KR101766194B1 - Novel 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine compounds as RET kinase inhibitor - Google Patents

Novel 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine compounds as RET kinase inhibitor Download PDF

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KR101766194B1
KR101766194B1 KR1020150111783A KR20150111783A KR101766194B1 KR 101766194 B1 KR101766194 B1 KR 101766194B1 KR 1020150111783 A KR1020150111783 A KR 1020150111783A KR 20150111783 A KR20150111783 A KR 20150111783A KR 101766194 B1 KR101766194 B1 KR 101766194B1
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pyrazolo
pyrimidin
amine
isopropyl
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KR20170017607A (en
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심태보
윤호종
곽연의
허우영
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한국과학기술연구원
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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

본 발명은 신규 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물, 이 화합물 제조방법, 그리고 이 화합물의 RET 키나아제 활성으로 야기되는 각종 암질환의 예방 및 치료에 사용하는 의약용도에 관한 것이다.The present invention relates to a novel 3- (isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin-4-amine compound, a method for producing the compound, and various cancer diseases caused by RET kinase activity And to the use of the medicament for the prophylaxis and treatment of such diseases.

Description

RET 키나아제 저해제인 신규 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물 {Novel 3-(isoxazol-3-yl)-pyrazolo[3,4-d]pyrimidin-4-amine compounds as RET kinase inhibitor}(Isoxazol-3-yl) -pyrazolo [3,4-d] pyrimidin-4-amine compound as a RET kinase inhibitor. d] pyrimidine-4-amine compounds as RET kinase inhibitor}

본 발명은 신규 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물, 이 화합물 제조방법, 그리고 이 화합물의 RET 키나아제 활성으로 야기되는 각종 암질환의 예방 및 치료에 사용하는 의약용도에 관한 것이다.
The present invention relates to a novel 3- (isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin-4-amine compound, a method for producing the compound, and various cancer diseases caused by RET kinase activity And to the use of the medicament for the prophylaxis and treatment of such diseases.

RET (Rearranged during transfaction) 키나아제는 교감, 부교감신경의 발달에 필요한 티로신 키나아제 수용체 (RTK; Receptor tyrosine kinase) 중의 하나이다. RET 유전자가 점 돌연변이, 염색체 자리바꿈, 유전자 증폭과 같은 비정상적인 기능을 하는 경우에, 다양한 종류의 갑상선암 (MEN2A, MEN2B, FMTC, PTC 등)을 유발하는 것으로 보고되어 있다. 상기 갑상선암 중 MEN2A, MEN2B, FMTC는 RET 유전자의 점 돌연변이에 의해 유발되고, PTC는 RET 유전자가 내부의 염색체 자리바꿈 (chromosomal translocation)에 의해 유발된다고 보고되어 있다. [비특허문헌 1. J. Med. Chem. 2012, 55, 4872-4876] Rearranged during transfection Kinase is one of the receptor tyrosine kinases (RTKs) necessary for the development of sympathetic and parasympathetic nerves. It has been reported that the RET gene causes various types of thyroid cancer (MEN2A, MEN2B, FMTC, PTC, etc.) in the case of abnormal function such as point mutation, chromosome inversion, gene amplification. Among the thyroid cancer, MEN2A, MEN2B, and FMTC are caused by point mutation of RET gene, and PTC is reported to be caused by chromosomal translocation of RET gene. [Non-Patent Document 1. J. Med. Chem . 2012 , 55 , 4872-4876]

최근에는 RET 키나아제가 폐암 유발 인자로서 주목을 받고 있다. [비특허문헌 2. Genome Res 2012, 22, 436-445] RET 유전자가 KIF5B 유전자 또는 CCDC6 유전자와 융합하여 암화능을 가진 융합형 티로신 키나아제 KIF5B-RET 또는 CCDC6-RET가 발현됨으로써 비소세포 폐암이 유발된다고 보고된 바 있다. 또한 비소세포 폐암 환자의 경우 RET 유전자가 NCOA4 또는 TRIM33 (tripartite motif-containing 33) 유전자와 융합된 융합형 티로신 키나아제 NCOA4-RET, TRIM33-RET가 존재하는 것이 보고된 바 있다. [비특허문헌 3. Cancer Discov 2013 3(6), 630-635]Recently, RET kinase has been attracting attention as a lung cancer inducer. [Non-patent document 2: Genome Res 2012 , 22 , 436-445] The expression of the fusion type tyrosine kinase KIF5B-RET or CCDC6-RET, in which the RET gene fuses with the KIF5B gene or the CCDC6 gene, . It has also been reported that NCOA4-RET and TRIM33-RET, a fusion type tyrosine kinase fused with the NCOA4 or TRIM33 (tripartite motif-containing 33) gene, are present in non-small cell lung cancer patients. [Non-Patent Document 3: Cancer Discov 2013 3 (6), 630-635]

따라서, RET 키나아제의 저해작용을 갖는 화합물은 각종 암의 예방 및 치료에 매우 유용하다.Therefore, a compound having an inhibitory action of RET kinase is very useful for the prevention and treatment of various cancers.

RET 티로신 키나아제 저해 물질로서는 소라페닙 (Sorafenib), 수니티닙 (Sunitinib), XL184, 반데타닙 (Vandetanib), 포나티닙 (Ponatinib) 등이 알려져 있으며, 이들은 KIF5B-RET를 발현하는 세포주에 대해 세포증식 저해작용을 나타내는 것이 보고되어 있다. 또한, RET 티로신 키나아제 저해 물질로서 카보잔티닙 (Cabozantinib)은 RET 융합 유전자 발현에 기인하는 비소세포 폐암에 대해 부분 효과를 나타낸 것으로 보고되어 있다.Soretenib, Sunitinib, XL184, Vandetanib, and Ponatinib have been known as RET tyrosine kinase inhibitors, and they have been shown to inhibit cell proliferation of KIF5B-RET-expressing cell lines Inhibitory activity is reported. In addition, Cabozantinib, a RET tyrosine kinase inhibitor, has been reported to have a partial effect on non-small cell lung cancer caused by RET fusion gene expression.

한편, 피라졸로[3,4-d]피리미딘-4-아민 모핵을 가지는 화합물이 다양한 단백질 키나아제에 대하여 우수한 억제 효과를 나타내는 것으로 보고되어 있다. 그 예로서 국제특허공개공보 WO 2013/010136호 (특허문헌 1)에는 하기 화학식 A로 표시되는 화합물이 개시되어 있다.On the other hand, it has been reported that compounds having a pyrazolo [3,4- d ] pyrimidin-4-amine parent nucleus exhibit an excellent inhibitory effect on various protein kinases. As an example thereof, International Patent Publication No. WO 2013/010136 (Patent Document 1) discloses a compound represented by the following formula (A).

[화학식 A](A)

Figure 112015076880414-pat00001
Figure 112015076880414-pat00001

특허문헌 1은 Btk (Bruton's Tyrosine Kinase) 단백질에 대하여 억제효능을 가지는 피라졸로[3,4-d]피리미딘-4-아민 계열의 화합물에 관한 발명으로, 피라졸로[3,4-d]피리미딘-4-아민 모핵의 C3 위치에 다양한 아릴 또는 헤테로아릴 그룹이 치환된 화합물이 개시되어 있고, 헤테로아릴 그룹으로서 상기 화학식 A로 표시되는 바와 같이 모핵의 C3 위치에 이속사졸-5-일 그룹이 치환된 화합물의 화학구조가 기재되어 있기도 한다. 하지만, 특허문헌 1은 피라졸로[3,4-d]피리미딘-4-아민 모핵의 C3 위치에 페녹시페닐 그룹이 치환된 화합물에 대한 합성 그리고 Btk 억제활성을 확인하여 림프종 종양 치료에 유효함을 밝힌데 블과하다. 즉, 특허문헌 1에서는 상기 화학식 A로 표시되는 피라졸로[3,4-d]피리미딘-4-아민 모핵의 C3 위치에 이속사졸-5-일 그룹이 치환된 화합물에 대해서는 화학구조만 개시하고 있을 뿐이고, 상기 화학식 A로 표시되는 화합물의 구체적인 합성예 및 Btk 억제활성 효과에 대해서는 전혀 개시되어 있지 않다.Patent Document 1 Btk (Bruton's Tyrosine Kinase) having inhibitory effects with respect to protein-pyrazolo [3,4- d] the invention relates to a compound of pyrimidin-4-amine series, pyrazolo [3,4- d] pyrimidin Amin-4-amine is substituted with various aryl or heteroaryl groups at the C3 position, and as the heteroaryl group, isoxazol-5-yl group is substituted at the C3 position of the mother nucleus, The chemical structure of the substituted compound may also be described. However, Patent Document 1 confirms the synthesis and Btk inhibitory activity of a compound in which a phenoxyphenyl group is substituted at the C3 position of the pyrazolor [3,4- d ] pyrimidin-4-amine parent nucleus and is effective for the treatment of lymphoma tumor I can not tell you. That is, in Patent Document 1, only the chemical structure is disclosed for the compound in which the isoxazol-5-yl group is substituted at the C3 position of the pyrazolo [3,4- d ] pyrimidin- And no specific synthesis examples of the compound represented by the above formula (A) and the effect of inhibiting the Btk activity are disclosed at all.

이에 반하여, 본 발명이 특징으로 하는 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물은 모핵의 C3 위치에 이속사졸-3-일 고리가 치환되어 있고, 상기 이속사졸-3-일 고리의 C5 위치에는 -(CH2)n-A (이때 A는 알킬, 아릴 또는 헤테로아릴기이고, n은 0~4 정수이다)가 치환된 구조로, 현재까지 이의 화학구조가 밝혀진 바가 없는 신규 화합물이다. 또한, 본 발명이 특징으로 하는 신규 화합물은 단백질 키나아제 중에서도 특히 RET 유전자의 활성을 억제하는 효능을 가지고 있음을 실험적으로 확인함을 바탕으로, RET 유전자 발현에 기인되는 갑상선암, 비소세포 폐암, 유방암 치료에 탁월한 의약적 용도를 가진다.
On the other hand, the 3- (isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin-4-amine compound of the present invention is characterized in that the isoxazol- It may be optionally substituted, wherein the C5 position of the isoxazole-3-yl ring has - a (CH 2) n -A (wherein a is alkyl, aryl or heteroaryl group, n is an integer of 0 to 4) is substituted with , A novel compound whose chemical structure has not been known to date. In addition, the inventors of the present invention have found that the novel compounds of the present invention have an effect of inhibiting the activity of the RET gene among protein kinases, and have been used for the treatment of thyroid cancer, non-small cell lung cancer, It has excellent medicinal use.

국제특허공개공보 WO 2013/010136호 "브루톤형 티로신 키나제 (Btk)의 억제제"International Patent Publication No. WO 2013/010136 "Inhibitor of Bruton Type Tyrosine Kinase (Btk)"

"Preparation of 3-substituted-1-isopropyl-1H-pyrazolo [3,4-d]pyrimidin-4-amines as RET Kinase Inhibitors", J. Med. Chem. 2012, 55, 4872-4876  Preparation of 3-substituted-1-isopropyl-1H-pyrazolo [3,4-d] pyrimidin-4-amines as RET Kinase Inhibitors ", J. Med. Chem. 2012, 55, 4872-4876 "A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing", Genome Res 2012, 22, 436-445 "A transformed KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing", Genome Res 2012, 22, 436-445 "Response to Cabozantinib in Patients with RET Fusion-Positive Lung Adenocarcinomas", Cancer Discov 2013, 3(6), 630-635 &Quot; Response to Cabozantinib in Patients with RET Fusion-Positive Lung Adenocarcinomas ", Cancer Discov 2013, 3 (6), 630-635

따라서 본 발명의 목적은 단백질 키나아제 중에서도 RET 키나아제에 대한 저해활성과 선택성이 우수한 신규 화합물을 제공하는데 있다.Accordingly, an object of the present invention is to provide a novel compound having excellent inhibitory activity and selectivity against RET kinase among protein kinases.

또한, 본 발명의 다른 목적은 상기한 신규 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 RET 키나아제의 비정상적인 발현으로 야기되는 암질환의 예방 및 치료용 약학적 조성물을 제공하는데 있다.Another object of the present invention is to provide a pharmaceutical composition for the prevention and treatment of cancers caused by abnormal expression of RET kinase containing the novel compound or a pharmaceutically acceptable salt thereof as an active ingredient.

또한, 본 발명의 다른 목적은 상기한 신규 화합물의 제조방법을 제공하는데 있다.Another object of the present invention is to provide a process for preparing the novel compounds.

또한, 본 발명의 다른 목적은 상기한 신규 화합물의 합성에 유용한 중간체 화합물을 제공하는데 있다.
Another object of the present invention is to provide an intermediate compound useful in the synthesis of the novel compounds.

상기한 과제를 해결하기 위하여, 본 발명은 하기 화학식 1로 표시되는 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물, 이의 약학적으로 허용되는 염, 이의 수화물, 이의 용매화물 및 이의 이성질체로 이루어진 군으로부터 선택된 화합물을 그 특징으로 한다.In order to solve the above problems, the present invention provides a pharmaceutical composition comprising 3- (isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin- A salt thereof, a hydrate thereof, a solvate thereof, and an isomer thereof.

[화학식 1][Chemical Formula 1]

Figure 112015076880414-pat00002
Figure 112015076880414-pat00002

상기 화학식 1에서,In Formula 1,

Figure 112015076880414-pat00003
는 단일결합 또는 이중결합을 나타내고;
Figure 112015076880414-pat00003
Represents a single bond or a double bond;

A는 수소원자; C1∼C10 알킬기; C6∼C15 아릴기; 또는 S 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각 내지 6각의 헤테로아릴기를 나타내고;A is a hydrogen atom; A C 1 to C 10 alkyl group; A C 6 -C 15 aryl group; Or a five to six-membered heteroaryl group containing 1 to 2 hetero atoms selected from S and N;

R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 또는 O 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각 내지 6각의 포화 또는 부분 포화된 헤테로사이클로알킬기를 나타내고;R is a hydrogen atom; A C 1 to C 10 alkyl group; C 1 ~C 10 hydroxyalkyl group; Benzyl group; Or a five to six-membered saturated or partially saturated heterocycloalkyl group containing from one to two heteroatoms selected from O and N;

n은 0 내지 4의 정수를 나타내고;n represents an integer of 0 to 4;

상기 아릴기 또는 헤테로사이클로알킬기는 각각 할로, C1∼C10 알킬, C1∼C10 알콕시, R1-C(O)- (이때, R1은 C1∼C10 알킬 또는 C2∼C10 알케닐이다), 또는 R2-S(O)2- (이때, R2는 C1∼C10 알킬이다) 로부터 선택된 치환기로 치환 또는 비치환될 수 있다.
Wherein said aryl or heterocycloalkyl group is optionally substituted with at least one substituent selected from the group consisting of halo, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, R 1 -C (O) - wherein R 1 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl), or R 2 -S (O) 2 -, wherein R 2 is C 1 -C 10 alkyl.

본 발명에 따른 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물은 RET 단백질 키나아제에 대한 우수한 억제 활성을 나타내므로, 비정상적인 세포 성장에 의해 유발되는 질환의 예방 또는 치료를 목적으로 사용될 수 있다.Since the 3- (isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin-4-amine compound according to the present invention exhibits an excellent inhibitory activity against RET protein kinase, For the purpose of preventing or treating a disease caused by a disease.

본 발명에서의 비정상적인 세포 성장에 의해 유발되는 질환은 예를 들면 갑상선암, 폐암, 유방암 등의 암 질환이 포함될 수 있다.The diseases caused by abnormal cell growth in the present invention may include, for example, cancer diseases such as thyroid cancer, lung cancer and breast cancer.

본 발명에 따른 상기 화학식 1로 표시되는 화합물의 약학적으로 허용 가능한 염은 당해 기술 분야에서 통상적인 방법에 의해 제조될 수 있다. 약학적으로 허용된 염은 인체에 독성이 낮고 모화합물의 생물학적 활성과 물리화학적 성질에 악영향을 주지 않아야 한다. 약학적으로 허용된 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. 약학적으로 허용된 염의 제조에 사용될 수 있는 유리산은 무기산과 유기산으로 나눌 수 있다. 무기산은 염산, 황산, 질산, 인산, 과염소산, 브롬산 등이 사용될 수 있다. 유기산은 초산, 메탄설폰산, 에탄설폰산, p-톨루엔설폰산, 푸마린산, 말레산, 말론산, 프탈산, 숙신산, 젖산, 구연산, 시트르산, 글루콘산, 타타르산, 살리실산, 말산, 옥살산, 벤조산, 엠본산, 아스파르트산, 글루탐산 등이 사용될 수 있다. 유기염기부가염 제조에 사용될 수 있는 유기염기는 트리스(하이드록시메틸)메틸아민, 디사이클로헥실아민 등이다. 아미노산부가염기 제조에 사용될 수 있는 아미노산은 알라닌, 글라이신 등의 천연아미노산이다. The pharmaceutically acceptable salts of the compound represented by the formula (1) according to the present invention can be prepared by a conventional method in the art. Pharmacologically 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 acceptable free acids, acid addition salts of base compounds of formula (I), and 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 free acids that can be used in the preparation of pharmaceutically acceptable salts can be divided into inorganic and organic acids. As the inorganic acid, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid and the like can be used. The organic acid may be selected from the group consisting of acetic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, tartaric acid, Benzoic acid, embonic acid, aspartic acid, glutamic acid and the like can be used. Organic bases that can be used to prepare organic base addition salts include tris (hydroxymethyl) methylamine, dicyclohexylamine, and the like. Amino acids that can be used in the production of amino acid addition bases are natural amino acids such as alanine and glycine.

본 발명에 따른 상기 화학식 1로 표시되는 화합물은 상기한 약학적으로 허용된 염과 더불어 모든 수화물 그리고 용매화물도 포함한다. 상기한 약학적으로 허용된 염은 통상적인 방법으로 제조될 수 있는데, 예를 들면 상기한 화학식 1의 염기 화합물을 메탄올, 에탄올, 아세톤, 1,4-디옥산과 같은 물과 섞일 수 있는 용매에 녹인 다음에 유리산 또는 유리염기를 가한 후에 결정화 또는 재결정화하여 제조될 수 있다. The compounds represented by Formula 1 according to the present invention include all hydrates and solvates as well as the pharmaceutically acceptable salts described above. The above-mentioned pharmaceutically acceptable salts can be prepared by a conventional method. For example, the base compound of Formula 1 may be dissolved in a solvent which can be mixed with water such as methanol, ethanol, acetone, 1,4-dioxane Followed by melting, followed by addition of a free acid or a free base, followed by crystallization or recrystallization.

또한, 본 발명에 따른 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 발명은 각 이성질체 또는 이들 이성질체 혼합물을 포함한다. 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 according to the present invention may have one or more asymmetric centers, and in the case of such a compound, an enantiomer or diastereomer may exist. Accordingly, the present invention includes each isomer or a mixture of these isomers. 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 발명은 본 발명에 따른 상기 화학식 1로 표시되는 화합물의 방사성 유도체를 포함하며, 이들 방사성 화합물은 생체연구 분야에 유용하다.The present invention also includes a radioactive derivative of the compound represented by Formula 1 according to the present invention, and these radioactive compounds are useful in the field of biomedical research.

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

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 '하이드록시알킬'은 상기에서 정의된 직쇄상 또는 분쇄상의 탄소사슬에 하이드록시기(-OH)가 하나 이상 결합된 지방족 포화탄화수소기를 의미한다. 이러한 하이드록시알킬기를 구체적으로 예시하면, 하이드록시메틸기, 2-하이드록시에틸기, 3-하이드록시프로필기, 1-하이드록시-이소프로필기, 2-하이드록시부틸기, 4-하이드록시부틸기, 2-메틸-2-하이드록시프로필기 등이 포함될 수 있다.The term "hydroxyalkyl" in the present invention means an aliphatic saturated hydrocarbon group in which at least one hydroxyl group (-OH) is bonded to a straight chain or branched chain carbon chain as defined above. Specific examples of such a hydroxyalkyl group include a hydroxymethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 1-hydroxy-isopropyl group, a 2-hydroxybutyl group, 2-methyl-2-hydroxypropyl group and the like.

본 발명에서의 '헤테로사이클로알킬'은 O 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함되고, 포화 또는 부분적으로 포화된 5각 내지 6각의 지방족고리기를 의미한다. 이러한 헤테로사이클로알킬기를 구체적으로 예시하면, 테트라하이드로푸라닐기, 2,3-디하이드로푸라닐기, 2,5-디하이드로푸라닐기, 피롤리디닐기, 2,3-디하이드로피롤리디닐기, 2,5-디하이드로피롤리디닐기, 테트라하이드로-2H-파이란일기, 3,4-디하이드로-2H-파이란일기, 4H-파이란일기, 피페리디닐기, 1,2,3,4-테트라하이드로피리디닐기, 1,4-디하이드로피리디닐기, 피페라지닐, N-보호된 피페라지닐, 몰포리노기 등이 포함될 수 있다. 피페라지닐의 N-보호기로는 통상적으로 알킬기가 포함될 수 있다.'Heterocycloalkyl' in the present invention means a saturated or partially saturated five to six-membered aliphatic ring group containing 1 to 2 hetero atoms selected from O and N. Specific examples of such a heterocycloalkyl group include a tetrahydrofuranyl group, a 2,3-dihydrofuranyl group, a 2,5-dihydrofuranyl group, a pyrrolidinyl group, a 2,3-dihydropyrrolidinyl group, Dihydropyrrolylinyl group, tetrahydro- 2H -pyranyl group, 3,4-dihydro- 2H -pyranyl group, 4H -pyranyl group, piperidinyl group, 1,2,3,4- Tetrahydropyridinyl group, 1,4-dihydropyridinyl group, piperazinyl, N -protected piperazinyl, morpholino group and the like. The N -protecting group of the piperazinyl may ordinarily include an alkyl group.

본 발명에서의 '아릴'은 6개에서 15개까지의 탄소원자를 가지는 단일고리, 두고리, 또는 세고리의 방향족 탄화수소기를 의미한다. 이러한 아릴기를 구체적으로 예시하면, 페닐기, 나프틸기, 안트라세닐기, 페난쓰레닐기 등이 포함될 수 있다. The term " aryl " in the present invention means a single ring, double ring, or three ring aromatic hydrocarbon group having 6 to 15 carbon atoms. Specific examples of such an aryl group include a phenyl group, a naphthyl group, an anthracenyl group, a phenanthrenyl group and the like.

본 발명에서의 '헤테로아릴'은 S 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함되고, 탄소원자가 4개 내지 13개를 가지는 단일고리, 두고리, 또는 세고리의 방향족고리기를 의미한다. 이러한 헤테로아릴은 피롤릴기, 피라졸릴기, 이미다졸릴기, 티아졸릴기, 이소티아졸릴기, 피리디닐기, 피라지닐기, 피리다지닐기, 피리미디닐기, 인돌릴기, 이소인돌릴기, 인다졸릴기, 벤즈이미다졸릴기, 벤조티아졸릴기, 벤즈이소티아졸릴기, 퀴놀리닐기, 이소퀴놀리닐기, 프탈라지닐기, 퀴나졸리닐기 등이 포함될 수 있다. 'Heteroaryl' in the present invention means an aromatic ring group of 1 to 2 hetero atoms selected from the group consisting of S and N, and a single ring, a nugget or a tricyclic ring having 4 to 13 carbon atoms. These heteroaryls may be substituted with at least one substituent selected from the group consisting of a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, a pyridinyl group, a pyrazinyl group, a pyridazinyl group, a pyrimidinyl group, An imidazolyl group, a benzimidazolyl group, a benzothiazolyl group, a benzisothiazolyl group, a quinolinyl group, an isoquinolinyl group, a phthalazinyl group, a quinazolinyl group and the like.

본 발명에 따른 화합물은 하기 화학식 1로 표시될 수 있다.The compound according to the present invention can be represented by the following formula (1).

[화학식 1][Chemical Formula 1]

Figure 112015076880414-pat00004
Figure 112015076880414-pat00004

상기 화학식 1에서,In Formula 1,

Figure 112015076880414-pat00005
는 단일결합 또는 이중결합을 나타내고;
Figure 112015076880414-pat00005
Represents a single bond or a double bond;

A는 수소원자; C1∼C10 알킬기; C6∼C15 아릴기; 또는 S 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각 내지 6각의 헤테로아릴기를 나타내고;A is a hydrogen atom; A C 1 to C 10 alkyl group; A C 6 -C 15 aryl group; Or a five to six-membered heteroaryl group containing 1 to 2 hetero atoms selected from S and N;

R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 또는 O 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각 내지 6각의 포화 또는 부분 포화된 헤테로사이클로알킬기를 나타내고;R is a hydrogen atom; A C 1 to C 10 alkyl group; C 1 ~C 10 hydroxyalkyl group; Benzyl group; Or a five to six-membered saturated or partially saturated heterocycloalkyl group containing from one to two heteroatoms selected from O and N;

n은 0 내지 4의 정수를 나타내고;n represents an integer of 0 to 4;

상기 아릴기 또는 헤테로사이클로알킬기는 각각 할로, C1∼C10 알킬, C1∼C10 알콕시, R1-C(O)- (이때, R1은 C1∼C10 알킬 또는 C2∼C10 알케닐이다), 또는 R2-S(O)2- (이때, R2는 C1∼C10 알킬이다) 로부터 선택된 치환기로 치환 또는 비치환될 수 있다.Wherein said aryl or heterocycloalkyl group is optionally substituted with at least one substituent selected from the group consisting of halo, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, R 1 -C (O) - wherein R 1 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl), or R 2 -S (O) 2 -, wherein R 2 is C 1 -C 10 alkyl.

상기 화학식 1로 표시되는 되는 화합물에 있어서, 바람직하기로는 상기 A가 수소원자; 메틸기, 에틸기, 노말프로필기, 이소프로필기, 사이클로프로필기, 사이클로프로필메틸기, 노말부틸기, 이소부틸기, tert-부틸기, 사이클로부틸기, 노말펜틸기, 이소펜틸기, 네오펜틸기, tert-펜틸기, 사이클로펜틸기, 노말헥실기, 이소헥실기, 사이클로헥실기 및 노말헵틸기로부터 선택된 알킬기; 할로, 메틸, 에틸, 노말프로필, 이소프로필, 사이클로프로필, 메톡시 및 에톡시로부터 선택된 치환기로 치환 또는 비치환된 페닐기; 치오펜일기; 또는 피리디닐기를 나타내는 화합물이다.In the compound represented by the above formula (1), it is preferable that A is a hydrogen atom; A tert -butyl group, a cyclobutyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert -butyl group, a tert -butyl group, a tert- An alkyl group selected from a pentyl group, a cyclopentyl group, a normal hexyl group, an isohexyl group, a cyclohexyl group and a normal heptyl group; A phenyl group substituted or unsubstituted with substituents selected from halo, methyl, ethyl, normal propyl, isopropyl, cyclopropyl, methoxy and ethoxy; A thiophene group; Or a pyridinyl group.

상기 화학식 1로 표시되는 되는 화합물에 있어서, 바람직하기로는 상기 R은 수소원자; 메틸기, 에틸기, 노말프로필기, 이소프로필기, 사이클로프로필기, 사이클로프로필메틸기, 노말부틸기, 이소부틸기, tert-부틸기, 사이클로부틸기, 노말펜틸기, 이소펜틸기, 네오펜틸기, tert-펜틸기, 사이클로펜틸기, 노말헥실기, 이소헥실기, 사이클로헥실기 및 노말헵틸기로부터 선택된 알킬기; 2-메틸-2-하이드록시프로필기, 2-하이드록시부틸기 및 4-하이드록시부틸기로부터 선택된 하이드록시알킬기; 벤질기; 테트라하이드로-2H-파이란일기; 또는 R1-C(O)- 또는 R2-S(O)2- 로 치환 또는 비치환된 피페리디닐기를 나타내고, 이때 R1은 C1∼C6 알킬기 또는 C2∼C6 알케닐기이고, R2는 C1∼C6 알킬기를 나타내는 화합물이다.In the compound represented by the general formula (1), R is preferably a hydrogen atom; A tert -butyl group, a cyclobutyl group, a n-pentyl group, an isopentyl group, a neopentyl group, a tert -butyl group, a tert -butyl group, a tert- An alkyl group selected from a pentyl group, a cyclopentyl group, a normal hexyl group, an isohexyl group, a cyclohexyl group and a normal heptyl group; A hydroxyalkyl group selected from a 2-methyl-2-hydroxypropyl group, a 2-hydroxybutyl group and a 4-hydroxybutyl group; Benzyl group; Tetrahydro-2H - pyranyl group; Or a piperidinyl group substituted or unsubstituted with R 1 -C (O) - or R 2 -S (O) 2 -, wherein R 1 is a C 1 -C 6 alkyl group or a C 2 -C 6 alkenyl group , R 2 is a compound representing a C 1 ~C 6 alkyl group.

상기 화학식 1로 표시되는 되는 화합물에 있어서, 특히 바람직하기로는 상기

Figure 112015076880414-pat00006
는 이중결합을 나타내고; 상기 A는 메틸기, 에틸기, 노말프로필기, 이소프로필기, 사이클로프로필기, 치오펜-2-일기 또는 치오펜-2-일기를 나타내고; 상기 R은 메틸기, 에틸기, 노말프로필기, 이소프로필기, 사이클로프로필기, 사이클로프로필메틸기, 노말부틸기, 이소부틸기, tert-부틸기, 사이클로부틸기, 노말펜틸기, 이소펜틸기, 네오펜틸기, tert-펜틸기, 사이클로펜틸기, 노말헥실기, 이소헥실기, 사이클로헥실기 및 노말헵틸기로부터 선택된 알킬기; 2-메틸-2-하이드록시프로필기, 2-하이드록시부틸기 및 4-하이드록시부틸기로부터 선택된 하이드록시알킬기; 벤질기; 또는 테트라하이드로-2H-파이란일기를 나타내고; 상기 n은 0을 나타내는 나타내는 화합물이다.In the compound represented by Formula 1, particularly preferably,
Figure 112015076880414-pat00006
Represents a double bond; A represents a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a thiophen-2-yl group or a thiophen-2-yl group; Wherein R is a methyl group, an ethyl group, a n-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, isopentyl group, neopentyl A tert -pentyl group, a cyclopentyl group, a normal hexyl group, an isohexyl group, a cyclohexyl group and a normal heptyl group; A hydroxyalkyl group selected from a 2-methyl-2-hydroxypropyl group, a 2-hydroxybutyl group and a 4-hydroxybutyl group; Benzyl group; Or a tetrahydro-2H - pyranyl group; And n represents 0.

상기 화학식 1로 표시되는 되는 화합물을 보다 구체적으로 예시하면 하기와 같다 :The compound represented by the formula (1) is more specifically exemplified as follows:

1-이소프로필-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 1);1-Isopropyl-3- (5-phenylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 1);

1-이소프로필-3-(5-사이클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 2);1-Isopropyl-3- (5-cyclopropylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 2);

1-이소프로필-3-(5-이소프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 3);1-Isopropyl-3- (5-isopropylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 3);

3-(5-(tert-부틸)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 4);3- (5- ( tert -Butyl) isoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 4);

3-(5-사이클로펜틸이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 5);3- (5-Cyclopentylisoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 5);

3-(5-사이클로헥실이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 6);3- (5-Cyclohexylisoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 6);

1-이소프로필-3-(5-(치오펜-3-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 7);3-yl) -1 H- pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 7);

1-이소프로필-3-(5-(치오펜-2-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 8);L-isopropyl-3- (5- (thiophen-2-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 8);

3-(5-(4-플루오로페닐)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 9);3- (5- (4-Fluorophenyl) isoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 9);

1-이소프로필-3-(5-(4-메톡시페닐)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 10);L-isopropyl-3- (5- (4-methoxyphenyl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 10);

3-(5-(3-클로로페닐)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 11);3- (5- (3-Chlorophenyl) isoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 11);

3-(5-(2-클로로페닐)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 12);3- (5- (2-Chlorophenyl) isoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 12);

1-이소프로필-3-(5-(피리딘-2-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 13);L-isopropyl-3- (5- (pyridin-2-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 13);

1-이소프로필-3-(5-(피리딘-3-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 14);L-isopropyl-3- (5- (pyridin-3-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 14);

3-(5-벤질이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 15);3- (5-benzylisoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 15);

1-이소프로필-3-(5-(페닐-4,5-디하이드로이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 16);1-isopropyl-3- (5- (phenyl-4,5-Hydro-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-4-amine (Compound No. 16) ;

3-(5-페닐이속사졸-3-일)-1-(테트라하이드로-2H-파이란-4-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 17);3- (5-phenyl-3-yl) -1- (tetrahydro -2 H- Failan-4-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-4-amine ( Compound No. 17);

1-(1-(메틸설포닐)피페리딘-4-일)-3-(5-(페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 18);1- (1- (methylsulfonyl) piperidin-4-yl) -3- (5- (phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin- 4-amine (Compound No. 18);

1-(4-(4-아미노-3-(5-(페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-일)에타논 (화합물번호 19); 1- (4- (4-amino-3- (5- (phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-1-yl) piperidin-yl ) Ethanone (Compound No. 19);

(±)-1-(3-(4-아미노-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-1-일)프로프-2-엔-1-온 (화합물번호 20);(±) -1- (3- (4- amino-3- (5-phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-1-yl) piperidine 1-yl) prop-2-en-1-one (Compound No. 20);

(R)-1-(3-(4-아미노-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-1-일)프로프-2-엔-1-온 (화합물번호 21);(4-amino-3- (5-phenylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin- 1-yl) prop-2-en-1-one (Compound No. 21);

3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 22);3- (5-cyclopropyl-a-3-yl) -1 H - pyrazolo [3,4- d] pyrimidin-4-amine (Compound No. 22);

1-시클로헥실-3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 23); L -Cyclohexyl-3- (5-cyclopropylisoxazol-3-yl) -1H-pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 23);

3-(5-시클로프로필이속사졸-3-일)-1-(테트라히드로-2H-파이란-4-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 24);3- (5-cyclopropyl-a-3-yl) -1- (tetrahydro -2 H - Failan-4-yl) -1 H - pyrazolo [3,4- d] pyrimidin-4-amine (Compound No. 24);

3-(5-시클로프로필이속사졸-3-일)-1-헵틸-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 25);3- (5-Cyclopropylisoxazol-3-yl) -1-heptyl-1 H -pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 25);

3-(5-시클로프로필이속사졸-3-일)-1-메틸-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 26);3- (5-Cyclopropylisoxazol-3-yl) -1-methyl- 1H -pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 26);

1-벤질-3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 27); L -Benzyl-3- (5-cyclopropylisoxazol-3-yl) -1H-pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 27);

1-(4-아미노-3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)-2-메틸프로판-2-올 (화합물번호 28);1- (4-Amino-3- (5-cyclopropyl-a-3-yl) -1 H - pyrazolo [3,4- d] pyrimidin-1-yl) -2-methyl-propan-2 Ol (Compound No. 28);

3-(5-에틸이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 29);3- (5-Ethylisoxazol-3-yl) -1-isopropyl- 1H -pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 29);

1-이소프로필-3-(이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 30).
1-Isopropyl-3- (isoxazol-3-yl) -1 H -pyrazolo [3,4- d ] pyrimidin-4-amine (Compound No. 30).

한편, 본 발명은 상기 화학식 1로 표시되는 화합물의 제조방법을 그 특징으로 한다. 본 발명에 따른 제조방법을 구체적으로 설명하면 하기와 같다.
The present invention also provides a process for producing the compound represented by the above formula (1). The production method according to the present invention will be described in detail as follows.

제조방법 1Production Method 1

하기 반응식 1에 따른 제조방법에 의하면, 하기 화학식 2로 표시되는 화합물을 출발물질로 사용하여 4 단계의 제조과정을 수행하여 상기 화학식 1로 표시되는 화합물을 제조할 수 있다.According to the preparation method according to the following Reaction Scheme 1, the compound represented by Formula 1 can be prepared by performing a four step process using a compound represented by Formula 2 below as a starting material.

[반응식 1] [Reaction Scheme 1]

Figure 112015076880414-pat00007
Figure 112015076880414-pat00007

(상기 반응식 1에서,

Figure 112015076880414-pat00008
, A, R 및 n은 각각 상기 화학식 1에서 정의한 바와 같다)(In the above Reaction Scheme 1,
Figure 112015076880414-pat00008
, A, R and n are each as defined in the above formula (1)

상기 반응식 1에 따른 제조방법을 각 반응별로 보다 구체적으로 설명하면 하기와 같다.The production method according to Reaction Scheme 1 will be described in detail below for each reaction.

ⅰ)반응은 상기 화학식 2로 표시되는 3-브로모-1H-피라졸로[3,4-d]피리미딘-4-아민과 R-X (이때, X는 할로겐원자를 나타낸다)로 표시되는 화합물을 반응시켜, 다양한 R가 도입된 상기 화학식 3으로 표시되는 화합물을 제조하는 과정이다. 상기 ⅰ)반응은 무기염기의 존재 하에서 70℃ 내지 80℃로 가열시키는 조건으로 진행될 수 있다. 이때 무기염기는 알칼리금속 또는 토금속의 수산화물, 산화물, 탄산염, 황산염 등으로부터 선택될 수 있으며, 좋기로는 탄산칼륨과 같은 알칼리금속의 탄산염을 사용할 수 있다. 반응용매로는 통상의 유기용매가 사용될 수 있으며, 본 발명의 실시예에서는 주로 디메틸포름아미드 (DMF)를 사용한 예를 구체적으로 예시하고 있지만, 본 발명의 용매가 이에 한정되는 것은 결코 아니다.I) The reaction is carried out by reacting 3-bromo-1 H- pyrazolo [3,4- d ] pyrimidin-4-amine and RX (wherein X represents a halogen atom) To thereby prepare a compound represented by the above formula (3) in which various R's are introduced. The reaction can be carried out under the condition that i) the reaction is heated to 70 to 80 캜 in the presence of an inorganic base. In this case, the inorganic base may be selected from hydroxides, oxides, carbonates, and sulfates of alkali metals or earth metals, and preferably an alkali metal carbonate such as potassium carbonate may be used. As the reaction solvent, a conventional organic solvent can be used. In the examples of the present invention, dimethylformamide (DMF) is mainly used. However, the solvent of the present invention is not limited thereto.

ⅱ)반응은 상기 화학식 3으로 표시되는 화합물을 스틸레 반응 (Stille reaction)에 의해 비닐기가 도입된 상기 화학식 4로 표시되는 화합물을 제조하는 과정이다. 스틸레 반응은 팔라듐 (Pd) 또는 니켈 (Ni)과 같은 금속 촉매와, 유기 주석화합물을 커플링 시약으로 사용하여 환류하는 조건에서 실시한다. 상기 금속 촉매로는 대표적으로 테트라키스(트리페닐포스핀)팔라듐 [Pd(PPh3)4]을 사용할 수 있고, 유기 주석화합물으로는 대표적으로는 트리부틸비닐주석을 사용할 수 있다. 반응용매로는 톨루엔과 같은 방향족 탄화수소류를 사용할 수 있으며, 반응용매는 사용된 용매의 환류온도로서 대략 120℃ 내지 150℃ 범위일 수 있다.Ii) The reaction is a process for preparing the compound represented by Chemical Formula 4 in which the vinyl group is introduced into the compound represented by Chemical Formula 3 by Stille reaction. Stille reaction is carried out under reflux conditions using a metal catalyst such as palladium (Pd) or nickel (Ni) and an organotin compound as a coupling reagent. As the metal catalyst, tetrakis (triphenylphosphine) palladium [Pd (PPh 3 ) 4 ] can be typically used, and tributylvinyltin can be used as the organic tin compound. As the reaction solvent, aromatic hydrocarbons such as toluene may be used, and the reaction solvent may be in the range of about 120 ° C to 150 ° C as the reflux temperature of the used solvent.

ⅲ)반응은 상기 화학식 4로 표시되는 화합물의 비닐 그룹을 산화적 절단반응 (oxdative cleavage)에 의해 알데하이드 그룹으로 전환한 후에 옥심 그룹으로 전환하여, 상기 화학식 5로 표시되는 화합물을 제조하는 과정이다. 비닐 그룹을 알데하이드 그룹으로 전환하기 위한 산화적 절단반응은 오존(O3)을 이용하여 진행될 수 있다. 또한, 상기 산화적 절단반응은 촉매로서 오스뮴 테트록사이드 (OsO4)와 산화제로서 N-메틸몰폴린-N-옥시드 (NMO)를 사용하는 수산화 반응을 실시한 후에, 연이어 소듐 퍼아이오데이트 (NaIO4)와의 반응을 실시하는 조건에서 진행될 수 있다. 그리고, 알데하이드 화합물은 하이드록실아민 (NH2OH)과 에탄올 용매 하에서 반응시켜, 옥심 그룹을 도입한다.Iii) The reaction is a process of converting the vinyl group of the compound of Formula 4 into an aldehyde group by oxdative cleavage and then converting it into an oxime group to produce the compound of Formula 5. [ The oxidative cleavage reaction to convert the vinyl group to an aldehyde group can proceed using ozone (O 3 ). The oxidative cleavage reaction is carried out by carrying out a hydroxylation reaction using osmium tetroxide (OsO 4 ) as a catalyst and N -methylmorpholine- N -oxide (NMO) as an oxidizing agent, and then sodium periodate 4 ). ≪ / RTI > Then, the aldehyde compound is reacted with hydroxylamine (NH 2 OH) in an ethanol solvent to introduce an oxime group.

ⅳ)반응은 상기 화학식 5로 표시되는 화합물을 니트릴 옥시드의 고리화 첨가반응 (Nitrile oxide cycloaddition)에 의해 상기 화학식 1로 표시되는 화합물을 제조하는 과정이다. 상기 고리화 첨가반응은 (디아세톡시아이오도)벤젠 또는 페닐아이오딘 비스(트리플루오로아세테이트) 등의 하이퍼밸런트 요오드 화합물 (Hypervalent iodine compound)을 반응시약으로 사용하고, 알콜과 물의 혼합용매 하에서 상온(20℃ 내지 30℃) 조건에서 실시한다.(Iv) The reaction is a process for preparing the compound represented by the above formula (1) by a nitrile oxide cycloaddition reaction of the compound represented by the formula (5). The cyclization addition reaction may be carried out by using a hypervalent iodine compound such as (diacetoxy iodo) benzene or phenyl iodine bis (trifluoroacetate) as a reaction reagent and in a mixed solvent of alcohol and water At room temperature (20 캜 to 30 캜).

상기 반응식 1에 따른 제조방법을 수행하는 중에 합성되는 핵심 중간체 화합물로서 상기 화학식 4로 표시되는 비닐 관능기가 도입된 화합물과 상기 화학식 5로 표시되는 옥심 관능기가 도입된 화합물은 각각 신규 화합물이다. 따라서 본 발명은 하기 화학식 4 또는 화학식 5로 표시되는 중간체 화합물에도 특징이 있다.As a core intermediate compound synthesized during the production process according to Reaction Scheme 1, the compound having the vinyl functional group represented by Formula 4 and the compound having the oxime functional group represented by Formula 5 are each a novel compound. Therefore, the present invention is also characterized by an intermediate compound represented by the following general formula (4) or (5).

[화학식 4][Chemical Formula 4]

Figure 112015076880414-pat00009
Figure 112015076880414-pat00009

(상기 화학식 4에서, R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 또는 O 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각 내지 6각의 포화 또는 부분 포화된 헤테로사이클로알킬기를 나타낸다.)(Wherein R is a hydrogen atom, a C 1 to C 10 alkyl group, a C 1 to C 10 hydroxyalkyl group, a benzyl group, or a five to six-membered heterocyclic group containing 1 to 2 hetero atoms selected from O and N Saturated or partially saturated heterocycloalkyl group.

[화학식 5][Chemical Formula 5]

Figure 112015076880414-pat00010
Figure 112015076880414-pat00010

(상기 화학식 5에서, R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 또는 O 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각 내지 6각의 포화 또는 부분 포화된 헤테로사이클로알킬기를 나타낸다.)Wherein R is a hydrogen atom, a C 1 to C 10 alkyl group, a C 1 to C 10 hydroxyalkyl group, a benzyl group, or a five to six-membered heterocyclic group containing 1 to 2 hetero atoms selected from O and N Saturated or partially saturated heterocycloalkyl group.

상기 화학식 4로 표시되는 중간체 화합물은, 대표적으로 1-이소프로필-3-비닐-1H-피라졸로[3,4-d]피리미딘-4-아민이 포함될 수 있다.The intermediate compound represented by Formula 4 may typically include 1-isopropyl-3-vinyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine.

상기 화학식 5로 표시되는 중간체 화합물은, 대표적으로 (E)-4-아미노-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-3-카바알데하이드 옥심이 포함될 수 있다.
The intermediate compound represented by Formula 5 may typically include ( E ) -4-amino-1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidine-3-carbaldehyde oxime.

제조방법 2Production Method 2

하기 반응식 2에 따른 제조방법에 의하면, 하기 화학식 6으로 표시되는 말로노니트릴 화합물을 출발물질로 사용하여 3 단계의 제조과정을 수행하여 하기 화학식 1로 표시되는 화합물을 제조할 수 있다.According to the production method according to the following Reaction Scheme 2, a compound represented by the following Formula 1 can be prepared by performing the three-step preparation process using the malononitrile compound represented by the following Formula 6 as a starting material.

[반응식 2][Reaction Scheme 2]

Figure 112015076880414-pat00011
Figure 112015076880414-pat00011

(상기 반응식 2에서,

Figure 112015076880414-pat00012
, A, R 및 n은 각각 상기 화학식 1에서 정의한 바와 같다)(In the above Reaction Scheme 2,
Figure 112015076880414-pat00012
, A, R and n are each as defined in the above formula (1)

상기 반응식 2에 따른 제조방법을 각 반응별로 보다 구체적으로 설명하면 하기와 같다.The production method according to Reaction Scheme 2 will be described in detail below for each reaction.

a)반응은 상기 화학식 6으로 표시되는 말로노니트릴 화합물과 히드라진 (NH2NH2) 수화물과 고리화 반응시켜, 상기 화학식 7로 표시되는 1H-피라졸-4-카보니트릴 화합물을 제조하는 과정이다. 상기 a)반응은 메탄올, 에탄올 등의 알콜류 용매에서 상온(20℃ 내지 30℃)의 조건으로 진행될 수 있다.a) The reaction is carried out by cyclizing a malononitrile compound represented by the formula (6) and hydrazine (NH 2 NH 2 ) hydrate to prepare a 1 H -pyrazole-4-carbonitrile compound represented by the formula to be. The reaction a) may be carried out in an alcoholic solvent such as methanol, ethanol or the like at a room temperature (20 ° C to 30 ° C).

b)반응은 상기 화학식 7로 표시되는 1H-피라졸-4-카보니트릴 화합물과 포름아미드 화합물 (HC(O)NH2)을 고리화 반응시켜, 상기 화학식 8로 표시되는 1H-피라졸로[3,4-d]피리미딘-4-아민 화합물을 제조하는 과정이다. 상기 b)반응은 130℃ 내지 180℃ 온도로 가열하는 조건에서 진행될 수 있다.b) reacting the 1 H represented by the formula 7 by cyclization of the pyrazole-4-carbonitrile compound to form an amide compound (HC (O) NH 2) , 1 H represented by the formula (8) -pyrazolo [3,4-d] pyrimidin-4-amine compound. The reaction b) may be carried out under a condition of heating from 130 ° C to 180 ° C.

c)반응은 상기 화학식 8로 표시되는 1H-피라졸로[3,4-d]피리미딘-4-아민 화합물과 ROH로 표시되는 알콜 화합물을 반응시켜, 다양한 R가 도입된 상기 화학식 1로 표시되는 화합물을 제조하는 과정이다. 상기 c)반응은 트리페닐포스핀 (PPh3)과 아조디카복실레이트 화합물을 사용하는 미츠노부 반응 (Mitsunobu reaction)을 통하여 진행된다. 상기 아조디카복실레이트 화합물은 예를 들면 디에틸 아조디카복실레이트 (DEAD) 또는 디이소프로필 아조디카복실레이트 (DIAD) 등이 포함될 수 있다. 상기 미츠노부 반응은 테트라하이드로푸란과 같은 극성용매를 사용하여 상온(20℃ 내지 30℃)의 조건으로 진행될 수 있다.
c) The reaction is carried out by reacting the 1 H -pyrazolo [3,4-d] pyrimidin-4-amine compound represented by the above formula (8) with an alcohol compound represented by ROH, ≪ / RTI > The c) reaction proceeds through a Mitsunobu reaction using triphenylphosphine (PPh 3 ) and an azodicarboxylate compound. The azodicarboxylate compound may include, for example, diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD). The Mitsunobu reaction can be carried out at room temperature (20 ° C to 30 ° C) using a polar solvent such as tetrahydrofuran.

한편, 본 발명은 상기 화학식 1로 표시되는 화합물, 약학적으로 허용되는 이의 염, 이의 용매화물, 이의 수화물이 유효성분으로 포함된 약제조성물을 포함한다.Meanwhile, the present invention includes a pharmaceutical composition comprising the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as an active ingredient.

상기 화학식 1로 표시되는 화합물은 RET 키나아제에 대한 우수한 억제 활성을 나타내므로, 비정상적인 세포 성장에 의해 유발되는 질환의 예방제 또는 치료제로 사용될 수 있다.Since the compound represented by Formula 1 exhibits an excellent inhibitory activity against RET kinase, it can be used as a preventive or therapeutic agent for diseases caused by abnormal cell growth.

본 발명에서의 비정상적인 세포 성장에 의해 유발되는 암 질환은 구체적으로 갑상선암, 폐암, 유방암이 포함될 수 있다. 특히 RET 키나아제의 활성을 저해하는 효과가 우수하므로, 갑상선 수질암, 비소세포성 폐암, 유방암의 예방 및 치료제로 유용하다.Cancer diseases caused by abnormal cell growth in the present invention may specifically include thyroid cancer, lung cancer, and breast cancer. In particular, it has an excellent effect of inhibiting the activity of RET kinase, and thus is useful as a prophylactic and therapeutic agent for thyroid carcinoma, non-small cell lung cancer and breast cancer.

본 발명의 약제조성물은 상기 화학식 1로 표시되는 화합물, 약학적으로 허용되는 이의 염, 이의 용매화물, 이의 수화물을 유효성분으로 함유하고, 여기에 통상의 무독성 약제학적으로 허용 가능한 담체, 보강제 및 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구투여용 제제 또는 비경구투여용 제제로 제제화할 수 있다. The pharmaceutical composition of the present invention comprises a compound represented by the general formula (1), a pharmaceutically acceptable salt thereof, a solvate thereof, and a hydrate thereof as an active ingredient, wherein a usual non-toxic pharmaceutically acceptable carrier, adjuvant and excipient And the like can be formulated into preparations for oral administration such as tablets, capsules, troches, liquids and suspensions, or parenteral administration preparations which are customary in the pharmaceutical field.

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 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환정도에 따라 달라질 수 있으며, 몸무게가 70kg인 성인환자를 기준으로 할 때 일반적으로 0.01 ∼ 1,000 mg/일이며, 의사 또는 약사의 판단에 따라 일정 시간간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.The dose of the compound according to the present invention to the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally 0.01 To 1,000 mg / day. Depending on the judgment of a doctor or a pharmacist, it may be administered once to several times a day at a predetermined interval.

이상에서 설명한 바와 같은 본 발명은 하기 실시예, 제제예, 및 실험예에 의거하여 더욱 상세히 설명하겠는 바, 하기의 실시예, 제제예, 및 실험예는 본 발명을 예시하는 것일 뿐 본 발명의 범위가 이들에 의해 한정되는 것은 아니다.
The present invention will now be described in more detail with reference to the following examples, preparation examples and experimental examples. However, the following examples, preparation examples and experimental examples are merely illustrative of the present invention, The present invention is not limited thereto.

[실시예] 화학식 1의 화합물의 합성
EXAMPLES Synthesis of Compound (1)

실시예 1. 1-이소프로필-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 1)의 합성Example 1. Synthesis of 1-isopropyl-3- (5-phenylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00013
Figure 112015076880414-pat00013

단계 1: 3-브로모-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민Step 1: 3-Bromo-l-isopropyl - lH - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00014
Figure 112015076880414-pat00014

둥근 바닥 플라스크에 3-브로모-1-H-피라졸로[3,4-d]피리미딘-4-아민 (3 g, 14.02 mmol)과 탄산칼륨 (7.75 g, 56.1 mmol)을 가한 후 내부를 질소로 충진하였다. 충진된 플라스크에 디메틸포름아미드 (93 mL)를 가한 후, 뒤이어 2-브로모프로판 (1.45 mL, 15.4 mmol)을 가하였다. 80℃에서 12시간 동안 교반한 후, 에틸 아세테이트를 이용하여 묽힌 후 물을 이용하여 반응을 종결하고 에틸 아세테이트와 물을 이용하여 추출하였다. 모아진 유기층을 여러 번 물로 씻어준 후, 무수 황산 마그네슘으로 건조하여 여과하고, 얻은 잔사를 관 크로마토그래피 (EtOAc : n-Hexane = 1 : 2)를 실시하여 표제화합물 (2.4 g, 67% 수율)을 얻었다.To a round bottom flask inside was added to 3-bromo -1- H- pyrazolo [3,4 -d] pyrimidin-4-amine (3 g, 14.02 mmol) and potassium carbonate (7.75 g, 56.1 mmol) And filled with nitrogen. To the filled flask was added dimethylformamide (93 mL), followed by 2-bromopropane (1.45 mL, 15.4 mmol). After stirring at 80 ° C for 12 hours, the reaction mixture was diluted with ethyl acetate and the reaction was terminated by using water. The reaction mixture was extracted with ethyl acetate and water. The obtained organic layer was washed with water several times, dried over anhydrous magnesium sulfate, and filtered. The resulting residue was purified by column chromatography (EtOAc: n- Hexane = 1: 2) to give the title compound (2.4 g, 67% .

1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 5.84 (bs, 2H), 5.09 (septet, J = 6.8 Hz, 1H), 1.54 (d, J =6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.32 (s, 1H), 5.84 (bs, 2H), 5.09 (septet, J = 6.8 Hz, 1H), 1.54 (d, J = 6.8 Hz, 6H)

단계 2: 1-이소프로필-3-비닐-1H-피라졸로[3,4-d]피리미딘-4-아민 Step 2: l-Isopropyl-3-vinyl - lH - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00015
Figure 112015076880414-pat00015

둥근 바닥 플라스크에 3-브로모-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (3.99 g, 15.6 mmol)과 Pd(PPh3)4 (3.6 g, 3.12 mmol)을 가한 후 내부를 질소로 충진하였다. 톨루엔 (156 mL) 및 트리부틸비닐주석 (5.57 mL, 18.7 mmol)을 가한 후 150℃에서 3시간 동안 환류하였다. 반응이 종결된 후 상온으로 식히고 용매를 감압 증류하여 제거한 후, 테트라하이드로푸란/1 N 염산 (3/1, 160 mL)을 가하여 상온에서 12시간 동안 교반하였다. 에틸 아세테이트를 이용하여 묽힌 후, 유기층을 1 N HCl로 여러 번 추출한 후, 모아진 수층을 둥근 바닥 플라스크에 넣어 탄산수소나트륨을 이용하여 중화하였다. 이후 얻은 수층을 염화메틸렌 용매로 추출한 후, 무수 황산 마그네슘으로 건조하여 여과하고, 얻은 잔사를 관 크로마토그래피 (EtOAc : n-Hexane = 1 : 1)를 실시하여 표제화합물 (2.59 g, 82% 수율)을 얻었다.To a round bottom flask was added 3-bromo-1-isopropyl -1 H- pyrazolo [3,4 -d] pyrimidin-4-amine (3.99 g, 15.6 mmol) and Pd (PPh 3) 4 (3.6 g, 3.12 mmol), and the inside was filled with nitrogen. Toluene (156 mL) and tributylvinyltin (5.57 mL, 18.7 mmol) were added thereto, followed by reflux at 150 ° C for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. To the residue was added tetrahydrofuran / 1 N hydrochloric acid (3/1, 160 mL) and the mixture was stirred at room temperature for 12 hours. After diluting with ethyl acetate, the organic layer was extracted several times with 1 N HCl, and the combined aqueous layers were neutralized with a sodium bicarbonate solution in a round bottom flask. The resulting residue was purified by column chromatography (EtOAc: n- Hexane = 1: 1) to give the title compound (2.59 g, 82% yield). MS: m / ≪ / RTI >

1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.25 (s, 1H), 6.97 (dd, J = 11.2 Hz, 18.0 Hz, 1H), 5.93 (d, J = 18.0 Hz, 1H), 5.65-5.62 (m, 3H), 5.10 (septet, J = 6.8 Hz, 1H), 1.54 (d, J =6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.33 (s, 1H), 7.25 (s, 1H), 6.97 (dd, J = 11.2 Hz, 18.0 Hz, 1H), 5.93 (d, J = 18.0 Hz, 1H ), 5.65-5.62 (m, 3H), 5.10 (septet, J = 6.8 Hz, 1H), 1.54 (d, J = 6.8 Hz,

단계 3: (E)-4-아미노-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-3-카바알데하이드 옥심 Step 3: ( E ) -4-Amino-l-isopropyl - lH - pyrazolo [3,4- d ] pyrimidine- 3-carbaldehyde oxime

Figure 112015076880414-pat00016
Figure 112015076880414-pat00016

둥근 바닥 플라스크에 1-이소프로필-3-비닐-1H-피라졸로[3,4-d]피리미딘-4-아민 (2.07 g, 10.19 mmol)을 넣고, 테트라하이드로푸란/물 (3/1, 140 mL)을 가하여 녹였다. 이후 0 ℃에서 N-메틸몰폴린-N-옥사이드 (4.77 mL, 20.38 mmol, 50 w/w% in 물)와 오스뮴 테트록사이드 (OsO4; 6.5 mL, 1.02 mmol, 4 w/w% in H2O)를 가하였다. 3시간 동안 상온에서 교반한 후, 아황산나트륨 용액을 이용하여 반응을 종결시킨 후, 클로로포름/이소프로필알콜 (4/1) 용매를 이용하여 수층을 여러 번 추출하였다. 모아진 유기용매를 감압 증류하여 건조한 후, 얻어진 잔사를 테트라하이드로푸란/물 (3/1, 140 mL)를 가하여 녹였다. 이후, 소듐 퍼아이오데이트 (NaIO4; 4.36 g, 20.38 mmol)을 가한 후 2시간 동안 상온에서 교반하였다. 반응이 종결된 후, 셀라이트를 이용하여 부유물을 여과한 후, 얻어진 잔사에 에탄올 (16 mL)을 가하였다. 이후 아세트산나트륨 (2 g, 24.46 mmol)과 하이드록실아민 염산염(841 mg, 25.48 mmol)을 가한 후 12시간 동안 상온에서 교반하였다. 용매를 감압 증류하여 제거한 후, 에틸 아세테이트와 물을 이용하여 추출하였다. 모아진 유기층을 여러 번 물로 씻어준 후, 무수 황산 마그네슘으로 건조하여 여과하고, 얻은 잔사를 관 크로마토그래피 (EtOAc : n-Hexane = 2 : 1)를 실시하여 표제화합물 (2 g, 89% 수율)을 얻었다.3-vinyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine (2.07 g, 10.19 mmol) was added to a round bottom flask, and tetrahydrofuran / water , 140 mL). In subsequent 0 ℃ N - methyl morpholine - N - oxide (4.77 mL, 20.38 mmol, 50 w / w% in water) and osmium tetroxide (OsO 4; 6.5 mL, 1.02 mmol, 4 w / w% in H 2 O). After stirring for 3 hours at room temperature, the reaction was terminated using sodium sulfite solution, and the aqueous layer was extracted several times with chloroform / isopropyl alcohol (4/1) solvent. The collected organic solvent was distilled under reduced pressure, and the residue was dissolved in tetrahydrofuran / water (3/1, 140 mL). Then, sodium periodate (NaIO 4 ; 4.36 g, 20.38 mmol) was added thereto, followed by stirring at room temperature for 2 hours. After the reaction was completed, the suspension was filtered using celite, and ethanol (16 mL) was added to the obtained residue. Subsequently, sodium acetate (2 g, 24.46 mmol) and hydroxylamine hydrochloride (841 mg, 25.48 mmol) were added thereto, followed by stirring at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate and water. The obtained organic layer was washed with water several times, dried over anhydrous magnesium sulfate and filtered. The resulting residue was subjected to column chromatography (EtOAc: n- Hexane = 2: 1) to give the title compound (2 g, 89% .

1H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 8.31 (s, 1H), 8.17 (bs, 1H), 5.81 (bs, 1H), 5.12 (septet, J = 6.8 Hz, 1H), 1.54 (d, J = 6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.39 (s, 1H), 8.31 (s, 1H), 8.17 (bs, 1H), 5.81 (bs, 1H), 5.12 (septet, J = 6.8 Hz, 1H) , 1.54 (d, J = 6.8 Hz, 6H)

단계 4: 1-이소프로필-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민Step 4: 1-Isopropyl-3- (5-phenylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00017
Figure 112015076880414-pat00017

둥근 바닥 플라스크에 (E)-4-아미노-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-3-카바알데하이드 옥심(220 mg, 1 mmol)을 가한 후, 메탄올/물(8.0 mL/1.6 mL) 혼합용매를 가하여 녹였다. 이후 에티닐벤젠 (0.15 mL, 1.1 mmol)을 가한 후, 페닐아이오딘 비스(트리플루오로아세테이트) (PIFA)를 2시간동안 3번에 걸쳐서 가하였다 (각각 215 mg, 0.5 mmol). 이후 4시간 동안 교반하고, 에틸 아세테이트를 이용하여 추출하였다. 모아진 유기층을 물로 여러 번 씻은 후, 무수 황산 마그네슘으로 건조하여 여과하고, 얻은 잔사를 관 크로마토그래피 (EtOAc : n-Hexane = 1 : 2)를 실시하여 표제화합물 (134 mg, 42% 수율)을 얻었다.Was added to a round bottom flask was added (E) -4- amino-1-isopropyl -1 H- pyrazolo [3,4 -d] pyrimidin-3-carbazole aldehyde oxime (220 mg, 1 mmol), methanol / And dissolved in a mixed solvent of water (8.0 mL / 1.6 mL). After the addition of thionylbenzene (0.15 mL, 1.1 mmol), phenyl iodine bis (trifluoroacetate) (PIFA) was added over 3 h (215 mg, 0.5 mmol each) over 2 h. Then, the mixture was stirred for 4 hours and extracted with ethyl acetate. The obtained organic layer was washed with water several times, dried over anhydrous magnesium sulfate, and filtered. The resulting residue was subjected to column chromatography (EtOAc: n- Hexane = 1: 2) to give the title compound (134 mg, 42% .

1H NMR (400 MHz, CDCl3) δ 8.91 (bs, 1H), 8.32 (s, 1H), 7.88-7.86 (m, 2H), 7.54-7.26 (m, 3H), 7.19 (s, 1H), 6.91 (bs, 1H), 5.19 (septet, J = 6.8 Hz, 1H), 1.61 (d, J =6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.91 (bs, 1H), 8.32 (s, 1H), 7.88-7.86 (m, 2H), 7.54-7.26 (m, 3H), 7.19 (s, 1H), 6.91 (bs, 1H), 5.19 (septet, J = 6.8 Hz, 1H), 1.61 (d, J = 6.8 Hz, 6H)

실시예 2 ∼ 16.Examples 2-16.

상기 실시예 1의 단계 4에 예시된 방법에 의거하여, (E)-4-아미노-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-3-카바알데하이드 옥심과 다양한 아세틸렌 화합물을 사용하여 니트릴 옥시드 고리화 첨가반응 (Nitrlie oxide cycloaddition)을 실시하여 각각의 표제 화합물을 합성하였다.
( E ) -4-Amino-1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidine-3-carbaldehyde oxime with a variety of diastereoisomers according to the method illustrated in step 4 of Example 1, Nitrile oxide cycloaddition was carried out using an acetylene compound to synthesize the respective title compounds.

실시예 2. 1-이소프로필-3-(5-사이클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 2)의 합성Example 2. Synthesis of 1-isopropyl-3- (5-cyclopropylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00018
Figure 112015076880414-pat00018

1H NMR (400 MHz, CDCl3) δ 8.72 (bs, 1H), 8.27 (s, 1H), 6.86 (bs, 1H), 6.52 (s, 1H), 5.11 (sep, J = 6.8 Hz, 1H), 2.11-2.04 (m, 1H), 1.53 (d, J = 6.8 Hz, 6H), 1.13-0.99 (m, 4H)
 1 H NMR (400 MHz, CDCl 3) δ 8.72 (bs, 1H), 8.27 (s, 1H), 6.86 (bs, 1H), 6.52 (s, 1H), 5.11 (sep, J = 6.8 Hz, 1H) , 2.11-2.04 (m, 1H), 1.53 (d, J = 6.8 Hz, 6H), 1.13-0.99 (m, 4H)

실시예 3. 1-이소프로필-3-(5-이소프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 3)의 합성Example 3. Synthesis of 1-isopropyl-3- (5-isopropylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00019
Figure 112015076880414-pat00019

1H NMR (400 MHz, CDCl3) δ 8.66 (bs, 1H), 8.33 (s, 1H), 6.64 (d, J = 0.8 Hz, 1H), 5.88 (bs, 1H), 5.15 (sep, J = 6.8 Hz, 1H), 3.16 (sep, J = 7.2 Hz, 1H), 1.58 (d, J = 6.8 Hz, 6H), 1.39 (d, J = 6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.66 (bs, 1H), 8.33 (s, 1H), 6.64 (d, J = 0.8 Hz, 1H), 5.88 (bs, 1H), 5.15 (sep, J = 6.8 Hz, 1H), 3.16 ( sep, J = 7.2 Hz, 1H), 1.58 (d, J = 6.8 Hz, 6H), 1.39 (d, J = 6.8 Hz, 6H)

실시예 4. 3-(5-(tert-부틸)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 4)의 합성Example 4. 3- (5- (tert - butyl) isoxazol-3-yl) -1-isopropyl -1 H- pyrazolo [3,4 -d] pyrimidin-4-amine (Compound No. 4) Synthesis of

Figure 112015076880414-pat00020
Figure 112015076880414-pat00020

1H NMR (400 MHz, CDCl3) δ 8.67 (bs, 1H), 8.33 (s, 1H), 6.63 (s, 1H), 5.85 (bs, 1H), 5.17 (sep, J = 6.8 Hz, 1H), 3.16 (sep, J = 7.2 Hz, 1H), 1.58 (d, J = 6.8 Hz, 6H), 1.43 (s, 9H)
 1 H NMR (400 MHz, CDCl 3) δ 8.67 (bs, 1H), 8.33 (s, 1H), 6.63 (s, 1H), 5.85 (bs, 1H), 5.17 (sep, J = 6.8 Hz, 1H) , 3.16 (sep, J = 7.2 Hz, 1H), 1.58 (d, J = 6.8 Hz, 6H)

실시예 5. 3-(5-사이클로펜틸이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 5)의 합성Example 5. Synthesis of 3- (5-cyclopentylisoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00021
Figure 112015076880414-pat00021

1H NMR (400 MHz, CDCl3) δ 8.67 (bs, 1H), 8.33 (s, 1H), 6.64 (s, 1H), 5.93 (bs, 1H), 5.15 (sep, J = 6.4 Hz, 1H), 3.27 (quin, J = 7.2 Hz, 1H), 2.18-2.12 (m, 2H), 1.82-1.72 (m, 6H), 1.57 (d, J = 6.4 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.67 (bs, 1H), 8.33 (s, 1H), 6.64 (s, 1H), 5.93 (bs, 1H), 5.15 (sep, J = 6.4 Hz, 1H) , 3.27 (quin, J = 7.2 Hz, 1H), 2.18-2.12 (m, 2H), 1.82-1.72 (m, 6H), 1.57 (d, J = 6.4 Hz,

실시예 6. 3-(5-사이클로헥실이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 6)의 합성Example 6. Synthesis of 3- (5-cyclohexylisoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00022
Figure 112015076880414-pat00022

1H NMR (400 MHz, CDCl3) δ 8.67 (bs, 1H), 8.33 (s, 1H), 6.62 (s, 1H), 5.94 (bs, 1H), 5.15 (sep, J = 6.8 Hz, 1H), 2.85 (tt, J = 3.6 Hz, 10.8 Hz, 1H), 2.14-2.11 (m, 2H), 1.85 (dt, J = 3.6 Hz, 9.6 Hz, 2H), 1.77-1.73 (m, 1H), 1.58 (d, J = 6.8 Hz, 6H), 1.56-1.25 (m, 5H)
 1 H NMR (400 MHz, CDCl 3) δ 8.67 (bs, 1H), 8.33 (s, 1H), 6.62 (s, 1H), 5.94 (bs, 1H), 5.15 (sep, J = 6.8 Hz, 1H) , 2.85 (tt, J = 3.6 Hz, 10.8 Hz, 1H), 2.14-2.11 (m, 2H), 1.85 (dt, J = 3.6 Hz, 9.6 Hz, 2H), 1.77-1.73 (m, 1H), 1.58 (d, J = 6.8 Hz, 6H), 1.56-1.25 (m, 5H)

실시예 7. 1-이소프로필-3-(5-(치오펜-3-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 7)의 합성Example 7. Synthesis of 1-isopropyl-3- (5- (thiophen-3-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin- No. 7)

Figure 112015076880414-pat00023
Figure 112015076880414-pat00023

1H NMR (400 MHz, CDCl3) δ 8.61 (bs, 1H), 8.35 (s, 1H), 7.87 (dd, J = 1.2 Hz, 2.8 Hz, 1H), 7.49 (dd, J = 1.2 Hz, 4.8 Hz, 1H), 7.46 (dd, J = 2.8 Hz, 4.8 Hz, 1H), 7.04 (s, 1H), 5.18 (sep, J = 6.4 Hz, 1H), 1.59 (d, J = 6.4 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.61 (bs, 1H), 8.35 (s, 1H), 7.87 (dd, J = 1.2 Hz, 2.8 Hz, 1H), 7.49 (dd, J = 1.2 Hz, 4.8 Hz, 1H), 7.46 (dd , J = 2.8 Hz, 4.8 Hz, 1H), 7.04 (s, 1H), 5.18 (sep, J = 6.4 Hz, 1H), 1.59 (d, J = 6.4 Hz, 6H)

실시예 8. 1-이소프로필-3-(5-(치오펜-2-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 8)의 합성Example 8. Synthesis of 1-isopropyl-3- (5- (thiophen-2-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin- No. 8)

Figure 112015076880414-pat00024
Figure 112015076880414-pat00024

1H NMR (400 MHz, CDCl3) δ 8.57 (bs, 1H), 8.35 (s, 1H), 7.61 (dd, J = 0.8 Hz, 4.0 Hz, 1H), 7.52 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.18 (dd, J = 4.0 Hz, 5.2 Hz, 1H), 5.87 (bs, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 1.60 (d, J = 6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.57 (bs, 1H), 8.35 (s, 1H), 7.61 (dd, J = 0.8 Hz, 4.0 Hz, 1H), 7.52 (dd, J = 1.2 Hz, 5.2 Hz, 1H), 7.18 (dd , J = 4.0 Hz, 5.2 Hz, 1H), 5.87 (bs, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 1.60 (d, J = 6.8 Hz, 6H)

실시예 9. 3-(5-(4-플루오로페닐)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 9)의 합성Example 9 Synthesis of 3- (5- (4-fluorophenyl) isoxazol-3-yl) -l-isopropyl-lH - pyrazolo [3,4- d ] pyrimidin- 9) Synthesis of

Figure 112015076880414-pat00025
Figure 112015076880414-pat00025

1H NMR (400 MHz, CDCl3) δ 8.59 (bs, 1H), 8.35 (s, 1H), 7.88-7.84 (m. 2H), 7.21 (t, J = 8.8 Hz, 2H), 7.14 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 5.84 (bs, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 1.59 (d, J = 6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.59 (bs, 1H), 8.35 (s, 1H), 7.88-7.84 (m. 2H), 7.21 (t, J = 8.8 Hz, 2H), 7.14 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 5.84 (bs, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 1.59 (d, J = 6.8 Hz, 6H)

실시예 10. 1-이소프로필-3-(5-(4-메톡시페닐)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 10)의 합성Example 10 1-Isopropyl-3- (5- (4-methoxyphenyl) isoxazol-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-4-amine (Compound No. 10)

Figure 112015076880414-pat00026
Figure 112015076880414-pat00026

1H NMR (400 MHz, CDCl3) δ 8.68 (bs, 1H), 8.35 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 7.02 (d, J = 8.8 Hz, 2H), 5.83 (bs, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 3.89 (s, 3H), 1.60 (d, J = 6.4 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.68 (bs, 1H), 8.35 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.08 (s, 1H), 7.02 (d, J = J = 6.8 Hz, 1H), 3.89 (s, 3H), 1.60 (d, J = 6.4 Hz, 6H)

실시예 11. 3-(5-(3-클로로페닐)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 11)의 합성Example 11 3- (5- (3-Chlorophenyl) isoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin- ) Synthesis of

Figure 112015076880414-pat00027
Figure 112015076880414-pat00027

1H NMR (400 MHz, CDCl3) δ 8.55 (bs, 1H), 8.35 (s, 1H), 7.86 (s, 1H), 7.77-7.74 (m, 1H), 7.48-7.45 (m, 2H), 7.23 (s, 1H), 5.90 (bs, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 1.59 (d, J = 6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.55 (bs, 1H), 8.35 (s, 1H), 7.86 (s, 1H), 7.77-7.74 (m, 1H), 7.48-7.45 (m, 2H), (S, 1H), 5.90 (bs, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 1.59 (d, J = 6.8 Hz,

실시예 12. 3-(5-(2-클로로페닐)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 12)의 합성Example 12. Synthesis of 3- (5- (2-chlorophenyl) isoxazol-3-yl) -l-isopropyl-lH - pyrazolo [3,4- d ] pyrimidin- ) Synthesis of

Figure 112015076880414-pat00028
Figure 112015076880414-pat00028

1H NMR (400 MHz, CDCl3) δ 8.59 (bs, 1H), 8.36 (s, 1H), 7.99-7.98 (m, 1H), 7.58-7.56 (m, 2H) 7.48-7.42 (m, 2H), 5.82 (bs, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 1.61 (d, J = 6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.59 (bs, 1H), 8.36 (s, 1H), 7.99-7.98 (m, 1H), 7.58-7.56 (m, 2H) 7.48-7.42 (m, 2H) , 5.82 (bs, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 1.61 (d, J = 6.8 Hz,

실시예 13. 1-이소프로필-3-(5-(피리딘-2-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 트리플루오로아세트산염 (화합물번호 13)의 합성Example 13. Synthesis of l-isopropyl-3- (5- (pyridin-2-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin- Synthesis of acetic acid salt (Compound No. 13)

Figure 112015076880414-pat00029
Figure 112015076880414-pat00029

1H NMR (400 MHz, CDCl3) δ 9.67 (bs, 1H), 8.75-8.74 (m, 1H), 8.30 (s, 1H), 7.99-7.97 (m, 1H), 7.89 (td, J = 1.6 Hz, 8.0 Hz, 1H), 7.57 (s, 1H), 7.43-7.39 (m, 1H), 5.18 (sep, J = 6.8 Hz, 1H), 1.61 (d, J = 6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 9.67 (bs, 1H), 8.75-8.74 (m, 1H), 8.30 (s, 1H), 7.99-7.97 (m, 1H), 7.89 (td, J = 1.6 J = 6.8 Hz, 1H), 1.61 (d, J = 6.8 Hz, 6H), 7.57 (s, 1H), 7.43-7.39

실시예 14. 1-이소프로필-3-(5-(피리딘-3-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 14)의 합성Example 14 Synthesis of 1-isopropyl-3- (5- (pyridin-3-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin- 14)

Figure 112015076880414-pat00030
Figure 112015076880414-pat00030

1H NMR (400 MHz, CDCl3) δ 9.13 (dd, J = 0.8 Hz, 2.0 Hz, 1H), 8.73 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 8.52 (bs, 1H), 8.36 (s, 1H), 8.16 (dt, J = 2.0 Hz, 8.0 Hz, 1H), 7.47 (ddd, J = 0.4 Hz, 4.8 Hz, 7.6 Hz, 1H), 7.30 (s, 1H), 5.83 (bs, 1H), 5.19 (sep, J = 6.8 Hz, 1H), 1.60 (d, J = 6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 9.13 (dd, J = 0.8 Hz, 2.0 Hz, 1H), 8.73 (dd, J = 1.6 Hz, 4.8 Hz, 1H), 8.52 (bs, 1H), 8.36 ( (s, 1H), 8.16 (dt, J = 2.0 Hz, 8.0 Hz, 1H), 7.47 (ddd, J = 0.4 Hz, 4.8 Hz, 7.6 Hz, 1H) ), 5.19 (sep, J = 6.8 Hz, 1H), 1.60 (d, J = 6.8 Hz,

실시예 15. 3-(5-벤질이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 15)의 합성Example 15. Synthesis of 3- (5-benzylisoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00031
Figure 112015076880414-pat00031

1H NMR (400 MHz, CDCl3) δ 8.60 (bs, 1H), 8.31 (s, 1H), 7.39-7.26 (m, 5H), 6.61 (s, 1H), 5.81 (bs, 1H), 5.14 (sep, J = 6.8 Hz, 1H), 4.15 (s, 2H), 1.54 (d, J = 6.4 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.60 (bs, 1H), 8.31 (s, 1H), 7.39-7.26 (m, 5H), 6.61 (s, 1H), 5.81 (bs, 1H), 5.14 ( sep, J = 6.8 Hz, 1H ), 4.15 (s, 2H), 1.54 (d, J = 6.4 Hz, 6H)

실시예 16. 1-이소프로필-3-(5-(페닐-4,5-디하이드로이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 16)의 합성Example 16. Synthesis of l-isopropyl-3- (5- (phenyl-4,5-dihydroisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin- Compound No. 16)

Figure 112015076880414-pat00032
Figure 112015076880414-pat00032

1H NMR (400 MHz, CDCl3) δ 8.42 (bs, 1H), 8.32 (s, 1H), 7.41-7.34 (m, 5H), 5.94 (bs, 1H), 5.78 (dd, J = 8.8 Hz, 11.2 Hz, 1H), 5.11 (sep, J = 6.8 Hz, 1H), 3.98 (dd, J = 11.2 Hz, 17.6 Hz, 1H), 3.57 (dd, J = 8.4 Hz, 17.6 Hz, 1H), 1.52 (t, J = 7.2 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.42 (bs, 1H), 8.32 (s, 1H), 7.41-7.34 (m, 5H), 5.94 (bs, 1H), 5.78 (dd, J = 8.8 Hz, J = 6.8 Hz, 1H), 3.98 (dd, J = 11.2 Hz, 17.6 Hz, 1H), 3.57 (dd, J = 8.4 Hz, 17.6 Hz, 1H), 1.52 t, J = 7.2 Hz, 6H)

실시예 17. 3-(5-페닐이속사졸-3-일)-1-(테트라하이드로-2H-파이란-4-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 17)의 합성Example 17. 3- (5-phenyl-3-yl) -1- (tetrahydro -2 H- Failan-4-yl) -1 H- pyrazolo [3,4 -d] pyrimidin- Synthesis of 4-amine (Compound No. 17)

Figure 112015076880414-pat00033

Figure 112015076880414-pat00033

단계 1: 2-(메톡시(5-페닐이속사졸-3-일)메틸렌)말로노니트릴 Step 1: 2- (Methoxy (5-phenylisoxazol-3-yl) methylene) malononitrile

Figure 112015076880414-pat00034
Figure 112015076880414-pat00034

둥근 바닥 플라스크에 5-페닐이속사졸-3-카복실산 (2 g, 10.57 mmol)을 가한 후 내부를 질소로 충진하였다. 충진된 플라스크에 메틸렌 클로라이드 (35 mL)와 촉매량의 디메틸포름아미드 (5 방울)를 가한 후, 옥살릴 클로라이드 (4.53 mL, 52.85 mmol)를 천천히 가하였다. 상온에서 2시간 동안 교반한 후, 감압 건조하여 얻은 잔사를 정제 없이 다음반응에 바로 이용하였다.5-Phenylisoxazole-3-carboxylic acid (2 g, 10.57 mmol) was added to a round bottom flask and the inside was filled with nitrogen. Methylene chloride (35 mL) and a catalytic amount of dimethylformamide (5 drops) were added to the flask, and oxalyl chloride (4.53 mL, 52.85 mmol) was added slowly. After stirring at room temperature for 2 hours, the residue was dried under reduced pressure and used directly for the next reaction without purification.

둥근 바닥 플라스크에 소듐 하이드라이드 (845 mg, 21.14 mmol)와 말로노니트릴 (768 mg, 11.63 mmol)을 가하고 질소로 충진한 후 테트라하이드로푸란 (35 mL)을 가하였다. 0 ℃로 냉각한 후, 이전에 얻은 잔사를 테트라하이드로푸란 용액 (20 mL)에 녹여 천천히 반응용액에 적가하였다. 22시간 동안 교반한 후, 디이소프로필에틸아민 (7.3 mL, 42.28 mmol)과 디메틸설페이트 (8 mL, 84.56 mmol)을 가한 후 90℃로 가온, 교반하였다. 12시간 동안 교반한 후, 물을 이용하여 반응을 종결시키고, 에틸 아세테이트와 물을 이용하여 추출하였다. 모아진 유기층을 여러 번 물로 씻어준 후, 무수 황산 마그네슘으로 건조하여 여과하여 표제 화합물을 얻었다.Sodium hydride (845 mg, 21.14 mmol) and malononitrile (768 mg, 11.63 mmol) were added to a round-bottomed flask, which was filled with nitrogen and then tetrahydrofuran (35 mL) was added. After cooling to 0 ° C, the previously obtained residue was dissolved in a tetrahydrofuran solution (20 mL) and slowly added dropwise to the reaction solution. After stirring for 22 hours, diisopropylethylamine (7.3 mL, 42.28 mmol) and dimethyl sulfate (8 mL, 84.56 mmol) were added and the mixture was warmed to 90 ° C and stirred. After stirring for 12 hours, the reaction was terminated with water and extracted with ethyl acetate and water. The combined organic layers were washed several times with water, dried over anhydrous magnesium sulfate and filtered to give the title compound.

1H NMR (400 MHz, CDCl3) δ 7.81-7.79 (m, 2H), 7.51-7.26 (m, 3H), 6.88 (s, 1H), 4.20 (s, 3H)
1 H NMR (400 MHz, CDCl 3) δ 7.81-7.79 (m, 2H), 7.51-7.26 (m, 3H), 6.88 (s, 1H), 4.20 (s, 3H)

단계 2: 5-아미노-3-(5-페닐이속사졸-3-일)-1H-피라졸-4-카보니트릴Step 2: 5-Amino-3- (5-phenylisoxazol-3-yl) -lH - pyrazole-4-carbonitrile

Figure 112015076880414-pat00035
Figure 112015076880414-pat00035

둥근 바닥 플라스크에 2-(메톡시(5-페닐이속사졸-3-일)메틸렌)말로노니트릴 (2.66 g, 10.57 mmol)을 가한 후, 상온에서 에탄올 (30 mL)를 가하였다. 반응 용액에 히드라진 수화물 (0.4 mL, 11.1 mmol)을 가한 후 12시간 동안 교반하였다. 이후, 물을 가하여 반응을 종결시킨 후, 이소프로필알콜/클로로포름 용액을 이용하여 추출하고, 무수 황산 마그네슘으로 건조하였다. 얻은 잔사를 에틸 아세테이트, 메틸렌 클로라이드로 수차례 씻어주어 표제 화합물을 얻었다.To the round bottom flask was added 2- (methoxy (5-phenylisoxazol-3-yl) methylene) malononitrile (2.66 g, 10.57 mmol), followed by ethanol (30 mL) at room temperature. Hydrazine hydrate (0.4 mL, 11.1 mmol) was added to the reaction solution, followed by stirring for 12 hours. Thereafter, water was added to terminate the reaction, followed by extraction with isopropyl alcohol / chloroform solution and drying with anhydrous magnesium sulfate. The resulting residue was washed several times with ethyl acetate and methylene chloride to give the title compound.

1H NMR (400 MHz, DMSO) δ 12.61 (bs, 2H), 7.94 (dd, J = 2.0 Hz, 8.0 Hz, 2H), 7.57-7.52 (m, 3H), 7.29 (s, 1H), 6.60 (bs, 1H)
 1 H NMR (400 MHz, DMSO ) δ 12.61 (bs, 2H), 7.94 (dd, J = 2.0 Hz, 8.0 Hz, 2H), 7.57-7.52 (m, 3H), 7.29 (s, 1H), 6.60 ( bs, 1H)

단계 3: 3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민Step 3: 3- (5-Phenylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00036
Figure 112015076880414-pat00036

둥근 바닥 플라스크에 5-아미노-3-(5-페닐이속사졸-3-일)-1H-피라졸-4-카보니트릴 (220 mg, 0.88 mmol)과 포름아미드 (4 mL)를 가한 후, 160 ℃에서 6시간동안 교반하였다. 서서히 고체가 생기면 온도를 상온으로 낮추고 물을 가하여 반응을 종결시켰다. 얻은 고체를 물, 클로로포름, 에탄올로 수차례 씻어주어 표제 화합물을 얻었다.(5-phenylisoxazol-3-yl) -1H - pyrazole-4-carbonitrile (220 mg, 0.88 mmol) and formamide (4 mL) were added to a round bottom flask , And the mixture was stirred at 160 DEG C for 6 hours. When a solid was gradually formed, the temperature was lowered to room temperature and water was added to terminate the reaction. The obtained solid was washed several times with water, chloroform and ethanol to obtain the title compound.

1H NMR (400 MHz, DMSO) δ 14.04 (bs, 1H), 8.22 (s, 1H), 8.05 (bs, 2H), 8.00 (dd, J = 2.0 Hz, 8.0 Hz, 2H), 7.63 (s, 1H), 7.60-7.53 (m, 3H)
 1 H NMR (400 MHz, DMSO ) δ 14.04 (bs, 1H), 8.22 (s, 1H), 8.05 (bs, 2H), 8.00 (dd, J = 2.0 Hz, 8.0 Hz, 2H), 7.63 (s, 1H), < / RTI > 7.60-7.53 (m, 3H)

단계 4: 3-(5-페닐이속사졸-3-일)-1-(테트라하이드로-2H-파이란-4-일)-1H-피라졸로[3,4-d]피리미딘-4-아민Step 4: 3- (5-phenyl-3-yl) -1- (tetrahydro -2 H- Failan-4-yl) -1 H- pyrazolo [3,4 -d] pyrimidin -4 - amine

Figure 112015076880414-pat00037
Figure 112015076880414-pat00037

둥근 바닥 플라스크에 4-하이드록시파이란 (17 mg, 0.108 mmol)과 3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (15 mg, 0.054 mmol), 트리페닐포스핀 (21 mg, 0.081 mmol)을 가한 후, 테트라하이드로푸란 (2 mL)를 가하여 녹였다. 이후 디이소프로필 아조디카복실레이트 (DIAD; 0.002 mL, 0.081 mmol)를 천천히 가하였다. 2시간 동안 교반한 후, 물을 가하여 반응을 종결시킨 후, 에틸 아세테이트를 이용하여 추출하였다. 모아진 유기층을 물로 여러 번 씻은 후, 무수 황산 마그네슘으로 건조하여 여과하고, 얻은 잔사는 관 크로마토그래피 (EtOAc : n-Hexane = 2 : 1)를 실시하여 표제화합물을 얻었다.(17 mg, 0.108 mmol) and 3- (5-phenylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine (15 mg, 0.054 mmol) and triphenylphosphine (21 mg, 0.081 mmol) were added thereto, followed by dissolution in tetrahydrofuran (2 mL). Diisopropyl azodicarboxylate (DIAD; 0.002 mL, 0.081 mmol) was then slowly added. After stirring for 2 hours, water was added to terminate the reaction, followed by extraction with ethyl acetate. The collected organic layer was washed with water several times, dried over anhydrous magnesium sulfate, and filtered. The obtained residue was subjected to column chromatography (EtOAc: n- Hexane = 2: 1) to obtain the title compound.

1H NMR (400 MHz, CDCl3) δ 8.46 (bs, 1H), 8.34 (s, 1H), 7.88-7.84 (m, 2H), 7.53-7.47 (m, 3H), 7.16 (s, 1H), 5.81 (bs, 1H), 5.01 (tt, J = 4.0 Hz, 12.0 Hz, 1H), 4.15 (dd, J = 4.0 Hz, 11.2 Hz, 2H), 3.63 (td, J = 2.0 Hz, 12.0 Hz, 2H), 2.42 (qd, J = 4.4 Hz, 12.4 Hz, 2H), 2.03-1.95 (m, 2H)
1 H NMR (400 MHz, CDCl 3) δ 8.46 (bs, 1H), 8.34 (s, 1H), 7.88-7.84 (m, 2H), 7.53-7.47 (m, 3H), 7.16 (s, 1H), 5.81 (bs, 1H), 5.01 (tt, J = 4.0 Hz, 12.0 Hz, 1H), 4.15 (dd, J = 4.0 Hz, 11.2 Hz, 2H), 3.63 (td, J = 2.0 Hz, 12.0 Hz, 2H ), 2.42 (qd, J = 4.4 Hz, 12.4 Hz, 2H), 2.03-1.95 (m, 2H)

실시예 18 ∼ 20.Examples 18-20.

상기 실시예 17의 단계 4에 예시된 방법에 의거하여, 3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민과 다양한 알코올 화합물을 사용하여 미츠노부 반응 (Mitsunobu reaction)을 실시하여 각각의 표제 화합물을 합성하였다.
On the basis of the method illustrated in Step 4 of Example 17, 3- (5-phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-4-amine with various Mitsunobu reaction was carried out using an alcohol compound to synthesize the respective title compounds.

실시예 18. 1-(1-(메틸설포닐)피페리딘-4-일)-3-(5-(페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 18)의 합성Example 18. 1- (1- (methylsulfonyl) piperidin-4-yl) -3- (5- (phenyl-3-yl) -1 H- pyrazolo [3,4 -d ] Pyrimidin-4-amine (Compound No. 18)

Figure 112015076880414-pat00038
Figure 112015076880414-pat00038

1H NMR (400 MHz, CDCl3) δ 8.68 (bs, 1H), 8.34 (s, 1H), 7.87-7.85 (m, 2H), 7.54-7.49 (m, 3H), 7.16 (s, 1H), 5.88 (bs, 1H), 4.92 (tt, J = 4.4 Hz, 11.6 Hz, 1H), 4.01 (d, J = 12.0 Hz, 2H), 2.99 (td, J = 2.4 Hz, 12.4 Hz, 2H), 2.87 (s, 3H), 2.47 (qd, J = 4.4 Hz, 12.0 Hz, 2H), 2.16-2.14 (m, 2H)
1 H NMR (400 MHz, CDCl 3) δ 8.68 (bs, 1H), 8.34 (s, 1H), 7.87-7.85 (m, 2H), 7.54-7.49 (m, 3H), 7.16 (s, 1H), 5.88 (bs, 1H), 4.92 (tt, J = 4.4 Hz, 11.6 Hz, 1H), 4.01 (d, J = 12.0 Hz, 2H), 2.99 (td, J = 2.4 Hz, 12.4 Hz, 2H), 2.87 (s, 3H), 2.47 (qd, J = 4.4 Hz, 12.0 Hz, 2H), 2.16-2.14

실시예 19. 1-(4-(4-아미노-3-(5-(페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-일)에타논 (화합물번호 19)의 합성Example 19. l- (4- (4-Amino-3- (5- (phenylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin- Ylidene) ethanone (Compound No. 19) Synthesis of

Figure 112015076880414-pat00039
Figure 112015076880414-pat00039

1H NMR (400 MHz, CDCl3) δ 8.66 (bs, 1H), 8.35 (s, 1H), 7.87-7.84 (m, 2H), 7.53-7.48 (m, 3H), 7.15 (s, 1H), 5.87 (bs, 1H), 5.02 (tt, J = 4.4 Hz, 7.2 Hz, 1H), 4.82-4.79 (m, 2H), 4.03-3.99 (m, 2H), 3.37-3.29 (m, 2H), 2.85 (td, J = 2.8 Hz, 13.2 Hz, 2H), 2.26 (qd, J = 4.8 Hz, 11.6 Hz, 2H), 2.17 (s, 3H), 2.16-1.99 (m, 3H)
1 H NMR (400 MHz, CDCl 3 )? 8.66 (bs, IH), 8.35 (s, IH), 7.87-7.84 (m, 2H), 7.53-7.48 2H), 3.37-3.29 (m, 2H), 2.85 (m, 2H), 5.87 (bs, 1H), 5.02 (tt, J = 4.4 Hz, 7.2 Hz, (t, J = 2.8 Hz, 13.2 Hz, 2H), 2.26 (qd, J = 4.8 Hz, 11.6 Hz, 2H), 2.17 (s,

실시예 20. (±)-1-(3-(4-아미노-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-1-일)프로프-2-엔-1-온 (화합물번호 20)의 합성Example 20. (±) -1- (3- ( 4- amino-3- (5-phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-1- Yl) piperidin-1-yl) prop-2-en-1-one (Compound No. 20)

Figure 112015076880414-pat00040
Figure 112015076880414-pat00040

1H NMR (400 MHz, CDCl3) δ 8.67 (bs, 1H), 8.36 (s, 1H), 7.88-7.86 (m, 2H), 7.54-7.50 (m, 3H), 7.16 (s, 1H), 6.63-6.53 (m, 1H), 6.30-6.27 (m, 1H), 5.90 (bs, 1H), 5.74-5.64 (m, 1H), 4.93-4.88 (m, 1H), 4.87-4.45 (m, 1H), 4.19-4.02 (m, 1H), 3.84-3.45 (m, 1H), 3.32-3.11 (m, 1H), 2.36-2.25 (m, 2H), 1.81-1.72 (m, 2H)
1 H NMR (400 MHz, CDCl 3) δ 8.67 (bs, 1H), 8.36 (s, 1H), 7.88-7.86 (m, 2H), 7.54-7.50 (m, 3H), 7.16 (s, 1H), (M, IH), 5.93 (m, IH), 4.93-4.85 (m, ), 4.19-4.02 (m, 1H), 3.84-3.45 (m, 1H), 3.32-3.11 (m,

실시예 21. (R)-1-(3-(4-아미노-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-1-일)프로프-2-엔-1-온 (화합물번호 21)의 합성Example 21. (R) -1- (3- ( 4- amino-3- (5-phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-1- Yl) piperidin-1-yl) prop-2-en-1-one (Compound No. 21)

Figure 112015076880414-pat00041
Figure 112015076880414-pat00041

1H NMR (400 MHz, CDCl3) δ 8.67 (bs, 1H), 8.36 (s, 1H), 7.88-7.86 (m, 2H), 7.54-7.50 (m, 3H), 7.16 (s, 1H), 6.63-6.53 (m, 1H), 6.30-6.27 (m, 1H), 5.90 (bs, 1H), 5.74-5.64 (m, 1H), 4.93-4.88 (m, 1H), 4.87-4.45 (m, 1H), 4.19-4.02 (m, 1H), 3.84-3.45 (m, 1H), 3.32-3.11 (m, 1H), 2.36-2.25 (m, 2H), 1.81-1.72 (m, 2H)
1 H NMR (400 MHz, CDCl 3) δ 8.67 (bs, 1H), 8.36 (s, 1H), 7.88-7.86 (m, 2H), 7.54-7.50 (m, 3H), 7.16 (s, 1H), (M, IH), 5.93 (m, IH), 4.93-4.85 (m, ), 4.19-4.02 (m, 1H), 3.84-3.45 (m, 1H), 3.32-3.11 (m,

실시예 22. 3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 22)의 합성Example 22. 3- (5-cyclopropyl-a-3-yl) -1 H - Synthesis of pyrazolo [3,4- d] pyrimidin-4-amine (Compound No. 22)

Figure 112015076880414-pat00042
Figure 112015076880414-pat00042

1H NMR (400 MHz, DMSO) δ 13.94 (bs, 1H), 8.20 (s, 1H), 8.06 (bs, 1H), 7.99 (bs, 1H), 6.77 (s, 1H), 2.27-2.21 (m, 1H), 1.15-1.10 (m, 2H), 1.03-0.99 (m, 2H)
 1 H NMR (400 MHz, DMSO) [delta] 13.94 (bs, IH), 8.20 (s, IH), 8.06 (bs, IH), 7.99 , ≪ / RTI > 1H), 1.15-1.10 (m, 2H), 1.03-0.99

실시예 23. 1-시클로헥실-3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 23)의 합성Example 23 1-cyclohexyl-3- (5-cyclopropyl-a-3-yl) -1 H - Synthesis of pyrazolo [3,4- d] pyrimidin-4-amine (Compound No. 23)

Figure 112015076880414-pat00043
Figure 112015076880414-pat00043

1H NMR (400 MHz, CDCl3) δ 8.62 (bs, 1H), 8.32 (s, 1H), 6.54 (s, 1H), 5.89 (bs, 1H), 4.78-4.70 (m, 1H), 2.14-2.07 (m, 1H), 2.05-1.99 (m, 3H), 1.94-1.91 (m, 1H), 1.76 (dt, J = 3.2 Hz, 12.8 Hz, 1H), 1.56-1.45 (m, 2H), 1.34 (tt, J = 3.2 Hz, 12.8 Hz, 1H), 1.28-1.25 (m, 1H), 1.16-1.11 (m, 2H), 1.08-1.02 (m, 2H)
 1 H NMR (400 MHz, CDCl 3) δ 8.62 (bs, 1H), 8.32 (s, 1H), 6.54 (s, 1H), 5.89 (bs, 1H), 4.78-4.70 (m, 1H), 2.14- 2H), 1.34 (m, 1H), 2.07 (m, 1H), 2.05-1.99 (m, 3H), 1.94-1.91 (m, 2H), 1.08-1.02 (m, 2H), 1.28-1.25 (m,

실시예 24. 3-(5-시클로프로필이속사졸-3-일)-1-(테트라히드로-2H-파이란-4-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 24)의 합성Example 24 3- (5-cyclopropyl-a-3-yl) -1- (tetrahydro -2 H - Failan-4-yl) -1 H - pyrazolo [3,4- d] pyrimidine -4-amine (Compound No. 24)

Figure 112015076880414-pat00044
Figure 112015076880414-pat00044

1H NMR (400 MHz, CDCl3) δ 8.65 (bs, 1H), 8.33 (s, 1H), 6.54 (s, 1H), 5.91 (bs, 1H), 4.99 (tt, J = 4.4 Hz, 11.6 Hz, 1H), 4.15 (dd, J = 4.4 Hz, 11.6 Hz, 2H), 3.63 (td, J = 1.6 Hz, 12.0 Hz, 2H), 2.39 (qd, J = 4.4 Hz, 12.0 Hz, 2H), 2.16-2.09 (m, 1H), 1.96 (dd, J = 2.4 Hz, 12.8 Hz, 2H), 1.17-1.11 (m, 2H), 1.09-1.04 (m, 2H)
 1 H NMR (400 MHz, CDCl 3) δ 8.65 (bs, 1H), 8.33 (s, 1H), 6.54 (s, 1H), 5.91 (bs, 1H), 4.99 (tt, J = 4.4 Hz, 11.6 Hz , 1H), 4.15 (dd, J = 4.4 Hz, 11.6 Hz, 2H), 3.63 (td, J = 1.6 Hz, 12.0 Hz, 2H), 2.39 (qd, J = 4.4 Hz, 12.0 Hz, 2H), 2.16 -2.09 (m, 1H), 1.96 (dd, J = 2.4 Hz, 12.8 Hz, 2H), 1.17-1.11 (m, 2H), 1.09-1.04 (m, 2H)

실시예 25. 3-(5-시클로프로필이속사졸-3-일)-1-헵틸-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 25)의 합성Example 25. Synthesis of 3- (5-cyclopropylisoxazol-3-yl) -1-heptyl- 1H -pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00045
Figure 112015076880414-pat00045

1H NMR (400 MHz, CDCl3) δ 8.63 (bs, 1H), 8.33 (s, 1H), 6.52 (s, 1H), 6.10 (bs, 1H), 4.39 (t, J = 7.2 Hz, 2H), 2.16-2.08 (m, 1H), 1.92 (quin, J = 7.2 Hz, 2H), 1.33-1.24 (m, 8H), 1.15-1.12 (m, 2H), 1.04-1.02 (m, 2H), 0.85 (t, J = 6.4 Hz, 3H)
 1 H NMR (400 MHz, CDCl 3) δ 8.63 (bs, 1H), 8.33 (s, 1H), 6.52 (s, 1H), 6.10 (bs, 1H), 4.39 (t, J = 7.2 Hz, 2H) , 2.16-2.08 (m, 1H), 1.92 (quin, J = 7.2 Hz, 2H), 1.33-1.24 (m, 8H) (t, J = 6.4 Hz, 3 H)

실시예 26. 3-(5-시클로프로필이속사졸-3-일)-1-메틸-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 26)의 합성Example 26. Synthesis of 3- (5-cyclopropylisoxazol-3-yl) -1-methyl- 1H -pyrazolo [3,4- d ] pyrimidin-

Figure 112015076880414-pat00046
Figure 112015076880414-pat00046

1H NMR (400 MHz, CDCl3) δ 8.60 (bs, 1H), 8.32 (s, 1H), 6.48 (s, 1H), 6.31 (bs, 1H), 4.02 (s, 3H), 2.14-2.05 (m, 1H), 1.14-1.03 (m, 2H), 1.02-1.01 (m, 2H)
 1 H NMR (400 MHz, CDCl 3) δ 8.60 (bs, 1H), 8.32 (s, 1H), 6.48 (s, 1H), 6.31 (bs, 1H), 4.02 (s, 3H), 2.14-2.05 ( m, 1 H), 1.14-1.03 (m, 2 H), 1.02-1.01 (m, 2 H)

실시예 27. 1-벤질-3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 27)의 합성Example 27. 1-Benzyl-3- (5-cyclopropyl-a-3-yl) -1 H - Synthesis of pyrazolo [3,4- d] pyrimidin-4-amine (Compound No. 27)

Figure 112015076880414-pat00047
Figure 112015076880414-pat00047

1H NMR (400 MHz, CDCl3) δ 8.64 (bs, 1H), 8.37 (s, 1H), 7.34-7.26 (m, 5H), 6.52 (s, 1H), 5.87 (bs, 1H), 5.60 (s, 2H), 2.13-2.07 (m, 1H), 1.16-1.05 (m, 2H), 1.05-1.00 (m, 2H)
 1 H NMR (400 MHz, CDCl 3) δ 8.64 (bs, 1H), 8.37 (s, 1H), 7.34-7.26 (m, 5H), 6.52 (s, 1H), 5.87 (bs, 1H), 5.60 ( (m, 2H), 2.13-2.07 (m, 1H), 1.16-1.05 (m, 2H), 1.05-1.00

실시예 28. 1-(4-아미노-3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)-2-메틸프로판-2-올 (화합물번호 28)의 합성Example 28. 1- (4-Amino-3- (5-cyclopropyl-a-3-yl) -1 H - pyrazolo [3,4- d] pyrimidin-1-yl) -2-methyl Propan-2-ol (Compound No. 28)

Figure 112015076880414-pat00048
Figure 112015076880414-pat00048

1H NMR (400 MHz, MeOD) δ 8.33 (s, 1H), 6.73 (s, 1H), 4.45 (s, 2H), 2.29-2.22 (m, 1H), 1.29 (s, 6H), 1.24-1.18 (m, 2H), 1.08-1.05 (m, 2H)
 1 H NMR (400 MHz, MeOD ) δ 8.33 (s, 1H), 6.73 (s, 1H), 4.45 (s, 2H), 2.29-2.22 (m, 1H), 1.29 (s, 6H), 1.24-1.18 (m, 2 H), 1.08 - 1.05 (m, 2 H)

실시예 29. 3-(5-에틸이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 29)의 합성Example 29. 4- (5-ethyl-a-3-yl) -1-isopropyl -1 H - Synthesis of pyrazolo [3,4- d] pyrimidin-4-amine (Compound No. 29)

Figure 112015076880414-pat00049
Figure 112015076880414-pat00049

1H NMR (400 MHz, CDCl3) δ 8.64 (bs, 1H), 8.33 (s, 1H), 6.66 (s, 1H), 5.90 (bs, 1H), 5.15 (sep, J = 6.8 Hz, 1H), 2.85 (q, J = 7.6 Hz, 2H), 1.57 (d, J = 6.8 Hz, 6H), 1.38 (t, J = 7.6 Hz, 3H)
 1 H NMR (400 MHz, CDCl 3) δ 8.64 (bs, 1H), 8.33 (s, 1H), 6.66 (s, 1H), 5.90 (bs, 1H), 5.15 (sep, J = 6.8 Hz, 1H) , 2.85 (q, J = 7.6 Hz, 2H), 1.57 (d, J = 6.8 Hz, 6H), 1.38 (t, J = 7.6 Hz, 3H)

실시예 30. 1-이소프로필-3-(이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민 (화합물번호 30)의 합성Synthesis of pyrazolo [3,4- d] pyrimidin-4-amine (Compound No. 30) - Example 30 1-Isopropyl-3- (isoxazol-3-yl) -1 H

Figure 112015076880414-pat00050
Figure 112015076880414-pat00050

1H NMR (400 MHz, CDCl3) δ 8.55 (bs, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.35 (s, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.01 (bs, 1H), 5.17 (sep, J = 6.8 Hz, 1H), 1.58 (d, J = 6.8 Hz, 6H)
 1 H NMR (400 MHz, CDCl 3) δ 8.55 (bs, 1H), 8.47 (d, J = 1.6 Hz, 1H), 8.35 (s, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.01 (bs, 1H), 5.17 (sep, J = 6.8 Hz, 1H), 1.58 (d, J = 6.8 Hz,

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] 약제 제조방법
[Formulation example] Method for preparing pharmaceutical agent

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

활성성분 5.0 ㎎을 체로 친 후, 락토스 14.1 ㎎, 크로스포비돈 USNF 0.8 ㎎ 및 마그네슘 스테아레이트 0.1 ㎎을 혼합하고 가압하여 정제로 만들었다.
After 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 ㎎을 체로 친 후, 락토스 16.0 ㎎과 녹말 4.0 ㎎을 섞었다. 폴리솔베이트 80 0.3 ㎎을 순수한 물에 녹인 후 이 용액의 적당량을 첨가한 다음, 미립화하였다. 건조 후에 미립을 체질한 후 콜로이달 실리콘 디옥사이드 2.7 ㎎ 및 마그네슘 스테아레이트 2.0 ㎎과 섞었다. 미립을 가압하여 정제로 만들었다.
After 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 캡슐제Formulation Example 3. Powder and Capsule

활성성분 5.0 ㎎을 체로 친 후에, 락토스 14.8 ㎎, 폴리비닐 피롤리돈 10.0 ㎎, 마그네슘 스테아레이트 0.2 ㎎와 함께 섞었다. 혼합물을 적당한 장치를 사용하여 단단한 No. 5 젤라틴 캡슐에 채웠다.
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. 주사제Formulation Example 4. Injection

활성성분으로서 100 mg을 함유시키고, 그 밖에도 만니톨 180 mg, Na2HPO4·12H2O 26 mg 및 증류수 2974 mg를 함유시켜 주사제를 제조하였다.
100 mg as an active ingredient, 180 mg of mannitol, 26 mg of Na 2 HPO 4 .12H 2 O and 2974 mg of distilled water were added to prepare an injection.

[실험예] 화합물의 생리활성 실험
[Experimental Example] Physiological activity test of compound

실험예 1. RET 키나아제 저해 활성 측정Experimental Example 1. Measurement of RET kinase inhibitory activity

본 발명에 따른 상기 화학식 1로 표시되는 화합물에 대해 RET (Rearranged during transfaction) 키나아제의 저해활성(%저해능)을 측정하여 하기 표 1에 나타내었다. The inhibitory activity (% inhibition) of RET (Rearranged during transfaction) kinase was measured for the compound represented by Formula 1 according to the present invention and is shown in Table 1 below.

구 분division RET (uM)RET (uM) 구 분division RET (uM)RET (uM) 화합물번호 1Compound No. 1 <1<1 화합물번호 16Compound No. 16 <1<1 화합물번호 2Compound No. 2 <0.01<0.01 화합물번호 17Compound No. 17 <1<1 화합물번호 3Compound No. 3 <0.1&Lt; 0.1 화합물번호 18Compound No. 18 <1<1 화합물번호 4Compound No. 4 <1<1 화합물번호 19Compound No. 19 <1<1 화합물번호 5Compound No. 5 <1<1 화합물번호 20Compound No. 20 <1<1 화합물번호 6Compound No. 6 <1<1 화합물번호 21Compound No. 21 <1<1 화합물번호 7Compound No. 7 <0.1&Lt; 0.1 화합물번호 22Compound No. 22 <0.1&Lt; 0.1 화합물번호 8Compound No. 8 <0.1&Lt; 0.1 화합물번호 23Compound No. 23 <0.1&Lt; 0.1 화합물번호 9Compound No. 9 <1<1 화합물번호 24Compound No. 24 <0.1&Lt; 0.1 화합물번호 10Compound No. 10 <1<1 화합물번호 25Compound No. 25 <0.1&Lt; 0.1 화합물번호 11Compound No. 11 <1<1 화합물번호 26Compound No. 26 <0.1&Lt; 0.1 화합물번호 12Compound No. 12 <5<5 화합물번호 27Compound No. 27 <0.1&Lt; 0.1 화합물번호 13Compound No. 13 <1<1 화합물번호 28Compound No. 28 <0.1&Lt; 0.1 화합물번호 14Compound No. 14 <5<5 화합물번호 29Compound No. 29 <0.1&Lt; 0.1 화합물번호 15Compound No. 15 <1<1 화합물번호 30Compound No. 30 <1<1

상기 표 1에 의하면, 본원 화합물은 대체로 RET 키나아제 저해 활성이 우수하였으며, 그 중에서도 화합물번호 2, 3, 7, 8, 22∼29의 화합물은 저해효능이 탁월함을 확인할 수 있다.
According to the results shown in Table 1, the compounds of the present invention were found to have excellent RET kinase inhibitory activity, and the compounds of Nos. 2, 3, 7, 8 and 22 to 29 were excellent in inhibitory activity.

실험예 2. RET 돌연변이종에 대한 저해활성 측정Experimental Example 2. Measurement of inhibitory activity against RET mutant species

본 발명에 따른 대표 화합물로서 화합물번호 2의 화합물에 대하여 RET 변이체 키나아제의 저해활성을 평가하였다. RET 변이체 키나아제의 저해활성을 평가하기 위하여 RET 키나아제 도메인 (Carna Biosciences, Millipore)의 N 말단에 GST 태그를 부가한 RET 변이체 키나아제를 사용하여 비오틴화 펩티드(EGPWLEEEEEAYGWMDF)의 인산화 반응의 저해활성을 지표로 행하였다. 인산화 비오틴화 펩티드의 검출은 유로퓸(Europium) 라벨을 결합시킨 항인산화 항체를 사용한 TR-FRET법에 의해 행하였다. RET 키나아제의 각 변이체에 대한 저해활성을 IC50 값으로 산출하여, 하기 표 2에 나타내었다.As a representative compound according to the present invention, the inhibitory activity of RET mutant kinase was evaluated against the compound of Compound No. 2. To evaluate the inhibitory activity of the RET mutant kinase, the inhibitory activity of the biotinylated peptide (EGPWLEEEEEAYGWMDF) was used as an indicator by using RET mutant kinase with GST tag added at the N terminus of the RET kinase domain (Carna Biosciences, Millipore) Respectively. Detection of the biotinylated phosphorylated peptide was carried out by the TR-FRET method using an antioxidant antibody conjugated with a Europium label. The inhibitory activity against each mutant of RET kinase was calculated by IC 50 value and is shown in Table 2 below.

RETRET IC50 (nM)IC 50 (nM) Cabozantinib
(대조약물)Cabozantinib
(Control drug) 화합물번호 2Compound No. 2 RET (wt)RET (wt) 99 <10<10 RET (G691S)RET (G691S) 1414 <10<10 RET (Y791F)RET (Y791F) 77 <10<10 RET (V804L)RET (V804L) 230230 <30<30 RET (V804M)RET (V804M) 358358 <10<10 RET (S891A)RET (S891A) 55 <10<10 RET (M918T)RET (M918T) 1818 <10<10

실험예 3. 갑상선암 세포주 및 정상세포주에 대한 저해활성 비교 측정Experimental Example 3. Comparison of inhibitory activity against thyroid cancer cell line and normal cell line

본 실험에서는 본 발명에 따른 상기 화학식 1로 표시되는 화합물에 대하여, 정상적인 갑상선 상피세포주 (Nthy-ori 3-1)와 RET 키나아제 활성화 변이(C634W)를 갖는 갑상선 수질암 세포주 TT (American Type Culture Collection)에 대한 세포 증식 저해활성을 비교하였고, 그리고 변형이 없는 Parental Ba/F3 세포주와 RET가 변이된 RET-Ba/F3 세포주에 대한 세포 증식 저해활성을 비교 측정하였다.In this experiment, the thyroid cancer cell line TT (American Type Culture Collection) having the normal thyroid epithelial cell line (Nthy-ori 3-1) and the RET kinase activating mutation (C634W) , And the cell proliferation inhibitory activities of Parental Ba / F3 cell line and RET-Ba / F3 cell line transformed without deformation were compared.

96웰 플레이트에 Nthy-ori 3-1 세포, TT 세포, Parental Ba/F3 세포, RET-Ba/F3 세포를 각각 1웰당 5,000 세포가 되도록 10% FBS를 포함하는 F-12K Nutrient Mixture (Life Technologies Corporation)로 파종하여 37℃, 5% CO2 존재 하에서 하룻밤 동안 배양하였다. 그 후, 실험화합물을 디메틸술폭사이드에 첨가하여 최종 농도 1 nM 내지 10 μM가 되도록 희석하여 96웰 플레이트에 첨가하였다. 37℃, 5% CO2 존재 하에서 5일간 배양한 후에 세포 수 측정시약 (CellTiter-Glo(R) Luminescent Cell Viability Assay)을 첨가하여 교반 후, 발광 측정장치 (Envision)를 사용하여 발광강도를 측정하였다. 하기 표 3에는 각 시험화합물의 GI50 값을 측정한 결과를 나타내었다.12K Nutrient Mixture (manufactured by Life Technologies Corporation (Japan)) containing 10% FBS so as to have 5,000 cells / well, Nthy-ori 3-1 cells, TT cells, Parental Ba / F3 cells and RET- ) And cultured overnight at 37 ° C in the presence of 5% CO 2 . The experimental compound was then added to dimethyl sulfoxide, diluted to a final concentration of 1 nM to 10 [mu] M and added to a 96 well plate. After incubation for 5 days in the presence of 5% CO 2 at 37 ° C, CellTiter-Glo (R) Luminescent Cell Viability Assay was added and stirred, and the luminescence intensity was measured using a luminescence measuring device (Envision) . Table 3 below shows the results of measuring the GI 50 values of each test compound.

구 분division GI50 (uM)GI 50 (uM) Nthy ori-3-1Nthy ori-3-1 TTTT Parental Ba/F3Parental Ba / F3 RET-Ba/F3RET-Ba / F3 CabozantinibCabozantinib 4.94.9 0.1150.115 >10> 10 0.050.05 화합물번호 2Compound No. 2 >10> 10 <0.3<0.3 >10> 10 <0.1&Lt; 0.1 화합물번호 8Compound No. 8 >10> 10 <5<5 N.A.N.A. N.A.N.A. 화합물번호 13Compound No. 13 >10> 10 <10<10 <10<10 <3<3 화합물번호 14Compound No. 14 >10> 10 <10<10 >10> 10 <10<10 화합물번호 16Compound No. 16 >10> 10 <5<5 >10> 10 <10<10 화합물번호 19Compound No. 19 >10> 10 <5<5 N.A.N.A. N.A.N.A. 화합물번호 20Compound No. 20 >10> 10 <10<10 N.A.N.A. N.A.N.A. 화합물번호 23Compound No. 23 >10> 10 <1<1 >10> 10 <1<1 화합물번호 24Compound No. 24 >2> 2 <1<1 >10> 10 <1<1 화합물번호 26Compound No. 26 >10> 10 <5<5 >10> 10 <3<3 화합물번호 28Compound No. 28 <10<10 <5<5 >10> 10 <3<3 화합물번호 29Compound No. 29 >10> 10 <5<5 >10> 10 <3<3 화합물번호 30Compound No. 30 >10> 10 <10<10 >10> 10 <5<5

상기 표 3의 결과에 의하면, 본 발명의 화합물은 정상세포주 (Nthy-ori 3-1 세포, Parental Ba/F3 세포)에 대해서는 저해활성을 나타내지 않으면서, 비정상적으로 발현된 세포주 (TT 세포 또는 RET-Ba/F3 세포)에 대해 선택적으로 저해활성이 우수하였음을 확인할 수 있다.
According to the results shown in the above Table 3, the compounds of the present invention exhibit an abnormally expressed cell line (TT cell or RET-1 cell line) without showing inhibitory activity against a normal cell line (Nthy-ori 3-1 cell, parental Ba / F3 cell) Ba / F3 cells) of the present invention.

Claims (15)

하기 화학식 1로 표시되는 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물, 이의 약학적으로 허용되는 염, 이의 수화물, 이의 용매화물 및 이의 입체이성질체(stereoisomer)로 이루어진 군으로부터 선택된 화합물 :
[화학식 1]
Figure 112017028024020-pat00051

상기 화학식 1에서,
ⅰ)
Figure 112017028024020-pat00061
가 단일결합일 때,
n은 0을 나타내고;
A는 페닐기를 나타내고;
R은 C1∼C10 알킬기를 나타내고,
ⅱ)
Figure 112017028024020-pat00062
가 이중결합일 때,
n은 0을 나타내고;
A는 수소원자; C1∼C10 알킬기; 할로 및 C1∼C10 알콕시로부터 선택된 치환기로 치환 또는 비치환 페닐기; 치오펜일기; 또는 피리디닐기를 나타내고;
R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 테트라하이드로-2H-파이란일기; 또는 R1-C(O)- (이때, R1은 C1∼C10 알킬 또는 C2∼C10 알케닐이다) 및 R2-S(O)2- (이때, R2는 C1∼C10 알킬이다) 로부터 선택된 치환기로 치환 또는 비치환된 피페리디닐기를 나타낸다.
A pharmaceutical composition comprising 3- (isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin-4-amine compound represented by the following formula 1, a pharmaceutically acceptable salt, a hydrate thereof, A stereoisomer; a compound selected from the group consisting of:
[Chemical Formula 1]
Figure 112017028024020-pat00051

In Formula 1,
I)
Figure 112017028024020-pat00061
Is a single bond,
n represents 0;
A represents a phenyl group;
R is C 1 ~C 10 represents an alkyl group,
Ii)
Figure 112017028024020-pat00062
Is a double bond,
n represents 0;
A is a hydrogen atom; A C 1 to C 10 alkyl group; Halo, and C 1 ~C 10 alkoxy substituted with a substituent selected from or unsubstituted phenyl group; A thiophene group; Or a pyridinyl group;
R is a hydrogen atom; A C 1 to C 10 alkyl group; C 1 ~C 10 hydroxyalkyl group; Benzyl group; Tetrahydro-2H - pyranyl group; Or R 1 -C (O) -, wherein R 1 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, and R 2 -S (O) 2 -, wherein R 2 is C 1 - with a substituent selected from a C 10 alkyl), a substituted or unsubstituted piperidinyl ring carbonyl.
제 1 항에 있어서,
상기
Figure 112017028024020-pat00063
가 이중결합이고,
상기 n은 0이고,
상기 A는 메틸기, 에틸기, 노말프로필기, 이소프로필기, 사이클로프로필기,tert-부틸기, 사이클로펜틸기, 또는 사이클로헥실기이고,
상기 R은 수소원자, 메틸기, 에틸기, 노말프로필기, 이소프로필기, 사이클로프로필기, 사이클로헥실기, 노말헵틸기, 2-메틸-2-하이드록시프로필기, 테트라하이드로-2H-파이란일기, 또는 벤질기를 나타내는 것을 특징으로 하는 화합물.
The method according to claim 1,
remind
Figure 112017028024020-pat00063
Is a double bond,
Wherein n is 0,
A is a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a tert -butyl group, a cyclopentyl group, or a cyclohexyl group,
Wherein R is a hydrogen atom, a methyl group, an ethyl group, a n-propyl group, isopropyl group, cyclopropyl group, cyclohexyl group, n heptyl group, 2-methyl-2-hydroxypropyl group, a tetrahydro -2 H- Failan group, Or a benzyl group.
제 1 항에 있어서,
상기
Figure 112017028024020-pat00064
가 이중결합이고,
상기 n은 0이고;
상기 A는 페닐기; 또는 클로로, 플루오로 및 메톡시로부터 선택된 치환기로 치환환 페닐기이고;
상기 R은 메틸기, 에틸기, 노말프로필기, 이소프로필기, 사이클로프로필기, 사이클로헥실기, 테트라하이드로-2H-파이란일기, 1-(메틸설포닐)피페리딘-4-일기, 1-(아세틸)피페리딘-4-일기, 또는 1-(프로프-2-에노일)피페리딘-3-일기를 나타내는 것을 특징으로 하는 화합물.
The method according to claim 1,
remind
Figure 112017028024020-pat00064
Is a double bond,
N is 0;
A is a phenyl group; Or a substituted phenyl group substituted with a substituent selected from chloro, fluoro and methoxy;
The R may be the same or different and represents a hydrogen atom or a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a cyclohexyl group, a tetrahydro-2H - pyranyl group, a 1- (methylsulfonyl) Acetyl) piperidin-4-yl group, or 1- (prop-2-enoyl) piperidin-3-yl group.
제 1 항에 있어서,
상기
Figure 112017028024020-pat00065
가 이중결합이고,
상기 n은 0이고;
상기 A는 치오펜일기, 또는 피리디닐기이고;
상기 R은 메틸기, 에틸기, 노말프로필기, 이소프로필기, 사이클로프로필기,tert-부틸기, 사이클로펜틸기, 또는 사이클로헥실기를 나타내는 것을 특징으로 하는 화합물.
The method according to claim 1,
remind
Figure 112017028024020-pat00065
Is a double bond,
N is 0;
A is a thiophen yl group, or a pyridinyl group;
Wherein R represents a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a cyclopropyl group, a tert -butyl group, a cyclopentyl group, or a cyclohexyl group.
제 1 항에 있어서,
1-이소프로필-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-이소프로필-3-(5-사이클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-이소프로필-3-(5-이소프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-(tert-부틸)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-사이클로펜틸이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-사이클로헥실이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-이소프로필-3-(5-(치오펜-3-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-이소프로필-3-(5-(치오펜-2-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-(4-플루오로페닐)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-이소프로필-3-(5-(4-메톡시페닐)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-(3-클로로페닐)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-(2-클로로페닐)이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-이소프로필-3-(5-(피리딘-2-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-이소프로필-3-(5-(피리딘-3-일)이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-이소프로필-3-(5-(페닐-4,5-디하이드로이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-페닐이속사졸-3-일)-1-(테트라하이드로-2H-파이란-4-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-(1-(메틸설포닐)피페리딘-4-일)-3-(5-(페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-(4-(4-아미노-3-(5-(페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-일)에타논;
1-(3-(4-아미노-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-1-일)프로프-2-엔-1-온;
(±)-1-(3-(4-아미노-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-1-일)프로프-2-엔-1-온;
(R)-1-(3-(4-아미노-3-(5-페닐이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)피페리딘-1-일)프로프-2-엔-1-온;
3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-시클로헥실-3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-시클로프로필이속사졸-3-일)-1-(테트라히드로-2H-파이란-4-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-시클로프로필이속사졸-3-일)-1-헵틸-1H-피라졸로[3,4-d]피리미딘-4-아민;
3-(5-시클로프로필이속사졸-3-일)-1-메틸-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-벤질-3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-(4-아미노-3-(5-시클로프로필이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-1-일)-2-메틸프로판-2-올;
3-(5-에틸이속사졸-3-일)-1-이소프로필-1H-피라졸로[3,4-d]피리미딘-4-아민;
1-이소프로필-3-(이속사졸-3-일)-1H-피라졸로[3,4-d]피리미딘-4-아민.
The method according to claim 1,
1-Isopropyl-3- (5-phenylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
L-Isopropyl-3- (5-cyclopropylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
1-Isopropyl-3- (5-isopropylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
3- (5- ( tert -Butyl) isoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
3- (5-Cyclopentylisoxazol-3-yl) -l-isopropyl-lH - pyrazolo [3,4- d ] pyrimidin-4-amine;
3- (5-Cyclohexylisoxazol-3-yl) -l-isopropyl-lH - pyrazolo [3,4- d ] pyrimidin-4-amine;
1-Isopropyl-3- (5- (thiophen-3-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
1-Isopropyl-3- (5- (thiophen-2-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
3- (5- (4-Fluorophenyl) isoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
1-Isopropyl-3- (5- (4-methoxyphenyl) isoxazol-3-yl) -1 H- pyrazolo [3,4- d ] pyrimidin-4-amine;
3- (5- (3-Chlorophenyl) isoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
3- (5- (2-Chlorophenyl) isoxazol-3-yl) -1-isopropyl-1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
1-Isopropyl-3- (5- (pyridin-2-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
1-Isopropyl-3- (5- (pyridin-3-yl) isoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
1-Isopropyl-3- (5- (phenyl-4,5-dihydroisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
3- (5-Phenylisoxazol-3-yl) -1- (tetrahydro-2H-pyran - 4-yl) -1H - pyrazolo [3,4- d ] pyrimidin-4-amine;
1- (1- (methylsulfonyl) piperidin-4-yl) -3- (5- (phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin- 4-amine;
1- (4- (4-amino-3- (5- (phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-1-yl) piperidin-yl ) Ethanone;
1- (3- (4-amino-3- (5-phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-1-yl) piperidin-1 Yl) prop-2-en-1-one;
(±) -1- (3- (4- amino-3- (5-phenyl-3-yl) -1 H- pyrazolo [3,4 -d] pyrimidin-1-yl) piperidine 1-yl) prop-2-en-1-one;
(4-amino-3- (5-phenylisoxazol-3-yl) -1H - pyrazolo [3,4- d ] pyrimidin- 1-yl) prop-2-en-1-one;
3- (5-cyclopropyl-a-3-yl) -1 H - pyrazolo [3,4- d] pyrimidin-4-amine;
1-cyclohexyl-3- (5-cyclopropyl-a-3-yl) -1 H - pyrazolo [3,4- d] pyrimidin-4-amine;
3- (5-cyclopropyl-a-3-yl) -1- (tetrahydro -2 H - Failan-4-yl) -1 H - pyrazolo [3,4- d] pyrimidin-4-amine ;
3- (5-Cyclopropylisoxazol-3-yl) -1-heptyl-1 H -pyrazolo [3,4- d ] pyrimidin-4-amine;
3- (5-Cyclopropylisoxazol-3-yl) -1-methyl- 1H -pyrazolo [3,4- d ] pyrimidin-4-amine;
L -Benzyl-3- (5-cyclopropylisoxazol-3-yl) -1H-pyrazolo [3,4- d ] pyrimidin-4-amine;
1- (4-Amino-3- (5-cyclopropyl-a-3-yl) -1 H - pyrazolo [3,4- d] pyrimidin-1-yl) -2-methyl-propan-2 Come;
3- (5-ethyl-a-3-yl) -1-isopropyl -1 H - pyrazolo [3,4- d] pyrimidin-4-amine;
1-isopropyl-3- (isoxazol-3-yl) -1 H - pyrazolo [3,4- d] pyrimidin-4-amine.
하기 화학식 1로 표시되는 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물, 이의 약학적으로 허용되는 염, 이의 수화물, 이의 용매화물 및 이의 입체이성질체(stereoisomer)로 이루어진 군으로부터 선택된 화합물을 유효성분으로 함유하는 갑상선암, 폐암 또는 유방암의 예방 및 치료용 약학적 조성물 :
[화학식 1]
Figure 112017028024020-pat00066

상기 화학식 1에서,
ⅰ)
Figure 112017028024020-pat00067
가 단일결합일 때,
n은 0을 나타내고;
A는 페닐기를 나타내고;
R은 C1∼C10 알킬기를 나타내고,
ⅱ)
Figure 112017028024020-pat00068
가 이중결합일 때,
n은 0을 나타내고;
A는 수소원자; C1∼C10 알킬기; 할로 및 C1∼C10 알콕시로부터 선택된 치환기로 치환 또는 비치환 페닐기; 치오펜일기; 또는 피리디닐기를 나타내고;
R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 테트라하이드로-2H-파이란일기; 또는 R1-C(O)- (이때, R1은 C1∼C10 알킬 또는 C2∼C10 알케닐이다) 및 R2-S(O)2- (이때, R2는 C1∼C10 알킬이다) 로부터 선택된 치환기로 치환 또는 비치환된 피페리디닐기를 나타낸다.
A pharmaceutical composition comprising 3- (isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin-4-amine compound represented by the following formula 1, a pharmaceutically acceptable salt, a hydrate thereof, A pharmaceutical composition for the prophylaxis and treatment of thyroid cancer, lung cancer or breast cancer containing, as an active ingredient, a compound selected from the group consisting of stereoisomers,
[Chemical Formula 1]
Figure 112017028024020-pat00066

In Formula 1,
I)
Figure 112017028024020-pat00067
Is a single bond,
n represents 0;
A represents a phenyl group;
R is C 1 ~C 10 represents an alkyl group,
Ii)
Figure 112017028024020-pat00068
Is a double bond,
n represents 0;
A is a hydrogen atom; A C 1 to C 10 alkyl group; Halo, and C 1 ~C 10 alkoxy substituted with a substituent selected from or unsubstituted phenyl group; A thiophene group; Or a pyridinyl group;
R is a hydrogen atom; A C 1 to C 10 alkyl group; C 1 ~C 10 hydroxyalkyl group; Benzyl group; Tetrahydro-2H - pyranyl group; Or R 1 -C (O) -, wherein R 1 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, and R 2 -S (O) 2 -, wherein R 2 is C 1 - with a substituent selected from a C 10 alkyl), a substituted or unsubstituted piperidinyl ring carbonyl.
하기 화학식 1로 표시되는 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물, 이의 약학적으로 허용되는 염, 이의 수화물, 이의 용매화물 및 이의 입체이성질체(stereoisomer)로 이루어진 군으로부터 선택된 화합물을 유효성분으로 함유하는 갑상선암 치료제 :
[화학식 1]
Figure 112017028024020-pat00069

상기 화학식 1에서,
ⅰ)
Figure 112017028024020-pat00070
가 단일결합일 때,
n은 0을 나타내고;
A는 페닐기를 나타내고;
R은 C1∼C10 알킬기를 나타내고,
ⅱ)
Figure 112017028024020-pat00071
가 이중결합일 때,
n은 0을 나타내고;
A는 수소원자; C1∼C10 알킬기; 할로 및 C1∼C10 알콕시로부터 선택된 치환기로 치환 또는 비치환 페닐기; 치오펜일기; 또는 피리디닐기를 나타내고;
R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 테트라하이드로-2H-파이란일기; 또는 R1-C(O)- (이때, R1은 C1∼C10 알킬 또는 C2∼C10 알케닐이다) 및 R2-S(O)2- (이때, R2는 C1∼C10 알킬이다) 로부터 선택된 치환기로 치환 또는 비치환된 피페리디닐기를 나타낸다.
A pharmaceutical composition comprising 3- (isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin-4-amine compound represented by the following formula 1, a pharmaceutically acceptable salt, a hydrate thereof, A therapeutic agent for thyroid cancer comprising, as an active ingredient, a compound selected from the group consisting of stereoisomers:
[Chemical Formula 1]
Figure 112017028024020-pat00069

In Formula 1,
I)
Figure 112017028024020-pat00070
Is a single bond,
n represents 0;
A represents a phenyl group;
R is C 1 ~C 10 represents an alkyl group,
Ii)
Figure 112017028024020-pat00071
Is a double bond,
n represents 0;
A is a hydrogen atom; A C 1 to C 10 alkyl group; Halo, and C 1 ~C 10 alkoxy substituted with a substituent selected from or unsubstituted phenyl group; A thiophene group; Or a pyridinyl group;
R is a hydrogen atom; A C 1 to C 10 alkyl group; C 1 ~C 10 hydroxyalkyl group; Benzyl group; Tetrahydro-2H - pyranyl group; Or R 1 -C (O) -, wherein R 1 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, and R 2 -S (O) 2 -, wherein R 2 is C 1 - with a substituent selected from a C 10 alkyl), a substituted or unsubstituted piperidinyl ring carbonyl.
하기 화학식 1로 표시되는 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물, 이의 약학적으로 허용되는 염, 이의 수화물, 이의 용매화물 및 이의 입체이성질체(stereoisomer)로 이루어진 군으로부터 선택된 화합물을 유효성분으로 함유하는 폐암 치료제 :
[화학식 1]
Figure 112017028024020-pat00072

상기 화학식 1에서,
ⅰ)
Figure 112017028024020-pat00073
가 단일결합일 때,
n은 0을 나타내고;
A는 페닐기를 나타내고;
R은 C1∼C10 알킬기를 나타내고,
ⅱ)
Figure 112017028024020-pat00074
가 이중결합일 때,
n은 0을 나타내고;
A는 수소원자; C1∼C10 알킬기; 할로 및 C1∼C10 알콕시로부터 선택된 치환기로 치환 또는 비치환 페닐기; 치오펜일기; 또는 피리디닐기를 나타내고;
R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 테트라하이드로-2H-파이란일기; 또는 R1-C(O)- (이때, R1은 C1∼C10 알킬 또는 C2∼C10 알케닐이다) 및 R2-S(O)2- (이때, R2는 C1∼C10 알킬이다) 로부터 선택된 치환기로 치환 또는 비치환된 피페리디닐기를 나타낸다.
A pharmaceutical composition comprising 3- (isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin-4-amine compound represented by the following formula 1, a pharmaceutically acceptable salt, a hydrate thereof, A therapeutic agent for lung cancer comprising as an active ingredient a compound selected from the group consisting of stereoisomers:
[Chemical Formula 1]
Figure 112017028024020-pat00072

In Formula 1,
I)
Figure 112017028024020-pat00073
Is a single bond,
n represents 0;
A represents a phenyl group;
R is C 1 ~C 10 represents an alkyl group,
Ii)
Figure 112017028024020-pat00074
Is a double bond,
n represents 0;
A is a hydrogen atom; A C 1 to C 10 alkyl group; Halo, and C 1 ~C 10 alkoxy substituted with a substituent selected from or unsubstituted phenyl group; A thiophene group; Or a pyridinyl group;
R is a hydrogen atom; A C 1 to C 10 alkyl group; C 1 ~C 10 hydroxyalkyl group; Benzyl group; Tetrahydro-2H - pyranyl group; Or R 1 -C (O) -, wherein R 1 is C 1 -C 10 alkyl or C 2 -C 10 alkenyl, and R 2 -S (O) 2 -, wherein R 2 is C 1 - with a substituent selected from a C 10 alkyl), a substituted or unsubstituted piperidinyl ring carbonyl.
ⅰ)하기 화학식 2로 표시되는 화합물과 R-X로 표시되는 화합물을 반응시켜, 다양한 R가 도입된 하기 화학식 3으로 표시되는 화합물을 제조하는 과정;
Figure 112015076880414-pat00054

(상기 반응식에서, R은 청구항 1에서 정의한 바와 같고; X는 할로겐 원자를 나타낸다)
ⅱ)하기 화학식 3으로 표시되는 화합물의 스틸레 반응 (Stille reaction)에 의해, 비닐기가 도입된 하기 화학식 4로 표시되는 화합물을 제조하는 과정;
Figure 112015076880414-pat00055

(상기 반응식에서, R은 청구항 1에서 정의한 바와 같다)
ⅲ)하기 화학식 4로 표시되는 화합물의 비닐 그룹을 산화적 절단반응(oxdative cleavage)에 의해 알데하이드 그룹으로 전환한 후에, 하이드록실아민(NH2OH)과의 반응에 의해 옥심 그룹으로 전환하여, 하기 화학식 5로 표시되는 화합물을 제조하는 과정;
Figure 112015076880414-pat00056

(상기 반응식에서, R은 청구항 1에서 정의한 바와 같다)
ⅳ)하기 화학식 5로 표시되는 화합물을 니트릴 옥시드의 고리화 첨가반응(Nitrile oxide cycloaddition)에 의해, 하기 화학식 1로 표시되는 화합물을 제조하는 과정;
Figure 112015076880414-pat00057

(상기 반응식에서,
Figure 112015076880414-pat00058
, A, R 및 n은 각각 청구항 1에서 정의한 바와 같다)
을 포함하는 3-(이속사졸-3-일)-피라졸로[3,4-d]피리미딘-4-아민 화합물의 제조방법.
(I) reacting a compound represented by the following formula (2) with a compound represented by RX to prepare a compound represented by the following formula (3) into which various Rs have been introduced;
Figure 112015076880414-pat00054

(Wherein R is as defined in claim 1 and X represents a halogen atom)
Ii) a step of preparing a compound represented by the following general formula (IV) in which a vinyl group is introduced by a Stille reaction of a compound represented by the following general formula (3);
Figure 112015076880414-pat00055

(In the above scheme, R is as defined in claim 1)
Iii) converting the vinyl group of the compound represented by the following formula (4) into an aldehyde group by oxdative cleavage and then converting it into an oxime group by reaction with hydroxylamine (NH 2 OH) A process for producing a compound represented by the formula (5);
Figure 112015076880414-pat00056

(In the above scheme, R is as defined in claim 1)
(Iv) preparing a compound represented by the following formula (1) by a nitrile oxide cycloaddition reaction of a compound represented by the following formula (5);
Figure 112015076880414-pat00057

(In the above scheme,
Figure 112015076880414-pat00058
, A, R and n are each as defined in claim 1,
(Isoxazol-3-yl) -pyrazolo [3,4- d ] pyrimidin-4-amine.
제 9 항에 있어서,
상기 ⅰ)반응은 알칼리토금속 탄산염의 염기 존재 하에 70℃ 내지 80℃로 가열시키는 조건에서 실시하는 것을 특징으로 하는 화합물의 제조방법.
10. The method of claim 9,
Wherein the i) reaction is carried out in the presence of a base of an alkaline earth metal carbonate at 70 캜 to 80 캜.
제 9 항에 있어서,
상기 ⅱ)스틸레 반응은 팔라듐 (Pd) 또는 니켈 (Ni)의 금속 촉매와, 유기 주석화합물의 커플링 시약을 사용하여 120℃ 내지 150℃ 온도로 환류하는 조건에서 실시하는 것을 특징으로 하는 화합물의 제조방법.
10. The method of claim 9,
(Ii) the Stille reaction is carried out under reflux at a temperature of 120 ° C to 150 ° C using a metal catalyst of palladium (Pd) or nickel (Ni) and a coupling reagent for an organotin compound Gt;
제 9 항에 있어서,
상기 ⅲ)산화적 절단반응은 오스뮴 테트록사이드 (OsO4) 촉매 및 N-메틸몰폴린-N-옥시드 산화제 존재 하에서 반응시킨 후에, 소듐 퍼아이오데이트 (NaIO4)를 첨가하여 반응시키는 조건에서 실시하는 것을 특징으로 하는 화합물의 제조방법.
10. The method of claim 9,
(Iii) the oxidative cleavage reaction is carried out in the presence of an osmium tetroxide (OsO 4 ) catalyst and an N -methylmorpholine- N -oxide oxidant, followed by the addition of sodium periodate (NaIO 4 ) &Lt; / RTI &gt;
제 9 항에 있어서,
상기 ⅳ)고리화 첨가반응은 (디아세톡시아이오도)벤젠 또는 페닐아이오딘 비스(트리플루오로아세테이트)로부터 선택된 하이퍼밸런트 요오드 화합물을 사용하는 조건에서 실시하는 것을 특징으로 하는 화합물의 제조방법.
10. The method of claim 9,
Wherein the iv) cyclization addition reaction is carried out under a condition using a hyperbalanced iodine compound selected from (diacetoxy iodo) benzene or phenyl iodine bis (trifluoroacetate).
하기 화학식 4로 표시되는 중간체 화합물 :
[화학식 4]
Figure 112015076880414-pat00059

상기 화학식 4에서,
R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 또는 O 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각 내지 6각의 포화 또는 부분 포화된 헤테로사이클로알킬기를 나타낸다.
An intermediate compound represented by the following formula (4):
[Chemical Formula 4]
Figure 112015076880414-pat00059

In Formula 4,
R is a hydrogen atom; A C 1 to C 10 alkyl group; C 1 ~C 10 hydroxyalkyl group; Benzyl group; Or a five to six-membered saturated or partially saturated heterocycloalkyl group containing from one to two heteroatoms selected from O and N;
하기 화학식 5로 표시되는 중간체 화합물 :
[화학식 5]
Figure 112015076880414-pat00060

상기 화학식 5에서,
R은 수소원자; C1∼C10 알킬기; C1∼C10 하이드록시알킬기; 벤질기; 또는 O 및 N 중에서 선택된 헤테로원자가 1 내지 2개 포함된 5각 내지 6각의 포화 또는 부분 포화된 헤테로사이클로알킬기를 나타낸다.
An intermediate compound represented by the following formula (5):
[Chemical Formula 5]
Figure 112015076880414-pat00060

In Formula 5,
R is a hydrogen atom; A C 1 to C 10 alkyl group; C 1 ~C 10 hydroxyalkyl group; Benzyl group; Or a five to six-membered saturated or partially saturated heterocycloalkyl group containing from one to two heteroatoms selected from O and N;
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