Figure pat00178

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 698.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 698.

실시예 94: Example 94: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri Preparation of midin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00179
Figure pat00179

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 680.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 680.

실시예 95: Example 95: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri Preparation of midin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00180
Figure pat00180

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 728.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 728.

실시예 96: Example 96: NN -(2-((5-브로모-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5 Preparation of -methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00181
Figure pat00181

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 712.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 712.

실시예 97: Example 97: NN -(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00182
Figure pat00182

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 712.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 712.

실시예 98: Example 98: NN -(2-((5-브로모-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5- Preparation of methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00183
Figure pat00183

상기 실시예 85의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 726.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 85 and the corresponding aniline. [M+H] + = 726.

실시예 99: Example 99: NN -(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-) Preparation of 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00184
Figure pat00184

단계 1) N-(4,5-다이클로로-2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (4,5-dichloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)methanesulfonamide

상기 실시예 80의 단계 1)에서 4,5-다이클로로-2-나이트로아닐린을 사용하는 것을 제외하고는, 상기 실시예 80의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. The title compound was obtained in the same manner as in step 3) of Example 80, except that 4,5-dichloro-2-nitroaniline was used in step 1) of Example 80.

단계 2) N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조Step 2) N -(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)) Preparation of piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 684.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used. [M+H] + = 684.

실시예 100: Example 100: NN -(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐메탄설폰아마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidine- Preparation of 1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenylmethanesulfonamide

Figure pat00185
Figure pat00185

상기 실시예 99의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 685.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 99. [M+H] + = 685.

실시예 101: Example 101: NN -(4,5-다이클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00186
Figure pat00186

상기 실시예 99의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 658.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 99. [M+H] + = 658.

실시예 102: Example 102: NN -(4,5-다이클로로-2-((5-클로로-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아민노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl) Preparation of )amineno)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00187
Figure pat00187

상기 실시예 99의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 691.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 99. [M+H] + = 691.

실시예 103: Example 103: NN -(4,5-다이클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노페닐)메탄설폰아마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine- Preparation of 1-yl)phenyl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide

Figure pat00188
Figure pat00188

상기 실시예 99의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 704.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 99. [M+H] + = 704.

실시예 104: Example 104: NN -(4,5-다이클로로-2-((5-클로로-2-((4-(4-((2-(다이메틸아미노)에틸)(메틸)아미노)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((4-(4-((2-(dimethylamino)ethyl)(methyl)amino)piperidin-1-yl) Preparation of -2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00189
Figure pat00189

상기 실시예 99의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 686.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 99. [M+H] + = 686.

실시예 105: Example 105: NN -(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(메틸(3-(4-메틸피페라진-1-일)프로필)아미노)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설포나마이드의 제조-(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(methyl(3-(4-methylpiperazin-1-yl)propyl)) Preparation of amino) phenyl) amino) pyrimidin-4-yl) amino) phenyl) methanesulfonamide

Figure pat00190
Figure pat00190

상기 실시예 99의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 672.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 99. [M+H] + = 672.

실시예 106: Example 106: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -4-methylphenyl) methanesulfonamide

Figure pat00191
Figure pat00191

단계 1) N-(2-((5-브로모-2-클로로피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (2-((5-bromo-2-chloropyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide

상기 실시예 24의 단계 1)에서 4-메틸-2-나이트로아닐린을 사용하는 것과 상기 실시예 24의 단계 3)에서 5-브로모-2,4-다이클로로피리미딘을 사용하는 것을 제외하고는, 상기 실시예 24의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. Except for using 4-methyl-2-nitroaniline in step 1) of Example 24 and using 5-bromo-2,4-dichloropyrimidine in step 3) of Example 24 was carried out in the same manner as in step 3) of Example 24 to obtain the title compound.

단계 2) N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드의 제조Step 2) N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 107: Example 107: NN -(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -4-methylphenyl) methanesulfonamide

Figure pat00192
Figure pat00192

상기 실시예 106의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 694.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 106. [M+H] + = 694.

실시예 108: Example 108: NN -(2-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메톡시-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methoxy-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -4-methylphenyl) methanesulfonamide

Figure pat00193
Figure pat00193

상기 실시예 106의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 677.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 106. [M+H] + = 677.

실시예 109: Example 109: NN -(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide

Figure pat00194
Figure pat00194

상기 실시예 106의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 678.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 106. [M+H] + = 678.

실시예 110: N -(5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)- N -(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드의 제조 Example 110 : N- (5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino)pyrimidin-4-yl)-N- ( 4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide

Figure pat00195
Figure pat00195

단계 1) N-(2,5-다이클로로피리미딘-4-일)-4-나이트로벤조[d]싸이아졸-5-아민의 제조Step 1) Preparation of N- (2,5-dichloropyrimidin-4-yl)-4-nitrobenzo[d]thiazol-5-amine

4-나이트로벤조[d]싸이아졸-5-아민 5.0 g (25.6 mmol)을 N,N-다이메틸포름아마이드 50 ml에 묽히고 60 % 수소화나트륨 883 mg (38.4 mmol)을 0 ℃에서 천천히 가한 후 상온에서 30 분 교반시켰다. 여기에 2,4,5-트라이클로로피리미딘 3.5 ml (30.7 mmol)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (40% 에틸 아세테이트/헥산) 정제하여 표제화합물 6.84 g (수율: 52%)을 얻었다.5.0 g (25.6 mmol) of 4-nitrobenzo[d]thiazol-5-amine was diluted in 50 ml of N,N-dimethylformamide, and 883 mg (38.4 mmol) of 60% sodium hydride was slowly added at 0 °C. Then, the mixture was stirred at room temperature for 30 minutes. 3.5 ml (30.7 mmol) of 2,4,5-trichloropyrimidine was slowly added thereto at 0° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (40% ethyl acetate/hexanes) to obtain 6.84 g (yield: 52%) of the title compound.

단계 2) N 5-(2,5-다이클로로피리미딘-4-일)벤조[d]싸이아졸-4,5-다이아민Step 2) N 5 -(2,5-dichloropyrimidin-4-yl)benzo[d]thiazole-4,5-diamine

상기 단계 1)에서 제조된 화합물 6.84 g (20.0 mmol)을 40 ml 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 묽힌 후 철 분말 11.2 g (200 mmol)와 염화 암모늄 10.8 g (200 mmol)를 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 5.6 g (수율: 90%)를 얻었다After diluting 6.84 g (20.0 mmol) of the compound prepared in step 1) in 40 ml tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), 11.2 g (200 mmol) of iron powder and 10.8 g of ammonium chloride ( 200 mmol) was added and stirred at 85 °C for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain 5.6 g (yield: 90%) of the title compound.

단계 3) N-(2,5-다이클로로피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드Step 3) N -(2,5-dichloropyrimidin-4-yl ) -N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide

상기 단계 2)에서 제조된 화합물 5.6 g (18.0 mmol)을 N,N-다이메틸포름아마이드 40 ml에 묽히고 트라이에틸아민 5.0 ml (36.0 mmol)와 메탄설포닐 클로라이드 3.2 ml (45.0 mmol)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (50% 에틸 아세테이트/헥산) 정제하여 표제화합물 7.02 g (수율: 83%)을 얻었다.5.6 g (18.0 mmol) of the compound prepared in step 2) was diluted in 40 ml of N,N-dimethylformamide, and 5.0 ml (36.0 mmol) of triethylamine and 3.2 ml (45.0 mmol) of methanesulfonyl chloride were added to 0 After adding slowly at ℃, the mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate/hexanes) to obtain 7.02 g (yield: 83%) of the title compound.

단계 4) N-(5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드의 제조Step 4) N- (5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl)-N-(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정을 수행하여 표제화합물을 얻었다. [M+H]+ = 750.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used. [M+H] + = 750.

실시예 111: Example 111: NN -(5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)--(5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidine- 4-day)- NN -(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드의 제조Preparation of -(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide

Figure pat00196
Figure pat00196

상기 실시예 110의 단계 3)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 737.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 3) of Example 110. [M+H] + = 737.

실시예 112: Example 112: NN -(5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)--(5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl) - NN -(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드의 제조Preparation of -(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide

Figure pat00197
Figure pat00197

상기 실시예 110의 단계 3)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 724.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 3) of Example 110. [M+H] + = 724.

실시예 113: Example 113: NN -(5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)--(5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidine- 4-day)- NN -(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드의 제조Preparation of -(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide

Figure pat00198
Figure pat00198

상기 실시예 110의 단계 3)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 725.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 3) of Example 110. [M+H] + = 725.

실시예 114: Example 114: NN -(5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)--(5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- 4-day)- NN -(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드의 제조Preparation of -(4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide

Figure pat00199
Figure pat00199

상기 실시예 110의 단계 3)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 770.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 3) of Example 110. [M+H] + = 770.

실시예 115: Example 115: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide

Figure pat00200
Figure pat00200

단계 1) N-(6-((2,5-다이클로로피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드의 제조Step 1) Preparation of N- (6-((2,5-dichloropyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide

상기 실시예 80의 단계 1)에서 6-나이트로퀴놀린-5-아민과 2,4-다이클로로피리미딘을 사용하는 것을 제외하고는, 상기 실시예 80과 동일한 공정으로 수행하여 표제화합물을 얻었다. The title compound was obtained in the same manner as in Example 80, except that 6-nitroquinolin-5-amine and 2,4-dichloropyrimidine were used in step 1) of Example 80.

단계 2)Step 2)

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 116: Example 116: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3) Preparation of -yl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide

Figure pat00201
Figure pat00201

상기 실시예 115의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 667.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 115. [M+H] + = 667.

실시예 117: Example 117: NN -(6-((5-클로로-2-((2-메톡시-6-(4-몰폴리노피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino ) Preparation of quinolin-5-yl) methanesulfonamide

Figure pat00202
Figure pat00202

상기 실시예 115의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 640.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 115. [M+H] + = 640.

실시예 118: Example 118: NN -(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메톡시피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methoxypiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) quinolin-5-yl) methanesulfonamide

Figure pat00203
Figure pat00203

상기 실시예 115의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 686. The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 115. [M+H] + = 686.

실시예 119: Example 119: NN -(6-((5-클로로-2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl ) Preparation of methanesulfonamide

Figure pat00204
Figure pat00204

상기 실시예 115의 단계 1)에서 제조된 화합물과 상응하는 하기 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 569.The title compound was obtained in the same manner as in Example 1 using the following aniline corresponding to the compound prepared in step 1) of Example 115. [M+H] + = 569.

실시예 120: N -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)메탄설폰아마이드의 제조 Example 120 : N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) Preparation of yl) phenyl) amino) pyrimidin-4-yl) (methyl) amino) phenyl) methanesulfonamide

Figure pat00205
Figure pat00205

단계 1) 2,5-다이클로로-N-메틸-N-(2-나이트로페닐)피리미딘-4-아민Step 1) 2,5-dichloro- N -methyl- N- (2-nitrophenyl)pyrimidin-4-amine

N-메틸-2-나이트로아닐린 5.0 g (32.9 mmol)을 N,N-다이메틸포름아마이드 50 ml에 묽히고 60 % 수소화나트륨 883 mg (38.4 mmol)을 0 ℃에서 천천히 가한 후 상온에서 30 분 교반시켰다. 여기에 2,4,5-트라이클로로피리미딘 4.6 ml (40.0 mmol)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (20% 에틸 아세테이트/헥산) 정제하여 표제화합물 5.98 g (수율: 61%)을 얻었다.5.0 g (32.9 mmol) of N -methyl-2-nitroaniline was diluted in 50 ml of N , N -dimethylformamide, 883 mg (38.4 mmol) of 60% sodium hydride was slowly added at 0 °C, and then at room temperature for 30 minutes. stirred. 4.6 ml (40.0 mmol) of 2,4,5-trichloropyrimidine was slowly added thereto at 0° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (20% ethyl acetate/hexanes) to obtain 5.98 g (yield: 61%) of the title compound.

단계 2) N 1-(2,5-다이클로로피리미딘-4-일)-N 1-메틸벤젠-1,2-다이아민의 제조Step 2) Preparation of N 1 -(2,5-dichloropyrimidin-4-yl) -N 1 -methylbenzene-1,2-diamine

상기 단계 1)에서 얻어진 화합물 5.98 g (20.0 mmol)을 40 ml 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말 11.8 g (200 mmol)와 염화 암모늄 10.8 g (200 mmol)를 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 추출하여 감압 여과한 후 농축하여 표제화합물 4.8 g (수율: 90%)를 얻었다.5.98 g (20.0 mmol) of the compound obtained in step 1) was dissolved in 40 ml tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), and then 11.8 g (200 mmol) of iron powder and 10.8 g (200 mmol) of ammonium chloride mmol) was added and stirred at 85 °C for 3 hours. After completion of the reaction, the reaction mixture was extracted with dichloromethane through a filter filled with celite, filtered under reduced pressure, and concentrated to obtain 4.8 g (yield: 90%) of the title compound.

단계 3) N-(2-((2,5-다이클로로피리미딘-4-일)(메틸)아미노)페닐)메탄설폰아마이드의 제조Step 3) Preparation of N- (2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide

상기 단계 2)에서 얻어진 화합물 4.8 g (18.0 mmol)을 상기 실시예 26의 단계 1)과 동일한 공정으로 실시하여 표제화합물을 얻었다.4.8 g (18.0 mmol) of the compound obtained in step 2) was carried out in the same manner as in step 1) of Example 26 to obtain the title compound.

단계 4) N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)메탄설폰아마이드의 제조Step 4) N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide

상기 단계 3)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The compound prepared in step 3) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 121: N -(2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)(메틸)아미노)페닐)메탄설폰아마이드의 제조 Example 121 : N- (2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) Preparation of yl)pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide

Figure pat00206
Figure pat00206

상기 실시예 120의 단계 3)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 2-클로로-6-메톡시-3-메틸-5-나이트로피리딘과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The compound prepared in step 3) of Example 120 and 2-chloro-6-methoxy-3-methyl-5-nitropyridine and 1-methyl-4-piperidine in step 2) of Example 1 The title compound was obtained in the same manner as in Example 1, except that -4-yl-piperazine hydrochloride was used.

실시예 122: (6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 122: (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) Preparation of pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00207
Figure pat00207

단계 1) 6-나이트로퀴녹살린의 제조Step 1) Preparation of 6-nitroquinoxaline

4-나이트로벤젠-1,2-다이아민 5.0 g, (32.7 mmol)을 에탄올 70 ml에 묽히고 40% 글리옥살 용액 (35 mmol) 가한 후 80 ℃에서 12시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 실온으로 냉각시키고 에틸 아세테이트와 증류수로 추출하여 감압 여과한 후 농축하여 표제화합물 4.9 g (수율: 86%)를 얻었다.5.0 g of 4-nitrobenzene-1,2-diamine, (32.7 mmol) was diluted in 70 ml of ethanol, and 40% glyoxal solution (35 mmol) was added thereto, followed by stirring at 80° C. for 12 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate and distilled water, filtered under reduced pressure, and concentrated to obtain 4.9 g (yield: 86%) of the title compound.

단계 2) 퀴녹살린-6-아민의 제조Step 2) Preparation of quinoxalin-6-amine

상기 단계 1)에서 얻어진 화합물 4.9 g (28.0 mmol)을 60 ml 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말 11.8 g (200 mmol)와 염화 암모늄 10.8 g (200 mmol)를 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 추출하여 감압 여과한 후 농축하여 표제화합물 3.6 g (수율: 89%)를 얻었다After dissolving 4.9 g (28.0 mmol) of the compound obtained in step 1) in 60 ml tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), 11.8 g (200 mmol) of iron powder and 10.8 g (200 mmol) of ammonium chloride mmol) was added and stirred at 85 °C for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted with dichloromethane through a filter filled with celite, filtered under reduced pressure, and concentrated to obtain 3.6 g (yield: 89%) of the title compound.

단계 3) 5-아이오도퀴녹살린-6-아민의 제조Step 3) Preparation of 5-iodoquinoxalin-6-amine

상기 단계 2)에서 얻어진 화합물 3.6 g (25.0 mmol)을 아세트산 60 ml에 묽히고 일염화 아이오딘 4.9 g (30.0 mmol)을 가한 후 상온에서 2시간 동안 교반 시켰다. 반응이 완결된 후 포화 중탄산나트륨 용액과 다이클로로메테인으로 농축하여 표제화합물 4.9 g (수율: 72%)을 얻었다.3.6 g (25.0 mmol) of the compound obtained in step 2) was diluted in 60 ml of acetic acid, 4.9 g (30.0 mmol) of iodine monochloride was added thereto, followed by stirring at room temperature for 2 hours. After the reaction was completed, it was concentrated with saturated sodium bicarbonate solution and dichloromethane to obtain 4.9 g (yield: 72%) of the title compound.

단계 4) (6-아미노퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Step 4) Preparation of (6-aminoquinoxalin-5-yl)dimethylphosphine oxide

상기 단계 3)에서 얻어진 화합물 4.9 g (18.0 mmol)과 다이메틸포스핀 옥사이드1.68 g (21.6 mmol)와 트라이포타슘 포스페이트 7.6 g (36.0 mmol)을 60 ml N,N-다이메틸포름아마이드 : 증류수 = 5 : 1 (부피비)에 묽히고 잔트포스와 팔라듐 다이아세테이트를 촉매량 가한 후 120 ℃에서 24시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 추출하여 감압 여과한 후 농축하여 표제화합물 2.2 g (수율: 56%)를 얻었다4.9 g (18.0 mmol) of the compound obtained in step 3), 1.68 g (21.6 mmol) of dimethylphosphine oxide, and 7.6 g (36.0 mmol) of tripotassium phosphate were mixed with 60 ml N , N -dimethylformamide: distilled water = 5 : Diluted to 1 (volume ratio), xanthoth and palladium diacetate were added in a catalytic amount, followed by stirring at 120 °C for 24 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with dichloromethane through a filter filled with celite, filtered under reduced pressure, and concentrated to obtain 2.2 g (yield: 56%) of the title compound.

단계 5) 6-((2,5-다이클로로피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스옥사이드의 제조Step 5) Preparation of 6-((2,5-dichloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethyl phosphate

상기 단계 4)에서 얻어진 화합물 2.2 g (10.0 mmol)을 N,N-다이메틸포름아마이드 20 ml에 묽히고 60 % 수소화나트륨 440 mg (19.2 mmol)을 0 ℃에서 천천히 가한 후 상온에서 30 분 교반시켰다. 여기에 2,4,5-트라이클로로피리미딘 2.3 ml (20.0 mmol)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (50% 에틸 아세테이트/헥산) 정제하여 표제화합물 2.2 g (수율: 60%)을 얻었다.2.2 g (10.0 mmol) of the compound obtained in step 4) was diluted in 20 ml of N , N -dimethylformamide, and 440 mg (19.2 mmol) of 60% sodium hydride was slowly added at 0° C., followed by stirring at room temperature for 30 minutes. . 2.3 ml (20.0 mmol) of 2,4,5-trichloropyrimidine was slowly added thereto at 0° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate/hexane) to obtain 2.2 g (yield: 60%) of the title compound.

단계 6) (6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Step 6) (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine) Preparation of -3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

상기 단계 5)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 2-클로로-6-메톡시-3-메틸-5-나이트로피리딘과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. The compound prepared in step 5) and 2-chloro-6-methoxy-3-methyl-5-nitropyridine and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used.

실시예 123: (6-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 123: (6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3- Preparation of yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00208
Figure pat00208

상기 실시예 122의 단계 5)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 637.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 5) of Example 122 and the corresponding aniline. [M+H] + = 637.

실시예 124: (6-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 124: (6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3- Preparation of yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00209
Figure pat00209

상기 실시예 122의 단계 5)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 623.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 5) of Example 122 and the corresponding aniline. [M+H] + = 623.

실시예 125: (6-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드의 제조Example 125: (6-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) Preparation of pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00210
Figure pat00210

상기 실시예 122의 단계 5)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 624.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 5) of Example 122 and the corresponding aniline. [M+H] + = 624.

실시예 126: (6-((5-클로로-2-((2-메톡시-6-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 126: (6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3- Preparation of yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00211
Figure pat00211

상기 실시예 122의 단계 5)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 582.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 5) of Example 122 and the corresponding aniline. [M+H] + = 582.

실시예 127: (6-((5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 127: (6-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine Preparation of -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00212
Figure pat00212

상기 실시예 122의 단계 5)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 568.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 5) of Example 122 and the corresponding aniline. [M+H] + = 568.

실시예 128: (6-((5-클로로-2-((2-메톡시-6-(피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 128: (6-((5-chloro-2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoc Preparation of salin-5-yl)dimethylphosphine oxide

Figure pat00213
Figure pat00213

상기 실시예 122의 단계 5)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 540.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 5) of Example 122 and the corresponding aniline. [M+H] + = 540.

실시예 129: 4-(5-((5-클로로-4-((5-(다이메틸포스포릴)퀴녹살린-6-일)아미노)피리미딘-2-일)아미노)-6-메톡시피리딘-2-일)싸이오몰폴린 1,1-다이옥사이드 의 제조Example 129: 4-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-6-methoxy Preparation of pyridin-2-yl)thiomorpholine 1,1-dioxide

Figure pat00214
Figure pat00214

상기 실시예 122의 단계 5)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 589.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 5) of Example 122 and the corresponding aniline. [M+H] + = 589.

실시예 130: (6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 130: (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00215
Figure pat00215

단계 1) 6-나이트로퀴녹살린-5-아민의 제조Step 1) Preparation of 6-nitroquinoxalin-5-amine

상기 실시예 122의 단계 1)에서 제조된 화합물 5.0 g (28.5 mmol)을 60 ml 메탄올에 묽히고 소듐 t-뷰톡사이드 5.8 g (60 mmol), 하이드록실아민 염산염 4.1 g (60 mmol)을 0 ℃에서 가한 후 65 ℃에서 4시간 동한 교반시켰다. 반응이 완결된 후 반응 혼합물을 실온으로 냉각시키고 다이클로로메탄으로 추출하여 감압 여과한 후 농축하여 표제화합물 3.2 g (수율: 60%)을 얻었다5.0 g (28.5 mmol) of the compound prepared in step 1) of Example 122 was diluted in 60 ml methanol, and sodium t-butoxide 5.8 g (60 mmol) and hydroxylamine hydrochloride 4.1 g (60 mmol) were added at 0 ° C. After addition, the mixture was stirred at 65 °C for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, extracted with dichloromethane, filtered under reduced pressure, and concentrated to obtain 3.2 g (yield: 60%) of the title compound.

단계 2) N-(메틸설포닐)-N-(6-나이트로퀴녹살린-5-일)메탄설폰아마이드의 제조Step 2) Preparation of N- (methylsulfonyl) -N- (6-nitroquinoxalin-5-yl)methanesulfonamide

상기 단계 1)에서 제조된 화합물 3.2 g (17 mmol)을 N,N-다이메틸포름아마이드 30 ml에 묽히고 60 % 수소화나트륨 575 mg (25 mmol)을 0 ℃에서 천천히 가한 후 상온에서 30 분 교반시켰다. 여기에 메탄설포닐 클로라이드 2.7 ml (36.0 mmol)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (50% 에틸 아세테이트/헥산) 정제하여 표제화합물 4.8 g (수율: 82%)을 얻었다.3.2 g (17 mmol) of the compound prepared in step 1) was diluted in 30 ml of N,N-dimethylformamide, 575 mg (25 mmol) of 60% sodium hydride was slowly added at 0° C., and stirred at room temperature for 30 minutes. did it 2.7 ml (36.0 mmol) of methanesulfonyl chloride was slowly added thereto at 0° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate/hexane) to obtain 4.8 g (yield: 82%) of the title compound.

단계 3) N-(6-아미노퀴녹살린-5-일)-N-(메틸설포닐)메탄설폰아마이드Step 3) N -(6-aminoquinoxalin-5-yl) -N- (methylsulfonyl)methanesulfonamide

상기 단계 2)에서 제조된 화합물 4.8 g (14.0 mmol)을 30 ml 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말 7.8 g (140 mmol)와 염화 암모늄 7.6 g (140 mmol)를 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 3.16 g (수율: 71%)를 얻었다.4.8 g (14.0 mmol) of the compound prepared in step 2) was dissolved in 30 ml tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), and then 7.8 g (140 mmol) of iron powder and 7.6 g of ammonium chloride ( 140 mmol) was added and stirred at 85 °C for 3 hours. After completion of the reaction, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain 3.16 g (yield: 71%) of the title compound.

단계 4) (6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Step 4) (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

상기 단계 3)에서 제조된 화합물을 사용하여 상시 실시예 1의 단계 1)과 단계 3)과동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 745.Using the compound prepared in step 3), the same process as steps 1) and 3) of Example 1 was always performed to obtain the title compound. [M+H] + = 745.

실시예 131: Example 131: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide

Figure pat00216
Figure pat00216

단계 1) N-(6-나이트로퀴녹살린-5-일)메탄설폰아마이드의 제조Step 1) Preparation of N- (6-nitroquinoxalin-5-yl)methanesulfonamide

상기 실시예 130의 단계 2)과 동일한 공정으로 제조된 화합물 5.0 g (28.5 mmol)을 40 ml 2 N 소듐 하이드록사리드 / 테트라하이드로퓨란 묽히고 상온에서 4시간 동한 교반시켰다. 반응이 완결된 후 반응 혼합물을 실온으로 냉각시키고 다이클로로메탄으로 추출하여 감압 여과한 후 농축하여 표제화합물 6.7 g (수율: 87%)을 얻었다5.0 g (28.5 mmol) of the compound prepared in the same process as step 2) of Example 130 was diluted with 40 ml 2 N sodium hydroxide / tetrahydrofuran and stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted with dichloromethane, filtered under reduced pressure, and concentrated to obtain 6.7 g (yield: 87%) of the title compound.

단계 2) N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드의 제조Step 2) N -(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide

상기 실시예 130의 단계 3)과 단계 4)와 동일한 공중을 수행하여 표제화합물을 얻었다. The same procedure as in step 3) and step 4) of Example 130 was carried out to obtain the title compound.

1H NMR (400 MHz, DMSO-d6) δ 9.92 (brs, 1H), 9.00 (d, J = 1.8 Hz, 1H), 8.96 (brs, 1H), 8.93 (d, J = 1.8 Hz, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.25-8.22 (m, 2H), 7.90 (d, J = 9.3 Hz, 1H), 7.38 (s, 1H), 6.72 (s, 1H), 3.76 (s, 3H), 3.16-2.96 (m, 5H), 2.74-2.27 (m, 11H), 2.21 (s, 3H), 2.02 (s, 3H), 1.93-1.80 (m, 2H), 1.65-1.48 (m, 2H). [M+H]+ = 667. 1 H NMR (400 MHz, DMSO-d6) δ 9.92 (brs, 1H), 9.00 (d, J = 1.8 Hz, 1H), 8.96 (brs, 1H), 8.93 (d, J = 1.8 Hz, 1H), 8.71 (d, J = 8.5 Hz, 1H), 8.25-8.22 (m, 2H), 7.90 (d, J = 9.3 Hz, 1H), 7.38 (s, 1H), 6.72 (s, 1H), 3.76 (s) , 3H), 3.16-2.96 (m, 5H), 2.74-2.27 (m, 11H), 2.21 (s, 3H), 2.02 (s, 3H), 1.93-1.80 (m, 2H), 1.65-1.48 (m) , 2H). [M+H] + = 667.

실시예 132: Example 132: NN -(6-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino Preparation of )pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide

Figure pat00217
Figure pat00217

상기 실시예 131에서 상응하는 아닐린을 사용하여 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 654.The same procedure was carried out using the corresponding aniline in Example 131 to obtain the title compound. [M+H] + = 654.

실시예 133: Example 133: NN -(6-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- Preparation of 4-yl)amino)quinoxalin-5-yl)methanesulfonamide

Figure pat00218
Figure pat00218

상기 실시예 131에서 상응하는 아닐린을 사용하여 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 653.The same procedure was carried out using the corresponding aniline in Example 131 to obtain the title compound. [M+H] + = 653.

실시예 134: Example 134: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3) Preparation of -yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide

Figure pat00219
Figure pat00219

상기 실시예 131에서 상응하는 아닐린을 사용하여 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 667.The same procedure was carried out using the corresponding aniline in Example 131 to obtain the title compound. [M+H] + = 667.

실시예 135: Example 135: NN -(6-((5-클로로-2-((2-메톡시-6-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3-yl)amino Preparation of )pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide

Figure pat00220
Figure pat00220

상기 실시예 131에서 상응하는 아닐린을 사용하여 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 598.The same procedure was carried out using the corresponding aniline in Example 131 to obtain the title compound. [M+H] + = 598.

실시예 136: Example 136: NN -(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-y일)아미노)퀴녹살린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yyl)amino)quinoxalin-5-yl)methanesulfonamide

Figure pat00221
Figure pat00221

상기 실시예 131에서 상응하는 아닐린을 사용하여 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 686.The same procedure was carried out using the corresponding aniline in Example 131 to obtain the title compound. [M+H] + = 686.

실시예 137: Example 137: NN -(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-(트라이플루오로메틸)페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide

Figure pat00222
Figure pat00222

상기 실시예 1의 단계 1)에서 N-(2-아미노-4-(트라이플루오로메틸)페닐)메탄설폰아마이드와 단계 2) 상응하는 아닐린을 사용한 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 703.The same procedure as in Example 1, except that in Step 1) of Example 1, N- (2-amino-4-(trifluoromethyl)phenyl)methanesulfonamide and Step 2) the corresponding aniline were used. was carried out to obtain the title compound. [M+H] + = 703.

실시예 138: Example 138: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-(트라이플루오로메틸)페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide

Figure pat00223
Figure pat00223

상기 실시예 137에서 상응하는 아닐린을 사용하여 상기 실시예 139과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 683.The title compound was obtained in the same manner as in Example 139 using the corresponding aniline in Example 137. [M+H] + = 683.

실시예 139: Example 139: NN -(2-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-(트라이플루오로메틸)페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino Preparation of )pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide

Figure pat00224
Figure pat00224

상기 실시예 137에서 상응하는 아닐린을 사용하여 상기 실시예 139과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 709.The title compound was obtained in the same manner as in Example 139 using the corresponding aniline in Example 137. [M+H] + = 709.

실시예 140: Example 140: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00225
Figure pat00225

상기 실시예 80의 단계 1)에서 6-나이트로-2,3-다이하이드로벤조퓨란-5-아민을사용 한 것을 제외하고는, 상기 실시예 83과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 657.The title compound was obtained in the same manner as in Example 83, except that 6-nitro-2,3-dihydrobenzofuran-5-amine was used in step 1) of Example 80. [M+H] + = 657.

실시예 141: Example 141: NN -(2-((6-아미노-5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((6-amino-5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00226
Figure pat00226

상기 실시예 1의 단계 1)에서 2,5,6-트라이클로로피리미딘-4-아민을 사용 한 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 648.The title compound was obtained in the same manner as in Example 1, except that 2,5,6-trichloropyrimidin-4-amine was used in step 1) of Example 1. [M+H] + = 648.

실시예 142: ((2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸-Example 142: ((2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl- λ λ 66 -설파논의 제조-Preparation of sulfanone

Figure pat00227
Figure pat00227

단계 1) N-(다이메틸옥시도-λ4-설파닐리덴)-2-나이트로-벤제나민의 제조Step 1) Preparation of N- (dimethyloxido-λ 4 -sulfanylidene)-2-nitro-benzenamine

1-옥소-1,7a-다이하이드로벤조[c][1,2,5]옥사다이아졸-1-이움 5.0 g (40.3 mmol) 을 다이메틸설폭사이드 80 ml에 묽히고 120 ℃에서 12 시간 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 에틸 아세테이트로 묽힌 후 증류수 세척하였다. 얻어진 잔사를 컬럼 크로마토그래피 (20% 에틸 아세테이트 / 헥산)으로 분리하여 표제화합물 4.28 g (수율: 50 %)을 얻었다.5.0 g (40.3 mmol) of 1-oxo-1,7a-dihydrobenzo[c][1,2,5]oxadiazol-1-ium was diluted in 80 ml of dimethyl sulfoxide and stirred at 120° C. for 12 hours. did it Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The obtained residue was separated by column chromatography (20% ethyl acetate / hexane) to obtain 4.28 g (yield: 50%) of the title compound.

단계 2) 다이메틸((2-나이트로페닐)이미노)-l6-설파논의 제조Step 2) Preparation of dimethyl((2-nitrophenyl)imino)-16-sulfanone

상기 단계 1)에서 제조된 화합물 4.28 g (20 mmol)을 40 ml 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말 0.3 g (2.7 mmol)와 염화 암모늄 0.16 g (2.7 mmol)를 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 3.3 g (수율: 90%)를 얻었다. 4.28 g (20 mmol) of the compound prepared in step 1) was dissolved in 40 ml of tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), and then 0.3 g (2.7 mmol) of iron powder and 0.16 g of ammonium chloride ( 2.7 mmol) was added and stirred at 85 °C for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain 3.3 g (yield: 90%) of the title compound.

단계 3) ((2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)이미노)다이메틸-l6-설파논의 제조Step 3) Preparation of ((2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)imino)dimethyl-16-sulfanone

상기 단계 2)에서 제조된 화합물 3.3 g (18 mmol)과 5-브로모-2,4-다이클로로피리미딘 3.37 ml (35.0 mmol)을 아이소프로필알코올 54 ml에 묽히고 N,N-다이아이소프로필에틸아민 9.3 ㎖ (53.8 mmol)을 가한 후, 60 ℃에서 12 시간 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 에틸 아세테이트로 묽힌 후 증류수 세척하였다. 얻어진 잔사를 컬럼 크로마토그래피 (50% 에틸 아세테이트 / 헥산)으로 분리하여 표제화합물 3.31 g (수율: 55 %)을 얻었다.Dilute 3.3 g (18 mmol) of the compound prepared in step 2) and 3.37 ml (35.0 mmol) of 5-bromo-2,4-dichloropyrimidine in 54 ml of isopropyl alcohol , N,N -diisopropyl After adding 9.3 ml (53.8 mmol) of ethylamine, the mixture was stirred at 60° C. for 12 hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with distilled water. The obtained residue was separated by column chromatography (50% ethyl acetate / hexane) to obtain 3.31 g (yield: 55%) of the title compound.

단계 4) ((2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸- λ 6-설파논의 제조Step 4) ((2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) ) phenyl) amino) pyrimidin-4-yl) amino) phenyl) imino) dimethyl- Preparation of λ 6 -sulfanone

상기 단계 3에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3 and the corresponding aniline.

[M+H]+ = 657[M+H] + = 657

실시예 143: ((2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸-Example 143: ((2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl- λ λ 66 -설파논의 제조-Preparation of sulfanone

Figure pat00228
Figure pat00228

상기 실시예 142의 단계 3)과 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 678.The title compound was obtained in the same manner as in Step 3) and Step 4) of Example 142. [M+H] + = 678.

실시예 144: ((2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸-Example 144: ((2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) ) phenyl) amino) pyrimidin-4-yl) amino) phenyl) imino) dimethyl- λλ 66 -설파논sulfanone의 제조-Production of sulfanone sulfanone

Figure pat00229
Figure pat00229

상기 실시예 142의 단계 3)과 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 662.The title compound was obtained in the same manner as in Step 3) and Step 4) of Example 142. [M+H] + = 662.

실시예 145: Example 145: NN -(2-((5-브로모-2-((2-메톡시-6-(1-메틸아제판-4-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-6-(1-methylazepan-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino) Preparation of -5-fluorophenyl)methanesulfonamide

Figure pat00230
Figure pat00230

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 594.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 594.

실시예 146: Example 146: NN -(2-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of )amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00231
Figure pat00231

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 681.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 681.

실시예 147: Example 147: NN -(2-((5-브로모-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) Preparation of amino) pyrimidin-4-yl) amino)-5-fluorophenyl) methanesulfonamide

Figure pat00232
Figure pat00232

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 696.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 696.

실시예 148: Example 148: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1') Preparation of -yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00233
Figure pat00233

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 730.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 730.

실시예 149: Example 149: NN -(2-((5-브로모-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2- Preparation of methoxyphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00234
Figure pat00234

상기 실시예 24의 단계 1)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 726.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 1) of Example 24 and the corresponding aniline. [M+H] + = 726.

실시예 150: Example 150: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1') Preparation of -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide

Figure pat00235
Figure pat00235

상기 실시예 85의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 747.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 85 and the corresponding aniline. [M+H] + = 747.

실시예 151: Example 151: NN -(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00236
Figure pat00236

상기 실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 650.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 650.

실시예 152: Example 152: NN -(4-클로로-2-((6-클로로-3-(( -2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-1,2,4-트리아진-5-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((6-chloro-3-(( -2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)phenyl)methanesulfonamide

Figure pat00237
Figure pat00237

단계 1) N-(4-클로로-2-((3,6-다이클로로-1,2,4-트리아진-5-일)아미노)페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (4-chloro-2-((3,6-dichloro-1,2,4-triazin-5-yl)amino)phenyl)methanesulfonamide

상기 실시예 1의 단계 1)에서 3,5,6-트라이클로로-1,2,4-트리아진과 N-(2-아미노-4-클로로페닐)메탄설폰아마이드를 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다.The step of Example 1 using 3,5,6-trichloro-1,2,4-triazine and N- (2-amino-4-chlorophenyl)methanesulfonamide in step 1) of Example 1 1) was carried out in the same manner to obtain the title compound.

단계 2) N-(4-클로로-2-((6-클로로-3-(( -2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-1,2,4-트리아진-5-일)아미노)페닐)메탄설폰아마이드의 제조Step 2) N -(4-chloro-2-((6-chloro-3-((-2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperid) Preparation of diin-1-yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)phenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물과 상기 실시예 1의 단계 2)에서 1-클로로-5-메톡시-2-메틸-4-나이트로벤젠과 1-메틸-4-피페리딘-4-일-피페라진 염산염을 사용하는 것을 제외하고는, 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 650.The compound prepared in step 1) and 1-chloro-5-methoxy-2-methyl-4-nitrobenzene and 1-methyl-4-piperidin-4-yl in step 2) of Example 1 - The title compound was obtained in the same manner as in Example 1, except that piperazine hydrochloride was used. [M+H] + = 650.

실시예 153: (4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)다이메틸포스핀 옥사이드의 제조Example 153: (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-) Preparation of 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

Figure pat00238
Figure pat00238

상기 실시예 1의 단계 1)에서 (2-아미노-4-클로로페닐)다이메틸포스핀 옥사이드를 사용하여 상기 실시예 1의 단계 1)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 632.The title compound was obtained in the same manner as in Step 1) of Example 1 using (2-amino-4-chlorophenyl)dimethylphosphine oxide in Step 1) of Example 1. [M+H] + = 632.

실시예 154: (4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)다이메틸포스핀 옥사이드의 제조Example 154: (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) Preparation of -yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

Figure pat00239
Figure pat00239

상기 실시예 153에서 상응하는 아닐린을 사용하여 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 637.The title compound was obtained in the same manner as in Example 153 using the corresponding aniline. [M+H] + = 637.

실시예 155: Example 155: NN -(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)--(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)pyrimidin-4-yl)amino)-4-chlorophenyl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00240
Figure pat00240

단계 1) N-(2-((5-브로모-2-클로로피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드의 제조Step 1) Preparation of N- (2-((5-bromo-2-chloropyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide

상기 실시예 1의 단계 1)에서 N-(2-아미노-4-클로로페닐)-N-메틸메탄설폰아마이드를 사용하는 것과 상기 실시예 24의 단계 3)에서 5-브로모-2,4-다이클로로피리미딘을 사용하는 것을 제외하고는, 상기 실시예 1의 단계 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. Using N- (2-amino-4-chlorophenyl) -N -methylmethanesulfonamide in step 1) of Example 1 and 5-bromo-2,4- in step 3) of Example 24 The title compound was obtained in the same manner as in Step 1 of Example 1, except that dichloropyrimidine was used.

단계 2) N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드의 제조Step 2) N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide

상기 단계 1)에서 제조된 화합물을 사용하여 실시예 1의 단계 2와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 708.The title compound was obtained in the same manner as in Step 2 of Example 1 using the compound prepared in Step 1). [M+H] + = 708.

실시예 156: Example 156: NN -(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)--(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)pyrimidin-4-yl)amino)-4-chlorophenyl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00241
Figure pat00241

상기 실시예 155에서 상응하는 아닐린을 사용하여 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 728.The title compound was obtained in the same manner as in Example 155 using the corresponding aniline. [M+H] + = 728.

실시예 157: Example 157: NN -(4-클로로-2-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl) Preparation of )-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00242
Figure pat00242

실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 668.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 668.

실시예 158: Example 158: NN -(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00243
Figure pat00243

실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 654.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 654.

실시예 159: Example 159: NN -(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00244
Figure pat00244

실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 670.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 670.

실시예 160: Example 160: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-아이소프로필페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide

Figure pat00245
Figure pat00245

단계 1) N-(2-((2,5-다이클로로피리미딘-4-일)아미노)-4-아이소프로필페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (2-((2,5-dichloropyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide

N-(2-아미노-4-아이소프로필페닐)메탄설폰아마이드(1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 2,4,5-트라이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 69%)을 얻었다. Dilute N- (2-amino-4-isopropylphenyl)methanesulfonamide (1 eq.) in isopropyl alcohol (0.3 M) with 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) was added and stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 69%).

단계 2) N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-아이소프로필페닐)메탄설폰아마이드의 제조Step 2) N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 30%)을 얻었다. [M+H]+ = 657.The compound (1 eq.) prepared in step 1) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 30%). [M+H] + = 657.

실시예 161: Example 161: NN -(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-아이소프로필페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide

Figure pat00246
Figure pat00246

실시예 160의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 677.The title compound was obtained in the same manner as in step 2) of Example 160. [M+H] + = 677.

실시예 162: Example 162: NN -(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine) Preparation of -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00247
Figure pat00247

실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 667.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 667.

실시예 163: Example 163: NN -(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-Chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperid) Preparation of diin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00248
Figure pat00248

실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 683.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 683.

실시예 164: Example 164: NN -(2-((6-클로로-3-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-1,2,4-트리아진-5-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((6-chloro-3-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )-1,2,4-triazin-5-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00249
Figure pat00249

단계 1) N-(2-((3,6-다이클로로-1,2,4-트리아진-5-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (2-((3,6-dichloro-1,2,4-triazin-5-yl)amino)-5-fluorophenyl)methanesulfonamide

N-(2-아미노-5-플루오로페닐)메탄설폰아마이드(1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 3,5,6-트라이클로로-1,2,4-트리아진(2 eq.)과 다이아이소프로필에틸아민 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 55%)을 얻었다. Dilute N- (2-amino-5-fluorophenyl)methanesulfonamide (1 eq.) in isopropyl alcohol (0.3 M) and 3,5,6-trichloro-1,2,4-triazine ( 2 eq.) and diisopropylethylamine (4 eq.) were added and stirred at 65° C. for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 55%).

단계 2) N-(2-((6-클로로-3-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-1,2,4-트리아진-5-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조Step 2) N -(2-((6-chloro-3-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)-1,2,4-triazin-5-yl)amino)-5-fluorophenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 34%)을 얻었다. The compound (1 eq.) prepared in step 1) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 34%).

[M+H]+ = 634.[M+H] + = 634.

실시예 165: Example 165: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00250
Figure pat00250

단계 1) N-(메틸설포닐)-N-(6-나이트로-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조Step 1) Preparation of N- (methylsulfonyl)-N-(6-nitro-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

6-나이트로-2,3-다이하이드로벤조퓨란-5-아민 (1 eq.)을 다이클로로메탄 (0.3 M)에 녹이고 0 ℃에서 트라이에틸아민 (4 eq.)을 가한 후 메테인설포닐 클로라이드 MsCl (3 eq.)을 천천히 가하였다. 상온에서 30분 동안 교반시키고 반응이 완결되면 반응 혼합물을 헥세인으로 묽히고 15분간 추가로 교반시켰다. 결과로 생성된 노란색 고체를 감압 여과하여 표제화합물을 얻었다.6-Nitro-2,3-dihydrobenzofuran-5-amine (1 eq.) was dissolved in dichloromethane (0.3 M), triethylamine (4 eq.) was added at 0 ° C., and then methanesulfonyl chloride MsCl (3 eq.) was added slowly. After stirring at room temperature for 30 minutes, upon completion of the reaction, the reaction mixture was diluted with hexane and further stirred for 15 minutes. The resulting yellow solid was filtered under reduced pressure to obtain the title compound.

단계 2) N-(6-나이트로-2,3-다이하이드로벤조퓨란-5-일)메탄설포닐아마이드Step 2) N -(6-nitro-2,3-dihydrobenzofuran-5-yl)methanesulfonylamide

상기 단계 1) 에서 제조된 화합물을 테트라하이드로퓨란 : 4 N NaOH 용액 (1:1, 0.2 M)에 녹인 후 상온에서 2 시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 감압 증류한 후 0 ℃에서 1 N HCl 용액으로 pH를 5~6으로 조절하였다. 결과로 생성된 노란색 고체를 감압 여과하여 표제화합물을 얻었다.The compound prepared in step 1) was dissolved in tetrahydrofuran: 4 N NaOH solution (1:1, 0.2 M) and stirred at room temperature for 2 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure, and the pH was adjusted to 5-6 with 1 N HCl solution at 0 °C. The resulting yellow solid was filtered under reduced pressure to obtain the title compound.

단계 3) N-(6-아미노-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조Step 3) Preparation of N- (6-amino-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

상기 단계 2) 에서 제조된 화합물을 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말와 염화 암모늄을 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 (수율: 91%, 3 단계)를 얻었다. The compound prepared in step 2) was dissolved in tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), iron powder and ammonium chloride were added thereto, followed by stirring at 85° C. for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 91%, 3 steps).

단계 4) N-(6-((2,5-다이클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조Step 4) Preparation of N- (6-((2,5-dichloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

상기 단계 3) 에서 제조된 화합물 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 2,4,5-트라이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 62%)을 얻었다.The compound (1 eq.) prepared in step 3) was diluted in isopropyl alcohol (0.3 M) and 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) were added thereto. The mixture was stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Then, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 62%).

단계 5) N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조Step 5) N -(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperid) Preparation of din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

상기 단계 4)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 33%)을 얻었다. [M+H]+ = 671.The compound (1 eq.) prepared in step 4) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 33%). [M+H] + = 671.

실시예 166: 5-클로로-Example 166: 5-Chloro- NN 4-(5-클로로-2-(14- (5-chloro-2- (1) HH -1,2,3-트리아졸-4-일)페닐)--1,2,3-triazol-4-yl)phenyl)- NN 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민의 제조Preparation of 2-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

Figure pat00251
Figure pat00251

단계 1) 2,5-다이클로로-N-(5-클로로-2-아이오도페닐)피리미딘-4-아민Step 1) 2,5-dichloro- N- (5-chloro-2-iodophenyl)pyrimidin-4-amine

5-클로로-2-아이오도아닐린 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 2,4,5-트라이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 62%)을 얻었다.5-chloro-2-iodoaniline (1 eq.) was diluted in isopropyl alcohol (0.3 M) and 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) were added. Then, the mixture was stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Then, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 62%).

단계 2) 5-클로로-N4-(5-클로로-2-아이도페닐)-N2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민의 제조Step 2) 5-chloro- N 4-(5-chloro-2-idophenyl) -N 2-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl) Preparation of )piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

상기 단계 1)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 45%)을 얻었다.The compound (1 eq.) prepared in step 1) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 45%).

단계 3) 5-클로로-N4-(5-클로로-2-에티닐페닐)-N2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민의 제조Step 3) 5-chloro- N 4-(5-chloro-2-ethynylphenyl)-N2-(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl) Preparation of piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

상기 단계 2)에서 제조된 화합물 (1 eq.), 트라이메틸실릴 아세틸렌 (1.5 eq.) Pd(PPh3)Cl2 (0.3 eq.), CuI (0.2 eq.)를 테트라하이드로퓨란 : 트라이에틸아민 = 2 : 1 용액에 녹인 후 상온에서 30분 간 교반시켰다. 반응이 완결되면 셀라이트로 충진된 필터로 감압 여과 및 감압 증류하였다. 결과로 얻어진 잔사를 메탄올 (0.3 M)에 묽힌 후 탄산 칼륨 (3 eq.)를 가한 후 상온에서 5분 간 교반시켰다. 반응이 종결되면 다이클로로메탄으로 묽힌 후 포화염수로 세척한 후 컬럼 크로마토그래피로 분리하였다 (수율: 42%).The compound (1 eq.) prepared in step 2), trimethylsilyl acetylene (1.5 eq.) Pd(PPh 3 )Cl 2 (0.3 eq.), CuI (0.2 eq.) was mixed with tetrahydrofuran: triethylamine = 2 : 1 After dissolving in a solution, the mixture was stirred at room temperature for 30 minutes. When the reaction was completed, it was filtered under reduced pressure through a filter filled with celite and distilled under reduced pressure. The resulting residue was diluted with methanol (0.3 M) and potassium carbonate (3 eq.) was added thereto, followed by stirring at room temperature for 5 minutes. Upon completion of the reaction, the mixture was diluted with dichloromethane, washed with saturated brine, and separated by column chromatography (yield: 42%).

단계 4) 5-클로로-N4-(5-chloro-2-(1H-1,2,3-트리아졸-4-일)페닐)-N2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민의 제조Step 4) 5-chloro- N 4-(5-chloro-2-(1 H -1,2,3-triazol-4-yl)phenyl) -N2- (2-methoxy-5-methyl- Preparation of 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

상기 단계 3)에서 제조된 화합물 (1 eq.), 트라이메틸실릴 아자이드 (1.5 eq.), 황산구리 (0.1 eq.), 아스코르브산나트륨 (0.2 eq)를 증류수 (0.3 M)에 묽힌 후 50 ℃에서 3 시간 동안 교반시켰다. 반응이 종결되면 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 컬럼 크로마토그래피로 정제하여 표제화합물을 얻었다 (수율: 33%). [M+H]+ = 623.The compound (1 eq.), trimethylsilyl azide (1.5 eq.), copper sulfate (0.1 eq.), and sodium ascorbate (0.2 eq.) prepared in step 3) were diluted in distilled water (0.3 M), and then at 50° C. was stirred for 3 hours. When the reaction was completed, extraction was performed with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Purification by column chromatography gave the title compound (yield: 33%). [M+H] + = 623.

실시예 167: Example 167: NN -(4-클로로-2-((5-클로로-2-((1-(3-(다이메틸아미노)프로필)-1-(4-chloro-2-((5-chloro-2-((1-(3-(dimethylamino)propyl)-1 HH -피라졸-4-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조Preparation of -pyrazol-4-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00252
Figure pat00252

실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 499.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 499.

실시예 168: Example 168: NN -(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00253
Figure pat00253

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. 1H NMR (300 MHz, DMSO) δ 8.45 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 7.20 (s, 1H), 6.77 (s, 1H), 4.56 (t, J = 8.6 Hz, 2H), 3.81 (s, 3H), 3.37-3.22 (m, 4H), 3.18 (t, J = 8.6 Hz, 3H), 2.9 (s, 3H), 2.64 (t, J = 11.0 Hz, 3H), 2.43-2.22 (m, 5H), 2.16 (s, 3H), 1.91-1.79 (m, 2H), 1.67-1.48 (m, 2H). [M+H]+ = 677.The title compound was obtained in the same manner as in step 5) of Example 165. 1H NMR (300 MHz, DMSO) δ 8.45 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 7.43 (s, 1H), 7.20 (s, 1H) , 6.77 (s, 1H), 4.56 (t, J = 8.6 Hz, 2H), 3.81 (s, 3H), 3.37-3.22 (m, 4H), 3.18 (t, J = 8.6 Hz, 3H), 2.9 ( s, 3H), 2.64 (t, J = 11.0 Hz, 3H), 2.43-2.22 (m, 5H), 2.16 (s, 3H), 1.91-1.79 (m, 2H), 1.67-1.48 (m, 2H) . [M+H] + = 677.

실시예 169: Example 169: NN -(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -2,3-dihydrobenzofuran-5-yl) methanesulfonamide

Figure pat00254
Figure pat00254

단계 1) N-(6-((5-브로모-2-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조Step 1) Preparation of N- (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

상기 실시예 165 단계 3) 에서 제조된 화합물 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 5-브로모-2,4-다이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 60%)을 얻었다.The compound (1 eq.) prepared in Example 165 step 3) was diluted in isopropyl alcohol (0.3 M), 5-bromo-2,4-dichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) was added and stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Then, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 60%).

단계 2) N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드Step 2) N -(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

상기 단계 1)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 34%)을 얻었다. 1H NMR (300 MHz, DMSO) δ 8.32 (s, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.20 (s, 1H), 6.68 (s, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.77 (s, 3H), 3.22-3.09 (m, 6H), 2.96 (s, 3H), 2.89-2.76 (m, 6H), 2.62(t, J = 11.0 Hz, 3H), 2.50 (s, 3H), 2.08 (s, 3H), 1.96-1.85 (m, 2H), 1.69-1.57 (m, 2H). [M+H]+ = 701.The compound (1 eq.) prepared in step 1) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 34%). 1H NMR (300 MHz, DMSO) δ 8.32 (s, 1H), 8.16 (s, 1H), 8.03 (s, 1H), 7.52 (s, 1H), 7.39 (s, 1H), 7.20 (s, 1H) , 6.68 (s, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.77 (s, 3H), 3.22-3.09 (m, 6H), 2.96 (s, 3H), 2.89-2.76 (m, 6H) ), 2.62 (t, J = 11.0 Hz, 3H), 2.50 (s, 3H), 2.08 (s, 3H), 1.96-1.85 (m, 2H), 1.69-1.57 (m, 2H). [M+H] + = 701.

실시예 170: Example 170: NN -(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)--(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)phenyl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00255
Figure pat00255

단계 1) N-(4-클로로-2-((2,5-다이클로로피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드의 제조Step 1) Preparation of N- (4-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide

상기 실시예 1의 단계 1)에서 N-(2-아미노-4-클로로페닐)-N-메틸메탄설폰아마이드를 사용하는 것을 제외하고는, 상기 실시예 1의 단계 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. Except for using N-(2-amino-4-chlorophenyl)-N - methylmethanesulfonamide in step 1) of Example 1, it was carried out in the same manner as in Step 1 of Example 1, and the title The compound was obtained.

단계 2) N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드의 제조Step 2) N -(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine) Preparation of -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide

상기 단계 1)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 32%)을 얻었다. [M+H]+ = 683.The compound (1 eq.) prepared in step 1) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 32%). [M+H] + = 683.

실시예 171: Example 171: NN -(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide

Figure pat00256
Figure pat00256

실시예 170의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 667.The title compound was obtained in the same manner as in step 2) of Example 170. [M+H] + = 667.

실시예 172: Example 172: NN -(6-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00257
Figure pat00257

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 675.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 675.

실시예 173: Example 173: NN -(6-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) Preparation of pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00258
Figure pat00258

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 661.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 661.

실시예 174: Example 174: NN -(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine-1- Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00259
Figure pat00259

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. 1H NMR (300 MHz, DMSO) δ 8.48 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.20 (s, 1H), 6.77 (s, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.22-3.12 (m, 3H), 2.93 (s, 3H), 2.82-2.64 (m, 6H), 2.64-2.52 (m, 6H), 2.28 (s, 3H), 1.84-1.68 (m, 4H), 1.65-1.53 (m, 2H) [M+H]+ = 691.The title compound was obtained in the same manner as in step 5) of Example 165. 1H NMR (300 MHz, DMSO) δ 8.48 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.69 (s, 1H), 7.44 (s, 1H), 7.20 (s, 1H) , 6.77 (s, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.22-3.12 (m, 3H), 2.93 (s, 3H), 2.82-2.64 (m, 6H) ), 2.64-2.52 (m, 6H), 2.28 (s, 3H), 1.84-1.68 (m, 4H), 1.65 1.53 (m, 2H) [M+H] + = 691.

실시예 175: Example 175: NN -(6-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00260
Figure pat00260

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 706.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 706.

실시예 176: Example 176: NN -(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00261
Figure pat00261

단계 1) N-(4-클로로-2-((2,5-다이클로로피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (4-chloro-2-((2,5-dichloropyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

상기 실시예 1의 단계 1)에서 N-(2-아미노-4-클로로-5-플루오로페닐)메탄설폰아마이드를 사용하는 것을 제외하고는, 상기 실시예 1의 단계 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. Except for using N- (2-amino-4-chloro-5-fluorophenyl)methanesulfonamide in step 1) of Example 1, it was carried out in the same manner as in Step 1 of Example 1, The title compound was obtained.

단계 2) N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조Step 2) N -(4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine) Preparation of -1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 35%)을 얻었다. 1H NMR (300 MHz, DMSO) δ 8.94 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.33 (s, 1H), 7.24 (s, 1H), 7.21 (s, 1H), 6.69 (s, 1H), 3.76 (s, 3H), 3.16-3.03 (m, 3H), 2.89-2.78 (m, 7H), 2.78 (s, 3H), 2.69-2.55 (m, 3H), 2.50 (s, 3H), 2.08 (s, 3H), 1.96-1.82 (m, 2H), 1.70-1.50 (m, 2H). [M+H]+ = 667.The compound (1 eq.) prepared in step 1) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 35%). 1H NMR (300 MHz, DMSO) δ 8.94 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.33 (s, 1H), 7.24 (s, 1H) , 7.21 (s, 1H), 6.69 (s, 1H), 3.76 (s, 3H), 3.16-3.03 (m, 3H), 2.89-2.78 (m, 7H), 2.78 (s, 3H), 2.69-2.55 (m, 3H), 2.50 (s, 3H), 2.08 (s, 3H), 1.96-1.82 (m, 2H), 1.70-1.50 (m, 2H). [M+H] + = 667.

실시예 177: Example 177: NN -(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide

Figure pat00262
Figure pat00262

단계 1) N-(2-((5-브로모-2-클로로피리미딘-4-일)아미노)-4-클로로-5-플루오로페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (2-((5-bromo-2-chloropyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide

상기 실시예 1의 단계 1)에서 N-(2-아미노-4-클로로-5-플루오로페닐)메탄설폰아마이드와 5-브로모-2,4-다이클로로피리미딘을 사용하는 것을 제외하고는, 상기 실시예 1의 단계 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. Except for using N- (2-amino-4-chloro-5-fluorophenyl)methanesulfonamide and 5-bromo-2,4-dichloropyrimidine in step 1) of Example 1 , was carried out in the same manner as in Step 1 of Example 1 to obtain the title compound.

단계 2) N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로-5-플루오로페닐)메탄설폰아마이드의 제조Step 2) N -(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide

상기 단계 1)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 33%)을 얻었다. [M+H]+ = 716.The compound (1 eq.) prepared in step 1) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 33%). [M+H] + = 716.

실시예 178: Example 178: NN -(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로-5-플루오로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -4-chloro-5-fluorophenyl) methanesulfonamide

Figure pat00263
Figure pat00263

실시예 177의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 732.The title compound was obtained in the same manner as in step 2) of Example 177. [M+H] + = 732.

실시예 179: Example 179: NN -(4-클로로-2-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)페닐)--(4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl) )-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00264
Figure pat00264

실시예 170의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 682.The title compound was obtained in the same manner as in step 2) of Example 170. [M+H] + = 682.

실시예 180: Example 180: NN -(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)--(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00265
Figure pat00265

실시예 170의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 682.The title compound was obtained in the same manner as in step 2) of Example 170. [M+H] + = 682.

실시예 181: Example 181: NN -(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00266
Figure pat00266

실시예 176의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 688.The title compound was obtained in the same manner as in step 2) of Example 176. [M+H] + = 688.

실시예 182: Example 182: NN -(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide

Figure pat00267
Figure pat00267

실시예 176의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 671.The title compound was obtained in the same manner as in step 2) of Example 176. [M+H] + = 671.

실시예 183: Example 183: NN -(6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -2,3-dihydrobenzofuran-5-yl) methanesulfonamide

Figure pat00268
Figure pat00268

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 772.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 772.

실시예 184: Example 184: NN -(6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -2,3-dihydrobenzofuran-5-yl) methanesulfonamide

Figure pat00269
Figure pat00269

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 715.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 715.

실시예 185: 5-클로로-Example 185: 5-Chloro- NN 4-(5-클로로-2-(14- (5-chloro-2- (1) HH -1,2,3-트라이졸-5-일)페닐)--1,2,3-trizol-5-yl)phenyl)- NN 2-(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민의 제조Preparation of 2-(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

Figure pat00270
Figure pat00270

상응하는 아이오도 화합물을 사용하여 상기 실시예 166의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 627.The title compound was obtained in the same manner as in step 4) of Example 166 using the corresponding iodo compound. [M+H] + = 627.

실시예 186: 5-클로로-Example 186: 5-Chloro- NN 44 -(5-클로로-2-(1-(5-chloro-2-(1) HH -1,2,3-트리아졸-5-일)페닐)--1,2,3-triazol-5-yl)phenyl)- NN 22 -(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

Figure pat00271
Figure pat00271

상응하는 아이오도 화합물을 사용하여 상기 실시예 166의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 643.The title compound was obtained in the same manner as in step 4) of Example 166 using the corresponding iodo compound. [M+H] + = 643.

실시예 187: 5-브로모-Example 187: 5-Bromo- NN 44 -(5-클로로-2-(1-(5-chloro-2-(1) HH -1,2,3-트리아졸-5-일)페닐)--1,2,3-triazol-5-yl)phenyl)- NN 22 -(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

Figure pat00272
Figure pat00272

상응하는 아이오도 화합물을 사용하여 상기 실시예 166의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 668.The title compound was obtained in the same manner as in step 4) of Example 166 using the corresponding iodo compound. [M+H] + = 668.

실시예 188: Example 188: NN -(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1) Preparation of -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00273
Figure pat00273

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 716.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 716.

실시예 189: Example 189: NN -(6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine-1) Preparation of -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00274
Figure pat00274

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 736.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 736.

실시예 190: (6-((5-클로로-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 190: (6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) Preparation of phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00275
Figure pat00275

실시예 122의 단계 6) 과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 664.The title compound was obtained in the same manner as in step 6) of Example 122. [M+H] + = 664.

실시예 191: Example 191: NN -(2-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드의 제조-(2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -4-chlorophenyl) methanesulfonamide

Figure pat00276
Figure pat00276

실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 708.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 708.

실시예 192: (6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 192: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00277
Figure pat00277

단계 1) (6-((5-브로모-2-클로로-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Step 1) Preparation of (6-((5-bromo-2-chloro-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

상기 실시예 122의 단계 4)에서 얻어진 화합물 (1 eq.)fmf N,N-다이메틸포름아마이드 (0.3 M)에 묽히고 60 % 수소화나트륨 (1.5 eq.)을 0 ℃에서 천천히 가한 후 상온에서 30 분 교반시켰다. 여기에 5-브로모5-트라이클로로피리미딘 (2 eq.)을 0 ℃에서 천천히 가한 후, 상온에서 2 시간 교반시켰다. 반응이 완결되면 결과의 혼합물을 에틸 아세테이트에 묽힌 후 증류수 및 포화염수로 세척하였다. 결과로 분리된 유기층을 무수황산나트륨으로건조한 뒤, 감압여과 및 감압 증류하였다. 결과로 얻어진 잔사를 크로마토 그래피 (50% 에틸 아세테이트/헥산) 정제하여 표제화합물 (수율: 60%)을 얻었다.The compound (1 eq.)fmf obtained in step 4) of Example 122) was diluted in N , N -dimethylformamide (0.3 M), 60% sodium hydride (1.5 eq.) was slowly added at 0 °C, and then at room temperature. Stirred for 30 minutes. 5-Bromo5-trichloropyrimidine (2 eq.) was slowly added thereto at 0° C., followed by stirring at room temperature for 2 hours. Upon completion of the reaction, the resulting mixture was diluted with ethyl acetate and washed with distilled water and saturated brine. The resulting organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure, and distilled under reduced pressure. The resulting residue was purified by chromatography (50% ethyl acetate/hexane) to obtain the title compound (yield: 60%).

단계 2) (6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Step 2) (6-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) Preparation of phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

상기 단계 1)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 33%)을 얻었다. [M+H]+ = 709.The compound (1 eq.) prepared in step 1) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 33%). [M+H] + = 709.

실시예 193: (6-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 193: (6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) Preparation of phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00278
Figure pat00278

실시예 192의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 699.The title compound was obtained in the same manner as in step 2) of Example 192. [M+H] + = 699.

실시예 194: (6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드의 제조Example 194: (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

Figure pat00279
Figure pat00279

실시예 192의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 715.The title compound was obtained in the same manner as in step 2) of Example 192. [M+H] + = 715.

실시예 195: 5-브로모-Example 195: 5-Bromo- NN 44 -(5-클로로-2-(1-(5-chloro-2-(1) HH -1,2,3-트리아졸-5-일)페닐)--1,2,3-triazol-5-yl)phenyl)- NN 22 -(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

Figure pat00280
Figure pat00280

상응하는 아이오도 화합물을 사용하여 상기 실시예 166의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 688.The title compound was obtained in the same manner as in step 4) of Example 166 using the corresponding iodo compound. [M+H] + = 688.

실시예 196: Example 196: NN -(6-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-Bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5) Preparation of -methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00281
Figure pat00281

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 730.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 730.

실시예 197: Example 197: NN -(6-((5-클로로-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5-methylphenyl) Preparation of )amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00282
Figure pat00282

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 689.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 689.

실시예 198: Example 198: NN -(4-클로로-2-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드의 제조-(4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of )amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Figure pat00283
Figure pat00283

실시예 80의 단계 3)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 673.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 3) of Example 80 and the corresponding aniline. [M+H] + = 673.

실시예 199: Example 199: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl) amino) -4-methoxyphenyl) methanesulfonamide

Figure pat00284
Figure pat00284

단계 1) N-(2-아미노-4-메톡시페닐)메탄설폰아마이드의 제조Step 1) Preparation of N- (2-amino-4-methoxyphenyl)methanesulfonamide

4-메톡시-2-나이트로아닐린을 사용하여 상기 실시예 165의 단계 1)에서 단계 3)과 동일한 공정을 수행하여 표제 화합물을 얻었다. The title compound was obtained in the same manner as in step 3) in step 1) of Example 165 using 4-methoxy-2-nitroaniline.

단계 2) N-(2-((2,5-다이클로로피리미딘-4-일)아미노)-4-메톡시페닐)Step 2) N- (2-((2,5-dichloropyrimidin-4-yl)amino)-4-methoxyphenyl)

메탄설폰아마이드의 제조Preparation of methanesulfonamide

상기 단계 1) 에서 제조된 화합물 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 2,4,5-트라이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 60%)을 얻었다.The compound (1 eq.) prepared in step 1) was diluted in isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) were added thereto. The mixture was stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Then, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 60%).

단계 3) N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조Step 3) N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

상기 단계 2)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 30%)을 얻었다. [M+H]+ = 645.The compound (1 eq.) prepared in step 2) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 30%). [M+H] + = 645.

실시예 200: Example 200: NN -(2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) Preparation of pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00285
Figure pat00285

실시예 199의 단계 3) 과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 649.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 649.

실시예 201: Example 201: NN -(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl) amino) -4-methoxyphenyl) methanesulfonamide

Figure pat00286
Figure pat00286

실시예 199의 단계 3) 과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 665.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 665.

실시예 202: Example 202: NN -(2-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri Preparation of midin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00287
Figure pat00287

실시예 199의 단계 3) 과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 669.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 669.

실시예 203: Example 203: NN -(2-((5-클로로-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of ) pyrimidin-4-yl) amino) -4-methoxyphenyl) methanesulfonamide

Figure pat00288
Figure pat00288

실시예 199의 단계 3) 과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 659.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 659.

실시예 204: Example 204: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00289
Figure pat00289

실시예 199의 단계 3) 과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 659.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 659.

실시예 205: Example 205: NN -(6-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri Preparation of midin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00290
Figure pat00290

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 681.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 681.

실시예 206: Example 206: NN -(6-((5-클로로-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00291
Figure pat00291

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 671.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 671.

실시예 207: Example 207: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine Preparation of -4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00292
Figure pat00292

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 643.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 643.

실시예 208: Example 208: NN -(6-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino Preparation of )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00293
Figure pat00293

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 683.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 683.

실시예 209: Example 209: NN -(6-((5-클로로-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 Preparation of -methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00294
Figure pat00294

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 671.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 671.

실시예 210: Example 210: NN -(6-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5- Preparation of methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00295
Figure pat00295

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 675.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 675.

실시예 211: Example 211: NN -(6-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy- Preparation of 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00296
Figure pat00296

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 716.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 716.

실시예 212: Example 212: NN -(6-((5-브로모-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl) Preparation of amino) pyrimidin-4-yl) amino) -2,3-dihydrobenzofuran-5-yl) methanesulfonamide

Figure pat00297
Figure pat00297

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 728.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 728.

실시예 213: Example 213: NN -(6-((5-브로모-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5 Preparation of -methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00298
Figure pat00298

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 720.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 720.

실시예 214: Example 214: NN -(6-((5-브로모-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-Bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5- Preparation of methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00299
Figure pat00299

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 734.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 734.

실시예 215: Example 215: NN -(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri Preparation of midin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00300
Figure pat00300

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 688.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 688.

실시예 216: Example 216: NN -(6-((5-브로모-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-Bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2- Preparation of methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00301
Figure pat00301

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 750.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 750.

실시예 217: Example 217: NN -(6-((5-브로모-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) Preparation of pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00302
Figure pat00302

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 726.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 726.

실시예 218: Example 218: NN -(6-((5-클로로-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5- Preparation of methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00303
Figure pat00303

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 685.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 685.

실시예 219: Example 219: NN -(6-((5-클로로-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methyl Preparation of toxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00304
Figure pat00304

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 705.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 705.

실시예 220: Example 220: NN -(6-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- Preparation of 4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00305
Figure pat00305

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 643.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 643.

실시예 221: Example 221: NN -(6-((5-클로로-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine-4 Preparation of -yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00306
Figure pat00306

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 647.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 647.

실시예 222: Example 222: NN -(6-((5-클로로-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Preparation of amino) pyrimidin-4-yl) amino) -2,3-dihydrobenzofuran-5-yl) methanesulfonamide

Figure pat00307
Figure pat00307

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 661.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 661.

실시예 223: Example 223: NN -(6-((5-클로로-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidine-4 Preparation of -yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00308
Figure pat00308

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 664.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 664.

실시예 224: Example 224: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-((1-메틸-1-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1) HH -피라졸-5-일)아미노)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조Preparation of -pyrazol-5-yl)amino)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00309
Figure pat00309

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 654.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 654.

실시예 225: Example 225: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-(트라이플루오로메틸)피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)piperidin-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00310
Figure pat00310

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 711.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 711.

실시예 226: Example 226: NN -(4-클로로-2-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)--(4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)phenyl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00311
Figure pat00311

실시예 170의 단계 2)와동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 688.The title compound was obtained in the same manner as in step 2) of Example 170. [M+H] + = 688.

실시예 227: Example 227: NN -(2-((5-브로모-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)--(2-((5-Bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5 -Methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00312
Figure pat00312

실시예 170의 단계 2)에서 5-브로모-2,4-다이클로로피리미딘을 사용한 것을 제외하고는 상응하는 아닐린을 사용하여 상기 실시예 170과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 726.The title compound was obtained in the same manner as in Example 170 using the corresponding aniline, except that 5-bromo-2,4-dichloropyrimidine was used in step 2) of Example 170. [M+H] + = 726.

실시예 228: Example 228: NN -(2-((5-브로모-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)--(2-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) pyrimidin-4-yl)amino)-4-chlorophenyl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00313
Figure pat00313

실시예 170의 단계 2)에서 5-브로모-2,4-다이클로로피리미딘을 사용한 것을 제외하고는 상응하는 아닐린을 사용하여 상기 실시예 170과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 732.The title compound was obtained in the same manner as in Example 170 using the corresponding aniline, except that 5-bromo-2,4-dichloropyrimidine was used in step 2) of Example 170. [M+H] + = 732.

실시예 229: Example 229: NN -(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine-1- Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00314
Figure pat00314

실시예 199의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 679.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 679.

실시예 230: Example 230: NN -(2-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-5- Preparation of methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00315
Figure pat00315

실시예 199의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 663.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 663.

실시예 231: Example 231: NN -(2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- Preparation of 4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00316
Figure pat00316

실시예 199의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 631.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 631.

실시예 232: Example 232: NN -(2-((5-클로로-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5- Preparation of methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00317
Figure pat00317

실시예 199의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 673.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 673.

실시예 233: Example 233: NN -(2-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino Preparation of ) pyrimidin-4-yl) amino) -4-methoxyphenyl) methanesulfonamide

Figure pat00318
Figure pat00318

실시예 199의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 671.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 671.

실시예 234: Example 234: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1'-) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00319
Figure pat00319

실시예 199의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 698.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 698.

실시예 235: Example 235: NN -(2-((5-클로로-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy-5 Preparation of -methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00320
Figure pat00320

실시예 199의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 659.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 659.

실시예 236: Example 236: NN -(2-((5-클로로-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-5-methylphenyl) Preparation of )amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00321
Figure pat00321

실시예 199의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 677.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 677.

실시예 237: Example 237: NN -(2-((5-클로로-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드의 제조-(2-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methyl Preparation of toxyphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide

Figure pat00322
Figure pat00322

실시예 199의 단계 3)과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 693.The title compound was obtained in the same manner as in step 3) of Example 199. [M+H] + = 693.

실시예 238: Example 238: NN -(6-((5-브로모-2-((2-메톡시-6-(4-메틸-1,4-다이아제판-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((2-methoxy-6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)amino)pyrimidine-4 Preparation of -yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00323
Figure pat00323

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 620.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 620.

실시예 239: Example 239: NN -(6-((5-브로모-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) Preparation of amino) pyrimidin-4-yl) amino) -2,3-dihydrobenzofuran-5-yl) methanesulfonamide

Figure pat00324
Figure pat00324

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 677.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 677.

실시예 240: Example 240: NN -(6-((5-브로모-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- Preparation of 3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00325
Figure pat00325

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 703.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 703.

실시예 241: Example 241: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3) Preparation of -yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00326
Figure pat00326

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 658.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 658.

실시예 242: Example 242: NN -(6-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino Preparation of )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00327
Figure pat00327

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 632.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 632.

실시예 243: Example 243: NN -(6-((5-브로모-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine Preparation of -4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00328
Figure pat00328

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 688.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 688.

실시예 244: Example 244: NN -(6-((5-브로모-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine Preparation of -4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00329
Figure pat00329

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 676.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 676.

실시예 245: Example 245: NN -(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine]-1') Preparation of -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00330
Figure pat00330

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 755.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 755.

실시예 246: Example 246: NN -(6-((5-브로모-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설포닐아마이드의 제조-(6-((5-Bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine- Preparation of 4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonylamide

Figure pat00331
Figure pat00331

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 692.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 692.

실시예 247: Example 247: NN -(6-((5-브로모-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-Bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino)pyrimidine- Preparation of 4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00332
Figure pat00332

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 709.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 709.

실시예 248: Example 248: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00333
Figure pat00333

단계 1) N-메틸-N-(6-나이트로-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조Step 1) Preparation of N -methyl- N- (6-nitro-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

상기 실시예 165의 단계 3)에서 제조된 화합물을 아세톤 (0.3 M)에 묽히고, 4 N NaOH 용액 (10 eq.)를 가한 후 0 ℃에서 다이메틸 설페이트 (1.8 eq)를 천천히 첨가하고 상온에서 2시간 동안 교반하였다. 반응이 완결된 후 반응 혼합물을 감압 증류한 후 0 ℃에서 1 N HCl 용액으로 pH를 5~6으로 조절하였다. 결과로 생성된 노란색 고체를 감압 여과하여 별도의 정제 없이 다음 반응에 사용하였다.The compound prepared in step 3) of Example 165 was diluted in acetone (0.3 M), 4 N NaOH solution (10 eq.) was added, and then dimethyl sulfate (1.8 eq) was slowly added at 0° C. and at room temperature. Stirred for 2 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure, and the pH was adjusted to 5-6 with 1 N HCl solution at 0 °C. The resulting yellow solid was filtered under reduced pressure and used in the next reaction without further purification.

단계 2) N-(6-아미노-2,3-다이하이드로벤조퓨란-5-일)-N-메틸설폰아마이드의 제조Step 2) Preparation of N- (6-amino-2,3-dihydrobenzofuran-5-yl) -N -methylsulfonamide

상기 단계 1) 에서 제조된 화합물을 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말와 염화 암모늄을 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 (수율: 95%, 2 단계)를 얻었다. The compound prepared in step 1) was dissolved in tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), iron powder and ammonium chloride were added thereto, followed by stirring at 85° C. for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 95%, 2 steps).

단계 3) N-(6-((2,5-다이클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드의 제조Step 3) Preparation of N- (6-((2,5-dichloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide

상기 단계 2) 에서 제조된 화합물 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 2,4,5-트라이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 60%)을 얻었다.The compound (1 eq.) prepared in step 2) was diluted in isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) were added thereto. The mixture was stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Then, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 60%).

단계 4) N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드의 제조Step 4) N -(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide

상기 단계 3)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 35%)을 얻었다. [M+H]+ = 671.The compound (1 eq.) prepared in step 3) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 35%). [M+H] + = 671.

실시예 249: Example 249: NN -(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00334
Figure pat00334

실시예 248의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 691.The title compound was obtained in the same manner as in step 4) of Example 248. [M+H] + = 691.

실시예 250: Example 250: NN -(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00335
Figure pat00335

단계 1) N-(6-((5-브로모-2-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드의 제조Step 1) Preparation of N- (6-((5-bromo-2-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide

상기 실시예 248의 단계 2)에서 제조된 화합물 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 5-브로모-2,4-다이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 52%)을 얻었다.The compound (1 eq.) prepared in step 2) of Example 248 was diluted in isopropyl alcohol (0.3 M), 5-bromo-2,4-dichloropyrimidine (2 eq.) and sodium bicarbonate ( 4 eq.) was added and stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 52%).

단계 2) N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드의 제조Step 2) N -(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) Preparation of yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide

상기 단계 1)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 29%)을 얻었다. 1H NMR (300 MHz, DMSO) δ 8.22 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 6.70 (s, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.76 (s, 3H), 3.23-3.13 (m, 4H), 3.14 (s, 3H), 3.10 (s, 3H), 2.68-2.54 (m, 5H), 2.45-2.23 (m, 6H), 2.18 (s, 3H), 2.12 (s, 3H), 1.91-1.80 (m, 2H), 1.67-1.50 (m, 2H). [M+H]+ = 716.The compound (1 eq.) prepared in step 1) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 29%). 1H NMR (300 MHz, DMSO) δ 8.22 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H) , 6.70 (s, 1H), 4.55 (t, J = 8.7 Hz, 2H), 3.76 (s, 3H), 3.23-3.13 (m, 4H), 3.14 (s, 3H), 3.10 (s, 3H), 2.68-2.54 (m, 5H), 2.45-2.23 (m, 6H), 2.18 (s, 3H), 2.12 (s, 3H), 1.91-1.80 (m, 2H), 1.67-1.50 (m, 2H). [M+H] + = 716.

실시예 251: Example 251: NN -(6-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00336
Figure pat00336

실시예 250의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 720.The title compound was obtained in the same manner as in step 2) of Example 250. [M+H] + = 720.

실시예 252: Example 252: NN -(6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00337
Figure pat00337

실시예 250의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 736.The title compound was obtained in the same manner as in step 2) of Example 250. [M+H] + = 736.

실시예 253: Example 253: NN -(6-((5-브로모-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00338
Figure pat00338

실시예 250의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 740.The title compound was obtained in the same manner as in step 2) of Example 250. [M+H] + = 740.

실시예 254: Example 254: NN -(6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00339
Figure pat00339

실시예 250의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 730.The title compound was obtained in the same manner as in step 2) of Example 250. [M+H] + = 730.

실시예 255: Example 255: NN -(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-(트라이플루오로메틸)피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00340
Figure pat00340

실시예 250의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 770.The title compound was obtained in the same manner as in step 2) of Example 250. [M+H] + = 770.

실시예 256: Example 256: NN -(6-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00341
Figure pat00341

실시예 250의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 720.The title compound was obtained in the same manner as in step 2) of Example 250. [M+H] + = 720.

실시예 257: Example 257: NN -(6-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine- 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00342
Figure pat00342

실시예 250의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 730.The title compound was obtained in the same manner as in step 2) of Example 250. [M+H] + = 730.

실시예 258: Example 258: NN -(6-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-Bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5) -Methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00343
Figure pat00343

실시예 250의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 744.The title compound was obtained in the same manner as in step 2) of Example 250. [M+H] + = 744.

실시예 259: Example 259: NN -(6-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri Midin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00344
Figure pat00344

실시예 248의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 696.The title compound was obtained in the same manner as in step 4) of Example 248. [M+H] + = 696.

실시예 260: Example 260: NN -(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)--(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-4-methoxyphenyl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00345
Figure pat00345

단계 1) N-(4-메톡시-2-나이트로페닐)-N-메틸메탄설폰아마이드의 제조Step 1) Preparation of N- (4-methoxy-2-nitrophenyl) -N -methylmethanesulfonamide

상기 실시예 229의 단계 1)에서 제조된 화합물 (1 eq.)를 아세톤에 묽히고, 4 N NaOH 용액 (10 eq.)를 가한 후 0 ℃에서 다이메틸 설페이트 (1.8 eq)를 천천히 첨가하고 상온에서 2시간 동안 교반하였다. 반응이 완결된 후 반응 혼합물을 감압 증류한 후 0 ℃에서 1 N HCl 용액으로 pH를 5~6으로 조절하였다. 결과로 생성된 노란색 고체를 감압 여과하여 별도의 정제 없이 다음 반응에 사용하였다.The compound (1 eq.) prepared in step 1) of Example 229 was diluted in acetone, 4 N NaOH solution (10 eq.) was added, and then dimethyl sulfate (1.8 eq) was slowly added at 0° C. and room temperature. was stirred for 2 hours. After the reaction was completed, the reaction mixture was distilled under reduced pressure, and the pH was adjusted to 5-6 with 1 N HCl solution at 0 °C. The resulting yellow solid was filtered under reduced pressure and used in the next reaction without further purification.

단계 2) N-(2-아미노-4-메톡시페닐)-N-메틸메탄설폰아마이드의 제조Step 2) Preparation of N- (2-amino-4-methoxyphenyl) -N -methylmethanesulfonamide

상기 단계 1) 에서 제조된 화합물을 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말와 염화 암모늄을 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 (수율: 95%, 2 단계)를 얻었다. The compound prepared in step 1) was dissolved in tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), iron powder and ammonium chloride were added thereto, followed by stirring at 85° C. for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 95%, 2 steps).

단계 3) N-(2-((2,5-다이클로로피리미딘-4-일)(메틸)아미노)-4-Step 3) N -(2-((2,5-dichloropyrimidin-4-yl)(methyl)amino)-4-

메톡시페닐)메탄설폰아마이드의 제조Preparation of methoxyphenyl)methanesulfonamide

상기 단계 2) 에서 제조된 화합물 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 2,4,5-트라이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 60%)을 얻었다.The compound (1 eq.) prepared in step 2) was diluted in isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) were added thereto. The mixture was stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Then, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 60%).

단계 4) N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)-N-메틸메탄설폰아마이드의 제조Step 4) N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl) -N -methylmethanesulfonamide

상기 단계 3)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 35%)을 얻었다. [M+H]+ = 659.The compound (1 eq.) prepared in step 3) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 35%). [M+H] + = 659.

실시예 261: Example 261: NN -(6-((5-브로모-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl) Amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00346
Figure pat00346

실시예 250의 단계 2)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 742.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 2) of Example 250 and the corresponding aniline. [M+H] + = 742.

실시예 262: Example 262: NN -(6-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-Bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxy- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00347
Figure pat00347

실시예 250의 단계 2)에서 제조된 화합물과 상응하는 아닐린을 사용하여 상기 실시예 1과 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 730.The title compound was obtained in the same manner as in Example 1 using the compound prepared in step 2) of Example 250 and the corresponding aniline. [M+H] + = 730.

실시예 263: Example 263: NN -(6-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00348
Figure pat00348

실시예 248의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 675.The title compound was obtained in the same manner as in step 4) of Example 248. [M+H] + = 675.

실시예 264: Example 264: NN -(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine-1- yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00349
Figure pat00349

실시예 248의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 705.The title compound was obtained in the same manner as in step 4) of Example 248. [M+H] + = 705.

실시예 265: Example 265: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00350
Figure pat00350

실시예 248의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 685.The title compound was obtained in the same manner as in step 4) of Example 248. [M+H] + = 685.

실시예 266: Example 266: NN -(6-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy-5-methylphenyl)amino )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00351
Figure pat00351

실시예 248의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 697.The title compound was obtained in the same manner as in step 4) of Example 248. [M+H] + = 697.

실시예 267: Example 267: NN -(6-((5-클로로-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)--(6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxy-5- Methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)- NN -메틸메탄설폰아마이드의 제조-Preparation of methylmethanesulfonamide

Figure pat00352
Figure pat00352

실시예 248의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 699.The title compound was obtained in the same manner as in step 4) of Example 248. [M+H] + = 699.

실시예 268: Example 268: NN -(6-((5-클로로-2-((2,5-다이플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) Preparation of pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00353
Figure pat00353

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 649.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 649.

실시예 269: Example 269: NN -(5-((5-브로모-2-((2,5-다이플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-4-일)메탄설폰아마이드의 제조-(5-((5-bromo-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanesulfonamide

Figure pat00354
Figure pat00354

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 649.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 649.

실시예 270: Example 270: NN -(6-((2-((5-브로모-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 Preparation of -chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00355
Figure pat00355

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. 1H NMR (300 MHz, DMSO) δ 8.43 (s, 1H), 8.14 (d, J = 1.8 Hz, 2H), 7.82 (s, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 6.80 (s, 1H), 4.56 (t, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.18 (t, J = 8.7 Hz, 3H), 2.95 (s, 3H), 2.65 (t, J = 10.8 Hz, 3H), 2.59-2.50 (m, 4H), 2.43-2.25 (m, 5H), 2.18 (s, 3H), 1.93-1.79 (m, 2H), 1.68-1.50 (m, 2H). [M+H]+ = 722.The title compound was obtained in the same manner as in step 5) of Example 165. 1H NMR (300 MHz, DMSO) δ 8.43 (s, 1H), 8.14 (d, J = 1.8 Hz, 2H), 7.82 (s, 1H), 7.43 (s, 1H), 7.19 (s, 1H), 6.80 (s, 1H), 4.56 (t, J = 8.7 Hz, 2H), 3.81 (s, 3H), 3.18 (t, J = 8.7 Hz, 3H), 2.95 (s, 3H), 2.65 (t, J = 10.8 Hz, 3H), 2.59-2.50 (m, 4H), 2.43-2.25 (m, 5H), 2.18 (s, 3H), 1.93-1.79 (m, 2H), 1.68-1.50 (m, 2H). [M+H] + = 722.

실시예 271: Example 271: NN -(6-((2-((5-브로모-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5 Preparation of -chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00356
Figure pat00356

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 766.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 766.

실시예 272: 5-클로로-Example 272: 5-Chloro- NN 22 -(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)--(2-Methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)- NN 44 -(1-메틸인돌린-6-일)피리미딘-2,4-다이아민의 제조Preparation of -(1-methylindolin-6-yl)pyrimidine-2,4-diamine

Figure pat00357
Figure pat00357

단계 1) 1-메틸-6-나이트로인돌린의 제조Step 1) Preparation of 1-methyl-6-nitroindoline

6-나이트로인돌린 (1 eq.)을 아세톤 (0.3 M)에 묽히고, 탄산칼륨 (4 eq.)을 가하고, 메틸 아이오다이드 (2 eq)을 가한 후 50 ℃에서 12 시간 동안 교반시켰다. 반응이 완결된 후 감압 증류 하여 컬럼 크로마토그래피로 분리하여 표제화합물을 얻었다 (수율: 68%)6-nitroindoline (1 eq.) was diluted in acetone (0.3 M), potassium carbonate (4 eq.) was added, and methyl iodide (2 eq.) was added, followed by stirring at 50° C. for 12 hours. . After completion of the reaction, the mixture was distilled under reduced pressure and separated by column chromatography to obtain the title compound (yield: 68%).

단계 2) 1-메틸인돌린-6-아민의 제조Step 2) Preparation of 1-methylindolin-6-amine

상기 단계 2) 에서 제조된 화합물을 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말와 염화 암모늄을 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 (수율: 70%)를 얻었다. The compound prepared in step 2) was dissolved in tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), iron powder and ammonium chloride were added thereto, followed by stirring at 85° C. for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 70%).

단계 3) N-(2,5-다이클로로피리미딘-4-일)-1-메틸인돌린-6-아민의 제조Step 3) Preparation of N- (2,5-dichloropyrimidin-4-yl)-1-methylindolin-6-amine

상기 단계 3) 에서 제조된 화합물 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 2,4,5-트라이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 61%)을 얻었다.The compound (1 eq.) prepared in step 3) was diluted in isopropyl alcohol (0.3 M) and 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) were added thereto. The mixture was stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 61%).

단계 4) 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(1-메틸인돌린-6-일)피리미딘-2,4-다이아민의 제조Step 4) 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 - Preparation of (1-methylindolin-6-yl)pyrimidine-2,4-diamine

상기 단계 4)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 35%)을 얻었다. [M+H]+ = 577.The compound (1 eq.) prepared in step 4) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 35%). [M+H] + = 577.

실시예 273: 5-클로로-Example 273: 5-Chloro- NN 22 -(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)--(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)- NN 44 -(1-메틸인돌린-6-일)피리미딘-2,4-다이아민의 제조Preparation of -(1-methylindolin-6-yl)pyrimidine-2,4-diamine

Figure pat00358
Figure pat00358

실시예 272의 단계 4와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 597.The title compound was obtained in the same manner as in step 4 of Example 272. [M+H] + = 597.

실시예 274: 5-클로로-Example 274: 5-Chloro- NN 22 -(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)--(2-Chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)- NN 44 -(1-메틸인돌린-6-일)피리미딘-2,4-다이아민의 제조Preparation of -(1-methylindolin-6-yl)pyrimidine-2,4-diamine

Figure pat00359
Figure pat00359

실시예 272의 단계 4와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 581.The title compound was obtained in the same manner as in step 4 of Example 272. [M+H] + = 581.

실시예 275: 5-클로로-Example 275: 5-Chloro- NN 22 -(2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)--(2-Methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl)- NN 44 -(1-메틸인돌린-6-일)피리미딘-2,4-다이아민의 제조Preparation of -(1-methylindolin-6-yl)pyrimidine-2,4-diamine

Figure pat00360
Figure pat00360

실시예 272의 단계 4와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 591.The title compound was obtained in the same manner as in step 4 of Example 272. [M+H] + = 591.

실시예 276: Example 276: NN -(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-1-메틸인돌린-5-일)메탄설폰아마이드의 제조-(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino Preparation of )pyrimidin-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide

Figure pat00361
Figure pat00361

단계 1) 5-브로모-6-나이트로인돌린의 제조Step 1) Preparation of 5-bromo-6-nitroindoline

5-브로모인돌린 (4.5 g, 22.7 mmol)을 황산 (98%, 20 mL)에 녹인 후 질산 칼륨 (2.35 g, 23 mmol)을 0 ℃에서 천천히 가하고, 0-10 ℃에서 4시간 동안 교반시켰다. 반응이 완결되면 얼음물에 천천히 가하고, 포화 탄산나트륨 용액으로 pH를 8이 되도록 조절하였다. 결과로 생성된 고체를 감압 여과 하여 별도의 정제 없이 다음 반응에 사용하였다. After 5-bromoindoline (4.5 g, 22.7 mmol) was dissolved in sulfuric acid (98%, 20 mL), potassium nitrate (2.35 g, 23 mmol) was slowly added at 0 °C, and stirred at 0-10 °C for 4 hours. . When the reaction was completed, it was slowly added to ice water, and the pH was adjusted to 8 with saturated sodium carbonate solution. The resulting solid was filtered under reduced pressure and used in the next reaction without further purification.

단계 2) 5-브로모-1-메틸-6-나이트로인돌린의 제조Step 2) Preparation of 5-bromo-1-methyl-6-nitroindoline

상기 단계 1)에서 제조된 화합물 (2.2 g, 9 mmol)을 아세톤 (30 mL)에 묽히고, 탄산칼륨 (5 g, 36 mmol)을 가하고, 메틸 아이오다이드 (0.9 mL, 14.4 mmol)을 가한 후 50 ℃에서 12 시간 동안 교반시켰다. 반응이 완결된 후 감압 증류 하여 컬럼 크로마토그래피로 분리하여 표제화합물 (1.57 g)을 얻었다 (수율: 68%, 2 단계)The compound (2.2 g, 9 mmol) prepared in step 1) was diluted in acetone (30 mL), potassium carbonate (5 g, 36 mmol) was added, and methyl iodide (0.9 mL, 14.4 mmol) was added. Then, the mixture was stirred at 50 °C for 12 hours. After completion of the reaction, the mixture was distilled under reduced pressure and separated by column chromatography to obtain the title compound (1.57 g) (yield: 68%, 2 steps).

단계 3) N-(1-메틸-6-나이트로인돌린-5-일)메탄설폰아마이드의 제조Step 3) Preparation of N- (1-methyl-6-nitroindolin-5-yl)methanesulfonamide

상기 단계 2)에서 제조된 화합물 (200 mg, 0.78 mmol), 메탄설폰아마이드 (220 mg, 3 eq.), 탄산 세슘 (1 g, 4 eq.), Xantphos (90 mg, 0.2 eq.), Pd(OAc)2 (20 mg, 0.1 eq.)를 dioxane에 묽히고 10 분 동안 degas한 후 100 ℃에서 24시간 동안 교반 시켰다. 반응이 완결되면 셀라이트가 충진된 필터로 감압 여과 한 후 에틸 아세테이트, 증류수, 포화염수로 세척하였다. 얻어진 잔사를 컬럼 크로마토그래피로 분리하여 표제화합물 (88 mg, 수율: 42%)를 얻었다.The compound prepared in step 2) (200 mg, 0.78 mmol), methanesulfonamide (220 mg, 3 eq.), cesium carbonate (1 g, 4 eq.), Xantphos (90 mg, 0.2 eq.), Pd (OAc) 2 (20 mg, 0.1 eq.) was diluted in dioxane, degassed for 10 minutes, and stirred at 100 °C for 24 hours. Upon completion of the reaction, the mixture was filtered under reduced pressure through a filter filled with celite and washed with ethyl acetate, distilled water, and saturated brine. The obtained residue was separated by column chromatography to obtain the title compound (88 mg, Yield: 42%).

단계 4) N-(6-아미노-1-메틸인돌린-5-일)메탄설폰아마이드의 제조Step 4) Preparation of N- (6-amino-1-methylindolin-5-yl)methanesulfonamide

상기 단계 3) 에서 제조된 화합물을 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말와 염화 암모늄을 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 (수율: 61%)를 얻었다. The compound prepared in step 3) was dissolved in tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), iron powder and ammonium chloride were added thereto, followed by stirring at 85° C. for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 61%).

단계 5) N-(6-((2,5-다이클로로-4-일)아미노)-1-메틸인돌린-5-일)메탄설폰아마이드의 제조Step 5) Preparation of N- (6-((2,5-dichloro-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide

상기 단계 4) 에서 제조된 화합물 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 2,4,5-트라이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 61%)을 얻었다.The compound (1 eq.) prepared in step 4) was diluted in isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) were added thereto. The mixture was stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 61%).

단계 6) N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-1-메틸인돌린-5-일)메탄설폰아마이드의 제조Step 6) N -(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) Preparation of )phenyl)amino)pyrimidin-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide

상기 단계 5)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 35%)을 얻었다. [M+H]+ = 670.The compound (1 eq.) prepared in step 5) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 35%). [M+H] + = 670.

실시예 277: 5-클로로-Example 277: 5-Chloro- NN 22 -(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)--(2-Chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)- NN 44 -(인돌린-6-일)피리미딘-2,4-다이아민의 제조Preparation of -(indolin-6-yl)pyrimidine-2,4-diamine

Figure pat00362
Figure pat00362

단계 1) 터트-뷰틸 6-나이트로인돌리-1-카복실레이트의 제조Step 1) Preparation of tert-butyl 6-nitroindoli-1-carboxylate

6-나이트로인돌린 (1 eq.)을 다이클로로메탄 (0.3 M)에 묽히고, 다이-터트-뷰틸 다이카보네이트 (2 eq.)와 DMAP (0.1 eq)를 가한 후 상온에서 12 시간 동안 교반 시켰다. 반응이 종결되면 다이클로로메탄으로 묽히고 포화염수로 세척한 후 감압 여과 및 감압 증류하여 별도의 정제 없이 다음 반응에 사용하였다.6-nitroindoline (1 eq.) was diluted in dichloromethane (0.3 M), di-tert-butyl dicarbonate (2 eq.) and DMAP (0.1 eq) were added thereto, followed by stirring at room temperature for 12 hours. did it When the reaction was completed, it was diluted with dichloromethane, washed with saturated brine, filtered under reduced pressure and distilled under reduced pressure, and used in the next reaction without further purification.

단계 2) 터트-뷰틸 6-아미노인돌린-1-카복실레이트Step 2) tert-butyl 6-aminoindoline-1-carboxylate

상기 단계 1) 에서 제조된 화합물을 테트라하이드로퓨란 : 메탄올 : 물 = 18 : 1: 1 (부피비)에 녹인 후 철 분말와 염화 암모늄을 가한 후 85 ℃에서 3시간 동안 교반 시켰다. 반응이 완결된 후 반응 혼합물을 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 농축하여 표제화합물 (수율: 75%)를 얻었다. The compound prepared in step 1) was dissolved in tetrahydrofuran : methanol : water = 18 : 1 : 1 (volume ratio), iron powder and ammonium chloride were added thereto, followed by stirring at 85° C. for 3 hours. After the reaction was completed, the reaction mixture was washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, and concentrated to obtain the title compound (yield: 75%).

단계 3) 터트-뷰틸 6-((2,5-다이클로로피리미딘-4-일)아미노)인돌린-1-카복실레이트의 제조Step 3) Preparation of tert-butyl 6-((2,5-dichloropyrimidin-4-yl)amino)indoline-1-carboxylate

상기 단계 2) 에서 제조된 화합물 (1 eq.)을 아이소프로필알코올 (0.3 M)에 묽히고 2,4,5-트라이클로로피리미딘 (2 eq.)과 중탄산나트륨 (4 eq.)를 가한 후 65 ℃에서 40 시간 동안 질소 분위기 하에서 교반시켰다. 반응이 완결되면 반응 혼합물을 실온으로 냉각시키고 셀라이트 충진된 필터에 다이클로로메탄으로 세척하여 감압 여과한 후 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)로 묽힌 후 증류수 세척하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (40% 테트라하이드로퓨란/헥세인)으로 분리하여 표제화합물 (수율: 65%)을 얻었다.The compound (1 eq.) prepared in step 2) was diluted in isopropyl alcohol (0.3 M), and 2,4,5-trichloropyrimidine (2 eq.) and sodium bicarbonate (4 eq.) were added thereto. The mixture was stirred at 65 °C for 40 hours under a nitrogen atmosphere. Upon completion of the reaction, the reaction mixture was cooled to room temperature, washed with dichloromethane in a filter filled with celite, filtered under reduced pressure, diluted with isopropyl alcohol: chloroform = 1: 4 (volume ratio), and washed with distilled water. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (40% tetrahydrofuran/hexane) to obtain the title compound (yield: 65%).

단계 4) 5-클로로-N 2-(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(인돌린-6-일)피리미딘-2,4-다이아민의 제조Step 4) 5-chloro- N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -( Preparation of indolin-6-yl)pyrimidine-2,4-diamine

상기 단계 5)에서 제조된 화합물 (1 eq.)과 상응하는 아닐린 (0.6 eq)을 아세트산 (0.3 M) : 1.25 M HCl/메탄올 용액 = 1: 1 (부피비)에 녹인 후 밀폐하여 120 ℃에서 3 시간 교반시켰다. 반응이 완결되면 결과의 반응 혼합물을 상온으로 냉각시키고 아이소프로필알코올 : 클로로포름 = 1 : 4 (부피비)와 포화 중탄산나트륨 수용액으로 추출하였다. 그 후 유기층을 무수황산나트륨으로 건조한 뒤, 감압여과 및 감압 증류하여 얻어진 잔사를 컬럼크로마토그래피 (10% 메탄올/다이클로로메탄)으로 분리하여 표제화합물 (수율: 35%)을 얻었다. [M+H]+ = 567.The compound (1 eq.) prepared in step 5) and the corresponding aniline (0.6 eq) were dissolved in acetic acid (0.3 M): 1.25 M HCl/methanol solution = 1: 1 (volume ratio), sealed and sealed at 120 °C for 3 time was stirred. Upon completion of the reaction, the resulting reaction mixture was cooled to room temperature, and extracted with isopropyl alcohol : chloroform = 1 : 4 (volume ratio) and saturated aqueous sodium bicarbonate solution. Thereafter, the organic layer was dried over anhydrous sodium sulfate, filtered under reduced pressure and distilled under reduced pressure, and the residue obtained was separated by column chromatography (10% methanol/dichloromethane) to obtain the title compound (yield: 35%). [M+H] + = 567.

실시예 278: 5-클로로-Example 278: 5-Chloro- NN 22 -(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)--(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)- NN 44 -(인돌린-6-일)피리미딘-2,4-다이아민의 제조Preparation of -(indolin-6-yl)pyrimidine-2,4-diamine

Figure pat00363
Figure pat00363

실시예 277의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 583.The title compound was obtained in the same manner as in step 4) of Example 277. [M+H] + = 583.

실시예 279: 5-클로로-Example 279: 5-Chloro- NN 44 -(인돌린-6-일)--(indolin-6-yl)- NN 22 -(2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민의 제조Preparation of -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine

Figure pat00364
Figure pat00364

실시예 277의 단계 4)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 549.The title compound was obtained in the same manner as in step 4) of Example 277. [M+H] + = 549.

실시예 280: Example 280: NN -(6-((2-((5-브로모-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2-methoxyphenyl) Preparation of amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00365
Figure pat00365

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 750.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 750.

실시예 281: Example 281: NN -(6-((5-브로모-2-((5-브로모-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((5-bromo-2-((5-bromo-4-(3-(dimethylamino)-[1,4′-bipiperidin]-1′-yl)-2 Preparation of -methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00366
Figure pat00366

상기 실시예 169의 단계 2)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 794.The title compound was obtained in the same manner as in step 2) of Example 169. [M+H] + = 794.

실시예 282: Example 282: NN -(6-((2-((5-브로모-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((2-((5-bromo-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl)phenyl) Preparation of )amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00367
Figure pat00367

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 735.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 735.

실시예 283: Example 283: NN -(6-((2-((5-브로모-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드의 제조-(6-((2-((5-bromo-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2-methoxyphenyl) Preparation of )amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide

Figure pat00368
Figure pat00368

상기 실시예 165의 단계 5)와 동일한 공정으로 수행하여 표제화합물을 얻었다. [M+H]+ = 735.The title compound was obtained in the same manner as in step 5) of Example 165. [M+H] + = 735.

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

[제제예] [Formulation example]

제제예 1 : 정제(직접 가압)Formulation Example 1: Tablet (Direct Pressurization)

활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 만들었다.After sieving 5.0 mg of the active ingredient, 14.1 mg of lactose, 0.8 mg of crospovidone USNF, and 0.1 mg of magnesium stearate were mixed and pressurized to make tablets.

제제예 2 : 정제(습식 조립)Formulation Example 2: Tablet (wet granulation)

활성성분 5.0 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다.After sieving 5.0 mg of the active ingredient, 16.0 mg of lactose and 4.0 mg of starch were mixed. After dissolving 0.3 mg of polysorbate 80 in pure water, an appropriate amount of this solution was added, followed by atomization. After drying, the fine particles were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The granules were pressurized to make tablets.

제제예 3 : 분말과 캡슐제Formulation Example 3: Powder and Capsule

활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다. After sieving 5.0 mg of the active ingredient, it was mixed with 14.8 mg of lactose, 10.0 mg of polyvinyl pyrrolidone, and 0.2 mg of magnesium stearate. Mix the mixture into a solid No. using a suitable device. Filled in 5 gelatin capsules.

제제예 4 : 주사제Formulation Example 4: Injection

활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4·12H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.An injection was prepared by containing 100 mg as an active ingredient, in addition to 180 mg of mannitol, 26 mg of Na 2 HPO 4 ·12H 2 O, and 2974 mg of distilled water.

[실험예] [Experimental example]

실험예 1. EGFR 키나아제 저해 활성 측정Experimental Example 1. Measurement of EGFR kinase inhibitory activity

본 실험예에서는 상기 실시예 1 내지 283에서 얻어진 화합물이 EGFR-wt, del19/T790M/C797S/ (EGFR-DTC), L858R/T790M/C797S (EGFR-LTC), del19/T790M (EGFR-DT), 및 L858R/T790M (EGFR-LT) 변이형을 발현하고 있는 Ba/F3 세포의 성장저해능을 확인하고자 하였다. In this experimental example, the compounds obtained in Examples 1 to 283 are EGFR-wt, del19/T790M/C797S/ (EGFR-DTC), L858R/T790M/C797S (EGFR-LTC), del19/T790M (EGFR-DT), and L858R/T790M (EGFR-LT) to determine the growth inhibitory ability of Ba/F3 cells expressing the mutant.

Partneal Ba/F3 세포주는 EGFR 변이형이 도입되지 않은 세포다. 구체적으로 각각의 변이형을 발현하는 100,000 cell/ 1ml의 세포주를 96 well plate에 100 ㎕ 넣어 주었다. 2 mM 의 화합물을 10 point, 1/4씩 연속 희석(serial dilution)하여 준비한다. 4 시간 후 화합물을 0.5 ㎕ (0.5% DMSO) 첨가하고, 5% CO2의 37℃조건에서 72시간 동안 배양하였다. 배양 후, Celltiter glo assay 키트(Promega)를 사용하여 살아있는 세포 수를 측정하고, 각각의 화합물의 50% 성장 억제 값(GI50, μM)을 측정하였다. 그 결과 정리하여 표 1에 나타내었다.The Partneal Ba/F3 cell line is a cell into which the EGFR mutant has not been introduced. Specifically, 100 μl of a cell line of 100,000 cells / 1 ml expressing each variant was placed in a 96 well plate. 2 mM of the compound is prepared by serial dilution at 10 points, 1/4 each. After 4 hours, 0.5 μl (0.5% DMSO) of the compound was added, and incubated for 72 hours at 37° C. in 5% CO 2 . After incubation, the number of viable cells was measured using a Celltiter glo assay kit (Promega), and the 50% growth inhibition value (GI50, μM) of each compound was measured. The results are summarized and shown in Table 1.

GIGI 5050 Ba/F3 ( Ba/F3 ( μμ M)M) 실시예Example Parentalparental EGFR-wtEGFR-wt EGFR-DTCEGFR-DTC EGFR-LTCEGFR-LTC EGFR-DTEGFR-DT EGFR-LTEGFR-LT 1One EE DD CC ndnd ndnd ndnd 22 DD CC AA ndnd ndnd ndnd 33 DD DD CC ndnd ndnd ndnd 44 EE EE DD ndnd ndnd ndnd 55 BB CC AA ndnd ndnd ndnd 66 FF DD DD DD DD DD 77 DD CC CC CC ndnd ndnd 88 EE EE CC DD ndnd ndnd 99 DD CC CC BB ndnd ndnd 1010 EE DD DD DD ndnd ndnd 1111 DD EE DD DD ndnd ndnd 1212 EE CC BB ndnd ndnd ndnd 1313 DD DD CC ndnd ndnd ndnd 1414 EE FF EE ndnd ndnd ndnd 1515 DD DD CC CC AA CC 1616 DD EE DD ndnd ndnd ndnd 1717 EE EE DD ndnd ndnd ndnd 1818 CC BB DD DD DD DD 1919 EE DD DD DD DD DD 2020 EE EE DD DD DD DD 2121 FF EE DD DD DD EE 2222 DD EE DD DD BB EE 2323 CC CC CC CC CC DD 2424 DD CC AA AA AA AA 2525 DD DD CC CC ndnd ndnd 2626 EE CC BB BB ndnd ndnd 2727 EE EE CC DD ndnd ndnd 2828 EE EE DD DD ndnd ndnd 2929 FF FF FF FF ndnd ndnd 3030 FF FF EE EE ndnd ndnd 3131 EE EE DD EE ndnd ndnd 3232 EE EE EE EE ndnd ndnd 3333 EE EE EE EE ndnd ndnd 3434 EE EE DD CC ndnd ndnd 3535 CC CC BB BB ndnd ndnd 3636 EE DD CC CC ndnd ndnd 3737 FF FF FF FF ndnd ndnd 3838 DD CC BB BB BB CC 3939 DD CC AA AA CC BB 4040 EE DD BB CC ndnd ndnd 4141 EE DD CC DD ndnd ndnd 4242 DD DD BB CC ndnd ndnd 4343 DD CC CC BB ndnd ndnd 4444 DD DD BB BB BB CC 4545 DD DD BB BB BB CC 4646 EE EE EE ndnd ndnd ndnd 4747 EE EE DD ndnd ndnd ndnd 4848 EE EE DD ndnd ndnd ndnd 4949 EE EE DD ndnd ndnd ndnd 5050 DD DD CC ndnd ndnd ndnd 5151 EE EE CC ndnd ndnd ndnd 5252 CC CC BB ndnd ndnd ndnd 5353 CC CC CC ndnd ndnd ndnd 5454 EE CC EE ndnd ndnd ndnd 5555 CC DD DD ndnd ndnd ndnd 5656 EE DD DD DD CC DD 5757 DD DD DD DD CC DD 5858 CC CC CC CC CC DD 5959 DD DD DD ndnd ndnd ndnd 6060 CC CC BB ndnd ndnd ndnd 6161 DD EE EE ndnd ndnd ndnd 6262 DD CC BB BB ndnd ndnd 6363 BB CC BB BB ndnd ndnd 6464 EE EE DD DD ndnd ndnd 6565 DD DD CC CC ndnd ndnd 6666 EE DD DD CC ndnd ndnd 6767 EE CC BB BB CC CC 6868 EE EE DD EE ndnd ndnd 6969 AA BB AA AA ndnd ndnd 7070 DD CC BB BB BB BB 7171 DD CC CC CC ndnd ndnd 7272 EE DD DD DD ndnd ndnd 7373 EE DD DD DD ndnd ndnd 7474 FF FF EE EE ndnd ndnd 7575 CC CC CC CC ndnd ndnd 7676 CC CC CC CC ndnd ndnd 7777 DD DD DD DD ndnd ndnd 7878 EE EE EE EE ndnd ndnd 7979 DD EE DD DD ndnd ndnd 8080 EE CC AA AA AA AA 8181 DD EE DD DD ndnd ndnd 8282 DD DD CC CC ndnd ndnd 8383 EE DD CC CC ndnd ndnd 8484 DD CC CC CC ndnd ndnd 8585 DD CC AA AA AA AA 8686 EE DD BB AA AA BB 8787 CC CC BB BB BB BB 8888 DD CC AA AA AA AA 8989 DD CC AA AA BB AA 9090 DD CC AA AA AA AA 9191 EE CC AA BB ndnd ndnd 9292 EE CC AA BB ndnd ndnd 9393 EE DD AA BB ndnd ndnd 9494 DD BB AA AA AA AA 9595 DD CC AA AA AA AA 9696 FF DD DD DD ndnd ndnd 9797 DD DD BB AA BB BB 9898 DD CC BB BB BB CC 9999 FF DD BB BB ndnd ndnd 100100 EE DD CC CC ndnd ndnd 101101 EE CC CC CC ndnd ndnd 102102 EE DD DD CC ndnd ndnd 103103 EE DD CC BB ndnd ndnd 104104 DD DD DD DD ndnd ndnd 105105 FF FF FF FF ndnd ndnd 106106 DD DD AA BB ndnd ndnd 107107 DD DD BB CC ndnd ndnd 108108 EE DD BB CC ndnd ndnd 109109 DD CC BB AA ndnd ndnd 110110 DD CC CC BB ndnd ndnd 111111 EE EE DD ndnd DD EE 112112 CC CC BB BB ndnd ndnd 113113 EE EE DD DD ndnd ndnd 114114 DD DD CC CC ndnd ndnd 115115 EE CC AA AA CC BB 116116 EE DD BB CC ndnd ndnd 117117 EE DD DD DD ndnd ndnd 118118 FF DD CC CC ndnd ndnd 119119 EE DD DD DD ndnd ndnd 120120 FF EE EE EE ndnd ndnd 121121 FF EE EE EE ndnd ndnd 122122 DD CC CC BB ndnd ndnd 123123 EE DD CC CC ndnd ndnd 124124 CC CC BB BB ndnd ndnd 125125 CC CC BB CC ndnd ndnd 126126 EE EE CC DD ndnd ndnd 127127 FF FF EE EE ndnd ndnd 128128 EE EE DD DD ndnd ndnd 129129 FF EE EE EE ndnd ndnd 130130 DD DD DD BB ndnd ndnd 131131 DD CC BB AA AA BB 132132 DD DD CC CC ndnd ndnd 133133 DD DD CC CC ndnd ndnd 134134 CC CC BB BB CC CC 135135 DD DD CC CC ndnd ndnd 136136 DD DD CC CC ndnd ndnd 137137 EE DD CC CC ndnd ndnd 138138 DD EE CC CC ndnd ndnd 139139 DD EE DD DD ndnd ndnd 140140 DD CC BB AA AA BB 141141 FF DD DD DD ndnd ndnd 142142 DD DD CC BB DD DD 143143 CC CC CC CC DD DD 144144 DD DD DD CC DD CC 145145 EE EE CC CC ndnd ndnd 146146 EE DD CC CC ndnd ndnd 147147 DD DD BB BB BB BB 148148 DD DD CC CC CC DD 149 149 CC CC CC BB CC CC 150 150 DD DD BB BB CC CC 151151 DD CC AA AA AA AA 152152 DD CC AA AA AA AA 153153 EE DD CC CC CC DD 154154 EE EE CC DD DD EE 155155 CC BB AA AA AA BB 156156 CC AA AA AA AA AA 157157 DD CC CC BB BB BB 158158 EE DD AA AA BB BB 159159 EE CC AA AA AA AA 160160 EE DD BB CC CC CC 161161 EE EE CC DD CC DD 162162 EE DD CC EE EE EE 163163 FF EE CC EE EE EE 164164 FF EE CC EE EE EE 165165 EE DD BB BB BB BB 166166 DD CC AA AA ndnd ndnd 167167 EE DD CC EE EE EE 168168 EE BB AA AA AA AA 169169 DD CC AA AA AA AA 170170 CC BB AA AA AA AA 171171 CC BB AA AA AA BB 172172 CC CC AA AA BB AA 173173 CC CC BB BB AA AA 174174 DD CC AA BB AA AA 175175 FF DD BB BB CC CC 176176 DD CC AA AA BB BB 177177 EE EE BB AA CC CC 178178 EE DD AA BB BB BB 179179 DD CC CC BB CC BB 180180 EE DD BB BB BB BB 181181 EE DD CC BB BB BB 182182 FF EE BB BB BB BB 183183 BB AA AA AA AA AA 184184 DD BB CC AA AA AA 185185 DD DD DD BB ndnd ndnd 186186 CC BB BB BB ndnd ndnd 187187 DD CC BB BB ndnd ndnd 188188 DD CC AA AA BB BB 189189 DD BB AA AA AA BB 190190 CC CC BB BB AA AA 191191 EE CC AA AA AA AA 192192 CC BB AA AA AA AA 193193 DD CC AA BB CC CC 194194 CC CC BB BB BB CC 195195 CC CC BB BB ndnd ndnd 196196 EE DD AA CC AA BB 197197 EE CC BB CC AA CC 198198 ndnd ndnd ndnd ndnd ndnd ndnd 199199 CC CC AA AA AA BB 200200 CC CC BB BB AA BB 201201 BB AA AA AA AA AA 202202 CC CC BB BB AA BB 203203 EE DD BB BB AA CC 204204 EE BB AA BB AA BB 205205 EE BB AA AA AA AA 206206 EE CC AA BB AA AA 207207 EE CC BB BB BB AA 208208 EE CC AA BB AA AA 209209 EE CC AA BB BB AA 210210 EE DD CC BB BB BB 211211 EE CC BB AA AA BB 212212 EE CC BB AA AA AA 213213 EE CC BB BB AA CC 214214 EE CC BB BB AA AA 215215 EE CC BB BB AA BB 216216 EE BB AA BB AA AA 217217 DD CC AA AA AA AA 218218 DD CC AA CC AA BB 219219 EE CC AA BB AA AA 220220 BB DD CC CC CC BB 221221 DD CC BB BB BB BB 222222 EE CC AA CC AA AA 223223 EE EE DD DD CC CC 224224 CC DD BB BB CC BB 225225 EE DD AA BB BB BB 226226 DD CC BB BB BB BB 227227 CC AA AA BB AA AA 228228 CC CC AA BB BB AA 229229 EE DD BB CC AA BB 230230 EE DD CC CC BB CC 231231 EE EE CC CC CC CC 232232 EE DD BB CC BB CC 233233 EE DD BB BB BB BB 234234 EE EE CC CC CC CC 235235 EE DD BB CC BB CC 236236 EE EE CC CC CC CC 237237 EE DD CC AA CC AA 238238 EE EE EE CC EE CC 239239 EE DD DD CC BB BB 240240 EE DD CC AA CC AA 241241 EE DD CC BB CC AA 242242 EE EE EE BB DD AA 243243 EE DD CC AA CC AA 244244 CC BB BB AA AA AA 245245 EE EE BB AA CC AA 246246 EE DD CC AA CC AA 247247 EE DD CC CC BB CC 248248 EE CC BB AA AA AA 249249 EE CC BB AA AA AA 250250 EE CC AA AA AA AA 251251 EE CC BB AA AA BB 252252 EE BB BB AA AA AA 253253 CC DD AA BB BB BB 254254 DD DD AA BB AA BB 255255 EE EE BB CC BB CC 256256 CC CC BB CC AA CC 257257 CC EE AA CC BB CC 258258 CC DD AA CC BB CC 259259 DD DD AA CC BB BB 260260 EE CC CC CC AA BB 261261 EE BB CC BB AA BB 262262 BB CC BB BB AA BB 263263 FF DD DD CC CC CC 264264 EE CC BB BB AA AA 265265 DD CC BB BB BB BB 266266 EE EE DD CC BB CC 267267 DD DD CC BB BB BB 268268 EE DD CC CC BB BB 269269 EE DD CC CC BB BB 270270 DD DD AA AA AA AA 271271 EE EE AA AA AA AA 272272 EE EE DD DD DD DD 273273 DD BB DD CC DD CC 274274 DD BB EE DD DD DD 275275 DD CC DD DD CC DD 276276 EE DD CC CC BB CC 277277 EE FF FF FF EE EE 278278 EE FF EE FF FF EE 279279 EE EE EE EE CC DD 280280 EE BB CC AA AA AA 281281 CC CC BB AA AA AA 282282 EE CC CC BB AA AA 283283 EE CC CC BB AA AA BBT-176BBT-176 DD DD CC CC BB CC TQB-3804TQB-3804 DD DD BB BB CC CC [GI50의 분류]
A: 0.001 μM ~ 0.025 μM, B: 0.025 μM ~ 0.100 μM, C: 0.100 μM ~ 0.500 μM, D: 0.500 μM ~ 2.0 μM, E: 2.0 μM ~ 10.0 μM, F: > 10.0 Μm, nd: not determined [Classification of GI 50 ]
A: 0.001 μM to 0.025 μM, B: 0.025 μM to 0.100 μM, C: 0.100 μM to 0.500 μM, D: 0.500 μM to 2.0 μM, E: 2.0 μM to 10.0 μM, F: > 10.0 Μm, nd: not determined

이상에서 설명한 바와 같이, 본 발명에 따른 상기 화학식 1로 표시되는 피리미딘 화합물 또는 이의 약제학적으로 허용 가능한 염은 EGFR 단백질 키나아제에 대한 저해활성을 나타내므로, EGFR 단백질 키나아제에 의해 유발되는 비정상적인 세포 대사 및 당 대사로 유발되는 질환으로서 예를 들면 당뇨, 비만 등의 대사성질환 및 자궁내막암, 방광암, 위암, 폐암, 간암, 대장암, 소장암, 췌장암, 뇌암, 뼈암, 흑색종, 유방암, 경화성선종, 두경부암, 식도암, 갑상선암, 부갑상선암, 신장암, 육종, 전립선암, 요도암, 백혈병, 다발성골수종, 골수이형성증후군과 같은 혈액암, 호치킨병과 비호치킨림프종과 같은 림프종, 또는 섬유선종으로 이루어진 군으로부터 선택되는 종양 질환의 예방 및 치료제로서 유용하다.As described above, since the pyrimidine compound represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention exhibits inhibitory activity against EGFR protein kinase, abnormal cell metabolism induced by EGFR protein kinase and As diseases induced by glucose metabolism, for example, metabolic diseases such as diabetes and obesity, endometrial cancer, bladder cancer, stomach cancer, lung cancer, liver cancer, colorectal cancer, small intestine cancer, pancreatic cancer, brain cancer, bone cancer, melanoma, breast cancer, sclerosing adenoma, Group consisting of head and neck cancer, esophageal cancer, thyroid cancer, parathyroid cancer, kidney cancer, sarcoma, prostate cancer, urethral cancer, leukemia, multiple myeloma, blood cancer such as myelodysplastic syndrome, lymphoma such as Hodgkin's disease and non-Hodgkin's lymphoma, or fibroadenoma It is useful as a preventive and therapeutic agent for a tumor disease selected from

Claims (18)

하기 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물:
[화학식 10]
Figure pat00369

[화학식 11]
Figure pat00370

[화학식 12]
Figure pat00371

상기 화학식 10 내지 12에서,
R1는 수소; 히드록시기; 할로겐기; C1-C13 알킬기; 또는 C1-C6 알콕시기;이고,
R2는 수소; 할로겐기; C1-C13 알킬기; C3-C10 사이클릴기; 아미노기(-NR8R9); 또는 니트로기(-N(O)2);이고,
R3는 및 R4는 각각 독립적으로 수소; C1-C13 알킬기; C3-C10 사이클릴기; 설피드기(-SR8); 술폰기(-S(O)2R8);또는 포스피릴기(-P(O)R8R9)이고;
R5, R6 및 R7는 각각 독립적으로 수소; 히드록시기; 할로겐기; C1-C13 알킬기; C1-C6 알콕시기; C3-C10 사이클릴기; C3-C10 헤테로사이클릴기; -C(O)-(C1-C13 알킬); 아미노기(-NR8R9); 니트로기(-N(O)2); 아마이드기(-(C=O)NR8R9); 카르복실산기(-C(O)OH); 니트릴기(-CN); 유레아기(-NR8(C=O)NR9-); 술폰아미드기(-NHS(O)2R8); 설피드기(-SR8); 술폰기(-S(O)2R8);또는 포스피릴기(-P(O)R8R9)이고;
X1, X2 및 X3 은 각각 독립적으로 탄소 또는 질소이고,
A는 C1-C13 알킬기; 아미노기(-NR8R9); C6-C10 아릴기; C3-C10 사이클릴기; C3-C10 헤테로아릴기; C3-C10 헤테로사이클릴기; 또는 A는 R6과 연결된 탄소 원자와 함께 N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, 또는 SO2 중 적어도 1종을 임의로 포함할 수 있고, 수소, C1-C13 알킬기, C6-C10 아릴기, C3-C10 헤테로아릴기, 히드록실기, 할라이드기 및 시아노기 중 적어도 1종으로 임의로 치환될 수 있는 3 내지 7원(membered) 포화 고리를 형성하고;
B는 C6-C10 아릴기; C3-C10 사이클릴기; C3-C10 헤테로아릴기; 또는 C3-C10 헤테로사이클릴기; 이고,
X1 또는 X3가 각각 독립적으로 질소일 때, R2 또는 R7은 치환되지 않으며,
상기 C1-C6 알콕시기, C1-C13 알킬기 또는 C3-C10 사이클릴기는, 수소; 히드록시기; 할로겐기; C1-C13 알킬기; C1-C6 알콕시기; 아미노기(-NR8R9); 니트로기(-N(O)2); 아마이드기(-(C=O)NR8R9); 카르복실산기(-C(O)OH); 니트릴기(-CN); 유레아기(-NR8(C=O)NR9-); 술폰아미드기(-NHS(O)2-); 설피드기(-S-); 술폰기(-S(O)2-); 포스피릴기(-P(O)R8R9); C6-C10 아릴기; C3-C10 헤테로아릴기; 및 C3-C10 헤테로사이클릴기로 이루어진 군으로부터 선택되는 1 이상의 치환기를 포함하며,
상기 C6-C10 아릴기, C3-C10 헤테로아릴기 또는 C3-C10 헤테로사이클릴기는, 수소; 히드록시기; 할로겐기; 카보닐기(-(C=O)R8R9); 할로겐 또는 C3-C10 헤테로사이클릴기로 치환 또는 비치환된 C1-C3 알킬기; 할로겐 또는 C3-C10 헤테로사이클릴기로 치환 또는 비치환된 C1-C3 알콕시기; C6-C10 페녹시; 아미노기(-NR8R9); 니트로기(-N(O)2); 아마이드기(-(C=O)NR8R9); 카르복실산기(-C(O)OH); 니트릴기(-CN); 유레아기(-NR8(C=O)NR9-); 술폰아미드기(-NHS(O)2-); 설피드기(-S-); 술폰기(-S(O)2-); 포스피릴기(-P(O)R8R9); C6-C10 아릴기; C3-C10 헤테로아릴기 및 C3-C10 헤테로사이클릴기로 이루어진 군에서 선택되는 1 이상의 치환기를 포함하고,
상기 R8 및 R9은 각각 독립적으로 수소; C1-C6 알킬기; C1-C6 알케닐기; C1-C6 알키닐기; C6-C10 아릴기; C3-C10 헤테로아릴기; C3-C10 헤테로사이클릴기; 또는 R8는 R9과 연결된 질소 또는 탄소 원자와 함께 N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, 또는 SO2 중 적어도 1종을 임의로 포함할 수 있고, 수소, C1-C13 알킬기, C6-C10 아릴기, C3-C10 헤테로아릴기, 히드록실기, 할라이드기 및 시아노기 중 적어도 1종으로 임의로 치환될 수 있는 3 내지 7원(membered) 포화 고리를 형성하고,
상기 C3-C10 헤테로아릴기 및 C3-C10 헤테로사이클릴기는 N, O, 및 S로 이루어지는 군에서 선택된 1종 이상의 헤테로원자를 포함한다.
A compound selected from a pyrimidine derivative compound represented by the following formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof:
[Formula 10]
Figure pat00369

[Formula 11]
Figure pat00370

[Formula 12]
Figure pat00371

In Formulas 10 to 12,
R 1 is hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; Or a C 1 -C 6 alkoxy group;
R 2 is hydrogen; halogen group; C 1 -C 13 alkyl group; C 3 -C 10 cyclyl group; an amino group (-NR 8 R 9 ); or a nitro group (—N(O) 2 );
R 3 and R 4 are each independently hydrogen; C 1 -C 13 alkyl group; C 3 -C 10 cyclyl group; sulfide group (-SR 8 ); a sulfone group (-S(O) 2 R 8 ); or a phospyryl group (-P(O)R 8 R 9 );
R 5 , R 6 and R 7 are each independently hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; C 1 -C 6 alkoxy group; C 3 -C 10 cyclyl group; C 3 -C 10 heterocyclyl group; -C(O)-(C 1 -C 13 alkyl); an amino group (-NR 8 R 9 ); nitro group (-N(O) 2 ); an amide group (-(C=O)NR 8 R 9 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 8 (C=O)NR 9 -); a sulfonamide group (—NHS(O) 2 R 8 ); sulfide group (-SR 8 ); a sulfone group (-S(O) 2 R 8 ); or a phospyryl group (-P(O)R 8 R 9 );
X 1 , X 2 and X 3 are each independently carbon or nitrogen,
A is a C 1 -C 13 alkyl group; an amino group (-NR 8 R 9 ); C 6 -C 10 aryl group; C 3 -C 10 cyclyl group; C 3 -C 10 heteroaryl group; C 3 -C 10 heterocyclyl group; or A together with the carbon atom connected to R 6 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 -, or SO 2 , which may optionally include at least one of hydrogen, a C 1 -C 13 alkyl group, a C 6 -C 10 aryl group, a C 3 -C 10 heteroaryl group, a hydroxyl group, a halide group, and a cyano group. form a 3 to 7 membered saturated ring which may be optionally substituted with at least one;
B is a C 6 -C 10 aryl group; C 3 -C 10 cyclyl group; C 3 -C 10 heteroaryl group; or a C 3 -C 10 heterocyclyl group; ego,
When X 1 or X 3 is each independently nitrogen, R 2 or R 7 is unsubstituted,
The C 1 -C 6 alkoxy group, C 1 -C 13 alkyl group, or C 3 -C 10 cyclyl group may include hydrogen; hydroxyl group; halogen group; C 1 -C 13 alkyl group; C 1 -C 6 alkoxy group; an amino group (-NR 8 R 9 ); nitro group (-N(O) 2 ); an amide group (-(C=O)NR 8 R 9 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 8 (C=O)NR 9 -); sulfonamide group (-NHS(O) 2 -); sulfide group (-S-); sulfonic group (-S(O) 2 -); a phospyryl group (-P(O)R 8 R 9 ); C 6 -C 10 aryl group; C 3 -C 10 heteroaryl group; and one or more substituents selected from the group consisting of a C 3 -C 10 heterocyclyl group,
The C 6 -C 10 aryl group, C 3 -C 10 heteroaryl group, or C 3 -C 10 heterocyclyl group may include hydrogen; hydroxyl group; halogen group; a carbonyl group (-(C=O)R 8 R 9 ); a C 1 -C 3 alkyl group unsubstituted or substituted with a halogen or C 3 -C 10 heterocyclyl group; a C 1 -C 3 alkoxy group unsubstituted or substituted with a halogen or C 3 -C 10 heterocyclyl group; C 6 -C 10 phenoxy; an amino group (-NR 8 R 9 ); nitro group (-N(O) 2 ); an amide group (-(C=O)NR 8 R 9 ); carboxylic acid group (-C(O)OH); nitrile group (-CN); urea group (-NR 8 (C=O)NR 9 -); sulfonamide group (-NHS(O) 2 -); sulfide group (-S-); sulfonic group (-S(O) 2 -); a phospyryl group (-P(O)R 8 R 9 ); C 6 -C 10 aryl group; Containing one or more substituents selected from the group consisting of a C 3 -C 10 heteroaryl group and a C 3 -C 10 heterocyclyl group,
wherein R 8 and R 9 are each independently hydrogen; C 1 -C 6 alkyl group; C 1 -C 6 alkenyl group; C 1 -C 6 alkynyl group; C 6 -C 10 aryl group; C 3 -C 10 heteroaryl group; C 3 -C 10 heterocyclyl group; or R 8 together with the nitrogen or carbon atom connected to R 9 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 - or SO 2 may optionally include at least one of hydrogen, C 1 -C 13 alkyl group, C 6 -C 10 aryl group, C 3 -C 10 heteroaryl group, hydroxyl group, halide group, and Forms a 3 to 7 membered saturated ring that may be optionally substituted with at least one of a cyano group,
The C 3 -C 10 heteroaryl group and the C 3 -C 10 heterocyclyl group include one or more heteroatoms selected from the group consisting of N, O, and S.
 제 1항에 있어서,
R1는 수소; 또는 할로겐기; 또는 C1-C3 알킬기; 이고,
R2는 수소; C1-C3 알킬기; 또는 아미노기(-NR8R9); 이며,
R3는 수소; C1-C3 알킬기; 설피드기(-SR8); 또는 술폰기(-S(O)2R8); 이고,
R4는 수소; 또는 C1-C3 알킬기;이며,
R5 는 수소; 히드록시기; 할로겐기; C1-C3 알킬기; 또는 C1-C6 알콕시기; 이고,
R6 는 수소; 할로겐기; 또는 C1-C3 알킬기; 이며,
R7는 수소; 또는 C1-C3 알킬기;인,
화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물.
The method of claim 1,
R 1 is hydrogen; or a halogen group; or a C 1 -C 3 alkyl group; ego,
R 2 is hydrogen; C 1 -C 3 alkyl group; or an amino group (-NR 8 R 9 ); is,
R 3 is hydrogen; C 1 -C 3 alkyl group; sulfide group (-SR 8 ); or a sulfone group (—S(O) 2 R 8 ); ego,
R 4 is hydrogen; Or a C 1 -C 3 alkyl group;
R 5 is hydrogen; hydroxyl group; halogen group; C 1 -C 3 alkyl group; or a C 1 -C 6 alkoxy group; ego,
R 6 is hydrogen; halogen group; or a C 1 -C 3 alkyl group; is,
R 7 is hydrogen; Or C 1 -C 3 alkyl group; phosphorus,
A compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
 제 1항에 있어서,
상기 A는 아미노기(-NR8R9); C3-C10 헤테로아릴기; C3-C10 헤테로사이클릴기; 또는 A는 R6과 연결된 탄소 원자와 함께 N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O)2-, 또는 SO2 중 적어도 1종을 임의로 포함할 수 있고, 수소, C1-C13 알킬기, C6-C10 아릴기, C3-C10 헤테로아릴기, 히드록실기, 할라이드기 및 시아노기 중 적어도 1종으로 임의로 치환될 수 있는 3 내지 7원(membered) 포화 고리를 형성하고;
상기 B는 C6-C10 아릴기; 또는 C3-C10 헤테로아릴기; 인,
화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물.
The method of claim 1,
The A is an amino group (-NR 8 R 9 ); C 3 -C 10 heteroaryl group; C 3 -C 10 heterocyclyl group; or A together with the carbon atom connected to R 6 is N, O, S, NH, C=N, C=O, -NHC(O)-, -NHC(O)NH-, -NHS(O) 2 -, or SO 2 , which may optionally include at least one of hydrogen, a C 1 -C 13 alkyl group, a C 6 -C 10 aryl group, a C 3 -C 10 heteroaryl group, a hydroxyl group, a halide group, and a cyano group. form a 3 to 7 membered saturated ring which may be optionally substituted with at least one;
The B is a C 6 -C 10 aryl group; or a C 3 -C 10 heteroaryl group; sign,
A compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
 제 1항에 있어서,
R1는 할로겐기; 이고,
R2는 수소; 또는 아미노기(-NR8R9); 이며,
R3는 수소; C1-C3 알킬기; 또는 술폰기(-S(O)2R8); 이고,
R4는 수소; 이며,
R5 는 수소; 할로겐기; 또는 C1-C6 알콕시기; 이고,
R6 는 수소; 할로겐기; 또는 C1-C3 알킬기; 이며,
R7는 수소; 이며,
A는 피페라진, 피페리딘, 모르포린, 피롤리딘 및 이미다졸로 이루어준 군에서 선택된 어느 하나이며,
B는 벤젠, 사이아졸, 사이오펜, 피라졸, 벤조사이오펜, 피리다진, 피라진, 이미다졸, 옥사디아졸, 트리아졸, 퓨란, 피리미딘, 옥사졸, 피롤, 피리딘, 옥사디아졸, 트리아진, 시아디아졸, 이속사졸, 및 테트라졸로 이루어진 군에서 선택된 어느 하나인,
화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물.
The method of claim 1,
R 1 is a halogen group; ego,
R 2 is hydrogen; or an amino group (-NR 8 R 9 ); is,
R 3 is hydrogen; C 1 -C 3 alkyl group; or a sulfone group (—S(O) 2 R 8 ); ego,
R 4 is hydrogen; is,
R 5 is hydrogen; halogen group; or a C 1 -C 6 alkoxy group; ego,
R 6 is hydrogen; halogen group; or a C 1 -C 3 alkyl group; is,
R 7 is hydrogen; is,
A is any one selected from the group consisting of piperazine, piperidine, morpholine, pyrrolidine and imidazole,
B is benzene, cyazole, thiophene, pyrazole, benzothiophene, pyridazine, pyrazine, imidazole, oxadiazole, triazole, furan, pyrimidine, oxazole, pyrrole, pyridine, oxadiazole, triazine Any one selected from the group consisting of , cyadiazole, isoxazole, and tetrazole,
A compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
 제 1항에 있어서,
R1는 Cl 또는 Br 이고,
R2는 수소 또는 -NH2 이며,
R3는 수소; -CH3; 또는 -S(O)2CH3; 이고,
R4는 수소; 이며,
R5 는 수소; Cl; Br; -OCH3; -OCH2CH3 또는 -OCH2CF3 이고,
R6 는 수소; Cl; Br; F; -CH3; 또는 -CF3; 이며,
R7는 수소; 이며,
A는 피페라진, 피페리딘, 모르포린 및 피롤리딘로 이루어진 군에서 선택된 어느 하나이며,
B는 벤젠, 벤조사이아졸, 퀴놀린 및 퀴녹살린으로 이루어진 군에서 선택된 어느 하나인,
화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물.
The method of claim 1,
R 1 is Cl or Br,
R 2 is hydrogen or —NH 2 ,
R 3 is hydrogen; -CH 3 ; or —S(O) 2 CH 3 ; ego,
R 4 is hydrogen; is,
R 5 is hydrogen; Cl; Br; -OCH 3 ; -OCH 2 CH 3 or -OCH 2 CF 3 and
R 6 is hydrogen; Cl; Br; F; -CH 3 ; or -CF 3 ; is,
R 7 is hydrogen; is,
A is any one selected from the group consisting of piperazine, piperidine, morpholine and pyrrolidine,
B is any one selected from the group consisting of benzene, benzocyazole, quinoline and quinoxaline,
A compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
 제 1항에 있어서,
상기 A는
Figure pat00372
,
Figure pat00373
,
Figure pat00374
,
Figure pat00375
,
Figure pat00376
,
Figure pat00377
,
Figure pat00378
,
Figure pat00379
,
Figure pat00380
,
Figure pat00381
,
Figure pat00382
,
Figure pat00383
,
Figure pat00384
,
Figure pat00385
,
Figure pat00386
,
Figure pat00387
,
Figure pat00388
,
Figure pat00389
,
Figure pat00390
,
Figure pat00391
,
Figure pat00392
,
Figure pat00393
,
Figure pat00394
,
Figure pat00395
,
Figure pat00396
,
Figure pat00397
,
Figure pat00398
,
Figure pat00399
및
Figure pat00400
중에서 선택된 어느 하나인,
화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물.
The method of claim 1,
The A is
Figure pat00372
,
Figure pat00373
,
Figure pat00374
,
Figure pat00375
,
Figure pat00376
,
Figure pat00377
,
Figure pat00378
,
Figure pat00379
,
Figure pat00380
,
Figure pat00381
,
Figure pat00382
,
Figure pat00383
,
Figure pat00384
,
Figure pat00385
,
Figure pat00386
,
Figure pat00387
,
Figure pat00388
,
Figure pat00389
,
Figure pat00390
,
Figure pat00391
,
Figure pat00392
,
Figure pat00393
,
Figure pat00394
,
Figure pat00395
,
Figure pat00396
,
Figure pat00397
,
Figure pat00398
,
Figure pat00399
and
Figure pat00400
Any one selected from
A compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
 제 1항에 있어서,
상기 B는
Figure pat00401
,
Figure pat00402
,
Figure pat00403
,
Figure pat00404
,
Figure pat00405
,
Figure pat00406
,
Figure pat00407
,
Figure pat00408
,
Figure pat00409
,
Figure pat00410
,
Figure pat00411
,
Figure pat00412
,
Figure pat00413
,
Figure pat00414
,
Figure pat00415
,
Figure pat00416
,
Figure pat00417
,
Figure pat00418
,
Figure pat00419
,
Figure pat00420
,
Figure pat00421
,
Figure pat00422
,
Figure pat00423
,
Figure pat00424
,
Figure pat00425
,
Figure pat00426
,
Figure pat00427
,
Figure pat00428
,
Figure pat00429
,
Figure pat00430
,
Figure pat00431
,
Figure pat00432
,
Figure pat00433
,
Figure pat00434
,
Figure pat00435
및
Figure pat00436
중에서 선택된 어느 하나인,
화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물.
The method of claim 1,
The B is
Figure pat00401
,
Figure pat00402
,
Figure pat00403
,
Figure pat00404
,
Figure pat00405
,
Figure pat00406
,
Figure pat00407
,
Figure pat00408
,
Figure pat00409
,
Figure pat00410
,
Figure pat00411
,
Figure pat00412
,
Figure pat00413
,
Figure pat00414
,
Figure pat00415
,
Figure pat00416
,
Figure pat00417
,
Figure pat00418
,
Figure pat00419
,
Figure pat00420
,
Figure pat00421
,
Figure pat00422
,
Figure pat00423
,
Figure pat00424
,
Figure pat00425
,
Figure pat00426
,
Figure pat00427
,
Figure pat00428
,
Figure pat00429
,
Figure pat00430
,
Figure pat00431
,
Figure pat00432
,
Figure pat00433
,
Figure pat00434
,
Figure pat00435
and
Figure pat00436
Any one selected from
A compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
 제 1항에 있어서,
R1는 Cl 또는 Br 이고,
R2는 수소 또는 -NH2 이며,
R3는 수소; -CH3; 또는 -S(O)2CH3; 이고,
R4는 수소; 이며,
R5 는 수소; Cl; Br; -OCH3; -OCH2CH3 또는 -OCH2CF3 이고,
R6 는 수소; Cl; Br; F; -CH3; 또는 -CF3; 이며,
R7는 수소; 이며,
A는
Figure pat00437
,
Figure pat00438
,
Figure pat00439
,
Figure pat00440
및
Figure pat00441
으로 이루어진 군에서 선택된 어느 하나이며,
B는
Figure pat00442
,
Figure pat00443
,
Figure pat00444
,
Figure pat00445
,
Figure pat00446
및
Figure pat00447
으로 이루어진 군에서 선택된 어느 하나인,
화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물.
The method of claim 1,
R 1 is Cl or Br,
R 2 is hydrogen or —NH 2 ,
R 3 is hydrogen; -CH 3 ; or —S(O) 2 CH 3 ; ego,
R 4 is hydrogen; is,
R 5 is hydrogen; Cl; Br; -OCH 3 ; -OCH 2 CH 3 or -OCH 2 CF 3 and
R 6 is hydrogen; Cl; Br; F; -CH 3 ; or -CF 3 ; is,
R 7 is hydrogen; is,
A is
Figure pat00437
,
Figure pat00438
,
Figure pat00439
,
Figure pat00440
and
Figure pat00441
Any one selected from the group consisting of
B is
Figure pat00442
,
Figure pat00443
,
Figure pat00444
,
Figure pat00445
,
Figure pat00446
and
Figure pat00447
Any one selected from the group consisting of
A compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
 제 1항에 있어서,
상기 화합물은 하기 화합물번호 1 내지 283로 이루어진 군으로부터 선택되는 어느 하나인 것을 특징으로 하는, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물:
화합물번호 1: N-(2-((5-클로로-2-((6-(4-에틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 2: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 3: N-(2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 4: N-(2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)-2-(2,2,2-트라이플루오로에톡시)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 5: N-(2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 6: N-(2-((5-클로로-2-((6-(1,1-다이옥시싸이오몰폴리노)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 7: N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메설폰아마이드;
화합물번호 8: N-(5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)-N-(2-(메틸설폰아마이도)페닐)메탄설폰아마이드;
화합물번호 9: N-(5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)-N-(2-(메틸설폰아마이도)페닐)메탄설폰아마이드;
화합물번호 10: N-(5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)-N-(2-(메틸설폰아마이도)페닐)메탄설폰아마이드;
화합물번호 11: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리디니-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)-N-메틸설폰아마이드;
화합물번호 12: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 13: N-(2-((5-클로로-2-((6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 14: N-(2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-yl)피페리딘-1-일)피리딘-3-일)아마이도)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 15: N-(2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 16: N-(2-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 17: N-(2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 18: N-(2-((5-클로로-2-((6-(4-(2-하이드록시메틸)피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 19: N-(2-((2-((6-(4-아세틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)-5-클로로피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 20: N-(2-((5-클로로-2-((2-메톡시-6-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 21: N-(2-((5-클로로-((6-(4-하이드록시피페리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 22: N-(2-((5-클로로-2-((2-메톡시-6-(4-(옥세탄-3-일)피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 23: N-(2-((5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 24: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아마이도)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 25: N-(2-((5-브로모-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 26: N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 27: N-(2-((5-브로모-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 28: N-(2-((5-브로모-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 29: N-(2-((5-브로모-2-((2-메톡시-6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 30: N-(2-((5-브로모-2-((6-(4-사이클로프로필피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 31: N-(2-((5-브로모-2-((2-메톡시-6-(4-몰폴리노피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 32: N-(2-((5-브로모-2-((6-(4,4-다이메틸피페리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드 ;
화합물번호 33: N-(2-((5-브로모-2-((6-(4,4-다이플루오로피페리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 34: N-(2-((5-브로모-2-((2-클로로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)-5-(트라이플루오로메틸)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 35: N-(2-((5-브로모-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드 ;
화합물번호 36: N-(2-((5-브로모-2-((2-메톡시-6-(4-(1-메틸피페리딘-4-일)피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 37: N-(2-((5-브로모-2-((2-메톡시-6-(4-(1-메틸-4-일)피페라진-1-일)-5-(트라이플루오로메틸)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 38: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 39: N-(2-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 40: N-(2-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 41: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-((1-메틸-1H-피라졸-5-일)아미노)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 42: N-(2-((5-브로모-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 43: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페리딘-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 44: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 45: N-(2-((5-브로모-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)플루오로페닐)메탄설폰아마이드;
화합물번호 46: 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민;
화합물번호 47: 5-클로로-N 2-(2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민;
화합물번호 48: 5-클로로-N 2-(4-(4-에틸피페라진-1-일)페닐)-N 4-(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민;
화합물번호 49: 5-클로로-N 2-(6-몰폴리노피리딘-3-일)-N 4-(2-(트라이플루오로메틸)페닐)피리미딘-2,4-다이아민;
화합물번호 50: 2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;
화합물번호 51: 2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;
화합물번호 52: 2-((5-클로로-2-((6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;
화합물번호 53: 2-((5-클로로-2-((6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;
화합물번호 54: 2-((5-클로로-2-((6-(4-에틸피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;
화합물번호 55: 2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;
화합물번호 56: 2-((5-클로로-2-((6-(4-(2-하이드록시에틸)피페라진-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;
화합물번호 57: 2-((5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;
화합물번호 58: 2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-메틸벤젠설폰아마이드;
화합물번호 59: 2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-사이클로프로필벤젠설폰아마이드;
화합물번호 60: 2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-N-사이클로프로필벤젠설폰아마이드;
화합물번호 61: 2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페라딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-N-사이클로프로필벤젠설폰아마이드;
화합물번호 62: 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민;
화합물번호 63: 5-클로로-N 2-(3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민;
화합물번호 64: 5-클로로-N 2-(2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)-N 4-(2-((메틸설포닐)메틸)페닐)피리미딘-2,4-다이아민;
화합물번호 65: N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 66: N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 67: N-(4-클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 68: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 69: N-(2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 70: N-(2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 71: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 72: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 73: N-(4,5-다이클로로-2-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 74: N-(4,5-다이클로로-2-((5-클로로-2-((6-몰폴리노피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 75: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 76: N-(4,5-다이클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 77: N-(4,5-다이클로로-2-((5-클로로-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)아세타마이드;
화합물번호 78: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)-N-메틸아세타마이드;
화합물번호 79: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)(메틸)아미노)페닐)-N-메틸아세타마이드;
화합물번호 80: N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 81: N-(4-클로로-2-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노페닐)메탄설폰아마이드;
화합물번호 82: N-(4-클로로-2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 83: N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 84: N-(4-클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 85: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노-4-클로로페닐)메탄설폰아마이드;
화합물번호 86: N-(2-((5-브로모-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 87: N-(2-((5-브로모-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 88: N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 89: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설포닐아마이드;
화합물번호 90: N-(2-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 91: N-(2-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 92: N-(2-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 93: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 94: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 95: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 96: N-(2-((5-브로모-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 97: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 98: N-(2-((5-브로모-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 99: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 100: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)페닐메탄설폰아마이드;
화합물번호 101: N-(4,5-다이클로로-2-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 102: N-(4,5-다이클로로-2-((5-클로로-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아민노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 103: N-(4,5-다이클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노페닐)메탄설폰아마이드;
화합물번호 104: N-(4,5-다이클로로-2-((5-클로로-2-((4-(4-((2-(다이메틸아미노)에틸)(메틸)아미노)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 105: N-(4,5-다이클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(메틸(3-(4-메틸피페라진-1-일)프로필)아미노)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설포나마이드;
화합물번호 106: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드;
화합물번호 107: N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드;
화합물번호 108: N-(2-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메톡시-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드;
화합물번호 109: N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메틸페닐)메탄설폰아마이드;
화합물번호 110: N-(5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드;
화합물번호 111: N-(5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드;
화합물번호 112: N-(5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드;
화합물번호 113: N-(5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드;
화합물번호 114: N-(5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)-N-(4-(메틸설폰아마이도)벤조[d]싸이아졸-5-일)메탄설폰아마이드;
화합물번호 115: N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드;
화합물번호 116: N-(6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드;
화합물번호 117: N-(6-((5-클로로-2-((2-메톡시-6-(4-몰폴리노피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드;
화합물번호 118: N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메톡시피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드;
화합물번호 119: N-(6-((5-클로로-2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴놀린-5-일)메탄설폰아마이드;
화합물번호 120: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)(메틸)아미노)페닐)메탄설폰아마이드;
화합물번호 121: N-(2-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)(메틸)아미노)페닐)메탄설폰아마이드;
화합물번호 122: (6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 123: (6-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 124: (6-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 125: (6-((5-클로로-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀옥사이드;
화합물번호 126: (6-((5-클로로-2-((2-메톡시-6-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 127: (6-((5-클로로-2-((6-(3-(다이메틸아미노)피롤리딘-1-일)-2-메톡시피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 128: (6-((5-클로로-2-((2-메톡시-6-(피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 129: 4-(5-((5-클로로-4-((5-(다이메틸포스포릴)퀴녹살린-6-일)아미노)피리미딘-2-일)아미노)-6-메톡시피리딘-2-일)싸이오몰폴린 1,1-다이옥사이드;
화합물번호 130: (6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 131: N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드;
화합물번호 132: N-(6-((5-클로로-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드;
화합물번호 133: N-(6-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드;
화합물번호 134: N-(6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드;
화합물번호 135: N-(6-((5-클로로-2-((2-메톡시-6-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)메탄설폰아마이드;
화합물번호 136: N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-y일)아미노)퀴녹살린-5-일)메탄설폰아마이드;
화합물번호 137: N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-(트라이플루오로메틸)페닐)메탄설폰아마이드;
화합물번호 138: N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-(트라이플루오로메틸)페닐)메탄설폰아마이드;
화합물번호 139: N-(2-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-(트라이플루오로메틸)페닐)메탄설폰아마이드;
화합물번호 140: N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 141: N-(2-((6-아미노-5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 142: ((2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸- λ 6-설파논;
화합물번호 143: ((2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸- λ 6-설파논;
화합물번호 144: ((2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)이미노)다이메틸-λ 6-설파논;
화합물번호 145: N-(2-((5-브로모-2-((2-메톡시-6-(1-메틸아제판-4-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 146: N-(2-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 147: N-(2-((5-브로모-2-((2-메톡시-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 148: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 149: N-(2-((5-브로모-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 150: N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 151: N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 152: N-(4-클로로-2-((6-클로로-3-(( -2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-1,2,4-트리아진-5-일)아미노)페닐)메탄설폰아마이드;
화합물번호 153 : (4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)다이메틸포스핀 옥사이드;
화합물번호 154 : (4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)다이메틸포스핀 옥사이드;
화합물번호 155 : N-(2-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드;
화합물번호 156 : N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드;
화합물번호 157 : N-(4-클로로-2-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 158 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 159 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 159 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 160 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-아이소프로필페닐)메탄설폰아마이드;
화합물번호 161 : N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-아이소프로필페닐)메탄설폰아마이드;
화합물번호 162 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 163 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 164 : N-(2-((6-클로로-3-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-1,2,4-트리아진-5-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 165 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 166 : 5-클로로-N4-(5-클로로-2-(1H-1,2,3-트리아졸-4-일)페닐)-N2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;
화합물번호 167 : N-(4-클로로-2-((5-클로로-2-((1-(3-(다이메틸아미노)프로필)-1H-피라졸-4-일)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 168 : N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 169 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 170 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;
화합물번호 171 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;
화합물번호 172 : N-(6-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 173 : N-(6-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 174 : N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 175 : N-(6-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 176 : N-(4-클로로-2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 177 : N-(2-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로-5-플루오로페닐)메탄설폰아마이드;
화합물번호 178 : N-(2-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로-5-플루오로페닐)메탄설폰아마이드;
화합물번호 179 : N-(4-클로로-2-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;
화합물번호 180 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;
화합물번호 181 : N-(4-클로로-2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 182 : N-(4-클로로-2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-5-플루오로페닐)메탄설폰아마이드;
화합물번호 183 : N-(6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드.
화합물번호 184 : N-(6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 185 : 5-클로로-N4-(5-클로로-2-(1H-1,2,3-트라이졸-5-일)페닐)-N2-(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;
화합물번호 186 : 5-클로로-N 4-(5-클로로-2-(1H-1,2,3-트리아졸-5-일)페닐)-N 2-(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;
화합물번호 187 : 5-브로모-N 4-(5-클로로-2-(1H-1,2,3-트리아졸-5-일)페닐)-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;
화합물번호 188 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 189 : N-(6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 190 : (6-((5-클로로-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 191 : N-(2-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)메탄설폰아마이드;
화합물번호 192 : (6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드.
화합물번호 193 : (6-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 194 : (6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)퀴녹살린-5-일)다이메틸포스핀 옥사이드;
화합물번호 195 : 5-브로모-N 4-(5-클로로-2-(1H-1,2,3-트리아졸-5-일)페닐)-N 2-(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;
화합물번호 196 : N-(6-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 197 : N-(6-((5-클로로-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 198 : N-(4-클로로-2-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)메탄설폰아마이드;
화합물번호 199 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 200 : N-(2-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 201 : N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드.
화합물번호 202 : N-(2-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 203 : N-(2-((5-클로로-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 204 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 205 : N-(6-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 206 : N-(6-((5-클로로-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 207 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 208 : N-(6-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 209 : N-(6-((5-클로로-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 210 : N-(6-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 211 : N-(6-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 212 : N-(6-((5-브로모-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 213 : N-(6-((5-브로모-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 214 : N-(6-((5-브로모-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 215 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 216 : N-(6-((5-브로모-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 217 : N-(6-((5-브로모-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 218 : N-(6-((5-클로로-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 219 : N-(6-((5-클로로-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 220 : N-(6-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 221 : N-(6-((5-클로로-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 222 : N-(6-((5-클로로-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 223 : N-(6-((5-클로로-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 224 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-((1-메틸-1H-피라졸-5-일)아미노)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 225 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-(트라이플루오로메틸)피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 226 : N-(4-클로로-2-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)페닐)-N-메틸메탄설폰아마이드;
화합물번호 227 : N-(2-((5-브로모-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드;
화합물번호 228 : N-(2-((5-브로모-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-클로로페닐)-N-메틸메탄설폰아마이드;
화합물번호 229 : N-(2-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 230 : N-(2-((5-클로로-2-((2-클로로-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 231 : N-(2-((5-클로로-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 232 : N-(2-((5-클로로-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 233 : N-(2-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 234 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 235 : N-(2-((5-클로로-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 236 : N-(2-((5-클로로-2-((2-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-5-메틸페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 237 : N-(2-((5-클로로-2-((5-클로로-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)메탄설폰아마이드;
화합물번호 238 : N-(6-((5-브로모-2-((2-메톡시-6-(4-메틸-1,4-다이아제판-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 239 : N-(6-((5-브로모-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 240 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 241 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 242 : N-(6-((5-클로로-2-((5-플루오로-6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 243 : N-(6-((5-브로모-2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 244 : N-(6-((5-브로모-2-((3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 245 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(트라이플루오로메틸)-[1,4'-바이피페리딘]-1'-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 246 : N-(6-((5-브로모-2-((2-클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설포닐아마이드;
화합물번호 247 : N-(6-((5-브로모-2-((2-(4-(4-메틸피페라진-1-일)피페리딘-1-일)퀴놀린-6-일)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 248 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 249 : N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 250 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 251 : N-(6-((5-브로모-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 252 : N-(6-((5-브로모-2-((5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 253 : N-(6-((5-브로모-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 254 : N-(6-((5-브로모-2-((5-에틸-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 255 : N-(6-((5-브로모-2-((2-메톡시-5-메틸-4-(4-(4-(트라이플루오로메틸)피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 256 : N-(6-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 257 : N-(6-((5-브로모-2-((5-플루오로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 258 : N-(6-((5-브로모-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 259 : N-(6-((5-클로로-2-((2,5-다이클로로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 260 : N-(2-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-4-메톡시페닐)-N-메틸메탄설폰아마이드;
화합물번호 261 : N-(6-((5-브로모-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 262 : N-(6-((5-브로모-2-((4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 263 : N-(6-((5-클로로-2-((2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 264 : N-(6-((5-클로로-2-((5-클로로-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 265 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 266 : N-(6-((5-클로로-2-((4-(4-(4-사이클로프로필피페라진-1-일)피페리딘-1-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 267 : N-(6-((5-클로로-2-((4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시-5-메틸페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)-N-메틸메탄설폰아마이드;
화합물번호 268 : N-(6-((5-클로로-2-((2,5-다이플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 269 : N-(5-((5-브로모-2-((2,5-다이플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-4-일)메탄설폰아마이드;
화합물번호 270 : N-(6-((2-((5-브로모-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 271 : N-(6-((2-((5-브로모-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 272 : 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(1-메틸인돌린-6-일)피리미딘-2,4-다이아민;
화합물번호 273 : 5-클로로-N 2-(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(1-메틸인돌린-6-일)피리미딘-2,4-다이아민;
화합물번호 274 : 5-클로로-N 2-(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(1-메틸인돌린-6-일)피리미딘-2,4-다이아민;
화합물번호 275 : 5-클로로-N 2-(2-메톡시-5-메틸-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)-N 4-(1-메틸인돌린-6-일)피리미딘-2,4-다이아민;
화합물번호 276 : N-(6-((5-클로로-2-((2-메톡시-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)피리미딘-4-일)아미노)-1-메틸인돌린-5-일)메탄설폰아마이드;
화합물번호 277 : 5-클로로-N 2-(2-클로로-5-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(인돌린-6-일)피리미딘-2,4-다이아민;
화합물번호 278 : 5-클로로-N 2-(5-클로로-2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-N 4-(인돌린-6-일)피리미딘-2,4-다이아민;
화합물번호 279 : 5-클로로-N 4-(인돌린-6-일)-N 2-(2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)피리미딘-2,4-다이아민;
화합물번호 280 : N-(6-((2-((5-브로모-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 281 : N-(6-((5-브로모-2-((5-브로모-4-(3-(다이메틸아미노)-[1,4'-바이피페리딘]-1'-일)-2-메톡시페닐)아미노)피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드;
화합물번호 282 : N-(6-((2-((5-브로모-2-메톡시-4-(4-(4-메틸-1,4-다이아제판-1-일)피페리딘-1-일)페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드; 및
화합물번호 283 : N-(6-((2-((5-브로모-4-(4-(3-(다이메틸아미노)피롤리딘-1-일)피페리딘-1-일)-2-메톡시페닐)아미노)-5-클로로피리미딘-4-일)아미노)-2,3-다이하이드로벤조퓨란-5-일)메탄설폰아마이드.

The method of claim 1,
The compound is a pyrimidine derivative compound represented by Formula 10, 11 or 12, characterized in that it is any one selected from the group consisting of Compound Nos. 1 to 283, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoscopic thereof Compounds selected from isomers:
Compound No. 1: N -(2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-4-yl) amino)phenyl)methanesulfonamide;
Compound No. 2: N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 3: N -(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino )pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 4: N -(2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-2-(2,2) ,2-trifluoroethoxy)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 5: N- (2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 6: N -(2-((5-chloro-2-((6-(1,1-dioxythiomorpholino)-2-methoxypyridin-3-yl)amino)pyrimidine-4 -yl)amino)phenyl)methanesulfonamide;
Compound No. 7: N -(2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)mesulphonamide;
Compound No. 8: N- (5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine-4 -yl) -N- (2-(methylsulfonamido)phenyl)methanesulfonamide;
Compound No. 9: N -(5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)-N- ( 2-(methylsulfonamido)phenyl)methanesulfonamide;
Compound No. 10: N- (5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) amino)pyrimidin-4-yl)-N- ( 2-(methylsulfonamido)phenyl)methanesulfonamide;
Compound No. 11: N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidini-1-yl)piperidini-1-yl) yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl) -N -methylsulfonamide;
Compound No. 12: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide;
Compound No. 13: N- (2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methane sulfonamides;
Compound No. 14: N- (2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amai Figure) pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 15: N- (2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 16: N- (2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 17: N- (2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 18: N- (2-((5-chloro-2-((6-(4-(2-hydroxymethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino )pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 19: N- (2-((2-((6-(4-acetylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)-5-chloropyrimidine-4- yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 20: N- (2-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 21: N- (2-((5-chloro-((6-(4-hydroxypiperidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4- yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 22: N- (2-((5-chloro-2-((2-methoxy-6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-3-yl) amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 23: N- (2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino) pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 24: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amido)-5-fluorophenyl)methanesulfonamide;
Compound No. 25: N- (2-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 26: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 27: N- (2-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 28: N- (2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 29: N- (2-((5-bromo-2-((2-methoxy-6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)-5- fluorophenyl)methanesulfonamide;
Compound No. 30: N- (2-((5-bromo-2-((6-(4-cyclopropylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine- 4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 31: N- (2-((5-bromo-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidine -4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 32: N- (2-((5-bromo-2-((6-(4,4-dimethylpiperidin-1-yl)-2-methoxypyridin-3-yl)amino) pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 33: N- (2-((5-bromo-2-((6-(4,4-difluoropiperidin-1-yl)-2-methoxypyridin-3-yl)amino) )pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 34: N- (2-((5-bromo-2-((2-chloro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5) -(trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 35: N- (2-((5-bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl) amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 36: N- (2-((5-bromo-2-((2-methoxy-6-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 37: N -(2-((5-bromo-2-((2-methoxy-6-(4-(1-methyl-4-yl)piperazin-1-yl)-5-( trifluoromethyl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 38: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 39: N- (2-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 40: N- (2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-) 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 41: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1H-pyrazol-5-yl)amino) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 42: N- (2-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy -5-methylphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 43: N- (2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperidin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 44: N- (2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 45: N- (2-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)fluorophenyl)methanesulfonamide;
Compound No. 46: 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine;
Compound No. 47: 5-chloro- N 2 -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(2- (trifluoromethyl)phenyl)pyrimidine-2,4-diamine;
Compound No. 48: 5-chloro- N 2 -(4-(4-ethylpiperazin-1-yl)phenyl) -N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-dia min;
Compound No. 49: 5-Chloro- N 2 -(6-morpholinopyridin-3-yl) -N 4 -(2-(trifluoromethyl)phenyl)pyrimidine-2,4-diamine;
Compound No. 50: 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino) -N -methylbenzenesulfonamide;
Compound No. 51: 2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri midin-4-yl)amino) -N -methylbenzenesulfonamide;
Compound No. 52: 2-((5-chloro-2-((6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)amino)pyrimidine -4-yl)amino) -N -methylbenzenesulfonamide;
Compound No. 53: 2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino) -N -methylbenzenesulfonamide;
Compound No. 54: 2-((5-chloro-2-((6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidin-4-yl)amino ) -N -methylbenzenesulfonamide;
Compound No. 55: 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) )amino)pyrimidin-4-yl)amino) -N -methylbenzenesulfonamide;
Compound No. 56: 2-((5-chloro-2-((6-(4-(2-hydroxyethyl)piperazin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine -4-yl)amino) -N -methylbenzenesulfonamide;
Compound No. 57: 2-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine- 4-yl)amino) -N -methylbenzenesulfonamide;
Compound No. 58: 2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine -3-yl)amino)pyrimidin-4-yl)amino) -N -methylbenzenesulfonamide;
Compound No. 59: 2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino) -N -cyclopropylbenzenesulfonamide;
Compound No. 60: 2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyri midin-4-yl)amino) -N -cyclopropylbenzenesulfonamide;
Compound No. 61: 2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperadin-1-yl)pyridin-3-yl) )amino)pyrimidin-4-yl)amino)-N-cyclopropylbenzenesulfonamide;
Compound No. 62: 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine;
Compound No. 63: 5-chloro- N 2 -(3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(2- ((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine;
Compound No. 64: 5-chloro- N 2 -(2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) -N 4 -(2-((methylsulfonyl)methyl)phenyl)pyrimidine-2,4-diamine;
Compound No. 65: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 66: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 67: N- (4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 68: N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 69: N- (2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 70: N- (2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 71: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 72: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 73: N- (4,5-dichloro-2-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 74: N- (4,5-dichloro-2-((5-chloro-2-((6-morpholinopyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl) acetamide;
Compound No. 75: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 76: N- (4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 77: N- (4,5-dichloro-2-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acetamide;
Compound No. 78: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl) -N -methylacetamide;
Compound No. 79: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl) -N -methylacetamide;
Compound No. 80: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 81: N- (4-chloro-2-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide;
Compound No. 82: N- (4-chloro-2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 83: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 84: N- (4-chloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 85: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino-4-chlorophenyl)methanesulfonamide;
Compound No. 86: N- (2-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 87: N- (2-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 88: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 89: N -(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonylamide;
Compound No. 90: N- (2-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 91: N- (2-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-) 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 92: N- (2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 93: N -(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 94: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 95: N -(2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 96: N- (2-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1) -yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 97: N -(2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 98: N- (2-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 99: N -(4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 100: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)phenylmethanesulfonamide;
Compound No. 101: N- (4,5-dichloro-2-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 102: N- (4,5-dichloro-2-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) quinolin-6-yl)amineno)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 103: N- (4,5-dichloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)aminophenyl)methanesulfonamide;
Compound No. 104: N- (4,5-dichloro-2-((5-chloro-2-((4-(4-((2-(dimethylamino)ethyl)(methyl)amino)piperidine -1-yl)-2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 105: N- (4,5-dichloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(methyl(3-(4-methylpiperazine-1) -yl)propyl)amino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 106: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;
Compound No. 107: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;
Compound No. 108: N- (2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methoxy-1-yl)piperidine-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;
Compound No. 109: N- (2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methylphenyl)methanesulfonamide;
Compound No. 110: N- (5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)-N- ( 4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;
Compound No. 111: N- (5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) amino)pyrimidin-4-yl)-N- ( 4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;
Compound No. 112: N- (5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidine -4-yl) -N- (4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;
Compound No. 113: N- (5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl) amino)pyrimidin-4-yl)-N- ( 4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;
Compound No. 114: N- (5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)-N- ( 4-(methylsulfonamido)benzo[d]thiazol-5-yl)methanesulfonamide;
Compound No. 115: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;
Compound No. 116: N -(6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;
Compound No. 117: N- (6-((5-chloro-2-((2-methoxy-6-(4-morpholinopiperidin-1-yl)pyridin-3-yl)amino)pyrimidine- 4-yl)amino)quinolin-5-yl)methanesulfonamide;
Compound No. 118: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methoxypiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)methanesulfonamide;
Compound No. 119: N- (6-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino) quinolin-5-yl)methanesulfonamide;
Compound No. 120: N -(2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide;
Compound No. 121: N -(2-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)(methyl)amino)phenyl)methanesulfonamide;
Compound No. 122: (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 123: (6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3- yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 124: (6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3- yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 125: (6-((5-chloro-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 126: (6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridin-3- yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 127: (6-((5-chloro-2-((6-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxypyridin-3-yl)amino)pyrimidine -4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 128: (6-((5-chloro-2-((2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoc salin-5-yl)dimethylphosphine oxide;
Compound No. 129: 4-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-6-methoxy pyridin-2-yl)thiomorpholine 1,1-dioxide;
Compound No. 130: (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 131: N -(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;
Compound No. 132: N- (6-((5-chloro-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;
Compound No. 133: N- (6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;
Compound No. 134: N- (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;
Compound No. 135: N- (6-((5-chloro-2-((2-methoxy-6-((3S,5R)-3,4,5-trimethylpiperazin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)methanesulfonamide;
Compound No. 136: N -(6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yyl)amino)quinoxalin-5-yl)methanesulfonamide;
Compound No. 137: N- (2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide;
Compound No. 138: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide;
Compound No. 139: N -(2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethyl)phenyl)methanesulfonamide;
Compound No. 140: N -(6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 141: N- (2-((6-amino-5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperid) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 142: ((2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl- λ 6 -sulfanone;
Compound No. 143: ((2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl- λ 6 -sulfanone;
Compound No. 144: ((2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)phenyl)imino)dimethyl- λ 6 -sulfanone;
Compound No. 145: N- (2-((5-bromo-2-((2-methoxy-6-(1-methylazepan-4-yl)pyridin-3-yl)amino)pyrimidine-4 -yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 146: N- (2-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 147: N- (2-((5-bromo-2-((2-methoxy-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 148: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperi) diin]-1′-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 149: N- (2-((5-bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 150: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperi) diin]-1′-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 151: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperid) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 152: N -(4-chloro-2-((6-chloro-3-((-2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)pi) peridin-1-yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)phenyl)methanesulfonamide;
Compound No. 153: (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;
Compound No. 154: (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide;
Compound No. 155: N- (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide;
Compound No. 156: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide;
Compound No. 157: N- (4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperi) din-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 158: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 159: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 159: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 160: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide;
Compound No. 161: N- (2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-isopropylphenyl)methanesulfonamide;
Compound No. 162: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepane-1-) yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 163: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1) -yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 164: N- (2-((6-chloro-3-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)-1,2,4-triazin-5-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 165: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 166: 5-chloro- N 4-(5-chloro-2-(1 H -1,2,3-triazol-4-yl)phenyl) -N 2-(2-methoxy-5-methyl -4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;
Compound No. 167: N- (4-chloro-2-((5-chloro-2-((1-(3-(dimethylamino)propyl) -1H -pyrazol-4-yl)amino)pyrimidine -4-yl)amino)phenyl)methanesulfonamide;
Compound No. 168: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 169: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 170: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide;
Compound No. 171: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)-N-methylmethanesulfonamide;
Compound No. 172: N- (6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperid) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 173: N- (6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 174: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 175: N- (6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 176: N- (4-chloro-2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 177: N- (2-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide;
Compound No. 178: N- (2-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chloro-5-fluorophenyl)methanesulfonamide;
Compound No. 179: N- (4-chloro-2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperi) din-1-yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide;
Compound No. 180: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methyl-1,4-diazepane-1-) yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide;
Compound No. 181: N- (4-chloro-2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperi) din-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 182: N- (4-chloro-2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidine) -1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-fluorophenyl)methanesulfonamide;
Compound No. 183: N- (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide.
Compound No. 184: N- (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 185: 5-chloro- N 4-(5-chloro-2-( 1H -1,2,3-trizol-5-yl)phenyl) -N2- (2-chloro-5-methyl- 4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;
Compound No. 186: 5-chloro- N 4 -(5-chloro-2-(1 H -1,2,3-triazol-5-yl)phenyl) -N 2 -(5-chloro-2-methoxy -4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;
Compound No. 187: 5-bromo- N 4 -(5-chloro-2-(1 H -1,2,3-triazol-5-yl)phenyl) -N 2 -(2-methoxy-5- methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;
Compound No. 188: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 189: N- (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 190: (6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 191: N- (2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl)methanesulfonamide;
Compound No. 192: (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide.
Compound No. 193: (6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 194: (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide;
Compound No. 195: 5-bromo- N 4 -(5-chloro-2-(1 H -1,2,3-triazol-5-yl)phenyl) -N 2 -(5-chloro-2-methyl oxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine;
Compound No. 196: N- (6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 197: N- (6-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl) )-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 198: N- (4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)methanesulfonamide;
Compound No. 199: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 200: N- (2-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 201: N- (2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide.
Compound No. 202: N- (2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 203: N- (2-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 204: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 205: N- (6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 206: N- (6-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 207: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 208: N- (6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 209: N- (6-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 210: N- (6-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 211: N- (6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-) 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 212: N- (6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy -5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 213: N- (6-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1) -yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 214: N- (6-((5-bromo-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 215: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(piperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 216: N- (6-((5-bromo-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1'-) yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 217: N- (6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 218: N- (6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 219: N- (6-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl) )-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 220: N- (6-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 221: N- (6-((5-chloro-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 222: N- (6-((5-chloro-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 223: N- (6-((5-chloro-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)amino )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 224: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-((1-methyl-1 H -pyrazol-5-yl)amino) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 225: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)pi) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 226: N- (4-chloro-2-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl) -N -methylmethanesulfonamide;
Compound No. 227: N- (2-((5-bromo-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1) -yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide;
Compound No. 228: N- (2-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-4-chlorophenyl) -N -methylmethanesulfonamide;
Compound No. 229: N- (2-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 230: N- (2-((5-chloro-2-((2-chloro-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 231: N- (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 232: N- (2-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 233: N- (2-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 234: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperidine) ]-1′-yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 235: N- (2-((5-chloro-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-2) -methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 236: N- (2-((5-chloro-2-((2-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl) )-5-methylphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 237: N- (2-((5-chloro-2-((5-chloro-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl) )-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl)methanesulfonamide;
Compound No. 238: N- (6-((5-bromo-2-((2-methoxy-6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)amino) )pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 239: N- (6-((5-bromo-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine) -3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 240: N- (6-((5-bromo-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 241: N- (6-((5-chloro-2-((2-methoxy-5-methyl-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)pyridin-3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 242: N- (6-((5-chloro-2-((5-fluoro-6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridine- 3-yl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 243: N- (6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 244: N- (6-((5-bromo-2-((3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 245: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(trifluoromethyl)-[1,4'-bipiperi) din]-1'-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 246: N- (6-((5-bromo-2-((2-chloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonylamide;
Compound No. 247: N- (6-((5-bromo-2-((2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)quinolin-6-yl)) amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 248: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 249: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 250: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 251: N- (6-((5-bromo-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 252: N- (6-((5-bromo-2-((5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 253: N- (6-((5-bromo-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 254: N- (6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1) -yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 255: N- (6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-(trifluoromethyl)piperazin-1-yl)) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 256: N- (6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-) 1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 257: N- (6-((5-bromo-2-((5-fluoro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl) )piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 258: N- (6-((5-bromo-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -Methoxy-5-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 259: N- (6-((5-chloro-2-((2,5-dichloro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)) phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 260: N- (2-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-4-methoxyphenyl) -N -methylmethanesulfonamide;
Compound No. 261: N- (6-((5-bromo-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy) -5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 262: N- (6-((5-bromo-2-((4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)-) 2-methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 263: N- (6-((5-chloro-2-((2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 264: N- (6-((5-chloro-2-((5-chloro-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 265: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)p) peridin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 266: N- (6-((5-chloro-2-((4-(4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl)-2-methoxy- 5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 267: N- (6-((5-chloro-2-((4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2- methoxy-5-methylphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl) -N -methylmethanesulfonamide;
Compound No. 268: N- (6-((5-chloro-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl) )phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 269: N- (5-((5-bromo-2-((2,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-4-yl)methanesulfonamide;
Compound No. 270: N- (6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 271: N- (6-((2-((5-bromo-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) )amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 272: 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;
Compound No. 273: 5-chloro- N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;
Compound No. 274: 5-chloro- N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 - (1-methylindolin-6-yl)pyrimidine-2,4-diamine;
Compound No. 275: 5-chloro- N 2 -(2-methoxy-5-methyl-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidin-1-yl) phenyl) -N 4 -(1-methylindolin-6-yl)pyrimidine-2,4-diamine;
Compound No. 276: N- (6-((5-chloro-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)piperidin-1-yl) yl)phenyl)amino)pyrimidin-4-yl)amino)-1-methylindolin-5-yl)methanesulfonamide;
Compound No. 277: 5-chloro- N 2 -(2-chloro-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 - (indolin-6-yl)pyrimidine-2,4-diamine;
Compound No. 278: 5-chloro- N 2 -(5-chloro-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl) -N 4 -(indolin-6-yl)pyrimidine-2,4-diamine;
Compound No. 279: 5-chloro- N 4 -(indolin-6-yl) -N 2 -(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1 -yl)phenyl)pyrimidine-2,4-diamine;
Compound No. 280: N- (6-((2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidin]-1'-yl)-2) -methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 281: N- (6-((5-bromo-2-((5-bromo-4-(3-(dimethylamino)-[1,4'-bipiperidine]-1') -yl)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide;
Compound No. 282: N- (6-((2-((5-bromo-2-methoxy-4-(4-(4-methyl-1,4-diazepan-1-yl)piperidine-) 1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide; and
Compound No. 283: N- (6-((2-((5-bromo-4-(4-(3-(dimethylamino)pyrrolidin-1-yl)piperidin-1-yl)- 2-Methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)-2,3-dihydrobenzofuran-5-yl)methanesulfonamide.

 제1항에 있어서,
상기 약학적으로 허용 가능한 염은 염산, 브롬화수소산, 황산, 인산, 질산, 아세트산, 글리콜산, 락트산, 피루브산, 말론산, 석신산, 글루타르산, 푸마르산, 말산, 만델산, 타타르산, 시트르산, 아스코빈산, 팔미트산, 말레인산, 하이드록시말레인산, 벤조산, 하이드록시벤조산, 페닐아세트산, 신남산, 살리실산, 메탄설폰산, 벤젠설폰산 및 톨루엔설폰산으로 구성된 군에서 선택되는 무기산 또는 유기산의 염인, 화학식 10, 11 또는 12로 표시되는 피리미딘 유도체 화합물, 이의 약학적으로 허용 가능한 염, 이의 수화물 및 이의 입체 이성질체로부터 선택된 화합물.
According to claim 1,
The pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, a salt of an inorganic or organic acid selected from the group consisting of ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; A compound selected from a pyrimidine derivative compound represented by Formula 10, 11 or 12, a pharmaceutically acceptable salt thereof, a hydrate thereof, and a stereoisomer thereof.
 제1항 내지 제10항 중 어느 한 항의 화합물이 유효성분으로 포함되어 있는, 암 예방, 경감 또는 치료용 약학 조성물.
A pharmaceutical composition for preventing, alleviating or treating cancer, wherein the compound of any one of claims 1 to 10 is included as an active ingredient.
 제11항에 있어서,
상기 암이 EGFR 돌연변이로 유발되는 것을 특징으로 하는, 암 예방, 경감 또는 치료용 약학 조성물.
12. The method of claim 11,
A pharmaceutical composition for preventing, alleviating or treating cancer, characterized in that the cancer is caused by EGFR mutation.
 제11항에 있어서,
상기 약학 조성물은 EGFR 돌연변이를 갖는 환자에 적용되는, 암 예방, 경감 또는 치료용 약학 조성물.
12. The method of claim 11,
The pharmaceutical composition is applied to a patient having an EGFR mutation, a pharmaceutical composition for preventing, alleviating or treating cancer.
 제11항에 있어서,
상기 암은 교모세포종, 삼중음성 유방암, 대장암, 폐암, 역형성대세포림프종, 위장관 간질종양, 다발성골수종, 급성골수성백혈병, 간암, 위암, 갑상선암 및 두경부암으로 이루어진 군으로부터 선택되는 1 이상인, 암 예방, 경감 또는 치료용 약학 조성물.
12. The method of claim 11,
The cancer is at least one selected from the group consisting of glioblastoma, triple-negative breast cancer, colorectal cancer, lung cancer, anaplastic large cell lymphoma, gastrointestinal stromal tumor, multiple myeloma, acute myeloid leukemia, liver cancer, stomach cancer, thyroid cancer and head and neck cancer, cancer A pharmaceutical composition for prophylaxis, alleviation or treatment.
 제14항에 있어서,
상기 암은 폐암인, 암 예방, 경감 또는 치료용 약학 조성물.
15. The method of claim 14,
The cancer is lung cancer, a pharmaceutical composition for preventing, alleviating or treating cancer.
 제11항에 있어서,
상기 약학 조성물은 EGFR 관련 돌연변이인 엑손19결손/T790M/C797S 의 삼중 돌연변이 또는 L858R/T790M/C797S 의 삼중 돌연변이를 보유한 환자에게 투여되는 것을 특징으로 하는, 암의 예방, 경감 또는 치료용 약학 조성물.
12. The method of claim 11,
The pharmaceutical composition is an EGFR-related mutation, exon 19 deletion / T790M / C797S triple mutation or L858R / T790M / C797S triple mutation, characterized in that administered to a patient carrying, the prevention, alleviation or treatment of cancer pharmaceutical composition.
 제11항에 있어서,
상기 약학 조성물은 EGFR 관련 돌연변이인 엑손19결손/T790M 의 이중 돌연변이 또는 L858R/T790M 의 이중 돌연변이를 보유한 환자에게 투여되는 것을 특징으로 하는, 암의 예방, 경감 또는 치료용 약학 조성물.
12. The method of claim 11,
The pharmaceutical composition is an EGFR-related mutation, exon 19 deletion / T790M double mutation or L858R / T790M double mutation, characterized in that administered to a patient carrying a cancer prevention, alleviation or treatment pharmaceutical composition.
 제11항에 있어서,
상기 약학 조성물은 EGFR 관련 돌연변이인 엑손19결손 돌연변이 또는 L858R 돌연변이를 보유한 환자에게 투여되는 것을 특징으로 하는, 암의 예방, 경감 또는 치료용 약학 조성물.
12. The method of claim 11,
The pharmaceutical composition is an EGFR-related mutation, characterized in that administered to a patient having an exon 19 deletion mutation or L858R mutation, the prevention, alleviation or treatment of cancer pharmaceutical composition.
KR1020220039968A 2021-04-01 2022-03-30 Pyrimidin derivatives as protein kinase inhibitors and pharmaceutical compositions for treating disease containing the same KR20220136931A (en)

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US18/279,348 US20240228458A1 (en) 2021-04-01 2022-04-01 Pyrimidine derivative having protein kinase inhibitory activity, and therapeutic pharmaceutical composition comprising same
AU2022250976A AU2022250976A1 (en) 2021-04-01 2022-04-01 Pyrimidine derivative having protein kinase inhibitory activity, and therapeutic pharmaceutical composition comprising same
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CA3207015A CA3207015A1 (en) 2021-04-01 2022-04-01 Pyrimidine derivative with inhibitory activity against protein kinases and therapeutic pharmaceutical composition including the same
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