KR101916773B1 - Diaminopyrimidine derivatives for kinase inhibitors - Google Patents

Diaminopyrimidine derivatives for kinase inhibitors Download PDF

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KR101916773B1
KR101916773B1 KR1020170084814A KR20170084814A KR101916773B1 KR 101916773 B1 KR101916773 B1 KR 101916773B1 KR 1020170084814 A KR1020170084814 A KR 1020170084814A KR 20170084814 A KR20170084814 A KR 20170084814A KR 101916773 B1 KR101916773 B1 KR 101916773B1
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ethoxy
phenylamino
pyrimidine
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이소하
유경호
김태영
에스람 모하메드 호스니 알리
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한국과학기술연구원
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Abstract

The present invention relates to a novel diaminopyrimidine compound and a pharmaceutically acceptable salt thereof, a method for producing the compound, and a medical use of the compound as an anticancer agent. According to the present invention, the novel compounds have outstanding activities against salt-Inducible kinase 2 (SIK2) kinase enzymes, thereby being useful as the anticancer agent for preventing and treating diseases such as ovarian cancer, prostate cancer, breast cancer, and the like.

Description

카이네이즈 저해활성을 갖는 디아미노피리미딘 유도체 {Diaminopyrimidine derivatives for kinase inhibitors}[0001] This invention relates to diaminopyrimidine derivatives for kinase inhibitors,

본 발명은 신규 디아미노피리미딘 화합물과 약제학적으로 허용 가능한 이의 염, 이 화합물의 제조방법, 그리고 이 화합물을 항암제로 사용하는 의약용도에 관한 것이다.
The present invention relates to a novel diaminopyrimidine compound, a pharmaceutically acceptable salt thereof, a process for producing the compound, and a medicinal use using the compound as an anticancer agent.

암세포는 정상세포와 마찬가지로 신호전달경로에 의해 성장하게 되는데, 세포에는 신호전달경로에 중요한 역할을 하는 다양한 단백질 카이네이즈가 존재하고 있다. 최근까지 알려진 다양한 카이네이즈 중 SIK 카이네이즈는 SIK1, SIK2, SIK3의 3 종류가 있다. SIK1는 SIK2, SIK3와 각각 카이네이즈 도메인에서 8%와 68%의 아미노산 유사성을 갖고 있으며, SIK1은 쥐의 부신, SIK2는 지방조직, SIK3는 주변 조직에서 많이 발현되고 있다. SIK2 카이네이즈 (salt-inducible kinase 2)는 AMP-활성화 단백질 카이네이즈 (AMPK) 계열에 속하는 세린/쓰레오닌 단백질 카이네이즈로서 난소암 환자의 30%에서 SIK2 카이네이즈가 과발현되어 있다 (Zhou J. et al., Clinical Cancer Research 2017, 23(8), 1945-1954). 전립선암은 일반적으로 수술로 치료가 잘 되는 암이지만 약 10-15%의 환자들은 수술이 어려워 약물치료가 필요하게 되는데 SIK2 카이네이즈가 전립선암 치료에 유효한 것으로 알려져 있다 (Bon. H et al., Mol. Cancer Res, 2015, 13(4), 620-635). 또한 SIK2 카이네이즈는 치료가 어려운 유방암으로서 삼중음성유방암 (Triple-negative breast cancer; TNBC)에도 관여하는 것으로 발표되고 있다 (Maxfield K. E et al., Molecular and Cellular Biology, 2016, 36(24), 3048-3057).Cancer cells grow by the signal transduction pathway like normal cells, and there are various protein kinases in cells that play an important role in the signal transduction pathway. Among the various kaneizes known to date, there are three types of SIK kinase: SIK1, SIK2, and SIK3. SIK1 has 8% and 68% amino acid similarity in SIK2 and SIK3, respectively, and SIK1 is expressed in rat adrenal, SIK2 in adipose tissue and SIK3 in peripheral tissue. SIK2 kinase 2 is a serine / threonine protein kinase belonging to the AMP-activated protein kinase (AMPK) family, and SIK2 kinase is overexpressed in 30% of ovarian cancer patients (Zhou J. et al. Clinical Cancer Research 2017, 23 (8), 1945-1954). Prostate cancer is generally treated surgically, but about 10-15% of patients are in need of medication due to difficulty in surgery. SIK2 kinase is known to be effective in the treatment of prostate cancer (Bon H et al., Mol Cancer Res, 2015, 13 (4), 620-635). In addition, SIK2 kinase has been reported to be involved in triple-negative breast cancer (TNBC) as an untreatable breast cancer (Maxfield K. E et al., Molecular and Cellular Biology, 2016, 36 (24), 3048 -3057).

이처럼 SIK2 수용체 카이네이즈는 난소암, 전립선암, 유방암 세포에서 매우 높은 빈도로 발생하는 것으로 밝혀짐에 따라, 최근 들어 카이네이즈 저해제의 새로운 표적으로써 가능성이 제시되고 있다. SIK2 카이네이즈 저해제로서 ARN-3236 및 HG-9-91-01 등이 연구 개발된 적은 있지만, 현재까지 SIK2 카이네이즈 저해제로 개발된 약물이 시판된 적은 없다.Thus, as SIK2 receptor kinase has been found to occur at a very high frequency in ovarian, prostate, and breast cancer cells, a potential new target for kynease inhibitors has recently been presented. Although ARN-3236 and HG-9-91-01 have been researched and developed as SIK2 kinase inhibitors, drugs developed as SIK2 kinase inhibitors have never been commercially available.

한편, 디아미노피리미딘 계열의 화합물로서 국제공개특허 WO2005/026130호에는 하기 화학식 A로 표시되는 화합물이 ALK 억제 활성을 갖는다고 개시되어 있다.On the other hand, as a diaminopyrimidine-based compound, WO 2005/026130 discloses that a compound represented by the following formula (A) has an ALK inhibitory activity.

[화학식 A](A)

Figure 112017063987139-pat00001
Figure 112017063987139-pat00001

(상기 화학식 A에서 X는 N 또는 CH이다)(X in formula (A) is N or CH)

하지만, 국제공개특허 WO2005/026130호에서는 X=CH인 화학식 A 화합물에 대하여 BaF3 세포주 성장 저해 활성을 확인하고 있을 뿐이다.
However, WO2005 / 026130 only confirms BaF3 cell line growth inhibitory activity against the compound of formula (A) wherein X = CH.

국제공개특허 WO2005/026130호WO2005 / 026130

Zhou J. et al., Clinical Cancer Research 2017, 23(8), 1945-1954 Zhou J. et al., Clinical Cancer Research 2017, 23 (8), 1945-1954 Bon. H et al., Mol. Cancer Res, 2015, 13(4), 620-635 Bon. H et al., Mol. Cancer Res, 2015, 13 (4), 620-635 Maxfield K. E et al., Molecular and Cellular Biology, 2016, 36(24), 3048-3057 Maxfield K. E et al., Molecular and Cellular Biology, 2016, 36 (24), 3048-3057

본 발명자들은 SIK2 카이네이즈의 활성을 저해할 수 있는 화합물들을 검색하던 중, 디아미노피리미딘 모핵에 결합된 두 개의 아민 그룹 중 한쪽에는 페닐그룹이 다른 한쪽에는 5각형의 헤테로고리기가 치환된 신규 화합물을 합성하고, 이들 신규 화합물에 대하여 SIK2 카이네이즈 저해활성을 확인함으로서 본 발명을 완성하게 되었다.The present inventors discovered that when searching for compounds capable of inhibiting the activity of SIK2 kinase, a novel compound in which one of the two amine groups bonded to the diaminopyrimidine mother nucleus is substituted with a phenyl group and the other is substituted with a pentagonal heterocyclic group And confirming SIK2 kinase inhibitory activity of these novel compounds, thereby completing the present invention.

따라서, 본 발명은 신규 디아미노피리미딘 화합물을 제공하는데 그 목적이 있다.Accordingly, the object of the present invention is to provide a novel diaminopyrimidine compound.

또한, 본 발명은 신규 디아미노피리미딘 화합물이 유효성분으로 포함된 항암제를 제공하는데 다른 목적이 있다.It is another object of the present invention to provide an anticancer agent comprising a novel diaminopyrimidine compound as an active ingredient.

또한, 본 발명은 신규 디아미노피리미딘 화합물의 제조방법을 제공하는데 또 다른 목적이 있다.
Further, the present invention has another object to provide a process for producing a novel diaminopyrimidine compound.

상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1로 표시되는 디아미노피리미딘 화합물, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염을 제공한다,In order to achieve the above object, the present invention provides a diaminopyrimidine compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:

Figure 112017063987139-pat00002
Figure 112017063987139-pat00002

상기 화학식 1에서,In Formula 1,

m 및 n은 1 내지 6의 정수를 나타내고;m and n represent an integer of 1 to 6;

A 및 B는 서로 같거나 다른 것으로서 CH 또는 N을 나타내고;A and B, equal to or different from each other, represent CH or N;

Het는 산소원자 및 질소원자 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각의 포화 또는 불포화된 헤테로고리기이고;Het is a pentane-containing saturated or unsaturated heterocyclic group containing 1 to 2 hetero atoms selected from an oxygen atom and a nitrogen atom;

R1은 수소원자, 할로겐원자, 아미노기, C1-C6 알킬기 또는 C1-C6 알콕시기로부터 선택되고;R 1 is selected from a hydrogen atom, a halogen atom, an amino group, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group;

R2 및 R3은 서로 같거나 다른 것으로서 수소원자 또는 C1-C6알킬기로부터 선택되고; 또는 R2 및 R3은 이들이 결합된 질소원자와 함께 결합하거나 또는 추가로 산소원자 및 질소원자 중에서 선택된 헤테로원자를 1 내지 2개 더 포함시켜 결합하여 5각 내지 6각의 포화 또는 불포화된 헤테로고리기를 형성할 수 있고;R 2 and R 3 are the same or different and are selected from a hydrogen atom or a C 1 -C 6 alkyl group; Or R < 2 > and R < 3 > may be bonded together with the nitrogen atom to which they are bonded or further include one or two further heteroatoms selected from oxygen and nitrogen atoms to form a saturated or unsaturated heterocycle Lt; / RTI >

상기 Het, R2 또는 R3의 정의에서 헤테로고리기는 C1-C6 알킬기로 치환 또는 비치환될 수 있다.In the definition of Het, R 2 or R 3 , the heterocyclic group may be substituted or unsubstituted with a C 1 -C 6 alkyl group.

또한, 본 발명은 상기 화학식 1로 표시되는 디아미노피리미딘 화합물, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염의 제조방법을 제공한다.The present invention also provides a process for preparing a diaminopyrimidine compound represented by the formula (1), a stereoisomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof.

나아가, 본 발명은 상기 화학식 1로 표시되는 디아미노피리미딘 화합물, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염을 활성성분으로 함유하는 약학 조성물을 제공한다.
Furthermore, the present invention provides a pharmaceutical composition comprising the diaminopyrimidine compound represented by Formula 1, a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명이 제공하는 신규 상기 화학식 1로 표시되는 디아미노피리미딘 화합물, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염은 SIK2 카이네이즈 저해 활성이 탁월하므로 각종 암 질환을 치료할 수 있는 새로운 표적 치료제로 유용하다. 본 발명이 제공하는 화합물에 의해 치료 및 예방될 수 있는 암 질환은 구체적으로 난소암, 전립선암, 유방암이 포함될 수 있으며, 특히 난소암 치료제로 상용화되어 있는 파클리탁셀(Paclitaxel)의 대체 약물로서도 유용하다.
The diaminopyrimidine compound represented by the above formula (1), a stereoisomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof according to the present invention is excellent in SIK2 kinase inhibitory activity, and thus can be used as a novel target It is useful as a remedy. The cancer diseases that can be treated and prevented by the compounds provided by the present invention may specifically include ovarian cancer, prostate cancer and breast cancer, and are particularly useful as an alternative drug for paclitaxel which is commercialized as an ovarian cancer therapeutic agent.

본 발명은 하기 화학식 1로 표시되는 디아미노피리미딘 화합물, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염을 제공한다.The present invention provides a diaminopyrimidine compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Chemical Formula 1]

Figure 112017063987139-pat00003
Figure 112017063987139-pat00003

상기 화학식 1에서,In Formula 1,

m 및 n은 1 내지 6의 정수를 나타내고;m and n represent an integer of 1 to 6;

A 및 B는 서로 같거나 다른 것으로서 CH 또는 N을 나타내고;A and B, equal to or different from each other, represent CH or N;

Het는 산소원자 및 질소원자 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각의 포화 또는 불포화된 헤테로고리기이고;Het is a pentane-containing saturated or unsaturated heterocyclic group containing 1 to 2 hetero atoms selected from an oxygen atom and a nitrogen atom;

R1은 수소원자, 할로겐원자, 아미노기, C1-C6 알킬기 또는 C1-C6 알콕시기로부터 선택되고;R 1 is selected from a hydrogen atom, a halogen atom, an amino group, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group;

R2 및 R3은 서로 같거나 다른 것으로서 수소원자 또는 C1-C6알킬기로부터 선택되고; 또는 R2 및 R3은 이들이 결합된 질소원자와 함께 결합하거나 또는 추가로 산소원자 및 질소원자 중에서 선택된 헤테로원자를 1 내지 2개 더 포함시켜 결합하여 5각 내지 6각의 포화 또는 불포화된 헤테로고리기를 형성할 수 있고;R 2 and R 3 are the same or different and are selected from a hydrogen atom or a C 1 -C 6 alkyl group; Or R < 2 > and R < 3 > may be bonded together with the nitrogen atom to which they are bonded or further include one or two further heteroatoms selected from oxygen and nitrogen atoms to form a saturated or unsaturated heterocycle Lt; / RTI >

상기 Het, R2 또는 R3의 정의에서 헤테로고리기는 C1-C6 알킬기로 치환 또는 비치환될 수 있다.In the definition of Het, R 2 or R 3 , the heterocyclic group may be substituted or unsubstituted with a C 1 -C 6 alkyl group.

본 발명에 따른 화합물은 상기 화학식 1로 표시되는 화합물의 약학적으로 허용 가능한 염을 포함한다. 상기 약학적으로 허용 가능한 염은 인체에 독성이 낮고 모화합물의 생물학적 활성과 물리화학적 성질에 악영향을 주지 않아야 한다. 약학적으로 허용 가능한 염은 약학적으로 사용 가능한 유리산과 화학식 1의 염기 화합물의 산부가염, 그리고 알칼리 금속염 (나트륨염 등)과 알칼리 토금속염 (칼슘염 등), 그리고 유기염과 화학식 1의 카르복실산의 유기염기부가염, 그리고 아미노산부가염으로 구성된다. 본 발명에서의 약제학적으로 허용 가능한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면 염산, 브롬산, 황산, 황산수소나트륨, 인산, 질산, 탄산 등과 같은 무기산과의 염, 개미산, 초산, 프로피온산, 옥살산, 석신산, 벤조산, 시트르산, 말레인산, 말론산, 타르타르산, 글루콘산, 락트산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과의 염, 글리신, 알라닌, 바닐린, 이소루신, 세린, 시스테인, 시스틴, 아스파라진산, 글루타민, 리진, 아르기닌, 타이로신, 프롤린 등과 같은 아미노산과의 염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, 톨루엔설폰산 등과 같은 설폰산과의 염을 비롯한 산부가염일 수 있다. 또한, 약제학적으로 허용 가능한 염은 나트륨, 칼륨 등의 알칼리금속과의 반응에 의한 금속염, 또는 암모늄 이온과의 염 일 수 있다. 상기한 약제학적으로 허용 가능한 염에 있어 특히 바람직하기로는 산부가염으로서 염산염, 황산염이다. The compound according to the present invention includes a pharmaceutically acceptable salt of the compound represented by the formula (1). The pharmaceutically acceptable salts should be low in toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include pharmaceutically usable free acids, acid addition salts of base compounds of formula (I), alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts) Organic base addition salts of acids, and amino acid addition salts. The pharmaceutically acceptable salts in the present invention can be prepared by conventional methods in the art and include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, Salts thereof, salts with organic acids such as salts, formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestic acid, fumaric acid, salicylic acid, Salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamine, lysine, arginine, tyrosine, proline and the like, methanesulfonic acid, ethanesulfonic acid , Benzenesulfonic acid, toluenesulfonic acid, and the like. In addition, the pharmaceutically acceptable salt may be a metal salt by reaction with an alkali metal such as sodium or potassium, or a salt with an ammonium ion. Particularly preferred as the acid addition salt in the above-mentioned pharmaceutically acceptable salts are hydrochloride and sulfate.

또한, 본 발명에 따른 화합물은 상기 화학식 1로 표시되는 화합물의 수화물 또는 용매화물도 포함한다. 상기한 수화물 또는 용매화물은 통상적인 방법으로 제조될 수 있는데, 예를 들면 상기한 화학식 1의 염기 화합물을 물, 메탄올, 에탄올, 아세톤, 1,4-다이옥산과 같은 용매에 녹인 다음에 유리산 또는 유리염기를 가한 후에 결정화 또는 재결정화하여 제조될 수 있다. The compound according to the present invention also includes a hydrate or a solvate of the compound represented by the formula (1). The hydrate or solvate may be prepared by a conventional method. For example, the base compound of Formula 1 may be dissolved in a solvent such as water, methanol, ethanol, acetone, or 1,4-dioxane, Followed by crystallization or recrystallization after addition of the free base.

또한, 상기 화학식 1로 표시되는 화합물은 하나 또는 그 이상의 비대칭 중심을 가질 수 있고, 이러한 화합물의 경우 거울상 이성질체 또는 부분입체이성질체가 존재할 수 있다. 따라서, 본 발명의 화합물에는 각 이성질체 또는 이들 이성질체 혼합물을 포함한다. 또한, 상이한 이성질체는 통상의 방법에 의해 분리되거나 또는 분해될 수 있거나, 또는 임의의 소정 이성질체는 통상의 합성법에 의해 또는 입체특이적 또는 비대칭적 합성에 의해 수득할 수 있다.In addition, the compound represented by Formula 1 may have one or more asymmetric centers, and in the case of such a compound, an enantiomer or diastereomer may exist. Thus, the compounds of this invention include each isomer or mixture of these isomers. In addition, the different isomers may be separated or cleaved by conventional methods, or any desired isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric synthesis.

또한, 본 발명의 화합물은 상기 화학식 1로 표시되는 화합물의 방사성 유도체를 포함하며, 이들 방사성 화합물은 생체연구 분야에 유용하다.
In addition, the compound of the present invention includes a radioactive derivative of the compound represented by the above formula (1), and these radioactive compounds are useful in the field of biological research.

상기 화학식 1로 표시되는 화합물을 정의하기 위해 사용된 치환기에 대해 보다 상세히 설명하면 다음과 같다.The substituents used to define the compound represented by the formula (1) will be described in more detail as follows.

본 발명에서의 '할로' 또는 '할로겐원자'는 서로 교환되어 사용이 가능한 용어로서, 클로로, 플루오로, 브로모, 요오도를 의미한다. In the present invention, the term "halo" or "halogen atom" refers to chloro, fluoro, bromo, or iodo, which can be used interchangeably.

본 발명에서의 '알킬'은 탄소수 1 내지 10개, 바람직하게는 탄소수 1 내지 6개, 보다 바람직하게는 탄소수 1 내지 4개를 갖는 것으로, 직쇄상, 분쇄상 또는 고리상의 지방족 포화탄화수소기를 의미한다. 이러한 알킬기를 구체적으로 예시하면, 메틸기, 에틸기, 노말프로필기, 이소프로필기, 사이클로프로필기, 사이클로프로필메틸기, 노말부틸기, 이소부틸기, tert-부틸기, 사이클로부틸기, 노말펜틸기, 이소펜틸기, 네오펜틸기, tert-펜틸기, 사이클로펜틸기, 노말헥실기, 이소헥실기, 사이클로헥실기, 노말헵틸기, 노말옥틸기 등이 포함될 수 있다.'Alkyl' in the present invention means a straight, branched or cyclic aliphatic saturated hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms . Specific examples of these alkyl groups, methyl group, ethyl group, normal propyl group, an isopropyl group, a cyclopropyl group, a cyclopropyl group, a normal butyl group, isobutyl group, tert - butyl group, cyclobutyl group, n-pentyl group, iso Pentyl group, neopentyl group, tert -pentyl group, cyclopentyl group, normal hexyl group, isohexyl group, cyclohexyl group, normal heptyl group, n-octyl group and the like.

본 발명에서의 '헤테로고리'는 O 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함되고, 포화 또는 불포화된 5각 내지 6각의 지방족 또는 방향족 헤테로고리기를 의미한다. 이러한 지방족 헤테로고리기를 구체적으로 예시하면, 테트라하이드로퓨란닐기, 2,3-다이하이드로퓨란닐기, 2,5-다이하이드로퓨란닐기, 피롤리딘닐기, 2,3-다이하이드로피롤리딘닐기, 2,5-다이하이드로피롤리딘닐기, 테트라하이드로-2H-피라닐기, 3,4-다이하이드로-2H-피라닐기, 4H-피라닐기, 피페리딘닐기, 1,2,3,4-테트라하이드로피리디닐기, 1,4-다이하이드로피리디닐기, 피페라지닐기, N-보호된 피페라지닐, 몰포리노기 등이 포함될 수 있다. 피페라지닐의 N-보호기로는 통상적으로 C1-C10 알킬기, C1-C10 알킬카보닐기, C1-C10 알킬기설포닐기가 포함될 수 있다. 또한 방향족 헤테로고리기를 구체적으로 예시하면, 피롤닐기, 피라졸닐기, 이미다졸닐기, 피리딘닐기, 피라진닐기, 피리다진닐기, 피리미딘닐기 등이 포함될 수 있다.
The term "heterocycle" in the present invention means a saturated or unsaturated five to six-membered aliphatic or aromatic heterocyclic group containing 1 to 2 hetero atoms selected from O and N. Specific examples of the aliphatic heterocyclic group include a tetrahydrofuranyl group, a 2,3-dihydrofuranyl group, a 2,5-dihydrofuranyl group, a pyrrolidinyl group, a 2,3-dihydropyrrolidinyl group, , A 5-dihydropyrrolidinyl group, a tetrahydro- 2H -pyranyl group, a 3,4-dihydro- 2H -pyranyl group, a 4H -pyranyl group, a piperidinyl group, - tetrahydropyridinyl group, 1,4-dihydropyridinyl group, piperazinyl group, N -protected piperazinyl, morpholino group and the like. Of N-piperazinyl-a protecting group typically it may include groups C 1 -C 10 alkyl, C 1 -C 10 alkyl carbonyl, C 1 -C 10 alkyl sulfonyl. Specific examples of the aromatic heterocyclic group include a pyrrolyl group, a pyrazolinyl group, an imidazolyl group, a pyridinyl group, a pyrazinyl group, a pyridazinyl group, a pyrimidinyl group and the like.

바람직하기로는 본 발명에 따른 상기 화학식 1로 표시되는 화합물에 있어, Het는 테트라하이드로퓨란닐기, (R)-테트라하이드로퓨란닐기, (S)-테트라하이드로퓨란닐기, 피롤리딘닐기, 퓨란닐기 또는 피롤닐기인 화합물이다.Preferably, in the compound represented by the formula (1) according to the present invention, Het is a tetrahydrofuranyl group, an (R) -tetrahydrofuranyl group, an (S) -tetrahydrofuranyl group, a pyrrolidinyl group, Pyrrolyl group.

바람직하기로는 본 발명에 따른 상기 화학식 1로 표시되는 화합물에 있어, R2 및 R3은 서로 같거나 다른 것으로서 수소원자 또는 C1-C6알킬기로부터 선택되는 치환그룹이 치환된 화합물이다.Preferably, R 2 and R 3 in the compound represented by the formula (1) according to the present invention are the same or different and each is a compound in which a substituent group selected from a hydrogen atom or a C 1 -C 6 alkyl group is substituted.

바람직하기로는 본 발명에 따른 상기 화학식 1로 표시되는 화합물에 있어, R2 및 R3은 이들이 결합된 질소원자와 함께 결합하여 피롤리딘-1-일, (S)-피롤리딘-1-일, 또는 피페리딘-1-일로부터 선택되는 헤테로고리기를 형성하고 있는 화합물이다.Preferably, in the compound represented by Formula 1 according to the present invention, R 2 and R 3 are bonded together with the nitrogen atom to which they are bonded to form pyrrolidin-1-yl, (S) -pyrrolidin- Yl, piperidin-1-yl, or piperidin-1-yl.

바람직하기로는 본 발명에 따른 상기 화학식 1로 표시되는 화합물에 있어, R2 및 R3은 이들이 결합된 질소원자와 추가로 산소원자 및 질소원자 중에서 선택된 헤테로원자를 더 포함시켜 결합하여 몰포린-4-일, 피페라진-1-일 또는 4-(C1-C6알킬)피페라진-1-일로부터 선택되는 헤테로고리기를 형성하고 있는 화합물이다.
Preferably, in the compound represented by Formula 1 according to the present invention, R 2 and R 3 may further include a hetero atom selected from an oxygen atom and a nitrogen atom, Yl, piperazin-1-yl or 4- (C 1 -C 6 alkyl) piperazin-1-yl.

본 발명에 따른 상기 화학식 1로 표시되는 화합물은 구체적으로 하기 화학식 1a로 표시되는 화합물일 수 있다.The compound represented by Formula 1 according to the present invention may be a compound represented by Formula 1a below.

[화학식 1a][Formula 1a]

Figure 112017063987139-pat00004
Figure 112017063987139-pat00004

(상기 화학식 1a에서, Het, R1, R2, R3, m 및 n은 각각 상기 화학식 1에서 정의한 바와 같다)(Wherein, Het, R 1 , R 2 , R 3 , m and n are as defined in Formula 1, respectively)

본 발명에 따른 상기 화학식 1로 표시되는 화합물은 구체적으로 하기 화학식 1b로 표시되는 화합물일 수 있다.The compound represented by Formula 1 according to the present invention may be a compound represented by Formula 1b.

[화학식 1b][Chemical Formula 1b]

Figure 112017063987139-pat00005
Figure 112017063987139-pat00005

(상기 화학식 1b에서,Het, R1, R2, R3, m 및 n은 각각 상기 화학식 1에서 정의한 바와 같다)
(Wherein Het, R 1 , R 2 , R 3 , m and n are the same as defined in the above formula (1)

본 발명에 따른 상기 화학식 1로 표시되는 신규 디아미노피리미딘을 구체적으로 예시하면 다음과 같다 :Specific examples of the novel diaminopyrimidine represented by the above formula (1) according to the present invention are as follows:

1) 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘; 1) 4- (Tetrahydrofuran-2-yl) methylamino-6- [4- {2- (pyrrolidin-1-yl) ethoxy} phenylamino] pyrimidine;

2) 4-(S)-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘;2) 4- (S) - (tetrahydrofuran-2-yl) methylamino-6- [4- {2- (pyrrolidin-1-yl) ethoxy} phenylamino] pyrimidine;

3) 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘;3) 4- (Tetrahydrofuran-2-yl) methylamino-6- [4- {2- (piperidin-1-yl) ethoxy} phenylamino] pyrimidine;

4) 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-((4-에틸)피페라진-1-일)에톡시}페닐아미노]피리미딘;4) 4- (Tetrahydrofuran-2-yl) methylamino-6- [4- {2 - ((4-ethyl) piperazin-1-yl) ethoxy} phenylamino] pyrimidine;

5) 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-몰포린-4-일)에톡시}페닐아미노]피리미딘;5) 4- (Tetrahydrofuran-2-yl) methylamino-6- [4- {2-morpholin-4-yl) ethoxy} phenylamino] pyrimidine;

6) 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(디메틸아미노)에톡시}페닐아미노]피리미딘;6) 4- (Tetrahydrofuran-2-yl) methylamino-6- [4- {2- (dimethylamino) ethoxy} phenylamino] pyrimidine;

7) 4-(퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘;7) 4- (furan-2-yl) methylamino-6- [4- {2- (pyrrolidin-1-yl) ethoxy} phenylamino] pyrimidine;

8) 4-(퓨란-2-일)메틸아미노-6-[4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘;8) 4- (Furan-2-yl) methylamino-6- [4- {2- (piperidin-1-yl) ethoxy} phenylamino] pyrimidine;

9) 4-(퓨란-2-일)메틸아미노-6-[4-{2-((4-에틸)피페라진-1-일)에톡시}페닐아미노]피리미딘;9) 4- (furan-2-yl) methylamino-6- [4- {2 - ((4-ethyl) piperazin-1-yl) ethoxy} phenylamino] pyrimidine;

10) 4-(퓨란-2-일)메틸아미노-6-[4-{2-몰포린-4-일)에톡시}페닐아미노]피리미딘;10) 4- (furan-2-yl) methylamino-6- [4- {2-morpholin-4-yl) ethoxy} phenylamino] pyrimidine;

11) 4-(퓨란-2-일)메틸아미노-6-[4-{2-(디메틸아미노)에톡시}페닐아미노]피리미딘;11) 4- (furan-2-yl) methylamino-6- [4- {2- (dimethylamino) ethoxy} phenylamino] pyrimidine;

12) 4-(퓨란-2-일)메틸아미노-6-[2-메톡시-4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘;12) 4- (furan-2-yl) methylamino-6- [2-methoxy-4- {2- (pyrrolidin-1-yl) ethoxy} phenylamino] pyrimidine;

13) 4-(퓨란-2-일)메틸아미노-6-[2-메톡시-4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘;13) 4- (Furan-2-yl) methylamino-6- [2-methoxy-4- {2- (piperidin-1-yl) ethoxy} phenylamino] pyrimidine;

14) 4-(퓨란-2-일)메틸아미노-2-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘;14) 4- (Furan-2-yl) methylamino-2- [4- {2- (pyrrolidin-1-yl) ethoxy} phenylamino] pyrimidine;

15) 4-(퓨란-2-일)메틸아미노-2-[4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘;15) 4- (Furan-2-yl) methylamino-2- [4- {2- (piperidin-1-yl) ethoxy} phenylamino] pyrimidine;

16) 4-(퓨란-2-일)메틸아미노-2-[4-{2-((4-에틸)피페라진-1-일)에톡시}페닐아미노]피리미딘;16) 4- (Furan-2-yl) methylamino-2- [4- {2 - ((4-ethyl) piperazin-1-yl) ethoxy} phenylamino] pyrimidine;

17) 4-(퓨란-2-일)메틸아미노-2-[4-{2-몰포린-4-일)에톡시}페닐아미노]피리미딘;17) 4- (furan-2-yl) methylamino-2- [4- {2-morpholin-4-yl) ethoxy} phenylamino] pyrimidine;

18) 4-(퓨란-2-일)메틸아미노-2-[4-{2-(디메틸아미노)에톡시}페닐아미노]피리미딘.
18) 4- (Furan-2-yl) methylamino-2- [4- {2- (dimethylamino) ethoxy} phenylamino] pyrimidine.

한편, 본 발명은 상기 화학식 1로 표시되는 신규 디아미노피리미딘의 제조방법을 제공한다. The present invention also provides a process for preparing a novel diaminopyrimidine represented by the general formula (1).

본 발명에 따른 화합물로서 화학식 1a로 표시되는 화합물의 제조방법은,As a method for producing the compound represented by the formula (Ia) as a compound according to the present invention,

(단계 a1) 아민염기 존재 하에서 하기 화학식 2로 표시되는 4,6-디클로로피리미딘과 하기 화학식 3으로 표시되는 아민 화합물을 반응시켜, 하기 화학식 4a로 표시되는 6-클로로-4-치환된아미노피리미딘 화합물을 제조하는 단계; 및(Step a1) reacting 4,6-dichloropyrimidine represented by the following formula (2) with an amine compound represented by the following formula (3) in the presence of an amine base to obtain 6-chloro-4-substituted aminopyridine Preparing a compound of formula < RTI ID = 0.0 > And

Figure 112017063987139-pat00006
Figure 112017063987139-pat00006

(상기 반응식에서, Het 및 n은 각각 상기 화학식 1에서 정의한 바와 같다)(In the above reaction formula, Het and n are the same as defined in Formula 1, respectively)

(단계 b1) 하기 화학식 4a로 표시되는 6-클로로-4-치환된아미노피리미딘 화합물과 하기 화학식 5로 표시되는 아닐린 화합물을 반응시켜, 하기 화학식 1a로 표시되는 디아미노피리미딘 화합물을 제조하는 단계; 를 포함한다. (Step b1) reacting a 6-chloro-4-substituted aminopyrimidine compound represented by the following formula (4a) with an aniline compound represented by the following formula (5) to prepare a diaminopyrimidine compound represented by the following formula ; .

Figure 112017063987139-pat00007
Figure 112017063987139-pat00007

(상기 반응식에서, Het, R1, R2, R3, m 및 n은 각각 상기 화학식 1에서 정의한 바와 같다)
(Wherein Het, R 1 , R 2 , R 3 , m and n are each as defined in the above formula (1)

본 발명에 따른 화합물로서 화학식 1b로 표시되는 화합물의 제조방법은,As a method for producing a compound represented by the formula (1b) as a compound according to the present invention,

(단계 a2) 아민염기 존재 하에서 하기 화학식 2로 표시되는 4,6-디클로로피리미딘과 하기 화학식 3으로 표시되는 아민 화합물을 반응시켜, 하기 화학식 4b로 표시되는 6-클로로-4-치환된아미노피리미딘 화합물을 제조하는 단계; 및(Step a2) reacting 4,6-dichloropyrimidine represented by the following formula (2) with an amine compound represented by the following formula (3) in the presence of an amine base to obtain 6-chloro-4-substituted aminopyridine Preparing a compound of formula < RTI ID = 0.0 > And

Figure 112017063987139-pat00008
Figure 112017063987139-pat00008

(상기 반응식에서, Het 및 n은 각각 상기 화학식 1에서 정의한 바와 같다)(In the above reaction formula, Het and n are the same as defined in Formula 1, respectively)

(단계 b2) 하기 화학식 4b로 표시되는 2-클로로-4-치환된아미노피리미딘 화합물과 하기 화학식 5로 표시되는 아닐린 화합물을 반응시켜, 하기 화학식 1b로 표시되는 디아미노피리미딘 화합물을 제조하는 단계; 를 포함한다.(Step b2) reacting a 2-chloro-4-substituted aminopyrimidine compound represented by the following formula (4b) with an aniline compound represented by the following formula (5) to prepare a diaminopyrimidine compound represented by the following formula ; .

Figure 112017063987139-pat00009
Figure 112017063987139-pat00009

(상기 반응식에서, Het, R1, R2, R3, m 및 n은 각각 상기 화학식 1에서 정의한 바와 같다)
(Wherein Het, R 1 , R 2 , R 3 , m and n are each as defined in the above formula (1)

상기 제조방법을 수행함에 있어, 아민 염기는 모노-, 디- 또는 트리-알킬 아민염기가 바람직하게 사용될 수 있으며, 구체적으로는 모노메틸아민, 디메틸아민, 트리메틸아민, 디아이소프로필에틸아민 등이 포함될 수 있다. In carrying out the above production process, the amine base may be a mono-, di- or tri-alkylamine base, and specifically includes monomethylamine, dimethylamine, trimethylamine, diisopropylethylamine and the like .

또한, 반응용매로는 통상의 유기용매가 사용될 수 있다. 바람직하게는 반응용매로서 알콜류가 사용될 수 있으며, 구체적으로는 메탄올, 에탄올, n-프로판올, 아이소프로판올, n-부탄올 등을 포함하는 지방족알콜, 및 메톡시메탄올, 메톡시에탄올, 에톡시에탄올 등을 포함하는 알콕시알콜 중에서 선택된 1종 이상이 사용될 수 있다.As the reaction solvent, a conventional organic solvent may be used. Preferably, alcohols may be used as a reaction solvent, and specific examples thereof include aliphatic alcohols containing methanol, ethanol, n-propanol, isopropanol, n-butanol, etc., and methoxy methanol, methoxy ethanol, ethoxy ethanol, May be used.

또한, 상기 제조방법을 통하여 제조된 화합물들은 일반적인 분리 정제과정 예를 들면 유기 용매로 희석 및 세척한 후 유기층을 감압 농축할 수 있으며, 필요시 관 크로마토그래피로 정제할 수 있다.
In addition, the compounds prepared through the above-described method can be purified by a conventional separation and purification process, for example, dilution with organic solvent and washing, followed by concentration of the organic layer under reduced pressure and, if necessary, purification by tube chromatography.

또한, 본 발명의 제조방법에서 반응원료로 사용되는 상기 화학식 5로 표시되는 아닐린 화합물에 다양한 치환그룹을 도입함으로써, 다양한 치환그룹이 도입된 상기 화학식 1로 표시되는 페닐아미노피리딘 화합물을 제조할 수 있다. In addition, by introducing various substitution groups into the aniline compound represented by Chemical Formula 5 used as a starting material in the production method of the present invention, the phenylaminopyridine compound represented by Chemical Formula 1 in which various substitution groups are introduced can be prepared .

하기 반응식 1, 2 및 3은 다양한 치환그룹을 가지는 상기 화학식 5로 표시되는 아닐린 화합물을 합성하기 위한 대표적인 제조방법을 예시한 것으로, 본 발명이 이에 한정되는 것은 아니다.The following Reaction Schemes 1, 2 and 3 illustrate representative processes for synthesizing aniline compounds represented by Formula 5 having various substituent groups, but the present invention is not limited thereto.

[반응식 1][Reaction Scheme 1]

Figure 112017063987139-pat00010
Figure 112017063987139-pat00010

[반응식 2][Reaction Scheme 2]

Figure 112017063987139-pat00011
Figure 112017063987139-pat00011

[반응식 3][Reaction Scheme 3]

Figure 112017063987139-pat00012

Figure 112017063987139-pat00012

한편, 본 발명에 따른 상기 화학식 1로 표시되는 화합물은 SIK2 카이네이즈 저해 활성이 탁월하므로 각종 인간 암 질환을 치료할 수 있는 새로운 표적 치료제로 유용하다. 상기 화학식 1로 표시되는 화합물에 의해 치료 및 예방될 수 있는 암 질환은 구체적으로 난소암, 전립선암, 유방암이 포함될 수 있다.Meanwhile, the compound represented by Formula 1 according to the present invention is excellent as a novel target treatment agent capable of treating various human cancer diseases because of its excellent SIK2 kinase inhibitory activity. Cancer diseases that can be treated or prevented by the compound represented by the formula (1) may specifically include ovarian cancer, prostate cancer, breast cancer.

따라서, 본 발명은 상기 화학식 1로 표시되는 디아미노피리미딘 화합물, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염이 유효성분으로 함유되어 있는 항암제를 권리범위로 포함한다.Accordingly, the scope of the present invention includes an anticancer drug containing the diaminopyrimidine compound represented by the above-mentioned formula (1), a stereoisomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명의 약제 조성물은 상기 화학식 1로 표시되는 디아미노피리미딘 화합물, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염을 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 경구 투여용 제제 또는 비경구 투여용 제제로 제조하여, 여러 종류의 종양 예방과 치료에 사용될 수 있다. In addition, the pharmaceutical composition of the present invention comprises a diaminopyrimidine compound represented by the above-mentioned formula (1), a stereoisomer thereof, a solvate thereof or a pharmaceutically acceptable salt thereof as an active ingredient, An acceptable carrier, a reinforcing agent and an excipient are added to prepare a preparation for oral administration or a preparation for parenteral administration such as tablets, capsules, troches, liquids and suspensions, which are customary in the pharmaceutical field, Can be used for tumor prevention and treatment.

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. Examples of excipients which can be used in the pharmaceutical composition of the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonizing agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers and fragrances. For example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, Water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, and the like.

또한, 본 발명에 따른 화학식 1로 표시되는 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질병정도에 따라 달라질 수 있으며, 몸무게가 70 kg인 성인 환자를 기준으로 할 때 일반적으로 1일 0.01 mg 내지 5000 mg이며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다. The dose of the compound of formula (I) according to the present invention may vary depending on the patient's age, body weight, sex, dosage form, health condition, and disease severity. , It is generally 0.01 mg to 5000 mg per day, and may be administered once or several times a day at a predetermined time interval according to the judgment of a doctor or a pharmacist.

이상에서 설명한 바와 같은 본 발명은 하기의 실시예, 제제예 및 실험예에 의거하여 더욱 상세히 설명하겠는 바, 본 발명이 이들에 의해 한정되는 것은 결코 아니다.
The present invention as described above will be described in more detail with reference to the following examples, preparation examples and experimental examples, but the present invention is by no means limited thereto.

[실시예][Example]

하기의 실시예는 단지 본 발명에 따른 화합물의 제조방법에 대한 이해를 돕기 위한 것으로 본 발명의 범위를 제한하는 것은 아니다.
The following examples are merely intended to aid in understanding the process for preparing the compounds according to the invention and are not intended to limit the scope of the invention.

실시예 1. 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조
Example 1 Preparation of 4- (tetrahydrofuran-2-yl) methylamino-6- [4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

1-1. 6-클로로-4-(테트라하이드로퓨란-2-일)메틸아미노피리미딘의 제조1-1. Preparation of 6-chloro-4- (tetrahydrofuran-2-yl) methylaminopyrimidine

Figure 112017063987139-pat00013
Figure 112017063987139-pat00013

둥근바닥플라스크에 4,6-디클로로피리미딘 (1 g, 6.71 mmol)을 넣고 n-부탄올 (40 mL)에 녹인 후, (테트라하이드로퓨란-2-일)메탄아민 (0.69 mL, 6.71 mmol)과 디아이소프로필에틸아민 (3.5 mL, 20.1 mmol)을 넣고 16시간 동안 80 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 물을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.8 g, 56 %)을 얻었다.Into the 4,6-dichloropyrimidine (1 g, 6.71 mmol) in a round bottom flask n - it was dissolved in butanol (40 mL), (tetrahydrofuran-2-yl) methanamine (0.69 mL, 6.71 mmol) and Diisopropylethylamine (3.5 mL, 20.1 mmol) was added thereto and stirred at 80 DEG C for 16 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography to obtain the title compound (0.8 g, 56%).

1H NMR (400 MHz, CDCl3) δ 1.55-1.7 (m, 1H), 1.92-2.05 (m, 2H), 2.05-2.1 (m, 1H), 3.32 (s, 1H), 3.65 (s, 1H), 3.77-3.82 (m, 1H), 3.88-3.93 (m, 1H), 4.06-4.13 (m, 1H), 6.46 (s, 1H), 8.36 (s, 1H).
1 H NMR (400 MHz, CDCl 3 )? 1.55-1.7 (m, IH), 1.92-2.05 (m, 2H), 2.05-2.1 (m, IH), 3.32 ), 3.77-3.82 (m, IH), 3.88-3.93 (m, IH), 4.06-4.13 (m, IH), 6.46 (s, IH), 8.36 (s, IH).

1-2. 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조1-2. Preparation of 4- (tetrahydrofuran-2-yl) methylamino-6- [4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00014
Figure 112017063987139-pat00014

둥근바닥플라스크에 6-클로로-(테트라하이드로퓨란-2-일)메틸아미노피리미딘 (0.1 g, 0.468 mmol)과 4-(2-(피롤리딘-1-일)에톡시)아닐린 (0.088 mL, 0.468 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액, 0.1 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.095 g, 52 %)을 얻었다. 녹는점 146-150 ℃; 1H NMR (400 MHz, CDCl3) δ 1.55-1.65 (m, 1H), 1.80-2.05 (m, 7H), 2.68 (s, 4H), 2.95 (t, 2H), 3.14-3.24 (m, 1H), 3.45 (s, 1H), 3.72-3.82 (m, 1H), 3.81-3.91 (m, 1H), 4.0-4.1 (m, 1H), 4.1-4.2 (m, 2H), 5.15 (s, 1H), 5.57 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.11 (s, 1H), 7.18 (d, J = 8.8 Hz, 2H), 8.1 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 23.49, 25.80, 28.77, 45.05, 54.71, 55.08, 67.35, 68.12, 115.37, 125.42, 131.45, 156.34, 158.23, 161.85, 163.20.
To a round bottom flask was added a solution of 6-chloro- (tetrahydrofuran-2-yl) methylaminopyrimidine (0.1 g, 0.468 mmol) and 4- (2- (pyrrolidin- 1- yl) ethoxy) , 0.468 mmol) was dissolved in 2-methoxyethanol (5 mL), and a hydrochloric acid solution (4M dioxane solution, 0.1 mL) was added thereto, followed by stirring at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.095 g, 52%). Melting point 146-150 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 1.55-1.65 (m, 1H), 1.80-2.05 (m, 7H), 2.68 (s, 4H), 2.95 (t, 2H), 3.14-3.24 (m, 1H 1H), 3.45 (s, 1H), 3.72-3.82 (m, 1H), 3.81-3.91 (m, ), 5.57 (s, IH), 6.94 (d, J = 8.8 Hz, 2H), 7.11 (s, IH), 7.18 (d, J = 8.8 Hz, 2H), 8.1 13 C NMR (400 MHz, CDCl 3) δ 23.49, 25.80, 28.77, 45.05, 54.71, 55.08, 67.35, 68.12, 115.37, 125.42, 131.45, 156.34, 158.23, 161.85, 163.20.

실시예 2. 4-(S)-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조
Example 2. Preparation of 4- (S) - (tetrahydrofuran-2-yl) methylamino-6- [4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

2-1. 6-클로로-4-(S)-(테트라하이드로퓨란-2-일)메틸아미노피리미딘의 제조2-1. Preparation of 6-chloro-4- (S) - (tetrahydrofuran-2-yl) methylaminopyrimidine

Figure 112017063987139-pat00015
Figure 112017063987139-pat00015

둥근바닥플라스크에 4,6-디클로로피리미딘 (1.473 g, 9.89 mmol)을 넣고 n-부탄올(60 mL)에 녹인 후 (테트라하이드로퓨란-2-일)메탄아민 (1.02 mL, 9.89 mmol)과 디아이소프로필에틸아민 (5.16 mL, 29.66 mmol)을 넣고 16시간 동안 80 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 물을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (1.24 g, 59 %)을 얻었다.To a round bottom flask was added 4,6-dichloropyrimidine (1.473 g, 9.89 mmol) into the n - was dissolved in butanol (60 mL) (tetrahydrofuran-2-yl) methanamine (1.02 mL, 9.89 mmol) and DI (5.16 mL, 29.66 mmol) was added thereto, and the mixture was stirred at 80 DEG C for 16 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography to obtain the title compound (1.24 g, 59%).

1H NMR (400 MHz, CDCl3) δ 1.47-1.57 (m, 1H), 1.81-1.91 (m, 2H), 1.92-2.02 (m, 1H), 3.2 (s, 1H), 3.53 (s, 1H), 3.67-3.77 (m, 1H), 3.75-3.85 (m, 1H), 3.95-4.05 (m, 1H), 5.57 (s, 1H), 6.3 (s, 1H), 8.27 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 25.79, 28.77, 45.11, 68.19, 158.40, 163.33.
 1 H NMR (400 MHz, CDCl 3 )? 1.47-1.57 (m, 1H), 1.81-1.91 (m, 2H), 1.92-2.02 ), 3.67-3.77 (m, IH), 3.75-3.85 (m, IH), 3.95-4.05 (m, IH), 5.57 (s, IH), 6.3 (s, IH), 8.27 13 C NMR (400 MHz, CDCl 3) δ 25.79, 28.77, 45.11, 68.19, 158.40, 163.33.

2-2. 4-(S)-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조2-2. Preparation of 4- (S) - (tetrahydrofuran-2-yl) methylamino-6- [4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00016
Figure 112017063987139-pat00016

둥근바닥플라스크에 6-클로로-4-(S)-(테트라하이드로퓨란-2-일)메틸아미노피리미딘 (0.1 g, 0.468 mmol)과 4-(2-(피롤리딘-1-일)에톡시)아닐린 (0.088 mL, 0.468 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인용액, 0.1 mL)을 넣고 24시간 동안 110 ℃에서 교반시킨다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.095 g, 53 %)을 얻었다.To a round bottom flask was added a solution of 6-chloro-4- (S) - (tetrahydrofuran-2-yl) methylaminopyrimidine (0.1 g, 0.468 mmol) and 4- (2- (pyrrolidin- (0.088 mL, 0.468 mmol) was dissolved in 2-methoxyethanol (5 mL), and a hydrochloric acid solution (4M dioxane solution, 0.1 mL) was added thereto, followed by stirring at 110 ° C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.095 g, 53%).

녹는점 146-150 ℃; 1H NMR (400 MHz, CDCl3) δ 1.54-1.64 (m, 1H), 1.78-1.88 (m, 4H), 1.85-1.95 (m, 2H), 1.93-2.03 (m, 1H), 2.65 (s, 4H), 2.88-2.98 (t, 2H), 3.14-3.24 (m, 1H), 3.44 (s, 1H), 3.72-3.82 (m, 1H), 3.81-3.91 (m, 1H), 4.0-4.1 (m, 1H), 4.1-4.2 (m, 2H), 5.25 (s, 1H), 5.57 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.41 (s, 1H), 8.15 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 23.50, 25.79, 28.78, 45.16, 54.74, 55.10, 67.38, 68.10, 81.27, 115.36, 125.38, 131.69, 156.28, 158.25, 162.01, 163.28.
Melting point 146-150 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 1.54-1.64 (m, 1H), 1.78-1.88 (m, 4H), 1.85-1.95 (m, 2H), 1.93-2.03 (m, 1H), 2.65 (s (M, 1H), 3.91-3. 141 (m, 1H), 4.04-3.24 (m, (m, 1H), 4.1-4.2 ( m, 2H), 5.25 (s, 1H), 5.57 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 7.41 (s, 1 H), 8.15 (s, 1 H); 13 C NMR (400 MHz, CDCl 3) δ 23.50, 25.79, 28.78, 45.16, 54.74, 55.10, 67.38, 68.10, 81.27, 115.36, 125.38, 131.69, 156.28, 158.25, 162.01, 163.28.

실시예 3. 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘의 제조Example 3. Preparation of 4- (tetrahydrofuran-2-yl) methylamino-6- [4- {2- (piperidin- 1 -yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00017
Figure 112017063987139-pat00017

둥근바닥플라스크에 6-클로로-4-(테트라하이드로퓨란-2-일)메틸아미노피리미딘 (0.03 g, 0.14 mmol)과 4-(2-(피페리딘-1-일)에톡시)아닐린 (0.029 mL, 0.14 mmol)을 2-메톡시에탄올 (3 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액, 0.0175 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.027 g, 48 %)을 얻었다.(Tetrahydrofuran-2-yl) methylaminopyrimidine (0.03 g, 0.14 mmol) and 4- (2- (piperidin- 1 -yl) ethoxy) aniline 0.029 mL, 0.14 mmol) was dissolved in 2-methoxyethanol (3 mL), a hydrochloric acid solution (4M dioxane solution, 0.0175 mL) was added, and the mixture was stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.027 g, 48%).

녹는점 138-140 ℃; 1H NMR (400 MHz, CDCl3) δ 1.43-1.53 (m, 2H), 1.6-1.7 (m, 5H), 1.87-1.97 (m, 2H), 1.95-2.05 (m, 1H), 2.55 (s, 4H), 2.77-2.87 (t, 2H), 3.15-3.25 (m, 1H), 3.47 (s, 1H), 3.73-3.82 (m, 1H), 3.82-3.92 (m, 1H), 4.0-4.1 (m, 1H), 4.15-4.25 (m, 2H), 5.06 (s, 1H), 5.57 (s, 1H), 6.83 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 8.18 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 24.23, 25.84, 25.98, 28.81, 45.17, 55.13, 57.99, 66.33, 68.16, 77.55, 81.47, 115.44, 125.52, 131.58, 156.40, 158.38, 162.00, 163.33.
Melting point 138-140 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 1.43-1.53 (m, 2H), 1.6-1.7 (m, 5H), 1.87-1.97 (m, 2H), 1.95-2.05 (m, 1H), 2.55 (s (M, IH), 4.01-4.15 (m, IH), 3.77-3.82 (s, 1H), 6.83 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.19 d, J = 8.8 Hz, 2H), 8.18 (s, 1H); 13 C NMR (400 MHz, CDCl 3) δ 24.23, 25.84, 25.98, 28.81, 45.17, 55.13, 57.99, 66.33, 68.16, 77.55, 81.47, 115.44, 125.52, 131.58, 156.40, 158.38, 162.00, 163.33.

실시예 4. 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-((4-에틸)피페라진-1-일)에톡시}페닐아미노]피리미딘의 제조Example 4. Preparation of 4- (tetrahydrofuran-2-yl) methylamino-6- [4- {2 - ((4-ethyl) piperazin-1-yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00018
Figure 112017063987139-pat00018

둥근바닥플라스크에 6-클로로-4-(테트라하이드로퓨란-2-일)메틸아미노피리미딘 (0.03 g, 0.14 mmol)과 4-(2-((4-에틸)피페라진-1-일)에톡시)아닐린 (0.033 mL, 0.14 mmol)을 2-메톡시에탄올 (3 mL)에 녹인 후, 염산 용액 (4M 다이옥세인용액의 0.0175 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.020 g, 33 %)을 얻었다.Yl) methylaminopyrimidine (0.03 g, 0.14 mmol) and 4- (2- ((4-ethyl) piperazin-1-yl) (0.033 mL, 0.14 mmol) was dissolved in 2-methoxyethanol (3 mL), followed by the addition of a hydrochloric acid solution (0.0175 mL of 4M dioxane solution) and stirring at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.020 g, 33%).

녹는점 110-118 ℃; 1H NMR (400 MHz, CDCl3) δ 1.07-1.13 (t, 3H), 1.55-1.65 (m, 1H), 1.87-1.97 (m, 2H), 1.95-2.05 (m, 1H), 2.40-2.45 (m, 3H), 2.55 (s, 3H), 2.68 (s, 4H), 2.81-2.91 (t, 2H), 3.15-3.25 (m, 1H), 3.47 (s, 1H), 3.73-3.82 (m, 1H), 3.82-3.92 (m, 1H), 4.0-4.1 (m, 1H), 4.14-4.24 (m, 2H), 5.07 (s, 1H), 5.57 (s, 1H), 6.89 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 8.17 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 11.99, 25.80, 28.76, 45.13, 52.31, 52.77, 53.66, 57.23, 66.24, 68.11, 115.40, 125.47, 131.60, 156.30, 158.32, 161.93, 163.28.
Melting point 110-118 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 1.07-1.13 (t, 3H), 1.55-1.65 (m, 1H), 1.87-1.97 (m, 2H), 1.95-2.05 (m, 1H), 2.40-2.45 (m, 3H), 2.55 (s, 3H), 2.68 (s, 4H), 2.81-2.91 (t, 2H), 3.15-3.25 (M, 2H), 5.07 (s, IH), 5.57 (s, IH), 6.89 ), 6.93 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 8.17 (s, 1H); 13 C NMR (400 MHz, CDCl 3) δ 11.99, 25.80, 28.76, 45.13, 52.31, 52.77, 53.66, 57.23, 66.24, 68.11, 115.40, 125.47, 131.60, 156.30, 158.32, 161.93, 163.28.

실시예 5. 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-몰포린-4-일)에톡시}페닐아미노]피리미딘의 제조Example 5. Preparation of 4- (tetrahydrofuran-2-yl) methylamino-6- [4- {2-morpholin-4- yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00019
Figure 112017063987139-pat00019

둥근바닥플라스크에 6-클로로-4-(테트라하이드로퓨란-2-일)메틸아미노피리미딘 (0.03 g, 0.14 mmol)과 4-(2-(몰포린-4-일)에톡시)아닐린 (0.031 g, 0.14 mmol)을 2-메톡시에탄올 (3 mL)에 녹인 후, 염산 용액 (4M 다이옥세인용액의 0.0175 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.025 g, 45 %)을 얻었다.To a round bottom flask was added a solution of 6-chloro-4- (tetrahydrofuran-2-yl) methylaminopyrimidine (0.03 g, 0.14 mmol) and 4- (2- (morpholin- g, 0.14 mmol) was dissolved in 2-methoxyethanol (3 mL), and a hydrochloric acid solution (0.0175 mL of 4M dioxane solution) was added thereto, followed by stirring at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.025 g, 45%).

녹는점 132-136 ℃; 1H NMR (400 MHz, CDCl3) δ 1.55-1.65 (m, 1H), 1.87-1.97 (m, 2H), 1.9-2.0 (m, 1H), 2.57-2.67 (t, 4H), 2.8-2.9 (t, 2H), 3.15-3.25 (m, 1H), 3.49 (s, 1H), 3.72-3.82 (m, 5H), 3.82-3.92 (m, 1H), 4.0-4.1 (m, 1H), 4.1-4.2 (m, 2H), 5.06 (s, 1H), 5.57 (s, 1H), 6.82 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 8.18 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 25.81, 28.78, 45.15, 54.12, 57.67, 66.14, 66.94, 68.13, 77.54, 115.41, 125.46, 131.68, 156.21, 158.21, 161.83, 163.24.
Melting point 132-136 DEG C; 1 H NMR (400 MHz, CDCl 3 )? 1.55-1.65 (m, 1 H), 1.87-1.97 (m, 2H), 1.9-2.0 (m, 2H), 3.15-3.25 (m, IH), 3.49 (s, IH), 3.72-3.82 J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H) 2H), 8.18 (s, 1 H); 13 C NMR (400 MHz, CDCl 3) δ 25.81, 28.78, 45.15, 54.12, 57.67, 66.14, 66.94, 68.13, 77.54, 115.41, 125.46, 131.68, 156.21, 158.21, 161.83, 163.24.

실시예 6. 4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(디메틸아미노)에톡시}페닐아미노]피리미딘의 제조Example 6 Preparation of 4- (tetrahydrofuran-2-yl) methylamino-6- [4- {2- (dimethylamino) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00020
Figure 112017063987139-pat00020

둥근바닥플라스크에 6-클로로-4-(테트라하이드로퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.234 mmol)과 4-(2-(디메틸아미노)에톡시)아닐린 (0.042 g, 0.234 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인용액, 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하고 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.046 g, 55 %)을 얻었다.To a round bottom flask was added a solution of 6-chloro-4- (tetrahydrofuran-2-yl) methylaminopyrimidine (0.05 g, 0.234 mmol) and 4- (2- (dimethylamino) ethoxy) aniline ) Was dissolved in 2-methoxyethanol (5 mL), a hydrochloric acid solution (4M dioxane solution, 0.03 mL) was added, and the mixture was stirred at 110 DEG C for 24 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture. The mixture was extracted with dichloromethane, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. (0.046 g, 55%).

녹는점 157-159 ℃; 1H NMR (400 MHz, CDCl3) δ 1.55-1.65 (m, 1H), 1.87-1.97 (m, 2H), 1.95-2.05 (m, 1H), 2.37 (s, 6H), 2.72-2.82 (t, 2H), 3.15-3.25 (m, 1H), 3.46 (s, 1H), 3.72-3.82 (m, 1H), 3.82-3.92 (m, 1H), 4.0-4.1 (m, 1H), 4.1-4.2 (m, 2H), 5.08 (s, 1H), 5.57 (s, 1H), 6.91 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H), 8.17 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 25.80, 28.76, 45.13, 45.94, 58.33, 66.32, 68.11, 77.50, 115.36, 125.46, 131.58, 156.35, 158.32, 161.56, 163.27.
Melting point 157-159 ° C; 1 H NMR (400 MHz, CDCl 3) δ 1.55-1.65 (m, 1H), 1.87-1.97 (m, 2H), 1.95-2.05 (m, 1H), 2.37 (s, 6H), 2.72-2.82 (t 2H), 3.15-3.25 (m, IH), 3.46 (s, IH), 3.72-3.82 (m, 2H), 5.08 ( s, 1H), 5.57 (s, 1H), 6.91 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.8 Hz, 2H) , 8.17 (s, 1 H); 13 C NMR (400 MHz, CDCl 3) δ 25.80, 28.76, 45.13, 45.94, 58.33, 66.32, 68.11, 77.50, 115.36, 125.46, 131.58, 156.35, 158.32, 161.56, 163.27.

실시예 7. 4-(퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조
Example 7. Preparation of 4- (furan-2-yl) methylamino-6- [4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

7-1. 4-(2-(피롤리딘-1-일)에톡시)아닐린의 제조7-1. Preparation of 4- (2- (pyrrolidin-1-yl) ethoxy) aniline

Figure 112017063987139-pat00021
Figure 112017063987139-pat00021

둥근바닥플라스크에 1-(2-클로로에틸)-피롤리딘 하이드로클로라이드 (2 g, 11.76 mmol)와 4-아미노페놀 (1.28 g, 11.76 mmol) 그리고 수산화나트륨 (1.176 g, 29.4 mmol)을 넣고 디메틸포름아미드 (15 mL)에 녹인 후 2시간 동안 75 ℃에서 교반시켰다. 반응이 종결되면 실온까지 식힌 후에 여과하였다. 여과액을 감압증류로 용매를 제거하고 반응혼합물에 염화나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.95 g, 39 %)을 얻었다.To a round bottom flask was added 1- (2-chloroethyl) -pyrrolidine hydrochloride (2 g, 11.76 mmol), 4-aminophenol (1.28 g, 11.76 mmol) and sodium hydroxide (1.176 g, 29.4 mmol) Formamide (15 mL), followed by stirring at 75 DEG C for 2 hours. When the reaction was completed, the solution was cooled to room temperature and filtered. The filtrate was distilled under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium chloride was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.95 g, 39%).

1H NMR (400 MHz, CDCl3) δ 1.59-1.69 (s, 4H), 2.40-2.50 (s, 4H), 2.65-2.75 (t, 2H), 3.45-3.55 (s, 2H), 3.82-3.92 (t, 2H), 6.36-6.46 (s, 2H), 6.54-6.64 (s, 2H); 13C NMR (400 MHz, CDCl3) δ 23.43, 54.50, 55.12, 67.57, 115.58, 116.06, 140.52, 140.55, 151.57.
 1 H NMR (400 MHz, CDCl 3) δ 1.59-1.69 (s, 4H), 2.40-2.50 (s, 4H), 2.65-2.75 (t, 2H), 3.45-3.55 (s, 2H), 3.82-3.92 (t, 2H), 6.36 - 6.46 (s, 2H), 6.54 - 6.64 (s, 2H); 13 C NMR (400 MHz, CDCl 3) δ 23.43, 54.50, 55.12, 67.57, 115.58, 116.06, 140.52, 140.55, 151.57.

7-2. 4-(퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조7-2. Preparation of 4- (furan-2-yl) methylamino-6- [4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00022
Figure 112017063987139-pat00022

둥근바닥플라스크에 6-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-(피롤리딘-1-일)에톡시)아닐린 (0.045 mL, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액, 0.1 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.025 g, 28 %)을 얻었다.Yl) methylaminopyrimidine (0.05 g, 0.239 mmol) and 4- (2- (pyrrolidin-1-yl) ethoxy) aniline (0.045 mL , 0.239 mmol) were dissolved in 2-methoxyethanol (5 mL), and a hydrochloric acid solution (4M dioxane solution, 0.1 mL) was added thereto, followed by stirring at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.025 g, 28%).

녹는점 130-133 ℃; 1H NMR (400 MHz, CDCl3) δ 1.8-1.9 (m, 3H), 2.0-2.1 (m, 1H), 2.63-2.73 (t, 4H), 2.9-3.0 (t, 2H), 4.09-4.19 (t, 2H), 4.36-4.46 (d, 2H), 5.38 (s, 1H), 5.62 (s, 1H), 6.21 (d, J = 2.4 Hz, 1H), 6.29-6.39 (t, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.04-7.14 (t, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.37 (s, 1H), 8.15 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 23.49, 38.72, 54.70, 55.05, 67.32, 81.34, 107.34, 110.36, 115.36, 125.44, 131.40, 142.19, 151.43, 156.40, 158.17, 162.03, 162.82.
Melting point 130-133 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 1.8-1.9 (m, 3H), 2.0-2.1 (m, 1H), 2.63-2.73 (t, 4H), 2.9-3.0 (t, 2H), 4.09-4.19 (t, 2H), 4.36-4.46 (d, 2H), 5.38 (s, IH), 5.62 (s, IH), 6.21 (d, J = 2.4 Hz, 2H), 7.04-7.14 (t, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.37 (s, 1H), 8.15 (s, 1H); 6.93 (d, J = 8.8 Hz, 2H). 13 C NMR (400 MHz, CDCl 3) δ 23.49, 38.72, 54.70, 55.05, 67.32, 81.34, 107.34, 110.36, 115.36, 125.44, 131.40, 142.19, 151.43, 156.40, 158.17, 162.03, 162.82.

실시예 8. 4-(퓨란-2-일)메틸아미노-6-[4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘의 제조Example 8. Preparation of 4- (furan-2-yl) methylamino-6- [4- {2- (piperidin- 1 -yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00023
Figure 112017063987139-pat00023

둥근바닥플라스크에 6-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-(피페리딘-1-일)에톡시)아닐린 (0.049 mL, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액, 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.05 g, 53 %)을 얻었다.(0.049 mL, 0.239 mmol) and 4- (2- (piperidin-1-yl) ethoxy) aniline , 0.239 mmol) was dissolved in 2-methoxyethanol (5 mL), a hydrochloric acid solution (4M dioxane solution, 0.03 mL) was added, and the mixture was stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying with anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.05 g, 53%).

녹는점 133-135 ℃; 1H NMR (400 MHz, CDCl3) δ 1.43-1.53 (m, 2H), 1.59-1.69 (m, 4H), 2.49-2.59 (t, 4H), 2.75-2.85 (t, 2H), 4.08-4.18 (t, 2H), 4.41 (d, J = 5.6 Hz, 2H), 5.29 (s, 1H), 5.61 (s, 1H), 6.21 (d, J = 2.4 Hz, 1H), 6.29-6.39 (t, 1H), 6.93 (d, J = 8.8 Hz, 3H), 7.16 (d, J = 8.8 Hz, 2H), 7.37 (s, 1H), 8.16 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 24.16, 25.91, 36.71, 55.09, 57.90, 66.27, 81.34, 107.33, 110.36, 115.36, 125.44, 130.40, 142.19, 151.46, 156.37, 153.31, 162.07, 162.83.
Melting point 133-135 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 1.43-1.53 (m, 2H), 1.59-1.69 (m, 4H), 2.49-2.59 (t, 4H), 2.75-2.85 (t, 2H), 4.08-4.18 (t, 2H), 4.41 ( d, J = 5.6 Hz, 2H), 5.29 (s, 1H), 5.61 (s, 1H), 6.21 (d, J = 2.4 Hz, 1H), 6.29-6.39 (t, 1H), 6.93 (d, J = 8.8 Hz, 3H), 7.16 (d, J = 8.8 Hz, 2H), 7.37 (s, 1H), 8.16 13 C NMR (400 MHz, CDCl 3) δ 24.16, 25.91, 36.71, 55.09, 57.90, 66.27, 81.34, 107.33, 110.36, 115.36, 125.44, 130.40, 142.19, 151.46, 156.37, 153.31, 162.07, 162.83.

실시예 9. 4-(퓨란-2-일)메틸아미노-6-[4-{2-((4-에틸)피페라진-1-일)에톡시}페닐아미노]피리미딘의 제조Example 9. Preparation of 4- (furan-2-yl) methylamino-6- [4- {2 - ((4-ethyl) piperazin-1-yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00024
Figure 112017063987139-pat00024

둥근바닥플라스크에 6-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-((4-에틸)피페라진-1-일)에톡시)아닐린 (0.056 mL, 0.239 mmol)을 2-메톡시에탄올(5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액, 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.028 g, 28 %)을 얻었다.2-yl) methylaminopyrimidine (0.05 g, 0.239 mmol) and 4- (2- ((4-ethyl) piperazin- 1 -yl) ethoxy) Aniline (0.056 mL, 0.239 mmol) was dissolved in 2-methoxyethanol (5 mL), and a hydrochloric acid solution (4M dioxane solution, 0.03 mL) was added and stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.028 g, 28%).

녹는점 108-110 ℃; 1H NMR (400 MHz, CDCl3) δ 1.03-1.13 (t, 3H), 2.36-2.46 (m, 3H), 2.46-2.56 (s, 3H), 2.59-2.69 (s, 4H), 2.78-2.88 (t, 2H), 4.06-4.16 (t, 2H), 4.41 (d, J = 5.6 Hz, 2H), 5.51 (s, 1H), 5.59 (s, 1H), 6.21 (d, J = 2.4 Hz, 1H), 6.26-6.36 (t, 1H), 6.89 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.22-7.32 (t, 1H), 7.34 (s, 1H), 8.1 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 12.00, 36.72, 52.31, 52.76, 53.66, 57.23, 66.20, 81.23, 107.33, 110.36, 115.36, 125.38, 131.57, 142.18, 151.46, 156.23, 158.26, 162.09, 162.85.
Melting point 108-110 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 1.03-1.13 (t, 3H), 2.36-2.46 (m, 3H), 2.46-2.56 (s, 3H), 2.59-2.69 (s, 4H), 2.78-2.88 (s, 1H), 6.21 (d, J = 2.4 Hz, 2H), 4.06-4.16 (t, 2H), 4.41 (d, J = 5.6 Hz, 2H), 5.51 1H), 6.26-6.36 (t, 1H ), 6.89 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.22-7.32 (t, 1H), 7.34 (s, 1H ), 8.1 (s, 1 H); 13 C NMR (400 MHz, CDCl 3) δ 12.00, 36.72, 52.31, 52.76, 53.66, 57.23, 66.20, 81.23, 107.33, 110.36, 115.36, 125.38, 131.57, 142.18, 151.46, 156.23, 158.26, 162.09, 162.85.

실시예 10. 4-(퓨란-2-일)메틸아미노-6-[4-{2-몰포린-4-일)에톡시}페닐아미노]피리미딘의 제조Example 10. Preparation of 4- (furan-2-yl) methylamino-6- [4- {2-morpholin-4- yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00025
Figure 112017063987139-pat00025

둥근바닥플라스크에 6-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-(몰포린-4-일)에톡시)아닐린 (0.053 g, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인용액의 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.035 g, 37 %)을 얻었다.(0.05 g, 0.239 mmol) and 4- (2- (morpholin-4-yl) ethoxy) aniline (0.053 g, 0.239 mmol) was dissolved in 2-methoxyethanol (5 mL), a hydrochloric acid solution (0.03 mL of 4M dioxane solution) was added, and the mixture was stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain the title compound (0.035 g, 37%).

녹는점 115-117 ℃; 1H NMR (400 MHz, CDCl3) δ 2.56-2.66 (t, 4H), 2.79-2.89 (t, 2H), 3.71-3.81 (t, 4H), 4.09-4.19 (t, 2H), 4.41 (d, J = 5.6 Hz, 2H), 5.46 (s, 1H), 5.62 (s, 1H), 6.21 (d, J = 2.4 Hz, 1H), 6.26-6.36 (t, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.21-7.31 (t, 1H), 7.37 (s, 1H) 8.14 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 38.72, 54.12, 57.66, 66.12, 66.94, 81.30, 107.33, 110.37, 115.37, 125.35, 131.66, 142.19, 151.45, 156.19, 158.26, 162.03, 162.85.
Melting point 115-117 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 2.56-2.66 (t, 4H), 2.79-2.89 (t, 2H), 3.71-3.81 (t, 4H), 4.09-4.19 (t, 2H), 4.41 (d , J = 5.6 Hz, 2H) , 5.46 (s, 1H), 5.62 (s, 1H), 6.21 (d, J = 2.4 Hz, 1H), 6.26-6.36 (t, 1H), 6.93 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 7.21-7.31 (t, 1H), 7.37 (s, 1H) 8.14 (s, 1H); 13 C NMR (400 MHz, CDCl 3 ) 隆 38.72, 54.12, 57.66, 66.12, 66.94, 81.30, 107.33, 110.37, 115.37, 125.35, 131.66, 142.19, 151.45, 156.19, 158.26, 162.03, 162.85.

실시예 11. 4-(퓨란-2-일)메틸아미노-6-[4-{2-(디메틸아미노)에톡시}페닐아미노]피리미딘의 제조Example 11 Preparation of 4- (furan-2-yl) methylamino-6- [4- {2- (dimethylamino) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00026
Figure 112017063987139-pat00026

둥근바닥플라스크에 6-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-(디메틸아미노)에톡시)아닐린 (0.043 g, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액, 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.0365 g, 43 %)을 얻었다. 4- (furan-2-yl) methylaminopyrimidine (0.05 g, 0.239 mmol) and 4- (2- (dimethylamino) ethoxy) aniline (0.043 g, 0.239 mmol) were added to a round bottom flask After dissolving in 2-methoxyethanol (5 mL), a hydrochloric acid solution (4M dioxane solution, 0.03 mL) was added, and the mixture was stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.0365 g, 43%).

녹는점 163-165 ℃; 1H NMR (400 MHz, CDCl3) δ 2.34 (s, 6H), 2.69-2.79 (t, 2H), 4.01-4.11 (t, 2H), 4.36 (d, J = 5.6 Hz, 2H), 5.59 (s, 2H), 6.18 (d, J = 2.4 Hz, 1H), 6.25-6.35 (t, 1H), 6.91 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.28-7.38 (t, 1H), 7.4 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 38.72, 45.90, 58.33, 66.33, 81.20, 107.33, 110.35, 115.33, 125.35, 131.56, 142.18, 151.46, 156.34, 158.22, 162.11, 162.87.
Melting point 163-165 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 2.34 (s, 6H), 2.69-2.79 (t, 2H), 4.01-4.11 (t, 2H), 4.36 (d, J = 5.6 Hz, 2H), 5.59 ( s, 2H), 6.18 (d , J = 2.4 Hz, 1H), 6.25-6.35 (t, 1H), 6.91 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.28-7.38 (t, 1 H), 7.4 (d, J = 2.4 Hz, 1 H), 8.09 (s, 1 H); 13 C NMR (400 MHz, CDCl 3 ) 隆 38.72, 45.90, 58.33, 66.33, 81.20, 107.33, 110.35, 115.33, 125.35, 131.56, 142.18, 151.46, 156.34, 158.22, 162.11, 162.87.

실시예 12. 4-(퓨란-2-일)메틸아미노-6-[2-메톡시-4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조
Example 12. Preparation of 4- (furan-2-yl) methylamino-6- [2-methoxy-4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

12-1. 6-클로로-4-(퓨란-2-일)메틸아미노피리미딘의 제조12-1. Preparation of 6-chloro-4- (furan-2-yl) methylaminopyrimidine

Figure 112017063987139-pat00027
Figure 112017063987139-pat00027

둥근바닥플라스크에 2,4-디클로로피리미딘 (1 g, 6.71 mmol)을 넣고 n-부탄올(40 mL)에 녹인 후, (테트라하이드로퓨란-2-일)메탄아민 (0.593 mL, 6.71 mmol)과 디아이소프로필에틸아민 (3.5 mL, 20.1 mmol)을 넣고 16시간 동안 80 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 물을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (1.3 g, 92 %)을 얻었다.To a round bottom flask was added 2,4-dichloropyrimidine (1 g, 6.71 mmol) into the n - was dissolved in butanol (40 mL), (tetrahydrofuran-2-yl) methanamine (0.593 mL, 6.71 mmol) and Diisopropylethylamine (3.5 mL, 20.1 mmol) was added thereto and stirred at 80 DEG C for 16 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (1.3 g, 92%).

1H NMR (400 MHz, CDCl3) δ 4.48-4.58 (s, 2H), 5.66-5.76 (s, 1H), 6.23-6.33 (s, 1H), 6.29-6.39 (s, 1H), 6.42 (d, J = 0.4 Hz, 1H), 7.33-7.43 (s, 1H), 8.29-8.39 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 38.52, 107.93, 110.55, 142.60, 150.32, 155.37, 158.44, 159.69, 162.96.
 1 H NMR (400 MHz, CDCl 3) δ 4.48-4.58 (s, 2H), 5.66-5.76 (s, 1H), 6.23-6.33 (s, 1H), 6.29-6.39 (s, 1H), 6.42 (d , J = 0.4 Hz, 1 H), 7.33-7.43 (s, 1 H), 8.29-8.39 (s, 1 H); 13 C NMR (400 MHz, CDCl 3) δ 38.52, 107.93, 110.55, 142.60, 150.32, 155.37, 158.44, 159.69, 162.96.

12-2. 2-메톡시-4-(2-(피롤리딘-1-일)에톡시)아닐린의 제조12-2. Preparation of 2-methoxy-4- (2- (pyrrolidin-1-yl) ethoxy) aniline

Figure 112017063987139-pat00028
Figure 112017063987139-pat00028

둥근바닥플라스크에 1-(2-클로로에틸)-피롤리딘 하이드로클로라이드 (0.183 g, 1.078 mmol)와 4-아미노-3-메톡시페놀 (0.15 g, 1.078 mmol) 그리고 수산화나트륨 (0.108 g, 2.694 mmol)을 넣고 디메틸포름아미드 (5 mL)에 녹인 후 2시간 동안 75 ℃에서 교반시켰다. 반응이 종결되면 실온까지 식힌 후에 여과하였다. 여과액을 감압증류로 용매를 제거하고 반응혼합물에 염화나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.112 g, 44 %)을 얻었다. To a round bottom flask was added 1- (2-chloroethyl) -pyrrolidine hydrochloride (0.183 g, 1.078 mmol), 4-amino-3-methoxyphenol (0.15 g, 1.078 mmol) and sodium hydroxide mmol) were dissolved in dimethylformamide (5 mL), and the mixture was stirred at 75 ° C for 2 hours. When the reaction was completed, the solution was cooled to room temperature and filtered. The filtrate was distilled under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium chloride was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.112 g, 44%).

1H NMR (400 MHz, CDCl3) δ 1.74-1.84 (s, 4H), 2.54-2.64 (s, 4H), 2.85 (d, J = 6 Hz, 2H), 3.48-3.58 (s, 2H), 3.78 (d, J = 6 Hz, 3H), 4.02 (d, J = 6 Hz, 2H), 6.29-6.39 (s, 1H), 6.49 (d, J = 3.2 Hz, 1H), 6.54-6.64 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 23.47, 54.64, 55.27, 55.40, 67.62, 100.14, 105.14, 115.06, 129.90, 148.19, 152.25.
 1 H NMR (400 MHz, CDCl 3) δ 1.74-1.84 (s, 4H), 2.54-2.64 (s, 4H), 2.85 (d, J = 6 Hz, 2H), 3.48-3.58 (s, 2H), 3.78 (d, J = 6 Hz , 3H), 4.02 (d, J = 6 Hz, 2H), 6.29-6.39 (s, 1H), 6.49 (d, J = 3.2 Hz, 1H), 6.54-6.64 (s , 1H); 13 C NMR (400 MHz, CDCl 3) δ 23.47, 54.64, 55.27, 55.40, 67.62, 100.14, 105.14, 115.06, 129.90, 148.19, 152.25.

12-3. 4-(퓨란-2-일)메틸아미노-6-[2-메톡시-4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조12-3. Preparation of 4- (furan-2-yl) methylamino-6- [2-methoxy-4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00029
Figure 112017063987139-pat00029

둥근바닥플라스크에 6-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 2-메톡시-4-(2-(피롤리딘-1-일)에톡시)아닐린 (0.051 mL, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액. 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.0715 g, 73 %)을 얻었다.2-yl) methylaminopyrimidine (0.05 g, 0.239 mmol) and 2-methoxy-4- (2- (pyrrolidin- 1 -yl) ethoxy ) Aniline (0.051 mL, 0.239 mmol) was dissolved in 2-methoxyethanol (5 mL), and a hydrochloric acid solution (4M dioxane solution, 0.03 mL) was added and stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resultant was purified by column chromatography to obtain the title compound (0.0715 g, 73%).

녹는점 126-130 ℃; 1H NMR (400 MHz, CDCl3) δ 1.75-1.85 (s, 4H), 2.56-2.66 (s, 4H), 2.84-2.94 (s, 2H), 3.71-3.81 (s, 3H), 4.04-4.14 (s, 2H), 4.35 (d, J = 5.6 Hz, 2H), 5.54-5.64 (s, 1H), 6.02-6.12 (s. 1H), 6.18 (d, J = 2.4 Hz, 1H), 6.29 (m, 1H), 6.46 (m. 1H), 6.55 (d, J = 2.4 Hz, 1H), 7.05-7.15 (s, 1H), 7.325 (d, J = 0.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 8.01-8.11 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 23.48, 38.74, 54.68, 55.13, 55.60, 67.32, 81.62, 100.00, 104.56, 107.23, 110.34, 121.22, 124.09, 142.07, 151.66, 152.81, 156.62, 158.06, 161.75, 162.90.
Melting point 126-130 캜; 1 H NMR (400 MHz, CDCl 3) δ 1.75-1.85 (s, 4H), 2.56-2.66 (s, 4H), 2.84-2.94 (s, 2H), 3.71-3.81 (s, 3H), 4.04-4.14 (s, 2H), 4.35 ( d, J = 5.6 Hz, 2H), 5.54-5.64 (s, 1H), 6.02-6.12 (s. 1H), 6.18 (d, J = 2.4 Hz, 1H), 6.29 ( m, 1H), 6.46 (m . 1H), 6.55 (d, J = 2.4 Hz, 1H), 7.05-7.15 (s, 1H), 7.325 (d, J = 0.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1 H), 8.01-8.11 (s, 1 H); 13 C NMR (400 MHz, CDCl 3 ) δ 23.48, 38.74, 54.68, 55.13, 55.60, 67.32, 81.62, 100.00, 104.56, 107.23, 110.34, 121.22, 124.09, 142.07, 151.66, 152.81, 156.62, 158.06, 161.75, .

실시예 13. 4-(퓨란-2-일)메틸아미노-6-[2-메톡시-4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘의 제조
Example 13 Preparation of 4- (furan-2-yl) methylamino-6- [2-methoxy-4- {2- (piperidin- 1 -yl) ethoxy} phenylamino] pyrimidine

13-1. 2-메톡시-4-(2-(피페리딘-1-일)에톡시)아닐린의 제조13-1. Preparation of 2-methoxy-4- (2- (piperidin-1-yl) ethoxy) aniline

Figure 112017063987139-pat00030
Figure 112017063987139-pat00030

둥근바닥플라스크에 1-(2-클로로에틸)-피페리딘 하이드로클로라이드 (0.198 g, 1.078 mmol)와 4-아미노-3-메톡시페놀 (0.15 g, 1.078 mmol) 그리고 수산화나트륨 (0.108 g, 2.694 mmol)을 넣고 디메틸포름아미드 (5 mL)에 녹인 후 2시간 동안 75 ℃에서 교반시켰다. 반응이 종결되면 실온까지 식힌 후에 여과하였다. 여과액을 감압증류로 용매를 제거하고 반응혼합물에 염화나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.162 g, 60 %)을 얻었다.To a round bottom flask was added 1- (2-chloroethyl) -piperidine hydrochloride (0.198 g, 1.078 mmol), 4-amino-3-methoxyphenol (0.15 g, 1.078 mmol) and sodium hydroxide mmol) were dissolved in dimethylformamide (5 mL), and the mixture was stirred at 75 ° C for 2 hours. When the reaction was completed, the solution was cooled to room temperature and filtered. The filtrate was distilled under reduced pressure to remove the solvent, and a saturated aqueous solution of sodium chloride was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.162 g, 60%).

1H NMR (400 MHz, CDCl3) δ 1.37-1.47 (m, 2H), 1.54-1.64 (m, 4H), 2.42-2.52 (m, 4H), 2.66-2.76 (t, 2H), 3.47-3.57 (s, 2H), 3.72-3.82 (s, 3H), 3.96-4.06 (t, 2H), 6.32 (m, 1H), 6.46 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 24.16, 25.91, 38.71, 55.09, 57.94, 66.27, 81.34, 107.33, 110.36, 115.36, 125.44, 131.41, 142.19, 151.46, 156.37, 158.31, 162.07, 162.83.
 1 H NMR (400 MHz, CDCl 3) δ 1.37-1.47 (m, 2H), 1.54-1.64 (m, 4H), 2.42-2.52 (m, 4H), 2.66-2.76 (t, 2H), 3.47-3.57 (s, 2H), 3.72-3.82 ( s, 3H), 3.96-4.06 (t, 2H), 6.32 (m, 1H), 6.46 (d, J = 2.4 Hz, 1H), 6.58 (d, J = 8.4 Hz, 1H); 13 C NMR (400 MHz, CDCl 3) δ 24.16, 25.91, 38.71, 55.09, 57.94, 66.27, 81.34, 107.33, 110.36, 115.36, 125.44, 131.41, 142.19, 151.46, 156.37, 158.31, 162.07, 162.83.

13-2. 4-(퓨란-2-일)메틸아미노-6-[2-메톡시-4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘의 제조13-2. Preparation of 4- (furan-2-yl) methylamino-6- [2-methoxy-4- {2- (piperidin- 1 -yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00031
Figure 112017063987139-pat00031

둥근바닥플라스크에 6-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 2-메톡시-4-(2-(피페리딘-1-일)에톡시)아닐린 (0.055 mL, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인용액의 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.0683 g, 68 %)을 얻었다. (0.05 g, 0.239 mmol) and 2-methoxy-4- (2- (piperidin-1-yl) ethoxy) ) Aniline (0.055 mL, 0.239 mmol) was dissolved in 2-methoxyethanol (5 mL), and a hydrochloric acid solution (0.03 mL of 4M dioxane solution) was added and stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.0683 g, 68%).

1H NMR (400 MHz, CDCl3) δ 1.39-1.49 (m, 2H), 1.55-1.65 (m, 4H), 2.45-2.55 (s, 4H), 2.71-2.81 (t, 2H), 3.72-3.82 (s, 3H), 4.04-4.14 (t, 2H), 4.36 (d, J = 5.6 Hz, 2H), 5.55-5.65 (s, 1H), 5.87-5.97 (s, 1H), 6.18 (d, J = 3.2 Hz, 1H), 6.29 (m, 1H), 6.46 (m. 1H), 6.53 (d, J = 2.8 Hz, 1H), 6.96-7.06 (s, 2H), 7.35 (d, J = 10.4 Hz, 1H), 8.03-8.13 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 24.20, 25.94, 38.74, 55.08, 55.61, 57.99, 66.22, 81.68, 99.90, 104.68, 107.24, 110.36, 121.20, 124.06, 142.10, 151.64, 152.77, 156.57, 158.10, 161.72, 162.88.
 1 H NMR (400 MHz, CDCl 3) δ 1.39-1.49 (m, 2H), 1.55-1.65 (m, 4H), 2.45-2.55 (s, 4H), 2.71-2.81 (t, 2H), 3.72-3.82 (s, 3H), 4.04-4.14 ( t, 2H), 4.36 (d, J = 5.6 Hz, 2H), 5.55-5.65 (s, 1H), 5.87-5.97 (s, 1H), 6.18 (d, J = 3.2 Hz, 1H), 6.29 (m, 1H), 6.46 (m. 1H), 6.53 (d, J = 2.8 Hz, 1H), 6.96-7.06 (s, 2H), 7.35 (d, J = 10.4 Hz , ≪ / RTI > 1H), 8.03-8.13 (s, 1H); 13 C NMR (400 MHz, CDCl 3) δ 24.20, 25.94, 38.74, 55.08, 55.61, 57.99, 66.22, 81.68, 99.90, 104.68, 107.24, 110.36, 121.20, 124.06, 142.10, 151.64, 152.77, 156.57, 158.10, 161.72 , 162.88.

실시예 14. 4-(퓨란-2-일)메틸아미노-2-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조
Example 14. Preparation of 4- (furan-2-yl) methylamino-2- [4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

14-1. 2-클로로-4-(퓨란-2-일)메틸아미노피리미딘의 제조14-1. Preparation of 2-chloro-4- (furan-2-yl) methylaminopyrimidine

Figure 112017063987139-pat00032
Figure 112017063987139-pat00032

둥근바닥플라스크에 2,4-디클로로피리미딘 (1 g, 6.71 mmol)을 넣고 에탄올(40 mL)에 녹인 후 펄퓨릴아민 (0.593 mL, 6.71 mmol)과 트리에틸아민(2.81 mL, 20.1 mmol)을 넣고 12시간 동안 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 물을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.74 g, 53 %)을 얻었다.To the round bottom flask was added 2,4-dichloropyrimidine (1 g, 6.71 mmol), dissolved in ethanol (40 mL), and pearylamine (0.593 mL, 6.71 mmol) and triethylamine (2.81 mL, 20.1 mmol) And stirred for 12 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.74 g, 53%).

1H NMR (400 MHz, CDCl3) δ 4.5-4.6 (s, 2H), 5.37-6.07 (s, 1H), 6.23-6.33 (s, 1H), 6.32 (d, J = 6.8 Hz, 2H), 7.32-7.42 (s, 1H), 7.99-8.09 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 38.53, 108.01, 110.56, 142.56, 150.30, 160.74, 163.43.
 1 H NMR (400 MHz, CDCl 3) δ 4.5-4.6 (s, 2H), 5.37-6.07 (s, 1H), 6.23-6.33 (s, 1H), 6.32 (d, J = 6.8 Hz, 2H), 7.32-7.42 (s, 1 H), 7.99-8.09 (s, 1 H); 13 C NMR (400 MHz, CDCl 3) δ 38.53, 108.01, 110.56, 142.56, 150.30, 160.74, 163.43.

실시예 14-2. 4-(퓨란-2-일)메틸아미노-2-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘의 제조Example 14-2. Preparation of 4- (furan-2-yl) methylamino-2- [4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00033
Figure 112017063987139-pat00033

둥근바닥플라스크에 2-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-(피롤리딘-1-일)에톡시)아닐린 (0.045 mL, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후 염산 용액 (4M 다이옥세인용액의 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시킨다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하고 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 화합물 (0.055 g, 60 %)을 얻었다. (0.045 mL, 0.239 mmol) and 4- (2- (pyrrolidin-1-yl) ethoxy) aniline , 0.239 mmol) was dissolved in 2-methoxyethanol (5 mL), and a hydrochloric acid solution (0.03 mL of 4M dioxane solution) was added thereto, followed by stirring at 110 DEG C for 24 hours. After the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture. The mixture was extracted with dichloromethane and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, 0.055 g, 60%).

녹는점 171-175 ℃; 1H NMR (400 MHz, DMSO-d6) δ 1.63-1.73 (s, 4H), 2.46-2.56 (s, 4H), 2.71-2.81 (t, 2H), 3.95-4.05 (t, 2H), 4.47-4.57 (s, 2H), 5.96 (d, J = 5.6 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 6.35-6.45 (s, 1H), 6.82 (d, J = 9.2 Hz, 2H), 7.49-7.59 (s, 1H), 7.61 (d, J = 3.6 Hz, 2H), 7.58-7.68 (s, 1H), 7.80 (d, J = 5.6 Hz, 1H), 8.75-8.85 (s, 1H); 13C NMR (400 MHz, DMSO-d6) δ 23.61, 37.21, 54.47, 54.95, 67.33, 107.29, 110.91, 114.62, 115.38, 115.78, 120.54, 134.98, 142.50, 153.23, 155.51, 160.24, 162.71.
Melting point 171-175 DEG C; 1 H NMR (400 MHz, DMSO -d 6) δ 1.63-1.73 (s, 4H), 2.46-2.56 (s, 4H), 2.71-2.81 (t, 2H), 3.95-4.05 (t, 2H), 4.47 -4.57 (s, 2H), 5.96 (d, J = 5.6 Hz, 1H), 6.30 (d, J = 2.8 Hz, 1H), 6.35-6.45 (s, 1H), 6.82 (d, J = 9.2 Hz, 2H), 7.49-7.59 (s, 1H ), 7.61 (d, J = 3.6 Hz, 2H), 7.58-7.68 (s, 1H), 7.80 (d, J = 5.6 Hz, 1H), 8.75-8.85 (s , 1H); 13 C NMR (400 MHz, DMSO -d 6) δ 23.61, 37.21, 54.47, 54.95, 67.33, 107.29, 110.91, 114.62, 115.38, 115.78, 120.54, 134.98, 142.50, 153.23, 155.51, 160.24, 162.71.

실시예 15. 4-(퓨란-2-일)메틸아미노-2-[4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘의 제조Preparation of 4- (furan-2-yl) methylamino-2- [4- {2- (piperidin- 1 -yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00034
Figure 112017063987139-pat00034

둥근바닥플라스크에 2-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-(피페리딘-1-일)에톡시)아닐린 (0.049 mL, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액, 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.065 g, 70 %)을 얻었다. (0.049 mL, 0.239 mmol) and 4- (2- (piperidin-1-yl) ethoxy) aniline , 0.239 mmol) was dissolved in 2-methoxyethanol (5 mL), a hydrochloric acid solution (4M dioxane solution, 0.03 mL) was added, and the mixture was stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.065 g, 70%).

녹는점 173-176 ℃; 1H NMR (400 MHz, DMSO-d6) δ 1.39 (d, J = 5.2 Hz, 2H) 1.45-1.55 (s, 4H), 2.37-2.47 (s, 4H), 2.57-2.67 (s, 2H), 3.95-4.05 (s, 2H), 4.51 (d, J = 3.2 Hz, 2H), 5.96 (d, J = 5.6 Hz, 1H), 6.25-6.35 (s, 1H), 6.35-6.45 (s, 1H), 6.82 (d, J = 9.2 Hz, 2H), 7.49-7.59 (s, 1H), 7.56-7.66 (s, 2H), 7.58-7.68 (s, 1H), 7.80 (d, J = 5.6 Hz, 1H), 8.75-8.85 (s, 1H); 13C NMR (400 MHz, DMSO-d6) δ 14.55, 24.43, 26.07, 54.92, 58.01, 66.23, 107.29, 110.91, 114.67, 120.53, 120.77, 134.99, 142.50, 153.24, 155.55, 160.24, 162.70.
Melting point 173-176 DEG C; 1 H NMR (400 MHz, DMSO -d 6) δ 1.39 (d, J = 5.2 Hz, 2H) 1.45-1.55 (s, 4H), 2.37-2.47 (s, 4H), 2.57-2.67 (s, 2H) (S, 2H), 4.51 (d, J = 3.2 Hz, 2H), 5.96 (d, J = 5.6 Hz, 1H), 6.25-6.35 2H), 7.58-7.68 (s, 1H), 7.80 (d, J = 5.6Hz, 1H), 6.82 (d, J = 9.2Hz, 2H), 7.49-7.59 1H), 8.75-8.85 (s, 1 H); 13 C NMR (400 MHz, DMSO -d 6) δ 14.55, 24.43, 26.07, 54.92, 58.01, 66.23, 107.29, 110.91, 114.67, 120.53, 120.77, 134.99, 142.50, 153.24, 155.55, 160.24, 162.70.

실시예 16. 4-(퓨란-2-일)메틸아미노-2-[4-{2-((4-에틸)피페라진-1-일)에톡시}페닐아미노]피리미딘의 제조Example 16 Preparation of 4- (furan-2-yl) methylamino-2- [4- {2 - ((4-ethyl) piperazin-1-yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00035
Figure 112017063987139-pat00035

둥근바닥플라스크에 2-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-((4-에틸)피페라진-1-일)에톡시)아닐린 (0.056 mL, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액, 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.04 g, 40 %)을 얻었다.2-yl) methylaminopyrimidine (0.05 g, 0.239 mmol) and 4- (2- ((4-ethyl) piperazin- 1 -yl) ethoxy) Aniline (0.056 mL, 0.239 mmol) was dissolved in 2-methoxyethanol (5 mL), and a hydrochloric acid solution (4M dioxane solution, 0.03 mL) was added and stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.04 g, 40%).

녹는점 50-60 ℃; 1H NMR (400 MHz, CDCl3) δ 1.02-1.12 (t, 3H), 2.41 (d, J = 7.2 Hz, 3H). 2.45-2.55 (s, 3H), 2.56-2.66 (s, 4H), 2.73-2.83 (s, 2H), 4.01-4.11 (t, 2H), 4.43-4.53 (s, 2H), 5.66-5.76 (s, 1H), 5.81 (d, J = 5.6 Hz, 1H), 6.18 (d, J = 2.4 Hz, 1H), 6.23-6.33 (s, 1H), 6.82 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 12.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 5.6 Hz, 1H), 7.90-8.0 (s, 1H); 13C NMR (400 MHz, CDCl3) δ 11.92, 29.67, 38.17, 52.26, 52.68, 53.56, 57.27, 66.18, 95.86, 107.24, 110.43, 114.77, 121.65, 133.43, 142.03, 151.81, 154.22, 155.68, 160.02, 162.61.
Melting point 50-60 ° C; 1 H NMR (400 MHz, CDCl 3 )? 1.02-1.12 (t, 3H), 2.41 (d, J = 7.2 Hz, 3H). 2H), 4.43-4.53 (s, 2H), 5.66-5.76 (s, 2H), 2.45-2.55 (s, 3H), 2.56-2.66 , 1H), 5.81 (d, J = 5.6 Hz, 1H), 6.18 (d, J = 2.4 Hz, 1H), 6.23-6.33 (s, 1H), 6.82 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 12.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 5.6 Hz, 1H), 7.90-8.0 (s, 1H); 13 C NMR (400 MHz, CDCl 3 ) 隆 11.92, 29.67, 38.17, 52.26, 52.68, 53.56, 57.27, 66.18, 95.86, 107.24, 110.43, 114.77, 121.65, 133.43, 142.03, 151.81, 154.22, 155.68, 160.02, 162.61 .

실시예 17. 4-(퓨란-2-일)메틸아미노-2-[4-{2-몰포린-4-일)에톡시}페닐아미노]피리미딘의 제조Example 17. Preparation of 4- (furan-2-yl) methylamino-2- [4- {2-morpholin-4- yl) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00036
Figure 112017063987139-pat00036

둥근바닥플라스크에 2-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-(몰포린-4-일)에톡시)아닐린 (0.053 g, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인용액의 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.010 g, 11 %)을 얻었다. 2-yl) methylaminopyrimidine (0.05 g, 0.239 mmol) and 4- (2- (morpholin-4-yl) ethoxy) aniline (0.053 g, 0.239 mmol) was dissolved in 2-methoxyethanol (5 mL), a hydrochloric acid solution (0.03 mL of 4M dioxane solution) was added, and the mixture was stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain the title compound (0.010 g, 11%).

녹는점 141-143 ℃; 1H NMR (400 MHz, CDCl3) δ 2.51-2.61 (t, 4H), 2.72-2.82 (t, 2H), 3.67-3.77 (t, 4H), 4.02-4.12 (t, 2H), 4.49 (d, J = 5.2 Hz, 2H), 5.32-5.42 (s, 1H), 5.83 (d, J = 5.6 Hz, 1H), 6.2 (d, J = 3.2 Hz, 1H), 6.25-6.35 (s, 1H), 6.84 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 5.2 Hz, 1H), 7.44 (d, J = 9.2 Hz, 2H), 7.49-7.59 (s, 1H), 7.89 (d, J = 6 Hz, 1H); 13C NMR (400 MHz, CDCl3) δ 38.24, 54.09, 57.73, 66.12, 66.93, 95.99, 107.28, 110.45, 114.85, 121.63, 133.53, 142.12, 151.78, 154.17, 156.29, 160.24, 162.61.
Melting point 141-143 DEG C; 1 H NMR (400 MHz, CDCl 3) δ 2.51-2.61 (t, 4H), 2.72-2.82 (t, 2H), 3.67-3.77 (t, 4H), 4.02-4.12 (t, 2H), 4.49 (d , J = 5.2 Hz, 2H) , 5.32-5.42 (s, 1H), 5.83 (d, J = 5.6 Hz, 1H), 6.2 (d, J = 3.2 Hz, 1H), 6.25-6.35 (s, 1H) , 6.84 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 5.2 Hz, 1H), 7.44 (d, J = 9.2 Hz, 2H), 7.49-7.59 J = 6 Hz, 1H); 13 C NMR (400 MHz, CDCl 3) δ 38.24, 54.09, 57.73, 66.12, 66.93, 95.99, 107.28, 110.45, 114.85, 121.63, 133.53, 142.12, 151.78, 154.17, 156.29, 160.24, 162.61.

실시예 18. 4-(퓨란-2-일)메틸아미노-2-[4-{2-(디메틸아미노)에톡시}페닐아미노]피리미딘의 제조Example 18. Preparation of 4- (furan-2-yl) methylamino-2- [4- {2- (dimethylamino) ethoxy} phenylamino] pyrimidine

Figure 112017063987139-pat00037

Figure 112017063987139-pat00037

둥근바닥플라스크에 2-클로로-4-(퓨란-2-일)메틸아미노피리미딘 (0.05 g, 0.239 mmol)과 4-(2-(디메틸아미노)에톡시)아닐린 (0.043 g, 0.239 mmol)을 2-메톡시에탄올 (5 mL)에 녹인 후, 염산 용액 (4M 다이옥세인 용액, 0.03 mL)을 넣고 24시간 동안 110 ℃에서 교반시켰다. 반응이 종결되면 감압증류로 용매를 제거하고 반응혼합물에 탄산수소나트륨 포화수용액을 가한 후 디클로로메테인으로 추출하였다. 무수 황산 마그네슘으로 건조시킨 후 감압증류로 용매를 제거하고 관 크로마토그래피로 분리하여 표제화합물 (0.044 g, 52 %)을 얻었다. (0.05 g, 0.239 mmol) and 4- (2- (dimethylamino) ethoxy) aniline (0.043 g, 0.239 mmol) were added to a round bottom flask After dissolving in 2-methoxyethanol (5 mL), a hydrochloric acid solution (4M dioxane solution, 0.03 mL) was added, and the mixture was stirred at 110 DEG C for 24 hours. When the reaction was completed, the solvent was removed by distillation under reduced pressure, and a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with dichloromethane. After drying over anhydrous magnesium sulfate, the solvent was removed by distillation under reduced pressure, and the resultant product was purified by column chromatography to obtain the title compound (0.044 g, 52%).

녹는점 168-170 ℃; 1H NMR (400 MHz, DMSO-d6) δ 2.2 (d, J = 7.2 Hz, 6H), 2.55-2.65 (t, 2H), 3.94-4.04 (t, 2H), 4.47-4.57 (s, 2H), 5.95 (d, J = 6 Hz, 1H), 6.29 (d, J = 2.8 Hz, 1H), 6.35-6.45 (t, 1H), 6.82 (d, J = 9.2 Hz, 2H), 7.48-7.58 (s, 1H), 7.61 (d, J = 3.2 Hz, 2H), 7.58-7.68 (s, 1H), 7.8 (d, J = 5.6 Hz, 1H), 8.74-8.84 (s, 1H); 13C NMR (400 MHz, DMSO-d6) δ 46.06, 58.31, 58.41, 66.43, 107.29, 110.91, 114.64, 115.38, 115.82, 120.54, 135.00, 142.51, 153.23, 160.24, 162.71.
Melting point 168-170 DEG C; 1 H NMR (400 MHz, DMSO -d 6) δ 2.2 (d, J = 7.2 Hz, 6H), 2.55-2.65 (t, 2H), 3.94-4.04 (t, 2H), 4.47-4.57 (s, 2H ), 5.95 (d, J = 6 Hz, 1H), 6.29 (d, J = 2.8 Hz, 1H), 6.35-6.45 (t, 1H), 6.82 (d, J = 9.2 Hz, 2H), 7.48-7.58 (s, 1H), 7.61 (d, J = 3.2 Hz, 2H), 7.58-7.68 (s, 1H), 7.8 (d, J = 5.6 Hz, 1H), 8.74-8.84 13 C NMR (400 MHz, DMSO -d 6) δ 46.06, 58.31, 58.41, 66.43, 107.29, 110.91, 114.64, 115.38, 115.82, 120.54, 135.00, 142.51, 153.23, 160.24, 162.71.

실시예 19. SIK2 카이네이즈 저해 활성 측정Example 19. Measurement of SIK2 kinase inhibitory activity

(1) SIK2 카이네이즈 스크리닝(1) SIK2 kinase screening

카이네이즈 스크리닝은 Reaction Biology Corporation에 의해 "HotSpot" assay platform 방법을 사용하여 수행하였다. 반응 버퍼 (buffer)로는 20 mM HEPES (pH 7.5), 10 mM MgCl2, 1 mM EGTA, 0.02% Brij35, 0.02 mg/mL BSA, 0.1 mM Na3VO4, 2 mM DTT, 1% DMSO를 사용하였다. 필요한 보조인자는 SIK2 카이네이즈 반응에 따라 넣었다. 신선하게 만들어진 완충용액과 보조인자가 20 μM의 농도로 선택된 엔자임 반응에 첨가되었다. 이 용액에, 실험화합물을 디메틸설폭사이드 (DMSO)에 용해하여 적당한 농도로 첨가하였다. 반응을 개시시키기 위하여 339-ATP (specific activity 500 μCi/μL)를 넣고 2시간 동안 실온에서 배양하였다. 그리고, 실험화합물 20 μM의 농도에서 시작하여 10-dose IC50 mode로 스크리닝하였다. 대조약물로 사용된 Ro 31-8220는 20 μM의 농도에서 시작하여 10-dose IC50 mode로 하여 IC50 값을 구하였다. 반응은 10 μM ATP 농도에서 수행하였고, 그 결과는 하기 표 1에 정리하여 나타내었다.
The kinase screening was performed by the Reaction Biology Corporation using the "HotSpot" assay platform method. As the reaction buffer, 20 mM HEPES (pH 7.5), 10 mM MgCl 2 , 1 mM EGTA, 0.02% Brij 35, 0.02 mg / mL BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT and 1% DMSO were used . The auxiliaries needed were placed according to the SIK2 kinase reaction. Freshly made buffer and cofactors were added to the selected enzyme reaction at a concentration of 20 μM. To this solution, the test compound was dissolved in dimethylsulfoxide (DMSO) and added at a suitable concentration. To initiate the reaction, 339-ATP (specific activity 500 μCi / μL) was added and cultured at room temperature for 2 hours. The test compound was screened at a concentration of 20 μM and in a 10-dose IC 50 mode. Ro 31-8220, used as a reference drug, was started at a concentration of 20 μM and the IC 50 value was determined using a 10-dose IC 50 mode. The reaction was carried out at a concentration of 10 μM ATP, and the results are summarized in Table 1 below.

실험화합물Experimental compound SIK2 카이네이즈 저해 활성 (IC50)SIK2 kinase inhibitory activity (IC 50 ) 실시예 1Example 1 2.42 μM2.42 [mu] M 실시예 2Example 2 4.30 μM4.30 [mu] M 실시예 3Example 3 5.65 μM5.65 [mu] M 실시예 4Example 4 8.01 μM8.01 [mu] M 실시예 5Example 5 11.3 μM11.3 [mu] M 실시예 6Example 6 6.36 μM6.36 [mu] M 실시예 7Example 7 0.56 μM0.56 [mu] M 실시예 8Example 8 0.69 μM0.69 μM 실시예 9Example 9 1.43 μM1.43 [mu] M 실시예 10Example 10 2.24 μM2.24 [mu] M 실시예 11Example 11 0.87 μM0.87 [mu] M 실시예 12Example 12 18.6 μM18.6 [mu] M 실시예 13Example 13 14.0 μM14.0 [mu] M 실시예 14Example 14 0.35 μM0.35 [mu] M 실시예 15Example 15 0.38 μM0.38 μM 실시예 16Example 16 0.78 μM0.78 [mu] M 실시예 17Example 17 1.45 μM1.45 [mu] M 실시예 18Example 18 0.48 μM0.48 [mu] M 대조약물
(Ro 31-8220)Control drug
(Ro 31-8220) 1.40 μM1.40 [mu] M Ro 31-8220: Reaction Biology Corporation 제공 Ro 31-8220: provided by Reaction Biology Corporation

상기 표 1에 의하면, 본 발명의 화합물은 SIK2 카이네이즈 저해 활성이 우수함을 확인할 수 있다. 특히, 실시예 6의 화합물은 대조약물(Ro 31-8220)에 대비하여 약 2.5배 더 우수한 활성을 보였다.
According to the above Table 1, it can be confirmed that the compound of the present invention has excellent SIK2 kinase inhibitory activity. In particular, the compound of Example 6 showed about 2.5 times better activity than the reference drug (Ro 31-8220).

(2) SIK2 카이네이즈 선택도(2) SIK2 kinetic selectivity

본 발명의 화합물을 대표하여 실시예 1의 화합물에 대하여 10 μM 농도에서 SIK1, SIK2 및 SIK3 카이네이즈에 대한 선택도를 조사하였다. 그 결과는 하기 표 2에 나타내었다.The selectivity for SIK1, SIK2 and SIK3 kinase at a concentration of 10 [mu] M was examined for the compound of Example 1 on behalf of the compound of the present invention. The results are shown in Table 2 below.

SIK1, SIK2 및 SIK3 카이네이즈에 대한 선택도Selectivity for SIK1, SIK2 and SIK3 kaineiz 실험화합물Experimental compound SIK1SIK1 SIK2SIK2 SIK3SIK3 실시예 1Example 1 9.65%9.65% 41.35%41.35% 15.35%15.35%

상기 표 2에 의하면, 본 발명의 화합물은 SIK 카이네이즈 저해제로서 유효함을 알 수 있으며, 특히 SIK2에 대한 선택성이 우수한 것을 알 수 있다.According to the above Table 2, it can be seen that the compound of the present invention is effective as a SIK kinase inhibitor, and in particular, has excellent selectivity for SIK2.

따라서 본 발명의 화합물은 난소암, 전립선암, 유방암 세포에서 매우 높은 빈도로 발생하는 SIK2 수용체 카이네이즈의 새로운 표적 치료제로 유용하다.
Therefore, the compound of the present invention is useful as a novel target treatment agent for SIK2 receptor canine, which occurs at a very high frequency in ovarian cancer, prostate cancer, and breast cancer cells.

[제제예][Formulation Example]

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.
Meanwhile, the novel compounds represented by Formula 1 according to the present invention can be formulated into various forms according to the purpose. The following is a description of some formulations containing the compound of Formula 1 according to the present invention as an active ingredient, but the present invention is not limited thereto.

제제예 1. 정제 (직접 가압) Formulation Example 1 Tablets (direct pressurization)

활성성분 5.0 mg을 체로 친 후, 락토스 14.1 mg, 크로스포비돈 USNF 0.8 mg 및 마그네슘 스테아레이트 0.1 mg을 혼합하고 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 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 assembly)

활성성분 5.0 mg을 체로 친 후, 락토스 16.0 mg과 녹말 4.0 mg을 섞었다. 폴리솔베이트 80 0.3 mg을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 mg 및 마그네슘 스테아레이트 2.0 mg과 섞었다. 미립을 가압하여 정제로 만들었다.
After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules 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 캡슐제 Formulation Example 3. Powder and Capsule

활성성분 5.0 mg을 체로 친 후에, 락토스 14.8 mg, 폴리비닐 피롤리돈 10.0 mg, 마그네슘 스테아레이트 0.2 mg와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.
5.0 mg of the active ingredient was sieved and mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was filtered through a hard No. 5 gelatin capsules.

제제예 4. 주사제 Formulation Example 4. Injection

활성성분 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4/H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.
Injections were prepared by adding 100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na 2 HPO 4 / H 2 O and 2974 mg of distilled water.

이상의 실험예를 통하여 확인된 바와 같이, 본 발명에 따른 신규 화합물들은 SIK2 카이네이즈 엔자임에 대하여 매우 우수한 활성을 나타내고 있으므로, 각종 인간 암, 난소암, 전립선암과 유방암의 치료 및 예방제로서 유용하게 사용될 수 있다.As has been confirmed through the above experimental examples, the novel compounds according to the present invention exhibit very excellent activity against SIK2 kinase enzymes, and thus can be usefully used as therapeutic and prophylactic agents for various human cancers, ovarian cancer, prostate cancer and breast cancer .

Claims (13)

하기 화학식 1로 표시되는 디아미노피리미딘 화합물, 이의 입체이성질체, 이의 용매화물 또는 이의 약학적으로 허용 가능한 염 :
[화학식 1]
Figure 112017063987139-pat00038

상기 화학식 1에서,
m 및 n은 1 내지 6의 정수를 나타내고;
A 및 B는 서로 같거나 다른 것으로서 CH 또는 N을 나타내고;
Het는 산소원자 및 질소원자 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각의 포화 또는 불포화된 헤테로고리기이고;
R1은 수소원자, 할로겐원자, 아미노기, C1-C6 알킬기 또는 C1-C6 알콕시기로부터 선택되고;
R2 및 R3은 서로 같거나 다른 것으로서 수소원자 또는 C1-C6알킬기로부터 선택되고; 또는 R2 및 R3은 이들이 결합된 질소원자와 함께 결합하거나 또는 추가로 산소원자 및 질소원자 중에서 선택된 헤테로원자를 1 내지 2개 더 포함시켜 결합하여 5각 내지 6각의 포화 또는 불포화된 헤테로고리기를 형성할 수 있고;
상기 Het, R2 또는 R3의 정의에서 헤테로고리기는 C1-C6 알킬기로 치환 또는 비치환될 수 있다.
Claims 1. A diaminopyrimidine compound represented by the following formula (1), a stereoisomer thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]
Figure 112017063987139-pat00038

In Formula 1,
m and n represent an integer of 1 to 6;
A and B, equal to or different from each other, represent CH or N;
Het is a pentane-containing saturated or unsaturated heterocyclic group containing 1 to 2 hetero atoms selected from an oxygen atom and a nitrogen atom;
R 1 is selected from a hydrogen atom, a halogen atom, an amino group, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group;
R 2 and R 3 are the same or different and are selected from a hydrogen atom or a C 1 -C 6 alkyl group; Or R < 2 > and R < 3 > may be bonded together with the nitrogen atom to which they are bonded or further include one or two further heteroatoms selected from oxygen and nitrogen atoms to form a saturated or unsaturated heterocycle Lt; / RTI >
In the definition of Het, R 2 or R 3 , the heterocyclic group may be substituted or unsubstituted with a C 1 -C 6 alkyl group.
청구항 1에 있어서,
하기 화학식 1a로 표시되는 것을 특징으로 하는 화합물.
[화학식 1a]
Figure 112017063987139-pat00039

(상기 화학식 1a에서, Het, R1, R2, R3, m 및 n은 각각 상기 청구항 1에서 정의한 바와 같다)
The method according to claim 1,
Lt; RTI ID = 0.0 > (Ia). ≪ / RTI >
[Formula 1a]
Figure 112017063987139-pat00039

(Wherein, Het, R 1 , R 2 , R 3 , m and n are as defined in claim 1, respectively)
청구항 1에 있어서,
하기 화학식 1b로 표시되는 것을 특징으로 하는 화합물.
[화학식 1b]
Figure 112017063987139-pat00040

(상기 화학식 1b에서,Het, R1, R2, R3, m 및 n은 각각 상기 청구항 1에서 정의한 바와 같다)
The method according to claim 1,
RTI ID = 0.0 > 1b. ≪ / RTI >
[Chemical Formula 1b]
Figure 112017063987139-pat00040

(Wherein, Het, R 1 , R 2 , R 3 , m and n are as defined in claim 1, respectively)
청구항 1에 있어서,
Het는 테트라하이드로퓨란닐기, (R)-테트라하이드로퓨란닐기, (S)-테트라하이드로퓨란닐기, 피롤리딘닐기, 퓨란닐기 또는 피롤닐기로부터 선택되는 것을 특징으로 하는 화합물.
The method according to claim 1,
Het is selected from tetrahydrofuranyl, (R) -tetrahydrofuranyl, (S) -tetrahydrofuranyl, pyrrolidinyl, furanyl or pyrrolyl.
청구항 1에 있어서,
R2 및 R3은 서로 같거나 다른 것으로서 수소원자 또는 C1-C6알킬기로부터 선택되는 것을 특징으로 하는 화합물.
The method according to claim 1,
R 2 and R 3 are the same or different and are selected from a hydrogen atom or a C 1 -C 6 alkyl group.
청구항 1에 있어서,
R2 및 R3은 이들이 결합된 질소원자와 함께 결합하여 피롤리딘-1-일, (S)-피롤리딘-1-일, 또는 피페리딘-1-일로부터 선택되는 헤테로고리기를 형성하고 있는 것을 특징으로 하는 화합물.
The method according to claim 1,
R 2 and R 3 are taken together with the nitrogen atom to which they are attached to form a heterocyclic group selected from pyrrolidin-1-yl, (S) -pyrrolidin-1-yl, or piperidin- Lt; / RTI >
청구항 1에 있어서,
R2 및 R3은 이들이 결합된 질소원자와 추가로 산소원자 및 질소원자 중에서 선택된 헤테로원자를 더 포함시켜 결합하여 몰포린-4-일, 피페라진-1-일 또는 4-(C1-C6알킬)피페라진-1-일로부터 선택되는 헤테로고리기를 형성하고 있는 것을 특징으로 하는 화합물.
The method according to claim 1,
R 2 and R 3 may further include a hetero atom selected from an oxygen atom and a nitrogen atom to form a morpholin-4-yl, piperazin-1-yl or 4- (C 1 -C 6- alkyl) piperazin-1-yl. ≪ / RTI >
청구항 1에 있어서,
4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘,
4-(S)-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘,
4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘,
4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-((4-에틸)피페라진-1-일)에톡시}페닐아미노]피리미딘,
4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-몰포린-4-일)에톡시}페닐아미노]피리미딘,
4-(테트라하이드로퓨란-2-일)메틸아미노-6-[4-{2-(디메틸아미노)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-6-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-6-[4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-6-[4-{2-((4-에틸)피페라진-1-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-6-[4-{2-몰포린-4-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-6-[4-{2-(디메틸아미노)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-6-[2-메톡시-4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-6-[2-메톡시-4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-2-[4-{2-(피롤리딘-1-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-2-[4-{2-(피페리딘-1-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-2-[4-{2-((4-에틸)피페라진-1-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-2-[4-{2-몰포린-4-일)에톡시}페닐아미노]피리미딘,
4-(퓨란-2-일)메틸아미노-2-[4-{2-(디메틸아미노)에톡시}페닐아미노]피리미딘,
또는 이의 용매화물 또는 이의 약학적으로 허용 가능한 염으로 이루어진 군으로부터 선택된 것을 특징으로 하는 화합물.
The method according to claim 1,
4- (tetrahydrofuran-2-yl) methylamino-6- [4- {2- (pyrrolidin- 1 -yl) ethoxy} phenylamino] pyrimidine,
Methylamino-6- [4- {2- (pyrrolidin-1-yl) ethoxy} phenylamino] pyrimidine,
4- (tetrahydropyran-2-yl) ethoxy} phenylamino] pyrimidine,
(4-ethyl) piperazin-1-yl) ethoxy} phenylamino] pyrimidine,
4- (tetrahydrofuran-2-yl) methylamino-6- [4- {2-morpholin-4- yl) ethoxy} phenylamino] pyrimidine,
4- (tetrahydrofuran-2-yl) methylamino-6- [4- {2- (dimethylamino) ethoxy} phenylamino] pyrimidine,
4- (2- (pyrrolidin-1-yl) ethoxy} phenylamino] pyrimidine,
4- (2- (piperidin-1-yl) ethoxy} phenylamino] pyrimidine,
(4-ethyl) piperazin-1-yl) ethoxy} phenylamino] pyrimidine,
4- (2-morpholin-4-yl) ethoxy} phenylamino] pyrimidine,
4- (furan-2-yl) methylamino-6- [4- {2- (dimethylamino) ethoxy} phenylamino] pyrimidine,
Methoxy-4- {2- (pyrrolidin-1-yl) ethoxy} phenylamino] pyrimidine,
4- (2- (piperidin-1-yl) ethoxy} phenylamino] pyrimidine,
4- (2- (pyrrolidin-1-yl) ethoxy} phenylamino] pyrimidine,
2- (4- {2- (piperidin-1-yl) ethoxy} phenylamino] pyrimidine,
2- (4- {2 - ((4-ethyl) piperazin-1-yl) ethoxy} phenylamino] pyrimidine,
4- (2-morpholin-4-yl) ethoxy} phenylamino] pyrimidine,
Methylamino-2- [4- {2- (dimethylamino) ethoxy} phenylamino] pyrimidine,
Or a solvate thereof, or a pharmaceutically acceptable salt thereof.
청구항 1 내지 8항 중에서 선택된 어느 한 항의 화합물이 활성성분으로 함유된 항암용 약제조성물.
A pharmaceutical composition for anticancer comprising a compound of any one of claims 1 to 8 as an active ingredient.
청구항 1 내지 8항 중에서 선택된 어느 한 항의 화합물이 활성성분으로 함유된 항암제.
An anticancer agent comprising a compound of any one of claims 1 to 8 as an active ingredient.
청구항 10에 있어서,
난소암, 전립선암과 유방암의 치료에 사용되는 항암제.
The method of claim 10,
An anticancer agent used in the treatment of ovarian cancer, prostate cancer and breast cancer.
하기의 제조단계를 수행하여 제조하는 디아미노피리미딘 화합물의 제조방법 :
(단계 a1) 아민염기 존재 하에서 하기 화학식 2로 표시되는 4,6-디클로로피리미딘과 하기 화학식 3으로 표시되는 아민 화합물을 반응시켜, 하기 화학식 4a로 표시되는 6-클로로-4-치환된아미노피리미딘 화합물을 제조하는 단계; 및
Figure 112018102204080-pat00041

(상기 반응식에서, Het는 산소원자 및 질소원자 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각의 포화 또는 불포화된 헤테로고리기이고, n은 1 내지 6의 정수를 나타낸다)
(단계 b1) 하기 화학식 4a로 표시되는 6-클로로-4-치환된아미노피리미딘 화합물과 하기 화학식 5로 표시되는 아닐린 화합물을 반응시켜, 하기 화학식 1a로 표시되는 디아미노피리미딘 화합물을 제조하는 단계.
Figure 112018102204080-pat00042

(상기 반응식에서, m 및 n은 1 내지 6의 정수를 나타내고;
Het는 산소원자 및 질소원자 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각의 포화 또는 불포화된 헤테로고리기이고;
R1은 수소원자, 할로겐원자, 아미노기, C1-C6 알킬기 또는 C1-C6 알콕시기로부터 선택되고;
R2 및 R3은 서로 같거나 다른 것으로서 수소원자 또는 C1-C6알킬기로부터 선택되고; 또는 R2 및 R3은 이들이 결합된 질소원자와 함께 결합하거나 또는 추가로 산소원자 및 질소원자 중에서 선택된 헤테로원자를 1 내지 2개 더 포함시켜 결합하여 5각 내지 6각의 포화 또는 불포화된 헤테로고리기를 형성할 수 있고;
상기 Het, R2 또는 R3의 정의에서 헤테로고리기는 C1-C6 알킬기로 치환 또는 비치환될 수 있다)
A process for preparing a diaminopyrimidine compound which is prepared by carrying out the following production steps:
(Step a1) reacting 4,6-dichloropyrimidine represented by the following formula (2) with an amine compound represented by the following formula (3) in the presence of an amine base to obtain 6-chloro-4-substituted aminopyridine Preparing a compound of formula < RTI ID = 0.0 > And
Figure 112018102204080-pat00041

(Wherein Het is a saturated or unsaturated five-membered heterocyclic group containing 1 to 2 hetero atoms selected from an oxygen atom and a nitrogen atom, and n represents an integer of 1 to 6)
(Step b1) reacting a 6-chloro-4-substituted aminopyrimidine compound represented by the following formula (4a) with an aniline compound represented by the following formula (5) to prepare a diaminopyrimidine compound represented by the following formula .
Figure 112018102204080-pat00042

(Wherein m and n represent an integer of 1 to 6;
Het is a pentane-containing saturated or unsaturated heterocyclic group containing 1 to 2 hetero atoms selected from an oxygen atom and a nitrogen atom;
R 1 is selected from a hydrogen atom, a halogen atom, an amino group, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group;
R 2 and R 3 are the same or different and are selected from a hydrogen atom or a C 1 -C 6 alkyl group; Or R < 2 > and R < 3 > may be bonded together with the nitrogen atom to which they are bonded or further include one or two further heteroatoms selected from oxygen and nitrogen atoms to form a saturated or unsaturated heterocycle Lt; / RTI >
The heterocyclic group in the definition of Het, R 2 or R 3 may be substituted or unsubstituted with a C 1 -C 6 alkyl group)
하기의 제조단계를 수행하여 제조하는 디아미노피리미딘 화합물의 제조방법 :
(단계 a2) 아민염기 존재 하에서 하기 화학식 2로 표시되는 4,6-디클로로피리미딘과 하기 화학식 3으로 표시되는 아민 화합물을 반응시켜, 하기 화학식 4b로 표시되는 6-클로로-4-치환된아미노피리미딘 화합물을 제조하는 단계; 및
Figure 112018102204080-pat00043

(상기 반응식에서, Het는 산소원자 및 질소원자 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각의 포화 또는 불포화된 헤테로고리기이고, n은 1 내지 6의 정수를 나타낸다)
(단계 b2) 하기 화학식 4b로 표시되는 2-클로로-4-치환된아미노피리미딘 화합물과 하기 화학식 5로 표시되는 아닐린 화합물을 반응시켜, 하기 화학식 1b로 표시되는 디아미노피리미딘 화합물을 제조하는 단계.
Figure 112018102204080-pat00044

(상기 반응식에서, m 및 n은 1 내지 6의 정수를 나타내고;
Het는 산소원자 및 질소원자 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각의 포화 또는 불포화된 헤테로고리기이고;
R1은 수소원자, 할로겐원자, 아미노기, C1-C6 알킬기 또는 C1-C6 알콕시기로부터 선택되고;
R2 및 R3은 서로 같거나 다른 것으로서 수소원자 또는 C1-C6알킬기로부터 선택되고; 또는 R2 및 R3은 이들이 결합된 질소원자와 함께 결합하거나 또는 추가로 산소원자 및 질소원자 중에서 선택된 헤테로원자를 1 내지 2개 더 포함시켜 결합하여 5각 내지 6각의 포화 또는 불포화된 헤테로고리기를 형성할 수 있고;
상기 Het, R2 또는 R3의 정의에서 헤테로고리기는 C1-C6 알킬기로 치환 또는 비치환될 수 있다)A process for preparing a diaminopyrimidine compound which is prepared by carrying out the following production steps:
(Step a2) reacting 4,6-dichloropyrimidine represented by the following formula (2) with an amine compound represented by the following formula (3) in the presence of an amine base to obtain 6-chloro-4-substituted aminopyridine Preparing a compound of formula < RTI ID = 0.0 > And
Figure 112018102204080-pat00043

(Wherein Het is a saturated or unsaturated five-membered heterocyclic group containing 1 to 2 hetero atoms selected from an oxygen atom and a nitrogen atom, and n represents an integer of 1 to 6)
(Step b2) reacting a 2-chloro-4-substituted aminopyrimidine compound represented by the following formula (4b) with an aniline compound represented by the following formula (5) to prepare a diaminopyrimidine compound represented by the following formula .
Figure 112018102204080-pat00044

(Wherein m and n represent an integer of 1 to 6;
Het is a pentane-containing saturated or unsaturated heterocyclic group containing 1 to 2 hetero atoms selected from an oxygen atom and a nitrogen atom;
R 1 is selected from a hydrogen atom, a halogen atom, an amino group, a C 1 -C 6 alkyl group or a C 1 -C 6 alkoxy group;
R 2 and R 3 are the same or different and are selected from a hydrogen atom or a C 1 -C 6 alkyl group; Or R < 2 > and R < 3 > may be bonded together with the nitrogen atom to which they are bonded or further include one or two further heteroatoms selected from oxygen and nitrogen atoms to form a saturated or unsaturated heterocycle Lt; / RTI >
The heterocyclic group in the definition of Het, R 2 or R 3 may be substituted or unsubstituted with a C 1 -C 6 alkyl group)
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WO2019198940A1 (en) * 2018-04-11 2019-10-17 한국과학기술연구원 Excellent kinase inhibitory activity-exhibiting pyrimidine derivative having various substituents

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WO2005026130A1 (en) 2003-09-18 2005-03-24 Novartis Ag 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders

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WO2005026130A1 (en) 2003-09-18 2005-03-24 Novartis Ag 2,4-di (phenylamino) pyrimidines useful in the treatment of proliferative disorders

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* Cited by examiner, † Cited by third party
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WO2019198940A1 (en) * 2018-04-11 2019-10-17 한국과학기술연구원 Excellent kinase inhibitory activity-exhibiting pyrimidine derivative having various substituents
KR20190118759A (en) * 2018-04-11 2019-10-21 한국과학기술연구원 multi-substituted pyrimidine derivatives showing excellent kinase inhibitory activities
KR102063155B1 (en) * 2018-04-11 2020-01-08 한국과학기술연구원 multi-substituted pyrimidine derivatives showing excellent kinase inhibitory activities
US10683282B2 (en) 2018-04-11 2020-06-16 Korea Institute Of Science And Technology Multi-substituted pyrimidine derivatives with excellent kinase inhibitory activities

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