KR20130112248A - Pyrazolopyrimidine derivatives, inhibiting composition of producing nitric oxide and pharmaceutical composition for prevention and treatment of diseases comprising the same - Google Patents

Pyrazolopyrimidine derivatives, inhibiting composition of producing nitric oxide and pharmaceutical composition for prevention and treatment of diseases comprising the same Download PDF

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KR20130112248A
KR20130112248A KR1020120034483A KR20120034483A KR20130112248A KR 20130112248 A KR20130112248 A KR 20130112248A KR 1020120034483 A KR1020120034483 A KR 1020120034483A KR 20120034483 A KR20120034483 A KR 20120034483A KR 20130112248 A KR20130112248 A KR 20130112248A
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nmr
mhz
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pyrazolo
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KR101379808B1 (en
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정찬성
김동진
박기덕
김윤경
표정인
김현태
황온유
아쉬라
송치만
김영수
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한국과학기술연구원
울산대학교 산학협력단
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

PURPOSE: A composition containing a pyrazolopyrimidine derivative compound for suppressing NO generation and a pharmaceutical composition containing the pyrazolopyrimidine derivative compound for preventing and treating neurological disorders are provided to suppress NO generation in vivo and to treat neurological disorders caused by functional disturbance and apoptosis of neural cells. CONSTITUTION: A pyrazolopyrimidine derivative compound of chemical formulas I-VII or a pharmaceutically acceptable salt thereof is provided. A pharmaceutical composition for suppressing NO generation contains a pharmaceutically acceptable carrier or diluent and the compounds as active ingredients. A composition for treating neurological disorders contains the pharmaceutically acceptable carrier or diluent and the compounds as active ingredients. The neurological diseases are selected among Parkinson's disease, Alzheimer's disease, Huntington's disease, amylotrophic lateral sclerosis, epilepsia, depression, pain, anxiety, and neurodegenerative diseases.

Description

피라졸로피리미딘 유도체 화합물, 이를 포함하는 산화질소 생성 억제용 조성물 및 뇌신경 질환 예방 및 치료용 약학적 조성물{Pyrazolopyrimidine derivatives, inhibiting composition of producing nitric oxide and pharmaceutical composition for prevention and treatment of diseases comprising the same}Pyrazolopyrimidine derivatives, inhibiting composition of producing nitric oxide and pharmaceutical composition for prevention and treatment of diseases comprising the same}

본 발명은 산화질소 생성 억제용 조성물 및 뇌신경 질환 예방 및 치료용 약학적 조성물에 관한 것으로서, 더욱 상세하게는 피라졸로피리미딘 유도체 화합물를 포함하는 산화질소 생성 억제용 조성물 및 뇌신경 질환 예방 및 치료용 약학적 조성물에 관한 것이다.The present invention relates to a composition for inhibiting nitric oxide production and a pharmaceutical composition for preventing and treating cerebral neurological diseases, and more particularly, a composition for inhibiting nitric oxide production and a pharmaceutical composition for preventing and treating cerebral neurological diseases, including pyrazolopyrimidine derivative compounds. It relates to a composition.

지속적인 생활수준의 향상과 보건 및 의료 기술의 발달로 국민들의 평균수명연장과 함께 노인 인구가 급증하였다. 따라서 인구 구조가 고령화되면서 필연적으로 야기되는 국민 보건 문제 가운데 노년층에서 흔히 관찰되는 퇴행성 신경질환인 노인성 치매와 파킨슨병 (Parkinson's disease)은 심각한 현안으로 대두되고 있다.With the continuous improvement of living standards and the development of health and medical technology, the elderly population increased rapidly with the average life expectancy of the people. As a result, aging dementia and Parkinson's disease, a degenerative neurological disease commonly observed in older people, are a serious problem among the public health problems inevitably caused by aging population.

파킨슨병은 60세 이상에서 1%, 70세 이상에서 3.4%, 80세 이상에서 4%의 발병률을 보이며 일차적인 증상으로는 느린 움직임, 정지시 떨림, 자세의 불안정, 근육경직이 특징적으로 나타나고, 병의 진행에 따라 우울증, 불면증, 치매 등의 2차적 증상을 동반한다 [1) de Lau et al., Lancet Neurol. 2006, 5, 525-535; 2) Chaudhuri et al., Lancet Neurol. 2009, 8, 464-474; 3) Fahn, In Handbook Exp. Pharmacol, 1989, 8, Calne, D.B., (Ed.) pp. 386-409]. 매해 50,000명 이상이 새롭게 진단을 받고 있으나 그 동안의 많은 연구에도 불구하고 병인의 기전에 대한 명확한 원인을 규명하지 못하였다 [Arevalo et al., Mov. Disord. 1997, 12, 277 284].The incidence of Parkinson's disease is 1% in patients over 60 years old, 3.4% in patients over 70 years old, and 4% in patients over 80 years old. The primary symptoms are slow motion, tremor at rest, instability of posture, It is associated with secondary symptoms such as depression, insomnia, and dementia as the disease progresses. [1] de Lau et al., Lancet Neurol. 2006, 5, 525-535; 2) Chaudhuri et al., Lancet Neurol. 2009, 8, 464-474; 3) Fahn, In Handbook Exp. Pharmacol, 1989, 8, Calne, D. B., (Ed.) Pp. 386-409]. More than 50,000 patients are diagnosed each year, but despite many studies, no clear cause for the pathogenesis has been identified [Arevalo et al., Mov. Disord. 1997, 12, 277 284.

그로 인해 현재 치료방법은 대증적 치료제를 이용하고 있고, 대표적으로는 도파민(dopamine)의 전구체인 L-3,4-dihydroxyphenylalanine (L-DOPA), monoamine oxidase inhibitor 그리고 dopamine receptor agonist 등이 있다. 그러나 이러한 방법들은 병의 진행을 지연시켜 줄 뿐 근원적인 치료가 되지 않으며, 장기간의 복용에 따른 부작용과 합병증을 동반한다. 따라서 최근에는 neuroprotection을 통한 병의 진행방향을 바꾸려는 노력이 활발히 진행되고 있다.As a result, current therapeutic methods use symptomatic therapeutic agents, such as L-3,4-dihydroxyphenylalanine (L-DOPA), a monoamine oxidase inhibitor, and dopamine receptor agonist, which are precursors of dopamine. However, these methods delay the progression of the disease but do not lead to the underlying treatment, and are associated with long-term side effects and complications. Recently, efforts have been actively made to change the path of disease progression through neuroprotection.

파킨슨병은 주로 흑질(substantia nigra pars compacta)로 불리는 중뇌 부위에서 신경전달물질(neurotransmitter)인 도파민을 포함하고 있는 도파민성 신경세포(dopaminergic neurons)의 손실에 의해 일어난다고 알려졌다. 파킨슨병의 원인을 규명하기 위하여 활발한 연구가 진행되고 있으며, 제초제나 살충제의 사용이 파킨슨병의 위험성을 증가시킨다는 보고, 바이러스성 뇌염등의 감염설, 선천적으로 발병한다는 유전설 등이 있으나 정확한 원인은 규명되지 않았다 [1) Corrigan et al., Exp. Neurol. 1998, 150, 339-342; 2) Schapira et al., Mov. Disord. 2011, 26, 1049-1055; 3) Ascherio et al., Annal. Neurol. 2001, 50, 56-63; 4) Warner et al., Annal. Neurol. 2003, 53 Suppl 3, S16-23].Parkinson's disease is known to be caused by the loss of dopaminergic neurons containing dopamine, a neurotransmitter, mainly in the middle brain, called the substantia nigra pars compacta. Active research is underway to determine the cause of Parkinson's disease, and reports of the use of herbicides and insecticides increase the risk of Parkinson's disease, infections such as viral encephalitis, and the heredity of congenital incidence. [1] Corrigan et al., Exp. Neurol. 1998, 150, 339-342; 2) Schapira et al., Mov. Disord. 2011, 26, 1049-1055; 3) Ascherio et al., Annal. Neurol. 2001, 50, 56-63; 4) Warner et al., Annal. Neurol. 2003, 53 Suppl 3, S16-23].

또한, 파킨슨병 환자의 10-15 %는 가족력을 가지고 있으며 현재까지 이들로부터 SNCA, PARKIN, UCHL1, PINK1, DJ-1, LRRK2, Omi/HtrA2 유전자 변이가 가족성 파킨슨병을 일으키는 것으로 밝혀졌다 [1) Paisan-Ruiz et al., Neuron 2004, 44, 595-600; 2) Zimprich et al., Neuron 2004, 44, 601-607; 3) Bonifati et al., Neurol. Sci. 2003, 24, 159-160; 4) Andres-Mateos et al., Proc. Natl. Acad. Sci. USA. 2007, 104, 14807-14812]. 상기 유전자로부터 밝혀진 파킨슨병의 환경요인 및 병인에는 1) 비정상적인 삼차원 구조를 가진 단백질 (a-synuclein)의 응집, 2) 미토콘드리아 이상, 3) Ubiquitin 단백분해 시스템 이상, 4) 산화성 스트레스 (oxidative stress), 5) 흥분성독성 (excitotoxicity), 6) 신경염증 (neuroinflammation)등이 관여하는 것으로 알려져 있다.In addition, 10-15% of Parkinson's disease patients have a family history, and to date, it has been shown that SNCA, PARKIN, UCHL1, PINK1, DJ-1, LRRK2, and Omi / HtrA2 gene mutations cause familial Parkinson's disease [1 ) Paisan-Ruiz et al., Neuron 2004, 44, 595-600; 2) Zimprich et al., Neuron 2004, 44, 601-607; 3) Bonifati et al., Neurol. Sci. 2003, 24, 159-160; 4) Andres-Mateos et al., Proc. Natl. Acad. Sci. USA. 2007, 104, 14807-14812. The environmental factors and etiology of Parkinson's disease revealed by the gene include 1) agglutination of a-synuclein with abnormal three-dimensional structure, 2) mitochondrial abnormalities, 3) ubiquitin proteolytic system abnormalities, 4) oxidative stress, 5) Excitotoxicity, 6) Neuroinflammation is known to be involved.

산화성 스트레스는 활성산소(reactive oxygen species; ROS)와 세포내의 항산화 활성간의 불균형으로 일어나며, 이는 파킨슨병에서 신경세포의 기능장애나 사멸을 야기하는 근본적인 이유로 생각되고 있다. 도파민의 대사과정이 산화성 스트레스와 관련되어 세포의 생장에 중요한 역할을 하는 세포 내 고분자들(macromolecules)의 변성(modification)을 일으킨다고 알려져 있다. 이러한 또한 활성화된 소교세포(microglia)에 의한 신경염증 반응과정에서 생성된 활성산소는 도파민성 신경세포가 분비하는 물질들에 의해 더욱 가속화되고, 신경세포의 사멸을 야기한다고 보고되었다 [1) Andersen et al., Nat. Med. 2004, 10 Suppl, S18-25; 2) Jenner et al., Annal. Neurol. 2003, 53 Suppl3, S26-36].Oxidative stress arises from an imbalance between reactive oxygen species (ROS) and the antioxidant activity in cells, which is thought to be a fundamental reason for causing neuronal dysfunction or death in Parkinson's disease. Dopamine metabolism is known to cause the modification of macromolecules (macromolecules) that play an important role in cell growth associated with oxidative stress. It has also been reported that free radicals generated during neuroinflammatory reactions by activated microglia are further accelerated by substances secreted by dopaminergic neurons and cause neuronal death [1] Andersen et. al., Nat. Med. 2004, 10 Suppl, S18-25; 2) Jenner et al., Annal. Neurol. 2003, 53 Suppl3, S26-36].

이러한 활성산소 가운데 산화질소 (nitric oxide, NO)는 생체 내에 존재하는 가스성 물질로써, nitrate (NO3 -), nitrite (NO2 -), peroxynitrite (ONOO-), 3-nitrotyrosine 등 매우 반응성이 높은 중간체로 쉽게 전환된다. NO가 과다 생성될 경우, NO나 그 중간체들은 세포를 구성하고 있는 DNA, 단백질 및 지질의 변형을 일으키는 nitrooxidative 스트레스를 유발한다. 특히 세포의 생존에 필요한 다양한 단백질들의 기능 장애로 인해 결과적으로 세포 기능장애와 세포사멸이 일어난다.These free radicals of nitrogen oxides (nitric oxide, NO) is as a gaseous substance existing in the living body, nitrate (NO 3 -), nitrite (NO 2 -), peroxynitrite (ONOO -), 3-nitrotyrosine , such as highly reactive with the high Easily converted to intermediate When NO is produced excessively, NO and its intermediates induce nitrooxidative stress that causes DNA, protein and lipid changes that make up the cells. In particular, the dysfunction of various proteins required for cell survival results in cell dysfunction and apoptosis.

신경세포는 특히 NO에 대해 취약하다. 그 이유는 첫째, NO가 신경세포에서 흥분성독성을 유발하고, 둘째, 소교세포가 만들어내는 superoxide와 함께 존재할 때 그 세포독성이 상승되기 때문이다. 그러므로 NO의 과다생성은 신경세포의 사멸을 초래하여 다양한 퇴행성 뇌질환의 발병에 기여할 수 있다. 실제로 파킨슨병의 경우 nitrite 농도가 척수액에서 증가하고 [Qureshi et al., Neuroreport 1995, 6(12), 1642-1644], 뇌병변 부위와 Lewy body에 존재하는 a-synuclein에서 3-nitrotyrosine이 증가하며 [Good et al., J Neuropathol. Exp. Neurol. 1998, 57(4), 338-342], 세포생존에 중요한 parkin, XIAP 등이 S-nitrosylation화 되어 있음이 발견되었다 [1)Yao et al., Proc. Natl. Acad. Sci. USA. 2004, 101(29), 10810-10814; 2) Tsang et al., Proc. Natl. Acad. Sci. USA. 2009, 106(12), 4900-4905; 3) Pathak et al., Biochim. Biophys. Acta 2008, 1777(7-8), 777-782). 또한, NO 과생산은 파킨슨병뿐만 아니라 알츠하이머치매, 헌팅턴병, 루게릭병, 뇌졸중 후에 나타나는 신경퇴행과도 관계가 있는 것으로 알려져 있다.Neurons are particularly vulnerable to NO. This is because, first, NO causes excitatory toxicity in neurons, and second, the cytotoxicity is enhanced when coexists with superoxide produced by microglia. Thus, overproduction of NO can lead to the death of neurons and contribute to the development of various degenerative brain diseases. Indeed, in Parkinson's disease, nitrite levels increase in spinal fluid (Qureshi et al., Neuroreport 1995, 6 (12), 1642-1644), and 3-nitrotyrosine in a-synuclein in brain lesions and in the Lewy body. Good et al., J Neuropathol. Exp. Neurol. 1998, 57 (4), 338-342], Parkin, XIAP, etc. important for cell survival was found to be S-nitrosylation [1) Yao et al., Proc. Natl. Acad. Sci. USA. 2004, 101 (29), 10810-10814; 2) Tsang et al., Proc. Natl. Acad. Sci. USA. 2009, 106 (12), 4900-4905; 3) Pathak et al., Biochim. Biophys. Acta 2008, 1777 (7-8), 777-782). In addition, NO overproduction is known to be associated with Parkinson's disease as well as Alzheimer's dementia, Huntington's disease, Lou Gehrig's disease, and neurodegeneration following stroke.

따라서, 파킨슨병의 예방 및 치료를 위해 NO의 생성을 효과적으로 억제할 수 있는 화합물이 절실히 요구되고 있다.Therefore, there is an urgent need for compounds that can effectively inhibit the production of NO for the prevention and treatment of Parkinson's disease.

따라서, 본 발명이 해결하고자 하는 과제는 생체 내에서 산화질소의 생성을 억제할 수 있고, 이에 의해서 산화질소의 과다 생성으로 인한 뇌신경 세포의 사멸을 방지할 수 있으며 각종 뇌신경 질환 치료용으로 활용할 수 있는 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염을 제공하는 것이다.Therefore, the problem to be solved by the present invention can suppress the production of nitric oxide in vivo, thereby preventing the death of neuronal cells due to the excessive production of nitric oxide can be utilized for the treatment of various brain neurological diseases It is to provide a pyrazolopyrimidine derivative compound or a pharmaceutically acceptable salt thereof.

또한, 본 발명이 해결하고자 하는 과제는 약학적 수용 가능한 담체 또는 희석제와 함께 활성성분으로서 피라졸로피리미딘 유도체 화합물을 함유하는 산화질소 생성 억제용 약학 조성물과 뇌신경 질환의 예방 및 치료용 약학 조성물을 제공하는 것이다.In addition, the problem to be solved by the present invention provides a pharmaceutical composition for inhibiting nitric oxide production containing a pyrazolopyrimidine derivative compound as an active ingredient with a pharmaceutically acceptable carrier or diluent and a pharmaceutical composition for the prevention and treatment of cerebral neurological diseases. It is.

본 발명은 상기 과제를 해결하기 위하여,In order to solve the above problems,

하기 [화학식 Ⅰ] 내지 [화학식 Ⅶ]로 표시되는 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염을 제공한다.Provided is a pyrazolopyrimidine derivative compound represented by the following [formula I] to [formula VII], or a pharmaceutically acceptable salt thereof.

[화학식 Ⅰ] [화학식 Ⅱ] [화학식 Ⅲ][Formula I] [Formula II] [Formula III]

Figure pat00001
Figure pat00002
Figure pat00003
Figure pat00001
Figure pat00002
Figure pat00003

[화학식 Ⅳ] [화학식 Ⅴ][Formula Ⅳ] [Formula Ⅴ]

Figure pat00004
Figure pat00005
Figure pat00004
Figure pat00005

[화학식 Ⅵ] [화학식 Ⅶ][Formula VI] [Formula VII]

Figure pat00006
Figure pat00007
Figure pat00006
Figure pat00007

상기 [화학식 Ⅰ] 내지 [화학식 Ⅶ]에서,In [Formula I] to [Formula VII],

상기 R1은 수소, 치환 또는 비치환된 탄소수 1 내지 12의 알킬기, 치환 또는 비치환된 탄소수 1 내지 12의 알릴기, 치환 또는 비치환된 탄소수 1 내지 10의 알콜기, 치환 또는 비치환된 탄소수 1 내지 10의 알콕시기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴옥시기 및 치환 또는 비치환된 탄소수 1 내지 5의 알킬카바메이트기 중에서 선택되는 어느 하나이고,R 1 is hydrogen, a substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C1-C12 allyl group, a substituted or unsubstituted C1-C10 alcohol group, a substituted or unsubstituted carbon number Selected from an alkoxy group having 1 to 10, a substituted or unsubstituted aryl group having 6 to 18 carbon atoms, a substituted or unsubstituted aryloxy group having 6 to 18 carbon atoms, and a substituted or unsubstituted alkyl carbamate group having 1 to 5 carbon atoms Which one is

상기 R2는 수소, 할로젠기, 치환 또는 비치환된 탄소수 1 내지 10의 알콕시기, 치환 또는 비치환된 탄소수 1 내지 12의 알릴기, 치환 또는 비치환된 탄소수 1 내지 10의 알콜기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴기, 치환 또는 비치환된 탄소수 3 내지 18의 헤테로아릴기, 치환 또는 비치환된 탄소수 1 내지 12의 알킬아민기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴아민기, 치환 또는 비치환된 탄소수 3 내지 18의 헤테로아릴아민기, 치환 또는 비치환된 탄소수 1 내지 10의 알킬티올기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴티올기 및 치환 또는 비치환된 탄소수 6 내지 18의 아릴옥시기 중에서 선택되는 어느 하나이며,R 2 is hydrogen, a halogen group, a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C1-C12 allyl group, a substituted or unsubstituted C1-C10 alcohol group, substituted Or an unsubstituted aryl group having 6 to 18 carbon atoms, a substituted or unsubstituted heteroaryl group having 3 to 18 carbon atoms, a substituted or unsubstituted alkylamine group having 1 to 12 carbon atoms, a substituted or unsubstituted carbon group having 6 to 18 carbon atoms Arylamine group, substituted or unsubstituted heteroarylamine group having 3 to 18 carbon atoms, substituted or unsubstituted alkylthiol group having 1 to 10 carbon atoms, substituted or unsubstituted arylthiol group having 6 to 18 carbon atoms, and substituted or unsubstituted Any one selected from an aryloxy group having 6 to 18 ring carbon atoms,

상기 R3는 O 또는 S이고,R 3 is O or S,

상기 R4는 수소, 치환 또는 비치환된 탄소수 1 내지 6의 알킬설파이닐기, 치환 또는 비치환된 탄소수 1 내지 6의 알킬설포닐기, 치환 또는 비치환된 탄소수 1 내지 12의 알킬아민기, 치환 또는 비치환된 탄소수 1 내지 10의 알콕시기 및 치환 또는 비치환된 탄소수 6 내지 18의 아릴아민기 중에서 선택되는 어느 하나이며,R 4 is hydrogen, a substituted or unsubstituted C1-C6 alkylsulfinyl group, a substituted or unsubstituted C1-C6 alkylsulfonyl group, a substituted or unsubstituted C1-C12 alkylamine group, substituted or It is any one selected from an unsubstituted alkoxy group having 1 to 10 carbon atoms and a substituted or unsubstituted arylamine group having 6 to 18 carbon atoms,

상기 X1은 수소, 할로젠기 및 치환 또는 비치환된 탄소수 6 내지 18의 아릴기 중에서 선택되는 어느 하나이다.X 1 is any one selected from hydrogen, a halogen group, and a substituted or unsubstituted aryl group having 6 to 18 carbon atoms.

본 발명의 일 실시예에 의하면, 상기 R1, R2 및 R4는 각각 독립적으로 탄소수 1 내지 6의 알킬기, 탄소수 1 내지 12의 알콕시기, 탄소수 1 내지 12의 알킬아민기, 탄소수 3 내지 18의 헤테로아릴기, 탄소수 3 내지 18의 헤테로아릴아민기, 시아노기 및 할로겐원자로 이루어지는 군으로부터 1종 이상 선택되어 치환될 수 있다.According to an embodiment of the present invention, the R 1 , R 2 And R 4 is each independently an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkylamine group having 1 to 12 carbon atoms, a heteroaryl group having 3 to 18 carbon atoms, a heteroarylamine group having 3 to 18 carbon atoms, One or more selected from the group consisting of a cyano group and a halogen atom may be substituted.

본 발명의 일 실시예에 의하면, 상기 피라졸로피리미딘 유도체 화합물은 약학적으로 수용 가능한 염을 형성할 수 있으며, 상기 약학적으로 수용 가능한 염은 염산, 브롬화수소산, 요오드화수소산, 황산, 질산, 인산, 메탄설폰산, 벤젠설폰산, 포름산, 아세트산, 트리플루오로 아세트산, 프로피온산, 옥살산, 말론산, 숙신산, 푸마르산, 말레산, 젖산, 말산, 타르타르산, 시트르산, 에탄설폰산, 아스파르트산 및 글루탐산으로 구성된 군에서 선택된 1종 이상일 수 있다.
According to an embodiment of the present invention, the pyrazolopyrimidine derivative compound may form a pharmaceutically acceptable salt, the pharmaceutically acceptable salt is hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid , Consisting of methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, trifluoro acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid It may be one or more selected from the group.

본 발명은 상기 과제를 해결하기 위하여,In order to solve the above problems,

약학적 수용 가능한 담체 또는 희석제와 함께 활성성분으로서 상기 피라졸로피리미딘 유도체 화합물을 함유하는 산화질소 생성 억제용 약학 조성물을 제공한다.It provides a pharmaceutical composition for inhibiting nitric oxide production containing the pyrazolopyrimidine derivative compound as an active ingredient together with a pharmaceutically acceptable carrier or diluent.

또한, 본 발명은 약학적 수용 가능한 담체 또는 희석제와 함께 활성성분으로서 상기 피라졸로피리미딘 유도체 화합물을 함유하는 뇌신경 질환 치료용 조성물을 제공한다.In addition, the present invention provides a composition for treating neurological diseases comprising the pyrazolopyrimidine derivative compound as an active ingredient together with a pharmaceutically acceptable carrier or diluent.

본 발명의 일 실시예에 의하면, 상기 뇌신경 질환은 파킨슨병, 알츠하이머 치매, 헌팅턴병, 루게릭병, 간질, 우울증, 통증 불안증 및 퇴행성 뇌신경 질환 중에서 선택되는 어느 하나일 수 있다.
According to an embodiment of the present invention, the neurological disease may be selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, pain anxiety, and degenerative brain disease.

본 발명에 따른 [화학식 ] 내지 [화학식 ]로 표시되는 피라졸로피리미딘 유도체 화합물의 치환기 및 용어에 대한 정의에서,In the definition of the substituents and terms of the pyrazolopyrimidine derivative compounds represented by [Formula] to [Formula] according to the present invention,

용어 '알콕시'는 달리 정의하지 않는 한 1 내지 10 개의 탄소 원자를 가지는 알킬옥시를 말하고, 바람직하게는 1 내지 3개의 탄소 원자를 가지는 알콕시기일 수 있다.The term "alkoxy" refers to alkyloxy having 1 to 10 carbon atoms unless otherwise defined, and preferably may be an alkoxy group having 1 to 3 carbon atoms.

용어 '알킬'은 지방족 탄화수소 라디칼을 의미한다. 알킬은 알케닐이나 알키닐 부위를 포함하지 않는 '포화(saturated alkyl)알킬'이거나, 적어도 하나의 알케닐 또는 알키닐 부위를 포함하는 '불포화(unsaturated alkyl)알킬'일 수 있다. '알케닐(alkenyl)'은 적어도 하나의 탄소-탄소 이중결합을 포함하는 그룹을 의미하며, '알키닐(alkynyl)'은 적어도 하나의 탄소-탄소 삼중결합을 포함하는 그룹을 의미한다. 알킬은 단독으로 또는 알콕시와 같이 조합하여 사용되는 경우에 각각 분지형 또는 직쇄형일 수 있다.The term " alkyl " means an aliphatic hydrocarbon radical. Alkyl may be 'saturated alkylalkyl' containing no alkenyl or alkynyl moieties, or 'unsaturated alkylalkyl' containing at least one alkenyl or alkynyl moieties. 'Alkenyl' refers to a group containing at least one carbon-carbon double bond, and 'alkynyl' refers to a group containing at least one carbon-carbon triple bond. Alkyl may be branched or straight chain, respectively, when used alone or in combination, such as alkoxy.

알킬 그룹은 달리 정의하지 않는 한 1 내지 12 개의 탄소 원자들을 가지는 알킬일 수도 있고, 바람직하게는 1 내지 6개의 탄소원자를 가지는 저급 알킬기일 수 있다. 전형적인 알킬 그룹에는 메틸, 에틸, 프로필, 이소프로필, n-부틸, 이소부틸, t-부틸, 펜틸, 헥실, 에테닐, 프로페닐, 부테닐 등이 포함되지만, 이들만으로 한정되는 것은 아니다. 예를 들어, 탄소수 1 내지 4의 알킬은 알킬쇄에 1 내지 4 개의 탄소 원자를 가지며, 메틸, 에틸, 프로필, 이소-프로필, n-부틸, 이소-부틸, sec-부틸 및 t-부틸로 이루어진 그룹에서 선택된다.The alkyl group may be an alkyl having 1 to 12 carbon atoms, and preferably a lower alkyl group having 1 to 6 carbon atoms unless otherwise defined. Typical alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, ethenyl, propenyl, butenyl and the like. For example, alkyl having 1 to 4 carbon atoms has 1 to 4 carbon atoms in the alkyl chain and consists of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl Is selected from the group.

용어 '아릴(aryl)'은 공유 파이 전자계를 가지는 적어도 하나의 환을 포함하며, 예를들어 모노사이클릭 또는 융합환 폴리사이클릭(즉, 탄소 원자들의 인접한 쌍들을 나눠가지는 링들)그룹을 포함한다. 즉, 본 명세서에서 아릴은 달리 정의하지 않는 한 페닐, 나프틸 등과 바이아릴을 포함할 수 있다.The term 'aryl' includes at least one ring having a shared pi electron field and includes, for example, a monocyclic or fused polycyclic (ie, rings which divide adjacent pairs of carbon atoms) groups. . That is, in the present specification, aryl may include phenyl, naphthyl, etc., and a biaryl, unless otherwise defined.

용어 '헤테로아릴'은 달리 정의하지 않는 한 N, O 및 S로 이루어진 그룹에서 선택된 1 내지 4개의 헤테로 원자를 포함하고, 바람직하게는 N을 1개 이상 포함하는 헤테로아릴일 수 있다. 모노사이클릭 헤테로아릴의 예로는 티아졸, 옥사졸, 티오펜, 퓨란, 피롤, 이미다졸, 이소옥사졸, 이소티아졸, 피라졸, 트리아졸, 트리아진, 티아디아졸, 테트라졸, 옥사디아졸, 피리딘, 피리다진, 피리미딘, 피라진 및 이와 유사한 그룹을 들 수 있으나, 이들로 제한되는 것은 아니다. 비사이클릭 헤테로아릴의 예로는 인돌, 인돌린, 벤조티오펜, 벤조퓨란, 벤즈이미다졸, 벤족사졸, 벤즈이속사졸, 벤즈티아졸, 벤즈티아디아졸, 벤즈트리아졸, 퀴놀린, 이소퀴놀린, 퓨린, 퓨로피리딘 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.The term 'heteroaryl' may be heteroaryl containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, preferably including one or more N, unless otherwise defined. Examples of monocyclic heteroaryl include thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, isothiazole, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadia Sol, pyridine, pyridazine, pyrimidine, pyrazine and similar groups, but is not limited to these. Examples of bicyclic heteroaryls include indole, indoline, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzthiadiazole, benztriazole, quinoline, isoquinoline, purine , Furopyridine, and similar groups.

용어 '할로겐기'의 구체적인 예로는 플루오르(F), 클로린(Cl), 브롬(Br) 등을들수있고, 바람직하게는 플루오르(F) 및 클로린(Cl)일 수 있다.Specific examples of the term 'halogen group' include fluorine (F), chlorine (Cl), bromine (Br), and the like, and preferably fluorine (F) and chlorine (Cl).

용어 '아릴옥시'는 R-O-로 표시되는 원자단으로서, 산소에 단일 결합으로 연결된 비치환 또는 치환된 알킬, 아릴 및 헤테로아릴을 포함한다.The term 'aryloxy' is an atomic group represented by R-O- and includes unsubstituted or substituted alkyl, aryl and heteroaryl linked by a single bond to oxygen.

용어 '카바메이트'는 일반적인 구조로 RNH (CO) OR'로 의미하며, R'는 알킬기일 수 있다.The term 'carbamate' is a general structure, meaning RNH (CO) OR ', and R' may be an alkyl group.

본 발명에 있어서, '치환 또는 비치환된' 이라는 용어는 알킬기, 알콕시기, 알킬아민기, 헤테로아릴기, 헤테로아릴아민기, 시아노기 및 할로겐원자로 이루어진 군에서 선택된 1개 이상의 치환기로 치환 또는 비치환되는 것을 의미한다.In the present invention, the term "substituted or unsubstituted" is substituted or unsubstituted with one or more substituents selected from the group consisting of an alkyl group, an alkoxy group, an alkylamine group, a heteroaryl group, a heteroarylamine group, a cyano group and a halogen atom It means that the ring.

상기 '치료'라 함은 발병 증상을 보이는 객체에 사용될 때 질병의 진행을 중단 또는 지연시키는 것을 의미한다.The term " treatment " refers to stopping or delaying the progress of a disease when used in an object having an onset symptom.

상기 '약학적 조성물'은 본 발명의 화합물과 함께 필요에 따라 약학적으로 허용되는 담체, 희석제, 부형제, 또는 이들의 조합을 포함할 수 있다.The 'pharmaceutical composition' may include, if necessary, a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof together with the compound of the present invention.

상기 '담체(carrier)'라 함은 세포 또는 조직 내로 화합물의 부가를 용이하게 하는 물질을 의미한다.The term "carrier" refers to a substance that facilitates the addition of a compound into a cell or tissue.

상기 '희석제(diluent)'라 함은 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키는 물에서 희석되는 물질로 정의된다.The term 'diluent' is defined as a substance that not only stabilizes the biologically active form of the compound of interest but also dilutes in water to dissolve the compound.

상기 '약학적으로 허용되는'이라 함은 화합물의 생물학적 활성과 물성을 손상시키지 않는 성질을 의미한다.The term " pharmaceutically acceptable " means a property that does not impair the biological activity and physical properties of the compound.

기타 본 명세서에서 사용된 용어와 약어들은 달리 정의되지 않는 한 본 발명이 속하는 기술 분야의 당업자에게 통상적으로 이해되는 의미로서 해석될 수 있다.Other terms and abbreviations used herein can be interpreted as commonly understood by a person skilled in the art to which the present invention belongs, unless otherwise defined.

본 발명에 따른 피라졸로피리미딘 유도체 화합물을 활성성분으로 함유하는 약학적 조성물은 생체 내 산화질소의 생성을 억제할 수 있고, 산화질소의 과다생성에 따른 신경 세포의 기능장애 및 사멸로 인하여 야기되는 뇌신경 질환, 특히 파킨슨병, 알츠하이머 치매, 헌팅턴병, 루게릭병, 간질, 우울증, 불면증, 불안증 및 퇴행성 뇌신경 질환 등을 치료하는데 사용할 수 있다.The pharmaceutical composition containing the pyrazolopyrimidine derivative compound according to the present invention as an active ingredient can inhibit the production of nitric oxide in vivo, and is caused by dysfunction and death of nerve cells due to overproduction of nitric oxide. It can be used to treat cranial nerve diseases, especially Parkinson's disease, Alzheimer's dementia, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, insomnia, anxiety and degenerative neurodegenerative diseases.

이하, 본 발명을 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.

산화질소(NO)는 세포 내에서 nitric oxide synthase (NOS) 효소에 의해 생성된다. 특히 inducible NOS (iNOS)는 뇌에 존재하는 소교세포와 성상세포에서 작용하는 효소이다. 평소에는 매우 낮은 농도로 존재하다가 세포가 활성될 경우 발현되고, 결과적으로 뇌 NO 농도를 현저히 (약 100 배) 증가시킨다. 퇴행성뇌질환 환자의 뇌에서는 이렇게 증가된 iNOS의 발현이 휴식상태로 되돌아가지 못하고 NO를 장기적, 지속적으로 생성한다. 그러므로 iNOS를 제어하는 것은 파킨슨병을 비롯한 퇴행성뇌질환의 예방 및 치료에 사용될 수 있을 것이다. 특히, 타 NOS (neuronal, endothelial type)의 활성에 영향을 주지 않으면서 iNOS의 발현을 휴식상태 수준으로 억제하는 방법은 NO의 정상기능에는 영향을 주지 않으므로 관련 부작용을 최소화할 수 있다.Nitric oxide (NO) is produced by the nitric oxide synthase (NOS) enzyme in the cell. In particular, inducible NOS (iNOS) is an enzyme that acts on microglia and astrocytes in the brain. It is usually present at very low concentrations and is expressed when cells are activated, resulting in a significant increase in brain NO concentration (about 100 times). In the brains of patients with degenerative brain diseases, this increased expression of iNOS does not return to rest and produces NO in the long term. Therefore, controlling iNOS may be used to prevent and treat degenerative brain diseases including Parkinson's disease. In particular, the method of inhibiting the expression of iNOS to a resting level without affecting the activity of other NOS (neuronal, endothelial type) does not affect the normal function of NO, so the related side effects can be minimized.

따라서, 본 발명은 iNOS의 발현을 휴식상태 수준으로 억제하여 뇌에서 산화질소의 과생산을 억제할 수 있는 약학 조성물로 적용할 수 있고, 이에 따라 뇌신경 질환을 치료할 수 있는 하기 [화학식 Ⅰ] 내지 [화학식 Ⅶ]로 표시되는 신규의 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염을 제공한다.Therefore, the present invention can be applied as a pharmaceutical composition capable of inhibiting the expression of iNOS to the resting state level, thereby inhibiting the overproduction of nitric oxide in the brain, and thus can treat the neurological diseases of the following formula [I] to [ It provides a novel pyrazolopyrimidine derivative compound represented by the formula (VII) or a pharmaceutically acceptable salt thereof.

[화학식 Ⅰ] [화학식 Ⅱ] [화학식 Ⅲ][Formula I] [Formula II] [Formula III]

Figure pat00008
Figure pat00009
Figure pat00010
Figure pat00008
Figure pat00009
Figure pat00010

[화학식 Ⅳ] [화학식 Ⅴ][Formula Ⅳ] [Formula Ⅴ]

Figure pat00011
Figure pat00012
Figure pat00011
Figure pat00012

[화학식 Ⅵ] [화학식 Ⅶ][Formula VI] [Formula VII]

Figure pat00013
Figure pat00014

Figure pat00013
Figure pat00014

상기 [화학식 Ⅰ] 내지 [화학식 Ⅶ]에서,In [Formula I] to [Formula VII],

상기 R1은 하기 [구조식 1]로 표시되는 군으로부터 선택되는 어느 하나일 수 있고,R 1 may be any one selected from the group represented by the following [Formula 1],

[구조식 1][Structural formula 1]

Figure pat00015
Figure pat00016
Figure pat00017
Figure pat00018
Figure pat00019
Figure pat00020
Figure pat00021
Figure pat00015
Figure pat00016
Figure pat00017
Figure pat00018
Figure pat00019
Figure pat00020
Figure pat00021

Figure pat00022
Figure pat00023
Figure pat00024
Figure pat00022
Figure pat00023
Figure pat00024

상기 R2는 하기 [구조식 2]로 표시되는 군으로부터 선택되는 어느 하나일 수 있으며,R 2 may be any one selected from the group represented by the following [Formula 2],

[구조식 2][Structural formula 2]

Figure pat00025
Figure pat00026
Figure pat00027
Figure pat00028
Figure pat00029
Figure pat00030
Figure pat00025
Figure pat00026
Figure pat00027
Figure pat00028
Figure pat00029
Figure pat00030

Figure pat00031
Figure pat00032
Figure pat00033
Figure pat00034
Figure pat00035
Figure pat00036
Figure pat00031
Figure pat00032
Figure pat00033
Figure pat00034
Figure pat00035
Figure pat00036

Figure pat00037
Figure pat00038
Figure pat00039
Figure pat00040
Figure pat00041
Figure pat00042
Figure pat00037
Figure pat00038
Figure pat00039
Figure pat00040
Figure pat00041
Figure pat00042

Figure pat00043
Figure pat00044
Figure pat00045
Figure pat00046
Figure pat00047
Figure pat00048
Figure pat00049
Figure pat00043
Figure pat00044
Figure pat00045
Figure pat00046
Figure pat00047
Figure pat00048
Figure pat00049

Figure pat00050
Figure pat00051
Figure pat00052
Figure pat00053
Figure pat00054
Figure pat00055
Figure pat00050
Figure pat00051
Figure pat00052
Figure pat00053
Figure pat00054
Figure pat00055

Figure pat00056
Figure pat00057
Figure pat00058
Figure pat00059
Figure pat00060
Figure pat00061
Figure pat00062
Figure pat00056
Figure pat00057
Figure pat00058
Figure pat00059
Figure pat00060
Figure pat00061
Figure pat00062

Figure pat00063
Figure pat00064
Figure pat00065
Figure pat00066
Figure pat00063
Figure pat00064
Figure pat00065
Figure pat00066

상기 R4는 하기 [구조식 3]으로 표시되는 군으로부터 선택되는 어느 하나일 수 있다.R 4 may be any one selected from the group represented by the following [Formula 3].

[구조식 3][Structural Formula 3]

Figure pat00067
Figure pat00068
Figure pat00069
Figure pat00070
Figure pat00071
Figure pat00072
Figure pat00067
Figure pat00068
Figure pat00069
Figure pat00070
Figure pat00071
Figure pat00072

Figure pat00073
Figure pat00074
Figure pat00075

Figure pat00073
Figure pat00074
Figure pat00075

또한, 본 발명의 범위가 이에 의해서 제한되지 않는다는 것은 당업계의 통상의 지식을 가진 자에게 자명할 것이나, 본 발명의 바람직한 실시예에 의하면, 본 발명에 따른 상기 [화학식 Ⅰ] 내지 [화학식 Ⅶ]의 화합물은 구체적으로 특허청구범위에 기재된 [화학식 4] 내지 [화학식 31k]로 표시되는 화합물들 중 어느 하나일 수 있다.In addition, it will be obvious to those skilled in the art that the scope of the present invention is not limited by this, but according to a preferred embodiment of the present invention, the above-mentioned [Formula I] to [Formula VII] The compound of may be specifically any one of the compounds represented by [Formula 4] to [Formula 31k] described in the claims.

본 발명에서 약학적으로 수용 가능한 염은 약학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들어,황산, 염산, 질산, 인산, 브롬화수소산, 요오드화수소산 등과 같은 무기산과, 타르타르산, 포름산, 시트르산, 아세트산, 트리플루오로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 젖산, 말론산, 말산, 살리실산, 숙신산, 옥살산, 프로피온산, 아스파르탄산, 글루탐산, 구연산 등과 같은 유기산과, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산, 나프탈렌설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염일 수 있고, 유리 카르복시 치환체를 포함하는 본 발명에 따르는 [화학식 Ⅰ] 내지 [화학식 Ⅶ]로 표시되는 피라졸로피리미딘 유도체 화합물은 상기의 산 부가염 및 나트륨, 칼슘 및 암모늄의 염일 수 있으며, 약학적으로 수용 가능한 염기 부가염, 예를 들어, 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 알칼리 금속 또는 알칼리 토금속 염과, 라이신,아르기닌, 구아니딘 등의 아미노산 염과, 디사이클로헥실아민, N-메틸-D-글루카민, 트리스 (하이드록시메틸)메틸아민, 디에탄올아민, 콜린, 트리에틸 아민 등과 같은 유기염일 수 있다.Pharmaceutically acceptable salts herein include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, such as inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and tartaric acid. Organic acids such as formic acid, citric acid, acetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, lactic acid, malonic acid, malic acid, salicylic acid, succinic acid, oxalic acid, propionic acid, aspartic acid, glutamic acid, citric acid, It may be an acid addition salt formed by sulfonic acids such as phenolic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and the like, and includes the free carboxyl substituents according to the present invention. The pyrazolopyrimidine derivative compounds represented by] may be the above acid addition salts and salts of sodium, calcium and ammonium, Base addition salts which are acceptable, for example, alkali or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, and the like, amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N-methyl Organic salts such as -D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline, triethyl amine and the like.

본 발명에 따른 피라졸로피리미딘 화합물은 통상적인 방법에 의해 그의 염으로 전환될 수 있으며, 염의 제조는 별도의 설명이 없이도 상기 [화학식 Ⅰ] 내지 [화학식 Ⅶ]의 구조를 바탕으로 당업자에 의해 용이하게 수행될 수 있을 것이다.The pyrazolopyrimidine compounds according to the present invention can be converted to their salts by conventional methods, and the preparation of the salts can be easily carried out by those skilled in the art based on the structures of the above Chemical Formulas I to XII without further explanation. May be performed.

이하에서 별도의 설명이 없는 한, 피라졸로피리미딘 유도체 화합물에는 약학적으로 수용 가능한 그의 염이 포함되며, 이들은 모두 본 발명의 범주에 포함되는 것으로 해석되어야 한다.Unless otherwise stated below, pyrazolopyrimidine derivative compounds include pharmaceutically acceptable salts thereof, all of which are to be construed as being within the scope of the present invention.

본 발명에 따른 피라졸로피리미딘 유도체 화합물은 뇌에서 산화질소의 과다 생성을 억제할 수 있는 저해제로서, 산화질소의 과다 생성으로 야기되는 파킨슨병, 알츠하이머 치매, 헌팅턴병, 루게릭병, 간질, 우울증, 통증 불안증 및 퇴행성 뇌신경 질환 등 다양한 뇌신경 질환을 예방 또는 치료제로 사용할 수 있다.The pyrazolopyrimidine derivative compounds according to the present invention are inhibitors capable of inhibiting the overproduction of nitric oxide in the brain and are caused by Parkinson's disease, Alzheimer's dementia, Huntington's disease, Lou Gehrig's disease, epilepsy, depression and pain caused by the overproduction of nitric oxide. Various neurological disorders such as anxiety and degenerative neurological disorders can be used as a prophylactic or therapeutic agent.

본 발명의 바람직한 일 실시예에 의하면, 버퍼 용액에 용해되어 있는 염을 희석제로 사용하고, 통상 사용되는 버퍼 용액은 인간 용액의 염 형태를 모방하고 있는 포스페이트 버퍼 식염수일 수 있다. 버퍼 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 버퍼 희석제가 화합물의 생물학적 활성을 변형시키지 않는다.According to a preferred embodiment of the present invention, the salt dissolved in the buffer solution is used as a diluent, and the buffer solution usually used may be phosphate buffer saline that mimics the salt form of the human solution. Since buffer salts can control the pH of the solution at low concentrations, the buffer diluent does not alter the biological activity of the compound.

본 발명의 화합물은 약학적으로 또는 수의학적으로 수용가능한 담체 또는 희석제를 또한 함유하는 약학적 또는 수의학적 조성물로 사용하기 위해 제형화할 수 있다. 본 발명에 따른 조성물은 통상적인 방법에 따라 일반적으로 제조하여, 약학적으로 또는 수의학적으로 적절한 형태로 투여할 수 있다.The compounds of the present invention may be formulated for use as pharmaceutical or veterinary compositions also containing a pharmaceutically or veterinarily acceptable carrier or diluent. The composition according to the present invention can be generally prepared according to a conventional method, and can be administered in a pharmaceutically or veterinarily appropriate form.

본 발명의 바람직한 실시예에 의하면, 정제, 캡슐, 당-코팅, 필름-코팅정제, 액체 용액 또는 현탁액의 형태와 같은 경구적으로 투여할 수 있고, 또는 피하나 근육내로 또는 정맥 내로 주사 또는 주입의 방법을 통하여 비경구적으로 투여할 수도 있다.According to a preferred embodiment of the invention, it can be administered orally, such as in the form of tablets, capsules, sugar-coated, film-coated tablets, liquid solutions or suspensions, or by injection or infusion subcutaneously or intramuscularly or intravenously. It can also be administered parenterally via the method.

환자의 연령, 체중 및 상태와 투여경로를 비롯한 각종 요인에 따라 투여량은 결정될 수 있다. 1일 투여용량은 광범위한 한도치 내에서 변할 수 있으며, 각각의 개별 경우에서 개인적 요건에 맞게 조정될 수 있다. 그러나 일반적으로, 본 화합물을 성인에게 단독 투여하는 경우, 투여 경로별로 채택된 투여용량은 0.0001 내지 50 ㎎/㎏ 체중이며, 0.001 내지 10 ㎎/㎏ 체중의 범위에서 예를 들면 0.01 내지 1 ㎎/㎏ 체중으로 할 수 있다.The dosage can be determined according to various factors including the patient's age, body weight and condition and administration route. The daily dosage may vary within wide limits and may be adjusted to individual requirements in each individual case. In general, however, when the present compound is administered alone to an adult, the dosages adopted by the route of administration are 0.0001 to 50 mg / kg body weight, for example 0.01 to 1 mg / kg in the range of 0.001 to 10 mg / kg body weight. You can do it by weight.

이러한 투여 용량은 예를 들면 1일 1 내지 5 회 제공할 수 있다. 정맥 내 주사의 경우, 적절한 1일 용량은 0.0001 내지 1 ㎎/㎏ 체중, 바람직하게는 0.0001 내지 0.1 ㎎/㎏ 체중이다. 1일 투여용량은 단일 투여분으로서 또는 분할용량 스케줄에 따라 투여할 수 있다.
Such dosages may be given, for example, 1 to 5 times a day. For intravenous injections, a suitable daily dose is 0.0001 to 1 mg / kg body weight, preferably 0.0001 to 0.1 mg / kg body weight. The daily dose may be administered as a single dose or according to a divided dose schedule.

이하, 바람직한 실시예를 들어 본 발명을 더욱 상세하게 설명한다. 그러나, 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이에 의하여 제한되지 않고, 본 발명의 범주 및 기술사상 범위 내에서 다양한 변경 및 수정이 가능함은 당업계의 통상의 지식을 가진 자에게 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to preferred examples. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. It will be clear to those who have knowledge.

또한, 본 발명이 속한 기술분야에서 통상의 지식을 가진 자라면 [화학식 Ⅰ] 내지 [화학식 Ⅶ]의 구조를 바탕으로 다양한 방법에 의해 [화학식 Ⅰ] 내지 [화학식 Ⅶ]의 화합물을 제조할 수 있으며, 이러한 방법들은 모두 본 발명의 범주에 포함되는 것으로 해석되어야 한다.In addition, a person having ordinary knowledge in the technical field to which the present invention belongs may prepare the compounds of [Formula I] to [Formula VII] by various methods based on the structure of [Formula I] to [Formula VII]. All these methods should be construed as being included in the scope of the present invention.

즉, 이하의 실시예에 구체적으로 기재된 합성방법 또는 선행기술에 개시된 여러 합성법들을 임의로 조합하여 [화학식 Ⅰ] 내지 [화학식 Ⅶ]의 화합물을 제조할 수 있고, 이는 본 발명의 범위에 속하는 것으로 이해되고, [화학식 Ⅰ] 내지 [화학식 Ⅶ] 화합물의 제조방법이 하기 설명된 것으로 제한되는 것은 아니다.
That is, the compound of [Formula I] to [Formula X] can be prepared by arbitrarily combining the synthesis method described in the following Examples or various synthesis methods disclosed in the prior art, which is understood to be within the scope of the present invention. , And the method for preparing the compound of Formula I to Compound VIII is not limited to those described below.

<실시예><Examples>

합성예 1. [화학식 A] 및 [화학식 B]의 합성Synthesis Example 1. Synthesis of [Formula A] and [Formula B]

하기 [반응식 1](반응조건 POCl3, DMF, 100 , 23 h)에 따라 [화학식 A], [화학식 B]로 표시되는 화합물을 합성하였다.Compounds represented by [Formula A] and [Formula B] were synthesized according to the following [Scheme 1] (reaction conditions POCl 3 , DMF, 100, 23 h).

[반응식 1][Reaction Scheme 1]

Figure pat00076
Figure pat00076

[화학식 A] [화학식 B][Formula A] [Formula B]

반응기에 POCl3 (6 eq, 7.07 mL)을 넣고 ice bath를 사용하여 0 ℃로 냉각 시킨 후 DMF(dimethylformamide, 2.1 eq. 2.03 mL)를 천천히 넣어주고 상온에서 1 시간 동안 교반하였다. 이후, 4,6-디하이드록시-2-(메틸티오)피리미딘 (2 g, 12.6 mmol)을 천천히 투여하고 23 시간 동안 100 ℃ 가열 교반하였다. 반응 종료 후 반응물을 상온으로 냉각시키고, 얼음물에 반응 혼합물을 붓고 6 시간 동안 정체시켰다. 이때 생성된 갈색 침전물은 여과를 통해서 분리하고 여액은 포화 NaHCO3 수용액과 EtOAc (2×30 mL)를 사용해서 추출하고 유기층은 무수 MgSO4을 사용하여 소량의 물을 제거하였으며, 감압 증류하여 용매를 제거하고 진공 건조한 후 EtOAc/hexanes을 이용한 결정화 방법으로 갈색의 고체상 화합물 [화학식 A], [화학식 B]을 얻었다.
POCl 3 in the reactor (6 eq, 7.07 mL) was added and the mixture was cooled to 0 ° C. using an ice bath. Then, DMF (dimethylformamide, 2.1 eq. 2.03 mL) was slowly added thereto and stirred at room temperature for 1 hour. Thereafter, 4,6-dihydroxy-2- (methylthio) pyrimidine (2 g, 12.6 mmol) was slowly administered and stirred with heating at 100 ° C. for 23 hours. After the reaction was completed, the reaction was cooled to room temperature, the reaction mixture was poured into iced water and held for 6 hours. The resulting brown precipitate is separated by filtration and the filtrate is saturated with NaHCO 3. Aqueous solution was extracted with EtOAc (2 × 30 mL) and the organic layer was removed with a small amount of water using anhydrous MgSO 4 , distilled under reduced pressure to remove the solvent, dried in vacuo and crystallized with EtOAc / hexanes to give a brown solid phase. The compound [Formula A] and [Formula B] were obtained.

(1) [화학식 A] 4,6-디클로로-2-(메틸티오)피리미딘-5-카바알데하이드(1) 4,6-dichloro-2- (methylthio) pyrimidine-5-carbaaldehyde

Yield: 65%; 1H NMR (400 MHz, CDCl3) δ 2.71 (s, 3H), 10.43 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.7, 119.0, 162.3, 177.0, 185.3.
Yield: 65%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.71 (s, 3H), 10.43 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.7, 119.0, 162.3, 177.0, 185.3.

(2) [화학식 B] 4,6-디클로로-2-(메틸티오)피리미딘(2) 4,6-dichloro-2- (methylthio) pyrimidine

Yield: 42%; 1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 7.04 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.4, 115.6, 161.2, 174.4.
Yield: 42%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.57 (s, 3H), 7.04 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.4, 115.6, 161.2, 174.4.

실시예 1. 4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘, [4]Example 1. 4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine, [4]

하기 [반응식 2](반응조건 PPh3, DIAD, R1OH, THF, N2, 0 ℃-상온, 6 h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [4]를 합성하였다.The pyrazolopyrimidine derivative compound [4] according to the present invention was synthesized by the following [Scheme 2] (reaction conditions PPh 3 , DIAD, R 1 OH, THF, N 2 , 0 ° C.-room temperature, 6 h).

[반응식 2][Reaction Scheme 2]

Figure pat00077
Figure pat00077

[화학식 A] [4]Formula A] [4]

4,6-디클로로-2-(메틸티오)피리미딘-5-카바알데하이드(1.2 g, 5.38 mmol)를 THF/H2O(3:1, 24 mL)에 넣고 교반하는 상태에서 H2O(4 mL)에 하이드라진 하이드레이트(1.5 eq, 0.39 mL)을 섞은 것을 가하고, 상온에서 4 시간을 교반하였다. 그 후 반응 용매의 부피를 줄인 후에 디에틸에테르를 가하였다. 그 후 유기층만을 따로 분리하여 무수 MgSO4로 수분을 제거한 후 감압증류를 하였다. 여기서 얻은 반응 혼합물을 flash chromatography (hexanes : EtOAc = 4:1)로 분리하여 옅은 노란색 고체상의 화합물, 4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [4]를 얻었다.4,6-Dichloro-2- (methylthio) pyrimidine-5-carbaaldehyde (1.2 g, 5.38 mmol) was added to THF / H 2 O (3: 1, 24 mL) and stirred with H 2 O ( 4 mL) was added to the mixture of hydrazine hydrate (1.5 eq, 0.39 mL), followed by stirring at room temperature for 4 hours. Thereafter, the volume of the reaction solvent was reduced and then diethyl ether was added. Thereafter, only the organic layer was separated, and water was removed with anhydrous MgSO 4 , followed by distillation under reduced pressure. The reaction mixture obtained here was separated by flash chromatography (hexanes: EtOAc = 4: 1) to give 4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [4] as a pale yellow solid. Got it.

Yield: 76%; 1H NMR (400 MHz, CDCl3) δ 2.67 (s, 3H), 8.13 (s, 1H), 11.45 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 14.6, 110.2, 134.0, 154.4, 155.5, 171.1.
Yield: 76%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.67 (s, 3H), 8.13 (s, 1H), 11.45 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.6, 110.2, 134.0, 154.4, 155.5, 171.1.

실시예 2. [5a] 내지 [5d]의 합성Example 2. Synthesis of [5a] to [5d]

하기 [반응식 3](반응조건 R1-N2H4, Hunig base, THF, 상온, 24 h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [5a] 내지 [5k]를 합성하였다.The pyrazolopyrimidine derivative compounds [5a] to [5k] were synthesized by the following Reaction Scheme 3 (reaction conditions R 1 -N 2 H 4 , Hunig base, THF, room temperature, 24 h).

[반응식 3]Scheme 3

Figure pat00078
Figure pat00078

[4] [5a] ~ [5d][4] [5a]-[5d]

상기 실시예 1에서 합성한 [4]와 Ph3P (1.5 eq)를 THF에 넣고 0 ℃로 낮추어 15분 동안 교반하였다. 그 후, R1OH (1.1 eq)을 넣고 다이아이소프로필 아조디카르복실레이트(1.5 eq)를 2 분간 천천히 가해준 후 2 시간 동안을 0 ℃로 유지한 상태에서 교반시켜준 후 4 시간을 상온에서 교반시켰다. 반응 혼합물을 감압증류를 시킨 후, flash chromatography (hexanes : EtOAc = 9:1)을 통하여 분리하여 원하는 화합물 [5a] 내지 [5d]를 얻었다.[4] and Ph 3 P (1.5 eq) synthesized in Example 1 were added to THF, and the mixture was stirred at 0 ° C. for 15 minutes. Then, R 1 OH (1.1 eq) was added and diisopropyl azodicarboxylate (1.5 eq) was added slowly for 2 minutes, and stirred for 2 hours at 0 ° C., followed by 4 hours at room temperature. Stirred at. The reaction mixture was evaporated under reduced pressure, and then separated through flash chromatography (hexanes: EtOAc = 9: 1) to obtain desired compounds [5a] to [5d].

[5a] 내지 [5d]에서 R1은 각각 하기 [표 1]과 같다.R 1 in [5a] to [5d] is as shown in the following [Table 1], respectively.

구분division R1 R 1 구분division R1 R 1 5a5a CH3 CH 3 5c5c

Figure pat00079
Figure pat00079
5b5b
Figure pat00080
Figure pat00080
 5d5d
Figure pat00081
Figure pat00081

(1) 1-메틸-4-클롤로-6-(메틸티오)피라졸로[3,4-d]피리미딘, [5a](1) 1-methyl-4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine, [5a]

Yield: 79%; 1H NMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H), 3.98 (s, 3H), 8.31 (s, 1H).
Yield: 79%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.64 (s, 3H), 3.98 (s, 3H), 8.31 (s, 1H).

(2) 1-알릴-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [5b](2) 1-allyl-4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [5b]

Yield: 70%; 1H NMR (400 MHz, CDCl3) δ 2.61 (s, 3H), 5.03 (d, J = 5.9Hz, 2H), 5.29 (d, J = 11.3 Hz, 2H), 5.98-6.08 (m, 1H), 8.07 (s, 1H).
Yield: 70%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.61 (s, 3H), 5.03 (d, J = 5.9 Hz, 2H), 5.29 (d, J = 11.3 Hz, 2H), 5.98-6.08 (m, 1H) , 8.07 (s, 1 H).

(3) 1-[2-(테트라하이드로피란-2-일옥시)에틸]-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [5c](3) 1- [2- (tetrahydropyran-2-yloxy) ethyl] -4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [5c]

Yield: 78%; 1H NMR (400 MHz, DMSO-d6) δ 2.61 (s, 3H), 3.86 (quar, J = 5.2 Hz, 2H), 4.43 (t, J = 5.6 Hz, 2H), 4.86 (t, J = 5.3 Hz, 1H), 8.34 (s, 1H).
Yield: 78%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.61 (s, 3H), 3.86 (quar, J = 5.2 Hz, 2H), 4.43 (t, J = 5.6 Hz, 2H), 4.86 (t, J = 5.3 Hz, 1H), 8.34 (s, 1H).

(4) 1-[N-t-Boc-(2-아미노에틸)]-4-클로로-6-(m메틸티오)피라졸로[3,4-d]피리미딘 [5d](4) 1- [N-t-Boc- (2-aminoethyl)]-4-chloro-6- (mmethylthio) pyrazolo [3,4-d] pyrimidine [5d]

Yield: 77%; 1H NMR (400 MHz, DMSO-d6) δ 1.23 (s, 9H), 2.62 (s, 3H), 3.37 (quar, J = 5.8 Hz, 2H), 4.42 (t, J = 5.4 Hz, 2H), 6.87 (t, J = 5.8 Hz, 1H), 8.33 (s, 1H).
Yield: 77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.23 (s, 9H), 2.62 (s, 3H), 3.37 (quar, J = 5.8 Hz, 2H), 4.42 (t, J = 5.4 Hz, 2H) , 6.87 (t, J = 5.8 Hz, 1H), 8.33 (s, 1H).

실시예 3. [5e] 내지 [5k]의 합성Example 3. Synthesis of [5e] to [5k]

하기 [반응식 4]에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [5a] 내지 [5k]를 합성하였다.The pyrazolopyrimidine derivative compounds [5a] to [5k] according to the present invention were synthesized by the following [Scheme 4].

[반응식 4][Reaction Scheme 4]

Figure pat00082
Figure pat00082

[화학식 A] [5e] ~ [5k]   [Formula A] [5e]-[5k]

[5a] 내지 [5d]에서 R1은 각각 하기 [표 2]와 같다.R 1 in [5a] to [5d] is as shown in the following [Table 2], respectively.

구분division R1 R 1 구분division R1 R 1 5e5e

Figure pat00083
Figure pat00083
5i5i
Figure pat00084
Figure pat00084
 5f5f
Figure pat00085
Figure pat00085
 5j5j
Figure pat00086
Figure pat00086
 5g5g
Figure pat00087
Figure pat00087
 5k5k
Figure pat00088
Figure pat00088
 5h5h
Figure pat00089
Figure pat00089

(1) 1-페닐-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [5e](1) 1-phenyl-4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [5e]

4,6-디클로로-2-(메틸티오)피리미딘-5-카바알데하이드 (1.3 g, 5.83 mmol)과 Hunig base (1 eq, 1.02 mL)를 THF/H2O (3:1, 20 mL)에 넣고 교반하는 상태에서 페닐하이드라진 (1.1 eq, 0.63 mL)을 가하고, 상온에서 4 시간을 교반하였다. 그 후 반응 용매의 부피를 줄인 후에 EtOAc를 가하였다. 유기층만을 따로 분리하여 무수 MgSO4로 수분을 제거한 후에 evaporation을 하였다. 여기서 얻은 반응 혼합물을 flash chromatography (hexanes : EtOAc = 8:1)로 분리하여 하얀색 고체상 화합물 [5e]를 얻었다.4,6-dichloro-2- (methylthio) pyrimidine-5-carbaaldehyde (1.3 g, 5.83 mmol) and Hunig base (1 eq, 1.02 mL) were mixed with THF / H 2 O (3: 1, 20 mL). Phenylhydrazine (1.1 eq, 0.63 mL) was added to the mixture, and stirred for 4 hours at room temperature. The volume of reaction solvent was then reduced and then EtOAc was added. Only the organic layer was separated and removed with anhydrous MgSO 4 , and then evaporated. The reaction mixture thus obtained was separated by flash chromatography (hexanes: EtOAc = 8: 1) to obtain a white solid compound [5e].

Yield: 61%; 1H NMR (400 MHz, DMSO-d6) δ 2.63 (s, 3H), 7.43 (t, J = 9.1 Hz, 1H), 7.60 (t, J = 8.0 Hz, 2H), 8.15 (d, J = 7.7 Hz, 2H), 8.60 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.5, 112.1, 121.3, 127.6, 129.9, 134.9, 138.3, 153.5, 153.9, 170.6.
Yield: 61%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.63 (s, 3H), 7.43 (t, J = 9.1 Hz, 1H), 7.60 (t, J = 8.0 Hz, 2H), 8.15 (d, J = 7.7 Hz, 2H), 8.60 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.5, 112.1, 121.3, 127.6, 129.9, 134.9, 138.3, 153.5, 153.9, 170.6.

(2) 1-벤질-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [5f](2) 1-benzyl-4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [5f]

상기 실시예 3-(1)과 동일한 방법으로 합성하고, 4,6-디클로로-2-(메틸티오)피리미딘-5-카바알데하이드와 벤질 하이드라진 모노하이드로클로라이드로부터 연한 노란색의 고체상 화합물 [5f]를 얻었다.Synthesis was carried out in the same manner as in Example 3- (1), and a pale yellow solid compound [5f] was obtained from 4,6-dichloro-2- (methylthio) pyrimidine-5-carbaaldehyde and benzyl hydrazine monohydrochloride. Got it.

Yield: 63%; 1H NMR (400 MHz, CDCl3) δ 2.62 (s, 3H), 5.57 (s, 2H), 7.25-7.36 (m, 5H), 8.01 (s, 1H).
Yield: 63%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.62 (s, 3H), 5.57 (s, 2H), 7.25-7.36 (m, 5H), 8.01 (s, 1H).

(3) 1-t-뷰틸-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [5g](3) 1-t-butyl-4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [5 g]

상기 실시예 3-(1)과 동일한 방법으로 합성하고, 4,6-디클로로-2-(메틸티오)피리미딘-5-카바알데하이드와 t-뷰틸하이드라진 디하이드로클로라이드로부터 연한 노란색의 고체상 화합물 [5g]를 얻었다.Synthesis was carried out in the same manner as in Example 3- (1), and was pale yellow solid compound from 4,6-dichloro-2- (methylthio) pyrimidine-5-carbaaldehyde and t-butylhydrazine dihydrochloride [5 g ] Was obtained.

Yield: 42%; 1H NMR (400 MHz, DMSO-d6) δ 1.65 (s, 9H), 2.54 (s, 3H), 8.82 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.3, 29.6, 62.4, 109.7, 124.5, 155.2, 159.7, 167.8.
Yield: 42%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.65 (s, 9H), 2.54 (s, 3H), 8.82 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.3, 29.6, 62.4, 109.7, 124.5, 155.2, 159.7, 167.8.

(4) 1-(4-플루오로페닐)-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [5h](4) 1- (4-fluorophenyl) -4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [5h]

상기 실시예 3-(1)과 동일한 방법으로 합성하고, 4,6-디클로로-2-(메틸티오)피리미딘-5-카바알데하이드와 4-플루오로페닐하이드라진 하이드로클로라이드로부터 연한 오렌지색의 고체상 화합물 [5h]를 얻었다.It was synthesized in the same manner as in Example 3- (1), and was pale orange solid compound from 4,6-dichloro-2- (methylthio) pyrimidine-5-carbaaldehyde and 4-fluorophenylhydrazine hydrochloride [ 5h].

Yield: 64%; 1H NMR (400 MHz, DMSO-d6) δ 2.63 (s, 3H), 7.46 (t, J = 8 Hz, 2H), 8.17 (dd, J = 4 Hz, 3 Hz, 2H), 8.61 (s, 1H)
Yield: 64%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.63 (s, 3H), 7.46 (t, J = 8 Hz, 2H), 8.17 (dd, J = 4 Hz, 3 Hz, 2H), 8.61 (s , 1H)

(5) 1-(4-메틸페닐)-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [5i](5) 1- (4-methylphenyl) -4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [5i]

상기 실시예 3-(1)과 동일한 방법으로 합성하고, 4,6-디클로로-2-(메틸티오)피리미딘-5-카바알데하이드와 4-메틸페닐하이드라진 하이드로클로라이드로부터 연한 노란색의 고체상 화합물 [5i]를 얻었다.It was synthesized in the same manner as in Example 3- (1), and was pale yellow solid compound from 4,6-dichloro-2- (methylthio) pyrimidine-5-carbaaldehyde and 4-methylphenylhydrazine hydrochloride [5i] Got.

Yield: 57%; 1H NMR (400 MHz, DMSO-d6) δ 2.43 (s, 3H), 2.61 (s, 3H), 7.37 (d, J = 8 Hz, 2H), 7.97 (d, J = 8 Hz, 2H), 8.56 (s, 1H); 13C NMR (400 MHz, DMSO-d6) δ 14.5, 21.0, 111.9, 121.2, 130.2, 134.5, 135.9, 137.0, 153.3, 153.8, 170.4.
Yield: 57%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.43 (s, 3H), 2.61 (s, 3H), 7.37 (d, J = 8 Hz, 2H), 7.97 (d, J = 8 Hz, 2H) , 8.56 (s, 1 H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.5, 21.0, 111.9, 121.2, 130.2, 134.5, 135.9, 137.0, 153.3, 153.8, 170.4.

(6) 1-(3-메톡시펜에틸)-4-클로로-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [5j](6) 1- (3-methoxyphenethyl) -4-chloro-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [5j]

상기 실시예 3-(1)과 동일한 방법으로 합성하고, 4,6-디클로로-2-(메틸티오)피리미딘-5-카바알데하이드와 3-메톡시펜에틸하이드라진 하이드로클로라이드로부터 연한 노란색의 고체상 화합물 [5j]를 얻었다.It was synthesized in the same manner as in Example 3- (1), and was pale yellow solid compound from 4,6-dichloro-2- (methylthio) pyrimidine-5-carbaaldehyde and 3-methoxyphenethylhydrazine hydrochloride. [5j] was obtained.

Yield: 76.46%; 1H NMR (400 MHz, DMSO-d6) δ 3.10 (t, J = 6.8 Hz, 2H), 3.30 (s, 3H), 3.61 (s, 3H), 4.59 (t, J = 6.8 Hz, 2H), 6.56-6.66 (m, 3H), 7.03 (t, J = 7.8 Hz, 1H), 8.27 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.2, 35.2, 48.6, 55.2, 100.8, 110.1, 112.3, 114.6, 121.2, 129.6, 132.9, 139.8, 153.1, 154.0, 159.5, 169.0.
Yield: 76.46%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.10 (t, J = 6.8 Hz, 2H), 3.30 (s, 3H), 3.61 (s, 3H), 4.59 (t, J = 6.8 Hz, 2H) , 6.56-6.66 (m, 3H), 7.03 (t, J = 7.8 Hz, 1H), 8.27 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.2, 35.2, 48.6, 55.2, 100.8, 110.1, 112.3, 114.6, 121.2, 129.6, 132.9, 139.8, 153.1, 154.0, 159.5, 169.0.

(7) 1-(2-메톡시펜에틸)-4-클로로-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [5k](7) 1- (2-methoxyphenethyl) -4-chloro-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [5k]

상기 실시예 3-(1)과 동일한 방법으로 합성하고, 4,6-디클로로-2-(메틸티오)피리미딘-5-카바알데하이드와 2-메톡시펜에틸하이드라진 하이드로클로라이드로부터 연한 노란색의 고체상 화합물 [5k]를 얻었다.It was synthesized in the same manner as in Example 3- (1), and was pale yellow solid compound from 4,6-dichloro-2- (methylthio) pyrimidine-5-carbaaldehyde and 2-methoxyphenethylhydrazine hydrochloride. [5k] was obtained.

Yield: 72.51%; 1H NMR (400 MHz, DMSO-d6) δ 2.51 (s, 3H), 3.10 (t, J = 6.8 Hz, 2H), 3.71 (s, 3H), 4.59 (t, J = 6.8 Hz, 2H), 6.70 (t, J = 7.3 Hz, 1H), 6.84-6.90 (m, 2H), 7.14 (t, J = 7.0Hz, 1H), 8.29 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.1, 30.7, 47.4, 55.6, 110.1, 110.9, 120.5, 126.0, 128.5, 130.5, 132.7, 153.1, 153.9, 157.7, 168.9.
Yield: 72.51%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.51 (s, 3H), 3.10 (t, J = 6.8 Hz, 2H), 3.71 (s, 3H), 4.59 (t, J = 6.8 Hz, 2H) , 6.70 (t, J = 7.3 Hz, 1H), 6.84-6.90 (m, 2H), 7.14 (t, J = 7.0 Hz, 1H), 8.29 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 30.7, 47.4, 55.6, 110.1, 110.9, 120.5, 126.0, 128.5, 130.5, 132.7, 153.1, 153.9, 157.7, 168.9.

실시예 4. [6a] 내지 [6y]의 합성Example 4. Synthesis of [6a] to [6y]

하기 [반응식 5](반응조건 R2N(1.1 eq), 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [6a] 내지 [6y]를 합성하였다.The pyrazolopyrimidine derivative compounds [6a] to [6y] were synthesized according to the following Reaction Scheme 5 (reaction conditions R 2 N (1.1 eq), 1,4-dioxane, reflux, 8h).

[반응식 5][Reaction Scheme 5]

Figure pat00090
Figure pat00090

[4] [6a] ~ [6y][4] [6a] to [6y]

[6a] 내지 [6y]에서 R1은 각각 하기 [표 3]과 같다.In [6a] to [6y], each R 1 is as shown in Table 3 below.

구분division NR2 NR 2 구분division NR2 NR 2 6a6a

Figure pat00091
Figure pat00091
6n6n
Figure pat00092
Figure pat00092
 6b6b
Figure pat00093
Figure pat00093
 6o6o
Figure pat00094
Figure pat00094
 6c6c
Figure pat00095
Figure pat00095
 6p6p
Figure pat00096
Figure pat00096
 6d6d
Figure pat00097
Figure pat00097
 6q6q
Figure pat00098
Figure pat00098
 6e6e
Figure pat00099
Figure pat00099
 6r6r
Figure pat00100
Figure pat00100
 6f6f
Figure pat00101
Figure pat00101
 6s6s
Figure pat00102
Figure pat00102
 6g6 g
Figure pat00103
Figure pat00103
 6t6t
Figure pat00104
Figure pat00104
 6h6h
Figure pat00105
Figure pat00105
 6u6u
Figure pat00106
Figure pat00106
 6i6i
Figure pat00107
Figure pat00107
 6v6v
Figure pat00108
Figure pat00108
 6j6j
Figure pat00109
Figure pat00109
 6w6w
Figure pat00110
Figure pat00110
 6k6k
Figure pat00111
Figure pat00111
 6x6x
Figure pat00112
Figure pat00112
 6l6l
Figure pat00113
Figure pat00113
 6y6y
Figure pat00114
Figure pat00114
 6m6m
Figure pat00115
Figure pat00115

(1) 4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6a](1) 4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6a]

상기 [4] (430 mg, 2.14 mmol)과 벤질아민 (1.1 eq, 0.26 mL)을 1,4-dioxane (5 mL)에 넣고 8 시간 동안 reflux를 하였다. 반응 혼합물을 EtOAc/H2O 혼합용매로 층 분리를 한 다음 유기층만 따로 분리하여 무수 MgSO4로 수분을 제거하고 감압증류 하였다. 반응 혼합물을 flash chromatography (CH2Cl2 : CH3OH = 10 : 1)로 분리하여 옅은 노란색의 고체상 화합물 [6a]를 얻었다.[4] (430 mg, 2.14 mmol) and benzylamine (1.1 eq, 0.26 mL) were added to 1,4-dioxane (5 mL) and refluxed for 8 hours. The reaction mixture was separated by EtOAc / H 2 O mixed solvent, and then the organic layer was separated and the water was removed with anhydrous MgSO 4 and distilled under reduced pressure. The reaction mixture was separated by flash chromatography (CH 2 Cl 2 : CH 3 OH = 10: 1) to give a pale yellow solid compound [6a].

Yield: 84%; 1H NMR (400 MHz, CD3OD-d4) δ 2.49 (s, 3H), 4.78 (s, 2H), 7.23 (t, J = 7 Hz, 1H), 7.31 (t, J = 7 Hz, 2H), 7.36 (d, J = 7 Hz, 2H), 7.97 (s, 1H) ; 13C NMR (100 MHz, CD3OD-d4) δ 12.8, 43.7, 97.8, 126.7, 127.3, 128.1, 132.0, 138.9, 155.3, 155.8, 170.2.
Yield: 84%; 1 H NMR (400 MHz, CD 3 OD-d 4 ) δ 2.49 (s, 3H), 4.78 (s, 2H), 7.23 (t, J = 7 Hz, 1H), 7.31 (t, J = 7 Hz, 2H), 7.36 (d, J = 7 Hz, 2H), 7.97 (s, 1H); 13 C NMR (100 MHz, CD 3 OD-d 4 ) δ 12.8, 43.7, 97.8, 126.7, 127.3, 128.1, 132.0, 138.9, 155.3, 155.8, 170.2.

(2) 4-알릴아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6b](2) 4-allylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6b]

상기 [4]와 알릴아민으로부터 옅은 노란색의 고체상 화합물 [6b]를 얻었다.A pale yellow solid compound [6b] was obtained from the above [4] and allylamine.

Yield: 78%; 1H NMR (400 MHz, DMSO-d6) δ 2.43 (s, 3H), 4.10 (t, J = 4.7 Hz, 2H), 5.12 (d, J = 10.2 Hz, 2H), 5.21 (d, J = 17.2 Hz, 2H), 5.89-5.98 (m, 1H), 8.02 (s, 1H), 8.39 (s, 1H), 13.20 (s, 1H).
Yield: 78%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.43 (s, 3H), 4.10 (t, J = 4.7 Hz, 2H), 5.12 (d, J = 10.2 Hz, 2H), 5.21 (d, J = 17.2 Hz, 2H), 5.89-5.98 (m, 1H), 8.02 (s, 1H), 8.39 (s, 1H), 13.20 (s, 1H).

(3) 4-펜에틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6c](3) 4-phenethylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6c]

상기 [4]와 펜에틸아민으로부터 옅은 노란색의 고체상 화합물 [6c]를 얻었다.A pale yellow solid compound [6c] was obtained from the above [4] and phenethylamine.

Yield: 56%; 1H NMR (400 MHz, DMSO-d6) δ 2.46 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 3.65 (quar, J = 6.8 Hz, 2H), 7.17-7.31 (m, 5H), 7.98 (s, 1H), 8.34 (t, J = 5.2 Hz, 1H), 13.18 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 14.0, 35.2, 42.0, 98.1, 126.6, 128.8, 129.1, 132.8, 139.8, 155.5, 155.7, 168.6.
Yield: 56%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 3.65 (quar, J = 6.8 Hz, 2H), 7.17-7.31 (m, 5H), 7.98 (s, 1 H), 8.34 (t, J = 5.2 Hz, 1 H), 13.18 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 35.2, 42.0, 98.1, 126.6, 128.8, 129.1, 132.8, 139.8, 155.5, 155.7, 168.6.

(4) 4-(4-플루오로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6d] (4) 4- (4-fluorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6d]

상기 [4]와 4-플루오로벤질아민으로부터 옅은 노란색의 고체상 화합물 [6d]를 얻었다.A pale yellow solid compound [6d] was obtained from the above [4] and 4-fluorobenzylamine.

Yield: 72%; 1H NMR (400 MHz, DMSO-d6) δ 2.42 (s, 3H), 4.66 (d, J = 5.6 Hz, 2H), 7.15 (t, J = 8.3 Hz, 2H), 7.38 (t, J = 6.7 Hz, 2H), 8.02 (s, 1H), 8.73 (t, J = 5.3 Hz, 1H), 13.24 (s, 1H); 13C NMR (400 MHz, DMSO-d6) δ 14.0, 42.9, 98.1, 115.4, 115.6, 129.9, 130.0, 132.9, 135.9, 155.6, 160.5, 162.9, 168.6.
Yield: 72%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.42 (s, 3H), 4.66 (d, J = 5.6 Hz, 2H), 7.15 (t, J = 8.3 Hz, 2H), 7.38 (t, J = 6.7 Hz, 2H), 8.02 (s, 1 H), 8.73 (t, J = 5.3 Hz, 1 H), 13.24 (s, 1 H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.0, 42.9, 98.1, 115.4, 115.6, 129.9, 130.0, 132.9, 135.9, 155.6, 160.5, 162.9, 168.6.

(5) 4-n-뷰틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6e](5) 4-n-butylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6e]

상기 [4]와 n-뷰틸아민으로부터 옅은 노란색의 고체상 화합물 [6e]를 얻었다.A pale yellow solid compound [6e] was obtained from the above [4] and n-butylamine.

Yield: 91%; 1H NMR (400 MHz, DMSO-d6) δ 0.90 (t, J = 7.3 Hz, 3H), 1.30-1.39 (m, 2H), 1.52-1.59 (m, 2H), 2.44 (s, 3H), 3.44 (quar, J = 6.5 Hz, 2H), 7.99 (s, 1H), 8.16 (s, 1H), 13.1 (s, 1H); 13C NMR (400 MHz, DMSO-d6) δ 13.9, 14.1, 20.1, 31.3, 98.1, 132.9, 155.4, 155.7, 168.6.
Yield: 91%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.90 (t, J = 7.3 Hz, 3H), 1.30-1.39 (m, 2H), 1.52-1.59 (m, 2H), 2.44 (s, 3H), 3.44 (quar, J = 6.5 Hz, 2H), 7.99 (s, 1H), 8.16 (s, 1H), 13.1 (s, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 13.9, 14.1, 20.1, 31.3, 98.1, 132.9, 155.4, 155.7, 168.6.

(6) 4-(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6f](6) 4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6f]

상기 [4]와 1-하이드록시에틸아민으로부터 옅은 노란색의 고체상 화합물 [6f]를 얻었다.The pale yellow solid compound [6f] was obtained from the above [4] and 1-hydroxyethylamine.

Yield: 84%; 1H NMR (400 MHz, DMSO-d6) δ 2.44 (s, 3H), 3.48-3.57 (m, 4H), 4.83 (t, J = 4.5 Hz, 1H), 8.02 (s, 1H), 8.25 (s, 1H), 13.16 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 13.9, 43.1, 59.9, 98.2, 133.0, 155.5, 155.9, 168.5.
Yield: 84%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 3.48-3.57 (m, 4H), 4.83 (t, J = 4.5 Hz, 1H), 8.02 (s, 1H), 8.25 ( s, 1 H), 13.16 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 43.1, 59.9, 98.2, 133.0, 155.5, 155.9, 168.5.

(7) 4-(2-피페리딘-1-일)에틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6g](7) 4- (2-piperidin-1-yl) ethylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6g]

상기 [4]와 2-(피페리딘-1-일)에틸아민으로부터 옅은 노란색의 고체상 화합물 [6g]를 얻었다.A pale yellow solid compound [6 g] was obtained from the above [4] and 2- (piperidin-1-yl) ethylamine.

Yield: 44%; 1H NMR (400 MHz, DMSO-d6) δ 1.36 (d, J = 5.0Hz, 2H), 1.47 (quin, J = 5.3 Hz, 4H), 2.37 (s, 4H), 2.44 (s, 3H), 3.54 (quar, J = 6.4 Hz, 2H), 7.99 (s, 1H), 8.16 (s, 1H), 13.19 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 13.9, 24.5, 26.0, 37.9, 54.6, 58.0, 98.2, 132.7, 155.6, 155.8, 168.5.
Yield: 44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.36 (d, J = 5.0 Hz, 2H), 1.47 (quin, J = 5.3 Hz, 4H), 2.37 (s, 4H), 2.44 (s, 3H) , 3.54 (quar, J = 6.4 Hz, 2H), 7.99 (s, 1H), 8.16 (s, 1H), 13.19 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 24.5, 26.0, 37.9, 54.6, 58.0, 98.2, 132.7, 155.6, 155.8, 168.5.

(8) 4-(피리딘-2-일)메틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6h](8) 4- (pyridin-2-yl) methylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6h]

상기 [4]와 (피리딘-2-일)메틸아민으로부터 옅은 노란색의 고체상 화합물 [6h]를 얻었다.A pale yellow solid compound [6h] was obtained from the above [4] and (pyridin-2-yl) methylamine.

Yield: 49%; 1H NMR (400 MHz, DMSO-d6) δ 2.31 (s, 3H), 4.76 (d, J = 5.7 Hz, 2H), 7.26 (t, J = 6.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 8.07 (s, 1H), 8.52 (d, J = 7.5 Hz, 1H), 8.86 (s, 1H), 13.2 (s, 1H).
Yield: 49%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.31 (s, 3H), 4.76 (d, J = 5.7 Hz, 2H), 7.26 (t, J = 6.1 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 7.5 Hz, 1H), 8.07 (s, 1H), 8.52 (d, J = 7.5 Hz, 1H), 8.86 (s, 1H), 13.2 (s, 1H) .

(9) 4-(3-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6i](9) 4- (3-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6i]

상기 [4]와 3-메톡시벤질아민으로부터 옅은 노란색의 고체상 화합물 [6i]를 얻었다.A pale yellow solid compound [6i] was obtained from the above [4] and 3-methoxybenzylamine.

Yield: 59%; 1H NMR (400 MHz, DMSO-d6) δ 2.43 (s, 3H), 3.71 (s, 3H), 4.65 (d, J = 5.7Hz, 2H), 6.82 (d, J = 7.0Hz, 1H), 6.89 (d, J = 9.4Hz, 2H), 7.24 (t, J = 7.8Hz, 1H), 8.03 (s, 1H), 8.72 (t, J = 5.3Hz, 1H), 13.23 (s, 1H).
Yield: 59%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.43 (s, 3H), 3.71 (s, 3H), 4.65 (d, J = 5.7 Hz, 2H), 6.82 (d, J = 7.0 Hz, 1H) , 6.89 (d, J = 9.4 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1H), 8.03 (s, 1H), 8.72 (t, J = 5.3 Hz, 1H), 13.23 (s, 1H) .

(10) 4-(1-사이클로헥실에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6j](10) 4- (1-cyclohexylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6j]

상기 [4]와 1-사이클로헥실에틸아민으로부터 옅은 노란색의 고체상 화합물 [6j]를 얻었다.A pale yellow solid compound [6j] was obtained from the above [4] and 1-cyclohexylethylamine.

Yield: 59%; 1H NMR (400MHz, DMSO-d6) δ 0.94-1.00 (m, 2H), 1.13 (d, J = 6.2Hz, 3H), 1.13 (br s, 3H), 1.43-1.76 (m, 6H), 2.42 (s, 3H), 4.17 (quar, J = 6.8Hz, 1H), 7.91 (d, J = 8.4Hz, 1H), 8.04 (s, 1H), 13.12 (s, 1H).
Yield: 59%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.94-1.00 (m, 2H), 1.13 (d, J = 6.2 Hz, 3H), 1.13 (br s, 3H), 1.43-1.76 (m, 6H), 2.42 (s, 3H), 4.17 (quar, J = 6.8 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 8.04 (s, 1H), 13.12 (s, 1H).

(11) (R)-4-(1-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6k](11) (R) -4- (1-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6k]

상기 [4]와 (R)-1-페닐에틸아민으로부터 옅은 노란색의 고체상 화합물 [6k]를 얻었다.A pale yellow solid compound [6k] was obtained from the above [4] and (R) -1-phenylethylamine.

Yield: 77%; 1H NMR (400 MHz, DMSO-d6) δ 1.51 (d, J = 7.0Hz, 3H), 2.37 (s, 3H), 5.42 (t, J = 7.1Hz, 1H), 7.21 (t, J = 7.2Hz, 1H), 7.31 (t, J = 7.5Hz, 2H), 7.38 (d, J = 7.4Hz, 2H), 8.09 (s, 1H), 8.59 (d, J = 7.5Hz, 1H), 13.1 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 13.9, 22.8, 49.4, 98.1, 126.5, 127.1, 128.7, 133.1, 145.1, 154.8, 155.6, 168.4.
Yield: 77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.51 (d, J = 7.0 Hz, 3H), 2.37 (s, 3H), 5.42 (t, J = 7.1 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.5 Hz, 2H), 7.38 (d, J = 7.4 Hz, 2H), 8.09 (s, 1H), 8.59 (d, J = 7.5 Hz, 1H), 13.1 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 22.8, 49.4, 98.1, 126.5, 127.1, 128.7, 133.1, 145.1, 154.8, 155.6, 168.4.

(12) 4-(2-하이드록시-1-다이메틸에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6l](12) 4- (2-hydroxy-1-dimethylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6l]

상기 [4]와 1-하이드록시-2-다이메틸에틸아민으로부터 옅은 노란색의 고체상 화합물 [6l]을 얻었다.A pale yellow solid compound [6l] was obtained from the above [4] and 1-hydroxy-2-dimethylethylamine.

Yield: 72%; 1H NMR (400MHz, DMSO-d6) δ 1.38 (s, 6H), 2.44 (s, 3H), 3.65 (d, J = 5.7Hz, 2H), 4.93 (t, J = 5.4Hz, 1H), 7.40 (s, 1H), 8.12 (s, 1H), 13.11 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 24.5, 56.4, 67.1, 98.7, 133.4, 155.4, 155.7, 167.8.
Yield: 72%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.38 (s, 6H), 2.44 (s, 3H), 3.65 (d, J = 5.7 Hz, 2H), 4.93 (t, J = 5.4 Hz, 1H), 7.40 (s, 1 H), 8.12 (s, 1 H), 13.11 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 24.5, 56.4, 67.1, 98.7, 133.4, 155.4, 155.7, 167.8.

(13) 4-(3-이미다졸-1-일)프로판아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6m](13) 4- (3-imidazol-1-yl) propanamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6m]

상기 [4]와 (3-이미다졸-1-일)프로판아민으로부터 옅은 노란색의 고체상 화합물 [6m]을 얻었다.A pale yellow solid compound [6m] was obtained from the above [4] and (3-imidazol-1-yl) propanamine.

Yield: 18%; 1H NMR (400MHz, DMSO-d6) δ 2.02 (t, J = 6.9Hz, 2H), 2.42 (s, 3H), 3.40 (quar, J = 6.2Hz, 2H), 4.04 (t, J = 6.7Hz, 2H), 6.88 (s, 1H), 7.20 (s, 1H), 7.64 (s, 1H), 8.23 (s, 1H).
Yield: 18%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.02 (t, J = 6.9 Hz, 2H), 2.42 (s, 3H), 3.40 (quar, J = 6.2 Hz, 2H), 4.04 (t, J = 6.7 Hz, 2H), 6.88 (s, 1H), 7.20 (s, 1H), 7.64 (s, 1H), 8.23 (s, 1H).

(14) 4-(4-메틸피페라지노)-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6n](14) 4- (4-methylpiperazino) -6- (methylthio) pyrazolo [3,4-d] pyrimidine [6n]

상기 [4]와 4-메틸피페라진으로부터 옅은 노란색의 고체상 화합물 [6n]을 얻었다.A pale yellow solid compound [6n] was obtained from the above [4] and 4-methylpiperazine.

Yield: 93%; 1H NMR (400MHz, CDCl3) δ 2.39 (s, 3H), 2.59 (d, J = 5.0Hz, 4H), 2.60 (s, 3H), 4.02 (m, 4H), 7.93 (s, 1H); 13C NMR (100MHz, CDCl3) δ 14.2, 45.9, 50.4, 54.5, 97.8, 133.7, 155.8, 156.8, 168.9.
Yield: 93%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.39 (s, 3H), 2.59 (d, J = 5.0 Hz, 4H), 2.60 (s, 3H), 4.02 (m, 4H), 7.93 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.2, 45.9, 50.4, 54.5, 97.8, 133.7, 155.8, 156.8, 168.9.

(15) 4-(디-2-하이드로에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6o](15) 4- (di-2-hydroethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6o]

상기 [4]와 디에탄올아민으로부터 하얀색의 고체상 화합물 [6o]를 얻었다.From the above [4] and diethanolamine, a white solid compound [6o] was obtained.

Yield: 92%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 3.66 (br s, 4H), 3.79 (br s, 4H), 4.78 (s, 1H), 4.97 (s, 1H), 7.97 (s, 1H), 13.26 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 52.0, 53.1, 58.9, 97.4, 134.5, 155.9, 156.5, 167.5.
Yield: 92%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 3.66 (br s, 4H), 3.79 (br s, 4H), 4.78 (s, 1H), 4.97 (s, 1H), 7.97 (s, 1 H), 13.26 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 52.0, 53.1, 58.9, 97.4, 134.5, 155.9, 156.5, 167.5.

(16) 4-(4-클로로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6p](16) 4- (4-chlorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6p]

상기 [4]와 4-클로로벤질아민으로부터 옅은 노란색의 고체상 화합물 [6p]를 얻었다.A pale yellow solid compound [6p] was obtained from the above [4] and 4-chlorobenzylamine.

Yield: 93%; 1H NMR (400MHz, DMSO-d6) δ 2.41 (s, 3H), 4.67 (d, J = 5.7Hz, 2H), 7.34-7.39 (m, 3H), 8.02 (s, 1H), 8.76 (t, J = 5.3Hz, 1H), 13.24 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 42.9, 98.1, 128.7, 129.7, 131.9, 132.9, 138.8, 155.6, 168.6.
Yield: 93%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.41 (s, 3H), 4.67 (d, J = 5.7 Hz, 2H), 7.34-7.39 (m, 3H), 8.02 (s, 1H), 8.76 (t , J = 5.3 Hz, 1H), 13.24 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 42.9, 98.1, 128.7, 129.7, 131.9, 132.9, 138.8, 155.6, 168.6.

(17) 4-(4-메틸벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6q](17) 4- (4-methylbenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6q]

상기 [4]와 4-메틸벤질아민으로부터 하얀색의 고체상 화합물 [6q]를 얻었다.White solid compound [6q] was obtained from the above [4] and 4-methylbenzylamine.

Yield: 75%; 1H NMR (400MHz, DMSO-d6) δ 2.20 (s, 3H), 2.42 (s, 3H), 4.63 (d, J = 5.6Hz, 2H), 7.13 (d, J = 7.8Hz, 2H), 7.23 (t, J = 7.9Hz, 2H), 8.02 (s, 1H), 8.68 (s, 1H), 13.21 (s, 1H).
Yield: 75%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.20 (s, 3H), 2.42 (s, 3H), 4.63 (d, J = 5.6 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 7.23 (t, J = 7.9 Hz, 2H), 8.02 (s, 1H), 8.68 (s, 1H), 13.21 (s, 1H).

(18) 4-(2-메틸벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6r](18) 4- (2-methylbenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6r]

상기 [4]와 2-메틸벤질아민으로부터 하얀색의 고체상 화합물 [6r]을 얻었다.White solid compound [6r] was obtained from the above [4] and 2-methylbenzylamine.

Yield: 80%; 1H NMR (400MHz, DMSO-d6) δ 2.32 (s, 3H), 2.42 (s, 3H), 4.65 (d, J = 5.4Hz, 2H), 7.14-7.17 (m, 3H), 7.28 (d, J = 5.9Hz, 1H), 8.06 (s, 1H), 8.56 (s, 1H), 13.2 (s, 1H).
Yield: 80%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.32 (s, 3H), 2.42 (s, 3H), 4.65 (d, J = 5.4 Hz, 2H), 7.14-7.17 (m, 3H), 7.28 (d , J = 5.9 Hz, 1H), 8.06 (s, 1H), 8.56 (s, 1H), 13.2 (s, 1H).

(19) 4-피페리디노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6s](19) 4-piperidino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6s]

상기 [4]와 피페리딘으로부터 옅은 노란색의 고체상 화합물 [6s]를 얻었다.A pale yellow solid compound [6s] was obtained from [4] and piperidine.

Yield: 98%; 1H NMR (400MHz, DMSO-d6) δ 1.59 (d, J = 3.5Hz, 4H), 1.66 (d, J = 4.4Hz, 2H), 2.44 (s, 3H), 3.85 (d, J = 5.2Hz, 4H), 8.14 (s, 1H), 13.3 (br s, 1H); 13C NMR (400MHz, DMSO-d6) δ 13.9, 24.3, 25.8, 97.4, 134,2, 155.5, 156.9, 167.6.
Yield: 98%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.59 (d, J = 3.5 Hz, 4H), 1.66 (d, J = 4.4 Hz, 2H), 2.44 (s, 3H), 3.85 (d, J = 5.2 Hz, 4H), 8.14 (s, 1 H), 13.3 (br s, 1 H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 13.9, 24.3, 25.8, 97.4, 134,2, 155.5, 156.9, 167.6.

(20) 4-사이클로헥실아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6t](20) 4-cyclohexylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6t]

상기 [4]와 사이클로헥실아민으로부터 하얀색의 고체상 화합물 [6t]를 얻었다.From the above [4] and cyclohexylamine, a white solid compound [6t] was obtained.

Yield: 57%; 1H NMR (400MHz, DMSO-d6) δ 1.13-1.37 (m, 6H), 1.61 (d, J = 12.5Hz, 1H), 1.74 (d, J = 10.0Hz, 2H), 1.93 (d, J = 9.9Hz, 2H), 2.43 (s, 3H), 3.98 (br s, 1H), 7.98 (d, J = 7.6Hz, 1H), 8.02 (s, 1H), 13.14 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 25.2, 25.7, 32.8, 49.2, 99.1, 133.0, 154.9, 155.5, 168.9.
Yield: 57%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.13-1.37 (m, 6H), 1.61 (d, J = 12.5 Hz, 1H), 1.74 (d, J = 10.0 Hz, 2H), 1.93 (d, J = 9.9 Hz, 2H), 2.43 (s, 3H), 3.98 (br s, 1H), 7.98 (d, J = 7.6 Hz, 1H), 8.02 (s, 1H), 13.14 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 25.2, 25.7, 32.8, 49.2, 99.1, 133.0, 154.9, 155.5, 168.9.

(21) 4-다이에틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6u](21) 4-diethylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6u]

상기 [4]와 다이에틸아민으로부터 옅은 노란색의 고체상 화합물 [6u]를 얻었다.A pale yellow solid compound [6u] was obtained from the above [4] and diethylamine.

Yield: 85%; 1H NMR (400MHz, CDCl3) δ 1.27 (br s, 6H), 2.63 (s, 3H), 3.66 (br s, 4H), 7.84 (s, 1H), 12.72 (br s, 1H); 13C NMR (100MHz, CDCl3) δ 13.0, 14.2, 43.8, 97.4, 134.3, 155.1, 156.5, 168.9.
Yield: 85%; 1 H NMR (400 MHz, CDCl 3 ) δ 1.27 (br s, 6H), 2.63 (s, 3H), 3.66 (br s, 4H), 7.84 (s, 1H), 12.72 (br s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 13.0, 14.2, 43.8, 97.4, 134.3, 155.1, 156.5, 168.9.

(22) 4-(2-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [6v](22) 4- (2-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [6v]

상기 [4]와 2-메톡시벤질아민으로부터 옅은 노란색의 고체상 화합물 [6v]를 얻었다.A pale yellow solid compound [6v] was obtained from the above [4] and 2-methoxybenzylamine.

Yield: 66%; 1H NMR (400MHz, DMSO-d6) δ 2.40 (s, 3H), 3.81 (s, 3H), 4.63 (d, J = 5.5Hz, 2H), 6.88 (t, J = 7.3Hz, 1H), 7.00 (d, J = 7.3Hz, 2H), 7.21-7.26 (m, 2H), 8.06 (s, 1H), 8.54 (s, 1H), 13.2 (s, 1H).
Yield: 66%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.40 (s, 3H), 3.81 (s, 3H), 4.63 (d, J = 5.5 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 7.00 (d, J = 7.3 Hz, 2H), 7.21-7.26 (m, 2H), 8.06 (s, 1H), 8.54 (s, 1H), 13.2 (s, 1H).

(23) N-(2-클로로벤질)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [6w](23) N- (2-chlorobenzyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [6w]

상기 [4]와 2-클로로벤질아민으로부터 하얀색의 고체상 화합물 [6w]를 얻었다.White solid compound [6w] was obtained from the above [4] and 2-chlorobenzylamine.

Yield: 92.03%; 1H NMR (400MHz, DMSO-d6) δ 2.40 (s, 3H), 4.76 (d, J = 5.5Hz, 2H), 7.30-7.33 (m, 2H), 7.40-7.42 (m, 1H), 7.47-7.49 (m, 1H), 8.09 (s, 1H), 8.75 (s, 1H), 13.28 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.3, 23.9, 33.2, 43.0, 97.6, 127.1, 128.7, 129.1, 132.1, 136.0, 155.1, 168.0, 174.2.
Yield: 92.03%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.40 (s, 3H), 4.76 (d, J = 5.5 Hz, 2H), 7.30-7.33 (m, 2H), 7.40-7.42 (m, 1H), 7.47 -7.49 (m, 1 H), 8.09 (s, 1 H), 8.75 (s, 1 H), 13.28 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.3, 23.9, 33.2, 43.0, 97.6, 127.1, 128.7, 129.1, 132.1, 136.0, 155.1, 168.0, 174.2.

(24) N-(4-메톡시벤질)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [6x](24) N- (4-methoxybenzyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [6x]

상기 [4]와 4-메톡시벤질아민으로부터 옅은 노란색의 고체상 화합물 [6x]를 얻었다.A pale yellow solid compound [6x] was obtained from the above [4] and 4-methoxybenzylamine.

Yield: 95.44%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 3.73 (s, 3H), 4.64 (d, J = 5.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0Hz, 2H), 8.06 (s, 1H), 8.68 (s, 1H), 13.25 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 13.9, 20.6, 42.6, 54.9, 59.6, 97.6, 113.7, 128.8, 131.0, 132.4, 155.0, 158.3, 168.1.
Yield: 95.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 3.73 (s, 3H), 4.64 (d, J = 5.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 8.06 (s, 1H), 8.68 (s, 1H), 13.25 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 13.9, 20.6, 42.6, 54.9, 59.6, 97.6, 113.7, 128.8, 131.0, 132.4, 155.0, 158.3, 168.1.

(25) 6-(메틸티오)-N-((피리딘-2-일)메틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [6y](25) 6- (methylthio) -N-((pyridin-2-yl) methyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [6y]

상기 [4]와 (피리딘-2-일)메탄아민으로부터 노란색의 고체상 화합물 [6y]를 얻었다.The yellow solid compound [6y] was obtained from the above [4] and (pyridin-2-yl) methanamine.

Yield: 96.02%; 1H NMR (400MHz, DMSO-d6) δ 2.39 (s, 3H), 4.79 (d, J = 5.5Hz, 2H), 7.32 (dd, J = 7.1Hz, 29.0Hz, 2H), 7.75 (t, J = 5.6Hz, 1H), 8.09 (s, 1H), 8.54 (d, J = 2.8Hz, 1H), 8.88 (s, 1H), 13.26 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 45.1, 97.7, 98.6, 121.3, 122.1, 132.5, 136.6, 148.9, 155.1, 155.2, 158.4, 168.0.
Yield: 96.02%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.39 (s, 3H), 4.79 (d, J = 5.5 Hz, 2H), 7.32 (dd, J = 7.1 Hz, 29.0 Hz, 2H), 7.75 (t, J = 5.6 Hz, 1H), 8.09 (s, 1H), 8.54 (d, J = 2.8 Hz, 1H), 8.88 (s, 1H), 13.26 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 45.1, 97.7, 98.6, 121.3, 122.1, 132.5, 136.6, 148.9, 155.1, 155.2, 158.4, 168.0.

실시예 5. [7a] 내지 [7b]의 합성Example 5. Synthesis of [7a] to [7b]

(1) 6-(메틸티오)피라졸로[3,4-d]피리미딘 [7a](1) 6- (methylthio) pyrazolo [3,4-d] pyrimidine [7a]

하기 [반응식 6](반응조건 10% Pd/C, NH4OH, abs. EtOH, H2(g), 상온, 24 h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [7a]를 합성하였다. (R=H)Synthesized pyrazolopyrimidine derivative compounds [7a] according to the present invention by the following Reaction Scheme 6 (reaction conditions 10% Pd / C, NH 4 OH, abs.EtOH, H 2 (g), room temperature, 24 h) It was. (R = H)

[반응식 6][Reaction Scheme 6]

Figure pat00116
Figure pat00116

[4] [7a][4] [7a]

ethanol (6 mL)에 상기 [4] (80 mg, 0.398 mmol)와 10% Pd/C (1 eq. 31 mg)을 넣은 후, NH4OH (5.5%, 0.33 mL)를 가하였다. 수분이 제거된 용기에 H2 (g)를 연결한 후 24 시간 동안 상온에서 교반하였다. 24 시간 후에는 H2 (g)를 제거하고, 반응 혼합물을 celite 545에 여과하여 10% Pd/C을 제거한 후에, 여과액의 부피를 줄였다. 이렇게 얻은 반응 혼합물을 flash chromatography (hexanes : EtOAc = 4 : 1)로 분리하면 옅은 노란색의 고체상 화합물 [7a]를 얻었다.To ethanol (6 mL) [4] (80 mg, 0.398 mmol) and 10% Pd / C (1 eq. 31 mg) were added, followed by NH 4 OH (5.5%, 0.33 mL). H 2 (g) was connected to the vessel from which the water was removed, followed by stirring at room temperature for 24 hours. After 24 hours, H 2 (g) was removed and the reaction mixture was filtered through celite 545 to remove 10% Pd / C, after which the volume of the filtrate was reduced. The reaction mixture thus obtained was separated by flash chromatography (hexanes: EtOAc = 4: 1) to obtain a pale yellow solid compound [7a].

Yield: 33%; 1H NMR (400MHz, DMSO-d6) δ 2.55 (s, 3H), 8.23 (s, 1H), 9.11 (s, 1H), 13.88 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 111.0, 134.5, 153.3, 155.0, 169.0.
Yield: 33%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.55 (s, 3H), 8.23 (s, 1H), 9.11 (s, 1H), 13.88 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 111.0, 134.5, 153.3, 155.0, 169.0.

(2) 1-페닐-6-(메틸티오)피라졸로[3,4-d]피리미딘 [7b](2) 1-phenyl-6- (methylthio) pyrazolo [3,4-d] pyrimidine [7b]

하기 [반응식 7](반응조건 10% Pd/C, NH4OH, abs. EtOH, H2(g), 상온, 24 h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [7b]를 합성하였다. (R=Ph)The pyrazolopyrimidine derivative compound [7b] according to the present invention was synthesized by the following [Scheme 7] (reaction conditions 10% Pd / C, NH 4 OH, abs.EtOH, H 2 (g), room temperature, 24 h). It was. (R = Ph)

[반응식 7][Reaction Scheme 7]

Figure pat00117
Figure pat00117

[5e] [7b][5e] [7b]

상기 [5e]를 이용하여 옅은 노란색의 고체상 화합물 [7b]를 얻었다.Using [5e], a pale yellow solid compound [7b] was obtained.

Yield: 25%; 1H NMR (400MHz, DMSO-d6) δ 2.49 (s, 3H), 7.37 (t, J = 6.9Hz, 1H), 7.58 (t, J = 8.0Hz, 2H), 8.19 (d, J = 7.7Hz, 2H), 8.51 (s, 1H), 9.20 (s, 1H); 13C NMR (400MHz, DMSO-d6) δ 14.3, 29.4, 113.1, 121.0, 127.0, 129.8, 136.1, 138.6, 152.8, 154.1, 170.5.
Yield: 25%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.49 (s, 3H), 7.37 (t, J = 6.9 Hz, 1H), 7.58 (t, J = 8.0 Hz, 2H), 8.19 (d, J = 7.7 Hz, 2H), 8.51 (s, 1 H), 9.20 (s, 1 H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.3, 29.4, 113.1, 121.0, 127.0, 129.8, 136.1, 138.6, 152.8, 154.1, 170.5.

실시예 6. [8a] 내지 [8b]의 합성Example 6. Synthesis of [8a] to [8b]

하기 [반응식 8](반응조건 10% Pd/C, NH4OH, abs. EtOH, H2(g), 상온, 24 h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [8a] 내지 [8d]를 합성하였다. ([8a] R=H; [8b] R=Ph)Pyrazolopyrimidine derivative compounds [8a] to [following scheme 8] (reaction conditions 10% Pd / C, NH 4 OH, abs.EtOH, H 2 (g), room temperature, 24 h) 8d] was synthesized. ([8a] R = H; [8b] R = Ph)

[반응식 8][Reaction Scheme 8]

Figure pat00118
Figure pat00118

[4], [5e] [8a] ~ [8b]     [4], [5e] [8a]-[8b]

(1) 6-(메틸티오)피라졸로[3,4-d]피리미딘-4-온 [8a](1) 6- (methylthio) pyrazolo [3,4-d] pyrimidin-4-one [8a]

상기 [4] (100 mg, 0.498 mmol)을 2N NaOH 수용액 (10 mL)에 넣은 후, 24 시간 동안 reflux를 시켰다. 24 시간 후 상온으로 냉각을 시키고, 진한 염산으로 pH 5로 조절하면 침전물이 형성되었다. 그 침전물을 여과하여 모은 후 물로 여러 번 씻어주고, 옅은 노란색의 고체상 화합물 [8a]를 얻었다.[4] (100 mg, 0.498 mmol) was added to a 2N NaOH aqueous solution (10 mL), followed by reflux for 24 hours. After 24 hours, the mixture was cooled to room temperature, and adjusted to pH 5 with concentrated hydrochloric acid to form a precipitate. The precipitate was collected by filtration and washed several times with water to obtain a pale yellow solid compound [8a].

Yield: 63%; 1H NMR (400MHz, DMSO-d6) δ 2.51 (s, 3H), 8.23 (s, 1H), 12.24 (s, 1H), 13.56 (s, 1H); 13C NMR (400MHz, DMSO-d6) δ 13.3, 103.1, 134.5, 153.3, 158.6, 160.3.
Yield: 63%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.51 (s, 3H), 8.23 (s, 1H), 12.24 (s, 1H), 13.56 (s, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 13.3, 103.1, 134.5, 153.3, 158.6, 160.3.

(2) 1-페닐-6-(메틸티오)피라졸로[3,4-d]피리미딘-4-온 [8b](2) 1-phenyl-6- (methylthio) pyrazolo [3,4-d] pyrimidin-4-one [8b]

상기 [5e]를 이용하여 옅은 노란색의 고체상 화합물 [8b]를 얻었다.Using [5e], a pale yellow solid compound [8b] was obtained.

Yield: 84%; 1H NMR (400MHz, DMSO-d6) δ 2.57 (s, 3H), 7.36 (t, J = 7.9Hz, 1H), 7.54 (t, J = 7.8Hz, 2H), 8.08 (d, J = 8.5Hz, 2H), 8.22 (d, J = 1.0Hz, 1H), 12.7 (s, 1H); 13C NMR (400MHz, DMSO-d6) δ 13.6, 104.9, 121.6, 127.2, 129.6, 136.5, 138.8, 151.9, 157.8, 162.1.
Yield: 84%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.57 (s, 3H), 7.36 (t, J = 7.9 Hz, 1H), 7.54 (t, J = 7.8 Hz, 2H), 8.08 (d, J = 8.5 Hz, 2H), 8.22 (d, J = 1.0 Hz, 1H), 12.7 (s, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 13.6, 104.9, 121.6, 127.2, 129.6, 136.5, 138.8, 151.9, 157.8, 162.1.

실시예 7. [9a] 내지 [9d]의 합성Example 7. Synthesis of [9a] to [9d]

하기 [반응식 9](반응조건 Thiourea, abs. EtOH, reflux, 4h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [8a] 내지 [8d]를 합성하였다. ([9a] R=H; [9b] R=Ph, [9c] R=Bn; [9d] R=t-Butyl)The pyrazolopyrimidine derivative compounds [8a] to [8d] were synthesized according to the following Scheme 9 (reaction conditions Thiourea, abs. EtOH, reflux, 4h). ([9a] R = H; [9b] R = Ph, [9c] R = Bn; [9d] R = t-Butyl)

[반응식 9]Scheme 9

Figure pat00119
Figure pat00119

[4], [5e], [5f], [5g] [9a] ~ [9d][4], [5e], [5f], [5g] [9a]-[9d]

(1) 6-(메틸티오)피라졸로[3,4-d]피리미딘-4-티온 [9a](1) 6- (methylthio) pyrazolo [3,4-d] pyrimidin-4-thione [9a]

상기 [4] (100 mg, 0.498 mmol)와 Thiourea (1.1 eq, 41 mg)를 ethanol (10 mL)에 넣고 4 시간 동안 reflux를 하였다. 4 시간 후에는 반응 혼합물의 용매는 감압기화를 시켜서 제거하였고, 남아있는 고체는 물로 여러 번 씻어내어 황토색의 고체상 화합물 [9a]를 얻었다.[4] (100 mg, 0.498 mmol) and Thiourea (1.1 eq, 41 mg) were added to ethanol (10 mL) and refluxed for 4 hours. After 4 hours, the solvent of the reaction mixture was removed by evaporation under reduced pressure, and the remaining solid was washed several times with water to obtain an ocher solid compound [9a].

Yield: 73%; 1H NMR (400MHz, DMSO-d6) δ 2.53 (s, 3H), 8.05 (s, 1H), 13.73 (s, 1H), 13.80 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 114.6, 137.9, 148.6, 160.5, 180.3.
Yield: 73%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.53 (s, 3H), 8.05 (s, 1H), 13.73 (s, 1H), 13.80 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 114.6, 137.9, 148.6, 160.5, 180.3.

(2) 1-페닐-6-(메틸티오)피라졸로[3,4-d]피리미딘-4-티온 [9b](2) 1-phenyl-6- (methylthio) pyrazolo [3,4-d] pyrimidin-4-thione [9b]

상기 [5e]와 Thiourea으로부터 옅은 갈색의 고체상 화합물 [15a]를 얻었다.A pale brown solid compound [15a] was obtained from [5e] and Thiourea.

Yield: 85%; 1H NMR (400MHz, DMSO-d6) δ 2.59 (s, 3H), 7.39 (t, J = 7.4Hz, 1H), 7.56 (t, J = 7.2Hz, 2H), 8.07 (d, J = 8.6Hz, 2H), 8.32 (s, 1H), 14.05 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 99.1, 116.5, 121.6, 127.5, 129.7, 138.4, 138.5, 161.9, 180.3.
Yield: 85%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.59 (s, 3H), 7.39 (t, J = 7.4 Hz, 1H), 7.56 (t, J = 7.2 Hz, 2H), 8.07 (d, J = 8.6 Hz, 2H), 8.32 (s, 1 H), 14.05 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 99.1, 116.5, 121.6, 127.5, 129.7, 138.4, 138.5, 161.9, 180.3.

(3) 1-벤질-6-(메틸티오)피라졸로[3,4-d]피리미딘-4-티온 [9c](3) 1-benzyl-6- (methylthio) pyrazolo [3,4-d] pyrimidin-4-thione [9c]

상기 [5f]와 Thiourea로부터 옅은 갈색의 고체상 화합물 [9c]를 얻었다.Light brown solid compound [9c] was obtained from [5f] and Thiourea.

Yield: 85%; 1H NMR (400MHz, DMSO-d6) δ 2.58 (s, 3H), 5.45 (s, 2H), 7.27-7.35 (m, 4H), 13.85 (s, 1H).
Yield: 85%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.58 (s, 3H), 5.45 (s, 2H), 7.27-7.35 (m, 4H), 13.85 (s, 1H).

(4) 1-t-뷰틸-6-(메틸티오)피라졸로[3,4-d]피리미딘-4-티온 [9d](4) 1-t-butyl-6- (methylthio) pyrazolo [3,4-d] pyrimidin-4-thione [9d]

상기 [5g]와 Thiourea로부터 옅은 갈색의 고체상 화합물 [9d]를 얻었다.A light brown solid compound [9d] was obtained from [5 g] and Thiourea.

Yield: 71%; 1H NMR (400MHz, DMSO-d6) δ 1.57 (s, 9H), 2.51 (s, 3H), 8.51 (s, 1H), 13.43 (s, 1H); 13C NMR (400MHz, DMSO-d6) δ 13.4, 29.5, 61.2, 115.0, 128.6, 153.1, 158.0, 182.7.
Yield: 71%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.57 (s, 9H), 2.51 (s, 3H), 8.51 (s, 1H), 13.43 (s, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 13.4, 29.5, 61.2, 115.0, 128.6, 153.1, 158.0, 182.7.

실시예 8. [10a] 내지 [10b]의 합성Example 8. Synthesis of [10a] to [10b]

하기 [반응식 10](반응조건 1M. NaOR/ROH, reflux, 6h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [10a] 내지 [10b]를 합성하였다. ([10a] R=Me; [10b] R=Et)The pyrazolopyrimidine derivative compounds [10a] to [10b] were synthesized according to the following Reaction Scheme 10 (reaction conditions 1 M. NaOR / ROH, reflux, 6h). ([10a] R = Me; [10b] R = Et)

[반응식 10][Reaction Scheme 10]

Figure pat00120
Figure pat00120

(1) 4-메톡시-6-(메틸티오)피라졸로[3,4-d]피리미딘 [10a](1) 4-methoxy-6- (methylthio) pyrazolo [3,4-d] pyrimidine [10a]

1M sodium methoxide/methanol (10 mL)에 상기 [4] (100 mg, 0.498 mmol)을 넣은 후 6 시간 동안 reflux를 하였다. 시간이 지나면 상온으로 냉각을 시키고 Et2O (7 mL)를 가하였다. 반응 혼합물에 있는 고체는 필터하여 제거하고, acetic acid를 사용하여 중성으로 조절한 후 용매를 농축하였다. 이렇게 얻은 고체는 물을 이용하여 씻어주고 하얀색의 고체상 화합물 [10a]를 얻었다.[4] (100 mg, 0.498 mmol) was added to 1M sodium methoxide / methanol (10 mL), followed by reflux for 6 hours. After the time was cooled to room temperature and Et 2 O (7 mL) was added. The solid in the reaction mixture was filtered off, neutralized with acetic acid and the solvent was concentrated. The solid thus obtained was washed with water to obtain a white solid compound [10a].

Yield: 81%; 1H NMR (400MHz, DMSO-d6) δ 2.55 (s, 3H), 4.05 (s, 3H), 8.10 (s, 1H), 13.77 (s, 1H); 13C NMR (400MHz, DMSO-d6) δ 14.1, 54.6, 132.4, 157.3, 162.8, 168.8.
Yield: 81%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.55 (s, 3H), 4.05 (s, 3H), 8.10 (s, 1H), 13.77 (s, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.1, 54.6, 132.4, 157.3, 162.8, 168.8.

(2) 4-에톡시-6-(메틸티오)피라졸로[3,4-d]피리미딘 [10b](2) 4-ethoxy-6- (methylthio) pyrazolo [3,4-d] pyrimidine [10b]

상기 [4]와 1M sodium ethoxide/ethanol (10 mL)를 사용하면 하얀색의 고체상 화합물 [10b]를 얻었다.[4] and 1M sodium ethoxide / ethanol (10 mL) were used to obtain a white solid compound [10b].

Yield: 57%; 1H NMR (400MHz, DMSO-d6) δ 1.39 (t, J = 7.3Hz, 3H), 2.52 (s, 3H), 4.52 (quar, J = 7.1Hz, 2H), 8.06 (s, 1H), 13.73 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 14.6, 63.3, 99.3, 132.4, 157.4, 162.4, 168.8.
Yield: 57%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.39 (t, J = 7.3 Hz, 3H), 2.52 (s, 3H), 4.52 (quar, J = 7.1 Hz, 2H), 8.06 (s, 1H), 13.73 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 14.6, 63.3, 99.3, 132.4, 157.4, 162.4, 168.8.

실시예 9. [11a] 내지 [11d]의 합성Example 9 Synthesis of [11a] to [11d]

하기 [반응식 11](반응조건 NIS, DMF, reflux, 30h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [11a] 내지 [11b]를 합성하였다.The pyrazolopyrimidine derivative compounds [11a] to [11b] according to the present invention were synthesized by the following Reaction Scheme 11 (reaction conditions NIS, DMF, reflux, 30h).

또한, 하기 [반응식 10](반응조건 NIS, ClCH2CH2Cl, reflux)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [11c] 내지 [11d]를 합성하였다.Further, pyrazolopyrimidine derivative compounds [11c] to [11d] according to the present invention were synthesized by the following Reaction Scheme 10 (reaction conditions NIS, ClCH 2 CH 2 Cl, reflux).

[반응식 11][Reaction Scheme 11]

Figure pat00121
Figure pat00121

[6a], [6f], [6u], [10a] [11a] ~ [11d][6a], [6f], [6u], [10a] [11a] to [11d]

[11a] 내지 [11d]에서 R은 각각 하기 [표 4]와 같다.R in [11a] to [11d] is as shown in Table 4 below, respectively.

구분division RR 구분division RR 11a11a

Figure pat00122
Figure pat00122
11c11c
Figure pat00123
Figure pat00123
 11b11b
Figure pat00124
Figure pat00124
 11d11d CH3OCH 3 O

(1) 3-아이오도-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [11a](1) 3-iodo-4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [11a]

상기 [6a] (70 mg, 0.258 mmol)와 N-iodosuccimide (2 eq, 116 mg)를 DMF (10 mL)에 넣고 reflux를 하였고, 12시간 후, 6시간 후 N-iodosuccimide (2 eq, 116 mg)을 더 넣어주고, 18 시간을 더 reflux를 하였다. 그 후에 용매를 감압증류하고, 남아있는 고체를 물로 여러 번 씻어준 다음 flash chromatography(hexanes : EtOAc = 1 : 1)로 분리하여 옅은 노란색의 고체상 화합물 [11a]를 얻었다.[6a] (70 mg, 0.258 mmol) and N-iodosuccimide (2 eq, 116 mg) were added to DMF (10 mL) and refluxed. After 12 hours, 6 hours later, N-iodosuccimide (2 eq, 116 mg). ), And refluxed for 18 hours. Thereafter, the solvent was distilled under reduced pressure, and the remaining solid was washed several times with water, and then separated by flash chromatography (hexanes: EtOAc = 1: 1) to obtain a pale yellow solid compound [11a].

Yield: 75%; 1H NMR (400MHz, DMSO-d6) δ 2.39 (s, 3H), 4.77 (d, J = 5.9Hz, 2H), 7.22-7.36 (m, 5H), 13.67 (br s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 43.9, 89.7, 100.9, 127.3, 127.7, 128.8, 139.6, 155.2, 155.9, 169.3.
Yield: 75%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.39 (s, 3H), 4.77 (d, J = 5.9 Hz, 2H), 7.22-7.36 (m, 5H), 13.67 (br s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 43.9, 89.7, 100.9, 127.3, 127.7, 128.8, 139.6, 155.2, 155.9, 169.3.

(2) 3-아이오도-4-(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [11b](2) 3-iodo-4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [11b]

상기 [6f]와 N-iodosuccimide으로부터 옅은 노란색의 고체상 화합물 [11b]를 얻었다.A pale yellow solid compound [11b] was obtained from [6f] and N-iodosuccimide.

Yield: 33%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 3.37 (s, 2H), 3.59 (s, 2H), 4.95 (s, 1H), 6.77 (s, 1H), 13.62 (br s, 1H).
Yield: 33%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 3.37 (s, 2H), 3.59 (s, 2H), 4.95 (s, 1H), 6.77 (s, 1H), 13.62 (br s, 1 H).

(3) 3-아이오도-4-다이에틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [11c](3) 3-iodo-4-diethylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [11c]

상기 [6u] (40 mg, 0.169 mmol)와 N-iodosuccimide (1.5 eq, 57 mg)를 1,2-dichloroethane (10 mL)에 넣고 37 시간 동안 reflux를 하였다. 그 후에 용매를 가압증류하고, 남아있는 고체를 물로 여러 번 씻어 준 다음 flash chromatography (hexanes : EtOAc = 1:1)로 분리하여 옅은 갈색의 고체상 화합물 [11c]를 얻었다.[6u] (40 mg, 0.169 mmol) and N-iodosuccimide (1.5 eq, 57 mg) were added to 1,2-dichloroethane (10 mL) and refluxed for 37 hours. Thereafter, the solvent was distilled under pressure, the remaining solid was washed several times with water, and then separated by flash chromatography (hexanes: EtOAc = 1: 1) to obtain a pale brown solid compound [11c].

Yield: 19%; 1H NMR (400MHz, CDCl3) δ 1.31 (t, J = 7Hz, 6H), 2.56 (s, 3H), 3.86 (quar, J = 7Hz, 4H), 11.19 (br s, 1H).
Yield: 19%; 1 H NMR (400 MHz, CDCl 3 ) δ 1.31 (t, J = 7 Hz, 6H), 2.56 (s, 3H), 3.86 (quar, J = 7 Hz, 4H), 11.19 (br s, 1H).

(4) 3-아이오도-4-메톡시-6-(메틸티오)피라졸로[3,4-d]피리미딘 [11d](4) 3-iodo-4-methoxy-6- (methylthio) pyrazolo [3,4-d] pyrimidine [11d]

상기 [10a]와 N-iodosuccimide으로부터 하얀색의 고체상 화합물 [11d]를 얻었다.A white solid compound [11d] was obtained from [10a] and N-iodosuccimide.

Yield: 67%; 1H NMR (400MHz, CD3CD-d4) δ 2.59 (s, 3H), 4.13 (s, 3H); 13C NMR (100MHz, CD3CD-d4) δ 12.8, 53.4, 87.6, 103.0, 157.1, 162.5, 170.7.
Yield: 67%; 1 H NMR (400 MHz, CD 3 CD-d 4 ) δ 2.59 (s, 3H), 4.13 (s, 3H); 13 C NMR (100 MHz, CD 3 CD-d 4 ) δ 12.8, 53.4, 87.6, 103.0, 157.1, 162.5, 170.7.

실시예 10. [12a] 내지 [12o]의 합성Example 10. Synthesis of [12a] to [12o]

하기 [반응식 12](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [12a] 내지 [12o]를 합성하였다.The pyrazolopyrimidine derivative compounds [12a] to [12o] according to the present invention were synthesized by the following Scheme 12 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 12][Reaction Scheme 12]

Figure pat00125
Figure pat00125

[5a] [12a] ~ [12o][5a] [12a] to [12o]

[12a] 내지 [12o]에서 NR2은 각각 하기 [표 5]와 같다.In [12a] to [12o], NR 2 is shown in Table 5 below, respectively.

구분division NR2 NR 2 구분division NR2 NR 2 12a12a

Figure pat00126
Figure pat00126
12i12i
Figure pat00127
Figure pat00127
 12b12b
Figure pat00128
Figure pat00128
 12j12j
Figure pat00129
Figure pat00129
 12c12c
Figure pat00130
Figure pat00130
 12k12k
Figure pat00131
Figure pat00131
 12d12d
Figure pat00132
Figure pat00132
 12l12l
Figure pat00133
Figure pat00133
 12e12e
Figure pat00134
Figure pat00134
 12m12m
Figure pat00135
Figure pat00135
 12f12f
Figure pat00136
Figure pat00136
 12n12n
Figure pat00137
Figure pat00137
 12g12g
Figure pat00138
Figure pat00138
 12o12o
Figure pat00139
Figure pat00139
 12h12h
Figure pat00140
Figure pat00140

(1) 1-메틸-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12a](1) 1-methyl-4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12a]

상기 [5a] (60 mg, 0.279 mmol)과 benzylamine (1.1 eq, 0.04 mL)을 1,4-dioxane (5 mL)에 넣고 8 시간 동안 reflux를 하였다. 반응 혼합물을 EtOAc/H2O 혼합용매로 층 분리를 한 다음 유기층만 따로 분리하여 MgSO4로 수분을 제거하고 감압증류를 하였다. 반응혼합물을 flash chromatography (hexanes : EtOAc = 4:1)로 분리하여 옅은 노란색의 고체상 화합물 [12a]를 얻었다.[5a] (60 mg, 0.279 mmol) and benzylamine (1.1 eq, 0.04 mL) were added to 1,4-dioxane (5 mL) and refluxed for 8 hours. The reaction mixture was separated by EtOAc / H 2 O mixed solvent, and then the organic layer was separated and the water was removed with MgSO 4 and distilled under reduced pressure. The reaction mixture was separated by flash chromatography (hexanes: EtOAc = 4: 1) to give a pale yellow solid compound [12a].

Yield: 76%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 3.81 (s, 3H), 4.70 (d, J = 5.7Hz, 2H), 7.25 (d, J = 6.2Hz, 1H), 7.33 (s, 4H), 8.02 (s, 1H), 8.85 (t, J = 5.3Hz, 1H).
Yield: 76%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 3.81 (s, 3H), 4.70 (d, J = 5.7 Hz, 2H), 7.25 (d, J = 6.2 Hz, 1H), 7.33 (s, 4 H), 8.02 (s, 1 H), 8.85 (t, J = 5.3 Hz, 1 H).

(2) 1-메틸-4-[(1-하이드록시-2,2-다이메틸)에틸]아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12b](2) 1-methyl-4-[(1-hydroxy-2,2-dimethyl) ethyl] amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12b]

상기 [5a]와 (1-hydroxy-2,2-dimethyl)ethylamine으로부터 하얀색의 고체상 화합물 [12b]를 얻었다.A white solid compound [12b] was obtained from the above [5a] and (1-hydroxy-2,2-dimethyl) ethylamine.

Yield: 45%; 1H NMR (400MHz, DMSO-d6) δ 1.39 (s, 6H), 2.48 (s, 3H), 3.66 (d, J = 5.7Hz, 2H), 3.78 (s, 3H), 4.91 (t, J = 5.8Hz, 1H), 7.47 (s, 1H), 8.12 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 24.4, 33.6, 56.5, 67.0, 99.1, 132.4, 153.6, 155.7, 168.0.
Yield: 45%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.39 (s, 6H), 2.48 (s, 3H), 3.66 (d, J = 5.7 Hz, 2H), 3.78 (s, 3H), 4.91 (t, J = 5.8 Hz, 1 H), 7.47 (s, 1 H), 8.12 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 24.4, 33.6, 56.5, 67.0, 99.1, 132.4, 153.6, 155.7, 168.0.

(3) 1-메틸-4-비스(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12c](3) 1-methyl-4-bis (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12c]

상기 [5a]와 diethanolamine으로부터 하얀색의 고체상 화합물 [12c]를 얻었다.A white solid compound [12c] was obtained from [5a] and diethanolamine.

Yield: 77%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 3.79 (d, J = 5.9Hz, 3H), 3.81 (s, 4H), 4.80 (s, 1H), 4.98 (s, 1H), 7.96 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 33.8, 52.1, 43.0, 58.8, 97.8, 133.6, 154.6, 156.0, 167.7.
Yield: 77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 3.79 (d, J = 5.9 Hz, 3H), 3.81 (s, 4H), 4.80 (s, 1H), 4.98 (s, 1H ), 7.96 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 33.8, 52.1, 43.0, 58.8, 97.8, 133.6, 154.6, 156.0, 167.7.

(4) 1-메틸-4-[3-(이미다졸-1-일)]프로필아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12d](4) 1-methyl-4- [3- (imidazol-1-yl)] propylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12d]

상기 [5a]와 3-(imidazol-1yl)propylamine으로부터 노란색의 고체상 화합물 [12d]를 얻었다.A yellow solid compound [12d] was obtained from the above [5a] and 3- (imidazol-1yl) propylamine.

Yield: 82%; 1H NMR (400MHz, DMSO-d6) δ 2.03 (quin, J = 6.8Hz, 2H), 2.45 (s, 3H), 3.42 (quar, J = 6.1Hz, 2H), 3.80 (s, 3H), 4.04 (t, J = 6.7Hz, 2H), 6.82 (s, 1H), 7.19 (s, 1H), 7.64 (s, 1H), 7.97 (s, 1H), 8.37 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 30.8, 33.7, 37.6, 44.2, 98.5, 119.7, 128.8, 131.9, 137.7, 153.7, 155.8, 168.7.
Yield: 82%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.03 (quin, J = 6.8 Hz, 2H), 2.45 (s, 3H), 3.42 (quar, J = 6.1 Hz, 2H), 3.80 (s, 3H), 4.04 (t, J = 6.7 Hz, 2H), 6.82 (s, 1H), 7.19 (s, 1H), 7.64 (s, 1H), 7.97 (s, 1H), 8.37 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 30.8, 33.7, 37.6, 44.2, 98.5, 119.7, 128.8, 131.9, 137.7, 153.7, 155.8, 168.7.

(5) 1-메틸-4-(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12e](5) 1-methyl-4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12e]

상기 [5a]와 1-hydroxyethylamine으로부터 하얀색의 고체상 화합물 [12e]를 얻었다.White solid compound [12e] was obtained from [5a] and 1-hydroxyethylamine.

Yield: 91%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 3.53 (d, J = 5.3Hz, 2H), 3.57 (br s, 2H), 3.80 (s, 3H), 4.81 (s, 1H), 8.01 (s, 1H), 8.32 (br s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 33.7, 43.2, 59.9, 98.6, 132.1, 153.7, 155.9, 168.6.
Yield: 91%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 3.53 (d, J = 5.3 Hz, 2H), 3.57 (br s, 2H), 3.80 (s, 3H), 4.81 (s, 1H), 8.01 (s, 1 H), 8.32 (br s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 33.7, 43.2, 59.9, 98.6, 132.1, 153.7, 155.9, 168.6.

(6) 1-메틸-4-(4-플루오로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12f](6) 1-methyl-4- (4-fluorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12f]

상기 [5a]와 4-fluorobenzylamine으로부터 옅은 노란색의 고체상 화합물 [12f]를 얻었다.The pale yellow solid compound [12f] was obtained from the above [5a] and 4-fluorobenzylamine.

Yield: 81%; 1H NMR (400MHz, DMSO-d6) δ 2.45 (s, 3H), 3.81 (s, 3H), 4.67 (d, J = 5.7Hz, 2H), 7.15 (t, J = 8.9Hz, 2H), 7.38 (quar, J = 4.7Hz, 2H), 8.00 (s, 1H), 8.80 (t, J = 5.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 33.7, 43.0, 98.5, 115.4, 115.6, 129.9, 130.0, 131.9, 135.8, 153.8, 155.6, 160.5, 162.9, 168.7.
Yield: 81%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (s, 3H), 3.81 (s, 3H), 4.67 (d, J = 5.7 Hz, 2H), 7.15 (t, J = 8.9 Hz, 2H), 7.38 (quar, J = 4.7 Hz, 2H), 8.00 (s, 1H), 8.80 (t, J = 5.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 33.7, 43.0, 98.5, 115.4, 115.6, 129.9, 130.0, 131.9, 135.8, 153.8, 155.6, 160.5, 162.9, 168.7.

(7) 1-메틸-4-(2-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12g](7) 1-methyl-4- (2-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12g]

상기 [5a]와 2-phenylethylamine으로 옅은 노란색의 고체상 화합물 [12g]를 얻었다.The pale yellow solid compound [12g] was obtained from [5a] and 2-phenylethylamine.

Yield: 79%; 1H NMR (400MHz, DMSO-d6) δ 2.50 (s, 3H), 2.90 (t, J = 9.8Hz, 2H), 3.67 (quar, J = 6.8Hz, 2H), 3.80 (s, 3H), 7.16-7.21 (m, 1H), 7.27 (quin, J = 7.2Hz, 3H), 7.94 (s, 1H), 8.42 (t, J = 5.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 33.7, 35.2, 42.1, 98.5, 126.6, 128.8,129.1, 131.9, 139.8, 153.7, 155.7, 168.7.
Yield: 79%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50 (s, 3H), 2.90 (t, J = 9.8 Hz, 2H), 3.67 (quar, J = 6.8 Hz, 2H), 3.80 (s, 3H), 7.16-7.21 (m, 1 H), 7.27 (quin, J = 7.2 Hz, 3H), 7.94 (s, 1H), 8.42 (t, J = 5.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 33.7, 35.2, 42.1, 98.5, 126.6, 128.8,129.1, 131.9, 139.8, 153.7, 155.7, 168.7.

(8) 1-메틸-4-(4-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12h](8) 1-methyl-4- (4-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12h]

상기 [5a]와 4-methoxybenzylamine으로 옅은 노란색의 고체상 화합물 [12h]를 얻었다.A pale yellow solid compound [12h] was obtained from [5a] and 4-methoxybenzylamine.

Yield: 91%; 1H NMR (400MHz, DMSO-d6) δ 2.49 (s, 3H), 3.72 (s, 3H), 3.83 (s, 3H), 4.64 (d, J = 5.6Hz, 2H), 6.90 (d, J = 8.5Hz, 2H), 7.29 (d, J = 8.5Hz, 2H), 8.02 (s, 1H), 8.75 (t, J = 5.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 33.7, 43.2, 55.5, 98.5, 114.2, 129.3, 131.4, 132.0, 153.8, 155.6, 158.8, 168.7.
Yield: 91%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.49 (s, 3H), 3.72 (s, 3H), 3.83 (s, 3H), 4.64 (d, J = 5.6 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 8.02 (s, 1H), 8.75 (t, J = 5.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 33.7, 43.2, 55.5, 98.5, 114.2, 129.3, 131.4, 132.0, 153.8, 155.6, 158.8, 168.7.

(9) 1-메틸-4-알릴아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12i](9) 1-methyl-4-allylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12i]

상기 [5a]와 allylamine으로 옅은 노란색의 고체상 화합물 12i를 얻었다.A pale yellow solid compound 12i was obtained from [5a] and allylamine.

Yield: 73%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 3.80 (s, 3H), 4.11 (t, J = 5.5Hz, 2H), 5.12 (dd, J = 1.5Hz, 10.2Hz, 1H), 5.21 (dd, J = 1.5Hz, 17.2Hz, 1H), 5.89-5.98 (m, 1H), 7.99 (s, 1H), 8.46 (t, J = 5.3Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 33.7, 42.6, 98.5, 116.3, 131.9, 135.4, 153.8, 155.6, 168.7.
Yield: 73%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 3.80 (s, 3H), 4.11 (t, J = 5.5 Hz, 2H), 5.12 (dd, J = 1.5 Hz, 10.2 Hz, 1H), 5.21 (dd, J = 1.5 Hz, 17.2 Hz, 1H), 5.89-5.98 (m, 1H), 7.99 (s, 1H), 8.46 (t, J = 5.3 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 33.7, 42.6, 98.5, 116.3, 131.9, 135.4, 153.8, 155.6, 168.7.

(10) 1-메틸-4-(2-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12j](10) 1-methyl-4- (2-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12j]

상기 [5a]와 2-methoxybenzylamine으로 옅은 노란색의 고체상 화합물 12j를 얻었다.A pale yellow solid compound 12j was obtained from [5a] and 2-methoxybenzylamine.

Yield: 73%; 1H NMR (400MHz, DMSO-d6) δ 2.45 (s, 3H), 3.83 (s, 3H), 3.83 (s, 3H), 4.66 (d, J = 5.4Hz, 2H), 6.90 (t, J = 7.4Hz, 1H), 7.02 (d, J = 8.1Hz, 1H), 7.25 (t, J = 6.4Hz, 2H), 8.06 (s, 1H), 8.63 (t, J = 5.1Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 33.2, 38.2, 55.2, 98.0, 110.5, 120.0, 126.2, 128.1, 128.2, 131.5, 153.2, 155.2, 156.7, 168.1.
Yield: 73%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (s, 3H), 3.83 (s, 3H), 3.83 (s, 3H), 4.66 (d, J = 5.4 Hz, 2H), 6.90 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 7.25 (t, J = 6.4 Hz, 2H), 8.06 (s, 1H), 8.63 (t, J = 5.1 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 33.2, 38.2, 55.2, 98.0, 110.5, 120.0, 126.2, 128.1, 128.2, 131.5, 153.2, 155.2, 156.7, 168.1.

(11) 1-메틸-4-(3-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12k](11) 1-methyl-4- (3-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12k]

상기 [5a]와 3-methoxybenzylamine으로 옅은 노란색의 고체상 화합물 12k를 얻었다.12k of pale yellow solid compound was obtained with [5a] and 3-methoxybenzylamine.

Yield: 30%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 3.71 (s, 3H), 3.81 (s, 3H), 4.66 (d, J = 5.8Hz, 2H), 6.82 (d, J = 7.7Hz, 1H), 6.91 (s, 2H), 7.24 (t, J = 7.8Hz, 1H), 8.79 (t, J = 5.6Hz, 1H); 13C NMR (400MHz, DMSO-d6) δ 14.0, 33.7, 43.7, 55.4, 98.5, 112.7, 113.7, 120.1, 129.9, 132.0, 141.2, 153.8, 155.7, 159.7, 168.7.
Yield: 30%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 3.71 (s, 3H), 3.81 (s, 3H), 4.66 (d, J = 5.8 Hz, 2H), 6.82 (d, J = 7.7 Hz, 1H), 6.91 (s, 2H), 7.24 (t, J = 7.8 Hz, 1H), 8.79 (t, J = 5.6 Hz, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.0, 33.7, 43.7, 55.4, 98.5, 112.7, 113.7, 120.1, 129.9, 132.0, 141.2, 153.8, 155.7, 159.7, 168.7.

(12) 1-메틸-4-(2-메틸벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12l](12) 1-methyl-4- (2-methylbenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12l]

상기 [5a]와 2-methybenzylamine으로 옅은 노란색의 고체상 화합물 12l를 얻었다.12l of a pale yellow solid compound was obtained from [5a] and 2-methybenzylamine.

Yield: 73%; 1H NMR (400MHz, DMSO-d6) δ 2.31 (s, 3H), 2.45 (s, 3H), 3.81 (s, 3H), 4.66 (d, J = 5.4Hz, 2H), 7.14-7.16 (m, 3H), 7.27 (d, J = 6.6Hz, 1H), 8.03 (s, 1H), 8.63 (t, J = 4.9Hz, 1H); 13C NMR (400MHz, DMSO-d6) δ 13.9, 19.2, 33.7, 42.0, 98.5, 126.3, 127.6, 128.5, 130.5, 132.1, 136.4, 137.0, 153.8, 155.6, 168.7.
Yield: 73%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.31 (s, 3H), 2.45 (s, 3H), 3.81 (s, 3H), 4.66 (d, J = 5.4 Hz, 2H), 7.14-7.16 (m , 3H), 7.27 (d, J = 6.6 Hz, 1 H), 8.03 (s, 1 H), 8.63 (t, J = 4.9 Hz, 1 H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 13.9, 19.2, 33.7, 42.0, 98.5, 126.3, 127.6, 128.5, 130.5, 132.1, 136.4, 137.0, 153.8, 155.6, 168.7.

(13) 1-메틸-4-(4-클로로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [12m](13) 1-methyl-4- (4-chlorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [12m]

상기 [5a]와 4-chlorobenzylamine으로 옅은 노란색의 고체상 화합물 12m을 얻었다.12m of pale yellow solid compound was obtained from [5a] and 4-chlorobenzylamine.

Yield: 44%; 1H NMR (400MHz, DMSO-d6) δ 2.45 (s, 3H), 3.83 (s, 3H), 4.70 (d, J = 5.8Hz, 2H), 7.35-7.41 (m, 4H), 8.02 (s, 1H), 8.85 (t, J = 5.6Hz, 1H).
Yield: 44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (s, 3H), 3.83 (s, 3H), 4.70 (d, J = 5.8 Hz, 2H), 7.35-7.41 (m, 4H), 8.02 (s , 1H), 8.85 (t, J = 5.6 Hz, 1H).

(14) N-벤질-1-메틸-6-(메틸티오)피라졸로[3,4-d]피리미딘-4-아민 [12n](14) N-benzyl-1-methyl-6- (methylthio) pyrazolo [3,4-d] pyrimidin-4-amine [12n]

상기 [5a]와 benzylamine으로 노란색의 고체상 화합물 12n을 얻었다.The yellow solid compound 12n was obtained from [5a] and benzylamine.

Yield: 82%; 1H NMR (400MHz, DMSO-d6) δ 2.25 (s, 3H), 2.45 (s, 3H), 3.81 (s, 3H), 4.64 (d, J = 5.8Hz, 2H), 7.12 (d, J = 7.9Hz, 2H), 7.22 (d, J = 8.0Hz, 2H), 8.00 (s, 1H), 8.75 (t, J = 5.7Hz, 1H); 13C NMR (400MHz, DMSO-d6) δ 14.01, 21.1, 33.7, 43.5, 60.6, 98.5, 127.9, 129.3, 132.0, 136.5, 153.8, 155.6, 168.7.
Yield: 82%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.25 (s, 3H), 2.45 (s, 3H), 3.81 (s, 3H), 4.64 (d, J = 5.8 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 8.00 (s, 1H), 8.75 (t, J = 5.7 Hz, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.01, 21.1, 33.7, 43.5, 60.6, 98.5, 127.9, 129.3, 132.0, 136.5, 153.8, 155.6, 168.7.

(15) 1-메틸-6-(메틸티오)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [12o](15) 1-methyl-6- (methylthio) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [12o]

상기 [5a]와 (R)-phenylethylamine으로 노란색의 고체상 화합물 12o을 얻었다.The yellow solid compound 12o was obtained from [5a] and (R) -phenylethylamine.

Yield: 74%; 1H NMR (400MHz, DMSO-d6) δ 1.53 (d, J = 7.0Hz, 3H), 2.41 (s, 2H), 3.85 (s, 3H), 7.23 (t, J = 7.1Hz, 1H), 7.33 (t, J = 7.5Hz, 2H), 7.40 (d, J = 7.4Hz, 2H), 8.10 (s, 1H), 8.67 (d, J = 7.7Hz, 1H); 13C NMR (400MHz, DMSO-d6) δ 14.0, 22.8, 33.7, 98.5, 126.4, 127.2, 128.7, 132.1, 145.1, 153.9, 154.9, 168.6.
Yield: 74%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.53 (d, J = 7.0 Hz, 3H), 2.41 (s, 2H), 3.85 (s, 3H), 7.23 (t, J = 7.1 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.40 (d, J = 7.4 Hz, 2H), 8.10 (s, 1H), 8.67 (d, J = 7.7 Hz, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.0, 22.8, 33.7, 98.5, 126.4, 127.2, 128.7, 132.1, 145.1, 153.9, 154.9, 168.6.

실시예 11. [13a] 내지 [13o]의 합성Example 11. Synthesis of [13a] to [13o]

하기 [반응식 13](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [13a] 내지 [13o]를 합성하였다.The pyrazolopyrimidine derivative compounds [13a] to [13o] were synthesized according to the following Reaction Scheme 13 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 13][Reaction Scheme 13]

Figure pat00141
Figure pat00141

[5b] [13a] ~ [13o][5b] [13a] to [13o]

[13a] 내지 [13o]에서 NR2은 각각 하기 [표 6]과 같다.In [13a] to [13o], NR 2 is shown in Table 6 below, respectively.

구분division NR2 NR 2 구분division NR2 NR 2 13a13a

Figure pat00142
Figure pat00142
13i13i
Figure pat00143
Figure pat00143
 13b13b
Figure pat00144
Figure pat00144
 13j13j
Figure pat00145
Figure pat00145
 13c13c
Figure pat00146
Figure pat00146
 13k13k
Figure pat00147
Figure pat00147
 13d13d
Figure pat00148
Figure pat00148
 13l13l
Figure pat00149
Figure pat00149
 13e13e
Figure pat00150
Figure pat00150
 13m13m
Figure pat00151
Figure pat00151
 13f13f
Figure pat00152
Figure pat00152
 13n13n
Figure pat00153
Figure pat00153
 13g13g
Figure pat00154
Figure pat00154
 13o13o
Figure pat00155
Figure pat00155
 13h13h
Figure pat00156
Figure pat00156

(1) 1-알릴-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [13a](1) 1-allyl-4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [13a]

상기 [5b]와 benzylamine으로 옅은 노란색의 고체상 화합물 13a를 얻었다.A pale yellow solid compound 13a was obtained from [5b] and benzylamine.

Yield: 85%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 4.72 (d, J = 5.6Hz, 2H), 4.85 (d, J = 4.7Hz, 2H), 5.01 (d, J = 17.1Hz, 1H), 5.15 (d, J = 10.3Hz, 1H), 5.94-6.03 (m, 1H), 7.24-7.27 (m, 1H), 7.32-7.37 (m, 4H), 8.08 (s, 1H), 8.85 (t, J = 5.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 43.2, 48.3, 97.9, 117.0, 126.9, 127.4, 128.3, 131.9, 133.3, 139.0, 153.2, 155.1, 168.3.
Yield: 85%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 4.72 (d, J = 5.6 Hz, 2H), 4.85 (d, J = 4.7 Hz, 2H), 5.01 (d, J = 17.1 Hz, 1H), 5.15 (d, J = 10.3 Hz, 1H), 5.94-6.03 (m, 1H), 7.24-7.27 (m, 1H), 7.32-7.37 (m, 4H), 8.08 (s, 1H) , 8.85 (t, J = 5.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 43.2, 48.3, 97.9, 117.0, 126.9, 127.4, 128.3, 131.9, 133.3, 139.0, 153.2, 155.1, 168.3.

(2) 1-알릴-4-알릴아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [13b](2) 1-allyl-4-allylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [13b]

상기 [5b]와 allyllamine으로 옅은 노란색의 고체상 화합물 13b를 얻었다.[5b] and allyllamine were obtained as a pale yellow solid compound 13b.

Yield: 88%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 4.14 (t, J = 5.5Hz, 2H), 4.85 (dd, J = 1.4Hz, 4.0Hz, 2H), 5.01 (dd, J = 1.3Hz, 17.1Hz, 1H), 5.12-5.17 (m, 2H), 5.24 (dd, J = 1.6Hz, 17.2Hz, 1H), 5.91-6.04 (m, 2H), 8.07 (s, 1H), 8.52 (t, J = 5.1Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 42.6, 48.9, 98.5, 116.3, 117.6, 132.4, 133.9, 135.3, 153.7, 155.6, 168.8.
Yield: 88%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 4.14 (t, J = 5.5 Hz, 2H), 4.85 (dd, J = 1.4 Hz, 4.0 Hz, 2H), 5.01 (dd, J = 1.3 Hz, 17.1 Hz, 1H), 5.12-5.17 (m, 2H), 5.24 (dd, J = 1.6 Hz, 17.2 Hz, 1H), 5.91-6.04 (m, 2H), 8.07 (s, 1H) , 8.52 (t, J = 5.1 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 42.6, 48.9, 98.5, 116.3, 117.6, 132.4, 133.9, 135.3, 153.7, 155.6, 168.8.

(3) 1-알릴-4-(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [13c](3) 1-allyl-4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [13c]

상기 [5b]와 benzylamine으로 하얀색의 고체상 화합물 13c를 얻었다.White solid compound 13c was obtained from [5b] and benzylamine.

Yield: 91%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 3.57 (dt, J = 5.2Hz, 17.3Hz, 4H), 4.81-4.85 (m, 2H), 4.99 (dd, J = 1.2Hz, 17.1Hz, 1H), 5.15 (dd, J = 1.1Hz, 10.3Hz, 1H), 5.94-6.03 (m, 1H), 8.07 (s, 1H), 8.38 (t, J = 5.1Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 42.7, 48.3, 59.3, 98.0, 116.9, 132.0, 133.4, 153.1, 155.4, 168.2.
Yield: 91%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 3.57 (dt, J = 5.2 Hz, 17.3 Hz, 4H), 4.81-4.85 (m, 2H), 4.99 (dd, J = 1.2 Hz, 17.1 Hz, 1H), 5.15 (dd, J = 1.1 Hz, 10.3 Hz, 1H), 5.94-6.03 (m, 1H), 8.07 (s, 1H), 8.38 (t, J = 5.1 Hz, 1H) ; 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 42.7, 48.3, 59.3, 98.0, 116.9, 132.0, 133.4, 153.1, 155.4, 168.2.

(4) 1-알릴-4-(4-플루오로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [13d](4) 1-allyl-4- (4-fluorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [13d]

상기 [5b]와 benzylamine으로 옅은 노란색의 고체상 화합물 13d를 얻었다.The pale yellow solid compound 13d was obtained from [5b] and benzylamine.

Yield: 82%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 4.69 (d, J = 5.6Hz, 2H), 4.85 (d, J = 5.3Hz, 2H), 5.01 (dd, J = 1.4Hz, 17.1Hz, 1H), 5.15 (dd, J = 1.4Hz, 10.3Hz, 1H), 5.94-6.03 (m, 1H), 7.14-7.20 (m, 2H), 7.41 (quar, J = 4.7Hz, 2H), 8.07 (s, 1H), 8.87 (t, J = 5.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 42.5, 48.3, 98.0, 114.9, 115.1, 117.0, 129.3, 129.4, 131.9, 133.3, 135.2, 153.2, 155.1, 159.9, 162.4, 168.3.
Yield: 82%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 4.69 (d, J = 5.6 Hz, 2H), 4.85 (d, J = 5.3 Hz, 2H), 5.01 (dd, J = 1.4 Hz, 17.1 Hz, 1H), 5.15 (dd, J = 1.4 Hz, 10.3 Hz, 1H), 5.94-6.03 (m, 1H), 7.14-7.20 (m, 2H), 7.41 (quar, J = 4.7 Hz, 2H), 8.07 (s, 1 H), 8.87 (t, J = 5.6 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 42.5, 48.3, 98.0, 114.9, 115.1, 117.0, 129.3, 129.4, 131.9, 133.3, 135.2, 153.2, 155.1, 159.9, 162.4, 168.3.

(5) N-(2-메톡시벤질)-1-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [13e](5) N- (2-methoxybenzyl) -1-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [13e]

상기 [5b]와 2-methoxybenzylamine으로 하얀색의 고체상 화합물 13e를 얻었다.White solid compound 13e was obtained from [5b] and 2-methoxybenzylamine.

Yield: 89.04%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 3.83 (s, 3H), 4.67 (s, 2H), 4.85 (s, 2H), 4.99-5.16 (m, 2H), 5.99 (s, 1H), 6.91 (s, 1H), 7.02 (s, 1H), 7.26 (s, 2H), 8.11 (s, 1H), 8.66 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 38.8, 48.9, 55.8, 98.6, 111.1, 117.6, 120.6, 126.7, 128.7, 132.6, 133.9, 153.7, 155.8, 157.3, 168.8.
Yield: 89.04%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 3.83 (s, 3H), 4.67 (s, 2H), 4.85 (s, 2H), 4.99-5.16 (m, 2H), 5.99 (s, 1H), 6.91 (s, 1H), 7.02 (s, 1H), 7.26 (s, 2H), 8.11 (s, 1H), 8.66 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 38.8, 48.9, 55.8, 98.6, 111.1, 117.6, 120.6, 126.7, 128.7, 132.6, 133.9, 153.7, 155.8, 157.3, 168.8.

(6) N-(4-클로로벤질)-1-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [13f](6) N- (4-chlorobenzyl) -1-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [13f]

상기 [5b]와 4-chlorobenzylamine으로 하얀색의 고체상 화합물 13f를 얻었다.White solid compound 13f was obtained from [5b] and 4-chlorobenzylamine.

Yield: 88.54%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 4.73 (d, J = 5.5Hz, 2H), 4.88 (d, J = 4.3Hz, 2H), 5.04 (d, J = 17.1Hz, 1H), 5.18 (d, J = 10.2Hz, 1H), 5.98-6.01 (m, 1H), 7.41 (s, 4H), 8.01 (s, 1H), 8.90 (d, J = 5.3Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 43.0, 48.9, 98.5, 117.6, 128.7, 129.7, 131.9, 132.4, 133.9, 138.7, 153.7, 155.7, 168.8.
Yield: 88.54%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 4.73 (d, J = 5.5 Hz, 2H), 4.88 (d, J = 4.3 Hz, 2H), 5.04 (d, J = 17.1 Hz, 1H), 5.18 (d, J = 10.2 Hz, 1H), 5.98-6.01 (m, 1H), 7.41 (s, 4H), 8.01 (s, 1H), 8.90 (d, J = 5.3 Hz, 1H ); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 43.0, 48.9, 98.5, 117.6, 128.7, 129.7, 131.9, 132.4, 133.9, 138.7, 153.7, 155.7, 168.8.

(7) N-(4-메틸벤질)-1-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 (13g)(7) N- (4-methylbenzyl) -1-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine (13 g)

상기 [5b]와 4-methylbenzylamine으로 하얀색의 고체상 화합물 13g를 얻었다.13g of white solid compound was obtained from [5b] and 4-methylbenzylamine.

Yield: 83.65%; 1H NMR (400MHz, DMSO-d6) δ 2.27 (s, 3H), 2.46 (s, 3H), 4.66 (d, J = 5.6Hz, 2H), 4.92 (d, J = 4.5Hz, 2H), 5.08 (dd, J = 1.4Hz, 44.4Hz, 1H), 5.16 (d, J = 8.7Hz, 1H), 5.94-6.02 (m, 1H), 7.20 (dd, J = 7.9Hz, 41.9Hz, 4H), 8.07 (s, 1H), 8.80 (t, J = 5.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 21.1, 43.5, 48.9, 98.5, 117.6, 128.0, 129.3, 132.5, 133.9, 136.5, 153.7, 155.7, 168.8.
Yield: 83.65%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.27 (s, 3H), 2.46 (s, 3H), 4.66 (d, J = 5.6 Hz, 2H), 4.92 (d, J = 4.5 Hz, 2H), 5.08 (dd, J = 1.4 Hz, 44.4 Hz, 1H), 5.16 (d, J = 8.7 Hz, 1H), 5.94-6.02 (m, 1H), 7.20 (dd, J = 7.9 Hz, 41.9 Hz, 4H) , 8.07 (s, 1 H), 8.80 (t, J = 5.5 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 21.1, 43.5, 48.9, 98.5, 117.6, 128.0, 129.3, 132.5, 133.9, 136.5, 153.7, 155.7, 168.8.

(8) N-(2-메틸벤질)-1-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [13h](8) N- (2-methylbenzyl) -1-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [13h]

상기 [5b]와 2-methylbenzylamine으로 하얀색의 고체상 화합물 13h를 얻었다.The white solid compound 13h was obtained from [5b] and 2-methylbenzylamine.

Yield: 86.42%; 1H NMR (400MHz, DMSO-d6) δ 2.37 (s, 3H), 2.46 (s, 3H), 4.72 (d, J = 5.2Hz, 2H), 4.89 (d, J = 4.7Hz, 2H), 5.05 (dd, J = 1.0Hz, 17.1Hz, 1H), 5.19 (d, J = 9.5Hz, 1H), 5.99-6.06 (m, 1H), 7.21 (s, 3H), 7.33 (d, J = 5.8Hz, 1H), 8.14 (s, 1H), 8.70 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 19.2, 42.0, 48.9, 98.5, 117.6, 126.3, 127.6, 128.6, 130.5, 132.6, 133.9, 136.4, 137.0, 153.7, 155.6, 168.8.
Yield: 86.42%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.37 (s, 3H), 2.46 (s, 3H), 4.72 (d, J = 5.2 Hz, 2H), 4.89 (d, J = 4.7 Hz, 2H), 5.05 (dd, J = 1.0 Hz, 17.1 Hz, 1H), 5.19 (d, J = 9.5 Hz, 1H), 5.99-6.06 (m, 1H), 7.21 (s, 3H), 7.33 (d, J = 5.8 Hz, 1H), 8.14 (s, 1H), 8.70 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 19.2, 42.0, 48.9, 98.5, 117.6, 126.3, 127.6, 128.6, 130.5, 132.6, 133.9, 136.4, 137.0, 153.7, 155.6, 168.8.

(9) 1-알릴-6-(메틸티오)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [13i](9) 1-allyl-6- (methylthio) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [13i]

상기 [5b]와 (S)-phenylethylamine으로 하얀색의 고체상 화합물 13i를 얻었다.A white solid compound 13i was obtained from the above [5b] and (S) -phenylethylamine.

Yield: 84.44%; 1H NMR (400MHz, DMSO-d6) δ 1.54 (d, J = 6.8Hz, 3H), 2.41 (s, 3H), 4.82 (s, 2H), 4.99 (d, J = 17.1Hz, 1H), 5.14 (d, J = 10.2Hz, 1H), 5.45 (t, J = 6.9Hz, 1H), 5.93-6.01 (m, 1H), 7.23 (t, J = 6.7Hz, 1H), 7.33 (t, J = 7.5Hz, 2H), 7.41 (d, J = 7.4Hz, 2H), 8.16 (s, 1H), 8.71 (d, J = 7.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 22.8, 48.8, 49.6, 98.5, 99.1, 117.5, 126.5, 127.2, 128.7, 132.6, 133.9, 145.0, 153.8, 154.9, 168.7.
Yield: 84.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.54 (d, J = 6.8 Hz, 3H), 2.41 (s, 3H), 4.82 (s, 2H), 4.99 (d, J = 17.1 Hz, 1H), 5.14 (d, J = 10.2 Hz, 1H), 5.45 (t, J = 6.9 Hz, 1H), 5.93-6.01 (m, 1H), 7.23 (t, J = 6.7 Hz, 1H), 7.33 (t, J = 7.5 Hz, 2H), 7.41 (d, J = 7.4 Hz, 2H), 8.16 (s, 1 H), 8.71 (d, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 22.8, 48.8, 49.6, 98.5, 99.1, 117.5, 126.5, 127.2, 128.7, 132.6, 133.9, 145.0, 153.8, 154.9, 168.7.

(10) N-(3-메톡시벤질)-1-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [13j](10) N- (3-methoxybenzyl) -1-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [13j]

상기 [5b]와 3-methoxybenzylamine으로 하얀색의 고체상 화합물 13j를 얻었다.White solid compound 13j was obtained from [5b] and 3-methoxybenzylamine.

Yield: 82.44%; 1H NMR (400MHz, DMSO-d6) δ 1.42 (s, 3H), 2.49 (s, 3H), 3.69 (d, J = 5.8Hz, 2H), 4.83 (d, J = 5.3Hz, 2H), 4.91-5.00 (m, 2H), 5.15 (dd, J = 1.4Hz, 10.3Hz, 1H), 5.95-5.99 (m, 1H), 7.25-7.57 (m, 2H), 7.61-7.64 (m, 2H), 8.20 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 23.9, 48.2, 56.0, 66.4, 98.6, 116.9, 128.6, 128.7, 131.3, 131.4, 131.9, 132.1, 132.4, 133.1, 133.4, 153.0, 155.2, 167.5.
Yield: 82.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.42 (s, 3H), 2.49 (s, 3H), 3.69 (d, J = 5.8 Hz, 2H), 4.83 (d, J = 5.3 Hz, 2H), 4.91-5.00 (m, 2H), 5.15 (dd, J = 1.4 Hz, 10.3 Hz, 1H), 5.95-5.99 (m, 1H), 7.25-7.57 (m, 2H), 7.61-7.64 (m, 2H) , 8.20 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 23.9, 48.2, 56.0, 66.4, 98.6, 116.9, 128.6, 128.7, 131.3, 131.4, 131.9, 132.1, 132.4, 133.1, 133.4, 153.0, 155.2, 167.5.

(11) 2-(1-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-일아미노)-2-메틸프로판-1-올 [13k](11) 2- (1-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) -2-methylpropan-1-ol [13k]

상기 [5b]와 1-hydroxy-2-methylpropan-2-amine으로 하얀색의 고체상 화합물 13k를 얻었다.13k was obtained from the above [5b] and 1-hydroxy-2-methylpropan-2-amine.

Yield: 80.35%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 3.74 (s, 3H), 4.69 (d, J = 5.7Hz, 2H), 4.86 (d, J = 5.3Hz, 2H), 5.02 (dd, J = 1.4Hz, 17.1Hz, 1H), 5.16 (dd, J = 1.3Hz, 10.3Hz, 1H), 5.96-6.00 (m, 1H), 6.84 (dd, J = 2.0Hz, 8.1Hz, 1H), 6.93-6.95 (m, 2H), 7.26 (t, J = 7.8Hz, 1H), 8.09 (s, 1H), 8.83 (d, J = 5.7Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 43.2, 48.4, 54.9, 98.0, 112.2, 113.3, 117.1, 119.7, 129.4, 132.0, 133.4, 140.7, 153.3, 155.2, 159.2, 168.3.
Yield: 80.35%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 3.74 (s, 3H), 4.69 (d, J = 5.7 Hz, 2H), 4.86 (d, J = 5.3 Hz, 2H), 5.02 (dd, J = 1.4 Hz, 17.1 Hz, 1H), 5.16 (dd, J = 1.3 Hz, 10.3 Hz, 1H), 5.96-6.00 (m, 1H), 6.84 (dd, J = 2.0 Hz, 8.1 Hz , 1H), 6.93-6.95 (m, 2H), 7.26 (t, J = 7.8 Hz, 1H), 8.09 (s, 1H), 8.83 (d, J = 5.7 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 43.2, 48.4, 54.9, 98.0, 112.2, 113.3, 117.1, 119.7, 129.4, 132.0, 133.4, 140.7, 153.3, 155.2, 159.2, 168.3.

(12) 1-알릴-N-뷰틸-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [13l](12) 1-allyl-N-butyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [13l]

상기 [5b]와 n-butylamine으로 하얀색의 고체상 화합물 13l를 얻었다.13l of a white solid compound was obtained from [5b] and n-butylamine.

Yield: 92.56%; 1H NMR (400MHz, DMSO-d6) δ 0.92 (t, J = 7.4Hz, 3H), 1.34-1.39 (m, 2H), 1.55-1.62 (m, 2H), 2.49 (s, 3H), 3.45-3.50 (m, 2H), 4.85 (d, J = 5.1Hz, 2H), 5.01 (d, J = 17.1Hz, 1H), 5.16 (d, J = 10.2Hz, 1H), 5.95-6.02 (m, 1H), 8.04 (s, 1H), 8.28 (t, J = 5.0Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 14.1, 20.1, 31.3, 48.8, 98.5, 117.5, 132.4, 133.9, 153.6, 155.8, 168.8.
Yield: 92.56%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.92 (t, J = 7.4 Hz, 3H), 1.34-1.39 (m, 2H), 1.55-1.62 (m, 2H), 2.49 (s, 3H), 3.45 -3.50 (m, 2H), 4.85 (d, J = 5.1 Hz, 2H), 5.01 (d, J = 17.1 Hz, 1H), 5.16 (d, J = 10.2 Hz, 1H), 5.95-6.02 (m, 1H), 8.04 (s, 1H), 8.28 (t, J = 5.0 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 14.1, 20.1, 31.3, 48.8, 98.5, 117.5, 132.4, 133.9, 153.6, 155.8, 168.8.

(13) N-(4-메톡시벤질)-1-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [13m](13) N- (4-methoxybenzyl) -1-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [13m]

상기 [5b]와 4-methoxybenzylamine으로 하얀색의 고체상 화합물 13m를 얻었다.13m of a white solid compound was obtained from [5b] and 4-methoxybenzylamine.

Yield: 81.38%; 1H NMR (400MHz, DMSO-d6) δ 2.50 (s,3H), 3.74 (s, 3H), 4.66 (d, J = 5.6Hz, 2H), 4.87 (d, J = 5.2Hz, 2H), 5.02 (dd, J = 1.2Hz, 17.1Hz, 1H), 5.17 (dd, J = 1.3Hz, 10.3Hz, 1H), 6.00-6.01 (m, 1H), 6.92 (d, J = 8.6Hz, 2H), 7.32 (d, J = 8.6Hz, 2H), 8.09 (s, 1H), 8.78 (t, J = 5.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 43.2, 48.9, 55.5, 98.5, 114.2, 117.6, 129.4, 131.4, 131.9, 132.0, 132.5, 133.5, 153.7, 155.6, 158.8, 168.8.
Yield: 81.38%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50 (s, 3H), 3.74 (s, 3H), 4.66 (d, J = 5.6 Hz, 2H), 4.87 (d, J = 5.2 Hz, 2H), 5.02 (dd, J = 1.2 Hz, 17.1 Hz, 1H), 5.17 (dd, J = 1.3 Hz, 10.3 Hz, 1H), 6.00-6.01 (m, 1H), 6.92 (d, J = 8.6 Hz, 2H) , 7.32 (d, J = 8.6 Hz, 2H), 8.09 (s, 1H), 8.78 (t, J = 5.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 43.2, 48.9, 55.5, 98.5, 114.2, 117.6, 129.4, 131.4, 131.9, 132.0, 132.5, 133.5, 153.7, 155.6, 158.8, 168.8.

(14) 1-알릴-6-(메틸티오)-N-((피리딘-2-일)메틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [13n](14) 1-allyl-6- (methylthio) -N-((pyridin-2-yl) methyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [13n]

상기 [5b]와 (pyridin-2-yl)methanamine으로 하얀색의 고체상 화합물 13n를 얻었다.White solid compound 13n was obtained from [5b] and (pyridin-2-yl) methanamine.

Yield: 90.84%; 1H NMR (400MHz, DMSO-d6) δ 2.40 (s, 3H), 4.80-4.95 (m, 4H), 5.02 (dd, J = 1.0Hz, 17.2Hz, 1H), 5.16 (d, J = 10.2Hz, 1H), 5.99-6.03 (m, 1H), 7.26-7.75 (m, 4H), 8.13 (s, 1H), 8.54 (d, J = 4.4Hz, 1H), 8.99 (t, J = 5.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 45.2, 48.4, 98.1, 117.1, 121.3, 122.2, 125.2, 128.6, 128.7, 131.4, 131.5, 132.0, 133.2, 133.4, 136.7, 148.9, 153.3, 155.3, 158.3, 168.3.
Yield: 90.84%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.40 (s, 3H), 4.80-4.95 (m, 4H), 5.02 (dd, J = 1.0 Hz, 17.2 Hz, 1H), 5.16 (d, J = 10.2 Hz, 1H), 5.99-6.03 (m, 1H), 7.26-7.75 (m, 4H), 8.13 (s, 1H), 8.54 (d, J = 4.4 Hz, 1H), 8.99 (t, J = 5.5 Hz , 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 45.2, 48.4, 98.1, 117.1, 121.3, 122.2, 125.2, 128.6, 128.7, 131.4, 131.5, 132.0, 133.2, 133.4, 136.7, 148.9, 153.3, 155.3, 158.3, 168.3.

(15) N-(2-클로로벤질)-1-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [13o](15) N- (2-chlorobenzyl) -1-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [13o]

상기 [5b]와 2-chlorobenzylamine으로 하얀색의 고체상 화합물 13o를 얻었다.White solid compound 13o was obtained by using [5b] and 2-chlorobenzylamine.

Yield: 81.39%; 1H NMR (400MHz, DMSO-d6) δ 2.45 (s, 3H), 4.86 (dd, J = 5.3Hz, 30.0Hz, 4H), 5.05 (dd, J = 1.4Hz, 17.1Hz, 1H), 5.19 (dd, J = 1.3Hz, 17.2Hz, 1H), 5.99-6.07 (m, 1H), 7.33-7.52 (m, 4H), 8.15 (s, 1H), 8.89 (d, J = 5.0Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 41.7, 48.9, 98.6, 117.7, 127.7, 129.3, 129.7, 132.5, 132.7, 133.9, 136.5, 153.8, 155.7, 168.8.
Yield: 81.39%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (s, 3H), 4.86 (dd, J = 5.3 Hz, 30.0 Hz, 4H), 5.05 (dd, J = 1.4 Hz, 17.1 Hz, 1H), 5.19 (dd, J = 1.3 Hz, 17.2 Hz, 1H), 5.99-6.07 (m, 1H), 7.33-7.52 (m, 4H), 8.15 (s, 1H), 8.89 (d, J = 5.0 Hz, 1H) ; 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 41.7, 48.9, 98.6, 117.7, 127.7, 129.3, 129.7, 132.5, 132.7, 133.9, 136.5, 153.8, 155.7, 168.8.

실시예 12. [14a] 내지 [14l]의 합성Example 12. Synthesis of [14a] to [14l]

하기 [반응식 14](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [14a] 내지 [14l]를 합성하였다.The pyrazolopyrimidine derivative compounds [14a] to [14l] were synthesized according to the following Scheme 14 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 14][Reaction Scheme 14]

Figure pat00157
Figure pat00157

[5d] [14a] ~ [14l][5d] [14a] to [14l]

[14a] 내지 [14l]에서 NR2은 각각 하기 [표 7]과 같다.NR 2 in [14a] to [14l] are as shown in the following [Table 7].

구분division NR2 NR 2 구분division NR2 NR 2 14a14a

Figure pat00158
Figure pat00158
14g14 g
Figure pat00159
Figure pat00159
 14b14b
Figure pat00160
Figure pat00160
 14h14h
Figure pat00161
Figure pat00161
 14c14c
Figure pat00162
Figure pat00162
 14i14i
Figure pat00163
Figure pat00163
 14d14d
Figure pat00164
Figure pat00164
 14j14j
Figure pat00165
Figure pat00165
 14e14e
Figure pat00166
Figure pat00166
 14k14k
Figure pat00167
Figure pat00167
 14f14f
Figure pat00168
Figure pat00168
 14l14l
Figure pat00169
Figure pat00169

(1) 1-(N-t-Boc-아미노에틸)-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [14a](1) 1- (N-t-Boc-aminoethyl) -4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [14a]

상기 [5d]와 benzylamine으로 옅은 노란색의 고체상 화합물 14a를 얻었다.A pale yellow solid compound 14a was obtained from [5d] and benzylamine.

Yield: 94%; 1H NMR (400MHz, DMSO-d6) δ 1.31 (s, 9H), 2.49 (s, 3H), 3.31 (t, J = 6.0Hz, 2H), 4.25 (t, J = 5.9Hz, 2H), 4.71 (d, J = 5.8Hz, 2H), 6.85 (t, J = 5.7Hz, 1H), 7.24-7.27 (m, 1H), 7.31-7.34 (m, 4H), 8.03 (s, 1H), 8.79 (t, J = 5.5Hz, 1H).
Yield: 94%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.31 (s, 9H), 2.49 (s, 3H), 3.31 (t, J = 6.0 Hz, 2H), 4.25 (t, J = 5.9 Hz, 2H), 4.71 (d, J = 5.8 Hz, 2H), 6.85 (t, J = 5.7 Hz, 1H), 7.24-7.27 (m, 1H), 7.31-7.34 (m, 4H), 8.03 (s, 1H), 8.79 (t, J = 5.5 Hz, 1H).

(2) 1-(N-t-Boc-아미노에틸)-4-(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [14b](2) 1- (N-t-Boc-aminoethyl) -4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [14b]

상기 [5d]와 1-hydroxyethylamine으로 옅은 노란색의 고체상 화합물 14b를 얻었다.A pale yellow solid compound 14b was obtained from [5d] and 1-hydroxyethylamine.

Yield: 68%; 1H NMR (400MHz, DMSO-d6) δ 1.32 (s, 9H), 2.49 (s, 3H), 3.31 (t, J = 6.0Hz, 2H), 3.56 (dt, J = 5.2Hz, 16.5Hz, 4H), 4.24 (t, J = 5.9Hz, 2H), 4.81 (t, J = 5.1Hz, 1H), 6.84 (t, J = 5.4Hz, 1H), 8.03 (s, 1H), 8.31 (s, 1H).
Yield: 68%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.32 (s, 9H), 2.49 (s, 3H), 3.31 (t, J = 6.0 Hz, 2H), 3.56 (dt, J = 5.2 Hz, 16.5 Hz, 4H), 4.24 (t, J = 5.9 Hz, 2H), 4.81 (t, J = 5.1 Hz, 1H), 6.84 (t, J = 5.4 Hz, 1H), 8.03 (s, 1H), 8.31 (s, 1H).

(3) 1-(N-t-Boc-아미노에틸)-4-(2-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [14c](3) 1- (N-t-Boc-aminoethyl) -4- (2-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [14c]

상기 [5d]와 2-mehoxybenzylamine으로 옅은 노란색 고체상 화합물 14c를 얻었다.A pale yellow solid compound 14c was obtained from [5d] and 2-mehoxybenzylamine.

Yield: 68%; 1H NMR (400MHz, DMSO-d6) δ 1.31 (s, 9H), 2.45 (s, 3H), 3.31 (t, J = 6.0Hz, 2H), 3.83 (s, 3H), 4.25 (t, J = 5.9Hz, 2H), 4.66 (d, J = 5.5Hz, 2H), 6.87 (dt, J = 6.5Hz, 20.5Hz, 2H), 7.02 (d, J = 8.1Hz, 1H), 7.25 (quar, J = 7.4Hz, 2H), 8.07 (s, 1H), 8.60 (t, J = 5.2Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 28.5, 38.8, 46.7, 55.8, 78.1, 98.6, 111.1, 120.6, 126.7, 128.6, 128.7, 132.4, 154.1, 155.8, 157.3, 168.6.
Yield: 68%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.31 (s, 9H), 2.45 (s, 3H), 3.31 (t, J = 6.0 Hz, 2H), 3.83 (s, 3H), 4.25 (t, J = 5.9 Hz, 2H), 4.66 (d, J = 5.5 Hz, 2H), 6.87 (dt, J = 6.5 Hz, 20.5 Hz, 2H), 7.02 (d, J = 8.1 Hz, 1H), 7.25 (quar, J = 7.4 Hz, 2H), 8.07 (s, 1 H), 8.60 (t, J = 5.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 28.5, 38.8, 46.7, 55.8, 78.1, 98.6, 111.1, 120.6, 126.7, 128.6, 128.7, 132.4, 154.1, 155.8, 157.3, 168.6.

(4) 1-(N-t-Boc-아미노에틸)-4-(3-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [14d](4) 1- (N-t-Boc-aminoethyl) -4- (3-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [14d]

상기 [5d]와 3-mehoxybenzylamine으로 하얀색 고체상 화합물 14d를 얻었다.The white solid compound 14d was obtained from [5d] and 3-mehoxybenzylamine.

Yield: 90%; 1H NMR (400MHz, DMSO-d6) δ 1.31 (s, 9H), 2.47 (s, 3H), 3.31 (t, J = 5.9Hz, 2H), 3.73 (s, 3H), 4.25 (t, J = 5.8Hz, 2H), 4.67 (d, J = 5.7Hz, 2H), 6.82-6.93 (m, 3H), 7.25 (t, J = 7.8Hz, 1H), 8.03 (s, 1H), 8.78 (t, J = 5.3Hz, 1H).
Yield: 90%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.31 (s, 9H), 2.47 (s, 3H), 3.31 (t, J = 5.9 Hz, 2H), 3.73 (s, 3H), 4.25 (t, J = 5.8 Hz, 2H), 4.67 (d, J = 5.7 Hz, 2H), 6.82-6.93 (m, 3H), 7.25 (t, J = 7.8 Hz, 1H), 8.03 (s, 1H), 8.78 (t , J = 5.3 Hz, 1H).

(5) 2-(4-(4-클로로벤질아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에틸카바메이트 (14e)(5) 2- (4- (4-chlorobenzylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethylcarbamate (14e)

상기 [5d]와 4-chlorobenzylamine으로 하얀색 고체상 화합물 14e를 얻었다.The white solid compound 14e was obtained from [5d] and 4-chlorobenzylamine.

Yield: 80.75%; 1H NMR (400MHz, DMSO-d6) δ 1.31 (s, 9H), 2.45 (s, 3H), 3.30-3.34 (m, 1H), 4.25 (t, J = 5.9Hz, 2H), 4.69 (d, J = 5.7Hz, 2H), 6.84 (s, 1H), 7.35-7.41 (m, 4H), 8.03 (s, 1H), 8.82 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 28.5, 43.0, 46.7, 78.1, 98.6, 128.7, 129.7, 131.9, 132.2, 138.8, 154.1, 155.6, 155.8, 168.6.
Yield: 80.75%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.31 (s, 9H), 2.45 (s, 3H), 3.30-3.34 (m, 1H), 4.25 (t, J = 5.9 Hz, 2H), 4.69 (d , J = 5.7 Hz, 2H), 6.84 (s, 1H), 7.35-7.41 (m, 4H), 8.03 (s, 1H), 8.82 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 28.5, 43.0, 46.7, 78.1, 98.6, 128.7, 129.7, 131.9, 132.2, 138.8, 154.1, 155.6, 155.8, 168.6.

(6) 2-(4-(4-플루오로벤질아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에틸카바메이트 [14f](6) 2- (4- (4-fluorobenzylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethylcarbamate [14f]

상기 [5d]와 4-fluorobenzylamine으로 하얀색 고체상 화합물 14f를 얻었다.The white solid compound 14f was obtained from [5d] and 4-fluorobenzylamine.

Yield: 87.44%; 1H NMR (400MHz, DMSO-d6) δ 1.31 (s, 9H), 1.51 (d, J = 6.7Hz, 2H), 2.43 (s, 3H), 3.27-3.35 (m, 2H), 4.19-4.23 (m, 2H), 5.41-5.44 (m, 1H), 6.80 (s, 1H), 7.20-7.42 (m, 5H), 8.12 (s, 1H), 8.61 (d, J = 7.3Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 28.2, 42.1, 46.4, 77.3, 98.0, 114.7, 115.0, 129.2, 131.3, 135.1, 153.5, 154.9, 155.1, 159.7, 162.6, 168.3.
Yield: 87.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.31 (s, 9H), 1.51 (d, J = 6.7 Hz, 2H), 2.43 (s, 3H), 3.27-3.35 (m, 2H), 4.19-4.23 (m, 2H), 5.41-5.44 (m, 1H), 6.80 (s, 1H), 7.20-7.42 (m, 5H), 8.12 (s, 1H), 8.61 (d, J = 7.3 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 28.2, 42.1, 46.4, 77.3, 98.0, 114.7, 115.0, 129.2, 131.3, 135.1, 153.5, 154.9, 155.1, 159.7, 162.6, 168.3.

(7) 2-(4-(1-페닐에틸아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에틸카바메이트 [14g](7) 2- (4- (1-phenylethylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethylcarbamate [14 g]

상기 [5d]와 (S)-phenylethylamine으로 하얀색 고체상 화합물 14g를 얻었다.14g of a white solid compound was obtained from the [5d] and (S) -phenylethylamine.

Yield: 92.88%; 1H NMR (400MHz, DMSO-d6) δ 1.30 (s, 9H), 1.53 (d, J = 6.9Hz, 2H), 2.41 (s, 3H), 3.29-3.34 (m, 2H), 4.21-4.24 (m, 2H), 5.42-5.46 (m, 1H), 6.83 (s, 1H), 7.22-7.40 (m, 5H), 8.10 (s, 1H), 8.64 (d, J = 7.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 28.0, 42.4, 46.2, 77.5, 98.1, 114.9, 115.1, 129.4, 131.7, 135.3, 153.6, 155.1, 155.3, 159.9, 162.4, 168.1.
Yield: 92.88%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.30 (s, 9H), 1.53 (d, J = 6.9 Hz, 2H), 2.41 (s, 3H), 3.29-3.34 (m, 2H), 4.21-4.24 (m, 2H), 5.42-5.46 (m, 1H), 6.83 (s, 1H), 7.22-7.40 (m, 5H), 8.10 (s, 1H), 8.64 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 28.0, 42.4, 46.2, 77.5, 98.1, 114.9, 115.1, 129.4, 131.7, 135.3, 153.6, 155.1, 155.3, 159.9, 162.4, 168.1.

(8) 2-(4-(1-하이드록시-2-메틸프로판-2-일아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에틸카바메이트 [14h](8) 2- (4- (1-hydroxy-2-methylpropan-2-ylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) Ethyl carbamate [14h]

상기 [5d]와 1-hydroxy-2-methylpropan-2-amine으로 하얀색 고체상 화합물 14h를 얻었다.The white solid compound 14h was obtained from [5d] and 1-hydroxy-2-methylpropan-2-amine.

Yield: 78.26%; 1H NMR (400MHz, DMSO-d6) δ 1.32 (s, 9H), 1.40 (s, 6H), 2.49 (s, 3H), 3.29-3.36 (m, 2H), 3.67 (d, J = 5.7Hz, 2H), 4.22 (t, J = 5.9Hz, 2H), 4.94 (t, J = 5.8Hz, 1H), 6.84 (s, 1H), 7.46 (s, 1H), 8.14 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 23.9, 28.0, 46.0, 55.9, 66.6, 77.5, 98.6, 132.2, 153.3, 154.5, 155.1, 155.3, 167.3, 170.2.
Yield: 78.26%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.32 (s, 9H), 1.40 (s, 6H), 2.49 (s, 3H), 3.29-3.36 (m, 2H), 3.67 (d, J = 5.7 Hz , 2H), 4.22 (t, J = 5.9 Hz, 2H), 4.94 (t, J = 5.8 Hz, 1H), 6.84 (s, 1H), 7.46 (s, 1H), 8.14 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 23.9, 28.0, 46.0, 55.9, 66.6, 77.5, 98.6, 132.2, 153.3, 154.5, 155.1, 155.3, 167.3, 170.2.

(9) 2-(4-(뷰틸아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에틸카바메이트 [14i](9) 2- (4- (butylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethylcarbamate [14i]

상기 [5d]와 n-butylamine으로 하얀색 고체상 화합물 14i를 얻었다.The white solid compound 14i was obtained from [5d] and n-butylamine.

Yield: 89.55%; 1H NMR (400MHz, DMSO-d6) δ 0.92 (d, J = 4.6Hz, 3H), 1.27 (s, 3H), 1.31 (s, 9H), 1.57 (s, 2H), 3.46 (s, 2H), 4.24 (s, 2H), 6.85 (d, J = 3.6Hz, 1H), 8.00 (d, J = 4.2Hz, 1H), 8.23 (d, J = 3.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 13.4, 19.5, 28.0, 30.8, 46.1, 77.5, 98.0, 131.7, 153.4, 155.2, 168.0.
Yield: 89.55%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.92 (d, J = 4.6 Hz, 3H), 1.27 (s, 3H), 1.31 (s, 9H), 1.57 (s, 2H), 3.46 (s, 2H ), 4.24 (s, 2H), 6.85 (d, J = 3.6 Hz, 1H), 8.00 (d, J = 4.2 Hz, 1H), 8.23 (d, J = 3.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 13.4, 19.5, 28.0, 30.8, 46.1, 77.5, 98.0, 131.7, 153.4, 155.2, 168.0.

(10) 2-(4-(4-메톡시벤질아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에틸카바메이트 [14j](10) 2- (4- (4-methoxybenzylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethylcarbamate [14j]

상기 [5d]와 4-methoxybenzylamine으로 하얀색 고체상 화합물 14j를 얻었다.The white solid compound 14j was obtained from [5d] and 4-methoxybenzylamine.

Yield: 87.48%; 1H NMR (400MHz, DMSO-d6) δ 1.31 (s, 9H), 2.49 (s, 3H), 3.72 (s, 3H), 4.25 (t, J = 6.0Hz, 2H), 4.63 (d, J = 5.7Hz, 2H), 6.84-6.91 (m, 4H), 7.28 (d, J = 8.4Hz, 2H), 8.02 (s, 1H), 8.71 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 28.5, 43.1, 46.7, 55.5, 78.1, 98.6, 114.2, 129.3, 131.5, 132.3, 154.1, 155.6, 155.9, 158.8, 168.6.
Yield: 87.48%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.31 (s, 9H), 2.49 (s, 3H), 3.72 (s, 3H), 4.25 (t, J = 6.0 Hz, 2H), 4.63 (d, J = 5.7 Hz, 2H), 6.84-6.91 (m, 4H), 7.28 (d, J = 8.4 Hz, 2H), 8.02 (s, 1H), 8.71 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 28.5, 43.1, 46.7, 55.5, 78.1, 98.6, 114.2, 129.3, 131.5, 132.3, 154.1, 155.6, 155.9, 158.8, 168.6.

(11) 2-(4-((피리딘-2-일)메틸아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에틸카바메이트 [14k](11) 2- (4-((pyridin-2-yl) methylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethylcarbamate [14k ]

상기 [5d]와 (pyridin-2-yl)methanamine으로 하얀색 고체상 화합물 14k를 얻었다.14k of white solid compound was obtained from [5d] and (pyridin-2-yl) methanamine.

Yield: 79.40%; 1H NMR (400MHz, DMSO-d6) δ 1.31 (s, 9H), 2.40 (s, 3H), 4.26 (d, J = 5.6Hz, 2H), 4.79 (d, J = 5.8Hz, 2H), 6.87 (d, J = 5.2Hz, 1H), 7.26-7.35 (m, 2H), 7.73-7.77 (m, 1H), 8.08 (s, 1H), 8.53 (d, J = 4.4Hz, 1H), 8.94 (d, J = 5.2Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 28.5, 45.7, 46.7, 78.1, 98.7, 121.7, 122.6, 132.3, 137.1, 149.4, 154.1, 155.7, 155.8, 158.9, 168.5.
Yield: 79.40%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.31 (s, 9H), 2.40 (s, 3H), 4.26 (d, J = 5.6 Hz, 2H), 4.79 (d, J = 5.8 Hz, 2H), 6.87 (d, J = 5.2 Hz, 1H), 7.26-7.35 (m, 2H), 7.73-7.77 (m, 1H), 8.08 (s, 1H), 8.53 (d, J = 4.4 Hz, 1H), 8.94 (d, J = 5.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 28.5, 45.7, 46.7, 78.1, 98.7, 121.7, 122.6, 132.3, 137.1, 149.4, 154.1, 155.7, 155.8, 158.9, 168.5.

(12) 2-(4-(2-클로로벤질아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에틸카바메이트 (14l)(12) 2- (4- (2-chlorobenzylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethylcarbamate (14l)

상기 [5d]와 2-chlorobenzylamine으로 하얀색 고체상 화합물 14l를 얻었다.14l of a white solid compound was obtained from [5d] and 2-chlorobenzylamine.

Yield: 83.42%; 1H NMR (400MHz, DMSO-d6) δ 1.30 (s, 9H), 2.42 (s, 3H), 4.26 (t, J = 5.7Hz, 2H), 4.77 (d, J = 5.5Hz, 2H), 6.86 (d, J = 5.2Hz, 1H), 7.30-7.33 (m, 2H), 7.38-7.41 (m, 1H), 7.46-7.49 (m, 1H), 8.07 (s, 1H), 8.79 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 28.5, 41.6, 46.7, 78.1, 127.6, 129.3, 129.7, 132.4, 132.7, 136.5, 155.6, 155.8, 168.5.
Yield: 83.42%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.30 (s, 9H), 2.42 (s, 3H), 4.26 (t, J = 5.7 Hz, 2H), 4.77 (d, J = 5.5 Hz, 2H), 6.86 (d, J = 5.2 Hz, 1H), 7.30-7.33 (m, 2H), 7.38-7.41 (m, 1H), 7.46-7.49 (m, 1H), 8.07 (s, 1H), 8.79 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 28.5, 41.6, 46.7, 78.1, 127.6, 129.3, 129.7, 132.4, 132.7, 136.5, 155.6, 155.8, 168.5.

실시예 13. [15a] 내지 [15zc]의 합성Example 13. Synthesis of [15a] to [15zc]

하기 [반응식 115](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [15a] 내지 [15zc]를 합성하였다.The pyrazolopyrimidine derivative compounds [15a] to [15zc] were synthesized according to the following Scheme 115 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 15][Reaction Scheme 15]

Figure pat00170
Figure pat00170

[5e] [15a] ~ [15zc][5e] [15a] to [15zc]

[15a] 내지 [15zc]에서 NR2은 각각 하기 [표 8]과 같다.NR 2 in [15a] to [15zc] are as shown in [Table 8], respectively.

구분division NR2 NR 2 구분division NR2 NR 2 15a15a

Figure pat00171
Figure pat00171
15p15p
Figure pat00172
Figure pat00172
 15b15b
Figure pat00173
Figure pat00173
 15q15q
Figure pat00174
Figure pat00174
 15c15c
Figure pat00175
Figure pat00175
 15r15r
Figure pat00176
Figure pat00176
 15d15d
Figure pat00177
Figure pat00177
 15s15s CH3OCH 3 O 15e15e
Figure pat00178
Figure pat00178
 15t15 t
Figure pat00179
Figure pat00179
 15f15f
Figure pat00180
Figure pat00180
 15u15 u
Figure pat00181
Figure pat00181
 15g15 g
Figure pat00182
Figure pat00182
 15v15v
Figure pat00183
Figure pat00183
 15h15h
Figure pat00184
Figure pat00184
 15w15w
Figure pat00185
Figure pat00185
 15i15i
Figure pat00186
Figure pat00186
 15x15x
Figure pat00187
Figure pat00187
 15j15j
Figure pat00188
Figure pat00188
 15y15y
Figure pat00189
Figure pat00189
 15k15k
Figure pat00190
Figure pat00190
 15z15z
Figure pat00191
Figure pat00191
 15l15l
Figure pat00192
Figure pat00192
 15za15za
Figure pat00193
Figure pat00193
 15m15m
Figure pat00194
Figure pat00194
 15zb15zb
Figure pat00195
Figure pat00195
 15n15n
Figure pat00196
Figure pat00196
 15zc15zc
Figure pat00197
Figure pat00197
 15o15o
Figure pat00198
Figure pat00198

(1) 1-페닐-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15a](1) 1-phenyl-4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15a]

상기 [5e]와 benzylamine으로 하얀색 고체상 화합물 15a를 얻었다.[5e] and benzylamine gave a white solid compound 15a.

Yield: 96%; 1H NMR (400MHz, DMSO-d6) δ 2.49 (s, 3H), 4.73 (d, J = 5.7Hz, 2H), 7.24-7.38 (m, 6H), 7.53 (t, J = 7.7Hz, 2H), 8.17 (d, J = 8.4Hz, 2H), 8.32 (s, 1H), 9.00 (t, J = 5.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.2, 43.8, 99.9, 120.7, 126.4, 127.5, 128.0, 128.9, 129.6, 134.4, 139.4, 153.8, 155.8, 170.2.
Yield: 96%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.49 (s, 3H), 4.73 (d, J = 5.7 Hz, 2H), 7.24-7.38 (m, 6H), 7.53 (t, J = 7.7 Hz, 2H ), 8.17 (d, J = 8.4 Hz, 2H), 8.32 (s, 1H), 9.00 (t, J = 5.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.2, 43.8, 99.9, 120.7, 126.4, 127.5, 128.0, 128.9, 129.6, 134.4, 139.4, 153.8, 155.8, 170.2.

(2) 1-페닐-4-(2-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15b](2) 1-phenyl-4- (2-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15b]

상기 [5e]와 2-phenylethylamine으로 옅은 노란색의 고체상 화합물 15b를 얻었다.A pale yellow solid compound 15b was obtained from [5e] and 2-phenylethylamine.

Yield: 70%; 1H NMR (400MHz, DMSO-d6) δ 2.53 (s, 3H), 2.93 (t, J = 7.3Hz, 2H), 3.71 (quar, J = 6.6Hz, 2H), 7.18-7.31 (m, 7H), 7.52 (t, J = 7.5Hz, 2H), 8.18 (d, J = 8.2Hz, 2H), 8.27 (s, 1H), 8.62 (t, J = 5.1Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 100.0, 116.5, 120.7, 126.3, 129.5, 134.4, 135.2, 139.4, 153.8, 155.7, 170.1.
Yield: 70%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.53 (s, 3H), 2.93 (t, J = 7.3 Hz, 2H), 3.71 (quar, J = 6.6 Hz, 2H), 7.18-7.31 (m, 7H ), 7.52 (t, J = 7.5 Hz, 2H), 8.18 (d, J = 8.2 Hz, 2H), 8.27 (s, 1H), 8.62 (t, J = 5.1 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 100.0, 116.5, 120.7, 126.3, 129.5, 134.4, 135.2, 139.4, 153.8, 155.7, 170.1.

(3) 1-페닐-4-(4-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15c](3) 1-phenyl-4- (4-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15c]

상기 [5e]와 4-methoxybenzylamine으로 옅은 노란색의 고체상 화합물 15c를 얻었다.The pale yellow solid compound 15c was obtained from [5e] and 4-methoxybenzylamine.

Yield: 75%; 1H NMR (400MHz, DMSO-d6) δ 2.51 (s, 3H), 3.71 (s, 3H), 4.65 (d, J = 5.5Hz, 2H), 6.91 (d, J = 8.2Hz, 2H), 7.29-7.32 (m, 3H), 7.53 (t, J = 7.7Hz, 2H), 8.18 (d, J = 8.3Hz, 2H), 8.31 (s, 1H), 8.91 (t, J = 5.5Hz, 1H).
Yield: 75%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.51 (s, 3H), 3.71 (s, 3H), 4.65 (d, J = 5.5 Hz, 2H), 6.91 (d, J = 8.2 Hz, 2H), 7.29-7.32 (m, 3H), 7.53 (t, J = 7.7 Hz, 2H), 8.18 (d, J = 8.3 Hz, 2H), 8.31 (s, 1H), 8.91 (t, J = 5.5 Hz, 1H ).

(4) 1-페닐-4-(1-하이드록식에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15d](4) 1-phenyl-4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15d]

상기 [5e]와 1-hydroxyethylamine으로 옅은 노란색의 고체상 화합물 15d를 얻었다.A pale yellow solid compound 15d was obtained from [5e] and 1-hydroxyethylamine.

Yield: 61%; 1H NMR (400MHz, DMSO-d6) δ 2.51 (s,3H), 3.55-3.61 (m, 4H), 4.85 (t, J = 5.1Hz, 1H), 7.31 (t, J = 7.4Hz, 1H), 7.53 (t, J = 7.9Hz, 2H), 8.18 (d, J = 8.5Hz, 2H), 8.32 (s, 1H), 8.55 (t, J = 5.1Hz, 1H).
Yield: 61%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.51 (s, 3H), 3.55-3.61 (m, 4H), 4.85 (t, J = 5.1 Hz, 1H), 7.31 (t, J = 7.4 Hz, 1H ), 7.53 (t, J = 7.9 Hz, 2H), 8.18 (d, J = 8.5 Hz, 2H), 8.32 (s, 1H), 8.55 (t, J = 5.1 Hz, 1H).

(5) 1-페닐-4-(4-플루오로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15e](5) 1-phenyl-4- (4-fluorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15e]

상기 [5e]와 4-fluorobenzylamine으로 옅은 노란색의 고체상 화합물 15e를 얻었다.The pale yellow solid compound 15e was obtained from [5e] and 4-fluorobenzylamine.

Yield: 94%; 1H NMR (400MHz, DMSO-d6) δ 2.49 (s, 3H), 4.71 (d, J = 5.4Hz, 2H), 7.17 (t, J = 8.2Hz, 2H), 7.32 (t, J = 7.0Hz, 1H), 7.41 (t, J = 6.5Hz, 2H), 7.53 (t, J = 7.3Hz, 2H), 8.17 (d, J = 8.3Hz, 2H), 8.30 (s, 1H), 9.00 (t, J = 5.3Hz, 1H).
Yield: 94%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.49 (s, 3H), 4.71 (d, J = 5.4 Hz, 2H), 7.17 (t, J = 8.2 Hz, 2H), 7.32 (t, J = 7.0 Hz, 1H), 7.41 (t, J = 6.5 Hz, 2H), 7.53 (t, J = 7.3 Hz, 2H), 8.17 (d, J = 8.3 Hz, 2H), 8.30 (s, 1H), 9.00 ( t, J = 5.3 Hz, 1H).

(6) 1-페닐-4-알릴아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15f](6) 1-phenyl-4-allylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15f]

상기 [5e]와 4-fluorobenzylamine으로 옅은 노란색의 고체상 화합물 15f를 얻었다.The pale yellow solid compound 15f was obtained from [5e] and 4-fluorobenzylamine.

Yield: 91%; 1H NMR (400MHz, DMSO-d6) δ 2.51 (s, 3H), 4.15 (t, J = 4.8Hz, 2H), 5.15 (dd, J = 1.2Hz, 10.3Hz, 1H), 5.25 (dd, J = 1.2Hz, 17.2Hz, 1H), 5.92-6.01 (m, 1H), 7.30 (t, J = 7.8Hz, 1H), 7.52 (t, J = 7.5Hz, 2H), 8.18 (d, J = 8.5Hz, 2H), 8.31 (s, 1H), 8.66 (t, J = 5.2Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 100.0, 116.5, 120.7, 126.3, 129.5, 134.4, 135.2, 139.4, 153.8, 155.7, 170.1.
Yield: 91%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.51 (s, 3H), 4.15 (t, J = 4.8 Hz, 2H), 5.15 (dd, J = 1.2 Hz, 10.3 Hz, 1H), 5.25 (dd, J = 1.2 Hz, 17.2 Hz, 1H), 5.92-6.01 (m, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 8.18 (d, J = 8.5 Hz, 2H), 8.31 (s, 1H), 8.66 (t, J = 5.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 100.0, 116.5, 120.7, 126.3, 129.5, 134.4, 135.2, 139.4, 153.8, 155.7, 170.1.

(7) 1-페닐-4-[2-(피페리딘-1-일)]에틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15g](7) 1-phenyl-4- [2- (piperidin-1-yl)] ethylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15g]

상기 [5e]와 2-(piperidin-1-yl)ethylamine으로 옅은 노란색의 고체상 화합물 15g를 얻었다.15 g of a pale yellow solid compound was obtained from [5e] and 2- (piperidin-1-yl) ethylamine.

Yield: 74%; 1H NMR (400MHz, DMSO-d6) δ 1.63 (br s, 4H), 1.68 (br s, 3H), 2.51 (s, 3H), 3.90 (s, 4H), 7.33 (t, J = 7.4Hz, 1H), 7.54 (t, J = 7.7Hz, 2H), 8.16 (d, J = 8.5Hz, 2H), 8.46 (s, 1H).
Yield: 74%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.63 (br s, 4H), 1.68 (br s, 3H), 2.51 (s, 3H), 3.90 (s, 4H), 7.33 (t, J = 7.4 Hz , 1H), 7.54 (t, J = 7.7 Hz, 2H), 8.16 (d, J = 8.5 Hz, 2H), 8.46 (s, 1H).

(8) (R)-1-페닐-4-(1-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15h](8) (R) -1-phenyl-4- (1-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15h]

상기 [5e]와 (R)-1-phenylethylamine으로 옅은 노란색의 고체상 화합물 15h를 얻었다.A pale yellow solid compound 15h was obtained from [5e] and (R) -1-phenylethylamine.

Yield: 89%; 1H NMR (400MHz, DMSO-d6) δ 1.55 (d, J = 5Hz, 2H), 2.44 (s, 3H), 5.47 (m, 1H), 7.22 (m, 1H), 7.30 (m, 3H), 7.40 (m, 2H), 7.52 (m, 2H), 8.14 (d, J = 7Hz, 2H), 8.39 (s, 1H), 8.64 (d, J = 7Hz, 1H).
Yield: 89%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.55 (d, J = 5 Hz, 2H), 2.44 (s, 3H), 5.47 (m, 1H), 7.22 (m, 1H), 7.30 (m, 3H) , 7.40 (m, 2H), 7.52 (m, 2H), 8.14 (d, J = 7 Hz, 2H), 8.39 (s, 1H), 8.64 (d, J = 7 Hz, 1H).

(9) 1-페닐-4-비스(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15i](9) 1-phenyl-4-bis (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15i]

상기 [5e]와 diethanolamine으로 하얀색의 고체상 화합물 15i를 얻었다.White solid compound 15i was obtained from [5e] and diethanolamine.

Yield: 74%; 1H NMR (400MHz, DMSO-d6) δ 2.50 (s, 3H), 3.67-3.73 (m, 4H), 3.84 (br s, 4H), 4.82 (s, 1H), 5.02 (s, 1H), 7.32 (t, J = 7.1Hz, 1H), 7.53 (t, J = 7.3Hz, 2H), 8.15 (d, J = 8.2Hz, 2H), 8.28 (d, J = 1.1Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 52.4, 53.1, 58.8, 99.1, 121.2, 126.5, 129.5, 136.0, 139.2, 154.7, 156.0, 168.9.
Yield: 74%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50 (s, 3H), 3.67-3.73 (m, 4H), 3.84 (br s, 4H), 4.82 (s, 1H), 5.02 (s, 1H), 7.32 (t, J = 7.1 Hz, 1H), 7.53 (t, J = 7.3 Hz, 2H), 8.15 (d, J = 8.2 Hz, 2H), 8.28 (d, J = 1.1 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 52.4, 53.1, 58.8, 99.1, 121.2, 126.5, 129.5, 136.0, 139.2, 154.7, 156.0, 168.9.

(10) 1-페닐-4-[(피리딘-2-일)메틸]아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15j](10) 1-phenyl-4-[(pyridin-2-yl) methyl] amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15j]

상기 [5e]와 (pyrindin-2-yl)methylamine으로 옅은 노란색의 고체상 화합물 15j를 얻었다.The light yellow solid compound 15j was obtained from [5e] and (pyrindin-2-yl) methylamine.

Yield: 62%; 1H NMR (400MHz, DMSO-d6) δ 2.43 (s, 3H), 4.82 (d, J = 5.7Hz, 2H), 7.26-7.32 (m, 1H), 7.38 (d, J = 7.8Hz, 1H), 7.53 (t, J = 7.6Hz, 2H), 7.76 (t, J = 7.6Hz, 1H), 8.17 (d, J = 8.4Hz, 2H), 8.36 (s, 1H), 8.53 (d, J = 4.4Hz, 1H), 9.13 (t, J = 5.7Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 45.7, 100.0, 120.8, 121.9, 122.7, 126.4, 129.6, 134.4, 137.2, 139.4, 149.5, 153.8, 155.9, 158.6, 170.1.
Yield: 62%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.43 (s, 3H), 4.82 (d, J = 5.7 Hz, 2H), 7.26-7.32 (m, 1H), 7.38 (d, J = 7.8 Hz, 1H ), 7.53 (t, J = 7.6 Hz, 2H), 7.76 (t, J = 7.6 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.36 (s, 1H), 8.53 (d, J = 4.4 Hz, 1H), 9.13 (t, J = 5.7 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 45.7, 100.0, 120.8, 121.9, 122.7, 126.4, 129.6, 134.4, 137.2, 139.4, 149.5, 153.8, 155.9, 158.6, 170.1.

(11) 1-페닐-4-[(1-하이드록시-2,2-다이메틸)에틸]아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15k](11) 1-phenyl-4-[(1-hydroxy-2,2-dimethyl) ethyl] amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15k]

상기 [5e]와 (1-hydroxy-2,2-dimethyl)ethylamine으로 하얀색의 고체상 화합물 15k를 얻었다.The white solid compound 15k was obtained from [5e] and (1-hydroxy-2,2-dimethyl) ethylamine.

Yield: 77%; 1H NMR (400MHz, DMSO-d6) δ 1.42 (s, 6H), 2.51 (s, 3H), 3.70 (d, J = 5.6Hz, 2H), 4.91 (t, J = 5.6Hz, 1H), 7.30 (t, J = 7.8Hz, 1H), 7.52 (t, J = 7.5Hz, 2H), 7.67 (s, 1H), 8.16 (d, J = 8.5Hz, 2H), 8.45 (d, J = 1.1Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.3, 24.4, 56.7, 66.8, 100.5, 120.7, 126.3, 129.5, 134.8, 139.4, 153.7, 155.8, 169.4.
Yield: 77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.42 (s, 6H), 2.51 (s, 3H), 3.70 (d, J = 5.6 Hz, 2H), 4.91 (t, J = 5.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.67 (s, 1H), 8.16 (d, J = 8.5 Hz, 2H), 8.45 (d, J = 1.1 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.3, 24.4, 56.7, 66.8, 100.5, 120.7, 126.3, 129.5, 134.8, 139.4, 153.7, 155.8, 169.4.

(12) 1-페닐-4-(3-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15l](12) 1-phenyl-4- (3-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15l]

상기 [5e]와 3-methoxybenzylamine으로 옅은 노란색의 고체상 화합물 15l를 얻었다.15l of a pale yellow solid compound was obtained from [5e] and 3-methoxybenzylamine.

Yield: 70%; 1H NMR (400MHz, DMSO-d6) δ 2.50 (s, 3H), 3.72 (s, 3H), 4.69 (s, 2H), 6.83 (d, J = 7.8Hz, 1H), 6.95 (s, 2H), 7.23-7.32 (m, 2H), 7.53 (t, J = 7.7Hz, 2H), 8.17 (d, J = 8.2Hz, 2H), 8.33 (s, 1H), 9.02 (br s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 43.7, 55.4, 99.9, 112.8, 113.8, 120.1, 120.8, 126.5, 129.6, 130.0, 134.3, 139.3, 141.0, 153.8, 155.8, 159.7, 170.2.
Yield: 70%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50 (s, 3H), 3.72 (s, 3H), 4.69 (s, 2H), 6.83 (d, J = 7.8 Hz, 1H), 6.95 (s, 2H ), 7.23-7.32 (m, 2H), 7.53 (t, J = 7.7 Hz, 2H), 8.17 (d, J = 8.2 Hz, 2H), 8.33 (s, 1H), 9.02 (br s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 43.7, 55.4, 99.9, 112.8, 113.8, 120.1, 120.8, 126.5, 129.6, 130.0, 134.3, 139.3, 141.0, 153.8, 155.8, 159.7, 170.2.

(13) 1-페닐-4-피페리디노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15m](13) 1-phenyl-4-piperidino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15m]

상기 [5e]와 piperidine으로 옅은 노란색의 고체상 화합물 15m을 얻었다.15m of a pale yellow solid compound was obtained from [5e] and piperidine.

Yield: 93%; 1H NMR (400MHz, DMSO-d6) δ 1.62 (br s, 4H), 1.67 (br s, 2H), 2.50 (s, 3H), 3.88 (br s, 4H), 7.32 (t, J = 7.4Hz, 1H), 7.53 (t, J = 7.3Hz, 2H), 8.15 (d, J = 8.1Hz, 2H), 8.44 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 24.2, 25.8, 46.2, 99.1, 121.2, 126.5, 129.5, 135.8, 139.2, 154.9, 155.5, 169.0.
Yield: 93%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.62 (br s, 4H), 1.67 (br s, 2H), 2.50 (s, 3H), 3.88 (br s, 4H), 7.32 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.3 Hz, 2H), 8.15 (d, J = 8.1 Hz, 2H), 8.44 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 24.2, 25.8, 46.2, 99.1, 121.2, 126.5, 129.5, 135.8, 139.2, 154.9, 155.5, 169.0.

(14) 1-페닐-4-(4-클로로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15n](14) 1-phenyl-4- (4-chlorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15n]

상기 [5e]와 4-chloro-benzylamine으로 옅은 노란색의 고체상 화합물 15n을 얻었다.A pale yellow solid compound 15n was obtained from [5e] and 4-chloro-benzylamine.

Yield: 82%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 4.71 (d, J = 5.7Hz, 2H), 7.31 (t, J = 7.4Hz, 1H), 7.39 (s, 4H), 7.53 (t, J = 7.8Hz, 2H), 8.17 (d, J = 8.2Hz, 2H), 8.31 (s, 1H), 9.02 (t, J = 5.7Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.2, 43.1, 100.0, 120.8, 126.4, 128.8, 129.6, 129.8, 132.0, 134.3, 138.5, 139.4, 153.8, 155.8, 170.2.
Yield: 82%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 4.71 (d, J = 5.7 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.39 (s, 4H), 7.53 (t, J = 7.8 Hz, 2H), 8.17 (d, J = 8.2 Hz, 2H), 8.31 (s, 1H), 9.02 (t, J = 5.7 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.2, 43.1, 100.0, 120.8, 126.4, 128.8, 129.6, 129.8, 132.0, 134.3, 138.5, 139.4, 153.8, 155.8, 170.2.

(15) 1-페닐-4-(2-메틸벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15o](15) 1-phenyl-4- (2-methylbenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15o]

상기 [5e]와 2-methylbenzylamine으로 옅은 노란색의 고체상 화합물 15o를 얻었다.A pale yellow solid compound 15o was obtained from [5e] and 2-methylbenzylamine.

Yield: 67%; 1H NMR (400MHz, DMSO-d6) δ 2.33 (s, 3H), 2.49 (s, 3H), 4.70 (d, J = 5.1Hz, 2H), 7.18 (br s, 3H), 7.30 (t, J = 6.9Hz, 2H), 7.52 (t, J = 7.6Hz, 2H), 8.18 (d, J = 8.1Hz, 2H), 8.35 (s, 1H), 8.81 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 19.2, 42.1, 99.9, 120.7, 126.3, 126.3, 127.7, 128.7, 129.6, 130.5, 134.5, 136.5, 136.8, 139.4, 153.8, 155.7, 170.1.
Yield: 67%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.33 (s, 3H), 2.49 (s, 3H), 4.70 (d, J = 5.1 Hz, 2H), 7.18 (br s, 3H), 7.30 (t, J = 6.9 Hz, 2H), 7.52 (t, J = 7.6 Hz, 2H), 8.18 (d, J = 8.1 Hz, 2H), 8.35 (s, 1H), 8.81 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 19.2, 42.1, 99.9, 120.7, 126.3, 126.3, 127.7, 128.7, 129.6, 130.5, 134.5, 136.5, 136.8, 139.4, 153.8, 155.7, 170.1.

(16) 1-페닐-4-(4-메틸벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15p](16) 1-phenyl-4- (4-methylbenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15p]

상기 [5e]와 4-methylbenzylamine으로 옅은 노란색의 고체상 화합물 15p를 얻었다.15p was obtained as a pale yellow solid compound using [5e] and 4-methylbenzylamine.

Yield: 46%; 1H NMR (400MHz, DMSO-d6) δ 2.26 (s, 3H), 2.50 (s, 3H), 4.68 (d, J = 5.7Hz, 2H), 7.14 (d, J = 7.9Hz, 2H), 7.25 (d, J = 11.9Hz, 2H), 7.31 (t, J = 7.4Hz, 1H), 7.53 (t, J = 8.0Hz, 2H), 8.17 (d, J = 7.7Hz, 2H), 8.31 (s, 1H), 8.95 (t, J = 5.7Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.2, 21.1, 43.5, 99.9, 120.7, 126.4, 128.0, 129.4, 129.6, 134.4, 136.3, 136.6, 139.4, 153.8, 155.7, 170.1.
Yield: 46%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.26 (s, 3H), 2.50 (s, 3H), 4.68 (d, J = 5.7 Hz, 2H), 7.14 (d, J = 7.9 Hz, 2H), 7.25 (d, J = 11.9 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 8.0 Hz, 2H), 8.17 (d, J = 7.7 Hz, 2H), 8.31 ( s, 1 H), 8.95 (t, J = 5.7 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.2, 21.1, 43.5, 99.9, 120.7, 126.4, 128.0, 129.4, 129.6, 134.4, 136.3, 136.6, 139.4, 153.8, 155.7, 170.1.

(17) 1-페닐-4-사이클로헥실아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15q](17) 1-phenyl-4-cyclohexylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15q]

상기 [5e]와 4-methylbenzylamine으로 옅은 노란색의 고체상 화합물 15q를 얻었다.The pale yellow solid compound 15q was obtained from [5e] and 4-methylbenzylamine.

Yield: 96%; 1H NMR (400MHz, DMSO-d6) δ 1.15-1.35 (m, 5H), 1.60-1.63 (m, 1H), 1.74 (br s, 2H), 1.96 (br s, 2H), 2.50 (s, 3H), 4.03 (br s, 1H), 7.29 (t, J = 7.4Hz, 1H), 7.51 (t, J = 7.9Hz, 2H), 8.17 (d, J = 8.5Hz, 2H), 8.27 (d, J = 7.4Hz, 1H), 8.31 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 25.2, 25.7, 32.7, 49.5, 99.8, 120.7, 126.3, 129.5, 134.5, 139.4, 153.8, 155.0, 170.1.
Yield: 96%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.15-1.35 (m, 5H), 1.60-1.63 (m, 1H), 1.74 (br s, 2H), 1.96 (br s, 2H), 2.50 (s, 3H), 4.03 (br s, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.9 Hz, 2H), 8.17 (d, J = 8.5 Hz, 2H), 8.27 (d , J = 7.4 Hz, 1 H), 8.31 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 25.2, 25.7, 32.7, 49.5, 99.8, 120.7, 126.3, 129.5, 134.5, 139.4, 153.8, 155.0, 170.1.

(18) (R)-1-페닐-4-(1-사이클로헥실에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15r](18) (R) -1-phenyl-4- (1-cyclohexylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15r]

상기 [5e]와 (R)-1-cyclohexylethylamine으로 옅은 노란색의 고체상 화합물 15r을 얻었다.The pale yellow solid compound 15r was obtained from [5e] and (R) -1-cyclohexylethylamine.

Yield: 92%; 1H NMR (400MHz, DMSO-d6) δ 0.94-1.03 (m, 2H), 1.08-1.20 (m, 3H), 1.16 (d, J = 6.7Hz, 4H), 1.47 (m, 1H), 1.44-1.51 (m, 1H), 1.58-1.61 (m, 1H), 1.68-1.78 (m, 4H), 2.50 (s, 3H), 4.17-4.30 (m, 1H), 7.30 (t, J = 7.4Hz, 1H), 7.52 (t, J = 8.0Hz, 2H), 8.16 (d, J = 7.9Hz, 2H), 8.19 (s, 1H), 8.34 (s, 1H).
Yield: 92%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.94-1.03 (m, 2H), 1.08-1.20 (m, 3H), 1.16 (d, J = 6.7 Hz, 4H), 1.47 (m, 1H), 1.44 -1.51 (m, 1H), 1.58-1.61 (m, 1H), 1.68-1.78 (m, 4H), 2.50 (s, 3H), 4.17-4.30 (m, 1H), 7.30 (t, J = 7.4 Hz , 1H), 7.52 (t, J = 8.0 Hz, 2H), 8.16 (d, J = 7.9 Hz, 2H), 8.19 (s, 1H), 8.34 (s, 1H).

(19) 1-페닐-4-메톡시-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15s](19) 1-phenyl-4-methoxy-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15s]

1 M sodium methoxide/methanol(10 mL)에 상기 [5e] (70 mg, 0.252 mmol)을 넣은 후 6 시간 동안 reflux를 하였다. 시간이 지나면 상온으로 냉각을 시키고 diethyl ether (7 mL)를 가하였다. 반응 혼합물에 있는 고체는 필터하여 제거하고, acetic acid를 이용하여 중성으로 조절한 후 용매를 제거한다. 이렇게 얻은 고체는 물을 이용하여 씻어 내주면 옅은 갈색의 고체상 화합물 15s를 얻었다.[5e] (70 mg, 0.252 mmol) was added to 1 M sodium methoxide / methanol (10 mL), followed by reflux for 6 hours. After the time was cooled to room temperature and diethyl ether (7 mL) was added. Solids in the reaction mixture are removed by filtration, neutralized with acetic acid and solvent removed. The solid thus obtained was washed with water to obtain a light brown solid compound 15s.

Yield: 95%; 1H NMR (400MHz, DMSO-d6) δ 2.60 (s, 3H), 4.09 (s, 3H), 7.37 (t, J = 7.4Hz, 1H), 7.57 (t, J = 7.9Hz, 2H), 8.17 (d, J = 7.9Hz, 2H), 8.38 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.4, 54.9, 100.8, 121.0, 127.0, 129.7, 133.8, 138.9, 163.0, 170.5.
Yield: 95%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.60 (s, 3H), 4.09 (s, 3H), 7.37 (t, J = 7.4 Hz, 1H), 7.57 (t, J = 7.9 Hz, 2H), 8.17 (d, J = 7.9 Hz, 2H), 8.38 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.4, 54.9, 100.8, 121.0, 127.0, 129.7, 133.8, 138.9, 163.0, 170.5.

(20) 1-페닐-4-n-뷰틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15t](20) 1-phenyl-4-n-butylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15t]

상기 [5e]와 n-butylamine으로 옅은 노란색의 고체상 화합물 15t를 얻었다.15t of pale yellow solid compound was obtained using [5e] and n-butylamine.

Yield: 63%; 1H NMR (400MHz, DMSO-d6) δ 0.91 (t, J = 7.3Hz, 3H), 1.31-1.45 (m, 2H), 1.55-1.62 (m, 2H), 2.51 (s, 3H), 3.48 (quar, J = 6.5Hz, 2H), 7.30 (t, J = 7.4Hz, 1H), 7.52 (t, J = 7.9Hz, 2H), 8.17 (d, J = 7.8Hz, 2H), 8.27 (s, 1H), 8.42 (t, J = 5.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) d 14.1, 20.1, 31.2, 99.9, 120.7, 126.3, 129.5, 134.3, 139.4, 153.8, 155.9, 170.1.
Yield: 63%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.91 (t, J = 7.3 Hz, 3H), 1.31-1.45 (m, 2H), 1.55-1.62 (m, 2H), 2.51 (s, 3H), 3.48 (quar, J = 6.5 Hz, 2H), 7.30 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.9 Hz, 2H), 8.17 (d, J = 7.8 Hz, 2H), 8.27 (s , 1H), 8.42 (t, J = 5.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) d 14.1, 20.1, 31.2, 99.9, 120.7, 126.3, 129.5, 134.3, 139.4, 153.8, 155.9, 170.1.

(21) 1-페닐-4-(4-메틸)피페라지노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15u](21) 1-phenyl-4- (4-methyl) piperazino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15u]

상기 [5e]와 4-methylpiperazine으로 옅은 노란색의 고체상 화합물 15u를 얻었다.15u of a pale yellow solid compound was obtained from [5e] and 4-methylpiperazine.

Yield: 63%; 1H NMR (400MHz, DMSO-d6) δ 2.22 (s, 3H), 2.44-2.45 (m, 4H), 2.50 (s, 3H), 3.91 (t, J = 4.7Hz, 4H), 7.33 (t, J = 7.9Hz, 1H), 7.48 (t, J = 8.0Hz, 2H), 8.15 (d, J = 8.5Hz, 2H), 8.48 (s, 1H).
Yield: 63%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.22 (s, 3H), 2.44-2.45 (m, 4H), 2.50 (s, 3H), 3.91 (t, J = 4.7 Hz, 4H), 7.33 (t , J = 7.9 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 8.15 (d, J = 8.5 Hz, 2H), 8.48 (s, 1H).

(22) 1-페닐-4-(2-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15v](22) 1-phenyl-4- (2-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15v]

상기 [5e]와 2-methylbenzylamine으로 옅은 노란색의 고체상 화합물 15v를 얻었다.A pale yellow solid compound 15v was obtained from [5e] and 2-methylbenzylamine.

Yield: 69%; 1H NMR (400MHz, DMSO-d6) δ 2.50 (s, 3H), 3.84 (s, 3H), 4.70 (d, J = 5.4Hz, 2H), 6.93 (t, J = 7.4Hz, 1H), 7.04 (d, J = 7.4Hz, 1H), 7.30 (quin, J = 8.0Hz, 3H), 7.54 (t, J = 7.4Hz, 2H), 8.20 (d, J = 8.4Hz, 2H), 8.38 (d, J = 1.1Hz, 1H), 8.82 (t, J = 5.3Hz, 1H); 13C NMR (400MHz, DMSO-d6) δ 14.1, 55.8, 100.0, 111.1, 120.6, 120.7, 126.4, 126.5, 128.8, 129.6, 134.5, 139.4, 155.9, 157.4, 170.1.
Yield: 69%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50 (s, 3H), 3.84 (s, 3H), 4.70 (d, J = 5.4 Hz, 2H), 6.93 (t, J = 7.4 Hz, 1H), 7.04 (d, J = 7.4 Hz, 1H), 7.30 (quin, J = 8.0 Hz, 3H), 7.54 (t, J = 7.4 Hz, 2H), 8.20 (d, J = 8.4 Hz, 2H), 8.38 ( d, J = 1.1 Hz, 1H), 8.82 (t, J = 5.3 Hz, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.1, 55.8, 100.0, 111.1, 120.6, 120.7, 126.4, 126.5, 128.8, 129.6, 134.5, 139.4, 155.9, 157.4, 170.1.

(23) 1-페닐-4-다이에틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [15w](23) 1-phenyl-4-diethylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [15w]

상기 [5e]와 diethylamine으로 옅은 투명한 액체상 화합물 15w를 얻었다.15 W of a light transparent liquid compound was obtained using [5e] and diethylamine.

Yield: 72%; 1H NMR (400MHz, CDCl3) δ 1.32 (s, 6H), 2.59 (s, 3H), 3.76 (d, J = 6.8Hz, 4H), 7.29 (t, J = 7.9Hz, 1H), 7.49 (t, J = 8.0Hz, 2H), 7.92 (s, 1H), 8.25 (dd, J = 0.9Hz, 8.6Hz, 2H); 13C NMR (100MHz, CDCl3) δ 12.9, 14.2, 43.6, 98.8, 121.2, 125.9, 128.8, 134.4, 139.3, 154.9, 155.1, 169.5.
Yield: 72%; 1 H NMR (400 MHz, CDCl 3 ) δ 1.32 (s, 6H), 2.59 (s, 3H), 3.76 (d, J = 6.8 Hz, 4H), 7.29 (t, J = 7.9 Hz, 1H), 7.49 ( t, J = 8.0 Hz, 2H), 7.92 (s, 1H), 8.25 (dd, J = 0.9 Hz, 8.6 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 12.9, 14.2, 43.6, 98.8, 121.2, 125.9, 128.8, 134.4, 139.3, 154.9, 155.1, 169.5.

(24) N-(2-클로로벤질)-6-(메틸티오)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [15x](24) N- (2-chlorobenzyl) -6- (methylthio) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [15x]

상기 [5e]와 2-chlorobenzylamine으로 옅은 투명한 액체상 화합물 15x를 얻었다.15x was obtained as a light transparent liquid compound with [5e] and 2-chlorobenzylamine.

Yield: 82.61%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 4.82 (d, J = 5.6Hz, 2H), 7.31-7.35 (m, 3H), 7.45-7.57 (m, 5H), 8.21 (d, J = 8.3Hz, 2H), 8.39 (s, 1H), 9.02 (t, J = 5.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 41.8, 100.0, 120.8, 126.4, 127.7, 129.3, 129.6, 129.7, 129.8, 132.8, 134.4, 136.3, 139.4, 153.8, 155.8, 170.1.
Yield: 82.61%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 4.82 (d, J = 5.6 Hz, 2H), 7.31-7.35 (m, 3H), 7.45-7.57 (m, 5H), 8.21 (d, J = 8.3 Hz, 2H), 8.39 (s, 1 H), 9.02 (t, J = 5.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 41.8, 100.0, 120.8, 126.4, 127.7, 129.3, 129.6, 129.7, 129.8, 132.8, 134.4, 136.3, 139.4, 153.8, 155.8, 170.1.

(25) 4-(p-톨릴티오)-6-(메틸티오)-1-페닐-1H-피라졸로[3,4-d]피리미딘 [15y](25) 4- (p-tolylthio) -6- (methylthio) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidine [15y]

상기 [5e]와 p-tolylthiol으로 하얀색의 고체상 화합물 15y를 얻었다.The white solid compound 15y was obtained from [5e] and p-tolylthiol.

Yield: 92.47%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 6H), 7.24 (s, 1H), 7.35-7.40 (m, 3H), 7.55 (t, J = 7.9Hz, 2H), 7.62 (d, J = 8.0Hz, 2H), 8.09 (d, J = 7.8Hz, 2H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 20.9, 109.5, 120.6, 122.5, 126.6, 129.1, 130.5, 133.1, 135.8, 137.9, 140.8, 151.8, 166.8, 168.7.
Yield: 92.47%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 6H), 7.24 (s, 1H), 7.35-7.40 (m, 3H), 7.55 (t, J = 7.9 Hz, 2H), 7.62 (d , J = 8.0 Hz, 2H), 8.09 (d, J = 7.8 Hz, 2H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 20.9, 109.5, 120.6, 122.5, 126.6, 129.1, 130.5, 133.1, 135.8, 137.9, 140.8, 151.8, 166.8, 168.7.

(26) N-((4-클로로페닐)(페닐)메틸)-6-(메틸티오)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [15z](26) N-((4-chlorophenyl) (phenyl) methyl) -6- (methylthio) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [15z]

상기 [5e]와 (4-chlorophenyl)(phenyl)methanamine으로 하얀색의 고체상 화합물 15z를 얻었다.White solid compound 15z was obtained from [5e] and (4-chlorophenyl) (phenyl) methanamine.

Yield: 94.25%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 6.69 (d, J = 7.6Hz, 1H), 7.31-7.56 (m, 12H), 8.16 (d, J = 7.8Hz, 2H), 8.48 (s, 1H), 9.26 (d, J = 7.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 28.9, 56.6, 99.5, 100.3, 120.3, 126.0, 127.4, 127.7, 128.4, 128.5, 129.1, 129.4, 131.7, 134.2, 138.8, 140.8, 141.2, 153.5, 154.5, 169.5.
Yield: 94.25%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 6.69 (d, J = 7.6 Hz, 1H), 7.31-7.56 (m, 12H), 8.16 (d, J = 7.8 Hz, 2H ), 8.48 (s, 1 H), 9.26 (d, J = 7.5 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 28.9, 56.6, 99.5, 100.3, 120.3, 126.0, 127.4, 127.7, 128.4, 128.5, 129.1, 129.4, 131.7, 134.2, 138.8, 140.8, 141.2, 153.5, 154.5, 169.5.

(27) N-(1-사이클로헥실에틸)-6-(메틸티오)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [15za](27) N- (1-cyclohexylethyl) -6- (methylthio) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [15za]

상기 [5e]와 (S)-cyclohexylethylamine으로 하얀색의 고체상 화합물 15za를 얻었다.White solid compound 15za was obtained from the above [5e] and (S) -cyclohexylethylamine.

Yield; 92.44%; 1H NMR (400MHz, DMSO-d6) δ 0.98-1.02 (m, 2H), 1.13-1.19 (m, 5H), 1.60-1.78 (m, 6H), 2.52 (s, 3H), 4.23-4.25 (m, 1H), 7.29-7.33 (m, 1H), 7.54 (t, J = 7.9Hz, 2H), 8.17-8.25 (m, 3H), 8.35 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 17.3, 25.7, 25.9, 28.6, 29.1, 42.5, 49.8, 120.2, 125.8, 129.0, 134.0, 139.0, 153.4, 155.0, 161.2, 169.5.
Yield; 92.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.98-1.02 (m, 2H), 1.13-1.19 (m, 5H), 1.60-1.78 (m, 6H), 2.52 (s, 3H), 4.23-4.25 ( m, 1H), 7.29-7.33 (m, 1H), 7.54 (t, J = 7.9 Hz, 2H), 8.17-8.25 (m, 3H), 8.35 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 17.3, 25.7, 25.9, 28.6, 29.1, 42.5, 49.8, 120.2, 125.8, 129.0, 134.0, 139.0, 153.4, 155.0, 161.2, 169.5.

(28) 6-(메틸티오)-1-페닐-N-(1-p-톨릴에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [15zb](28) 6- (methylthio) -1-phenyl-N- (1-p-tolylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [15zb]

상기 [5e]와 1-p-tolylethanamine으로 하얀색의 고체상 화합물 15zb를 얻었다.15zb of a white solid compound was obtained using [5e] and 1-p-tolylethanamine.

Yield: 92.70%; 1H NMR (400MHz, DMSO-d6) δ 1.54 (d, J = 6.9Hz, 3H), 2.26 (s, 3H), 2.47 (s, 3H), 5.44 (t, J = 7.1Hz, 1H), 7.15 (d, J = 7.9Hz, 2H), 7.32 (t, J = 7.1Hz, 3H), 7.54 (t, J = 7.9Hz, 1H), 8.18 (d, J = 8.4Hz, 2H), 8.40 (s, 1H), 8.82 (d, J = 7.7Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 20.5, 22.2, 48.9, 99.4, 120.2, 125.8, 125.9, 128.8, 129.0, 134.0, 135.8, 138.9, 141.3, 153.4, 154.4, 169.5.
Yield: 92.70%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.54 (d, J = 6.9 Hz, 3H), 2.26 (s, 3H), 2.47 (s, 3H), 5.44 (t, J = 7.1 Hz, 1H), 7.15 (d, J = 7.9 Hz, 2H), 7.32 (t, J = 7.1 Hz, 3H), 7.54 (t, J = 7.9 Hz, 1H), 8.18 (d, J = 8.4 Hz, 2H), 8.40 ( s, 1 H), 8.82 (d, J = 7.7 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 20.5, 22.2, 48.9, 99.4, 120.2, 125.8, 125.9, 128.8, 129.0, 134.0, 135.8, 138.9, 141.3, 153.4, 154.4, 169.5.

(29) N-((S)-1-(4-메톡시페닐)에틸)-6-(메틸티오))-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [15zc](29) N-((S) -1- (4-methoxyphenyl) ethyl) -6- (methylthio))-1-phenyl-1H-pyrazolo [3,4-d] pyrimidine-4- Amine [15zc]

상기 [5e]와 (R)-4-(methoxyphenyl)ethylamine으로 하얀색의 고체상 화합물 15zc를 얻었다.White solid compound 15zc was obtained from [5e] and (R) -4- (methoxyphenyl) ethylamine.

Yield: 94.56%; 1H NMR (400MHz, DMSO-d6) δ 1.55 (d, J = 6.9Hz, 3H), 2.49 (s, 3H), 3.73 (s, 3H), 5.45-5.46 (m, 1H), 6.91 (d, J = 8.6Hz, 2H), 7.30-7.36 (m, 3H), 7.54 (t, J = 7.9Hz, 2H), 8.19 (d, J = 8.3Hz, 1H), 8.40 (s, 1H), 8.80 (d, J = 7.7Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 22.1, 48.5, 54.9, 99.4, 113.6, 120.2, 125.8, 127.2, 129.0, 133.9, 136.1, 138.9, 153.3, 154.4, 158.0, 169.5.
Yield: 94.56%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.55 (d, J = 6.9 Hz, 3H), 2.49 (s, 3H), 3.73 (s, 3H), 5.45-5.46 (m, 1H), 6.91 (d , J = 8.6Hz, 2H), 7.30-7.36 (m, 3H), 7.54 (t, J = 7.9Hz, 2H), 8.19 (d, J = 8.3Hz, 1H), 8.40 (s, 1H), 8.80 (d, J = 7.7 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 22.1, 48.5, 54.9, 99.4, 113.6, 120.2, 125.8, 127.2, 129.0, 133.9, 136.1, 138.9, 153.3, 154.4, 158.0, 169.5.

실시예 14. [16a] 내지 [16zi]의 합성Example 14 Synthesis of [16a] to [16zi]

하기 [반응식 16](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [16a] 내지 [16zi]를 합성하였다.The pyrazolopyrimidine derivative compounds [16a] to [16zi] were synthesized according to the following Reaction Scheme 16 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 16][Reaction Scheme 16]

Figure pat00199
Figure pat00199

[5f] [16a] ~ [16zi][5f] [16a]-[16zi]

[16a] 내지 [16zi]에서 NR2은 각각 하기 [표 9]와 같다.NR 2 in [16a] to [16zi] are as shown in Table 9 below, respectively.

구분division NR2 NR 2 구분division NR2 NR 2 16a16a

Figure pat00200
Figure pat00200
16s16s
Figure pat00201
Figure pat00201
 16b16b
Figure pat00202
Figure pat00202
 16t16t
Figure pat00203
Figure pat00203
 16c16c
Figure pat00204
Figure pat00204
 16u16 u
Figure pat00205
Figure pat00205
 16d16d
Figure pat00206
Figure pat00206
 16v16v
Figure pat00207
Figure pat00207
 16e16e
Figure pat00208
Figure pat00208
 16w16w
Figure pat00209
Figure pat00209
 16f16f
Figure pat00210
Figure pat00210
 16x16x
Figure pat00211
Figure pat00211
 16g16 g
Figure pat00212
Figure pat00212
 16y16y
Figure pat00213
Figure pat00213
 16h16h
Figure pat00214
Figure pat00214
 16z16z
Figure pat00215
Figure pat00215
 16i16i
Figure pat00216
Figure pat00216
 16za16za
Figure pat00217
Figure pat00217
 16j16j
Figure pat00218
Figure pat00218
 16zb16zb
Figure pat00219
Figure pat00219
 16k16k
Figure pat00220
Figure pat00220
 16zc16zc
Figure pat00221
Figure pat00221
 16l16l
Figure pat00222
Figure pat00222
 16zd16zd
Figure pat00223
Figure pat00223
 16m16m
Figure pat00224
Figure pat00224
 16ze16ze
Figure pat00225
Figure pat00225
 16n16n
Figure pat00226
Figure pat00226
 16zf16zf
Figure pat00227
Figure pat00227
 16o16o
Figure pat00228
Figure pat00228
 16zg16zg
Figure pat00229
Figure pat00229
 16p16p
Figure pat00230
Figure pat00230
 16zh16zh
Figure pat00231
Figure pat00231
 16q16q
Figure pat00232
Figure pat00232
 16zi16zi
Figure pat00233
Figure pat00233
 16r16r
Figure pat00234
Figure pat00234

(1) 1-벤질-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16a](1) 1-benzyl-4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16a]

상기 [5f]와 benzylamine으로 옅은 노란색의 고체상 화합물 16a를 얻었다[5f] and benzylamine gave pale yellow solid compound 16a.

Yield: 71%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 4.70 (d, J = 5.8Hz, 2H), 5.43 (s, 2H), 7.22-7.31 (m, 6H), 7.36-7.41 (m, 4H), 8.07 (s, 1H), 8.90 (t, J = 5.8Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 43.1, 50.2, 98.6, 127.9, 128.0, 128.8, 128.9, 129.7, 131.9, 132.6, 137.7, 138.7, 153.9, 155.7, 169.1.
Yield: 71%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 4.70 (d, J = 5.8 Hz, 2H), 5.43 (s, 2H), 7.22-7.31 (m, 6H), 7.36-7.41 (m, 4H), 8.07 (s, 1 H), 8.90 (t, J = 5.8 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 43.1, 50.2, 98.6, 127.9, 128.0, 128.8, 128.9, 129.7, 131.9, 132.6, 137.7, 138.7, 153.9, 155.7, 169.1.

(2) 1-벤질-4-(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16b](2) 1-benzyl-4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16b]

상기 [5f]와 1-hydroxyethylamine 으로 하얀색의 고체상 화합물 16a를 얻었다.[5f] and 1-hydroxyethylamine gave a white solid compound 16a.

Yield: 84%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 3.55 (dt, J = 5.2Hz, 16.8Hz, 4H), 4.81 (t, J = 5.0Hz, 1H), 5.41 (s, 2H), 7.18-7.31 (m, 5H), 8.06 (s, 1H), 8.39 (t, J = 4.9Hz, 1H).
Yield: 84%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 3.55 (dt, J = 5.2 Hz, 16.8 Hz, 4H), 4.81 (t, J = 5.0 Hz, 1H), 5.41 (s, 2H), 7.18-7.31 (m, 5H), 8.06 (s, 1H), 8.39 (t, J = 4.9 Hz, 1H).

(3) 1-벤질-4-(4-플루오로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16c](3) 1-benzyl-4- (4-fluorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16c]

상기 [5f]와 4-fluorobenzylamine으로 옅은 노란색의 고체상 화합물 16c를 얻었다.A pale yellow solid compound 16c was obtained from [5f] and 4-fluorobenzylamine.

Yield: 64%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 4.68 (d, J = 5.7Hz, 2H), 5.42 (s, 2H), 7.15 (t, J = 8.8Hz, 2H), 7.22 (t, J = 8.3Hz, 3H), 7.29 (quar, J = 7.5Hz, 3H), 7.39 (t, J = 4.7Hz, 2H), 8.05 (s, 1H), 8.86 (t, J = 5.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 43.0, 50.1, 98.6, 115.4, 115.7, 127.9, 128.0, 128.9, 129.9, 130.0, 132.6, 135.7, 137.7, 153.9, 155.6, 169.1.
Yield: 64%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 4.68 (d, J = 5.7 Hz, 2H), 5.42 (s, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.22 (t, J = 8.3 Hz, 3H), 7.29 (quar, J = 7.5 Hz, 3H), 7.39 (t, J = 4.7 Hz, 2H), 8.05 (s, 1H), 8.86 (t, J = 5.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 43.0, 50.1, 98.6, 115.4, 115.7, 127.9, 128.0, 128.9, 129.9, 130.0, 132.6, 135.7, 137.7, 153.9, 155.6, 169.1.

(4) 1-벤질-4-(2-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16d](4) 1-benzyl-4- (2-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16d]

상기 [5f]와 2-phenylethylamine으로 옅은 노란색의 고체상 화합물 16d를 얻었다.16d was obtained as a pale yellow solid compound using [5f] and 2-phenylethylamine.

Yield: 77%; 1H NMR (400MHz, DMSO-d6) δ 2.50 (s, 3H), 2.91 (t, J = 7.4Hz, 2H), 3.67 (quar, J = 6.7Hz, 2H), 5.41 (s, 2H), 7.19 (d, J = 6.3Hz, 3H), 7.21-7.32 (m, 8H), 8.01 (s, 1H), 8.48 (t, J = 5.2Hz, 1H); 13C NMR (400MHz, DMSO-d6) δ 14.1, 42.1, 50.1, 98.6, 126.6, 127.9, 128.0, 128.8, 128.9, 129.1, 132.6, 137.7, 153.9, 155.7, 169.0.
Yield: 77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50 (s, 3H), 2.91 (t, J = 7.4 Hz, 2H), 3.67 (quar, J = 6.7 Hz, 2H), 5.41 (s, 2H), 7.19 (d, J = 6.3 Hz, 3H), 7.21-7.32 (m, 8H), 8.01 (s, 1H), 8.48 (t, J = 5.2 Hz, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.1, 42.1, 50.1, 98.6, 126.6, 127.9, 128.0, 128.8, 128.9, 129.1, 132.6, 137.7, 153.9, 155.7, 169.0.

(5) (R)-1-벤질-4-(1-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16e](5) (R) -1-benzyl-4- (1-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16e]

상기 [5f]와 (R)-1-phenylethylamine으로 옅은 노란색의 고체상 화합물 16e를 얻었다.The pale yellow solid compound 16e was obtained from [5f] and (R) -1-phenylethylamine.

Yield: 83.68%; 1H NMR (400MHz, DMSO-d6) δ 1.52 (d, J = 6.9Hz, 3H), 2.40 (s, 3H), 5.40 (s, 2H), 5.44 (t, J = 6.9Hz, 1H), 7.19 (t, J = 6.4Hz, 3H), 7.24 (d, J = 7.0Hz, 1H), 7.30 (quar, J = 8.0Hz, 4H), 7.39 (t, J = 7.6Hz, 2H), 8.13 (s, 1H), 8.71 (d, J = 7.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 22.3, 49.1, 49.6, 98.0, 126.0, 126.7, 127.4, 127.5, 128.3, 128.4, 132.3, 137.2, 144.5, 153.5, 154.4, 168.4.
Yield: 83.68%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.52 (d, J = 6.9 Hz, 3H), 2.40 (s, 3H), 5.40 (s, 2H), 5.44 (t, J = 6.9 Hz, 1H), 7.19 (t, J = 6.4 Hz, 3H), 7.24 (d, J = 7.0 Hz, 1H), 7.30 (quar, J = 8.0 Hz, 4H), 7.39 (t, J = 7.6 Hz, 2H), 8.13 ( s, 1 H), 8.71 (d, J = 7.6 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 22.3, 49.1, 49.6, 98.0, 126.0, 126.7, 127.4, 127.5, 128.3, 128.4, 132.3, 137.2, 144.5, 153.5, 154.4, 168.4.

(6) 1-벤질-4-(2-메틸벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16f](6) 1-benzyl-4- (2-methylbenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16f]

상기 [5f]와 2-methylbenzylamine으로 옅은 노란색의 고체상 화합물 16f를 얻었다.16f was obtained as a pale yellow solid compound using [5f] and 2-methylbenzylamine.

Yield: 64%; 1H NMR (400MHz, DMSO-d6) δ 2.32 (s, 3H), 2.45 (s, 3H), 4.66 (d, J = 5.5Hz, 2H), 5.42 (s, 2H), 7.14-7.48 (m, 9H), 8.09 (s, 1H), 8.69 (t, J = 5.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 19.2, 42.0, 50.1, 98.5, 126.3, 127.6, 127.9, 128.1, 128.6, 128.9, 130.5, 132.8, 136.4, 137.0, 137.7, 153.9, 155.6, 169.0.
Yield: 64%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.32 (s, 3H), 2.45 (s, 3H), 4.66 (d, J = 5.5 Hz, 2H), 5.42 (s, 2H), 7.14-7.48 (m , 9H), 8.09 (s, 1 H), 8.69 (t, J = 5.4 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 19.2, 42.0, 50.1, 98.5, 126.3, 127.6, 127.9, 128.1, 128.6, 128.9, 130.5, 132.8, 136.4, 137.0, 137.7, 153.9, 155.6, 169.0.

(7) 1-벤질-4-(4-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16g](7) 1-benzyl-4- (4-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16 g]

상기 [5f]와 4-methoxybenzylamine으로 옅은 노란색의 고체상 화합물 16g를 얻었다.16 g of a pale yellow solid compound was obtained using [5f] and 4-methoxybenzylamine.

Yield: 64%; 1H NMR (400MHz, DMSO-d6) d 2.47 (s, 3H), 3.71 (s, 3H), 4.62 (d, J = 5.6Hz, 2H), 5.41 (s, 2H), 6.89 (d, J = 8.5Hz, 2H), 7.19-7.31 (m, 7H), 8.05 (s, 1H), 8.78 (t, J = 5.6Hz, 1H).
Yield: 64%; 1 H NMR (400 MHz, DMSO-d 6 ) d 2.47 (s, 3H), 3.71 (s, 3H), 4.62 (d, J = 5.6 Hz, 2H), 5.41 (s, 2H), 6.89 (d, J = 8.5 Hz, 2H), 7.19-7.31 (m, 7H), 8.05 (s, 1H), 8.78 (t, J = 5.6 Hz, 1H).

(8) 1-벤질-4-알릴아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16h](8) 1-benzyl-4-allylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16h]

상기 [5f]와 allylamine으로 옅은 노란색의 액체상 화합물 16h를 얻었다.16h was obtained as a pale yellow liquid compound using [5f] and allylamine.

Yield: 65%; 1H NMR (400MHz, CDCl3) δ 2.58 (s, 3H), 4.21 (s, 2H), 5.18 (d, J = 10.0Hz, 1H), 5.27 (d, J = 17.1Hz, 1H), 5.48 (s, 2H), 5.89-5.99 (m, 1H), 7.21-7.32 (m, 5H), 7.76 (s, 1H); 13C NMR (400MHz, CDCl3) δ 14.2, 43.3, 50.5, 60.4, 117.2, 127.7, 128.1, 128.5, 133.6, 136.7, 154.3, 169.6.
Yield: 65%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.58 (s, 3H), 4.21 (s, 2H), 5.18 (d, J = 10.0 Hz, 1H), 5.27 (d, J = 17.1 Hz, 1H), 5.48 ( s, 2H), 5.89-5.99 (m, 1 H), 7.21-7.32 (m, 5H), 7.76 (s, 1H); 13 C NMR (400 MHz, CDCl 3 ) δ 14.2, 43.3, 50.5, 60.4, 117.2, 127.7, 128.1, 128.5, 133.6, 136.7, 154.3, 169.6.

(9) 1-벤질-4-비스(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16i](9) 1-benzyl-4-bis (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16i]

상기 [5f]와 diethanolamine으로 하얀색의 고체상 화합물 16i를 얻었다.[5f] and diethanolamine yielded a white solid compound 16i.

Yield: 68%; 1H NMR (400MHz, DMSO-d6) δ 2.49 (s, 3H), 3.66 (br s, 4H), 3.81 (s, 4H), 4.80 (br s, 1H), 4.99 (br s, 1H), 5.44 (s, 2H), 7.20-7.33 (m, 5H), 8.03 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 49.5, 51.5, 52.5, 58.2, 97.3, 127.3, 127.4, 128.3, 133.7, 137.1, 154.2, 155.4, 167.3.
Yield: 68%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.49 (s, 3H), 3.66 (br s, 4H), 3.81 (s, 4H), 4.80 (br s, 1H), 4.99 (br s, 1H), 5.44 (s, 2 H), 7.20-7.33 (m, 5 H), 8.03 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 49.5, 51.5, 52.5, 58.2, 97.3, 127.3, 127.4, 128.3, 133.7, 137.1, 154.2, 155.4, 167.3.

(10) 1-벤질-4-[(1-하이드록시-2,2-다이메틸)에틸]아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [16j](10) 1-benzyl-4-[(1-hydroxy-2,2-dimethyl) ethyl] amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [16j]

상기 [5f]와 1-hydroxy-2,2-dimethylethylamine으로 하얀색의 고체상 화합물 16j를 얻었다.White solid compound 16j was obtained from [5f] and 1-hydroxy-2,2-dimethylethylamine.

Yield: 68%; 1H NMR (400MHz, DMSO-d6) δ 1.40 (s, 6H), 2.49 (s, 3H), 3.68 (d, J = 5.8Hz, 2H), 4.92 (t, J = 5.9Hz, 1H), 5.41 (s, 2H), 7.19-7.33 (m, 5H), 7.54 (s, 1H), 8.19 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.2, 24.4, 50.0, 56.5, 66.9, 99.2, 127.9, 127.9, 128.9, 133.1, 137.8, 153.7, 155.7, 168.3.
Yield: 68%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.40 (s, 6H), 2.49 (s, 3H), 3.68 (d, J = 5.8 Hz, 2H), 4.92 (t, J = 5.9 Hz, 1H), 5.41 (s, 2 H), 7.19-7.33 (m, 5 H), 7.54 (s, 1 H), 8.19 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.2, 24.4, 50.0, 56.5, 66.9, 99.2, 127.9, 127.9, 128.9, 133.1, 137.8, 153.7, 155.7, 168.3.

(11) 1-벤질-6-(메틸티오)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16k](11) 1-benzyl-6- (methylthio) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16k]

상기 [5f]와 1-phenylethylamine으로 얇은 노란색의 고체상 화합물 16k를 얻었다.The thin yellow solid compound 16k was obtained from [5f] and 1-phenylethylamine.

Yield: 90.24%; 1H NMR (400MHz, DMSO-d6) δ 1.54 (d, J = 7.0Hz, 3H), 2.42 (s, 3H), 5.42-5.45 (m, 3H), 7.20-7.34 (m, 8H), 7.41 (d, J = 7.2Hz, 2H), 8.17 (s, 1H), 8.74 (d, J = 7.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 22.3, 49.1, 49.6, 98.0, 126.0, 126.7, 127.4, 127.5, 128.2, 128.4, 132.3, 137.2, 144.5, 153.5, 154.4, 168.4.
Yield: 90.24%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.54 (d, J = 7.0 Hz, 3H), 2.42 (s, 3H), 5.42-5.45 (m, 3H), 7.20-7.34 (m, 8H), 7.41 (d, J = 7.2 Hz, 2H), 8.17 (s, 1 H), 8.74 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 22.3, 49.1, 49.6, 98.0, 126.0, 126.7, 127.4, 127.5, 128.2, 128.4, 132.3, 137.2, 144.5, 153.5, 154.4, 168.4.

(12) 1-벤질-4-(에틸티오)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16l](12) 1-benzyl-4- (ethylthio) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16l]

상기 [5f]와 ethylthiol으로 노란색의 고체상 화합물 16l를 얻었다.16l of a yellow solid compound was obtained from [5f] and ethylthiol.

Yield: 90.58%; 1H NMR (400MHz, DMSO-d6) δ 1.36 (t, J = 7.3Hz, 3H), 2.60 (s, 3H), 3.34 (t, J = 7.3Hz, 2H), 5.54 (s, 2H), 7.24-7.33 (m, 5H), 8.19 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 14.4, 23.0, 50.0, 108.8, 127.6, 128.5, 132.0, 136.6, 151.3, 164.3, 168.0.
Yield: 90.58%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.36 (t, J = 7.3 Hz, 3H), 2.60 (s, 3H), 3.34 (t, J = 7.3 Hz, 2H), 5.54 (s, 2H), 7.24-7.33 (m, 5 H), 8.19 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 14.4, 23.0, 50.0, 108.8, 127.6, 128.5, 132.0, 136.6, 151.3, 164.3, 168.0.

(13) 1-벤질-4-(뷰틸티오)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16m](13) 1-benzyl-4- (butylthio) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16m]

상기 [5f]와 n-butylthiol으로 노란색의 고체상 화합물 16m를 얻었다.16m of a yellow solid compound was obtained from [5f] and n-butylthiol.

Yield: 93.10%; 1H NMR (400MHz, DMSO-d6) δ 0.91 (t, J = 7.3Hz, 3H), 1.39-1.46 (m, 2H), 1.67-1.72 (m, 2H), 2.60 (s, 3H), 3.33 (t, J = 7.2Hz, 2H), 5.54 (s, 2H), 7.25-7.34 (m, 5H), 8.19 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 13.7, 21.3, 27.9, 30.8, 50.0, 108.9, 127.6, 128.5, 132.0, 136.6, 151.3, 164.3, 168.0.
Yield: 93.10%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.91 (t, J = 7.3 Hz, 3H), 1.39-1.46 (m, 2H), 1.67-1.72 (m, 2H), 2.60 (s, 3H), 3.33 (t, J = 7.2 Hz, 2H), 5.54 (s, 2H), 7.25-7.34 (m, 5H), 8.19 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 13.7, 21.3, 27.9, 30.8, 50.0, 108.9, 127.6, 128.5, 132.0, 136.6, 151.3, 164.3, 168.0.

(14) 1-벤질-4-(이소부틸티오)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16n](14) 1-benzyl-4- (isobutylthio) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16n]

상기 [5f]와 isobutylthiol으로 노란색의 액체상 화합물 16n를 얻었다.[5f] and isobutylthiol yielded a yellow liquid compound 16n.

Yield: 79.30% 1H NMR (400MHz, DMSO-d6) δ 1.01 (d, J = 6.6Hz, 6H), 1.96-1.99 (m, 1H), 2.61 (s, 3H), 3.26 (d, J = 6.6Hz, 2H), 5.54 (s, 2H), 7.25-7.34 (m, 5H), 8.20 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 21.4, 28.0, 36.3, 50.0, 108.9, 127.6, 128.5, 132.0, 136.5, 151.3, 164.3, 167.9.
Yield: 79.30% 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.01 (d, J = 6.6 Hz, 6H), 1.96-1.99 (m, 1H), 2.61 (s, 3H), 3.26 (d, J = 6.6 Hz, 2H), 5.54 (s, 2H), 7.25-7.34 (m, 5H), 8.20 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 21.4, 28.0, 36.3, 50.0, 108.9, 127.6, 128.5, 132.0, 136.5, 151.3, 164.3, 167.9.

(15) 4-(3-클로로프로필티오)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16o](15) 4- (3-chloropropylthio) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16o]

상기 [5f]와 4-chloropropylthiol으로 노란색의 액체상 화합물 16o를 얻었다.[5f] and 4-chloropropylthiol to obtain a yellow liquid compound 16o.

Yield: 83.40%; 1H NMR (400MHz, DMSO-d6) δ 2.17-2.22 (m, 2H), 2.61 (s, 3H), 3.45 (t, J = 7.1Hz, 2H), 3.77 (t, J = 6.4Hz, 2H), 5.54 (s, 2H), 7.25-7.34 (m, 5H), 8.20 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 25.8, 31.7, 44.0, 50.1, 109.0, 127.7, 128.6, 132.1, 136.6, 151.4, 163.8, 168.2.
Yield: 83.40%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.17-2.22 (m, 2H), 2.61 (s, 3H), 3.45 (t, J = 7.1 Hz, 2H), 3.77 (t, J = 6.4 Hz, 2H ), 5.54 (s, 2H), 7.25-7.34 (m, 5H), 8.20 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 25.8, 31.7, 44.0, 50.1, 109.0, 127.7, 128.6, 132.1, 136.6, 151.4, 163.8, 168.2.

(16) 4-(p-톨릴티오)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16p](16) 4- (p-tolylthio) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16p]

상기 [5f]와 p-Tolylthiol으로 노란색의 고체상 화합물 16p를 얻었다.The yellow solid compound 16p was obtained by the above [5f] and p-Tolylthiol.

Yield: 94.59%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (d, J = 12.8Hz, 6H), 5.49 (s, 2H), 6.92 (s, 1H), 7.23-7.33 (m, 5H), 7.38 (d, J = 7.9Hz, 2H), 7.62 (d, J = 7.9Hz, 2H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 20.8, 49.9, 108.1, 122.6, 127.6, 127.7, 128.5, 130.4, 131.7, 135.9, 136.3, 140.8, 152.0, 166.7, 167.7.
Yield: 94.59%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (d, J = 12.8 Hz, 6H), 5.49 (s, 2H), 6.92 (s, 1H), 7.23-7.33 (m, 5H), 7.38 (d , J = 7.9 Hz, 2H), 7.62 (d, J = 7.9 Hz, 2H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 20.8, 49.9, 108.1, 122.6, 127.6, 127.7, 128.5, 130.4, 131.7, 135.9, 136.3, 140.8, 152.0, 166.7, 167.7.

(17) 4-(4-메톡시페닐티오)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16q](17) 4- (4-methoxyphenylthio) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16q]

상기 [5f]와 4-methoxyphenylthiol으로 노란색의 고체상 화합물 16q를 얻었다.The yellow solid compound 16q was obtained from [5f] and 4-methoxyphenylthiol.

Yield: 85.22%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 3.85 (s, 3H), 5.49 (s, 2H), 6.87 (s, 1H), 7.12 (d, J = 8.8Hz, 2H), 7.22-7.30 (m, 5H), 7.65 (d, J = 8.8Hz, 2H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 49.9, 55.4, 108.0, 115.4, 116.4, 127.6, 127.7, 128.4, 131.7, 136.3, 137.7, 152.1, 161.3, 167.5, 167.7.
Yield: 85.22%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 3.85 (s, 3H), 5.49 (s, 2H), 6.87 (s, 1H), 7.12 (d, J = 8.8 Hz, 2H ), 7.22-7.30 (m, 5H), 7.65 (d, J = 8.8 Hz, 2H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 49.9, 55.4, 108.0, 115.4, 116.4, 127.6, 127.7, 128.4, 131.7, 136.3, 137.7, 152.1, 161.3, 167.5, 167.7.

(18) 4-(4-클로로페닐티오)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16r](18) 4- (4-chlorophenylthio) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16r]

상기 [5f]와 4-chlorophenylthiol으로 노란색의 고체상 화합물 16r를 얻었다.[5f] and 4-chlorophenylthiol to give a yellow solid compound 16r.

Yield: 97.03%; 1H NMR (400MHz, DMSO-d6) δ 2.39 (s, 3H), 5.52 (s, 2H), 7.23-7.31 (m, 5H), 7.54 (s, 1H), 7.62 (d, J = 8.5Hz, 2H), 7.74 (d,J = 8.3Hz, 2H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 50.1, 108.4, 125.1, 127.8, 128.6, 129.8, 131.9, 135.7, 136.5, 137.6, 152.1, 164.8, 168.1.
Yield: 97.03%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.39 (s, 3H), 5.52 (s, 2H), 7.23-7.31 (m, 5H), 7.54 (s, 1H), 7.62 (d, J = 8.5 Hz , 2H), 7.74 (d, J = 8.3 Hz, 2H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 50.1, 108.4, 125.1, 127.8, 128.6, 129.8, 131.9, 135.7, 136.5, 137.6, 152.1, 164.8, 168.1.

(19) 4-(2-클로로벤질티오)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16s](19) 4- (2-chlorobenzylthio) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16s]

상기 [5f]와 2-chlorobenzylthiol으로 노란색의 고체상 화합물 16s를 얻었다.The yellow solid compound 16s was obtained from [5f] and 2-chlorobenzylthiol.

Yield: 93.86%; 1H NMR (400MHz, DMSO-d6) δ 2.61 (s, 3H), 4.71 (s, 2H), 5.54 (s, 2H), 7.25-7.34 (m, 7H), 7.47-7.50 (m, 1H), 7.62-7.65 (m, 1H), 8.22 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 30.1, 50.0, 108.4, 127.3, 127.7, 128.5, 129.1, 131.4, 132.0, 133.3, 134.4, 136.5, 151.4, 163.0, 168.1.
Yield: 93.86%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.61 (s, 3H), 4.71 (s, 2H), 5.54 (s, 2H), 7.25-7.34 (m, 7H), 7.47-7.50 (m, 1H) , 7.62-7.65 (m, 1 H), 8.22 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 30.1, 50.0, 108.4, 127.3, 127.7, 128.5, 129.1, 131.4, 132.0, 133.3, 134.4, 136.5, 151.4, 163.0, 168.1.

(20) 4-(2,6-다이클로로페닐티오)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16t](20) 4- (2,6-dichlorophenylthio) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16t]

상기 [5f]와 2,6-dichlorophenylthiol으로 노란색의 고체상 화합물 16t를 얻었다.16t of a yellow solid compound was obtained from [5f] and 2,6-dichlorophenylthiol.

Yield: 95.31%; 1H NMR (400MHz, DMSO-d6) δ 2.29 (s, 3H), 5.54 (s, 2H), 7.26-7.35 (m, 5H), 7.64-7.68 (m, 1H), 7.76 (d, J = 7.8Hz, 2H), 7.84 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 50.1, 98.5, 108.1, 125.1, 127.7, 128.5, 129.1, 131.5, 133.4, 136.3, 141.0, 151.9, 161.9, 168.0.
Yield: 95.31%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.29 (s, 3H), 5.54 (s, 2H), 7.26-7.35 (m, 5H), 7.64-7.68 (m, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.84 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 50.1, 98.5, 108.1, 125.1, 127.7, 128.5, 129.1, 131.5, 133.4, 136.3, 141.0, 151.9, 161.9, 168.0.

(21) 4-(4-플루오로페닐티오)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘 [16u](21) 4- (4-fluorophenylthio) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine [16u]

상기 [5f]와 4-Fluorophenylthiol으로 노란색의 고체상 화합물 16u를 얻었다.The yellow solid compound 16u was obtained from [5f] and 4-Fluorophenylthiol.

Yield: 92.42%, 1H NMR (400MHz, DMSO-d6) δ 2.39 (s, 3H), 5.52 (s, 2H), 7.24-7.31 (m, 5H), 7.39-7.43 (m, 3H), 7.77-7.79 (m, 3H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 50.1, 108.2, 116.7, 116.9, 121.7, 127.6, 128.5, 131.7, 136.3, 138.3, 138.4, 151.9, 162.2, 164.7, 165.4, 167.8.
Yield: 92.42%, 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.39 (s, 3H), 5.52 (s, 2H), 7.24-7.31 (m, 5H), 7.39-7.43 (m, 3H), 7.77 -7.79 (m, 3 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 50.1, 108.2, 116.7, 116.9, 121.7, 127.6, 128.5, 131.7, 136.3, 138.3, 138.4, 151.9, 162.2, 164.7, 165.4, 167.8.

(22) 1-벤질-6-(메틸티오)-4-(옥틸티오)-1H-피라졸로[3,4-d]피리미딘 [16v](22) 1-benzyl-6- (methylthio) -4- (octylthio) -1H-pyrazolo [3,4-d] pyrimidine [16v]

상기 [5f]와 n-octylthiol으로 노란색의 고체상 화합물 16v를 얻었다.The yellow solid compound 16v was obtained from [5f] and n-octylthiol.

Yield: 78.35%; 1H NMR (400MHz, DMSO-d6) δ 0.83 (t, J = 6.8Hz, 3H), 1.22-1.26 (m, 8H), 1.36-1.40 (m, 2H), 1.67-1.71 (m, 2H), 2.59 (s, 3H), 3.31 (t, J = 7.3Hz, 2H), 5.53 (s, 2H), 7.24-7.33 (m, 5H), 8.18 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 13.8, 22.0, 28.1, 28.2, 28.4, 28.4, 28.7, 31.1, 49.9, 108.8, 127.6, 128.4, 132.0, 136.5, 151.3, 164.3, 168.0.
Yield: 78.35%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.83 (t, J = 6.8 Hz, 3H), 1.22-1.26 (m, 8H), 1.36-1.40 (m, 2H), 1.67-1.71 (m, 2H) , 2.59 (s, 3H), 3.31 (t, J = 7.3 Hz, 2H), 5.53 (s, 2H), 7.24-7.33 (m, 5H), 8.18 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 13.8, 22.0, 28.1, 28.2, 28.4, 28.4, 28.7, 31.1, 49.9, 108.8, 127.6, 128.4, 132.0, 136.5, 151.3, 164.3, 168.0.

(23) 1-벤질-4-(도데실티오)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘(16w)(23) 1-benzyl-4- (dodecylthio) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidine (16w)

상기 [5f]와 n-dodecylthiol으로 노란색의 액체상 화합물 16w를 얻었다.[5f] and n-dodecylthiol gave a yellow liquid compound 16w.

Yield: 91.66%; 1H NMR (400MHz, DMSO-d6) δ 0.85 (t, J = 3.4Hz, 3H), 1.24 (s, 16H), 1.42 (s, 2H), 1.71-1.74 (m, 2H), 2.59 (s, 3H), 3.31 (t, J = 7.2Hz, 2H), 5.52 (s, 2H), 7.23-7.32 (m, 5H), 8.02 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 22.2, 28.3, 28.4, 28.6, 28.8, 28.9, 29.0, 29.1, 31.4, 50.1, 78.4, 78.7, 79.0, 109.0, 127.6, 127.7, 128.4, 131.7, 136.4, 151.4, 164.3, 168.1.
Yield: 91.66%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.85 (t, J = 3.4 Hz, 3H), 1.24 (s, 16H), 1.42 (s, 2H), 1.71-1.74 (m, 2H), 2.59 (s , 3H), 3.31 (t, J = 7.2 Hz, 2H), 5.52 (s, 2H), 7.23-7.32 (m, 5H), 8.02 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 22.2, 28.3, 28.4, 28.6, 28.8, 28.9, 29.0, 29.1, 31.4, 50.1, 78.4, 78.7, 79.0, 109.0, 127.6, 127.7, 128.4, 131.7, 136.4, 151.4, 164.3, 168.1.

(24) 1-벤질-6-(메틸티오)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16x](24) 1-benzyl-6- (methylthio) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16x]

상기 [5f]와 (S)-phenylethylamine으로 얇은 노란색의 액체상 화합물 16x를 얻었다.[5f] and (S) -phenylethylamine afforded a thin yellow liquid compound 16x.

Yield: 92.02%; 1H NMR (400MHz, DMSO-d6) δ 1.54 (d, J = 6.5Hz, 3H), 2.42 (s, 3H), 5.42 (s, 3H), 7.19-7.41 (m, 8H), 7.41 (d, J = 7.1Hz, 2H), 8.15 (s, 1H), 8.74 (d, J = 7.1Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 22.3, 49.1, 49.6, 98.0, 126.0, 126.7, 127.4, 127.5, 128.3, 128.4, 132.3, 137.2, 144.5, 153.5, 154.4, 168.4.
Yield: 92.02%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.54 (d, J = 6.5 Hz, 3H), 2.42 (s, 3H), 5.42 (s, 3H), 7.19-7.41 (m, 8H), 7.41 (d , J = 7.1 Hz, 2H), 8.15 (s, 1H), 8.74 (d, J = 7.1 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 22.3, 49.1, 49.6, 98.0, 126.0, 126.7, 127.4, 127.5, 128.3, 128.4, 132.3, 137.2, 144.5, 153.5, 154.4, 168.4.

(25) 1-벤질-N-((4-클로로페닐)(페닐)메틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16y](25) 1-benzyl-N-((4-chlorophenyl) (phenyl) methyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16y]

상기 [5f]와 4-(chlorophenyl)(phenyl)methylamine으로 하얀색의 고체상 화합물 16y를 얻었다.White solid compound 16y was obtained from [5f] and 4- (chlorophenyl) (phenyl) methylamine.

Yield: 91.08%; 1H NMR (400MHz, DMSO-d6) δ 2.41 (s, 3H), 5.43 (s, 2H), 6.67 (d, J = 7.6Hz, 1H), 7.20-7.44 (m, 14H), 8.23 (s, 1H), 9.14 (d, J = 7.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) d 13.6, 14.0, 28.9, 49.6, 56.6, 98.1, 127.3, 127.4, 127.5, 127.6, 128.3, 138.4, 128.5, 129.3, 131.7, 132.6, 137.2, 140.9, 141.3, 153.6, 154.4, 168.4.
Yield: 91.08%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.41 (s, 3H), 5.43 (s, 2H), 6.67 (d, J = 7.6 Hz, 1H), 7.20-7.44 (m, 14H), 8.23 (s , 1H), 9.14 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) d 13.6, 14.0, 28.9, 49.6, 56.6, 98.1, 127.3, 127.4, 127.5, 127.6, 128.3, 138.4, 128.5, 129.3, 131.7, 132.6, 137.2, 140.9, 141.3, 153.6, 154.4, 168.4.

(26) 1-벤질-N-(1-사이클로헥실에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16z](26) 1-benzyl-N- (1-cyclohexylethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16z]

상기 [5f]와 (S)-cyclohexylethylamine으로 노란색의 고체상 화합물 16z를 얻었다.The yellow solid compound 16z was obtained from the above [5f] and (S) -cyclohexylethylamine.

Yield: 93.22%; 1H NMR (400MHz, DMSO-d6) δ 0.94-1.02 (m, 2H), 1.15 (d, J = 6.8Hz, 3H), 1.17-1.22 (m, 2H), 1.46-1.61 (m, 2H), 1.68-1.77 (m, 4H), 2.48 (s, 3H), 4.18-4.23 (m, 1H), 5.44-5.41 (m, 2H), 7.21-7.33 (m, 5H), 8.05 (d, J = 8.5Hz, 1H), 8.10 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 17.2, 25.6, 25.7, 25.8, 28.6, 29.1, 42.4, 49.5, 49.7, 97.9, 127.3, 127.5, 128.4, 132.2, 137.2, 153.4, 154.9, 168.3.
Yield: 93.22%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.94-1.02 (m, 2H), 1.15 (d, J = 6.8 Hz, 3H), 1.17-1.22 (m, 2H), 1.46-1.61 (m, 2H) , 1.68-1.77 (m, 4H), 2.48 (s, 3H), 4.18-4.23 (m, 1H), 5.44-5.41 (m, 2H), 7.21-7.33 (m, 5H), 8.05 (d, J = 8.5 Hz, 1 H), 8.10 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 17.2, 25.6, 25.7, 25.8, 28.6, 29.1, 42.4, 49.5, 49.7, 97.9, 127.3, 127.5, 128.4, 132.2, 137.2, 153.4, 154.9, 168.3.

(27) 1-벤질-6-(메틸티오)-N-(1-p-톨릴에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16za](27) 1-benzyl-6- (methylthio) -N- (1-p-tolylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16za]

상기 [5f]와 p-tolylethylamine으로 하얀색의 고체상 화합물 16za를 얻었다.The solid solid compound 16za was obtained from the above [5f] and p-tolylethylamine.

Yield: 93.78%; 1H NMR (400MHz, DMSO-d6) δ 1.52 (d, J = 6.9Hz, 3H), 2.25 (s, 3H), 2.43 (s, 3H), 5.42 (s, 3H), 7.13 (d, J = 7.6Hz, 2H), 7.19-7.31 (m, 8H), 8.15 (s, 1H), 8.68 (d, J = 7.6Hz, 1H); 13C NMR(100MHz, DMSO-d6) δ 13.5, 20.5, 22.2, 48.8, 49.6, 98.0, 125.9, 127.4, 127.5, 128.4, 128.8, 132.3, 135.7, 137.2, 141.5, 153.5, 154.4, 168.4.
Yield: 93.78%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.52 (d, J = 6.9 Hz, 3H), 2.25 (s, 3H), 2.43 (s, 3H), 5.42 (s, 3H), 7.13 (d, J = 7.6 Hz, 2H), 7.19-7.31 (m, 8H), 8.15 (s, 1H), 8.68 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 20.5, 22.2, 48.8, 49.6, 98.0, 125.9, 127.4, 127.5, 128.4, 128.8, 132.3, 135.7, 137.2, 141.5, 153.5, 154.4, 168.4.

(28) 1-벤질-N-((S)-1-(4-메톡시페닐)에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16zb](28) 1-benzyl-N-((S) -1- (4-methoxyphenyl) ethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16zb]

상기 [5f]와 (R)-4-methoxyphenylethylamine으로 얇은 노란색의 고체상 화합물 16zb를 얻었다.The thin yellow solid compound 16zb was obtained from [5f] and (R) -4-methoxyphenylethylamine.

Yield: 96.33%; 1H NMR (400MHz, DMSO-d6) δ 1.52 (d, J = 6.8Hz, 3H), 2.45 (s, 3H), 3.71 (s, 3H), 5.42 (s, 3H), 6.89 (d, J = 8.5Hz, 2H), 7.19-7.33 (m, 8H), 8.14 (s, 1H), 8.65 (d, J = 7.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 22.2, 38.8, 48.4, 49.6, 54.9, 98.0, 113.6, 127.2, 127.4, 127.5, 128.4, 132.3, 136.3, 137.2, 153.5, 154.3, 158.0, 168.4.
Yield: 96.33%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.52 (d, J = 6.8 Hz, 3H), 2.45 (s, 3H), 3.71 (s, 3H), 5.42 (s, 3H), 6.89 (d, J = 8.5 Hz, 2H), 7.19-7.33 (m, 8H), 8.14 (s, 1H), 8.65 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 22.2, 38.8, 48.4, 49.6, 54.9, 98.0, 113.6, 127.2, 127.4, 127.5, 128.4, 132.3, 136.3, 137.2, 153.5, 154.3, 158.0, 168.4.

(29) N-(2-메톡시벤질)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16zc](29) N- (2-methoxybenzyl) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16zc]

상기 [5f]와 2-Methoxybenzylamine으로 하얀색의 고체상 화합물 16zc를 얻었다.White solid compound 16zc was obtained from [5f] and 2-Methoxybenzylamine.

Yield: 88.82%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 3.83 (s, 3H), 4.69 (d, J = 4.4Hz, 2H), 5.44 (s, 2H), 6.91 (t, J = 7.0Hz, 1H), 7.01 (d, J = 8.0Hz, 1H), 7.25-7.31 (m, 7H), 8.14 (s, 1H), 8.69 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 38.3, 49.6, 55.2, 98.1, 110.5, 120.1, 126.2, 127.3, 127.5, 128.2, 128.4, 132.3, 137.2, 153.3, 155.3, 156.8, 168.5.
Yield: 88.82%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 3.83 (s, 3H), 4.69 (d, J = 4.4 Hz, 2H), 5.44 (s, 2H), 6.91 (t, J = 7.0 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.25-7.31 (m, 7H), 8.14 (s, 1H), 8.69 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 38.3, 49.6, 55.2, 98.1, 110.5, 120.1, 126.2, 127.3, 127.5, 128.2, 128.4, 132.3, 137.2, 153.3, 155.3, 156.8, 168.5.

(30) N-(4-클로로벤질)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16zd](30) N- (4-chlorobenzyl) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16zd]

상기 [5f]와 4-chlorobenzylamine으로 하얀색의 고체상 화합물 16zd를 얻었다.The solid solid compound 16zd was obtained from [5f] and 4-chlorobenzylamine.

Yield: 92.77%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 4.71 (d, J = 4.5Hz, 2H), 5.45 (s, 2H), 7.25-7.31 (m, 5H), 7.39 (s, 4H), 8.10 (s, 1H), 8.91 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 43.1, 50.2, 98.6, 127.9, 128.0, 128.8, 128.9, 139.7, 132.0, 132.6, 137.7, 138.6, 153.9, 155.7, 169.1.
Yield: 92.77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 4.71 (d, J = 4.5 Hz, 2H), 5.45 (s, 2H), 7.25-7.31 (m, 5H), 7.39 (s , 4H), 8.10 (s, 1 H), 8.91 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 43.1, 50.2, 98.6, 127.9, 128.0, 128.8, 128.9, 139.7, 132.0, 132.6, 137.7, 138.6, 153.9, 155.7, 169.1.

(31) N-(4-메틸벤질)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16ze](31) N- (4-methylbenzyl) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16ze]

상기 [5f]와 4-methylbenzylamine으로 하얀색의 고체상 화합물 16ze를 얻었다.White solid compound 16ze was obtained from [5f] and 4-methylbenzylamine.

Yield: 85.30%; 1H NMR (400MHz, DMSO-d6) δ 2.27 (s, 3H), 2.48 (s, 3H), 4.66 (d, J = 5.0Hz, 2H), 5.43 (s, 2H), 7.14 (d, J = 7.4Hz, 2H), 7.21-7.32 (m, 7H), 8.08 (s, 1H), 8.82 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.8, 29.7, 37.9, 42.9, 49.6, 98.0, 110.5, 120.1, 127.4, 128.4, 128.8, 131.4, 132.1, 135.9, 137.2, 153.4, 155.1, 168.5.
Yield: 85.30%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.27 (s, 3H), 2.48 (s, 3H), 4.66 (d, J = 5.0 Hz, 2H), 5.43 (s, 2H), 7.14 (d, J = 7.4 Hz, 2H), 7.21-7.32 (m, 7H), 8.08 (s, 1H), 8.82 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.8, 29.7, 37.9, 42.9, 49.6, 98.0, 110.5, 120.1, 127.4, 128.4, 128.8, 131.4, 132.1, 135.9, 137.2, 153.4, 155.1, 168.5.

(32) N-(3-메톡시벤질)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16zf](32) N- (3-methoxybenzyl) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16zf]

상기 [5f]와 3-methoxybenzylamine으로 얇은 노란색의 고체상 화합물 16zf를 얻었다.The thin yellow solid compound 16zf was obtained from [5f] and 3-methoxybenzylamine.

Yield: 86.37%; 1H NMR (400MHz, DMSO-d6) δ 2.49 (s, 3H), 3.73 (s, 3H), 4.70 (d, J = 5.6Hz, 2H), 5.45 (s, 2H), 6.84 (d, J = 8.0Hz, 1H), 6.96 (t, J = 6.3Hz, 2H), 7.22-7.33 (m, 6H), 8.11 (s, 1H), 8.87 (t, J = 5.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 43.2, 49.6, 54.8, 98.1, 112.2, 113.3, 119.6, 127.4, 127.5, 128.4, 129.4, 132.2, 137.2, 140.6, 153.4, 155.2, 159.2, 168.5.
Yield: 86.37%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.49 (s, 3H), 3.73 (s, 3H), 4.70 (d, J = 5.6 Hz, 2H), 5.45 (s, 2H), 6.84 (d, J = 8.0 Hz, 1H), 6.96 (t, J = 6.3 Hz, 2H), 7.22-7.33 (m, 6H), 8.11 (s, 1H), 8.87 (t, J = 5.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 43.2, 49.6, 54.8, 98.1, 112.2, 113.3, 119.6, 127.4, 127.5, 128.4, 129.4, 132.2, 137.2, 140.6, 153.4, 155.2, 159.2, 168.5.

(33) 1-벤질-N-뷰틸-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16zg](33) 1-benzyl-N-butyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16zg]

상기 [5f]와 n-butylamine으로 얇은 노란색의 고체상 화합물 16zg를 얻었다.16zg of a thin yellow solid compound was obtained using [5f] and n-butylamine.

Yield: 97.04%; 1H NMR (400MHz, DMSO-d6) δ 0.92 (t, J = 7.3Hz, 3H), 1.34-1.41 (m, 2H), 1.55.-1.62 (m, 2H), 2.51 (s, 3H), 3.45-3.50 (m, 2H), 5.43 (s, 2H), 7.22-7.33 (m, 5H), 8.06 (s, 1H), 8.31 (t, J = 5.2Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 13.7, 19.6, 30.9, 49.7, 98.1, 100.4, 127.4, 127.6, 128.5, 132.2, 137.3, 153.4, 155.4, 168.6.
Yield: 97.04%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.92 (t, J = 7.3 Hz, 3H), 1.34-1.41 (m, 2H), 1.55.-1.62 (m, 2H), 2.51 (s, 3H), 3.45-3.50 (m, 2H), 5.43 (s, 2H), 7.22-7.33 (m, 5H), 8.06 (s, 1H), 8.31 (t, J = 5.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 13.7, 19.6, 30.9, 49.7, 98.1, 100.4, 127.4, 127.6, 128.5, 132.2, 137.3, 153.4, 155.4, 168.6.

(34) 1-벤질-6-(메틸티오)-N-((피리딘-2-일)메틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16zh](34) 1-benzyl-6- (methylthio) -N-((pyridin-2-yl) methyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16zh]

상기 [5f]와 (pyridin-2-yl)methanamine으로 하얀색의 고체상 화합물 16zh를 얻었다.The white solid compound 16zh was obtained from [5f] and (pyridin-2-yl) methanamine.

Yield: 89.26%; 1H NMR (400MHz, DMSO-d6) δ 2.41 (s, 3H), 4.80 (d, J = 5.7Hz, 2H), 5.44 (s, 2H), 7.22-7.36 (m, 7H), 7.75 (t, J = 7.6Hz, 1H), 8.12 (s, 1H), 8.53 (d, J = 4.4Hz, 1H), 9.00 (t, J = 5.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 45.1, 49.6, 98.1, 121.3, 122.1, 127.3, 127.5, 128.4, 132.2, 136.6, 137.1, 148.8, 153.4, 155.2, 158.2, 168.4.
Yield: 89.26%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.41 (s, 3H), 4.80 (d, J = 5.7 Hz, 2H), 5.44 (s, 2H), 7.22-7.36 (m, 7H), 7.75 (t , J = 7.6 Hz, 1H), 8.12 (s, 1H), 8.53 (d, J = 4.4 Hz, 1H), 9.00 (t, J = 5.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 45.1, 49.6, 98.1, 121.3, 122.1, 127.3, 127.5, 128.4, 132.2, 136.6, 137.1, 148.8, 153.4, 155.2, 158.2, 168.4.

(35) N-(2-클로로벤질)-1-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [16zi](35) N- (2-chlorobenzyl) -1-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [16zi]

상기 [5f]와 2-chlorobenzylamine으로 하얀색의 고체상 화합물 16zi를 얻었다.White solid compound 16zi was obtained from [5f] and 2-chlorobenzylamine.

Yield: 92.44%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 4.79 (d, J = 5.4Hz, 2H), 5.45 (s, 2H), 7.23-7.33 (m, 7H), 7.43 (t, J = 4.4Hz, 1H), 7.48 (t, J = 4.5Hz, 1H), 8.13 (s, 1H), 8.88 (t, J = 5.3Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 41.2, 49.6, 98.1, 126.8, 127.1, 127.4, 127.5, 128.0, 128.4, 128.7, 129.1, 129.2, 132.2, 135.9, 137.1, 153.4, 155.1, 168.5.
Yield: 92.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 4.79 (d, J = 5.4 Hz, 2H), 5.45 (s, 2H), 7.23-7.33 (m, 7H), 7.43 (t , J = 4.4 Hz, 1H), 7.48 (t, J = 4.5 Hz, 1H), 8.13 (s, 1H), 8.88 (t, J = 5.3 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 41.2, 49.6, 98.1, 126.8, 127.1, 127.4, 127.5, 128.0, 128.4, 128.7, 129.1, 129.2, 132.2, 135.9, 137.1, 153.4, 155.1, 168.5.

실시예 15. [17a] 내지 [17q]의 합성Example 15. Synthesis of [17a] to [17q]

하기 [반응식 17](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [17a] 내지 [17q]를 합성하였다.The pyrazolopyrimidine derivative compounds [17a] to [17q] according to the present invention were synthesized by the following Scheme 17 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 17][Reaction Scheme 17]

Figure pat00235
Figure pat00235

[5g] [17a] ~ [17q][5g] [17a]-[17q]

[17a] 내지 [17q]에서 NR2은 각각 하기 [표 10]과 같다.NR 2 in [17a] to [17q] are as shown in Table 10 below, respectively.

구분division NR2 NR 2 구분division NR2 NR 2 17a17a

Figure pat00236
Figure pat00236
17j17j
Figure pat00237
Figure pat00237
 17b17b
Figure pat00238
Figure pat00238
 17k17k
Figure pat00239
Figure pat00239
 17c17c
Figure pat00240
Figure pat00240
 17l17l
Figure pat00241
Figure pat00241
 17d17d
Figure pat00242
Figure pat00242
 17m17 m
Figure pat00243
Figure pat00243
 17e17e
Figure pat00244
Figure pat00244
 17n17n
Figure pat00245
Figure pat00245
 17f17f
Figure pat00246
Figure pat00246
 17o17o
Figure pat00247
Figure pat00247
 17g17g
Figure pat00248
Figure pat00248
 17p17p
Figure pat00249
Figure pat00249
 17h17h
Figure pat00250
Figure pat00250
 17q17q
Figure pat00251
Figure pat00251
 17i17i
Figure pat00252
Figure pat00252

(1) 1-t-뷰틸-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [17a](1) 1-t-butyl-4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [17a]

상기 [5g]와 benzylamine으로 옅은 노란색의 고체상 화합물 17a를 얻었다.The pale yellow solid compound 17a was obtained from [5 g] and benzylamine.

Yield: 85%; 1H NMR (400MHz, DMSO-d6) δ 1.57 (s, 9H), 2.40 (s, 3H), 4.66 (d, J = 5.4Hz, 2H), 7.25-7.34 (m, 5H), 8.38 (s, 1H), 8.57 (t, J = 5.3Hz, 1H).
Yield: 85%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.57 (s, 9H), 2.40 (s, 3H), 4.66 (d, J = 5.4 Hz, 2H), 7.25-7.34 (m, 5H), 8.38 (s , 1H), 8.57 (t, J = 5.3 Hz, 1H).

(2) (R)-1-t-뷰틸-4-(1-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [17b](2) (R) -1-t-butyl-4- (1-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [17b]

상기 [5g]와 (R)-1-phenylethylamine으로 옅은 노란색의 고체상 화합물 17b를 얻었다.The pale yellow solid compound 17b was obtained from [5 g] and (R) -1-phenylethylamine.

Yield: 69%; 1H NMR (400MHz, DMSO-d6) δ 1.50 (d, J = 6.9Hz, 3H), 1.58 (s, 9H), 2.36 (s, 3H), 5.37-5.44 (m, 1H), 7.22 (t, J = 7.1Hz, 1H), 7.32 (d, J = 7.5Hz, 2H), 7.39 (d, J = 7.6Hz, 2H), 8.46 (d, J = 9.1Hz, 1H).
Yield: 69%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.50 (d, J = 6.9 Hz, 3H), 1.58 (s, 9H), 2.36 (s, 3H), 5.37-5.44 (m, 1H), 7.22 (t , J = 7.1 Hz, 1H), 7.32 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 8.46 (d, J = 9.1 Hz, 1H).

(3) 1-t-뷰틸-4-(4-플루오로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [17c](3) 1-t-butyl-4- (4-fluorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [17c]

상기 [5g]와 4-fluorobenzylamine으로 옅은 노란색의 고체상 화합물 17c를 얻었다.The pale yellow solid compound 17c was obtained from [5 g] and 4-fluorobenzylamine.

Yield: 63%; 1H NMR (400MHz, DMSO-d6) δ 1.57 (s, 9H), 2.40 (s, 3H), 4.64 (d, J = 5.5Hz, 2H), 7.16 (d, J = 8.8Hz, 2H), 7.39 (quar, J = 8.8Hz, 2H), 8.37 (s, 1H), 8.58 (t, J = 5.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.8, 29.6, 43.0, 60.2, 99.5, 115.4, 121.8, 130.1, 135.7, 156.7, 160.0, 168.9.
Yield: 63%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.57 (s, 9H), 2.40 (s, 3H), 4.64 (d, J = 5.5 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.39 (quar, J = 8.8 Hz, 2H), 8.37 (s, 1 H), 8.58 (t, J = 5.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.8, 29.6, 43.0, 60.2, 99.5, 115.4, 121.8, 130.1, 135.7, 156.7, 160.0, 168.9.

(4) 1-t-뷰틸-4-(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [17d](4) 1-t-butyl-4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [17d]

상기 [5g]와 4-fluorobenzylamine으로 하얀색의 고체상 화합물 17d를 얻었다.[5g] and 4-fluorobenzylamine gave white solid compound 17d.

Yield: 77%; 1H NMR (400MHz, DMSO-d6) δ 1.57 (s, 9H), 2.40 (s, 3H), 3.53 (dt, J = 5.3Hz, 21.2Hz, 4H), 4.81 (t, J = 5.2Hz, 1H), 8.14 (t, J = 5.0Hz, 1H), 8.41 (s, 1H).
Yield: 77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.57 (s, 9H), 2.40 (s, 3H), 3.53 (dt, J = 5.3 Hz, 21.2 Hz, 4H), 4.81 (t, J = 5.2 Hz, 1H), 8.14 (t, J = 5.0 Hz, 1H), 8.41 (s, 1H).

(5) 1-t-뷰틸-4-(4-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [17e](5) 1-t-butyl-4- (4-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [17e]

상기 [5g]와 4-methoxybenzylamine으로 갈색의 고체상 화합물 17e를 얻었다.[5g] and 4-methoxybenzylamine gave brown solid compound 17e.

Yield: 98%; 1H NMR (400MHz, CDCl3) δ 1.58 (s, 9H), 2.54 (s, 3H), 3.75 (s, 3H), 4.66 (s, 2H), 6.27 (br s, 1H), 6.79 (d, J = 8.1Hz, 2H), 7.23 (d, J = 8.4Hz, 2H), 7.96 (s, 1H).
Yield: 98%; 1 H NMR (400 MHz, CDCl 3 ) δ 1.58 (s, 9H), 2.54 (s, 3H), 3.75 (s, 3H), 4.66 (s, 2H), 6.27 (br s, 1H), 6.79 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.96 (s, 1H).

(6) 1-t-뷰틸-4-알릴아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [17f](6) 1-t-butyl-4-allylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [17f]

상기 [5g]와 4-methoxybenzylamine으로 옅은 노란색의 고체상 화합물 17f를 얻었다.The pale yellow solid compound 17f was obtained from [5 g] and 4-methoxybenzylamine.

Yield: 92%; 1H NMR (400MHz, DMSO-d6) δ 1.58 (s, 9H), 2.40 (s, 3H), 4.08 (t, J = 4.9Hz, 2H), 5.13 (dd, J = 1.3Hz, 10.3Hz, 1H), 5.23 (dd, J = 1.5Hz, 17.2Hz, 1H), 5.88-5.97 (m, 1H), 8.25 (t, J = 5.1Hz, 1H), 8.38 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.8, 29.6, 42.5, 60.1, 99.6, 116.3, 121.8, 135.3, 156.7, 160.0, 168.0.
Yield: 92%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.58 (s, 9H), 2.40 (s, 3H), 4.08 (t, J = 4.9 Hz, 2H), 5.13 (dd, J = 1.3 Hz, 10.3 Hz, 1H), 5.23 (dd, J = 1.5 Hz, 17.2 Hz, 1H), 5.88-5.97 (m, 1H), 8.25 (t, J = 5.1 Hz, 1H), 8.38 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.8, 29.6, 42.5, 60.1, 99.6, 116.3, 121.8, 135.3, 156.7, 160.0, 168.0.

(7) (R)-1-t-뷰틸-4-(1-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [17g](7) (R) -1-t-butyl-4- (1-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [17 g]

상기 [5g]와 (R)-1-phenylethylamine으로 갈색의 고체상 화합물 17g를 얻었다.17g of the brown solid compound was obtained from the above [5g] and (R) -1-phenylethylamine.

Yield: 63%; 1H NMR (400MHz, CDCl3) d 1.62 (s, 9H), 2.58 (s, 3H), 2.95 (t, J = 7.0Hz, 2H), 3.84 (t, J = 6.5Hz, 2H), 5.84 (br s, 1H), 7.18-7.33 (m, 5H), 7.86 (s, 1H).
Yield: 63%; 1 H NMR (400 MHz, CDCl 3 ) d 1.62 (s, 9H), 2.58 (s, 3H), 2.95 (t, J = 7.0 Hz, 2H), 3.84 (t, J = 6.5 Hz, 2H), 5.84 ( br s, 1 H), 7.18-7.33 (m, 5 H), 7.86 (s, 1 H).

(8) 1-t-뷰틸-4-(2-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [17h](8) 1-t-butyl-4- (2-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [17h]

상기 [5g]와 2-phenylethylamine으로 갈색의 고체상 화합물 17h를 얻었다.[5g] and 2-phenylethylamine gave 17h of a brown solid compound.

Yield: 63%; 1H NMR (400MHz, CDCl3) δ 1.50 (d, J = 6.9Hz, 3H), 1.58 (s, 9H), 2.36 (s, 3H), 5.41 (d, J = 7.0Hz, 1H), 7.22 (t, J = 7.1Hz, 1H), 7.32 (d, J = 7.5Hz, 2H), 7.39 (d, J = 7.6Hz, 2H), 8.44 (s, 1H), 8.47 (s, 1H).
Yield: 63%; 1 H NMR (400 MHz, CDCl 3 ) δ 1.50 (d, J = 6.9 Hz, 3H), 1.58 (s, 9H), 2.36 (s, 3H), 5.41 (d, J = 7.0 Hz, 1H), 7.22 ( t, J = 7.1 Hz, 1H), 7.32 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 8.44 (s, 1H), 8.47 (s, 1H).

(9) N-(2-메톡시벤질)-1-t-뷰틸-6-(methylthio)-1H-피라졸로[3,4-d]피리미딘-4-아민 [17i](9) N- (2-methoxybenzyl) -1-t-butyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [17i]

상기 [5g]와 2-methoxybenzylamine으로 하얀색의 고체상 화합물 17i를 얻었다.White solid compound 17i was obtained from [5g] and 2-methoxybenzylamine.

Yield: 89.25%; 1H NMR (400MHz, DMSO-d6) δ 1.59 (s, 9H), 2.41 (s, 3H), 3.83 (s, 3H), 4.63 (d, J = 4.4Hz, 2H), 6.97 (dd, J = 7.8Hz, 39.9Hz, 2H), 7.27 (t, J = 3.2Hz, 2H), 8.43 (d, J = 23.0Hz, 2H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 29.2, 55.4, 59.7, 99.2, 110.7, 120.2, 121.6, 126.2, 128.5, 128.6, 156.5, 157.0, 159.6, 167.6.
Yield: 89.25%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.59 (s, 9H), 2.41 (s, 3H), 3.83 (s, 3H), 4.63 (d, J = 4.4 Hz, 2H), 6.97 (dd, J = 7.8 Hz, 39.9 Hz, 2H), 7.27 (t, J = 3.2 Hz, 2H), 8.43 (d, J = 23.0 Hz, 2H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 29.2, 55.4, 59.7, 99.2, 110.7, 120.2, 121.6, 126.2, 128.5, 128.6, 156.5, 157.0, 159.6, 167.6.

(10) N-(4-클로로벤질)-1-t-뷰틸-6-(methylthio)-1H-피라졸로[3,4-d]피리미딘-4-아민 [17j](10) N- (4-chlorobenzyl) -1-t-butyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [17j]

상기 [5g]와 4-chlorobenzylamine으로 하얀색의 고체상 화합물 17j를 얻었다.[5g] and 4-chlorobenzylamine to obtain a white solid compound 17j.

Yield: 92.44%; 1H NMR (400MHz, DMSO-d6) δ 1.59 (s, 9H), 2.41 (s, 3H), 4.67 (d, J = 5.5Hz, 2H), 7.36-7.41 (m, 4H), 8.39 (s, 1H), 8.63 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 29.1, 42.5, 59.7, 99.0, 121.4, 128.3, 129.4, 131.5, 138.1, 156.3, 159.6, 167.6.
Yield: 92.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.59 (s, 9H), 2.41 (s, 3H), 4.67 (d, J = 5.5 Hz, 2H), 7.36-7.41 (m, 4H), 8.39 (s , 1H), 8.63 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 29.1, 42.5, 59.7, 99.0, 121.4, 128.3, 129.4, 131.5, 138.1, 156.3, 159.6, 167.6.

(11) N-(3-메톡시벤질)-1-t-뷰틸-6-(methylthio)-1H-피라졸로[3,4-d]피리미딘-4-아민 [17k](11) N- (3-methoxybenzyl) -1-t-butyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [17k]

상기 [5g]와 3-methoxybenzylamine으로 하얀색의 고체상 화합물 17k를 얻었다.17k was obtained as a white solid compound using [5g] and 3-methoxybenzylamine.

Yield: 90.86%; 1H NMR (400MHz, DMSO-d6) δ 1.61 (s, 9H), 2.44 (s, 3H), 3.75 (s, 3H), 4.66 (d, J = 4.4Hz, 2H), 6.91 (dd, J = 9.4Hz, 38.5Hz, 3H), 7.28 (t, J = 7.1Hz, 1H), 8.42 (s, 1H), 8.59 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 29.6, 43.7, 55.4, 60.1, 99.5, 112.8, 114.0, 120.3, 121.9, 129.9, 141.0, 156.8, 159.7, 160.1, 168.0.
Yield: 90.86%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.61 (s, 9H), 2.44 (s, 3H), 3.75 (s, 3H), 4.66 (d, J = 4.4 Hz, 2H), 6.91 (dd, J = 9.4 Hz, 38.5 Hz, 3H), 7.28 (t, J = 7.1 Hz, 1H), 8.42 (s, 1H), 8.59 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 29.6, 43.7, 55.4, 60.1, 99.5, 112.8, 114.0, 120.3, 121.9, 129.9, 141.0, 156.8, 159.7, 160.1, 168.0.

(12) 1-t-뷰틸-N-뷰틸-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [17l](12) 1-t-butyl-N-butyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [17l]

상기 [5g]와 n-buthylamine으로 하얀색의 고체상 화합물 17l를 얻었다.17 L of white solid compound was obtained from [5 g] and n-buthylamine.

Yield: 91.22%; 1H NMR (400MHz, DMSO-d6) δ 0.92 (t, J = 6.3Hz, 3H), 1.34-1.39 (m, 2H), 1.59 (s, 9H), 2.42 (s, 3H), 3.44 (d, J = 4.6Hz, 2H), 8.04 (s, 1H), 8.36 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.3, 13.6, 19.5, 29.0, 30.7, 59.5, 99.0, 121.1, 156.3, 159.4, 167.5.
Yield: 91.22%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.92 (t, J = 6.3 Hz, 3H), 1.34-1.39 (m, 2H), 1.59 (s, 9H), 2.42 (s, 3H), 3.44 (d , J = 4.6 Hz, 2H), 8.04 (s, 1H), 8.36 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.3, 13.6, 19.5, 29.0, 30.7, 59.5, 99.0, 121.1, 156.3, 159.4, 167.5.

(13) 1-t-뷰틸-6-(메틸티오)-N-((피리딘-2-일)메틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [17m](13) 1-t-butyl-6- (methylthio) -N-((pyridin-2-yl) methyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [17m]

상기 [5g]와 (pyridin-2-yl)methanamine으로 하얀색의 고체상 화합물 17m를 얻었다.17 m of a white solid compound was obtained from [5 g] and (pyridin-2-yl) methanamine.

Yield: 93.44%; 1H NMR (400MHz, DMSO-d6) δ 1.60 (s, 9H), 2.38 (s, 3H), 4.77 (d, J = 5.6Hz, 2H), 7.29 (t, J = 6.1Hz, 1H), 7.36 (d, J = 7.8Hz, 1H), 7.76 (t, J = 5.6Hz, 1H), 8.45 (s, 1H), 8.54 (d, J = 4.3Hz, 1H), 8.71 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.2, 29.0, 45.0, 59.6, 99.0, 120.9, 121.4, 121.8, 122.1, 126.3, 136.6, 137.7, 148.4, 148.8, 156.3, 158.1, 159.5, 167.4.
Yield: 93.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.60 (s, 9H), 2.38 (s, 3H), 4.77 (d, J = 5.6 Hz, 2H), 7.29 (t, J = 6.1 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.76 (t, J = 5.6 Hz, 1H), 8.45 (s, 1H), 8.54 (d, J = 4.3 Hz, 1H), 8.71 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.2, 29.0, 45.0, 59.6, 99.0, 120.9, 121.4, 121.8, 122.1, 126.3, 136.6, 137.7, 148.4, 148.8, 156.3, 158.1, 159.5, 167.4.

(14) N-(2-클로로벤질)-1-t-뷰틸-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [17n](14) N- (2-chlorobenzyl) -1-t-butyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [17n]

상기 [5g]와 2-chlorobenzylamine으로 하얀색의 고체상 화합물 17n를 얻었다.White solid compound 17n was obtained from [5 g] and 2-chlorobenzylamine.

Yield: 85.40%; 1H NMR (400MHz, DMSO-d6) δ 1.62 (s, 9H), 2.42 (s, 3H), 4.76 (s, 2H), 7.34-7.49 (m, 4H), 8.46 (s, 1H), 8.60 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.2, 29.0, 41.2, 59.6, 98.9, 121.4, 127.1, 128.8, 129.1, 129.5, 132.4, 135.8, 156.2, 159.5, 167.4.
Yield: 85.40%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.62 (s, 9H), 2.42 (s, 3H), 4.76 (s, 2H), 7.34-7.49 (m, 4H), 8.46 (s, 1H), 8.60 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.2, 29.0, 41.2, 59.6, 98.9, 121.4, 127.1, 128.8, 129.1, 129.5, 132.4, 135.8, 156.2, 159.5, 167.4.

(15) 2-(1-t-뷰틸-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-일아미노)-2-메틸프로판-1-올 [17o](15) 2- (1-t-butyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-ylamino) -2-methylpropan-1-ol [17o]

상기 [5g]와 2-amino-2-methylpropan-1-ol으로 하얀색의 고체상 화합물 17o를 얻었다.The white solid compound 17o was obtained from [5g] and 2-amino-2-methylpropan-1-ol.

Yield: 95.36%; 1H NMR (400MHz, DMSO-d6) δ 1.40 (s, 6H), 1.60 (s, 9H), 2.44 (s, 3H), 3.67 (d, J = 4.3Hz, 2H), 5.0 (s, 1H), 7.38 (m, 1H), 8.57 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 23.9, 29.1, 56.0, 59.5, 66.7, 99.6, 121.9, 156.1, 159.4, 166.7.
Yield: 95.36%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.40 (s, 6H), 1.60 (s, 9H), 2.44 (s, 3H), 3.67 (d, J = 4.3 Hz, 2H), 5.0 (s, 1H ), 7.38 (m, 1 H), 8.57 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 23.9, 29.1, 56.0, 59.5, 66.7, 99.6, 121.9, 156.1, 159.4, 166.7.

(16) 1-t-뷰틸-N-(1-사이클로헥실에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [17p](16) 1-t-butyl-N- (1-cyclohexylethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [17p]

상기 [5g]와 (R)-cyclohexylethylamine으로 하얀색의 고체상 화합물 17p를 얻었다.White solid compound 17p was obtained from the above [5g] and (R) -cyclohexylethylamine.

Yield: 90.52%; 1H NMR (400MHz, DMSO-d6) δ 0.97-1.04 (m, 2H), 1.15 (d, J = 7.1Hz, 3H), 1.42-1.46 (m, 2H), 1.59 (s, 9H), 1.62 (s, 2H), 1.69-1.75 (m, 4H), 2.40 (s, 3H), 4.16 (d, J = 7.1Hz, 1H), 7.79 (d, J = 8.5Hz, 1H), 8.42 (s, 1H)
Yield: 90.52%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.97-1.04 (m, 2H), 1.15 (d, J = 7.1 Hz, 3H), 1.42-1.46 (m, 2H), 1.59 (s, 9H), 1.62 (s, 2H), 1.69-1.75 (m, 4H), 2.40 (s, 3H), 4.16 (d, J = 7.1 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 8.42 (s, 1H)

(17) 1-t-뷰틸-N-(1-사이클로헥실에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [17q](17) 1-t-butyl-N- (1-cyclohexylethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [17q]

상기 [5g]와 (S)-cyclohexylethylamine으로 하얀색의 고체상 화합물 17q를 얻었다.The white solid compound 17q was obtained from the above [5g] and (S) -cyclohexylethylamine.

Yield: 88.20%; 1H NMR (400MHz, DMSO-d6) δ 0.98-1.04 (m, 2H), 1.14 (d, J = 7.1Hz, 3H), 1.19-1.22 (m, 2H), 1.43-1.44 (m, 2H), 1.60 (s, 9H), 1.70-1.75 (m, 4H), 2.42 (s, 3H), 4.17 (d, J = 7.3Hz, 1H), 7.80 (d, J = 8.5Hz, 1H), 8.44 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.8, 17.9, 26.2, 26.4, 29.1, 29.6, 43.0, 49.9, 60.0, 99.5, 121.9, 156.5, 160.1, 168.0.
Yield: 88.20%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.98-1.04 (m, 2H), 1.14 (d, J = 7.1 Hz, 3H), 1.19-1.22 (m, 2H), 1.43-1.44 (m, 2H) , 1.60 (s, 9H), 1.70-1.75 (m, 4H), 2.42 (s, 3H), 4.17 (d, J = 7.3 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 8.44 ( s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.8, 17.9, 26.2, 26.4, 29.1, 29.6, 43.0, 49.9, 60.0, 99.5, 121.9, 156.5, 160.1, 168.0.

실시예 16. [18a] 내지 [18i]의 합성Example 16. Synthesis of [18a] to [18i]

하기 [반응식 18](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [18a] 내지 [18i]를 합성하였다.The pyrazolopyrimidine derivative compounds [18a] to [18i] were synthesized according to the following Reaction Scheme 18 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 18][Reaction Scheme 18]

Figure pat00253
Figure pat00253

[5j] [18a] ~ [18i][5j] [18a] to [18i]

[18a] 내지 [18i]에서 NR2은 각각 하기 [표 11]과 같다.In [18a] to [18i], NR 2 is shown in Table 11 below, respectively.

구분division NR2 NR 2 구분division NR2 NR 2 18a18a

Figure pat00254
Figure pat00254
18f18f
Figure pat00255
Figure pat00255
 18b18b
Figure pat00256
Figure pat00256
 18g18g
Figure pat00257
Figure pat00257
 18c18c
Figure pat00258
Figure pat00258
 18h18h
Figure pat00259
Figure pat00259
 18d18d
Figure pat00260
Figure pat00260
 18i18i
Figure pat00261
Figure pat00261
 18e18e
Figure pat00262
Figure pat00262
Figure pat00263
Figure pat00263

(1) N-(2-클로로벤질)-1-(3-메톡시펜에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [18a](1) N- (2-chlorobenzyl) -1- (3-methoxyphenethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [18a]

상기 [5j]와 2-chlorobenzylamine으로 노란색의 고체상 화합물 18a를 얻었다.The yellow solid compound 18a was obtained from [5j] and 2-chlorobenzylamine.

Yield: 79.53%; 1H NMR (400MHz, DMSO-d6) δ 2.38 (s, 3H), 3.10 (t, J = 6.9Hz, 2H), 3.65 (s, 3H), 4.46 (t, J = 7.0Hz, 2H), 4.75 (d, J = 5.6Hz, 2H), 6.70 (t, J = 6.3Hz, 3H), 7.12 (t, J = 7.8Hz, 1H), 7.30 (t, J = 4.6Hz, 2H), 7.39 (t, J = 4.5Hz, 1H), 7.46 (t, J = 4.5Hz, 1H), 8.07 (s, 1H), 8.78 (t, J = 5.3Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 35.3, 41.7, 47.6, 55.2, 98.5, 112.4, 114.5, 121.3, 127.7, 129.3, 129.7, 132.2, 132.7, 136.5, 140.3, 153.8, 155.6, 159.6, 168.6.
Yield: 79.53%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.38 (s, 3H), 3.10 (t, J = 6.9 Hz, 2H), 3.65 (s, 3H), 4.46 (t, J = 7.0 Hz, 2H), 4.75 (d, J = 5.6 Hz, 2H), 6.70 (t, J = 6.3 Hz, 3H), 7.12 (t, J = 7.8 Hz, 1H), 7.30 (t, J = 4.6 Hz, 2H), 7.39 ( t, J = 4.5 Hz, 1H), 7.46 (t, J = 4.5 Hz, 1H), 8.07 (s, 1H), 8.78 (t, J = 5.3 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 35.3, 41.7, 47.6, 55.2, 98.5, 112.4, 114.5, 121.3, 127.7, 129.3, 129.7, 132.2, 132.7, 136.5, 140.3, 153.8, 155.6, 159.6, 168.6.

(2) N-(2-메톡시벤질)-1-(3-메톡시펜에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [18b](2) N- (2-methoxybenzyl) -1- (3-methoxyphenethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [18b ]

상기 [5j]와 2-methoxybenzylamine으로 하얀색의 고체상 화합물 18b를 얻었다.The white solid compound 18b was obtained from [5j] and 2-methoxybenzylamine.

Yield: 84.95%; 1H NMR (400MHz, DMSO-d6) δ 2.41 (s, 3H), 3.10 (t, J = 7.0Hz, 2H), 3.65 (s, 3H), 3.90 (s, 3H), 4.45 (t, J = 7.0Hz, 2H), 4.63 (d, J = 5.5Hz, 2H), 6.70 (t, J = 5.9Hz, 3H), 6.89 (t, J = 7.4Hz, 1H), 7.00 (d, J = 8.1Hz, 1H), 7.12 (t, J = 7.8Hz, 1H), 7.24 (quar, J = 7.3Hz, 2H), 8.07 (s, 1H), 8.58 (t, J = 5.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.8, 35.3, 38.8, 47.6, 55.2, 55.8, 98.5, 111.1, 112.3, 114.5, 120.6, 121.3, 126.7, 128.8, 129.7, 132.3, 140.3, 153.8, 155.7, 157.3, 159.6, 168.5.
Yield: 84.95%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.41 (s, 3H), 3.10 (t, J = 7.0 Hz, 2H), 3.65 (s, 3H), 3.90 (s, 3H), 4.45 (t, J = 7.0 Hz, 2H), 4.63 (d, J = 5.5 Hz, 2H), 6.70 (t, J = 5.9 Hz, 3H), 6.89 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.24 (quar, J = 7.3 Hz, 2H), 8.07 (s, 1H), 8.58 (t, J = 5.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.8, 35.3, 38.8, 47.6, 55.2, 55.8, 98.5, 111.1, 112.3, 114.5, 120.6, 121.3, 126.7, 128.8, 129.7, 132.3, 140.3, 153.8, 155.7, 157.3, 159.6, 168.5.

(3) N-(2-메틸벤질)-1-(3-메톡시펜에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [18c](3) N- (2-methylbenzyl) -1- (3-methoxyphenethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [18c]

상기 [5j]와 2-methylbenzylamine으로 하얀색의 고체상 화합물 18c를 얻었다.The white solid compound 18c was obtained from [5j] and 2-methylbenzylamine.

Yield: 80.21%; 1H NMR (400MHz, DMSO-d6) δ 2.31 (s, 3H), 2.42 (s, 3H), 3.10 (t, J = 6.6Hz, 2H), 3.64 (s, 3H), 4.45 (t, J = 6.7Hz, 2H), 4.65 (d, J = 5.2Hz, 2H), 6.69 (t,J = 6.7Hz, 3H), 7.09-7.17 (m, 4H), 7.27 (d, J = 5.9Hz, 1H), 8.07 (s, 1H), 8.60 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 19.2, 35.3, 42.0, 47.6, 55.2, 98.5, 112.3, 114.5, 121.3, 126.3, 127.6, 128.6, 129.7, 130.5, 132.3, 136.4, 137.0, 140.3, 153.8, 155.5, 159.6, 168.6.
Yield: 80.21%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.31 (s, 3H), 2.42 (s, 3H), 3.10 (t, J = 6.6 Hz, 2H), 3.64 (s, 3H), 4.45 (t, J = 6.7 Hz, 2H), 4.65 (d, J = 5.2 Hz, 2H), 6.69 (t, J = 6.7 Hz, 3H), 7.09-7.17 (m, 4H), 7.27 (d, J = 5.9 Hz, 1H ), 8.07 (s, 1 H), 8.60 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 19.2, 35.3, 42.0, 47.6, 55.2, 98.5, 112.3, 114.5, 121.3, 126.3, 127.6, 128.6, 129.7, 130.5, 132.3, 136.4, 137.0, 140.3, 153.8, 155.5, 159.6, 168.6.

(4) N-(3-메톡시벤질)-1-(3-메톡시펜에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [18d](4) N- (3-methoxybenzyl) -1- (3-methoxyphenethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [18d ]

상기 [5j]와 3-methoxybenzylamine으로 노란색의 고체상 화합물 18d를 얻었다.The yellow solid compound 18d was obtained from [5j] and 3-methoxybenzylamine.

Yield: 94.66%; 1H NMR (400MHz, DMSO-d6) δ 2.45 (s, 3H), 3.12 (t, J = 6.6Hz, 2H), 3.67 (s, 3H), 3.74 (s, 3H), 4.48 (t, J = 6.6Hz, 2H), 4.68 (d, J = 4.9Hz, 2H), 6.71 (t, J = 6.2Hz, 2H), 6.84 (d, J = 8.1Hz, 1H), 6.94 (d, J = 9.3Hz, 2H), 7.13 (t, J = 7.17Hz, 1H), 7.26 (t, J = 5.2Hz, 1H), 8.07 (s, 1H), 8.78 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 14.0, 19.7, 34.8, 43.2, 47.1, 54.7, 54.9, 59.7, 98.0, 100.3, 111.8, 112.2, 113.3, 114.0, 119.6, 120.8, 129.2, 129.4, 131.6, 139.8, 140.7, 153.3, 155.1, 159.1, 159.2, 168.1.
Yield: 94.66%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (s, 3H), 3.12 (t, J = 6.6 Hz, 2H), 3.67 (s, 3H), 3.74 (s, 3H), 4.48 (t, J = 6.6 Hz, 2H), 4.68 (d, J = 4.9 Hz, 2H), 6.71 (t, J = 6.2 Hz, 2H), 6.84 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 9.3 Hz, 2H), 7.13 (t, J = 7.17 Hz, 1H), 7.26 (t, J = 5.2 Hz, 1H), 8.07 (s, 1H), 8.78 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 14.0, 19.7, 34.8, 43.2, 47.1, 54.7, 54.9, 59.7, 98.0, 100.3, 111.8, 112.2, 113.3, 114.0, 119.6, 120.8, 129.2, 129.4, 131.6, 139.8, 140.7, 153.3, 155.1, 159.1, 159.2, 168.1.

(5) 1-(3-메톡시펜에틸)-N-(4-메톡시벤질)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [18e](5) 1- (3-methoxyphenethyl) -N- (4-methoxybenzyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [18e ]

상기 [5j]와 4-methoxybenzylamine으로 노란색의 고체상 화합물 18e를 얻었다.The yellow solid compound 18e was obtained from [5j] and 4-methoxybenzylamine.

Yield: 76.44%; 1H NMR (400MHz, DMSO-d6) δ 2.49 (s, 3H), 3.15 (t, J = 7.1Hz, 2H), 3.70 (s, 3H), 3.76 (s, 3H), 4.50 (t, J = 7.1Hz, 2H), 4.66 (d, J = 5.7Hz, 2H), 6.73-6.77 (m, 3H), 6.94 (d, J = 6.8Hz, 2H), 7.17 (t, J = 7.8Hz, 1H), 7.34 (t, J = 10.4Hz, 2H), 8.08 (s, 3H), 8.75 (t, J = 5.7Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 14.0, 19.7, 34.8, 42.7, 47.1, 54.7, 55.0, 59.7, 98.0, 111.8, 113.7, 114.0, 120.8, 128.9, 129.2, 130.9, 131.6, 139.8, 153.3, 155.0, 158.3, 159.1, 168.1.
Yield: 76.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.49 (s, 3H), 3.15 (t, J = 7.1 Hz, 2H), 3.70 (s, 3H), 3.76 (s, 3H), 4.50 (t, J = 7.1 Hz, 2H), 4.66 (d, J = 5.7 Hz, 2H), 6.73-6.77 (m, 3H), 6.94 (d, J = 6.8 Hz, 2H), 7.17 (t, J = 7.8 Hz, 1H ), 7.34 (t, J = 10.4 Hz, 2H), 8.08 (s, 3H), 8.75 (t, J = 5.7 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 14.0, 19.7, 34.8, 42.7, 47.1, 54.7, 55.0, 59.7, 98.0, 111.8, 113.7, 114.0, 120.8, 128.9, 129.2, 130.9, 131.6, 139.8, 153.3, 155.0, 158.3, 159.1, 168.1.

(6) 1-(3-메톡시펜에틸)-N-(4-메틸벤질)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [18f](6) 1- (3-methoxyphenethyl) -N- (4-methylbenzyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [18f]

상기 [5j]와 4-methylbenzylamine으로 노란색의 고체상 화합물 18f를 얻었다.The yellow solid compound 18f was obtained by using [5j] and 4-methylbenzylamine.

Yield: 88.47%; 1H NMR (400MHz, DMSO-d6) δ 2.27 (s, 3H), 2.44 (s, 3H), 3.11 (t, J = 7.0Hz, 2H), 3.66 (s, 3H), 4.46 (t, J = 7.0Hz, 2H), 4.65 (d, J = 5.6Hz, 2H), 6.69-6.72 (m, 3H), 7.13 (t, J = 7.9Hz, 3H), 7.24 (d, J = 7.8Hz, 2H), 8.05 (s, 1H), 8.74 (t, J = 5.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 19.6, 34.8, 43.0, 47.1, 54.7, 98.0, 111.8, 114.0, 120.8, 127.4, 129.8, 129.2, 131.6, 136.0, 139.8, 153.3, 155.1, 159.1, 168.1.
Yield: 88.47%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.27 (s, 3H), 2.44 (s, 3H), 3.11 (t, J = 7.0 Hz, 2H), 3.66 (s, 3H), 4.46 (t, J = 7.0 Hz, 2H), 4.65 (d, J = 5.6 Hz, 2H), 6.69-6.72 (m, 3H), 7.13 (t, J = 7.9 Hz, 3H), 7.24 (d, J = 7.8 Hz, 2H ), 8.05 (s, 1 H), 8.74 (t, J = 5.6 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 19.6, 34.8, 43.0, 47.1, 54.7, 98.0, 111.8, 114.0, 120.8, 127.4, 129.8, 129.2, 131.6, 136.0, 139.8, 153.3, 155.1, 159.1, 168.1.

(7) 1-(3-메톡시펜에틸)-N-(4-플루오로벤질)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [18g](7) 1- (3-methoxyphenethyl) -N- (4-fluorobenzyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [18 g ]

상기 [5j]와 4-fluorobenzylamine으로 하얀색의 고체상 화합물 18g를 얻었다.18g of a white solid compound was obtained from [5j] and 4-fluorobenzylamine.

Yield: 87.04%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 3.12 (t, J = 7.0Hz, 2H), 3.66 (s, 3H), 4.47 (t, J = 7.0Hz, 2H), 4.68 (d, J = 5.6Hz, 2H), 4.76-4.80 (m, 1H), 6.70-6.73 (m, 3H), 7.13-7.19 (m, 3H), 7.37-7.41 (m, 2H), 8.04 (s, 1H), 8.79 (t, J = 5.2Hz, 1H), 8.90 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 21.8, 34.7, 42.4, 47.1, 54.7, 98.0, 111.8, 113.9, 114.9, 115.1, 120.7, 129.1, 129.4, 131.6, 135.2, 139.7, 153.3, 155.0, 156.1, 159.0, 162.4, 168.1.
Yield: 87.04%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 3.12 (t, J = 7.0 Hz, 2H), 3.66 (s, 3H), 4.47 (t, J = 7.0 Hz, 2H), 4.68 (d, J = 5.6 Hz, 2H), 4.76-4.80 (m, 1H), 6.70-6.73 (m, 3H), 7.13-7.19 (m, 3H), 7.37-7.41 (m, 2H), 8.04 ( s, 1 H), 8.79 (t, J = 5.2 Hz, 1 H), 8.90 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 21.8, 34.7, 42.4, 47.1, 54.7, 98.0, 111.8, 113.9, 114.9, 115.1, 120.7, 129.1, 129.4, 131.6, 135.2, 139.7, 153.3, 155.0, 156.1, 159.0, 162.4, 168.1.

(8) 1-(3-메톡시펜에틸)-N-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [18h](8) 1- (3-methoxyphenethyl) -N-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [18h]

상기 [5j]와 benzylamine으로 하얀색의 고체상 화합물 18h를 얻었다.The white solid compound 18h was obtained from [5j] and benzylamine.

Yield: 89.45%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 3.12 (t, J = 7.0Hz, 2H), 3.66 (s, 3H), 4.47 (t, J = 7.0Hz, 2H), 4.71 (d, J = 5.6Hz, 2H), 4.75-4.80 (m, 1H), 6.71 (t, J = 6.1Hz, 3H), 7.13 (t, J = 7.8Hz, 1H), 7.24-7.35 (m, 5H), 8.06 (s, 1H), 8.80 (d, J = 5.5Hz, 1H), 8.90 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 22.3, 35.3, 43.7, 47.6, 55.2, 98.5, 112.3, 114.5, 121.3, 127.4, 128.0, 128.8, 129.7, 132.2, 139.6, 140.3, 153.8, 155.6, 156.6, 159.6, 168.6.
Yield: 89.45%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 3.12 (t, J = 7.0 Hz, 2H), 3.66 (s, 3H), 4.47 (t, J = 7.0 Hz, 2H), 4.71 (d, J = 5.6 Hz, 2H), 4.75-4.80 (m, 1H), 6.71 (t, J = 6.1 Hz, 3H), 7.13 (t, J = 7.8 Hz, 1H), 7.24-7.35 (m , 5H), 8.06 (s, 1H), 8.80 (d, J = 5.5 Hz, 1H), 8.90 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 22.3, 35.3, 43.7, 47.6, 55.2, 98.5, 112.3, 114.5, 121.3, 127.4, 128.0, 128.8, 129.7, 132.2, 139.6, 140.3, 153.8, 155.6, 156.6, 159.6, 168.6.

(9) 1-(3-메톡시펜에틸)-N-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [18i](9) 1- (3-methoxyphenethyl) -N-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [18i]

상기 [5j]와 allylamine으로 하얀색의 고체상 화합물 18i를 얻었다.White solid compound 18i was obtained from [5j] and allylamine.

Yield: 90.21%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 3.12 (t, J = 6.9Hz, 2H), 3.67 (s, 3H), 4.11 (s, 2H), 4.47 (t, J = 6.9Hz, 2H), 4.76-4.81 (m, 1H), 5.12-5.25 (m, 2H), 5.92-5.99 (m, 1H), 6.72 (t, J = 5.7Hz, 2H), 7.13 (t, J = 7.7Hz, 1H), 8.04 (s, 1H), 8.45 (s, 1H), 8.89 (s, 1H), 8.89 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 21.8, 34.7, 42.0, 47.0, 54.7, 98.0, 111.8, 113.9, 115.8, 120.7, 129.1, 131.6, 134.8, 139.7, 153.2, 155.0, 159.0, 168.0.
Yield: 90.21%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 3.12 (t, J = 6.9 Hz, 2H), 3.67 (s, 3H), 4.11 (s, 2H), 4.47 (t, J = 6.9 Hz, 2H), 4.76-4.81 (m, 1H), 5.12-5.25 (m, 2H), 5.92-5.99 (m, 1H), 6.72 (t, J = 5.7 Hz, 2H), 7.13 (t, J = 7.7 Hz, 1H), 8.04 (s, 1H), 8.45 (s, 1H), 8.89 (s, 1H), 8.89 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 21.8, 34.7, 42.0, 47.0, 54.7, 98.0, 111.8, 113.9, 115.8, 120.7, 129.1, 131.6, 134.8, 139.7, 153.2, 155.0, 159.0, 168.0.

실시예 17. [19a] 내지 [19i]의 합성Example 17. Synthesis of [19a] to [19i]

하기 [반응식 19](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [19a] 내지 [19i]를 합성하였다.The pyrazolopyrimidine derivative compounds [19a] to [19i] were synthesized according to the following Reaction Scheme 19 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 19]Scheme 19

Figure pat00264
Figure pat00264

[5k] [19a] ~ [19i][5k] [19a]-[19i]

[19a] 내지 [19i]에서 NR2은 각각 하기 [표 12]와 같다.NR 2 in [19a] to [19i] are as shown in Table 12 below, respectively.

구분division NR2 NR 2 구분division NR2 NR 2 19a19a

Figure pat00265
Figure pat00265
19f19f
Figure pat00266
Figure pat00266
 19b19b
Figure pat00267
Figure pat00267
 19g19 g
Figure pat00268
Figure pat00268
 19c19c
Figure pat00269
Figure pat00269
 19h19h
Figure pat00270
Figure pat00270
 19d19d
Figure pat00271
Figure pat00271
 19i19i
Figure pat00272
Figure pat00272
 19e19e
Figure pat00273
Figure pat00273

(1) 1-(2-메톡시펜에틸)-N-(3-메톡시벤질)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [19a](1) 1- (2-methoxyphenethyl) -N- (3-methoxybenzyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [19a ]

상기 [5k]와 3-methoxybenzylamine으로 하얀색의 고체상 화합물 19a를 얻었다.White solid compound 19a was obtained by using [5k] and 3-methoxybenzylamine.

Yield: 96.88%; 1H NMR (400MHz, DMSO-d6) δ 2.45 (s, 3H), 3.09 (t, J = 6.6Hz, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 4.44 (t, J = 6.6Hz, 2H), 4.67 (d, J = 4.6Hz, 2H), 6.77 (t, J = 7.3Hz, 1H), 6.84 (d, J = 8.1Hz, 1H), 6.95 (t, J = 10.8Hz, 4H), 7.17 (t, J = 7.7Hz, 1H), 7.26 (t, J = 7.8Hz, 1H), 8.04 (s, 1H), 8.75 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 30.2, 43.2, 45.9, 54.9, 55.2, 98.0, 110.5, 112.2, 113.3, 119.6, 120.1, 125.9, 127.8, 129.4, 129.9, 131.5, 140.7, 153.2, 155.1, 157.3, 159.2, 168.0.
Yield: 96.88%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (s, 3H), 3.09 (t, J = 6.6 Hz, 2H), 3.73 (s, 3H), 3.78 (s, 3H), 4.44 (t, J = 6.6 Hz, 2H), 4.67 (d, J = 4.6 Hz, 2H), 6.77 (t, J = 7.3 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.95 (t, J = 10.8 Hz, 4H), 7.17 (t, J = 7.7 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 8.04 (s, 1H), 8.75 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 30.2, 43.2, 45.9, 54.9, 55.2, 98.0, 110.5, 112.2, 113.3, 119.6, 120.1, 125.9, 127.8, 129.4, 129.9, 131.5, 140.7, 153.2, 155.1, 157.3, 159.2, 168.0.

(2) 1-(2-메톡시펜에틸)-N-(4-메톡시벤질)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [19b](2) 1- (2-methoxyphenethyl) -N- (4-methoxybenzyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [19b ]

상기 [5k]와 4-methoxybenzylamine으로 얇은 노란색의 고체상 화합물 19b를 얻었다.The thin yellow solid compound 19b was obtained from [5k] and 4-methoxybenzylamine.

Yield: 93.57%; 1H NMR (400MHz, DMSO-d6) δ 2.45 (s, 3H), 3.08 (t, J = 6.8Hz, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 4.43 (t, J = 6.8Hz, 2H), 4.62 (d, J = 5.2Hz, 2H), 6.76 (t, J = 7.3Hz, 1H), 6.89-6.97 (m, 4H), 7.16 (t, J = 7.7Hz, 1H), 7.28 (d, J = 8.3Hz, 2H), 8.02 (s, 1H), 8.68 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 30.2, 42.7, 45.8, 55.0, 55.2, 97.9, 110.5, 113.7, 120.1, 125.9, 127.8, 128.9, 129.9, 130.9, 131.5, 153.2, 155.0, 157.3, 158.3, 168.0.
Yield: 93.57%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (s, 3H), 3.08 (t, J = 6.8 Hz, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 4.43 (t, J = 6.8 Hz, 2H), 4.62 (d, J = 5.2 Hz, 2H), 6.76 (t, J = 7.3 Hz, 1H), 6.89-6.97 (m, 4H), 7.16 (t, J = 7.7 Hz, 1H ), 7.28 (d, J = 8.3 Hz, 2H), 8.02 (s, 1H), 8.68 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 30.2, 42.7, 45.8, 55.0, 55.2, 97.9, 110.5, 113.7, 120.1, 125.9, 127.8, 128.9, 129.9, 130.9, 131.5, 153.2, 155.0, 157.3, 158.3, 168.0.

(3) 1-(2-메톡시펜에틸)-N-(4-메톡시벤질)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [19c](3) 1- (2-methoxyphenethyl) -N- (4-methoxybenzyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [19c ]

상기 [5k]와 4-methylbenzylamine으로 하얀색의 고체상 화합물 19c를 얻었다.[5k] and 4-methylbenzylamine gave white solid compound 19c.

Yield: 90.54%; 1H NMR (400MHz, DMSO-d6) δ 2.27 (s, 3H), 2.44 (s, 3H), 3.08 (t, J = 7.1Hz, 2H), 3.78 (s, 3H), 4.43 (t, J = 7.2Hz, 2H), 4.64 (d, J = 5.7Hz, 2H), 6.76 (t, J = 7.2Hz, 1H), 6.92-6.97 (m, 2H), 7.13-7.16 (m, 3H), 7.24 (d,J = 8.0Hz, 2H), 8.03 (s, 1H), 8.71 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 21.1, 30.7, 43.4, 46.3, 55.7, 98.5, 111.0, 120.6, 126.4, 128.0, 128.3, 129.3, 130.4,132.0, 136.5, 153.7, 155.6, 157.8, 168.5.
Yield: 90.54%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.27 (s, 3H), 2.44 (s, 3H), 3.08 (t, J = 7.1 Hz, 2H), 3.78 (s, 3H), 4.43 (t, J = 7.2 Hz, 2H), 4.64 (d, J = 5.7 Hz, 2H), 6.76 (t, J = 7.2 Hz, 1H), 6.92-6.97 (m, 2H), 7.13-7.16 (m, 3H), 7.24 (d, J = 8.0 Hz, 2H), 8.03 (s, 1H), 8.71 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 21.1, 30.7, 43.4, 46.3, 55.7, 98.5, 111.0, 120.6, 126.4, 128.0, 128.3, 129.3, 130.4,132.0, 136.5, 153.7, 155.6, 157.8, 168.5.

(4) 1-(2-메톡시펜에틸)-N-(4-플루오로벤질)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [19d](4) 1- (2-methoxyphenethyl) -N- (4-fluorobenzyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [19d ]

상기 [5k]와 4-fluorobenzylamine으로 갈색의 고체상 화합물 19d를 얻었다.[5k] and 4-fluorobenzylamine obtained the brown solid compound 19d.

Yield: 84.37%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 3.08 (t, J = 7.0Hz, 2H), 3.78 (s, 3H), 4.43 (t, J = 7.0Hz, 2H), 4.67 (d, J = 5.4Hz, 2H), 4.76-4.80 (m, 1H), 6.77 (t, J = 7.3Hz, 1H), 6.95 (t, J = 9.5Hz, 2H), 7.17 (t, J = 8.1Hz, 3H), 7.37-7.40 (m, 2H), 8.01 (s, 1H), 8.76 (t, J = 5.3Hz, 1H), 8.89 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.3, 21.8, 30.1, 42.4, 45.8, 55.1, 97.9, 100.3, 110.5, 114.9, 115.1, 120.0, 125.8, 127.8, 129.4, 129.9, 131.4, 135.2, 155.0, 156.0, 157.2, 167.9.
Yield: 84.37%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 3.08 (t, J = 7.0 Hz, 2H), 3.78 (s, 3H), 4.43 (t, J = 7.0 Hz, 2H), 4.67 (d, J = 5.4 Hz, 2H), 4.76-4.80 (m, 1H), 6.77 (t, J = 7.3 Hz, 1H), 6.95 (t, J = 9.5 Hz, 2H), 7.17 (t, J = 8.1 Hz, 3H), 7.37-7.40 (m, 2H), 8.01 (s, 1H), 8.76 (t, J = 5.3 Hz, 1H), 8.89 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.3, 21.8, 30.1, 42.4, 45.8, 55.1, 97.9, 100.3, 110.5, 114.9, 115.1, 120.0, 125.8, 127.8, 129.4, 129.9, 131.4, 135.2, 155.0, 156.0, 157.2, 167.9.

(5) 1-(2-메톡시펜에틸)-N-벤질-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [19e](5) 1- (2-methoxyphenethyl) -N-benzyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [19e]

상기 [5k]와 benzylamine으로 갈색의 고체상 화합물 19e를 얻었다.[5k] and benzylamine gave brown solid compound 19e.

Yield: 81.24%, 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 3.08 (t, J = 7.1Hz, 2H), 3.79 (s, 3H), 4.43 (t, J = 7.1Hz, 2H), 4.70 (d, J = 5.7Hz, 2H), 4.76-4.80 (m, 1H), 6.77 (t, J = 7.2Hz, 1H), 6.95 (t, J = 9.1Hz, 2H), 7.26 (t, J = 7.9Hz, 3H), 7.32-7.36 (m, 3H), 8.03 (s, 1H), 8.76 (t, J = 5.2Hz, 1H), 8.89 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.8, 21.8, 30.2, 43.2, 45.8, 55.1, 97.9, 101.3, 110.5, 114.9, 115.1, 120.0, 125.8, 127.8, 129.4, 129.9, 131.4, 135.2, 155.1, 156.1, 157.2, 168.0.
Yield: 81.24%, 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 3.08 (t, J = 7.1 Hz, 2H), 3.79 (s, 3H), 4.43 (t, J = 7.1 Hz, 2H), 4.70 (d, J = 5.7 Hz, 2H), 4.76-4.80 (m, 1H), 6.77 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 9.1 Hz, 2H), 7.26 (t, J = 7.9 Hz, 3H), 7.32-7.36 (m, 3H), 8.03 (s, 1 H), 8.76 (t, J = 5.2 Hz, 1H), 8.89 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.8, 21.8, 30.2, 43.2, 45.8, 55.1, 97.9, 101.3, 110.5, 114.9, 115.1, 120.0, 125.8, 127.8, 129.4, 129.9, 131.4, 135.2, 155.1, 156.1, 157.2, 168.0.

(6) 1-(2-메톡시펜에틸)-N-알릴-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 (19f)(6) 1- (2-methoxyphenethyl) -N-allyl-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine (19f)

상기 [5k]와 allylamine으로 하얀색의 고체상 화합물 19f를 얻었다.White solid compound 19f was obtained from [5k] and allylamine.

Yield: 78.53%; 1H NMR (400MHz, DMSO-d6) δ 2.45 (s, 3H), 3.08 (t, J = 7.1Hz, 2H), 3.78 (s, 3H), 4.09-4.12 (m, 2H), 4.43 (t, J = 7.2Hz, 2H), 4.76-4.81 (m, 1H), 5.11-5.24 (m, 2H), 5.94-5.97 (m, 1H), 6.76 (t, J = 7.3Hz, 1H), 6.95 (t, J = 8.6Hz, 2H), 7.14-7.18 (m, 1H), 8.02 (s, 1H), 8.43 (d, J = 5.2Hz, 1H), 8.89 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.3, 30.1, 42.0, 55.1, 97.9, 110.4, 115.7, 120.0, 125.9, 127.8, 129.9, 131.4, 134.8, 153.1, 155.0, 156.0, 157.2, 167.9.
Yield: 78.53%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (s, 3H), 3.08 (t, J = 7.1 Hz, 2H), 3.78 (s, 3H), 4.09-4.12 (m, 2H), 4.43 (t , J = 7.2 Hz, 2H), 4.76-4.81 (m, 1H), 5.11-5.24 (m, 2H), 5.94-5.97 (m, 1H), 6.76 (t, J = 7.3 Hz, 1H), 6.95 ( t, J = 8.6 Hz, 2H), 7.14-7.18 (m, 1H), 8.02 (s, 1H), 8.43 (d, J = 5.2 Hz, 1H), 8.89 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.3, 30.1, 42.0, 55.1, 97.9, 110.4, 115.7, 120.0, 125.9, 127.8, 129.9, 131.4, 134.8, 153.1, 155.0, 156.0, 157.2, 167.9.

(7) N-(2-메톡시벤질)-1-(2-메톡시펜에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [19g](7) N- (2-methoxybenzyl) -1- (2-methoxyphenethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [19 g ]

상기 [5k]와 2-methylbenzylamine으로 하얀색의 고체상 화합물 19g를 얻었다.19g of white solid compound was obtained by using [5k] and 2-methylbenzylamine.

Yield: 89.52%; 1H NMR (400MHz, DMSO-d6) δ 2.33 (s, 3H), 2.44 (s, 3H), 3.09 (t, J = 6.3Hz, 2H), 3.78 (s, 3H), 4.44 (t, J = 6.5Hz, 2H), 4.67 (d, J = 4.8Hz, 2H), 6.77 (t, J = 5.2Hz, 1H), 6.92-6.99 (m, 2H), 7.18 (m, 4H), 7.30 (d, J = 5.6Hz, 1H), 8.07 (s, 1H), 8.60 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.3, 18.7, 30.2, 41.5, 45.8, 55.1, 97.9, 110.5, 120.0, 125.7, 125.9, 127.0, 127.8, 128.0, 129.9, 129.9, 131.6, 135.9, 136.5, 153.2, 155.0, 157.2, 167.9.
Yield: 89.52%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.33 (s, 3H), 2.44 (s, 3H), 3.09 (t, J = 6.3 Hz, 2H), 3.78 (s, 3H), 4.44 (t, J = 6.5 Hz, 2H), 4.67 (d, J = 4.8 Hz, 2H), 6.77 (t, J = 5.2 Hz, 1H), 6.92-6.99 (m, 2H), 7.18 (m, 4H), 7.30 (d , J = 5.6 Hz, 1H), 8.07 (s, 1H), 8.60 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.3, 18.7, 30.2, 41.5, 45.8, 55.1, 97.9, 110.5, 120.0, 125.7, 125.9, 127.0, 127.8, 128.0, 129.9, 129.9, 131.6, 135.9, 136.5, 153.2, 155.0, 157.2, 167.9.

(8) N-(2-클로로벤질)-1-(2-메톡시펜에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [19h](8) N- (2-chlorobenzyl) -1- (2-methoxyphenethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [19h]

상기 [5k]와 2-chlorobenzylamine으로 하얀색의 고체상 화합물 19h를 얻었다.A white solid compound 19h was obtained from [5k] and 2-chlorobenzylamine.

Yield: 86.02%; 1H NMR (400MHz, DMSO-d6) δ 2.40 (s, 3H), 3.09 (t, J = 7.0Hz, 2H), 3.78 (s, 3H), 4.44 (t, J = 7.0Hz, 2H), 4.76 (d, J = 5.5Hz, 2H), 6.77 (t, J = 7.3Hz, 1H), 6.92-6.98 (m, 2H), 7.17 (t, J = 7.7Hz, 1H), 7.32 (t, J = 4.5Hz, 2H), 7.41 (t, J = 4.2Hz, 1H), 7.48 (t, J = 4.4Hz, 1H), 8.08 (s, 1H), 8.77 (t, J = 5.0Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.8, 30.7, 41.7, 46.4, 55.7, 98.5, 111.0, 120.6, 126.4, 127.7, 128.4, 129.3, 129.7, 130.4, 132.1, 132.8, 136.5, 153.8, 155.6, 157.8, 168.4.
Yield: 86.02%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.40 (s, 3H), 3.09 (t, J = 7.0 Hz, 2H), 3.78 (s, 3H), 4.44 (t, J = 7.0 Hz, 2H), 4.76 (d, J = 5.5 Hz, 2H), 6.77 (t, J = 7.3 Hz, 1H), 6.92-6.98 (m, 2H), 7.17 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 4.5 Hz, 2H), 7.41 (t, J = 4.2 Hz, 1H), 7.48 (t, J = 4.4 Hz, 1H), 8.08 (s, 1H), 8.77 (t, J = 5.0 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.8, 30.7, 41.7, 46.4, 55.7, 98.5, 111.0, 120.6, 126.4, 127.7, 128.4, 129.3, 129.7, 130.4, 132.1, 132.8, 136.5, 153.8, 155.6, 157.8, 168.4.

(9) N-(2-메톡시벤질)-1-(2-메톡시펜에틸)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [19i](9) N- (2-methoxybenzyl) -1- (2-methoxyphenethyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [19i ]

상기 [5k]와 2-methoxybenzylamine으로 하얀색의 고체상 화합물 19i를 얻었다.White solid compound 19i was obtained from [5k] and 2-methoxybenzylamine.

Yield: 88.34%; 1H NMR (400MHz, DMSO-d6) δ 2.42 (s, 3H), 3.08 (t, J = 7.1Hz, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 4.43 (t, J = 7.2Hz, 2H), 4.65 (d, J = 5.6Hz, 2H), 6.77 (t, J = 7.3Hz, 1H), 6.88-7.02 (m, 4H), 7.14-7.28 (m, 3H), 8.07 (s, 1H), 8.57 (t, J = 5.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.3, 30.2, 38.3, 45.8, 55.2, 55.3, 98.0, 110.5, 110.6, 120.1, 125.9, 126.2, 127.8, 128.2, 128.3, 129.9, 131.6, 153.2, 155.3, 156.8, 157.3, 167.9.
Yield: 88.34%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.42 (s, 3H), 3.08 (t, J = 7.1 Hz, 2H), 3.78 (s, 3H), 3.83 (s, 3H), 4.43 (t, J = 7.2 Hz, 2H), 4.65 (d, J = 5.6 Hz, 2H), 6.77 (t, J = 7.3 Hz, 1H), 6.88-7.02 (m, 4H), 7.14-7.28 (m, 3H), 8.07 (s, 1 H), 8.57 (t, J = 5.5 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.3, 30.2, 38.3, 45.8, 55.2, 55.3, 98.0, 110.5, 110.6, 120.1, 125.9, 126.2, 127.8, 128.2, 128.3, 129.9, 131.6, 153.2, 155.3, 156.8, 157.3, 167.9.

실시예 18. [20a] 내지 [20f]의 합성Example 18. Synthesis of [20a] to [20f]

하기 [반응식 20](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [20a] 내지 [20f]를 합성하였다.The pyrazolopyrimidine derivative compounds [20a] to [20f] were synthesized according to the following Reaction Scheme 20 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 20][Reaction Scheme 20]

Figure pat00274
Figure pat00274

[5h] [20a] ~ [20f][5h] [20a] to [20f]

[20a] 내지 [20f]에서 NR2은 각각 하기 [표 13]과 같다.In [20a] to [20f], NR 2 is shown in the following [Table 13].

구분division NR2 NR 2 구분division NR2 NR 2 20a20a

Figure pat00275
Figure pat00275
20d20d
Figure pat00276
Figure pat00276
 20b20b
Figure pat00277
Figure pat00277
 20e20e
Figure pat00278
Figure pat00278
 20c20c
Figure pat00279
Figure pat00279
 20f20f
Figure pat00280
Figure pat00280

(1) N-(2-클로로벤질)-1-(4-플루오로페닐)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [20a](1) N- (2-chlorobenzyl) -1- (4-fluorophenyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [20a]

상기 [5h]와 2-chlorobenzylamine으로 하얀색의 고체상 화합물 20a를 얻었다.[5h] and 2-chlorobenzylamine to obtain a white solid compound 20a.

Yield: 82.17%; 1H NMR (400MHz, DMSO-d6) δ 2.35 (s, 3H), 4.63 (d, J = 4.9Hz, 2H), 6.36 (s, 1H), 7.31-7.37 (m, 3H), 7.47 (t, J = 4.2Hz, 1H), 8.28 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.3, 41.6, 99.3, 127.2, 128.8, 129.2, 132.2, 135.8, 156.6, 162.3, 171.2.
Yield: 82.17%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.35 (s, 3H), 4.63 (d, J = 4.9 Hz, 2H), 6.36 (s, 1H), 7.31-7.37 (m, 3H), 7.47 (t , J = 4.2 Hz, 1 H), 8.28 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.3, 41.6, 99.3, 127.2, 128.8, 129.2, 132.2, 135.8, 156.6, 162.3, 171.2.

(2) N-(2-메톡시벤질)-1-(4-플루오로페닐)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [20b](2) N- (2-methoxybenzyl) -1- (4-fluorophenyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [20b]

상기 [5h]와 2-methoxybenzylamine으로 하얀색의 고체상 화합물 20b를 얻었다.The white solid compound 20b was obtained from [5h] and 2-methoxybenzylamine.

Yield: 88.32%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 3.82 (s, 3H), 4.68 (d, J = 5.2Hz, 2H), 6.90 (t, J = 7.3Hz, 1H), 7.00 (d, J = 7.9Hz, 1H), 7.25 (t, J = 7.8Hz, 2H), 7.36 (t, J = 8.7Hz, 2H), 8.16-8.19 (m, 2H), 8.34 (s, 1H), 8.81 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 39.0, 55.8, 99.9, 111.1, 116.2, 116.4, 120.6, 122.6, 126.5, 128.8, 134.5, 135.8, 153.6, 155.8, 157.3, 170.2.
Yield: 88.32%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 3.82 (s, 3H), 4.68 (d, J = 5.2 Hz, 2H), 6.90 (t, J = 7.3 Hz, 1H), 7.00 (d, J = 7.9 Hz, 1H), 7.25 (t, J = 7.8 Hz, 2H), 7.36 (t, J = 8.7 Hz, 2H), 8.16-8.19 (m, 2H), 8.34 (s, 1H ), 8.81 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 39.0, 55.8, 99.9, 111.1, 116.2, 116.4, 120.6, 122.6, 126.5, 128.8, 134.5, 135.8, 153.6, 155.8, 157.3, 170.2.

(3) N-(2-메틸벤질)-1-(4-프루오로페닐)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [20c](3) N- (2-methylbenzyl) -1- (4-fluorofluoro) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [20c]

상기 [5h]와 2-methylbenzylamine으로 하얀색의 고체상 화합물 20c를 얻었다.The white solid compound 20c was obtained from [5h] and 2-methylbenzylamine.

Yield: 77.24%; 1H NMR (400MHz, DMSO-d6) δ 2.29 (s, 3H), 2.39 (s, 3H), 4.52 (s, 2H), 6.30 (s, 1H), 7.16-7.24 (m, 5H), 8.12 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.3, 18.6, 39.9, 99.2, 125.8, 127.1, 128.1, 130.0, 135.9, 136.3, 156.5, 162.2, 171.2.
Yield: 77.24%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.29 (s, 3H), 2.39 (s, 3H), 4.52 (s, 2H), 6.30 (s, 1H), 7.16-7.24 (m, 5H), 8.12 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.3, 18.6, 39.9, 99.2, 125.8, 127.1, 128.1, 130.0, 135.9, 136.3, 156.5, 162.2, 171.2.

(4) N-(3-메톡시벤질)-1-(4-플루오로페닐)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [20d](4) N- (3-methoxybenzyl) -1- (4-fluorophenyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [20d]

상기 [5h]와 3-methoxybenzylamine으로 노란색의 고체상 화합물 20d를 얻었다.The yellow solid compound 20d was obtained from [5h] and 3-methoxybenzylamine.

Yield: 96.53%; 1H NMR (400MHz, DMSO-d6) δ 2.51 (s, 3H), 3.75 (s, 3H), 4.72 (d, J = 5.6Hz, 2H), 6.86 (d, J = 7.0Hz, 1H), 6.97 (d, J = 8.3Hz, 2H), 7.28 (t, J = 7.8Hz, 1H), 7.39 (t, J = 8.7Hz, 2H), 8.18-8.22 (m, 2H), 8.33 (s, 1H), 9.01 (t, J = 5.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 43.3, 54.9, 99.3, 112.3, 113.3, 115.7, 115.9, 119.7, 122.1, 122.2, 129.4, 133.9, 135.3, 140.4, 153.2, 155.3, 158.6, 159.3, 161.0, 169.7.
Yield: 96.53%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.51 (s, 3H), 3.75 (s, 3H), 4.72 (d, J = 5.6 Hz, 2H), 6.86 (d, J = 7.0 Hz, 1H), 6.97 (d, J = 8.3 Hz, 2H), 7.28 (t, J = 7.8 Hz, 1H), 7.39 (t, J = 8.7 Hz, 2H), 8.18-8.22 (m, 2H), 8.33 (s, 1H ), 9.01 (t, J = 5.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 43.3, 54.9, 99.3, 112.3, 113.3, 115.7, 115.9, 119.7, 122.1, 122.2, 129.4, 133.9, 135.3, 140.4, 153.2, 155.3, 158.6, 159.3, 161.0, 169.7.

(5) N-(4-메톡시벤질)-1-(4-플루오로페닐)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [20e](5) N- (4-methoxybenzyl) -1- (4-fluorophenyl) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [20e]

상기 [5h]와 3-methoxybenzylamine으로 얇은 노란색의 고체상 화합물 20e를 얻었다.The thin yellow solid compound 20e was obtained from [5h] and 3-methoxybenzylamine.

Yield: 92.58%; 1H NMR (400MHz, DMSO-d6) δ 2.52 (s, 3H), 3.74 (s, 3H), 4.68 (d, J = 5.5Hz, 2H), 6.93 (d, J = 8.4Hz, 2H), 7.33 (d, J = 8.4Hz, 2H), 7.39 (t, J = 8.8Hz, 2H), 8.19-8.22 (m, 2H), 8.32 (s, 1H), 8.95 (t, J = 5.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 42.8, 55.0, 99.3, 113.7, 115.7, 115.9, 122.1, 122.1, 128.9, 130.6, 133.9, 135.3, 153.2, 155.1, 158.4, 158.5, 161.0, 169.7.
Yield: 92.58%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.52 (s, 3H), 3.74 (s, 3H), 4.68 (d, J = 5.5 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.39 (t, J = 8.8 Hz, 2H), 8.19-8.22 (m, 2H), 8.32 (s, 1H), 8.95 (t, J = 5.5 Hz, 1H ); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 42.8, 55.0, 99.3, 113.7, 115.7, 115.9, 122.1, 122.1, 128.9, 130.6, 133.9, 135.3, 153.2, 155.1, 158.4, 158.5, 161.0, 169.7.

(6) N-(4-메틸벤질)-1-(4-프루오로페닐)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-4-아민 [20f](6) N- (4-methylbenzyl) -1- (4-fluorofluoro) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [20f]

상기 [5h]와 4-methylbenzylamine으로 노란색의 고체상 화합물 20f를 얻었다.The yellow solid compound 20f was obtained from [5h] and 4-methylbenzylamine.

Yield: 86.42%; 1H NMR (400MHz, DMSO-d6) δ 2.19 (d, J = 6.3Hz, 3H), 3.29 (s, 3H), 4.57 (dd, J = 5.1Hz, 38.1Hz, 2H), 7.03-7.12 (m, 3H), 7.20 (d, J = 7.3Hz, 1H), 7.30 (t, J = 8.7Hz, 1H), 8.11-8.25 (m, 2H), 8.89 (s, 1H), 9.95 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 20.6, 43.1, 92.0, 99.3, 115.7, 115.9, 122.1, 127.5, 128.8, 128.9, 133.9, 135.7, 136.1, 153.2, 155.2, 158.5, 160.9, 169.8, 174.9, 186.0.
Yield: 86.42%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.19 (d, J = 6.3 Hz, 3H), 3.29 (s, 3H), 4.57 (dd, J = 5.1 Hz, 38.1 Hz, 2H), 7.03-7.12 ( m, 3H), 7.20 (d, J = 7.3 Hz, 1H), 7.30 (t, J = 8.7 Hz, 1H), 8.11-8.25 (m, 2H), 8.89 (s, 1H), 9.95 (s, 1H ); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 20.6, 43.1, 92.0, 99.3, 115.7, 115.9, 122.1, 127.5, 128.8, 128.9, 133.9, 135.7, 136.1, 153.2, 155.2, 158.5, 160.9, 169.8, 174.9, 186.0.

실시예 19. [21a] 내지 [21j]의 합성Example 19. Synthesis of [21a] to [21j]

하기 [반응식 21](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [21a] 내지 [21j]를 합성하였다.The pyrazolopyrimidine derivative compounds [21a] to [21j] were synthesized according to the following Reaction Scheme 21 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 21][Reaction Scheme 21]

Figure pat00281
Figure pat00281

[5i] [21a] ~ [21j][5i] [21a]-[21j]

[21a] 내지 [21j]에서 NR2은 각각 하기 [표 14]와 같다.NR 2 in [21a] to [21j] are as shown in Table 14 below, respectively.

구분division NR2 NR 2 구분division NR2 NR 2 21a21a

Figure pat00282
Figure pat00282
21f21f
Figure pat00283
Figure pat00283
 21b21b
Figure pat00284
Figure pat00284
 21g21g
Figure pat00285
Figure pat00285
 21c21c
Figure pat00286
Figure pat00286
 21h21h
Figure pat00287
Figure pat00287
 21d21d
Figure pat00288
Figure pat00288
 21i21i
Figure pat00289
Figure pat00289
 21e21e
Figure pat00290
Figure pat00290
 21j21j
Figure pat00291
Figure pat00291

(1) N-(2-클로로벤질)-6-(메틸티오)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [21a](1) N- (2-chlorobenzyl) -6- (methylthio) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [21a]

상기 [5i]와 2-chlorobenzylamine으로 얇은 노란색의 고체상 화합물 21a를 얻었다.The thin yellow solid compound 21a was obtained from [5i] and 2-chlorobenzylamine.

Yield: 80.05%; 1H NMR (400MHz, DMSO-d6) δ 2.31 (s, 3H), 2.43 (s, 3H), 4.78 (d, J = 5.3Hz, 2H), 7.29 (d, J = 7.7Hz, 4H), 7.42-7.45 (m, 2H), 8.02 (d, J = 8.0Hz, 2H), 8.32 (s, 1H), 8.95 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 20.9, 41.7, 99.9, 116.8, 120.7, 127.7, 129.0, 129.3, 129.7, 129.7, 129.9, 132.4, 132.8, 134.1, 135.7, 136.3, 137.0, 153.6, 155.8, 161.2, 169.9, 173.6.
Yield: 80.05%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.31 (s, 3H), 2.43 (s, 3H), 4.78 (d, J = 5.3 Hz, 2H), 7.29 (d, J = 7.7 Hz, 4H), 7.42-7.45 (m, 2H), 8.02 (d, J = 8.0 Hz, 2H), 8.32 (s, 1H), 8.95 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 20.9, 41.7, 99.9, 116.8, 120.7, 127.7, 129.0, 129.3, 129.7, 129.7, 129.9, 132.4, 132.8, 134.1, 135.7, 136.3, 137.0, 153.6, 155.8, 161.2, 169.9, 173.6.

(2) N-(2-메톡시벤질)-6-(메틸티오)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [21b](2) N- (2-methoxybenzyl) -6- (methylthio) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [21b]

상기 [5i]와 2-methoxybenzylamine으로 얇은 노란색의 고체상 화합물 21b를 얻었다.The thin yellow solid compound 21b was obtained from [5i] and 2-methoxybenzylamine.

Yield: 79.84%; 1H NMR (400MHz, DMSO-d6) δ 2.32 (s, 3H), 2.46 (s, 3H), 3.81 (s, 3H), 4.67 (d, J = 4.4Hz, 2H), 6.90 (t, J = 7.0Hz, 1H), 7.00 (d, J = 7.8Hz, 1H), 7.28 (dd, J = 7.5Hz, 18.6Hz, 4H), 8.02 (d, J = 7.7Hz, 2H), 8.32 (s, 1H), 8.77 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 20.9, 55.8, 99.9, 111.1, 120.6, 120.7, 126.5, 128.8, 128.8, 129.9, 134.2, 135.6, 137.0, 153.6, 155.9, 157.3, 169.9.
Yield: 79.84%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.32 (s, 3H), 2.46 (s, 3H), 3.81 (s, 3H), 4.67 (d, J = 4.4 Hz, 2H), 6.90 (t, J = 7.0 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 7.28 (dd, J = 7.5 Hz, 18.6 Hz, 4H), 8.02 (d, J = 7.7 Hz, 2H), 8.32 (s, 1H), 8.77 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 20.9, 55.8, 99.9, 111.1, 120.6, 120.7, 126.5, 128.8, 128.8, 129.9, 134.2, 135.6, 137.0, 153.6, 155.9, 157.3, 169.9.

(3) N-(2-메틸벤질)-6-(메틸티오)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [21c](3) N- (2-methylbenzyl) -6- (methylthio) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [21c]

상기 [5i]와 2-methylbenzylamine으로 갈색의 고체상 화합물 21c를 얻었다.[5i] and 2-methylbenzylamine obtained the brown solid compound 21c.

Yield: 82.33%; 1H NMR (400MHz, DMSO-d6) δ 2.35 (s, 6H), 2.50 (s, 3H), 4.71 (d, J = 4.7Hz, 2H), 7.26 (dd, J = 8.1Hz, 56.7Hz, 7H), 8.05 (d, J = 7.9Hz, 2H), 8.34 (s, 1H), 8.81 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 18.7, 20.4, 41.6, 99.3, 120.3, 125.8, 127.1, 128.1, 129.4, 130.0, 133.6, 135.2, 136.0, 136.3, 136.5, 153.1, 155.2, 165.5.
Yield: 82.33%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.35 (s, 6H), 2.50 (s, 3H), 4.71 (d, J = 4.7 Hz, 2H), 7.26 (dd, J = 8.1 Hz, 56.7 Hz, 7H), 8.05 (d, J = 7.9 Hz, 2H), 8.34 (s, 1H), 8.81 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 18.7, 20.4, 41.6, 99.3, 120.3, 125.8, 127.1, 128.1, 129.4, 130.0, 133.6, 135.2, 136.0, 136.3, 136.5, 153.1, 155.2, 165.5.

(4) N-(3-메톡시벤질)-6-(메틸티오)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [21d](4) N- (3-methoxybenzyl) -6- (methylthio) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [21d]

상기 [5i]와 3-methoxybenzylamine으로 갈색의 고체상 화합물 21d를 얻었다.[5i] and 3-methoxybenzylamine were obtained as a brown solid compound 21d.

Yield: 75.89%; 1H NMR (400MHz, DMSO-d6) δ 2.35 (s, 3H), 2.51 (s, 3H), 3.74 (s, 3H), 4.72 (d, J = 4.8Hz, 2H), 6.91 (dd, J = 8.9Hz, 45.0Hz, 3H), 7.25-7.34 (m, 3H), 8.05 (d, J = 7.7Hz, 2H), 8.31 (s, 1H), 8.97 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 20.4, 43.3, 54.9, 99.3, 112.3, 113.3, 119.7, 120.3, 129.4, 133.5, 135.2, 136.5, 140.5, 153.1, 155.3, 159.3, 169.5.
Yield: 75.89%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.35 (s, 3H), 2.51 (s, 3H), 3.74 (s, 3H), 4.72 (d, J = 4.8 Hz, 2H), 6.91 (dd, J = 8.9 Hz, 45.0 Hz, 3H), 7.25-7.34 (m, 3H), 8.05 (d, J = 7.7 Hz, 2H), 8.31 (s, 1H), 8.97 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 20.4, 43.3, 54.9, 99.3, 112.3, 113.3, 119.7, 120.3, 129.4, 133.5, 135.2, 136.5, 140.5, 153.1, 155.3, 159.3, 169.5.

(5) N-(4-메톡시벤질)-6-(메틸티오)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [21e](5) N- (4-methoxybenzyl) -6- (methylthio) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [21e]

상기 [5i]와 4-methoxybenzylamine으로 하얀색의 고체상 화합물 21e를 얻었다.White solid compound 21e was obtained from [5i] and 4-methoxybenzylamine.

Yield: 92.46%; 1H NMR (400MHz, DMSO-d6) δ 2.35 (s, 3H), 2.52 (s, 3H), 3.74 (s, 3H), 4.67 (d, J = 5.4Hz, 2H), 6.92 (d, J = 8.4Hz, 2H), 7.31-7.34 (m, 4H), 8.05 (d, J = 8.2Hz, 2H), 8.30 (s, 1H), 8.91 (t, J = 5.2Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 20.4, 42.8, 55.0, 99.3, 113.7, 120.2, 128.9, 129.4, 130.7, 13 3.6, 135.1, 136.5, 153.1, 155.2, 158.4, 169.5.
Yield: 92.46%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.35 (s, 3H), 2.52 (s, 3H), 3.74 (s, 3H), 4.67 (d, J = 5.4 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.31-7.34 (m, 4H), 8.05 (d, J = 8.2 Hz, 2H), 8.30 (s, 1H), 8.91 (t, J = 5.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 20.4, 42.8, 55.0, 99.3, 113.7, 120.2, 128.9, 129.4, 130.7, 13 3.6, 135.1, 136.5, 153.1, 155.2, 158.4, 169.5.

(6) N-(4-메틸벤질)-6-(메틸티오)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [21f](6) N- (4-methylbenzyl) -6- (methylthio) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [21f]

상기 [5i]와 4-methylbenzylamine으로 얇은 붉은색의 고체상 화합물 21f를 얻었다.The thin red solid compound 21f was obtained from [5i] and 4-methylbenzylamine.

Yield: 81.85%; 1H NMR (400MHz, DMSO-d6) δ 2.26 (s, 3H), 2.34 (s, 3H), 2.50 (s, 3H), 4.69 (d, J = 5.4Hz, 2H), 7.13-7.18 (m, 2H), 7.27 (d, J = 7.7Hz, 2H), 7.33 (d, J = 8.2Hz, 2H), 8.04 (d, J = 8.3Hz, 2H), 8.30 (s, 1H), 8.94 (t, J = 5.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 20.5, 20.6, 43.0, 99.3, 120.2, 127.2, 127.5, 128.9, 129.4, 133.9, 135.2, 135.8, 136.1, 136.5, 153.1, 155.2, 169.5.
Yield: 81.85%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.26 (s, 3H), 2.34 (s, 3H), 2.50 (s, 3H), 4.69 (d, J = 5.4 Hz, 2H), 7.13-7.18 (m , 2H), 7.27 (d, J = 7.7 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 8.04 (d, J = 8.3 Hz, 2H), 8.30 (s, 1H), 8.94 (t , J = 5.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 20.5, 20.6, 43.0, 99.3, 120.2, 127.2, 127.5, 128.9, 129.4, 133.9, 135.2, 135.8, 136.1, 136.5, 153.1, 155.2, 169.5.

(7) N-((4-클로로페닐)(페닐)메틸)-6-(메틸티오)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [21g](7) N-((4-chlorophenyl) (phenyl) methyl) -6- (methylthio) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [21 g ]

상기 [5i]와 (4-chlorophenyl)(phenyl)methanamine으로 하얀색의 고체상 화합물 21g를 얻었다.21 g of a white solid compound was obtained from [5i] and (4-chlorophenyl) (phenyl) methanamine.

Yield: 89.42%; 1H NMR (400MHz, DMSO-d6) δ 2.35 (s, 3H), 2.42 (s, 3H), 6.68 (d, J = 7.5Hz, 1H), 7.32-7.45 (m, 11H), 8.00 (d, J = 8.0Hz, 2H), 8.44 (s, 1H), 9.23 (d, J = 7.8Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 20.4, 56.5, 99.3, 120.3, 127.3, 127.6, 128.3, 128.4, 129.4, 131.7, 133.9, 135.2, 136.4, 140.8, 141.2, 153.2, 154.4, 169.3.
Yield: 89.42%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.35 (s, 3H), 2.42 (s, 3H), 6.68 (d, J = 7.5 Hz, 1H), 7.32-7.45 (m, 11H), 8.00 (d , J = 8.0 Hz, 2H), 8.44 (s, 1H), 9.23 (d, J = 7.8 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 20.4, 56.5, 99.3, 120.3, 127.3, 127.6, 128.3, 128.4, 129.4, 131.7, 133.9, 135.2, 136.4, 140.8, 141.2, 153.2, 154.4, 169.3.

(8) N-(1-사이클로헥실에틸)-6-(메틸티오)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [21h](8) N- (1-cyclohexylethyl) -6- (methylthio) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [21h]

상기 [5i]와 (S)-cyclohexylethylamine으로 하얀색의 고체상 화합물 21h를 얻었다.The white solid compound 21h was obtained from [5i] and (S) -cyclohexylethylamine.

Yield: 94.28%; 1H NMR (400MHz, DMSO-d6) δ 0.99-1.04 (m, 2H), 1.12-1.20 (m, 5H), 1.48-1.69 (m, 6H), 2.35 (s, 3H), 2.52 (s, 3H), 4.21-4.27 (m, 1H), 7.33 (d, J = 8.4Hz, 2H), 8.04 (d, J = 8.4Hz, 2H), 8.17 (d, J = 8.4Hz, 1H), 8.34 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 17.3, 20.4, 25.6, 25.7, 25.9, 28.6, 29.1, 42.4, 49.8, 98.6, 99.2, 120.2, 129.4, 133.6, 135.0, 136.6, 153.1, 155.0, 169.3.
Yield: 94.28%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.99-1.04 (m, 2H), 1.12-1.20 (m, 5H), 1.48-1.69 (m, 6H), 2.35 (s, 3H), 2.52 (s, 3H), 4.21-4.27 (m, 1H), 7.33 (d, J = 8.4 Hz, 2H), 8.04 (d, J = 8.4 Hz, 2H), 8.17 (d, J = 8.4 Hz, 1H), 8.34 ( s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 17.3, 20.4, 25.6, 25.7, 25.9, 28.6, 29.1, 42.4, 49.8, 98.6, 99.2, 120.2, 129.4, 133.6, 135.0, 136.6, 153.1, 155.0, 169.3.

(9) 6-(메틸티오)-1-p-톨릴-N-(1-p-톨릴에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [21i](9) 6- (methylthio) -1-p-tolyl-N- (1-p-tolylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [21i]

상기 [5i]와 p-tolylethylamine으로 하얀색의 고체상 화합물 21i를 얻었다.White solid compound 21i was obtained from [5i] and p-tolylethylamine.

Yield: 91.97%; 1H NMR (400MHz, DMSO-d6) δ 1.54 (d, J = 6.8Hz, 3H), 2.26 (s, 3H), 2.34 (s, 3H), 2.46 (s, 3H), 5.45 (t, J = 7.0Hz, 1H), 7.14 (d, J = 7.8Hz, 2H), 7.31 (t, J = 6.2Hz, 4H), 8.03 (d, J = 8.2Hz, 2H), 8.38 (s, 1H), 8.79 (d, J = 7.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 20.4, 20.5, 22.1, 48.8, 99.2, 120.2, 125.9, 128.8, 129.4, 133.6, 135.1, 135.7, 136.5, 141.3, 153.1, 154.4, 169.3.
Yield: 91.97%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.54 (d, J = 6.8 Hz, 3H), 2.26 (s, 3H), 2.34 (s, 3H), 2.46 (s, 3H), 5.45 (t, J = 7.0 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.31 (t, J = 6.2 Hz, 4H), 8.03 (d, J = 8.2 Hz, 2H), 8.38 (s, 1H), 8.79 (d, J = 7.6 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 20.4, 20.5, 22.1, 48.8, 99.2, 120.2, 125.9, 128.8, 129.4, 133.6, 135.1, 135.7, 136.5, 141.3, 153.1, 154.4, 169.3.

(10) N-((S)-1-(4-메톡시페닐)에틸)-6-(메틸티오)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [21j](10) N-((S) -1- (4-methoxyphenyl) ethyl) -6- (methylthio) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidine-4 Amines [21j]

상기 [5i]와 (R)-4-(methoxyphenyl)ethylamine으로 하얀색의 고체상 화합물 21j를 얻었다.White solid compound 21j was obtained from [5i] and (R) -4- (methoxyphenyl) ethylamine.

Yield: 88.03%; 1H NMR (400MHz, DMSO-d6) δ 1.54 (d, J = 6.7Hz, 3H), 2.34 (s, 3H), 2.47 (s, 3H), 2.73 (s, 3H), 5.44 (t, J = 6.9Hz, 1H), 6.91 (d, J = 8.2Hz, 2H), 7.34 (t, J = 8.9Hz, 4H), 8.03 (d, J = 8.0Hz, 2H), 8.37 (s, 1H), 8.76 (d, J = 7.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 20.4, 22.1, 48.4, 54.9, 99.2, 113.6, 120.2, 127.1, 129.4, 133.6, 135.1, 136.1, 136.5, 153.1, 154.4, 158.0, 169.3.
Yield: 88.03%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.54 (d, J = 6.7 Hz, 3H), 2.34 (s, 3H), 2.47 (s, 3H), 2.73 (s, 3H), 5.44 (t, J = 6.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 2H), 7.34 (t, J = 8.9 Hz, 4H), 8.03 (d, J = 8.0 Hz, 2H), 8.37 (s, 1H), 8.76 (d, J = 7.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 20.4, 22.1, 48.4, 54.9, 99.2, 113.6, 120.2, 127.1, 129.4, 133.6, 135.1, 136.1, 136.5, 153.1, 154.4, 158.0, 169.3.

실시예 20. [22a] 내지 [22p]의 합성Example 20. Synthesis of [22a] to [22p]

하기 [반응식 22](mCPBA, CH2Cl2 , 0 ℃, 2h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [22a] 내지 [22p]를 합성하였다.The pyrazolopyrimidine derivative compounds [22a] to [22p] according to the present invention were synthesized by the following Reaction Scheme 22 (mCPBA, CH 2 Cl 2 , 0 ° C, 2h).

[반응식 22][Reaction Scheme 22]

Figure pat00292
Figure pat00292

[22a] ~ [22p][22a] to [22p]

[22a] 내지 [22p]에서 NR2는 각각 하기 [표 15]와 같다.In [22a] to [22p], NR 2 is shown in Table 15 below, respectively.

(R1은 [5e], [5f], [5h]~[5k]에서와 동일하고, R3는

Figure pat00293
이다.)(R 1 is the same as in [5e], [5f], [5h] to [5k], and R 3 is
Figure pat00293
to be.)

구분division NR2 NR 2 구분division NR2 NR 2 22a22a

Figure pat00294
Figure pat00294
22i22i
Figure pat00295
Figure pat00295
 22b22b
Figure pat00296
Figure pat00296
 22j22j
Figure pat00297
Figure pat00297
 22c22c
Figure pat00298
Figure pat00298
 22k22k
Figure pat00299
Figure pat00299
 22d22d
Figure pat00300
Figure pat00300
 22l22l
Figure pat00301
Figure pat00301
 22e22e
Figure pat00302
Figure pat00302
 22m22 m
Figure pat00303
Figure pat00303
 22f22f
Figure pat00304
Figure pat00304
 22n22n
Figure pat00305
Figure pat00305
 22g22 g
Figure pat00306
Figure pat00306
 22o22o
Figure pat00307
Figure pat00307
 22h22h
Figure pat00308
Figure pat00308
 22p22p
Figure pat00309
Figure pat00309

(1) N-(2-클로로벤질)-6-(메틸설파이닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [22a](1) N- (2-chlorobenzyl) -6- (methylsulfinyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [22a]

상기 [15x]를 CH2Cl2 5 mL에 녹인 후 0 ℃에서 천천히 2.4 eq mCPBA를 투여하였다. 반응은 0 ℃에서 3 시간 진행시켰다. 반응 종료 후 반응물은 0 ℃에서 포화 NaHCO3 수용액을 천천히 투여하고 CH2Cl2 (2×30 mL)를 이용하여 추출하고 유기층은 무수 MgSO4을 사용하여 소량의 물을 제거하였으며, 감압 증류하여 용매를 제거하였다. 여기서 얻은 반응 혼합물을 flash chromatography (hexanes : EtOAc = 1 : 1)로 분리하여 하얀색의 고체상 화합물 22a를 얻었다.The [15x] was dissolved in 5 mL of CH 2 Cl 2 and slowly administered 2.4 eq mCPBA at 0 ° C. The reaction proceeded at 0 ° C. for 3 hours. After completion of reaction the reaction was saturated with NaHCO 3 at 0 ° C. Slowly administer the aqueous solution and CH 2 Cl 2 Extracted using (2 x 30 mL) and the organic layer was removed a small amount of water using anhydrous MgSO 4 , the solvent was removed by distillation under reduced pressure. The reaction mixture obtained here was separated by flash chromatography (hexanes: EtOAc = 1: 1) to obtain a white solid compound 22a.

Yield: 85.94%; 1H NMR (400MHz, DMSO-d6) δ 2.78 (s, 3H), 4.86 (t, J = 6.7Hz, 2H), 7.32-7.41 (m, 3H), 7.49-7.60 (m, 4H), 8.18 (d, J = 7.6Hz, 2H), 8.53 (s, 1H), 9.46 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 41.7, 101.8, 120.9, 126.6, 127.2, 129.1, 129.2, 129.9, 132.5, 134.1, 135.3, 138.4, 152.6, 171.4.
Yield: 85.94%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.78 (s, 3H), 4.86 (t, J = 6.7 Hz, 2H), 7.32-7.41 (m, 3H), 7.49-7.60 (m, 4H), 8.18 (d, J = 7.6 Hz, 2H), 8.53 (s, 1H), 9.46 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 41.7, 101.8, 120.9, 126.6, 127.2, 129.1, 129.2, 129.9, 132.5, 134.1, 135.3, 138.4, 152.6, 171.4.

(2) N-(2-메톡시벤질)-6-(메틸설파이닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [22b](2) N- (2-methoxybenzyl) -6- (methylsulfinyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [22b]

상기 [15v]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22b를 얻었다.[15v] was reacted with 2.4 eq mCPBA to obtain a white solid compound 22b.

Yield: 88.05%; 1H NMR (400MHz, DMSO-d6) δ 2.83 (s, 3H), 3.85 (s, 3H), 4.76 (d, J = 5.4Hz, 2H), 6.93 (t, J = 7.3Hz, 1H), 7.05 (d, J = 8.2Hz, 1H), 7.29-7.40 (m, 3H), 7.58 (t, J = 6.0Hz, 2H), 8.19 (d, J = 6.8Hz, 2H), 8.54 (s, 1H), 9.28 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 20.7, 55.4, 59.7, 101.7, 110.7, 120.1, 120.8, 125.5, 126.5, 128.6, 128.8, 129.2, 134.2, 138.5, 152.6, 156.4, 157.0, 171.4.
Yield: 88.05%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.83 (s, 3H), 3.85 (s, 3H), 4.76 (d, J = 5.4 Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 7.29-7.40 (m, 3H), 7.58 (t, J = 6.0 Hz, 2H), 8.19 (d, J = 6.8 Hz, 2H), 8.54 (s, 1H ), 9.28 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 20.7, 55.4, 59.7, 101.7, 110.7, 120.1, 120.8, 125.5, 126.5, 128.6, 128.8, 129.2, 134.2, 138.5, 152.6, 156.4, 157.0, 171.4.

(3) N-(2-메톡시벤질)-6-(메틸설파이닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [22c](3) N- (2-methoxybenzyl) -6- (methylsulfinyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [22c]

상기 [15o]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22c를 얻었다.The reaction of [15o] with 2.4 eq mCPBA afforded a white solid compound 22c.

Yield: 91.77%; 1H NMR (400MHz, DMSO-d6) δ 2.36 (s, 3H), 2.82 (s, 3H), 4.76 (t, J = 5.0Hz, 2H), 7.18-7.22 (m, 3H), 7.35-7.38 (m, 2H), 7.58 (t, J = 7.2Hz, 2H), 8.18 (d, J = 8.2Hz, 2H), 8.51 (s, 1H), 9.31 (s, 1H).
Yield: 91.77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.36 (s, 3H), 2.82 (s, 3H), 4.76 (t, J = 5.0 Hz, 2H), 7.18-7.22 (m, 3H), 7.35-7.38 (m, 2H), 7.58 (t, J = 7.2 Hz, 2H), 8.18 (d, J = 8.2 Hz, 2H), 8.51 (s, 1H), 9.31 (s, 1H).

(4) N-뷰틸-6-(메틸설파이닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [22d](4) N-butyl-6- (methylsulfinyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [22d]

상기 [15t]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22d를 얻었다.[15t] was reacted with 2.4 eq mCPBA to obtain a white solid compound 22d.

Yield: 63.15% 1H NMR (400MHz, DMSO-d6) δ 0.94 (t, J = 7.1Hz, 3H), 1.37-1.42 (m, 2H), 1.63 (t, J = 7.0Hz, 2H), 2.88 (s, 3H), 3.55 (s, 2H), 7.39 (t, J = 7.0Hz, 1H), 7.58 (t, J = 7.5Hz, 2H), 8.19 (d, J = 7.6Hz, 2H), 8.45 (s, 1H), 8.92 (s, 1H), 13C NMR (100MHz,DMSO-d6) δ 13.6, 19.5, 30.6, 100.3, 101.7, 120.8, 121.0, 126.5, 129.2, 134.0, 138.5, 152.5, 156.4, 171.4.
Yield: 63.15% 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.94 (t, J = 7.1 Hz, 3H), 1.37-1.42 (m, 2H), 1.63 (t, J = 7.0 Hz, 2H), 2.88 (s, 3H), 3.55 (s, 2H), 7.39 (t, J = 7.0 Hz, 1H), 7.58 (t, J = 7.5 Hz, 2H), 8.19 (d, J = 7.6 Hz, 2H), 8.45 (s, 1H), 8.92 (s, 1H), 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 19.5, 30.6, 100.3, 101.7, 120.8, 121.0, 126.5, 129.2, 134.0, 138.5, 152.5, 156.4 , 171.4.

(5) N-(2-메톡시벤질)-1-(4-플루오로페닐)-6-(메틸설파이닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [22e](5) N- (2-methoxybenzyl) -1- (4-fluorophenyl) -6- (methylsulfinyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidine-4 Amines [22e]

상기 [20b]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22e를 얻었다.The reaction of [20b] with 2.4 eq mCPBA afforded a white solid compound 22e.

Yield: 85.63%; 1H NMR (400MHz, DMSO-d6) δ 2.81 (s, 3H), 3.84 (s, 3H), 4.74 (t, J = 6.3Hz, 2H), 6.99 (dd, J = 7.8Hz, 44.7Hz, 2H), 7.27-7.45 (m, 4H), 8.17-8.21 (m, 2H), 8.52 (s, 1H), 9.29 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 55.4, 98.6, 101.6, 110.7, 115.9, 116.1, 120.1, 122.8, 122.9, 125.4, 128.6, 128.8, 134.2, 134.9, 152.5, 157.0, 171.5.
Yield: 85.63%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.81 (s, 3H), 3.84 (s, 3H), 4.74 (t, J = 6.3 Hz, 2H), 6.99 (dd, J = 7.8 Hz, 44.7 Hz, 2H), 7.27-7.45 (m, 4H), 8.17-8.21 (m, 2H), 8.52 (s, 1H), 9.29 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 55.4, 98.6, 101.6, 110.7, 115.9, 116.1, 120.1, 122.8, 122.9, 125.4, 128.6, 128.8, 134.2, 134.9, 152.5, 157.0, 171.5.

(6) N-(2-클로로벤질)-6-(메틸설파이닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [22f](6) N- (2-chlorobenzyl) -6- (methylsulfinyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [22f]

상기 [21a]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22f를 얻었다.[21a] was reacted with 2.4 eq mCPBA to obtain a white solid compound 22f.

Yield: 94.27%; 1H NMR (400MHz, DMSO-d6) δ 2.37 (s, 3H), 2.77 (s, 3H), 4.85 (t, J = 6.7Hz, 2H), 7.32-7.39 (m, 4H), 7.49-7.52 (m, 2H), 8.02 (d, J = 8.4Hz, 2H), 8.50 (s, 1H), 9.43 (s, 1H).
Yield: 94.27%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.37 (s, 3H), 2.77 (s, 3H), 4.85 (t, J = 6.7 Hz, 2H), 7.32-7.39 (m, 4H), 7.49-7.52 (m, 2H), 8.02 (d, J = 8.4 Hz, 2H), 8.50 (s, 1H), 9.43 (s, 1H).

(7) N-(2-메톡시벤질)-6-(메틸설파이닐)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [22g](7) N- (2-methoxybenzyl) -6- (methylsulfinyl) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [22g]

상기 [21b]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22g를 얻었다.[21b] was reacted with 2.4 eq mCPBA to obtain 22 g of a white solid compound.

Yield; 89.35%; 1H NMR (400MHz, DMSO-d6) δ 2.37 (s, 3H), 2.80 (s, 3H), 3.84 (s, 3H), 4.73 (t, J = 6.3Hz, 2H), 6.98 (dd, J = 7.8Hz, 46.0Hz, 2H), 7.28-7.38 (m, 4H), 8.02 (d, J = 8.1Hz, 2H), 8.49 (s, 1H), 9.25 (s, 1H)
Yield; 89.35%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.37 (s, 3H), 2.80 (s, 3H), 3.84 (s, 3H), 4.73 (t, J = 6.3 Hz, 2H), 6.98 (dd, J = 7.8 Hz, 46.0 Hz, 2H), 7.28-7.38 (m, 4H), 8.02 (d, J = 8.1 Hz, 2H), 8.49 (s, 1H), 9.25 (s, 1H)

(8) 1-벤질-6-(메틸설파이닐)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [22h](8) 1-benzyl-6- (methylsulfinyl) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [22h]

상기 [16x]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22h를 얻었다.[16x] was reacted with 2.4 eq mCPBA to obtain a white solid compound 22h.

Yield: 28.59%; 1H NMR (400MHz, DMSO-d6) δ 1.58 (d, J = 6.5Hz, 3H), 2.82 (s, 3H), 5.39 (t, J = 6.8Hz, 1H), 5.54 (s, 2H), 7.22-7.36 (m, 8H), 7.46 (d, J = 7.2Hz, 2H), 8.35 (s, 1H), 9.23 (d, J = 7.2Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 21.8, 49.4, 49.9, 100.1, 126.0, 126.2, 126.9, 127.4, 128.3, 128.5, 132.8, 136.8, 143.8, 144.1, 152.9, 155.4, 162.6.
Yield: 28.59%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.58 (d, J = 6.5 Hz, 3H), 2.82 (s, 3H), 5.39 (t, J = 6.8 Hz, 1H), 5.54 (s, 2H), 7.22-7.36 (m, 8H), 7.46 (d, J = 7.2 Hz, 2H), 8.35 (s, 1H), 9.23 (d, J = 7.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 21.8, 49.4, 49.9, 100.1, 126.0, 126.2, 126.9, 127.4, 128.3, 128.5, 132.8, 136.8, 143.8, 144.1, 152.9, 155.4, 162.6.

(9) 1-벤질-6-(메틸설파이닐)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [22i](9) 1-benzyl-6- (methylsulfinyl) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [22i]

상기 [16e]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22i를 얻었다.The reaction of [16e] with 2.4 eq mCPBA afforded a white solid compound 22i.

Yield: 78.32%; 1H NMR (400MHz, DMSO-d6) δ 1.57 (d, J = 6.9Hz, 3H), 2.81 (s, 3H), 5.36-5.53 (m, 3H), 7.22-7.45 (m, 8H), 7.49 (d, J = 7.6Hz, 2H), 8.34 (s, 1H), 9.24 (d, J = 7.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 21.8, 49.4, 49.9, 100.2, 126.0, 126.2, 126.8, 127.4, 127.5, 128.3, 128.5, 132.8, 136.8, 143.8, 152.8, 155.2, 170.6.
Yield: 78.32%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.57 (d, J = 6.9 Hz, 3H), 2.81 (s, 3H), 5.36-5.53 (m, 3H), 7.22-7.45 (m, 8H), 7.49 (d, J = 7.6 Hz, 2H), 8.34 (s, 1H), 9.24 (d, J = 7.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 21.8, 49.4, 49.9, 100.2, 126.0, 126.2, 126.8, 127.4, 127.5, 128.3, 128.5, 132.8, 136.8, 143.8, 152.8, 155.2, 170.6.

(10) 1-벤질-6-(메틸설파이닐)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [22j](10) 1-benzyl-6- (methylsulfinyl) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [22j]

상기 [16k]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22j를 얻었다.[16k] was reacted with 2.4 eq mCPBA to obtain a white solid compound 22j.

Yield: 74.55%; 1H NMR (400MHz, DMSO-d6) δ 1.57 (d, J = 6.5Hz, 3H), 2.81 (s, 3H), 5.39-5.54 (m, 3H), 7.22-7.31 (m, 8H), 7.42 (d, J = 6.6Hz, 2H), 8.34 (s, 1H), 9.21 (d, J = 7.3Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 21.8, 49.4, 49.9, 100.2, 126.1, 126.9, 127.5, 127.6, 128.4, 128.5, 132.9, 136.6, 143.7, 151.9, 155.4, 170.4.
Yield: 74.55%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.57 (d, J = 6.5 Hz, 3H), 2.81 (s, 3H), 5.39-5.54 (m, 3H), 7.22-7.31 (m, 8H), 7.42 (d, J = 6.6 Hz, 2H), 8.34 (s, 1H), 9.21 (d, J = 7.3 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 21.8, 49.4, 49.9, 100.2, 126.1, 126.9, 127.5, 127.6, 128.4, 128.5, 132.9, 136.6, 143.7, 151.9, 155.4, 170.4.

(11) N-(2-클로로벤질)-1-(3-메톡시펜에틸)-6-(메틸설파이닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [22k](11) N- (2-chlorobenzyl) -1- (3-methoxyphenethyl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [22k ]

상기 [18a]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22k를 얻었다.[18a] was reacted with 2.4 eq mCPBA to give a white solid compound 22k.

Yield: 78.69%; 1H NMR (400MHz, DMSO-d6) δ 2.69 (s, 3H), 3.16 (t, J = 7.0Hz, 2H), 3.65 (s, 3H), 4.58 (t, J = 7.0Hz, 2H), 4.81 (t, J = 6.7Hz, 1H), 6.66-6.72 (m, 3H), 7.11 (t, J = 7.8Hz, 1H), 7.33 (t, J = 4.6Hz, 2H), 7.46-7.49 (m, 2H), 7.68-7.72 (m, 1H), 8.28 (s, 1H), 9.26 (s, 1H)
Yield: 78.69%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.69 (s, 3H), 3.16 (t, J = 7.0 Hz, 2H), 3.65 (s, 3H), 4.58 (t, J = 7.0 Hz, 2H), 4.81 (t, J = 6.7 Hz, 1H), 6.66-6.72 (m, 3H), 7.11 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 4.6 Hz, 2H), 7.46-7.49 (m , 2H), 7.68-7.72 (m, 1H), 8.28 (s, 1H), 9.26 (s, 1H)

(12) N-(2-메톡시벤질)-1-(3-메톡시펜에틸)-6-(메틸설파이닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [22l](12) N- (2-methoxybenzyl) -1- (3-methoxyphenethyl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [ 22l]

상기 [18b]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22l를 얻었다.The reaction of [18b] with 2.4 eq mCPBA afforded 22 l of a white solid compound.

Yield: 83.66%; 1H NMR (400MHz, DMSO-d6) δ 2.71 (s, 3H), 3.15 (t, J = 7.0Hz, 2H), 3.65 (s, 3H), 3.82 (s, 3H), 4.57 (t, J = 7.0Hz, 2H), 4.70 (t, J = 6.1Hz, 2H), 6.66-6.71 (m, 3H), 6.91 (t, J = 7.4Hz, 1H), 7.02 (d, J = 8.4Hz, 1H), 7.11 (t,J = 7.8Hz, 1H), 7.27 (t, J = 7.3Hz, 2H), 8.26 (s, 1H), 9.07 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 34.8, 47.4, 54.7, 55.3, 59.7, 100.1, 110.6, 111.9, 113.9, 120.1, 120.8, 125.7, 128.5, 128.7, 129.2, 132.2, 139.6, 152.7, 156.3, 156.9, 159.0, 170.2.
Yield: 83.66%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.71 (s, 3H), 3.15 (t, J = 7.0 Hz, 2H), 3.65 (s, 3H), 3.82 (s, 3H), 4.57 (t, J = 7.0 Hz, 2H), 4.70 (t, J = 6.1 Hz, 2H), 6.66-6.71 (m, 3H), 6.91 (t, J = 7.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H ), 7.11 (t, J = 7.8 Hz, 1H), 7.27 (t, J = 7.3 Hz, 2H), 8.26 (s, 1H), 9.07 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 34.8, 47.4, 54.7, 55.3, 59.7, 100.1, 110.6, 111.9, 113.9, 120.1, 120.8, 125.7, 128.5, 128.7, 129.2, 132.2, 139.6, 152.7, 156.3, 156.9, 159.0, 170.2.

(13) N-(2-메틸벤질)-1-(3-메톡시펜에틸)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [22m](13) N- (2-methylbenzyl) -1- (3-methoxyphenethyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [22m ]

상기 [18c]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22m를 얻었다.The reaction of [18c] with 2.4 eq mCPBA afforded 22m of a white solid compound.

Yield: 89.17%; 1H NMR (400MHz, DMSO-d6) δ 2.34 (s, 3H), 3.16 (t, J = 6.7Hz, 2H), 3.26 (s, 3H), 3.65 (s, 3H), 4.59 (t, J = 6.7Hz, 2H), 4.75 (t, J = 4.9Hz, 2H), 6.70 (t,J = 7.6Hz, 3H), 7.11 (t, J = 7.8Hz, 2H), 7.18-7.21 (m, 2H), 7.35 (d, J = 6.6Hz, 1H), 8.30 (s, 1H), 9.26 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 18.7, 34.8, 42.1, 47.7, 54.7, 100.3, 100.6, 111.9, 114.0, 120.8, 125.8, 127.4, 128.5, 129.2, 130.1, 132.4, 135.8, 136.2, 139.5, 151.7, 156.4, 159.1, 162.5.
Yield: 89.17%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.34 (s, 3H), 3.16 (t, J = 6.7 Hz, 2H), 3.26 (s, 3H), 3.65 (s, 3H), 4.59 (t, J = 6.7 Hz, 2H), 4.75 (t, J = 4.9 Hz, 2H), 6.70 (t, J = 7.6 Hz, 3H), 7.11 (t, J = 7.8 Hz, 2H), 7.18-7.21 (m, 2H ), 7.35 (d, J = 6.6 Hz, 1 H), 8.30 (s, 1 H), 9.26 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 18.7, 34.8, 42.1, 47.7, 54.7, 100.3, 100.6, 111.9, 114.0, 120.8, 125.8, 127.4, 128.5, 129.2, 130.1, 132.4, 135.8, 136.2, 139.5, 151.7, 156.4, 159.1, 162.5.

(14) 1-(2-메톡시펜에틸)-N-(3-메톡시벤질)-6-(메틸설파이닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [22n](14) 1- (2-methoxyphenethyl) -N- (3-methoxybenzyl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [ 22n]

상기 [19a]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22n를 얻었다.[19a] was reacted with 2.4 eq mCPBA to obtain a white solid compound 22n.

Yield: 88.04%; 1H NMR (400MHz, DMSO-d6) δ 2.73 (s, 3H), 3.11 (t, J = 6.4Hz, 2H), 3.73 (s, 3H), 3.79 (s, 3H), 4.55 (t, J = 6.5Hz, 2H), 4.70 (d, J = 4.6Hz, 2H), 6.71 (t, J = 7.2Hz, 1H), 6.83-6.96 (m, 5H), 7.14 (t, J = 7.5Hz, 1H), 7.25 (t, J = 7.9Hz, 1H), 8.20 (s, 1H), 9.20 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 30.6, 43.8, 46.4, 55.2, 55.5, 98.9, 100.3, 110.8, 112.8, 113.6, 120.1, 120.2, 126.0, 128.1, 129.7, 130.1, 132.2, 140.4, 152.9, 156.4, 157.6, 159.6, 170.3.
Yield: 88.04%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.73 (s, 3H), 3.11 (t, J = 6.4 Hz, 2H), 3.73 (s, 3H), 3.79 (s, 3H), 4.55 (t, J = 6.5 Hz, 2H), 4.70 (d, J = 4.6 Hz, 2H), 6.71 (t, J = 7.2 Hz, 1H), 6.83-6.96 (m, 5H), 7.14 (t, J = 7.5 Hz, 1H ), 7.25 (t, J = 7.9 Hz, 1 H), 8.20 (s, 1 H), 9.20 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 30.6, 43.8, 46.4, 55.2, 55.5, 98.9, 100.3, 110.8, 112.8, 113.6, 120.1, 120.2, 126.0, 128.1, 129.7, 130.1, 132.2, 140.4, 152.9, 156.4, 157.6, 159.6, 170.3.

(15) 1-(2-메톡시펜에틸)-N-(4-메톡시벤질)-6-(메틸설파이닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [22o](15) 1- (2-methoxyphenethyl) -N- (4-methoxybenzyl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [ 22o]

상기 [19b]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22o를 얻었다.[19b] was reacted with 2.4 eq mCPBA to obtain a white solid compound 22o.

Yield: 82.07%; 1H NMR (400MHz, DMSO-d6) δ 2.74 (s, 3H), 3.10 (t, J = 6.7Hz, 2H), 3.72 (s, 3H), 3.79 (s, 3H), 4.54 (t, J = 6.7Hz, 2H), 4.65 (d, J = 4.8Hz, 2H), 6.72 (t, J = 7.1Hz, 1H), 6.91 (t, J = 6.9Hz, 4H), 7.14 (t, J = 7.5Hz, 1H), 7.30 (d, J = 8.0Hz, 2H), 8.17 (s, 1H), 9.12 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 30.8, 43.5, 46.6, 55.5, 55.7, 99.1, 100.5, 111.1, 114.2, 120.5, 126.2, 128.4, 129.6, 130.3, 130.9, 132.4, 153.1, 156.5, 157.8, 158.9, 170.6.
Yield: 82.07%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.74 (s, 3H), 3.10 (t, J = 6.7 Hz, 2H), 3.72 (s, 3H), 3.79 (s, 3H), 4.54 (t, J = 6.7 Hz, 2H), 4.65 (d, J = 4.8 Hz, 2H), 6.72 (t, J = 7.1 Hz, 1H), 6.91 (t, J = 6.9 Hz, 4H), 7.14 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 8.17 (s, 1H), 9.12 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 30.8, 43.5, 46.6, 55.5, 55.7, 99.1, 100.5, 111.1, 114.2, 120.5, 126.2, 128.4, 129.6, 130.3, 130.9, 132.4, 153.1, 156.5, 157.8, 158.9, 170.6.

(16) 1-(2-메톡시펜에틸)-N-(4-메틸벤질)-6-(메틸설파이닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [22p](16) 1- (2-methoxyphenethyl) -N- (4-methylbenzyl) -6- (methylsulfinyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [22p ]

상기 [19c]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 22p를 얻었다.[19c] was reacted with 2.4 eq mCPBA to obtain a white solid compound 22p.

Yield: 80.25%; 1H NMR (400MHz, DMSO-d6) δ 2.27 (s, 3H), 2.74 (s, 3H), 3.12 (t, J = 6.4Hz, 2H), 3.79 (s, 3H), 4.55 (t, J = 6.3Hz, 2H), 4.69 (d, J = 4.0Hz, 2H), 6.72 (t, J = 6.9Hz, 1H), 6.91 (t, J = 5.5Hz, 2H), 7.14 (d, J = 7.1Hz, 3H), 7.26 (d, J = 7.4Hz, 2H), 8.20 (s, 1H), 9.16 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 20.6, 30.3, 43.3, 46.1, 46.4, 55.2, 100.0, 110.5, 119.9, 125.7, 127.6, 127.8, 128.8, 129.8, 131.9, 135.4, 136.1, 152.6, 156.1, 157.3, 170.1.
Yield: 80.25%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.27 (s, 3H), 2.74 (s, 3H), 3.12 (t, J = 6.4 Hz, 2H), 3.79 (s, 3H), 4.55 (t, J = 6.3 Hz, 2H), 4.69 (d, J = 4.0 Hz, 2H), 6.72 (t, J = 6.9 Hz, 1H), 6.91 (t, J = 5.5 Hz, 2H), 7.14 (d, J = 7.1 Hz, 3H), 7.26 (d, J = 7.4 Hz, 2H), 8.20 (s, 1 H), 9.16 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 20.6, 30.3, 43.3, 46.1, 46.4, 55.2, 100.0, 110.5, 119.9, 125.7, 127.6, 127.8, 128.8, 129.8, 131.9, 135.4, 136.1, 152.6, 156.1, 157.3, 170.1.

실시예 21. [23a] 내지 [23zh]의 합성Example 21.Synthesis of [23a] to [23zh]

하기 [반응식 23](mCPBA, CH2Cl2 , 0 ℃, 2h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [23a] 내지 [23zh]를 합성하였다.The pyrazolopyrimidine derivative compounds [23a] to [23zh] were synthesized according to Scheme 23 (mCPBA, CH 2 Cl 2 , 0 ° C., 2h).

[반응식 23][Reaction Scheme 23]

Figure pat00310
Figure pat00310

[23a] ~ [23zh][23a]-[23zh]

[23a] 내지 [23zh]에서 NR2는 각각 하기 [표 16]과 같다.NR 2 in [23a] to [23zh] are as shown in Table 16 below, respectively.

(R1은 [5e]~[5k]에서와 동일하고, R3는

Figure pat00311
이다.)(R 1 is the same as in [5e] to [5k], and R 3 is
Figure pat00311
to be.)

구분division NR2 NR 2 구분division NR2 NR 2 23a23a

Figure pat00312
Figure pat00312
23r23r
Figure pat00313
Figure pat00313
 23b23b
Figure pat00314
Figure pat00314
 23s23s
Figure pat00315
Figure pat00315
 23c23c
Figure pat00316
Figure pat00316
 23t23 t
Figure pat00317
Figure pat00317
 23d23d
Figure pat00318
Figure pat00318
 23u23u
Figure pat00319
Figure pat00319
 23e23e
Figure pat00320
Figure pat00320
 23v23v
Figure pat00321
Figure pat00321
 23f23f
Figure pat00322
Figure pat00322
 23w23w
Figure pat00323
Figure pat00323
 23g23 g
Figure pat00324
Figure pat00324
 23x23x
Figure pat00325
Figure pat00325
 23h23h
Figure pat00326
Figure pat00326
 23y23y
Figure pat00327
Figure pat00327
 23i23i
Figure pat00328
Figure pat00328
 23z23z
Figure pat00329
Figure pat00329
 23j23j
Figure pat00330
Figure pat00330
 23za23za
Figure pat00331
Figure pat00331
 23k23k
Figure pat00332
Figure pat00332
 23zb23zb
Figure pat00333
Figure pat00333
 23l23l
Figure pat00334
Figure pat00334
 23zc23zc
Figure pat00335
Figure pat00335
 23m23m
Figure pat00336
Figure pat00336
 23zd23zd
Figure pat00337
Figure pat00337
 23n23n
Figure pat00338
Figure pat00338
 23ze23ze
Figure pat00339
Figure pat00339
 23o23o
Figure pat00340
Figure pat00340
 23zf23zf
Figure pat00341
Figure pat00341
 23p23p
Figure pat00342
Figure pat00342
 23zg23zg
Figure pat00343
Figure pat00343
 23q23q
Figure pat00344
Figure pat00344
 23zh23zh
Figure pat00345
Figure pat00345

(1) N-뷰틸-6-(메틸설포닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [23a](1) N-butyl-6- (methylsulfonyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [23a]

상기 [15t]를 CH2Cl2 5 mL에 녹인 후 0 ℃에서 천천히 2.4 eq mCPBA를 투여하였다. 반응은 상온에서 4 시간 진행시켰다. 반응 종료 후 반응물은 0 ℃에서 포화 NaHCO3 수용액을 천천히 투여하고 CH2Cl2 (2×10 mL)를 이용하여 추출하고 유기층은 무수 MgSO4을 사용하여 소량의 물을 제거하였으며, 감압 증류하여 용매를 제거하였다. 여기서 얻은 반응 혼합물을 flash chromatography (hexanes : EtOAc = 1 : 1)로 하여 분리하면 하얀색의 고체상 화합물 23a를 얻었다.After dissolving [15t] in 5 mL of CH 2 Cl 2 , 2.4 eq mCPBA was slowly administered at 0 ° C. The reaction was carried out at room temperature for 4 hours. After completion of reaction the reaction was saturated with NaHCO 3 at 0 ° C. Slowly administer the aqueous solution and CH 2 Cl 2 (2 × 10 mL) was used to extract the organic layer, and a small amount of water was removed using anhydrous MgSO 4 , and the solvent was distilled off under reduced pressure. The reaction mixture obtained here was separated by flash chromatography (hexanes: EtOAc = 1: 1) to give a white solid compound 23a.

Yield: 95.27%; 1H NMR (400MHz, DMSO-d6) δ 0.98 (t, J = 7.3Hz, 3H), 1.41-1.48 (m, 2H), 1.66-1.71 (m, 2H), 3.42, (s, 3H), 3.59-3.64 (m, 2H), 7.43 (t, J = 7.0Hz, 1H), 7.63 (t, J = 7.9Hz, 2H), 8.16 (d, J = 8.5Hz, 2H), 8.54 (s, 1H), 9.15 (s, 1H); 13C NMR(100MHz,DMSO-d6) δ 13.6, 19.5, 30.5, 102.5, 120.9, 121.1, 126.8, 129.3, 134.1, 138.2, 151.5, 156.8, 163.4.
Yield: 95.27%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.98 (t, J = 7.3 Hz, 3H), 1.41-1.48 (m, 2H), 1.66-1.71 (m, 2H), 3.42, (s, 3H), 3.59-3.64 (m, 2H), 7.43 (t, J = 7.0 Hz, 1H), 7.63 (t, J = 7.9 Hz, 2H), 8.16 (d, J = 8.5 Hz, 2H), 8.54 (s, 1H ), 9.15 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 19.5, 30.5, 102.5, 120.9, 121.1, 126.8, 129.3, 134.1, 138.2, 151.5, 156.8, 163.4.

(2) N-(2-클로로벤질)-6-(메틸설포닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [23b](2) N- (2-chlorobenzyl) -6- (methylsulfonyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [23b]

상기 [15x]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23b를 얻었다.[15x] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23b.

Yield: 93.28%; 1H NMR (400MHz, DMSO-d6) δ 3.32 (s, 3H), 4.90 (s, 2H), 7.34-7.43 (m, 3H), 7.50-7.62 (m, 4H), 8.13 (d, J = 8.4Hz, 2H), 8.58 (s, 1H), 9.64 (s, 1H)
Yield: 93.28%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.32 (s, 3H), 4.90 (s, 2H), 7.34-7.43 (m, 3H), 7.50-7.62 (m, 4H), 8.13 (d, J = 8.4 Hz, 2H), 8.58 (s, 1H), 9.64 (s, 1H)

(3) N-(2-메톡시벤질)-6-(메틸설포닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [23c](3) N- (2-methoxybenzyl) -6- (methylsulfonyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [23c]

상기 [15v]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23c를 얻었다.The reaction of [15v] with 2.4 eq mCPBA afforded a white solid compound 23c.

Yield: 96.45%; 1H NMR (400MHz, DMSO-d6) δ 3.35 (s, 3H), 3.84 (s, 3H), 4.78 (d, J = 5.2Hz, 2H), 6.94 (t, J = 7.4Hz, 1H), 7.06 (d, J = 8.2Hz, 1H), 7.28-7.42 (m, 3H), 7.60 (t, J = 7.1Hz, 2H), 8.13 (d, J = 7.6Hz, 2H), 8.58 (s, 1H), 9.47 (s, 1H)
Yield: 96.45%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.35 (s, 3H), 3.84 (s, 3H), 4.78 (d, J = 5.2 Hz, 2H), 6.94 (t, J = 7.4 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 7.28-7.42 (m, 3H), 7.60 (t, J = 7.1 Hz, 2H), 8.13 (d, J = 7.6 Hz, 2H), 8.58 (s, 1H ), 9.47 (s, 1 H)

(4) N-(2-메톡시벤질)-6-(메틸설포닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [23d](4) N- (2-methoxybenzyl) -6- (methylsulfonyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [23d]

상기 [15o]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23d를 얻었다.The reaction of [15o] with 2.4 eq mCPBA afforded a white solid compound 23d.

Yield: 93.48%; 1H NMR (400MHz, DMSO-d6) δ 2.37 (s, 3H), 2.50 (s, 3H), 4.80 (s, 2H), 7.20-7.23 (m, 3H), 7.38-7.42 (m, 2H), 7.60 (t, J = 7.1Hz, 2H), 8.13 (d, J = 6.8Hz, 2H), 8.57 (s, 1H), 9.50 (s,1H).
Yield: 93.48%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.37 (s, 3H), 2.50 (s, 3H), 4.80 (s, 2H), 7.20-7.23 (m, 3H), 7.38-7.42 (m, 2H) , 7.60 (t, J = 7.1 Hz, 2H), 8.13 (d, J = 6.8 Hz, 2H), 8.57 (s, 1H), 9.50 (s, 1H).

(5) N-((4-클로로페닐)(페닐)메틸)-6-(메틸설포닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [23e](5) N-((4-chlorophenyl) (phenyl) methyl) -6- (methylsulfonyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [23e]

상기 [15z]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23e를 얻었다.[15z] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23e.

Yield: 91.43%; 1H NMR (400MHz, DMSO-d6) δ 3.26 (s, 3H), 6.75 (d, J = 7.4Hz, 1H), 7.34-7.92 (m, 12H), 8.13 (d, J = 7.7Hz, 2H), 8.71 (s, 1H), 9.94 (d, J = 7.3Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 28.9, 56.6, 99.5, 102.8, 120.3, 126.0, 127.4, 127.7, 128.4, 128.5, 129.1, 129.4, 131.0, 133.8, 135.1, 140.6, 141.2, 151.9, 155.8, 166.0.
Yield: 91.43%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.26 (s, 3H), 6.75 (d, J = 7.4 Hz, 1H), 7.34-7.92 (m, 12H), 8.13 (d, J = 7.7 Hz, 2H ), 8.71 (s, 1 H), 9.94 (d, J = 7.3 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 28.9, 56.6, 99.5, 102.8, 120.3, 126.0, 127.4, 127.7, 128.4, 128.5, 129.1, 129.4, 131.0, 133.8, 135.1, 140.6, 141.2, 151.9, 155.8, 166.0.

(6) N-(1-사이클로헥실에틸)-6-(메틸설포닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [23f](6) N- (1-cyclohexylethyl) -6- (methylsulfonyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [23f]

상기 [15za]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23f를 얻었다.[15za] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23f.

Yield: 90.97%; 1H NMR (400MHz, DMSO-d6) δ 1.01-1.07 (m, 2H), 1.13-1.24 (m,5H), 1.60-1.80 (m, 6H), 3.39 (s, 3H), 4.28-4.29 (m, 1H), 7.39-7.42 (m, 1H), 7.53-7.61 (m, 3H), 8.12-8.14 (m, 2H), 8.58 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 17.7, 26.1, 26.3, 29.2, 29.5, 42.9, 51.3, 121.4, 127.2, 129.2, 134.8, 139.8, 152.1, 156.8, 163.9, 166.5.
Yield: 90.97%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.01-1.07 (m, 2H), 1.13-1.24 (m, 5H), 1.60-1.80 (m, 6H), 3.39 (s, 3H), 4.28-4.29 ( m, 1H), 7.39-7.42 (m, 1H), 7.53-7.61 (m, 3H), 8.12-8.14 (m, 2H), 8.58 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 17.7, 26.1, 26.3, 29.2, 29.5, 42.9, 51.3, 121.4, 127.2, 129.2, 134.8, 139.8, 152.1, 156.8, 163.9, 166.5.

(7) 6-(메틸설포닐)-1-페닐-N-(1-p-톨릴에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23g](7) 6- (methylsulfonyl) -1-phenyl-N- (1-p-tolylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23 g]

상기 [15zb]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23g를 얻었다.[15zb] was reacted with 2.4 eq mCPBA to obtain 23 g of a white solid compound.

Yield: 95.39%; 1H NMR (400MHz, DMSO-d6) δ 1.61 (d, J = 6.8Hz, 3H), 2.26 (s, 3H), 3.32 (s, 3H), 5.50 (t, J = 7.0Hz, 1H), 7.17 (d, J = 7.6Hz, 2H), 7.36 (t, J = 7.2Hz, 3H), 7.57 (t, J = 7.5Hz, 1H), 8.13 (d, J = 8.0Hz, 2H), 8.61 (s, 1H), 9.48 (d, J = 7.4Hz, 1H); 13C NMR(100MHz, DMSO-d6) δ 14.0, 20.5, 21.8, 49.6, 99.4, 120.7, 126.6, 127.3, 128.3, 129.2, 133.7, 134.8, 138.7, 141.0, 151.7, 155.7, 163.2.
Yield: 95.39%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.61 (d, J = 6.8 Hz, 3H), 2.26 (s, 3H), 3.32 (s, 3H), 5.50 (t, J = 7.0 Hz, 1H), 7.17 (d, J = 7.6 Hz, 2H), 7.36 (t, J = 7.2 Hz, 3H), 7.57 (t, J = 7.5 Hz, 1H), 8.13 (d, J = 8.0 Hz, 2H), 8.61 ( s, 1 H), 9.48 (d, J = 7.4 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 20.5, 21.8, 49.6, 99.4, 120.7, 126.6, 127.3, 128.3, 129.2, 133.7, 134.8, 138.7, 141.0, 151.7, 155.7, 163.2.

(8) N-((S)-1-(4-메톡시페닐)에틸)-6-(메틸설포닐)-1-페닐-1H-피라졸로[3,4-d]피리미딘-4-아민 [23h](8) N-((S) -1- (4-methoxyphenyl) ethyl) -6- (methylsulfonyl) -1-phenyl-1H-pyrazolo [3,4-d] pyrimidine-4- Amines [23h]

상기 [15zc]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23h를 얻었다.[15zc] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23h.

Yield: 91.88%; 1H NMR (400MHz, DMSO-d6) δ 1.61 (d, J = 6.4Hz, 3H), 3.33 (s, 3H), 3.73 (s, 3H), 5.49-5.51 (m, 1H), 6.93 (d, J = 8.0Hz, 2H), 7.40-7.53 (m, 3H), 7.59 (t, J = 7.7Hz, 2H), 8.14 (d, J = 8.8Hz, 1H), 8.60 (s, 1H), 9.45 (d, J = 7.2Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 22.2, 49.8, 55.5, 99.1, 114.2, 121.4, 127.3, 127.9, 128.3, 129.2, 133.1, 134.8, 138.7, 156.2, 158.8, 163.7, 166.5.
Yield: 91.88%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.61 (d, J = 6.4 Hz, 3H), 3.33 (s, 3H), 3.73 (s, 3H), 5.49-5.51 (m, 1H), 6.93 (d , J = 8.0 Hz, 2H), 7.40-7.53 (m, 3H), 7.59 (t, J = 7.7 Hz, 2H), 8.14 (d, J = 8.8 Hz, 1H), 8.60 (s, 1H), 9.45 (d, J = 7.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 22.2, 49.8, 55.5, 99.1, 114.2, 121.4, 127.3, 127.9, 128.3, 129.2, 133.1, 134.8, 138.7, 156.2, 158.8, 163.7, 166.5.

(9) N-(2-메톡시벤질)-1-(4-플루오로페닐)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23i](9) N- (2-methoxybenzyl) -1- (4-fluorophenyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23i ]

상기 [20b]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23i를 얻었다.The reaction of [20b] with 2.4 eq mCPBA afforded a white solid compound 23i.

Yield: 93.25%; 1H NMR (400MHz, DMSO-d6) δ 3.35 (s, 3H), 3.85 (s, 3H), 4.78 (d, J = 5.1Hz, 2H), 7.00 (dd, J = 7.7Hz, 43.2Hz, 2H), 7.31-7.47 (m, 4H), 8.13-8.16 (m, 2H), 8.57 (s, 1H), 9.48 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 55.4, 102.1, 110.8, 116.0, 116.2, 120.2, 123.0, 123.1, 125.2, 128.8, 129.0, 134.4, 134.6, 151.5, 156.8, 157.0, 159.1, 163.3.
Yield: 93.25%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.35 (s, 3H), 3.85 (s, 3H), 4.78 (d, J = 5.1 Hz, 2H), 7.00 (dd, J = 7.7 Hz, 43.2 Hz, 2H), 7.31-7.47 (m, 4H), 8.13-8.16 (m, 2H), 8.57 (s, 1H), 9.48 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 55.4, 102.1, 110.8, 116.0, 116.2, 120.2, 123.0, 123.1, 125.2, 128.8, 129.0, 134.4, 134.6, 151.5, 156.8, 157.0, 159.1, 163.3.

(10) N-(2-클로로벤질)-1-(4-플루오로페닐)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23j](10) N- (2-chlorobenzyl) -1- (4-fluorophenyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23j]

상기 [20a]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23j를 얻었다.The reaction of [20a] with 2.4 eq mCPBA afforded a white solid compound 23j.

Yield: 73.29%; 1H NMR (400MHz, DMSO-d6) δ 3.26 (s, 3H), 4.64 (t, J = 25.2Hz, 2H), 6.86 (d, J = 22.1Hz, 1H), 7.34 (t, J = 4.1Hz, 2H), 7.47 (s, 2H), 8.91 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 20.7, 42.1, 42.8, 59.7, 102.3, 106.2, 127.3, 129.2, 129.3, 130.0, 132.5, 134.9, 157.2, 163.3, 165.2.
Yield: 73.29%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.26 (s, 3H), 4.64 (t, J = 25.2 Hz, 2H), 6.86 (d, J = 22.1 Hz, 1H), 7.34 (t, J = 4.1 Hz, 2H), 7.47 (s, 2H), 8.91 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 20.7, 42.1, 42.8, 59.7, 102.3, 106.2, 127.3, 129.2, 129.3, 130.0, 132.5, 134.9, 157.2, 163.3, 165.2.

(11) N-(2-메틸벤질)-1-(4-플루오로페닐)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23k](11) N- (2-methylbenzyl) -1- (4-fluorophenyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23k]

상기 [20c]를 2.4 eq mCPBA로 반응시켜 하얀색의 액체상 화합물 23k를 얻었다.[20c] was reacted with 2.4 eq mCPBA to obtain a white liquid compound 23k.

Yield: 71.48%; 1H NMR (400MHz, DMSO-d6) δ 2.31 (s, 3H), 3.28 (s, 3H), 4.52 (dd, J = 5.4Hz, 41.8Hz, 2H), 6.80 (d, J = 20.5Hz, 1H), 7.19 (t, J = 5.3Hz, 2H), 7.31 (d, J = 6.9Hz, 2H), 8.76 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 18.7, 20.7, 42.3, 42.8, 59.7, 102.3, 106.0, 125.8, 126.2, 127.1, 127.5, 128.5, 130.1, 134.7, 135.5, 136.2, 157.0, 163.2, 165.2.
Yield: 71.48%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.31 (s, 3H), 3.28 (s, 3H), 4.52 (dd, J = 5.4 Hz, 41.8 Hz, 2H), 6.80 (d, J = 20.5 Hz, 1H), 7.19 (t, J = 5.3 Hz, 2H), 7.31 (d, J = 6.9 Hz, 2H), 8.76 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 18.7, 20.7, 42.3, 42.8, 59.7, 102.3, 106.0, 125.8, 126.2, 127.1, 127.5, 128.5, 130.1, 134.7, 135.5, 136.2, 157.0, 163.2, 165.2.

(12) N-(2-클로로벤질)-6-(메틸설포닐)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [23l](12) N- (2-chlorobenzyl) -6- (methylsulfonyl) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [23l]

상기 [21a]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23l를 얻었다.[21a] was reacted with 2.4 eq mCPBA to obtain 23 l of a white solid compound.

Yield: 92.18%; 1H NMR (400MHz, DMSO-d6) δ 2.37 (s, 3H), 3.32 (s, 3H), 4.89 (d, J = 5.3Hz, 2H), 7.34-7.40 (m, 4H), 7.50-7.56 (m, 2H), 7.98 (d, J = 8.2Hz, 2H), 8.56 (s, 1H), 9.61 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 20.5, 39.9, 102.2, 121.0, 127.3, 129.2, 129.3, 129.7, 130.0, 132.5, 134.0, 135.0, 135.8, 136.4, 151.4, 156.7, 163.1.
Yield: 92.18%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.37 (s, 3H), 3.32 (s, 3H), 4.89 (d, J = 5.3 Hz, 2H), 7.34-7.40 (m, 4H), 7.50-7.56 (m, 2H), 7.98 (d, J = 8.2 Hz, 2H), 8.56 (s, 1H), 9.61 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 20.5, 39.9, 102.2, 121.0, 127.3, 129.2, 129.3, 129.7, 130.0, 132.5, 134.0, 135.0, 135.8, 136.4, 151.4, 156.7, 163.1.

(13) N-(2-메톡시벤질)-6-(메틸설포닐)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [23m](13) N- (2-methoxybenzyl) -6- (methylsulfonyl) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [23m]

상기 [21b]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23m를 얻었다.[21b] was reacted with 2.4 eq mCPBA to obtain 23m of a white solid compound.

Yield: 96.42%; 1H NMR (400MHz, DMSO-d6) δ 2.37 (s, 3H), 3.34 (s, 3H), 3.85 (s, 3H), 4.78 (d, J = 5.0Hz, 2H), 7.00 (dd, J = 7.8Hz, 42.1Hz, 2H), 7.30-7.39 (m, 4H), 7.98 (d, J = 8.2Hz, 2H), 8.55 (s, 1H), 9.44 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 20.5, 55.4, 102.1, 110.7, 120.2, 120.9, 125.3, 128.7, 129.0, 129.6, 134.0, 135.8, 136.2, 151.4, 156.8, 157.0, 163.2.
Yield: 96.42%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.37 (s, 3H), 3.34 (s, 3H), 3.85 (s, 3H), 4.78 (d, J = 5.0 Hz, 2H), 7.00 (dd, J = 7.8 Hz, 42.1 Hz, 2H), 7.30-7.39 (m, 4H), 7.98 (d, J = 8.2 Hz, 2H), 8.55 (s, 1H), 9.44 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 20.5, 55.4, 102.1, 110.7, 120.2, 120.9, 125.3, 128.7, 129.0, 129.6, 134.0, 135.8, 136.2, 151.4, 156.8, 157.0, 163.2.

(14) N-(2-메틸벤질)-1-(4-메틸페닐)-6-(메틸설포닐)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [23n](14) N- (2-methylbenzyl) -1- (4-methylphenyl) -6- (methylsulfonyl) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidine-4- Amines [23n]

상기 [21c]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23n를 얻었다.[21c] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23n.

Yield: 91.04%; 1H NMR (400MHz, DMSO-d6) δ 2.37 (s, 6H), 3.35 (s, 3H), 4.80 (d, J = 5.3Hz, 2H), 7.17-7.23 (m, 4H), 7.39 (d, J = 8.0Hz, 2H), 7.98 (d, J = 8.3Hz, 2H), 8.54 (s, 1H), 9.45 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 18.8, 20.5, 42.2, 102.1, 121.0, 125.9, 127.4, 128.6, 129.7, 130.1, 134.0, 135.6, 135.8, 136.2, 151.4, 156.6, 163.2.
Yield: 91.04%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.37 (s, 6H), 3.35 (s, 3H), 4.80 (d, J = 5.3 Hz, 2H), 7.17-7.23 (m, 4H), 7.39 (d , J = 8.0 Hz, 2H), 7.98 (d, J = 8.3 Hz, 2H), 8.54 (s, 1H), 9.45 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 18.8, 20.5, 42.2, 102.1, 121.0, 125.9, 127.4, 128.6, 129.7, 130.1, 134.0, 135.6, 135.8, 136.2, 151.4, 156.6, 163.2.

(15) N-(4-메톡시벤질)-6-(메틸설포닐)-1-p-톨릴-1H-피라졸로[3,4-d]피리미딘-4-아민 [23o](15) N- (4-methoxybenzyl) -6- (methylsulfonyl) -1-p-tolyl-1H-pyrazolo [3,4-d] pyrimidin-4-amine [23o]

상기 [21e]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23o를 얻었다.[21e] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23o.

Yield: 88.45%; 1H NMR (400MHz, DMSO-d6) δ 1.21 (s, 4H), 2.37 (s, 3H), 3.73 (s, 3H), 4.74 (d, J = 5.6Hz, 2H), 6.93 (d, J = 8.6Hz, 2H), 7.35-7.40 (m, 4H), 7.89-7.97 (m, 3H), 8.49 (s, 1H), 9.55 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 20.5, 28.9, 43.3, 55.0, 102.1, 113.8, 121.0, 127.8, 128.7, 129.2, 129.7, 130.0, 133.9, 135.8, 136.3, 151.4, 156.5, 158.5, 163.3.
Yield: 88.45%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.21 (s, 4H), 2.37 (s, 3H), 3.73 (s, 3H), 4.74 (d, J = 5.6 Hz, 2H), 6.93 (d, J = 8.6 Hz, 2H), 7.35-7.40 (m, 4H), 7.89-7.97 (m, 3H), 8.49 (s, 1H), 9.55 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 20.5, 28.9, 43.3, 55.0, 102.1, 113.8, 121.0, 127.8, 128.7, 129.2, 129.7, 130.0, 133.9, 135.8, 136.3, 151.4, 156.5, 158.5, 163.3.

(16) 1-벤질-6-(메틸설포닐)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23p](16) 1-benzyl-6- (methylsulfonyl) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23p]

상기 [16x]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23p를 얻었다.[16x] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23p.

Yield: 70.78%; 1H NMR (400MHz, DMSO-d6) δ 1.60 (d, J = 6.5Hz, 3H), 3.26 (s, 3H), 5.49 (t, J = 6.8Hz, 1H), 5.55 (s, 2H), 7.22-7.36 (m, 8H), 7.46 (d, J = 7.2Hz, 2H), 8.39 (s, 1H), 9.39 (d, J = 7.2Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 21.9, 49.9, 50.1, 100.7, 125.6, 126.1, 126.9, 127.5, 127.6, 128.4, 128.5, 132.9, 136.6, 143.7, 151.9, 155.6, 162.8.
Yield: 70.78%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.60 (d, J = 6.5 Hz, 3H), 3.26 (s, 3H), 5.49 (t, J = 6.8 Hz, 1H), 5.55 (s, 2H), 7.22-7.36 (m, 8H), 7.46 (d, J = 7.2 Hz, 2H), 8.39 (s, 1H), 9.39 (d, J = 7.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 21.9, 49.9, 50.1, 100.7, 125.6, 126.1, 126.9, 127.5, 127.6, 128.4, 128.5, 132.9, 136.6, 143.7, 151.9, 155.6, 162.8.

(17) 1-벤질-6-(메틸설포닐)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23q](17) 1-benzyl-6- (methylsulfonyl) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23q]

상기 [16e]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23q를 얻었다.[16e] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23q.

Yield: 87.44%; 1H NMR (400MHz, DMSO-d6) δ 1.59 (d, J = 6.9Hz, 3H), 3.24 (s, 3H), 5.47-5.54 (m, 3H), 7.20-7.36 (m, 8H), 7.45 (d, J = 7.6Hz, 2H), 8.37 (s, 1H), 9.37 (d, J = 7.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 21.9, 49.8, 50.1, 100.7, 126.1, 126.9, 127.5, 127.6, 128.4, 128.5, 132.9, 136.6, 143.7, 151.9, 155.6, 162.8.
Yield: 87.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.59 (d, J = 6.9 Hz, 3H), 3.24 (s, 3H), 5.47-5.54 (m, 3H), 7.20-7.36 (m, 8H), 7.45 (d, J = 7.6 Hz, 2H), 8.37 (s, 1 H), 9.37 (d, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 21.9, 49.8, 50.1, 100.7, 126.1, 126.9, 127.5, 127.6, 128.4, 128.5, 132.9, 136.6, 143.7, 151.9, 155.6, 162.8.

(18) 1-벤질-6-(메틸설포닐)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23r](18) 1-benzyl-6- (methylsulfonyl) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23r]

상기 [16k]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23r를 얻었다.[16k] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23r.

Yield: 90.37%; 1H NMR (400MHz, DMSO-d6) δ 1.60 (d, J = 6.6Hz, 3H), 3.25 (s, 3H), 5.47-5.55 (m, 3H), 7.21-7.36 (m, 8H), 7.46 (d, J = 6.8Hz, 2H), 8.38 (s, 1H), 9.39 (d, J = 7.1Hz, 1H); 13C NMR 100MHz, DMSO-d6) δ 13.5, 21.9, 49.8, 50.1, 100.7, 126.1, 126.9, 127.5, 127.6, 128.4, 128.5, 132.9, 136.6, 143.7, 151.9, 155.6, 162.8.
Yield: 90.37%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.60 (d, J = 6.6 Hz, 3H), 3.25 (s, 3H), 5.47-5.55 (m, 3H), 7.21-7.36 (m, 8H), 7.46 (d, J = 6.8 Hz, 2H), 8.38 (s, 1 H), 9.39 (d, J = 7.1 Hz, 1H); 13 C NMR 100 MHz, DMSO-d 6 ) δ 13.5, 21.9, 49.8, 50.1, 100.7, 126.1, 126.9, 127.5, 127.6, 128.4, 128.5, 132.9, 136.6, 143.7, 151.9, 155.6, 162.8.

(19) 1-벤질-N-((4-클로로페닐)(페닐)메틸)-6-(메틸설포닐)-N-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23s](19) 1-benzyl-N-((4-chlorophenyl) (phenyl) methyl) -6- (methylsulfonyl) -N- (1-phenylethyl) -1H-pyrazolo [3,4-d] Pyrimidin-4-amine [23s]

상기 [16y]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23s를 얻었다.[16y] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23s.

Yield: 97.05%; 1H NMR (400MHz, DMSO-d6) δ 3.23 (s, 3H), 5.56 (s, 2H), 6.70 (d, J = 7.4Hz, 1H), 7.22-7.57 (m, 14H), 8.23 (s, 1H), 9.79 (d, J = 7.2Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.6, 14.0, 28.9, 50.6, 57.7, 101.3, 128.0, 128.1, 128.3, 128.9, 129.0, 129.2, 129.9, 131.0, 133.1, 133.3, 133.8, 137.0, 141.2, 156.1, 163.1, 166.6.
Yield: 97.05%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.23 (s, 3H), 5.56 (s, 2H), 6.70 (d, J = 7.4 Hz, 1H), 7.22-7.57 (m, 14H), 8.23 (s , 1H), 9.79 (d, J = 7.2 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.6, 14.0, 28.9, 50.6, 57.7, 101.3, 128.0, 128.1, 128.3, 128.9, 129.0, 129.2, 129.9, 131.0, 133.1, 133.3, 133.8, 137.0, 141.2, 156.1, 163.1, 166.6.

(20) 1-벤질-N-(1-사이클로헥실에틸)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23t](20) 1-benzyl-N- (1-cyclohexylethyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23t]

상기 [16z]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23t를 얻었다.[16z] was reacted with 2.4 eq mCPBA to give a white solid compound 23t.

Yield: 96.20%; 1H NMR (400MHz, DMSO-d6) δ 0.98-1.01 (m, 2H), 1.15 (d, J = 6.8Hz, 3H), 1.17-1.22 (m, 2H), 1.46-1.61 (m, 2H), 1.70-1.77 (m, 4H), 2.48 (s, 3H), 4.19-4.24 (m, 1H), 5.54 (s, 2H), 7.21-7.33 (m, 5H), 8.05 (d, J = 8.5Hz, 1H), 8.10 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 17.7, 26.2, 26.3, 29.1, 29.5, 42.9, 50.6, 51.2, 128.1, 128.3, 129.0, 129.2, 131.0, 133.1, 133.4, 133.7, 152.3, 166.5.
Yield: 96.20%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.98-1.01 (m, 2H), 1.15 (d, J = 6.8 Hz, 3H), 1.17-1.22 (m, 2H), 1.46-1.61 (m, 2H) , 1.70-1.77 (m, 4H), 2.48 (s, 3H), 4.19-4.24 (m, 1H), 5.54 (s, 2H), 7.21-7.33 (m, 5H), 8.05 (d, J = 8.5 Hz , 1H), 8.10 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 17.7, 26.2, 26.3, 29.1, 29.5, 42.9, 50.6, 51.2, 128.1, 128.3, 129.0, 129.2, 131.0, 133.1, 133.4, 133.7, 152.3, 166.5.

(21) 1-벤질-6-(메틸설포닐)-N-(1-p-톨릴에틸)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23u](21) 1-benzyl-6- (methylsulfonyl) -N- (1-p-tolylethyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23u]

상기 [16za]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23u를 얻었다.[16za] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23u.

Yield: 95.68%; 1H NMR (400MHz, DMSO-d6) δ 1.57 (d, J = 6.8Hz, 3H), 2.26 (s, 3H), 3.28 (s, 3H), 5.43-5.55 (m, 3H), 7.15 (d, J = 7.4Hz, 2H), 7.21-7.91 (m, 8H), 8.37 (s, 1H), 9.35 (d, J = 7.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 21.0, 22.3, 50.0, 50.6, 101.2, 126.6, 128.0, 127.5, 128.3, 129.0, 131.0, 133.4, 136.6, 137.1, 141.1, 152.4, 156.1, 166.5.
Yield: 95.68%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.57 (d, J = 6.8 Hz, 3H), 2.26 (s, 3H), 3.28 (s, 3H), 5.43-5.55 (m, 3H), 7.15 (d , J = 7.4 Hz, 2H), 7.21-7.91 (m, 8H), 8.37 (s, 1H), 9.35 (d, J = 7.4 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 21.0, 22.3, 50.0, 50.6, 101.2, 126.6, 128.0, 127.5, 128.3, 129.0, 131.0, 133.4, 136.6, 137.1, 141.1, 152.4, 156.1, 166.5.

(22) 1-벤질-N-((S)-1-(4-메톡시페닐)에틸)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23v](22) 1-benzyl-N-((S) -1- (4-methoxyphenyl) ethyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidine-4- Amine [23v]

상기 [16zb]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23v를 얻었다.The [16zb] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23v.

Yield: 93.22%; 1H NMR (400MHz, DMSO-d6) δ 1.57 (d, J = 6.8Hz, 3H), 3.30 (s, 3H), 3.72 (s, 3H), 5.44-5.55 (s, 3H), 6.91 (d, J = 8.5Hz, 2H), 7.21-7.91 (m, 8H), 8.36 (s, 1H), 9.32 (d, J = 7.5Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 21.7, 49.1, 50.1, 54.9, 100.6, 113.9, 127.3, 127.4, 127.6, 128.5, 130.5, 132.9, 135.4, 136.6, 151.9, 155.5, 158.2, 162.8.
Yield: 93.22%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.57 (d, J = 6.8 Hz, 3H), 3.30 (s, 3H), 3.72 (s, 3H), 5.44-5.55 (s, 3H), 6.91 (d , J = 8.5 Hz, 2H), 7.21-7.91 (m, 8H), 8.36 (s, 1H), 9.32 (d, J = 7.5 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 21.7, 49.1, 50.1, 54.9, 100.6, 113.9, 127.3, 127.4, 127.6, 128.5, 130.5, 132.9, 135.4, 136.6, 151.9, 155.5, 158.2, 162.8.

(23) N-(2-클로로벤질)-1-(3-메톡시펜에틸)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23w](23) N- (2-chlorobenzyl) -1- (3-methoxyphenethyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23w ]

상기 [18a]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23w를 얻었다.[18a] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23w.

Yield: 89.11%; 1H NMR (400MHz, DMSO-d6) δ 2.39 (s, 3H), 3.11 (t, J = 6.9Hz, 2H), 3.66 (s, 3H), 4.47 (t, J = 7.0Hz, 2H), 4.76 (d, J = 5.6Hz, 2H), 6.71 (t, J = 6.9Hz, 3H), 7.13 (t, J = 7.8Hz, 1H), 7.30-7.33 (m, 2H), 7.39 (t, J = 4.5Hz, 1H), 7.48 (t, J = 4.5Hz, 1H), 8.08 (s, 1H), 8.79 (s, 1H).
Yield: 89.11%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.39 (s, 3H), 3.11 (t, J = 6.9 Hz, 2H), 3.66 (s, 3H), 4.47 (t, J = 7.0 Hz, 2H), 4.76 (d, J = 5.6 Hz, 2H), 6.71 (t, J = 6.9 Hz, 3H), 7.13 (t, J = 7.8 Hz, 1H), 7.30-7.33 (m, 2H), 7.39 (t, J = 4.5 Hz, 1H), 7.48 (t, J = 4.5 Hz, 1H), 8.08 (s, 1H), 8.79 (s, 1H).

(24) N-(2-메톡시벤질)-1-(3-메톡시펜에틸)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23x](24) N- (2-methoxybenzyl) -1- (3-methoxyphenethyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [ 23x]

상기 [18b]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23x를 얻었다.[18b] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23x.

Yield: 90.88%; 1H NMR (400MHz, DMSO-d6) δ 2.42 (s, 3H), 3.11 (t, J = 7.0Hz, 2H), 3.66 (s, 3H), 3.82 (s, 3H), 4.46 (t, J = 7.0Hz, 2H), 4.65 (d, J = 5.5Hz, 2H), 6.71 (t, J = 6.0Hz, 3H), 6.90 (t, J = 4.5Hz, 1H), 7.02 (d, J = 8.1Hz, 1H), 7.13 (t, J = 4.5Hz, 1H), 7.22-7.26 (m, 2H), 8.08 (s, 1H), 8.59 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.3, 34.8, 38.3, 47.1, 54.7, 55.3, 98.0, 110.6, 111.8, 114.0, 120.1, 120.8, 126.2, 128.2, 128.3, 129.2, 131.8, 139.8, 153.3, 155.2, 156.8, 159.1, 168.0.
Yield: 90.88%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.42 (s, 3H), 3.11 (t, J = 7.0 Hz, 2H), 3.66 (s, 3H), 3.82 (s, 3H), 4.46 (t, J = 7.0 Hz, 2H), 4.65 (d, J = 5.5 Hz, 2H), 6.71 (t, J = 6.0 Hz, 3H), 6.90 (t, J = 4.5 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 7.13 (t, J = 4.5 Hz, 1H), 7.22-7.26 (m, 2H), 8.08 (s, 1H), 8.59 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.3, 34.8, 38.3, 47.1, 54.7, 55.3, 98.0, 110.6, 111.8, 114.0, 120.1, 120.8, 126.2, 128.2, 128.3, 129.2, 131.8, 139.8, 153.3, 155.2, 156.8, 159.1, 168.0.

(25) N-(2-메틸벤질)-1-(3-메톡시펜에틸)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23y](25) N- (2-methylbenzyl) -1- (3-methoxyphenethyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23y ]

상기 [18c]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23y를 얻었다.[18c] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23y.

Yield: 89.17%; 1H NMR (400MHz, DMSO-d6) δ 2.34 (s, 3H), 3.16 (t, J = 6.7Hz, 2H), 3.26 (s, 3H), 3.65 (s, 3H), 4.59 (t, J = 6.7Hz, 2H), 4.75 (t, J = 4.9Hz, 2H), 6.70 (t,J = 7.6Hz, 3H), 7.11 (t, J = 7.8Hz, 2H), 7.18-7.21 (m, 2H), 7.35 (d, J = 6.6Hz, 1H), 8.30 (s, 1H), 9.26 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 18.7, 34.8, 42.1, 47.7, 54.7, 100.3, 100.6, 111.9, 114.0, 120.8, 125.8, 127.4, 128.5, 129.2, 130.1, 132.4, 135.8, 136.2, 139.5, 151.7, 156.4, 159.1, 162.5.
Yield: 89.17%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.34 (s, 3H), 3.16 (t, J = 6.7 Hz, 2H), 3.26 (s, 3H), 3.65 (s, 3H), 4.59 (t, J = 6.7 Hz, 2H), 4.75 (t, J = 4.9 Hz, 2H), 6.70 (t, J = 7.6 Hz, 3H), 7.11 (t, J = 7.8 Hz, 2H), 7.18-7.21 (m, 2H ), 7.35 (d, J = 6.6 Hz, 1 H), 8.30 (s, 1 H), 9.26 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 18.7, 34.8, 42.1, 47.7, 54.7, 100.3, 100.6, 111.9, 114.0, 120.8, 125.8, 127.4, 128.5, 129.2, 130.1, 132.4, 135.8, 136.2, 139.5, 151.7, 156.4, 159.1, 162.5.

(26) 1-(2-메톡시펜에틸)-N-(3-메톡시벤질)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23z](26) 1- (2-methoxyphenethyl) -N- (3-methoxybenzyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [ 23z]

상기 [19a]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23z를 얻었다.[19a] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23z.

Yield: 79.38%, 1H NMR (400MHz, DMSO-d6) δ 3.11 (t, J = 6.9Hz, 2H), 3.26 (s, 3H), 3.73 (s, 3H), 3.76 (s, 3H), 4.55 (t, J = 6.9Hz, 2H), 4.73 (d, J = 5.6Hz, 2H), 6.73 (t, J = 7.4Hz, 1H), 6.83-6.99 (m, 5H), 7.21 (dd, J=7.8Hz, 47.4Hz, 2H), 8.24 (s, 1H), 9.39 (t, J = 5.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 30.8, 44.2, 46.9, 55.4, 55.7, 99.1, 101.1, 111.0, 113.2, 113.9, 120.4, 120.5, 126.1, 128.4, 130.0, 130.4, 132.6, 140.4, 152.2, 157.0, 157.8, 159.8, 162.9.
Yield: 79.38%, 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.11 (t, J = 6.9 Hz, 2H), 3.26 (s, 3H), 3.73 (s, 3H), 3.76 (s, 3H), 4.55 (t, J = 6.9 Hz, 2H), 4.73 (d, J = 5.6 Hz, 2H), 6.73 (t, J = 7.4 Hz, 1H), 6.83-6.99 (m, 5H), 7.21 (dd, J = 7.8 Hz, 47.4 Hz, 2H), 8.24 (s, 1H), 9.39 (t, J = 5.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 30.8, 44.2, 46.9, 55.4, 55.7, 99.1, 101.1, 111.0, 113.2, 113.9, 120.4, 120.5, 126.1, 128.4, 130.0, 130.4, 132.6, 140.4, 152.2, 157.0, 157.8, 159.8, 162.9.

(27) 1-(2-메톡시펜에틸)-N-(4-메톡시벤질)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23za](27) 1- (2-methoxyphenethyl) -N- (4-methoxybenzyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [ 23za]

상기 [19b]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23za를 얻었다.[19b] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23za.

Yield: 84.88%; 1H NMR (400MHz, DMSO-d6) δ 3.12 (t, J = 6.6Hz, 2H), 3.28 (s, 3H), 3.73 (s, 3H), 3.77 (s, 3H), 4.55 (t, J = 6.7Hz, 2H), 4.69 (d, J = 5.2Hz, 2H), 6.73 (t, J = 7.2Hz, 1H), 6.92 (d, J = 8.0Hz, 4H), 7.15 (t, J = 7.3Hz, 1H), 7.34 (d, J = 8.2Hz, 2H), 8.24 (s, 1H), 9.34 (d, J = 5.1Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 30.8, 43.7, 46.9, 55.5, 55.7, 101.1, 111.0, 114.3, 120.5, 126.1, 128.4, 129.7, 130.4, 130.7, 132.6, 152.2, 156.8, 157.8, 159.0, 163.0.
Yield: 84.88%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 3.12 (t, J = 6.6 Hz, 2H), 3.28 (s, 3H), 3.73 (s, 3H), 3.77 (s, 3H), 4.55 (t, J = 6.7 Hz, 2H), 4.69 (d, J = 5.2 Hz, 2H), 6.73 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 8.0 Hz, 4H), 7.15 (t, J = 7.3 Hz, 1H), 7.34 (d, J = 8.2 Hz, 2H), 8.24 (s, 1H), 9.34 (d, J = 5.1 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 30.8, 43.7, 46.9, 55.5, 55.7, 101.1, 111.0, 114.3, 120.5, 126.1, 128.4, 129.7, 130.4, 130.7, 132.6, 152.2, 156.8, 157.8, 159.0, 163.0.

(28) 1-(2-메톡시펜에틸)-N-(4-메톡시벤질)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23zb](28) 1- (2-methoxyphenethyl) -N- (4-methoxybenzyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [ 23zb]

상기 [19c]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23zb를 얻었다.[19c] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23zb.

Yield: 90.32%; 1H NMR (400MHz, DMSO-d6) δ 2.27 (s, 3H), 3.11 (t, J = 7.0Hz, 2H), 3.26 (s, 3H), 3.77 (s, 3H), 4.55 (t, J = 7.0Hz, 2H), 4.71 (d, J = 5.6Hz, 2H), 6.73 (t, J = 5.8Hz, 1H), 6.92 (d, J = 7.6Hz, 2H), 7.13-7.16 (m, 3H), 7.28 (d, J = 7.8Hz, 2H), 8.23 (s, 1H), 9.35 (t, J = 5.3Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 21.1, 30.8, 44.0, 46.9, 55.7, 101.1, 111.0, 120.5, 126.1, 127.0, 128.2, 128.4, 129.4, 130.4, 132.6, 135.7, 136.8, 152.2, 156.9, 157.8, 163.0.
Yield: 90.32%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.27 (s, 3H), 3.11 (t, J = 7.0 Hz, 2H), 3.26 (s, 3H), 3.77 (s, 3H), 4.55 (t, J = 7.0 Hz, 2H), 4.71 (d, J = 5.6 Hz, 2H), 6.73 (t, J = 5.8 Hz, 1H), 6.92 (d, J = 7.6 Hz, 2H), 7.13-7.16 (m, 3H ), 7.28 (d, J = 7.8 Hz, 2H), 8.23 (s, 1H), 9.35 (t, J = 5.3 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 21.1, 30.8, 44.0, 46.9, 55.7, 101.1, 111.0, 120.5, 126.1, 127.0, 128.2, 128.4, 129.4, 130.4, 132.6, 135.7, 136.8, 152.2, 156.9, 157.8, 163.0.

(29) N-(4-메톡시벤질)-1-t-뷰틸-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23zc](29) N- (4-methoxybenzyl) -1-t-butyl-6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23zc]

상기 [17e]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23zc를 얻었다.[17e] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23zc.

Yield: 83.33%; 1H NMR (400MHz, DMSO-d6) δ 1.63 (s, 9H), 3.28 (s, 3H), 3.73 (s, 3H), 4.69 (d, J = 5.4Hz, 2H), 6.91 (t, J = 4.3Hz, 2H), 7.34 (d, J = 8.5Hz, 2H), 8.60 (s, 1H), 9.18 (s, 1H).
Yield: 83.33%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.63 (s, 9H), 3.28 (s, 3H), 3.73 (s, 3H), 4.69 (d, J = 5.4 Hz, 2H), 6.91 (t, J = 4.3 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 8.60 (s, 1H), 9.18 (s, 1H).

(30) N-(4-클로로벤질)-1-t-뷰틸-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23zd](30) N- (4-chlorobenzyl) -1-t-butyl-6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23zd]

상기 [17j]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23zd를 얻었다.[17j] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23zd.

Yield: 89.06%; 1H NMR (400MHz, DMSO-d6) δ 1.64 (s, 9H), 3.26 (s, 3H), 4.76 (d, J = 5.7Hz, 2H), 7.43 (t, J = 5.6Hz, 4H), 8.60 (s, 1H), 9.29 (s, 1H)
Yield: 89.06%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.64 (s, 9H), 3.26 (s, 3H), 4.76 (d, J = 5.7 Hz, 2H), 7.43 (t, J = 5.6 Hz, 4H), 8.60 (s, 1 H), 9.29 (s, 1 H)

(31) N-(2-클로로벤질)-1-t-뷰틸-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23ze](31) N- (2-chlorobenzyl) -1-t-butyl-6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23ze]

상기 [17n]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23ze를 얻었다.[17n] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23ze.

Yield: 90.89%; 1H NMR (400MHz, DMSO-d6) δ 1.60 (s, 9H), 4.79 (d, J = 5.5Hz, 2H), 6.92 (d, J = 8.4Hz, 2H), 7.37 (d, J = 8.3Hz, 2H), 8.63 (s, 1H), 9.20 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 28.7, 43.7, 55.0, 98.4, 113.8, 126.6, 129.2, 149.4, 155.1, 158.5, 165.5.
Yield: 90.89%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.60 (s, 9H), 4.79 (d, J = 5.5 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.3 Hz, 2H), 8.63 (s, 1 H), 9.20 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 28.7, 43.7, 55.0, 98.4, 113.8, 126.6, 129.2, 149.4, 155.1, 158.5, 165.5.

(32) 1-t-뷰틸-N-(1-사이클로헥실에틸)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23zf](32) 1-t-butyl-N- (1-cyclohexylethyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23zf]

상기 [17q]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23zf를 얻었다.[17q] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23zf.

Yield: 83.95%; 1H NMR (400MHz, DMSO-d6) δ 0.99-1.05 (m, 2H), 1.18 (d, J = 7.1Hz, 3H), 1.17-1.19 (m, 2H), 1.44-1.48 (m, 2H), 1.64 (s, 9H), 1.71-1.78 (m, 4H), 3.27 (s, 3H), 4.24 (d, J = 6.9Hz, 1H), 7.90 (s, 1H), 8.51 (s, 1H).
Yield: 83.95%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.99-1.05 (m, 2H), 1.18 (d, J = 7.1 Hz, 3H), 1.17-1.19 (m, 2H), 1.44-1.48 (m, 2H) , 1.64 (s, 9H), 1.71-1.78 (m, 4H), 3.27 (s, 3H), 4.24 (d, J = 6.9 Hz, 1H), 7.90 (s, 1H), 8.51 (s, 1H).

(33) 1-t-뷰틸-N-(1-사이클로헥실에틸)-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23zh](33) 1-t-butyl-N- (1-cyclohexylethyl) -6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23zh]

상기 [17p]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23zh를 얻었다.[17p] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23zh.

Yield: 86.27%; 1H NMR (400MHz, DMSO-d6) δ 0.99-1.03 (m, 2H), 1.16 (d, J = 7.1Hz, 3H), 1.17-1.19 (m, 2H), 1.44-1.48 (m, 2H), 1.64 (s, 9H), 1.69-1.77 (m, 4H), 3.27 (s, 3H), 4.25 (d, J = 6.7Hz, 1H), 7.90 (s, 1H), 8.50 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 17.2, 25.6, 25.8, 28.6, 28.8, 29.0, 42.6, 50.3, 60.6, 100.9, 122.5, 127.7, 128.7, 130.5, 132.5, 133.2, 157.5, 163.2, 165.9.
Yield: 86.27%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.99-1.03 (m, 2H), 1.16 (d, J = 7.1 Hz, 3H), 1.17-1.19 (m, 2H), 1.44-1.48 (m, 2H) , 1.64 (s, 9H), 1.69-1.77 (m, 4H), 3.27 (s, 3H), 4.25 (d, J = 6.7 Hz, 1H), 7.90 (s, 1H), 8.50 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 17.2, 25.6, 25.8, 28.6, 28.8, 29.0, 42.6, 50.3, 60.6, 100.9, 122.5, 127.7, 128.7, 130.5, 132.5, 133.2, 157.5, 163.2, 165.9.

(34) 1-t-뷰틸-N-뷰틸-6-(메틸설포닐)-1H-피라졸로[3,4-d]피리미딘-4-아민 [23zi](34) 1-t-butyl-N-butyl-6- (methylsulfonyl) -1H-pyrazolo [3,4-d] pyrimidin-4-amine [23zi]

상기 [17l]를 2.4 eq mCPBA로 반응시켜 하얀색의 고체상 화합물 23zi를 얻었다.[17l] was reacted with 2.4 eq mCPBA to obtain a white solid compound 23zi.

Yield: 90.10%; 1H NMR (400MHz, DMSO-d6) δ 0.93 (t, J = 7.3Hz, 3H), 1.36-1.41 (m, 2H), 1.59-1.61 (m, 2H), 1.64 (s, 9H), 3.28 (s, 3H), 3.52-3.56 (m, 2H), 8.59 (s, 1H), 8.75 (t, J = 5.1Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.5, 19.4, 29.0, 30.5, 60.6, 101.1, 122.3, 157.4 , 158.3, 163.2.
Yield: 90.10%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.93 (t, J = 7.3 Hz, 3H), 1.36-1.41 (m, 2H), 1.59-1.61 (m, 2H), 1.64 (s, 9H), 3.28 (s, 3H), 3.52-3.56 (m, 2H), 8.59 (s, 1H), 8.75 (t, J = 5.1 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.5, 19.4, 29.0, 30.5, 60.6, 101.1, 122.3, 157.4, 158.3, 163.2.

실시예 22. [24a] 내지 [24j]의 합성Example 22. Synthesis of [24a] to [24j]

하기 [반응식 24](R3 , n-BuOH : DMSO = 4 : 1, 90 ℃)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [24a] 내지 [24j]를 합성하였다.The pyrazolopyrimidine derivative compounds [24a] to [24j] were synthesized according to the following Reaction Scheme 24 (R 3 , n-BuOH: DMSO = 4: 1, 90 ° C).

[반응식 24]Scheme 24

Figure pat00346
Figure pat00346

[24a] ~ [24j][24a] to [24j]

[24a] 내지 [24j]에서 R3는 각각 하기 [표 17]과 같다.In [24a] to [24j], each of R 3 is shown in Table 17 below.

(NR2은 [16e], [16x]에서와 동일하다.)(NR 2 is the same as in [16e], [16x].)

구분division R3 R 3 구분division R3 R 3 24a24a

Figure pat00347
Figure pat00347
24f24f
Figure pat00348
Figure pat00348
 24b24b
Figure pat00349
Figure pat00349
 24g24 g
Figure pat00350
Figure pat00350
 24c24c
Figure pat00351
Figure pat00351
 24h24h
Figure pat00352
Figure pat00352
 24d24d
Figure pat00353
Figure pat00353
 24i24i
Figure pat00354
Figure pat00354
 24e24e
Figure pat00355
Figure pat00355
 24j24j
Figure pat00356
Figure pat00356

(1) 2-(4-(1-페닐에틸아미노)-1-벤질-1H-피라졸로[3,4-d]피리미딘-6-일아미노)에탄올 [24a](1) 2- (4- (1-phenylethylamino) -1-benzyl-1H-pyrazolo [3,4-d] pyrimidin-6-ylamino) ethanol [24a]

상기 [23p]를 용매 (n-BuOH : DMSO = 4 : 1)비율로 녹인 다음 1.2 eq 2-aminoethanol을 상온에서 넣어주고 90 ℃에서 overnight 반응으로 진행시킨다. 반응종료 후 반응물은 CH2Cl2 (2×30 mL), H2O를 이용하여 추출하고 유기층은 무수 MgSO4을 사용하여 소량의 물을 제거하였으며, 감압 증류하여 용매를 제거하였다. 여기서 얻은 반응 혼합물을 flash chromatography (hexanes : EtOAc = 1 : 1)로 하여 분리하면 하얀색의 고체상 화합물 24a를 얻었다.[23p] was dissolved in a solvent (n-BuOH: DMSO = 4: 1) ratio, and then 1.2 eq 2-aminoethanol was added at room temperature, followed by overnight reaction at 90 ° C. After completion of reaction, the reactant is CH 2 Cl 2 (2 × 30 mL), extracted with H 2 O, and the organic layer was removed with a small amount of water using anhydrous MgSO 4 , the solvent was removed by distillation under reduced pressure. The reaction mixture obtained here was separated by flash chromatography (hexanes: EtOAc = 1: 1) to give a white solid compound 24a.

Yield: 66.57%; 1H NMR (400MHz, DMSO-d6) δ 1.51 (d, J = 6.9Hz, 3H), 3.32 (s, 2H), 3.48 (s, 2H), 4.65 (s, 1H), 5.27-5.43 (m, 3H), 6.48 (s, 1H), 7.19-7.33 (m, 8H), 7.41 (d, J = 7.5Hz, 2H), 7.94 (s, 1H), 8.15 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 22.8, 44.2, 49.5, 60.6, 95.8, 126.6, 127.0, 127.6, 128.7, 128.8, 132.6, 138.3, 156.0, 161.9.
Yield: 66.57%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.51 (d, J = 6.9 Hz, 3H), 3.32 (s, 2H), 3.48 (s, 2H), 4.65 (s, 1H), 5.27-5.43 (m , 3H), 6.48 (s, 1H), 7.19-7.33 (m, 8H), 7.41 (d, J = 7.5 Hz, 2H), 7.94 (s, 1H), 8.15 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 22.8, 44.2, 49.5, 60.6, 95.8, 126.6, 127.0, 127.6, 128.7, 128.8, 132.6, 138.3, 156.0, 161.9.

(2) 3-(4-(1-페닐에틸아미노)-1-벤질-1H-피라졸로[3,4-d]피리미딘-6-일아미노)프로판-1-올 [24b](2) 3- (4- (1-phenylethylamino) -1-benzyl-1H-pyrazolo [3,4-d] pyrimidin-6-ylamino) propan-1-ol [24b]

상기 [23q]를 3-aminopropan-1-ol으로 하얀색의 고체상 화합물 24b를 얻었다.[23q] was obtained as white solid compound 24b as 3-aminopropan-1-ol.

Yield: 71.235; 1H NMR (400MHz, DMSO-d6) δ 1.51 (d, J = 6.9Hz, 3H), 1.64 (s, 2H), 3.29 (s, 2H), 3.45 (s, 2H), 4.47 (s, 1H), 5.27-5.44 (m, 3H), 6.58 (s, 1H), 7.19-7.33 (m, 8H), 7.42 (d, J = 7.5Hz, 2H), 7.93 (s, 1H), 8.13 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 22.9, 49.5, 59.3, 99.1, 126.6, 126.5, 127.1, 128.1, 128.3, 132.1, 137.9, 155.5, 161.4.
Yield: 71.235; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.51 (d, J = 6.9 Hz, 3H), 1.64 (s, 2H), 3.29 (s, 2H), 3.45 (s, 2H), 4.47 (s, 1H ), 5.27-5.44 (m, 3H), 6.58 (s, 1H), 7.19-7.33 (m, 8H), 7.42 (d, J = 7.5 Hz, 2H), 7.93 (s, 1H), 8.13 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 22.9, 49.5, 59.3, 99.1, 126.6, 126.5, 127.1, 128.1, 128.3, 132.1, 137.9, 155.5, 161.4.

(3) 4-(4-(1-페닐에틸아미노)-1-벤질-1H-피라졸로[3,4-d]피리미딘-6-일아미노)부탄-1-올 [24c](3) 4- (4- (1-phenylethylamino) -1-benzyl-1H-pyrazolo [3,4-d] pyrimidin-6-ylamino) butan-1-ol [24c]

상기 [23q]와 4-aminobutan-1-ol으로 하얀색의 고체상 화합물 24c를 얻었다.The white solid compound 24c was obtained from [23q] and 4-aminobutan-1-ol.

Yield: 61.44%; 1H NMR (400MHz, DMSO-d6) δ 1.43 (s, 4H), 1.51 (d, J = 6.9Hz, 3H), 3.21 (s, 2H), 3.43 (s, 2H), 4.37 (t, J = 5.1Hz, 1H), 5.26-5.43 (m, 3H), 6.61 (s, 1H), 7.20-7.33 (m, 8H), 7.41 (d, J = 7.4Hz, 2H), 7.92 (s, 1H), 8.12 (s, 1H); 13C NMR 100MHz, DMSO-d6) δ 22.6, 26.4, 30.6, 49.5, 61.1, 95.6, 126.5, 126.4, 127.1, 1281, 128.3, 132.0, 137.9, 155.5, 161.4.
Yield: 61.44%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.43 (s, 4H), 1.51 (d, J = 6.9 Hz, 3H), 3.21 (s, 2H), 3.43 (s, 2H), 4.37 (t, J = 5.1 Hz, 1H), 5.26-5.43 (m, 3H), 6.61 (s, 1H), 7.20-7.33 (m, 8H), 7.41 (d, J = 7.4 Hz, 2H), 7.92 (s, 1H) , 8.12 (s, 1 H); 13 C NMR 100 MHz, DMSO-d 6 ) δ 22.6, 26.4, 30.6, 49.5, 61.1, 95.6, 126.5, 126.4, 127.1, 1281, 128.3, 132.0, 137.9, 155.5, 161.4.

(4) 2-(2-(4-(1-페닐에틸아미노)-1-벤질-1H-피라졸로[3,4-d]피리미딘-6-일아미노)에톡시)에탄올 [24d](4) 2- (2- (4- (1-phenylethylamino) -1-benzyl-1H-pyrazolo [3,4-d] pyrimidin-6-ylamino) ethoxy) ethanol [24d]

상기 [23q]와 2-(2-aminoethoxy)ethanol으로 하얀색의 고체상 화합물 24d를 얻었다.The white solid compound 24d was obtained from [23q] and 2- (2-aminoethoxy) ethanol.

Yield: 59.76%; 1H NMR (400MHz, DMSO-d6) δ 1.51 (d, J = 6.5Hz, 3H), 3.48 (s, 4H), 3.49 (s, 4H), 3.60 (s, 1H), 5.27-5.43 (m, 3H), 6.55 (s, 1H), 7.20-7.34 (m, 8H), 7.41 (d, J = 6.6Hz, 2H), 7.94 (s, 1H), 8.11 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 22.5, 49.0, 60.1, 69.1, 72.0, 98.6, 126.0, 126.5, 127.1, 128.2, 128.3, 132.1, 137.9, 155.6, 161.2.
Yield: 59.76%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.51 (d, J = 6.5 Hz, 3H), 3.48 (s, 4H), 3.49 (s, 4H), 3.60 (s, 1H), 5.27-5.43 (m , 3H), 6.55 (s, 1H), 7.20-7.34 (m, 8H), 7.41 (d, J = 6.6 Hz, 2H), 7.94 (s, 1H), 8.11 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 22.5, 49.0, 60.1, 69.1, 72.0, 98.6, 126.0, 126.5, 127.1, 128.2, 128.3, 132.1, 137.9, 155.6, 161.2.

(5) N6,1-디벤질-N4-(1-페닐에틸)-1-벤질-1H-피라졸로[3,4-d]피리미딘-4,6-디아민 [24e](5) N 6 , 1-dibenzyl-N 4- (1-phenylethyl) -1-benzyl-1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine [24e]

상기 [23p]와 benzylamine으로 하얀색의 고체상 화합물 24e를 얻었다.[23p] and benzylamine gave a white solid compound 24e.

Yield: 48.39%; 1H NMR (400MHz, DMSO-d6) δ 1.48 (d, J = 6.6Hz, 3H), 4.41-4.45 (m, 2H), 5.25-5.41 (m, 3H), 7.16-7.35 (m, 15H), 7.93 (s, 1H), 8.1 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 22.3, 44.3, 49.0, 95.4, 98.6, 126.0, 126.2, 126.5, 127.1, 127.3, 127.9, 128.1, 128.3, 132.1, 137.8, 141.1, 144.8, 155.6, 161.2.
Yield: 48.39%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.48 (d, J = 6.6 Hz, 3H), 4.41-4.45 (m, 2H), 5.25-5.41 (m, 3H), 7.16-7.35 (m, 15H) , 7.93 (s, 1 H), 8.1 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 22.3, 44.3, 49.0, 95.4, 98.6, 126.0, 126.2, 126.5, 127.1, 127.3, 127.9, 128.1, 128.3, 132.1, 137.8, 141.1, 144.8, 155.6, 161.2.

(6) 1-벤질-N6-뷰틸-N4-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4,6-디아민 [24f](6) 1-benzyl-N 6 -butyl-N 4- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine [24f]

상기 [23p]와 n-butylamine으로 하얀색의 고체상 화합물 24f를 얻었다.[23p] and n-butylamine gave a white solid compound 24f.

Yield: 62.49%; 1H NMR (400MHz, DMSO-d6) δ 0.86 (t, J = 6.4Hz, 3H), 1.15-1.23 (m, 4H), 1.51 (d, J = 6.9Hz, 3H), 3.24 (s, 2H), 5.26-5.43 (m, 3H), 6.60 (s, 1H), 7.18-7.32 (m, 8H), 7.40 (d, J = 6.9Hz, 2H), 7.93 (s, 1H), 8.12 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.2, 20.1, 22.9, 29.4, 31.9, 49.5, 126.5, 126.9, 127.6, 128.6, 128.8, 132.5, 138.4, 156.0, 161.9.
Yield: 62.49%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.86 (t, J = 6.4 Hz, 3H), 1.15-1.23 (m, 4H), 1.51 (d, J = 6.9 Hz, 3H), 3.24 (s, 2H ), 5.26-5.43 (m, 3H), 6.60 (s, 1H), 7.18-7.32 (m, 8H), 7.40 (d, J = 6.9 Hz, 2H), 7.93 (s, 1H), 8.12 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.2, 20.1, 22.9, 29.4, 31.9, 49.5, 126.5, 126.9, 127.6, 128.6, 128.8, 132.5, 138.4, 156.0, 161.9.

(7) 1-벤질-N6,N6-디메틸-N4-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4,6-디아민 [24g](7) 1-benzyl-N 6 , N 6 -dimethyl-N 4- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine [24 g]

상기 [23p]와 dimethylamine으로 하얀색의 고체상 화합물 24g를 얻었다.24g of a white solid compound was obtained using [23p] and dimethylamine.

Yield: 87.34%; 1H NMR (400MHz, DMSO-d6) δ 1.51 (d, J = 7.0Hz, 3H), 3.03 (s, 6H), 5.28-5.35 (m, 3H), 7.19-7.31 (m, 8H), 7.40 (d, J = 7.4Hz, 2H), 7.94 (s, 1H), 8.21 (d, J = 7.3Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 23.0, 37.1, 49.5, 49.7, 95.0, 126.4, 126.9, 127.6, 128.0, 128.6, 128.8, 132.5, 138.4, 146.0, 155.6, 156.2, 161.5.
Yield: 87.34%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.51 (d, J = 7.0 Hz, 3H), 3.03 (s, 6H), 5.28-5.35 (m, 3H), 7.19-7.31 (m, 8H), 7.40 (d, J = 7.4 Hz, 2H), 7.94 (s, 1H), 8.21 (d, J = 7.3 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 23.0, 37.1, 49.5, 49.7, 95.0, 126.4, 126.9, 127.6, 128.0, 128.6, 128.8, 132.5, 138.4, 146.0, 155.6, 156.2, 161.5.

(8) 1-벤질-N6-(2-메톡시에틸)-N4-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4,6-디아민 [24h](8) 1-benzyl-N 6- (2-methoxyethyl) -N 4- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine [24h]

상기 [23p]와 2-methoxyethanamine으로 하얀색의 고체상 화합물 24h를 얻었다.The white solid compound 24h was obtained from [23p] and 2-methoxyethanamine.

Yield: 67.29%; 1H NMR (400MHz, DMSO-d6) δ 1.23 (S, 3H), 1.51 (d, J = 6.9Hz, 3H), 3.18-3.24 (m, 4H), 5.27-5.43 (m, 3H), 6.54 (s, 1H), 7.18-7.33 (m, 8H), 7.40 (d, J = 7.1Hz, 2H), 7.94 (s, 1H), 8.12 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.9, 22.0, 22.4, 25.2, 28.6, 29.0, 31.2, 35.2, 38.2, 49.0, 57.7, 70.7, 95.3, 126.0, 126.5, 127.1, 127.3, 128.1, 128.3, 132.1, 137.9, 145.1, 155.6, 161.2.
Yield: 67.29%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.23 (S, 3H), 1.51 (d, J = 6.9 Hz, 3H), 3.18-3.24 (m, 4H), 5.27-5.43 (m, 3H), 6.54 (s, 1H), 7.18-7.33 (m, 8H), 7.40 (d, J = 7.1 Hz, 2H), 7.94 (s, 1H), 8.12 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.9, 22.0, 22.4, 25.2, 28.6, 29.0, 31.2, 35.2, 38.2, 49.0, 57.7, 70.7, 95.3, 126.0, 126.5, 127.1, 127.3, 128.1, 128.3, 132.1, 137.9, 145.1, 155.6, 161.2.

(9) 1-벤질-N6-(3-에톡시프로필)-N4-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4,6-디아민 [24j](9) 1-benzyl-N 6- (3-ethoxypropyl) -N 4- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine [24j]

상기 [23p]와 3-ethoxypropan-1-amine으로 하얀색의 고체상 화합물 24j를 얻었다.The white solid compound 24j was obtained from [23p] and 3-ethoxypropan-1-amine.

Yield: 69.36%; 1H NMR (400MHz, DMSO-d6) δ 1.09 (t, J = 7.0Hz, 3H), 1.23 (s, 3H), 1.51 (d, J = 7.0Hz, 3H), 1.60-1.69 (m, 2H), 3.29 (t, J = 7.2Hz, 3H), 5.27-5.43 (m, 3H), 6.60 (s, 1H), 7.18-7.32 (m, 8H), 7.41 (d, J = 7.3Hz, 2H), 7.94 (s, 1H), 8.13 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.4, 15.6, 22.5, 22.9, 25.7, 29.1, 29.1, 29.9, 31.7, 35.8, 36.1, 38.8, 49.5, 65.7, 67.9, 68.4, 95.7, 126.5, 126.9, 127.6, 128.6, 128.8, 130.1, 132.6, 138.4, 145.6, 156.0, 161.9.
Yield: 69.36%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.09 (t, J = 7.0 Hz, 3H), 1.23 (s, 3H), 1.51 (d, J = 7.0 Hz, 3H), 1.60-1.69 (m, 2H ), 3.29 (t, J = 7.2 Hz, 3H), 5.27-5.43 (m, 3H), 6.60 (s, 1H), 7.18-7.32 (m, 8H), 7.41 (d, J = 7.3 Hz, 2H) , 7.94 (s, 1 H), 8.13 (s, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.4, 15.6, 22.5, 22.9, 25.7, 29.1, 29.1, 29.9, 31.7, 35.8, 36.1, 38.8, 49.5, 65.7, 67.9, 68.4, 95.7, 126.5, 126.9, 127.6, 128.6, 128.8, 130.1, 132.6, 138.4, 145.6, 156.0, 161.9.

(10) 1-벤질-N6-뷰틸-N4-(1-페닐에틸)-1H-피라졸로[3,4-d]피리미딘-4,6-디아민 [24i](10) 1-benzyl-N 6 -butyl-N 4- (1-phenylethyl) -1H-pyrazolo [3,4-d] pyrimidine-4,6-diamine [24i]

상기 [23q]와 n-butylamine으로 하얀색의 고체상 화합물 24d를 얻었다.The white solid compound 24d was obtained from [23q] and n-butylamine.

Yield: 58.56%; 1H NMR (400MHz, DMSO-d6) δ 0.86 (t, J = 7.0Hz, 3H), 1.28 (s, 2H), 1.42 (s, 2H), 1.51 (d, J = 7.0Hz, 3H), 3.24 (s, 2H), 5.24-5.27 (m, 3H), 6.60 (s, 1H), 7.18-7.40 (m, 9H), 7.93 (s, 1H), 8.12 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.7, 19.6, 22.3, 31.4, 48.9, 95.1, 125.9, 126.4, 127.0, 128.0, 128.2, 132.0, 137.9, 155.5, 161.3.
Yield: 58.56%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 0.86 (t, J = 7.0 Hz, 3H), 1.28 (s, 2H), 1.42 (s, 2H), 1.51 (d, J = 7.0 Hz, 3H), 3.24 (s, 2H), 5.24-5.27 (m, 3H), 6.60 (s, 1H), 7.18-7.40 (m, 9H), 7.93 (s, 1H), 8.12 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.7, 19.6, 22.3, 31.4, 48.9, 95.1, 125.9, 126.4, 127.0, 128.0, 128.2, 132.0, 137.9, 155.5, 161.3.

실시예 23. [25a] 내지 [25b]의 합성Example 23. Synthesis of [25a] to [25b]

하기 [반응식 25](alkyl halide, KOH, EtOH, reflux, 4h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [24a] 내지 [25b]를 합성하였다.The pyrazolopyrimidine derivative compounds [24a] to [25b] were synthesized according to Scheme 25 (alkyl halide, KOH, EtOH, reflux, 4h).

[반응식 25][Reaction Scheme 25]

Figure pat00357
Figure pat00357

[9b] [25a] ~ [25b][9b] [25a]-[25b]

[25a] 내지 [25b]에서 SR2는 각각 하기 [표 18]과 같다.SR 2 in [25a] to [25b] is as follows.

구분division SR2 SR 2 구분division SR2 SR 2 25a25a

Figure pat00358
Figure pat00358
25b25b
Figure pat00359
Figure pat00359

(1) 1-페닐-4-벤질티오-6-(메틸티오)피라졸로[3,4-d]피리미딘 [25a](1) 1-phenyl-4-benzylthio-6- (methylthio) pyrazolo [3,4-d] pyrimidine [25a]

상기 [9b] (50 mg, 0.182 mmol)와 KOH (1 eq, 10 mg), benzyl chloride (1,1 eq, 0.02 mL)를 ethanol (10 mL)에 넣고 4 시간 동안 reflux를 하였다. 4 시간 후에는 반응 혼합물의 용매는 감압기화를 시켜서 제거하였고, 남아있는 반응 혼합물은 flash chromatography (hexanes : EtOAc = 4 : 1)로 분리하여 옅은 노란색의 고체상 화합물 25a를 얻었다.[9b] (50 mg, 0.182 mmol), KOH (1 eq, 10 mg) and benzyl chloride (1,1 eq, 0.02 mL) were added to ethanol (10 mL) and refluxed for 4 hours. After 4 hours, the solvent of the reaction mixture was removed by evaporation under reduced pressure, and the remaining reaction mixture was separated by flash chromatography (hexanes: EtOAc = 4: 1) to obtain a pale yellow solid compound 25a.

Yield: 85%; 1H NMR (400MHz, DMSO-d6) δ 2.61 (s, 3H), 4.64 (s, 2H), 7.27 (quar, J = 6.6Hz, 2H), 7.31-7.38 (m, 3H), 7.47 (d, J = 7.5Hz, 2H), 7.57 (t, J = 7.6Hz, 3H), 8.14 (d, J = 8.6Hz, 2H), 8.44 (s, 1H).
Yield: 85%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.61 (s, 3H), 4.64 (s, 2H), 7.27 (quar, J = 6.6 Hz, 2H), 7.31-7.38 (m, 3H), 7.47 (d , J = 7.5 Hz, 2H), 7.57 (t, J = 7.6 Hz, 3H), 8.14 (d, J = 8.6 Hz, 2H), 8.44 (s, 1H).

(2) 1-페닐-4-알릴티오-6-(메틸티오)피라졸로[3,4-d]피리미딘 [25b](2) 1-phenyl-4-allylthio-6- (methylthio) pyrazolo [3,4-d] pyrimidine [25b]

상기 [9b] (50 mg, 0.182 mmol)와 allyll iodide를 이용하여 옅은 노란색의 고체상 화합물 25b를 얻었다.Light yellow solid compound 25b was obtained using [9b] (50 mg, 0.182 mmol) and allyll iodide.

Yield: 55%; 1H NMR (400MHz, CDCl3) δ 2.64 (s, 3H), 4.03 (dd, J = 0.7Hz, 6.9Hz, 2H), 5.20 (d, J = 10.0Hz, 1H), 5.38 (dd, J = 1.1Hz, 16.9Hz, 1H), 5.94-6.04 (m, 1H), 7.31 (t, J = 7.8Hz, 1H), 7.50 (t, J = 7.7Hz, 2H), 8.08 (s, 1H), 8.22 (dd, J = 0.8Hz, 7.8Hz, 2H); 13C NMR (100MHz, CDCl3) δ 14.4, 31.6, 110.6, 118.7, 120.9, 126.4, 129.0, 132.6, 133.0, 138.8, 151.7, 164.1, 169.6.
Yield: 55%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.64 (s, 3H), 4.03 (dd, J = 0.7 Hz, 6.9 Hz, 2H), 5.20 (d, J = 10.0 Hz, 1H), 5.38 (dd, J = 1.1Hz, 16.9Hz, 1H), 5.94-6.04 (m, 1H), 7.31 (t, J = 7.8Hz, 1H), 7.50 (t, J = 7.7Hz, 2H), 8.08 (s, 1H), 8.22 (dd, J = 0.8 Hz, 7.8 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.4, 31.6, 110.6, 118.7, 120.9, 126.4, 129.0, 132.6, 133.0, 138.8, 151.7, 164.1, 169.6.

실시예 24. [26a] 내지 [26b]의 합성Example 24. Synthesis of [26a] to [26b]

하기 [반응식 26](chloromethyl pivalate, K2CO3, THF, rt, 2h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [26a] 내지 [26b]를 합성하였다.Pyrazolopyrimidine derivative compounds [26a] to [26b] were synthesized by the following Reaction Scheme 26 (chloromethyl pivalate, K 2 CO 3 , THF, rt, 2h).

[반응식 26][Reaction Scheme 26]

Figure pat00360
Figure pat00360

[4], [10a] [26a] ~ [26b]    [4], [10a] [26a]-[26b]

[26a] 내지 [26b]에서 R2는 각각 하기 [표 19]와 같다.In [26a] to [26b], each of R 2 is shown in Table 19 below.

구분division R2 R 2 구분division R2 R 2 26a26a

Figure pat00361
Figure pat00361
26b26b
Figure pat00362
Figure pat00362

(1) (4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘-1-일)메틸피발레이트 [26a](1) (4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidin-1-yl) methylpivalate [26a]

상기 [4] (50 mg, 0.249 mmol)와 chloromethyl pivalate (1.2 eq, 0.04 mL), K2CO3 (1.2 eq, 41 mg)을 THF (7 mL)에 넣고 상온에서 48 시간 동안 교반하였다. 그 후 용매는 감압기화시키고, flash chromatography (hexanes : EtOAc = 4 : 1)로 분리하면 하얀색의 고체상 화합물 26a를 얻었다.[4] (50 mg, 0.249 mmol), chloromethyl pivalate (1.2 eq, 0.04 mL) and K 2 CO 3 (1.2 eq, 41 mg) were added to THF (7 mL) and stirred at room temperature for 48 hours. The solvent was then evaporated under reduced pressure and separated by flash chromatography (hexanes: EtOAc = 4: 1) to obtain a white solid compound 26a.

Yield: 26%; 1H NMR (400MHz, CDCl3) δ 1.18 (s, 9H), 2.64 (s, 3H), 6.35 (s, 2H), 8.08 (s, 1H); 13C NMR (100MHz, CDCl3) δ 14.6, 26.9, 38.9, 68.3, 110.8, 134.3, 154.1, 155.0, 171.4, 177.2.
Yield: 26%; 1 H NMR (400 MHz, CDCl 3 ) δ 1.18 (s, 9H), 2.64 (s, 3H), 6.35 (s, 2H), 8.08 (s, 1H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.6, 26.9, 38.9, 68.3, 110.8, 134.3, 154.1, 155.0, 171.4, 177.2.

(2) (4-메톡시-(메틸티오)피라졸로[3,4-d]피리미딘-1-일)메틸피발레이트 [26b](2) (4-methoxy- (methylthio) pyrazolo [3,4-d] pyrimidin-1-yl) methylpivalate [26b]

상기 [10a]와 chloromethyl pivalate으로 하얀색 고체상 화합물 26b를 얻었다.[10a] and chloromethyl pivalate to obtain a white solid compound 26b.

Yield: 51%; 1H NMR (400MHz, CD3OD-d4) δ 1.15 (s, 9H), 2.62 (s, 3H), 4.13 (s, 3H), 6.31 (s, 2H), 8.05 (s, 1H); 13C NMR (100MHz, CD3OD-d4) δ 12.9, 25.8, 38.4, 53.6, 68.0, 99.9, 133.2, 156.2, 156.4, 162.9, 171.3, 177.2.
Yield: 51%; 1 H NMR (400 MHz, CD 3 OD-d 4 ) δ 1.15 (s, 9H), 2.62 (s, 3H), 4.13 (s, 3H), 6.31 (s, 2H), 8.05 (s, 1H); 13 C NMR (100 MHz, CD 3 OD-d 4 ) δ 12.9, 25.8, 38.4, 53.6, 68.0, 99.9, 133.2, 156.2, 156.4, 162.9, 171.3, 177.2.

실시예 25. [27a] 내지 [27i]의 합성Example 25. Synthesis of [27a] to [27i]

하기 [반응식 27]((i) R2N, 1,4-dioxane, reflux, 8h, (ⅱ) p-TsOH, MeOH, rt, 24h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [27a] 내지 [27b]를 합성하였다.The pyrazolopyrimidine derivative compounds according to the present invention [27a] by the following Reaction Scheme 27 ((i) R 2 N, 1,4-dioxane, reflux, 8h, (ii) p-TsOH, MeOH, rt, 24h) ] To [27b] were synthesized.

[반응식 27][Reaction Scheme 27]

Figure pat00363
Figure pat00363

[5c] [27a] ~ [27i]     [5c] [27a] to [27i]

[27a] 내지 [27i]에서 NR2는 각각 하기 [표 20]과 같다.In [27a] to [27i], NR 2 is shown in Table 20 below, respectively.

구분division NR2 NR 2 구분division NR2 NR 2 27a27a

Figure pat00364
Figure pat00364
27f27f CH3OCH 3 O 27b27b
Figure pat00365
Figure pat00365
 27g27g
Figure pat00366
Figure pat00366
 27c27c
Figure pat00367
Figure pat00367
 27h27h
Figure pat00368
Figure pat00368
 27d27d
Figure pat00369
Figure pat00369
 27i27i
Figure pat00370
Figure pat00370
 27e27e
Figure pat00371
Figure pat00371

(1) 1-(1-하이드록시에틸)-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [27a](1) 1- (1-hydroxyethyl) -4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [27a]

상기 [5c] (57 mg, 0.178 mmol)과 benzylamine을 1,4-dioxane (7 mL)에 넣은 후 8 시간 동안 reflux를 하였다. 그 후 용매를 감압증류하여 얻게 된 반응 혼합물을 EtOAc/H2O로 희석한 후 유기층만 따로 분리하고, 분리된 유기층은 무수 MgSO4로 수분을 제거하고 감압증류 하여 무색의 액체상 화합물을 얻었다. 이 화합물을 p-toluenesulfonic acid monohydrate (1 eq)와 함께 methanol (7 mL)에 넣고 24 시간 동안 상온에서 교반하였다. 그 후 1M NaOH 수용액으로 pH 7~8 사이로 조절한 후 감압증류한 후 EtOAc/H2O로 희석시킨 후 유기층만 따로 분리하였다. 분리된 유기층은 무수 MgSO4로 수분을 제거하고 감압증류 하고, 이렇게 얻게 된 반응 혼합물을 flash chromatography (hexanes : EtOAc = 1 : 1)로 분리하여 하얀색 고체상 화합물 27a를 얻었다.[5c] (57 mg, 0.178 mmol) and benzylamine were added to 1,4-dioxane (7 mL), followed by reflux for 8 hours. Thereafter, the reaction mixture obtained by distillation of the solvent under reduced pressure was diluted with EtOAc / H 2 O, and then the organic layer was separated separately. The separated organic layer was distilled under reduced pressure with anhydrous MgSO 4 to obtain a colorless liquid compound. The compound was added to methanol (7 mL) with p-toluenesulfonic acid monohydrate (1 eq) and stirred at room temperature for 24 hours. Thereafter, the mixture was adjusted to pH 7-8 with 1M aqueous NaOH solution, distilled under reduced pressure, diluted with EtOAc / H 2 O, and only an organic layer was separated. The separated organic layer was dried with anhydrous MgSO 4 , distilled under reduced pressure, and the reaction mixture was separated by flash chromatography (hexanes: EtOAc = 1: 1) to obtain a white solid compound 27a.

Yield: 51%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 3.78 (quar, J = 5.8Hz, 2H), 4.26 (t, J = 6.0Hz, 2H), 4.71 (d, J = 5.8Hz, 2H), 4.83 (t, J = 5.6Hz, 1H), 7.23-7.27 (m, 1H), 7.31-7.39 (m, 4H), 8.04 (s, 1H), 8.81 (t, J = 5.7Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 43.7, 49.3, 59.6, 98.6, 127.4, 127.9, 128.8, 132.1, 139.6, 154.1, 155.7, 168.5.
Yield: 51%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 3.78 (quar, J = 5.8 Hz, 2H), 4.26 (t, J = 6.0 Hz, 2H), 4.71 (d, J = 5.8 Hz, 2H), 4.83 (t, J = 5.6 Hz, 1H), 7.23-7.27 (m, 1H), 7.31-7.39 (m, 4H), 8.04 (s, 1H), 8.81 (t, J = 5.7 Hz , 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 43.7, 49.3, 59.6, 98.6, 127.4, 127.9, 128.8, 132.1, 139.6, 154.1, 155.7, 168.5.

(2) 1-(1-하이드록시에틸)-4-(4-플루오로벤질)벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [27b](2) 1- (1-hydroxyethyl) -4- (4-fluorobenzyl) benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [27b]

상기 [5c]와 4-fluorobenzylamine으로 하얀색 고체상 화합물 27b를 얻었다.[5c] and 4-fluorobenzylamine gave white solid compound 27b.

Yield: 41%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 3.78 (t, J = 5.9Hz, 2H), 4.25 (t, J = 6.0Hz, 2H), 4.69 (d, J = 5.6Hz, 2H), 4.83 (br s, 1H), 7.16 (t, J = 8.9Hz, 2H), 7.39 (quar, J = 4.7Hz, 2H), 8.03 (s, 1H), 8.82 (t, J = 5.6Hz, 1H).
Yield: 41%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 3.78 (t, J = 5.9 Hz, 2H), 4.25 (t, J = 6.0 Hz, 2H), 4.69 (d, J = 5.6 Hz, 2H), 4.83 (br s, 1H), 7.16 (t, J = 8.9 Hz, 2H), 7.39 (quar, J = 4.7 Hz, 2H), 8.03 (s, 1H), 8.82 (t, J = 5.6 Hz, 1H).

(3) 1-(1-하이드록시에틸)-4-알릴아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [27d](3) 1- (1-hydroxyethyl) -4-allylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [27d]

상기 [5c]와 allylamine으로 하얀색 고체상 화합물 27c를 얻었다.The white solid compound 27c was obtained from [5c] and allylamine.

Yield: 72%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 3.78 (quar, J = 5.6Hz, 2H), 4.13 (t, J = 5.5Hz, 2H), 4.25 (t, J = 6.1Hz, 2H), 4.84 (t, J = 5.2Hz, 1H), 5.13 (dd, J = 1.5Hz, 10.3Hz, 1H), 5.22 (dd, J = 1.6Hz, 17.2Hz, 1H), 5.90-6.00 (m, 1H), 8.03 (s, 1H), 8.47 (t, J = 5.4Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 14.0, 42.6, 49.3, 59.6, 98.6, 116.3, 132.1, 135.4, 154.1, 155.6, 168.5.
Yield: 72%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 3.78 (quar, J = 5.6 Hz, 2H), 4.13 (t, J = 5.5 Hz, 2H), 4.25 (t, J = 6.1 Hz, 2H), 4.84 (t, J = 5.2 Hz, 1H), 5.13 (dd, J = 1.5 Hz, 10.3 Hz, 1H), 5.22 (dd, J = 1.6 Hz, 17.2 Hz, 1H), 5.90-6.00 (m, 1 H), 8.03 (s, 1 H), 8.47 (t, J = 5.4 Hz, 1 H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.0, 42.6, 49.3, 59.6, 98.6, 116.3, 132.1, 135.4, 154.1, 155.6, 168.5.

(4) 1-(1-하이드록시에틸)-4-(3-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [27d](4) 1- (1-hydroxyethyl) -4- (3-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [27d]

상기 [5c]와 3-methoxybenzylamine으로 하얀색 고체상 화합물 27d를 얻었다.A white solid compound 27d was obtained from [5c] and 3-methoxybenzylamine.

Yield: 76%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 3.73 (s, 3H), 3.78 (quar, J = 5.6Hz, 2H), 4.26 (t, J = 5.9Hz, 2H), 4.68 (d, J = 5.7Hz, 2H), 4.83 (t, J = 5.2Hz, 1H), 6.83 (d, J = 7.8Hz, 1H), 6.92 (d, J = 8.3Hz, 2H), 7.25 (t, J = 7.8Hz, 1H), 8.04 (s, 1H), 8.79 (t, J = 5.6Hz, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.4, 43.1, 48.7, 54.8, 59.1, 98.0, 112.1, 113.2, 119.5, 129.3, 131.5, 140.7, 155.1, 159.2, 167.9.
Yield: 76%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 3.73 (s, 3H), 3.78 (quar, J = 5.6 Hz, 2H), 4.26 (t, J = 5.9 Hz, 2H), 4.68 (d, J = 5.7 Hz, 2H), 4.83 (t, J = 5.2 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.92 (d, J = 8.3 Hz, 2H), 7.25 ( t, J = 7.8 Hz, 1H), 8.04 (s, 1H), 8.79 (t, J = 5.6 Hz, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.4, 43.1, 48.7, 54.8, 59.1, 98.0, 112.1, 113.2, 119.5, 129.3, 131.5, 140.7, 155.1, 159.2, 167.9.

(5) 1-(1-하이드록시에틸)-4-(4-메톡시벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [27e](5) 1- (1-hydroxyethyl) -4- (4-methoxybenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [27e]

상기 [5c]와 4-methoxybenzylamine으로 하얀색 고체상 화합물 27e를 얻었다.The white solid compound 27e was obtained from [5c] and 4-methoxybenzylamine.

Yield: 72%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 3.72 (s, 3H), 3.77 (br s, 2H), 4.25 (t, J = 6.1Hz, 2H), 4.63 (d, J = 5.7Hz, 2H), 4.83 (br s, 1H), 6.90 (dt, J = 2.4Hz, 9.3Hz, 2H), 7.28 (d, J = 8.6Hz, 2H), 8.03 (s, 1H), 8.74 (t, J = 5.6Hz, 1H); 13C NMR (400MHz, DMSO-d6) δ 14.0, 43.2, 49.3, 55.5, 59.6, 98.6, 114.2, 129.3, 131.5, 132.1, 154.1, 155.6, 158.8, 168.5.
Yield: 72%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 3.72 (s, 3H), 3.77 (br s, 2H), 4.25 (t, J = 6.1 Hz, 2H), 4.63 (d, J = 5.7 Hz, 2H), 4.83 (br s, 1H), 6.90 (dt, J = 2.4 Hz, 9.3 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 8.03 (s, 1H), 8.74 (t, J = 5.6 Hz, 1H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 14.0, 43.2, 49.3, 55.5, 59.6, 98.6, 114.2, 129.3, 131.5, 132.1, 154.1, 155.6, 158.8, 168.5.

(6) 2-(4-메톡시-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에탄올 [27f](6) 2- (4-methoxy-6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethanol [27f]

상기 [5c]와 sodium methoxide으로 하얀색 고체상 화합물 27f를 얻었다.[5c] and sodium methoxide afforded a white solid compound 27f.

Yield: 32%; 1H NMR (400MHz, DMSO-d6) δ 2.59 (s, 3H), 3.83 (quar, J = 5.8Hz, 2H), 4.07 (s, 3H), 4.36 (t, J = 5.8Hz, 2H), 4.85 (t, J = 5.6Hz, 1H), 8.11 (s, 1H); 13C NMR (400MHz, DMSO-d6) δ 0.56, 14.2, 49.8, 54.7, 59.5, 99.7, 131.6, 155.8, 162.8, 168.8.
Yield: 32%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.59 (s, 3H), 3.83 (quar, J = 5.8 Hz, 2H), 4.07 (s, 3H), 4.36 (t, J = 5.8 Hz, 2H), 4.85 (t, J = 5.6 Hz, 1 H), 8.11 (s, 1 H); 13 C NMR (400 MHz, DMSO-d 6 ) δ 0.56, 14.2, 49.8, 54.7, 59.5, 99.7, 131.6, 155.8, 162.8, 168.8.

(7) 2-(4-(2-메틸벤질아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에탄올 [27g](7) 2- (4- (2-methylbenzylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethanol [27 g]

상기 [5c]와 2-methylbenzylamine으로 하얀색 고체상 화합물 27g를 얻었다.27g of a white solid compound was obtained from [5c] and 2-methylbenzylamine.

Yield: 67.77%; 1H NMR (400MHz, DMSO-d6) δ 1.24 (d, J = 5.8Hz, 3H), 2.47 (s, 3H), 3.82 (t, J = 5.5Hz, 2H), 4.30 (t, J = 5.9Hz, 2H), 4.81-4.86 (m, 2H), 7.72 (s, 2H), 8.02 (s, 2H), 9.19 (s, 1H), 9.85 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.8, 22.3, 49.5, 59.5, 69.0, 96.9, 125.9, 128.5, 131.7, 132.4, 154.3, 155.1, 156.4, 156.8, 160.0, 168.2.
Yield: 67.77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.24 (d, J = 5.8 Hz, 3H), 2.47 (s, 3H), 3.82 (t, J = 5.5 Hz, 2H), 4.30 (t, J = 5.9 Hz, 2H), 4.81-4.86 (m, 2H), 7.72 (s, 2H), 8.02 (s, 2H), 9.19 (s, 1H), 9.85 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.8, 22.3, 49.5, 59.5, 69.0, 96.9, 125.9, 128.5, 131.7, 132.4, 154.3, 155.1, 156.4, 156.8, 160.0, 168.2.

(8) 2-(4-(2-클로로벤질아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에탄올 [27h](8) 2- (4- (2-chlorobenzylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethanol [27h]

상기 [5c]와 2-chlorobenzylamine으로 하얀색 고체상 화합물 27h를 얻었다.The white solid compound 27h was obtained from [5c] and 2-chlorobenzylamine.

Yield: 71.29%; 1H NMR (400MHz, DMSO-d6) δ 2.51 (s, 3H), 3.78-3.83 (m, 2H), 4.30 (t, J = 5.9Hz, 2H), 4.82-4.87 (m, 2H), 7.72 (s, 2H), 8.01 (s, 2H), 9.22 (s, 1H), 9.84 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.2, 21.8, 48.8, 58.9, 59.0, 68.0, 68.4, 96.3, 131.1, 131.8, 154.5, 155.8, 167.6.
Yield: 71.29%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.51 (s, 3H), 3.78-3.83 (m, 2H), 4.30 (t, J = 5.9 Hz, 2H), 4.82-4.87 (m, 2H), 7.72 (s, 2H), 8.01 (s, 2H), 9.22 (s, 1H), 9.84 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.2, 21.8, 48.8, 58.9, 59.0, 68.0, 68.4, 96.3, 131.1, 131.8, 154.5, 155.8, 167.6.

(9) 2-(4-(2-메톡시벤질아미노)-6-(메틸티오)-1H-피라졸로[3,4-d]피리미딘-1-일)에탄올 [27i](9) 2- (4- (2-methoxybenzylamino) -6- (methylthio) -1H-pyrazolo [3,4-d] pyrimidin-1-yl) ethanol [27i]

상기 [5c]와 2-methoxybenzylamine으로 하얀색 고체상 화합물 27i를 얻었다.A white solid compound 27i was obtained from [5c] and 2-methoxybenzylamine.

Yield: 69.47%; 1H NMR (400MHz, DMSO-d6) δ 1.24 (S, 3H), 2.51 (s, 3H), 3.81 (s, 2H), 4.30 (d, J = 4.5Hz, 2H), 4.84-4.88 (m, 2H), 7.71 (s, 2H), 8.04 (s, 2H), 9.27 (s, 1H), 9.83 (s, 1H); 13C NMR (100MHz, DMSO-d6) δ 13.2, 21.8, 48.8, 58.9, 59.0, 68.0, 68.4, 96.3, 131.1, 131.8, 154.5, 155.8, 167.6.
Yield: 69.47%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.24 (S, 3H), 2.51 (s, 3H), 3.81 (s, 2H), 4.30 (d, J = 4.5 Hz, 2H), 4.84-4.88 (m , 2H), 7.71 (s, 2H), 8.04 (s, 2H), 9.27 (s, 1H), 9.83 (s, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 13.2, 21.8, 48.8, 58.9, 59.0, 68.0, 68.4, 96.3, 131.1, 131.8, 154.5, 155.8, 167.6.

실시예 26. [Ⅵ] 내지 [Ⅶ]의 합성Example 26. Synthesis of [VI] to [VII]

하기 [반응식 28]((i) Benzaldehyde, LDA, N2, THF, -78 ℃, 2h; (ⅱ) CrO3, acetone, N2, 0 ℃, 3h; (ⅲ) Benzoyl chloride, LDA, N2, THF, -78 ℃, 6h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [Ⅵ] 내지 [Ⅶ]를 합성하였다.(Scheme 28) ((i) Benzaldehyde, LDA, N 2 , THF, -78 ° C, 2h; (ii) CrO 3 , acetone, N 2 , 0 ° C, 3h; (iii) Benzoyl chloride, LDA, N 2 , THF, -78 ° C, 6h) to synthesize pyrazolopyrimidine derivative compounds [VI] to [VII] according to the present invention.

[반응식 28][Reaction Scheme 28]

Figure pat00372
Figure pat00372

[3] [Ⅵ] [Ⅶ]
[3] [Ⅵ] [Ⅶ]

(1) 1-[(4,6-다이클로로-2-(메틸티오)피리미딘)-5-일]-벤질알콜 [Ⅵ](1) 1-[(4,6-dichloro-2- (methylthio) pyrimidin) -5-yl] -benzyl alcohol [VI]

상기 [3] (100 mg, 0.513 mmol)이 녹아있는 THF (5 mL)를 N2 (g)하에 -78 ℃로 냉각시킨 다음 lithium diisopropylamide (1.8 eq, 0.5 mL)을 천천히 넣어주었다. 20 분간 교반한 후, benzaldehyde (2 eq, 0.1 mL)를 천천히 넣어주었다. 그리고 2 시간을 교반한 후, 상온으로 온도를 올리고 포화 NH4Cl 수용액 (5 mL)으로 여분의 lithium diisopropylamide를 제거하였다. 그리고 EtOAc (5 mL)을 가하여 30 분을 교반한 후, 유기층만을 분리하여 무수 MgSO4로 수분을 제거하였다. 분리된 유기층은 감압증류하고 생성된 혼합물은 flash chromatography (hexanes : EtOAc = 5 : 1)로 분리하여 갈색의 액체상 화합물 [Ⅵ]를 얻었다.THF (5 mL) in which [3] (100 mg, 0.513 mmol) was dissolved was cooled to −78 ° C. under N 2 (g) , and lithium diisopropylamide (1.8 eq, 0.5 mL) was slowly added thereto. After stirring for 20 minutes, benzaldehyde (2 eq, 0.1 mL) was added slowly. After stirring for 2 hours, the temperature was raised to room temperature and excess lithium diisopropylamide was removed with a saturated NH 4 Cl aqueous solution (5 mL). Then, EtOAc (5 mL) was added, the mixture was stirred for 30 minutes, and only the organic layer was separated, and water was removed with anhydrous MgSO 4 . The separated organic layer was distilled under reduced pressure and the resulting mixture was separated by flash chromatography (hexanes: EtOAc = 5: 1) to obtain a brown liquid compound [VI].

Yield: 32%; 1H NMR (400MHz, CDCl3) δ 2.57 (s, 3H), 3.19 (d, J = 6.7Hz, 1H), 6.49 (d, J = 5.4Hz, 1H), 7.34 (m, 5H); 13C NMR (100MHz, CDCl3) δ 14.4, 70.6, 125.2, 126.8, 127.8, 128.5, 139.8, 161.0, 172.4.
Yield: 32%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.57 (s, 3H), 3.19 (d, J = 6.7 Hz, 1H), 6.49 (d, J = 5.4 Hz, 1H), 7.34 (m, 5H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.4, 70.6, 125.2, 126.8, 127.8, 128.5, 139.8, 161.0, 172.4.

(2) 1-[(4,6-다이클로로-2-(메틸티오)피리미딘)-5-일]-페닐케톤 [Ⅶ](2) 1-[(4,6-dichloro-2- (methylthio) pyrimidin) -5-yl] -phenylketone [Ⅶ]

상기 [3] (100 mg, 0.513 mmol)을 N2 (g)하에서 chromic oxide(V) (3 eq, 50 mg)을 aetone (5 mL)에 녹인 후 0 ℃로 냉각시켰다. 냉각이 되어 있는 반응 용기에 acetone (2 mL)에 녹인 상기 [Ⅵ] (50 mg, 0.166 mmol)을 넣어주고 3 시간 동안 교반하였다. 과량의 chromic oxide(V)은 포화 NaHCO3 수용액을 가하면 침전되는데, 이 침전물은 여과하여 제거하고, 여과액에 Et2O를 가하여 추출하였다. 유기층만을 분리하여 무수 MgSO4로 수분을 제거하고, 감압증류 시켜서 옅은 노란색의 고체상 화합물 [Ⅶ]를 얻었다.[3] (100 mg, 0.513 mmol) was dissolved in chromic oxide (V) (3 eq, 50 mg) in aetone (5 mL) under N 2 (g) and cooled to 0 ° C. [VI] (50 mg, 0.166 mmol) dissolved in acetone (2 mL) was added to a cooled reaction vessel, followed by stirring for 3 hours. Excess chromic oxide (V) was precipitated by addition of saturated aqueous NaHCO 3 solution. The precipitate was filtered off and extracted by adding Et 2 O to the filtrate. Only the organic layer was separated, the water was removed with anhydrous MgSO 4 , and distilled under reduced pressure to obtain a pale yellow solid compound [VIII].

Yield: 82%; 1H NMR (400MHz, CDCl3) δ 2.62 (s, 3H), 7.53 (t, J = 7.7Hz, 2H), 7.68 (quar, J = 7.7Hz, 1H), 7.85 (d, J = 7.9Hz, 2H); 13C NMR (100MHz, CDCl3) δ 14.5, 125.7, 129.2, 129.5, 134.9, 157.9, 174.3, 189.3.
Yield: 82%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.62 (s, 3H), 7.53 (t, J = 7.7 Hz, 2H), 7.68 (quar, J = 7.7 Hz, 1H), 7.85 (d, J = 7.9 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.5, 125.7, 129.2, 129.5, 134.9, 157.9, 174.3, 189.3.

실시예 27. [30a] 내지 [30c]의 합성Example 27. Synthesis of [30a] to [30c]

하기 [반응식 29](R1-N2H4, Hunig base, THF, rt, 24h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [30a] 내지 [30c]를 합성하였다.The pyrazolopyrimidine derivative compounds [30a] to [30c] were synthesized according to the following Reaction Scheme 29 (R 1 -N 2 H 4 , Hunig base, THF, rt, 24h).

[반응식 29][Reaction Scheme 29]

Figure pat00373
Figure pat00373

[Ⅶ] [30a] ~ [30c]       [Ⅶ] [30a] ~ [30c]

[30a] 내지 [30c]에서 R1은 각각 하기 [표 21]과 같다.In [30a] to [30c], R 1 is as shown in Table 21 below.

구분division R1 R 1 구분division R1 R 1 30a30a

Figure pat00374
Figure pat00374
30c30c
Figure pat00375
Figure pat00375
 30b30b
Figure pat00376
Figure pat00376

(1) 1-페닐-3-페닐-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [30a](1) 1-phenyl-3-phenyl-4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [30a]

상기 [Ⅶ] (200 mg, 0.668 mmol)과 Hunig base (1 eg, 0.02 mL)을 THF에 넣고 교반 중에 phenylhydrazine을 천천히 가하면서, 모두 가한 후에 24 시간 동안 상온에서 교반한 후 용매를 감압증류 하여 감소시키고 EtOAc/H2O로 희석시킨 후 유기층만 따로 분리하였다. 분리된 유기층은 무수 MgSO4로 수분을 제거하고 여기서 얻게 된 반응 혼합물을 flash chromatography (hexanes : EtOAc = 8 : 1)로 하여 분리하여 옅은 노란색의 고체상 화합물 30a을 얻었다.Add [iii] (200 mg, 0.668 mmol) and Hunig base (1 eg, 0.02 mL) to THF, slowly add phenylhydrazine while stirring, and after adding all, stir at room temperature for 24 hours, and then reduce the solvent by distillation under reduced pressure. And diluted with EtOAc / H 2 O, only the organic layer was separated. The separated organic layer was dried with anhydrous MgSO 4 , and the obtained reaction mixture was separated by flash chromatography (hexanes: EtOAc = 8: 1) to obtain a pale yellow solid compound 30a.

Yield: 72%; 1H NMR (400MHz, DMSO-d6) δ 2.59 (s, 3H), 7.40-7.68 (m, 10H); 13C NMR (100MHz, DMSO-d6) δ 14.4, 109.2, 126.6, 127.6, 128.7, 129.5, 129.8, 130.5, 131.6, 138.9, 139.4, 156.2, 159.7, 168.7.
Yield: 72%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.59 (s, 3H), 7.40-7.68 (m, 10H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.4, 109.2, 126.6, 127.6, 128.7, 129.5, 129.8, 130.5, 131.6, 138.9, 139.4, 156.2, 159.7, 168.7.

(2) 1-벤질-3-페닐-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [30b](2) 1-benzyl-3-phenyl-4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [30b]

상기 [Ⅶ]와 benzylhydrazine dihydrochloride으로 옅은 노란색의 고체상 화합물 30b를 얻었다.[B] and benzylhydrazine dihydrochloride were obtained as a pale yellow solid compound 30b.

Yield: 61%; 1H NMR (400MHz, DMSO-d6) δ 2.63 (s, 3H), 5.64 (s, 2H), 7.28-7.36 (m, 5H), 7.48-7.50 (m, 3H), 7.71-7.73 (m, 2H); 13C NMR (100MHz, DMSO-d6) δ 14.4, 51.0, 107.9, 128.3, 128.4, 128.6, 129.1, 129.6, 130.6, 131.2, 136.6, 145.1, 153.9, 154.9, 169.4.
Yield: 61%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.63 (s, 3H), 5.64 (s, 2H), 7.28-7.36 (m, 5H), 7.48-7.50 (m, 3H), 7.71-7.73 (m, 2H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.4, 51.0, 107.9, 128.3, 128.4, 128.6, 129.1, 129.6, 130.6, 131.2, 136.6, 145.1, 153.9, 154.9, 169.4.

(3) 1-t-뷰틸-3-페닐-4-클로로-6-(메틸티오)피라졸로[3,4-d]피리미딘 [30c](3) 1-t-butyl-3-phenyl-4-chloro-6- (methylthio) pyrazolo [3,4-d] pyrimidine [30c]

상기 [Ⅶ]와 t-butylhydrazine hydrochloride으로 옅은 노란색의 고체상 화합물 30c를 얻었다.A pale yellow solid compound 30c was obtained from [K] and t-butylhydrazine hydrochloride.

Yield: 8%; 1H NMR (400MHz, CDCl3) δ 1.60 (s, 9H), 2.66 (s, 3H), 7.40 (d, J = 7.9Hz, 2H), 7.47-7.56 (m, 3H).
Yield: 8%; 1 H NMR (400 MHz, CDCl 3 ) δ 1.60 (s, 9H), 2.66 (s, 3H), 7.40 (d, J = 7.9 Hz, 2H), 7.47-7.56 (m, 3H).

실시예 28. [31a] 내지 [31k]의 합성Example 28. Synthesis of [31a] to [31k]

하기 [반응식 30](R2N, 1,4-dioxane, reflux, 8h)에 의해서 본 발명에 따른 피라졸로피리미딘 유도체 화합물 [31a] 내지 [31k]를 합성하였다.The pyrazolopyrimidine derivative compounds [31a] to [31k] were synthesized according to the following Reaction Scheme 30 (R 2 N, 1,4-dioxane, reflux, 8h).

[반응식 30][Reaction Scheme 30]

Figure pat00377
Figure pat00377

[30a] ~ [30c] [31a] ~ [31k]   [30a] to [30c] [31a] to [31k]

[31a] 내지 [31k]에서 R2는 각각 하기 [표 22]와 같다.R 2 in [31a] to [31k] is as shown in [Table 22], respectively.

구분division R1 R 1 구분division R1 R 1 31a31a

Figure pat00378
Figure pat00378
31g31 g
Figure pat00379
Figure pat00379
 31b31b
Figure pat00380
Figure pat00380
 31h31h
Figure pat00381
Figure pat00381
 31c31c
Figure pat00382
Figure pat00382
 31i31i
Figure pat00383
Figure pat00383
 31d31d
Figure pat00384
Figure pat00384
 31j31j
Figure pat00385
Figure pat00385
 31e31e
Figure pat00386
Figure pat00386
 31k31k
Figure pat00387
Figure pat00387
 31f31f
Figure pat00388
Figure pat00388

(1) 1-페닐-3-페닐-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31a](1) 1-phenyl-3-phenyl-4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31a]

상기 [30a](28 mg, 0.079 mmol)와 benzylamine (1.1 eq, 0.01 mL)을 1,4-dioxane에 넣고, 8시간동안 reflux 하였다. 그 후 용매는 감압증류를 하여 얻은 반응혼합물은 EA/H2O로 희석을 한 후 유기층만 따로 분리하였다. 분리된 유기층은 무수 MgSO4로 수분을 제거한 후, flash chromatography (MC : MeOH = 10 : 1)로 분리하여 옅은 갈색의 고체상 화합물 31a를 얻었다.[30a] (28 mg, 0.079 mmol) and benzylamine (1.1 eq, 0.01 mL) were added to 1,4-dioxane and refluxed for 8 hours. After that, the solvent was distilled under reduced pressure, and the reaction mixture was diluted with EA / H 2 O, and only the organic layer was separated. The separated organic layer was dried with anhydrous MgSO 4 , and then separated by flash chromatography (MC: MeOH = 10: 1) to give a pale brown solid compound 31a.

Yield: 95%; 1H NMR (400MHz, CDCl3) δ 2.62 (s, 3H), 4.69 (d, J = 5.3Hz, 2H), 5.29 (br s, 1H), 7.18 (d, J = 6.9Hz, 2H), 7.24-7.41 (m, 13H); 13C NMR (100MHz, CDCl3) δ 14.2, 44.6, 100.2, 125.3, 127.4, 127.4, 128.1, 128.2, 128.6, 128.8, 129.4, 129.5, 129.7, 130.7, 135.8, 137.8, 139.0, 156.7, 160.7, 161.9, 170.6.
Yield: 95%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.62 (s, 3H), 4.69 (d, J = 5.3 Hz, 2H), 5.29 (br s, 1H), 7.18 (d, J = 6.9 Hz, 2H), 7.24 -7.41 (m, 13 H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.2, 44.6, 100.2, 125.3, 127.4, 127.4, 128.1, 128.2, 128.6, 128.8, 129.4, 129.5, 129.7, 130.7, 135.8, 137.8, 139.0, 156.7, 160.7, 161.9, 170.6.

(2) 1-페닐-3-페닐-4-(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31b](2) 1-phenyl-3-phenyl-4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31b]

상기 [30a]와 1-hydroxyethylamine으로 하얀색의 고체상 화합물 31b를 얻었다.White solid compound 31b was obtained by using [30a] and 1-hydroxyethylamine.

Yield: 90%; 1H NMR (400MHz, DMSO-d6) δ 2.48 (s, 3H), 3.44 (s, 4H), 4.71 (br s, 1H), 5.85 (br s, 1H), 7.29-7.48 (m, 10H).
Yield: 90%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.48 (s, 3H), 3.44 (s, 4H), 4.71 (br s, 1H), 5.85 (br s, 1H), 7.29-7.48 (m, 10H) .

(3) 1-페닐-3-페닐-4-(4-플루오로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31c](3) 1-phenyl-3-phenyl-4- (4-fluorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31c]

상기 [30a]와 4-fluorobenzylamine으로 옅은 노란색의 고체상 화합물 31c를 얻었다.A pale yellow solid compound 31c was obtained from [30a] and 4-fluorobenzylamine.

Yield: 97%; 1H NMR (400MHz, DMSO-d6) δ 2.44 (s, 3H), 4.59 (d, J = 5.7Hz, 2H), 6.36 (t, J = 5.8Hz, 1H), 7.12 (t, J = 8.9Hz, 2H), 7.27-7.30 (m, 4H), 7.34-7.48 (m, 8H).
Yield: 97%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.44 (s, 3H), 4.59 (d, J = 5.7 Hz, 2H), 6.36 (t, J = 5.8 Hz, 1H), 7.12 (t, J = 8.9 Hz, 2H), 7.27-7.30 (m, 4H), 7.34-7.48 (m, 8H).

(4) 1-페닐-3-페닐-4-[2-(피페리딘-1-일)]에칠아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31d](4) 1-phenyl-3-phenyl-4- [2- (piperidin-1-yl)] ethylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31d]

상기 [30a]와 2-(piperidin-1-yl)ethylamine으로 옅은 노란색의 고체상 화합물 31d를 얻었다.A pale yellow solid compound 31d was obtained from [30a] and 2- (piperidin-1-yl) ethylamine.

Yield: 52%; 1H NMR (400MHz, DMSO-d6) δ 1.26 (br s, 6H), 2.15 (br s, 4H), 2.33 (t, J = 5.6Hz, 2H), 2.49 (s, 3H), 3.42-3.43 (m, 2H), 5.96 (s, 1H), 7.28-7.50 (m, 10H).
Yield: 52%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 1.26 (br s, 6H), 2.15 (br s, 4H), 2.33 (t, J = 5.6 Hz, 2H), 2.49 (s, 3H), 3.42-3.43 (m, 2H), 5.96 (s, 1H), 7.28-7.50 (m, 10H).

(5) 1-페닐-3-페닐-4-(2-페닐에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31e](5) 1-phenyl-3-phenyl-4- (2-phenylethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31e]

상기 [30a]와 2-phenylethylamine으로 옅은 노란색의 고체상 화합물 31e를 얻었다.A pale yellow solid compound 31e was obtained from [30a] and 2-phenylethylamine.

Yield: 90%; 1H NMR (400MHz, DMSO-d6) δ 2.50 (s, 3H), 2.78 (t, J = 6.7Hz, 2H), 3.63 (quar, J = 6.3Hz, 2H), 5.66 (t, J = 5.2Hz, 1H), 7.09 (d, J = 7.7Hz, 2H), 7.18-7.27 (m, 7H), 7.35-7.38 (m, 5H), 7.44-7.47 (m, 1H).
Yield: 90%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.50 (s, 3H), 2.78 (t, J = 6.7 Hz, 2H), 3.63 (quar, J = 6.3 Hz, 2H), 5.66 (t, J = 5.2 Hz, 1H), 7.09 (d, J = 7.7 Hz, 2H), 7.18-7.27 (m, 7H), 7.35-7.38 (m, 5H), 7.44-7.47 (m, 1H).

(6) 1-페닐-3-페닐-4-(피리딘-2-일)메틸아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31f](6) 1-phenyl-3-phenyl-4- (pyridin-2-yl) methylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31f]

상기 [30a]와 (pyridin-2-yl)methylamine으로 옅은 노란색의 고체상 화합물 31f를 얻었다.A pale yellow solid compound 31f was obtained from [30a] and (pyridin-2-yl) methylamine.

Yield: 99%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 4.67 (d, J = 4.2Hz, 2H), 7.06 (t, J = 4.2Hz, 1H), 7.26 (t, J = 6.1Hz, 1H), 7.36-7.41 (m, 6H), 7.47-7.57 (m, 6H), 7.75 (t, J = 6.9Hz, 1H), 8.31 (d, J = 4.7Hz, 1H).
Yield: 99%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 4.67 (d, J = 4.2 Hz, 2H), 7.06 (t, J = 4.2 Hz, 1H), 7.26 (t, J = 6.1 Hz, 1H), 7.36-7.41 (m, 6H), 7.47-7.57 (m, 6H), 7.75 (t, J = 6.9 Hz, 1H), 8.31 (d, J = 4.7 Hz, 1H).

(7) 1-페닐-3-페닐-4-알릴아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31g](7) 1-phenyl-3-phenyl-4-allylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31 g]

상기 [30a]와 allylamine으로 옅은 노란색의 고체상 화합물 31g를 얻었다.31 g of a pale yellow solid compound was obtained using [30a] and allylamine.

Yield: 98%; 1H NMR (400MHz, DMSO-d6) δ 2.47 (s, 3H), 4.03 (s, 2H), 4.99-5.04 (m, 2H), 5.79-5.88 (m, 2H), 7.28-7.30 (m, 2H), 7.36-7.49 (m, 8H).
Yield: 98%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.47 (s, 3H), 4.03 (s, 2H), 4.99-5.04 (m, 2H), 5.79-5.88 (m, 2H), 7.28-7.30 (m, 2H), 7.36-7.49 (m, 8H).

(8) 1-벤질-3-페닐-4-벤질아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31h](8) 1-benzyl-3-phenyl-4-benzylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31h]

상기 [30b]와 benzylamine으로 옅은 노란색의 고체상 화합물 31h를 얻었다.31h was obtained as a pale yellow solid compound using [30b] and benzylamine.

Yield: 78%; 1H NMR (400MHz, DMSO-d6) δ 2.46 (s, 3H), 4.68 (d, J = 5.7Hz, 2H), 5.49 (s, 2H), 6.98 (t, J = 5.6Hz, 1H), 7.08-7.39 (m, 9H), 7.42-7.51 (m, 4H), 7.65 (d, J = 7.8Hz, 2H); 13C NMR (100MHz, DMSO-d6) δ 14.1, 44.4, 50.2, 95.8, 127.2, 127.6, 128.0, 128.2, 128.6, 128.7, 129.0, 133.2, 137.5, 139.6, 144.4, 155.2, 156.0, 169.0.
Yield: 78%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.46 (s, 3H), 4.68 (d, J = 5.7 Hz, 2H), 5.49 (s, 2H), 6.98 (t, J = 5.6 Hz, 1H), 7.08-7.39 (m, 9H), 7.42-7.51 (m, 4H), 7.65 (d, J = 7.8 Hz, 2H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 14.1, 44.4, 50.2, 95.8, 127.2, 127.6, 128.0, 128.2, 128.6, 128.7, 129.0, 133.2, 137.5, 139.6, 144.4, 155.2, 156.0, 169.0.

(9) 1-벤질-3-페닐-4-(1-하이드록시에틸)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31i](9) 1-benzyl-3-phenyl-4- (1-hydroxyethyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31i]

상기 [30b]와 1-hydroxyethylamine으로 하얀색의 고체상 화합물 31i를 얻었다.White solid compound 31i was obtained from [30b] and 1-hydroxyethylamine.

Yield: 79%; 1H NMR (400MHz, CDCl3) δ 2.57 (s, 3H), 3.70 (dt, J = 4.6Hz, 34.4Hz, 4H), 5.53 (s, 2H), 5.79 (t, J = 5.1Hz, 1H), 7.22-7.31 (m, 3H), 7.37-7.48 (m, 5H), 7.62 (d, J = 7.0Hz, 2H); 13C NMR (100MHz, CDCl3) δ 14.2, 43.8, 50.6, 62.6, 96.2, 127.7, 128.2, 128.3, 128.5, 129.0, 129.3, 133.3, 136.7, 144.4, 154.8, 156.5, 169.6.
Yield: 79%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.57 (s, 3H), 3.70 (dt, J = 4.6 Hz, 34.4 Hz, 4H), 5.53 (s, 2H), 5.79 (t, J = 5.1 Hz, 1H) , 7.22-7.31 (m, 3H), 7.37-7.48 (m, 5H), 7.62 (d, J = 7.0 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.2, 43.8, 50.6, 62.6, 96.2, 127.7, 128.2, 128.3, 128.5, 129.0, 129.3, 133.3, 136.7, 144.4, 154.8, 156.5, 169.6.

(10) 1-벤질-3-페닐-4-(4-플루오로벤질)아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31j](10) 1-benzyl-3-phenyl-4- (4-fluorobenzyl) amino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31j]

상기 [30b]와 4-fluorobenzylamine으로 옅은 노란색의 고체상 화합물 31j를 얻었다.A pale yellow solid compound 31j was obtained from [30b] and 4-fluorobenzylamine.

Yield: 77%; 1H NMR (400MHz, DMSO-d6) δ 2.45 (s, 3H), 4.63 (d, J = 5.6Hz, 2H), 5.48 (s, 2H), 7.01-7.18 (m, 4H), 7.23-7.39 (m, 8H), 7.64 (d, J = 7.8Hz, 2H).
Yield: 77%; 1 H NMR (400 MHz, DMSO-d 6 ) δ 2.45 (s, 3H), 4.63 (d, J = 5.6 Hz, 2H), 5.48 (s, 2H), 7.01-7.18 (m, 4H), 7.23-7.39 (m, 8H), 7.64 (d, J = 7.8 Hz, 2H).

(11) 1-벤질-3-페닐-4-알릴아미노-6-(메틸티오)피라졸로[3,4-d]피리미딘 [31k](11) 1-benzyl-3-phenyl-4-allylamino-6- (methylthio) pyrazolo [3,4-d] pyrimidine [31k]

상기 [30b]와 allylamine으로 옅은 노란색의 고체상 화합물 31k를 얻었다.31k of pale yellow solid compound was obtained using [30b] and allylamine.

Yield: 69%; 1H NMR (400MHz, CDCl3) δ 2.59 (s, 3H), 4.19 (t, J = 5.4Hz, 2H), 5.10-5.12 (m, 1H), 5.15 (s, 1H), 5.38 (t, J = 5.1Hz, 1H), 5.54 (s, 2H), 5.84-5.94 (m, 1H), 7.22-7.31 (m, 3H), 7.38-7.51 (m, 5H), 7.64 (d, J = 7.9Hz, 2H); 13C NMR (100MHz, CDCl3) δ 14.3, 43.0, 50.6, 96.3, 116.3, 127.7, 128.2, 128.4, 128.5, 129.0, 129.3, 133.5, 133.9, 136.9, 144.2, 155.1, 155.7, 169.8.
Yield: 69%; 1 H NMR (400 MHz, CDCl 3 ) δ 2.59 (s, 3H), 4.19 (t, J = 5.4 Hz, 2H), 5.10-5.12 (m, 1H), 5.15 (s, 1H), 5.38 (t, J = 5.1 Hz, 1H), 5.54 (s, 2H), 5.84-5.94 (m, 1H), 7.22-7.31 (m, 3H), 7.38-7.51 (m, 5H), 7.64 (d, J = 7.9 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 14.3, 43.0, 50.6, 96.3, 116.3, 127.7, 128.2, 128.4, 128.5, 129.0, 129.3, 133.5, 133.9, 136.9, 144.2, 155.1, 155.7, 169.8.

실험예 1. Nitric oxide(NO) 정량Experimental Example 1. Determination of Nitric oxide (NO)

BV-2 세포를 96 well plate에 2×104 cells/well씩 넣고 배양한 후 lipopolysaccharide(LPS) (0.2 ㎍/mL)로 처리하여 활성을 유도하였다. 이때 적절 농도의 시험대상 화합물을 공동처리였다. 24 시간 후에 배양액에 존재하는 nitrite, 즉 NO 산화물질을 다음 Griess reaction 방법으로 정량하였다. 각 well에서 200 ㎕의 배양액을 취하여 새 96 well plate로 옮기고 100 ㎕의 Griess reagent (1% sulphanilamide, 0.1% naphthylethylenediamine dihydrochloride, 2.5% H3PO4)를 첨가한 후 상온에서 10 분간 반응시켰다. SpectraMax Plus microplate spectrophotometer (Molecular Devices)를 사용하여 540 ㎚ 파장에서 흡광도를 측정한다. NaNO2 에 대한 표준 곡선을 매번 작성하고, 이를 기준으로 Nitrite를 정량하였다.본 발명에 따른 피라졸로피리미딘 유도체 화합물의 NO 생성에 대한 %억제율 결과는 하기 [표 23] 내지 [표 30]에 나타내었다.BV-2 cells were incubated in 96 well plates at 2 × 10 4 cells / well and incubated with lipopolysaccharide (LPS) (0.2 ㎍ / mL) to induce activity. Appropriate concentration of the test subject compound was cotreated. After 24 hours, the nitrite, ie NO oxide, present in the culture was quantified by the following Griess reaction method. 200 μl of the culture solution was taken from each well, transferred to a new 96 well plate, and 100 μl of Griess reagent (1% sulphanilamide, 0.1% naphthylethylenediamine dihydrochloride, 2.5% H 3 PO 4 ) was added and allowed to react at room temperature for 10 minutes. Absorbance is measured at a wavelength of 540 nm using a SpectraMax Plus microplate spectrophotometer (Molecular Devices). NaNO 2 And a standard curve for Nitrite was quantified. The% inhibition rate results for NO production of the pyrazolopyrimidine derivative compounds according to the present invention are shown in the following Tables 23 to 30.

화합물compound NO (% of LPS)NO (% of LPS) 화합물compound NO (% of LPS)NO (% of LPS) 20 μM20 μM 30 μM30 μM 20 μM20 μM 30 μM30 μM 4
(KST004076)4
(KST004076) 19±4.119 ± 4.1 6i
(KKC080087)6i
(KKC080087) 48±1048 ± 10 5a
(KKC080055)5a
(KKC080055) 51±251 ± 2 6j
(KKC080062)6j
(KKC080062) 66±1066 ± 10 5b
(KKC080071)5b
(KKC080071) 63±863 ± 8 6k
(KKC080070)6k
(KKC080070) 16±1716 ± 17 5c
(KKC080164)5c
(KKC080164) 49±949 ± 9 6l
(KKC080041)6l
(KKC080041) 125±14125 ± 14 5d
(KKC080165)5d
(KKC080165) 48±448 ± 4 6m
(KKC080094)6m
(KKC080094) 97±697 ± 6 5e
(KKC080090)5e
(KKC080090) 50±750 ± 7 6n
(KKC080036)6n
(KKC080036) 114±9114 ± 9 5f
(KKC080053)5f
(KKC080053) 69±369 ± 3 6o
(KKC080035)6o
(KKC080035) 106±10106 ± 10 5g
(KKC080056)5g
(KKC080056) 15±1815 ± 18 6p
(KKC080039)6p
(KKC080039) 50±2350 ± 23 5h
(KKC080173)5h
(KKC080173) 9±42.29 ± 42.2 59.6359.63 6q
(KKC080042)6q
(KKC080042) 90±1590 ± 15 5i
(KKC080174)5i
(KKC080174) 54±2.754 ± 2.7 6r
(KKC080043)6r
(KKC080043) 64±364 ± 3 5j
(KKC080175)5j
(KKC080175) 5±49.75 ± 49.7 6s
(KKC080044)6s
(KKC080044) 85±1585 ± 15 5k
(KKC080188)5k
(KKC080188) 5±62.95 ± 62.9 6t
(KKC080046)6t
(KKC080046) 106±5106 ± 5 6a
(KST004077)6a
(KST004077) 35±4
(50 μM)35 ± 4
(50 [mu] M) 6u
(KKC080048)6u
(KKC080048) 87±887 ± 8 6b
(KKC080038)6b
(KKC080038) 100±4100 ± 4 6v
(KKC080102)6v
(KKC080102) 36±736 ± 7 6c
(KKC080045)6c
(KKC080045) 91±491 ± 4 6w
(KKC080287)6w
(KKC080287) 46±2.946 ± 2.9 6d
(KKC080040)6d
(KKC080040) 84±884 ± 8 6x
(KKC080288)6x
(KKC080288) 115±3.2115 ± 3.2 6e
(KKC080037)6e
(KKC080037) 83±983 ± 9 6y
(KKC080289)6y
(KKC080289) 90±2.990 ± 2.9 6f
(KKC080049)6f
(KKC080049) 87±687 ± 6 7a
(KKC080027)7a
(KKC080027) 79±179 ± 1 6g
(KKC080034)6 g
(KKC080034) 102±6102 ± 6 7b
(KKC080132)7b
(KKC080132) 78±478 ± 4 6h
(KKC080033)6h
(KKC080033) 97±597 ± 5 8a
(KKC08032)8a
(KKC08032) 75±0.975 ± 0.9

화합물compound NO (% of LPS)NO (% of LPS) 화합물compound NO (% of LPS)NO (% of LPS) 20 μM20 μM 30 μM30 μM 20 μM20 μM 30 μM30 μM 8b
(KKC080125)8b
(KKC080125) 75±375 ± 3 12h
(KKC080152)12h
(KKC080152) 33±1033 ± 10 9a
(KKC080031)9a
(KKC080031) 98±5.598 ± 5.5 12i
(KKC080140)12i
(KKC080140) 101±3101 ± 3 9b
(KKC080078)9b
(KKC080078) 94±794 ± 7 12j
(KKC080144)12j
(KKC080144) 40±540 ± 5 9c
(KKC080100)9c
(KKC080100) 79±579 ± 5 12k
(KKC080134)12k
(KKC080134) 94±594 ± 5 9d
(KKC080067)9d
(KKC080067) 108±5108 ± 5 12l
(KKC080141)12l
(KKC080141) 69±069 ± 0 10a
(KKC0800028)10a
(KKC0800028) 91±2.491 ± 2.4 12m
(KKC080153)12m
(KKC080153) 53±653 ± 6 10b
(KKC080047)10b
(KKC080047) 93±993 ± 9 12n
(KKC080138)12n
(KKC080138) 51±151 ± 1 11a
(KKC080050)11a
(KKC080050) II 27±1127 ± 11 12o
(KKC080156)12o
(KKC080156) 70±570 ± 5 11b
(KKC080051)11b
(KKC080051) II 82±782 ± 7 13a
(KKC080161)13a
(KKC080161) 15±2515 ± 25 11c11c II 13b
(KKC080157)13b
(KKC080157) 86±986 ± 9 11d
(KKC080086)11d
(KKC080086) II 91±391 ± 3 13c
(KKC080158)13c
(KKC080158) 77±777 ± 7 11e
(KKC080083)11e
(KKC080083) BrBr 98±998 ± 9 13d
(KKC080160)13d
(KKC080160) 14±3914 ± 39 11f
(KKC080190)11f
(KKC080190) BrBr -1±165.5-1 ± 165.5 13e
(KKC080311)13e
(KKC080311) 22.4±0.422.4 ± 0.4 12a
(KKC080116)12a
(KKC080116) 77±277 ± 2 13f
(KKC080312)13f
(KKC080312) 11.0±2.911.0 ± 2.9 12b
(KKC080118)12b
(KKC080118) 90±790 ± 7 13g
(KKC080313)13 g
(KKC080313) 12.2±3.812.2 ± 3.8 12c
(KKC080119)12c
(KKC080119) 115±6115 ± 6 13h
(KKC080314)13h
(KKC080314) 25.0±0.325.0 ± 0.3 12d
(KKC080120)12d
(KKC080120) 75±175 ± 1 13i
(KKC080315)13i
(KKC080315) 9.5±3.89.5 ± 3.8 12e
(KKC080124)12e
(KKC080124) 91±291 ± 2 13j
(KKC080316)13j
(KKC080316) 87.0±0.287.0 ± 0.2 12f
(KKC080133)12f
(KKC080133) 72±272 ± 2 13k
(KKC080317)13k
(KKC080317) 15.9±0.615.9 ± 0.6 12g
(KKC080136)12g
(KKC080136) 92±192 ± 1 13l
(KKC080318)13l
(KKC080318) 43.3±1.143.3 ± 1.1

화합물compound NO (% of LPS)NO (% of LPS) 화합물compound NO (% of LPS)NO (% of LPS) 20 μM20 μM 30 μM30 μM 20 μM20 μM 30 μM30 μM 13m
(KKC080319)13m
(KKC080319) 8.6±2.78.6 ± 2.7 15f
(KKC080079)15f
(KKC080079) 60±1760 ± 17 13n
(KKC080320)13n
(KKC080320) 17.6±0.717.6 ± 0.7 15g
(KKC080088)15g
(KKC080088) 64±764 ± 7 13o
(KKC080321)13o
(KKC080321) 17.5±1.517.5 ± 1.5 15h
(KKC080305)15h
(KKC080305) 29±4.629 ± 4.6 14a
(KKC080146)14a
(KKC080146) 58±658 ± 6 15i
(KKC080114)15i
(KKC080114) 90±390 ± 3 14b
(KKC080147)14b
(KKC080147) 102±4102 ± 4 15j
(KKC080117)15j
(KKC080117) 30±1430 ± 14 14c
(KKC080149)14c
(KKC080149) 54±554 ± 5 15k
(KKC080121)15k
(KKC080121) 70±370 ± 3 14d
(KKC080163)14d
(KKC080163) 49±1249 ± 12 15l
(KKC080122)15l
(KKC080122) 50±950 ± 9 14e
(KKC080323)14e
(KKC080323) 26.8±0.126.8 ± 0.1 15m
(KKC080123)15 m
(KKC080123) 92±492 ± 4 14f
(KKC080324)14f
(KKC080324) 38.3±1.338.3 ± 1.3 15n
(KKC080126)15n
(KKC080126) 63±663 ± 6 14g
(KKC080325)14 g
(KKC080325) 33.5±1.333.5 ± 1.3 15o
(KKC080127)15o
(KKC080127) 57±157 ± 1 14h
(KKC080326)14h
(KKC080326) 78.9±1.678.9 ± 1.6 15p
(KKC080128)15p
(KKC080128) 71±571 ± 5 14i
(KKC080327)14i
(KKC080327) 54.2±2.354.2 ± 2.3 15q
(KKC080129)15q
(KKC080129) 54±154 ± 1 14j
(KKC080328)14j
(KKC080328) 25.8±3.025.8 ± 3.0 15r
(KKC080130)15r
(KKC080130) 41±141 ± 1 14k
(KKC080329)14k
(KKC080329) 61.0±0.861.0 ± 0.8 15s
(KKC080131)15 s
(KKC080131) 93±293 ± 2 14l
(KKC080330)14l
(KKC080330) 24.2±1.724.2 ± 1.7 15t
(KKC080135)15 t
(KKC080135) 48±848 ± 8 15a
(KKC080084)15a
(KKC080084) 53±1253 ± 12 15u
(KKC080139)15 u
(KKC080139) 64±064 ± 0 15b
(KKC080081)15b
(KKC080081) 72±872 ± 8 15v
(KKC080142)15v
(KKC080142) 41±241 ± 2 15c
(KKC080069)15c
(KKC080069) 61±661 ± 6 15w
(KKC080143)15w
(KKC080143) 79±379 ± 3 15d
(KKC080072)15d
(KKC080072) 68±768 ± 7 15x
(KKC080179)15x
(KKC080179) 15e
(KKC080073)15e
(KKC080073) 46±1046 ± 10 15y
(KKC080241)15y
(KKC080241) 85±2.385 ± 2.3

화합물compound NO (% of LPS)NO (% of LPS) 화합물compound NO (% of LPS)NO (% of LPS) 20 μM20 μM 30 μM30 μM 20 μM20 μM 30 μM30 μM 15z
(KKC080263)15z
(KKC080263) 46±.646 ± .6 16q
(KKC080247)16q
(KKC080247) 40±1.840 ± 1.8 15za
(KKC080264)15za
(KKC080264) 36±.736 ± .7 16r
(KKC080248)16r
(KKC080248) 20±1.920 ± 1.9 15zb
(KKC080267)15zb
(KKC080267) 51±.151 ± .1 16s
(KKC080249)16s
(KKC080249) 66±2.666 ± 2.6 15zc
(KKC080268)15zc
(KKC080268) 42±.942 ± .9 16t
(KKC080250)16t
(KKC080250) 43±1.243 ± 1.2 16a
(KKC080306)16a
(KKC080306) 35±.535 ± .5 16u
(KKC080251)16 u
(KKC080251) 28±1.828 ± 1.8 16b
(KKC080074)16b
(KKC080074) 83±683 ± 6 16v
(KKC080252)16v
(KKC080252) 95±4.095 ± 4.0 16c
(KKC080103)16c
(KKC080103) 32.3±332.3 ± 3 16w
(KKC080253)16w
(KKC080253) 16d
(KKC080104)16d
(KKC080104) 54±154 ± 1 16x
(KKC080254)16x
(KKC080254) 34±1.434 ± 1.4 16e
(KKC080106)16e
(KKC080106) 36±436 ± 4 16y
(KKC080257)16y
(KKC080257) 41±0.941 ± 0.9 16f
(KKC080137)16f
(KKC080137) 35±635 ± 6 16z
(KKC080258)16z
(KKC080258) 26±2.426 ± 2.4 16g
(KKC080166)16g
(KKC080166) 37±637 ± 6 16za
(KKC080265)16za
(KKC080265) 40±1.340 ± 1.3 16h
(KKC080167)16h
(KKC080167) 66±966 ± 9 16zb
(KKC080266)16zb
(KKC080266) 49±2.449 ± 2.4 16i
(KKC080145)16i
(KKC080145) 79±379 ± 3 16zc
(KKC080290)16zc
(KKC080290) 50±1.150 ± 1.1 16j
(KKC080154)16j
(KKC080154) 48±848 ± 8 16zd
(KKC080291)16zd
(KKC080291) 46±1.946 ± 1.9 16k
(KKC080228)16k
(KKC080228) 31±0.531 ± 0.5 16ze
(KKC080292)16ze
(KKC080292) 51±3.451 ± 3.4 16l
(KKC080242)16l
(KKC080242) 48±5.148 ± 5.1 16zf
(KKC080293)16zf
(KKC080293) 49±0.649 ± 0.6 16m
(KKC080243)16m
(KKC080243) 58±1.958 ± 1.9 16zg
(KKC080294)16zg
(KKC080294) 55±1.955 ± 1.9 16n
(KKC080244)16n
(KKC080244) 56±4.556 ± 4.5 16zh
(KKC080295)16zh
(KKC080295) 53±7.253 ± 7.2 16o
(KKC080245)16o
(KKC080245) 43±4.643 ± 4.6 16zi
(KKC080296)16zi
(KKC080296) 39±3.139 ± 3.1 16p
(KKC080246)16p
(KKC080246) 34±1.734 ± 1.7 17a
(KKC080109)17a
(KKC080109) 73±373 ± 3

화합물compound NO (% of LPS)NO (% of LPS) 화합물compound NO (% of LPS)NO (% of LPS) 20 μM20 μM 30 μM30 μM 20 μM20 μM 30 μM30 μM 17b
(KKC080107)17b
(KKC080107) 61±161 ± 1 18e
(KKC080220)18e
(KKC080220) 44±1.344 ± 1.3 17c
(KKC080110)17c
(KKC080110) 59±259 ± 2 18f
(KKC080221)18f
(KKC080221) 56±3.156 ± 3.1 17d
(KKC080091)17d
(KKC080091) 93±293 ± 2 18g
(KKC080284)18g
(KKC080284) 58±4.858 ± 4.8 17e
(KKC080096)17e
(KKC080096) 21±2721 ± 27 18h
(KKC080285)18h
(KKC080285) 56±3.156 ± 3.1 17f
(KKC080099)17f
(KKC080099) 89±889 ± 8 18i
(KKC080286)18i
(KKC080286) 78±4.478 ± 4.4 17g
(KKC080108)17 g
(KKC080108) 42±1842 ± 18 19a
(KKC080222)19a
(KKC080222) 32±1.132 ± 1.1 17h
(KKC080107)17h
(KKC080107) 61±161 ± 1 19b
(KKC080223)19b
(KKC080223) 27±6.827 ± 6.8 17i
(KKC080298)17i
(KKC080298) 45±5.945 ± 5.9 19c
(KKC080224)19c
(KKC080224) 25±1.925 ± 1.9 17j
(KKC080299)17j
(KKC080299) 19±3.919 ± 3.9 19d
(KKC080281)19d
(KKC080281) 40±1.140 ± 1.1 17k
(KKC080300)17k
(KKC080300) 51±551 ± 5 19e
(KKC080282)19e
(KKC080282) 60±5.960 ± 5.9 17l
(KKC080301)17l
(KKC080301) 82±9.582 ± 9.5 19f
(KKC080283)19f
(KKC080283) 75±8.775 ± 8.7 17m
(KKC080302)17m
(KKC080302) 92±6.692 ± 6.6 19g
(KKC080332)19 g
(KKC080332) 27.4±0.727.4 ± 0.7 17n
(KKC080303)17n
(KKC080303) 38±2.938 ± 2.9 19h
(KKC080333)19h
(KKC080333) 18.0±1.218.0 ± 1.2 17o
(KKC080322)17o
(KKC080322) 73.6±2.473.6 ± 2.4 19i
(KKC080334)19i
(KKC080334) 23.1±0.523.1 ± 0.5 17p
(KKC080345)17p
(KKC080345) 20a
(KKC080182)20a
(KKC080182) 48±17.248 ± 17.2 17q
(KKC080346)17q
(KKC080346) 20b
(KKC080183)20b
(KKC080183) 48±27.148 ± 27.1 18a
(KKC080176)18a
(KKC080176) 43±18.143 ± 18.1 20c
(KKC080184)20c
(KKC080184) 47±8.047 ± 8.0 18b
(KKC080177)18b
(KKC080177) 37±17.637 ± 17.6 20d
(KKC080213)20d
(KKC080213) 43±5.943 ± 5.9 18c
(KKC080178)18c
(KKC080178) 37±7.937 ± 7.9 20e
(KKC080214)20e
(KKC080214) 235±235 ± 18d
(KKC080219)18d
(KKC080219) 39±4.839 ± 4.8 20f
(KKC080215)20f
(KKC080215) 62±3.862 ± 3.8

화합물compound NO (% of LPS)NO (% of LPS) 화합물compound NO (% of LPS)NO (% of LPS) 20 μM20 μM 30 μM30 μM 20 μM20 μM 30 μM30 μM 21a
(KKC080185)21a
(KKC080185) 37±10.737 ± 10.7 22k
(KKC080192)22k
(KKC080192) 58±258 ± 2 21b
(KKC080186)21b
(KKC080186) 44±25.244 ± 25.2 22l
(KKC080194)22l
(KKC080194) 60±3.360 ± 3.3 21c
(KKC080187)21c
(KKC080187) 47±6.847 ± 6.8 22m
(KKC080195)22 m
(KKC080195) 62±2.862 ± 2.8 21d
(KKC080216)21d
(KKC080216) 42±5.242 ± 5.2 22n
(KKC080338)22n
(KKC080338) 21e
(KKC080217)21e
(KKC080217) 39±3.039 ± 3.0 22o
(KKC080339)22o
(KKC080339) 21f
(KKC080218)21f
(KKC080218) 49±5.949 ± 5.9 22p
(KKC080340)22p
(KKC080340) 21g
(KKC080277)21 g
(KKC080277) 79±1.879 ± 1.8 23a
(KKC080189)23a
(KKC080189) 40±7.140 ± 7.1 21h
(KKC080278)21h
(KKC080278) 73±2.673 ± 2.6 23b
(KKC080197)23b
(KKC080197) 93±293 ± 2 21i
(KKC080279)21i
(KKC080279) 57±157 ± 1 23c
(KKC080199)23c
(KKC080199) 41±2.341 ± 2.3 21j
(KKC080280)21j
(KKC080280) 52±1.752 ± 1.7 23d
(KKC080201)23d
(KKC080201) 35±7.435 ± 7.4 22a
(KKC080198)22a
(KKC080198) 24±12.924 ± 12.9 23e
(KKC080271)23e
(KKC080271) 36±3.636 ± 3.6 22b
(KKC080200)22b
(KKC080200) 28±4.128 ± 4.1 23f
(KKC080272)23f
(KKC080272) 23±0.623 ± 0.6 22c
(KKC080202)22c
(KKC080202) 55±455 ± 4 23g
(KKC080275)23 g
(KKC080275) 46±3.946 ± 3.9 22d
(KKC080209)22d
(KKC080209) 46±8.346 ± 8.3 23h
(KKC080276)23h
(KKC080276) 41±5.741 ± 5.7 22e
(KKC080204)22e
(KKC080204) 31±6.931 ± 6.9 23i
(KKC080203)23i
(KKC080203) 35±7.335 ± 7.3 22f
(KKC080206)22f
(KKC080206) 58±3.758 ± 3.7 23j
(KKC080210)23j
(KKC080210) 28±19.328 ± 19.3 22g
(KKC080208)22g
(KKC080208) 42±2.342 ± 2.3 23k
(KKC080211)23k
(KKC080211) 35±4.635 ± 4.6 22h
(KKC080226)22h
(KKC080226) 59±1.459 ± 1.4 23l
(KKC080205)23l
(KKC080205) 30±37.430 ± 37.4 22i
(KKC080230)22i
(KKC080230) 81±7.581 ± 7.5 23m
(KKC080207)23m
(KKC080207) 35±3.335 ± 3.3 22j
(KKC080232)22j
(KKC080232) 70±3.970 ± 3.9 23n
(KKC080212)23n
(KKC080212) 82±3.182 ± 3.1

화합물compound NO (% of LPS)NO (% of LPS) 화합물compound NO (% of LPS)NO (% of LPS) 20 μM20 μM 30 μM30 μM 20 μM20 μM 30 μM30 μM 23o
(KKC080259)23o
(KKC080259) 30±2.430 ± 2.4 24a
(KKC080233)24a
(KKC080233) 78±1.478 ± 1.4 23p
(KKC080225)23p
(KKC080225) 40±4.940 ± 4.9 24b
(KKC080234)24b
(KKC080234) 137±5.7137 ± 5.7 23q
(KKC080229)23q
(KKC080229) 122±2.8122 ± 2.8 24c
(KKC080235)24c
(KKC080235) 123±5.4123 ± 5.4 23r
(KKC080231)23r
(KKC080231) 87±7.187 ± 7.1 24d
(KKC080236)24d
(KKC080236) 130±1.8130 ± 1.8 23s
(KKC080269)23 s
(KKC080269) 54±2.354 ± 2.3 24e
(KKC080237)24e
(KKC080237) 41±16.341 ± 16.3 23t
(KKC080270)23 t
(KKC080270) 42±2.642 ± 2.6 24f
(KKC080238)24f
(KKC080238) 9±19 ± 1 23u
(KKC080273)23u
(KKC080273) 120±3.1120 ± 3.1 24g
(KKC080239)24g
(KKC080239) 63±2.663 ± 2.6 23v
(KKC080274)23v
(KKC080274) 59±359 ± 3 24h
(KKC080255)24h
(KKC080255) 44±4.244 ± 4.2 23w
(KKC080191)23w
(KKC080191) 54±2.354 ± 2.3 24i
(KKC080256)24i
(KKC080256) 42±0.842 ± 0.8 23x
(KKC080193)23x
(KKC080193) 35±4.335 ± 4.3 24j
(KKC080344)24j
(KKC080344) 23y
(KKC080195)23y
(KKC080195) 54±3.554 ± 3.5 25a
(KKC080068)25a
(KKC080068) 23z
(KKC080260)23z
(KKC080260) 51±3.551 ± 3.5 25b
(KKC080098)25b
(KKC080098) 89±689 ± 6 23za
(KKC080261)23za
(KKC080261) 56±3.656 ± 3.6 26a
(KKC080063)26a
(KKC080063) 23zb
(KKC080262)23zb
(KKC080262) 49±2.949 ± 2.9 26b
(KKC080052)26b
(KKC080052) 23zc
(KKC080341)23zc
(KKC080341) 27a
(KKC080148)27a
(KKC080148) 77±577 ± 5 23zd
(KKC080342)23zd
(KKC080342) 27b
(KKC080151)27b
(KKC080151) 73±1073 ± 10 23ze
(KKC080343)23ze
(KKC080343) 27c
(KKC080155)27c
(KKC080155) 98±698 ± 6 23zf
(KKC080347)23zf
(KKC080347) 27d
(KKC080162)27d
(KKC080162) 49±1249 ± 12 23zg
(KKC080348)23zg
(KKC080348) 27e
(KKC080159)27e
(KKC080159) 56±656 ± 6 23zh
(KKC080349)23zh
(KKC080349) 27f
(KKC080150)27f
(KKC080150) 86±386 ± 3

화합물compound NO (% of LPS)NO (% of LPS) 화합물compound NO (% of LPS)NO (% of LPS) 20 μM20 μM 30 μM30 μM 20 μM20 μM 30 μM30 μM 27g
(KKC080335)27 g
(KKC080335) 82±2.582 ± 2.5 31c
(KKC080065)31c
(KKC080065) 100±4100 ± 4 27h
(KKC080336)27h
(KKC080336) 87.4±1.287.4 ± 1.2 31d
(KKC080089)31d
(KKC080089) 27i
(KKC080337)27i
(KKC080337) 83.5±3.183.5 ± 3.1 31e
(KKC080066)31e
(KKC080066) 105±10105 ± 10 2828 31f
(KKC080064)31f
(KKC080064) 100±5100 ± 5 29
(KKC080093)29
(KKC080093) 35±1235 ± 12 31g
(KKC080077)31 g
(KKC080077) 71±371 ± 3 30a
(KKC080076)30a
(KKC080076) 13±1813 ± 18 32a
(KKC080115)32a
(KKC080115) 53±353 ± 3 30b
(KKC080054)30b
(KKC080054) 31±1931 ± 19 32b
(KKC080111)32b
(KKC080111) 49±949 ± 9 30c
(KKC080085)30c
(KKC080085) 21±2221 ± 22 32c
(KKC080112)32c
(KKC080112) 69±869 ± 8 31a
(KKC080075)31a
(KKC080075) 68±2868 ± 28 32d
(KKC080113)32d
(KKC080113) 46±246 ± 2 31b
(KKC080082)31b
(KKC080082) 55±555 ± 5

Claims (10)

하기 [화학식 Ⅰ] 내지 [화학식 Ⅶ]로 표시되는 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염:
[화학식 Ⅰ] [화학식 Ⅱ] [화학식 Ⅲ]
Figure pat00389
Figure pat00390
Figure pat00391

[화학식 Ⅳ] [화학식 Ⅴ]
Figure pat00392
Figure pat00393

[화학식 Ⅵ] [화학식 Ⅶ]
Figure pat00394
Figure pat00395

상기 [화학식 Ⅰ] 내지 [화학식 Ⅶ]에서,
상기 R1은 수소, 치환 또는 비치환된 탄소수 1 내지 12의 알킬기, 치환 또는 비치환된 탄소수 1 내지 12의 알릴기, 치환 또는 비치환된 탄소수 1 내지 10의 알콜기, 치환 또는 비치환된 탄소수 1 내지 10의 알콕시기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴옥시기 및 치환 또는 비치환된 탄소수 1 내지 5의 알킬카바메이트기 중에서 선택되는 어느 하나이고,
상기 R2는 수소, 할로젠기, 치환 또는 비치환된 탄소수 1 내지 10의 알콕시기, 치환 또는 비치환된 탄소수 1 내지 12의 알릴기, 치환 또는 비치환된 탄소수 1 내지 10의 알콜기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴기, 치환 또는 비치환된 탄소수 3 내지 18의 헤테로아릴기, 치환 또는 비치환된 탄소수 1 내지 12의 알킬아민기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴아민기, 치환 또는 비치환된 탄소수 3 내지 18의 헤테로아릴아민기, 치환 또는 비치환된 탄소수 1 내지 10의 알킬티올기, 치환 또는 비치환된 탄소수 6 내지 18의 아릴티올기 및 치환 또는 비치환된 탄소수 6 내지 18의 아릴옥시기 중에서 선택되는 어느 하나이며,
상기 R3는 O 또는 S이고,
상기 R4는 수소, 치환 또는 비치환된 탄소수 1 내지 6의 알킬설파이닐기, 치환 또는 비치환된 탄소수 1 내지 6의 알킬설포닐기, 치환 또는 비치환된 탄소수 1 내지 12의 알킬아민기, 치환 또는 비치환된 탄소수 1 내지 10의 알콕시기 및 치환 또는 비치환된 탄소수 6 내지 18의 아릴아민기 중에서 선택되는 어느 하나이며,
상기 X1은 수소, 할로젠기 및 치환 또는 비치환된 탄소수 6 내지 18의 아릴기 중에서 선택되는 어느 하나이다.A pyrazolopyrimidine derivative compound represented by the following Chemical Formula I to Chemical Formula X or a pharmaceutically acceptable salt thereof:
[Formula I] [Formula II] [Formula III]
Figure pat00389
Figure pat00390
Figure pat00391

[Formula IV] [Formula V]
Figure pat00392
Figure pat00393

(VI) &lt; RTI ID = 0.0 &gt; [VII]
Figure pat00394
Figure pat00395

In [Formula I] to [Formula VII],
R 1 is hydrogen, a substituted or unsubstituted C1-C12 alkyl group, a substituted or unsubstituted C1-C12 allyl group, a substituted or unsubstituted C1-C10 alcohol group, a substituted or unsubstituted carbon number Selected from an alkoxy group having 1 to 10, a substituted or unsubstituted aryl group having 6 to 18 carbon atoms, a substituted or unsubstituted aryloxy group having 6 to 18 carbon atoms, and a substituted or unsubstituted alkyl carbamate group having 1 to 5 carbon atoms Which one is
R 2 is hydrogen, a halogen group, a substituted or unsubstituted C1-C10 alkoxy group, a substituted or unsubstituted C1-C12 allyl group, a substituted or unsubstituted C1-C10 alcohol group, substituted Or an unsubstituted aryl group having 6 to 18 carbon atoms, a substituted or unsubstituted heteroaryl group having 3 to 18 carbon atoms, a substituted or unsubstituted alkylamine group having 1 to 12 carbon atoms, a substituted or unsubstituted carbon group having 6 to 18 carbon atoms Arylamine group, substituted or unsubstituted heteroarylamine group having 3 to 18 carbon atoms, substituted or unsubstituted alkylthiol group having 1 to 10 carbon atoms, substituted or unsubstituted arylthiol group having 6 to 18 carbon atoms, and substituted or unsubstituted Any one selected from an aryloxy group having 6 to 18 ring carbon atoms,
R 3 is O or S,
R 4 is hydrogen, a substituted or unsubstituted C1-C6 alkylsulfinyl group, a substituted or unsubstituted C1-C6 alkylsulfonyl group, a substituted or unsubstituted C1-C12 alkylamine group, substituted or It is any one selected from an unsubstituted alkoxy group having 1 to 10 carbon atoms and a substituted or unsubstituted arylamine group having 6 to 18 carbon atoms,
X 1 is any one selected from hydrogen, a halogen group, and a substituted or unsubstituted aryl group having 6 to 18 carbon atoms. 제 1 항에 있어서,
상기 R1, R2 및 R4는 각각 독립적으로 탄소수 1 내지 6의 알킬기, 탄소수 1 내지 12의 알콕시기, 탄소수 1 내지 12의 알킬아민기, 탄소수 3 내지 18의 헤테로아릴기, 탄소수 3 내지 18의 헤테로아릴아민기, 시아노기 및 할로겐원자로 이루어지는 군으로부터 1종 이상 선택되어 치환되는 것을 특징으로 하는 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염.The method of claim 1,
Wherein R 1 , R 2 And R 4 is each independently an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, an alkylamine group having 1 to 12 carbon atoms, a heteroaryl group having 3 to 18 carbon atoms, a heteroarylamine group having 3 to 18 carbon atoms, A pyrazolopyrimidine derivative compound or a pharmaceutically acceptable salt thereof, wherein at least one selected from the group consisting of a cyano group and a halogen atom is substituted. 제 1 항에 있어서,
상기 R1은 하기 [구조식 1]로 표시되는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염:
[구조식 1]
Figure pat00396
Figure pat00397
Figure pat00398
Figure pat00399
Figure pat00400
Figure pat00401
Figure pat00402

Figure pat00403
Figure pat00404
Figure pat00405
The method of claim 1,
R 1 is any one selected from the group represented by the following [formula 1] pyrazolopyrimidine derivative compound or a pharmaceutically acceptable salt thereof:
[Structural formula 1]
Figure pat00396
Figure pat00397
Figure pat00398
Figure pat00399
Figure pat00400
Figure pat00401
Figure pat00402

Figure pat00403
Figure pat00404
Figure pat00405
 제 1 항에 있어서,
상기 R2는 하기 [구조식 2]로 표시되는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염:
[구조식 2]
Figure pat00406
Figure pat00407
Figure pat00408
Figure pat00409
Figure pat00410
Figure pat00411

Figure pat00412
Figure pat00413
Figure pat00414
Figure pat00415
Figure pat00416
Figure pat00417

Figure pat00418
Figure pat00419
Figure pat00420
Figure pat00421
Figure pat00422
Figure pat00423

Figure pat00424
Figure pat00425
Figure pat00426
Figure pat00427
Figure pat00428
Figure pat00429
Figure pat00430

Figure pat00431
Figure pat00432
Figure pat00433
Figure pat00434
Figure pat00435
Figure pat00436

Figure pat00438
Figure pat00439
Figure pat00440
Figure pat00441
Figure pat00442
Figure pat00443

Figure pat00444
Figure pat00445
Figure pat00446
Figure pat00447
The method of claim 1,
R 2 is any one selected from the group represented by the following [formula 2] pyrazolopyrimidine derivative compound or a pharmaceutically acceptable salt thereof:
[Structural formula 2]
Figure pat00406
Figure pat00407
Figure pat00408
Figure pat00409
Figure pat00410
Figure pat00411

Figure pat00412
Figure pat00413
Figure pat00414
Figure pat00415
Figure pat00416
Figure pat00417

Figure pat00418
Figure pat00419
Figure pat00420
Figure pat00421
Figure pat00422
Figure pat00423

Figure pat00424
Figure pat00425
Figure pat00426
Figure pat00427
Figure pat00428
Figure pat00429
Figure pat00430

Figure pat00431
Figure pat00432
Figure pat00433
Figure pat00434
Figure pat00435
Figure pat00436

Figure pat00438
Figure pat00439
Figure pat00440
Figure pat00441
Figure pat00442
Figure pat00443

Figure pat00444
Figure pat00445
Figure pat00446
Figure pat00447
 제 1 항에 있어서,
상기 R4는 하기 [구조식 3]으로 표시되는 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염:
[구조식 3]
Figure pat00448
Figure pat00449
Figure pat00450
Figure pat00451
Figure pat00452
Figure pat00453

Figure pat00454
Figure pat00455
Figure pat00456
The method of claim 1,
R 4 is any one selected from the group represented by the following [Formula 3] pyrazolopyrimidine derivative compound or a pharmaceutically acceptable salt thereof:
[Structural Formula 3]
Figure pat00448
Figure pat00449
Figure pat00450
Figure pat00451
Figure pat00452
Figure pat00453

Figure pat00454
Figure pat00455
Figure pat00456
 제 1 항에 있어서,
상기 [화학식 ] 내지 [화학식 ]는 하기 [화학식 4] 내지 [화학식 31k]로 표시되는 군에서 선택되는 어느 하나인 것을 특징으로 하는 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염:
[화학식 4] [화학식 5a] [화학식 5b]
Figure pat00457
Figure pat00458
Figure pat00459

[화학식 5c] [화학식 5d]
Figure pat00460
Figure pat00461

[화학식 5e] [화학식 5f]
Figure pat00462
Figure pat00463

[화학식 5g] [화학식 5h] [화학식 5i]
Figure pat00464
Figure pat00465
Figure pat00466

[화학식 5j] [화학식 5k] [화학식 6a]
Figure pat00467
Figure pat00468
Figure pat00469

[화학식 6b] [화학식 6c] [화학식 6d]
Figure pat00470
Figure pat00471
Figure pat00472

[화학식 6e] [화학식 6f] [화학식 6g]
Figure pat00473
Figure pat00474
\
Figure pat00475

[화학식 6h] [화학식 6i] [화학식 6j]
Figure pat00476
Figure pat00477
Figure pat00478

[화학식 6k] [화학식 6l] [화학식 6m]
Figure pat00479
Figure pat00480
Figure pat00481

[화학식 6n] [화학식 6o] [화학식 6p]
Figure pat00482
Figure pat00483
Figure pat00484

[화학식 6q] [화학식 6r] [화학식 6s]
Figure pat00485
Figure pat00486
Figure pat00487

[화학식 6t] [화학식 6u] [화학식 6v]
Figure pat00488
Figure pat00489
Figure pat00490

[화학식 6w] [화학식 6x] [화학식 6y]
Figure pat00491
Figure pat00492
Figure pat00493

[화학식 7a] [화학식 7b] [화학식 8a]
Figure pat00494
Figure pat00495
Figure pat00496

[화학식 8b] [화학식 9a] [화학식 9b]
Figure pat00497
Figure pat00498
Figure pat00499

[화학식 9c] [화학식 9d] [화학식 10a]
Figure pat00500
Figure pat00501
Figure pat00502

[화학식 10b] [화학식 11a] [화학식 11b]
Figure pat00503
Figure pat00504
Figure pat00505

[화학식 11c] [화학식 11d] [화학식 12a]
Figure pat00506
Figure pat00507
Figure pat00508

[화학식 12b] [화학식 12c] [화학식 12d]
Figure pat00509
Figure pat00510
Figure pat00511

[화학식 12e] [화학식 12f] [화학식 12g]
Figure pat00512
Figure pat00513
Figure pat00514

[화학식 12h] [화학식 12i] [화학식 12j]
Figure pat00515
Figure pat00516
Figure pat00517

[화학식 12k] [화학식 12l] [화학식 12m]
Figure pat00518
Figure pat00519
Figure pat00520

[화학식 12n] [화학식 12o] [화학식 13a]
Figure pat00521
Figure pat00522
Figure pat00523

[화학식 13b] [화학식 13c] [화학식 13d]
Figure pat00524
Figure pat00525
Figure pat00526

[화학식 13e] [화학식 13f] [화학식 13g]
Figure pat00527
Figure pat00528
Figure pat00529

[화학식 13h] [화학식 13i] [화학식 13j]
Figure pat00530
Figure pat00531
Figure pat00532

[화학식 13k] [화학식 13l] [화학식 13m]
Figure pat00533
Figure pat00534
Figure pat00535

[화학식 13n] [화학식 13o] [화학식 14a]
Figure pat00536
Figure pat00537
Figure pat00538

[화학식 14b] [화학식 14c]
Figure pat00539
Figure pat00540

[화학식 14d] [화학식 14e]
Figure pat00541
Figure pat00542

[화학식 14f] [화학식 14g]
Figure pat00543
Figure pat00544

[화학식 14h] [화학식 14i]
Figure pat00545
Figure pat00546

[화학식 14j] [화학식 14k]
Figure pat00547
Figure pat00548

[화학식 14l] [화학식 15a]
Figure pat00549
Figure pat00550

[화학식 15b] [화학식 15c]
Figure pat00551
Figure pat00552

[화학식 15d] [화학식 15e]
Figure pat00553
Figure pat00554

[화학식 15f] [화학식 15g]
Figure pat00555
Figure pat00556

[화학식 15h] [화학식 15i] [화학식 15j]
Figure pat00557
Figure pat00558
Figure pat00559

[화학식 15k] [화학식 15l] [화학식 15m]
Figure pat00560
Figure pat00561
Figure pat00562

[화학식 15n] [화학식 15o] [화학식 15p]
Figure pat00563
Figure pat00564
Figure pat00565

[화학식 15q] [화학식 15r] [화학식 15s]
Figure pat00566
Figure pat00567
Figure pat00568

[화학식 15t] [화학식 15u] [화학식 15v]
Figure pat00569
Figure pat00570
Figure pat00571

[화학식 15w] [화학식 15x] [화학식 15y]
Figure pat00572
Figure pat00573
Figure pat00574

[화학식 15z] [화학식 15za] [화학식 15zb]
Figure pat00575
Figure pat00576
Figure pat00577

[화학식 15zc] [화학식 16a] [화학식 16b]
Figure pat00578
Figure pat00579
Figure pat00580

[화학식 16c] [화학식 16d]
Figure pat00581
Figure pat00582

[화학식 16e] [화학식 16f]
Figure pat00583
Figure pat00584

[화학식 16g] [화학식 16h]
Figure pat00585
Figure pat00586

[화학식 16i] [화학식 16j]
Figure pat00587
Figure pat00588

[화학식 16k] [화학식 16l]
Figure pat00589
Figure pat00590

[화학식 16m] [화학식 16n]
Figure pat00591
Figure pat00592

[화학식 16o] [화학식 16p]
Figure pat00593
Figure pat00594

[화학식 16q] [화학식 16r]
Figure pat00595
Figure pat00596

[화학식 16s] [화학식 16t]
Figure pat00597
Figure pat00598

[화학식 16u] [화학식 16v]
Figure pat00599
Figure pat00600

[화학식 16w] [화학식 16x]
Figure pat00601
Figure pat00602

[화학식 16y] [화학식 16z]
Figure pat00603
Figure pat00604

[화학식 16za] [화학식 16zb]
Figure pat00605
Figure pat00606

[화학식 16zc] [화학식 16zd]
Figure pat00607
Figure pat00608

[화학식 16ze] [화학식 16zf]
Figure pat00609
Figure pat00610

[화학식 16zg] [화학식 16zh]
Figure pat00611
Figure pat00612

[화학식 15zi] [화학식 17a]
Figure pat00613
Figure pat00614

[화학식 17b] [화학식 17c] [화학식 17d]
Figure pat00615
Figure pat00616
Figure pat00617

[화학식 17e] [화학식 17f] [화학식 17g]
Figure pat00618
Figure pat00619
Figure pat00620

[화학식 17h] [화학식 17i] [화학식 17j]
Figure pat00621
Figure pat00622
Figure pat00623

[화학식 17k] [화학식 17l] [화학식 17m]
Figure pat00624
Figure pat00625
Figure pat00626

[화학식 17n] [화학식 17o] [화학식 17p]
Figure pat00627
Figure pat00628
Figure pat00629

[화학식 17q] [화학식 18a] [화학식 18b]
Figure pat00630
Figure pat00631
Figure pat00632

[화학식 18c] [화학식 18d] [화학식 18e]
Figure pat00633
Figure pat00634
Figure pat00635

[화학식 18f] [화학식 18g] [화학식 18h]
Figure pat00636
Figure pat00637
Figure pat00638

[화학식 18i] [화학식 19a] [화학식 19b]
Figure pat00639
Figure pat00640
Figure pat00641

[화학식 19c] [화학식 19d] [화학식 19e]
Figure pat00642
Figure pat00643
Figure pat00644

[화학식 19f] [화학식 19g] [화학식 19h]
Figure pat00645
Figure pat00646
Figure pat00647

[화학식 19i] [화학식 20a] [화학식 20b]
Figure pat00648
Figure pat00649
Figure pat00650

[화학식 20c] [화학식 20d] [화학식 20e]
Figure pat00651
Figure pat00652
Figure pat00653

[화학식 20f] [화학식 21a] [화학식 21b]
Figure pat00654
Figure pat00655
Figure pat00656

[화학식 21c] [화학식 21d] [화학식 21e]
Figure pat00657
Figure pat00659

[화학식 21f] [화학식 21g] [화학식 21h]
Figure pat00660
Figure pat00661
Figure pat00662

[화학식 21i] [화학식 21j] [화학식 22a]
Figure pat00663
Figure pat00664
Figure pat00665

[화학식 22b] [화학식 22c] [화학식 22d]
Figure pat00666
Figure pat00667
Figure pat00668

[화학식 22e] [화학식 22f] [화학식 22g]
Figure pat00669
Figure pat00670
Figure pat00671

[화학식 22h] [화학식 22i] [화학식 22j]
Figure pat00672
Figure pat00673

[화학식 22k] [화학식 22l] [화학식 22m]
Figure pat00675
Figure pat00676
Figure pat00677

[화학식 22n] [화학식 22o] [화학식 22p]
Figure pat00678
Figure pat00679
Figure pat00680

[화학식 23a] [화학식 23b] [화학식 23c]
Figure pat00682
Figure pat00683

[화학식 23d] [화학식 23e] [화학식 23f]
Figure pat00684
Figure pat00685
Figure pat00686

[화학식 23g] [화학식 23h] [화학식 23i]
Figure pat00687
Figure pat00688
Figure pat00689

[화학식 23j] [화학식 23k] [화학식 23l]
Figure pat00690
Figure pat00691
Figure pat00692

[화학식 23m] [화학식 23n] [화학식 23o]
Figure pat00693
Figure pat00694
Figure pat00695

[화학식 23p] [화학식 23q] [화학식 23r]
Figure pat00696
Figure pat00697
Figure pat00698

[화학식 23s] [화학식 23t] [화학식 23u]
Figure pat00699
Figure pat00700
Figure pat00701

[화학식 23v] [화학식 23w] [화학식 23x]
Figure pat00702
Figure pat00703
Figure pat00704

[화학식 23y] [화학식 23z] [화학식 23za]
Figure pat00705
Figure pat00706
Figure pat00707

[화학식 23zb] [화학식 23zc] [화학식 23zd]
Figure pat00708
Figure pat00709
Figure pat00710

[화학식 23ze] [화학식 23zf] [화학식 23zg]
Figure pat00711
Figure pat00712
Figure pat00713

[화학식 23zh] [화학식 24a]
Figure pat00714
Figure pat00715

[화학식 24b] [화학식 24c]
Figure pat00717

[화학식 24d] [화학식 24e]
Figure pat00718
Figure pat00719

[화학식 24f] [화학식 24g]
Figure pat00720
Figure pat00721

[화학식 24h] [화학식 24i]
Figure pat00722
Figure pat00723

[화학식 24j] [화학식 25a]
Figure pat00724
Figure pat00725

[화학식 25b] [화학식 26a] [화학식 26b]
Figure pat00726
Figure pat00727
Figure pat00728

[화학식 27a] [화학식 27b] [화학식 27c]
Figure pat00729
Figure pat00730
Figure pat00731

[화학식 27d] [화학식 27e] [화학식 27f]
Figure pat00732
Figure pat00733
Figure pat00734

[화학식 27g] [화학식 27h] [화학식 27i]
Figure pat00735
Figure pat00736
Figure pat00737

[화학식 30a] [화학식 30b] [화학식 30c]
Figure pat00738
Figure pat00739
Figure pat00740

[화학식 31a] [화학식 31b] [화학식 31c]
Figure pat00741
Figure pat00742

[화학식 31d] [화학식 31e]
Figure pat00744
Figure pat00745

[화학식 31f] [화학식 31g] [화학식 31h]
Figure pat00746
Figure pat00747
Figure pat00748

[화학식 31i] [화학식 31j] [화학식 31k]
Figure pat00749
Figure pat00750
Figure pat00751
The method of claim 1,
[Formula] to [Formula] is a pyrazolopyrimidine derivative compound or a pharmaceutically acceptable salt thereof characterized in that any one selected from the group represented by [Formula 4] to [Formula 31k]:
[Formula 4] [Formula 5a] [Formula 5b]
Figure pat00457
Figure pat00458
Figure pat00459

[Formula 5c] [Formula 5d]
Figure pat00460
Figure pat00461

[Formula 5e] [Formula 5f]
Figure pat00462
Figure pat00463

[Formula 5g] [Formula 5h] [Formula 5i]
Figure pat00464
Figure pat00465
Figure pat00466

[Formula 5j] [Formula 5k] [Formula 6a]
Figure pat00467
Figure pat00468
Figure pat00469

[Formula 6b] [Formula 6c] [Formula 6d]
Figure pat00470
Figure pat00471
Figure pat00472

[Formula 6e] [Formula 6f] [Formula 6g]
Figure pat00473
Figure pat00474
\
Figure pat00475

[Formula 6h] [Formula 6i] [Formula 6j]
Figure pat00476
Figure pat00477
Figure pat00478

[Formula 6k] [Formula 6l] [Formula 6m]
Figure pat00479
Figure pat00480
Figure pat00481

[Formula 6n] [Formula 6o] [Formula 6p]
Figure pat00482
Figure pat00483
Figure pat00484

[Formula 6q] [Formula 6r] [Formula 6s]
Figure pat00485
Figure pat00486
Figure pat00487

[Formula 6t] [Formula 6u] [Formula 6v]
Figure pat00488
Figure pat00489
Figure pat00490

[Formula 6w] [Formula 6x] [Formula 6y]
Figure pat00491
Figure pat00492
Figure pat00493

[Formula 7a] [Formula 7b] [Formula 8a]
Figure pat00494
Figure pat00495
Figure pat00496

[Formula 8b] [Formula 9a] [Formula 9b]
Figure pat00497
Figure pat00498
Figure pat00499

[Formula 9c] [Formula 9d] [Formula 10a]
Figure pat00500
Figure pat00501
Figure pat00502

[Formula 10b] [Formula 11a] [Formula 11b]
Figure pat00503
Figure pat00504
Figure pat00505

[Formula 11c] [Formula 11d] [Formula 12a]
Figure pat00506
Figure pat00507
Figure pat00508

[Formula 12b] [Formula 12c] [Formula 12d]
Figure pat00509
Figure pat00510
Figure pat00511

[Formula 12e] [Formula 12f] [Formula 12g]
Figure pat00512
Figure pat00513
Figure pat00514

[Formula 12h] [Formula 12i] [Formula 12j]
Figure pat00515
Figure pat00516
Figure pat00517

[Formula 12k] [Formula 12l] [Formula 12m]
Figure pat00518
Figure pat00519
Figure pat00520

[Formula 12n] [Formula 12o] [Formula 13a]
Figure pat00521
Figure pat00522
Figure pat00523

[Formula 13b] [Formula 13c] [Formula 13d]
Figure pat00524
Figure pat00525
Figure pat00526

[Formula 13e] [Formula 13f] [Formula 13g]
Figure pat00527
Figure pat00528
Figure pat00529

[Formula 13h] [Formula 13i] [Formula 13j]
Figure pat00530
Figure pat00531
Figure pat00532

[Formula 13k] [Formula 13l] [Formula 13m]
Figure pat00533
Figure pat00534
Figure pat00535

[Formula 13n] [Formula 13o] [Formula 14a]
Figure pat00536
Figure pat00537
Figure pat00538

[Formula 14b] [Formula 14c]
Figure pat00539
Figure pat00540

[Formula 14d] [Formula 14e]
Figure pat00541
Figure pat00542

[Formula 14f] [Formula 14g]
Figure pat00543
Figure pat00544

[Formula 14h] [Formula 14i]
Figure pat00545
Figure pat00546

[Formula 14j] [Formula 14k]
Figure pat00547
Figure pat00548

[Formula 14l] [Formula 15a]
Figure pat00549
Figure pat00550

[Chemical Formula 15b] [Chemical Formula 15c]
Figure pat00551
Figure pat00552

[Chemical Formula 15d] [Chemical Formula 15e]
Figure pat00553
Figure pat00554

[Chemical Formula 15f] [Chemical Formula 15g]
Figure pat00555
Figure pat00556

[Formula 15h] [Formula 15i] [Formula 15j]
Figure pat00557
Figure pat00558
Figure pat00559

[Formula 15k] [Formula 15l] [Formula 15m]
Figure pat00560
Figure pat00561
Figure pat00562

[Formula 15n] [Formula 15o] [Formula 15p]
Figure pat00563
Figure pat00564
Figure pat00565

[Formula 15q] [Formula 15r] [Formula 15s]
Figure pat00566
Figure pat00567
Figure pat00568

[Formula 15t] [Formula 15u] [Formula 15v]
Figure pat00569
Figure pat00570
Figure pat00571

[Formula 15w] [Formula 15x] [Formula 15y]
Figure pat00572
Figure pat00573
Figure pat00574

[Formula 15z] [Formula 15za] [Formula 15zb]
Figure pat00575
Figure pat00576
Figure pat00577

[Formula 15zc] [Formula 16a] [Formula 16b]
Figure pat00578
Figure pat00579
Figure pat00580

[Formula 16c] [Formula 16d]
Figure pat00581
Figure pat00582

[Formula 16e] [Formula 16f]
Figure pat00583
Figure pat00584

[Formula 16g] [Formula 16h]
Figure pat00585
Figure pat00586

[Formula 16i] [Formula 16j]
Figure pat00587
Figure pat00588

[Formula 16k] [Formula 16l]
Figure pat00589
Figure pat00590

[Formula 16m] [Formula 16n]
Figure pat00591
Figure pat00592

[Formula 16o] [Formula 16p]
Figure pat00593
Figure pat00594

[Formula 16q] [Formula 16r]
Figure pat00595
Figure pat00596

[Formula 16s] [Formula 16t]
Figure pat00597
Figure pat00598

[Formula 16u] [Formula 16v]
Figure pat00599
Figure pat00600

[Formula 16w] [Formula 16x]
Figure pat00601
Figure pat00602

[Formula 16y] [Formula 16z]
Figure pat00603
Figure pat00604

[Formula 16za] [Formula 16zb]
Figure pat00605
Figure pat00606

[Formula 16zc] [Formula 16zd]
Figure pat00607
Figure pat00608

[Formula 16ze] [Formula 16zf]
Figure pat00609
Figure pat00610

[Formula 16zg] [Formula 16zh]
Figure pat00611
Figure pat00612

[Formula 15zi] [Formula 17a]
Figure pat00613
Figure pat00614

[Formula 17b] [Formula 17c] [Formula 17d]
Figure pat00615
Figure pat00616
Figure pat00617

[Formula 17e] [Formula 17f] [Formula 17g]
Figure pat00618
Figure pat00619
Figure pat00620

[Formula 17h] [Formula 17i] [Formula 17j]
Figure pat00621
Figure pat00622
Figure pat00623

[Formula 17k] [Formula 17l] [Formula 17m]
Figure pat00624
Figure pat00625
Figure pat00626

[Formula 17n] [Formula 17o] [Formula 17p]
Figure pat00627
Figure pat00628
Figure pat00629

[Formula 17q] [Formula 18a] [Formula 18b]
Figure pat00630
Figure pat00631
Figure pat00632

[Formula 18c] [Formula 18d] [Formula 18e]
Figure pat00633
Figure pat00634
Figure pat00635

[Formula 18f] [Formula 18g] [Formula 18h]
Figure pat00636
Figure pat00637
Figure pat00638

[Formula 18i] [Formula 19a] [Formula 19b]
Figure pat00639
Figure pat00640
Figure pat00641

[Formula 19c] [Formula 19d] [Formula 19e]
Figure pat00642
Figure pat00643
Figure pat00644

[Formula 19f] [Formula 19g] [Formula 19h]
Figure pat00645
Figure pat00646
Figure pat00647

[Formula 19i] [Formula 20a] [Formula 20b]
Figure pat00648
Figure pat00649
Figure pat00650

[Formula 20c] [Formula 20d] [Formula 20e]
Figure pat00651
Figure pat00652
Figure pat00653

[Formula 20f] [Formula 21a] [Formula 21b]
Figure pat00654
Figure pat00655
Figure pat00656

[Formula 21c] [Formula 21d] [Formula 21e]
Figure pat00657
Figure pat00659

[Formula 21f] [Formula 21g] [Formula 21h]
Figure pat00660
Figure pat00661
Figure pat00662

[Formula 21i] [Formula 21j] [Formula 22a]
Figure pat00663
Figure pat00664
Figure pat00665

[Formula 22b] [Formula 22c] [Formula 22d]
Figure pat00666
Figure pat00667
Figure pat00668

[Formula 22e] [Formula 22f] [Formula 22g]
Figure pat00669
Figure pat00670
Figure pat00671

[Formula 22h] [Formula 22i] [Formula 22j]
Figure pat00672
Figure pat00673

[Formula 22k] [Formula 22l] [Formula 22m]
Figure pat00675
Figure pat00676
Figure pat00677

[Formula 22n] [Formula 22o] [Formula 22p]
Figure pat00678
Figure pat00679
Figure pat00680

[Formula 23a] [Formula 23b] [Formula 23c]
Figure pat00682
Figure pat00683

[Formula 23d] [Formula 23e] [Formula 23f]
Figure pat00684
Figure pat00685
Figure pat00686

[Formula 23g] [Formula 23h] [Formula 23i]
Figure pat00687
Figure pat00688
Figure pat00689

[Formula 23j] [Formula 23k] [Formula 23l]
Figure pat00690
Figure pat00691
Figure pat00692

[Formula 23m] [Formula 23n] [Formula 23o]
Figure pat00693
Figure pat00694
Figure pat00695

[Formula 23p] [Formula 23q] [Formula 23r]
Figure pat00696
Figure pat00697
Figure pat00698

[Formula 23s] [Formula 23t] [Formula 23u]
Figure pat00699
Figure pat00700
Figure pat00701

[Formula 23v] [Formula 23w] [Formula 23x]
Figure pat00702
Figure pat00703
Figure pat00704

[Formula 23y] [Formula 23z] [Formula 23za]
Figure pat00705
Figure pat00706
Figure pat00707

[Formula 23zb] [Formula 23zc] [Formula 23zd]
Figure pat00708
Figure pat00709
Figure pat00710

[Formula 23ze] [Formula 23zf] [Formula 23zg]
Figure pat00711
Figure pat00712
Figure pat00713

[Formula 23zh] [Formula 24a]
Figure pat00714
Figure pat00715

[Formula 24b] [Formula 24c]
Figure pat00717

[Formula 24d] [Formula 24e]
Figure pat00718
Figure pat00719

[Formula 24f] [Formula 24g]
Figure pat00720
Figure pat00721

[Formula 24h] [Formula 24i]
Figure pat00722
Figure pat00723

[Formula 24j] [Formula 25a]
Figure pat00724
Figure pat00725

[Formula 25b] [Formula 26a] [Formula 26b]
Figure pat00726
Figure pat00727
Figure pat00728

[Formula 27a] [Formula 27b] [Formula 27c]
Figure pat00729
Figure pat00730
Figure pat00731

[Formula 27d] [Formula 27e] [Formula 27f]
Figure pat00732
Figure pat00733
Figure pat00734

[Formula 27g] [Formula 27h] [Formula 27i]
Figure pat00735
Figure pat00736
Figure pat00737

[Formula 30a] [Formula 30b] [Formula 30c]
Figure pat00738
Figure pat00739
Figure pat00740

[Formula 31a] [Formula 31b] [Formula 31c]
Figure pat00741
Figure pat00742

[Formula 31d] [Formula 31e]
Figure pat00744
Figure pat00745

[Formula 31f] [Formula 31g] [Formula 31h]
Figure pat00746
Figure pat00747
Figure pat00748

[Formula 31i] [Formula 31j] [Formula 31k]
Figure pat00749
Figure pat00750
Figure pat00751
 제 1 항에 있어서,
상기 약학적으로 수용 가능한 염은 염산, 브롬화수소산, 요오드화수소산, 황산, 질산, 인산, 메탄설폰산, 벤젠설폰산, 포름산, 아세트산, 트리플루오로 아세트산, 프로피온산, 옥살산, 말론산, 숙신산, 푸마르산, 말레산, 젖산, 말산, 타르타르산, 시트르산, 에탄설폰산, 아스파르트산 및 글루탐산으로 구성된 군에서 선택된 1종 이상인 것을 특징으로 하는 피라졸로피리미딘 유도체 화합물 또는 이의 약학적으로 수용 가능한 염.The method of claim 1,
The pharmaceutically acceptable salts include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, acetic acid, trifluoro acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, A pyrazolopyrimidine derivative compound or a pharmaceutically acceptable salt thereof characterized in that it is at least one member selected from the group consisting of maleic acid, lactic acid, malic acid, tartaric acid, citric acid, ethanesulfonic acid, aspartic acid and glutamic acid. 약학적 수용 가능한 담체 또는 희석제와 함께 활성성분으로서 제 1 항 내지 제 7 항 중 어느 한 항에 따른 화합물을 함유하는 산화질소 생성 억제용 약학 조성물.A pharmaceutical composition for inhibiting nitric oxide production, which contains a compound according to any one of claims 1 to 7 as an active ingredient together with a pharmaceutically acceptable carrier or diluent. 약학적 수용 가능한 담체 또는 희석제와 함께 활성성분으로서 제 1 항 내지 제 7 항 중 어느 한 항에 따른 화합물을 함유하는 뇌신경 질환 치료용 조성물.A composition for treating cranial nerve disease, comprising the compound according to any one of claims 1 to 7 as an active ingredient together with a pharmaceutically acceptable carrier or diluent. 제 9 항에 있어서,
상기 뇌신경 질환은 파킨슨병, 알츠하이머 치매, 헌팅턴병, 루게릭병, 간질, 우울증, 통증 불안증 및 퇴행성 뇌신경 질환 중에서 선택되는 어느 하나인 것을 특징으로 하는 뇌신경 질환 치료용 조성물.The method of claim 9,
Wherein the cranial nerve disease is any one selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, Lou Gehrig's disease, epilepsy, depression, pain anxiety, and degenerative brain disease.
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