KR20230088763A - 표적 단백질 분해를 위한 방법 및 조성물 - Google Patents
표적 단백질 분해를 위한 방법 및 조성물 Download PDFInfo
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- KR20230088763A KR20230088763A KR1020237016236A KR20237016236A KR20230088763A KR 20230088763 A KR20230088763 A KR 20230088763A KR 1020237016236 A KR1020237016236 A KR 1020237016236A KR 20237016236 A KR20237016236 A KR 20237016236A KR 20230088763 A KR20230088763 A KR 20230088763A
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A—HUMAN NECESSITIES
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Description
관련 출원
본 출원은 그 전체 내용이 본원에서 참조 인용되는, 2020년 10월 14일에 출원된 국제출원 PCT/CN2020/120927에 대한 우선권을 주장한다.
단백질 항상성, 또는 단백질항상성(proteostasis)은, 단백질의 합성, 폴딩, 이동(trafficking) 및 분해를 조절하는 세포의 능력을 나타낸다. 특히, 적절하게 조절된 단백질 분해는 세포의 정상적인 기능, 예컨대 이의 증식, 분화 및 사멸에 필요하고, 흔히 암 및 다른 질환에서 잘 조절되지 않는다(문헌[Van Die, Chin J Cancer, 2011, 30:124-137]).
유비퀴틴-프로테아좀 시스템(UPS: ubiquitin-proteasome system)은 단백질의 폐기 및 대사성 재활용을 매개하는 세포에서의 주요 경로 중 하나이다(문헌[Yu and Matouschek, Annu Rev Biophys, 2017, 46:149-173]; 문헌[Navon and Ciechanover, J Biol Chem, 2009, 284:33713-33718]). 유비퀴틴은 보편적으로 발현되는 76개의 아미노산-잔기 단백질이다. UPS에 의한 단백질 분해에 대하여, 유비퀴틴화 과정은 유비퀴틴이 기질 단백질의 라이신 아미노산 잔기에 부착될 때 발생하고, 이는 일련의 효소적 단계를 포함한다. 첫 번째로, 유비퀴틴은 E1 유비퀴틴-활성화 효소로 전달된다. 두 번째로, 활성화된 유비퀴틴은 E1로부터 E2 유비퀴틴-접합 효소로 전달된다. 세 번째로, 수백 가지의 상이한 E3 유비퀴틴 리가아제 효소 중 하나는 유비퀴틴을 기질 단백질의 라이신 잔기에 연결한다. 이러한 효소적 과정의 반복은, 폴리유비퀴틴 사슬에 의한 기질 단백질의 태깅을 야기한다. 상기 유비퀴틴-태깅된 단백질은 이후 프로테아좀, 단백질을 분해하는 거대 다중-소단위 복합체에 전달될 수 있다. 단백질을 UPS로 향하게 하는 일부 세포 샤페론 단백질 및 샤페론 복합체의 능력은, E3 유비퀴틴 리가아제와의 이의 직접적 상호작용에 의해 촉진된다(문헌[Amm et al., Biochim Biophys Acta, 2014, 1843:182-196]; 문헌[Taipale et al., Cell, 2012,150:987-1001]). 단백질 분해 이외에, 단백질의 유비퀴틴화는 또한 다른 과정, 예컨대 하위세포 국소화, 활성 및 단백질-단백질 상호작용을 조절할 수 있다.
화학적으로 유도된, 표적 단백질 분해(TPD: targeted protein degradation)는 소분자 약물 개발을 위한 신규한 양식으로서 알려졌다. 소분자는 표적 단백질 또는 단백질과 다양한 세포 단백질 분해 경로의 구성성분 또는 구성성분들의 상호작용을 촉진하는 데 사용되어, 질환을 치료하는 방식으로서 표적 단백질 또는 단백질들의 분해를 유도할 수 있다.
특히, 단백질분해-표적 키메라(PROTAC)는 UPS를 선택하여 특정 단백질의 단백질 분해를 의도적으로 유도하는 상기 소분자의 예이다(문헌[Burslem and Crews, Cell, 2020, 181:102-114]; 문헌[Pettersson and Crews, Drug Discov Today Technol, 2019, 31:15-27]). PROTAC 분자는 표적 단백질 또는 단백질들 및 E3 유비퀴틴 리가아제에 동시에 결합하여, 표적 단백질(들), PROTAC 분자 및 E3 리가아제 단백질 사이에서 세포에 삼원 복합체를 생성하는 이관능성 소분자이다. 표적 단백질(들) 및 E3 리가아제의 유도된 근접성은, 표적 단백질(들)의 유비퀴틴화 및 프로테아좀에 의한 표적 단백질(들)의 후속 분해를 야기한다. 다중 단백질에 무차별적으로 결합하는 표적 단백질 결합제를 혼입하는 PROTAC이 흔히 다중 단백질을 분해할 수 있기는 하지만, 일부 경우에서 개별 표적과 E3 리가아제 사이의 단백질-단백질 상호작용은, 예를 들어 주어진 표적 단백질과 E3 리가아제 쌍 사이의 전하 반발 및 입체 충돌로 인한 일부 삼원 복합체의 형성을 저해하는 것에 의한, 관찰된 분해의 능력 및 선택성을 증가 또는 감소시킬 수 있다(문헌[Pettersson and Crews, Drug Discov Today Technol, 2019, 31:15-27]; 문헌[Bondeson et al., Cell Chem Biol, 2018, 25:78-87]; 문헌[Gadd et al., Nat Chem Biol, 2017, 13:514-521]; 문헌[Zengerle et al., ACS Chem Biol, 2015, 10:1770-1777]).
TPD를 화학적으로 유도하는 다른 방법, 예컨대 분자 접착제(문헌[Che et al., Bioog Med Chem Lett, 2018, 28:2585-2592]), AUTAC, ATTEC 및 LYTAC(문헌[Ding et al., Trends Pharmacol Sci, 2020, 41:464-474])가 또한 기재되었다. 예를 들어, AUTAC 기술은 유도된 근접성의 유사한 원리를 따르지만, 자가포식(autophagy)을 통한 분해를 위해 단백질을 표적으로 한다(문헌[Daiki et al., Mol Cell, 2019, 76:797-810]).
총체적으로, TPD 기술은 통상적인 생화학적 저해제에 비해 많은 이점을 갖는다(문헌[Pettersson and Crews, Drug Discov Today Technol, 2019, 31:15-27]; 문헌[Ding et al., Trends Pharmacol Sci, 2020, 41:464-474]). 예를 들어, 통상적인 저해제와 달리, TPD 작용제는 아화학량론적으로 작용하고, 표적 단백질(들)의 다중 분자의 순차적 분해를 매개할 수 있어, 흔히 이들이 혼입하는 단리된 표적 결합 모이어티 및 다른 생화학적 저해제보다 더 큰 효능을 야기할 수 있다. 또한, TPD 작용제에 의한 표적 단백질(들) 기능의 저해는 생화학적 저해만이 아니라 분해에 주로 기인하기 때문에, 표적 단백질(들)의 기능의 회복은 전형적으로는 생화학적 저해제에 대해 관찰되는 것보다 더 느리다. TPD 작용제는 또한 생화학적 저해제보다 개선된 표적 선택성을 가질 수 있다. 마지막으로, TPD 작용제는 표적의 생화학적 활성에 영향을 주지 않지만 여전히 이의 분해를 허용하는 결합 포켓과 상호작용함으로써 생화학적 저해에 순응하지 않는 단백질을 표적으로 할 수 있다.
그러나, 일부 단점은 현재의 TPD 기술과 연관된다. 이는 표적 단백질(들)이 질환 과정에 관여하는 조직(들) 및 기관(들)뿐만 아니라 많은 조직 및 기관에서 표적 단백질(들)의 무차별적 분해를 포함하고, 이는 치료의 원치 않는 부작용을 야기할 것으로 예상된다. 또한, 이러한 기술에 대한 저항성은 치료적 효능의 상실을 야기하는, E3 리가아제와 같은 UPS의 구성성분의 발현에서 돌연변이 또는 변경을 통해 발생할 수 있다(문헌[Ottis et al., ACS Chem Biol, 2019, 14:2215-2223]; 문헌[Zhang et al., Mol Cancer Ther, 2019, 18:1302-1311]). 상기와 같이, TPD를 위한 개선된/대안적 방법 및 조성물에 대한 요구가 존재한다.
암 및 다른 질환과 연관된 단백질의 분해를 매개하는 개선된/대안적 TPD 작용제를 개발하는 것이 또한 바람직하다. KRAS에서 돌연변이의 활성화는 인간 암에서 발견되는 가장 빈번한 발암성 변화 중의 하나이다(문헌[Simanshu et al., Cell, 2017, 170:17-33]). 특히, 돌연변이된 KRAS(G12C)는 폐 선암종의 ~15%, 결직장 암종의 ~8% 및 췌장 선암종의 ~4%, 뿐만 아니라 다른 암에서 발견된다(문헌[Jiao and Yang, Innovation (N Y), 2020, 1:100035]). 비록 돌연변이된 KRAS는 역사적으로 약효가 없는 암 약물 표적으로 고려되었지만, 최근의 진전은 KRAS(G12C)의 공유 결합 약리학적 저해제의 개발을 야기하였다(문헌[Ostrem et al., Nature, 2013, 503:548-551]; 문헌[Cannon et al., Nature, 2019, 575:217-223]; 문헌[O'Bryan, Pharmacol Res, 2019, 139:503-511]; 문헌[Hallin et al., Cancer Discov, 2020, 10:54-71]). 비록 임상에서 암 환자에서의 상기 저해제에 대한 효능이 관찰되었지만, 선천적 내성 및 종양 재발이 또한 보고되었다(문헌[Cannon et al., Nature, 2019, 575:217-223]). 공유결합 KRAS(G12C) 저해제에 대한 선천적 및 후천적 저항성의 기저에 있는 메커니즘이 또한 명료해지기 시작하였는데, 예를 들어 높은 EGFR 신호전달을 통해 매개된다(문헌[Adachi et al., Clin Cancer Res, 2020, in press]; 문헌[Amodio et al., Cancer Discov, 2020]; 문헌[Hata and Shaw, Nat Med, 2020, 26:169-170]; 문헌[Jiao and Yang, Innovation (N Y), 2020, 1:100035]; 문헌[Koleilat and Kwong, Cancer Discov, 2020, 10:1094-1096]; 문헌[Ryan et al., Clin Cancer Res, 2020, 26:1633-1643]; 문헌[Xue et al., Nature, 2020, 577:421-425]). 이와 같이, KRAS(G12C)는 매력적인 약물 표적을 나타내고, KRAS(G12C)의 TPD를 유도하는 작용제를 개발하는 것이 바람직하다. KRAS(G12C) 및 하나 이상의 다른 단백질, 특히 KRAS(G12C) 저해제에 대한 저항성의 매개와 연관되는 것 둘 모두의 분해를 유도하는 작용제를 개발하는 것이 또한 바람직하다.
본 개시내용은, 표적 단백질(예를 들어, KRAS(G12C)) 또는 단백질들에 결합할 수 있는 제1 모이어티 및 샤페론 복합체의 샤페론 단백질 또는 단백질들 또는 단백질 구성성분(예를 들어, HSP90)을 결합할 수 있는 제2 모이어티를 포함하는 샤페론-매개된 단백질 디그레이더(degrader)(CHAMP)로 칭해지는, 종양-표적 단백질 분해 키메라를 제공한다. 상기 CHAMP 화합물은 하기 화학식 I을 갖는 것, 및 이의 약학적으로 허용가능한 염을 포함한다:
식 중에서, L, A, Q1, Q2, R5, R7, R8, 및 j는 본원에서 정의된 바와 같음.
개시된 화학식 I의 화합물을 포함하는 조성물뿐만 아니라 이의 제조 방법이 또한 제공된다. 한 양태에서, 개시된 화합물은 종양-선택적 방식으로 표적 종양원성 단백질 분해를 유도하고, 암 및 관련 병상의 치료에 유용하다.
1.
화합물의 일반적 설명
본원에서 제공되는 것은 하기 화학식 I을 갖는 CHAMP 화합물, 또는 이의 약학적으로 허용가능한 염이다:
식 중에서,
A는 HSP90 단백질에 결합하는 화학적 모이어티이고;
L은 연결기이고;
Q1은 질소 함유 헤테로아릴 또는 헤테로시클릴 고리이고, 이들 각각은 선택적으로는 R6으로부터 선택된 1 내지 3개의 기에 의해 치환되고;
R5는 ―C(O)Y 또는 ―S(O)2Y이고;
Y는 (C1-C6)알킬, 할로(C1-C6)알킬, (C2-C6)알케닐, 할로(C2-C6)알케닐, NH2, -NH(C1-C6)알킬, -N[(C1-C6)알킬]2, NHNH2, 또는 NHOH이고, 여기서 상기 (C2-C6)알케닐은, 단독으로 또는 할로(C2-C6)알케닐에서 언급된 바와 같이, 선택적으로는 (C1-C6)알킬, 할로(C1-C6)알킬, 헤테로알킬, 히드록시(C1-C6)알킬, -C(O)NH2, -C(O)NH(C1-C6)알킬, 또는 -C(O)N[(C1-C6)알킬]2에 의해 치환되고;
R6은 (C1-C6)알킬, 할로(C1-C6)알킬, (C1-C6)알콕시, 할로(C1-C6)알콕시, 히드록시(C1-C6)알킬, 시아노(C1-C6)알킬, 옥소, 시아노, 헤테로알킬, -C(O)OH, -C(O)O(C1-C6)알킬, -C(O)NH2, -C(O)NH(C1-C6)알킬, 또는 -C(O)N[(C1-C6)알킬]2이고, 여기서 상기 (C1-C6)알킬은 선택적으로는 헤테로아릴에 의해 치환되고;
R7은 할로, 히드록실, (C1-C6)알킬, 할로(C1-C6)알킬, (C1-C6)알콕시, 할로(C1-C6)알콕시, 시클로알킬, 헤테로알킬, 히드록시(C1-C6)알킬, 또는 S(C1-C6)알킬이고;
j는 1 또는 2이고;
Q2는 결합, -C(O)-, 또는 (C1-C3)알킬렌이고;
R8은 시클로알킬, 헤테로시클릴, 아릴, 또는 헤테로아릴이고, 이들 각각은 선택적으로는 R9로부터 선택된 1 내지 3개의 기에 의해 치환되고;
R9는 할로, (C1-C6)알킬, (C2-C6)알케닐, 할로(C2-C6)알케닐, (C2-C6)알키닐, 옥소, 시아노, -(C1-C6)알킬ORc, -(C1-C6)알킬N(Rd)2, -(C1-C6)알킬C(O)ORd, OH, -(C1-C6)알킬C(O)N(Rd)2, -(C1-C6)알킬O(C1-C6)알킬N(Rd)2, -(C1-C6)알킬SORd, -(C1-C6)알킬S(O)2Rd, -(C1-C6)알킬SON(Rd)2, -(C1-C6)알킬SO2N(Rd)2, -(C1-C6)알킬시클로알킬, -(C1-C6)알킬헤테로시클릴, -(C1-C6)알킬헤테로아릴, -(C1-C6)알킬아릴, -(C1-C6)알콕시, 할로(C1-C6)알콕시, CN, 아릴, 헤테로아릴, 시클로알킬, 헤테로시클로알킬, -C(O)Rd, -C(O)ORd, -C(O)N(Rd)2, N(Rd)2, -C(O)NRd(C1-C6)알킬N(Rd)2, -NRd(C1-C6)알킬N(Rd)2, -NRd(C1-C6)알킬ORd, -SORd, -S(O)2Rd, -SON(Rd)2, -SO2N(Rd)2, 또는 CN이고, 여기서 각각의 아릴, 시클로알킬, 헤테로시클릴, 및 헤테로아릴은 단독으로 및 -(C1-C6)알킬시클로알킬, -(C1-C6)알킬헤테로시클릴, -(C1-C6)알킬헤테로아릴, -(C1-C6)알킬아릴과 관련하여 선택적으로는 Re로부터 선택된 1 내지 3개의 기에 의해 치환되고;
Rc 및 Rd는 각각 독립적으로는 수소, (C1-C6)알킬, 및 할로(C1-C6)알킬로부터 선택되고;
Re는 할로, 옥소, CN, NO2, -N(Rd)2, -ORd, -C(O)ORd, (C1-C6)알킬, -(C1-C6)알킬ORc, 할로(C1-C6)알킬, (C1-C6)알콕시, 할로(C1-C6)알콕시, -(C1-C6)알킬C(O)ORd, -(C1-C6)알킬C(O)N(Rd)2, (C2-C6)알케닐, 할로(C2-C6)알케닐, (C2-C6)알키닐, -(C1-C6)알킬SRd, -(C1-C6)알킬ORc, -(C1-C6)알킬N(Rd)2, -C(O)N(Rd)2, -C(O)NRdC1-6알킬N(Rd)2, -NRdC1-6알킬N(Rd)2, -NRdC1-6알킬ORd, -SORd, -S(O)2Rd, -SON(Rd)2, -SO2N(Rd)2, 아릴, 헤테로아릴, 시클로알킬, 및 헤테로시클로알킬로부터 선택됨.
2.
정의
본원에서 사용되는 바와 같은, 관사는 관사의 문법적 대상 중 하나 이상, 예를 들어, 적어도 하나를 나타낸다. 본원에서 용어 "포함하는"과 조합하여 사용될 때 관사의 사용은 "하나"를 의미할 수 있지만, 이는 또한 "하나 이상의", "적어도 하나", 및 "하나 또는 하나 초과"의 의미와 일치한다.
본원에 사용된 바와 같은, "약" 및 "대략"은 일반적으로 측정값의 성질 또는 정밀도를 고려하여 측정된 양에 대한 허용가능한 오차 정도를 의미한다. 예시적인 오차 정도는 주어진 값의 범위의 20 퍼센트(%) 이내, 전형적으로 10% 이내, 더 전형적으로 5% 이내이다. 용어 "실질적으로"는 50% 초과, 바람직하게는 80% 초과, 가장 바람직하게는 90% 초과 또는 95% 초과를 의미한다.
본원에 사용된 바와 같은, 용어 "포함하는" 또는 "포함하다"는, 주어진 실시형태에 제시되어 있지만, 명시되지 않은 요소를 포함할 수도 있는, 조성물, 방법, 및 이의 각각의 구성요소(들)에 관하여 사용된다.
본원에 사용된 바와 같은, 용어 "~로 본질적으로 이루어지는"은 주어진 실시형태에 필요한 요소를 나타낸다. 용어는 개시내용의 실시형태의 기본적이고 신규하거나 기능적인 특징(들)에 실질적으로 영향을 주지 않는 추가적 요소들의 존재를 허용한다.
용어 "~로 이루어지는"은 실시형태의 상세한 설명에서 언급되지 않은 임의의 요소를 배제한, 본원에 기재된 조성물, 방법 및 이의 각각의 구성성분을 나타낸다.
본원에 사용된 바와 같은, 용어 "알킬"은 달리 명시되지 않는 한, 1 내지 10개의 탄소 원자를 갖는 포화 직쇄 또는 분지형 비(非)시클릭 탄화수소, 예를 들어 (C1-C6)알킬 또는 (C1-C4)알킬을 의미한다. 대표적인 직쇄 알킬은 메틸, 에틸, n-프로필, n-부틸, n-펜틸, n-헥실, n-헵틸, n-옥틸, n-노닐 및 n-데실을 포함하는 한편; 포화 분지형 알킬은 이소프로필, sec-부틸, 이소부틸, tert-부틸, 이소펜틸, 2-메틸부틸, 3-메틸부틸, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 2-메틸헥실, 3-메틸헥실, 4-메틸헥실, 5-메틸헥실, 2,3-디메틸부틸, 2,3-디메틸펜틸, 2,4-디메틸펜틸, 2,3-디메틸헥실, 2,4-디메틸헥실, 2,5-디메틸헥실, 2,2-디메틸펜틸, 2,2-디메틸헥실, 3,3-디메틸펜틸, 3,3-디메틸헥실, 4,4-디메틸헥실, 2-에틸펜틸, 3-에틸펜틸, 2-에틸헥실, 3-에틸헥실, 4-에틸헥실, 2-메틸-2-에틸펜틸, 2-메틸-3-에틸펜틸, 2-메틸-4-에틸펜틸, 2-메틸-2-에틸헥실, 2-메틸-3-에틸헥실, 2-메틸-4-에틸헥실, 2,2-디에틸펜틸, 3,3-디에틸헥실, 2,2-디에틸헥실, 3,3-디에틸헥실 등을 포함한다.
본원에 사용된 바와 같은, 용어 "알케닐"은 달리 명시되지 않는 한, 2 내지 10개의 탄소 원자를 갖는(예를 들어, (C2-C6)알케닐 또는 (C2-C4)알케닐) 그리고 적어도 하나의 탄소-탄소 이중 결합을 갖는 포화 직쇄 또는 분지형 비시클릭 탄화수소를 의미한다. 대표적 직쇄 및 분지형 (C2-C10)알케닐은 비닐, 알릴, 1-부테닐, 2-부테닐, 이소부틸레닐, 1-펜테닐, 2-펜테닐, 3-메틸-1-부테닐, 2-메틸-2-부테닐, 2,3-디메틸-2-부테닐, 1-헥세닐, 2-헥세닐, 3-헥세닐, 1-헵테닐, 2-헵테닐, 3-헵테닐, 1-옥테닐, 2-옥테닐, 3-옥테닐, 1-노네닐, 2-노네닐, 3-노네닐, 1-데세닐, 2-데세닐, 3-데세닐 등을 포함한다.
본원에 사용된 바와 같은, 용어 "알키닐"은 달리 명시되지 않는 한, 2 내지 10개의 탄소 원자를 갖는(예를 들어, (C2-C6)알키닐 또는 (C2-C4)알키닐) 그리고 적어도 하나 탄소-탄소 삼중 결합을 갖는 포화 직쇄 또는 분지형 비시클릭 탄화수소를 의미한다. 대표적 직쇄 및 분지형 알키닐은 아세틸레닐, 프로피닐, 1-부티닐, 2-부티닐, 1-펜티닐, 2-펜티닐, 3-메틸-1-부티닐, 4-펜티닐, 1-헥시닐, 2-헥시닐, 5-헥시닐, 1-헵티닐, 2-헵티닐, 6-헵티닐, 1-옥티닐, 2-옥티닐, 7-옥티닐, 1-노니닐, 2-노니닐, 8-노니닐, 1-데시닐, 2-데시닐, 9-데시닐, 등을 포함한다.
본원에 사용된 바와 같은, 용어 "시클로알킬"은 예를 들어, 3 내지 10개의 탄소 원자(예를 들어, 4 내지 6개의 탄소 원자)를 갖는 포화, 모노시클릭 알킬 라디칼을 의미한다. 대표적 시클로알킬은 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실, 시클로헵틸, 시클로옥틸, 시클로노닐, 및 시클로데카닐을 포함한다.
용어 "옥소"는 기 =O를 나타낸다.
본원에 사용된 바와 같은, 용어 "할로알킬"은 하나 이상의(모두를 포함) 수소 라디칼이 할로 기로 대체되는 알킬 기를 의미하고, 여기서 각각의 할로 기는 독립적으로 -F, -Cl, -Br, 및 -I로부터 선택된다. 대표적 할로알킬 기는 트리플루오로메틸, 브로모메틸, 1,2-디클로로에틸, 4-요오도부틸, 2-플루오로펜틸, 등을 포함한다.
본원에 사용된 바와 같은, "알콕시"는 산소 연결기를 통해 또 다른 모이어티에 부착되는 알킬 기이다.
본원에 사용된 바와 같은, "할로알콕시"는 산소 연결기를 통해 또 다른 모이어티에 부착되는 할로알킬 기이다.
본원에 사용된 바와 같은, 용어 "알킬렌"은 2개의 부착 지점을 갖는 알킬 기를 나타낸다. 직쇄 알킬렌 기가 바람직하다. 알킬렌 기의 비제한적 예는 메틸렌 에틸렌, n-프로필렌, 이소프로필렌, 등을 포함한다. 알킬렌 기는 선택적으로는 하나 이상의 치환기로 치환될 수 있다.
본원에 사용된 바와 같은, 용어 "헤테로시클릴"은, 크기 및 원자가가 허용하는 한, 질소, 산소, 및 황으로부터 독립적으로 선택되는 5개 이하의 헤테로원자를 포함하는 포화 고리 또는 불포화 비(非)방향족 고리인 모노시클릭 헤테로시클릭 고리계를 의미한다. 헤테로사이클은 임의의 헤테로원자 또는 탄소 원자를 통해 부착될 수 있다. 대표적 헤테로사이클은 모르폴리닐, 티오모르폴리닐, 피롤리디노닐, 피롤리디닐, 피페리디닐, 피페라지닐, 옥시라닐, 옥세타닐, 테트라히드로푸라닐, 테트라히드로피라닐, 테트라히드로피린디닐, 테트라히드로피리미디닐, 등을 포함한다.
본원에 사용된 바와 같은, 용어 "헤테로아릴"은, 정의된 크기가 허용하는 한, 탄소 원자 고리원 및 질소, 산소, 및 황으로부터 선택되는 하나 이상의 헤테로원자 고리원을 포함하는 모노시클릭 또는 폴리시클릭 헤테로방향족 고리를 의미한다. 대표적인 헤테로아릴 기는 피리딜, 푸라닐, 티에닐, 피롤릴, 옥사졸릴, 이미다졸릴, 티아졸릴, 이속사졸릴, 퀴놀리닐, 피라졸릴, 이소티아졸릴, 피리다지닐, 피리미디닐, 피라지닐, 트리아지닐, 트리아졸릴, 티아디아졸릴, 이소퀴놀리닐, 인다졸릴, 벤족사졸릴, 벤조푸릴, 인돌리지닐, 이미다조피리딜, 테트라졸릴, 벤지미다졸릴, 벤조티아졸릴, 벤조티아디아졸릴, 벤족사디아졸릴, 인돌릴, 테트라히드로인돌릴, 아자인돌릴, 이미다조피리딜, 퀴나졸리닐, 푸리닐, 벤조티에닐, 등을 포함한다. 또 다른 기에 대한 헤테로방향족 또는 헤테로아릴 고리의 부착 지점은, 헤테로방향족 또는 헤테로아릴 고리의 헤테로원자 또는 탄소 원자일 수 있다.
본원에 사용된 바와 같은, 용어 "할로겐" 또는 "할로"는 F, Cl, Br 또는 I를 의미한다.
헤테로시클릴 또는 헤테로아릴 기가 질소 원자를 함유하는 경우, 이는 원자가가 허용하는 한, 치환 또는 비치환될 수 있다.
상호교환적으로 사용된 용어 "연결기" 또는 "테더(tether)"는, 2개의 다른 모이어티(예를 들어, 제1 결합 모이어티 및 제2 결합 모이어티)를 결합하는 화학적 모이어티를 나타낸다. 연결기는 제1 결합 모이어티 및 제2 결합 모이어티를 공유 결합시킬 수 있다. 한 양태에서, 연결기는 생체내(in vivo)에서 분해불가능하다. 한 양태에서, 연결기는 하나 이상의 시클릭 고리계를 포함한다. 또 다른 양태에서, 연결기는 선택적으로는 하나 이상의 화학적 기에 의해 치환되고/되거나 이것이 개재된 알킬 사슬을 포함한다. 한 양태에서, 연결기는 최적의 치료적 활성을 유발하기 위한 최적의 공간적 및 화학적 특성을 포함한다. 한 양태에서, 연결기는 이의 각각의 표적(예를 들어, HSP90 및 KRAS(G12C))에 결합하는 제1 결합 모이어티 및/또는 제2 결합 모이어티의 능력을 방해하지 않는다. 한 양태에서, 연결기는 이의 각각의 표적(예를 들어, HSP90 및 KRAS(G12C))에 결합하는 제1 결합 모이어티 및/또는 제2 결합 모이어티의 능력을 바꾼다.
용어 "KRAS"는 KRAS 원종양 유전자, GTPase 유전자의 단백질 생성물을 나타낸다.
용어 "KRAS(G12C)"는 시스테인에 의해 대체되는 KRAS의 위치 12에서 글라이신 아미노산을 야기하는 돌연변이를 수반하는 KRAS 유전자의 단백질 생성물을 나타낸다.
용어 "HSP90"은 총체적으로, 개별적으로 또는 다양한 조합으로 열 쇼크 단백질 90(90 kDa) 유전자 패밀리, 예컨대: HSP90AA1(HSP90-알파 또는 HSP90α), HSP90AB1(HSP90-베타 또는 HSP90β), HSP90B1(GRP94) 및 TRAP1의 구성원의 단백질 생성물을 나타낸다.
다중 부착 지점을 가질 수 있는 화학적 기를 기재하기 위해 연계하여 사용되는 경우, 하이픈(-)은 이것이 정의되는 변수에 대한 해당 기의 부착 지점을 나타낸다. 예를 들어, -NRaRb 및 -C(O)NRa(C1-4알킬렌)NRaR은 이러한 기에 대한 부착 지점이 각각 질소 원자 및 탄소 원자 상에서 발생한다는 것을 의미한다.
개시된 화합물의 입체화학이 구조에 의해 명명되거나 도시될 경우, 명명되거나 도시된 입체 이성질체는 다른 입체 이성질체 모두에 대해 적어도 60 중량%, 70 중량%, 80 중량%, 90 중량%, 99 중량% 또는 99.9 중량% 순수하다. 다른 입체 이성질체 모두에 대한 중량 백분율 순도는, 다른 입체 이성질체의 중량에 대한 하나의 입체 이성질체의 중량의 비율이다. 예를 들어, 단일 거울상 이성질체가 구조에 의해 명명되거나 도시될 경우, 도시되거나 명명된 거울상 이성질체는 적어도 60 중량%, 70 중량%, 80 중량%, 90 중량%, 99 중량% 또는 99.9 중량% 광학적으로 순수하다. 중량 백분율 광학 순도는 거울상 이성질체의 중량 대 거울상 이성질체의 중량에 더한 이의 광학 이성질체의 중량의 비율이다.
의약에서 사용하기 위해, 개시된 화합물의 약학적으로 허용가능한 염은 비독성 "약학적으로 허용가능한 염"을 나타낸다. 약학적으로 허용가능한 염 형태는 약학적으로 허용가능한 산성/음이온성 또는 염기성/양이온성 염을 포함한다. 본원에 기재된 화합물의 적합한 약학적으로 허용가능한 산 부가 염은 예를 들어 무기 산(예컨대 염산, 브롬화수소산, 인산, 질산 및 황산)의 염 및 유기 산(예컨대 아세트산, 벤젠술폰산, 벤조산, 메탄술폰산 및 p-톨루엔술폰산)의 염을 포함한다. 산성 기 예컨대 카르복시산과 함께 교시되는 본 발명의 화합물은 약학적으로 허용가능한 염기(들)과 약학적으로 허용가능한 염을 형성할 수 있다. 적합한 약학적으로 허용가능한 염기성 염은 예를 들어, 암모늄 염, 알칼리 금속 염(예컨대 나트륨 및 칼륨 염) 및 알칼리 토금속 염(예컨대 마그네슘 및 칼슘 염)을 포함한다. 4차 암모늄 기를 갖는 화합물은 또한 반대이온 예컨대 클로라이드, 브로마이드, 요오다이드, 아세테이트, 퍼클로레이트 등을 함유한다. 상기 염의 다른 예는 히드로클로라이드, 히드로브로마이드, 술페이트, 메탄술포네이트, 니트레이트, 벤조에이트 및 아미노산 예컨대 글루탐산과의 염을 포함한다.
용어 "약학적으로 허용가능한 담체"는 이와 함께 제형화되는 화합물의 약리학적 활성을 파괴하지 않는 비독성 담체, 아쥬반트 또는 비히클을 나타낸다. 본원에 기재된 조성물에서 사용될 수 있는 약학적으로 허용가능한 담체, 아쥬반트 또는 비히클은, 이온 교환체, 알루미나, 알루미늄 스테아레이트, 레시틴, 혈청 단백질, 예컨대 인간 혈청 알부민, 완충 물질 예컨대 포스페이트, 글리신, 소르브산, 칼륨 소르베이트, 포화 식물성 지방산의 부분 글리세라이드 혼합물, 물, 염 또는 전해질, 예컨대 프로타민 술페이트, 이나트륨 히드로겐 포스페이트, 칼륨 히드로겐 포스페이트, 나트륨 클로라이드, 아연 염, 콜로이드성 실리카, 마그네슘 트리실리케이트, 폴리비닐 피롤리돈, 셀룰로오스계 물질, 폴리에틸렌 글리콜, 나트륨 카르복시메틸셀룰로오스, 폴리아크릴레이트, 왁스, 폴리에틸렌-폴리옥시프로필렌-블록 중합체, 폴리에틸렌 글리콜 및 양모 지방을 포함하지만, 이에 제한되지는 않는다.
본원에 제공된 임의의 조성물 또는 방법은 본원에 제공된 임의의 다른 조성물 및 방법 중 하나 이상과 조합될 수 있다.
본원에 사용된 바와 같은, 용어 "대상체"는 인간, 및 가축 대상체를 포함한 비인간 동물을 나타낸다. 용어 "비인간 동물"은 모든 척추동물, 예를 들어 포유류 및 비포유류, 예컨대 비인간 영장류, 마우스, 토끼, 양, 개, 고양이, 말, 소, 닭, 양서류, 및 파충류를 포함한다. 바람직한 실시형태에서, 대상체는 인간이고 환자로서 나타내어질 수 있다.
본원에 사용된 바와 같은, 용어 "치료하다", "치료하는" 또는 "치료"는, 바람직하게는, 검출 가능하든지 또는 검출 불가능하든지 간에, 질환 또는 병상의 하나 이상의 징후 또는 증상의 경감 또는 개선, 질환 정도의 축소, 질환 상태의 안정성(즉, 악화되지 않음), 질환 상태의 개선 또는 완화, 진행 속도 또는 진행까지의 시간의 축소, 및 관해(부분 또는 완전)를 포함하지만 이로 제한되지는 않는, 유익하거나 원하는 임상적 결과를 얻기 위한 행위를 나타낸다. "치료"는 또한 치료의 부재 하에 예상되는 생존율과 비교하여 생존율을 연장시키는 것을 의미할 수 있다. 치료는 치유력이 있을 필요는 없다.
"치료적 유효량"은, 대상체에서 질환을 치료하기에 충분한 양이다. 치료적 유효량은 하나 이상의 투여로 투여될 수 있다. 한 양태에서, 치료적 유효량은 약 0.01 내지 약 100 mg/kg 체중/일의 투여량을 나타낸다.
용어 "투여하다", "투여하는" 또는 "투여"는, 약학 조성물 또는 작용제를 대상체의 시스템 내로 또는 대상체 내의 또는 대상체 상의 특정 영역에 전달하는 임의의 방법을 포함한다. 본 발명의 특정 실시형태에서, 작용제는 정맥내로, 근육내로, 피하로, 피내로, 비강내로, 경구로, 경피로, 또는 점막으로 투여된다. 바람직한 실시형태에서, 작용제는 정맥내로 투여된다. 또 다른 바람직한 실시형태에서, 작용제는 경구로 투여된다. 작용제의 투여는 협력하여 작업하는 많은 사람들에 의해 수행될 수 있다. 작용제의 투여는 예를 들어, 자가-전달에 의해, 예를 들어, 경구 전달, 피하 전달, 중심 라인(central line)을 통한 정맥내 전달 등에 의해; 또는 숙련된 전문가에 의한 전달, 예를 들어, 정맥내 전달, 근육내 전달, 종양내 전달 등에 의해 특정 작용제를 복용하기 위해, 직접적으로 또는 또 다른 것을 통해, 대상체에게 투여될 작용제를 처방하고/하거나 지시사항을 제공하는 것을 포함한다.
3.
화합물
제1 실시형태에서, 제공되는 것은 하기 화학식 I의 화합물, 또는 이의 약학적으로 허용가능한 염이다:
식 중에서, 변수는 상기 기재된 바와 같음.
제2 실시형태에서, 화학식 I의 화합물의 A는
Q 및 U는 각각 독립적으로는 페닐, 헤테로아릴, 헤테로시클릴, 및 시클로알킬로부터 선택되고, 이들 각각은 선택적으로는 R2로부터 선택된 1 내지 3개의 기에 의해 치환되고;
R13 및 R14는 각각 독립적으로는 수소, 할로, -CN, (C1-C4)알킬, 할로(C1-C4)알킬, 및 -C(O)NRaRb로부터 선택되고;
R15는 수소, (C1-C4)알킬, 또는 할로(C1-C4)알킬이고;
W는 선택적으로는 R2로부터 선택되는 1 내지 3개의 기로 치환된 5-원 또는 6-원 헤테로아릴이고;
V는 페닐, 또는 선택적으로는 R3으로부터 선택되는 1 내지 3개의 기로 치환된 5-원 내지 9-원 헤테로아릴이고;
R1은 할로, (C1-C4)알킬, 할로(C1-C4)알킬, (C1-C4)알콕시, 또는 할로(C1-C4)알콕시이고;
R2는 (C1-C4)알킬, 할로(C1-C4)알킬, (C2-C6)알케닐, 할로(C2-C6)알케닐, (C2-C6)알키닐, 할로(C2-C6)알키닐, CN, -C1-4알킬ORa, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(O)NRa(C1-4알킬렌)ORa, -C(O)NRa(C1-4알킬렌)NRaRb, -C(O)NRa(C1-4알킬렌)OR, -NRaRb, -O(C1-4알킬렌)NRaRb, -SH, -S(C1-4알킬), -C1-4알킬NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(C1-4알킬)ORa, -NRa(C1-4알킬)NRaRb, -C1-6알킬C(O)NRaRb, 페닐 또는 5-원 내지 7-원 헤테로아릴이고, 여기서 상기 페닐 및 5-원 내지 7-원 헤테로아릴은 각각 선택적으로는 및 독립적으로는 R4로부터 선택된 1 내지 3개의 기에 의해 치환되고;
Ra 및 Rb는 각각 독립적으로는 수소 및 (C1-C4)알킬로부터 선택되고, 여기서 상기 (C1-C4)알킬은 선택적으로는 하나 이상의 할로 또는 3-원 내지 7-원 헤테로시클릴, 또는 둘 모두에 의해 치환되고;
R3 및 R4는 각각 독립적으로는 할로, -NRaRb, (C1-C4)알킬, 할로(C1-C4)알킬, (C1-C4)알콕시, 또는 할로(C1-C4)알콕시이고, 여기서 나머지 변수는 화학식 I에 대해 상기 기재된 바와 같다.
제3 실시형태에서, 화학식 I의 화합물의 A는 이고, 식 중에서 나머지 변수는 화학식 I 또는 제2 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제3 실시형태의 일부로서, 화학식 I의 화합물의 A는 예시된 화합물 187 내지 351에서 위치 A에 상응하는 구조로부터 선택되고, 여기서 나머지 변수는 화학식 I 또는 제2 실시형태에 대해 상기 기재된 바와 같다.
제4 실시형태에서, 화학식 I의 화합물은 하기 화학식의 것, 또는 이의 약학적으로 허용가능한 염이다:
식 중에서, 나머지 변수는 화학식 I 또는 제2, 또는 제3 실시형태에 대해 상기 기재된 바와 같음.
제5 실시형태에서, R5는 ―C(O)Y이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 또는 제4 실시형태에 대해 상기 기재된 바와 같다.
제6 실시형태에서, Y는 (C1-C6)알킬, 할로(C1-C6)알킬, (C2-C6)알케닐, 할로(C2-C6)알케닐, 또는 NH2이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 또는 제5 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제6 실시형태의 일부로서, Y는 C(O)CH3, C(O)CHCH2, C(O)CH2CH3, C(O)CF3, C(O)CFCH2, C(O)CCH3, 또는 C(O)NH2이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 또는 제5 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제6 실시형태의 일부로서, Y는 C(O)CHCH2이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 또는 제5 실시형태에 대해 상기 기재된 바와 같다.
제7 실시형태에서, R6은 시아노(C1-C6)알킬이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 또는 제6 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제7 실시형태의 일부로서, R6은 CH2CN이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 또는 제6 실시형태에 대해 상기 기재된 바와 같다.
제8 실시형태에서, j는 0이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 또는 제7 실시형태에 대해 상기 기재된 바와 같다.
제9 실시형태에서, Q2는 결합이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 또는 제8 실시형태에 대해 상기 기재된 바와 같다.
제10 실시형태에서, R8은 선택적으로는 R9로부터 선택된 1 내지 3개의 기에 의해 치환된 아릴이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 또는 제9 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제10 실시형태의 일부로서, R8은 선택적으로는 R9로부터 선택된 1 내지 3개의 기에 의해 치환된 나프틸이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 또는 제9 실시형태에 대해 상기 기재된 바와 같다.
제11 실시형태에서, R9는 할로, (C1-C6)알킬, 및 OH로부터 선택되고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 또는 제10 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제11 실시형태의 일부로서, R9는 클로로 및 OH로부터 선택되고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 또는 제10 실시형태에 대해 상기 기재된 바와 같다.
제12 실시형태에서, A는 , , , , , , , , , , , 및 로부터 선택되고; Z는 N 또는 CH이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 또는 제11 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제12 실시형태의 일부로서, A는 상기 화학식으로부터 선택되고; Z는 CH이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 또는 제11 실시형태에 대해 상기 기재된 바와 같다.
제13 실시형태에서, R3은 독립적으로는 (C1-C4)알킬 또는 할로이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 또는 제12 실시형태에 대해 상기 기재된 바와 같다.
제14 실시형태에서, A는
, , , , , , , 또는 이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 또는 제13 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제14 실시형태의 일부로서, A는 , , , 또는 이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 또는 제13 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제14 실시형태의 일부로서, A는 , , 또는 이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 또는 제13 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제14 실시형태의 일부로서, A는 이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 또는 제13 실시형태에 대해 상기 기재된 바와 같다. 또 다른 대안에서, 제14 실시형태의 일부로서, 예시된 화합물 187 내지 화합물 351의 위치 A에 상응하는 구조로부터 선택되고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 또는 제13 실시형태에 대해 상기 기재된 바와 같다.
제15 실시형태에서, R1은 할로 또는 (C1-C4)알킬이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 또는 제14 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제15 실시형태의 일부로서, R1은 클로로, 이소프로필, 메틸, 프로필, 또는 에틸이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 또는 제14 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제15 실시형태의 일부로서, R1은 클로로, 이소프로필 또는 에틸이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 또는 제14 실시형태에 대해 상기 기재된 바와 같다.
제16 실시형태에서, R2는 -ORa, -SRa, -C(O)NRaRb, 또는 -C(O)NRa(C1-4알킬렌)NRaRb이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 또는 제15 실시형태에 대해 상기 기재된 바와 같다.
제17 실시형태에서, Ra 및 Rb는 각각 독립적으로는 수소 및 (C1-C4)알킬로부터 선택되고, 여기서 상기 (C1-C4)알킬은 선택적으로는 1 내지 3개의 할로 또는 6-원 헤테로시클릴에 의해 치환되고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 또는 제16 실시형태에 대해 상기 기재된 바와 같다.
제18 실시형태에서, R2는 OH, -C(O)NHCH2CF3, -C(O)NHCH2CH3, -C(O)NHCH(CH3)2, -C(O)NH(CH2CH3)2, -C(O)NHCH(CH3)CF3, -C(O)NH시클로프로필, -C(O)NH메틸시클로프로필, C(O)NH2, 또는 -C(O)NH(CH2)2피페리디닐이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 또는 제17 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제18 실시형태의 일부로서, R2는 -C(O)NHCH2CF3 또는 OH이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 또는 제17 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제18 실시형태의 일부로서, R2는 OH이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 또는 제17 실시형태에 대해 상기 기재된 바와 같다.
제19 실시형태에서, L은 -Het1-X1-, -Het1-, -Het1-Het2-X1-, -Het1-Het2-, -NRd-(CH2)m-X3-NRc-(CH2)m-Het1-X1-Het2-X2-, -NRc-(CH2)m-Het1-X1-Het2-X2-, -Het1-X1-Het2-X2-, O-(CH2)m-NRc-X1-(CH2)m-NRd-, -X1-NRc-X2-O-(CH2)m-NRd-, -X1-Het1-X2-Het2-(CH2)mO-, O-Het1-, O-Het1-X1-, -X1(OCH2CH2)n-NRc-, -(CH2)mNRc-, -(CH2)m-, -O-, X1NRc-, -NRc-(CH2)m-X1-Het1-X2-, -NRd-(CH2)m-X3-NRc-(CH2)m-Het1-X1-Het2-X2-, O-Het1-X1-(CH2)m-NRd-, -X1-NRc-X2-(CH2)m-NRd-, X1-Het1-X2-NRc-X3-Het2-(OCH2CH2)n-(CH2)m-NRd-(CH2)m-, -NRd-(CH2)m-X1-NRc-(CH2CH2O)n-, -NRc-(CH2)m-X1-NRc-(CH2)p-, X1-Het1-X2-NRc-X3-Het2-(OCH2CH2)n-NRd-(CH2)m-, -NRc-(CH2)m-X1-Het1-X2-Het2-X3-, O-X1-Het1-, -O(CH2)m-X1-Het1-X2-Het2-X3-, -O(CH2)m-X1-NRc-(CH2)p-Het1-X2-Het2-X3-, O-(CH2)m-NRc-, O-X1-Het1-X2-, -X1-NRc-(CH2)m-Het1-X2-Het2-X3-(CH2)p-NRd-(CH2)p-, -NRc-(CH2)m-X1-(CH)CH3-Het1-X2-Het3-X3-, -NRc-(CH2)m-X1-(CH2)p-Het1-X2-Het2-X3-, -NRc-(CH2)m-X1-NRd-(CH2)p-Het1-X2-Het2-X3-, -NRc-(CH2)m-NRd-X1-Het1-X2-, Het1-X1-Het2-X2-, -Het1-X1-Het2-X2-O-, -O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-, -O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-, -Het1-O-(CH2)m-X1-Het2-X2-, -Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-, -Het1-X1-NRc-(CH2)m-, -Het1-X1-Het2-Het3-X2-, -Het1-X1-NRc-(CH2CH2O)n(CH2)m-, -Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2-, -Het1-X1-NRc-(CH2CH2O)n-, -Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-, -Het1-X1-Het2-(CH2)m-Het3-X2-, -Het1-X1-Het2-, -Het1-X1-NRc-, -Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-, -Het1-X1-Het2-Het3-, -Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-, -Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-, -Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-, -Het1-X1-Het2-(CH2CH2O)n-, -Het1-X1-(CH2)m-Het2-X2-, -(CH2CH2O)o-(CH2)p-Het1-X1-Het2-(CH2CH2O)n, -(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2, -Het1-X1-Phe-X2-NRc-X3-, -(CH2CH2O)o-(CH2)p-Het1-X1-Phe-X2-NRc-(CH2CH2O)n-, -(CH2CH2O)n-(CH2)m-NRc-Phe-X1-, -(CH2CH2O)o-(CH2)p-NRc-Phe-(CH2CH2O)n-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-, -(CH2CH2O)n-(CH2)m-NRc-(CH2CH2O)n-(CH2)m-C(O)-NRd-(CH2CH2O)o-(CH2)p-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-(CH2CH2O)o, -NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2, -NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2-(CH2CH2O)o, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Phe-X1-NRc-(CH2CH2O)o-(CH2)p-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-(CH2CH2O)n-, -(CH2CH2O)n-(CH2)m-NRc-(CH2)m-C(O)-NRd-Het1-X1-Het2-(CH2CH2O)o-(CH2)p, 또는 -NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-X2-, C(O)O- -X1-Het1-(CH2CH2O)o-(CH2)m-NRc-, -Het1-(CH2)m-Het2-, -Het1-X1-Het2-(CH2)p-O-(CH2)m-, O(CH2)mC(O), -OC(O)-NRc-(CH2)m-NRd-, -OC(O)-NRc-(CH2)m-O-(CH2)m-NRd-, OC(O)Het1, -OC(O)-NRc-(CH2CH2O)o-NRd-, OC(O)Het1-Het2-, -OC(O)-NRc-(CH2)mC(O)-Het1-X1-Het2-, O-(CH2)m-Het1-, 및 O-(CH2)m-Het1-X1-Het2로부터 선택되고;
Het1, Het2, 및 Het3은 각각 독립적으로는 페닐, 4-원 내지 6-원 헤테로시클릴, 5-원 내지 7-원 헤테로아릴, 또는 4-원 내지 6-원 시클로알킬이고, 이들 각각은 선택적으로는 (C1-C4)알킬에 의해 치환되고;
X1, X2, 및 X3은 각각 독립적으로는 C(O) 또는 (CH2)r이고;
m, n, o, p, q 및 r은 각각 독립적으로는 0, 1, 2, 3, 4, 5, 및 6으로부터 선택되는 정수이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 제17, 또는 제18 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제19 실시형태의 일부로서, L은 -Het1-X1-, -Het1-Het2-X1-, -X1-Het1-X2-Het2-(CH2)mO-, -NRc-(CH2)m-X1-Het1-X2-, -NRc-(CH2)m-X1-NRc-(CH2CH2O)n-, -NRc-(CH2)m-X1-NRc-(CH2)p-, -NRc-(CH2)m-X1-Het1-X2-Het2-X3-, -O(CH2)m-X1-Het1-X2-Het2-X3-, -O(CH2)m-X1-NRc-(CH2)p-Het1-X2-Het2-X3-, -X1-NRc-(CH2)m-Het1-X2-Het2-X3-(CH2)p-NRd-(CH2)p-, -NRc-(CH2)m-X1-(CH)CH3-Het1-X2-Het3-X3-, -NRc-(CH2)m-X1-(CH2)p-Het1-X2-Het2-X3-, -NRc-(CH2)m-X1-NRd-(CH2)p-Het1-X2-Het2-X3-, -NRc-(CH2)m-NRd-X1-Het1-X2-, Het1-X1-Het2-X2-, -Het1-X1-Het2-X2-O-, -O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-, -Het1-O-(CH2)m-X1-Het2-X2-, -Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-, -Het1-X1-NRc-(CH2)m-, -Het1-X1-Het2-Het3-X2-, -Het1-X1-NRc-(CH2CH2O)n(CH2)m-, -Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2-, -Het1-X1-NRc-(CH2CH2O)n-, -Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-, -Het1-X1-Het2-(CH2)m-Het3-X2-, -Het1-X1-Het2-, -Het1-X1-NRc-, -Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-, -Het1-X1-Het2-Het3-, -Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-, -Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-, -Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-, -Het1-X1-Het2-(CH2CH2O)n-, -Het1-X1-(CH2)m-Het2-X2-, -(CH2CH2O)o-(CH2)p-Het1-X1-Het2-(CH2CH2O)n, -(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2, -Het1-X1-Phe-X2-NRc-X3-, -(CH2CH2O)o-(CH2)p-Het1-X1-Phe-X2-NRc-(CH2CH2O)n-, -(CH2CH2O)n-(CH2)m-NRc-Phe-X1-, -(CH2CH2O)o-(CH2)p-NRc-Phe-(CH2CH2O)n-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-, -(CH2CH2O)n-(CH2)m-NRc-(CH2CH2O)n-(CH2)m-C(O)-NRd-(CH2CH2O)o-(CH2)p-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-(CH2CH2O)o, -NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2, -NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2-(CH2CH2O)o, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Phe-X1-NRc-(CH2CH2O)o-(CH2)p-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-, -(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-(CH2CH2O)n-, -(CH2CH2O)n-(CH2)m-NRc-(CH2)m-C(O)-NRd-Het1-X1-Het2-(CH2CH2O)o-(CH2)p, 및 -NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-X2-로부터 선택되고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 제17, 또는 제18 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제19 실시형태의 일부로서, L은 -Het1-X1-*, -Het1-Het2-X1-*, *-X1-Het1-X2-Het2-(CH2)mO-, -NRc-(CH2)m-X1-Het1-X2-*, -NRc-(CH2)m-X1-NRc-(CH2CH2O)n-*, -NRc-(CH2)m-X1-NRc-(CH2)p-*, -NRc-(CH2)m-X1-Het1-X2-Het2-X3-*, -O(CH2)m-X1-Het1-X2-Het2-X3-*, -O(CH2)m-X1-NRc-(CH2)p-Het1-X2-Het2-X3-*, *-X1-NRc-(CH2)m-Het1-X2-Het2-X3-(CH2)p-NRd-(CH2)p-, -NRc-(CH2)m-X1-(CH)CH3-Het1-X2-Het3-X3-*, -NRc-(CH2)m-X1-(CH2)p-Het1-X2-Het2-X3-*, -NRc-(CH2)m-X1-NRd-(CH2)p-Het1-X2-Het2-X3-*, -NRc-(CH2)m-NRd-X1-Het1-X2-*, *Het1-X1-Het2-X2-, *-Het1-X1-Het2-X2-O-, *-O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-, -O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-*-Het1-O-(CH2)m-X1-Het2-X2-, *-Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-, *-Het1-X1-NRc-(CH2)m-, *-Het1-X1-Het2-Het3-X2-, *-Het1-X1-NRc-(CH2CH2O)n(CH2)m-, *-Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2-, *-Het1-X1-NRc-(CH2CH2O)n-, *-Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-, *-Het1-X1-Het2-(CH2)m-Het3-X2-, *-Het1-X1-Het2-, *-Het1-X1-NRc-, *-Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-, *-Het1-X1-Het2-Het3-, *-Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-, *-Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-, *-Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-, *-Het1-X1-Het2-(CH2CH2O)n-, *-Het1-X1-(CH2)m-Het2-X2-, *-(CH2CH2O)o-(CH2)p-Het1-X1-Het2-(CH2CH2O)n, *-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2, *-Het1-X1-Phe-X2-NRc-X3-, *-(CH2CH2O)o-(CH2)p-Het1-X1-Phe-X2-NRc-(CH2CH2O)n-, *-(CH2CH2O)n-(CH2)m-NRc-Phe-X1-, *-(CH2CH2O)o-(CH2)p-NRc-Phe-(CH2CH2O)n-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-, *-(CH2CH2O)n-(CH2)m-NRc-(CH2CH2O)n-(CH2)m-C(O)-NRd-(CH2CH2O)o-(CH2)p-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-(CH2CH2O)o, *-NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2, *-NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2-(CH2CH2O)o, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Phe-X1-NRc-(CH2CH2O)o-(CH2)p-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-(CH2CH2O)n-, *-(CH2CH2O)n-(CH2)m-NRc-(CH2)m-C(O)-NRd-Het1-X1-Het2-(CH2CH2O)o-(CH2)p, 또는 *-NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-X2-이고; 여기서 *는 A에 대한 부착 지점을 나타내고, 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 제17, 또는 제18 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제19 실시형태의 일부로서, L은 -Het1-X1-*, -Het1-Het2-X1-*, *-X1-Het1-X2-Het2-(CH2)mO-, -NRc-(CH2)m-X1-Het1-X2-*, -NRc-(CH2)m-X1-NRc-(CH2CH2O)n-*, -NRc-(CH2)m-X1-NRc-(CH2)p-*, -NRc-(CH2)m-X1-Het1-X2-Het2-X3-*, -O(CH2)m-X1-Het1-X2-Het2-X3-*, -O(CH2)m-X1-NRc-(CH2)p-Het1-X2-Het2-X3-*, *-X1-NRc-(CH2)m-Het1-X2-Het2-X3-(CH2)p-NRd-, -NRc-(CH2)m-X1-(CH)CH3-Het1-X2-Het2-X3-*, -NRc-(CH2)m-X1-(CH2)p-Het1-X2-Het2-X3-*, -NRc-(CH2)m-X1-NRd-(CH2)p-Het1-X2-Het2-X3-*, -NRc-(CH2)m-NRd-X1-Het1-X2-*, *Het1-X1-Het2-X2-, *-Het1-X1-Het2-X2-O-, *-O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-, 또는 *-Het1-X1-Het2-이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 제17, 또는 제18 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제19 실시형태의 일부로서, L은 -NRc-(CH2)m-X1-NRc-(CH2)p-* 또는 -NRc-(CH2)m-X1-Het1-X2-Het2-X3-*이고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 제17, 또는 제18 실시형태에 대해 상기 기재된 바와 같다.
제20 실시형태에서, Het1 및 Het2는 각각 독립적으로는 페닐 또는 4-원 내지 6-원 헤테로시클릴이고, 여기서 나머지 변수는 제19 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제20 실시형태의 일부로서, Het1 및 Het2는 각각 독립적으로는 피페리디닐, 페닐, 아제티디닐, 피페라지닐, 또는 피롤리디닐이고, 여기서 나머지 변수는 제19 실시형태에 대해 상기 기재된 바와 같다.
제21 실시형태에서, m, n, o, p, q 및 r은 각각 독립적으로는 0, 1, 2, 및 3으로부터 선택되는 정수이고, 여기서 나머지 변수는 제19 또는 제20 실시형태에 대해 상기 기재된 바와 같다.
제22 실시형태에서, L은
, , , , , , , , , , , , , , , , , , , ,, , , , , , , , , , , , , , , , , 및 로부터 선택되고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 제17, 제18, 제19, 제20, 또는 제21 실시형태에 대해 상기 기재된 바와 같다. 대안적으로는, 제22 실시형태의 일부로서, L은 , , 및 로부터 선택되고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 제11, 제12, 제13, 제14, 제15, 제16, 제17, 제18, 제19, 제20, 또는 제21 실시형태에 대해 상기 기재된 바와 같다. 또 다른 대안에서, 제12 실시형태의 일부로서, 예시된 화합물 187 내지 화합물 351에서 위치 L에 상응하는 구조로부터 선택되고, 여기서 나머지 변수는 화학식 I 또는 제2, 제3, 제4, 제5, 제6, 제7, 제8, 제9, 제10, 또는 제11 실시형태에 대해 상기 기재된 바와 같다.
구체적 화합물은 아래에 예시되어 있고, 본 발명의 일부로서 포함된다. 이러한 화합물의 유리 염기 및 염 형태가 또한 포함된다.
4.
용도, 제형 및 투여
본원에 기재된 화합물 및 조성물은 일반적으로 항암 요법으로서 유용하다. 한 양태에서, 개시된 화합물 및 조성물은 샤페론-매개된 단백질 디그레이더(CHAMP)로서 거동하고, 여기서 화합물의 한 부분은 KRAS(G12C)의 결합을 담당하고 다른 부분은 샤페론 복합체의 HSP90 또는 다른 샤페론 단백질 또는 단백질 구성성분(예를 들어, HSP70 패밀리의 구성원)에 대한 결합을 담당한다. 이의 작용 메커니즘은, 제한 없이, KRAS(G12C)의 분해, 및 이에 따른 암 세포 성장의 저해 및/또는 암 세포 사멸 또는 다른 KRAS 또는 KRAS(G12C) 기능의 유도를 야기할 수 있는 다운-스트림 신호의 지연을 포함한다. 한 양태에서, 개시된 화합물은 KRAS(G12C)의 분해를 유발한다.
한 양태에서, 개시된 화합물 및 조성물은 상이한 결합 친화도의 범위를 갖는 샤페론 또는 샤페론 복합제 결합제를 포함한다. 상이한 실시형태에서, 고친화도 결합제, 중간-친화도 결합제 또는 저친화도 결합제를 사용하는 것이 바람직하다. HSP90의 N-말단 ATP-결합 포켓과 상호작용하는 HSP90-결합 모이어티는 HSP90 활성을 저해하고 HSP90 클라이언트 단백질의 분해를 유도할 수 있으므로(문헌[Schopf et al., Nat Rev Mol Cell Biol, 2017, 18:345-360]), 일부 CHAMP 분자는 원하는 표적 단백질 또는 단백질들(이는 HSP90 클라이언트 단백질일 수 있거나 아닐 수 있음)의 분해를 유도할 수 있을 뿐만 아니라, 또한 동시에 HSP90 클라이언트 단백질의 분해를 유도할 수 있다. EGFR 및 ERBB2(HER2)는 2개의 상기 HSP90 클라이언트 단백질이다(문헌[Xu et al., J Biol Chem, 2001, 276:3702-3708]). 분해 활성의 상기 조합은, 동일한 표적(들)로 향하는 다른 TPD 기술의 것보다 CHAMP 분자의 생물학적 활성을 증가시킬 수 있고, EGFR 경로에 의해 매개되는 것과 같은 KRAS(G12C) 저해제 및 디그레이더에 대한 저항성의 메커니즘을 회피할 수 있다.
한 양태에서, 개시된 화합물 및 조성물은 종양-표적 CHAMP로서 거동하고, 여기서 화합물의 한 부분은 KRAS(G12C)의 결합을 담당하고 다른 부분은 샤페론 복합체의 HSP90 또는 다른 샤페론 단백질 또는 단백질 구성성분(예를 들어, HSP70 패밀리의 구성원)에 대한 결합을 담당한다. 한 양태에서, 개시된 화합물 및 조성물은 정상 세포, 조직 및 기관에 비하여 암 세포 및 종양에서 연장된 약동학적 노출을 갖는다(문헌[Kamal et al., Nature, 2003, 425:407-410]; 문헌[Vilenchik et al., Chem Biol, 2004, 11:787-797]). 한 양태에서, 개시된 화합물은 다른 KRAS(G12C) 디그레이더 및 저해제에 비하여 증가된 치료적 지수를 갖는다.
따라서, 본원에서 제공되는 것은 본원에 기재된 하나 이상의 화합물 또는 조성물의 치료적 유효량을 이를 필요로 하는 대상체에게 투여하는 것을 포함하는, KRAS(G12C)의 분해에 반응하는 병상의 치료 방법이다. 또한 제공되는 것은 KRAS(G12C)의 분해에 반응하는 병상의 치료를 위한 약제의 제조에서 본원에 기재된 하나 이상의 화합물 또는 조성물의 용도이다. 또한 제공되는 것은 KRAS(G12C)의 분해에 반응하는 병상의 치료를 위한 본원에 기재된 화합물 또는 조성물의 용도이다.
한 양태에서, 본 발명의 화합물 및 조성물에 의해 치료된 병상은 암이다. 용어 "암" 또는 "종양"은 당업계에 잘 알려져 있고, 예를 들어, 대상체에서, 암-유발 세포에 전형적인 특징, 예컨대 비제어된 증식, 불멸, 전이 잠재력, 급속한 성장 및 증식 속도, 감소된 세포 사멸/세포자멸사, 및 특정한 특징적인 형태학적 특징을 지니는 세포의 존재를 나타낸다. 암 세포는 흔히 고형 종양의 형태이다. 그러나, 암은 또한 비고형 종양, 예를 들어 혈액 종양, 예를 들어 백혈병을 포함하고, 여기서 암 세포는 골수로부터 유래된다. 본원에 사용된 바와 같은, 용어 "암"은 전악성뿐만 아니라 악성 암을 포함한다. 암은 청각 신경종, 급성 백혈병, 급성 림프구성 백혈병, 급성 골수구성 백혈병(단핵구, 골수모구, 선암종, 혈관육종, 성상세포종, 골수단핵구 및 전골수구성), 급성 T-세포 백혈병, 기저 세포 암종, 담관 암종, 방광암, 뇌암, 유방암, 기관지 암종, 자궁경부암, 연골육종, 척색종, 융모막 암종, 만성 백혈병, 만성 림프구성 백혈병, 만성 골수구성(과립구) 백혈병, 만성 골수성 백혈병, 대장암, 결장암, 두개인두종, 낭선암종, 미만성 거대 B-세포 림프종, 버킷 림프종(Burkitt's lymphoma), 이상증식성 변화(이형성증 및 화생(metaplasias)), 배아성 암종, 자궁내막암, 내피육종, 뇌실막종, 상피 암종, 적백혈병, 식도 암, 에스트로겐-수용체 양성 유방암, 본태성 혈소판혈증, 유윙 종양(Ewing's tumor), 섬유육종, 여포성 림프종, 생식 세포 고환 암, 신경교종, 중쇄 질환, 혈관모세포종, 간종양, 간세포 암, 호르몬 불감성 전립선 암, 평활근육종, 지방육종, 폐암, 림프관내피육종, 림프관육종, 림프모구 백혈병, 림프종(호지킨(Hodgkin) 및 비호지킨(non-Hodgkin)), 방광, 유방, 결장, 폐, 난소, 췌장, 전립선, 피부, 및 자궁의 악성종양 및 과증식성 장애, T-세포 또는 B-세포 기원의 림프성 악성종양, 백혈병, 림프종, 수질 암종, 수모세포종, 흑색종, 수막종, 중피종, 다발성 골수종, 골수성 백혈병, 골수종, 점액육종, 신경아세포종, 비소세포 폐암, 희소돌기아교세포종, 구강 암, 골육종, 난소암, 췌장암, 유두 선암, 유두 암종, 송과체종, 진성다혈구증, 전립선암, 직장암, 신세포 암종, 망막아종, 횡문근육종, 육종, 피지샘 암종, 정상피종, 피부암, 소세포 폐 암종, 고형 종양(암종 및 육종), 소세포 폐암, 위암, 편평상피 세포 암종, 윤활막종, 땀샘 암종, 갑상선암, 발텐스트롬 마크로글로불린혈증(Waldenstrom's macroglobulinemia), 고환 종양, 자궁암, 및 윌름스 종양(Wilms' tumor)을 포함하나, 이에 제한되지는 않는다. 다른 암은 원발성 암, 전이성 암, 구인두암, 하인두암, 간암, 담낭암, 담관암, 소장암, 요로암, 신장암, 요로상피암, 여성생식기 암, 자궁암, 임신영양막병, 남성 생식기 암, 정낭암, 고환암, 생식 세포 종양, 내분비선 종양, 갑상선암, 부신암, 뇌하수체 암, 혈관종, 뼈 및 연조직으로부터 발생하는 육종, 카포시 육종(Kaposi's sarcoma), 신경 암, 안구암, 뇌막 암, 교아종, 신경종, 신경아세포종, 신경초종(Schwannomas), 조혈 악성종양 예컨대 백혈병으로부터 발생하는 고형 종양, 전이성 흑색종, 재발성 또는 지속성 난소 상피 암, 나팔관 암, 원발성 복막 암, 위장관 간질성 종양, 결장암, 위암, 흑색종, 다형성교아종, 비편평상피 비소세포 폐암, 악성 신경교종, 상피 난소 암, 원발성 복막 장액 암, 전이성 간암, 신경내분비 암종, 내화성 악성종양, 삼중 음성 유방암, HER2-증폭 유방암, 비인두암, 구강암, 담도, 간세포 암종, 두경부의 편평상피 세포 암종(SCCHN), 비수질 갑상선 암종, 재발성 다형성교아종, 신경섬유종증 1형, CNS 암, 지방육종, 평활근육종, 침샘암, 점막 흑색종, 말단/흑자 흑색종, 부신경절종, 크롬 친화성 세포종, 진행성 전이성 암, 고형 종양, 삼중 음성 유방암, 결장암, 육종, 흑색종, 신장 암종, 자궁내막 암, 갑상선 암, 횡문근육종, 다발성 골수종, 난소암, 교아종, 위장관 간질성 종양, 외투 세포 림프종, 및 내화성 악성종양을 포함한다.
3차원을 갖는 비정상적 성장으로서 촉진(palpate)되거나 이미지화 방법을 사용해 검출될 수 있는 임의의 병원성 종양으로서 이해된다. 고형 종양은 혈액 종양 예컨대 백혈병과 구별된다. 그러나, 혈액 종양의 세포는 골수로부터 유래되므로; 암 세포를 생성하는 조직은 저산소 상태일 수 있는 고형 조직이다.
"종양 조직" 또는 "종양성 조직"은 세포, 세포외 매트릭스, 및 고형 종양과 연관된 다른 자연 발생 성분으로서 이해된다.
임의의 특정 환자에 대한 특이적인 투여량 및 치료 요법은 사용된 구체적 화합물의 활성, 연령, 체중, 일반적인 건강, 성별, 식이 요법, 투여 시간, 배설 속도, 약물 조합, 및 치료 의사의 판단 및 치료할 특정 질환의 중증도를 포함한 다양한 인자에 따라 달라질 것이다. 조성물 중 본원에 기재된 화합물의 양은 또한 조성물 중 특정 화합물에 따라 달라질 것이다.
실시예
실시예 1: 화합물 148 합성
화합물 148에 대한 대표적 합성 도식은 아래 나타나 있다. 중간체의 구체적 합성 경로가 또한 나타나 있다.
중간체 2:
메틸 1-(4-니트로벤질)피페리딘-4-카르복실레이트
DMF(300 mL) 중 1-(브로모메틸)-4-니트로벤젠(40 g, 185.16 mmol) 및 메틸 피페리딘-4-카르복실레이트(26.51 g, 185.16 mmol)의 혼합물에 K2CO3(51.18 g, 370.22 mmol)을 첨가하였다. 혼합물을 밤새 실온에서 교반하였다. 혼합물을 500 mL의 H2O에 부었다. 이를 EA(500 mL*2)로 추출하였다. 합쳐진 유기상을 H2O 및 염수로 세척하였다. 이를 건조시키고(Na2SO4), 여과하고, 농축시켜, 중간체 2를 황색 고체(49 g)로서 생성하였다.
중간체 3:
메틸 1-(4-아미노벤질)피페리딘-4-카르복실레이트
MeOH/H2O(25 mL/25 mL) 중 메틸 1-(4-니트로벤질)피페리딘-4-카르복실레이트(5.0 g, 17.97 mmol) 및 NH4Cl(4.81 g, 89.83 mmol)의 혼합물에 Fe 분말(5.02 g 89.83 mmol)을 첨가하였다. 혼합물을 밤새 환류 하에 교반하였다. 실온으로 냉각한 이후, 혼합물을 여과하고, 여과액을 농축하였다. 이를 EA(50 mL*2)로 추출하였다. 합쳐진 유기상을 H2O 및 염수로 세척하였다. 이를 건조시키고(Na2SO4), 여과하고, 농축시켜, 중간체 3을 갈색 오일(3.8 g)로서 생성하였다.
중간체 4:
메틸 1-(4-(2,4-디히드록시-5-이소프로필페닐티오아미도)벤질)피페리딘-4-카르복실레이트
DMF(100 mL) 중 화합물 3a(20.69 g, 90.61 mmol), ClCH2COONa(10.55 g, 90.61 mmol) 및 NaHCO3(15.22 g, 181.22 mmol)의 용액을 40°C에서 3시간 동안 교반하였다. DMF(50 mL) 중 중간체 3(15.0 g, 60.41 mmol)을 혼합물에 첨가하였다. 생성된 혼합물을 80°C에서 밤새 가열하였다. 반응 혼합물을 물에 붓고, 침전된 고체를 여과에 의해 수집하였다. 모액을 EA(200 mL*2)로 추출하였다. 합쳐진 유기상을 H2O 및 염수로 세척하였다. 이를 건조시키고(Na2SO4), 여과하고, 농축시켰다. 이를 여과된 고체와 합치고, SGC에 의해 정제하여 중간체 4(22.1 g)를 황색 고체로서 생성하였다.
중간체 5:
메틸 1-(4-(7-히드록시-6-이소프로필-2-옥소-4-티옥소-2H-벤조[e][1,3]옥사진-3(4H)-일)벤질)피페리딘-4-카르복실레이트
THF(80 mL) 중 중간체 4(8.0 g, 18.08 mmol) 및 CDI(11.72 g, 72.3 mmol)의 용액을 실온에서 2시간 동안 교반하였다. 반응 용액을 염수(1 L)에 붓고, EtOAc(200 mL*3)로 추출하였다. 합쳐진 유기 층을 염수로 세척하고, Na2SO4로 건조시키고, 농축시켜, 중간체 5(미정제)를 생성하고, 이를 정제 없이 추가 반응에 사용하였다.
중간체 6:
메틸 1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복실레이트
EtOH(80 mL) 중 중간체 5(8.0 g, 17.07 mmol)의 용액에 NH2NH2H2O(1.11 g, 22.2 mmol)를 첨가하였다. 이후 생성된 혼합물을 실온에서 밤새 교반하였다. 침전된 고체를 여과하고, 건조시켜, 중간체 6(4 g)을 백색 고체로서 생성하였다.
중간체 7:
1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복시산
MeOH/THF(1:1, 30 mL) 중 중간체 6(4.0 g 8.57 mmol)의 용액에 LiOH H2O(1.8 g, 42.87 mmol)의 용액(15 mL)을 첨가하였다. 이후 생성된 혼합물을 실온에서 3시간 동안 교반하였다. pH를 2 N HCl을 사용하여 5-6으로 조정하였다. 침전된 고체를 여과하고, 건조시켜, 중간체 7(2.5 g)을 백색 고체로서 생성하였다.
중간체 9:
(S)-tert-부틸 4-(4-((벤질옥시)카르보닐)-3-(시아노메틸)피페라진-1-일)-2-클로로-5,6-디히드로피리도[3,4-d]피리미딘-7(8H)-카르복실레이트(2)
디옥산(300 mL) 중 tert-부틸 2,4-디클로로-5,6-디히드로피리도[3,4-d]피리미딘-7(8H)-카르복실레이트 8(28 g, 92.4 mmol) 및 (S)-벤질 2-(시아노메틸)피페라진-1-카르복실레이트 8a(23.2 g, 89.5 mmol)의 혼합물에 DIPEA(36.8 mL, 223 mmol)를 첨가하였다. 혼합물을 N2 분위기 하에 50°C에서 밤새 교반하였다. 혼합물을 물(300 mL)로 희석하고, 에틸 아세테이트(300 mL x 3)로 추출하였다. 합쳐진 유기상을 염수(200 mL)로 세척하고, Na2SO4로 건조시키고, 농축하였다. 잔여물을 실리카 겔 컬럼 크로마토그래피(PE/EtOAc = 5/1 → 1/1)에 의해 정제하여, 표제 중간체 9(45 g, 수율 90.7%)를 백색 고체로서 생성하였다. 1H NMR (DMSO-d 6, 400 MHz), δ 7.39-7.33 (m, 5H), 5.17-5.11 (m, 2H), 4.58-4.26 (m, 3H), 4.05-3.92 (m, 3H), 3.66-3.63 (m, 1H), 3.31-2.90 (m, 6H), 2.69-2.68 (m, 2H), 1.43 (s, 9H); LC-MS: m/z 527.3 [M+H]+.
중간체 10:
(S)-벤질 4-(2-클로로-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-2-(시아노메틸)피페라진-1-카르복실레이트(3)
DCM(150 mL) 중 (S)-tert-부틸 4-(4-((벤질옥시)카르보닐)-3-(시아노메틸)피페라진-1-일)-2-클로로-5,6-디히드로피리도[3,4-d]피리미딘-7(8H)-카르복실레이트 9(45 g, 85.5 mmol)의 용액에 TFA(50 mL)를 첨가하였다. 혼합물을 실온에서 2시간 동안 교반하고, 감압 하에 농축하였다. 잔여물을 EtOAc(500 mL) 및 포화 NaHCO3(500 mL)에 희석하였다. 유기상을 분리하고, 염수(500 mL)로 세척하고, Na2SO4로 건조시키고, 농축시켜, 표제 중간체 10(33 g, 수율 90.6%)을 백색 고체로서 생성하였다. LC-MS: m/z 427.2[M+H]+.
중간체 11:
(S)-벤질 4-(2-클로로-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-2-(시아노메틸)피페라진-1-카르복실레이트
톨루엔(200 mL) 중 (S)-벤질 4-(2-클로로-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-2-(시아노메틸)피페라진-1-카르복실레이트 10(25 g, 58.6 mmol)의 용액에 1-브로모-8-클로로나프탈렌(14.1 g, 58.6 mmol), Cs2CO3(57.3 g, 176 mmol) 및 Ruphos Pd G3(9.8 g, 11.7 mmol)을 첨가하였다. 혼합물을 N2에 의해 3회 탈기시켰다. 이후 혼합물을 75°C에서 16시간 동안 가열하였다. 실온으로 냉각시킨 이후, 고체를 여과 제거하였다. 여과액을 진공 하에 농축하였다. 잔여물을 실리카 겔 컬럼 크로마토그래피(PE:EtOAc = 5:1 → 2:1)에 의해 정제하여, 중간체 11(5 g, 수율 14.5%)을 황백색 고체로서 생성하였다. 1H NMR (CDCl3, 400 MHz), δ 7.75 (d, J = 8.4 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.52 (d, J = 6.0 Hz, 1H), 7.47-7.43 (m, 1H), 7.40-7.31 (m, 6H), 7.22-7.17 (m, 1H), 5.20 (s, 2H), 4.67 (s, 1H), 4.50-4.42 (m, 1H), 4.21-3.84 (m, 4H), 3.60-3.42 (m, 2H), 3.34-3.04 (m, 4H), 2.94-2.56 (m, 3H). LC-MS: m/z 587.2 [M+H]+.
중간체 12:
(S)-벤질 4-(2-(((R)-1-(tert-부톡시카르보닐)피롤리딘-3-일) 메톡시)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-2-(시아노메틸)피페라진-1-카르복실레이트
톨루엔(150 mL) 중 중간체 11(3.0 g, 5.11 mmol), Cs2CO3(5.0 g, 15.3 mmol), (R)-tert-부틸 3-(히드록시메틸)피롤리딘-1-카르복실레이트(3.1 g, 15.3 mmol) 및 XPhos Pd G2(600 mg, 0.77 mmol)의 혼합물을 N2 분위기 하에 16시간 동안 85°C에서 교반하였다. 반응물을 여과하고, 진공 하에 농축시켜 잔여물을 생성하였고, 이를 실리카 겔 크로마토그래피 컬럼(PE:EtOAc = 4:1 → 2:1)에 의해 정제하여 중간체 12(5.0 g, 미정제 생성물)를 황색 오일로서 생성하였다. LC-MS: m/z 752.2 [M+H]+.
중간체 13:
(R)-tert-부틸 3-(((7-(8-클로로나프탈렌-1-일)-4-((S)-3-(시아노메틸) 피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-카르복실레이트
MeOH(100 mL) 중 중간체 12(5.0 g, 5.11 mmol, 미정제), 암모늄 포르메이트(6.4 g, 102 mmol) 및 Pd/C(300 mg, 10% 습식)의 혼합물을 N2 분위기 하에 0.5시간 동안 환류시켰다. 반응물을 여과하고 진공 하에 농축시켜, 잔여물을 생성하고, 이를 C18 플래시 크로마토그래피 컬럼(ACN:H2O = 80:20 → 85:15)에 의해 정제하여 중간체 13(1.4 g, 44.4% 수율)을 백색 고체로서 생성하였다. LC-MS: m/z 618.1 [M+H]+.
중간체 14:
(R)-tert-부틸 3-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-카르복실레이트의 합성
DCM(20 mL) 중 중간체 13(1.4 g, 2.26 mmol) 및 DIPEA(730 mg, 5.66 mmol)의 용액에 아크릴로일 클로라이드(245 mg, 2.71 mmol)를 0°C에서 첨가하고, 반응물을 N2 분위기 하에 1시간 동안 실온에서 교반하였다. 반응물을 진공 하에 농축시켜 잔여물을 생성하였고, 이를 실리카 겔 크로마토그래피 컬럼(PE:EtOAc = 3:2 → 2:3)에 의해 정제하여 중간체 14(1.5 g, 98.8% 수율)를 백색 고체로서 생성하였다. 1H NMR (DMSO-d 6 , 400 MHz): δ 7.92 (d, J = 7.6 Hz, 1H), 7.75-7.72 (m, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.53 (q, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.33 (dd, J = 15.2 Hz, 7.2 Hz, 1H), 6.85 (brs, 1H), 6.18 (d, J = 28.8 Hz, 1H), 5.77 (d, J = 12.4 Hz, 1H), 4.97-4.77 (m, 1H), 4.42-3.36 (m, 10H), 3.24-2.86 (m, 8H), 2.67-2.51 (m, 2H), 1.96 (brs, 1H), 1.66 (brs, 1H), 1.38 (s, 9H). LC-MS: m/z 672.1 [M+H]+.
중간체 15:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((R)-피롤리딘-3-일메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
DCM(3 mL) 중 중간체 14(600 mg, 0.89 mmol)의 용액에 TFA(1 mL)를 0°C에서 첨가하고, 반응물을 N2 분위기 하에 1시간 동안 실온에서 교반하였다. 반응물을 진공 하에 농축시켜 미정제 중간체 15(550 mg)를 황색 오일로서 생성하였고, 이를 다음 단계에 바로 사용하였다. LC-MS: m/z 572.5 [M+H]+.
화합물 148:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
DMF(8 mL) 중 화합물 5(600 mg, 0.87 mmol, 미정제), 중간체 15(453 mg, 0.96 mmol), PyBOP(545 mg, 1.05 mmol) 및 DIPEA(338 mg, 2.62 mmol)를 16시간 동안 실온에서 교반하였다. 혼합물을 분취-HPLC(TFA)에 의해 정제하여, 화합물 148(260 mg, 29.6% 수율)을 백색 고체로서 생성하였다. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.59 (s, 1H), 9.42 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.53 (q, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.36-7.27 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.84 (brs, 1H), 6.75 (s, 1H), 6.26 (s, 1H), 6.18 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 4.96-4.73 (m, 1H), 4.41-4.12 (m, 4H), 4.02-3.40 (m, 10H), 3.28-2.54 (m, 14H), 2.38-2.31 (m, 2H), 1.64-1.51 (m, 4H), 0.92 (dd, J = 6.8 Hz, 2.0 Hz, 6H). LC-MS: m/z 1006.4 [M+H]+.
실시예 2: 화합물 175 합성
화합물 175에 대한 대표적 합성 도식은 아래 나타나 있다. 중간체의 구체적 합성 경로가 또한 나타나 있다.
중간체 2:
H2O(1 L) 중 4-이소프로필벤젠-1,3-디올(100 g, 658 mmol)의 용액에 KHCO3(493 g, 4.9 mol)를 첨가하였다. 생성된 혼합물을 CO2를 버블링하면서 밤새 환류 하에 교반하였다. 반응 용액을 실온으로 냉각시키고, 2 N HCl을 천천히 첨가하여 pH를 1로 조정하였다. 침전된 고체를 여과에 의해 수집하고, 건조시켜 표적 화합물(70 g, 54% 수율)을 백색 고체로서 생성하였다.
중간체 4:
메틸 2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-카르복실레이트
DMF(10 mL) 중 2,4-디히드록시-5-이소프로필벤조산(254 mg, 1.3 mmol), 메틸 이소인돌린-5-카르복실레이트(191 mg, 1.08 mmol), PyBOP(1.1 g, 2.2 mmol) 및 DIPEA(557 mg, 4.3 mmol)의 혼합물을 3시간 동안 실온에서 교반하였다. 혼합물을 H2O(40 mL)에 부었다. 침전물을 여과하고 분취-TLC(EA)에 의해 정제하여, 메틸 2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-카르복실레이트(301 mg, 78% 수율)를 적색 고체로서 생성하였다.
1H NMR (DMSO-d 6 , 400 MHz): δ 10.06-10.02 (m, 1H), 9.61 (s, 1H), 7.95-7.88 (m, 2H), 7.50-7.44 (m, 1H), 7.05 (s, 1H), 6.40 (s, 1H), 4.84 (s, 4H), 3.85 (s, 3H), 3.13-3.06 (m, 1H), 1.13 (d, J = 6.8 Hz, 6H). LC-MS: m/z 356.1 [M+H]+.
중간체 5:
2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-카르복시산
MeOH/H2O(50 mL/10 mL) 중 메틸 2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-카르복실레이트(301 mg, 0.85 mmol) 및 LiOH . H2O(110 mg, 2.6 mmol)의 혼합물을 실온에서 24시간 동안 교반하였다. 반응물을 진공 하에 농축시켜 잔여물을 생성하였고, 이를 PH를 4로 조정하였다. 침전물을 여과하고, THF(20 mL) 및 PE(150 mL)의 혼합물과 함께 분쇄하여, 2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-카르복시산(210 mg, 72% 수율)을 백색 고체로서 생성하였다.
1H NMR (DMSO-d 6 , 400 MHz): δ 12.94 (brs, 1H), 10.04-10.02 (m, 1H), 9.62 (s, 1H), 7.95-7.84 (m, 2H), 7.49-7.41 (m, 1H), 7.04 (s, 1H), 6.40 (s, 1H), 4.82 (s, 4H), 3.12-3.05 (m, 1H), 1.13 (d, J = 6.4 Hz, 6H). LC-MS: m/z 342.0 [M+H]+.
화합물 175
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
DMF(4 mL) 중 2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((R)-피롤리딘-3-일메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴(63 mg, 0.11 mmol), 2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-카르복시산(35 mg, 0.11 mmol), DPPA(71 mg, 0.26 mmol) 및 TEA(42 mg, 0.42 mmol)의 혼합물을 17시간 동안 실온에서 교반하였다. 혼합물을 H2O(15 mL)에 부었다. 침전물을 여과하고, 분취-HPLC(TFA)에 의해 정제하여 화합물 175
(5.1 mg, 5.5% 수율)를 백색 고체로서 생성하였다.
1H NMR (CD3OD, 400 MHz): δ 7.87 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 8.0, 4.0 Hz, 1H), 7.60-7.36 (m, 7H), 7.18 (d, J = 5.6 Hz, 1H), 6.82-6.80 (m, 1H), 6.38 (s, 1H), 6.32 (d, J = 16.4 Hz, 1H), 5.86 (d, J = 10.4 Hz, 1H), 4.96 (s, 4H), 4.76-4.29 (m, 6H), 4.18-4.16 (m, 1H), 3.88-3.37 (m, 9H), 3.27-3.15 (m, 2H), 3.08-2.79 (m, 4H), 2.29-2.16 (m, 1H), 2.01-1.90 (m, 1H), 1.22 (d, J = 7.2 Hz, 3H), 1.20 (d, J = 7.2 Hz, 3H). LC-MS: m/z 895.4 [M+H]+.
실시예 3: 화합물 178 합성
화합물 178에 대한 대표적 합성 도식은 아래 나타나 있다. 중간체의 구체적 합성 경로가 또한 나타나 있다.
중간체 3:
(E)-N'-(3,3-디메틸-5-옥소시클로헥실리덴)-4-메틸벤젠술포노히드라자이드
톨루엔(8 L) 중 1(200 g, 1426.72 mmol), 2(265.71 g, 1426.7167 mmol) 및 p-톨루엔 술폰산(24.54 g, 142.67 mmol)의 혼합물을 120℃로 가열하였다. 1시간 이후, 혼합물을 냉각시켰고, 톨루엔(1.2 L)의 첨가가 뒤따랐다. 혼합물을 이후 1시간 동안 환류시켰다. 반응물을 주변 온도로 냉각시켰다. 침전된 고체를 여과에 의해 수집하고, 에테르로 3회 세척하고, 진공 하에 건조시켜 중간체 3(360 g, 1167.30 mmol, 81.82%)을 생성하였다. LCMS: m/z 309 [M+H]+.
중간체 4:
6,6-디메틸-3-(트리플루오로메틸)-1,5,6,7-테트라히드로-4H-인다졸-4-온
THF(3 L) 중 3(360 g, 1167.30 mmol) 및 TEA(486.67 mL, 3501.33 mmol)의 현탁액에 트리플루오로아세틸 2,2,2-트리플루오로아세테이트(243.51 mL, 1750.67 mmol)를 0 ℃에서 첨가하였다. 생성된 반응물을 3시간 동안 55℃로 가열하고, 반응 혼합물을 주변 온도로 냉각시켰다. 혼합물에 메탄올(1.4 L) 및 1 N NaOH(1.4 L)를 첨가하였다. 3시간 동안 교반한 이후, 반응 혼합물을 포화 암모늄 클로라이드(3 L)로 희석하고, 에틸 아세테이트로 3회 추출하고, 합쳐진 유기 층을 염수로 세척하고, 나트륨 술페이트로 건조시키고, 진공 하에 농축하였다. 잔여물을 컬럼 크로마토그래피에 의해 정제하여, 중간체 4(160 g, 689.05 mmol, 59.04%)를 생성하였다. LCMS: m/z 233 [M+H]+.
중간체 6:
2-브로모-4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)벤조니트릴
NaH(15.50 g, 645.98 mmol)를 DMSO(2 L) 중 4(150 g, 645.98 mmol)의 용액에 실온에서 첨가하였다. 15분 이후, 2-브로모-4-플루오로벤조니트릴(129.20 g, 645.98 mmol)을 고체로서 첨가하였다. 반응 혼합물을 45℃에서 밤새 가열하였다. 혼합물을 실온으로 냉각시키고, 포화 수성 NH4Cl로 켄칭하였다. 혼합물을 물로 희석하고, EtOAc로 추출하였다. 합쳐진 유기 층을 염수로 세척하고, 무수 나트륨 술페이트로 건조시키고, 진공 하에 농축하였다. 잔여물을 컬럼 크로마토그래피에 의해 정제하여, 중간체 6(180 g, 436.67 mmol, 67.59%)을 생성하였다. LCMS: m/z 412 [M+H]+.
중간체 8:
2-((4-(벤질옥시)페닐)아미노)-4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)벤조니트릴
톨루엔(500 mL) 중 6(50 g, 121.30 mmol)의 용액에 7(24.17 g, 121.30 mmol) 및 Cs2CO3(79.04 g, 242.59 mmol)을 첨가하였다. 이후 BINAP(15.10 g, 24.26 mmol) 및 Pd(OAc)2(2.74 g, 12.13 mmol)를 질소 보호 하에 연속으로 첨가하였다. 혼합물 반응물을 3시간 동안 120℃로 가열하였다. 여과된 이후, 여과액을 진공 하에 농축시키고, 잔여물을 실리카 겔 크로마토그래피에 의해 정제하여, 중간체 8(40 g, 75.39 mmol, 62.16%)을 생성하였다. LCMS: m/z 531 [M+H]+.
중간체 9:
2-((4-(벤질옥시)페닐)아미노)-4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)벤즈아미드
EtOH(400 mL) 및 DMSO(100 mL) 중 8(40 g, 75.39 mmol)의 용액에 1 N NaOH(226.18 mL, 226.18 mmol) 및 H2O2(25.63 g, 226.18 mmol)를 0℃에서 연속으로 적가하였다. 이후 혼합물을 2시간 동안 실온에서 교반한 후, 물로 희석시키고, 이를 EtOAc로 추출하고, 염수로 세척하고, 나트륨 술페이트로 건조시켰다. 유기 층을 진공 하에 농축시키고, 잔여물을 실리카 겔 컬럼에 의해 정제하여 중간체 9(35 g, 63.80 mmol, 84.63%)를 생성하였다. LCMS: m/z 549 [M+H]+.
중간체 10:
4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)-2-((4-히드록시페닐)아미노)벤즈아미드
MeOH(400 mL) 중 9(35 g, 63.80 mmol)의 용액에 Pd/C 10%(6.7 g, 6.38 mmol)를 첨가하고, 혼합물을 H2 존재 하에 밤새 실온에서 교반하였다. 이를 여과한 이후, EA 이후 DCM으로 세척하고, 충전제를 진공 하에 농축시켜, 중간체 10(26 g, 56.71 mmol, 88.89%)을 고체로서 생성하였다. LCMS: m/z 459 [M+H]+.
중간체 11:
2-(4-((2-카르바모일-5-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)페닐)아미노)페녹시)아세트산
DMF(20 mL) 중 2-브로모아세트산(0.6 g, 4.59 mmol)의 용액에 10(1.89 g, 4.13 mmol) 및 K2CO3(1.90 g, 13.76 mmol)을 첨가하고, 혼합물을 90℃에서 밤새 교반하였다. 물을 첨가한 이후, 이를 EA로 추출하고, 포화 염수로 세척하고, 나트륨 술페이트로 건조시키고, 진공 하에 농축시키고, 잔여물을 실리카 겔 컬럼에 의해 정제하여, 중간체(1.6 g, 2.48 mmol, 54.01%)를 고체로서 생성하였다. LCMS: 518 [M+H]+.
화합물 178:
2-((4-(2-((R)-3-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-일)-2-옥소에톡시)페닐)아미노)-4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)벤즈아미드
DMF(8 mL) 중 중간체 11(340 mg, 0.7 mmol), HATU(290 mg, 0.77 mmol) 및 DIEA(450 mg, 3.48 mmol)의 용액에 중간체 12(350 mg, 0.7 mmol)를 첨가하였다. 생성된 혼합물을 실온에서 2시간 동안 교반하였다. 혼합물을 분취-HPLC에 의해 정제하여, 화합물 178(230 mg)을 황색 고체로서 생성하였다. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.09 (s, 1H), 8.19 (s, 1H), 7.92-7.88 (m, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.58-7.53 (m, 3H), 7.50 (t, J = 7.2 Hz, 1H),7.44-7.30 (m, 1H), 7.20 (brs, 2H), 7.03 (s, 1H), 6.95-6.82 (m, 4H), 6.18 (d, J = 16.4 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 4.96-4.75 (m, 1H), 4.71 (s, 2H), 4.41-4.14 (m, 4H), 4.03-3.48 (m, 9H), 3.24-3.15 (m, 5H), 3.09 (s, 3H), 3.02-2.54 (m, 2H), 2.40 (d, J = 5.6 Hz, 2H), 2.12-1.61 (m, 3H), 1.02 (s, 6H). LC-MS: m/z 1070.4 [M+H]+.
하기를 포함하는 추가적 화합물을 실시예에 나타낸 일반적 과정 및 도식에 따라 제조하였다:
화합물 1:
1-(4-(2-((3-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.94(s, 1H), 9.76(s, 1H), 9.63(s, 1H), 9.44(s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.68(d, J = 8.4 Hz, 1H), 7.42-7.08(m, 6H), 6.92-6.70(m, 4H), 6.30-6.08(m, 2H), 5.77-5.71(m, 1H), 4.42-4.32(m, 1H), 4.12 (s, 1H), 3.90-3.50(m, 15H), 3.27-3.19 (m, 2H), 3.00-2.86(m, 3H), 2.70-2.59(m, 2H), 1.80-1.50(m, 3H), 1.29-1.20 (m, 2H), 0.92 (d, J = 6.8 Hz, 6H).LCMS(ESI): m/z 실측치 893.5[M-CF3COOH+H]+.
화합물 2:
1-(4-(2-((3-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페닐)피페라진-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.87(s, 1H), 9.90-9.35(m, 3H), 7.99(d, J = 8.4 Hz, 1H), 7.85-7.61(m, 2H), 7.44-7.24(m, 2H), 7.07-6.75(m, 8H), 6.31-6.09(m, 2H), 5.82-5.68(m, 1H), 4.17(s, 2H), 3.91-3.57(m, 14H), 3.27-3.10(m, 6H), 3.03-2.88 (m, 3H), 2.78-2.67(m, 2H), 0.96(d, J = 7.2 Hz, 6H).LCMS(ESI): m/z 실측치 880.4[M-CF3COOH+H]+
화합물 3:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(2-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.89(s, 1H), 9.90-9.35(m, 3H), 8.31-8.23(m, 1H), 8.06-7.62(m, 3H), 7.44-7.24(m, 2H), 7.11-6.74(m, 8H), 6.29-6.14(m, 2H), 5.79-5.69(m, 1H), 4.16(s, 2H), 4.00-3.56(m, 14H), 3.27-3.21(m, 2H), 3.03-2.86(m, 3H), 2.48-2.44(m, 2H), 0.97(d, J = 7.2 Hz, 6H). LCMS(ESI): m/z 실측치 855.4[M-CF3COOH+H]+.
화합물 4:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페네틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.91 (s, 1H), 9.76-9.38 m, 3H), 8.18-7.94 (m, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.43-7.07 (m, 6H), 6.94-6.72 (m, 4H), 6.28-6.12 (m, 2H), 5.74 (dd, J = 10.4, 2.2 Hz, 1H), 4.15 (s, 2H), 3.92-3.53 (m, 10H), 3.03-2.87 (m, 3H), 2.74-2.65 (m, 2H), 2.46-2.39 (m, 3H), 2.08-1.93 (m, 1H), 1.24 (s, 3H), 0.96 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 839.4[M-CF3COOH+H]+.
화합물 5:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(2-(2-(2-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에톡시)에톡시)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD) δ 8.04 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.33 (dt, J = 15.0, 7.2 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.98-6.66 (m, 6H), 6.33-6.21 (m, 2H), 5.81 (d, J = 9.6 Hz, 1H), 5.11-4.92 (m, 5H), 4.20-3.31 (m, 27H), 3.00-2.85 (m, 2H), 2.54 (t, J = 6.2 Hz, 2H), 2.34 (q, J = 7.5 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H). LCMS(ESI): m/z 실측치 929.2[M-CF3COOH+H]+.
화합물 6:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(2-(2-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에톡시)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.85 (s, 1H), 9.76 (s, 1H), 9.56 (s, 1H), 9.34 (s, 1H), 8.16-7.93 (m, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.42-7.26 (m, 2H), 7.14-6.70 (m, 9H), 6.30-6.11 (m, 2H), 5.74 (d, J = 12.6 Hz, 1H), 4.18-3.68 (m, 15H), 3.29-3.20 (m, 5H), 3.01-2.84 (m, 2H), 2.49-2.30 (m, 6H), 0.99 (t, J = 7.6 Hz, 3H). LCMS(ESI): 실측치 885.4[M-CF3COOH+H]+.
화합물 7:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.91 (s, 1H), 9.79 (s, 1H), 9.60 (s, 1H), 9.37 (s, 1H), 8.52 (t, J = 5.6 Hz, 1H), 8.03-7.66 (m, 3H), 7.41 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 7.4 Hz, 1H), 7.23 (d, J = 8.3 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.90 (s, 1H), 6.84 (s, 1H), 6.82-6.74 (m, 2H), 6.24 (s, 1H), 6.17 (m, 1H), 5.74 (m, 2.0 Hz, 1H), 4.27 (d, J = 5.7 Hz, 2H), 4.16 (s, 2H), 3.87 (s, 4H), 3.79-3.59 (m, 7H), 3.25 (s, 3H), 2.97 (m, 3H), 0.99 (d, J = 6.9 Hz, 6H). LCMS(ESI): m/z 실측치 825.6 [M-CF3COOH+H]+.
화합물 8:
1-(4-(2-((3-(4-((4-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)피페라진-1-일)메틸)피페리딘-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.99 (s, 1H), 9.77 (s, 1H), 9.62 (s, 1H), 9.38 (s, 1H), 8.06-7.93 (m, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.35 (m, 3H), 7.16- 6.68 (m, 6H), 6.30-6.10 (m, 2H), 5.75 (d, J = 12.5 Hz, 1H), 4.38 (m, 1H), 4.16 (s, 2H), 3.89 (m, 17H), 3.25 (s, 2H), 3.11-2.83 (m, 8H), 2.79-2.55 (m, 6H), 2.45-2.28 (m, 3H), 2.01 (s, 1H), 1.73 (m, 2H), 1.02 (t, J = 7.5 Hz, 3H). LCMS(ESI): S m/z 실측치 995.3 [M-CF3COOH+H]+.
화합물 9:
3-((5-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(2-(2-(2-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에톡시)에톡시)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 9.80 (s, 1H), 9.62 (s, 1H), 9.40 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.28 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 6.91 (d, J = 9.1 Hz, 3H), 6.85-6.75 (m, 3H), 6.26 (s, 1H), 6.17 (dd, J = 16.7, 2.1 Hz, 1H), 5.74 (dd, J = 10.5, 2.0 Hz, 1H), 4.15 (s, 2H), 4.08-4.03 (m, 2H), 3.88 (s, 4H), 3.73 (m, 7H), 3.60-3.52 (m, 7H), 3.22 (m, 5.5 Hz, 4H), 2.97 (m, 3H), 2.44 (t, J = 6.6 Hz, 2H), 0.98 (d, J = 6.9 Hz, 6H). LCMS(ESI): m/z 실측치 943.6 [M-CF3COOH+H]+.
화합물 10:
4-(4-((4-((1-(3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.85-9.67 (m, 4H), 7.97 (d, J = 5.2 Hz, 1H), 7.68 (d, J = 5.2 Hz, 1H), 7.41-7.28 (m, 6H), 6.90-6.74 (m, 4H), 6.28-6.15 (m, 2H), 5.78-5.72 (m, 1H), 4.44-4.38 (m, 1H), 4.16 (s, 3H), 3.94-3.80 (m, 10H), 3.66-3.60 (m, 4H), 3.31-3.24 (m, 4H), 3.09-2.85 (m, 9H), 2.67-2.58 (s, 4H), 2.42-2.32 (m, 6H), 1.87 (s, 3H), 1.75-1.69 (m, 2H). LCMS(ESI): m/z 실측치 1073.1[M-CF3COOH+H]+
화합물 11:
4-(4-((1-(3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.78-9.60 (m, 3H), 8.00-7.98 (m, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.42-7.38 (m, 1H), 7.30-7.23 (m, 6H), 6.89-6.75 (m, 3H), 6.61 (s, 1H), 6.35 (s, 1H), 4.43-4.35 (m, 2H), 4.18-4.15 (m, 3H), 3.95-3.68 (m, 18H), 3.27-3.22 (m, 7H), 2.94-2.89 (m, 5H), 0.82 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 1003.0[M-CF3COOH+H]+.
화합물 12:
1-(4-(2-((3-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)메틸)피페리딘-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD): δ 8.06 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.39-7.21 (m, 7H), 6.91-6.70 (m, 4H), 6.30-6.25 (m, 2H), 5.81 (d, J = 10.4 Hz, 1H), 4.20-4.00 (m, 9H), 3.85-3.75 (m, 6H), 3.61-3.57 (m, 2H), 3.05-2.93 (m, 5H), 2.77-2.64 (m, 6H), 2.12-1.97 (m, 1H), 1.92-1.85(m, 4H), 1.59-1.44 (m, 2H), 1.33 (s, 6H), 0.90 (d, J = 6.4 Hz, 6H). LCMS(ESI): m/z 실측치 990.7[M-CF3COOH+H]+.
화합물 13:
1-(4-(2-((3-(4-((4-(4-(3-(2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 8.05(d, J = 8.4 Hz, 1H), 7.64(d, J = 8.0 Hz, 1H), 7.48-7.25(m, 6H), 7.03(d, J = 8.4 Hz, 1H), 6.93-6.75(m, 3H), 6.31-6.15(m, 3H), 5.84-5.78(m, 1H), 4.59-4.49(m, 2H), 4.18(s, 2H), 4.04-3.94(m, 7H), 3.88-3.72(m, 6H), 3.19-2.93(m, 11H), 2.82-2.73(m, 4H), 2.71-2.62(m, 1H), 2.08-1.98(m, 1H), 1.90-1.78(m, 2H), 1.38-1.06(m, 3H). LCMS(ESI): m/z 실측치 949.6[M-CF3COOH+H]+.
화합물 14:
1-(4-(2-((3-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 8.06(d, J = 7.6 Hz, 1H), 7.72-7.28(m, 8H), 6.95-6.77(m, 4H), 6.30-6.22(m, 2H), 5.83-5.76(m, 1H), 4.48-4.38(m, 4H), 4.27-3.67(m, 14H), 3.40-3.29(m, 2H), 3.17-2.65(m, 15H), 2.10-1.73(m, 3H), 1.37-1.10(m, 4H), 1.00-0.87(m, 7H). LCMS(ESI): 실측치 991.1[M-CF3COOH+H]+.
화합물 15:
1-(4-(2-(3-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-3-옥소프로폭시)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.97(s, 1H), 9.80-9.30(m, 2H), 8.00(d, J = 8.4 Hz, 1H), 7.74-7.18(m, 7H), 6.92-6.75(m, 3H), 6.33-6.12(m, 2H), 5.78-5.70(m, 1H), 4.54-4.33(m, 3H), 4.16-3.83(m, 12H), 3.58-3.42(m, 7H), 3.34-2.73(m, 16H), 2.08-1.71(m, 3H), 1.26-1.10(m, 2H), 1.00(d, J = 6.8 Hz, 6H). LCMS(ESI): 실측치 992.1[M-CF3COOH+H]+.
화합물 16:
4-(4-(((4-((1-(3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD) δ 8.06(d, J = 7.8 Hz, 1H), 7.66-7.25(m, 12H), 6.93-6.75(m, 4H), 6.32-6.23 (m, 2H), 5.81(dd, J = 10.6, 1.8 Hz, 1H), 4.19(s, 1H), 4.02-3.70(m, 12H), 3.06-2.93 (m, 3H), 2.74(s, 5H), 2.68-2.54(m, 2H), 2.08-1.81(m, 1H), 1.77-1.56(m, 4H), 1.32-1.25(m, 10H), 1.24-1.05(m, 4H), 0.97-0.93(m, 7H). LCMS(ESI): m/z 실측치 1135.3[M-CF3COOH+H]+.
화합물 17:
4-(4-((4-((1-(3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.91-9.50(m, 3H), 7.99(d, J = 7.6 Hz, 1H), 7.69(d, J = 8.0 Hz, 1H), 7.48-7.14(m, 7H), 6.94-6.60(m, 5H), 6.35-6.11 (m, 2H), 5.75(d, J = 10.4 Hz, 1H), 5.36-5.28(m, 1H), 4.39(d, J = 14.0 Hz, 1H), 4.16(s, 1H), 4.02-3.90(m, 4H), 3.90-3.79(m, 7H), 3.01-2.90(m, 7H), 2.69-2.26(m, 4H), 2.30-2.24(m, 5H), 2.03-1.97 (m, 4H), 1.74(d, J = 10.4 Hz, 3H), 1.50-1.37(m, 3H), 0.87(dd, J = 15.6, 7.2 Hz, 6H). LCMS(ESI): m/z 실측치 1086.7[M-CF3COOH+H]+.
화합물 18:
(R)-3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(1-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)메틸)페닐)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.92(s, 1H), 9.77-9.61(m, 1H), 9.39-9.31(m, 1H), 8.44 (s, 1H), 7.99(d, J = 8.4 Hz, 1H), 7.68(d, J = 8.6 Hz, 1H), 7.41-7.08(m, 11H), 6.89-6.74(m, 3H), 6.29-6.11(m, 2H), 5.74(d, J = 12.6 Hz, 1H), 5.00-4.90(m, 1H), 4.16 (d, J = 31.2 Hz, 3H), 3.88-3.68(m, 7H), 3.34-3.22(m, 6H), 2.89-2.77(m, 5H), 2.05-1.94(m, 2H), 1.77-1.69(m, 2H), 1.42-1.19(m, 12H), 0.94(d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 1026.7[M-CF3COOH+H]+.
화합물 19:
1-(4-(2-((3-(4-(4-(((4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)(메틸)아미노)메틸)벤질)피페리딘-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD) δ 8.06 (d, J = 8.1 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.42-7.25 (m, 9H), 6.92-6.74 (m, 5H), 6.35-6.17 (m, 3H), 5.81 (d, J = 12.1 Hz, 2H), 4.51 (m, 2H), 4.19 (s, 4H), 3.99 (s, 5H), 3.85 (s, 5H), 3.74 (s, 2H), 3.09-2.97 (m, 4H), 2.76-2.55 (m, 9H), 2.22-2.14 (m, 1H), 2.03 (d, J = 5.5 Hz, 1H), 1.87 (s, 1H), 1.67 (m, 2H), 1.19-1.09 (m, 2H), 1.01 (d, J = 6.9 Hz, 6H). LCMS(ESI): 1026.5[M-CF3COOH+H]+.
화합물 20:
(S)-1-((2S,5S)-18-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-2-시클로헥실-5-메틸-4,16-디옥소-9,12-디옥사-3,6,15-트리아자옥타데카노일)-N-(4-페닐-1,2,3-티아디아졸-5-일)피롤리딘-2-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD) δ 8.06 (t, J = 9.2 Hz, 1H), 7.81-7.46 (m, 7H), 7.39 (t, J = 7.0 Hz, 1H), 7.29 (t, J = 7.1 Hz, 1H), 6.90 (s, 1H), 6.86-6.74 (m, 2H), 6.28 (dd, J = 16.8, 1.8 Hz, 1H), 5.81 (dd, J = 10.6, 1.7 Hz, 1H), 4.83-4.79 (m, 1H), 4.50 (d, J = 8.0 Hz, 1H), 4.27-3.35 (m, 28H), 3.22-2.90 (m, 5H), 2.56 (m, 2H), 2.10 (m, 4H), 1.86-1.63 (m, 6H), 1.53-1.43 (m, 3H), 1.37-0.98 (m, 8H). LCMS(ESI): m/z 실측치 1100.0 [M-CF3COOH+H]+.
화합물 21:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-1-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)프로판-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H), 7.29 (m, 3H), 6.91 (d, J = 1.8 Hz, 1H), 6.83-6.77 (m, 2H), 6.25 (s, 1H), 4.55 (d, J = 12.6 Hz, 1H), 4.19 (s, 2H), 3.97 (m, 8H), 3.74 (s, 7H), 3.07 (m, 12H), 2.74 (m, 7H), 2.16 (s, 3H), 2.03 (s, 2H), 1.85 (t, J = 13.5 Hz, 2H), 1.31-1.08 (m, 4H), 0.92 (m, 7H). LCMS(ESI): m/z 실측치 979.1 [M-CF3COOH+H]+.
화합물 22:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페네틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD): δ 8.05(d, J = 8.4 Hz, 1H), 7.64(d, J = 8.0 Hz, 1H), 7.40-7.17(m, 6H), 6.91-6.68(m, 3H), 6.26 (s, 1H), 5.38-5.34 (m, 1H), 4.19(s, 2H), 4.01-3.91(m, 3H), 3.75-3.68(m, 6H), 3.45 (t, J = 7.2 Hz, 2H), 3.01-2.81(m, 5H), 2.53 (t, J = 6.4 Hz, 2H), 2.19-1.98(m, 4H), 1.68-1.53(m, 1H), 0.88(d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 827.1[M-CF3COOH+H]+.
화합물 23:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-((4-(4-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-카르보닐)시클로헥실)메틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 12.45(s, 1H), 10.46(s, 1H), 9.79-9.62(m, 3H), 8.11-7.99(m, 2H), 7.69(d, J = 6.8 Hz, 1H), 7.41-7.27(m, 10H), 6.89 (s, 1H), 6.75(s, 1H), 6.60(s, 1H), 6.34(s, 1H), 6.19-6.15 (m, 1H), 5.76-5.72(m, 1H), 4.24-4.15(m, 4H), 4.03-3.90 (m, 3H), 3.80-3.60(m, 6H), 3.43-3.22(m, 8H), 2.80-2.61(m, 6H), 2.44-2.38 (m, 3H), 1.78-1.71(m, 3H), 1.45-1.38(m, 2H), 1.24(s, 2H), 0.82(d, J = 6.4 Hz, 6H). LCMS(ESI): m/z 실측치 1020.0[M-CF3COOH+H]+.
화합물 24:
4-(4-((1-(4-(2-(3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)에틸)벤질)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 10.48(s, 1H), 9.89-9.60(m, 3H), 8.15-7.93(m, 3H), 7.71-7.68(m, 2H), 7.45-7.22(m, 11H), 6.92-6.52(m, 4H), 6.37-6.21(m, 1H), 5.71-5.68 (m, 1H), 5.38(s, 1H), 4.23-4.12(m, 4H), 3.97-3.97(m, 2H), 3.75-3.66 m, 6H), 2.96-2.90(m, 5H), 2.76-2.67(m, 5H), 2.35-2.33(m, 5H), 2.04-1.95(m, 4H), 1.74-1.72 (m, 2H), 1.48-1.37(m, 2H), 0.85-0.80(m, 8H). LCMS(ESI): m/z 실측치 1135.5[M-CF3COOH+H]+.
화합물 25:
4-(4-((1-(4-((3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)메틸)벤질)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.78(s, 1H), 9.61(s, 1H), 9.58(s, 1H), 8.54(s, 1H), 7.99(d, J = 8.4 Hz, 1H), 7.68(d, J = 8.4 Hz, 1H), 7.43-7.40(m, 4H), 7.35-7.26(m, 8H), 6.96-6.75 (m, 3H), 6.60(s, 1H), 6.34(s, 1H), 6.18(d, J =10.4 Hz, 1H), 5.75(d, J = 8.4 Hz, 1H), 4.31(s, 3H), 4.24(s, 2H), 4.15(s, 2H), 3.88-3.76(m, 7H), 3.34-3.21(m, 7H), 2.97-2.78(m, 8H), 1.78-1.70(m, 3H), 1.39-1.25(m, 2H), 1.23(s, 2H), 0.82(d, J = 6.0 Hz, 6H). LCMS(ESI): m/z 실측치 1121.5[M-CF3COOH+H]+.
화합물 26:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-1-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)프로판-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD): δ 8.06 (d, J = 6.0 Hz, 1H), 7.75-7.60 (m, 3H), 7.41-7.17 (m, 6H), 6.85-6.66 (m, 3H), 6.27 (s, 1H), 4.57 (s, 1H), 4.12-4.06 (m, 3H), 3.72-3.48 (m, 13H), 3.02-2.69 (m, 5H), 2.41-2.36 (m, 4H), 2.15 (s, 3H), 2.06-1.98 (m, 1H), 0.87 (d, J = 7.6 Hz, 6H). LCMS(ESI): m/z 실측치 882.0[M-CF3COOH+H]+.
화합물 27:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD) δ 8.04 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.39 (t, J = 7.1 Hz, 1H), 7.28 (dd, J = 13.1, 7.9 Hz, 3H), 7.16 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 6.77 (dd, J = 16.9, 10.7 Hz, 2H), 6.31-6.15 (m, 3H), 5.80 (dd, J = 10.6, 1.8 Hz, 1H), 4.39 (s, 2H), 4.17 (s, 2H), 3.97 (s, 4H), 3.80 (s, 6H), 2.96 (s, 2H), 2.60 (t, J = 6.1 Hz, 2H). LCMS(ESI): m/z 실측치 783.3 [M-CF3COOH+H]+.
화합물 28:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-1-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)프로판-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD) δ 8.06 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.48-7.13 (m, 6H), 6.91 (s, 1H), 6.81 (s, 1H), 6.67 (s, 1H), 6.28 (s, 1H), 5.34 (s, 1H), 4.51 (s, 1H), 4.19 (s, 2H), 3.95 (d, J = 19.4 Hz, 4H), 3.61 (m, 12H), 3.00 (m, 5H), 2.75 (s, 2H), 2.67-2.53 (m, 3H), 2.17 (m, 3H), 2.04 (s, 1H), 1.85 (s, 1H), 1.73 (s, 2H), 1.60 (s, 1H), 0.88 (t, J = 7.6 Hz, 6H). LCMS(ESI): m/z 실측치 881.8 [M-CF3COOH+H]+.
화합물 29:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-1-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)메틸)피페리딘-1-일)프로판-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD): δ 8.06 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.46-7.16 (m, 8H), 6.97-6.64 (m, 3H), 6.27 (s, 1H), 5.34 (t, J = 4.8 Hz, 2H), 4.64-4.53 (m, 1H), 4.18 (s, 2H), 4.04-3.90 (m, 5H), 3.74 (s, 6H), 3.60-3.53 (m, 10H), 2.98-2.91 (m, 5H), 2.82-2.74 (m, 4H), 2.05-2.00 (m, 3H), 1.95-1.78 (m, 6H), 1.64-1.55 (m, 3H), 0.91-0.89 (m, 6H). LCMS(ESI): m/z 실측치 979.0[M-CF3COOH+H]+.
화합물 30:
N-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.86 (s, 1H), 9.74 (s, 1H), 9.55 (s, 1H), 9.30 (s, 1H), 8.49 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.49-6.67 (m, 10H), 6.22 (s, 1H), 4.27 (d, J = 5.8 Hz, 2H), 4.16 (s, 2H), 3.86 (s, 4H), 3.61 (s, 6H), 3.24 (s, 2H), 2.91 (s, 2H), 2.72-2.64 (m, 1H), 2.41-2.31 (m, 3H), 1.95 (s, 3H), 1.01 (t, J = 7.6 Hz, 3H). LCMS(ESI): m/z 실측치 799.3[M-CF3COOH+H]+.
화합물 31:
N-(4-(3-(2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.88(s, 1H), 9.84-9.52(m, 3H), 8.55-8.45(m, 1H), 7.99(d, J = 8.4 Hz, 1H), 7.69(d, J = 8.0 Hz, 2H), 7.50-6.65(m, 10H), 6.25-6.11(m, 2H), 4.33-4.07(m, 5H), 3.94-3.78(m, 6H), 3.55-3.54(m, 2H), 3.30-3.18(m, 3H), 2.98-2.86(m, 2H), 2.40-2.31(m, 4H), 1.04-0.98(m, 3H). LCMS(ESI): m/z 실측치 785.3[M-CF3COOH+H]+.
화합물 32:
N-(4-(3-(2,4-디히드록시-5-프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.87(s, 1H), 9.74(s, 1H), 9.53-9.29(m, 2H), 8.48 (s, 1H), 7.98(d, J = 8.4 Hz, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.45-6.70(m, 10H), 6.23(s, 1H), 4.30-4.13(m, 4H), 3.95-3.75(m, 4H), 3.64-3.58(m, 6H), 3.27-3.20(m, 2H), 2.97-2.85(m, 2H), 2.41-2.27(m, 5H), 1.45-1.35(m, 2H), 1.01(t, J = 7.2 Hz, 3H), 0.78(t, J = 7.2 Hz, 3H). LCMS(ESI): m/z 실측치 827.7[M-CF3COOH+H]+.
화합물 33:
N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.95(s, 1H), 9.75-9.57(m, 2H), 9.37(s, 1H), 8.47(s, 1H), 7.99(d, J = 8.0 Hz, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.45-7.22(m, 3H), 7.13-6.69(m, 6H), 6.24(s, 1H), 5.98(s, 1H), 5.52 s, 2H), 4.33-4.25(m, 3H), 4.17-4.09(s, 2H), 3.94-3.74(m, 5H), 3.63-3.58(m, 5H), 3.06-2.86(m, 4H), 2.39-2.32(m, 3H), 1.05-1.01(m, 9H). LCMS(ESI): m/z 실측치 845.7[M-CF3COOH+H]+.
화합물 34:
N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.95(s, 1H), 9.74(s, 1H), 9.58(s, 1H), 9.37(s, 1H), 8.48(s, 1H), 7.99(d, J = 8.4 Hz, 1H), 7.68(d, J = 8.8 Hz, 1H), 7.44-7.38(m, 1H), 7.32-7.20(m, 2H), 7.10-7.02(m, 1H), 6.98-6.88(m, 3H), 6.75(s, 1H), 6.24(s, 1H), 4.33-4.25(m, 2H), 4.19-4.10(m, 2H), 3.95-3.79(m, 4H), 3.66-3.54(m, 8H), 3.27-3.20(m, 2H), 2.99-2.83(m, 2H), 2.41-2.32(m, 5H), 1.05-0.98(m, 6H). LCMS(ESI): m/z 실측치 831.3[M-CF3COOH+H]+.
화합물 35:
1-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.96(s, 1H), 9.80-9.58(m, 2H), 9.34(s, 1H), 7.99(d, J = 8.8 Hz, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.54-7.20(m, 6H), 6.89-6.73(m, 2H), 6.25(s, 1H), 4.45-4.25(m, 2H), 4.21-4.09(m, 2H), 3.90-3.76(m, 5H), 3.71-3.59(m, 11H), 3.41-3.36(m, 4H), 3.29-3.22(m, 3H), 3.03-2.90(m, 4H), 2.71-2.65(m, 3H), 2.40-2.31(m, 3H), 1.06-0.94(m, 9H). LCMS(ESI): S m/z 실측치 896.4[M-CF3COOH+H]+.
화합물 36:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-(트리플루오로메틸)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 12.01 (s, 1H), 9.66 (d, J = 58.8 Hz, 2H), 9.35 (s, 1H), 8.58 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.55-7.25 (m, 5H), 6.99-6.72 (m, 4H), 6.26-6.12 (m, 2H), 5.77-5.70 (m, 1H), 4.43 (d, J = 7.0 Hz, 2H), 4.15 (s, 2H), 3.88 (s, 3H), 3.78-3.68 (m, 4H), 3.63-3.58 (m, 3H), 3.31-3.23 (m, 3H), 3.05-3.01 (m, 1H), 2.97-2.87 (m, 2H), 2.60-2.55 (m, 2H), 1.03 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 893.3[M-CF3COOH+H]+.
화합물 37:
N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.87 (s, 1H), 9.73 (s, 1H), 9.53 (s, 1H), 9.33 (s, 1H), 8.47 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.45-7.06 (m, 7H), 6.88-6.75 (m, 3H), 6.23 (s, 1H), 4.27 (d, J = 5.8 Hz, 2H), 4.12 (s, 2H), 3.89-3.75 (m, 2H), 3.60 (s, 6H), 3.27-3.19 (m, 3H), 2.89 (s, 2H), 2.35 (dd, J = 14.8, 7.2 Hz, 6H), 1.00 (t, J = 7.2 Hz, 7H). LCMS(ESI): m/z 실측치 813.2[M-CF3COOH+H]+.
화합물 38:
1-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.91 (s, 1H), 9.73 (s, 1H), 9.60 (s, 1H), 9.42 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.41-7.09 (m, 6H), 6.93-6.84 (m, 1H), 6.79-6.68 (m, 2H), 6.27 (s, 1H), 4.42-4.32 (m, 1H), 4.11 (s, 1H), 3.83-3.74 (m, 3H), 3.67-3.48 (m, 9H), 3.43-3.39 (m, 5H), 3.26-3.19 (m, 3H), 3.01-2.86 (m, 3H), 2.69-2.60 (m, 2H), 2.41-2.30 (m, 3H), 1.79-1.67 (m, 1H), 1.63-1.51 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H), 0.92 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 895.4[M-CF3COOH+H]+.
화합물 39:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-(트리플루오로메틸)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO) δ 12.01 (s, 1H), 9.75 (s, 1H), 9.58 (s, 1H), 9.36 (s, 1H), 8.58 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.42 (m, 3H), 7.33-7.24 (m, 1H), 6.97 (d, J = 5.9 Hz, 1H), 6.89 (s, 1H), 6.85-6.72 (m, 2H), 6.18 (m, 2H), 5.74 (d, J = 12.6 Hz, 1H), 4.43 (d, J = 5.4 Hz, 2H), 4.15 (s, 2H), 3.87 (s, 3H), 3.72 (m, 4H), 3.62 (s, 3H), 3.24 (s, 2H), 2.91 (s, 2H), 2.56 (d, J = 6.7 Hz, 2H), 2.37 (m, 3H), 1.02 (t, J = 7.4 Hz, 3H). LCMS(ESI): m/z 실측치 879.0 [M-CF3COOH+H]+.
화합물 40:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (s, 1H), 9.77 (s, 1H), 9.56 (s, 1H), 9.34 (s, 1H), 8.50 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.33-7.25 (m, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 9.8 Hz, 2H), 6.84-6.72 (m, 2H), 6.26-6.09 (m, 2H), 5.78-5.70 (m, 1H), 4.27 (d, J = 5.7 Hz, 2H), 4.16 (s, 2H), 3.88 (s, 4H), 3.72 (d, J = 22.9 Hz, 4H), 3.62 (s, 3H), 3.24 (s, 2H), 2.92 (s, 2H), 2.53 (s, 1H), 2.35 (m, 2H), 0.99 (t, J = 7.5 Hz, 3H). LCMS(ESI): m/z 실측치 881.3 [M-CF3COOH+H]+.
화합물 41:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 9.76 (s, 1H), 9.59 (s, 1H), 9.38 (s, 1H), 8.49 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.82 (s, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.33-7.20 (m, 2H), 7.05 (d, J = 11.0 Hz, 1H), 6.92 (m, 3H), 6.87-6.71 (m, 2H), 6.24 (s, 1H), 6.16 (m, 1H), 5.74 (d, J = 12.6 Hz, 1H), 4.29 (d, J = 5.3 Hz, 2H), 4.15 (s, 2H), 3.88 (s, 4H), 3.72 (m, 5H), 3.59 (s, 2H), 3.25 (s, 2H), 2.92 (s, 2H), 2.38 (dd, J = 14.9, 7.5 Hz, 2H), 1.02 (t, J = 7.5 Hz, 3H). LCMS(ESI): m/z 실측치 829.3 [M-CF3COOH+H]+.
화합물 42:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-(트리플루오로메틸)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 12.01 (s, 1H), 9.75-9.35 (m, 3H), 8.58 (s, 1H), 7.80-7.67 (m, 3H), 7.51-7.26 (m, 5H), 6.97-6.75 (m, 3H), 6.23 (s, 1H), 4.43 (d, J = 4.4 Hz, 2H), 4.15 (s, 2H), 3.86-3.77 (m, 4H), 3.60 (s, 6H), 3.29 (s, 2H), 3.04-2.88 (m, 3H), 2.58-2.54 (m, 2H), 2.04 (s, 3H), 1.03 (d, J = 6.8 Hz, 7H). LCMS(ESI): m/z 실측치 881.0[M-CF3COOH+H]+.
화합물 43:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)프로판아미드. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.95 (s, 1H), 9.76-9.37 (m, 3H), 8.49 (t, J = 6.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.91-7.67 (m, 2H), 7.42-6.75 (m, 9H), 6.24 (s, 1H), 4.30-4.15 (m, 4H), 3.87-3.78 (m, 4H), 3.65 (s, 6H), 3.31-3.24 (m, 2H), 2.91-2.88 (m, 2H), 2.41-2.35 (m, 3H), 2.04-1.98 (m, 4H), 1.02 (t, J = 7.2 Hz, 3H). LCMS(ESI): m/z 실측치 817.3[M+H]+.
화합물 44:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.86 (s, 1H), 9.77-9.32 (m, 3H), 8.49 (t, J = 5.6 Hz, 1H), 8.00-7.68 (m, 3H), 7.42-6.75 (m, 9H), 6.23 (s, 1H), 4.28-4.15 (s, 4H), 3.96-3.82 (m, 4H), 3.77-3.60 (m, 9H), 3.24 (s, 2H), 2.96-2.85 (m, 2H), 2.04 (s, 3H), 1.95 (s, 3H). LCMS(ESI): m/z 실측치 785.3[M-CF3COOH+H]+.
화합물 45:
N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-(트리플루오로메틸)벤질)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 12.01(s, 1H), 9.82-9.30(m, 3H), 8.58(s, 1H), 7.98(d, J = 8.4 Hz, 1H), 7.74-6.72(m, 11H), 6.23 (s, 1H), 4.47-4.39(m, 2H), 4.14(s, 2H), 3.94-3.78(m, 4H), 3.63-3.58(m, 5H), 3.28-3.21(m, 2H), 2.96-2.84(m, 2H), 2.59-2.54(m, 2H), 2.42-2.32(m, 5H), 1.06-0.98(m, 6H). LCMS(ESI): m/z 실측치 881.0[M-CF3COOH+H]+.
화합물 46:
N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-(트리플루오로메틸)벤질)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로펜아미드. 1H NMR (400 MHz, DMSO-d 6 ): δ 12.01(s, 1H), 9.84-9.28(m, 3H), 8.57(s, 1H), 7.99(d, J = 8.0 Hz, 1H), 7.77-6.69(m, 11H), 6.23(s, 1H), 4.47-4.39(m, 2H), 4.13(s, 2H), 3.87-3.75(m, 2H), 3.64-3.57(m, 6H), 3.27-3.20(m, 3H), 3.06-2.99(m, 1H), 2.95-2.84(m, 2H), 2.58-2.54(m, 2H), 2.39-2.31(m, 3H), 1.06-0.99(m, 9H). LCMS(ESI): m/z 실측치 895.0[M+H]+.
화합물 47:
3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)프로펜아미드. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.96(s, 1H), 9.82-9.34(m, 3H), 8.50(s, 1H), 8.06-7.57(m, 3H), 7.45-6.74(m, 10H), 6.28-6.12(m, 2H), 5.77-5.71(m, 1H), 4.32-4.26(m, 2H), 4.16(s, 2H), 3.93-3.83(m, 4H), 3.78-3.68(m, 4H), 3.63-3.56(m, 3H), 3.28-3.21(m, 2H), 3.07-2.88(m, 3H), 1.03(d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 843.3[M +H]+.
화합물 48:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.88 (s, 1H), 9.77 (s, 1H), 9.56 (s, 1H), 9.33 (s, 1H), 8.50 (t, J = 6.0 Hz, 1H), 8.04-7.63 (m, 3H), 7.44-7.07 (m, 7H), 6.93-6.72 (m, 3H), 6.23 (s, 1H), 4.30-4.12 (m, 4H), 3.85 (d, J = 22.4 Hz, 4H), 3.60 (s, 6H), 3.24 (s, 2H), 2.91 (s, 2H), 2.40-2.31 (m, 2H), 2.08-1.97 (m, 4H), 0.99 (t, J = 7.6 Hz, 3H). LCMS(ESI): m/z 실측치 799.3[M-CF3COOH+H]+.
화합물 49:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.96 (s, 1H), 9.84-9.28 (m, 3H), 8.50 (t, J = 5.6 Hz, 1H), 8.06-7.62 (m, 3H), 7.48-6.67 (m, 9H), 6.25 (s, 1H), 4.29 (d, J = 5.4 Hz, 2H), 4.16 (s, 2H), 3.85 (d, J = 21.8 Hz, 4H), 3.60 (s, 6H), 3.24 (s, 2H), 3.05-2.87 (m, 3H), 2.10-1.96 (m, 4H), 1.03 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 831.3[M-CF3COOH+H]+.
화합물 50:
N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.89 (s, 1H), 9.75 (s, 1H), 9.57 (s, 1H), 9.35 (s, 1H), 8.49 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.31-7.21 (m, 3H), 7.11 (d, J = 8.3 Hz, 2H), 6.89 (s, 1H), 6.84 (s, 1H), 6.75 (s, 1H), 6.24 (s, 1H), 4.27 (d, J = 5.6 Hz, 2H), 4.14 (s, 2H), 3.82 (s, 4H), 3.61 (s, 6H), 3.43 (s, 3H), 3.24 (s, 2H), 3.02-2.88 (m, 3H), 2.36 (dd, J = 14.7, 7.4 Hz, 2H), 1.00 (m, 9H). LCMS(ESI): m/z 실측치 827.1 [M-CF3COOH+H]+.
화합물 51:
N-(2-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에틸)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 9.74 (s, 1H), 9.57 (s, 1H), 9.37 (s, 1H), 8.23 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.30-7.25 (m, 1H), 7.10 (d, J = 8.9 Hz, 2H), 6.95-6.88 (m, 3H), 6.80 (s, 1H), 6.75 (s, 1H), 6.25 (s, 1H), 4.15 (s, 2H), 3.96 (d, J = 5.4 Hz, 2H), 3.83 (s, 4H), 3.62 (s, 8H), 3.24 (s, 3H), 3.01-2.88 (m, 3H), 2.46 (s, 1H), 2.36 (m, 3H), 1.07-0.91 (m, 9H). LCMS(ESI): m/z 실측치 857.0 [M-CF3COOH+H]+.
화합물 52:
1-(4-((4-(4-(3-(2,4-디히드록시-5-프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판-1-온. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.91 (s, 1H), 9.74 (s, 1H), 9.56 (s, 1H), 9.35 (s, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.43-7.36 (m, 1H), 7.3-7.23 (m, 2H), 7.12 (s, 2H), 7.00 (s, 1H), 6.88 (s, 1H), 6.82 (s, 1H), 6.75 (s, 1H), 6.25 (s, 1H), 4.35 (s, 1H), 4.08 (s, 1H), 3.85 (s, 2H), 3.60 (s, 4H), 3.54-3.47 (m, 8H), 2.99 (s, 10H), 2.65 (m, 2H), 2.43-2.24 (m, 8H), 2.19-1.86 (m, 3H), 1.71 (s, 3H), 1.45-1.36 (m, 2H), 1.24 (s, 2H), 1.01 (t, J = 7.2 Hz, 3H), 0.78 (t, J = 7.3 Hz, 3H). LCMS(ESI): m/z 실측치 993.5[M+H]+.
화합물 53:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-(트리플루오로메틸)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 12.01 (s, 1H), 9.74 (s, 1H), 9.59 (s, 1H), 9.36 (s, 1H), 8.57 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.53 (s, 1H), 7.43-7.36 (m, 3H), 7.28 (t, J = 7.5 Hz, 1H), 6.98 (s, 1H), 6.89 (s, 1H), 6.75 (s, 1H), 6.23 (s, 1H), 4.42 (s, 2H), 4.14 (s, 2H), 3.83-3.68 (m, 4H), 3.60 (s, 8H), 3.24 (s, 2H), 2.90 (s, 2H), 2.41-2.34 (m, 2H), 2.04 (s, 3H), 1.23 (s, 1H), 1.02 (t, J = 7.5 Hz, 3H). LCMS(ESI): m/z 실측치 867.3[M-CF3COOH+H]+.
화합물 54:
4-(4-((1-(4-((3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)메틸)벤질)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.79 (s, 2H), 9.59 (d, J = 6.1 Hz, 1H), 9.49 (s, 1H), 8.53 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.46-7.21 (m, 12H), 6.90 (s, 1H), 6.76 (s, 1H), 6.60 (s, 1H), 6.34 (s, 1H), 4.32 (d, J = 5.4 Hz, 2H), 4.23 (s, 2H), 4.15 (s, 2H), 3.92-3.78 (m, 12H), 3.33 (d, J = 10.2 Hz, 2H), 3.26 (s, 2H), 3.14 (s, 1H), 2.89-2.80 (m, 6H), 2.05 (s, 3H), 2.00 (d, J = 7.6 Hz, 1H), 1.88-1.62 (m, 4H), 1.48-1.37 (m, 2H), 0.82 (d, J = 6.9 Hz, 6H). LCMS(ESI): m/z 실측치 1109.5[M-CF3COOH+H]+.
화합물 55:
4-(4-((4-((1-(3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-N-이소프로필-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.76(s, 1H), 9.71(s, 1H), 8.80(d, J = 8.0 Hz, 1H), 7.99(d, J = 8.0 Hz, 1H), 7.69(d, J = 8.0 Hz, 1H), 7.53-6.97(m, 8H), 6.90(s, 1H), 6.76(s, 1H), 6.62(s, 1H), 6.31(s, 1H), 4.44-4.34(m, 2H), 4.16(s, 2H), 3.99-3.85(m, 15H), 3.28-3.23(m, 2H), 3.10-2.80(m, 10H), 2.68-2.63(m, 2H), 2.31-2.20(m, 4H), 2.06(s, 3H), 2.03-1.96(m, 2H), 1.78-1.71(m, 2H), 1.50-1.28(m, 2H), 1.10(d, J = 6.4 Hz, 6H), 0.89-0.84(m, 3H). LCMS(ESI): m/z 실측치 1034.5[M-CF3COOH+H]+.
화합물 56:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-1-(4-((2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-일)메틸)피페라진-1-일)프로판-1-온, 트리플루오로아세트산.
1H NMR (400 MHz, DMSO-d 6 ): δ 10.02(s, 1H), 9.75(s, 1H), 9.64(s, 1H), 7.99(d, J = 8.0 Hz, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.55-7.23(m, 6H), 7.03(s, 1H), 6.89(s, 1H), 6.75(s, 1H), 6.40(s, 1H), 4.87-4.75(m, 4H), 4.54-4.28(m, 3H), 4.14(s, 2H), 3.95-3.60(m, 14H), 3.27-3.24(m, 2H), 3.13-3.07(m, 2H), 2.97-2.85(m, 4H), 2.70-2.66(m, 2H), 2.05(s, 3H), 1.13(d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 868.4[M-CF3COOH+H]+.
화합물 57:
1-(4-((2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-일)메틸)피페라진-1-일)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판-1-온, 트리플루오로아세트산.
1H NMR (400 MHz, DMSO-d 6 ): δ 10.01(s, 1H), 9.75(s, 1H), 9.64(s, 1H), 7.99(d, J = 8.0 Hz, 1H), 7.68(d, J = 8.4 Hz, 1H), 7.54-7.23(m, 6H), 7.03(s, 1H), 6.89(s, 1H), 6.75(s, 1H), 6.40(s, 1H), 4.86-4.76(m, 4H), 4.52-4.30(m, 3H), 4.15(s, 2H), 4.00-3.74(m, 10H), 3.40-3.30(m, 4H), 3.27-3.22(m, 2H), 3.13-3.05(m, 2H), 3.00-2.84(m, 4H), 2.71-2.65(m, 2H), 2.40-2.34(m, 2H), 1.13(d, J = 6.8 Hz, 6H), 1.05-0.99(m, 3H). LCMS(ESI): m/z 실측치 882.4[M-CF3COOH+H]+.
화합물 58:
1-(4-(2-((3-(4-((2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-일)메틸)피페라진-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온
1H NMR (400 MHz, DMSO-d 6 ): δ 10.25-9.90 (m, 2H), 9.78 (s, 1H), 9.66 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.55-7.20 (m, 6H), 7.03 (s, 1H), 6.89 (s, 1H), 6.88-6.79 (m, 1H), 6.75 (s, 1H), 6.41 (s, 1H), 6.17 (dd, J = 16.3, 1.9 Hz, 1H), 5.75 (dd, J = 10.5, 1.8 Hz, 1H), 4.88-4.72 (m, 4H), 4.52-4.26 (m, 3H), 4.14 (s, 2H), 4.06-3.64 (m, 14H), 3.26 (s, 2H), 3.13-3.05 (m, 2H), 2.98-2.84 (m, 4H), 2.72-2.66 (m, 2H), 1.13 (d, J = 6.8 Hz, 6H). LCMS(ESI): S m/z 실측치 880.4[M+H]+.
화합물 59:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-1-(4-((4-(4-(3-(2,4-디히드록시-5-프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)프로판-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.89-9.18 (m, 3H), 8.00 (d, J = 6.8 Hz, 1H), 7.66 (d, J = 6.8 Hz, 1H), 7.48-7.02 (m, 7H), 6.92-6.70 (m, 3H), 6.62-6.44 (m, 1H), 6.25 (s, 1H), 4.36 (d, J = 12.4 Hz, 1H), 4.05-3.82 (m, 3H), 3.56 (s, 6H), 3.02-2.87 (m, 3H), 2.85-2.60 (m, 6H), 2.40-2.23 (m, 10H), 2.05 (s, 7H), 1.79-1.57 (m, 4H), 1.42-1.31 (m, 2H), 1.00-0.84 (m, 2H), 0.80-0.72 (m, 3H). LCMS(ESI): m/z 실측치 979.5[M-CF3COOH+H]+.
화합물 60:
(R)-3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(1-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)메틸)페닐)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.92 (s, 1H), 9.77 (s, 1H), 9.61 (s, 1H), 9.40 (s, 2H), 8.47 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.52-7.34 (m, 5H), 7.31-7.25 (m, 1H), 7.21-7.14 (m, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.89 (s, 1H), 6.78-6.72 (m, 2H), 6.26 (s, 1H), 5.02-4.92 (m, 1H), 4.24-4.17 (m, 2H), 4.13 (s, 2H), 3.92-3.60 (m, 10H), 3.34-3.08 (m, 8H), 3.03-2.77 (m, 6H), 2.05 (s, 3H), 1.77-1.66 (m, 3H), 1.43-1.29 (m, 5H), 0.94 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 1014.5[M-CF3COOH+H]+.
화합물 61:
(R)-N-(1-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)메틸)페닐)에틸)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.92 (s, 1H), 9.77 (s, 1H), 9.61 (s, 1H), 9.40 (s, 1H), 9.36-9.28 (m, 1H), 8.46 (s, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.38 (t, J = 6.9 Hz, 5H), 7.30-7.26 (m, 1H), 7.17 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.3 Hz, 2H), 6.89 (s, 1H), 6.75 (d, J = 5.7 Hz, 2H), 6.26 (s, 1H), 4.97 (d, J = 7.3 Hz, 1H), 4.20 (s, 2H), 4.12 (s, 2H), 3.66 (m, 9H), 3.32 (s, 6H), 3.17-3.06 (m, 2H), 2.93 (m, 6H), 2.36 (d, J = 7.5 Hz, 2H), 1.72 (d, J = 11.5 Hz, 3H), 1.34 (d, J = 6.8 Hz, 5H), 1.01 (t, J = 7.3 Hz, 3H), 0.94 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 1028.6 [M-CF3COOH+H]+.
화합물 62:
5-(2,4-디히드록시-5-이소프로필페닐)-4-(4-((1-(4-((3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)메틸)벤질)피페리딘-4-일)메틸)페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 12.28 (s, 1H), 9.80 (s, 1H), 9.60 (t, J = 6.3 Hz, 1H), 9.29 (s, 1H), 8.54 (s, 1H), 7.96-7.95 (m, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.42-7.41 (m, 3H), 7.28 (m, 7H), 6.88 (s, 1H), 6.73 (s, 1H), 6.58 (s, 1H), 6.32 (s, 1H), 4.25-4.23 (m, 7H), 3.91 (m, 7H), 3.25 (m, 6H), 2.97-2.77 (m, 5H), 2.70 (t, J = 16.4 Hz, 1H), 2.53 (d, J = 5.7 Hz, 3H), 2.34 (q, J = 7.4 Hz, 2H), 2.02-2.01 (m, 1H), 1.74-1.73 (m, 3H), 1.37 (d, J = 13.0 Hz, 2H), 1.21 (s, 1H), 0.99 (t, J = 7.3 Hz, 3H), 0.80 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 1123.6 [M-CF3COOH+H]+.
화합물 63:
(R)-3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(1-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)메틸)페닐)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.98 (s, 1H), 9.75-9.37 (m, 4H), 7.99 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.51-7.25 (m, 12H), 6.89 (d, J = 3.6 Hz, 2H), 6.75 (s, 1H), 6.24 (s, 1H), 4.45-4.35 (m, 3H), 4.17 (s, 4H), 3.93-3.72 (m, 5H), 3.63 (s, 7H), 3.25 (s, 2H), 3.10-2.77 (m, 5H), 2.64 (s, 2H), 2.41-2.31 (m, 2H), 1.82-1.50 (m, 3H), 1.24 (s, 3H), 1.16-0.88 (m, 11H). LCMS(ESI): m/z 실측치 1028.5[M-CF3COOH+H]+.
화합물 64:
5-(5-에틸-2,4-디히드록시페닐)-4-(4-((4-((1-(3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-N-이소프로필-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.74 (s, 2H), 8.80 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.90-7.62 (m, 2H), 7.51-7.22 (m, 8H), 6.90 (s, 1H), 6.76 (s, 1H), 6.64 (s, 1H), 6.31 (s, 1H), 4.39 (d, J = 10.8 Hz, 1H), 4.17 (s, 3H), 3.94-3.82 (m, 9H), 3.26 (s, 4H), 3.03-2.81 (m, 11H), 2.40-2.20 (m, 5H), 2.08-1.91 (m, 2H), 1.86-1.65 (m, 3H), 1.12-0.83 (m, 18H). LCMS(ESI): m/z 실측치 1048.6[M-CF3COOH+H]+.
화합물 65:
1-(4-((4-(4-(3-(2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.67 (s, 2H), 8.00 (s, 1H), 7.66 (s, 1H), 7.39 (s, 1H), 7.32-7.19 (m, 4H), 7.13-7.03 (m, 3H), 6.85 (s, 1H), 6.75 (s, 1H), 6.50 (s, 1H), 6.25-6.14 (m, 2H), 5.34 (s, 1H), 4.61 (s, 2H), 4.38-4.34 (m, 1H), 3.98 (s, 3H), 3.53 (s, 6H), 2.94-2.67 (m, 10H), 2.38-2.27 (m, 10H), 2.05-1.94 (m, 4H), 1.69-1.63 (m, 3H), 1.51-1.43 (m, 2H), 1.02-0.99 (m, 3H). LCMS(ESI): m/z 실측치 951.6[M+H]+.
화합물 66
1-(4-((2-(5-에틸-2,4-디히드록시벤조일)이소인돌린-5-일)메틸)피페라진-1-일)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판-1-온, 트리플루오로아세트산.
1H NMR (400 MHz, DMSO-d 6 ): δ 10.10(s, 1H), 9.79-9.61(m, 2H), 7.99(d, J = 8.4 Hz, 1H), 7.68(d, J = 8.0 Hz, 1H), 7.52-7.21(m, 5H), 7.05-6.84(m, 2H), 6.75(s, 1H), 6.40(s, 1H), 4.88-4.74(m, 4H), 4.50-4.26(m, 2H), 4.18-4.08(m, 2H), 3.92-3.72(m, 4H), 3.68-3.52(m, 11H), 3.27-3.22(m, 2H), 3.00-2.81(m, 5H), 2.70-2.64(m, 2H), 2.47-2.42 (m, 2H), 2.40-2.30(m, 3H), 2.08-1.96(m, 1H), 1.12-1.07(m, 3H), 1.01(t, J = 7.2 Hz, 3H). LCMS(ESI): m/z 실측치 868.4[M-CF3COOH+H]+.
화합물 67
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-1-(4-((2-(5-에틸-2,4-디히드록시벤조일)이소인돌린-5-일)메틸)피페라진-1-일)프로판-1-온, 트리플루오로아세트산.
1H NMR (400 MHz, DMSO-d 6 ): δ 10.41-9.94(m, 2H), 9.82-9.63(m, 2H), 7.99(d, J = 8.8 Hz, 1H), 7.69(d, J = 8.0 Hz, 1H), 7.56-7.22(m, 6H), 7.05-6.70(m 3H), 6.41(s, 1H), 4.88-4.74(m, 4H), 4.55-4.30(m, 3H), 4.22-4.08(m, 3H), 3.94-3.79(m, 4H), 3.63-3.58(m, 7H), 3.28-3.21(m, 3H), 3.00-2.82(m, 6H), 2.7-2.64(m, 3H), 2.47-2.41(m, 3H), 2.05(s, 4H), 1.09(t, J = 7.6 Hz, 3H). LCMS(ESI): m/z 실측치 854.4[M-CF3COOH+H]+.
화합물 68
1-(4-(2-((3-(4-((2-(5-에틸-2,4-디히드록시벤조일)이소인돌린-5-일)메틸)피페라진-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산.
1H NMR (400 MHz, DMSO-d 6 ): δ 10.10(s, 1H), 9.80-9.61(m, 2H), 7.99(d, J = 8.0 Hz, 1H), 7.68(d, J = 8.4 Hz, 1H), 7.52-7.22(m, 5H), 7.06-6.73(m, 4H), 6.41(s, 1H), 6.21-6.13(m, 1H), 5.78-5.72(m, 1H), 4.88-4.74(m, 4H), 4.46-4.28(m, 2H), 4.19-4.09(m, 2H), 3.90-3.68(m 10H), 3.42-3.33(m, 4H), 3.29-3.20(m, 3H), 2.98-2.83(m, 4H), 2.74-2.62(m, 3H), 2.47-2.42(m, 2H), 1.10(t, J = 7.6 Hz, 3H). LCMS(ESI): m/z 실측치 866.4[M-CF3COOH+H]+.
화합물 69:
4-(4-((4-((1-(3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.82-9.65 (m, 2H), 8.32 (s, 1H), 7.99 (d, J = 8.8 Hz, 1H), 7.78-7.62 (m, 3H), 7.46-7.23 (m, 7H), 6.90-6.59 (m, 3H), 6.31 (s, 1H), 4.39 (d, J = 12.3 Hz, 2H), 4.17 (s, 3H), 3.94-3.79 (m, 6H), 3.62 (s, 8H), 3.25 (s, 2H), 3.08 -2.87 (m, 7H), 2.67-2.64 (m, 1H), 2.34-2.21 (m, 5H), 2.06 (s, 4H), 1.75 (d, J = 14.9 Hz, 3H), 1.13-0.97 (m, 2H), 0.86 (t, J = 7.4 Hz, 4H). LCMS(ESI): m/z 실측치 992.5[M-CF3COOH+H]+.
화합물 70:
3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(2-(2-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에톡시)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.87 (s, 1H), 9.75 (s, 1H), 9.58 (s, 1H), 9.38 (s, 1H), 8.15-7.93 (m, 2H), 7.68 (d, J = 8.2 Hz, 1H), 7.42-7.26 (m, 2H), 7.14-6.71 (m, 7H), 6.25 (s, 1H), 4.19-4.03 (m, 4H), 3.97-3.77 (m, 4H), 3.73-3.69 (m, 2H), 3.65-3.58 (m, 4H), 3.50-3.45 (m, 5H), 3.29-3.20 (m, 4H), 3.02-2.87 (m, 3H), 2.45-2.40 (m, 2H), 2.06 (d, J = 10.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 887.4[M-CF3COOH+H]+.
화합물 71:
4-(4-((4-((1-(3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.74 (d, J = 23.0 Hz, 2H), 8.31 (s, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.76-7.64 (m, 3H), 7.45-7.25 m, 6H), 6.93-6.56(m, 4H), 6.34-6.12 (m, 2H), 5.75 (d, J = 10.4 Hz, 1H), 4.46-4.29 (m, 3H), 4.15(s, 3H), 3.78-3.70(m, 10H), 3.28-3.21 (s, 3H), 3.06-2.88 (m, 10H), 2.72-2.62(m, 5H), 2.29-2.20(m, 2H), 1.82-1.69 (m, 2H), 1.14- 0.98 (m, 2H), 0.93-0.79 (m, 4H). LCMS(ESI): m/z 실측치 1004.4[M+H]+.
화합물 72:
(R)-3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(1-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)메틸)페닐)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.86 (s, 1H), 9.75 (s, 1H), 9.58 (s, 1H), 9.38 (s, 1H), 8.07 (s, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.32-7.24 (m, 1H), 7.09 (d, J = 8.9 Hz, 2H), 6.92 (m, 3H), 6.84-6.74 (m, 3H), 6.25 (s, 1H), 6.17-6.15 (m, 1H), 5.74 (d, J = 12.6 Hz, 1H), 4.15 (s, 2H), 4.07 (s, 2H), 3.87 (s, 3H), 3.73-3.71 (m, 6H), 3.48 (d, J = 5.8 Hz, 5H), 3.25 (d, J = 5.7 Hz, 4H), 2.96-2.93 (m, 3H), 2.45-2.43 (m, 2H), 2.08 (d, J = 4.4 Hz, 1H), 0.97 (d, J = 6.9 Hz, 6H). LCMS(ESI): m/z 실측치 899.6[M+H]+.
화합물 73:
N-(2-(2-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에톡시)에틸)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.87 (s, 1H), 9.77 (s, 1H), 9.60 (s, 1H), 9.39 (s, 1H), 8.10-7.95 (m, 2H), 7.68 (d, J = 7.9 Hz, 1H), 7.45-7.36 (m, 1H), 7.32-7.24 (m, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.98-6.85 (m, 3H), 6.81 (s, 1H), 6.75 (s, 1H), 6.25 (s, 1H), 4.10-4.08 (m, 4H), 3.76-3.75 (m, 5H), 3.58-3.56 (m, 6H), 3.46 (d, J = 5.9 Hz, 3H), 3.24 (d, J = 5.4 Hz, 4H), 2.96-2.95 (m, 3H), 2.46-2.29 (m, 5H), 1.00-0.99 (m, 9H). LCMS(ESI): m/z 실측치 901.4 [M-CF3COOH+H]+.
화합물 74:
N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페네틸)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.90 (s, 1H), 9.74 (s, 1H), 9.58 (s, 1H), 9.37 (s, 1H), 8.10 (s, 1H), 7.99 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.43-7.37 (m, 1H), 7.30-7.25 (m, 1H), 7.21 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 6.89 (s, 1H), 6.78 (s, 1H), 6.75 (s, 1H), 6.25 (s, 1H), 4.15 (s, 2H), 3.83 (s, 4H), 3.59-3.58 (m, 7H), 3.26 (s, 5H), 2.99-2.89 (m, 3H), 2.72 (d, J = 7.5 Hz, 3H), 2.42 (s, 2H), 2.38-2.32 (m, 2H), 1.07-0.90 (m, 9H). LCMS(ESI): m/z 실측치 841.8 [M-CF3COOH+H]+.
화합물 75:
5-(5-에틸-2,4-디히드록시페닐)-4-(4-((4-((1-(3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.81-9.72 (m, 2H), 8.31 (s, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.80-7.59 (m, 3H), 7.46-7.23 (m, 6H), 6.90 (s, 1H), 6.75 (s, 1H), 6.61 (s, 1H), 6.31 (s, 1H), 4.48-4.37 (m, 2H), 4.15 (s, 3H), 3.94-3.78 (m, 9H), 3.50-3.38 (m, 7H), 3.30-3.20 (m, 2H), 3.09-2.83 (m, 10H), 2.69-2.58 (m, 4H), 2.41-2.30 (m, 2H), 2.29-2.18 (m, 2H), 1.78-1.65 (m, 2H), 1.02 (t, J = 7.4 Hz, 5H), 0.92-0.79 (m, 3H). LCMS(ESI): m/z 실측치 1006.5[M-CF3COOH+H]+.
화합물 76:
(R)-4-(4-((4-((1-(3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.74-9.63 (m, 2H), 8.15 (d, J = 5.2 Hz, 1H), 7.96-7.93 (m, 1H), 7.83 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.59-7.17 (m, 10H), 6.95-6.87 (m, 1H), 6.67 (s, 1H), 6.31 (s, 1H), 6.21 (d, J = 15.9 Hz, 1H), 5.80 (d, J = 10.5 Hz, 1H), 4.95-4.79 (m, 1H), 4.45-4.32 (m, 3H), 4.21 (s, 3H), 3.97-4.80 (m, 3H), 3.66-3.48 (m, 5H), 3.31-3.18 (m, 3H), 3.08-2.80 (m, 9H), 2.68-2.53 (m, 3H), 2.29-2.23 (m, 3H), 2.03-1.88 (m, 2H), 1.78-1.64 (m, 3H), 1.29-1.15 (m, 3H), 1.11-0.93 (m, 2H), 0.88 (t, J = 7.4 Hz, 4H). LCMS(ESI): m/z 실측치 1110.1[M-CF3COOH+H]+.
화합물 77:
(R)-4-(4-((4-((1-(3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.74-9.64 (m, 2H), 8.17 (d, J = 4.8 Hz, 1H), 8.16-7.93 (m, 2H), 7.69 (d, J = 8.0 Hz, 1H), 7.69-7.32 (m, 10H), 7.21 (d, J = 7.2 Hz, 1H), 6.97-6.78 (m, 1H), 6.28 (s, 1H), 6.22 (d, J = 17.6 Hz, 1H), 5.81 (d, J = 11.6 Hz, 1H), 4.95-4.77 (m, 1H), 4.53-4.25 (m, 4H), 4.21 (s, 3H), 4.04-3.75 (m, 4H), 3.70-3.48 (m, 5H), 3.31-3.18 (m, 4H), 3.08-2.80 (m, 9H), 2.68-2.53 (m, 3H), 2.01-1.90 (m, 1H), 1.87 (s, 5H), 1.82-1.70 (m, 3H), 1.11-0.97 (m, 3H). LCMS(ESI): m/z 실측치 1096.2[M-CF3COOH+H]+.
화합물 78:
(R)-2-(1-아크릴로일-4-(2-((3-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-3-옥소프로필)아미노)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.96(s, 1H), 9.70-9.35(m, 2H), 8.17(s, 1H), 8.00-7.80 (m, 2H), 7.75-7.13(m, 10H), 6.94-6.78(m, 2H), 6.30-6.14 (m, 2H), 5.80(d, J = 11.2 Hz, 1H), 5.00-4.78(m, 1H), 4.52-4.36(m, 3H), 4.25-4.18(m, 2H), 4.12-3.85(m, 7H), 3.35-3.18(m, 5H), 3.08-2.88(m, 9H), 2.69-2.62(m, 3H), 2.59-2.55(m, 2H), 2.06-1.88(m, 2H), 1.79-1.68(m, 2H), 1.32-1.22(m, 2H), 1.10-0.90(m, 8H). LCMS(ESI): m/z 실측치 1014.2[M+H]+.
화합물 79:
(R)-4-(4-((4-((1-(3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.81-9.61(m, 3H), 8.01-7.76(m, 4H), 7.64-7.32(m, 9H), 6.98-6.68(m, 2H), 6.35-6.14(m, 2H), 5.79(d, J = 10.0 Hz, 1H), 5.00-4.75(m, 2H), 4.55-4.20(m, 9H), 3.98-3.78(m, 10H), 3.68-3.32(m, 9H), 3.15-2.85(m, 9H), 2.72-2.59(m, 2H), 1.87(s, 3H), 1.78-1.70(m, 3H), 1.12-0.96(m, 2H). LCMS(ESI): m/z 실측치 1129.3[M-CF3COOH+H]+.
화합물 80:
(R)-4-(4-((4-((1-(3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.90-9.60(m, 3H), 8.05-7.76(m, 3H), 7.64-7.26(m, 9H), 7.16-7.00(m, 1H), 6.94-6.76(m, 1H), 6.67(s, 1H), 6.36-6.16(m, 2H), 5.79(d, J = 10.8 Hz, 1H), 5.07-4.72(m, 2H), 4.46-4.32(m, 4H), 4.05-3.90(m, 11H), 3.65-3.40(m, 7H), 3.18-2.93(m, 9H), 2.71-2.58(m, 5H), 2.31-2.22(m, 2H), 2.05-1.88(m, 1H), 1.80-1.69(m, 2H), 1.18-0.97(m, 2H), 0.88(t, J = 7.6 Hz, 3H). LCMS(ESI): m/z 실측치 1143.3[M-CF3COOH+H]+.
화합물 81
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로펜아미드. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.88 (s, 1H), 9.62 (d, J = 26.0 Hz, 2H), 8.47 (s, 1H), 8.25-8.11 (m, 1H), 8.01-7.89 (m, 1H), 7.75-7.40 (m, 5H), 7.33-6.76 (m, 8H), 6.30-6.09 (m, 3H), 5.79 (d, J = 10.4 Hz, 1H), 5.02-4.75 (m, 1H), 4.44-4.07 (m, 7H), 3.66-3.56 (m, 4H), 3.28-3.12 (m, 4H), 2.95 (d, J = 18.7 Hz, 4H). LCMS(ESI): m/z 실측치 806.8[M+H]+.
화합물 82:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-(트리플루오로메틸)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 12.01 (s, 1H), 9.59 (s, 1H), 9.35 (s, 1H), 8.58 (s, 1H), 8.21-8.12 (m, 1H), 7.98-7.91 (m, 1H), 7.71-7.39 (m, 8H), 7.20 (d, J = 7.6 Hz, 1H), 7.04-6.77 (m, 2H), 6.20 (d, J = 19.2 Hz, 2H), 5.79 (d, J = 9.6 Hz, 1H), 5.02-4.74 (m, 1H), 4.48-4.39 (m, 3H), 4.20 (s, 2H), 3.60-3.57 (m, 3H), 3.38-3.14 (m, 5H), 3.06-2.88 (m, 5H), 2.60-2.54 (m, 3H), 1.03 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 916.8[M-CF3COOH+H]+.
화합물 83:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.95 (d, J = 0.4 Hz, 1H), 9.58 (s, 1H), 9.37 (s, 1H), 8.46 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.83-7.75 (m, 1H), 7.66-6.81 (m, 9H), 6.27-6.15 (m, 2H), 5.78 (d, J = 11.0 Hz, 1H), 4.34-4.20 (m, 4H), 3.82-3.67 (m, 6H), 3.50-3.40 (m, 5H), 3.18-3.00 (m, 4H), 2.71-2.65 (m, 2H), 2.40-2.34 (m, 3H), 1.01 (t, J = 7.2 Hz, 3H). LCMS(ESI): m/z 실측치 886.8[M-CF3COOH+H]+.
화합물 84:
(R)-2-(1-아크릴로일-4-(2-((3-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)-3-옥소프로필)아미노)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.94 (s, 1H), 9.64 (s, 1H), 9.44 (s, 1H), 8.17 (s, 1H), 7.94 (s, 1H), 7.84-7.42 (m, 5H), 7.34-7.07 (m, 5H), 6.81 (m, 2H), 6.36-6.14 (m, 2H), 5.80 (d, J = 10.3 Hz, 1H), 4.89 (m, 1H), 4.26 (m, 7H), 3.80 (d, J = 12.7 Hz, 2H), 3.17 (s, 4H), 2.94 (m, 6H), 2.68 (m, 3H), 1.66 (m, 4H), 1.24 (s, 2H), 1.12-0.77 (m, 8H). LCMS(ESI): m/z 실측치 916.1 [M-CF3COOH+H]+.
화합물 85:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페네틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.94 (s, 1H), 9.62 (s, 1H), 9.41 (s, 1H), 8.16 (s, 2H), 7.96 (s, 1H), 7.79-7.46 (m, 5H), 7.17 (m, 6H), 6.80 (s, 2H), 6.32-6.16 (m, 2H), 5.81 (d, J = 11.0 Hz, 1H), 4.96 (s, 1H), 4.32 (m, 6H), 3.60 (s, 5H), 2.96 (m, 5H), 2.73 (d, J = 7.5 Hz, 3H), 2.43 (s, 3H), 0.97 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 862.0[M-CF3COOH+H]+.
화합물 86:
1-(4-(2-((3-(4-((2-(2,4-디히드록시벤조일)이소인돌린-5-일)메틸)피페라진-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 10.11-9.92 (m, 1H), 9.75 (s, 1H), 7.99 (d, J = 9.0 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.60-7.05 (m, 6H), 6.99-6.68 (m, 3H), 6.40-6.10 (m, 3H), 5.75 (d, J = 11.0 Hz, 1H), 4.79 (s, 4H), 4.35 (s, 3H), 4.20-3.57 (m, 12H), 3.35-3.17 (m, 5H), 2.91 (s, 5H), 2.67 (s, 4H). LCMS(ESI): m/z 실측치 838.4 [M-CF3COOH+H]+.
화합물 87:
(R)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((3-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-3-옥소프로필)아미노)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 9.65-9.48 (m, 2H), 8.06-7.72 (m, 3H), 7.49-7.37 (m, 9H), 7.21 (d, J = 7.1 Hz, 2H), 6.82 (s, 2H), 6.34-6.15 (m, 2H), 5.80 (d, J = 10.6 Hz, 1H), 4.92-4.73 (m, 2H), 4.31-4.45 (m, 3H), 4.29-4.09 (m, 4H), 3.83-3.75 (m, 5H), 3.18-3.11 (s, 3H), 3.05-2.95 (m, 6H), 2.70-2.60 (m, 5H), 2.42 (s, 2H), 2.01-1.88 (m, 2H), 1.75-1.68 (m, 3H), 1.24 (s, 2H), 1.13-1.01 (m, 1H), 0.97 (d, J = 6.9 Hz, 7H). LCMS(ESI): m/z 실측치 1048.5[M-CF3COOH+H]+.
화합물 88:
(R)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((3-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페닐)피페라진-1-일)-3-옥소프로필)아미노)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD): δ 7.92-7.74 (m, 2H), 7.72-7.30 (m, 4H), 7.22-7.05 (m, 4H), 6.95-6.66 (m, 1H), 6.45-6.20 (m, 2H), 5.88 (s, 1H), 5.41 (s, 1H), 3.94-3.50 (m, 8H), 3.30-3.11 (m, 8H), 3.08-2.88 (m, 5H), 2.25-2.01 (m, 1H), 1.43-1.25 (m, 6H), 0.90 (d, J = 6.4 Hz, 6H). LCMS(ESI): m/z 실측치 937.4[M-CF3COOH+H]+.
화합물 89:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로펜아미드. 1H NMR (400 MHz, CD3OD) δ 7.86-7.72 (m, 2H), 7.59-7.14 (m, 8H), 6.90-6.63 (m, 2H), 6.35-6.20 (m, 2H), 5.84 (d, J = 9.4 Hz, 1H), 5.07-4.99 (m, 2H), 4.46-4.22 (m, 3H), 3.87-3.72 (m, 3H), 3.62-3.47 (m, 3H), 3.22-3.14 (m, 2H), 3.02-2.85 (m, 2H), 2.76-2.55 (m, 3H), 2.30 (t, J = 6.8 Hz, 2H), 1.43-1.21 (m, 5H), 0.76 (t, J = 6.0 Hz, 3H). LCMS(ESI): m/z 실측치 882.7[M+H]+.
화합물 90:
(R)-2-(1-아크릴로일-4-(2-((3-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페닐)피페라진-1-일)-3-옥소프로필)아미노)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 8.28-8.19(m, 1H), 7.93-7.85(m, 1H), 7.69-7.43(m, 4H), 7.24-7.06(m, 5H), 6.88-6.62(m, 2H), 6.36-6.24(m, 2H), 5.89-5.79(m, 1H), 5.09-4.96 (m, 1H), 4.53-4.40 (m, 3H), 4.26-4.14(m, 3H), 3.84-3.69(m, 7H), 3.04-2.93(m, 6H), 2.85-2.79(m, 3H), 2.24-1.99(m, 2H), 1.36-1.27(m, 6H), 0.90-0.84(m, 7H). LCMS(ESI): m/z 실측치 904.0M-CF3COOH+H]+.
화합물 91:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.88(s, 1H), 9.54-9.30(m, 2H), 8.50(s, 1H), 8.20-7.90(m, 3H), 7.75-7.43(m, 6H), 7.25-7.05(m, 7H), 6.92-6.78(m, 2H), 6.25-6.16(m, 2H), 5.79(d, J = 10.4 Hz, 1H), 4.98-4.76(m, 1H), 4.34-4.16(m, 6H), 3.69-3.57(m, 6H), 3.02-2.87(m, 5H), 2.35-2.26(m, 4H), 2.04-1.95(m, 1H), 1.51-1.34(m, 3H), 0.88-0.74(m, 4H). LCMS(ESI): m/z 실측치 848.9[M-CF3COOH+H]+.
화합물 92:
(S)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(2-(2-(2-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에톡시)에톡시)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.91(s, 1H), 9.72-9.40(m, 2H), 8.27-7.91(m, 3H), 7.82-7.47(m, 4H), 7.30-6.79(m, 7H), 6.38-6.12(m, 2H), 5.81(d, J = 10.0 Hz, 1H), 5.02-4.80(m, 1H), 4.53-4.39(m , 1H), 4.20(s, 2H), 4.07(s, 2H), 3.78-3.72(m, 5H), 3.61-3.57(m, 6H), 3.28-3.22(m, 8H), 3.03-2.94 (m, 4H), 2.81-2.77(m, 1H), 2.48-2.40(m, 3H), 0.98(d, J = 6.4 Hz, 6H). LCMS(ESI): m/z 실측치 966.5[M-CF3COOH+H]+.
화합물 93:
(S)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(2-(2-(2-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에톡시)에톡시)에틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.91 (s, 1H), 9.75-9.30 (m, 2H), 8.90-7.33(m, 6H), 7.22-6.73 (m, 6H), 6.33-6.15(m, 1H), 5.80 (d, J = 9.2 Hz, 1H), 5.03-4.80(m, 1H), 4.33-4.18 (m, 3H), 4.07(s, 4H), 3.79-3.68 (m, 11H), 3.25-3.11(m, 9H), 3.03-2.94 (m, 3H), 2.81-2.68 (m, 2H), 2.47-2.40(m, 2H), 0.99 (d, J = 6.0 Hz, 6H). LCMS(ESI): m/z 실측치 1000.4[M-CF3COOH+H]+.
화합물 94:
1-(4-(2-((3-(4-((2-(2,4-디히드록시-5-프로필벤조일)이소인돌린-5-일)메틸)피페라진-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산.
1H NMR (400 MHz, DMSO-d 6 ): δ 10.12 (s, 1H), 9.75-9.62 (m, 1H), 7.99 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.50-7.23 (m, 6H), 7.14-6.72 (m, 4H), 6.40 (s, 1H), 6.22-6.11 (m, 1H), 5.79-5.70 (m, 1H), 4.80 (s, 4H), 4.49-4.30 (m, 2H), 4.18-4.07 (m, 2H), 4.06-3.94 (m, 2H), 3.80-3.68 (m, 6H), 3.33-3.16 (m, 6H), 3.00-2.84 (m, 4H), 2.70-2.64 (m, 3H), 2.45-2.37 (m, 3H), 1.55-1.46 (m, 2H), 1.24 (s, 2H), 0.88 (t, J = 7.4 Hz, 4H). LCMS(ESI): m/z 실측치 880.3[M-CF3COOH+H]+.
화합물 95:
(R)-4-(4-((1-(4-((3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)메틸)벤질)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.79 (s, 1H), 9.62 (s, 1H), 9.44 (s, 1H), 8.54 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.72-7.66 (m, 1H), 7.62-7.53 (m, 2H), 7.58-7.41 (m, 3H), 7.39-7.18 (m, 6H), 7.10 (s, 1H), 6.97 (s, 1H), 6.92-6.76 (m, 1H), 6.60 (s, 1H), 6.34 (s, 1H), 6.21(d, J = 14.4 Hz, 1H), 5.84-5.75 (m, 1H), 5.04-4.77(m, 2H), 4.39-4.29 (m, 3H), 4.28-4.15(m, 4H), 4.02-3.89 (m, 4H), 3.39-3.29(m, 4H), 3.24-3.10 (m, 3H), 3.08-2.66 (m, 10H), 1.82-1.63(m, 3H), 1.48-1.32(m, 2H), 1.28-1.15 (m, 2H), 0.82 (d, J = 6.0 Hz, 6H). LCMS(ESI): m/z 실측치 1144.6[M-CF3COOH+H]+.
화합물 96:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.94 (s, 1H), 9.59 (s, 1H), 9.38 (s, 1H), 8.34 (s, 1H), 8.17 (s, 1H), 7.91 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.47 (m, 3H), 7.22 (m, 2H), 7.03 (d, J = 10.8 Hz, 1H), 6.92 (d, J = 7.4 Hz, 3H), 6.58 (s, 1H), 6.26-6.14 (m, 2H), 5.77 (d, J = 11.3 Hz, 1H), 5.00 (s, 1H), 4.76 (s, 1H), 4.40 (s, 1H), 4.27 (d, J = 4.9 Hz, 2H), 4.02 (s, 2H), 3.88 (s, 2H), 3.46 (d, J = 6.8 Hz, 3H), 3.10-2.93 (m, 4H), 2.85 (s, 3H), 2.44 (m, 3H), 1.02 (d, J = 6.9 Hz, 6H). LCMS(ESI): m/z 실측치 866.8 [M-CF3COOH+H]+.
화합물 97:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)-2-플루오로벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.97 (s, 1H), 9.61 (s, 1H), 9.38 (s, 1H), 8.48 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.66-7.20 (m, 6H), 7.12-6.75 (m, 5H), 6.30-6.12 (m, 2H), 5.78 (d, J = 10.6 Hz, 1H), 4.78 (s, 1H), 4.26 (m, 5H), 4.10-3.98 (m, 1H), 3.97-3.63 (m, 6H), 3.01 (m, 6H), 2.67 (s, 2H), 1.02 (d, J = 6.7 Hz, 6H). LCMS(ESI): m/z 실측치 900.8 [M-CF3COOH+H]+.
화합물 98:
(R)-4-(4-((4-((1-(3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.72 (s, 1H), 8.32 (s, 1H), 8.17 (s, 1H), 7.95 (s, 1H), 7.76-7.68 (m, 3H), 7.57-7.55 (m, 2H), 7.49 (t, J = 8.0 Hz, 1H), 7.37 (m, 4H), 7.21 (d, J = 7.4 Hz, 1H), 6.61 (s, 1H), 6.38-6.15 (m, 2H), 5.81 (d, J = 10.2 Hz, 1H), 4.88 (m, 2H), 4.41 (s, 3H), 4.21-4.20 (m, 4H), 4.05-4.03 (m, 2H), 3.82-3.81 (m, 2H), 3.62 (s, 6H), 3.32 (s, 2H), 3.17 (s, 3H), 3.00-2.99 (m, 6H), 2.65 (s, 3H), 2.24 (d, J = 7.2 Hz, 3H), 1.99 (s, 1H), 1.73-1.72 (m, 2H), 1.24-1.23 (m, 2H), 1.00-1.09 (m, 2H), 0.86 (t, J = 7.3 Hz, 4H). LCMS(ESI): m/z 실측치 1028.0 [M-CF3COOH+H]+.
화합물 99:
(R)-4-(4-((4-((1-(3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 1H), 8.32 (s, 1H), 7.98-7.31 (m, 11H), 6.94-6.58 (m, 1H), 6.35-6.16 (m, 1H), 5.80 (d, J = 10.7 Hz, 1H), 5.12-3.90 (m, 12H), 3.93-2.87 (m, 16H), 2.72-2.59 (m, 2H), 2.30-2.20 (m, 3H), 1.97 (s, 2H), 1.81-1.60 (m, 3H), 1.34-0.95 (m, 6H), 0.86 (t, J = 7.4 Hz, 5H). LCMS(ESI): m/z 실측치 1061.5[M-CF3COOH+H]+.
화합물 100:
(R)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((3-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)-3-옥소프로필)아미노)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.98 (s, 1H), 10.47-9.11 (m, 3H), 7.97-7.65 (m, 2H), 7.64-7.05 (m, 8H), 6.89-6.75 (m, 2H), 6.29-6.15 (m, 2H), 5.85-5.72 (m, 1H), 4.56-2.73 (m, 28H), 1.00 (d, J = 6.3 Hz, 9H). LCMS(ESI): m/z 실측치 951.4[M-CF3COOH+H]+.
화합물 101:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-((1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페리딘-4-일)메틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.98 (s, 1H), 9.69-9.25 (m, 3H), 8.25-7.88 (m, 3H), 7.69 (d, J = 7.9 Hz, 1H), 7.59-7.44 (m, 5H), 7.31-7.18 (m, 3H), 6.87 (s, 2H), 6.30-6.15 (m, 2H), 5.80 (d, J = 10.3 Hz, 1H), 5.01-4.76 (m, 1H), 4.30-4.15 (m, 6H), 4.01-3.92 (m, 3H), 3.63-3.55 (s, 5H), 3.38-3.21 (m, 6H), 3.02-2.91 (m, 9H), 2.45-2.37 (m, 4H), 1.82-1.57 (m, 7H), 1.07-0.80 (m, 8H). LCMS(ESI): m/z 실측치 1057.1[M-CF3COOH+H]+.
화합물 102:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-((1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페리딘-4-일)메틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.98(s, 1H), 9.69-9.27(m, 3H), 8.03-7.91(m, 2H), 7.82-7.76(m, 1H), 7.647.23(m, 9H), 6.92-6.78(m, 2H), 6.30-6.15(m, 2H), 5.79(d, J = 10.4 Hz, 1H), 4.38-4.16(m, 6H), 3.95-3.76(m, 6H), 3.62-3.44(m, 7H), 3.15-2.90(m, 10H), 2.70-2.63(m, 1H), 2.35-2.30(m, 2H), 1.82-1.29(m, 8H), 1.05-0.85(m, 10H). LCMS(ESI): m/z 실측치 1090.8[M-CF3COOH+H]+.
화합물 103:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-((1-(1-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페리딘-4-일)메틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.96(s, 1H), 9.67-9.26(m, 3H), 8.19-8.14(m, 1H), 8.05-7.90(m, 2H), 7.71-7.44(m, 7H), 7.29-7.19(m, 3H), 6.96-6.80(m, 2H), 6.27-6.17(m, 2H), 5.80(d, J = 12.4 Hz, 1H), 5.00-4.75(m, 1H), 4.46-4.16(m, 8H), 4.08-3.91(m, 3H), 3.74-3.66(m, 3H), 3.39-3.25(m, 5H), 3.07-2.83(m, 11H), 2.44-2.33(m, 4H), 1.89-1.58(m, 7H), 1.08-0.86(m, 5H). LCMS(ESI): m/z 실측치 1042.5[M-CF3COOH+H]+.
화합물 104:
(R)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-((1-(1-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페리딘-4-일)메틸)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 11.96(s, 1H), 9.66-9.29(m, 3H), 7.97-7.91(m, 2H), 7.80-7.75(m, 1H), 7.66-7.21(m, 9H), 6.95-6.75(m, 2H), 6.29-6.13(m, 2H), 5.79(d, J = 11.2 Hz, 1H), 4.41-4.16(m, 6H), 4.10-3.88(m, 3H), 3.57-3.51(m, 4H), 3.16-2.84(m, 13H), 2.70-2.63(m, 2H), 2.42-2.32(m, 5H), 1.90-1.54(m, 8H), 1.09-0.80(m, 6H). LCMS(ESI): m/z 실측치 1076.5[M-CF3COOH+H]+.
화합물 105:
1-(4-(2-((3-(4-((2-(2,4-디히드록시벤조일)-4-플루오로이소인돌린-5-일)메틸)피페라진-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 10.34 (s, 1H), 9.77 (s, 2H), 7.99 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.44-7.14 (m, 5H), 6.94-6.70 (m, 3H), 6.43-6.11 (m, 3H), 5.75 (d, J = 10.6 Hz, 1H), 4.85 (s, 4H), 4.38-4.11 (m, 4H), 3.92-3.68 (m, 10H), 3.65-3.54 (m, 6H), 2.98-2.63 (m, 9H). LCMS(ESI): m/z 실측치 856.8[M-CF3COOH+H]+.
화합물 106:
1-(4-(2-((3-(4-((2-(2,4-디히드록시벤조일)-4-플루오로이소인돌린-5-일)메틸)피페라진-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산.
1H NMR (400 MHz, DMSO-d 6 ): δ 10.34 (s, 1H), 9.77 (s, 2H), 7.99 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.44-7.14 (m, 5H), 6.94-6.70 (m, 3H), 6.43-6.11 (m, 3H), 5.75 (d, J = 10.6 Hz, 1H), 4.85 (s, 4H), 4.38-4.11 (m, 4H), 3.92-3.68 (m, 10H), 3.65-3.54 (m, 6H), 2.98-2.63 (m, 9H). LCMS(ESI): m/z 실측치 856.8[M-CF3COOH+H]+.
화합물 107:
1-(4-(2-((3-(4-((2-(2,4-디히드록시-5-메틸벤조일)-4-플루오로이소인돌린-5-일)메틸)피페라진-1-일)-3-옥소프로필)아미노)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-1-일)프로프-2-엔-1-온, 트리플루오로아세트산.
1H NMR (400 MHz, DMSO-d 6 ): δ 10.05 (s, 1H), 9.72 (d, J = 27.4 Hz, 2H), 7.99 (d, J = 8.6 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.45-7.16 (m, 5H), 7.07-6.71 (m, 5H), 6.41 (s, 1H), 6.17 (d, J = 14.8 Hz, 1H), 5.74 (d, J = 12.0 Hz, 1H), 4.84 (s, 4H), 4.50-4.25 (m, 2H), 4.13 (s, 2H), 3.84-3.67 (m, 10H), 3.29-3.21 (m, 4H), 3.00-2.83 (m, 6H), 2.70-2.64 (m, 3H), 2.03 (s, 3H). LCMS(ESI): m/z 실측치 870.3[M-CF3COOH+H]+.
화합물 108:
(R)-4-(4-((1-(4-(2-(3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)에틸)벤질)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. , 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.79 (s, 1H), 9.61 (t, J = 6.6 Hz, 1H), 9.40 (s, 1H), 8.20-8.08 (m, 2H), 7.97-7.91 (m, 1H), 7.69 (d, J = 8.2 Hz, 1H), 7.55-7.54 (m, 2H), 7.52-7.46 (m, 1H), 7.41 (d, J = 7.9 Hz, 2H), 7.26 (m, 7H), 6.60 (s, 1H), 6.34 (s, 1H), 6.21 (m, 1H), 5.80 (d, J = 12.2 Hz, 1H), 4.89 (d, J = 48.9 Hz, 2H), 4.37 (s, 3H), 4.21 (d, J = 11.1 Hz, 4H), 3.98-3.93 (m, 2H), 3.58 (s, 2H), 3.31 (s, 4H), 3.21-3.12 (m, 2H), 2.92 (m, 7H), 2.78-2.72 (m, 2H), 2.54 (s, 2H), 2.43 (d, J = 6.5 Hz, 2H), 1.76 (d, J = 10.7 Hz, 4H), 1.40 (d, J = 5.8 Hz, 2H), 0.82 (d, J = 6.9 Hz, 6H). LCMS(ESI): m/z 실측치 1158.6 [M-CF3COOH+H]+.
화합물 109:
(R)-4-(4-(((4-((4-(3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페라진-1-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 10.17 (s, 1H), 9.70 (d, J = 27.9 Hz, 2H), 8.15 (s, 1H), 7.99-7.89 (m, 1H), 7.77-7.37 (m, 9H), 7.21 (d, J = 7.4 Hz, 1H), 6.75 (s, 2H), 6.35-6.14 (m, 2H), 5.80 (d, J = 11.8 Hz, 1H), 4.95 (s, 2H), 4.43 (s, 3H), 4.19 (s, 6H), 3.94 (dd, J = 16.1, 9.0 Hz, 4H), 3.61 (s, 5H), 3.28 (d, J = 50.5 Hz, 6H), 2.96 (d, J = 20.5 Hz, 6H), 2.68 (s, 3H), 2.00 (d, J = 7.6 Hz, 1H), 1.58 (s, 2H), 0.87 (dd, J = 20.6, 6.3 Hz, 5H). LCMS(ESI): m/z 실측치 1160.1 [M-CF3COOH+H]+.
화합물 110:
(R)-4-(4-(((4-((1-(3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.88 (s, 1H), 9.69 (d, J = 8.5 Hz, 2H), 8.17 (s, 1H), 7.96 (s, 2H), 7.69 (d, J = 7.6 Hz, 2H), 7.60-7.18 (m, 12H), 6.76 (s, 2H), 6.29 (s, 1H), 6.20 (d, J = 17.0 Hz, 1H), 5.80 (d, J = 10.5 Hz, 1H), 4.90-4.81 (m, 1H), 4.40 (s, 6H), 4.21 (s, 6H), 3.96 (s, 3H), 3.83 (s, 1H), 3.59 (s, 4H), 3.21 (s, 3H), 2.95 (d, J = 16.9 Hz, 5H), 2.63 (s, 3H), 1.59 (s, 1H), 1.13 (s, 2H), 0.90 (d, J = 6.2 Hz, 6H). LCMS(ESI): m/z 실측치 1158.3 [M-CF3COOH+H]+.
화합물 111:
(S)-3-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)-N-(4-(3-(2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로판아미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 11.89 (s, 1H), 9.75-9.50 (m, 2H), 8.59-8.38 (m, 1H), 8.03-7.67 (m, 3H), 7.65-7.31 (m, 4H), 7.26-7.00 (m, 5H), 6.95-6.75 (m, 1H), 6.28-6.12 (m, 3H), 5.79 (d, J = 10.3 Hz, 1H), 5.08-4.70 (m, 2H), 4.46-4.18 (m, 6H), 3.88-3.56 (m, 8H), 3.18-2.88 (m, 5H), 2.71-2.64 (m, 1H). LCMS(ESI): m/z 실측치 840.3[M-CF3COOH+H]+.
화합물 112:
4-(4-(((4-((1-(3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.82-9.58 (m, 3H), 7.99 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.8 Hz, 2H), 7.62-7.06 (m, 12H), 6.90 (s, 1H), 6.76 (s, 2H), 6.30 (s, 1H), 4.51-4.31 (m, 4H), 4.26-4.12 (m, 5H), 4.01-3.78 (m, 6H), 3.62 (s, 6H), 3.30-3.20 (m, 2H), 3.08-2.85 (m, 4H), 2.70-2.62 (m, 2H), 2.58-2.53 (m, 4H), 2.05 (s, 4H), 1.84-1.74 (m, 1H), 1.65-1.52 (m, 2H), 1.27-0.97 (m, 2H), 0.90 (d, J = 6.6 Hz, 6H). LCMS(ESI): m/z 실측치 1123.3[M-CF3COOH+H]+.
화합물 113:
4-(4-(((4-((1-(3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.77-9.62 (m, 3H), 7.99 (d, J = 9.2 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.59-7.24 (m, 11H), 6.89 (s, 1H), 6.75 (s, 2H), 6.28 (s, 1H), 4.50-4.33 (m, 3H), 4.25-4.12 (m, 4H), 4.03-3.92 (m, 4H), 3.89-3.78 (m, 6H), 3.67-3.57 (m, 9H), 3.30-3.21 (m, 2H), 3.02-2.86 (m, 3H), 2.70-2.62 (m, 3H), 2.36-2.23 (m, 3H), 2.05 (s, 3H), 1.84-1.73 (m, 1H), 1.65-1.52 (m, 2H), 1.24 (s, 2H), 0.91 (t, J = 7.2 Hz, 3H). LCMS(ESI): m/z 실측치 1109.3[M-CF3COOH+H]+.
화합물 114:
4-(4-(((4-((1-(3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.85-9.62(m, 3H), 7.99(d, J = 8.4 Hz, 1H), 7.69(d, J = 8.4 Hz, 1H), 7.55-7.23(m, 11H), 6.90(s, 1H), 6.81-6.74(m, 2H), 6.26(s, 1H), 4.52-4.33(m, 4H), 4.25-4.13(m, 5H), 4.01-3.85(m, 7H), 3.68-3.56(m, 7H), 3.29-3.20(m, 2H), 3.00-2.86(m, 3H), 2.70-2.60(m, 3H), 2.55-2.52(m, 4H), 2.05(s, 3H), 1.88(s, 3H), 1.83-1.71(m, 1H), 1.65-1.53(m, 2H), 1.16-1.95(m, 2H). LCMS(ESI): m/z 실측치 1095.3[M-CF3COOH+H]+.
화합물 115:
4-(4-(((4-((4-(3-((4-(4-아세틸피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페라진-1-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.80-9.65(m, 2H), 7.99(d, J = 8.8 Hz, 1H), 7.75-7.25(m, 11H), 6.89(s, 1H), 6.75(s, 1H), 6.30(s, 1H), 4.52-4.41(m, 2H), 4.32-4.41(m, 3H), 4.17-4.09(m, 3H), 4.00-3.90(m, 4H), 3.61-3.53(m, 17H), 3.30-3.20(m, 4H), 3.02-2.82(m, 6H), 2.72-2.64(m, 4H), 2.05(s, 3H), 0.95-0.85(m, 6H). LCMS(ESI): m/z 실측치 1124.3[M-CF3COOH+H]+.
화합물 116:
N-시클로프로필-5-(5-에틸-2,4-디히드록시페닐)-4-(4-((4-((1-(3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.81-9.69(m, 2H), 9.07(d, J = 4.4 Hz, 1H), 7.99(d, J = 8.4 Hz, 1H), 7.69(d, J = 8.4 Hz, 2H), 7.46-4.25(m, 6H), 6.90(s, 1H), 6.75(s, 1H), 6.63(s, 1H), 6.30(s, 1H), 4.43-4.35(m, 2H), 4.20-4.13(m, 3H), 3.94-3.76(m, 7H), 3.68-3.56(m, 8H), 3.29-3.20(m, 2H), 3.07-2.86(m, 7H), 2.76-2.61(m, 3H), 2.40-2.33(m, 4H), 2.30-2.18(m, 4H), 1.81-1.69(m, 3H), 1.05-0.98(m, 4H), 0.89-0.84(m, 3H), 0.66-0.57(m, 4H). LCMS(ESI): m/z 실측치 1046.4 [M-CF3COOH+H]+.
화합물 117:
5-(5-에틸-2,4-디히드록시페닐)-4-(4-((4-((1-(3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-N-(펜탄-3-일)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.74 (d, J = 27.7 Hz, 1H), 8.65 (d, J = 9.2 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.47-7.23 (m, 5H), 6.90 (s, 1H), 6.75 (d, J = 1.6 Hz, 1H), 6.70-6.61 (m, 1H), 6.31 (s, 1H), 4.43-4.35 (m, 1H), 4.15 (s, 2H), 3.99-3.76 (m, 9H), 3.71-3.47 (m, 14H), 3.25 (s, 3H), 3.10-2.83 (m, 8H), 2.71-2.61 (m, 2H), 2.42-2.19 (m, 6H), 1.84-1.67 (m, 2H), 1.55-1.34 (m, 4H), 1.02 (t, J = 7.4 Hz, 4H), 0.93-0.84 (m, 3H), 0.78 (t, J = 7.3 Hz, 6H). LCMS(ESI): m/z 실측치 1076.4[M-CF3COOH+H]+.
화합물 118:
(R)-4-(4-(((4-((1-(3-((4-(4-아세틸-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD) δ 8.22 (d, J = 8.9 Hz, 1H), 7.91-7.85 (m, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.58-7.48 (m, 5H), 7.47-7.44 (m, 2H), 7.38 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 7.4 Hz, 1H), 6.78 (s, 1H), 6.24 (s, 1H), 5.02-4.93 (m, 2H), 4.75-4.36 (m, 7H), 4.23 (s, 3H), 4.03-3.92 (m, 3H), 3.81-3.64 (m, 4H), 3.16-2.87 (m, 7H), 2.82-2.67 (m, 6H), 2.66-2.58 (m, 2H), 2.40-2.25 (m, 3H), 2.21-2.16 (m, 2H), 1.86 (s, 1H), 1.75-1.61 (m, 2H), 1.39-1.12 (m, 6H), 0.95 (t, J = 7.6 Hz, 3H). LCMS(ESI): m/z 실측치 1132.5[M-CF3COOH+H]+.
화합물 119:
5-(5-에틸-2,4-디히드록시페닐)-4-(4-((4-((1-(3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-N-(1,1,1-트리플루오로프로판-2-일)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ): δ 9.93-9.53 (m, 3H), 7.99 (d, J = 8.4 Hz, 1H), 7.88-7.66(m, 2H), 7.55-7.20 (m, 6H), 6.90 (s, 1H), 6.79-6.65 (m, 2H), 6.30 (s, 1H), 4.71-4.58 (m, 1H), 4.39 (d, J = 14.4 Hz, 1H), 4.16 (s, 2H), 3.96-3.72 (m, 6H), 3.70-3.37 (m, 10H), 3.25 (s, 2H), 3.11-2.83 (m, 7H), 2.72-2.56 (m, 2H), 2.45-2.21 (m, 8H), 2.09-1.95 (m, 1H), 1.75 (d, J = 11.6 Hz, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.19-1.07 (m, 1H), 1.02 (t, J = 7.4 Hz, 4H), 0.89 (t, J = 7.4 Hz, 3H). LCMS(ESI): m/z 실측치 1103.0[M-CF3COOH+H]+.
화합물 120:
5-(5-에틸-2,4-디히드록시페닐)-4-(4-((4-((1-(3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-N-(1-메틸시클로프로필)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.70 (s, 1H), 9.64 (s, 1H), 9.09 (s, 1H), 8.00 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.32 (m, 7H), 6.84 (s, 1H), 6.74 (s, 1H), 6.55 (s, 2H), 6.31 (s, 1H), 4.36 (d, J = 11.8 Hz, 1H), 3.97 (s, 3H), 3.57-3.56 (m, 4H), 3.47-3.45 (m, 6H), 3.31 (s, 3H), 3.23-3.20 (m, 2H), 2.96-2.95 (m, 1H), 2.79 (s, 2H), 2.36 (d, J = 7.4 Hz, 9H), 2.21 (d, J = 7.4 Hz, 3H), 2.10 (s, 3H), 1.67 (m, 2H), 1.23 (s, 4H), 1.01 (m, 5H), 0.83-0.82 (m, 5H), 0.63-0.62 (m, 2H), 0.52-0.51 (m, 2H). LCMS(ESI): m/z 실측치 1060.4 [M-CF3COOH+H]+.
화합물 121:
N-에틸-5-(5-에틸-2,4-디히드록시페닐)-4-(4-((4-((1-(3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.73 (s, 2H), 9.01 (t, J = 5.8 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.86 (s, 1H), 7.69 (d, J = 8.3 Hz, 1H), 7.41 (t, J = 7.4 Hz, 3H), 7.37-7.26 (m, 3H), 6.90 (s, 1H), 6.76 (s, 1H), 6.62 (s, 1H), 6.31 (s, 1H), 4.39 (d, J = 13.0 Hz, 1H), 4.17 (s, 2H), 3.88 (d, J = 12.8 Hz, 7H), 3.63 (s, 8H), 3.31-3.13 (m, 6H), 2.97 (d, J = 28.2 Hz, 8H), 2.74-2.53 (m, 6H), 2.37 (dd, J = 14.9, 7.4 Hz, 4H), 2.25 (dd, J = 14.8, 7.4 Hz, 3H), 1.99 (s, 1H), 1.75 (d, J = 9.2 Hz, 2H), 1.13-0.95 (m, 9H), 0.87 (t, J = 7.4 Hz, 3H). LCMS(ESI): m/z 실측치 1034.4 [M-CF3COOH+H]+.
화합물 122:
(R)-4-(4-(((4-((1-(3-((4-(4-아세틸-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 10.08 (s, 1H), 9.83 (s, 1H), 9.60 (t, J = 6.3 Hz, 1H), 8.18 (s, 1H), 7.97-7.85 (m, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.53 (s, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.22 (dd, J = 19.3, 8.2 Hz, 5H), 7.10 (d, J = 7.6 Hz, 2H), 6.64 (s, 1H), 6.55 (s, 1H), 6.38 (s, 1H), 4.91 (s, 1H), 4.53 (s, 1H), 4.36 (d, J = 12.2 Hz, 2H), 4.13-3.72 (m, 8H), 3.46 (d, J = 20.4 Hz, 6H), 3.17-2.76 (m, 8H), 2.68 (s, 1H), 2.44 (t, J = 10.6 Hz, 3H), 2.21-2.00 (m, 6H), 1.79 (s, 3H), 1.71 (s, 1H), 1.55 (d, J = 11.8 Hz, 2H), 1.23 (s, 3H), 1.00 (dd, J = 35.9, 11.1 Hz, 2H). LCMS(ESI): m/z 실측치 1118.5 [M-CF3COOH+H]+.
화합물 123:
(R)-4-(4-(((4-((1-(3-((4-(4-아세틸-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페리딘-4-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.97 (s, 1H), 9.80-9.60 (m, 2H), 8.17 (s, 1H), 7.99-7.91 (m, 1H), 7.87-7.17 (m, 13H), 6.76 (s, 1H), 6.30 (s, 1H), 4.85 (s, 1H), 4.62-4.15 (m, 10H), 4.04-3.78 (m, 5H), 3.36-3.11 (m, 4H), 3.10-2.87 (m, 5H), 2.70-2.52 (m, 8H), 2.23-1.94 (m, 4H), 1.85-1.71 (m, 1H), 1.67-1.50 (m, 2H), 1.37-1.06 (m, 4H), 1.05-0.82 (m, 7H). LCMS(ESI): m/z 실측치 1146.5[M-CF3COOH+H]+.
화합물 124:
(R)-4-(4-(((4-((4-(3-((4-(4-아세틸-3-(시아노메틸)피페라진-1-일)-7-(나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로파노일)피페라진-1-일)메틸)벤질)(메틸)아미노)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 10.45 (s, 1H), 9.75 (s, 1H), 9.60 (t, J = 6.0 Hz, 1H), 8.17 (s, 1H), 7.96-7.86 (m, 1H), 7.66-7.14 (m, 13H), 6.64-6.50 (m, 2H), 6.33 (s, 1H), 4.55-4.30 (m, 1H), 4.10-3.74 (m, 6H), 3.56-3.41 (m, 9H), 3.10-2.79 (m, 7H), 2.75-2.60 (m, 1H), 2.60-2.51 (m, 3H), 2.31 (s, 4H), 2.18-1.93 (m, 7H), 1.23 (s, 5H), 0.77 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 1147.6[M-CF3COOH+H]+.
화합물 125:
4-(4-((1-(4-((3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)메틸)벤질)피페리딘-4-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.47-7.23 (m, 10H), 6.92-6.75 (m, 2H), 6.58 (s, 1H), 6.35-6.24 (m, 2H), 5.85-5.75 (m, 1H), 5.40-5.23 (m, 1H), 4.42 (s, 1H), 4.30-4.15 (m, 3H), 4.04-3.75 (m, 10H), 3.50-3.15 (m, 6H), 3.03-2.80 (m, 3H), 2.70-2.60 (m, 3H), 2.30-2.22 (m, 1H), 1.95-1.80 (m, 2H), 1.30 (s, 8H), 0.86 (t, J = 7.4 Hz, 3H). LCMS(ESI): m/z 실측치 1107.3[M-CF3COOH+H]+.
화합물 126:
4-(4-((1-(4-((3-((4-(4-아크릴로일피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)메틸)벤질)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-이소프로필-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, DMSO-d 6 ) δ 9.90-9.74 (m, 2H), 9.61-9.37 (m, 1H), 8.80 (s, 1H), 8.54 (s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.50-7.25 (m, 9H), 6.94-6.74 (m, 2H), 6.63-6.54 (m, 1H), 6.34 (s, 1H), 6.28-6.10 (m, 1H), 5.75 (d, J = 10.7 Hz, 1H), 4.35-4.12 (m, 7H), 3.94-3.60 (m, 20H), 3.35-3.23 (s, 3H), 2.97-2.82 (m, 4H), 2.38-2.30 (m, 3H), 1.81-1.68 (m, 2H), 1.45-1.37 (m, 1H), 1.24 (s, 1H), 1.13-1.02 (m, 4H), 0.81 (d, J = 6.8 Hz, 6H). LCMS(ESI): m/z 실측치 1081.5[M-CF3COOH+H]+.
화합물 127:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2,2,2-트리플루오로아세틸)피페라진-2-일)아세토니트릴. 1H NMR (CD3OD, 400 MHz): δ 7.71 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.0, 2.0 Hz, 1H), 7.43-7.34 (m, 4H), 7.28-7.14 (m, 4H), 6.63 (s, 1H), 6.16 (s, 1H), 4.58-3.21 (m, 13H), 3.06-2.69 (m, 15H), 2.54-2.43 (m, 4H), 2.16-2.09 (m, 1H), 1.89-1.84 (m , 2H), 1.07-0.98 (m, 2H), 0.82 (d, J = 6.8 Hz, 6H); LC-MS: m/z 1019.4 [M+H]+.
화합물 128:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-프로피오닐피페라진-2-일)아세토니트릴. 1H NMR (CD3OD, 400 MHz): δ 7.83 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 8.0 Hz, 3.6 Hz, 1H), 7.55-7.45 (m, 4H), 7.38 (t, J = 8.0 Hz, 1H), 7.34-7.26 (m, 4H), 6.75 (s, 1H), 6.28 (s, 1H), 5.06-4.89 (m, 1H), 4.70-4.53 (m, 3H), 4.16 (dd, J = 16.8 Hz, 5.2 Hz, 1H), 4.07-3.43 (m, 8H), 3.23-2.82 (m, 10H), 2.66-2.47 (m, 11H), 2.34 (d, J = 7.2 Hz, 2H), 1.87-1.78 (m, 3H), 1.19-1.15 (m, 3H), 0.94 (d, J = 7.2 Hz, 6H). LC-MS: m/z 979.4 [M+H]+.
화합물 129:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴. 1H NMR (CD3OD, 400 MHz): δ 7.76 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.49-7.41 (m, 4H), 7.32-7.22 (m, 4H), 6.69 (s, 1H), 6.15 (s, 1H), 5.32-5.21 (m, 2H), 4.47-3.37 (m, 12H), 3.17-2.86 (m, 16H), 2.66-2.58 (m, 4H), 2.01-1.96 (m, 1H), 1.89-1.83 (m, 2H), 1.28-1.21 (m, 2H), 0.85 (d, J = 6.8 Hz, 6H); LC-MS: m/z 665.4 [M+H]+.
화합물 130:
N-(2-(2-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)페녹시)에톡시)에틸)-5-(6-플루오로-7-(2-플루오로-6-히드록시페닐)-4-((S)-2-메틸-4-프로피오닐피페라진-1-일)-2-옥소피리도[2,3-d]피리미딘-1(2H)-일)피콜린아미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.89 (s, 1H), 10.13 (s, 1H), 9.62 (s, 1H), 9.48 (s, 1H),8.78 (t, J = 6.0 Hz, 1H), 8.58 (s, 1H), 8.26 (dd, J = 8.8 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 7.97-7.94 (m, 1H), 7.29-7.23 (m, 1H), 7.08 (d, J = 9.2 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.82 (s, 1H), 6.74-6.68 (m, 2H), 6.25 (s, 1H), 4.86 (s, 1H) 4.369-4.23 (m, 2H), 4.08-3.38 (m, 11H), 3.14-2.95 (m, 2H), 2.41-2.34 (m, 2H), 1.39-1.23 (m, 3H), 1.07-0.97 (m, 9H). LC-MS: m/z 947.4 [M+H]+.
화합물 131:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-((4-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2,2,2-트리플루오로아세틸)피페라진-2-일)아세토니트릴. 1H NMR (CD3OD, 400 MHz): δ 7.71 (d, J = 8.0 Hz, 1H), 7.56-7.54 (m, 1H), 7.43-7.17 (m, 6H), 7.13 (d, J = 8.0 Hz, 2H), 6.63 (s, 1H), 6.13 (s, 1H), 4.93-4.85 (m, 1H), 4.58-4.55 (m, 2H), 4.16 (d, J = 16.8 Hz, 1H), 3.98-3.42 (m, 8H), 3.06-2.69 (m, 9H), 2.55-2.37 (m, 8H), 2.25 (q, J = 8.0 Hz, 2H), 2.21-2.11 (m, 2H),1.94-1.62 (m, 3H), 1.070.98 (m, 2H), 0.85 (t, J = 7.8 Hz, 3H). LC-MS: m/z 1005.4 [M+H]+.
화합물 132:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴. 1H NMR (CD3OD, 400 MHz): δ 7.83 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 8.0, 2.8 Hz, 1H), 7.55-7.45 (m, 4H), 7.40-7.25 (m, 4H), 6.75 (s, 1H), 6.28 (s, 1H), 5.38-5.33 (m, 2H), 4.83-4.76 (m, 2H), 4.31-3.50 (m, 11H), 3.18-2.53 (m, 16H), 1.99-1.94 (m, 2H), 1.52-1.32 (m, 4H), 0.94 (d, J = 6.8 Hz, 6H); LC-MS: m/z 1006.1 [M+H]+.
화합물 133:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-((4-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-프로피오닐피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (CD3OD, 400 MHz): δ 7.87 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 7.60-7.50 (m, 4H), 7.42 (t, J = 8.0 Hz, 1H), 7.39-7.32 (m, 4H), 6.82 (s, 1H), 6.24 (s, 1H), 5.02-4.90 (m, 1H), 4.79-4.73 (m, 1H), 4.57-4.39 (m, 5H), 4.02-3.49 (m, 8H), 3.32-2.86 (m, 14H), 2.76 (s, 2H), 2.52-2.48 (m, 2H), 2.41 (q, J = 7.6 Hz, 2H), 2.11 (s, 1H), 1.98-1.94 (m, 2H), 1.39-1.29 (m, 2H), 1.19-1.15 (m, 3H), 1.00 (t, J = 7.6 Hz, 3H). LC-MS: m/z 965.5 [M-CF3COOH+H]+.
화합물 134:
(S)-N-(3-((7-(8-클로로나프탈렌-1-일)-4-(3-(시아노메틸)-4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로필)-1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복사미드, 트리플루오로아세트산. 1H NMR (CD3OD, 400 MHz): δ 7.86 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 8.0 Hz, 2.4 Hz, 1H), 7.59-7.50 (m, 4H), 7.43-7.36 (m, 4H), 6.89 (s, 1H), 6.24 (s, 1H), 5.04-4.92 (m, 1H), 4.78-4.31 (m, 7H), 4.01-3.50 (m, 9H), 3.30-2.49 (m, 13H), 2.08-1.85 (m, 6H), 1.18-1.14 (m, 3H), 1.03 (d, J = 7.2 Hz, 6H). LC-MS: m/z 981.5 [M-CF3COOH+H]+.
화합물 135:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-((4-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴. 1H NMR (CD3OD, 400 MHz): δ 7.87 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.60-7.50 (m, 4H), 7.44-7.33 (m, 4H), 6.82 (s, 1H), 6.24 (s, 1H), 5.43-5.32 (m, 2H), 4.558-4.4 (m, 5H), 4.02-3.50 (m, 9H), 3.17-2.71 (m, 17H), 2.41 (q, J = 7.2 Hz, 2H), 2.15-2.06 (m, 1H), 1.97-1.95 (m, 2H), 1.38-1.29 (m, 2H), 1.00 (t, J = 7.6 Hz, 3H); LC-MS: m/z 981.4 [M+H]+.
화합물 136:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2,2,2-트리플루오로아세틸)피페라진-2-일)아세토니트릴. 1H NMR (CD3OD, 400 MHz): δ 7.83 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.55-7.45 (m, 4H), 7.40-7.26 (m, 4H), 6.75 (s, 1H), 6.28 (s, 1H), 5.07-5.00 (m, 2H), 4.30-3.38 (m, 11H), 3.26-2.58 (m, 20H), 2.06-1.97 (m, 2H), 1.64-1.42 (m, 2H), 0.94 (d, J = 6.8 Hz, 6H); LC-MS: m/z 1005.4 [M+H]+.
화합물 137:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)메틸)피페리딘-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴, 아세트산.
1H NMR (CD3OD, 400 MHz): δ 7.80 (d, J = 8.0 Hz, 1H), 7.65-7.62 (m, 1H), 7.52-7.26 (m, 6H), 7.20 (d, J = 8.0 Hz, 2H), 6.68 (s, 1H), 6.27 (s, 1H), 5.34-5.26 (m, 2H), 4.68 (d, J = 10.8 Hz, 2H), 4.27-3.46 (m, 11H), 3.16-2.50 (m, 17H), 1.81-1.74 (m, 4H), 1.91 (s, 3H), 1.76-1.74 (m, 4H), 1.47-1.37 (m, 2H), 1.21-1.14 (m, 2H), 0.88 (d, J = 6.8 Hz, 6H); LC-MS: m/z 994.5 [M-CH3COOH+H]+.
화합물 138:
(S)-4-(4-((4-((1-(7-(8-클로로나프탈렌-1-일)-4-(3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (CD3OD, 400 MHz): δ 7.74 (d, J = 8.4 Hz, 1H), 7.59-7.56 (m, 1H), 7.46-7.20 (m, 8H), 6.56 (s, 1H), 6.21 (s, 1H), 5.28-5.17 (m, 2H), 4.59 (d, J = 12.8 Hz, 2H), 4.21-4.16 (m, 1H), 4.00-3.88 (m, 10H), 3.19-2.43 (m, 19H), 2.25-2.20 (m, 4H), 1.75-1.70 (m, 2H), 1.27-1.05 (m, 2H), 0.83 (t, J = 7.2 Hz, 3H); LC-MS: m/z 1090.5 [M+H]+.
화합물 139:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((S)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.94 (s, 1H), 9.62 (d, J = 11.2 Hz, 1H), 9.43 (d, J = 10.4 Hz, 1H), 7.92-7.84 (m, 1H), 7.75-7.72 (m, 1H), 7.58-7.29 (m, 5H), 7.14-7.03 (m, 3H), 6.83 (brs, 1H), 6.73 (d, J = 12.4 Hz, 2H), 6.27 (d, J = 11.6 Hz, 1H), 6.18 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 4.96-4.75 (m, 1H), 4.30-3.69 (m, 8H), 3.51-3.48 (m, 3H), 3.18-2.79 (m, 10H), 2.63-2.57 (m, 1H), 2.41-2.35 (m, 1H), 2.03-1.82 (m, 6H), 1.63-1.46 (m, 5H), 0.91 (t, J = 7.2 Hz, 6H). LC-MS: m/z 1006.4 [M+H]+.
화합물 140:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((S)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-프로피오닐피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.94 (s, 1H), 9.59 (d, J = 12.4 Hz, 1H), 9.43 (d, J = 10.4 Hz, 1H), 7.92-7.84 (m, 1H), 7.75-7.72 (m, 1H), 7.58-7.28 (m, 5H), 7.14-7.03 (m, 3H), 6.74 (d, J = 10.4 Hz, 1H), 6.27 (d, J = 12.4 Hz, 1H), 4.89-4.55 (m, 1H), 4.38-3.70 (m, 8H), 3.53-3.45 (m, 3H), 3.48-2.51 (m, 13H), 2.44-2.32 (m, 3H), 1.99-1.45 (m, 10H), 1.02 (brs, 3H), 0.91 (t, J = 6.8 Hz, 6H). LC-MS: m/z 1008.5 [M+H]+.
화합물 141:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-프로피오닐피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.59 (s, 1H), 9.41 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.53 (q, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.33 (dd, J = 16.0 Hz, J = 8.0 Hz, 1H), 7.30 (d, J = 7.2 Hz, 2H), 7.13 (d, J = 7.2 Hz, 2H), 6.76 (s, 1H), 6.26 (s, 1H), 4.92-4.54 (m, 1H), 4.39-4.13 (m, 3H), 4.03-3.46 (m, 9H), 3.27-2.54 (m, 14H), 2.44-2.32 (m, 3H), 2.06-1.93 (m, 3H), 1.77-1.54 (m, 5H), 1.03-1.00 (m, 3H), 0.93 (dd, J = 6.8 Hz, 2.4 Hz, 6H). LC-MS: m/z 1008.5 [M+H]+.
화합물 142:
(S)-4-(4-((1-(7-(8-클로로나프탈렌-1-일)-4-(3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (CD3OD, 400 MHz): δ 7.71 (d, J = 8.4 Hz, 1H), 7.56-7.54 (m, 1H), 7.44-7.35 (m, 2H), 7.28-7.16 (m, 6H), 6.56 (s, 1H), 6.23 (s, 1H), 5.26-5.14 (m, 2H), 4.59 (d, J = 12.0 Hz, 1H), 4.20-4.15 (m, 1H), 3.92-3.85 (m, 4H), 3.61-3.38 (m, 3H), 3.09-2.53 (m, 14H), 1.93-1.92 (m, 1H), 1.78-1.74 (m, 1H), 1.64 (d, J = 12.8 Hz, 2H), 1.16-1.08 (m, 2H), 0.75 (d, J = 6.8 Hz, 6H); LC-MS: m/z 1006.4 [M+H]+.
화합물 143:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(4-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴. 1H NMR (CD3OD, 400 MHz): δ 7.73 (d, J = 7.6 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.47-7.36 (m, 4H), 7.30-7.19 (m, 4H), 6.78 (s, 1H), 6.10 (s, 1H), 5.28-5.16 (m, 2H), 4.31-3.92 (m, 8H), 3.63-3.34 (m, 7H), 3.13-2.58 (m, 10H),2.31 (q, J = 7.6 Hz, 2H), 0.92 (t, J = 7.6 Hz, 3H); LC-MS: m/z 884.3 [M+H]+.
화합물 144:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((S)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93-11.92 (m, 1H), 9.61-9.58 (m, 1H), 9.43-9.41 (m, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58-7.27 (m, 5H), 7.13-7.00 (m, 3H), 6.75-6.73 (m, 1H), 6.29-6.26 (m, 1H), 5.38 (dd, J = 17.6, 4.0 Hz, 1H), 5.33-5.20 (m, 1H), 4.87-4.64 (m, 1H), 4.31-3.71 (m, 8H), 3.50-3.43 (m, 3H), 3.32-2.32 (m, 11H), 2.01-1.83 (m, 6H), 1.63-1.47 (m, 5H), 0.93-0.85 (m, 6H). LC-MS: m/z 1024.3 [M+H]+.
화합물 145:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴, 아세트산. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.59 (s, 1H), 9.41 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.59-7.28 (m, 6H), 7.12 (d, J = 8.0 Hz, 2H), 6.75 (s, 1H), 6.26 (s, 1H), 5.41-5.20 (m, 2H), 4.86-4.65 (m, 1H), 4.23-3.70 (m, 8H), 3.51-3.41 (m, 4H), 3.30-2.32 (m, 14H), 2.06-1.88 (m, 2H), 1.77-1.50 (m, 5H), 0.93 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 7.2 Hz, 3H). LC-MS: m/z 1024.3 [M-CH3COOH+H]+.
화합물 146:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-((1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)아제티딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-프로피오닐피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.59 (s, 1H), 9.42 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 8.0 Hz, J = 3.2 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.53 (q, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 16.0 Hz, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.75 (s, 1H), 6.26 (s, 1H), 4.89-4.55 (m, 1H), 4.34-3.41 (m, 13H), 3.26-2.67 (m, 12H), 2.55 (brs, 1H), 2.44-2.32 (m, 2H), 2.17-2.12 (m, 1H), 1.94-1.89 (m, 2H), 1.57-1.45 (m, 4H), 1.03-1.00 (m, 3H), 0.92 (d, J = 7.2 Hz, 6H). LC-MS: m/z 994.5 [M+H]+.
화합물 147:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-((1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페리딘-4-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-프로피오닐피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.59 (s, 1H), 9.41 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.75-7.72 (m, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.53 (q, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 17.2 Hz, J = 7.6 Hz, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.76 (s, 1H), 6.26 (s, 1H), 4.89-4.56 (m, 1H), 4.42-3.43 (m, 11H), 3.26-2.64 (m, 12H), 2.55 (brs, 2H), 2.44-2.30 (m, 2H), 1.98 (brs, 3H), 1.79-1.54 (m, 6H), 1.03-1.00 (m, 3H), 0.93 (d, J = 7.2 Hz, 6H). LC-MS: m/z 1023.4 [M+H]+.
화합물 149:
5-(2,4-디히드록시-5-이소프로필페닐)-4-(4-((1-(4-(2-(3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)에틸)벤질)피페리딘-4-일)메틸)페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.54 (s, 1H), 9.76 (s, 1H), 9.63 (s, 1H), 9.57 (t, J = 6.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.90 (t, J = 6.0 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.37 (dd, J = 7.6, 7.2 Hz, 1H), 7.27-7.10 (m, 9H), 6.84 (d, J = 2.0 Hz, 1H), 6.75 (s, 1H), 6.59 (s, 1H), 6.45 (brs, 1H), 6.34 (s, 1H), 3.98-3.92 (m, 4H), 3.56-3.22 (m, 18H), 2.92-2.65 (m, 7H), 2.38-2.32 (m, 4H), 1.83-1.77 (m, 2H), 1.53-1.44 (m, 3H), 1.23-1.17 (m, 2H), 1.01 (t, J = 7.2 Hz, 1H), 0.80 (d, J = 6.8 Hz, 1H). LC-MS: m/z 1137.6 [M+H]+.
화합물 150:
1-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)프로판-1-온. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.95 (s, 1H), 9.62 (brs, 1H), 9.38 (brs, 1H), 8.11 (t, J = 4.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.41-7.37 (m, 3H), 7.27 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 7.2 Hz, 2H), 6.87 (d, J = 1.6 Hz, 1H), 6.83 (s, 1H), 6.76 (d, J = 1.6 Hz, 1H), 6.26 (s, 1H), 4.48 (t, J = 6.0 Hz, 3H), 4.38 (d, J = 13.2 Hz, 1H), 4.23 (d, J = 3.6 Hz, 3H), 4.10 (s, 3H), 3.92 (d, J = 12.4 Hz, 4H), 3.60 (s, 9H), 3.26 (brs, 2H), 3.04-3.53 (m, 12H), 2.37 (q, J = 7.6 Hz, 2H), 1.96 (brs, 1H), 1.73 (d, J = 12.0 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H), 0.97 (d, J = 7.2 Hz, 6H). LC-MS: m/z 994.5 [M+H]+.
화합물 151:
5-(2,4-디히드록시-5-이소프로필페닐)-4-(4-((1-(4-(2-(3-((7-(3-히드록시나프탈렌-1-일)-4-(4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)프로판아미도)에틸)벤질)피페리딘-4-일)메틸)페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 9.79 (brs, 1H), 9.60 (t, J = 4.8 Hz, 1H), 9.35 (brs, 1H), 8.11 (t, J = 4.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.46-7.24 (m, 10H), 6.87 (d, J = 1.6 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.60 (s, 1H), 6.34 (s, 1H), 4.46 (t, J = 6.0 Hz, 3H), 4.36 (s, 1H), 4.23 (d, J = 3.6 Hz, 3H), 4.10 (s, 3H), 4.00-3.91 (m, 4H), 3.60 (s, 8H), 3.35-3.26 (m, 6H), 2.94-2.73 (m, 7H), 2.56-2.53 (m, 3H), 2.37 (q, J = 7.2 Hz, 2H), 1.76-1.71 (m, 3H), 1.39 (dd, J = 16.0 Hz, J = 8.8 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H), 0.82 (d, J = 7.2 Hz, 6H). LC-MS: m/z 1138.5 [M+H]+.
화합물 152:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((S)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)아제티딘-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-프로피오닐피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.98 (s, 1H), 9.62-9.61 (m, 1H), 9.36-9.33 (m, 1H), 8.72 (brs, 2H), 7.93-7.87 (m, 1H), 7.75-7.72 (m, 1H), 7.57-7.25 (m, 7H), 7.11-6.73 (m, 2H), 6.28-6.24 (m, 1H), 4.88-4.79 (m, 1H), 4.58-3.74 (m, 15H), 3.07-2.67 (m, 11H), 2.41-1.68 (m, 11H), 2.63-2.57 (m, 1H), 2.41-2.35 (m, 1H), 2.03-1.82 (m, 6H), 1.52 (d, J = 6.8 Hz, 3H), 1.02-1.0.98 (m, 6H). LC-MS: m/z 994.4 [M-CF3COOH+H]+.
화합물 153:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(4-히드록시-5-이소프로필-2-메톡시벤조일)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 9.62 (brs, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.59-7.50 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.37-7.30 (m, 1H), 6.88 (d, J = 11.2 Hz, 1H), 6.84 (brs, 1H), 6.45 (s, 1H), 6.18 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 10.4 Hz, 1H), 4.95-4.75 (m, 1H), 4.32-3.72 (m, 6H), 3.67 (d, J = 11.2 Hz, 3H), 3.58-3.36 (m, 3H), 3.25-2.83 (m, 11H), 2.68-2.55 (m, 2H), 2.07-1.93 (m, 1H), 1.73-1.66 (m, 1H), 1.11-1.03 (m, 6H). LC-MS: m/z 764.3 [M+H]+.
화합물 154:
5-(2,4-디히드록시-5-이소프로필페닐)-4-(4-((1-(4-((3-((4-(4-(2-플루오로아크릴로일)피페라진-1-일)-7-(3-히드록시나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)메틸)벤질)피페리딘-4-일)메틸)페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.54 (s, 1H), 9.76 (s, 1H), 9.63 (s, 1H), 9.57 (t, J = 6.4 Hz, 1H), 8.30 (t, J = 6.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.37 (t, J = 7.2 Hz, 1H), 7.27-7.14 (m, 10H), 6.84 (s, 1H), 6.75 (s, 1H), 6.59 (s, 2H), 6.34 (s, 1H), 5.34-5.29 (m, 2H), 5.16 (d, J = 4 Hz, 1H), 4.24 (d, J = 5.6 Hz, 2H), 3.98-3.93 (m, 4H), 3.66 (s, 4H) 3.49-3.33 (m, 6H), 3.28-3.24 (m, 3H), 2.89-2.72 (m, 6H), 2.51-2.42 (m, 5H), 1.84-1.75 (m, 2H), 1.54-1.43 (m, 2H), 0.80 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1139.5 [M+H]+.
화합물 155:
2-((S)-1-아크릴로일-4-(2-(((S)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-2-일)메톡시)-7-(8-메틸나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.99-11.97 (m, 1H), 9.60 (brs, 1H), 9.52 (brs, 1H), 9.33 (brs, 1H), 7.76-7.66 (m, 2H), 7.49-7.25 (m, 7H), 7.14 (d, J = 8.0 Hz, 1H), 6.86-6.75 (m, 2H), 6.27-6.17 (m, 2H), 5.77 (d, J = 10.0 Hz, 1H), 4.96-4.75 (m, 1H), 4.44-3.93 (m, 9H), 3.36-2.90 (m, 14H), 2.85 (s, 3H), 2.70-2.67 (m, 2H), 2.02-1.75 (m, 6H), 0.99 (d, J = 6.8 Hz, 6H). LC-MS: m/z 986.5 [M-CF3COOH+H]+.
화합물 156:
5-(2,4-디히드록시-5-이소프로필페닐)-4-(4-((1-(4-((3-((7-(3-히드록시나프탈렌-1-일)-4-(4-피발로일피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)아미노)프로판아미도)메틸)벤질)피페리딘-4-일)메틸)페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.54 (s, 1H), 9.80 (s, 2H), 8.54(s, 1H), 7.99(d, J = 8.4 Hz,1H), 7.77-7.67 (m, 1H), 7.46-7.24 (m, 10H), 6.89 (s, 1H), 6.75 (s, 2H), 6.60 (s, 2H), 6.34 (s, 2H), 4.44-3.57 (m, 20H), 2.87-2.64 (m, 6H), 1.47-1.21 (m, 13H), 0.80 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1152.6 [M+H]+.
화합물 157:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(2,4-디히드록시-5-이소프로필벤조일)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 10.50 (brs, 1H), 9.62 (brs, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.60-7.51 (m, 2H), 7.45 (t, J = 8.0 Hz, 1H), 7.34 (dd, J = 13.2 Hz, 7.2 Hz, 1H), 7.05 (s, 1H), 6.83 (brs, 1H), 6.32 (s, 1H), 6.18 (d, J = 16.8 Hz, 1H), 5.78 (d, J = 14.4 Hz, 1H), 4.93-4.75 (m, 1H), 4.41-3.72 (m, 9H), 3.17-3.03 (m, 9H), 2.71-2.63 (m, 2H), 2.06-1.97 (m, 2H), 1.75-1.71 (m, 1H), 1.10 (J = 7.2 Hz, 6H). LC-MS: m/z 750.3 [M+H]+.
화합물 158:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(5-에틸-2,4-디히드록시벤조일)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 10.56 (brs, 1H), 9.66 (brs, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.53 (q, J = 7.2 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 16.4 Hz, 7.6 Hz, 1H), 7.03 (s, 1H), 6.84 (brs, 1H), 6.32 (s, 1H), 6.18 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 4.95-4.74 (m, 1H), 4.41-3.48 (m, 13H), 3.18-2.61 (m, 6H), 2.41 (dd, J = 14.8 Hz, 7.2 Hz, 2H), 2.03-1.97 (m, 2H), 1.73-1.70 (m, 1H), 1.07-1.03 (m, 3H). LC-MS: m/z 736.4 [M+H]+.
화합물 159:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(2-히드록시-5-이소프로필-4-메톡시벤조일)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 11.36 (brs, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.53 (q, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.33 (dd, J = 15.6 Hz, 7.6 Hz, 1H), 7.09 (s, 1H), 6.84 (brs, 1H), 6.44 (d, J = 0.8 Hz, 1H), 6.18 (d, J = 17.2 Hz, 1H), 5.77 (d, J = 12.0 Hz, 1H), 4.96-4.74 (m, 1H), 4.38-3.88 (m, 7H), 3.76 (s, 1H), 3.62-3.49 (m, 5H), 3.12-2.64 (m, 8H), 2.04-1.95 (m, 2H), 1.76-1.70 (m, 1H), 0.99 (d, J = 6.8 Hz, 6H). LC-MS: m/z 764.3 [M+H]+.
화합물 160:
3-(3-((S)-2-(((7-(8-클로로나프탈렌-1-일)-4-((S)-3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-일)프로폭시)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로펜아미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.87 (s, 1H), 9.54 (s, 1H), 9.35 (s, 1H), 8.31 (brs, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.73 (dd, J = 8.0, 2.8 Hz, 1H), 7.58-7.42 (m, 2H), 7.33 (dd, J = 14.8, 7.2 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.85 (s, 1H), 6.23 (s, 1H), 5.41-5.20 (m, 2H), 4.85-4.58 (m, 1H), 4.21-4.14 (m, 4H), 4.03-3.70 (m, 5H), 3.54-3.48 (m, 3H), 3.37-3.31 (m, 4H), 3.23-2.67 (m, 12H), 2.33-2.11 (m, 4H), 1.90-1.63 (m, 6H), 0.99 (d, J = 7.2 Hz, 6H). LC-MS: m/z 1042.5 [M+H]+.
화합물 161:
3-(3-((S)-2-(((7-(8-클로로나프탈렌-1-일)-4-((S)-3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-일)프로폭시)-N-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로판아미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.85 (s, 1H), 9.51 (s, 1H), 9.33 (s, 1H), 8.30 (t, J = 5.2 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.73 (dd, J = 8.0, 3.2 Hz, 1H), 7.58-7.42 (m, 2H), 7.33 (dd, J = 15.2, 7.6 Hz, 1H), 7.17(d, J = 10.4 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.87 (s, 1H), 6.22 (s, 1H), 5.40-5.20 (m, 2H), 4.83-4.64 (m, 1H), 4.21-4.14 (m, 4H), 4.03-3.70 (m, 4H), 3.53-3.47 (m, 3H), 3.36-2.71 (m, 13H), 2.38-2.30 (m, 4H), 2.17-1.83 (m, 3H), 1.70-1.58 (m, 6H), 0.99 (t, J = 7.2 Hz, 3H). LC-MS: m/z 1028.6 [M+H]+.
화합물 162:
2-((4-(2-((R)-3-(((7-(8-클로로나프탈렌-1-일)-4-((S)-3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-일)-2-옥소에톡시)페닐)아미노)-4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)벤즈아미드
1H NMR (DMSO-d 6 , 400 MHz): δ 10.09 (s, 1H), 8.18 (s, 1H), 7.92-7.90 (m, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.58-7.50 (m, 3H), 7.43 (dt, J = 8.0 Hz, 3.2 Hz, 1H), 7.36-7.30 (m, 1H), 7.22-7.18 (m, 2H), 7.02 (s, 1H), 6.95-6.92 (m, 3H), 5.38 (dd, J = 18.0 Hz, 4.4 Hz, 1H), 5.27 (d, J = 50.0 Hz, 1H), 4.84-4.71 (m, 1H), 4.70 (s, 2H), 4.27-3.48 (m, 13H), 3.26-2.89 (m, 10H), 3.27-2.55 (m, 3H), 2.40 (d, J = 5.6 Hz, 2H), 2.12-1.62 (m, 3H), 1.02 (d, J = 2.4 Hz, 6H). LC-MS: m/z 1088.4 [M+H]+.
화합물 163:
2-((4-((R)-3-(((7-(8-클로로나프탈렌-1-일)-4-((S)-3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-카르보닐)페닐)아미노)-4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)벤즈아미드
1H NMR (DMSO-d 6 , 400 MHz): δ 10.33 (s, 1H), 8.26 (s, 1H), 7.94-7.90 (m, 2H), 7.75-7.72 (m, 2H), 7.57-7.27 (m, 9H), 7.14 (dd, J = 12.8 Hz, 8.8 Hz, 1H), 5.38 (d, J = 16.0 Hz, 1H), 5.27 (d, J = 48.8 Hz, 1H), 4.84-4.71 (m, 1H), 4.27-3.38 (m, 12H), 3.30 (s, 2H), 3.10-2.63 (m, 7H), 2.42-2.32 (m, 4H), 2.04 (brs, 1H), 1.73 (brs, 1H), 1.02 (s, 6H),. LC-MS: m/z 1058.4 [M+H]+.
화합물 164:
2-((4-(2-((S)-2-(((7-(8-클로로나프탈렌-1-일)-4-((S)-3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-일)-2-옥소에톡시)페닐)아미노)-4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)벤즈아미드
1H NMR (DMSO-d 6 , 400 MHz): δ 10.08 (brs, 1H), 8.20 (brs, 1H), 7.93-7.84 (m, 2H), 7.73-7.67 (m, 1H), 7.59 (brs, 1H), 7.56-7.25 (m, 4H), 7.17-6.81 (m, 6H), 5.39-5.19 (m, 2H), 5.00-4.70 (m, 3H), 4.36-3.62 (m, 10H), 3.28-2.65 (m, 10H), 2.40-2.34 (m, 2H), 2.05-1.91 (m, 4H), 1.02-0.96 (m, 6H). LC-MS: m/z 1088.4 [M+H]+.
화합물 165:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(2-(2,4-디히드록시-5-이소프로필벤조일)이소인돌린-5-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 10.06 (brs, 1H), 9.66 (brs, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.59-7.29 (m, 7H), 7.02 (s, 1H), 6.40 (s, 1H), 5.39 (d, J = 18.0 Hz, 1H), 5.27 (d, J = 50.4 Hz, 1H), 4.78 (brs, 4H), 4.26-3.47 (m, 12H), 3.22-2.86 (m, 8H), 2.71-2.54 (m, 1H), 2.06-1.73 (m, 3H), 1.14-1.11 (m, 6H). LC-MS: m/z 913.4 [M+H]+.
화합물 166:
4-(4-((4-((R)-3-(((7-(8-클로로나프탈렌-1-일)-4-((S)-3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.65 (brs, 1H), 9.81 (brs, 1H), 8.26 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.58 (d, J = 6.8 Hz, 1H), 7.53 (dd, J = 13.6 Hz, 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.38-7.28 (m, 5H), 6.56 (d, J = 2.0 Hz, 1H), 6.35 (s, 1H), 5.39 (dd, J = 18.4 Hz, 3.6 Hz, 1H), 5.27 (d, J = 46.4 Hz, 1H), 4.86 (brs, 1H), 4.27-3.46 (m, 15H), 3.14-2.67 (m, 10H), 2.38-2.31 (m, 2H), 2.08-1.95 (m, 4H), 1.79-1.56 (m, 5H), 0.79 (dd, J = 6.8 Hz, 3.6 Hz, 6H). LC-MS: m/z 1051.4 [M+H]+.
화합물 167:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(1-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.90 (s, 1H), 9.56 (s, 1H), 9.37 (s, 1H), 9.57 (t, J = 6.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.58-7.32 (m, 6H), 7.11 (d, J = 7.6 Hz, 1H), 6.81 (s, 1H), 6.25 (s, 1H), 5.17-5.49 (m, 2H), 4.21-3.44 (m, 14H), 3.33-2.52 (m, 10H), 2.35-2.32 (m, 3H), 2.12-1.48 (m, 10H), 0.95 (t, J = 7.6 Hz, 3H). LC-MS: m/z 1010.4 [M+H]+.
화합물 168:
4-(4-((4-((R)-3-(((7-(8-클로로나프탈렌-1-일)-4-((S)-3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.51 (s, 1H), 9.59 (t, J = 6.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.59-7.30 (m, 9H), 6.61 (s, 1H), 6.35 (s, 1H), 5.41-5.37 (m, 2H), 4.21-3.36 (m, 19H), 3.25-3.16 (m, 5H), 1.99-1.59 (m, 12H), 1.23 (s, 2H), 0.82-0.80 (m, 6H). LC-MS: m/z 1133.4 [M+H]+.
화합물 169:
(S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-2-(시아노메틸)피페라진-1-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.58 (s, 1H), 9.40 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.58-7.42 (m, 3H), 7.36-7.29 (m, 3H), 7.13 (d, J = 7.6 Hz, 2H), 6.75 (s, 1H), 6.26 (s, 1H), 6.22 (brs, 2H), 4.54-4.52 (m, 1H), 4.25-4.13 (m, 3H), 4.02-3.45 (m, 9H), 3.26-2.35 (m, 15H), 2.07-1.75 (m, 3H), 1.63-1.51 (m, 4H), 0.93 (d, J = 6.4 Hz, 6H). LC-MS: m/z 995.5 [M+H]+.
화합물 170:
3-(3-((R)-3-(((7-(8-클로로나프탈렌-1-일)-4-((S)-3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-일)프로폭시)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로펜아미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.86 (brs, 1H), 9.59 (brs, 1H), 9.45 (brs, 1H), 8.34 (d, J = 6.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.74 (dd, J = 8.0, 3.2 Hz, 1H), 7.58-7.50 (m, 2H), 7.44 (dd, J = 8.0, 7.6 Hz, 1H), 7.33 (dd, J = 14.8, 7.6 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.85 (s, 1H), 6.22 (s, 1H), 5.41-5.20 (m, 2H), 4.85-4.60 (m, 1H), 4.25-3.37 (m, 15H), 3.12-2.88 (m, 6H), 2.69-2.27 (m, 9H), 2.02-1.97 (m, 1H), 1.65-1.60 (m, 2H), 1.45-1.29 (m, 3H), 0.99 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1042.5 [M+H]+.
화합물 171:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(2,4-디히드록시-5-이소프로필벤조일)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 10.501 (s, 1H), 9.67 (s, 1H), 7.92-7.90 (d, 1H), 7.75-7.72 (dd, 1H), 7.58-7.50 (m, 2H), 7.46-7.42 (t, 1H), 7.36-7.30 (dd, 3H), 7.04 (s, 1H), 6.31 (s, 1H), 5.41-5.40 (dd, 1H), 5.36-5.20 (d, 1H), 4.28-3.88 (m, 12H), 3.09-2.59 (m, 8H), 2.03-1.98 (m, 2H), 1.74-1.69 (m, 1H), 1.10-1.08 (d, 6H) LC-MS: m/z 768.3 [M+H]+.
화합물 172:
2-((4-(3-(4-((1-(2-((R)-3-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-일)-2-옥소에틸)피페리딘-4-일)메틸)피페리딘-1-일)프로폭시)페닐)아미노)-4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)벤즈아미드
1H NMR (DMSO-d 6 , 400 MHz): δ 10.13 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.59-7.30 (m, 9H), 7.17-6.85 (m, 5H), 6.18 (d, J = 8.4 Hz, 1H), 5.75 (d, J = 8.4 Hz, 1H), 4.93-4.71 (m, 1H), 4.22-3.75 (m, 8H), 2.86-2.67 (m, 8H), 2.41-2.33 (m, 10H), 2.16-1.38 (m, 17H), 1.32-0.89 (m, 17H). LC-MS: m/z 1293.6 [M+H]+.
화합물 173:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(2-(2-히드록시-5-이소프로필-4-메톡시벤조일)이소인돌린-5-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 10.19 (brs, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.58-7.32 (m, 7H), 6.50 (s, 1H), 6.18 (d, J = 16.0 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 4.94-4.79 (m, 1H), 4.78 (d, J = 27.2 Hz, 4H), 4.39-3.89 (m, 7H), 3.78 (s, 3H), 3.71-3.50 (m, 12H), 3.16-3.01 (m, 1H), 2.67 (brs, 1H), 2.06-1.97 (m, 2H), 1.74 (brs, 1H), 1.13 (t, J = 5.6 Hz, 6H). LC-MS: m/z 909.4 [M+H]+.
화합물 174:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(5-에틸-2,4-디히드록시벤조일)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 7.90-7.88 (d, 1H), 7.76-7.73 (d, 2H), 7.61-7.53 (m, 2H), 7.46-7.38 (m, 1H), 7.15 (s, 1H), 6.38 (s, 1H), 5.68-5.32 (dd, 2H), 4.50-4.21 (m, 6H), 3.89-3.58 (m, 7H), 3.29-2.80 (m, 8H), 2.62-2.54 (q, 2H), 2.26-2.11 (m, 3H), 1.22-1.17 (t, 3H), 0.97-0.95 (m, 1H) LC-MS: m/z 754.3 [M+H]+
화합물 176:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(2-(5-에틸-2,4-디히드록시벤조일)이소인돌린-5-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 10.13 (brs, 1H), 9.64 (brs, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.57-7.31 (m, 7H), 7.03 (s, 1H), 6.18 (d, J = 17.2 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 4.96-4.80 (m, 1H), 4.79 (s, 4H), 4.39-3.63 (m, 13H), 3.10-3.03 (m, 3H), 2.91-2.83 (m, 1H), 2.63 (brs, 2H), 2.46-2.44 (m, 4H), 2.01-1.72 (m, 4H), 1.11-1.06 (m, 3H). LC-MS: m/z 909.4 [M+H]+.
화합물 177:
2-((S)-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2,2,2-트리플루오로아세틸)피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.98 (s, 1H), 9.62 (s, 1H), 9.45 (brs, 1H), 9.34 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.59-7.43 (m, 5H), 7.37-7.32 (m, 1H), 7.26 (d, J = 6.0 Hz, 2H), 6.86 (s, 1H), 6.24 (s, 1H), 4.91-4.51 (m, 1H), 4.33-3.63 (m, 11H), 3.25-2.92 (m, 12H), 2.72-2.67 (m, 2H), 2.10-1.45 (m, 8H), 0.99 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1048.4 [M+H]+.
화합물 179:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페리딘-4-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.84 (s, 1H), 9.61 (s, 1H), 9.43 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.52-7.45 (m, 6H), 7.12 (d, J = 8.0 Hz, 2H), 6.91-6.72 (m, 2H), 6.27 (s, 1H), 6.21 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 4.96-4.73 (m, 1H), 4.42 (d, J = 8.0 Hz, 1H),4.32-3.81 (m, 7H), 3.51-3.42 (m, 5H), 3.08-2.77 (m, 9H), 2.01-1.32 (m, 15H), 0.92 (dd, J = 6.8 Hz, 2.0 Hz, 6H). LC-MS: m/z 1020.5 [M+H]+.
화합물 180:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(1-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.97 (s, 1H), 9.63 (brs, 1H), 9.52 (brs, 1H), 9.31 (brs, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.60-7.45 (m, 5H), 7.34 (dd, J = 14.0, 8.0 Hz, 1H), 7.25 (d, J = 6.4 Hz, 2H), 6.95 (s, 1H), 6.85-6.82 (m, 1H), 6.22 (s, 1H), 6.19 (d, J = 20.4 Hz, 1H), 5.78 (d, J = 10.0 Hz, 1H), 4.95-4.75 (m, 1H), 4.41-3.95 (m, 9H), 3.80-3.70 (m, 2H), 3.36-2.84 (m, 13H), 2.71-2.57 (m, 3H), 2.10-1.64 (m, 7H), 1.97 (s, 3H). LC-MS: m/z 978.4 [M+H]+.
화합물 181:
2-((4-((R)-3-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-카르보닐)페닐)아미노)-4-(6,6-디메틸-4-옥소-3-(트리플루오로메틸)-4,5,6,7-테트라히드로-1H-인다졸-1-일)벤즈아미드
1H NMR (DMSO-d 6 , 400 MHz): δ 10.33 (s, 1H), 8.26 (s, 1H), 7.94-7.90 (m, 2H), 7.75-7.73 (m, 2H), 7.57-7.42 (m, 6H), 7.34-7.27 (m, 3H), 7.14 (d, J = 8.4 Hz, 1H), 6.86-6.82 (m, 1H), 6.17 (d, J = 16.4 Hz, 1H), 5.76 (d, J = 10.8 Hz, 2H), 4.95-4.73 (m, 1H), 4.37-3.89 (m, 6H), 3.72-3.36 (m, 6H), 3.29-2.67 (m, 10H), 2.45-2.33 (m, 3H), 2.07-2.01 (m, 1H), 1.74-1.71 (m, 1H), 1.03 (s, 6H). LC-MS: m/z 1040.4 [M+H]+.
화합물 182:
3-(3-((R)-3-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-일)프로폭시)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)프로판아미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 7.85 (d, J = 8.4 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.55-7.49 (m, 2H), 7.41-7.37 (m, 3H), 7.32 (dd, J = 10.8, 8.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.87-6.73 (m, 2H), 6.32 (d, J = 16.8 Hz, 1H), 6.27 (s, 1H), 5.86 (d, J = 10.8 Hz, 1H), 5.11-5.06 (m, 1H), 4.41-4.06 (m, 7H), 3.74-3.58 (m, 7H), 3.21-2.64 (m, 15H), 2.52 (t, J = 6.0 Hz, 2H), 2.20-2.18 (m, 1H), 2.06-1.83 (m, 4H), 0.93 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1024.5 [M+H]+.
화합물 183:
4-(4-((4-((R)-3-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.63 (s, 1H), 9.76 (s, 1H), 8.25 (s, 2H), 7.92-7.90(dd, 1H), 7.72 (s, 2H), 7.58-7.52 (m, 2H), 7.46-7.29 (m, 6H), 6.82 (s, 1H), 6.56 (s, 1H), 6.35 (s, 1H), 5.78-5.76 (dd, 1H), 4.94-4.77 (d, 1H), 4.63-3.21 (m, 10H), 3.20-2.60 (m, 10H) 2.57 (s, 2H), 2.38-1.60 (m, 10H), 0.79 (s, 6H) LC-MS: m/z 1033.5[M+H]+.
화합물 184:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((S)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.59 (s, 1H), 9.41 (s, 1H), 7.92-7.90(dd, 1H), 7.73 (s, 1H), 7.58-7.52 (dd, 2H), 7.46-7.44 (t, 1H), 7.29-7.27 (m, 4H), 7.13-7.11 (d, 2H), 6.89-6.83 (m, 1H), 6.74 (s, 1H), 6.26 (s, 1H), 6.21-6.17 (d, 1H), 5.79-5.77 (d, 1H) 4.98-4.76 (m, 1H), 4.17-3.41 (m, 10H), 3.25-2.67 (m, 11H) 2.54 (s, 2H), 2.32-1.52 (m, 11H), 0.92-0.91 (d, 6H) LC-MS: m/z 1006.4[M+H]+.
화합물 185:
4-(4-((4-((R)-3-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 9.75 (s, 1H), 9.59 (t, J = 6.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.59-7.30 (m, 8H), 6.81 (s, 1H), 6.61 (s, 1H), 6.35 (s, 1H), 6.18 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H),4.98-4.64 (m, 1H), 4.22-3.34 (m, 14H), 3.24-2.67 (m, 12H), 2.08-1.60 (m, 9H), 1.23 (s, 2H), 0.82-0.80 (m, 6H). LC-MS: m/z 1115.4 [M+H]+.
화합물 186:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(3-(2,4-디히드록시-5-이소프로필페닐)-3-옥소프로필)피롤리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산.
1H NMR (DMSO-d 6, 400 MHz): δ 11.84 (s, 1H), 10.69 (s, 1H), 9.50 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.75 (dd, J = 8.0, 3.6 Hz, 1H), 7.59-7.51 (m, 3H), 7.45 (dd, J = 8.0, 7.2 Hz, 1H), 7.34 (dd, J = 16.0, 7.6 Hz, 1H), 6.85-6.83 (m, 1H), 6.35 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.78 (d, J = 11.6 Hz, 1H), 4.97-4.74 (m, 1H), 4.42-3.70 (m, 17H), 3.42-2.67 (m, 8H), 2.40-1.71 (m, 3H), 1.17 (d, J = 6.8 Hz, 6H). LC-MS: m/z 778.5 [M-CF3COOH+H]+.
화합물 187:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((1-(1-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)아제티딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.0 Hz, 4H), 7.38 (t, J = 8.3 Hz, 4H), 6.90 (s, 1H), 6.88 ― 6.74 (m, 1H), 6.30 (d, J = 16.5 Hz, 1H), 6.17 (s, 1H), 5.85 (s, 1H), 5.34 (t, J = 4.6 Hz, 1H), 4.58 (m, 1H), 4.41 (m, 1H), 4.35 (m, 1H), 4.30 (m, 3H), 4.20 (m, 1H), 4.16 (m, 1H), 4.12 (m, 1H), 4.08 ― 4.02 (m, 1H), 3.90 (m, 1H), 3.81 (m, 1H), 3.75 (m, 1H), 3.66 ― 3.59 (m, 2H), 3.54 (m, 1H), 3.50 ― 3.46 (m, 2H), 3.03 (m, 2H), 2.92 (m, 1H), 2.80 (m, 1H), 2.61 (m, 1H), 2.35 (m, 1H), 2.19 (m, 1H), 2.02 (m, 3H), 1.99 (s, 3H), 1.85 (m, 1H), 1.60 (m, 3H). LC-MS: m/z 964.3 [M+H]+.
화합물 188:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)아제티딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.58 ― 7.48 (m, 4H), 7.42 ― 7.32 (m, 4H), 6.88 ― 6.72 (m, 2H), 6.30 (m, 1H), 6.21 (s,1H), 5.85 (d, J = 10.7 Hz, 1H), 4.65 (d, J = 5.7 Hz, 2H), 4.52 ― 4.45 (m, 1H), 4.44 ― 4.30 (m, 5H), 4.20 ― 4.09 (m, 3H), 3.91 ― 3.85 (m, 1H), 3.82 ― 3.75 (m, 1H), 3.66 ― 3.57 (m, 2H),3.55 ― 3.46 (m, 3H), 3.26 ― 3.15 (m, 3H), 3.14 ― 2.99 (m, 5H), 2.96 ― 2.90 (m, 1H), 2.84 ― 2.77 (m, 1H), 2.66 ― 2.54 (m, 1H), 2.05 ― 1.79 (m, 5H), 1.00 (d, J = 6.9 Hz, 6H). LC-MS: m/z 992.4 [M+H]+.
화합물 189:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((S)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)아제티딘-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, MeOD) δ 7.90 ― 7.60 (m, 2H), 7.58 ― 7.45 (m, 3H), 7.40 ― 7.20 (m, 4H), 6.96 ― 6.54 (m, 3H), 6.37 ― 6.19 (m, 2H), 5.83 (d, J = 12.4 Hz, 1H), 5.15 ― 4.97 (m, 1H), 4.72 ― 4.50 (m, 3H), 4.42 ― 4.04(m, 7H), 3.99 ― 3.94 (m, 1H), 3.80 ― 3.45 (m, 5H), 3.22 ― 2.90 (m, 8H), 2.82 ― 2.25 (m, 4H), 2.10 ― 1.75 (m, 5H), 1.00 (d, J = 6.5 Hz, 3H), 0.94 ― 0.77 (m, 3H). LC-MS: m/z 992.7 [M+H]+.
화합물 190:
4-(4-((4-((S)-2-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)아제티딘-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.89 ― 7.67 (m, 1.5H), 7.61 ― 7.46 (m, 4H), 7.41 ― 7.35 (m, 2H), 7.28 ― 7.14 (m, 1.5H), 6.93 ― 6.67 (m, 2H), 6.65 ― 6.54 (m, 0.5H), 6.49 ― 6.24 (m, 2.5H), 5.84 (d, J = 11.6 Hz, 1H), 4.67― 4.60 (m, 2H), 4.40 ― 4.31 (m, 3H), 4.25 ― 4.12 (m, 3H), 4.00 ― 3.96 (m, 1H), 3.81 ― 3.74 (m, 1H), 3.63 ― 3.53 (m, 3H), 3.11 ― 2.99 (m, 4H), 2.96 ― 2.86 (m, 2H), 2.81 ― 2.52 (m, 4H), 2.23 ― 2.14 (m, 2H), 2.05 ― 1.99(m, 4H), 1.63 ― 1.56 (m, 2H), 0.90 (m, 6H), 0.85 ― 0.73 (m, 3H). LC-MS: m/z 1019.8 [M+H]+.
화합물 191:
(S)-4-(4-((4-(3-(((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)아제티딘-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.61 ― 7.43 (m, 6H), 7.41 ― 7.32 (m, 2H), 6.88 ― 6.69 (m, 2H), 6.33 ― 6.22 (m, 2H), 5.84 (d, J = 10.8Hz, 1H), 4.74 ― 4.52 (m, 3H), 4.46 ― 4.23 (m, 6H), 4.21 ― 4.06 (m, 3H), 3.91 ― 3.85 (m, 1H), 3.82 ― 3.65 (m, 2H), 3.63 ― 3.39 (m, 5H), 3.25 ― 2.88 (m, 8H), 2.83 ― 2.59 (m, 2H), 2.04 ―1.81 (m, 4H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1019.3 [M+H]+.
화합물 192:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페라진-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, MeOD) δ 7.84 (dd, J = 8.3, 1.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.58 ― 7.47 (m, 4H), 7.41 ― 7.29 (m, 4H), 6.90 ― 6.73 (m, 2H), 6.29 (d, J = 17.1 Hz, 1H), 6.22 (s,1H), 5.84 (d, J = 10.4 Hz, 1H), 4.80 ― 4.69 (m, 3H), 4.40 ― 4.05 (m, 6H), 3.96 ― 3.69 (m, 5H), 3.66 ― 3.36 (m, 11H), 3.24 ― 3.15 (m, 2H), 3.14 ― 2.86 (m, 7H), 2.80 ― 2.67 (m, 1H), 2.17 ―1.79 (m, 4H), 1.01 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1035.4 [M+H]+.
화합물 193:
(S)-4-(4-((4-(4-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 7.4 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.57 ― 7.47 (m, 4H), 7.41 ― 7.32 (m, 2H), 6.85 ― 6.70 (m, 2H), 6.36 ―6.23 (m, 2H), 5.85 (d, J = 10.3 Hz, 1H), 4.45 ― 4.26 (m, 5H), 4.06 ― 3.74 (m, 6H), 3.71 ― 3.54 (m, 6H), 3.52 ― 3.39 (m, 6H), 3.26 ― 3.19 (m, 2H), 3.15 ― 2.92 (m, 7H), 2.87 ― 2.77(m, 2H), 2.07 ― 1.88 (m, 5H), 0.93 (d, J = 6.9 Hz, 6H) . LC-MS: m/z 1062.4 [M+H]+.
화합물 194:
N-((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)-1-(4-(3-카르바모일-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 7.8 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.57 ― 7.47 (m, 4H), 7.41 ― 7.32 (m, 2H), 6.97 ― 6.70 (m, 2H), 6.38 ― 6.22 (m, 2H), 5.84 (d, J = 10.8 Hz, 1H), 4.69 ― 4.62 (m, 2H), 4.53 ― 4.11 (m, 9H), 4.05 ― 3.97 (m, 1H), 3.84 ― 3.71 (m, 2H), 3.61 ― 3.51 (m, 3H), 3.26 ― 3.18 (m, 3H), 3.15 ― 2.90 (m, 9H), 2.81 ― 2.70 (m, 1H), 2.63 ― 2.51 (m, 1H), 2.46 ― 2.33 (m, 2H), 2.21 ―2.04 (m, 3H), 1.98 ― 1.90 (m, 2H), 0.97 ― 0.88 (m, 6H). LC-MS: m/z 1062.4 [M+H]+.
화합물 195:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤조일)피페라진-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.59 ― 7.47 (m, 4H), 7.42 ― 7.29 (m, 4H), 6.92 ― 6.72 (m, 2H), 6.30 (d, J = 17.0 Hz, 1H), 6.21 (s, 1H), 5.84 (d, J = 10.1 Hz, 1H), 4.78 ― 4.65 (m, 1H), 4.54 ― 4.29 (m, 3H), 4.11 (m, 1H), 4.03 ― 3.65 (m, 8H), 3.65 ― 3.40 (m, 7H), 3.28 ― 2.88 (m, 5H), 2.84 ― 2.68 (m, 1H), 2.22 ― 1.97 (m, 1H), 1.82 ― 1.42 (m, 1H), 1.02 (d, J = 6.9 Hz, 6H). LC-MS: m/z 938.8 [M+H]+.
화합물 196:
N-((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)-4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤즈아미드, 트리플루오로아세트산. 1H NMR (400 MHz, MeOD) δ 7.86 (dd, J = 20.5, 8.1 Hz, 3H), 7.69 (d, J = 9.0 Hz, 1H), 7.55 ― 7.48 (m, 2H), 7.41 ― 7.30 (m, 4H), 6.93 ― 6.74 (m, 2H), 6.29 (d, J = 16.9 Hz, 1H), 6.21 (s, 1H), 5.83 (d, J = 9.4 Hz, 1H), 4.66 ― 4.60 (m, 2H), 4.36 ― 4.04 (m, 7H), 3.77 ― 3.48 (m, 5H), 3.26 ― 3.03 (m, 9H), 2.95 ― 2.89 (m, 1H), 2.78 ― 2.69 (m, 1H), 2.53 ― 2.45 (m, 2H), 1.02 (d, 6H). LC-MS: m/z 938.3 [M+H]+.
화합물 197:
4-(4-((4-((S)-3-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-4-메틸피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR(400 MHz, MeOD) δ 7.83 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 7.6, 3.5 Hz, 1H), 7.63 ― 7.41 (m, 6H), 7.40 ― 7.30 (m, 2H), 6.87 ― 6.66 (m, 2H), 6.30 (d, J = 12.4 Hz, 2H), 5.84 (d, J = 10.6 Hz, 1H), 4.76 ― 4.51 (m, 3H), 4.43 ― 4.02 (m, 7H), 3.82 ― 3.45 (m, 9H), 3.27 ― 3.17 (m, 4H), 3.15 ― 2.82 (m, 10H), 2.79 ― 2.68 (m, 1H), 2.26 ― 1.75 (m, 5H), 0.93 (d, J = 6.2 Hz, 6H). LC-MS: m/z 1060.5 [M+H]+.
화합물 198:
N-((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)-1-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복사미드, 트리플루오로아세트산. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.56 ― 7.47 (m, 4H), 7.44 ― 7.28 (m, 4H), 6.97 ― 6.69 (m, 2H), 6.29 (d, J = 16.4 Hz, 1H), 6.18 (s, 1H), 5.83 (d, J = 11.4 Hz, 1H), 5.11 ― 4.97 (m, 1H), 4.66 ― 4.43 (m, 4H), 4.39 ― 4.26 (m, 4H), 4.16 ― 3.99 (m, 3H), 3.80 ― 3.70 (m, 3H), 3.66 ― 3.58 (m, 2H), 3.55 ― 3.48 (m, 2H), 3.24 ― 3.19 (m, 2H), 3.13 ― 3.06 (m, 5H), 3.04 ― 3.00 (m, 1H), 2.97 ― 2.86 (m, 2H), 2.81 ― 2.67 (m, 2H), 2.46 ― 2.33 (m, 2H), 2.06 ― 1.98 (m, 8H), 1.47 ― 1.40 (m, 4H). LC-MS: m/z 1007.3 [M+H]+.
화합물 199:
4-(4-((4-((S)-3-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-4-메틸피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (dd, J = 10.1, 5.7 Hz, 1H), 7.69 (dd, J = 9.0, 2.6 Hz, 1H), 7.64 ― 7.44 (m, 6H), 7.42 ― 7.30 (m, 2H), 6.88 ― 6.70 (m, 2H), 6.30 (d, J = 14.2 Hz, 2H), 5.84 (d, J = 10.4 Hz, 1H), 4.77 ― 4.52 (m, 3H), 4.45 ― 4.06 (m, 7H), 3.98 (dd, J = 18.6, 9.3 Hz, 2H), 3.79 ― 3.46 (m, 9H), 3.27 ― 3.16 (m, 4H), 3.15 ― 2.99 (m, 8H), 2.95 ― 2.65 (m, 3H), 2.13 ― 1.83 (m, 5H), 0.94 (d, J = 6.7 Hz, 6H). LC-MS: m/z 1044.5 [M+H]+.
화합물 200:
N-((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)-1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-((2,2,2-트리플루오로에틸)카르바모일)-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.81 (d, J = 9.0 Hz, 1H), 7.67 (d, J = 10.3 Hz, 1H), 7.53 ― 7.46 (m, 4H), 7.38 ― 7.29 (m, 4H), 6.93 ― 6.75 (m, 1H), 6.67 (s, 1H), 6.33 ― 6.24 (m, 2H), 5.82 (d, J = 11.7 Hz, 1H), 4.39 ―4.26 (m, 5H), 4.21 ― 4.08 (m, 2H), 4.01 ― 3.94 (m, 2H), 3.77 ― 3.62 (m, 2H), 3.57 ― 3.55 (m, 2H), 3.38 ― 3.34 (m, 2H), 3.22 ― 3.07 (m, 4H), 3.03 ― 2.86 (m, 6H), 2.73 ― 2.64 (m, 1H), 2.47 (s, 3H), 2.24 ― 2.17 (m, 2H), 2.13 ― 2.04 (m, 3H), 2.03 ― 2.03 (m, 3H), 1.96 ― 1.78 (m, 3H), 0.86 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1144.4 [M+H]+.
화합물 201:
N-((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)-1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-((2-(4-메틸피페라진-1-일)에틸)카르바모일)-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.81 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 10.3 Hz, 1H), 7.53 ― 7.44 (m, 4H), 7.39 ― 7.28 (m, 4H), 6.92 ― 6.74 (m, 1H), 6.66 (s, 1H), 6.36 ― 6.23 (m, 2H), 5.82 (d, J = 10.8 Hz, 1H), 4.45 ― 4.24 (m, 5H), 4.20 ― 4.03 (m, 2H), 3.77 ― 3.53 (m, 5H), 3.46 ― 3.35 (m, 4H), 3.23 ― 3.07 (m, 4H), 3.01 ― 2.89 (m, 5H), 2.74 ― 2.44 (m, 13H), 2.28 (s, 3H), 2.24 ― 2.02 (m, 6H), 1.95 ― 1.69 (m, 6H), 0.86 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1188.6 [M+H]+.
화합물 202:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((S)-4-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)-1-메틸피페라진-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 7.8 Hz, 1H), 7.69 (dd, J = 9.4, 4.5 Hz, 1H), 7.59 ― 7.47 (m, 4H), 7.43 ― 7.27 (m, 4H), 6.88 ― 6.69 (m, 2H), 6.29 (d, J = 16.8 Hz, 1H), 6.22 (s, 1H), 5.84 (d, J = 10.5 Hz, 1H), 4.75 ― 4.47 (m, 3H), 4.41 ― 3.98 (m, 7H), 3.83 ― 3.42 (m, 9H), 3.26 ― 3.14 (m, 4H), 3.07 (m, 8H), 2.96 ― 2.67 (m, 3H), 2.13 ― 1.81 (m, 5H), 1.01 (d, J = 6.2 Hz, 6H). LC-MS: m/z 1033.5 [M+H]+.
화합물 203:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((S)-4-(1-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)-1-메틸피페라진-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴, 트리플루오로아세트산. 1H NMR(400 MHz, MeOD) δ 7.84 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.55 ― 7.47 (m, 4H), 7.41 ― 7.32 (m, 4H), 6.92 ― 6.78 (m, 2H), 6.30 (d, J = 16.5 Hz, 1H), 6.18 (s, 1H), 5.84 (d, J = 10.1 Hz, 1H), 4.70 ― 4.63 (m, 2H), 4.40 ― 4.28 (m, 5H), 4.23 ― 4.09 (m, 2H), 3.77 ― 3.69 (m, 2H), 3.67 ― 3.57 (m, 5H), 3.55 ― 3.46 (m, 3H), 3.26 ― 3.17 (m, 4H), 3.13 ― 3.01 (m, 8H), 2.96 ― 2.88 (m, 2H), 2.79 ― 2.72 (m, 1H), 2.06 ― 1.98 (m, 7H). LC-MS: m/z 1007.4 [M+H]+.
화합물 204:
N-((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)-1-(4-(3-((2-(디에틸아미노)에틸)카르바모일)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 10.5 Hz, 1H), 7.53 ― 7.42 (m, 4H), 7.38 ― 7.29 (m, 2H), 7.25 ― 7.22 (m, 2H), 6.89 ― 6.70 (m, 2H), 6.33 ― 6.23 (m, 2H), 5.82 (d, J = 10.1 Hz, 1H), 4.37 ― 4.29 (m, 4H), 4.20 ― 4.07 (m, 2H), 3.74 ― 3.67 (m, 1H), 3.54 ― 3.52 (m, 2H), 3.18 ― 3.13 (m, 8H), 3.03 ― 2.99 (m, 1H), 2.95 ― 2.90 (m, 3H), 2.47 (s, 3H), 2.21 ― 2.02 (m, 5H), 1.90 ― 1.83 (m, 8H), 1.78 ― 1.74 (m, 1H), 0.90 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1061.5 [M+H]+.
화합물 205:
N-((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)-1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 10.4 Hz, 1H), 7.54 ― 7.45 (m, 4H), 7.39 ― 7.29 (m, 4H), 6.93 ― 6.74 (m, 1H), 6.66 (s, 1H), 6.35 ― 6.23 (m, 2H), 5.83 (d, J = 12.0 Hz, 1H), 4.42 ― 4.26 (m, 5H), 4.21 ― 4.07 (m, 2H), 3.77 ― 3.62 (m, 2H), 3.57 ― 3.55 (m, 2H), 3.41 ― 3.36 (m, 3H), 3.21 ― 3.10 (m, 3H), 3.01 ― 2.89 (m, 5H), 2.68 ― 2.59 (m, 6H), 2.47 (s, 3H), 2.25 ― 2.02 (m, 6H), 1.93 ― 1.88 (m, 1H), 1.82 ― 1.71 (m, 4H), 1.34 ― 1.28 (m, 4H), 1.05 (t, J = 7.2 Hz, 6H), 0.86 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1035.5 [M+H]+.
화합물 206:
(S)-4-(4-((4-(4-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드, 트리플루오로아세트산. 1H NMR(400 MHz, MeOD) δ 7.84 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.56 ― 7.46 (m, 4H), 7.44 ― 7.30 (m, 2H), 6.92 ― 6.67 (m, 2H), 6.30 (d, J = 16.1 Hz, 2H), 5.84 (d, J = 11.1 Hz, 1H), 4.47 ― 4.24 (m, 5H), 4.21 ― 4.04 (m, 1H), 4.04 ― 3.72 (m, 8H), 3.69 ― 3.57 (m, 5H), 3.56 ― 3.38 (m, 7H), 3.27 ― 3.18 (m, 2H), 3.16 ― 2.91 (m, 6H), 2.90 ― 2.66 (m, 2H), 2.13 ― 1.77 (m, 5H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1144.5 [M+H]+.
화합물 207:
(S)-4-(4-((4-(4-(2-((7-(8-클로로나프탈렌-1-일)-4-(3-(시아노메틸)-4-(2-플루오로아크릴로일)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.55 ― 7.47 (m, 5H), 7.40 ― 7.33 (m, 2H), 6.75 (s, 1H), 6.27 (s, 1H), 5.39 ― 5.28 (m, 2H), 4.40 ― 4.20 (m, 6H), 4.01 ― 3.95 (m, 3H), 3.65 ― 3.58 (m, 5H), 3.49 ― 3.41 (m, 5H), 3.15 ― 2.96 (m, 8H), 2.05 ― 1.93 (m, 4H), 1.71 ― 1.60 (m, 4H), 1.07 ― 1.00 (m, 4H), 0.94 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1163.9 [M+H]+.
화합물 208:
(S)-4-(4-((4-(4-(2-((7-(8-클로로나프탈렌-1-일)-4-(3-(시아노메틸)-4-프로피오닐피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR(400 MHz, MeOD) δ 7.82 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.54 ― 7.45 (m, 4H), 7.38 ― 7.28 (m, 4H), 6.68 (s, 1H), 6.30 (s, 1H), 4.53 ― 4.48 (m, 2H), 4.34 ― 4.27 (m, 1H), 4.18 ― 4.13 (m, 1H), 4.02 ― 3.92 (m, 3H), 3.71 ― 3.48 (m, 9H), 3.23 ― 3.10 (m, 3H), 3.04 ― 2.93 (m, 4H), 2.87 ― 2.78 (m, 3H), 2.72 ― 2.47 (m, 8H), 2.16 ― 2.08 (m, 2H), 2.03 (s, 3H), 1.82 ― 1.66 (m, 4H), 1.19 ― 1.13 (m, 3H), 0.86 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1146.5 [M+H]+.
화합물 209:
(S)-4-(4-((4-(9-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)-3,9-디아자스피로[5.5]운데칸-3-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 7.6 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.65 ― 7.60 (m, 2H), 7.56 ― 7.47 (m, 4H), 7.42 ― 7.28 (m, 2H), 6.90 ― 6.72 (m, 2H), 6.30 (d, J = 18.2 Hz, 2H), 5.84 (d, J = 10.2 Hz, 1H), 4.81 ― 4.70 (m, 3H), 4.42 ― 4.20 (m, 5H), 4.03 ― 3.95 (m, 2H), 3.87 ― 3.67 (m, 2H), 3.65 ― 3.46 (m, 12H), 3.27 ― 3.17 (m, 3H), 3.15 ― 2.87 (m, 7H), 2.81 ― 2.69 (m, 1H), 2.06 ― 1.89 (m, 6H), 1.83 ― 1.61 (m, 5H), 1.58 ― 1.40 (m, 2H), 1.32 ― 1.26 (m, 1H), 0.94 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1210.7 [M+H]+.
화합물 210:
(S)-4-(4-((4-(9-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)-3,9-디아자스피로[5.5]운데칸-3-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.85 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.57 ― 7.46 (m, 4H), 7.44 ― 7.31 (m, 2H), 6.89 ― 6.69 (m, 2H), 6.36 ― 6.21 (m, 2H), 5.85 (d, J = 10.7 Hz, 1H), 4.53 (d, J = 14.7 Hz, 1H), 4.45 ― 4.27 (m, 4H), 4.20 ― 4.05 (m, 1H), 3.90 ― 3.77 (m, 2H), 3.71 ― 3.44 (m, 14H), 3.27 ― 3.19 (m, 3H), 3.15 ― 2.92 (m, 6H), 2.86 ― 2.73 (m, 1H), 2.01 ― 1.83 (m, 6H), 1.83 ― 1.56 (m, 5H), 1.55 ― 1.38 (m, 2H), 1.35 ― 1.22 (m, 1H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1130.5 [M+H]+.
화합물 211:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-카르보닐)피페리딘-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 8.45 (br, 5H), 7.83 (d, J = 8.8 Hz, 1H), 7.68 (s, 1H), 7.53 (d, J = 7.5 Hz, 2H), 7.40 ― 7.18 (m, 7H), 6.69 (s, 1H), 6.28 (s, 2H), 4.58 (m, 4H), 4.53 ― 4.48 (m, 3H), 4.19 (m, 2H), 4.05 ― 3.98 (m, 2H), 3.72 (m, 2H), 3.48 (m, 8H), 3.07 ― 3.00 (m, 4H), 2.61 (m, 3H), 2.23 ― 2.15 (m, 2H), 2.03 (m, 5H), 1.89 (m, 8H), 0.89 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1034.5 [M+H]+.
화합물 212:
(S)-4-(4-((1-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.81 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.59 ― 7.46 (m, 2H), 7.32 (m, 7H), 6.81 (s, 1H), 6.66 (s, 1H), 6.38 ―6.23 (m, 2H), 5.83 (m, 1H), 4.50 (m, 4H), 4.31 (m, 2H), 4.04 (m, 7H), 3.73 (m, 1H), 3.59 (m, 1H), 3.19 (m, 3H), 3.14 ― 3.04 (m, 5H), 2.99 ― 2.87 (m, 2H), 2.81 (m, 2H), 2.68 (m, 5H), 2.56 (m, 1H), 2.25 (m, 2H), 1.76 (m, 9H), 0.86 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1143.5 [M+H]+.
화합물 213:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.85 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.51 (dd, J = 11.7, 7.4 Hz, 4H), 7.37 (dd, J = 10.6, 8.6 Hz, 4H), 6.90 ― 6.73 (m, 2H), 6.37 ― 6.11 (m, 2H), 5.85 (d, J = 10.5 Hz, 1H), 4.72 (dd, J = 11.5, 5.7 Hz, 2H), 4.34 (d, J = 16.1 Hz, 3H), 4.12 (d, J = 3.9 Hz, 1H), 3.84 (dd, J = 18.4, 9.2 Hz, 3H), 3.61 (dd, J = 12.6, 2.6 Hz, 3H), 3.52 ― 3.46 (m, 3H), 3.40 ― 3.37 (m, 3H), 3.27 ― 3.22 (m, 2H), 3.13 (t, J = 13.1 Hz, 8H), 2.79 (dd, J = 8.0, 7.1 Hz, 1H), 1.97 (s, 2H). LC-MS: m/z 896.8 [M+H]+.
화합물 214:
N-((3S,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)-1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.79 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.54 ― 7.46 (m, 2H), 7.37 ― 7.31 (m, 2H), 7.23 (dd, J = 8.4, 2.1 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 6.80 (s, 1H), 6.70 (s, 1H), 6.29 (d, J = 13.2 Hz, 2H), 5.83 (m, 1H), 4.58 ― 4.43 (m, 2H), 4.40 ― 4.23 (m, 4H), 4.13 (m, 2H), 3.68 (m, 3H), 3.17(m, 6H), 3.02 ― 2.98 (m, 1H), 2.92 ― 2.86 (m, 2H), 2.75 (m, 4H), 2.56 (m, 1H), 2.43 (m, 3H), 2.28 (m, 1H), 1.92 ― 1.83 (m, 3H), 1.71 (m, 5H), 1.30 (m, 1H), 0.90 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1035.4 [M+H]+.
화합물 215:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((2S,4R)-4-((4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)아미노)-1-메틸피롤리딘-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.63 ― 7.47 (m, 5H), 7.37 (dt, J = 6.9, 3.3 Hz, 4H), 6.89 (s, 1H), 6.75 (s, 1H), 6.30 (d, J = 17.2 Hz, 1H), 6.19 (s, 1H), 5.84 (d, J = 10.6 Hz, 1H), 4.79 ― 4.75 (m, 1H), 4.62 (m, 2H), 4.32 (m, 5H), 4.03 (m, 4H), 3.76 (m, 1H), 3.63 (m, 1H), 3.22 (m, 1H), 3.16 ― 2.98 (m, 6H), 2.93 (m, 1H), 2.78 (m, 1H), 2.54 (m, 2H), 1.02 (m, 7H). LC-MS: m/z 924.3 [M+H]+.
화합물 216:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(2,4-디히드록시-5-이소프로필벤질)피페라진-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.54 ― 7.45 (m, 2H), 7.39 ― 7.28 (m, 2H), 6.90 ― 6.69 (m, 2H), 6.35 ― 6.18 (m, 2H), 5.82 (d, J = 10.8 Hz, 1H), 4.49 (t, J = 5.4 Hz, 2H), 4.36 ― 4.01 (m, 4H), 3.75 ― 3.46 (m, 5H), 3.25 ― 3.01 (m, 6H), 2.95 ― 2.77 (m, 4H), 2.75 ― 2.52 (m, 7H), 1.34 ― 1.26 (m, 2H), 1.15 (d, J = 6.9 Hz, 6H). LC-MS: m/z 765.4 [M+H]+.
화합물 217:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(9-(2,4-디히드록시-5-이소프로필벤질)-3,9-디아자스피로[5.5]운데칸-3-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 7.8 Hz, 1H), 7.70 ― 7.64 (m, 1H), 7.54 ― 7.45 (m, 2H), 7.40 ― 7.28 (m, 2H), 6.94 ― 6.72 (m, 2H), 6.28 (d, J = 17.0 Hz, 1H), 6.22 (s, 1H), 5.83 (d, J = 10.0 Hz, 1H), 4.50 (t, J = 5.6 Hz, 2H), 4.33 ― 4.27 (m, 1H), 4.23 ― 3.98 (m, 3H), 3.76 ― 3.53 (m, 5H), 3.51 ― 3.40 (m, 1H), 3.24 ― 3.04 (m, 6H), 2.94 ― 2.87 (m, 1H), 2.82 (t, J = 5.6 Hz, 2H), 2.75 ― 2.55 (m, 9H), 1.32 ― 1.26 (m, 8H), 1.15 (d, J = 6.9 Hz, 6H). LC-MS: m/z 833.2 [M+H]+.
화합물 218:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(9-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)-3,9-디아자스피로[5.5]운데칸-3-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.1 Hz, 1H), 7.70 (dd, J = 7.7, 2.5 Hz, 1H), 7.58 ― 7.49 (m, 4H), 7.42 ― 7.32 (m, 4H), 6.88 ― 6.78 (m, 2H), 6.29 (d, J = 16.9 Hz, 1H), 6.22 (s, 1H), 5.84 (d, J = 10.6 Hz, 1H), 4.77 ― 4.66 (m, 3H), 4.38 ― 4.20 (m, 5H), 4.17 ― 4.10 (m, 1H), 3.74 (t, J = 17.6 Hz, 1H), 3.65 ― 3.49 (m, 12H), 3.28 ― 3.16 (m, 5H), 3.14 ― 2.86 (m, 8H), 2.80 ― 2.68 (m, 1H), 2.01 ― 1.87 (m, 6H), 1.36 ― 1.24 (m, 5H), 1.01 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1104.0 [M+H]+.
화합물 219:
(S)-4-(4-((4-(3-(((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)아제티딘-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 15.9 Hz, 1H), 7.62 ― 7.48 (m, 4H), 7.47 ― 7.30 (m, 4H), 6.90 ― 6.71 (m, 2H), 6.31 (d, J = 16.6 Hz, 1H), 6.22 (s, 1H), 5.85 (d, J = 10.3 Hz, 1H), 4.75 ― 4.62 (m, 2H), 4.61 ― 4.49 (m, 1H), 4.48 ― 4.29 (m, 5H), 4.26 ― 4.08 (m, 3H), 4.03 ― 3.94 (m, 2H), 3.93 ― 3.67 (m, 3H), 3.67 ― 3.41 (m, 5H), 3.27 ― 2.58 (m, 9H), 2.09 ― 1.79 (m, 7H), 1.45 ― 1.14 (m, 1H). LC-MS: m/z 1074.0 [M+H]+.
화합물 220:
(S)-4-(4-((4-(3-(((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)아제티딘-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR(400 MHz, MeOD) δ 7.84 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.57 ― 7.44 (m, 4H), 7.41 ― 7.34 (m, 2H), 6.75 (s, 2H), 6.37 ― 6.17 (m, 2H), 5.84 (d, J = 10.9 Hz, 1H), 5.04 (d, J = 36.6 Hz, 1H), 4.64 (d, J = 5.3 Hz, 2H), 4.51 ― 4.28 (m, 6H), 4.15 (dd, J = 18.8, 9.2 Hz, 3H), 3.98 (q, J = 9.2 Hz, 2H), 3.93 ― 3.69 (m, 3H), 3.59 (dt, J = 41.9, 16.1 Hz, 4H), 3.25 ― 2.92 (m, 7H), 2.82 ― 2.60 (m, 2H), 2.05 ― 1.83 (m, 4H), 1.32 (dd, J = 13.3, 5.6 Hz, 2H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1102.0 [M+H]+.
화합물 221:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤조일)아제티딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.3 Hz, 2H), 7.57 ― 7.44 (m, 4H), 7.41 ― 7.34 (m, 2H), 6.93 ― 6.58 (m, 2H), 6.37 ― 6.17 (m, 2H), 5.84 (d, J = 10.9 Hz, 1H), 5.12 ― 4.90 (m, 1H), 4.64 (d, J = 5.3 Hz, 2H), 4.51 ― 4.28 (m, 6H), 4.26 ― 4.06 (m, 3H), 4.02 ― 3.94 (m, 2H), 3.93 ― 3.69 (m, 3H), 3.64 ― 3.48 (m, 4H), 3.25 ― 2.92 (m, 7H), 2.82 ― 2.60 (m, 2H), 2.05 ― 1.83 (m, 4H), 1.35 ― 1.28 (m, 2H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 896.0 [M+H]+.
화합물 222:
(S)-4-(4-((4-(4-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.59 ― 7.48 (m, 4H), 7.48 ― 7.30 (m, 4H), 6.89 ― 6.74 (m, 2H), 6.29 (d, J = 17.2 Hz, 1H), 6.22 (s, 1H), 5.84 (d, J = 10.3 Hz, 1H), 4.79 ― 4.72 (m, 2H), 4.41 ― 4.23 (m, 4H), 4.04 ― 3.86 (m, 6H), 3.80 ― 3.54 (m, 7H), 3.52 ― 3.38 (m, 6H), 3.25 ― 3.16 (m, 2H), 3.14 ― 2.99 (m, 4H), 2.98 ― 2.87 (m, 2H), 2.85 ― 2.65 (m, 1H), 2.06 ― 1.92 (m, 7H), 1.33 ― 1.27 (m, 2H). LC-MS: m/z 1116.2 [M+H]+.
화합물 223:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(1-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페라진-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 7.4 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.56 ― 7.49 (m, 4H), 7.41 ― 7.32 (m, 4H), 6.91 ― 6.74 (m, 2H), 6.30 (d, J = 17.2 Hz, 1H), 6.18 (s, 1H), 5.84 (d, J = 10.5 Hz, 1H), 5.11 ― 4.96 (m, 2H), 4.41 ― 4.11 (m, 6H), 4.02 ― 3.85 (m, 4H), 3.83 ― 3.61 (m, 6H), 3.56 ― 3.39 (m, 9H), 3.26 ― 3.16 (m, 2H), 3.14 ― 2.64 (m, 7H), 2.04 ― 1.89 (m, 7H), 1.33 ― 1.28 (m, 1H). LC-MS: m/z 1107.4 [M+H]+.
화합물 224:
(S)-2-(4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페라진-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로아크릴로일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.86 ― 7.82 (m, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.58 ― 7.48 (m, 4H), 7.41 ― 7.32 (m, 4H), 6.86 (s, 1H), 6.22 (s, 1H), 5.42 ― 5.20 (m, 3H), 4.83 ― 4.77 (m, 3H), 4.44 ― 4.18 (m, 6H), 4.00 ― 3.86 (m, 4H), 3.68 ― 3.52 (m, 9H), 3.28 ― 2.96 (m, 9H), 2.04 ― 1.90 (m, 4H), 1.40 ― 1.27 (m, 3H), 1.00 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1053.5 [M+H]+.
화합물 225:
(R)-4-(4-((4-(4-(2-((7-(8-클로로나프탈렌-1-일)-4-(4-(2-플루오로아크릴로일)-3-(이소시아노메틸)피페라진-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 7.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.62 ― 7.58 (m, 2H), 7.54 ― 7.47 (m, 4H), 7.40 ― 7.31 (m, 2H), 6.74 (s, 1H), 6.27 (s, 1H), 5.40 ― 5.27 (m, 2H), 4.78 ― 4.73 (m, 2H), 4.54 ― 4.16 (m, 6H), 3.98 ― 3.86 (m, 3H), 3.79 ― 3.57 (m, 7H), 3.53 ― 3.38 (m, 6H), 3.24 ― 2.97 (m, 8H), 2.06 ― 1.91 (m, 4H), 1.35 ― 1.26 (m, 3H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1081.0 [M+H]+.
화합물 226:
(R)-1-(4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤조일)피페라진-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)-2-(이소시아노메틸)피페라진-1-일)-2-플루오로프로프-2-엔-1-온. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.56 ― 7.50 (m, 4H), 7.40 ― 7.32 (m, 4H), 6.90 (s, 1H), 6.21 (s, 1H), 5.44 ― 5.23 (m, 3H), 4.84 ― 4.76 (m, 3H), 4.40 ― 4.21 (m, 3H), 3.81 ― 3.60 (m, 7H), 3.54 ― 3.43 (m, 6H), 3.25 ― 2.92 (m, 5H), 1.34 ― 1.28 (m, 3H), 1.02 (d, J = 6.9 Hz, 6H). LC-MS: m/z 956.0 [M+H]+.
화합물 227:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-{[4-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]메틸}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.88 (s, 1H), 9.55 (s, 1H), 9.31 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.1, 4.3 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.56 ― 7.50 (m, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.39 ― 7.28 (m, 1H), 7.24 (d, J = 7.8 Hz, 2H), 7.10 (d, J = 8.2 Hz, 2H), 6.89 (s, 2H), 6.26 ― 6.15 (m, 2H), 5.78 (d, J = 10.8 Hz, 1H), 5.01 ― 4.73 (m, 1H), 4.51 ― 3.88 (m, 7H), 3.88 ― 3.57 (m, 2H), 3.62 (s, 1H), 3.49 (s, 2H), 3.25 ― 2.81 (m, 8H), 2.45 ― 2.23 (m, 10H), 2.21 ― 2.11 (m, 2H), 1.94 (s, 2H), 1.69 ― 1.41 (m, 3H), 1.28 (s, 2H), 1.24 (s, 3H), 1.14 (s, 1H). LC-MS: m/z 979.2 [M+H]+.
화합물 228:
2-[(2S)-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-[9-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)-3,9-디아자스피로[5.5]운데칸-3-일]-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘 -4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.87 (s, 1H), 9.55 (s, 1H), 9.31 (s, 1H), 7.96 ― 7.88 (m, 1H), 7.86 ― 7.68 (m, 1H), 7.65 ― 7.49 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.39 ― 7.28 (m, 3H), 7.18 ― 7.01 (m, 2H), 6.88 (d, J = 0.9 Hz, 1H), 6.82 ― 6.78 (m, 1H), 6.22 (d, J = 8.1 Hz, 1H), 6.17 (s, 1H), 5.82 ― 5.72 (m, 1H), 5.02 ― 4.82 (d, 1H), 4.60 ― 3.98 (m, 6H), 3.91 ― 3.70 (m, 2H), 3.65 ― 3.45 (m, 6H), 3.38 (s, 2H), 3.34 ― 3.26 (m, 4H), 3.24 ― 3.01 (m, 5H), 3.00 ― 2.81 (m, 3H), 2.80 ― 2.68 (m, 4H), 2.32 ― 2.22 (m, 3H), 2.02 ― 1.82 (m, 4H), 1.80 ― 1.64 (m, 2H), 1.56 (s, 4H), 1.24 (s, 1H), 0.85 (d, J = 7.0 Hz, 6H). LC-MS: m/z 1033.2 [M+H]+.
화합물 229:
(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일) 피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸) -N- [(3 R )-1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-3-일]-1-메틸피롤리딘-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.60 (s, 1H), 9.41 (s, 1H), 7.91 (dd, J = 8.3, 1.3 Hz, 1H), 7.74 (dd, J = 8.2, 3.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.61 ― 7.48 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.33 (dd, J = 11.7, 7.5 Hz, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 6.27 (s, 1H), 6.19 (dd, J = 16.5, 2.3 Hz, 1H), 5.78 (dd, J = 10.4, 2.3 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.48 ― 4.20 (m, 2H), 4.16 ― 4.10 (m, 1H), 4.06 ― 3.91 (m, 2H), 3.90 ― 3.54 (m, 2H), 3.50 ― 3.46 (m, 1H), 3.43 ― 3.37 (m, 2H), 3.15 ― 2.99 (m, 6H), 2.98 ― 2.80 (m, 3H), 2.73 (t, J = 8.5 Hz, 1H), 2.69 ― 2.54 (m, 2H), 2.39 (t, J = 8.8 Hz, 3H), 2.35 ― 2.26 (m, 3H), 2.19 ― 2.13 (m, 1H), 2.00 (s, 2H), 1.77 (s, 1H), 1.62 ― 1.54 (d, J = 15.3 Hz, 2H), 1.41 (d, J = 10.6 Hz, 1H), 1.31 ― 1.10 (m, 1H), 0.92 (dd, J = 6.9, 2.0 Hz, 6H). LC-MS: m/z 1035.2 [M+H]+.
화합물 230:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-[7-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)-2,7-디아자스피로[3.5]노난-2-카르보닐]-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.60 (s, 1H), 9.42 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.1, 4.4 Hz, 1H), 7.62 ― 7.48 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 18.0, 7.4 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.16 ― 7.08 (m, 2H), 6.83 (d, J = 27.4 Hz, 1H), 6.76 (s, 1H), 6.27 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.78 (d, J = 11.8 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.48 ― 3.91 (m, 6H), 3.90 ― 3.57 (m, 4H), 3.50 (s, 3H), 3.39 (s, 2H), 3.12 ― 3.06 (m, 2H), 2.97 (q, J = 6.9 Hz, 3H), 2.93 ― 2.82 (m, 2H), 2.68 (p, J = 1.9 Hz, 1H), 2.58 (d, J = 7.2 Hz, 2H), 2.40 (t, J = 9.0 Hz, 1H), 2.35 ― 2.19 (m, 6H), 2.09 (q, J = 9.8, 8.2 Hz, 1H), 1.84 ― 1.73 (m, 1H), 1.66 (s, 4H), 0.94 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1061.2 [M+H]+.
화합물 231:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)아제티딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.83 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.56 ― 7.47 (m, 4H), 7.37 (dd, J = 15.1, 7.7 Hz, 4H), 6.86 ― 6.76 (m, 2H), 6.29 (d, J = 16.8 Hz, 1H), 6.23 ― 6.18 (m, 1H), 5.83 (d, J = 10.7 Hz, 1H), 4.54 ― 4.43 (m, 5H), 4.39 ― 4.31 (m, 2H), 4.28 ― 4.11 (m, 6H), 3.74 (dd, J = 16.3, 7.5 Hz, 1H), 3.66 ― 3.53 (m, 2H), 3.25 ― 3.16 (m, 2H), 3.13 ― 2.98 (m, 3H), 2.94 ― 2.87 (m, 1H), 2.83 ― 2.70 (m, 1H), 1.32 ― 1.26 (m, 2H), 0.97 (d, J = 6.9 Hz, 6H). LC-MS: m/z 881.2 [M+H]+.
화합물 232:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((1-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)아제티딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.56 ― 7.45 (m, 4H), 7.42 ― 7.28 (m, 4H), 6.90 ― 6.78 (m, 2H), 6.29 (d, J = 16.3 Hz, 1H), 6.20 ― 6.13 (m, 1H), 5.84 (d, J = 10.4 Hz, 1H), 4.58 ― 4.40 (m, 5H), 4.39 ― 4.08 (m, 8H), 3.81 ― 3.70 (m, 1H), 3.68 ― 3.50 (m, 2H), 3.27 ― 3.18 (m, 2H), 3.14 ― 2.87 (m, 3H), 2.84 ― 2.68 (m, 1H), 1.98 (s, 3H), 1.32 ― 1.26 (m, 2H). LC-MS: m/z 853.3 [M+H]+.
화합물 233:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-{4-[4-({4-[3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-카르보닐]피페리딘-1-일}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.90 (s, 1H), 9.56 (s, 1H), 9.35 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.74 (dd, J = 8.1, 4.3 Hz, 1H), 7.60 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 17.6, 7.5 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.14 ― 7.09 (m, 2H), 6.83 (s, 2H), 6.24 (s, 1H), 6.21 ― 6.16 (m, 1H), 5.88 ― 5.72 (m, 1H), 4.96 ― 4.76 (m, 1H), 4.40 ― 4.12 (m, 4H), 4.03 ― 3.94 (m, 3H), 3.83 ― 3.49 (m, 3H), 3.44 (s, 7H), 3.25 ― 3.01 (m, 4H), 3.00 ― 2.93 (m, 2H), 2.91 ― 2.71 (m, 4H), 2.41 ― 2.23 (m,10H), 2.12 ― 1.91 (m, 3H), 1.53 (s, 5H), 1.24 (s, 1H), 0.97 (t, J = 7.5 Hz, 3H). LC-MS: m/z 1090.2 [M+H]+.
화합물 234:
4-{4-[(4-{1-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]피페리딘-4-카르보닐}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- 메틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.55 (s, 1H), 9.76 (s, 1H), 8.89 (d, J = 4.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.1, 4.3 Hz, 1H), 7.61 ― 7.50 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.44 ― 7.36 (m, 1H), 7.33 ― 7.27 (m,5H), 6.85 (s, 1H), 6.59 (s, 1H), 6.34 (s, 1H), 6.20 ― 6.16 (m, 1H), 5.79 ― 5.76 (m, 1H), 4.79 ― 4.76 (m, 1H), 4.51 ― 4.11 (m, 4H), 4.08 ― 3.95 (m, 2H), 3.91 ― 3.66 (m, 2H), 3.58 ― 3.41 (m, 8H), 3.24 ― 2.74 (m, 12H), 2.68 (t, J = 3.2 Hz, 4H), 2.38 (s, 2H), 2.35 ― 2.21 (m, 6H), 2.08 ― 1.93 (m, 3H), 1.54 (s, 5H) , 0.81 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1145.2 [M+H]+.
화합물 235:
N-((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)-1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-((2,2,2-트리플루오로에틸)카르바모일)-4H-1,2,4-트리아졸-4-일)벤질)-N-메틸피페리딘-4-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.85 (d, J = 8.1 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.3 Hz, 2H), 7.58 ― 7.47 (m, 5H), 7.46 ― 7.30 (m, 3H), 6.76 (s, 1H), 6.33 ― 6.28 (m, 2H), 5.84 (d, J = 10.4 Hz, 1H), 4.79 ― 4.70 (m, 2H), 4.62 ― 4.23 (m, 8H), 4.03 ― 3.94 (m, 3H), 3.90 ― 3.78 (m, 3H), 3.66 ― 3.52 (m, 5H), 3.20 ― 2.89 (m, 15H), 2.11 ― 1.90 (m, 5H), 1.34 ― 1.27 (m, 1H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1158.6 [M+H]+.
화합물 236:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(4-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)피페리딘-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.85 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.53 (dd, J = 15.5, 7.7 Hz, 4H), 7.42 ― 7.33 (m, 4H), 6.91 ― 6.74 (m, 2H), 6.31 (d, J = 16.8 Hz, 1H), 6.19 (s, 1H), 5.85 (d, J = 10.4 Hz, 1H), 4.56 ― 4.14 (m, 6H), 3.87 ― 3.39 (m, 11H), 3.23 (s, 7H), 3.12 ― 2.67 (m, 9H), 2.18 ― 2.11 (m, 2H), 2.03 ― 1.94 (m, 5H), 1.31 (m, 1H). LC-MS: m/z 979.4 [M+H]+.
화합물 237:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)피페리딘-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.52 (ddd, J = 12.8, 10.1, 6.7 Hz, 4H), 7.44 ― 7.28 (m, 4H), 6.84 (s, 2H), 6.34 ― 6.19 (m, 2H), 5.84 (d, J = 10.1 Hz, 1H), 4.81 (s, 3H), 4.51 ― 4.00 (m, 6H), 3.77 (m, 4H), 3.61 (s, 4H), 3.19 (m, 7H), 3.06 (m, 2H), 3.00 ― 2.73 (m, 6H), 2.21 ― 1.86 (m, 5H), 1.33 (m, 5H), 0.99 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1007.5 [M+H]+.
화합물 238:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(4-((4-(4-(3-(2,5-디히드록시-4-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-1-일)메틸)피페리딘-1-카르보닐)피페리딘-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.97 (t, J = 7.0 Hz, 1H), 7.82 (d, J = 2.9 Hz, 1H), 7.67 (s, 1H), 7.53 ― 7.48 (m, 2H), 7.36 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.3 Hz, 2H), 6.74 (d, J = 47.0 Hz, 2H), 6.29 (d, J = 10.8 Hz, 2H), 5.84 (s, 1H), 4.55 (d, J = 23.4 Hz, 6H), 4.30 (d, J = 16.8 Hz, 2H), 4.17 (s, 1H), 4.05 (s, 2H), 3.77 ― 3.58 (m, 3H), 3.48 (s, 1H), 3.13 (s, 8H), 2.99 (d, J = 6.7 Hz, 1H), 2.90 (s, 3H), 2.71 (s, 2H), 2.62 (d, J = 6.6 Hz, 3H), 2.36 (s, 2H), 2.18 (d, J = 7.8 Hz, 1H), 2.03 (s, 2H), 1.76 (d, J = 15.0 Hz, 5H), 1.29 (s, 6H), 1.17 (s, 3H), 0.88 (d, J = 6.9 Hz, 6H) LC-MS: m/z 1131.6 [M+H]+.
화합물 239:
(S)-4-(4-((4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-메틸-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.55 ― 7.47 (m, 4H), 7.41 ― 7.31 (m, 2H), 6.89 ― 6.72 (m, 2H), 6.30 (d, J = 16.4 Hz, 2H), 5.84 (d, J = 10.3 Hz, 1H), 4.81 ― 4.73 (m, 3H), 4.44 ― 4.30 (m, 4H), 4.27 ― 4.06 (m, 2H), 4.02 ― 3.67 (m, 7H), 3.65 ― 3.54 (m, 4H), 3.42 ― 3.33 (m, 4H), 3.27 ― 2.98 (m, 8H), 2.96 ― 2.89 (m, 1H), 2.84 (s, 3H), 2.81 ― 2.70 (m, 1H), 2.08 ― 2.00 (m, 4H), 1.34 ― 1.28 (m, 1H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1076.5 [M+H]+.
화합물 240:
4-(4-{[4-(4-{[(2 R ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-2-일]메틸}피페라진-1-카르보닐)피페리딘-1-일]메틸}페닐)-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.62 (s, 1H), 9.75 (s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.0, 4.4 Hz, 1H), 7.61 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.40 ― 7.34 (m, 3H), 7.29 (d, J = 8.4 Hz, 2H), 6.85 (s, 1H), 6.58 (s, 1H), 6.34 (s, 1H), 6.18 (dd, J = 16.7, 2.3 Hz, 1H), 5.77 (dd, J = 10.4, 2.3 Hz, 1H), 5.03-4.72 (m, 1H), 4.52 ― 4.09 (m, 3H), 4.09 ― 3.92 (m, 3H), 3.88 ― 3.61 (m, 2H), 3.46 (d, J = 8.2 Hz, 7H), 3.27 ― 2.98 (m, 7H), 2.97 ― 2.85 (m, 2H), 2.84 ― 2.79 (m, 2H), 2.78 ― 2.61 (m, 2H), 2.60 ― 2.52 (m, 2H), 2.47 ― 2.25 (m, 8H), 2.20 (dd, J = 12.6, 6.8 Hz, 1H), 1.99 (s, 2H), 1.85 (s, 2H), 1.73-1.32 (m, 6H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1173.1 [M+H]+.
화합물 241:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.95 (s, 1H), 9.60 (s, 1H), 9.39 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.82 ― 7.70 (m, 1H), 7.60 ― 7.51 (m, 2H), 7.48 ― 7.41 (m, 1H), 7.40 ― 7.34 (m, 1H), 7.29 ― 7.24 (m, 2H), 7.23 (s, 2H), 7.15 ― 7.08 (m,1H), 6.97 (s, 2H), 6.27 (s, 1H), 6.19 (d, J = 16.5 Hz, 1H), 5.78 (d, J = 10.6 Hz, 1H), 4.96 ― 4.70 (m, 1H), 4.60 ― 4.14 (m, 4H), 4.12 ― 3.95 (m, 2H), 3.91 ― 3.65 (m, 2H), 3.50 ― 3.46 (m, 3H), 3.25 ― 2.82 (m, 12H), 2.80 ― 2.75 (m, 1H), 2.52 ― 2.10 (m, 9H), 1.88 ― 1.81 (m, 1H), 1.11 ― 0.80 (m, 6H). LC-MS: m/z 993.2 [M+H]+.
화합물 242:
(S)-4-(4-((4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2-(4-(메틸술포닐)피페라진-1-일)에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.50 (dd, J = 16.1, 7.9 Hz, 4H), 7.38 ― 7.29 (m, 4H), 6.74 (d, J = 56.5 Hz, 2H), 6.28 (d, J = 18.4 Hz, 2H), 5.83 (d, J = 10.4 Hz, 1H), 4.58 (s, 4H), 4.50 (s, 2H), 4.30 (d, J = 17.0 Hz, 2H), 4.16 (s, 1H), 4.10 ― 4.02 (m, 1H), 3.71 (s, 1H), 3.61 (s, 7H), 3.43 (m, 3H), 3.20 (s, 5H), 3.09 (s, 3H), 3.04 ― 2.95 (m, 2H), 2.91 (m, 1H), 2.84 (s, 4H), 2.67 (s, 2H), 2.57 (m, 5H), 2.49 (m, 4H), 2.28 (s, 2H), 1.81 ― 1.70 (m, 4H), 1.29 (s, 1H), 0.87 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1253.0 [M+H]+.
화합물 243:
(S)-N-(2-(4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)에틸)-5-(2,4-디히드록시-5-이소프로필페닐)-4-페닐-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.81 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.53 ― 7.45 (m, 5H), 7.35 (ddd, J = 15.9, 10.2, 4.3 Hz, 4H), 6.71 (d, J = 72.7 Hz, 2H), 6.29 (d, J = 20.7 Hz, 2H), 5.82 (d, J = 10.6 Hz, 1H), 4.58 (s, 1H), 4.49 (t, J = 5.5 Hz, 2H), 4.33 ― 4.27 (m, 1H), 4.17 (m, 2H), 3.72 (m, 1H), 3.55 (s, 5H), 3.43 (m, 3H), 3.25 ― 2.87 (m, 9H), 2.80 (m, 2H), 2.67 (m, 2H), 2.58 ― 2.43 (m, 6H), 2.24 (t, J = 11.6 Hz, 2H), 1.73 (m, 4H), 1.31 (m, 1H), 0.85 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1076.5 [M+H]+.
화합물 244:
4-(4-{[4-(4-{[(2 R ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-2-일]메틸}피페라진-1-카르보닐)피페리딘-1-일]메틸}페닐) -N- 에틸-5-(5-에틸-2,4-디히드록시페닐)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.39 (s, 1H), 9.68 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.1, 4.4 Hz, 1H), 7.61 ― 7.48 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.37 ― 7.28 (m, 3H), 7.25 (d, J = 8.0 Hz, 2H), 6.84 (s, 1H), 6.53 (s, 1H), 6.32 (s, 1H), 6.18 (d, J = 16.8 Hz, 1H), 5.77 (d, J = 10.6 Hz, 1H), 4.99 ― 4.75 (m, 1H), 4.46 ― 4.11 (m, 3H), 4.01 (s, 3H), 3.89 ― 3.68 (m, 3H), 3.47 (s, 8H), 3.17 (p, J = 7.2 Hz, 2H), 3.12 ― 2.95 (m, 8H), 2.92 ― 2.85 (m, 1H), 2.80 (d, J = 10.7 Hz, 2H), 2.72 ― 2.68 (m, 1H), 2.37 (s, 5H), 2.29 (s, 1H), 2.21 (q, J = 7.5 Hz, 3H), 1.99 (s, 2H), 1.85 (s, 2H), 1.56 (s, 6H), 1.04 (t, J = 7.2 Hz, 3H), 0.83 (t, J = 7.5 Hz, 3H). LC-MS: m/z 1159.2 [M+H]+.
화합물 245:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-({4-[1-({4-[3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-일}메틸)-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도 [3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.88 (s, 1H), 9.53 (s, 1H), 9.35 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 6.4 Hz, 1H), 7.54 (dt, J = 16.3, 7.9 Hz, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.41 ― 7.28 (m, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 6.80 (s, 2H), 6.24 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 5.01 ― 4.72 (m, 1H), 4.45 ― 4.13 (m, 2H), 4.10 ― 3.60 (m, 5H), 3.41 (s, 6H), 3.24 ― 2.84 (m, 6H), 2.76 (d, J = 10.5 Hz, 2H), 2.72 ― 2.61 (m, 2H), 2.43 ― 2.27 (m, 12H), 2.24 ― 2.11 (m, 2H), 1.95 (s, 2H), 1.84 (s, 2H), 1.53 (s, 6H), 1.24 (s, 1H), 0.95 (t, J = 7.4 Hz, 3H). LC-MS: m/z 1104.7 [M+H]+.
화합물 246:
2-[(2 S )-4-(2-{[(2 S ,4 S )-4-{4-[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-카르보닐]피페리딘-1-일}-1-메틸피롤리딘-2-일]메톡시}-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.91 (s, 1H), 9.57 (s, 1H), 9.38 (s, 1H), 8.22 ― 8.15 (m, 1H),, 7.96 ― 7.89 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.58 ― 7.50 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 7.4 Hz, 1H), 7.17 ― 7.10 (m, 2H), 6.86 (s, 1H), 6.77 (s, 1H), 6.26 (s, 1H), 6.23 ― 6.14 (m, 1H), 5.83 ― 5.74 (m, 1H), 5.08 ― 4.72 (m,1H), 4.35 ― 4.27 (m, 3H), 4.24 ― 4.11 (m, 2H), 4.10 ― 3.94 (m, 3H), 3.45 (s, 7H), 3.27 ― 3.10 (m, 3H), 3.09 ― 2.91 (m, 7H), 2.88 ― 2.79 (m, 2H), 2.67 (p, J = 1.8 Hz, 2H), 2.52 (d, J = 1.8 Hz, 8H), 2.19 ― 1.85 (m, 3H), 1.54 (s, 5H), 0.94 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1070.4 [M+H]+.
화합물 247:
2-[(2 S )-4-(2-{[(2 S ,4 S )-4-{4-[4-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-카르보닐]피페리딘-1-일}-1-메틸 피롤리딘-2-일]메톡시}-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.86 (s, 1H), 9.54 (s, 1H), 9.30 (s, 1H), 8.22 ― 8.15 (m, 1H), 7.92 (dt, J = 7.8, 2.7 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.59 ― 7.50 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.30 ― 7.20 (m, 3H), 7.14 ― 7.08 (m, 2H), 6.89 (s, 2H), 6.22 (d, J = 5.7 Hz, 1H), 6.17 (d, J = 2.3 Hz, 1H), 5.79 ― 5.76 (m, 1H), 4.98 ― 4.77 (m, 1H), 4.29 (d, J = 4.9 Hz, 2H), 4.22 ― 3.93 (m, 5H), 3.44 (s, 8H), 3.31 (s, 3H), 3.11 ― 2.79 (m, 8H), 2.69 ― 2.54 (m, 2H), 2.41 ― 2.21 (m, 8H), 1.94 (s, 6H), 1.54 (s, 5H). LC-MS: m/z 1042.4 [M+H]+.
화합물 248:
2-[(2 S )-4-(2-{[(2 S ,4 S )-4-[9-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)-3,9-디아자스피로[5.5]운데칸-3-일]-1-메틸피롤리딘-2-일]메톡시}-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.91 (s, 1H), 9.57 (s, 1H), 9.40 (s, 1H), 8.19 ― 8.17 (m, 1H), 7.92 (dt, J = 7.8, 2.7 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.55 ― 7.52 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.27 ― 7.21 (m, 3H), 7.12 ― 7.10 (m, 2H), 6.86 (s, 1H), 6.75 (s, 1H), 6.26 (s, 1H), 6.19 (dd, J = 16.6, 2.3 Hz, 1H), 5.78 (dd, J = 10.4, 2.3 Hz, 1H), 4.98 ― 4.79 (m, 1H), 4.43 ― 4.00 (m, 7H), 3.56 ― 3.39 (m, 3H), 3.19 (s, 3H), 3.00 ― 2.93 (m, 8H), 2.56 (s, 1H), 2.33 ― 2.28 (m, 10H), 2.02 ― 1.97 (m, 1H), 1.54 (s,1H), 1.37 (s, 8H), 1.25 ― 1.23 (m, 1H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1027.4 [M+H]+.
화합물 249:
(S)-4-(4-((4-(4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-일)피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.50 (dd, J = 22.9, 7.9 Hz, 4H), 7.39 ― 7.30 (m, 4H), 6.67 (s, 2H), 6.29 (d, J = 16.7 Hz, 2H), 5.84 (s, 1H), 4.58 (s, 4H), 4.50 (s, 2H), 4.30 (d, J = 17.8 Hz, 2H), 4.16 (s, 2H), 3.70 (s, 1H), 3.58 (s, 6H), 3.22 ― 3.20 (m, 1H), 3.13 (s, 2H), 2.97 (m, 2H), 2.92 ― 2.88 (m, 1H), 2.82 (s, 2H), 2.68 (s, 1H), 2.60 (s, 2H), 2.55 (s, 2H), 2.32 (s, 1H), 2.21 (s, 2H), 2.12 (s, 2H), 2.03 (s, 1H), 1.87 (s, 2H), 1.79 (m, 2H), 1.70 (s, 2H), 1.58 (m, 2H), 1.29 (s, 2H), 1.17 (m, 2H), 0.87 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1145.6 [M+H]+.
화합물 250:
(S)-4-(4-((4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.81 (d, J = 7.7 Hz, 1H), 7.67 (d, J = 5.6 Hz, 1H), 7.53 ― 7.25 (m, 8H), 6.72 (d, J = 74.0 Hz, 2H), 6.33 ― 6.20 (m, 2H), 5.81 (s, 1H), 4.49 (s, 3H), 4.30 (m, 2H), 4.15 (s, 2H), 3.98 (m, 3H), 3.70 (s, 2H), 3.60 (s, 6H), 3.19 (d, 3H), 3.09 (s, 3H), 2.91 (s, 1H), 2.80 (s, 2H), 2.66 (s, 2H), 2.46 (d, 4H), 2.22 (m, 2H), 1.87 (s, 3H), 1.80 ― 1.68 (m, 4H), 1.28 (s, 1H). LC-MS: m/z 1116.5 [M+H]+.
화합물 251:
(S)-4-(4-((4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.55 ― 7.41 (m, 4H), 7.39 ― 7.28 (m, 2H), 7.24 (d, J = 8.3 Hz, 2H), 6.73 (s, 2H), 6.28 (d, J = 19.1 Hz, 2H), 5.83 (d, J = 11.0 Hz, 1H), 4.62 ― 4.45 (m, 5H), 4.21 (m, 5H), 3.75 ― 3.52 (m, 5H), 3.20 (m, 2H), 3.08 (s, 4H), 3.03 ― 2.99 (m, 1H), 2.91 (m, 1H), 2.81 (s, 2H), 2.68 (m, 7H), 2.52 (s, 4H), 2.26 (s, 2H), 2.01 ― 1.64 (m, 7H), 1.29 (s, 3H), 0.91 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1118.6 [M+H]+.
화합물 252:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-[4-({4-[3-(2,4―디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.81 (s, 1H), 9.53 (s, 1H), 9.30 (s, 1H), 8.01 ― 7.82 (m, 1H), 7.78 ― 7.70 (m, 1H), 7.61 ― 7.50 (m, 2H), 7.51 (s, 1H), 7.39 ― 7.29 (m, 1H), 7.28 ― 7.16 (m, 2H), 7.12 ― 7.05 (m, 2H), 6.90 ― 6.86 (m, 2H), 6.81 (s, 1H), 6.21 (d, J = 8.2 Hz, 1H), 6.16 (d, J = 2.1 Hz, 1H), 5.83 ― 5.72 (m, 1H), 5.05 ― 4.76 (m, 1H), 4.65 ― 3.90 (m, 6H), 3.88 ― 3.69 (m, 2H), 3.60 ― 3.55 (m, 1H), 3.54 ― 3.37 (m, 2H), 3.21 ― 3.00 (m, 4H), 2.99 ― 2.95 (m, 2H), 2.93 ― 2.85 (m, 2H), 2.60 ― 2.55 (m, 2H), 2.44 ― 2.32 (m, 7H), 2.30 ― 2.26 (d, J = 3.8 Hz, 4H), 2.11 ― 2.03 (m, 1H), 1.94 (s, 3H), 1.60 ― 1.44 (m, 1H). LC-MS: m/z 965.1 [M+H]+.
화합물 253:
(S)-4-(4-((4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) (400 MHz, MeOD) δ 7.83 ― 7.74 (m, 1H), 7.65 (dd, J = 16.4, 8.3 Hz, 1H), 7.55 ― 7.38 (m, 3H), 7.38 ― 7.20 (m, 4H), 7.15 ― 7.07 (m, 1H), 6.89 ― 6.47 (m, 2H), 6.28 (d, J = 10.1 Hz, 2H), 5.82 (d, J = 10.4 Hz, 1H), 4.67 (s, 1H), 4.45 (s, 1H), 4.31 (m, 2H), 4.17 (m, 1H), 4.05 (s, 1H), 4.03 ― 3.87 (m, 3H), 3.81 ― 3.33 (m, 7H), 3.22 ― 3.03 (m, 4H), 3.02 ― 2.78 (m, 5H), 2.66 (m, 3H), 2.44 (m, 3H), 2.38 ― 1.90 (m, 4H), 1.69 (m, 7H), 1.31 (m, 1H). LC-MS: m/z 1116.4 [M+H]+.
화합물 254:
(S)-4-(4-((4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.80 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 20.5 Hz, 3H), 7.38 ― 7.27 (m, 4H), 7.20 (d, J = 7.3 Hz, 1H), 6.91 ― 6.55 (m, 2H), 6.31 (dd, J = 18.4, 11.3 Hz, 2H), 5.83 (d, J = 9.3 Hz, 1H), 4.73 ― 4.63 (m, 2H), 4.46 (s, 1H), 4.28 (s, 2H), 4.17 (s, 1H), 4.07 (s, 1H), 3.96 (s, 1H), 3.68 (m, 2H), 3.58 (s, 2H), 3.48 (s, 2H), 3.41 (s, 3H), 3.15 (m, 4H), 2.96 (s, 3H), 2.86 (s, 2H), 2.67 (s, 4H), 2.54 (m, 6H), 2.45 (s, 5H), 2.29 (m, 4H), 2.17 (s, 1H), 2.02 (s, 1H), 1.72 (s, 3H), 1.60 (s, 1H), 1.31 (m, 4H), 0.85 (m, 6H). LC-MS: m/z 1188.5 [M+H]+.
화합물 255:
2-[(2 S )-4-(2-{[(2 S ,5 R )-5-({4-[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-일}메틸)-1-메틸피롤리딘-2-일]메톡시}-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.59 (s, 1H), 9.41 (s, 1H), 8.22 ― 8.15 (m, 1H), 7.96 ― 7.89 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.58 ― 7.50 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.25 (m, 3H), 7.12 (d, J = 8.1 Hz, 2H), 6.87 (s, 1H), 6.76 (s, 1H), 6.26 (s, 1H), 6.19 (m, 1H), 5.78 (d, J = 11.2 Hz, 1H), 5.08 ― 4.72 (m, 1H), 4.51 ― 4.10 (m, 4H), 4.04 (s, 3H), 3.57 (s, 1H), 3.41 (s, 7H), 3.18 (s, 3H), 2.99 (d, J = 6.8 Hz, 5H), 2.93 (d, J = 6.7 Hz, 2H), 2.78 (d, J = 10.6 Hz, 1H), 2.70 (s, 2H), 2.45 ― 2.28 (m, 8H), 2.25 ― 2.16 (m, 1H), 1.95 (s, 2H), 1.86 (s, 2H), 1.54 (s, 6H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1084.2 [M+H]+.
화합물 256:
2-[(2 S )-4-(2-{[(2 S ,5 R )-5-({4-[1-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-일}메틸)-1-메틸피롤리딘-2-일]메톡시}-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.88 (s, 1H), 9.55 (s, 1H), 9.32 (s, 1H), 8.22 ― 8.15 (m, 1H), 7.93 (dd, J = 6.8, 3.0 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.58 ― 7.42 (m, 3H), 7.23 (t, J = 7.3 Hz, 3H), 7.09 (d, J = 8.0 Hz, 2H), 6.88 (s, 2H), 6.31 ― 6.08 (m, 2H), 5.82 ― 5.74 (m, 1H), 5.06 ― 4.72 (m, 1H), 4.50 ― 4.08 (m, 4H), 4.03 (s, 3H), 3.41 (s, 7H), 3.18 (s, 3H), 3.09 ― 2.97 (m, 4H), 2.94 (s, 2H), 2.76 (d, J = 10.6 Hz, 2H), 2.73 ― 2.63 (m, 2H), 2.39 (s, 8H), 2.25 ― 2.17 (m, 1H), 2.09 ― 1.71 (m, 7H), 1.54 (s, 6H). LC-MS: m/z 1056.2 [M+H]+.
화합물 257:
(S)-4-(4-((4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.55 ― 7.44 (m, 4H), 7.40 ― 7.29 (m, 4H), 6.90 ― 6.73 (m, 1H), 6.67 (s, 1H), 6.29 (d, J = 16.9 Hz, 2H), 5.83 (d, J = 10.8 Hz, 1H), 4.53 ― 4.26 (m, 5H), 4.22 ― 3.98 (m, 3H), 3.75 ― 3.47 (m, 8H), 3.27 ― 3.08 (m, 7H), 3.02 ― 2.83 (m, 6H), 2.76 ― 2.63 (m, 3H), 2.59 ― 2.44 (m, 1H), 2.14 (m, 2H), 1.90 ― 1.65 (m, 6H), 1.23 ― 1.07 (m, 2H), 0.87 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1102.5 [M+H]+.
화합물 258:
(S)-4-(4-((4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.50 (dd, J = 17.4, 8.0 Hz, 4H), 7.39 ― 7.29 (m, 4H), 6.74 (d, J = 51.2 Hz, 2H), 6.28 (d, J = 17.1 Hz, 2H), 5.83 (d, J = 10.1 Hz, 1H), 4.55 (m, 5H), 4.37 ― 4.00 (m, 5H), 3.71 (m, 2H), 3.60 (m, 7H), 3.48 (s, 1H), 3.20 (m, 5H), 2.98 (m, 4H), 2.90 (s, 3H), 2.77 ― 2.63 (m, 3H), 2.58 (m, 4H), 2.32 (s, 3H), 2.17 (m, 2H), 1.91 (m, 2H), 1.79 (m, 2H), 1.70 (m, 2H), 1.61 (m, 2H), 1.30 (d, J = 7.4 Hz, 1H), 1.15 (t, J = 7.3 Hz, 3H), 0.87 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1173.6 [M+H]+.
화합물 259:
4-[4-({9-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3S)-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]-3,9-디아자스피로[5.5]운데칸-3-일}메틸)페닐]-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.59 (s, 1H), 9.76 (s, 1H), 8.96 (t, J = 5.9 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.2, 3.5 Hz, 1H), 7.59 ― 7.50 (m, 2H), 7.46 ― 7.42 (m, 1H), 7.39 ― 7.31 (m, 4H), 7.28 (d, J = 8.0 Hz, 2H), 6.85 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 10.4 Hz, 1H), 5.06 ― 4.96 (m,1H), 4.73 (t, J = 5.7 Hz, 1H), 4.27 ― 4.14 (m, 3H), 4.01 ― 3.86 (m,2H), 3.78 ― 3.69 (m, 2H), 3.46 ― 3.42 (m, 3H), 3.16 (p, J = 7.1 Hz, 3H), 3.10 ― 3.05 (m, 4H), 2.93 ― 2.86 (m, 3H), 2.34 ― 2.28 (m, 10H), 2.07 (s, 2H), 1.91 ― 1.84 (m, 2H), 1.40 (s, 9H), 1.24 (s, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1116.2 [M+H]+.
화합물 260:
4-(4-((4-((S)-4-(2-((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)-3-((디메틸아미노)메틸)피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.85 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.64 ― 7.35 (m, 8H), 6.93 ― 6.67 (m, 2H), 6.31 (d, J = 15.6 Hz, 2H), 5.85 (d, J = 10.3 Hz, 1H), 4.69 ― 4.52 (m, 3H), 4.44 ― 4.22 (m, 5H), 4.19 ― 4.01 (m, 2H), 3.82 ― 3.70 (m, 2H), 3.66 ― 3.47 (m, 6H), 3.44 ― 3.35 (m, 3H), 3.27 ― 3.18 (m, 3H), 3.15 ― 3.02 (m, 7H), 3.01 ― 2.86 (m, 9H), 2.07 ― 1.97 (m, 3H), 1.35 ― 1.27 (m, 3H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1119.5 [M+H]+.
화합물 261:
4-{4-[(4-{4-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]피페라진-1-카르보닐}피페리딘-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.47 (s, 1H), 9.76 (s, 1H), 9.58 (t, J = 6.5 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 6.4 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.57 ― 7.53 (m, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.39 ― 7.27 (m, 5H), 6.85 (s, 1H), 6.61 (s, 1H), 6.34 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 10.6 Hz, 1H), 4.97 ― 4.75 (m, 1H), 4.45 ― 4.12 (m, 5H), 4.05 ― 3.91 (m, 5H), 3.82 ― 3.70 (m, 2H), 3.50 ― 3.48 (m, 3H), 3.15 ― 3.03 (m, 4H), 3.02 ― 2.88 (s, 7H), 2.85 ― 2.73 (m, 4H), 2.42 ― 2.38 (m, 2H), 2.32 ― 2.20 (m, 6H), 2.12 ― 1.90 (m, 4H), 1.65 ― 1.52 (m, 5H), 1.22 (s, 1H),0.92 ― 0.78 (m, 6H). LC-MS: m/z 1213.1 [M+H]+.
화합물 262:
(S)-4-(4-((4-(1-(2-((4-(4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)피페리딘-4-카르보닐)피페라진-1-일)메틸)페닐)-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.57 ― 7.42 (m, 4H), 7.41 ― 7.26 (m, 4H), 6.95 ― 6.72 (m, 1H), 6.29 (d, J = 19.8 Hz, 2H), 5.83 (d, J = 9.9 Hz, 1H), 4.52 (m, 6H), 4.36 ― 4.25 (m, 2H), 4.23 ― 3.92 (m, 6H), 3.76 ― 3.47 (m, 8H), 3.27 ― 3.05 (m, 7H), 3.04 ― 2.88 (m, 6H), 2.80 ― 2.60 (m, 3H), 2.57 ― 2.39 (m, 1H), 2.20 ― 2.05 (m, 2H), 1.92 ― 1.74 (m, 4H), 1.68 (m, 2H), 1.39 ― 1.22 (m, 2H), 1.22 ― 1.02 (m, 3H), 0.87 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1184.5 [M+H]+.
화합물 263:
4-{4-[(4-{[(2 R ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-2-일]메틸}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.59 (s, 1H), 9.74 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.78 ― 7.70 (m, 1H), 7.54 (dt, J = 16.1, 7.9 Hz, 2H), 7.44 (td, J = 7.8, 1.4 Hz, 1H), 7.36 (d, J = 8.1 Hz, 3H), 7.28 (d, J = 8.3 Hz, 2H), 6.85 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.81 ― 5.73 (m, 1H), 5.06 ― 4.71 (m, 1H), 4.52 ― 3.90 (m, 6H), 3.89 ― 3.67 (m, 2H), 3.47 (s, 3H), 3.23 ― 2.78 (m, 10H), 2.38 (s, 12H), 2.22 ― 2.15 (m, 2H), 1.87 (s, 3H), 1.57 ― 1.42 (m, 2H), 1.24 (s, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1062.2 [M+H]+.
화합물 264:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-{4-[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-일}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.04 (s, 1H), 9.61 (s, 1H), 7.95 ― 7.88 (m, 1H), 7.74 (dd, J = 4.2 Hz, 1H), 7.61 ― 7.48 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 7.4 Hz, 1H), 7.17 (s, 3H), 7.04 (s, 1H), 6.85 (s, 1H), 6.39 (s, 1H), 6.18 (d, J = 16.5 Hz, 1H), 5.77 (d, J = 10.7 Hz, 1H), 4.96 ― 4.75 (s, 5H), 4.27 (d, J = 8.9 Hz, 1H), 4.19 (d, J = 15.7 Hz, 3H), 4.01 (d, J = 14.2 Hz, 2H), 3.49 (s, 2H), 3.39 (s, 1H), 3.30 (s, 2H), 3.08 (q, J = 6.9 Hz, 5H), 2.97 (s, 2H), 2.91 ― 2.87 (m, 3H), 2.48 (d, J = 2.7 Hz, 1H), 2.29 ― 2.23 (m, 9H), 2.02 (s, 2H), 1.53 (s, 1H), 1.36 (s, 9H), 1.13 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1104.1 [M+H]+.
화합물 265:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-{4-[1-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-일}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.88 (s, 1H), 9.56 (s, 1H), 9.32 (s, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.85 ― 7.70 (m, 1H), 7.68 ― 7.52 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.38 ― 7.30 (m, 1H), 7.24 (d, J = 7.9 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.88 (s, 2H), 6.31 ― 6.05 (m, 2H), 5.81 ― 5.73 (m, 1H), 5.02 ― 4.56 (m, 1H), 4.52 ― 3.61 (m, 8H), 3.53 ― 3.35 (m, 8H), 3.22 ― 2.84 (s, 8H), 2.82 ― 2.70 (m, 2H), 2.41 ― 2.13 (m, 9H), 2.10 ― 1.86 (m, 6H), 1.70 ― 1.44 (s, 5H), 1.39 (s, 1H), 1.28 ― 1.25 (m, 1H), 0.85 ― 0.78 (m, 1H). LC-MS: m/z 1076.1 [M+H]+.
화합물 266:
4-(4-((4-((R)-4-(2-((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)에틸)-3-((디메틸아미노)메틸)피페라진-1-카르보닐)피페리딘-1-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드. 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.3 Hz, 2H), 7.51 (dd, J = 16.8, 7.8 Hz, 4H), 7.44 ― 7.28 (m, 2H), 6.88 ― 6.72 (m, 2H), 6.29 (d, J = 17.1 Hz, 2H), 5.84 (d, J = 10.8 Hz, 1H), 4.54 ― 4.48 (m, 2H), 4.41 ― 4.24 (m, 4H), 4.10 ― 3.92 (m, 4H), 3.81 ― 3.66 (m, 3H), 3.65 ― 3.53 (m, 6H), 3.49 ― 3.38 (m, 3H), 3.25 ― 3.17 (m, 3H), 3.13 ― 3.00 (m, 6H), 2.97 ― 2.88 (m, 8H), 2.79 ― 2.68 (m, 1H), 2.07 ― 1.97 (m, 3H), 1.34 ― 1.26 (m, 4H), 0.94 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1201.5 [M+H]+.
화합물 267:
(S)-2-(1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(2-(4-(1-(4-(3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-일)피페라진-1-일)에톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴. 1H NMR (400 MHz, MeOD) δ 7.82 (d, J = 7.9 Hz, 1H), 7.70 ― 7.64 (m, 1H), 7.51 (d, J = 16.1, 7.4 Hz, 2H), 7.41 ― 7.29 (m, 4H), 7.22 (d, J = 8.1 Hz, 2H), 6.77 (s, 2H), 6.33 ― 6.16 (m, 2H), 5.83 (d, J = 9.9 Hz, 1H), 4.36 ― 4.26 (m, 2H), 4.22 ― 3.95 (m, 4H), 3.82 ― 3.51 (m, 7H), 3.24 ― 3.11 (m, 4H), 3.01 ― 2.87 (m, 4H), 2.84 ― 2.81 (m, 2H), 2.72 ― 2.67 (m, 4H), 2.37 ― 2.32 (m, 1H), 2.19 (t, J = 7.6 Hz, 3H), 2.05 ― 2.03 (m, 2H), 1.96 ― 1.93 (m, 3H), 1.61 ― 1.58 (m, 2H), 0.91 ― 0.88 (m, 3H). LC-MS: m/z 979.5 [M+H]+.
화합물 268:
2-[(2 S )-4-[7-(8-클로로-7-플루오로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-{[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]메틸}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피라미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.58 (s, 1H), 9.40 (s, 1H), 8.02 (dd, J = 9.0, 5.8 Hz, 1H), 7.79 (dd, J = 8.1, 4.2 Hz, 1H), 7.61 ― 7.50 (m, 2H), 7.45 ― 7.38 (m, 1H), 7.27 (d, J = 7.9 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.85 (s, 1H), 6.75 (s, 1H), 6.26 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 10.6 Hz, 1H), 4.95 ― 4.76 (m, 1H), 4.18 ― 3.72 (m, 7H), 3.41 (s, 3H), 3.15 ― 2.85 (m, 9H), 2.67 (p, J = 1.9 Hz, 1H), 2.36 ― 2.32 (m, 12H), 2.17 (d, J = 8.3 Hz, 2H), 1.83 (s, 2H), 1.51 ― 1.44 (m, 2H), 1.24 (s, 1H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1025.1 [M+H]+.
화합물 269:
4-(4-{[4-(4-{[(2 R ,5 S )-5-({[7-(8-클로로-7-플루오로나프탈렌-1-일)-4-[(3 S )-3-(시아노 메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-2-일]메틸}피페라진-1-카르보닐)피페리딘-1-일]메틸}페닐)-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.62 (s, 1H), 9.75 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.02 (dd, J = 9.1, 5.8 Hz, 1H), 7.79 (dd, J = 8.1, 4.3 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.53 (q, J = 8.2 Hz, 1H), 7.46 ― 7.36 (m, 3H), 7.30 ― 7.28 (m, 2H), 6.83 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 11.2 Hz, 1H), 4.95 ― 4.77 (m, 1H), 4.41 ― 3.62 (m, 7H), 3.47 ― 3.40 (m, 7H), 3.20 ― 3.05 (m, 8H), 2.91 (q, J = 6.9 Hz, 1H), 2.84 ― 2.81 (m, 2H), 2.68 ― 2.66 (m, 2H),2.42 ― 2.32 (m, 9H), 2.21 ― 2.17 (m, 1H), 1.99 (s, 2H), 1.84 (d, J = 7.2 Hz, 3H), 1.56 (s, 6H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1191.2 [M+H]+.
화합물 270:
2-[(2 S )-4-(2-{[(2 S ,4 S )-4-[4-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2, 4-트리아졸-4-일]페닐}메틸)피페라진-1-일]-1-메틸피롤리딘-2-일]메톡시}-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.86 (s, 1H), 9.54 (s, 1H), 9.30 (s, 1H), 8.22 ― 8.15 (m, 1H), 7.99 ― 7.84 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.56 ― 7.44 (m, 3H), 7.25 ― 7.21 (m, 3H), 7.09 ― 7.07 (m, 2H), 6.88 (s, 2H), 6.22 (d, J = 3.8 Hz, 1H), 6.17 (d, J = 2.4 Hz, 1H), 5.78 (dd, J = 10.4, 2.3 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.59 ― 3.86 (m, 7H), 3.40 (s, 3H), 3.25 ― 2.78 (m, 10H), 2.68 ― 2.59 (m, 1H), 2.47 ― 2.19 (m, 12H), 2.13 ― 2.01 (m, 1H), 1.94 (s, 3H), 1.53 (d, J = 10.5 Hz, 1H). LC-MS: m/z 931.2 [M+H]+.
화합물 271:
4-[4-({4-[(3 S ,5 S )-5-[({4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시)메틸]-1-메틸 피롤리딘-3-일]피페라진-1-일}메틸)페닐]-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.59 (s, 1H), 9.74 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.22 ― 8.15 (m, 1H), 7.93 ― 7.91 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.57 ― 7.51 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 7.4 Hz, 1H), 6.86 (s, 1H), 6.57 ― 6.52 (m, 1H), 6.34 (s, 1H), 6.21 ― 6.17 (m, 1H), 5.79 ― 5.76 (m, 1H), 5.06 ― 4.65 (m, 1H), 4.51 ― 4.27 (m, 2H), 4.24 ― 4.13 (m, 3H), 4.11 ― 3.91 (m, 3H), 3.47 (s, 3H), 3.16 (p, J = 7.0 Hz, 5H), 3.11 ― 2.84 (m, 8H), 2.67 (p, J = 1.9 Hz, 1H), 2.57 (d, J = 8.2 Hz, 5H), 2.39 (s, 4H), 2.14 ― 2.01 (m, 1H), 1.55 (d, J = 6.0 Hz, 1H), 1.24 (s, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1014.4 [M+H]+.
화합물 272:
2-[(2 S )-4-(2-{[(2 S ,5 R )-5-{[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]메틸}-1-메틸피롤리딘-2-일]메톡시}-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.91 (s, 1H), 9.58 (s, 1H), 9.40 (s, 1H), 8.21 ― 8.15 (m, 1H), 7.96 ― 7.89 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.57 ― 7.50 (m, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 8.3 Hz, 2H), 6.87 (s, 1H), 6.75 (s, 1H), 6.26 (s, 1H), 6.23 ― 6.14 (m, 1H), 5.78 (d, J = 11.6 Hz, 1H), 5.13 ― 4.64 (m, 1H), 4.49 ― 3.95 (m, 7H), 3.41 (s, 3H), 3.18 (s, 4H), 3.14 ― 2.81 (m, 6H), 2.67 (s, 1H), 2.45 ― 2.10 (m, 13H), 1.84 (s, 2H), 1.63 ― 1.42 (m, 2H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 973.6 [M+H]+.
화합물 273:
2-[(2 S )-4-(2-{[(2 S ,5 R )-5-{[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]메틸}-1-메틸피롤리딘-2-일]메톡시}-7-(8-메틸나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.91 (s, 1H), 9.58 (s, 1H), 9.40 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.72 ― 7.61 (m, 1H), 7.45 (q, J = 8.0 Hz, 1H), 7.40 ― 7.30 (m, 2H), 7.27 (d, J = 7.4 Hz, 3H), 7.15 ― 7.00 (m, 2H), 6.85 (s, 1H), 6.75 (s, 1H), 6.26 (s, 1H), 6.22 ― 6.15 (m, 1H), 5.81 ― 5.69 (m, 1H), 5.01 ― 4.71 (m, 1H), 4.52 ― 4.15 (m, 2H), 4.11 ― 3.79 (m, 5H), 3.78 ― 3.45 (m, 2H), 3.41 (s, 4H), 3.16 ― 2.98 (m, 5H), 2.97 ― 2.88 (m, 2H), 2.86 (s, 3H), 2.76 ― 2.60 (m, 2H), 2.58 ― 2.50 (m, 2H), 2.40 ― 2.30 (m, 9H), 2.20 ― 2.09 (m, 1H), 1.82 (s, 2H), 1.51 (s, 2H), 1.04 ― 0.85 (m, 6H). LC-MS: m/z 987.4 [M+H]+.
화합물 274:
4-(4-{[4-(4-{[(2 R ,5 S )-5-[({4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-7-(8-메틸나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시)메틸]-1-메틸피롤리딘-2-일]메틸}피페라진-1-카르보닐)피페리딘-1-일]메틸}페닐)-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.62 (s, 1H), 9.75 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 7.88 ― 7.66 (m, 2H), 7.45 (q, J = 8.0 Hz, 1H), 7.40 ― 7.14 (m, 7H), 6.85 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.21 ― 6.15 (m, 1H), 5.85 ― 5.71 (m, 1H), 5.03 ― 4.71 (m, 1H), 4.58 ― 4.10 (m, 2H), 4.08 ― 3.75 (m, 5H), 3.74 ― 3.61 (m, 1H), 3.52 ― 3.39 (m, 7H), 3.25 ― 2.99 (m, 7H), 2.98 ― 2.78 (m, 7H), 2.76 ― 2.65 (m, 2H), 2.51 (d, J = 1.8 Hz, 2H), 2.43 ― 2.24 (m, 8H), 2.21 ― 2.06 (m, 1H), 1.99 (s, 2H), 1.84 (s, 2H), 1.56 (s, 6H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1153.3 [M+H]+.
화합물 275:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-(4-{[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-일]메틸}피페라진-1-일)-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.91 (s, 1H), 9.58 (s, 1H), 9.40 (s, 1H), 7.92 (dd, J = 8.2, 1.3 Hz, 1H), 7.78 ― 7.70 (m, 1H), 7.61 ― 7.49 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 16.6, 7.5 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.84 (s, 1H), 6.75 (s, 1H), 6.26 (s, 1H), 6.24 ― 6.11 (m, 1H), 5.77 (dd, J = 10.4, 2.3 Hz, 1H), 4.96 ― 4.77 (m, 1H), 4.58 ― 4.13 (m, 4H), 4.09 ― 3.93 (m, 2H), 3.90 ― 3.61 (m, 2H), 3.53 ― 3.41 (m, 1H), 3.39 (s, 3H), 3.22 ― 3.04 (m, 4H), 2.97 (q, J = 6.7 Hz, 3H), 2.93 ― 2.71 (m, 5H), 2.63 ― 2.55 (m, 2H), 2.42 ― 2.32 (m, 4H), 2.31 ― 2.21 (m, 6H), 2.05 (d, J = 7.2 Hz, 3H), 1.94 ― 1.86 (m, 2H), 1.69 ― 1.59 (m, 2H), 1.42 (s, 2H), 1.15 ― 1.01 (m, 2H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1090.2 [M+H]+.
화합물 276:
4-(4-{[4-({4-[(3
S
,5
S
)-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3
S
)-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]피페라진-1-일}메틸)피페리딘-1-일]메틸}페닐)-5-(2,4-디히드록시-5-이소프로필페닐)
-N-
에틸-1,2,4-트리아졸-3-카르복사미드.
1H NMR (DMSO-d 6 , 400 MHz): δ 10.62 (s, 1H), 9.75 (s, 1H), 8.94 (s, 1H), 7.92 (dd, J = 8.2, 1.3 Hz, 1H), 7.74 (ddd, J = 8.4, 3.9, 1.1 Hz, 1H), 7.59 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 9.0, 6.8 Hz, 3H), 7.31 ― 7.27 (m, 2H), 6.84 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.24 ― 6.15 (m, 1H), 5.79 (s, 1H), 4.96 ― 4.77 (m, 1H), 4.51 ― 4.13 (m, 4H), 4.10 ― 3.84 (m, 3H), 3.83 ― 3.59 (m, 2H), 3.46 (s, 4H), 3.24 ― 3.15 (m, 3H), 3.14 ― 3.02 (m, 3H), 3.01 ― 2.93 (m, 2H), 2.91 ― 2.83 (m, 3H), 2.81 ― 2.75 (m, 2H), 2.74 ― 2.69 (m, 1H), 2.33 (p, J = 1.9 Hz, 2H), 2.27 (d, J = 3.2 Hz, 9H), 2.06 (t, J = 9.8 Hz, 3H), 1.98 ― 1.86 ( m, 2H), 1.69 ― 1.61 (m, 2H), 1.57 ― 1.37 (m, 2H), 1.03 (t, J = 7.2 Hz, 5H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1145.2 [M+H]+.
화합물 277:
2-[(2 S )-4-[7-(8-클로로-7-플루오로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-[4-({4-[3-(2,4―디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.91 (s, 1H), 9.57 (s, 1H), 9.39 (s, 1H), 8.01 (dd, J = 9.0, 5.9 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.61 ― 7.56 (m, 1H), 7.53 (q, J = 7.9 Hz, 1H), 7.45 ― 7.38 ( m, 1H), 7.27 (dd, J = 8.2, 3.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.83 (s, 1H), 6.76 (s, 1H), 6.26 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 11.0 Hz, 1H), 4.95 ― 4.75 (m, 1H), 4.26 ― 3.76 (m, 11H), 3.40 (s, 5H), 3.09 ― 2.83 (m, 8H), 2.34 ― 2.25 (m, 10H), 2.03 (s, 1H), 1.52 (s, 1H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1011.1 [M+H]+.
화합물 278:
4-[4-({4-[(3 S ,5 S )-5-({[7-(8-클로로-7-플루오로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]피페라진-1-일}메틸)페닐]-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR 10.59 (s, 1H), 9.74 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 8.01 (dd, J = 9.1, 5.8 Hz, 1H), 7.78 (dd, J = 8.1, 3.1 Hz, 1H), 7.60 (dd, J = 8.9, 1.7 Hz, 1H), 7.55 ― 7.50 (m, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.35 (dd, J = 8.5, 3.1 Hz, 2H), 7.29 ― 7.26 (m, 2H), 6.84 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 10.5 Hz, 1H), 4.96 ― 4.75 (m, 1H), 4.40 ― 3.72 (m, 8H), 3.62 (s, 1H), 3.46 (s, 4H), 3.19 ― 3.12 (m, 4H), 3.10 ― 3.00 (m, 5H), 2.92 ― 2.84 (m, 3H), 2.67 ― 2.66 (m, 1H), 2.38 ― 2.28 (m, 10H), 2.05 (s, 1H), 1.54 (s, 1H), 1.03 (t, J = 7.2 Hz, 3H), 0.81 ― 0.78 (m, 6H). LC-MS: m/z 1066.2 [M+H]+.
화합물 279:
2-[(2 S )-4-(2-{[(2 S ,4 S )-4-[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]-1-메틸피롤리딘-2-일]메톡시}-7-(8-메틸나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.81 (s, 1H), 9.45 (s, 1H), 9.33 (s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.68 ― 7.61 (m, 1H), 7.44 (q, J = 8.0 Hz, 1H), 7.39 ― 7.21 (m, 5H), 7.18 ― 7.08 (m, 2H), 6.91 ― 6.82 (m, 1H), 6.72 (s, 1H), 6.27 (s, 1H), 6.19 ― 6.11 (m, 1H), 5.86 ― 5.69 (m, 1H), 4.87 (s, 1H), 4.33 ― 4.24 (m, 1H), 4.18 ― 4.11 (m, 1H), 4.09 ― 3.93 (m, 3H), 3.92 ― 3.53 (m, 2H), 3.40 (d, J = 3.5 Hz, 3H), 3.18 ― 2.89 (m, 8H), 2.88 ― 2.81 (m, 5H), 2.80 ― 2.65 (m, 1H), 2.58 ― 2.48 (m, 1H),2.43 ― 2.29 (m, 9H), 2.27 (d, J = 4.4 Hz, 4H), 2.09 ― 2.01 (m, 1H), 1.65 ― 1.51 (m, 1H), 0.91 (d, J = 6.9 Hz, 6H). LC-MS: m/z 973.2 [M+H]+.
화합물 280:
4-[4-({4-[(3 S ,5 S )-5-[({4-[(3S)-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-7-(8-메틸나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시)메틸]-1-메틸피롤리딘-3-일]피페라진-1-일}메틸)페닐]-5-(2,4-디히드록시-5-이소-프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.60 (s, 1H), 9.62 (s, 1H), 8.79 (t, J = 5.9 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.69 ― 7.61 (m, 1H), 7.43 (q, J = 7.7 Hz, 1H), 7.40 ― 7.20 (m, 7H), 6.92 ― 6.68 (m, 1H), 6.55 (s, 1H), 6.35 (s, 1H), 6.16 ― 6.08 (m, 1H), 5.80 ― 5.70 (m, 1H), 4.86 (s, 1H), 4.28 (t, J = 6.0 Hz, 1H), 4.16 (m, 1H), 4.10 ― 3.83 (m, 3H), 3.81 ― 3.70 (m, 1H), 3.53 ― 3.36 (m, 3H), 3.14 ― 2.94 (m, 10H), 2.93 ― 2.80 (m, 6H), 2.78 ― 2.64 (m, 1H), 2.52 ― 2.42 (m, 2H), 2.39 (s, 7H), 2.28 (d, J = 4.5 Hz, 4H), 2.05 (m, 1H), 1.55 (s, 13H), 1.04 ― 0.98 (m, 3H), 0.85 ― 0.70 (m, 6H). LC-MS: m/z 1028.4 [M+H]+.
화합물 281:
2-[(2 S )-4-(2-{[(2 S ,5 R )-5-{[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]메틸}-1-메틸피롤리딘-2-일]메톡시}-7-(2,3-디메틸페닐)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.91 (s, 1H), 9.58 (s, 1H), 9.40 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.12 ― 7.07 (m, 3H) , 6.97 (d, J = 7.9 Hz, 4H), 6.26 (s, 1H), 6.18 (dd, J = 16.7, 2.3 Hz, 1H), 5.77 (dd, J = 10.4, 2.3 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.22 (d, J = 6.9 Hz, 5H), 3.96 (d, J = 13.6 Hz, 2H), 3.88 (s, 4H), 3.10 ― 3.07 (m, 3H) , 2.95 (dd, J = 11.7, 6.0 Hz, 4H), 2.78 (s, 3H), 2.66 (s, 1H), 2.36 (d, J = 13.8 Hz, 10H), 2.22 (d, J = 11.2 Hz, 8H), 1.83 (s, 2H), 1.46 (s, 2H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 951.4 [M+H]+.
화합물 282:
4-{4-[(4-{[(2 R ,5 S )-5-[({4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-7-(2,3-디메틸페닐)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시)메틸]-1-메틸피롤리딘-2-일]메틸}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.59 (s, 1H), 9.74 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 7.36 (t, J = 8.1 Hz, 2H), 7.29 (t, J = 8.2 Hz, 2H), 7.07 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 6.83 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.18 (t, J = 6.5 Hz, 1H), 5.77 (t, J = 3.9 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.75 (s, 1H), 4.38 (s, 1H),4.24 (s, 1H),4.22 (t, J = 7.0 Hz, 6H), 3.47 (t, J = 6.8 Hz, 2H), 3.31 (s, 1H), 3.15 (q, J = 6.8 Hz, 5H), 2.92 (m, 3H), 2.89 (s, 2H), 2.87 (s, 2H),2.79 (s, 9H), 2.39 (t, J = 3.6 Hz, 8H), 1.84 (s, 2H), 1.51 (s, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (t, J = 6.9 Hz, 6H). LC-MS: m/z 1006.2 [M+H]+.
화합물 283:
4-{4-[(4-{4-[(3S,5S)-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3S)-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]피페라진-1-카르보닐}피페리딘-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.61 (s, 1H), 9.74 (s, 1H), 8.95 (t, J = 5.8 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.0, 4.3 Hz, 1H), 7.62 ― 7.41 (m, 2H), 7.40 ― 7.26 (m, 6H), 6.85 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.18 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 11.1 Hz, 1H), 4.96 (s, 1H), 4.76 (s, 6H), 4.28 (s, 2H), 4.18 (t, J = 15.3 Hz, 8H), 3.16 (dd, J = 7.4, 6.0 Hz, 2H), 3.03 ― 2.94 (m, 9H), 2.93 ― 2.88 (m, 2H), 2.86 ― 2.78 (m, 9H), 2.37 (s, 4H), 2.30 ― 2.26 (m, 5H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1159.2 [M+H]+.
화합물 284:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-[(1-{[4-({4-[3-(2,4-디히드록시-5-이소프로필 페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]메틸}시클로 프로필)메톡시]-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.57 (s, 1H), 9.40 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.84 (J = 9.6 Hz, 1H), 7.73 ― 7.72 (m, 2H), 7.58 ― 7.56 (m, 1H), 7.53 ― 7.52 (m, 1H), 7.46 ― 7.44 (m, 2H), 7.36 ― 7.10 (m, 2H), 6.74 (br, 1H), 6.69 (s, 1H), 6.26 (s, 1H), 6.17 (d, J = 8.4 Hz, 1H), 5.77 (d, J = 12.0 Hz, 1H), 4.96 ― 4.68 (m, 1H), 4.11 ― 3.67 (m, 8H), 3.60 ― 3.55 (m, 1H), 3.50 ― 3.48 (m, 2H), 2.29 ― 2.11 (m, 2H), 3.07 ― 2.98 (m, 2H), 2.45 ― 2.25 (m, 6H), 2.06 ― 1.97 (m, 1H), 1.23 ― 1.09 (m, 6H), 0.91 ― 0.84 (m, 6H), 0.55 (s, 2H), 0.36 (s, 2H). LC-MS: m/z 964.2 [M+H]+.
화합물 285:
4-{4-[(4-{[1-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)시클로프로필]메틸}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.70 (s, 1H), 9.83 (s, 1H), 9.00 (t, J = 5.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.81 (dd, J = 8.6, 3.6 Hz, 1H), 7.62 (dd, J = 18.3, 7.7 Hz, 2H), 7.55 ― 7.45 (m, 1H), 7.44 ― 7.30 (m, 5H), 6.91 (s, 1H), 6.63 (s, 1H), 6.41 (s, 1H), 6.25 (d, J = 16.6 Hz, 1H), 5.84 (d, J = 10.6 Hz, 1H), 4.93 ― 4.74 (m, 1H), 4.23 ― 3.46 (m, 9H), 3.43 ― 2.83 (m, 9H), 2.55 ― 2.45 (m, 8H), 1.30 (s,3H), 1.10 (t, J = 7.2 Hz, 3H), 0.85 (d, J = 6.9 Hz, 6H), 0.64 (s, 2H), 0.44 (s, 2H). LC-MS: m/z 1019.3 [M+H]+.
화합물 286:
2-[(2S)-4-(2-{[(2S,5R)-5-{[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4 -트리아졸-4-일]페닐}메틸) 피페라진-1-일]메틸}-1-메틸피롤리딘-2-일]메톡시}-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일)-1-(2-플루오로프로프-2-에노일) 피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.91 (s, 1H), 9.57 (s, 1H), 9.40 (s, 1H), 8.18 (dt, J = 6.4, 3.5 Hz, 1H), 7.92 (dt, J = 6.9, 3.5 Hz, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.54 (dt, J = 6.3, 3.4 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.28 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 7.4 Hz, 1H), 7.15 ― 7.09 (m, 2H), 6.75 (s, 1H), 6.26 (s, 1H), 5.45 ― 5.37 (m, 1H), 5.36 ― 5.19 (m, 1H), 5.05 ― 4.18 (m, 3H), 4.14 (s, 2H), 4.04 (d, J = 12.8 Hz, 4H), 3.83 ― 3.52 (m, 1H), 3.42 (s, 3H), 3.26 ― 3.14 (m, 3H), 3.09 ― 2.85 (m, 5H), 2.68 (s, 1H), 2.37 (s, 12H), 2.22 ― 2.14 (m, 1H), 1.84 (s, 2H), 1.61 ― 1.38 (m, 2H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 991.7 [M+H]+.
화합물 287:
4-{4-[(4-{[(2R,5S)-5-[({4-[(3S)-3-(시아노메틸)-4-(2-플루오로프로프-2-에노일)피페라진-1-일]-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시)메틸]-1-메틸피롤리딘-2-일]메틸}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐)-N-에틸-1,2,4-트리아졸-3-카르복사미드 1H NMR (DMSO-d 6 , 400 MHz): δ 10.60 (s, 1H), 9.74 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 8.18 (dt, J = 6.4, 3.5 Hz, 1H), 7.96 ― 7.88 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.54 (dt, J = 6.3, 3.3 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 7.4 Hz, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 5.44 ― 5.37 (m, 1H), 5.36 ― 5.20 (m, 1H), 4.84 (s, 1H), 4.24 (dd, J = 10.6, 4.7 Hz, 1H), 4.14 (s, 2H), 4.11 ― 3.61 (m, 4H), 3.48 (s, 2H), 3.24 ― 3.10 (m, 8H), 3.06 ― 2.84 (m, 5H), 2.70 (s, 1H), 2.40 (s, 12H), 2.19 (dd, J = 12.2, 6.8 Hz, 1H), 1.85 (s, 2H), 1.59 ― 1.42 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1046.7 [M+H]+.
화합물 288:
4-{4-[(4-{[(2R,5S)-5-[({4-[(3S)-3-(시아노메틸)-4-(프로프-2-에노일) 피페라진-1-일]-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시) 메틸]-1-메틸피롤리딘-2-일]메틸}피페라진-1-일) 메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐)-N-에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.60 (s, 1H), 9.74 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 8.22 ― 8.15 (m, 1H), 7.96 ― 7.89 (m, 1H), 7.64 (d, J = 8.2 Hz, 1H), 7.54 (dt, J = 5.1, 3.4 Hz, 2H), 7.46 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 7.23 (d, J = 7.4 Hz, 1H), 6.86 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.24 ― 6.15 (m, 1H), 5.78 (dd, J = 10.4, 2.3 Hz, 1H), 5.06 ― 4.70 (m, 1H), 4.52 ― 3.92 (m, 7H), 3.48 (s, 3H), 3.23 ― 3.11 (m, 5H), 3.10 ― 2.82 (m, 6H), 2.70 (s, 1H), 2.40 (s, 12H), 2.20 (s, 2H), 1.86 (s, 2H), 1.62 ― 1.42 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1028.4 [M+H]+.
화합물 289:
4-{4-[(4-{[(2 R ,5 S )-5-[({4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-7-(8-메틸나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시)메틸]-1-메틸피롤리딘-2-일]메틸}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- 에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.59 (s, 1H), 9.74 (s, 1H), 8.94 (t, J = 5.9 Hz, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.69 (dd, J = 8.1, 5.3 Hz, 1H), 7.50 ― 7.40 (m, 1H), 7.40 ― 7.22 (m, 7H), 6.85 (s, 1H), 6.57 (s, 1H), 6.34 (s, 1H), 6.22 ― 6.10 (m, 1H), 5.86 ― 5.70 (m, 1H), 5.02 ― 4.70 (m, 1H), 4.54 ― 3.82 (m, 6H), 3.80 ― 3.60 (m, 1H), 3.47 (s, 3H), 3.28 ― 3.02 (m, 11H), 2.95 ― 2.78 (m, 6H), 2.45 ― 2.32 (m, 10H), 2.18 (s, 2H), 1.84 (s, 2H), 1.49 (s, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1042.3 [M+H]+.
화합물 290:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2S,4S)-4-{4-[(1-{[2-(2,4-디히드록시-5-이소프로필벤조일)-1,3-디히드로이소인돌-5-일]메틸}피페리딘-4-일)메틸]피페라진-1-일}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.07 (s, 1H), 9.60 (s, 1H), 7.95 ― 7.87 (m, 1H), 7.74 (dd, J = 8.2, 4.1 Hz, 1H), 7.61 ― 7.48 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.39 ― 7.29 (m, 1H), 7.23 ― 7.19 (m, 3H), 7.05 (s, 1H), 6.85 (s, 1H), 6.39 (s, 1H), 6.26 ― 6.08 (m, 1H), 5.89 ― 5.72 (m, 1H), 4.95 ― 4.40 (m, 6H), 4.30 ― 3.92 (m, 6H), 3.89 ― 3.71 (m, 2H), 3.62 ― 3.46 (m, 2H), 3.40 (s, 2H), 3.14 ― 3.01 (m, 5H), 2.98 ― 2.89 (m, 2H), 2.85 (s,1H), 2.78 ― 2.65 (m,3H), 2.41 ― 2.21 (m, 10H), 2.05 (d, J = 7.1 Hz, 3H), 1.86 (s, 2H), 1.66 ― 1.56 (m, 2H), 1.45 (s, 2H), 1.38 (d, J = 2.8 Hz, 2H), 1.23 (s, 1H), 1.13 (d, J = 6.9 Hz, 6H), 1.11 ― 1.02 (m, 2H). LC-MS: m/z 1076.2 [M+H]+.
화합물 291:
4-(4-{[4-({1-[({4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-7-(2,3-디메틸페닐)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시)메틸]시클로프로필}-메틸)피페라진-1-일]메틸}페닐)-5-(2,4-디히드록시-5-이소프로필페닐)- N -에틸-1,2,4-트리아졸-3-카르복사미드. 1H NMR (CDCl3, 400 MHz): δ 10.62 (s, 1H), 9.75 (s, 1H), 8.95 (t, J = 5.9 Hz, 1H), 7.35 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.07 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 7.9 Hz, 2H), 6.94 ― 6.74 (m, 1H), 6.56 (s, 1H), 6.34 (s, 1H), 6.18 (dd, J = 16.6, 2.3 Hz, 1H), 5.77 (d, J = 11.0 Hz, 1H), 5.02 ― 4.75 (m, 1H), 4.43 ― 4.12 (m, 3H), 4.02 ― 3.88 (m, 5H), 3.47 (s, 3H), 3.24 ― 3.05 (m, 6H), 3.05 ― 2.92 (m, 3H), 2.87 (q, J = 6.9 Hz, 2H), 2.79 (s, 2H), 2.36 (s, 5H), 2.28 (s, 2H), 2.23 (d, J = 10.0 Hz, 6H), 1.03 (t, J = 7.2 Hz, 3H), 0.79 (d, J = 6.9 Hz, 6H), 0.57 (s, 2H), 0.37 (s, 2H). LC-MS: m/z 963.3 [M+H]+.
화합물 292:
2-[(2 S )-4-{2-[(1-{[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]메틸}시클로프로필)메톡시]-7-(2,3-디메틸페닐)-5H,6H,8H-피리도[3,4-d]피리미딘-4-일}-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.59 (s, 1H), 9.41 (s, 1H), 7.30 ― 7.23 (m, 2H), 7.16 ― 7.03 (m, 3H), 7.01 ― 6.92 (m, 2H), 6.85 (s, 1H), 6.75 (s, 1H) , 6.25 ― 6.15(m, 2H), 5.77 (dd, J = 10.3, 2.2 Hz, 1H),4.95 ― 4.75 (m, 1H), 4.40 (s, 1H), 4.11 (s, 2H), 4.08 ― 4.01 (m, 2H), 3.88 (s, 2H), 3.52 (s, 1H), 3.40 (s, 2H), 3.33 (s, 2H), 3.11 (t, J = 15.1 Hz,3H),2.95 ― 2.85 (m, 4H), 2.79 (s, 2H), 2.48 ― 2.31 (m, 6H), 2.19 ― 2.15 (m, 8H), 0.92 (d, J = 6.9 Hz, 6H), 0.55 (d, J = 4.5 Hz, 2H), 0.37 (d, J = 5.1 Hz, 2H). LC-MS: m/z 908.2 [M+H]+.
화합물 293:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((R)-1-(1-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페리딘-4-카르보닐)피페리딘-3-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.59 (s, 1H), 9.42 (s, 1H), 7.91 (d, J = 6.8 Hz, 2H), 7.59-7.09 (m, 8H), 6.75-6.61 (m, 2H), 6.27-6.16 (m, 2H), 5.77 (d, J = 10.4 Hz, 1H), 5.06-4.81 (m, 1H), 4.22-3.29 (m, 12H), 3.14-2.67 (m, 13H), 1.98-1.23 (m, 12H), 0.94-0.91 (m, 6H). LC-MS: m/z 1220.5 [M+H]+.
화합물 294:
(3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일 4-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-카르복실레이트.
1H NMR (CD3OD, 400 MHz): δ 7.74 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.47-7.38 (m, 4H), 7.30-7.22 (m, 4H), 6.79 (s, 1H), 6.73-6.67 (m, 1H), 6.19 (d, J = 16.4 Hz, 1H), 6.11 (s, 1H), 5.74 (d, J = 10.8 Hz, 1H), 5.28 (m, 1H), 4.96-4.86 (m, 1H), 4.53-4.50 (m, 2H), 4.28-3.98 (m, 7H), 3.72-3.39 (m, 7H), 3.18-2.97 (m, 12H), 2.82-2.58 (m, 3H), 2.45-2.32 (m, 2H), 2.32 (q, J = 7.6 Hz, 2H), 0.93 (t, J = 7.6 Hz, 3H). LC-MS: m/z 1023.5 [M+H]+.
화합물 295:
(3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일 4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질카르바메이트
1H NMR (DMSO-d 6 , 400 MHz): δ 11.87 (s, 1H), 10.09 (brs, 1H), 9.54 (s, 1H), 9.33 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.76 (dd, J = 7.6, 3.6 Hz, 1H), 7.59-7.51 (m, 2H), 7.45 (dd, J = 8.0, 7.6 Hz, 1H), 7.35 (dd, J = 16.0, 7.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 6.87-6.85 (m, 1H), 6.23 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.79 (d, J = 10.8 Hz, 1H), 5.18-5.17 (m, 1H), 4.97-4.95 (m, 1H), 4.77-4.45 (m, 3H), 4.24-4.18 (m, 4H), 3.95-3.92 (m, 2H), 3.81-3.51 (m, 4H), 3.30-3.06 (m, 6H), 3.00 (s, 3H), 2.92-2.67 (m, 2H), 2.39-2.21 (m, 4H), 1.00 (t, J = 7.6 Hz, 3H). LC-MS: m/z 954.4 [M+H]+.
화합물 296:
((2R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-2-일)메틸4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질카르바메이트
1H NMR (DMSO-d 6 , 400 MHz): δ 11.86 (s, 1H),9.51 (s, 1H), 9.32 (s, 1H), 7.92 (d, 1H), 7.90-7.73 (m, 2H), 7.69-7.52 (m, 2H), 7.66-7.64 (t, 1H), 7.34-7.30 (dd, 1H), 7.21-7.19 (d, 2H), 7.11-7.09 (d, 2H) 6.86 (m, 1H),6.22-6.19 (m, 2H), 5.78 (d, 1H), 4.98-4.73 (m, 1H), 4.41-3.92 (m, 13H), 3.29-2.54 (m, 8H) 2.39-2.32 (m, 5H),1.97-1.53 (m, 4H), 1.01-0.97 (t, 3H). LC-MS: m/z 968.4 [M+H]+
화합물 297:
2-((2S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((5-((2-(4-(4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)-2-옥소에톡시)메틸)피롤리딘-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 11.95 (s, 1H), 9.72 (brs, 1H), 9.58 (s, 1H), 9.32 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 8.0 Hz, 3.6 Hz, 1H), 7.58-7.24 (m, 8H), 6.84 (brs, 1H), 6.24 (s, 1H), 6.18 (d, J = 17.2 Hz, 1H), 5.78 (d, J = 10.4 Hz, 1H), 4.97-4.76 (m, 1H), 4.51-2.75 (m, 31H), 2.39-2.32 (m, 3H), 2.14-2.08 (m, 2H), 1.78 (brs, 2H), 0.99 (t, J = 7.2 Hz, 3H). LC-MS: m/z 1037.5 [M+H]+.
화합물 298:
4-(4-((1-((5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)피롤리딘-2-일)메틸)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드
1H NMR (DMSO-d 6 , 400 MHz): δ 9.78 (s, 1H), 9.60 (t, J = 6.0 Hz, 1H). 9.39 (brs, 1H), 9.24 (brs, 1H), 8.81 (brs, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.75 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.55 (q, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.38-7.27 (m, 5H), 6.84 (brs, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.79 (d, J = 12.0 Hz, 1H), 4.97-4.76 (m, 1H), 4.54-2.60 (m, 31H), 2.22-2.13 (m, 3H), 1.79 (brs, 5H), 1.44 (brs, 2H), 0.82 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1101.7 [M+H]+.
화합물 299:
2-((2S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-((5-(((4-(3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)아미노)메틸)피롤리딘-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 11.95 (s, 1H), 9.61 (s, 1H), 9.49 (brs, 1H). 9.35 (s, 1H), 9.16 (brs, 1H), 9.09 (brs, 1H), 8.79 (brs, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.58 (d, J = 6.0 Hz, 1H), 7.55 (q, J = 8.0 Hz, 1H), 7.47-7.43 (m, 3H), 7.35 (dd, J = 19.6 Hz, 7.6 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 6.93 (s, 1H), 6.84 (brs, 1H), 6.23 (s, 1H), 6.20 (d, J = 17.2 Hz, 1H), 5.80 (d, J = 11.2 Hz, 1H), 4.97-4.76 (m, 1H), 4.57-2.67 (m, 22H), 2.38 (q, J = 8.0 Hz, 1H), 2.21-2.14 (m, 2H), 1.79 (brs, 2H), 1.02 (t, J = 7.2 Hz, 3H). LC-MS: m/z 910.4 [M+H]+.
화합물 300:
4-(4-((4-((1-(2-(((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)옥시)아세틸)피페리딘-4-일)메틸)피페라진-1-일)메틸)페닐)-5-(5-에틸-2,4-디히드록시페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드
1H NMR (DMSO-d 6 , 400 MHz): δ 10.46 (brs, 1H), 10.07 (brs, 1H), 9.72 (brs, 1H), 9.63 (t, J = 6.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.76 (dd, J = 8.0, 3.2 Hz, 1H), 7.59-7.51 (m, 2H), 7.47-7.27 (m, 6H), 6.85-6.82 (m, 1H), 6.60 (s, 1H), 6.31 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.79 (d, J = 12.0 Hz, 1H), 4.96-4.75 (m, 1H), 4.61-4.44 (m, 2H), 4.28-4.17 (m, 6H), 4.00-3.94 (m, 4H), 3.82-3.50 (m, 6H), 3.34-2.86 (m, 20H), 2.74-2.54 (m, 4H), 2.36-2.32 (m, 1H), 2.26 (q, J = 7.6 Hz, 2H), 2.06-1.99 (m, 1H), 1.85-1.72 (m, 4H), 1.12-0.99 (m, 2H), 0.88 (t, J = 7.6 Hz, 3H). LC-MS: m/z 1243.6 [M+H]+.
화합물 301:
2-((S)-1-아크릴로일-4-(7-(8-클로로나프탈렌-1-일)-2-(((2S,4R)-4-(2-(4-((4-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)피페라진-1-일)메틸)피페리딘-1-일)-2-옥소에톡시)-1-메틸피롤리딘-2-일)메톡시)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-4-일)피페라진-2-일)아세토니트릴
1H NMR (DMSO-d 6 , 400 MHz): δ 11.95 (s, 1H), 10.00 (brs, 1H), 9.62 (s, 1H), 9.37 (s, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.76 (dd, J = 7.6, 3.6 Hz, 1H), 7.59-7.51 (m, 2H), 7.45 (dd, J = 7.6, 8.0 Hz, 1H), 7.38-7.32 (m, 3H), 7.22-7.20 (m, 2H), 6.97-6.86 (m, 1H), 6.81 (s, 1H), 6.26 (s, 1H), 6.19 (d, J = 17.2 Hz, 1H), 5.79 (d, J = 11.6 Hz, 1H), 4.98-4.75 (m, 1H), 4.60-4.43 (m, 4H), 4.31-4.17 (m, 7H), 4.07-3.97 (m, 5H), 3.81-3.48 (m, 6H), 3.34-3.30 (m, 2H), 3.18-2.82 (m, 16H), 2.74-2.50 (m, 2H), 2.42-2.32 (m, 3H), 2.02-1.98 (m, 1H), 1.71-1.70 (m, 2H), 1.12-1.06 (m, 1H), 0.88 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1148.6 [M+H]+.
화합물 302:
2-(((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)옥시)-N-(4-(3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-4H-1,2,4-트리아졸-4-일)벤질)아세트아미드
1H NMR (DMSO-d 6 , 400 MHz): δ 11.90 (s, 1H), 9.95 (brs, 1H), 9.58 (s, 1H), 9.37 (s, 1H), 8.42 (t, J = 6.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.76 (dd, J = 8.0, 3.6 Hz, 1H), 7.59-7.51 (m, 2H), 7.45 (dd, J = 7.6, 8.4 Hz, 1H), 7.35 (dd, J = 15.6, 7.6 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.90-6.83 (m, 1H), 6.85 (s, 1H), 6.23 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.79 (d, J = 11.6 Hz, 1H), 4.97-4.94 (m, 1H), 4.77-4.44 (m, 3H), 4.31-4.29 (m, 3H), 4.24-4.14 (m, 1H), 4.02-3.76 (m, 5H), 3.54-3.36 (m, 2H), 3.16-2.70 (m, 11H), 2.43-2.38 (m, 1H), 2.04-1.96 (m, 1H), 1.84-1.81 (m, 1H), 0.99 (d, J = 7.2 Hz, 6H). LC-MS: m/z 982.5 [M+H]+.
화합물 303:
4-(4-((1-(2-(((3R,5S)-5-(((4-((S)-4-아크릴로일-3-(시아노메틸)피페라진-1-일)-7-(8-클로로나프탈렌-1-일)-5,6,7,8-테트라히드로피리도[3,4-d]피리미딘-2-일)옥시)메틸)-1-메틸피롤리딘-3-일)옥시)아세틸)피페리딘-4-일)메틸)페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-4H-1,2,4-트리아졸-3-카르복사미드
1H NMR (DMSO-d 6 , 400 MHz): δ 9.95 (brs, 1H), 9.79 (s, 1H), 9.60 (t, J = 6.4 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.75 (dd, J = 8.0, 3.2 Hz, 1H), 7.59-7.51 (m, 2H), 7.45 (dd, J = 8.0, 7.6 Hz, 1H), 7.38-7.22 (m, 5H), 6.88-6.82 (m, 1H), 6.61 (s, 1H), 6.35 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.78 (d, J = 12.4 Hz, 1H), 4.99-4.94 (m, 1H), 4.97-4.95 (m, 1H), 4.77-4.43 (m, 4H), 4.32-4.17 (m, 5H), 4.00-3.91 (m, 4H), 3.81-3.51 (m, 5H), 3.35-3.06 (m, 7H), 3.00 (s, 3H), 2.94-2.70 (m, 4H), 2.56-2.54 (m, 2H), 2.04-1.98 (m, 1H), 1.83-1.61 (m, 4H), 1.23-1.01 (m, 2H), 0.82 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1159.5 [M+H]+.
화합물 304:
4-{4-[(4-{4-[(2 R ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-2-카르보닐]피페라진-1-카르보닐}피페리딘-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (CDCl3, 400 MHz): δ 11.42 (s, 1H), 7.76 ― 7.72 (m, 2H), 7.65 ― 7.44 (m, 5H), 7.37 ― 7.28 (m, 3H), 7.25 ― 7.23 (m, 1H), 6.55 ― 6.38 (m, 5H), 5.82 (s, 1H), 5.08 ― 4.44 (m, 1H), 4.39 ― 4.04 (m, 3H), 4.02 ― 3.80 (m, 8H), 3.60 ― 2.97 (m, 17H), 2.91 ― 2.45 (m, 8H), 2.44 ― 1.91 (m, 7H), 1.90 ― 1.59 (m, 2H), 1.48 ― 1.28 (m, 1H), 1.27 (s, 1H), 0.73 (d, J = 6.8 Hz, 6H). 19F NMR (CDCl3, 376.6 MHz) δ -72.16. LC-MS: m/z 1241.3 [M+H]+.
화합물 305:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-{4-[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-카르보닐}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (CDCl3, 400 MHz): δ 11.28 (s, 1H), 9.79 (s, 1H), 9. 10 ― 8.40 (m, 1H), 7.75 ― 7.73 (m, 1H), 7.62 ― 7.60 (m, 1H), 7.50 ― 7.44 (m, 4H), 7.34 ― 7.32 (m, 1H), 7.28 ― 7.20 (m, 3H), 6.59 ― 6.47 (m, 4H), 5.82 ― 5.07 (m, 1H), 4.38 ― 4.07 (m, 4H), 3.93 ― 2.82 (m, 24H), 2.59 ― 2.29 (m, 5H), 2.28 ― 2.10 (m, 4H), 2.09 ― 1.87 (m, 6H), 1.65 ― 1.48 (m, 2H), 1.27 (s, 1H), 0.67 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1132.4 [M+H]+.
화합물 306:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-{4-[1-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-카르보닐}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도 [3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (CDCl3, 400 MHz): δ 10.42 ― 9.40 (m, 1H), 7.77 ― 7.75 (d, J = 5.3 Hz, 1H), 7.64 ― 7.60 (m, 1H), 7.54 ― 7.41 (m, 4H), 7.36 ― 7.32 (m, 2H), 7.28 ― 7.02 (m, 2H), 6.61 ― 6.48 (m, 1H), 6.41 ― 6.37 (m, 1H), 6.36 ― 6.28 (m, 1H), 6.27 ― 6.18 (m, 1H), 5.84 (s, 1H), 4.43 ― 4.39 (m, 3H), 4.29 ― 3.79 (m, 7H), 3.74 ― 3.27 (m, 10H), 3.26 ― 2.71 (m, 9H), 2.64 ― 2.40 (m, 5H), 2.07 ― 1.88 (m, 4H), 1.87 ― 1.77 (m, 4H), 1.76 ― 1.61 (m, 3H), 1.60 ― 1.28 (m, 5H). LC-MS: m/z 1104.3 [M+H]+.
화합물 307:
N -[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]-1-[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-[(2,2,2-트리-플루오로에틸)카르바모일]-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페리딘-4-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.47 (s, 1H), 9.77 (s, 1H), 9.65 (t, J = 6.7 Hz, 1H), 7.93 ― 7.91 (m, 2H), 7.80 ― 7.59 (m, 1H), 7.57 (dd, J = 7.4, 1.3 Hz, 2H), 7.44 ― 7.38 (m, 1H), 7.36 ― 7.30 (m, 5H), 6.85 (s, 1H), 6.62 (d, J = 2.1 Hz, 1H), 6.34 (s, 1H), 6.18 (d, J = 16.7 Hz, 1H), 5.77 (d, J = 10.6 Hz, 1H), 4.96 ― 4.76 (m, 1H), 4.60 ― 4.21 (m, 4H), 4.20 ― 3.98 (m, 7H), 3.96 ― 3.94 (m, 1H), 3.47 (s, 3H), 3.35 ― 3.26 (m, 2H), 3.19 ― 3.00 (m, 4H), 2.98 ― 2.86 (m, 3H), 2.80 ― 2.63 (m, 4H), 2.45 ― 2.35 (m, 5H), 2.30 ― 2.10 (m, 3H), 2.05 ― 1.75 (m, 3H), 1.72 ― 1.46 (m, 7H), 1.45 ― 1.27 (m, 2H), 0.82 (d, J = 6.9 Hz, 6H). 19F NMR (DMSO-d 6 , 376.6 MHz) δ -70.32. LC-MS: m/z 1255.3 [M+H]+.
화합물 308:
N -[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]-1-[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-[(2,2,3,3,3-펜타플루오로프로필)카르바모일]-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페리딘-4-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.47 (s, 1H), 9.77 (s, 1H), 9.65 (t, J = 6.7 Hz, 1H), 7.93 ― 7.91 (m, 1H), 7.90 ― 7.85 (m, 1H),7.80 ― 7.70 (m, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H) , 7.54 ― 7.50 (m, 1H), 7.48 ― 7.41 (m, 3H), 7.40 ― 7.28 (m, 2H), 6.85 (s, 1H), 6.62 (s, 1H), 6.34 (s, 1H), 6.18 (d, J = 16.7 Hz, 1H), 5.77 (d, J = 10.6 Hz, 1H), 4.96 ― 4.76 (m, 1H), 4.60 ― 4.21 (m, 4H), 4.20 ― 3.85 (m, 7H), 3.80 ― 3.68 (m, 1H), 3.62― 3.41 (m, 4H), 3.40 ― 3.23 (m, 5H), 3.19 ― 3.00 (m, 3H), 2.98 ― 2.86 (m, 4H), 2.80 ― 2.63 (m, 3H), 2.45 ― 2.35 (m, 3H), 2.30 ― 2.10 (m, 3H), 2.05 ― 1.90 (m, 2H), 1.85 ― 1.61 (m, 3H), 1.60 ― 1.45 (m, 4H), 1.44 ― 1.27 (m, 2H), 0.83 (d, J = 6.9 Hz, 6H). 19F NMR (DMSO-d 6 , 376.6 MHz) δ -83.61, -120.21. LC-MS: m/z 1305.4 [M+H]+.
화합물 309:
N -[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]-1-[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2, 4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페리딘-4-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.96 (s, 1H), 9.86 ― 9.20 (m, 2H), 7.95 ― 7.85 (m, 2H), 7.77 (d, J = 7.4, 1H), 7.60― 7.51 (m, 2H),7.50 ― 7.41 (m, 1H), 7.40 ― 7.25 (m, 3H), 7.15 (d, J = 7.4, 2H), 6.95 ― 6.70 (m, 2H), 6.26 (s, 1H), 6.18 (d, J = 16.7 Hz, 1H), 5.77 (d, J = 10.6 Hz, 1H), 4.96 ― 4.76 (m, 1H), 4.55 ― 3.80 (m, 9H), 3.50― 3.41 (m, 2H), 3.30 ― 3.13 (m, 3H), 2.98 ― 2.81 (m, 3H), 2.80 ― 2.63 (m, 2H), 2.60 ― 2.55 (s, 5H), 2.30 ― 2.26 (m, 4H), 2.25 ― 2.01 (m, 3H), 2.00 ― 1.86 (m, 3H), 1.85 ― 1.35 (m, 9H), 1.30 ― 1.20 (m, 2H), 0.91 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1146.4 [M+H]+.
화합물 310:
4-(4-{[4-(4-{[(2 R ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-2-일]메틸}피페라진-1-카르보닐)피페리딘-1-일]메틸}페닐)-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.47 (s, 1H), 9.77 (s, 1H), 9.59 (d, J = 6.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.75 (dd, J = 8.1, 4.5 Hz, 1H), 7.59 (d, J = 7.4 Hz, 1H), 7.56 ― 7.50 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.39 ― 7.29 (m, 5H), 6.86 (s, 1H), 6.62 (s, 1H), 6.34 (s, 1H), 6.19 (d, J = 16.7 Hz, 1H), 5.78 (d, J = 10.5 Hz, 1H), 5.04 ― 4.72 (m, 1H), 4.49 ― 4.11 (m, 3H), 4.10 ― 3.82 (m, 6H), 3.81 ― 3.68 (m, 1H), 3.67 ― 3.38 (m 8H), 3.20 ― 2.99 (m, 5H), 2.91 (t, J = 6.7 Hz, 2H), 2.82 (d, J = 10.5 Hz, 3H), 2.68 (s, 2H), 2.38 (s, 6H), 2.33 (s, 2H), 2.20 (dd, J = 12.0, 6.5 Hz, 1H), 1.99 (s, 2H), 1.86 (s, 2H), 1.56 (s, 6H), 0.83 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1227.4 [M+H]+.
화합물 311:
4-{4-[(4-{9-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3S)-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]-3,9-디아자스피로[5.5]운데칸-3-카르보닐}피페리딘-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.48 (s, 1H), 9.77 (s, 1H), 9.60 (t, J = 6.5 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (d, J = 8.2, 1H), 7.59 (d, J = 7.5 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.41 ― 7.26 (m, 5H), 6.86 (s, 1H), 6.62 (s, 1H), 6.35 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.78 (d, J = 10.6 Hz, 1H), 5.98 ― 4.76 (m, 1H), 4.49 ― 4.09 (m, 4H), 4.08 ― 3.89 (m, 4H), 3.88 ― 3.70 (m,1H), 3.47 (s, 3H), 3.40 (s, 4H), 3.17 (d, J = 5.0 Hz, 1H), 3.16 ― 3.05 (m, 3H), 3.04 ― 2.87 (m, 4H), 2.85 ― 2.80 (m, 2H), 2.68 (p, J = 1.9 Hz, 1H), 2.55 (s, 3H), 2.49 ― 2.19 (m, 8H), 2.10 ― 1.99 (m, 3H), 1.70 ― 1.52 (m, 5H), 1.50 ― 1.35 (m, 6H), 1.30 (s, 2H), 1.24 (s, 1H), 0.83 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1281.4 [M+H]+.
화합물 312:
N -[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]-1-[1-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페리딘-4-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.96 (s, 1H), 9.55 (s, 1H), 9.35 (s, 1H), 7.91 (d, J = 8.4, 1H), 7.85 (d, J = 7.8, 1H), 7.75 (d, J = 7.7, 1H), 7.60 ― 7.51 (m, 2H), 7.50 ― 7.41 (m, 1H), 7.40 ― 7.30 (m, 1H) , 7.28 ― 7.20 (m, 2H), 7.12 (d, J = 8.5, 2H), 6.85 (s, 2H), 6.23 ― 6.15 (m, 2H), 5.77 (d, J = 10.6 Hz, 1H), 4.96 ― 4.76 (m, 1H), 4.60 ― 4.41 (m, 2H), 4.40 ― 4.21 (m, 2H), 4.20 ― 4.05 (m, 3H), 4.00 ― 3.85 (m, 1H) 3.80 ― 3.65 (m, 2H),3.60 ― 358 (m, 2H), 3.52― 3.41 (m, 2H), 3.40 ― 3.23 (m, 2H), 3.19 ― 3.03 (m, 3H), 3.00 ― 2.95 (m, 1H), 2.80 ― 2.63 (m, 2H), 2.45 ― 2.30 (m, 4H), 2.25 ― 2.16 (m, 1H), 2.15 ― 2.07 (m, 3H), 2.05 ― 1.80 (m, 6H), 1.78 ― 1.65 (m, 1H), 1.63 ― 1.51 (m, 1H), 1.50 ― 1.41 (m, 3H) ,1.40 ― 1.36 (m, 5H), 1.35 ― 1.28 (m, 2H). LC-MS: m/z 1118.3 [M+H]+.
화합물 313:
2-[(2
S
)-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2
S
,5
R
)-5-({4-[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-일}메틸)-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도 [3,4-d]피리미딘-4-일]-1-(프로프-2-에노일) 피페라진-2-일]아세토니트릴.
1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.60 (s, 1H), 9.42 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.3, 4.5 Hz, 1H), 7.62 ― 7.57 (m, 1H), 7.56 ― 7.50 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 18.6, 7.6 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 6.76 (s, 2H), 6.27 (s, 1H), 6.19 (d, J = 16.5 Hz, 1H), 5.78 (d, J = 10.7 Hz, 1H), 5.02 ― 4.83 (m, 1H), 4.51 ― 3.94 (m, 7H), 3.88 ― 3.57 (m, 2H), 3.42 (s, 8H), 3.10 ― 2.85 (m, 8H), 2.83 ― 2.73 (m, 2H), 2.68 (p, J = 1.9 Hz, 1H), 2.37 (s, 6H), 2.35 ― 2.27 (m, 2H), 2.19 (dd, J = 12.5, 6.7 Hz, 1H), 1.96 (s, 2H), 1.85 (s, 2H), 1.54 (s, 6H), 0.94 (d, J = 7.0 Hz, 6H). LC-MS: m/z 1118.3 [M+H]+.
화합물 314:
4-{4-[(4-{1-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]피페리딘-4-카르보닐}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.45 (s, 1H), 9.78 (s, 1H), 9.55 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.2, 4.3 Hz, 1H), 7.60 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.34 ― 7.31 (m, 5H), 6.85 (s, 1H), 6.63 (s, 1H), 6.34 (s, 1H),6.19 (d, J = 16.7 Hz, 1H), 5.78 (d, J = 10.7 Hz, 1H), 4.95 ― 4.74 (m, 1H), 4.70 ― 4.51 (m, 1H), 4 .46 ― 4.25 (m, 2H), 4.21 ― 4.12 (m, 2H), 4.06 ― 3.92 (m, 4H), 3.83 ― 3.69 (m, 2H), 3.65 ―3.45 (m, 2H), 3.40 ― 3.24 (m, 4H), 3.23 ― 3.18 (m, 2H), 3.15 ― 3.05 (m, 3 H), 3.04 ― 2.95 (m, 2H), 2.89 ― 2.71 (m, 3H), 2.65― 2.45 (m, 4H), 2.43― 2.35 (m, 2H), 2.34― 2.26 (m, 4H), 2.07― 1.75 (m, 4H), 1.59 ― 1.39 (m, 5H), 1.25 (m, 1H), 0.85 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1213.3 [M+H]+.
화합물 315:
N -[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]-1-{4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]벤조일}피페리딘-4-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.97 (s, 1H), 9.60 (s, 1H), 9.38 (s, 1H), 7.92 ― 7.85 (m, 2H), 7.75 (t, J = 7.8 Hz, 1H), 7.58 (dd, J = 8.2, 4.3 Hz, 2H), 7.55 (t, J = 7.8 Hz, 1H), 7.42 ― 7.31 (m, 3H), 7.30 ― 7.20 (m, 2H), 6.86 (s, 2H), 6.21 (s, 1H), 6.16 (d, J = 16.7 Hz, 1H), 5.78 (d, J = 10.7 Hz, 1H), 4.95 ― 4.74 (m, 1H), 4.50 ― 4.35 (m, 1H), 4.34 ― 3.90 (m, 7H), 3.80 ― 3.70 (m, 1H), 3.60 ― 3.45 (m, 2H), 3.40 ― 3.24 (m, 3H), 3.20 ― 2.81 (m, 8H), 2.80 ― 2.70 (m, 2H), 2.55 ― 2.30 (m, 3H), 2.24 ― 2.20 (m, 3H), 1.80 ― 1.40 (m, 5H), 0.99 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1049.2 [M+H]+.
화합물 316:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(3 R )-1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피롤리딘-3-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.58 (s, 1H), 9.41 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.1, 4.0 Hz, 1H), 7.63 ― 7.50 (m, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.42 ― 7.22 (m, 3H), 7.15 ― 7.07 (m, 2H), 6.84 (s, 1H), 6.76 (s, 1H), 6.26 (s, 1H), 6.23 ― 6.15 (m, 1H), 5.78 (d, J = 10.7 Hz, 1H), 4.98 ― 4.75 (m, 1H), 4.34 ― 3.94 (m, 7H), 3.55 (s, 1H), 3.50 (d, J = 10.4 Hz, 1H), 3.18 ― 2.82 (m, 6H), 2.07 ― 1.84 (m, 3H), 1.48 (s, 1H), 1.24 (s, 6H), 0.99 ― 0.81 (m, 6H). LC-MS: m/z 895.2 [M+H]+.
화합물 317:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-{4-[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-카르보닐]피페리딘-1-일}-1-메틸피롤리딘-2yl]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.60 (s, 1H), 9.40 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.2, 4.3 Hz, 1H), 7.60 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.28 ― 7.20 (m, 3H), 7.14 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.5 Hz, 1H), 6.78 (s, 1H), 6.27 (s, 1H), 6.19 (d, J = 16.7 Hz, 1H), 5.78 (d, J = 10.7 Hz, 1H), 4.98 ― 4.76 (m, 1H), 4.46 ― 4.25 (m, 1H), 4.21 ― 4.12 (m, 2H), 4.06 ― 3.92 (m, 2H), 3.83 ― 3.69 (m, 1H), 3.45 ― 3.42 (m, 7H), 3.20 ― 3.04 (m, 4H), 2.98 ― 2.94 (m, 4H), 2.89 ― 2.71 (m, 3H), 2.27 (d, J = 3.8 Hz, 6H), 2.07 (s, 4H), 1.54 (s, 6H), 1.28 ― 1.11 (m, 3H), 1.08 (s, 1H), 0.95 (d, J = 6.9 Hz, 6H), 0.89 ― 0.80 (m, 1H). LC-MS: m/z 1104.3 [M+H]+.
화합물 318:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-{9-[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]-3,9-디아자스피로[5.5]운데칸-3-일}-1-메틸피롤리딘-2-일]메톡시}-5H,6 H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): 11.93 (s, 1H), 9.60 (s, 1H), 9.42 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.2, 4.2 Hz, 1H), 7.59 ― 7.51 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.40 ― 7.25 (m, 3H), 7.13 (d, J = 8.1 Hz, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 6.27 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.78 (d, J = 10.6 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.55 ― 3.89 (m, 6H), 3.86 ― 3.45 (m, 3H), 3.39 (s, 6H), 3.19 ― 2.89 (m, 8H), 2.80 ― 2.77 (m, 2H), 2.45 ― 2.41 (m,2 H) 2.31 ― 2.22 (m, 5H), 2.19 ― 1.89 (m, 4H), 1.53 (d, J = 8.5 Hz, 5H), 1.42 (s, 4H), 1.36 ― 1.25 (m, 5H), 1.24 (s, 2H), 0.94 (d, J = 6.9 Hz, 6H), 0.89 ― 0.85 (m, 1H) . LC-MS: m/z 1172.4 [M+H]+.
화합물 319:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-({4-[1-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-일}메틸)-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도 [3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.87 (s, 1H), 9.54 (s, 1H), 9.31 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.1, 4.5 Hz, 1H), 7.62 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.35 (dd, J = 18.3, 7.4 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 6.88 (s, 2H), 6.27 ― 6.13 (m, 2H), 5.78 (d, J = 11.2 Hz, 1H), 5.03 ― 4.77 (m, 1H), 4.31 ― 4.10 (m, 3H), 4.00 (d, J = 10.7 Hz, 4H), 3.83 ― 3.55 (m, 3H), 3.41 (s, 5H), 3.14 ― 2.82 (m, 6H), 2.77 (d, J = 10.7 Hz, 2H), 2.37 (t, J = 1.6 Hz, 7H), 2.28 ― 2.16 (m, 4H), 1.94 (s, 5H), 1.85 (s, 2H), 1.54 (s, 6H), 1.24 (s, 2H). LC-MS: m/z 1090.3 [M+H]+.
화합물 320:
N -[2-(4-{1-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]피페리딘-4-카르보닐}피페라진-1-일)에틸]-5-(2,4-디히드록시-5-이소프로필페닐)-4-페닐-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.40 (s, 1H), 9.72 (s, 1H), 8.80 (t, J = 5.8 Hz, 1H), 7.92 (dd, J = 8.4, 1.2 Hz, 1H), 7.75 (dd, J = 8.0, 4.4 Hz, 1H), 7.58 (d, J=7.6 Hz,1H), 7.53 (t, J=7.6 Hz,1H), 7.47 ― 7.42 (m, 4H), 7.38 - 7.32 (m, 3H), 6.85 (s, 1H), 6.60 (s, 1H), 6.33 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.78 (d, J = 11.5 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.31 ― 4.28 (m, 1H), 4.24 ― 3.87 (m, 5H), 3.86 ― 3.77 (m, 1H), 3.65 ― 3.45 (m, 2H), 3.41 (s, 4H), 3.28 (s, 4H), 3.06 ― 2.94 (m, 4H), 2.93 ― 2.86 (m, 5H), 2.83 (d, J = 10.7 Hz, 3H), 2.42 (s, 3H), 2.34 (s, 2H), 2.30 (s, 2H), 2.27 (s, 3H), 2.10 ― 1.96 (m, 3H), 1.54 (s, 5H), 0.84 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1145.3 [M+H]+.
화합물 321:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2S,4S)-4-{4-[4-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-카르보닐]피페리딘-1-일}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4d]-피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.88 (s, 1H), 9.56 (s, 1H), 9.32 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.2, 4.1 Hz, 1H), 7.63 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.41 ― 7.22 (m, 3H), 7.11 (d, J = 8.0 Hz, 2H), 6.90 ― 6.84 (m, 2H), 6.27 ― 6.14 (m, 2H), 5.78 (d, J = 10.5 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.60 ― 4.41 (m, 1H), 4.31 ― 4.27 (m, 1H), 4.21 ― 4.12 (m, 2H), 4.06 ― 3.92 (m, 2H), 3.83 ― 3.69 (m, 2H), 3.42 (s, 6H), 3.20 ― 3.04 (m, 4H), 2.98 ― 2.94 (m, 4H), 2.89 ― 2.71 (m, 3H), 2.27 (d, J = 3.8 Hz, 6H), 1.95 (s, 6H), 1.54 (s, 6H), 1.35 ― 1.06 (m, 3H), 0.94 ― 0.86 (m, 1H). LC-MS: m/z 1076.3 [M+H]+.
화합물 322:
4-{4-[(4-{1-[(3 S ,5 S )-5-[({4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시)메틸]-1-메틸피롤리딘-3-일]피페리딘-4-카르보닐}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (CDCl3, 400 MHz): δ 11.34 (s, 1H), 8.24 ― 8.21 (m, 1H), 7.89 ― 7.86 (m, 1H), 7.74 ― 7.71 (t, J = 6.7 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.56 ― 7.50 (m, 4H), 7.45 (t, J = 7.8 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 7.2 Hz 1H), 6.55 (d, J = 8.5 Hz, 3H), 6.43 (d, J = 16.6 Hz, 1H), 5.85 (d, J = 10.0 Hz, 1H), 5.16 ― 4.39 (m, 2H), 4.28 (s, 3H), 4.12 ― 3.95 (m, 4H), 3.63 (s, 6H), 3.57 ― 3.29 (m, 7H), 3.18 (s, 3H), 3.06 ― 2.72 (m, 8H), 2.50 (s, 8H), 0.78 (dd, J = 6.9, 1.8 Hz, 7H). LC-MS: m/z 1179.4 [M+H]+.
화합물 323:
4-{4-[(4-{1-[(3 S ,5 S )-5-[({4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-7-(나프탈렌-1-일)-5H,6H,8H-피리도[3,4-d]피리미딘-2-일}옥시)메틸]-1-메틸피롤리딘-3-일]피페리딘-4-카르보닐}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.37 (s, 1H), 9.76 (s, 1H), 9.59 (t, J = 6.5 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.75 (dd, J = 8.3, 4.2 Hz, 1H), 7.62 ― 7.49 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 8.6 Hz, 4H), 6.85 (s, 1H), 6.65 (s, 1H), 6.34 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.78 (d, J = 10.8 Hz, 1H), 4.97 ― 4.77 (m,1H), 4.50 ― 4.11 (m, 4H), 4.03 ― 3.98 (m, 4H), 3.75 ― 3.71 (m, 2H), 3.53 ― 3.41 (m, 8H), 3.33 ― 2.70 (m, 12H), 2.38 (s, 3H), 2.30 ― 2.25 (m, 6H), 1.91 (s, 3H), 1.55 (s, 6H). LC-MS: m/z 1263.3 [M+H]+.
화합물 324:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-카르보닐]-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.59 (s, 1H), 9.40 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (dd, J = 8.1, 4.8 Hz, 1H), 7.59 ― 7.60 (m, 2H), 7.44 (dd, J = 7.8, 4.0 Hz, 1H), 7.37 ― 7.28 (m, 3H), 7.13 (dd, J = 8.4, 2.0 Hz, 2H), 6.85 (s, 1H), 6.77 (s, 1H), 6.27 (s, 1H), 6.18 (d, J = 16.4 Hz,1H), 5.77 (d, J = 10.4 Hz, 1H), 4.96 ― 4.77 (m, 1H), 4.40 ― 3.94 (m, 6H), 3.79 ― 3.68 (m, 3H), 3.52 ― 3.46 (m, 3H), 3.43 (s, 3H), 3.30 ― 3.28 (m, 4H), 3.14 ― 2.93 (m, 7H), 2.28 (d, J = 3.4 Hz, 2H), 1.97 (d, J = 7.2 Hz, 2H), 1.67 (s, 2H), 0.94 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1021.3 [M+H]+.
화합물 325:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-[4-({4-[3-(2,4-디히드록시-5-메틸페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-카르보닐]-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.89 (s, 1H), 9.56 (s, 1H), 9.32 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.75 (t, J = 6.6 Hz, 1H), 7.59 ― 7.50 (m, 2H), 7.45 (t, J = 7.7 Hz, 1H), 7.32 (d, J = 35.6 Hz, 3H), 7.12 (s, 2H), 6.89 (s, 1H), 6.24 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.78 (d, J = 10.3 Hz, 1H), 4.99 ― 4.65 (m, 3H), 4.37 ― 3.75 (m, 7H), 3.50 ― 3.42 (m, 5H), 3.12 ― 3.09 (m, 5H), 2.92 (s, 3H), 2.34 (p, J = 1.9 Hz, 3H), 2.27 (s, 4H), 1.95 ― 1.91 (m, 5H), 1.84 (s, 2H), 1.70 ― 1.67 (m, 1H), 1.25 ― 1.24 (m,1H), 1.18 (t, J = 7.3 Hz, 1H). LC-MS: m/z 993.2 [M+H]+.
화합물 326:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-{[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]-페닐}메틸)피페라진-1-일]메틸}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.59 (s, 1H), 9.41 (s, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 7.65 ― 7.49 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.38 ― 7.20 (m, 3H), 7.12 (d, J = 7.9 Hz, 2H), 6.76 (s, 2H), 6.26 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.78 (d, J = 10.6 Hz, 1H), 5.13 ― 4.79 (m, 1H), 4.47 ― 3.91 (m, 6H), 3.89 ― 3.45 (m, 3H), 3.41 (s, 2H), 3.21 ― 2.86 (m, 8H), 2.68 (s, 2H), 2.40 ― 2.23 (m, 12H), 2.22 ― 2.09 (m, 1H), 1.83 (s, 2H), 1.52 ― 1.35 (m, 2H), 0.94 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1007.2 [M+H]+.
화합물 327:
4-{4-[(4-{1-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]피페리딘-4-카르보닐}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- [2-(4-메탄술포닐피페라진-1-일)에틸]-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.50 (s, 1H), 9.73 (s, 1H), 8.78 (t, J = 5.9 Hz, 1H), 7.92 (d, J = 8.3 Hz, 1H), 7.75 (dd, J = 8.1, 4.3 Hz, 1H), 7.62 ― 7.49 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.41 ― 7.31 (m, 5H), 6.86 (s, 1H), 6.60 (s, 1H), 6.34 (s, 1H), 6.19 (d, J = 16.7 Hz, 1H), 5.77 (d, J = 10.9 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.32 ― 4.13 (m, 4H), 4.04 ― 4.00 (m, 2H), 3.87 ― 3.65 (m, 2H), 3.52 (s, 7H), 3.38 ― 3.35 (m, 5H), 3.08 (t, J = 4.9 Hz, 8H), 2.98 (d, J = 10.2 Hz, 2H), 2.92 (s, 2H), 2.88 (s, 3H), 2.80 (s, 3H), 2.47 (s, 7H), 2.39 (s, 2H), 2.41 ― 2.18 (m, 5H), 2.02 ― 1.98 (m, 3H), 1.55 (s, 5H), 0.82 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1321.4 [M+H]+.
화합물 328:
1-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸 피롤리딘-3-일] -N- (2-{4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}에틸)피페리딘-4-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.89 (s, 1H), 9.57 (s, 1H), 9.38 (s, 1H), 7.96 ― 7.89 (m, 1H), 7.81 (t, J = 5.5 Hz, 1H), 7.75 (dd, J = 8.1, 4.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 7.35 (dd, J = 17.1, 7.5 Hz, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 6.80 (s, 2H), 6.25 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 11.3 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.29 (dd, J = 10.8, 4.9 Hz, 2H), 4.19 ― 4.11 (m, 2H), 4.04 ― 4.00 (m, 2H), 3.73 (s, 2H), 3.51 (m, 4H), 3.23 (s, 2H), 3.17 ― 3.04 (m, 4H), 3.01 ― 2.83 (m, 3H), 2.81 (m, 5H), 2.27 (d, J = 3.6 Hz, 3H), 2.02 s, 2H), 1.88 (s, 2H), 1.58 (s, 6H), 0.97 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1049.3 [M+H]+.
화합물 329:
2-[(2 S )-4[7-(8클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-{4-[(2,4-디히드록시-5-이소프로필페닐)메틸]피페라진-1-카르보닐}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 9.66 (s, 1H), 9.01 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.1, 4.8 Hz, 1H), 7.60 ― 7.51 (m, 2H), 7.47 ― 7.43 (m, 1H), 7.38 ― 7.31 (m,1H), 6.84 (s, 1H), 6.75 (s, 1H), 6.23 (s, 1H), 6.19 (d, J = 16.8 Hz,1H), 5.78 (d, J = 10.5 Hz, 1H), 4.96 ― 4.77 (m,1H), 4.39 ― 4.22 (m, 2H), 4.19 ― 3.94 (m, 5H), 3.82 ― 3.49 (m, 6H), 3.46 (s, 2H), 3.12 ― 2.91 (m, 8H), 2.69 ― 2.67 (m, 1H), 2.40 (s, 2H), 2.33 ― 2.27 (m, 5H), 1.97 (s, 2H), 1.67 (s, 2H), 1.09 (d, J = 6.9 Hz, 6H). LC-MS: m/z 862.3 [M+H]+.
화합물 330:
1-[(3S,5S)-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3S)-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸 피롤리딘-3-일]-N-[2-(4-{[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-[(2,2,2-트리플루오로에틸)카르바모일]-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-1-일]메틸}페닐)에틸]피페리딘-4-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.55 (s, 1H), 9.77 (s, 1H), 9.58 (t, J = 6.6 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.78 ― 7.71 (m, 2H), 7.61 ― 7.48 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 16.7, 7.5 Hz, 1H), 7.30 ― 7.20 (m, 4H), 7.18 (d, J = 7.8 Hz, 2H), 7.11 (d, J = 7.8 Hz, 2H), 6.85 (s, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 10.9 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.43 ― 4.09 (m, 4H), 4.06 ― 3.89 (m, 4H), 3.77 ― 3.45 (m, 1H), 3.37 (s, 2H), 3.23 (s, 3H), 3.17 ― 2.99 (m, 4H), 2.96 (s, 1H), 2.95 ― 2,86 (m, 4H), 2.77 ― 2.75 (m, 3H), 2.66 (d, J = 7.6 Hz, 3H), 2.54 (s, 2H), 2.34 ― 2.24 (m, 4H), 2.05 ― 1.97 (m, 2H), 1.95 ― 1.76 (m, 4H), 1.55 ― 1.43 (m, 8H), 1.26 ― 1.17 (m, 3H), 0.80 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1345.4 [M+H]+.
화합물 331:
4-(4-{4-[(2R,5S)-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3S)-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-2-카르보닐]피페라진-1-카르보닐}페닐)-5-(2,4-디히드록시-5-이소프로필페닐)-N-(2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.15 (s, 1H), 9.72 (s, 1H), 9.64 (t, J = 6.5 Hz, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.74 (dd, J = 8.0, 5.0 Hz, 1H), 7.58 ― 7.32 (m, 7H), 6.85 (s, 1H), 6.72 (s, 1H), 6.33 (s, 1H), 6.18 (d, J = 16.0 Hz, 1H), 5.76 (d, J = 10.5 Hz, 1H), 4.96 ― 4.76 (m,1H), 4.39 ― 4.13 (m, 3H), 3.99 ― 3.95 (m, 6H), 3.74 ― 3.63 (m, 4H), 3.49 (s, 2H), 3.22 (s, 2H), 3.21 ― 3.08 (m, 5H), 2.97 ― 2.92 (m, 2H), 2.70 ― 2.66 (m, 1H), 2.50 (s, 4H), 2.30 ― 2.29 (m, 3H), 2.08 ― 1.99 (m, 2H), 1.73 (s, 2H), 0.89 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1144.2 [M+H]+.
화합물 332:
4-{4-[(4-{4-[(2R,5S)-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3S)-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-2-카르보닐]피페라진-1-카르보닐}피페리딘-1-일)메틸]페닐}-5-(2,4-디히드록시-5-메틸페닐)-N-(2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.06 (s, 1H), 9.68 (s, 1H), 9.60 (t, J = 6.5 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.61 ― 7.59 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.38 ― 7.23 (m, 5H), 6.85 (s, 1H), 6.64 (s, 1H), 6.30 (s, 1H), 6.19 (d, J = 16.5 Hz, 1H), 5.77 (d, J = 10.6 Hz, 1H), 4.97 ― 4.78 (m,1H), 4.24 ― 4.15 (m, 4H), 4.01 ― 3.92 (m, 4H), 3.81 ― 3.77 (m, 2H), 3.53 ― 3.48 (d, 7H), 3.42 ― 3.39 (m,4H), 3.30 (s,3H), 3.10 ― 3.07 (m, 5H), 2.78 ― 2.66 (m, 4H), 2.29 (s, 3H), 2.00 (s, 4H), 1.84 (s, 3H), 1.72 (s, 2H), 1.57 (s 4H). LC-MS: m/z 1213.3 [M+H]+.
화합물 333:
4-[4-({4-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-카르보닐]피페라진-1-일}메틸)페닐]-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.41 (s, 1H), 9.75 (s, 1H), 9.59 (t, J = 6.5 Hz, 1H), 7.96 ― 7.86 (m, 1H), 7.75 (dd, J = 7.9, 4.2 Hz, 1H), 7.63 ― 7.49 (m, 2H), 7.48 ― 7.41 (m, 1H), 7.39 ― 7.28 (m, 5H), 6.85 (s, 1H), 6.64 (s, 1H), 6.34 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.78 (d, J = 11.1 Hz, 1H), 4.96 ― 4.77 (m, 1H), 4.52 ― 4.08 (m, 4H), 4.05 ― 3.91 (m, 4H), 3.90 ― 3.62 (m, 2H), 3.55 ― 3.41 (m, 7H), 3.26 ― 2.98 (m, 2H), 2.96 ― 2.83 (m, 2H), 2.68 (m, 3H), 2.66 ― 2.54 (m, 1H), 2.38 (s, 3H), 2.35 ― 2.33 (m, 2H), 2.31 ― 2.29 (m, 4H), 2.18 ― 2.09 (m, 1H), 1.89 (d, J = 10.6 Hz, 1H), 0.84 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1130.2 [M+H]+.
화합물 334:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-[9-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)-3,9-디아자스피로[5.5]운데칸-3-일]-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 9.59 (s, 1H), 9.41 (s, 1H), 7.92 (dd, J = 8.3, 1.3 Hz, 1H), 7.75 (dd, J = 8.0, 3.9 Hz, 1H), 7.60 ― 7.51 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.3 Hz, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 6.27 (s, 1H), 6.19 (d, J = 16.7 Hz, 1H), 5.78 (d, J = 10.5 Hz, 1H), 4.96 ― 4.78 (m,1H), 4.41 ― 4.14 (m, 4H), 4.03 ― 3.94 (m, 3H), 3.80 ― 3.70 (m, 1H), 3.49 (s, 2H), 3.39 (s, 3H), 3.16 ― 3.05 (m, 3H), 3.00 ― 2.94 (m, 3H), 2.87 ― 2.85 (m, 2H), 2.34 (p, J = 1.9 Hz, 9H), 2.03 ― 1.99 (m, 2H), 1.52 ― 1.45 (m, 2H), 1.37 (s, 6H), 1.24 (s, 4H), 0.94 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1061.2 [M+H]+.
화합물 335:
1-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸 피롤리딘-3-일] -N- [2-(2-{4-[3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-1,2,4-트리아졸-4-일]페녹시}에톡시)에틸]피페리딘-4-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.82 (s, 1H), 9.54 (s, 1H), 9.34 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.80 ― 7.71 (m, 2H), 7.58 ― 7.54 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.37 ― 7.31 (m, 1H), 7.07 (d, J = 8.9 Hz, 2H), 6.95 ― 6.80 (m, 4H), 6.25 ― 6.15 (m, 2H), 5.78 (d, J = 10.7 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.43 ― 4.10 (m, 4H), 4.09 ― 3.92 (m, 4H), 3.88 ― 3.65 (m, 4H), 3.50 (s, 1H), 3.44 (t, J = 5.9 Hz, 2H), 3.19 (q, J = 6.0 Hz, 3H), 3.12 ― 2.93 (m, 5H), 2.92 ― 2.78 (m, 4H), 2.54 (s, 2H), 2.41 ― 2.31 (m, 2H), 2.27 (d, J = 3.0 Hz, 4H), 2.06 ― 1.99 (m, 2H), 1.90 ― 1.87 (m, 2H), 1.56 ― 1.48 (m, 5H), 1.00 (t, J = 7.4 Hz, 3H). LC-MS: m/z 1095.2 [M+H]+.
화합물 336:
4-{4-[(4-{1-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]피페리딘-4-카르보닐}피페라진-1-일)메틸]페닐}-5-(2,4-디히드록시-5-메틸페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 9.99 (s, 1H), 9.68 (s, 1H), 9.60 (t, J = 6.5 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.78 ― 7.71 (m, 1H), 7.62 ― 7.51 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.38 ― 7.34 (m, 3H), 7.25 (d, J = 8.4 Hz, 2H), 6.86 (s, 1H), 6.67 (s, 1H), 6.29 (s, 1H), 6.17 (d, J = 16.0 Hz, 1H), 5.78 (d, J = 11.0 Hz, 2H), 4.97 ― 4.87 (m, 1H), 4.45 ― 4.11 (m, 4H), 4.06 ― 3.93 (m, 4H), 3.81 ― 3.75 (m, 2H), 3.51 (s, 3H), 3.46 (s, 4H), 3.22 ― 3.03 (m, 4H), 3.01 ― 2.65 (m, 6H), 2.55 (d, J = 5.9 Hz, 3H), 2.36 (s, 2H), 2.15 (s, 6H), 2.14 ― 2.01 (m, 3H), 1.85 (s, 3H), 1.54 (s, 5H). LC-MS: m/z 1185.3 [M+H]+.
화합물 337:
4-(4-{[4-(3-{[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일](메틸) 아미노}프로파노일)피페라진-1-일]메틸}페닐)-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.39 (s, 1H), 9.60 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.2, 4.3 Hz, 1H), 7.60 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.36 ― 7.32 (m, 5H), 6.85 (d, J = 8.5 Hz, 1H), 6.78 (s, 1H), 6.27 (s, 1H), 6.19 (d, J = 16.7 Hz, 1H), 5.78 (d, J = 10.7 Hz, 1H), 4.97 ― 4.77 (m , 1H), 4.46 ― 4.08 (m, 4H), 4.06 ― 3.92 (m, 4H), 3.83 ― 3.69 (m, 2H), 3.59 (s, 3H), 3.45 (s, 5H), 3.20 ― 3.05 (m, 4H), 3.04 ― 2.82 (m, 3H), 2.79 (s, 2H), 2.68 (s, 1H), 2.45 ― 2.37 (m, 4H), 2.27 (d, J = 3.8 Hz, 6H), 2.07 (s, 3H), 2.01 (s, 1H), 1.54 (s, 1H), 0.95 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1187.3 [M+H]+.
화합물 338:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-{9-[(2,4-디히드록시-5-이소프로필페닐)메틸]-3,9-디아자스피로[5.5]운데칸-3-일}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.50 (s, 1H), 8.97 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.1, 4.3 Hz, 1H), 7.60 ― 7.52 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.38 ― 7.32 (m, 1H), 6.85 (s, 1H), 6.69 (d, J = 2.6 Hz, 1H), 6.21 ― 6.16 (m, 2H), 5.78 (d, J = 10.6 Hz, 1H), 4.96 ― 4.76 (m, 1H), 4.41 ― 3.93 (m, 7H), 3.80 ― 3.62 (m, 3H), 3.50 (s, 3H), 3.16 ― 3.04 (m, 5H), 2.98 ― 2.96 (m, 2H), 2.88 ― 2.86 (m, 2H), 2.37 (s, 3H), 2.34 ― 2.26 (m, 9H), 2.02 (d, J = 4.7 Hz, 1H), 1.55 ― 1.52 (m, 1H), 1.39 (s, 8H), 1.24 (s, 2H), 1.09 (d, J = 6.9 Hz, 6H). LC-MS: m/z 902.3 [M+H]+.
화합물 339
4-[4-({4-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-카르보닐]피페라진-1-일}메틸)페닐]-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,3,3,3-펜타플루오로프로필)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.37 (s, 1H), 9.76 (s, 1H), 9.59 (t, J = 6.5 Hz, 1H), 7.99 ― 7.86 (m, 1H), 7.75 (dd, J = 8.1, 4.3 Hz, 1H), 7.60 ― 7.49 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.40 ― 7.26 (m, 5H), 6.85 (s, 1H), 6.64 (s, 1H), 6.34 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.78 (dd, J = 10.4, 2.3 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.48 ― 3.91 (m, 8H), 3.90 ― 3.60 (m 2H), 3.52 (s, 3H), 3.46 (s, 4H), 3.20 (s, 3H), 3.15 ― 3.02 (m, 4H), 2.99 ― 2.83 (m, 3H), 2.76 ― 2.56 (m, 2H), 2.41 ― 2.36 (m, 2H), 2.35 ― 2.24 (m, 5H), 2.14 (s, 1H), 1.87 (q, J = 10.5, 9.3 Hz, 1H), 0.84 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1180.2 [M+H]+.
화합물 340:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-[4-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-카르보닐]-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.60 (s, 1H), 9.40 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.75 (dt, J = 8.1, 2.7 Hz, 1H), 7.59 (dd, J = 8.5, 2.1 Hz, 1H), 7.56 ― 7.49 (m, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 25.7, 8.0 Hz, 3H), 7.14 (d, J = 8.2 Hz, 2H), 6.85 (s, 2H), 6.78 (s, 1H), 6.26 (s, 1H), 6.19 (d, J = 16.4 Hz, 1H), 5.78 (d, J = 10.5 Hz, 1H), 4.97 ― 4.77 (m, 1H), 4.47 ― 4.25 (m, 2H), 4.25 ― 3.92 (m, 5H), 3.90 ― 3.64 (m, 2H), 3.55 ― 3.35 (m, 8H), 3.17 (s, 3H), 3.13 ― 3.03 (m, 4H), 3.02 ― 2.83 (m, 3H), 2.68 (p, J = 1.9 Hz, 1H), 2.39 ― 2.22 (m, 5H), 2.10 (d, J = 17.0 Hz, 1H), 1.89 (d, J = 18.1 Hz, 1H), 1.24 (s, 1H), 0.95 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1021.2 [M+H]+.
화합물 341:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,5 R )-5-{4-[1-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-카르보닐}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.60 (s, 1H), 9.42 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.74 (t, J = 6.3 Hz, 1H), 7.56 (dd, J = 18.9, 7.7 Hz, 2H), 7.51 ― 7.43 (m, 1H), 7.42 ― 7.18 (m, 3H), 7.13 (d, J = 7.9 Hz, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 6.27 (s, 1H), 6.25 ― 6.15 (m, 1H), 5.77 (d, J = 10.5 Hz, 1H), 5.02 ― 4.72 (m, 1H), 4.51 ― 3.93 (m, 6H), 3.92 ― 3.80 (m, 2H), 3.76 ― 3.48 (m, 6H), 3.46 ― 3.42 (m, 2H), 3.26 (s, 4H), 3.22 ― 3.02 (m, 5H), 2.96 (p, J = 6.7 Hz, 3H), 2.86 ― 2.66 (m, 4H), 2.32 ― 2.20 (m, 3H), 2.08 ― 1.82 (m, 4H), 1.72 (s, 2H), 1.55 (s, 4H), 1.24 (s, 1H), 0.94 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1132.3 [M+H]+.
화합물 342:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 R ,5 S )-5-{4-[1-({4-[3-(2,4-디히드록시-5―이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페리딘-4-카르보닐]피페라진-1-카르보닐}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.93 (s, 1H), 9.60 (s, 1H), 9.42 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.78 ― 7.70 (m, 1H), 7.64 ― 7.52 (m, 2H), 7.51 ― 7.41 (m, 1H), 7.40 ― 7.19 (m, 3H), 7.16 ― 7.08 (m, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 6.27 (s, 1H), 6.24 ― 6.13 (m, 1H), 5.84 ― 5.70 (m, 1H), 5.02 ― 4.82 (m, 1H), 4.53 ― 3.93 (m, 6H), 3.83 (s, 2H), 3.68 ― 3.40 (m, 7H), 3.30 ― 3.26 (m, 4H),3.20 ― 2.89 (m, 7H) 2.88 ― 2.65 (m, 4H), 2.48 ― 2.44 (m, 2H), 2.38 ― 2.22 (m, 3H), 2.04 ― 1.80 (m, 4H), 1.72 (s, 2H), 1.56 (s, 4H), 0.94 (d, J = 6.8 Hz, 6H). LC-MS: m/z 1132.2 [M+H]+.
화합물 343:
N -(2-{4-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-카르보닐]피페라진-1-일}에틸)-5-(2,4-디히드록시-5-이소프로필페닐)-4-페닐-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.39 (s, 1H), 9.72 (s, 1H), 8.82 (t, J = 5.8 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.79 ― 7.71 (m, 1H), 7.62 ― 7.50 (m, 2H), 7.49 ― 7.40 (m, 4H), 7.39 ― 7.29 (m, 3H), 6.85 (s, 1H), 6.60 (s, 1H), 6.32 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.78 (d, J = 11.6 Hz, 1H), 4.98 ― 4.78 (m, 1H), 4.46 ― 3.91 (m, 6H), 3.90 ― 3.55 (m, 2H), 3.54 ― 3.36 (m, 5H), 3.28 (t, J = 6.4 Hz, 2H), 3.18 (d, J = 9.2 Hz, 2H), 3.14 ― 2.99 (m, 4H), 2.98 ― 2.85 (m, 2H), 2.74 ― 2.55 (m, 2H), 2.42 (t, J = 7.1 Hz, 4H), 2.36 (s, 3H), 2.29 (d, J = 3.7 Hz, 4H), 2.17 ― 2.09 (m, 1H), 1.87 (s, 1H), 0.84 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1062.2 [M+H]+.
화합물 344:
4-[4-({4-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3S)-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-카르보닐]피페라진-1-일}메틸)페닐]-5-(2,4-디히드록시-5-이소프로필페닐) -N- [2-(4-메탄술포닐피페라진-1-일)에틸]-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.50 (s, 1H), 9.75 (s, 1H), 8.81 (t, J = 5.9 Hz, 1H), 7.93 (dd, J = 8.2, 1.3 Hz, 1H), 7.75 (dd, J = 8.3, 4.4 Hz, 1H), 7.62 ― 7.53 (m, 2H), 7.51 ― 7.41 (m, 1H), 7.40 ― 7.34 (m, 3H), 7.31 (d, J = 8.2 Hz, 2H), 6.86 (s, 1H), 6.60 (s, 1H), 6.34 (s, 1H), 6.19 (d, J = 16.5 Hz, 1H), 5.81 ― 5.74 (m, 1H), 4.98 ― 4.78 (m, 1H), 4.47 ― 4.26 (m, 2H), 4.24 ― 3.98 (m, 3H), 3.92 ― 3.65 (m, 2H), 3.52 (s, 2H), 3.47 (s, 5H), 3.28 (t, J = 6.3 Hz, 2H), 3.20 (s, 3H), 3.08 (s, 9H), 2.91 (t, J = 6.7 Hz, 1H), 2.88 (s, 3H), 2.68 (s, 2H), 2.47 (t, J = 6.4 Hz, 8H), 2.39 (s, 3H), 2.29 (d, J = 3.9 Hz, 4H), 2.13 (s, 1H), 1.88 (d, J = 8.7 Hz, 1H), 0.82 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1238.3 [M+H]+.
화합물 345:
(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3S)-3-(시아노메틸)-4-(프로프-2-엔o-일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸) -N- (2-{4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}에틸)-1-메틸피롤리딘-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.89 (s, 1H), 9.57 (s, 1H), 9.39 (d, J = 1.6 Hz, 1H), 7.92 (dt, J = 8.2, 2.1 Hz, 1H), 7.82 (t, J = 5.6 Hz, 1H), 7.74 (dd, J = 8.2, 4.4 Hz, 1H), 7.62 ― 7.49 (m, 2H), 7.48 ― 7.40 (m, 1H), 7.34 (dd, J = 17.9, 7.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H), 7.11 ― 7.04 (m, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.25 (s, 1H), 6.23 ― 6.14 (m, 1H), 5.77 (dd, J = 10.3, 2.3 Hz, 1H), 5.06 ― 4.69 (m, 1H), 4.50 ― 4.09 (m, 4H), 4.02 (d, J = 14.6 Hz, 2H), 3.88 ― 3.56 (m, 2H), 3.48 (d, J = 12.2 Hz, 1H), 3.27 ― 3.20 (m, 3H), 3.15 ― 2.90 (m, 7H), 2.78 ― 2.63 (m, 3H), 2.57 (dd, J = 13.1, 7.1 Hz, 1H), 2.38 (t, J = 8.9 Hz, 1H), 2.29 (dd, J = 7.2, 3.8 Hz, 4H), 2.13 (dd, J = 12.6, 8.2 Hz, 1H), 1.82 (dt, J = 13.6, 7.4 Hz, 1H), 0.96 (d, J = 6.9 Hz, 6H). LC-MS: m/z 966.2 [M+H]+.
화합물 346:
4-{4-[(1-{[4-(2-{[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-일]포름아미도}에틸)페닐]메틸}피페리딘-4-일)메틸]페닐}-5-(2,4-디히드록시-5-이소프로필페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 10.54 (s, 1H), 9.77 (s, 1H), 9.58 (t, J = 6.5 Hz, 1H), 7.92 (dd, J = 8.3, 1.3 Hz, 1H), 7.80 ― 7.69 (m, 2H), 7.62 ― 7.48 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.40 ― 7.17 (m, 6H), 7.13 (q, J = 8.0 Hz, 4H), 6.85 (s, 1H), 6.60 (s, 1H), 6.35 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 11.4 Hz, 1H), 4.86 (m, 1H), 4.50 ― 4.22 (m, 2H), 4.18 ― 3.85 (m, 7H), 3.83-3.72 (m, 2H), 3.67 ― 3.41 (m, 2H), 3.28 ― 3.24 (m, 2H), 3.06 (m, 6H), 2.95 ― 2.82 (m, 3H), 2.75 ― 2.70 (m, 4H), 2.44 ― 2.30 (m, 1H), 2.29 ― 2.26 (m, 3H), 2.20 ― 2.04 (m, 3H), 1.85 ― 1.72 (m, 3H), 1.61 ― 1.38 (m, 4H), 1.30 ― 1.09 (m, 3H), 0.84 ― 0.78 (m, 6H). LC-MS: m/z 1262.3 [M+H]+.
화합물 347:
4-[4-({4-[(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸)-1-메틸피롤리딘-3-카르보닐]피페라진-1-일}메틸)페닐]-5-(2,4-디히드록시-5-메틸페닐) -N- (2,2,2-트리플루오로에틸)-1,2,4-트리아졸-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 9.99 (s, 1H), 9.69 (s, 1H), 9.61 (t, J = 6.6 Hz, 1H), 7.96 ― 7.89 (m, 1H), 7.75 (dd, J = 8.0, 4.3 Hz, 1H), 7.59 (d, J = 7.4 Hz, 2H), 7.44 (q, J = 8.0 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.32 (dd, J = 18.1, 7.7 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.86 (s, 1H), 6.67 (s, 1H), 6.29 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.80 ― 5.75 (m, 1H),5.00 ― 4.79 (m, 1H), 4.60 ― 4.22 (m, 3H), 4.21 ― 4.10 (m, 2H), 4.08 ― 3.92 (m, 4H), 3.91 ― 3.60 (m, 6.6 Hz, 3H), 3.55 ― 3.50 m, 2H), 3.48 ― 3.42 (m, 4H), 3.32 (s, 3H), 3.22 ― 3.15 (m, 2H), 3.14 ― 2.93 (m, 5H), 2.90 ― 2.85 (m, 1H), 2.52 ― 2.45 (m, 1H), 2.33 ― 2.25 (m, 4H), 2.18 ― 2.07 (s, 1H), 1.85 (s, 3H). LC-MS: m/z 1102.2 [M+H]+.
화합물 348:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2S,4S)-4-{4-[7-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)-2,7-디아자스피로 [3.5]노난-2-카르보닐]피페리딘-1-일}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.94 (s, 1H), 9.61 (s, 1H), 9.42 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.78 ― 7.71 (m, 1H), 7.63 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 7.4 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.0 Hz, 2H), 6.77 (s, 2H), 6.27 ― 6.17 (m, 2H), 5.78 (d, J = 10.5 Hz, 1H), 5.01 ― 4.96 (m, 1H), 4.29 (s, 2H),4.21 ― 4.07 (m, 2H), 4.03 (s, 2H), 3.88 ― 3.72 (m, 4H), 3.48 (s, 4H), 3.19 ― 3.05 (m, 6H), 3.01 ― 2.91 (m, 4H), 2.34 ― 2.25 (m, 4H), 1.64 (s, 6H), 1.50 (s, 4H), 1.24 (s, 4H), 1.15 (s, 6H), 0.94 (d, J = 6.9 Hz, 6H), 0.85 (d, J = 7.0 Hz, 1H). LC-MS: m/z 1144.4 [M+H]+.
화합물 349:
(3 S ,5 S )-5-({[7-(8-클로로나프탈렌-1-일)-4-[(3 S )-3-(시아노메틸)-4-(프로프-2-에노일)피페라진-1-일]-5H,6H,8H-피리도[3,4-d]피리미딘-2-일]옥시}메틸) -N- [2-(2-{4-[3-(5-에틸-2,4-디히드록시페닐)-5-히드록시-1,2,4-트리아졸-4-일]페녹시}에톡시)에틸]-1-메틸피롤리딘-3-카르복사미드. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.83 (s, 1H), 9.54 (s, 1H), 9.33 (s, 1H), 7.96 ― 7.88 (m, 1H), 7.81 (t, J = 5.5 Hz, 1H), 7.78 ― 7.70 (m, 1H), 7.59 ― 7.48 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.38 ― 7.30 (m, 1H), 7.06 (d, J = 8.7 Hz, 2H), 6.91 ― 6.83 (m, 4H), 6.24 (s, 1H), 6.19 (d, J = 16.6 Hz, 1H), 5.77 (d, J = 10.8 Hz, 1H), 5.02 ― 4.75 (m, 1H), 4.54 ― 3.96 (m, 9H), 3.91 ― 3.54 (m, 5H), 3.52 ― 3.46 (m, 3H), 3.26 ― 3.20 (m, 3H), 3.16 ― 2.96 (m, 5H), 2.95 ― 2.83 (m, 1H), 2.80 ― 2.75 (m, 1H), 2.62 (d, J = 1.8 Hz, 1H), 2.45 ― 2.36 (m, 2H), 2.28 (d, J = 3.8 Hz, 3H), 2.20 ― 2.05 (m, 1H), 1.84 ― 1.75 (s, 1H), 0.99 (t, J = 7.5 Hz, 3H). LC-MS: m/z 1012.1 [M+H]+.
화합물 350:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{[(2 S ,4 S )-4-{4-[2-({4-[3-(2,4-디히드록시-5-이소프로필페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)-2,7-디아자스피로[3.5]노난-7-카르보닐]피페리딘-1-일}-1-메틸피롤리딘-2-일]메톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.91 (s, 1H), 9.58 (s, 1H), 9.40 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 8.2, 4.7 Hz, 1H), 7.61 ― 7.50 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.38 ― 7.31 (m, 1H), 7.26 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 6.84 ― 6.77 (m, 2H), 6.26 (s, 1H), 6.21 ― 6.16 (m, 1H), 5.79 ― 5.76 (m, 1H), 4.95 ― 4.76 (m, 1H), 4.56 (s, 1H), 4.40 ― 4.11 (m, 4H), 4.08 ― 3.91 (m, 2H), 3.84 (s,1H), 3.76 (s, 1H), 3.74 ― 3.42 (m, 5H), 3.20 ― 3.02 (m, 5H), 3.01 ― 2.85 (m, 9H), 2.81 (s, 3H), 2.35 ― 2.25 (m, 4H), 2.14 ― 1.87 (m, 4H), 1.73-1.45 (m, 10H), 0.96 (d, J = 6.9 Hz, 6H). LC-MS: m/z 1144.2 [M+H]+.
화합물 351:
2-[(2 S )-4-[7-(8-클로로나프탈렌-1-일)-2-{2-[4-({4-[3-(2,4-디히드록시-5-이소프로필 페닐)-5-히드록시-1,2,4-트리아졸-4-일]페닐}메틸)피페라진-1-일]에톡시}-5H,6H,8H-피리도[3,4-d]피리미딘-4-일]-1-(프로프-2-에노일)피페라진-2-일]아세토니트릴. 1H NMR (DMSO-d 6 , 400 MHz): δ 11.92 (s, 1H), 9.58 (s, 1H), 9.41 (s, 1H), 7.92 (dd, J = 8.3, 1.3 Hz, 1H), 7.75 (dd, J = 8.0, 3.8 Hz, 1H), 7.63 ― 7.51 (m, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.41 ― 7.26 (m, 3H), 7.13 (d, J = 8.1 Hz, 2H), 6.85 (s, 1H), 6.76 (s, 1H), 6.27 (s, 1H), 6.21 ― 6.16 (m, 1H), 5.78 (d, J = 10.5 Hz, 1H), 4.96 ― 4.76 (m, 1H), 4.54 ― 4.13 (m, 4H), 4.11 ― 3.92 (m, 2H), 3.91 ― 3.59 (m,2H), 3.58 ― 3.46 (m, 1H), 3.43 (s, 2H), 3.25 ― 3.02 (m, 4H), 3.01 ― 2.81 (m,3H), 2.68 (p, J = 1.9 Hz,3H), 2.64 (s, 4H), 2.36 (s, 2H), 2.34 (p, J = 1.9 Hz, 2H), 0.93 (d, J = 6.9 Hz, 6H). LC-MS: m/z 924.2 [M+H]+.
실시예 4: 다양한 CHAMP 분자의 시험
물질 및 방법
세포주
하기 암 세포주를 사용하였다: BT-474 인간 유방 암종(ATCC, #HTB-20); MIA PaCa-2 인간 췌장 암종[2 카피 KRAS(G12C)](ATCC, #CRL-1420); NCI-H23 인간 비소세포 폐암[1 카피 KRAS(G12C)](ATCC, #CRL-5800); NCI-H358 인간 비소세포 폐암[1 카피 KRAS(G12C)](ATCC, #CRL-5807); LU65A 인간 폐 암종(Pharmaron, 중국 베이징 소재). 세포주를 본질적으로 ATCC 및 Pharmaron 권장사항에 따라 배양하였다.
HSP90α-결합 형광 편광(FP) 검정
명시된 바를 제외하고는, 제조사의 지침에 따라, HSP90α(N-말단) 검정 키트(BPS Bioscience, #50298)를 사용하여 형광 편광(FP)에 의해 HSP90α 단백질에 대한 시험 화합물의 결합을 측정하였다. 형광 라벨링된 HSP90-결합 화합물, 제공된 FITC-겔다나마이신(5 nM 최종 농도) 또는 RNK04010, 피페리진-페닐 연결기를 통해 BODIPY에 의해 라벨링된 트리아졸론-기반 HSP90 결합 소분자(5 nM 최종 농도)를 사용하였다. 20 μM 내지 5.2 nM의 범위의 각각의 시험 화합물의 2.5배 연속 희석액을 HSP90α에 대한 결합에 관하여 검정하였다. 각각의 검정 웰에 대한 HSP90α 단백질의 첨가의 최종 단계 이후, 플레이트를 짧은 진탕에 의해 혼합하고, FITC-겔다나마이신의 경우 120분 동안 또는 RNK04010의 경우 300분 동안 25°C에서 인큐베이션하고, PerkinElmer EnVision Plate Reader를 사용하여 형광을 측정하였다. 백그라운드-차감된 mP 값을 미가공 데이터로부터 계산하고, 4-매개변수 "log[저해제] 대 반응" 곡선을 피팅하고, IC50 값(최대 저해의 50%가 발생하는 농도)을 GraphPad Prism 7 소프트웨어를 사용하여 계산하였다.
KRAS(G12C)/SOS1 균질 시간-분해 형광(HTRF) 검정
결국 SOS1 단백질과의 KRAS(G12C) 상호작용을 차단하는 KRAS(G12C) 단백질에 대한 시험 화합물의 결합을, 나타낸 바를 제외하고는, 제조사의 지침에 따라, KRAS-G12C/SOS1 결합 검정 키트(Cisbio, #63ADK000CB16PEG)를 사용하여 균질 시간-분해 형광(HTRF)에 의해 GTP의 부재 하에 측정하였다. 20 μM 내지 1.02 nM의 범위의 각각의 시험 화합물의 3배 연속 희석액을 제조하였다. 시험 화합물을 혼합하고 반응 구성성분과 함께 인큐베이션하고, 4°C에서 3시간 동안 밀봉된 플레이트에서 인큐베이션하고, PerkinElmer Envision 플레이트 리더를 사용하여 형광을 측정하였다. %저해 및 IC50 값(최대 저해의 50%가 발생하는 농도)을 계산하고 GraphPad Prism 7 소프트웨어를 사용하여 플로팅하였다.
KRAS(G12C) 웨스턴 블롯 단백질 분해 검정
KRAS(G12C)를 발현하는 MIA PaCa-2 인간 췌장 암종 세포주 및 LU65A 인간 폐암 세포주를, 6-웰 또는 12-웰 조직 배양 플레이트에 시딩하고, 1시간 이후, 시험 화합물을 다양한 농도에서 첨가하고, 37°C/5% CO2에서 각각 48시간(MIA Paca-2) 및 6시간(LU65A) 동안 인큐베이션하였다. 세포를 이후 차가운 PBS로 세척하고, 흡입하고, 프로테아제/포스파타아제 저해제 칵테일을 함유하는 차가운 RIPA 완충액을 첨가하여 세포를 용해시켰다. 원심분리 이후, 세포 용해물의 총 단백질 농도를 BCA 단백질 검정을 사용하여 측정하였다. 샘플을 동등한 단백질 농도에 대하여 정규화하고, 5X SDS-PAGE 로딩 완충액을 첨가하고, 10분 동안 100°C에서 변성시켰다. 20 μl의 각각의 샘플/웰을 SDS-PAGE 겔 상에 로딩하고, 20분 동안 80 V에서, 이후 120 V에서 1.5시간 동안 전기영동하였다. 겔을 이후 2.5시간 동안 250 mA에서 습식-전달 방법을 사용하여 니트로셀룰로오스 막에 일렉트로블롯팅(electroblotting)하였다. 1시간 동안 블로킹 완충액과 함께 막을 인큐베이션하고, 5분 동안 TBST로 3 번 세척하였다. 막을 이후 제조사의 권장사항에 따라 밤새 4°C에서 블로킹 완충액 중에 희석된 항-KRAS(Sigma-Aldrich, #SAB1404011) 및 항-β-액틴 모노클로날 항체(Cell Signaling Technology, #3700)와 함께 인큐베이션하였다. 3회 세척 이후, 블롯을 실온에서 1시간 동안 적절하게 라벨링된 2차 항체와 함께 인큐베이션하고, 또다시 세척하였다. 형광 이미징 및 정량화를 LI-COR Odyssey를 사용하여 수행하였다. 결과를 GraphPad Prism 7 소프트웨어를 사용하여 분석하였다. 화합물 분해를 하기 수식에 의해 측정하고, DC50 값(KRAS의 최대 분해의 50%가 발생하는 농도)을 GraphPad Prism 7 소프트웨어를 사용하여 계산하였다:
% 저해 = 100 - (D - B) / (S - B) * 100%.
S: 항체와 함께 세포의 형광 세기
D: 항체와 함께 화합물-처리된 세포의 형광 세기
B: 항체가 없는 세포의 형광 세기
ERBB2(HER2) 유세포 분석 단백질 분해 검정
250,000개의 세포/웰로 24-웰 조직 배양 플레이트에서 BT-474 인간 유방 암종 세포를 플레이팅하고, 37°C/5% CO2에서 24시간 동안 인큐베이션하였다. 세포를 이후 다양한 농도로 시험 화합물로 처리하고, 37°C/5% CO2에서 24시간 동안 인큐베이션하였다. 유세포 분석에 의해 ERBB2 단백질 수준의 변화를 분석하기 위하여, 세포를 트립신으로 분리하고, 세척하고, 계수하고, 10 μl/106 세포 PE-접합된, 항-ERBB2 모노클로날 항체(R&D Systems, #FAB1129P)로 어둠 속에서 30분 동안 25°C에서 처리하였다. 세포를 이후 세척하고, 200 μl 1% 파라포름알데히드 중에 재현탁시키고, 유세포 분석에 의해 분석하였다. 화합물 저해를 하기 수식에 의해 측정하고, DC50 값(ERBB2의 최대 분해의 50%가 발생하는 농도)을 GraphPad Prism 7 소프트웨어를 사용하여 계산하였다:
% 분해 = 100 - (D - B) / (S - B) * 100%.
S: 항체와 함께 세포의 형광 세기
D: 항체와 함께 화합물-처리된 세포의 형광 세기
B: 항체가 없는 세포의 형광 세기
암 세포주 증식(CCK-8) 검정
4,000개의 세포/웰로 96-웰 조직 배양 플레이트에 세포를 플레이팅하고, 37°C/5% CO2에서 24시간 동안 인큐베이션하였다. 20 μM 내지 1.02 nM의 범위의 각각의 시험 화합물의 3배 연속 희석액을 제조하였다. 세포를 이후 0.5% DMSO/웰의 최종 농도로 다양한 농도의 시험 화합물로 처리한 후, 37°C/5% CO2에서 72시간 동안 인큐베이션하였다. 각각의 웰에 10 μl의 세포 증식 검출 시약 CCK-8(Dojindo Molecular Technologies, #CK04)을 첨가하고, 37°C/5% CO2에서 3-4시간 동안 인큐베이션하고, Perkin Elmer EnVision Plate Reader를 사용하여 450 nm에서의 흡광도를 측정하였다. 화합물 저해를 하기 수식에 의해 측정하고, EC50 값(최대 저해의 50%가 발생하는 농도)을 GraphPad Prism 7 소프트웨어를 사용하여 계산하였다:
% 저해 = 100 - (D - B) / (S - B) * 100%.
S: DMSO로 처리된 세포의 흡광도
D: 화합물-처리된 세포의 흡광도
B: 세포 없이 DMSO와 함께 배지의 흡광도
결과
KRAS(G12C)-CHAMP 분자로 칭해지는, KRAS(G12C)를 분해하기 위해 고안된 다양한 CHAMP 분자를 구성하도록 다수의 합성 도식이 개발되었다. 각각 KRAS(G12C) 결합제에 연결된 HSP90 결합제로 이루어지는 대표적인 예가 나타나 있다. 유사한 화학이 이러한 특정 HSP90- 및 KRAS(G12C)-결합 모이어티에 제한되지 않는 다른 CHAMP 분자에 적용될 수 있다.
형광 라벨링된 HSP90 결합제, FITC-겔다나마이신 또는 RNK04010(BODIPY-라벨링됨)과의 경쟁을 측정하는 HSP90α-결합 형광 편광(FP) 검정을 적용하여, HSP90에 대한 CHAMP 분자의 결합 능력을 평가하였다. 표 1에 나타낸 바와 같이, 문헌에 기록된 HSP90-결합 모이어티를 함유하는 CHAMP 분자는 일반적으로는 공개된 구조 활성 관계(SAR: structure activity relationship)와 일치하였다.
CHAMP에의 HSP90 결합제와 유사한 분자량의 KRAS(G12C) 결합제의 혼입은, 이러한 검정에서 HSP90α에 대한 CHAMP 분자의 결합에 대한 오로지 최소의 영향만을 가졌다(표 1). 여기에는 하기와 같은 다수의 이유가 있다: 첫 번째로, 이러한 모이어티와 이의 상응하는 단백질의 공결정 구조가 이용가능하고, 정확한 구조-기반 분자 디자인을 허용하며; 두 번째로, 연결기는 적합한 길이와 함께 강성을 제공하도록 구성됨.
KRAS(G12C)에 대한 다양한 CHAMP 분자에 의한 결합을, 표 1에 나타낸 바와 같이, HTRF 생화학적 검정에서 SOS1과의 KRAS(G12C) 상호작용의 저해를 측정함으로써 평가하였다. 문헌에 기록된 KRAS(G12C)-결합 모이어티를 함유하는 CHAMP 분자는 일반적으로는 공개된 SAR과 일치하였다.
샤페론-결합 모이어티, 예컨대 HSP90 결합제의 혼입은, 전형적으로는 이러한 검정에 의해 측정된 KRAS(G12C)에 대한 CHAMP 분자의 결합에 대한 최소한의 영향만을 가졌다. 여기에는 하기와 같은 다수의 이유가 있다: 첫 번째로, 이러한 모이어티와 이의 상응하는 단백질의 공결정 구조가 이용가능하고, 정확한 구조-기반 분자 디자인을 허용하며; 두 번째로, 연결기는 적합한 길이와 함께 강성을 제공하도록 구성됨.
KRAS(G12C)-결합 모이어티 및 HSP90-결합 모이어티 둘 모두를 갖는 이종이관능성 CHAMP 분자를 고안하여, KRAS(G12C)의 표적 단백질 분해(TPD)를 유도하였다. 표 2에 나타낸 바와 같이, KRAS(G12C)를 발현하는 MIA PaCa-2 인간 췌장 암종 세포를 다양한 농도의 CHAMP 화합물로 48시간 동안 처리하고, KRAS(G12C)의 분해를 웨스턴 블롯팅에 의해 관찰하였다.
CHAMP 분자는 상이한 결합 친화도의 범위를 갖는 샤페론 또는 샤페론 복합체 결합제를 포함할 수 있다. 상이한 실시형태에서, 고친화도 결합제, 중간-친화도 결합제 또는 저친화도 결합제를 사용하는 것이 바람직하다. HSP90의 N-말단 ATP-결합 포켓과 상호작용하는 HSP90-결합 모이어티는 HSP90 활성을 저해하고 HSP90 클라이언트 단백질의 분해를 유도할 수 있고, 일부 CHAMP 분자는 원하는 표적 단백질 또는 단백질들(이는 HSP90 클라이언트 단백질일 수 있거나 아닐 수 있음)의 분해를 유도할 수 있을 뿐만 아니라, 또한 동시에 HSP90 클라이언트 단백질의 분해를 유도할 수 있다. 표 2에 나타낸 바와 같이, CHAMP 화합물은 또한 ERBB2-발현 BT-474 인간 유방 암종 세포에서 유세포 분석에 의해 평가된 바와 같은 HSP90 클라이언트 단백질 ERBB2의 다양한 수준의 분해를 나타냈다.
표 1에 나타낸 바와 같이, 다양한 KRAS(G12C)-CHAMP 분자는 또한 CCK-8 세포주 증식 검정에 의해 측정된 바와 같이 암 세포주의 패널의 성장 및/또는 생존을 저해하였다.
[표 1]
[표 2]
본 개시내용의 기재된 방법 및 조성물의 변경 및 변형은 본 개시내용의 범주 및 취지로부터 벗어나지 않으면서 당업자에게 명백할 것이다. 비록 본 개시내용이 특정 실시형태와 관련하여 기재되었지만, 청구된 개시내용이 상기 특정 실시형태에 지나치게 제한되지 않아야 함이 이해되어야 한다. 실제로, 본 개시내용을 수행하기 위해 기재된 방식의 다양한 변경이 관련 분야의 당업자에 의해 의도 및 이해되며, 여기서 이러한 개시내용은 하기 청구범위에 의해 나타내어지는 바와 같은 개시내용의 범주 이내에 있다.
참조 인용
본 명세서에 언급된 모든 특허 및 간행물은, 각각의 독립적 특허 및 간행물이 구체적으로 그리고 개별적으로 참조 인용되는 것으로 나타내어지는 것과 동일한 정도로 본원에서 참조 인용된다.
Claims (43)
- 하기 화학식 I의 화합물, 또는 이의 약학적으로 허용가능한 염:
(I);
식 중에서,
A는 HSP90 단백질에 결합하는 화학적 모이어티이고;
L은 연결기이고;
Q1은 질소 함유 헤테로아릴 또는 헤테로시클릴 고리이고, 이들 각각은 선택적으로는 R6으로부터 선택된 1 내지 3개의 기에 의해 치환되고;
R5는 ―C(O)Y 또는 ―S(O)2Y이고;
Y는 (C1-C6)알킬, 할로(C1-C6)알킬, (C2-C6)알케닐, 할로(C2-C6)알케닐, NH2, -NH(C1-C6)알킬, -N[(C1-C6)알킬]2, NHNH2, 또는 NHOH이고, 여기서 상기 (C2-C6)알케닐은, 단독으로 또는 할로(C2-C6)알케닐에서 언급된 바와 같이, 선택적으로는 (C1-C6)알킬, 할로(C1-C6)알킬, 헤테로알킬, 히드록시(C1-C6)알킬, -C(O)NH2, -C(O)NH(C1-C6)알킬, 또는 -C(O)N[(C1-C6)알킬]2에 의해 치환되고;
R6은 (C1-C6)알킬, 할로(C1-C6)알킬, (C1-C6)알콕시, 할로(C1-C6)알콕시, 히드록시(C1-C6)알킬, 시아노(C1-C6)알킬, 옥소, 시아노, 헤테로알킬, -C(O)OH, -C(O)O(C1-C6)알킬, -C(O)NH2, -C(O)NH(C1-C6)알킬, 또는 -C(O)N[(C1-C6)알킬]2이고, 여기서 상기 (C1-C6)알킬은 선택적으로는 헤테로아릴에 의해 치환되고;
R7은 할로, 히드록실, (C1-C6)알킬, 할로(C1-C6)알킬, (C1-C6)알콕시, 할로(C1-C6)알콕시, 시클로알킬, 헤테로알킬, 히드록시(C1-C6)알킬, 또는 S(C1-C6)알킬이고;
j는 1 또는 2이고;
Q2는 결합, -C(O)-, 또는 (C1-C3)알킬렌이고;
R8은 시클로알킬, 헤테로시클릴, 아릴, 또는 헤테로아릴이고, 이들 각각은 선택적으로는 R9로부터 선택된 1 내지 3개의 기에 의해 치환되고;
R9는 할로, (C1-C6)알킬, (C2-C6)알케닐, 할로(C2-C6)알케닐, (C2-C6)알키닐, 옥소, 시아노, -(C1-C6)알킬ORc, -(C1-C6)알킬N(Rd)2, -(C1-C6)알킬C(O)ORd, OH, -(C1-C6)알킬C(O)N(Rd)2, -(C1-C6)알킬O(C1-C6)알킬N(Rd)2, -(C1-C6)알킬SORd, -(C1-C6)알킬S(O)2Rd, -(C1-C6)알킬SON(Rd)2, -(C1-C6)알킬SO2N(Rd)2, -(C1-C6)알킬시클로알킬, -(C1-C6)알킬헤테로시클릴, -(C1-C6)알킬헤테로아릴, -(C1-C6)알킬아릴, -(C1-C6)알콕시, 할로(C1-C6)알콕시, CN, 아릴, 헤테로아릴, 시클로알킬, 헤테로시클로알킬, -C(O)Rd, -C(O)ORd, -C(O)N(Rd)2, N(Rd)2, -C(O)NRd(C1-C6)알킬N(Rd)2, -NRd(C1-C6)알킬N(Rd)2, -NRd(C1-C6)알킬ORd, -SORd, -S(O)2Rd, -SON(Rd)2, -SO2N(Rd)2, 또는 CN이고, 여기서 각각의 아릴, 시클로알킬, 헤테로시클릴, 및 헤테로아릴은 단독으로 및 -(C1-C6)알킬시클로알킬, -(C1-C6)알킬헤테로시클릴, -(C1-C6)알킬헤테로아릴, -(C1-C6)알킬아릴과 관련하여 선택적으로는 Re로부터 선택된 1 내지 3개의 기에 의해 치환되고;
Rc 및 Rd는 각각 독립적으로는 수소, (C1-C6)알킬, 및 할로(C1-C6)알킬로부터 선택되고;
Re는 할로, 옥소, CN, NO2, -N(Rd)2, -ORd, -C(O)ORd, (C1-C6)알킬, -(C1-C6)알킬ORc, 할로(C1-C6)알킬, (C1-C6)알콕시, 할로(C1-C6)알콕시, -(C1-C6)알킬C(O)ORd, -(C1-C6)알킬C(O)N(Rd)2, (C2-C6)알케닐, 할로(C2-C6)알케닐, (C2-C6)알키닐, -(C1-C6)알킬SRd, -(C1-C6)알킬ORc, -(C1-C6)알킬N(Rd)2, -C(O)N(Rd)2, -C(O)NRdC1-6알킬N(Rd)2, -NRdC1-6알킬N(Rd)2, -NRdC1-6알킬ORd, -SORd, -S(O)2Rd, -SON(Rd)2, -SO2N(Rd)2, 아릴, 헤테로아릴, 시클로알킬, 및 헤테로시클로알킬로부터 선택됨. - 제1항에 있어서, A가
, , , , , , , 및 로부터 선택되고; 식 중에서
Q 및 U는 각각 독립적으로는 페닐, 헤테로아릴, 헤테로시클릴, 및 시클로알킬로부터 선택되고, 이들 각각은 선택적으로는 R2로부터 선택된 1 내지 3개의 기에 의해 치환되고;
R13 및 R14는 각각 독립적으로는 수소, 할로, -CN, (C1-C4)알킬, 할로(C1-C4)알킬, 및 -C(O)NRaRb로부터 선택되고;
R15는 수소, (C1-C4)알킬, 또는 할로(C1-C4)알킬이고;
W는 선택적으로는 R2로부터 선택되는 1 내지 3개의 기로 치환된 5-원 또는 6-원 헤테로아릴이고;
V는 페닐, 또는 선택적으로는 R3으로부터 선택되는 1 내지 3개의 기로 치환된 5-원 내지 9-원 헤테로아릴이고;
R1은 할로, (C1-C4)알킬, 할로(C1-C4)알킬, (C1-C4)알콕시, 또는 할로(C1-C4)알콕시이고;
R2는 (C1-C4)알킬, 할로(C1-C4)알킬, (C2-C6)알케닐, 할로(C2-C6)알케닐, (C2-C6)알키닐, 할로(C2-C6)알키닐, CN, -C1-4알킬ORa, -ORa, -C(O)Ra, -C(O)ORa, -C(O)NRaRb, -C(O)NRa(C1-4알킬렌)ORa, -C(O)NRa(C1-4알킬렌)NRaRb, -C(O)NRa(C1-4알킬렌)OR, -NRaRb, -O(C1-4알킬렌)NRaRb, -SH, -S(C1-4알킬), -C1-4알킬NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, -S(O)NRaRb, -SO2NRaRb, -NRa(C1-4알킬)ORa, -NRa(C1-4알킬)NRaRb, -C1-6알킬C(O)NRaRb, 페닐 또는 5-원 내지 7-원 헤테로아릴이고, 여기서 상기 페닐 및 5-원 내지 7-원 헤테로아릴은 각각 선택적으로는 및 독립적으로는 R4로부터 선택된 1 내지 3개의 기에 의해 치환되고;
Ra 및 Rb는 각각 독립적으로는 수소 및 (C1-C4)알킬로부터 선택되고, 여기서 상기 (C1-C4)알킬은 선택적으로는 하나 이상의 할로 또는 3-원 내지 7-원 헤테로시클릴, 또는 둘 모두에 의해 치환되고;
R3 및 R4는 각각 독립적으로는 할로, -NRaRb, (C1-C4)알킬, 할로(C1-C4)알킬, (C1-C4)알콕시, 또는 할로(C1-C4)알콕시인, 화합물, 또는 이의 약학적으로 허용가능한 염. - 제1항 내지 제4항 중 어느 한 항에 있어서, R5가 ―C(O)Y인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제5항 중 어느 한 항에 있어서, Y가 (C1-C6)알킬, 할로(C1-C6)알킬, (C2-C6)알케닐, 할로(C2-C6)알케닐, 또는 NH2인 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제6항 중 어느 한 항에 있어서, Y가 C(O)CH3, C(O)CHCH2, C(O)CH2CH3, C(O)CF3, C(O)CFCH2, C(O)CCH3, 또는 C(O)NH2인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제7항 중 어느 한 항에 있어서, Y가 C(O)CHCH2인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제8항 중 어느 한 항에 있어서, R6이 시아노(C1-C6)알킬인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제9항 중 어느 한 항에 있어서, R6이 CH2CN인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제10항 중 어느 한 항에 있어서, j가 0인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제11항 중 어느 한 항에 있어서, Q2가 결합인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제12항 중 어느 한 항에 있어서, R8이 선택적으로는 R9로부터 선택된 1 내지 3개의 기에 의해 치환된 아릴인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제13항 중 어느 한 항에 있어서, R8이 선택적으로는 R9로부터 선택된 1 내지 3개의 기에 의해 치환된 나프틸인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제14항 중 어느 한 항에 있어서, R9가 할로, (C1-C6)알킬, 및 OH로부터 선택되는, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제15항 중 어느 한 항에 있어서, R9가 클로로 및 OH로부터 선택되는, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제17항에 있어서,
Z가 CH인, 화합물, 또는 이의 약학적으로 허용가능한 염. - 제1항 내지 제18항 중 어느 한 항에 있어서, 각각의 R3이 독립적으로는 (C1-C4)알킬 또는 할로인, 화합물.
- 제1항 내지 제23항 중 어느 한 항에 있어서, R1이 할로 또는 (C1-C4)알킬인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제24항 중 어느 한 항에 있어서, R1이 클로로, 이소프로필, 메틸, 프로필, 또는 에틸인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제25항 중 어느 한 항에 있어서, R1이 이소프로필 또는 에틸인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제26항 중 어느 한 항에 있어서, R2가 -ORa, -SRa, -C(O)NRaRb, 또는 -C(O)NRa(C1-4알킬렌)NRaRb인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제27항 중 어느 한 항에 있어서, Ra 및 Rb가 각각 독립적으로는 수소 및 (C1-C4)알킬로부터 선택되고, 여기서 상기 (C1-C4)알킬은 선택적으로는 1 내지 3개의 할로 또는 6-원 헤테로시클릴에 의해 치환되는, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제28항 중 어느 한 항에 있어서, R2가 OH, -C(O)NHCH2CF3, -C(O)NHCH2CH3, -C(O)NHCH(CH3)2, -C(O)NH(CH2CH3)2, -C(O)NHCH(CH3)CF3, -C(O)NH시클로프로필, -C(O)NH메틸시클로프로필, C(O)NH2, 또는 -C(O)NH(CH2)2피페리디닐인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제29항 중 어느 한 항에 있어서, R2가 -C(O)NHCH2CF3 또는 OH인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제30항 중 어느 한 항에 있어서, R2가 OH인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제31항 중 어느 한 항에 있어서,
L이 -Het1-X1-*, -Het1-Het2-X1-*, *-X1-Het1-X2-Het2-(CH2)mO-, -NRc-(CH2)m-X1-Het1-X2-*, -NRc-(CH2)m-X1-NRc-(CH2CH2O)n-*, -NRc-(CH2)m-X1-NRc-(CH2)p-*, -NRc-(CH2)m-X1-Het1-X2-Het2-X3-*, -O(CH2)m-X1-Het1-X2-Het2-X3-*, -O(CH2)m-X1-NRc-(CH2)p-Het1-X2-Het2-X3-*, *-X1-NRc-(CH2)m-Het1-X2-Het2-X3-(CH2)p-NRd-(CH2)p-, -NRc-(CH2)m-X1-(CH)CH3-Het1-X2-Het3-X3-*, -NRc-(CH2)m-X1-(CH2)p-Het1-X2-Het2-X3-*, -NRc-(CH2)m-X1-NRd-(CH2)p-Het1-X2-Het2-X3-*, -NRc-(CH2)m-NRd-X1-Het1-X2-*, *Het1-X1-Het2-X2-, *-Het1-X1-Het2-X2-O-, *-O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-, -O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-*, *-Het1-O-(CH2)m-X1-Het2-X2-, *-Het1-O-(CH2)m-X1-NRc-(CH2CH2O)n(CH2)m-Het2-X2-, *-Het1-X1-NRc-(CH2)m-, *-Het1-X1-Het2-Het3-X2-, *-Het1-X1-NRc-(CH2CH2O)n(CH2)m-, *-Het1-X1-NRc-(CH2CH2O)nHet2-(CH2)m-X2-, *-Het1-X1-NRc-(CH2CH2O)n-, *-Het1-X1-NRc-(CH2)m-Het2-X2-Het3-(CH2)m-, *-Het1-X1-Het2-(CH2)m-Het3-X2-, *-Het1-X1-Het2-, *-Het1-X1-NRc-, *-Het1-X1-NRc-(CH2)m-Phe-X2-Het2-(CH2)m-, *-Het1-X1-Het2-Het3-, *-Het1-X1-Het2-(CH2)m-Het3-X2-(CH2)p-NRc-(CH2)m-, *-Het1-X1-Het2-(CH2)m-Het3-(CH2)m-O-, *-Het1-X1-Het2-(CH2)m-Het3-(CH2)p-NRc-(CH2)m-, *-Het1-X1-Het2-(CH2CH2O)n-, *-Het1-X1-(CH2)m-Het2-X2-, *-(CH2CH2O)o-(CH2)p-Het1-X1-Het2-(CH2CH2O)n, *-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2, *-Het1-X1-Phe-X2-NRc-X3-, *-(CH2CH2O)o-(CH2)p-Het1-X1-Phe-X2-NRc-(CH2CH2O)n-, *-(CH2CH2O)n-(CH2)m-NRc-Phe-X1-, *-(CH2CH2O)o-(CH2)p-NRc-Phe-(CH2CH2O)n-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-, *-(CH2CH2O)n-(CH2)m-NRc-(CH2CH2O)n-(CH2)m-C(O)-NRd-(CH2CH2O)o-(CH2)p-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-Het2-X2-(CH2CH2O)o, *-NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2, *-NRc-(CH2CH2O)n-(CH2)m-Phe-NH-X1-Het1-X2-(CH2CH2O)o, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Phe-X1-NRc-(CH2CH2O)o-(CH2)p-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-, *-(CH2CH2O)o-(CH2)p-NRc-(CH2CH2O)n-(CH2)m-Het1-X1-(CH2CH2O)n-, *-(CH2CH2O)n-(CH2)m-NRc-(CH2)m-C(O)-NRd-Het1-X1-Het2-(CH2CH2O)o-(CH2)p, 또는 *-NRc-(CH2)m-C(O)-NRd-(CH2)m-Het1-X1-Het2-X2-이고;
*가 A에 대한 부착 지점을 나타내고;
Het1, Het2, 및 Het3이 각각 독립적으로는 페닐, 4-원 내지 6-원 헤테로시클릴, 5-원 내지 7-원 헤테로아릴, 또는 4-원 내지 6-원 시클로알킬이고, 이들 각각은 선택적으로는 (C1-C4)알킬에 의해 치환되고;
X1, X2, 및 X3이 각각 독립적으로는 C(O) 또는 (CH2)r이고;
m, n, o, p, q 및 r이 각각 독립적으로 0, 1, 2, 3, 4, 5, 및 6으로부터 선택되는 정수인, 화합물, 또는 이의 약학적으로 허용가능한 염. - 제1항 내지 제32항 중 어느 한 항에 있어서, L이 -Het1-X1-*, -Het1-Het2-X1-*, *-X1-Het1-X2-Het2-(CH2)mO-, -NRc-(CH2)m-X1-Het1-X2-*, -NRc-(CH2)m-X1-NRc-(CH2CH2O)n-*, -NRc-(CH2)m-X1-NRc-(CH2)p-*, -NRc-(CH2)m-X1-Het1-X2-Het2-X3-*, -O(CH2)m-X1-Het1-X2-Het2-X3-*, -O(CH2)m-X1-NRc-(CH2)p-Het1-X2-Het2-X3-*, *-X1-NRc-(CH2)m-Het1-X2-Het2-X3-(CH2)p-NRd-, -NRc-(CH2)m-X1-(CH)CH3-Het1-X2-Het2-X3-*, -NRc-(CH2)m-X1-(CH2)p-Het1-X2-Het2-X3-*, -NRc-(CH2)m-X1-NRd-(CH2)p-Het1-X2-Het2-X3-*, -NRc-(CH2)m-NRd-X1-Het1-X2-*, *Het1-X1-Het2-X2-, *-Het1-X1-Het2-X2-O-, *-O(CH2)m-Het1-(CH2)p-O(CH2)m-NRc-X2-, 또는 *-Het1-X1-Het2-인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항 내지 제33항 중 어느 한 항에 있어서, L이 -NRc-(CH2)m-X1-NRc-(CH2)p-* 또는 -NRc-(CH2)m-X1-Het1-X2-Het2-X3-*인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제32항 내지 제34항 중 어느 한 항에 있어서, Het1 및 Het2가 각각 독립적으로는 페닐 또는 4-원 내지 6-원 헤테로시클릴인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제32항 내지 제35항 중 어느 한 항에 있어서, Het1 및 Het2가 각각 독립적으로는 피페리디닐, 페닐, 아제티디닐, 피페라지닐, 또는 피롤리디닐인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제32항 내지 제36항 중 어느 한 항에 있어서, m, n, o, p, q 및 r이 각각 독립적으로는 0, 1, 2, 및 3으로부터 선택되는 정수인, 화합물, 또는 이의 약학적으로 허용가능한 염.
- 제1항에 있어서, 화합물이 하기 구조식:
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로부터 선택되는 화합물, 또는 상기 중 어느 하나의 약학적으로 허용가능한 염. - 제1항에 있어서, 화합물이 화합물 187 내지 351, 또는 화합물 187 내지 351 중 어느 하나의 약학적으로 허용가능한 염으로부터 선택되는, 화합물.
- 제1항 내지 제41항 중 어느 한 항의 화합물, 또는 이의 약학적으로 허용가능한 염; 및 약학적으로 허용가능한 담체를 포함하는 약학 조성물.
- 제1항 내지 제41항 중 어느 한 항의 화합물, 또는 이의 약학적으로 허용가능한 염, 또는 제42항의 조성물의 치료적 유효량을 대상체에게 투여하는 것을 포함하는, 암의 치료 방법.
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