KR20220099825A - Compounds for inhibiting Bruton's tyrosine kinase and medical uses thereof - Google Patents

Compounds for inhibiting Bruton's tyrosine kinase and medical uses thereof Download PDF

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KR20220099825A
KR20220099825A KR1020210002162A KR20210002162A KR20220099825A KR 20220099825 A KR20220099825 A KR 20220099825A KR 1020210002162 A KR1020210002162 A KR 1020210002162A KR 20210002162 A KR20210002162 A KR 20210002162A KR 20220099825 A KR20220099825 A KR 20220099825A
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phenyl
oxy
amino
dihydrofuro
acrylamide
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김성은
이선호
이용협
공윤정
백민서
김민정
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주식회사 온코빅스
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Abstract

The present invention provides a compound, having a specific chemical structure, which has a Bruton's tyrosine kinase (BTK)-inhibiting activity, or a pharmaceutically acceptable salt thereof. The present invention provides a composition comprising the compound or the pharmaceutically acceptable salt thereof. The present invention provides a pharmaceutical use, for treating or preventing BTK-related diseases, of the compound according to the present invention, a salt thereof, and a composition comprising the compound or the salt. The present invention also provides a method for treating or preventing BTK-related diseases. The method comprises administering an effective amount of the compound according to the present invention, a salt thereof, or a composition comprising the compound or the salt to a subject in need of treatment.

Description

브루톤 타이로신 키나제 억제용 화합물 및 이들의 의약 용도{Compounds for inhibiting Bruton's tyrosine kinase and medical uses thereof}Compounds for inhibiting Bruton's tyrosine kinase and medical uses thereof

본 발명은 브루톤 타이로신 키나제(Bruton's tyrosine kinase, Btk)를 억제하고, B 세포의 이상(aberrant) 활성화에 의해 유발된 종양학적 자가면역 및 염증성 질환의 치료에 유용한 신규한 화합물 및 이의 의약 용도에 관한 것이다.The present invention inhibits Bruton's tyrosine kinase (Btk), and relates to a novel compound useful for the treatment of oncological autoimmune and inflammatory diseases caused by aberrant activation of B cells, and a pharmaceutical use thereof will be.

Tec 패밀리는 단백질 타이로신 키나제 중의 하위 패밀리이며, Tec, Btk, Itk/Tsk/Emt, Bmx, Txk/Rlk 등이 속해 있다. 이들 중 많은 키나제가 조혈 조직의 성장 및 분화 자극에 반응하여 활성화되는 것으로 나타났기 때문에 생체 내에서 중요한 신호 매개체로 기능하는 것으로 추정된다. Tec 계열 구성원의 특징 중 하나는 단백질 구조에 pleckstrin 상동성 도메인이 존재한다는 것인데, 이는 인지질 의존 신호 전달 경로와의 물리적 및 기능적 상호 작용을 시사한다 (문헌 [Int J Hematol 1999 Jan;69(1):6-12]).The Tec family is a subfamily of protein tyrosine kinases, and includes Tec, Btk, Itk/Tsk/Emt, Bmx, Txk/Rlk, and the like. Since many of these kinases have been shown to be activated in response to stimulation of growth and differentiation of hematopoietic tissues, they are presumed to function as important signaling mediators in vivo. One of the hallmarks of Tec family members is the presence of pleckstrin homology domains in their protein structures, suggesting physical and functional interactions with phospholipid-dependent signaling pathways (Int J Hematol 1999 Jan;69(1): 6-12]).

이러한 타이로신 키나제는 세포 성장, 이동 및 분화를 조절하는 것으로 알려져 있으며, 비정상적인 키나아제 활성은 암, 자가면역 및 염증성 질환을 비롯한 다양한 인간 질환에 연루되어 있다. 단백질 키나제는 세포 신호의 핵심 조절자 중 하나이므로, 소분자 키나아제 억제제로 세포 기능을 조절하는 표적이 된다. These tyrosine kinases are known to regulate cell growth, migration and differentiation, and aberrant kinase activity has been implicated in a variety of human diseases, including cancer, autoimmune and inflammatory diseases. Since protein kinases are one of the key regulators of cellular signaling, they are targets for regulating cellular functions with small molecule kinase inhibitors.

한편, B 세포가 자가면역 및/또는 염증성 질환의 발병에 있어서 핵심 역할을 한다는 좋은 증거가 있다. B 세포를 고갈시키는 단백질계 치료제, 예를 들면 리툭산(Rituxan)은 자가항체-유도된 염증성 질환, 예를 들면 류마티스 관절염에 효과적이다(문헌 [Rastetter et al. Annu Rev Med 2004 55:477]). 따라서, B 세포 활성화에서 역할을 하는 단백질 키나제의 억제제는 B 세포-매개된 질환의 병증, 예를 들면 자가항체 생산에 대한 유용한 치료제일 수 있다. On the other hand, there is good evidence that B cells play a key role in the pathogenesis of autoimmune and/or inflammatory diseases. Protein-based therapeutics that deplete B cells, such as Rituxan, are effective in autoantibody-induced inflammatory diseases such as rheumatoid arthritis (Rastetter et al. Annu Rev Med 2004 55:477). Thus, inhibitors of protein kinases that play a role in B cell activation may be useful therapeutic agents for conditions of B cell-mediated diseases, for example autoantibody production.

B 세포 수용체(BCR)를 통한 신호는 성숙한 항체 생산 세포로의 증식 및 분화를 포함하는 다양한 B 세포 반응을 제어한다. BCR은 B 세포 활성에 대한 핵심 조절 요소이고, 이상 신호는 다수의 자가면역 및/또는 염증성 질환을 초래하는 병원성 자가항체의 형성 및 탈조절된 B 세포 증식을 야기할 수 있다. 브루톤 타이로신 키나제(Btk)는, 막 근위성(membrane proximal)이고, BCR의 바로 하류인 비-BCR 회합 키나아제이다. Btk의 결핍은 BCR 신호를 차단하는 것으로 나타났고, 따라서 Btk의 억제는 B 세포-매개된 질환 과정을 차단하는데 유용한 치료적 접근이다.Signaling through the B cell receptor (BCR) controls a variety of B cell responses, including proliferation and differentiation into mature antibody-producing cells. The BCR is a key regulatory element for B cell activity, and aberrant signaling can lead to the formation of pathogenic autoantibodies and deregulated B cell proliferation leading to a number of autoimmune and/or inflammatory diseases. Bruton's tyrosine kinase (Btk) is a non-BCR-associated kinase that is membrane proximal and immediately downstream of the BCR. Depletion of Btk has been shown to block BCR signaling, and thus inhibition of Btk is a useful therapeutic approach to block B cell-mediated disease processes.

앞서 설명한 바와 같이, Btk는 타이로신 키나제의 Tec 패밀리의 일원이고, 초기 B 세포 발달, 및 성숙한 B 세포 활성화 및 생존의 중요한 조절자인 것으로 나타났다(문헌 [Khan et al. Immunity 1995 3:283] 및 [Ellmeier et al. J. Exp. Med. 2000 192:1611]). 인간에서의 Btk 돌연변이는 X-연관성 무감마글로불린혈증(XLA) 질환을 초래한다(문헌 [Rosen et al. New Eng. J. Med. 1995 333:431] 및 [Lindvall et al. Immunol. Rev. 2005 203:200]). 이러한 환자들은 면역이 손상되고, B 세포의 손상된 성숙, 감소된 면역글로불린 및 말초 B 세포 수준, 줄어든 T 세포 독립성 면역 반응뿐만 아니라 BCR 자극 후 약화된 칼슘 가동화를 나타낸다.As previously described, Btk is a member of the Tec family of tyrosine kinases and has been shown to be an important regulator of early B cell development, and mature B cell activation and survival (Khan et al. Immunity 1995 3:283 and Ellmeier). et al. J. Exp. Med. 2000 192:1611]). Btk mutations in humans result in X-linked agammaglobulinemia (XLA) disease (Rosen et al. New Eng. J. Med. 1995 333:431 and Lindvall et al. Immunol. Rev. 2005). 203:200]). These patients exhibit compromised immunity, impaired maturation of B cells, decreased immunoglobulin and peripheral B cell levels, reduced T cell independent immune responses, as well as weakened calcium mobilization following BCR stimulation.

자가면역 및 염증성 질환에서 Btk의 역할에 대한 증거는 또한 Btk-결핍 마우스 모델에 의해 제공되었다. 전신 홍반성 루푸스(SLE)의 임상전 뮤린 모델에서, Btk-결핍 마우스는 질환 진행의 현저한 개선을 나타낸다. 또한, Btk-결핍 마우스는 콜라겐-유도 관절염에 대해 내성이 있다(문헌 [Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459]). 선택적인 Btk 억제제는 마우스 관절염 모델에서 투여량-의존적 효능이 있는 것으로 입증되었다 (문헌 [Z. Pan et al., Chem. Med Chem. 2007 2:58-61]).Evidence for a role for Btk in autoimmune and inflammatory diseases has also been provided by a Btk-deficient mouse model. In a preclinical murine model of systemic lupus erythematosus (SLE), Btk-deficient mice show a marked improvement in disease progression. In addition, Btk-deficient mice are resistant to collagen-induced arthritis (Jansson and Holmdahl Clin. Exp. Immunol. 1993 94:459). Selective Btk inhibitors have been demonstrated to have dose-dependent efficacy in a mouse arthritis model (Z. Pan et al., Chem. Med Chem. 2007 2:58-61).

Btk는 또한 질환 과정에 수반될 수 있는 B 세포 이외의 세포에 의해 발현된다. 예를 들면, Btk는 비만 세포에 의해 발현되고, Btk-결핍 골수 유래된 비만 세포는 손상된 항원-유도된 탈과립화(degranulation)를 입증한다(문헌 [Iwaki et al. J. Biol. Chem. 2005 280:40261]). 이는 Btk가 병적 비만 세포 반응, 예를 들면 알레르기 및 천식을 치료하는데 유용할 수 있음을 나타낸다. 또한, Btk 활성이 없는 XLA 환자로부터의 단핵구는 자극 후 감소된 TNF 알파 생산을 나타낸다(문헌 [Horwood et al. J Exp Med 197:1603, 2003]). 따라서, TNF 알파 매개된 염증은 소분자 Btk 억제제에 의해 조절될 수 있다. 또한, Btk는 세포자멸(apoptosis) 시 역할을 하는 것으로 보고되었고(문헌[Islam and Smith Immunol. Rev. 2000 178:49]), 따라서 Btk 억제제는 특정 B 세포 림프종 및 백혈병의 치료에 유용할 수 있다(문헌 [Feldhahn et al. J. Exp. Med. 2005 201:1837]).Btk is also expressed by cells other than B cells, which may be involved in the disease process. For example, Btk is expressed by mast cells, and Btk-deficient bone marrow derived mast cells demonstrate impaired antigen-induced degranulation (Iwaki et al. J. Biol. Chem. 2005 280). :40261]). This indicates that Btk may be useful in treating pathological mast cell responses such as allergies and asthma. In addition, monocytes from XLA patients without Btk activity show decreased TNF alpha production after stimulation (Horwood et al. J Exp Med 197:1603, 2003). Thus, TNF alpha mediated inflammation can be modulated by small molecule Btk inhibitors. In addition, Btk has been reported to play a role in apoptosis (Islam and Smith Immunol. Rev. 2000 178:49), thus Btk inhibitors may be useful in the treatment of certain B cell lymphomas and leukemias. (Feldhahn et al. J. Exp. Med. 2005 201:1837).

한편, Btk 억제제는 다발성 경화증의 치료에도 유용한 것으로 알려져 있다(문헌 [N Engl J Med 2019; 380:2406-2417, DOI: 10.1056/NEJMoa1901981]). On the other hand, Btk inhibitors are also known to be useful in the treatment of multiple sclerosis (N Engl J Med 2019; 380:2406-2417, DOI: 10.1056/NEJMoa1901981).

한국 등록특허 제10-1824346호Korean Patent Registration No. 10-1824346

따라서 본 발명이 해결하고자 하는 과제는 Btk 억제 활성을 가지는 화합물, 이들을 유효성분으로 포함하는 약학 조성물, 및 이들의 다양한 질환의 치료 또는 예방용 의약 용도를 제공하는 것이다. Accordingly, an object of the present invention is to provide a compound having Btk inhibitory activity, a pharmaceutical composition comprising the same as an active ingredient, and a pharmaceutical use for treating or preventing various diseases thereof.

본 발명이 해결하고자 하는 다른 과제는 Btk를 억제하는 것을 특징으로 하는, 본 발명에 따른 화합물을 다양한 질환의 치료, 개선 또는 예방이 필요한 환자에게 투여하는 것을 특징으로 하는 다양한 질환의 치료 또는 개선 방법을 제공하는 것이다.Another problem to be solved by the present invention is to provide a method for treating or ameliorating various diseases, characterized in that the compound according to the present invention is administered to a patient in need of treatment, improvement or prevention of various diseases, characterized in that it inhibits Btk will provide

본 발명의 화합물compounds of the present invention

상기 해결하고자 하는 과제를 달성하기 위하여, 일 양태에서, 본 발명은 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다. In order to achieve the above object, in one aspect, the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

Figure pat00001
Figure pat00001

상기 화학식 1에서, In Formula 1,

X는

Figure pat00002
,
Figure pat00003
,
Figure pat00004
,
Figure pat00005
,
Figure pat00006
, 또는
Figure pat00007
이고, 여기에서 Y는 직접 연결 또는
Figure pat00008
이며,X is
Figure pat00002
,
Figure pat00003
,
Figure pat00004
,
Figure pat00005
,
Figure pat00006
, or
Figure pat00007
, where Y is a direct connection or
Figure pat00008
is,

Z은

Figure pat00009
또는
Figure pat00010
이고, 여기에서
Figure pat00011
는 단일 결합 또는 이중 결합이며,Z is
Figure pat00009
or
Figure pat00010
and here
Figure pat00011
is a single bond or a double bond,

R1은 C1-4알킬 (바람직하게는, methyl, ethyl, 또는 isopropyl), C1-4알킬-C(O)- (바람직하게는, methyl-C(O)-), (1,2-dithiolan-3-yl)pentanoyl, H, 6-methyl-2,6-diazaspiro[3.3]heptan-2-yl, 또는 2-oxy-6-azaspiro[3.3]heptan-6-yl이고, R 1 is C 1-4 alkyl (preferably, methyl, ethyl, or isopropyl), C 1-4 alkyl-C(O)- (preferably, methyl-C(O)-), (1,2 -dithiolan-3-yl)pentanoyl, H, 6-methyl-2,6-diazaspiro[3.3]heptan-2-yl, or 2-oxy-6-azaspiro[3.3]heptan-6-yl,

R2는 H, 할로겐 (바람직하게는 F), 또는 C1-3알콕시 (바람직하게는, methoxy)이고,R 2 is H, halogen (preferably F), or C 1-3 alkoxy (preferably, methoxy),

R3 및 R4는 서로 독립적으로 H 또는 C1-4알킬 (바람직하게는, methyl)이고, R 3 and R 4 are each independently H or C 1-4 alkyl (preferably, methyl),

R5는 H 또는 C1-4알킬 (바람직하게는, methyl)임.R 5 is H or C 1-4 alkyl (preferably, methyl).

본 발명자들은 앞서 언급한 목적을 달성하기 위하여, 특히 Btk 억제 활성은 높고, 다양한 Tec family에 효과를 보이며, 결과적으로 염증성 질환, 자가면역 질환 등을 포함하는 다양한 질환의 치료 또는 예방 효과는 좋고 다른 부작용이 감소한 화합물들을 찾고자 노력하였다. 이를 위해 다양한 화합물들을 합성 후 다양한 평가실험을 수행하였으며, 최종적으로 본 발명의 화합물들이 본 발명의 목적에 적합함을 확인하여 본 발명을 완성하였다.In order to achieve the above-mentioned object, the present inventors, in particular, have high Btk inhibitory activity, show effects on various Tec families, and as a result, have good therapeutic or preventive effects on various diseases including inflammatory diseases and autoimmune diseases and other side effects Efforts were made to find these reduced compounds. To this end, various evaluation experiments were performed after synthesizing various compounds, and finally the present invention was completed by confirming that the compounds of the present invention were suitable for the purpose of the present invention.

특히, 본 발명의 화합물들은 5,7-다이하이드로퓨로[3,4-d]피리미딘을 중심으로 하는 특징적인 구조를 가지며, 이러한 구조적 특징으로 인해 유사한 화합물들보다 Btk 억제 등의 측면에서 다 나은 약효를 보인다. 또, 본 발명의 화합물들은 Tec family에 해당하는 다양한 kinase들을 저해하는 활성을 나타내어 시너지즘 효과를 나타낼 수 있으며, 이를 통해 류마티스, 염증 등을 포함하는 다양한 질환의 효과적인 치료제가 될 수 있다. In particular, the compounds of the present invention have a characteristic structure centered on 5,7-dihydrofuro[3,4-d]pyrimidine, and due to these structural characteristics, they are different from similar compounds in terms of Btk inhibition, etc. shows better efficacy. In addition, the compounds of the present invention can exhibit a synergistic effect by inhibiting various kinases corresponding to the Tec family, thereby becoming an effective therapeutic agent for various diseases including rheumatism and inflammation.

보다 바람직한 본 발명의 일 태양에 있어, 상기 화학식 1에서 In a more preferred aspect of the present invention, in Formula 1

X는

Figure pat00012
이고, 여기에서 Y는 직접 연결이며,X is
Figure pat00012
, where Y is a direct connection,

Z은

Figure pat00013
이고, 여기에서
Figure pat00014
는 단일 결합 또는 이중 결합이며,Z is
Figure pat00013
and here
Figure pat00014
is a single bond or a double bond,

R1은 methyl, ethyl, 또는 isopropyl이고, R 1 is methyl, ethyl, or isopropyl;

R2는 H, 또는 F이고,R 2 is H, or F;

R3 및 R4는 H이다.R 3 and R 4 are H.

본 발명에 있어 "약학적으로 허용 가능한 염"은 여기서 언급한 화합물들에서 발견되는 특정 치환체에 의존하는 비교적 비독성 산으로 제조된 활성 화합물의 염들을 포함한다. 산성 부가 염들은 충분한 양의 원하는 산, 순수한 또는 적당한 비활성(inert) 용매로 그러한 화합물들의 중성 형태를 접촉하여 얻을 수 있다. 약학적으로 허용 가능한 산성 부가 염의 예들은 초산, 프로피온산, 이소부틸산, 옥살릭산(oxalic), 마레익(maleic), 말로닉(malonic), 안식향성, 숙신산, 수버릭(suberic), 푸마릭(fumaric), 만데릭(mandelic), 프탈릭(phthalic), 벤젠설포닉(benzenesulfonic), p-토릴설포닉(tolylsulfonic), 구연산, 주석산, 메탄솔포닉(methanesulfonic), 및 그 유사체를 포함하는 상대적으로 비독성 유기산에서 유래한 염들 뿐만 아니라, 염화수소, 브롬화 수소, 질산, 탄산, 일수소탄산(monohydrogencarbonic), 인산(phosphoric), 일수소인산, 이수소인산, 황산, 일수소황산, 요오드화수소 또는 아인산(phosphorous acid) 및 그 유사체를 포함한다. 또한 알긴네이트(arginate)와 그 유사체와 같은 아미노산의 염 및 글루쿠로닉(glucuronic) 또는 갈락투노릭(galactunoric) 산들과 그 유사체와 같은 유기산의 유사체를 포함한다. 염들의 다른 예들은 본 발명이 속한 분야에서 공지된 문헌들로부터 파악할 수 있다. "Pharmaceutically acceptable salts" in the present invention include salts of the active compounds prepared with relatively non-toxic acids which depend on the particular substituents found on the compounds mentioned herein. Acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, neat or with a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts are acetic acid, propionic acid, isobutyric acid, oxalic acid, maleic, malonic, benzoic, succinic, suberic, fumaric ( fumaric), mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric acid, tartaric acid, methanesulfonic, and the like. As well as salts derived from non-toxic organic acids, hydrogen chloride, hydrogen bromide, nitric acid, carbonic acid, monohydrogencarbonic, phosphoric, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydrogen iodide or phosphorous acid ( phosphorous acid) and its analogs. Also included are salts of amino acids such as arginate and analogues thereof and analogues of organic acids such as glucuronic or galactunoric acids and analogues thereof. Other examples of salts can be found in literature known in the art.

본 명세서에서 사용된 용어인 "본 발명의 화합물"은 화학식 1의 각각의 화합물들뿐만 아니라, 이들의 클라드레이트(clathrates), 수화물, 용매화물, 또는 다형체를 포함하는 의미이다. 또한 용어 “본 발명의 화합물”은 이의 약학적으로 허용 가능한 염이 언급되지 않을 경우 본 발명 화합물의 약학적으로 허용 가능한 염도 포함하는 의미이다. 일 실시예에 본 발명의 화합물은 입체이성질체적으로 순수한 화합물들(예를 들어, 다른 입체이성질체가 실질적으로 없는(예를 들어, 85% ee 이상, 90% ee 이상, 95% ee 이상, 97% ee 이상, 또는 99% ee 이상))로 존재할 수 있다. 즉, 본 발명에 따른 화학식 1의 화합물 또는 그의 염이 호변이성적(tautomeric) 이성질체 및/또는 입체이성질체(예를 들어, 기하이성질체(geometrical isomer) 및 배좌 이성질체(conformational isomers))일 경우 그들의 분리된 이성질체 및 혼합물 각각 또한 본 발명의 화합물의 범주에 포함된다. 본 발명의 화합물 또는 그의 염이 구조 내에 비대칭 탄소(asymmetric carbon)를 가지고 있는 경우에, 그들의 광학 활성 화합물 및 라세믹 혼합물들 또한 본 발명의 화합물의 범위에 포함된다. As used herein, the term "compound of the present invention" is meant to include each compound of Formula 1, as well as clathrates, hydrates, solvates, or polymorphs thereof. In addition, the term “compound of the present invention” is meant to include a pharmaceutically acceptable salt of the compound of the present invention unless a pharmaceutically acceptable salt thereof is mentioned. In one embodiment, a compound of the invention is a stereoisomerically pure compound (e.g., substantially free of other stereoisomers (e.g., at least 85% ee, at least 90% ee, at least 95% ee, 97% ee or more, or 99% ee or more)). That is, when the compound of Formula 1 or a salt thereof according to the present invention is a tautomeric isomer and/or stereoisomer (eg, geometrical isomer and conformational isomers), their separated isomers and mixtures, respectively, are also included within the scope of the compounds of the present invention. When the compound of the present invention or a salt thereof has an asymmetric carbon in its structure, their optically active compounds and racemic mixtures are also included in the scope of the compound of the present invention.

본 명세서에서 사용될 경우, 용어 "결정다형(polymorph)"은 본 발명의 화합물의 고체 결정 형태 또는 그것의 복합체를 의미한다. 같은 화합물의 다른 결정다형은 다른 물리적, 화학적 그리고/또는 스펙트럼적 특성을 보인다. 물리적 특성 측면의 차이점으로는 안정성(예를 들어, 열 또는 빛 안정성), 압축성과 밀도(제제화 및 생산물 제조에 중요함), 그리고 용해율(생물학적 이용률에 영향을 줄 수 있음)을 포함하나, 이에 한정되지 아니한다. 안정성에서 차이는 화학반응성 변화들(예를 들어, 또 다른 다형으로 구성되었을 때보다 하나의 다형으로 구성되었을 때 더 빠르게 변색이 되는 것 같은 차별적 산화) 또는 기계적인 특징들(예를 들어 동역학적으로 선호된 다형체로서 저장된 정제 파편들이 열역학 적으로 더 안정된 다형으로 변환) 또는 둘 다(하나의 다형의 정제는 높은 습도에서 더 분해에 예민)를 야기한다. 결정다형의 다른 물리적 성질들은 그들의 가공에 영향을 줄 수 있다. 예를 들어, 한 결정다형은 또 다른 결정다형에 비하여, 예를 들어, 그것의 형태 또는 입자의 크기 분포에 기인하여 용매화합물을 형성할 가능성이 많을 수 있거나, 여과 또는 세척이 더 어려울 수 있다.As used herein, the term “polymorph” refers to a solid crystalline form of a compound of the present invention or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and/or spectral properties. Differences in physical properties include, but are not limited to, stability (eg, thermal or light stability), compressibility and density (important for formulation and product manufacturing), and dissolution rate (which may affect bioavailability). doesn't happen Differences in stability may be due to changes in chemical reactivity (e.g., differential oxidation, such as a faster discoloration when composed of one polymorph than when composed of another polymorph) or mechanical properties (e.g., kinetically Tablet fragments stored as the preferred polymorph are converted to the thermodynamically more stable polymorph) or both (tablets of one polymorph are more susceptible to degradation at high humidity). Other physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate than another polymorph, for example due to its shape or particle size distribution, or it may be more difficult to filter or wash.

본 명세서에서 사용된 용어 "용매 화합물"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 용매를 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다. 바람직한 용매들은 휘발성이고, 비독성이며, 인간에게 극소량 투여될 수 있다.As used herein, the term "solvent compound" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, comprising a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and can be administered in trace amounts to humans.

본 명세서에서 사용된 용어 "수화물(hydrate)"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 물을 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다. As used herein, the term "hydrate" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, comprising a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. .

본 명세서에서 사용된 용어 "클라드레이트(clathrate)"은 게스트 분자(예를 들어, 용매 또는 물)를 가두어 놓은 공간(예를 들어, 채널(channel))을 포함한 결정 격자의 형태의 본 발명의 화합물 또는 그것의 염을 의미한다. As used herein, the term "clathrate" refers to a compound of the present invention in the form of a crystal lattice containing spaces (eg, channels) that confine guest molecules (eg, solvent or water). or salts thereof.

본 명세서에서 사용된 용어 "정제된(purified)"은 분리될 때, 분리체는 90% 이상 순수한 것을 의미하며, 일 실시예에서는 95% 이상 순수하고, 다른 실시 예에서는 99% 이상 순수하고, 또 다른 실시예에서는 99.9% 이상 순수한 것을 의미한다.The term "purified" as used herein, when isolated, means that the isolate is at least 90% pure, in one embodiment at least 95% pure, in another embodiment at least 99% pure, and In another embodiment, it means at least 99.9% pure.

비-한정적인, 본 발명에 따른 화합물의 예로는 하기 화합물 및 이의 약학적으로 허용 가능한 염을 포함한다.Non-limiting examples of compounds according to the present invention include the following compounds and pharmaceutically acceptable salts thereof.

N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드, N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide,

N-(3-((7,7-다이메틸-2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드, N-(3-((7,7-dimethyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d ]pyrimidin-4-yl)oxy)phenyl)acrylamide,

N-(3-((2-((3-플루오로-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드, N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide,

N-(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide,

N-(3-((2-((2-플루오로-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide,

N-(3-((2-((4-몰포리노페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((4-morpholinophenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide,

N-(3-((2-((4-(4-이소프로필피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidine-4- yl) oxy) phenyl) acrylamide,

N-(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide,

N-(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((4-(2-methoxyethoxy)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy) phenyl) acrylamide,

N-(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide,

N-(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidine-4- yl) oxy) phenyl) acrylamide,

N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)프로피온아마이드,N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl ) oxy) phenyl) propionamide,

N-(3-((2-((4-((3-메틸이소싸이아졸-5-일)아미노)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((4-((3-methylisothiazol-5-yl)amino)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidine -4-yl) oxy) phenyl) acrylamide,

(R)-N-(3-((2-((4-(4-(5-(1,2-다이싸이올란-3-일)펜타노일)피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,(R)-N-(3-((2-((4-(4-(5-(1,2-dithiolan-3-yl)pentanoyl)piperazin-1-yl)phenyl)amino) -5,7-dihydrofuro [3,4-d] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N-(3-((2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5,7-di hydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide,

N-(3-((2-((2-메톡시-4-(4-몰포리노피페리딘-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d ]pyrimidin-4-yl)oxy)phenyl)acrylamide,

(R)-1-(3-((2-((4-(4-(5-(1,2-아이싸이올란-3-일)펜타노일)피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)-1H-피롤-2,5-다이온,(R)-1-(3-((2-((4-(4-(5-(1,2-Ithiolan-3-yl)pentanoyl)piperazin-1-yl)phenyl)amino) -5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1H-pyrrole-2,5-dione,

N-(3-((2-((4-(4-(5-(1,2-다이싸이올란-3-일)펜타노일)피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((4-(4-(5-(1,2-dithiolan-3-yl)pentanoyl)piperazin-1-yl)phenyl)amino)-5,7 -dihydrofuro [3,4-d] pyrimidin-4-yl) oxy) phenyl) acrylamide,

N-(3-((2-((4-(피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,N-(3-((2-((4-(piperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy) phenyl) acrylamide,

N-(3-((2-((2-메톡시-4-(4-(6-메틸-2,6-다이아자스피로[3.3]헵탄-2-일)피페리딘-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드, 또는N-(3-((2-((2-methoxy-4-(4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl) phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide, or

N-(3-((2-(4-(4-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피페리딘-1-일)-2-메톡시벤질)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드.N-(3-((2-(4-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)piperidin-1-yl)-2-methoxybenzyl)-5 ,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide.

보다 바람직하게, 본 발명에 따른 화합물로는 N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드, N-(3-((2-((3-플루오로-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드, N-(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드, 또는 이의 약학적으로 허용 가능한 염이 본 발명의 목적상 바람직하다. More preferably, the compound according to the present invention is N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3 ,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide, N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl) Amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide, N-(3-((2-((4-(4-ethylpipeline) Razin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide, or a pharmaceutically acceptable salt thereof It is preferred for the purposes of the invention.

본 발명 화합물의 의약 용도 및 치료 방법Pharmaceutical Uses and Methods of Treatment of the Compounds of the Invention

본 발명의 Btk 억제용 화합물들은 다양한 치료학적 또는 예방학적 용도에 유용하다. 이러한 화합물들은 Btk를 억제하기 위하여 사용될 수 있어, Btk를 억제하여 개선될 수 있는 다양한 질환의 치료 또는 예방에 유용하다. 따라서 본 발명은 세포 내 Btk를 억제하는 방법을 제공한다. 이러한 방법에서 상기 세포는 본 발명의 화합물의 유효한 양과 접촉하게 된다. 일 실시예에서, 상기 세포는 개체 (예를 들어, 환자) 내에 존재한다. The compounds for inhibiting Btk of the present invention are useful for a variety of therapeutic or prophylactic applications. These compounds can be used to inhibit Btk, and are useful for the treatment or prevention of various diseases that can be ameliorated by inhibiting Btk. Accordingly, the present invention provides a method for inhibiting intracellular Btk. In this method the cells are contacted with an effective amount of a compound of the invention. In one embodiment, the cell is present in a subject (eg, a patient).

즉, 본 발명은 하나 이상의 상기와 같은 화합물의 치료적으로 유효한 양을 개체에게 투여함으로써 Btk를 억제하여 개선될 수 있는 다양한 질환, 예를 들어, 다발성 경화증; 염증 등을 포함하는 염증성 질환; 두드러기, 전신 홍반성 루푸스, 알레르기, 류마티스 관절염, 천식 등을 포함하는 자가면역 질환; 또는 발덴스트롬 마크로글로불린혈증, B 세포 림프종, 백혈병 등을 포함하는 B 세포 관련 암을 갖거나 갖기 쉬운 개체에서 해당 질병 또는 상태(condition)를 치료하는 방법을 더 제공한다. 일 양태에서, 상기 치료는 예방 치료(preventative treatment)이다. 또 다른 양태에서, 상기 치료는 완화 치료(palliative treatment)이다. 또 다른 양태에서, 상기 치료는 회복 치료(restorative treatment)이다.That is, the present invention relates to a variety of diseases that can be ameliorated by inhibiting Btk by administering to a subject a therapeutically effective amount of one or more of the above compounds, for example, multiple sclerosis; inflammatory diseases including inflammation and the like; autoimmune diseases including urticaria, systemic lupus erythematosus, allergies, rheumatoid arthritis, asthma and the like; or a method of treating the disease or condition in a subject having or prone to having a B cell-associated cancer, including Waldenstrom's macroglobulinemia, B cell lymphoma, leukemia, and the like. In one aspect, the treatment is a preventative treatment. In another embodiment, the treatment is a palliative treatment. In another embodiment, the treatment is a restorative treatment.

본 명세서에서 사용된 "유효량" 또는 "유효한 양"은 본 발명 치료 또는 예방 대상 질환의 확장을 늦추거나 또는 최소화하거나; 또는 치료 또는 관리에서 치료상 이점을 제공하기에 충분한 본 발명의 화합물의 양을 말한다. "유효량"은 또한 생체외(in vitro) 또는 생체내(in vivo) 어떤 쪽이든 Btk 활성을 억제 또는 줄이기에 충분한 양을 말한다. As used herein, “effective amount” or “effective amount” means slowing or minimizing the spread of the disease to be treated or prevented by the present invention; or an amount of a compound of the invention sufficient to provide a therapeutic benefit in treatment or management. "Effective amount" also refers to an amount sufficient to inhibit or reduce Btk activity, either in vitro or in vivo.

본 발명에 따라 치료될 적합한 개체는 포유동물 개체를 포함한다. 본 발명에 따른 포유동물은, 이에 한정되는 것은 아니지만, 인간, 개(canine), 고양잇과동물(feline), 소(bovine), 염소(caprine), 말(equine), 양(ovine), 돼지(porcine), 설치류(rodents), 토끼목(lagomorphs), 영장류(primates) 등을 포함하고, 자궁 내의(in utero) 포유동물을 포함한다. 개체는 양쪽 성(性) 모두 일 수 있고 발생(development)의 임의의 단계일 수 있다. 일 양태에서, 본 발명에 따른 치료될 적합한 개체는 인간이다.Suitable subjects to be treated according to the present invention include mammalian subjects. Mammals according to the present invention include, but are not limited to, humans, canine, feline, bovine, goat (caprine), equine, sheep (ovine), pig (porcine), rodents (rodents), lagomorphs (lagomorphs), primates (primates) and the like, including in utero ( in utero ) mammals. An individual may be of both sexes and may be at any stage of development. In one aspect, a suitable individual to be treated according to the invention is a human.

본 발명의 화합물은 일반적으로 치료적으로 유효한 양이 투여된다.The compounds of the present invention are generally administered in a therapeutically effective amount.

본 발명의 화합물은 임의의 적합한 경로에 의하여 이러한 경로에 적당한 약학 조성물의 형태, 그리고 의도된 치료를 위하여 효과적인 투여량으로 투여될 수 있다. 효과적인 투여량은 단일 또는 분할 투여로 일반적으로 약 0.001 내지 약 100 mg/체중kg/일이고, 바람직하게는 약 0.01 내지 약 30 mg/kg/일이다. 나이, 종, 및 치료될 질병 또는 상태(condition)에 따라 이 범위의 하한 미만의 투여량 수준이 적합할 수 있다. 다른 경우에는, 여전히 더 큰 투여량이 해로운 부작용없이 사용될 수 있다. 더 큰 투여량은 하루 동안 투여를 위하여, 여러 작은 투여량으로 분할될 수 있다. 적절한 투여량을 결정하기 위한 방법들이 본 발명이 속한 분야에 잘 알려져 있다. The compounds of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition suitable for such route, and in an effective dosage for the intended treatment. An effective dosage is generally from about 0.001 to about 100 mg/kg body weight/day, preferably from about 0.01 to about 30 mg/kg/day, in single or divided doses. Dosage levels below the lower limit of this range may be suitable depending on the age, species, and disease or condition being treated. In other cases, still larger doses can be used without deleterious side effects. The larger dose may be divided into several smaller doses for administration throughout the day. Methods for determining the appropriate dosage are well known in the art.

본 발명의 화합물은 본 명세서에서 설명되는 약학 조성물의 형태로 상기 치료 또는 예방이 필요한 개체에 투여될 수 있다.The compound of the present invention may be administered to a subject in need of such treatment or prevention in the form of a pharmaceutical composition described herein.

약학 조성물, 제형 및 투여 경로Pharmaceutical Compositions, Formulations and Routes of Administration

다른 양태에서, 본 발명은 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염, 및 약학적으로 허용 가능한 담체 또는 첨가제를 포함하는 약학 조성물이 제공한다.In another aspect, the present invention provides a pharmaceutical composition comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

본 발명의 다른 양태에서, 본 발명은 유효 성분으로 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는, Btk를 억제하여 개선될 수 있는 다양한 질환(예를 들어, 다발성 경화증; 염증 등을 포함하는 염증성 질환; 두드러기, 전신 홍반성 루푸스, 알레르기, 류마티스 관절염, 천식 등을 포함하는 자가면역 질환; 또는 발덴스트롬 마크로글로불린혈증, B 세포 림프종, 백혈병 등을 포함하는 B 세포 관련 암)의 치료 또는 예방용 약학 조성물을 제공한다. In another aspect of the present invention, the present invention includes a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and various diseases that can be improved by inhibiting Btk (e.g., multiple sclerosis; inflammation, etc.) inflammatory diseases including; autoimmune diseases including urticaria, systemic lupus erythematosus, allergies, rheumatoid arthritis, asthma, etc.; or B-cell-associated cancers including Waldenstrom's macroglobulinemia, B-cell lymphoma, leukemia, etc.); or A pharmaceutical composition for prevention is provided.

본 발명에서 사용된 용어 "약학적으로 허용 가능한"은 약학적 제제로 사용하기에 적합한 것을 의미하며, 일반적으로 이러한 사용을 위하여 안전한 것으로 간주되며, 이러한 사용을 위하여 국가의 관리 기관에 의하여 공식적으로 승인되거나 한국 약전 또는 미국 약전의 명단에 있는 것을 의미한다. As used herein, the term "pharmaceutically acceptable" means suitable for use as a pharmaceutical preparation, and is generally considered safe for such use, and is officially approved for such use by a national administrative agency. or is listed in the Korean Pharmacopoeia or the United States Pharmacopoeia.

상기 설명된 질병 또는 상태(condition)의 치료를 위하여, 본 명세서에서 설명된 상기 화합물 또는 이의 약학적으로 허용 가능한 염은 다음과 같이 투여될 수 있다.For the treatment of the above-described disease or condition, the compound described herein or a pharmaceutically acceptable salt thereof may be administered as follows.

구강 투여(Oral administration)Oral administration

본 발명의 화합물은 구강으로 투여될 수 있으며, 구강은 연하(swallowing)를 포함하는 개념이다. 구강 투여에 의하여 본 발명의 화합물이 위장관(gastrointestinal tract)에 들어가거나, 예를 들어, 구강(buccal) 또는 설하(sublingual) 투여와 같이, 입으로부터 혈류로 직접적으로 흡수될 수 있다. The compound of the present invention may be administered orally, and the oral cavity is a concept including swallowing. By oral administration, the compound of the present invention may enter the gastrointestinal tract or may be absorbed directly into the bloodstream from the mouth, such as, for example, buccal or sublingual administration.

구강 투여를 위한 적합한 조성물은 고형상, 액상, 겔(gel), 또는 파우더 형상일 수 있으며, 정제(tablet), 로젠지(lozenge), 캡슐(capsule), 과립제, 산제 등의 제형을 가질 수 있다. Suitable compositions for oral administration may be in solid, liquid, gel, or powder form, and may have formulations such as tablets, lozenges, capsules, granules, and powders. .

구강 투여를 위한 조성물은 선택적으로 장용 코팅(enteric coating)될 수 있으며, 장용 코팅을 통하여 지연된(delayed) 또는 지속된(sustained) 방출을 나타낼 수 있다. 즉, 본 발명에 따른 구강 투여를 위한 조성물은 즉시 또는 변형된(modified) 방출 패턴을 가진 제형일 수 있다. Compositions for oral administration may optionally be enteric coated and may exhibit delayed or sustained release through the enteric coating. That is, the composition for oral administration according to the present invention may be a formulation having an immediate or modified release pattern.

액체 제형은 용액, 시럽 및 현탁액을 포함할 수 있으며, 이러한 액상 조성물은 연질 또는 경질 캡슐 내에 함유된 형태일 수 있다. 이러한 제형은 약학적으로 허용 가능한 담체, 예를 들어, 물, 에탄올, 폴리에틸렌글리콜, 셀룰로오스, 또는 오일(oil)을 포함할 수 있다. 상기 제형은 또한 하나 이상의 유화제 및/또는 현탁제를 포함할 수 있다.Liquid formulations may include solutions, syrups and suspensions, and such liquid compositions may be in the form contained within soft or hard capsules. Such formulations may contain a pharmaceutically acceptable carrier, for example, water, ethanol, polyethylene glycol, cellulose, or oil. The formulation may also contain one or more emulsifying and/or suspending agents.

정제(tablet) 제형에서, 활성 성분인 약물의 양은 정제 총 중량 대비 약 0.05 중량% 내지 약 95 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 50 중량%로 존재할 수 있다. 또한, 정제는 약 0.5 중량% 내지 약 35 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 25 중량%를 포함하는 붕해제를 함유할 수 있다. 붕해제의 예로는 유당, 전분, 소디움스타치글리콜레이트, 크로스포비돈, 크로스카멜로스소디움(croscarmellose sodium), 말토덱스트린 또는 이들의 혼합물이 사용될 수 있으나 이에 한정되는 것은 아니다.In tablet formulations, the amount of drug as the active ingredient may be present in an amount of from about 0.05% to about 95% by weight relative to the total weight of the tablet, more typically from about 2% to about 50% by weight of the dosage form. Tablets may also contain from about 0.5% to about 35% by weight of a disintegrant, more typically from about 2% to about 25% by weight of the dosage form. Examples of the disintegrant include, but are not limited to, lactose, starch, sodium starch glycolate, crospovidone, croscarmellose sodium, maltodextrin, or mixtures thereof.

정제로 제조하기 위해 포함되는 적합한 활택제는 약 0.1 중량% 내지 약 5 중량% 양으로 존재할 수 있고, 탈크(talc), 이산화규소, 스테아린산, 칼슘, 아연 또는 마그네슘 스테아레이트, 소듐 스테아릴 푸마레이트 등이 활택제로 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다. Suitable glidants included for the preparation of tablets may be present in an amount from about 0.1% to about 5% by weight, and include talc, silicon dioxide, stearic acid, calcium, zinc or magnesium stearate, sodium stearyl fumarate, and the like. This lubricant may be used, but the present invention is not limited to the types of these additives.

정제로 제조하기 위한 결합제(binder)로는 젤라틴, 폴리에틸렌글리콜, 당(sugar), 검(gum), 녹말(starch), 폴리비닐피롤리돈, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스 등이 사용될 수 있으며, 정제로 제조하기 위한 적합한 희석제로는 만니톨, 자일리톨, 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 녹말(starch), 미결정셀룰로오스 등이 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다. Gelatin, polyethylene glycol, sugar, gum, starch, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, etc. may be used as a binder for manufacturing tablets. In addition, suitable diluents for preparing tablets include mannitol, xylitol, lactose, dextrose, sucrose, sorbitol, starch, microcrystalline cellulose, etc., but the present invention is not limited to the types of these additives. .

선택적으로 정제에 포함될 수 있는 가용화제는 정제 총 중량 대비 약 0.1 중량% 내지 약 3 중량% 양이 사용될 수 있고, 예를 들어, 폴리소르베이트, 소디움 라우릴설페이트, 소디움 도데실설페이트, 프로필렌 카보네이트, 디에틸렌글리콜모노에틸에테르, 디메틸이소소르비드, 폴리옥시에틸렌글리콜화된 천연 또는 수소화 피마자유, HCORTM(Nikkol), 올레일에스테르, 젤루시어(GelucireTM), 카프릴릭/카프릴산 모노/디글리세리드, 소르비탄지방산에스테르, 솔루톨HSTM 등이 본 발명에 따른 약학 조성물에 사용될 수 있으나, 본 발명은 이러한 가용화제의 구체적 종류에 한정되는 것은 아니다.Optionally, the solubilizing agent that may be included in the tablet may be used in an amount of about 0.1% to about 3% by weight based on the total weight of the tablet, for example, polysorbate, sodium lauryl sulfate, sodium dodecyl sulfate, propylene carbonate, Diethylene glycol monoethyl ether, dimethyl isosorbide, polyoxyethylene glycolated natural or hydrogenated castor oil, HCOR TM (Nikkol), oleyl ester, Gelucire TM , caprylic/caprylic acid mono/ Diglyceride, sorbitan fatty acid ester, Solutol HS TM , etc. may be used in the pharmaceutical composition according to the present invention, but the present invention is not limited to the specific type of the solubilizer.

비경구 투여(Parenteral Administration)Parenteral Administration

본 발명의 화합물은 혈류, 근육, 또는 내장 내로 직접 투여될 수 있다. 비경구 투여를 위한 적합한 방법은 정맥내(intravenous), 근육내(intra-muscular), 피하 동맥내(subcutaneous intraarterial), 복강내(intraperitoneal), 척추강내(intrathecal), 두개내(intracranial) 주사 등을 포함한다. 비경구 투여를 위한 적합한 장치는 (바늘 및 바늘 없는 주사기를 포함하는) 주사기(injector) 및 주입 방법(infusion method)을 포함한다.The compounds of the present invention may be administered directly into the bloodstream, muscle, or intestine. Suitable methods for parenteral administration include intravenous, intra-muscular, subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial injection, and the like. include Suitable devices for parenteral administration include injectors (including needle and needleless syringes) and infusion methods.

비경구 투여를 위한 조성물은 즉시 또는 변형된 방출 패턴을 가진 제형일 수 있으며, 변형된 방출 패턴은 지연된(delayed) 또는 지속된(sustained) 방출 패턴일 수 있다. Compositions for parenteral administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.

대부분의 비경구 제형은 액상 조성물이며, 이러한 액상 조성물은 본 발명에 따른 약효 성분, 염, 완충제, 등장화제 등을 포함하는 수용액이다.Most parenteral formulations are liquid compositions, and the liquid composition is an aqueous solution containing the active ingredient according to the present invention, a salt, a buffer, an isotonic agent, and the like.

비경구 제형은 또한 건조된 형태(예를 들어, 동결 건조) 또는 멸균 비-수용액으로서 제조될 수 있다. 이들 제형은 멸균수(sterile water)와 같은 적합한 비히클(vehicle)과 함께 사용될 수 있다. 용해도 증강제(solubility-enhancing agents) 또한 비경구 용액의 제조에 사용될 수 있다.Parenteral formulations may also be prepared in dried form (eg, lyophilized) or as sterile non-aqueous solutions. These formulations may be used with a suitable vehicle such as sterile water. Solubility-enhancing agents may also be used in the preparation of parenteral solutions.

국소 투여(Topical Administration)Topical Administration

본 발명의 화합물은 피부 또는 경피로 국소적으로 투여될 수 있다. 이 국소 투여를 위한 제형은 로션, 용액, 크림, 젤, 하이드로젤, 연고, 폼(foam), 임플란트(implant), 패치 등을 포함한다. 국소 투여 제형을 위한 약학적으로 허용 가능한 담체는 물, 알코올, 미네랄 오일, 글리세린, 폴리에틸렌글리콜 등을 포함할 수 있다. 국소 투여는 또한 전기천공법(electroporation), 이온도입법(iontophoresis), 음파영동(phonophoresis) 등에 의하여 수행될 수 있다.The compounds of the present invention may be administered topically dermally or transdermally. Formulations for topical administration include lotions, solutions, creams, gels, hydrogels, ointments, foams, implants, patches, and the like. Pharmaceutically acceptable carriers for topical dosage forms may include water, alcohol, mineral oil, glycerin, polyethylene glycol, and the like. Topical administration may also be performed by electroporation, iontophoresis, phonophoresis, and the like.

국소 투여를 위한 조성물은 즉시 또는 변형된 방출 패턴을 가진 제형일 수 있으며, 변형된 방출 패턴은 지연된(delayed) 또는 지속된(sustained) 방출 패턴일 수 있다.Compositions for topical administration may be formulations with an immediate or modified release pattern, and the modified release pattern may be a delayed or sustained release pattern.

본 발명은 Btk를 억제하여 다양한 약리 활성을 나타낼 수 있는 화합물, 이들을 유효 성분으로 포함하는 약학 조성물, 이들의 의약 용도 및 이들을 치료 또는 예방이 필요한 개체에게 투여하는 것을 포함하는 치료 방법을 제공한다. 본 발명에 따른 화합물 또는 이들의 약학적으로 허용 가능한 염은 안전성이 우수하고, Btk 억제 측면에서의 우수한 효과를 나타낼 수 있다.The present invention provides a compound capable of exhibiting various pharmacological activities by inhibiting Btk, a pharmaceutical composition comprising the same as an active ingredient, a pharmaceutical use thereof, and a treatment method comprising administering the same to an individual in need of treatment or prevention. The compound according to the present invention or a pharmaceutically acceptable salt thereof has excellent safety and may exhibit excellent effects in terms of Btk inhibition.

이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 본 발명이 속한 분야에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be construed as being limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art to which the present invention pertains.

Scheme (실시예 1):Scheme (Example 1):

Figure pat00015
Figure pat00015

Step 1: 2-클로로-4-(3-나이트로페녹시)-5,7-다이하이드로퓨라노[3,4-d]피리미딘의 합성Step 1: Synthesis of 2-chloro-4- (3-nitrophenoxy) -5,7-dihydrofurano [3,4-d] pyrimidine

Figure pat00016
Figure pat00016

3-나이트로페놀 (1.0 당량)을 이소프로필알콜에 용해하고 2,4-다이클로로-5,7-다이하이드로퓨라노[3,4-d]피리미딘 (1.0 당량)와 N,N-다이이소프로필에틸아민 (2.5 당량)를 실온에서 첨가하였다. 그 후 80℃에서 밤샘 교반하였다. 반응 종결 후, 감압 증발하고 물과 디클로로메탄을 사용하여 추출하였다. 유기층을 감압 증발하고 컬럼크로마토그래피를 하여 목표화합물을 얻었다. (50% 헥산/에틸아세테이트)3-Nitrophenol (1.0 equiv.) was dissolved in isopropyl alcohol and 2,4-dichloro-5,7-dihydrofurano[3,4-d]pyrimidine (1.0 equiv.) and N,N-di Isopropylethylamine (2.5 eq) was added at room temperature. Then, it stirred at 80 degreeC overnight. After completion of the reaction, it was evaporated under reduced pressure and extracted using water and dichloromethane. The organic layer was evaporated under reduced pressure and column chromatography was performed to obtain the target compound. (50% hexane/ethyl acetate)

Step B-1: 1-메틸-4-(4-나이트로페닐)피페라진의 합성Step B-1: Synthesis of 1-methyl-4-(4-nitrophenyl)piperazine

Figure pat00017
Figure pat00017

1-플루오로-4-나이트로벤젠 (1.0 당량)를 아세토나이트릴에 용해하고 포타슘카보네이트 (1.2 당량)와 N-메틸피페라진 (1.2 당량)을 실온에서 첨가하였다. 환류하여 밤샘 교반하였다. 반응 종결 후, 물과 에틸아세테이트로 추출하여 유기층을 모았다. 유기층을 감압 증발하고 컬럼크로마토 그래피를 사용하여 목표화합물을 얻었다. (10% 메탄올:디클로로메탄)1-Fluoro-4-nitrobenzene (1.0 equiv.) was dissolved in acetonitrile and potassium carbonate (1.2 equiv.) and N-methylpiperazine (1.2 equiv.) were added at room temperature. The mixture was refluxed and stirred overnight. After completion of the reaction, the organic layer was collected by extraction with water and ethyl acetate. The organic layer was evaporated under reduced pressure and the target compound was obtained using column chromatography. (10% methanol:dichloromethane)

Step B-2: 4-(4-메틸피페라진-1-일)아닐린의 합성Step B-2: Synthesis of 4-(4-methylpiperazin-1-yl)aniline

Figure pat00018
Figure pat00018

1-메틸-4-(4-나이트로페닐)피페라진 (1.0 당량)을 메탄올에 용해하고 10% 팔라듐/차콜 (0.2 당량)을 첨가하였다. 수소하에서 2시간 동안 교반하였다. 반응 종결 후, 셀라이트를 사용하여 여과하였다. 여액을 감압 증발하였다. 분리과정 없이 다음 반응에 사용하였다.1-Methyl-4-(4-nitrophenyl)piperazine (1.0 equiv) was dissolved in methanol and 10% palladium/charcoal (0.2 equiv) was added. Stirred under hydrogen for 2 hours. After completion of the reaction, filtration was performed using Celite. The filtrate was evaporated under reduced pressure. It was used in the next reaction without separation.

Step 2: N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-나이트로페녹시)-5,7-다이하이드로퓨라노[3,4-d]피리미딘-2-아민의 합성Step 2: N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-nitrophenoxy)-5,7-dihydrofurano[3,4-d]pyrimidine Synthesis of -2-amines

Figure pat00019
Figure pat00019

피리미딘 유도체 (1.0 당량)을 톨루엔에 용해하고 아닐린 유도체 (1.0 당량)과 팔라듐아세테이트 (0.1 당량), (2,2'-비스(다이페닐포스피노)-1,1'-바이나프틸 (0.2 당량, BINAP), 및 세슘카보네이트 (2.0 당량)을 실온에서 첨가하였다. 환류하여 밤샘 교반하였다. 반응 종결 후, 감압 증발하여 용매를 제거하고 물과 디클로로메탄을 사용하여 추출하였다. 유기층을 감압 증발하고 컬럼크로마토그래피를 하여 목표화합물을 얻었다. (10% 메탄올/디클로로메탄)A pyrimidine derivative (1.0 equiv.) was dissolved in toluene and an aniline derivative (1.0 equiv.) and palladium acetate (0.1 equiv.), (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.2 Equivalent, BINAP) and cesium carbonate (2.0 equivalent) were added at room temperature.Recirculated and stirred overnight.After completion of the reaction, evaporated under reduced pressure to remove the solvent, and extracted using water and dichloromethane.The organic layer was evaporated under reduced pressure The target compound was obtained by column chromatography (10% methanol/dichloromethane).

Step 3: 4-(3-아미노페녹시)-N-(4-(4-메틸피페라진-1-일)페닐)-5,7-다이하이드로퓨라노[3,4-d]피리미딘-2-아민의 합성Step 3: 4-(3-aminophenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)-5,7-dihydrofurano[3,4-d]pyrimidine- Synthesis of 2-amines

Figure pat00020
Figure pat00020

N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-나이트로페녹시)-5,7-다이하이드로퓨라노[3,4-d]피리미딘-2-아민 (1.0 당량)을 메탄올에 용해하고 10% 팔라듐/차콜 (0.2 당량)을 첨가하였다. 수소하에서 2시간동안 교반하였다. 반응 종결 후, 셀라이트를 사용하여 여과하였다. 여액을 감압 증발하였다. 분리과정 없이 다음 반응에 사용하였다.N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-nitrophenoxy)-5,7-dihydrofurano[3,4-d]pyrimidine-2- The amine (1.0 equiv) was dissolved in methanol and 10% palladium/charcoal (0.2 equiv) was added. Stirred under hydrogen for 2 hours. After completion of the reaction, filtration was performed using Celite. The filtrate was evaporated under reduced pressure. It was used in the next reaction without separation.

Step 4: N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨라노[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드의 합성Step 4: N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofurano[3,4-d]pyrimidine- Synthesis of 4-yl)oxy)phenyl)acrylamide

Figure pat00021
Figure pat00021

4-(3-아미노페녹시)-N-(4-(4-메틸피페라진-1-일)페닐)-5,7-다이하이드로퓨라노[3,4-d]피리미딘-2-아민 (1.0 당량)을 테트라히드로퓨란과 물에 용해하고 3-클로로프로피오닐 클로라이드 (1.2 당량)을 0±5°C에서 첨가하였다. 같은 온도에서 15분간 교반하였다. 반응 종결 후, 수산화나트륨 (4.0 당량)을 같은 온도에서 첨가하였다. 반응기 온도를 올려서 65℃에서 밤새 교반하였다. 반응 종결 후, 감압 증발하여 용매를 제거하고 물과 10% 메탄올/디클로로메탄 혼합액을 사용하여 추출하였다. 유기층을 감압 증발하고 컬럼크로마토그래피를 하여 목표화합물을 얻었다. (10% 메틸알콜/다이클로로메탄)4-(3-aminophenoxy)-N-(4-(4-methylpiperazin-1-yl)phenyl)-5,7-dihydrofurano[3,4-d]pyrimidin-2-amine (1.0 equiv.) was dissolved in tetrahydrofuran and water and 3-chloropropionyl chloride (1.2 equiv.) was added at 0±5°C. The mixture was stirred at the same temperature for 15 minutes. After completion of the reaction, sodium hydroxide (4.0 equivalents) was added at the same temperature. The reactor temperature was raised and stirred at 65° C. overnight. After completion of the reaction, the solvent was removed by evaporation under reduced pressure, and extraction was performed using a mixture of water and 10% methanol/dichloromethane. The organic layer was evaporated under reduced pressure and column chromatography was performed to obtain the target compound. (10% methyl alcohol/dichloromethane)

실시예 1Example 1

N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide

Figure pat00022
Figure pat00022

Yield : 58.7%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.16 (s, 3H). MS: ESI m/z 473.1 [M+H]+Yield: 58.7%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d) , J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H) , 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.16 (s, 3H). MS: ESI m/z 473.1 [M+H]+

실시예 2Example 2

N-(3-((7,7-다이메틸-2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((7,7-dimethyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d ]pyrimidin-4-yl)oxy)phenyl)acrylamide

Figure pat00023
Figure pat00023

Yield : 60.1%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.92 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.16 (s, 3H), 1.67 (s, 6H). MS: ESI m/z 501.0 [M+H]+Yield: 60.1%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d) , J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H) , 4.92 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.16 (s, 3H), 1.67 (s, 6H). MS: ESI m/z 501.0 [M+H]+

실시예 3Example 3

N-(3-((2-((3-플루오로-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide

Figure pat00024
Figure pat00024

Yield : 53.4%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.54 (s, 1H), 7.91 (dd, J = 8.1, 1.6 Hz, 1H), 7.44 (dd, J = 7.5, 1.5 Hz, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 6.91 (dd, J = 7.5, 5.1 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.33 (dd, J = 16.8, 10.0 Hz, 1H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.90 (s, 2H), 4.79 (s, 2H), 3.34 - 3.24 (m, 4H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.16 (s, 3H). MS: ESI m/z 491.0 [M+H]+Yield: 53.4%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.54 (s, 1H), 7.91 (dd, J = 8.1, 1.6 Hz, 1H), 7.44 (dd , J = 7.5, 1.5 Hz, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 6.91 (dd, J = 7.5, 5.1 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.33 (dd, J = 16.8, 10.0 Hz, 1H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.90 (s, 2H), 4.79 (s, 2H), 3.34 - 3.24 (m, 4H), 2.93 - 2.91 (m, 4H) , 2.40 - 2.33 (m, 4H), 2.16 (s, 3H). MS: ESI m/z 491.0 [M+H]+

실시예 4Example 4

N-(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide

Figure pat00025
Figure pat00025

Yield : 61.4%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.21 (s, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.60 (dd, J = 7.5, 1.5 Hz, 1H), 6.40 - 6.27 (m, 2H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 (s, 2H), 4.79 (s, 2H), 3.85 (s, 3H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.16 (s, 3H). MS: ESI m/z 503.1 [M+H]+Yield: 61.4%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.21 (s, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.24 (t, J) = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.60 (dd , J = 7.5, 1.5 Hz, 1H), 6.40 - 6.27 (m, 2H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 ( s, 2H), 4.79 (s, 2H), 3.85 (s, 3H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.16 (s, 3H). MS: ESI m/z 503.1 [M+H]+

실시예 5Example 5

N-(3-((2-((2-플루오로-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide

Figure pat00026
Figure pat00026

Yield : 47.5%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.18 (s, 1H), 7.86 (dd, J = 7.5, 5.0 Hz, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.73 (dd, J = 8.1, 1.5 Hz, 1H), 6.55 (dd, J = 7.6, 1.5 Hz, 1H), 6.33 (dd, J = 16.8, 10.0 Hz, 1H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.90 (s, 2H), 4.78 (s, 2H), 3.32 (t, J = 7.0 Hz, 4H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.16 (s, 3H). MS: ESI m/z 491.0 [M+H]+Yield: 47.5%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.18 (s, 1H), 7.86 (dd, J = 7.5, 5.0 Hz, 1H), 7.35 (t) , J = 1.5 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.73 (dd, J = 8.1, 1.5 Hz, 1H), 6.55 (dd, J = 7.6, 1.5 Hz, 1H), 6.33 (dd, J = 16.8, 10.0 Hz, 1H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.90 (s, 2H), 4.78 (s, 2H), 3.32 (t, J = 7.0 Hz, 4H), 2.93 - 2.91 (m) , 4H), 2.40 - 2.33 (m, 4H), 2.16 (s, 3H). MS: ESI m/z 491.0 [M+H]+

실시예 6Example 6

N-(3-((2-((4-몰포리노페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-morpholinophenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

Figure pat00027
Figure pat00027

Yield : 63.1%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.41 (s, 1H), 7.60 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 6.92 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.62 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.0, 2.0 Hz, 1H), 4.93 (s, 2H), 4.79 (s, 2H), 3.72 - 3.60 (m, 4H), 2.97 - 2.83 (m, 4H). MS: ESI m/z 460.1 [M+H]+Yield: 63.1%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.41 (s, 1H), 7.60 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.27 (d, J = 8.3 Hz, 2H), 6.92 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.62 (d) , J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.0, 2.0 Hz, 1H) , 4.93 (s, 2H), 4.79 (s, 2H), 3.72 - 3.60 (m, 4H), 2.97 - 2.83 (m, 4H). MS: ESI m/z 460.1 [M+H]+

실시예 7Example 7

N-(3-((2-((4-(4-이소프로필피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidine-4- yl) oxy) phenyl) acrylamide

Figure pat00028
Figure pat00028

Yield : 59.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.38 (s, 1H), 7.60 (t, J = 2.1 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.24 (m, 2H), 6.91 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.61 (d, J = 8.3 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.92 (s, 2H), 4.78 (s, 2H), 2.91 (m, 4H), 2.63 (m, 1H), 2.49 (m, 4H), 0.96 (d, J = 6.5 Hz, 6H). MS: ESI m/z 501.1 [M+H]+Yield: 59.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.38 (s, 1H), 7.60 (t, J = 2.1 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.24 (m, 2H), 6.91 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.61 (d, J = 8.3 Hz) , 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.92 (s, 2H), 4.78 (s, 2H), 2.91 (m, 4H), 2.63 (m, 1H), 2.49 (m, 4H), 0.96 (d, J = 6.5 Hz, 6H). MS: ESI m/z 501.1 [M+H]+

실시예 8Example 8

N-(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide

Figure pat00029
Figure pat00029

Yield : 57.4%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.1 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 16.9, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.92 (s, 2H), 4.79 (s, 2H), 2.93 (m, 4H), 2.42 (m, 4H), 2.31 (q, J = 7.1 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). MS: ESI m/z 487.1 [M+H]+Yield: 57.4%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.1 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d) , J = 8.5 Hz, 2H), 6.39 (dd, J = 16.9, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.1 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H) , 4.92 (s, 2H), 4.79 (s, 2H), 2.93 (m, 4H), 2.42 (m, 4H), 2.31 (q, J = 7.1 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). MS: ESI m/z 487.1 [M+H]+

실시예 9Example 9

N-(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-(2-methoxyethoxy)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy) phenyl) acrylamide

Figure pat00030
Figure pat00030

Yield : 46.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.92 (s, 2H), 4.79 (s, 2H), 4.23 (t, J = 7.1 Hz, 2H), 3.55 (t, J = 7.0 Hz, 2H), 3.37 (s, 3H). MS: ESI m/z 449.0 [M+H]+Yield: 46.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d) , J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H) , 4.92 (s, 2H), 4.79 (s, 2H), 4.23 (t, J = 7.1 Hz, 2H), 3.55 (t, J = 7.0 Hz, 2H), 3.37 (s, 3H). MS: ESI m/z 449.0 [M+H]+

실시예 10Example 10

N-(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide

Figure pat00031
Figure pat00031

Yield : 53.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.10 (s, 3H). MS: ESI m/z 501.1 [M+H]+Yield: 53.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d) , J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H) , 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.10 (s, 3H). MS: ESI m/z 501.1 [M+H]+

실시예 11Example 11

N-(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidine-4- yl) oxy) phenyl) acrylamide

Figure pat00032
Figure pat00032

Yield : 38.6%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.48 (s, 1H), 7.64 (t, J = 2.1 Hz, 1H), 7.56 - 7.48 (m, 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 6.92 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.58 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 16.9, 10.1 Hz, 1H), 6.22 (dd, J = 16.9, 2.0 Hz, 1H), 5.78 - 5.69 (m, 1H), 4.94 (s, 2H), 4.88 - 4.73 (m, 3H), 3.86 - 3.62 (m, 4H), 2.18 - 2.02 (m, 1H), 1.87 - 1.81 (m, 1H). MS: ESI m/z 461.0 [M+H]+Yield: 38.6%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.48 (s, 1H), 7.64 (t, J = 2.1 Hz, 1H), 7.56 - 7.48 (m , 1H), 7.39 (t, J = 8.1 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 6.92 (ddd, J = 8.1, 2.3, 1.0 Hz, 1H), 6.58 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 16.9, 10.1 Hz, 1H), 6.22 (dd, J = 16.9, 2.0 Hz, 1H), 5.78 - 5.69 (m, 1H), 4.94 (s, 2H), 4.88 - 4.73 (m, 3H), 3.86 - 3.62 (m, 4H), 2.18 - 2.02 (m, 1H), 1.87 - 1.81 (m, 1H). MS: ESI m/z 461.0 [M+H]+

실시예 12Example 12

N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)프로피온아마이드N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)propionamide

Figure pat00033
Figure pat00033

Yield : 57.2%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.38 (q, J = 8.0 Hz, 2H), 2.16 (s, 3H), 1.16 (t, J = 8.0 Hz, 3H). MS: ESI m/z 475.1 [M+H]+Yield: 57.2%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d) , J = 8.5 Hz, 2H), 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 2.38 (q, J = 8.0 Hz, 2H), 2.16 (s, 3H), 1.16 (t, J = 8.0 Hz, 3H). MS: ESI m/z 475.1 [M+H]+

실시예 13Example 13

N-(3-((2-((4-((3-메틸이소싸이아졸-5-일)아미노)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-((3-methylisothiazol-5-yl)amino)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidine -4-yl)oxy)phenyl)acrylamide

Figure pat00034
Figure pat00034

Yield : 43.5%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.52 (s, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.26 (t, J = 7.4 Hz, 1H), 7.19 (dt, J = 7.5, 1.6 Hz, 1H), 7.15 (s, 1H), 6.80 (dt, J = 7.3, 1.5 Hz, 1H), 6.34 (dd, J = 16.9, 9.9 Hz, 1H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 (s, 2H), 4.78 (s, 2H), 2.28 (s, 3H). MS: ESI m/z 487.0 [M+H]+Yield: 43.5%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.52 (s, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.26 (t, J) = 7.4 Hz, 1H), 7.19 (dt, J = 7.5, 1.6 Hz, 1H), 7.15 (s, 1H), 6.80 (dt, J = 7.3, 1.5 Hz, 1H), 6.34 (dd, J = 16.9, 9.9 Hz, 1H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 (s, 2H), 4.78 (s, 2H), 2.28 ( s, 3H). MS: ESI m/z 487.0 [M+H]+

실시예 14Example 14

(R)-N-(3-((2-((4-(4-(5-(1,2-다이싸이올란-3-일)펜타노일)피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드(R)-N-(3-((2-((4-(4-(5-(1,2-dithiolan-3-yl)pentanoyl)piperazin-1-yl)phenyl)amino) -5,7-dihydrofuro [3,4-d] pyrimidin-4-yl) oxy) phenyl) acrylamide

Figure pat00035
Figure pat00035

Yield : 30.7%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 3.57 - 3.54 (m, 4H), 3.49 - 3.43 (m, 1H), 3.29 - 3.26 (m, 4H), 3.17 - 3.12 (m, 2H), 2.36 - 2.33 (m, 2H), 2.07 - 1.95 (m, 2H), 1.66 - 1.39 (m, 6H). MS: ESI m/z 647.1 [M+H]+Yield: 30.7%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d) , J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H) , 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 3.57 - 3.54 (m, 4H), 3.49 - 3.43 (m, 1H) , 3.29 - 3.26 (m, 4H), 3.17 - 3.12 (m, 2H), 2.36 - 2.33 (m, 2H), 2.07 - 1.95 (m, 2H), 1.66 - 1.39 (m, 6H). MS: ESI m/z 647.1 [M+H]+

실시예 15Example 15

N-(3-((2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5,7-di hydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

Figure pat00036
Figure pat00036

Yield : 56.4%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.21 (s, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.60 (dd, J = 7.5, 1.5 Hz, 1H), 6.40 - 6.27 (m, 2H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 (s, 2H), 4.79 (s, 2H), 3.72 (s, 3H), 3.67 (d, J = 12.0 Hz, 2H), 2.62 (td, J = 12.2, 2.4 Hz, 2H), 2.52 - 2.42 (m, 4H), 2.30 - 2.22 (m, 5H), 2.10 (s, 3H), 1.81 (d, J = 12.3 Hz, 2H), 1.48 (qd, J = 12.0, 3.8 Hz, 2H). MS: ESI m/z 586.2 [M+H]+Yield: 56.4%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.21 (s, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.24 (t, J) = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.60 (dd , J = 7.5, 1.5 Hz, 1H), 6.40 - 6.27 (m, 2H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 ( s, 2H), 4.79 (s, 2H), 3.72 (s, 3H), 3.67 (d, J = 12.0 Hz, 2H), 2.62 (td, J = 12.2, 2.4 Hz, 2H), 2.52 - 2.42 (m) , 4H), 2.30 - 2.22 (m, 5H), 2.10 (s, 3H), 1.81 (d, J = 12.3 Hz, 2H), 1.48 (qd, J = 12.0, 3.8 Hz, 2H). MS: ESI m/z 586.2 [M+H]+

실시예 16Example 16

N-(3-((2-((2-메톡시-4-(4-몰포리노피페리딘-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d ]pyrimidin-4-yl)oxy)phenyl)acrylamide

Figure pat00037
Figure pat00037

Yield : 53.7%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.21 (s, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.24 (t, J = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.60 (dd, J = 7.5, 1.5 Hz, 1H), 6.40 - 6.27 (m, 2H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 (s, 2H), 4.79 (s, 2H), 3.72 (s, 3H), 3.62 - 3.55 (m, 6H), 2.62 (td, J = 12.2, 2.4 Hz, 2H), 2.53 - 2.50 (m, 4H), 1.81 (d, J = 12.3 Hz, 2H), 1.48 (qd, J = 12.0, 3.8 Hz, 2H). MS: ESI m/z 573.1 [M+H]+Yield: 53.7%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.21 (s, 1H), 7.35 (t, J = 1.5 Hz, 1H), 7.24 (t, J) = 7.4 Hz, 1H), 7.17 (dt, J = 7.5, 1.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.60 (dd , J = 7.5, 1.5 Hz, 1H), 6.40 - 6.27 (m, 2H), 6.04 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 ( s, 2H), 4.79 (s, 2H), 3.72 (s, 3H), 3.62 - 3.55 (m, 6H), 2.62 (td, J = 12.2, 2.4 Hz, 2H), 2.53 - 2.50 (m, 4H) , 1.81 (d, J = 12.3 Hz, 2H), 1.48 (qd, J = 12.0, 3.8 Hz, 2H). MS: ESI m/z 573.1 [M+H]+

실시예 17Example 17

(R)-1-(3-((2-((4-(4-(5-(1,2-아이싸이올란-3-일)펜타노일)피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)-1H-피롤-2,5-다이온(R)-1-(3-((2-((4-(4-(5-(1,2-Ithiolan-3-yl)pentanoyl)piperazin-1-yl)phenyl)amino) -5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1H-pyrrole-2,5-dione

Figure pat00038
Figure pat00038

Yield : 28.5%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 7.18 (s, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 3.57 - 3.54 (m, 4H), 3.49 - 3.43 (m, 1H), 3.29 - 3.26 (m, 4H), 3.17 - 3.12 (m, 2H), 2.36 - 2.33 (m, 2H), 2.07 - 1.95 (m, 2H), 1.66 - 1.39 (m, 6H). MS: ESI m/z 673.1 [M+H]+Yield: 28.5%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.39 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 7.18 (s, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz) , 1H), 6.61 (d, J = 8.5 Hz, 2H), 4.92 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 3.57 - 3.54 (m, 4H), 3.49 - 3.43 (m, 1H), 3.29 - 3.26 (m, 4H), 3.17 - 3.12 (m, 2H), 2.36 - 2.33 (m, 2H), 2.07 - 1.95 (m, 2H) ), 1.66 - 1.39 (m, 6H). MS: ESI m/z 673.1 [M+H]+

실시예 18Example 18

N-(3-((2-((4-(4-(5-(1,2-다이싸이올란-3-일)펜타노일)피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-(4-(5-(1,2-dithiolan-3-yl)pentanoyl)piperazin-1-yl)phenyl)amino)-5,7 -dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

Figure pat00039
Figure pat00039

Yield : 25.5%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.38 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.91 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 3.57 - 3.54 (m, 4H), 3.49 - 3.43 (m, 1H), 3.29 - 3.26 (m, 4H), 3.17 - 3.12 (m, 2H), 2.36 - 2.33 (m, 2H), 2.07 - 1.95 (m, 2H), 1.66 - 1.39 (m, 6H). MS: ESI m/z 647.1 [M+H]+Yield: 25.5%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 9.38 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d) , J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H) , 4.91 (s, 2H), 4.79 (s, 2H), 2.93 - 2.91 (m, 4H), 2.40 - 2.33 (m, 4H), 3.57 - 3.54 (m, 4H), 3.49 - 3.43 (m, 1H) , 3.29 - 3.26 (m, 4H), 3.17 - 3.12 (m, 2H), 2.36 - 2.33 (m, 2H), 2.07 - 1.95 (m, 2H), 1.66 - 1.39 (m, 6H). MS: ESI m/z 647.1 [M+H]+

실시예 19Example 19

N-(3-((2-((4-(피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((4-(piperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy) phenyl) acrylamide

Figure pat00040
Figure pat00040

Yield : 45.8%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.43 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d, J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H), 4.88 (s, 2H), 4.74 (s, 2H), 3.40 - 3.37 (m, 4H), 3.10 - 3.07 (m, 4H), 2.56 (p, J = 5.1 Hz, 1H). MS: ESI m/z 459.1 [M+H]+Yield: 45.8%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.43 (s, 1H), 7.61 (t, J = 2.2 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 7.38 (t, J = 8.1 Hz, 1H), 7.25 (d, J = 6.6 Hz, 2H), 6.91 (ddd, J = 8.1, 2.4, 1.0 Hz, 1H), 6.61 (d) , J = 8.5 Hz, 2H), 6.39 (dd, J = 17.0, 10.1 Hz, 1H), 6.22 (dd, J = 17.0, 2.0 Hz, 1H), 5.74 (dd, J = 10.1, 2.1 Hz, 1H) , 4.88 (s, 2H), 4.74 (s, 2H), 3.40 - 3.37 (m, 4H), 3.10 - 3.07 (m, 4H), 2.56 (p, J = 5.1 Hz, 1H). MS: ESI m/z 459.1 [M+H]+

실시예 20Example 20

N-(3-((2-((2-메톡시-4-(4-(6-메틸-2,6-다이아자스피로[3.3]헵탄-2-일)피페리딘-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-((2-methoxy-4-(4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl) phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide

Figure pat00041
Figure pat00041

Yield : 51.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.20 (s, 1H), 7.33 (t, J = 1.5 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 7.15 (dt, J = 7.5, 1.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.40 - 6.27 (m, 3H), 6.02 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 (s, 2H), 4.79 (s, 2H), 3.72 (s, 3H), 3.67 (d, J = 12.0 Hz, 2H), 3.06 (s, 4H), 3.02 (s, 4H), 2.62 (td, J = 12.2, 2.4 Hz, 2H), 2.30 - 2.22 (m, 1H), 2.10 (s, 3H), 1.81 (d, J = 12.3 Hz, 2H), 1.48 (m, 2H). MS: ESI m/z 598.2 [M+H]+Yield: 51.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.20 (s, 1H), 7.33 (t, J = 1.5 Hz, 1H), 7.22 (t, J) = 7.4 Hz, 1H), 7.15 (dt, J = 7.5, 1.6 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 6.81 (dt, J = 7.5, 1.6 Hz, 1H), 6.40 - 6.27 (m, 3H), 6.02 (dd, J = 16.8, 3.1 Hz, 1H), 5.91 (dd, J = 9.9, 3.1 Hz, 1H), 4.91 (s, 2H), 4.79 (s, 2H), 3.72 ( s, 3H), 3.67 (d, J = 12.0 Hz, 2H), 3.06 (s, 4H), 3.02 (s, 4H), 2.62 (td, J = 12.2, 2.4 Hz, 2H), 2.30 - 2.22 (m) , 1H), 2.10 (s, 3H), 1.81 (d, J = 12.3 Hz, 2H), 1.48 (m, 2H). MS: ESI m/z 598.2 [M+H]+

실시예 21Example 21

N-(3-((2-(4-(4-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피페리딘-1-일)-2-메톡시벤질)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드N-(3-((2-(4-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)piperidin-1-yl)-2-methoxybenzyl)-5 , 7-dihydrofuro [3,4-d] pyrimidin-4-yl) oxy) phenyl) acrylamide

Figure pat00042
Figure pat00042

Yield : 45.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.31 (t, J = 1.5 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.15 (dt, J = 7.5, 1.6 Hz, 1H), 7.02 (dt, J = 7.6, 1.1 Hz, 1H), 6.78 (dt, J = 7.3, 1.5 Hz, 1H), 6.36 - 6.24 (m, 3H), 6.00 (dd, J = 16.8, 3.1 Hz, 1H), 5.86 (dd, J = 9.9, 3.1 Hz, 1H), 4.92 (s, 2H), 4.46 (s, 2H), 4.00 (d, J = 0.9 Hz, 2H), 3.77 (s, 3H), 3.75 - 3.61 (m, 7H), 3.32 (dt, J = 12.4, 7.1 Hz, 2H), 3.15 (s, 2H), 3.10 (s, 2H), 2.40 (p, J = 7.0 Hz, 1H), 1.82 (m, 5H). MS: ESI m/z 585.1 [M+H]+Yield: 45.3%, White solid, 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 7.31 (t, J = 1.5 Hz, 1H), 7.22 (t, J = 7.5 Hz, 1H), 7.15 (dt, J = 7.5, 1.6 Hz, 1H), 7.02 (dt, J = 7.6, 1.1 Hz, 1H), 6.78 (dt, J = 7.3, 1.5 Hz, 1H), 6.36 - 6.24 (m, 3H) , 6.00 (dd, J = 16.8, 3.1 Hz, 1H), 5.86 (dd, J = 9.9, 3.1 Hz, 1H), 4.92 (s, 2H), 4.46 (s, 2H), 4.00 (d, J = 0.9) Hz, 2H), 3.77 (s, 3H), 3.75 - 3.61 (m, 7H), 3.32 (dt, J = 12.4, 7.1 Hz, 2H), 3.15 (s, 2H), 3.10 (s, 2H), 2.40 (p, J = 7.0 Hz, 1H), 1.82 (m, 5H). MS: ESI m/z 585.1 [M+H]+

시험예1: Kinase 활성 억제 효과 측정Test Example 1: Measurement of Kinase Activity Inhibition Effect

상기 실시예들에서 얻어진 화합물에 대하여 BTK 및 관련 Kinase들의 활성 억제효과를 측정하였다. For the compounds obtained in the above Examples, the inhibitory effect of BTK and related kinases was measured.

Kinase 활성은 Promega 사의 ADP-Glo?? Kinase Assay 키트를 이용하여 측정하였다. 투명 plate에 ATP, ADP stock solution(dilution은 3'dw 사용)으로 ATP to ADP conversion curve를 그려주었다. 이를 통해 assay에 사용할 적정 kinase의 양을 결정하였다. Kinase buffer를 사용하여 enzyme, substrate, ATP, inhibitor를 dilution하여 준비하였다. Ep-tube에 substrate와 ATP를 넣고 섞어준 뒤, enzyme와 inhibitor(시험 화합물)를 넣고 짧게 vortexing해주었다. 그 후 실온에서 60분 동안 incubation하였다. 각 tube에 ADP-Glo reagent를 넣어준 다음 살짝 vortexing 후 차광하여 실온에서 40 분간 incubation하였다. 그 다음 Kinase detection reagent를 넣고 살짝 vortexing 후 실온에서 30 분간 차광 incubation하였다. 투명 plate에 bubble이 생기지 않게 주의하여 분주한 뒤 luminescence를 측정하였다. Kinase activity is Promega's ADP-Glo?? Measurements were made using a Kinase Assay kit. ATP to ADP conversion curve was drawn with ATP and ADP stock solution (use 3'dw for dilution) on a transparent plate. Through this, the appropriate amount of kinase to be used in the assay was determined. It was prepared by dilution of enzyme, substrate, ATP, and inhibitor using kinase buffer. After mixing the substrate and ATP into the Ep-tube, the enzyme and inhibitor (test compound) were added and briefly vortexed. Then, incubated at room temperature for 60 minutes. After adding ADP-Glo reagent to each tube, it was incubated at room temperature for 40 minutes after light vortexing. Then, a kinase detection reagent was added, vortexed slightly, and incubated for 30 minutes at room temperature to block light. The luminescence was measured after dispensing carefully so as not to create bubbles on the transparent plate.

각 화합물이 Kinase 활성을 50% 억제한 농도로 IC50 값을 산출하여, 그 결과를 하기 표 1에 A, B, C로 나타냈다. 여기에서 A는 IC50 ≤ 50nM, B는 IC50이 50 초과 내지 100nM, C는 IC50 > 100nM임을 의미한다. 대조약물로는 이브루티닙(Ibrutinib)을 사용하였다.IC 50 values were calculated at a concentration in which each compound inhibited the kinase activity by 50%, and the results are shown as A, B, and C in Table 1 below. Here, A means IC 50 ≤ 50 nM, B means IC 50 >50 to 100 nM, and C means IC 50 > 100 nM. As a control drug, Ibrutinib was used.

실시예Example Bmx (h)Bmx (h) BTK (h)BTK (h) Itk (h)Itk (h) Tec(h) activatedTec(h) activated Txk (h)Txk (h) 1One AA AA AA AA AA 22 BB BB BB CC BB 33 AA AA AA AA AA 44 AA AA AA AA AA 55 BB AA AA AA AA 66 BB BB AA BB AA 77 AA AA BB AA AA 88 AA AA AA AA AA 99 BB AA AA BB AA 1010 BB BB BB AA AA 1111 CC BB BB CC CC 1212 CC CC CC CC CC 1313 BB BB CC AA CC 1414 BB BB BB BB CC 1515 AA AA AA AA AA 1616 BB AA BB BB BB 1717 CC CC CC CC CC 1818 AA AA BB AA AA 1919 BB AA CC BB BB 2020 AA AA AA AA AA 2121 AA BB BB BB AA IbrutinibIbrutinib AA AA BB AA BB

상기 표 1에서 나타낸 바와 같이, 본 발명의 화합물은 BTK 및 관련 Kinase들에 대해 우수한 억제 활성을 나타내었으며, 특히, 실시예 1, 3, 및 8 화합물들이 BTK 패밀리 Kinase들의 활성에 대한 더욱 우수한 억제 효과를 나타냈다.As shown in Table 1 above, the compounds of the present invention exhibited excellent inhibitory activity against BTK and related kinases, and in particular, the compounds of Examples 1, 3, and 8 showed more excellent inhibitory effect on the activity of BTK family kinases. showed

Claims (9)

하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염.
[화학식 1]
Figure pat00043

상기 화학식 1에서,
X는
Figure pat00044
,
Figure pat00045
,
Figure pat00046
,
Figure pat00047
,
Figure pat00048
, 또는
Figure pat00049
이고, 여기에서 Y는 직접 연결 또는
Figure pat00050
이며,
Z은
Figure pat00051
또는
Figure pat00052
이고, 여기에서
Figure pat00053
는 단일 결합 또는 이중 결합이며,
R1은 methyl, ethyl, isopropyl, methyl-C(O)-, (1,2-dithiolan-3-yl)pentanoyl, H, 6-methyl-2,6-diazaspiro[3.3]heptan-2-yl, 또는 2-oxy-6-azaspiro[3.3]heptan-6-yl이고,
R2는 H, F, 또는 methoxy이고,
R3 및 R4는 서로 독립적으로 H 또는 methyl이고,
R5는 H 또는 methyl임.A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
[Formula 1]
Figure pat00043

In Formula 1,
X is
Figure pat00044
,
Figure pat00045
,
Figure pat00046
,
Figure pat00047
,
Figure pat00048
, or
Figure pat00049
, where Y is a direct connection or
Figure pat00050
is,
Z is
Figure pat00051
or
Figure pat00052
and here
Figure pat00053
is a single bond or a double bond,
R 1 is methyl, ethyl, isopropyl, methyl-C(O)-, (1,2-dithiolan-3-yl)pentanoyl, H, 6-methyl-2,6-diazaspiro[3.3]heptan-2-yl, or 2-oxy-6-azaspiro[3.3]heptan-6-yl,
R 2 is H, F, or methoxy,
R 3 and R 4 are each independently H or methyl,
R 5 is H or methyl. 제1항에 있어서, 상기
X는
Figure pat00054
이고, 여기에서 Y는 직접 연결이며,
Z은
Figure pat00055
이고, 여기에서
Figure pat00056
는 단일 결합 또는 이중 결합이며,
R1은 methyl, ethyl, 또는 isopropyl이고,
R2는 H, 또는 F이고,
R3 및 R4는 H인,
화합물 또는 이의 약학적으로 허용 가능한 염.The method of claim 1, wherein the
X is
Figure pat00054
, where Y is a direct connection,
Z is
Figure pat00055
and here
Figure pat00056
is a single bond or a double bond,
R 1 is methyl, ethyl, or isopropyl;
R 2 is H, or F;
R 3 and R 4 are H;
A compound or a pharmaceutically acceptable salt thereof. 제1항에 있어서, 상기 화합물은
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((7,7-다이메틸-2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((3-플루오로-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((2-메톡시-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((2-플루오로-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((4-몰포리노페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((4-(4-이소프로필피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((4-(2-메톡시에톡시)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((4-(4-아세틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((4-((테트라하이드로퓨란-3-일)옥시)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)프로피온아마이드,
N-(3-((2-((4-((3-메틸이소싸이아졸-5-일)아미노)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
(R)-N-(3-((2-((4-(4-(5-(1,2-다이싸이올란-3-일)펜타노일)피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((2-메톡시-4-(4-몰포리노피페리딘-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
(R)-1-(3-((2-((4-(4-(5-(1,2-아이싸이올란-3-일)펜타노일)피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)-1H-피롤-2,5-다이온,
N-(3-((2-((4-(4-(5-(1,2-다이싸이올란-3-일)펜타노일)피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((4-(피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((2-메톡시-4-(4-(6-메틸-2,6-다이아자스피로[3.3]헵탄-2-일)피페리딘-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드, 또는
N-(3-((2-(4-(4-(2-옥사-6-아자스피로[3.3]헵탄-6-일)피페리딘-1-일)-2-메톡시벤질)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드인
화합물 또는 이의 약학적으로 허용 가능한 염.The method of claim 1, wherein the compound is
N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide,
N-(3-((7,7-dimethyl-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d ]pyrimidin-4-yl)oxy)phenyl)acrylamide,
N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide,
N-(3-((2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide,
N-(3-((2-((2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide,
N-(3-((2-((4-morpholinophenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide,
N-(3-((2-((4-(4-isopropylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidine-4- yl) oxy) phenyl) acrylamide,
N-(3-((2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide,
N-(3-((2-((4-(2-methoxyethoxy)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy) phenyl) acrylamide,
N-(3-((2-((4-(4-acetylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide,
N-(3-((2-((4-((tetrahydrofuran-3-yl)oxy)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidine-4- yl) oxy) phenyl) acrylamide,
N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl ) oxy) phenyl) propionamide,
N-(3-((2-((4-((3-methylisothiazol-5-yl)amino)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidine -4-yl) oxy) phenyl) acrylamide,
(R)-N-(3-((2-((4-(4-(5-(1,2-dithiolan-3-yl)pentanoyl)piperazin-1-yl)phenyl)amino) -5,7-dihydrofuro [3,4-d] pyrimidin-4-yl) oxy) phenyl) acrylamide,
N-(3-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5,7-di hydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide,
N-(3-((2-((2-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d ]pyrimidin-4-yl)oxy)phenyl)acrylamide,
(R)-1-(3-((2-((4-(4-(5-(1,2-Ithiolan-3-yl)pentanoyl)piperazin-1-yl)phenyl)amino) -5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)-1H-pyrrole-2,5-dione,
N-(3-((2-((4-(4-(5-(1,2-dithiolan-3-yl)pentanoyl)piperazin-1-yl)phenyl)amino)-5,7 -dihydrofuro [3,4-d] pyrimidin-4-yl) oxy) phenyl) acrylamide,
N-(3-((2-((4-(piperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy) phenyl) acrylamide,
N-(3-((2-((2-methoxy-4-(4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)piperidin-1-yl) phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl)oxy)phenyl)acrylamide, or
N-(3-((2-(4-(4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)piperidin-1-yl)-2-methoxybenzyl)-5 , 7-dihydrofuro [3,4-d] pyrimidin-4-yl) oxy) phenyl) acrylamide
A compound or a pharmaceutically acceptable salt thereof. 제3항에 있어서, 상기 화합물은
N-(3-((2-((4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드,
N-(3-((2-((3-플루오로-4-(4-메틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드, 또는
N-(3-((2-((4-(4-에틸피페라진-1-일)페닐)아미노)-5,7-다이하이드로퓨로[3,4-d]피리미딘-4-일)옥시)페닐)아크릴아마이드인
화합물 또는 이의 약학적으로 허용 가능한 염.4. The method of claim 3, wherein the compound is
N-(3-((2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide,
N-(3-((2-((3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyri midin-4-yl)oxy)phenyl)acrylamide, or
N-(3-((2-((4-(4-ethylpiperazin-1-yl)phenyl)amino)-5,7-dihydrofuro[3,4-d]pyrimidin-4-yl )oxy)phenyl)acrylamide
A compound or a pharmaceutically acceptable salt thereof. 제1항 내지 제4항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염, 및 약학적으로 허용 가능한 담체를 포함하는 조성물.A composition comprising the compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 유효 성분으로 제1항 내지 제4항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염을 포함하는 것을 특징으로 하는 다발성 경화증; 염증성 질환; 자가면역 질환; 또는 암의 치료 또는 예방용 약학 조성물.Multiple sclerosis, characterized in that it comprises the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient; inflammatory diseases; autoimmune diseases; Or a pharmaceutical composition for the treatment or prevention of cancer. 제6항에 있어서, 상기 조성물은 다발성 경화증, 염증, 두드러기, 전신 홍반성 루푸스, 알레르기, 류마티스 관절염, 천식, B 세포 림프종, 또는 백혈병의 치료 또는 예방용인 약학 조성물. The pharmaceutical composition according to claim 6, wherein the composition is for treatment or prevention of multiple sclerosis, inflammation, urticaria, systemic lupus erythematosus, allergy, rheumatoid arthritis, asthma, B-cell lymphoma, or leukemia. 제1항 내지 제4항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염의 치료적으로 또는 예방적으로 유효한 양을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는 다발성 경화증; 염증성 질환; 자가면역 질환; 또는 암의 치료 또는 예방 방법. Multiple sclerosis, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof; inflammatory diseases; autoimmune diseases; or a method of treating or preventing cancer. 제8항에 있어서, 상기 방법은 다발성 경화증, 염증, 두드러기, 전신 홍반성 루푸스, 알레르기, 류마티스 관절염, 천식, B 세포 림프종, 또는 백혈병의 치료 또는 예방 방법인, 방법.9. The method of claim 8, wherein the method is a method of treating or preventing multiple sclerosis, inflammation, urticaria, systemic lupus erythematosus, allergy, rheumatoid arthritis, asthma, B cell lymphoma, or leukemia.
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