KR20240054850A - Shp2 단백질 분해용 화합물 및 이들의 의약 용도 - Google Patents
Shp2 단백질 분해용 화합물 및 이들의 의약 용도 Download PDFInfo
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- KR20240054850A KR20240054850A KR1020230016449A KR20230016449A KR20240054850A KR 20240054850 A KR20240054850 A KR 20240054850A KR 1020230016449 A KR1020230016449 A KR 1020230016449A KR 20230016449 A KR20230016449 A KR 20230016449A KR 20240054850 A KR20240054850 A KR 20240054850A
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- cancer
- methyl
- carboxamido
- thio
- pyrazin
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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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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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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Abstract
본 개시는 SHP2 단백질을 분해하는 측면에서 우수한 활성을 갖는 특정 화학구조의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 약학적으로 허용 가능한 염을 제공한다. 본 개시는 또한 이러한 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 약학적으로 허용 가능한 염을 포함하는 조성물을 제공한다. 본 개시는 또한 본 개시에 따른 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 염 및 이들을 포함하는 조성물의 SHP2 관련 질환(예를 들어, 암)의 치료 또는 예방용 의약 용도를 제공한다. 본 개시는 또한 본 개시에 따른 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 염 또는 이들을 포함하는 조성물의 유효한 양을 치료가 필요한 개체에게 투여하는 것을 포함하는 SHP2 관련 질환(예를 들어, 암)의 치료 또는 예방 방법을 제공한다.
Description
본 개시는 SHP2 단백질 분해 활성을 가지는 일 군의 화합물에 관한 것이다. 특히, 본 개시는 특정 구조를 가져 SHP2 단백질을 분해하는 활성이 우수한 일 군의 화합물에 관한 것이다. 본 개시는 또한 이러한 화합물을 이용하여, SHP2 단백질 관련 질환을 치료하는 조성물 또는 방법에 관한 것이다. 즉, 본 개시는 본 개시에 따른 화합물들의 SHP2 단백질 관련 질환을 치료 또는 예방하기 위한 의약 용도에 관한 것이다.
Src 상동성 2 도메인-함유 포스파타제(Src homology 2 domain-containing phosphatase, SHP2)는 단백질 티로신 포스파타제이다. SHP2의 돌연변이는 누난(Noonan) 신드롬 및 LEOPARD 신드롬에 널리 퍼져있다. 또 SHP2의 활성화된 돌연변이는 소아 골수단구성 백혈병, 골수이형성 증후군, B-세포 급성 림프모구성 백혈병 및 급성 골수성 백혈병에서도 확인되었다. SHP2의 체세포 활성화 돌연변이는 폐 선암종, 결장암, 신경모세포종, 교모세포종, 흑색종, 간세포 암종, 전립선암 및 유방암을 비롯한 여러 유형의 고형 종양과 관련이 있다 (Bentires-Alj et al., Cancer. Res. 2004, 64, 8816-8820).
SHP2는 암 세포 내에서 RAS-ERK, JAK-STAT, PI3K-AKT, NF-κB 및 mTOR 경로와 같은 다양한 신호 전달 프로세스에 관여하는 것으로 알려져 있다. RAS-ERK 경로에서 SHP2는 RAS-RAF-MEK-ERK 키나제 캐스케이드 신호 전달을 촉진하기 위해 업스트림에서 양성 조절자 역할을 한다. 따라서 SHP2 억제는 RAS-RAF-MEK-ERK 경로의 발암성 기능을 저해하여, 결과적으로 암세포에서 세포 성장 억제 및 세포 자멸사를 유도한다. SHP2는 또한 면역세포에서 PD-1/PD-L1에 의한 T 세포 활성화 억제 신호 전달 경로상의 중요 단백질로서 면역 회피에 기여한다. 요약하면, SHP2는 매우 매력적인 암 치료 표적이다. 예를 들어, SHP2 억제제인 SHP099는 SHP2 포스파타제 활성을 선택적으로 차단하고 시험관 내에서의 암세포 성장과 이종이식 마우스 모델에서의 종양 성장을 억제하는 것으로 나타났다 (Chen et al., Nature 2016, 535, 148-152; Garcia Fortanet et al., J. Med. Chem. 2016, 59, 7773-7782).
알로스테릭 SHP2 억제제는 Kirsten 래트 육종(KRAS)-돌연변이 인간 암의 전임상 모델에서 효과적인 것으로 나타났다. 예를 들어, CRISPR-Cas9에 의한 SHP2 비활성화는 KRAS-돌연변이 종양의 이종이식 모델에서 노화를 유도하고 종양의 성장을 억제한다는 것이 입증되었다.
SHP2 단백질의 제거는 SHP2 활성 억제를 위한 대안적이고 더 효과적인 전략을 제공할 수 있다. 따라서 본 발명이 해결하고자 하는 과제는 Src 상동성 2 도메인-함유 포스파타제(Src homology 2 domain-containing phosphatase, SHP2) 분해 활성을 가지는 화합물, 이를 유효성분으로 포함하는 약학 조성물, 및 이들의 SHP2 관련 질환 (암 또는 종양 등) 치료 또는 예방용 의약 용도를 제공하는 것이다.
본 발명이 해결하고자 하는 다른 과제는 SHP2를 분해하여 결과적으로 SHP2 수준을 낮추는 것을 특징으로 하는, 본 발명에 따른 화합물을 SHP2 관련 질환의 치료, 개선 또는 예방이 필요한 환자에게 투여하는 것을 특징으로 하는 SHP2 관련 질환(바람직하게는, 암 또는 종양)의 치료 또는 예방 방법을 제공하는 것이다.
본 개시는 E3 유비퀴틴 리가아제의 유비퀴틴화(ubiquitination)를 통해 SHP2 단백질을 표적화하여 분해시킬 수 있는 SHP2 표적 단백질 분해 화합물 (TPD, Targeted protein degradation), 이를 유효성분으로 포함하는 약학 조성물, 이들을 이용한 SHP2 관련 질환 치료 또는 예방 방법에 관한 것이다.
본 개시의 화합물
본 발명의 일 구체예에 따른 화합물은 'SHP2 결합 리간드-링커(L)-VHL 리간드'의 표적 단백질 분해 화합물이다. 일 양태에서, 본 출원은 표적 단백질의 분해를 유도함으로써 단백질 활성을 조절하는 데 유용한 이작용성 화합물에 관한 것이다. 일부 구현예에서, 이작용성 화합물은 E3 유비퀴틴 리가아제 결합 모이어티인 VHL 리간드 및 바람직하게는, 본원에서 달리 기술된 바와 같이, 연결기 (링커) 모이어티를 통해 연결된 표적 단백질 결합 모이어티를 포함한다. E3 유비퀴틴 리가아제는 기질 단백질의 분해를 위해 유비퀴틴을 전달하여 표적화하는 단백질 군을 지칭한다. VHL은 E3 유비퀴틴 리가아제 단백질로서, E2 유비퀴틴 접합 효소와 조합하여, 표적 단백질 상의 리신에 유비퀴틴이 부착되도록 하고, 이를 통해 프로테아좀에 의한 분해를 유도한다. 따라서 이작용성 화합물은 VHL 및 표적 단백질에 동시에 결합하여, 표적 단백질이 VHL에 근접하게 함으로써, 유비퀴틴화를 통한 분해를 유도하고, 결과적으로 표적 단백질의 활성을 저해/억제한다. 소정의 구현예에서, 이작용성 화합물은, 예를 들어, 화학적 연결기 L에 공유적으로, 직접적으로 또는 간접적으로 연결된 SHP2 결합 리간드 및 VHL 리간드를 포함한다. 본 발명의 일 측면은 하기 화학식 1의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물 또는 이들의 약학적으로 허용 가능한 염을 제공한다.
[화학식 1]
상기 화학식 1에서,
R1은 , , 또는 이고,
R11은 H, C1-6alkyl, hydroxy, halogen, C1-6hydroxyalkyl, C1-6haloalkyl, C3-10cycloalkyl, heterocycle, aryl, 또는 heteroaryl이고, 여기에서 aryl 및 heteroaryl은 서로 독립적이면서 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, hydroxy, halogen, C1-3hydroxyalkyl, C1-3haloalkyl, 또는 C1-3alkoxy로 치환되며,
R12는 amino, C1-6aminoalkyl, 또는 C1-6alkylamino이고,
R13a 및 R13b는 서로 독립적으로 H, C1-6alkyl, hydroxy, halogen, C1-6hydroxyalkyl, C1-6haloalkyl, 또는 C1-6alkoxy이고,
R14는 서로 독립적으로 H, C1-6alkyl, hydroxyl, halogen, 또는 CN이고,
Z는 -O-, -S-, -NH-, 또는 -CH2-이고,
고리(ring) C는 aryl 또는 heteroaryl이고,
n은 0 내지 5의 정수이고,
R2는 H, C1-6alkyl, 또는 -NH2이고,
R3는 H, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl, -C(O)R9a, -C(O)OR9a, -C(O)NR9aR9b, 또는 CN이고,
R4는 H, C1-6alkyl, halogen, 또는 C1-6haloalkyl이고,
R5는 H, C1-6alkyl, C2-6alkynyl, halogen, -CN, 또는 heteroaryl이고, 여기에서 heteroaryl은 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, halogen, 또는 C1-3haloalkyl로 치환되며,
R6는 -NHC(O)R7 또는 heteroaryl이고, 여기에서 heteroaryl은 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, halogen, 또는 C1-3haloalkyl로 치환되며,
R7은 C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 또는 heterocycle이고, 여기에서 cycloalkyl 및 heterocycle은 서로 독립적이면서 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, halogen, 또는 -CN로 치환되며,
R8a 및 R8b는 서로 독립적으로 H 또는 C1-6alkyl이고,
X는 -S-, -O-, -N(R9a)-, -CH2-, -CHCH-, -CC-, -CH2O-, 또는 -OCH2-이고,
Y는 CH 또는 N이고,
W는 직접 결합, -O-, 또는 -N(R9a)-이고,
R9a 및 R9b는 서로 독립적으로 H, C1-6alkyl, 또는 C1-6haloalkyl이고,
L은 하기 화학식 2이며,
[화학식 2]
화학식 2에서,
A1 및 A2는 서로 독립적으로 직접 결합, C3-10cycloalkyl, heterocycle, aryl, 또는 heteroaryl이며, 여기에서 cycloalkyl, heterocycle, aryl, 또는 heteroaryl은 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, halogen, C1-3haloalkyl, -OH, 또는 =O로 치환되며,
B1 및 B2는 서로 독립적으로 직접 결합, -O-, -N(R10)- -C(O)-, -C(O)N(R10)-, 또는 -N(R10)C(O)-이고,
R10은 서로 독립적으로 H 또는 C1-6alkyl이고,
q1, q2, q3, q4, 및 q5는 서로 독립적으로 0 내지 10의 정수임.
본 명세서에서 용어 "치환기(substituent)", "라디칼(radical)", "기(group)", "모이어티(moiety)", 및 "절편(fragment)"은 서로 바꾸어 사용할 수 있다.
만약 치환기가 "임의로 치환된" 또는 “선택적으로 치환된”으로 설명된다면, 상기 치환기는 치환되지 않는 것이거나, 또는 정의된 치환기들 중 하나 이상으로 치환되는 것을 의미한다. 만약 치환 가능한 위치가 치환되지 않은 경우 기본(default) 치환기는 수소이다.
본 명세서에서 사용된 용어 "알킬"은 (탄소수가 특별히 한정되지 않은 경우) 탄소수 1 내지 10을 가진 포화된 직쇄상 또는 분지상의 비-고리(cyclic) 탄화수소를 의미한다. "저급 알킬"은 탄소수가 1 내지 4인 직쇄상 또는 분지상 알킬을 의미한다. 대표적인 포화 직쇄상 알킬은 -메틸, -에틸, -n-프로필, -n-부틸, -n-펜틸, -n-헥실, -n-헵틸, -n-옥틸, -n-노닐 과 -n-데실을 포함하고, 반면에 포화 분지상 알킬은 -이소프로필, -sec-부틸, -이소부틸, -tert-부틸, 이소펜틸, 2-메틸헥실, 3-메틸부틸, 2-메틸펜틸, 3-메틸펜틸, 4-메틸펜틸, 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, 및 3,3-디에틸헥실을 포함한다. 본 발명의 바람직한 일 양태에서, 알킬은 메틸, 에틸, n-프로필이다.
본 명세서에서 사용된 용어 "알키닐"은 (탄소수가 특별히 한정되지 않은 경우) 2 내지 10개의 탄소 원자를 가지고 있고, 적어도 하나의 탄소-탄소 삼중 결합을 포함한 직쇄상 또는 곁가지의 비-고리 탄화수소를 의미한다. 대표적인 직쇄상 또는 분지상 (C2-C10) 알키닐은 -아세티레닐, -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, 및 -9-데시닐을 포함한다. 이러한 알키닐 그룹은 선택적으로 치환될 수 있다.
본 명세서에서 “C1-6”, "C1-6", 또는 "C1-C6"와 같이 기재될 경우 이는 탄소 수가 1 내지 6개임을 의미한다. 예를 들어, C1-6 알킬은 탄소 수가 1 내지 6인 알킬을 의미한다.
본 명세서에서 사용된 용어 "할로겐" 및 "할로"는 플루오린, 클로린, 브로민 또는 아이오딘을 의미한다. 본 발명의 바람직한 일 양태에 있어, 할로겐은 클로린 또는 플루오린이다.
본 명세서에서 사용된 용어 "할로알킬"은 각각 하나 이상의 수소 원자가 할로겐 원자로 치환된 알킬 그룹을 의미한다. 예를 들어, 할로알킬은 -CF3, -CHF2, -CH2F, -CBr3, -CHBr2, -CH2Br, -CCl3, -CHCl2, -CH2CI, -CI3, -CHI2, -CH2I, -CH2-CF3, -CH2-CHF2, -CH2-CH2F, -CH2-CBr3, -CH2-CHBr2, -CH2-CH2Br, -CH2-CCl3, -CH2-CHCl2, -CH2-CH2CI, -CH2-CI3, -CH2-CHI2, -CH2-CH2I, 및 이와 유사한 것을 포함한다. 본 발명의 바람직한 일 양태에서, 할로알킬은 CF3이다. 여기에서 알킬 및 할로겐은 위에서 정의된 것과 같다.
본 명세서에서 사용한 용어 "하이드록시알킬"은 하나 이상의 하이드록시 그룹으로 치환된 선형 또는 분지형 C1-10알킬을 나타내며, 하이드록시알킬 그룹의 예에는 하이드록시메틸, 하이드록시에틸, 하이드록시프로필 및 하이드록시부틸이 포함되지만, 이에 한정되는 것은 아니다.
본 명세서에서 사용된 용어 "사이클로알킬"은 탄소 및 수소 원자를 가지며 탄소-탄소 다중 결합을 가지지 않는 모노사이클릭 또는 폴리사이클릭 포화 고리(ring)를 의미한다. 모노사이클릭 고리의 예는 (C3-C7) 사이클로알킬 (예를 들어, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 및 사이클로헵틸)을 포함하나 이에 한정되는 것은 아니다. 폴리사이클릭 고리의 예는 octahydropentalene, decahydronaphthalene 등과 같은 융합된(fused) 바이사이클릭(bicyclic) 고리; spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[4.5]decane, spiro[5.5]undecane 등과 같은 스피로 고리; 및 bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane 등과 같은 가교된(bridged) 바이사이클릭 고리를 포함하나 이에 한정되는 것은 아니다. 사이클로알킬 그룹은 선택적으로 치환될 수 있다. 일 실시예에서, 사이클로알킬 그룹은 모노사이클릭 링(고리)이다. 본 발명의 바람직한 일 양태에서, 사이클로알킬은 사이클로프로필이다.
본 명세서에서 사용된 "헤테로사이클(헤테로고리, heterocycle)" 또는 “헤테로사이클로알킬”은 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4의 헤테로 원자를 함유하는 포화된 5- 내지 7-멤버의 모노사이클릭, 또는 7- 내지 12-멤버의 바이사이클릭 링(고리)를 의미하며, 여기에서 질소 및 황 헤테로 원자는 선택적으로 산화될 수 있고, 질소 헤테로 원자는 선택적으로 사가화(quaternized)될 수 있다. 대표적인 헤테로고리는 옥시란(oxiran), 옥세탄(oxetan), 테트라하이드로퓨란(tetrahydrofuran), 테트라하이드로피란(tetrahydropyran), 1,4-디옥산(1,4-dioxane), 아지리딘(aziridine), 아제티딘(azetidine), 피롤리딘(pyrrolidine), 피페리딘(piperidine), 피페라진(piperazine), 피롤리디논(pyrrolidinone), 히단토인(hydantoine), 발레롤락탐(valerolactam), 티이란(thiirane), 티에탄(thietane), 테트라하이드로티오펜(tetrahydrothiophene), 테트라하이드로티오피란(tetrahydrothiopyran), 모포린(morpholine), 테트라하이드로피리딘(tetrahydropyridine), 테트라하이드로피리미딘(tetrahydropyrimidine) 등을 포함한다. 헤테로사이클에는 헤테로고리 중 일부가 벤젠 또는 cyclopenta-1,3-diene 고리에 융합한 바이사이클릭 링이 포함된다. 헤테로고리는 헤테로 원자 또는 탄소 원자에 의하여 부착될 수 있다. 또한, 헤테로사이클에는 앞서 언급된 폴리사이클릭 고리의 1개 이상의 탄소 원자가 질소, 산소 또는 황 원자로 치환된 융합된(fused) 바이사이클릭(bicyclic) 고리, 스피로 고리 및 가교된(bridged) 바이사이클릭 고리가 포함된다. 이러한 예로는, 예를 들어, 헤테로 원자가 질소일 경우 octahydrocyclopenta[c]pyrrole, octahydropyrrolo[3,4-c]pyrrole, decahydroisoquinoline, decahydro-2,6-naphthyridine 등과 같은 융합된(fused) 헤테로바이사이클릭(bicyclic) 고리; 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.4]octane, 2,6-diazaspiro[3.4]octane, 2-azaspiro[3.5]nonane, 2,7-diazaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 2,7-diazaspiro[4.4]nonane, 8-azaspiro[4.5]decane, 2,8-diazaspiro[4.5]decane, 3-azaspiro[5.5]undecane, 3,9-diazaspiro[5.5]undecane 등과 같은 스피로 고리; 및 2-azabicyclo[2.1.1]hexane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.2]octane, 2,5-diazabicyclo[2.2.2]octane 등과 같은 가교된(bridged) 헤테로바이사이클릭 고리를 포함하나 이에 한정되는 것은 아니다. 본 발명의 바람직한 일 양태에서, 헤테로사이클은 아제티딘, 디아제티딘, 피페리딘, 피페라진, azaspiro[3.5]nonane, diazabicyclo[3.2.1]octane 등에서 선택된 어느 하나이다.
본 명세서에서 사용된 용어 "아릴"은 5 내지 10의 고리 원자를 함유하는 탄소고리 방향족 그룹을 의미한다. 대표적인 예는 페닐, 톨일(tolyl), 자이릴(xylyl), 나프틸, 테트라하이드로나프틸, 안트라세닐(anthracenyl), 플루오레닐(fluorenyl), 인데닐(indenyl), 아주레닐(azulenyl) 등을 포함하나 이에 한정되는 것은 아니다. 탄소고리 방향족 그룹은 선택적으로 치환될 수 있다.
본 명세서에서 사용된 "헤테로아릴"은 질소, 산소 및 황으로 구성된 군으로부터 선택된 적어도 하나의 헤테로원자를 가지고, 모노- 및 바이사이클릭 링 시스템을 포함하는 적어도 하나의 탄소 원자를 포함하는 5 내지 10 멤버의 방향족 헤테로고리(heterocycle) 링이다. 대표적인 헤테로아릴은 furan, 4H-pyran, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine, thiophene, ozaxole, isoxazole, thiazole, isothiazole, oxadiazole, benzofuran, benzothiophene, quinoline, indole, benzoxazole, benzimidazole, benzothiazole, cinnoline, phthalazine, quinazoline, 1H-azepine 등이다. 본 발명의 바람직한 일 양태에서, 헤테로아릴은 thiazole, 피리딘, 또는 피라진이다.
본 명세서에 있어, * 또는 은 다른 moiety와 연결되어 있는 것을 의미한다.
본 발명에 있어 "약학적으로 허용 가능한 염"은 여기서 언급한 화합물들에서 발견되는 특정 치환체에 의존하는 비교적 비독성 산 및 염기로 제조된 활성 화합물의 염들을 포함한다. 본 개시의 화합물들은 상대적으로 산성 기능성을 포함할 때, 염기(base) 부가 염들은 충분한 양의 원하는 염기, 순수한 또는 적당한 비활성(inert) 용매로 그러한 화합물들의 중성 형태를 접촉하여 얻을 수 있다. 약학적으로 허용 가능한 염기 부가 염의 예들은 나트륨, 칼륨, 칼슘, 암모늄, 유기 아미노 또는 마그네슘 염 또는 유사한 염을 포함한다. 본 개시의 화합물들은 상대적으로 염기성 기능성을 포함할 때, 산성 부가 염들은 충분한 양의 원하는 산, 순수한 또는 적당한 비활성(inert) 용매로 그러한 화합물들의 중성 형태를 접촉하여 얻을 수 있다. 약학적으로 허용 가능한 산성 부가 염의 예들은 초산, 프로피온산, 이소부틸산, 옥살릭산(oxalic), 마레익(maleic), 말로닉(malonic), 안식향산, 숙신산, 수버릭(suberic), 푸마릭(fumaric), 만데릭(mandelic), 프탈릭(phthalic), 벤젠설포닉(benzenesulfonic), p-토릴설포닉(tolylsulfonic), 구연산, 주석산, 메탄솔포닉(methanesulfonic), 및 그 유사체를 포함하는 상대적으로 비독성 유기산에서 유래한 염들 뿐만 아니라, 염화수소, 브롬화 수소, 질산, 탄산, 일수소탄산(monohydrogencarbonic), 인산(phosphoric), 일수소인산, 이수소인산, 황산, 일수소황산, 요오드화수소 또는 아인산(phosphorous acid) 및 그 유사체를 포함한다. 또한 알긴네이트(arginate)와 그 유사체와 같은 아미노산의 염 및 글루쿠로닉(glucuronic) 또는 갈락투노릭(galactunoric) 산들과 그 유사체와 같은 유기산의 유사체를 포함한다. 본 발명의 일부 특정한 화합물들은 화합물들을 염기성 또는 산성 부가(addition) 염들로 전환하게 하는 염기성 및 산성 기능성 모두를 갖는다. 염들의 다른 예들은 본 발명이 속한 분야에서 공지된 문헌들을 통해 잘 알려져 있다.
본 명세서에서 사용된 용어인 "본 개시의 화합물"은 화학식 1 각각의 화합물들뿐만 아니라, 이들의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 또는 용매화물을 포함하는 의미이다. 또한 용어 “본 개시의 화합물”은 이의 약학적으로 허용 가능한 염이 언급되지 않을 경우 본 개시 화합물의 약학적으로 허용 가능한 염도 포함하는 의미이다. 일 실시예에 본 개시의 화합물은 입체이성질체적으로 순수한 화합물들(예를 들어, 다른 입체이성질체가 실질적으로 없는(예를 들어, 85% ee 이상, 90% ee 이상, 95% ee 이상, 97% ee 이상, 또는 99% ee 이상))로 존재할 수 있다. 즉, 본 발명에 따른 화학식 1의 화합물 또는 그의 염이 호변이성적(tautomeric) 이성질체 및/또는 입체이성질체(예를 들어, 기하이성질체(geometrical isomer) 및 배좌 이성질체(conformational isomers))일 경우 그들의 분리된 이성질체 및 혼합물 각각 또한 본 발명의 화합물의 범주에 포함된다. 본 발명의 화합물 또는 그의 염이 구조 내에 비대칭 탄소(asymmetric carbon)를 가지고 있는 경우에, 그들의 광학 활성 화합물 및 라세믹 혼합물들 또한 본 발명의 화합물의 범위에 포함된다.
본 명세서에서 사용될 경우, 용어 "동위원소 변형체"는 화합물을 구성하는 하나 이상의 원자에서의 비정상적인 비율의 동위원소를 포함하는 화합물을 의미한다. 예를 들면, 화합물의 동위원소 변형체는 방사성 표지될 수 있으며, 예를 들면 수소원자는 수소, 중수소 및 삼중수소로부터 선택된 것일 수 있고, 탄소-13(13C), 질소-15(15N) 등을 함유할 수 있다.
본 명세서에서 사용된 용어 "용매 화합물"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 용매를 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다. 바람직한 용매들은 휘발성이고, 비독성이며, 인간에게 극소량 투여될 수 있다.
본 명세서에서 사용된 용어 "수화물(hydrate)"은 비공유 분자간의 힘에 의해 결합된 화학량론적 또는 비-화학량론적인 양의 물을 포함하는 본 발명의 화합물 또는 이의 약학적으로 허용 가능한 염을 의미한다.
본 명세서에서 사용된 용어 "정제된(purified)"은 분리될 때, 분리체는 90% 이상 순수한 것을 의미하며, 일 실시예에서는 95% 이상 순수하고, 다른 실시 예에서는 99% 이상 순수하고, 또 다른 실시예에서는 99.9% 이상 순수한 것을 의미한다.
본 발명 화합물의 의약 용도 및 치료 방법
본 발명의 일 측면은 하나 이상의 상기와 같은 화합물의 치료적으로 유효한 양을 개체에게 투여함으로써 하기 질병 또는 상태(condition)를 갖거나 갖기 쉬운 개체에서 하기 질병 또는 상태(condition)를 치료하는 방법을 더 제공한다. 일 양태에서, 상기 치료는 예방 치료(preventative treatment)이다. 또 다른 양태에서, 상기 치료는 완화 치료(palliative treatment)이다. 또 다른 양태에서, 상기 치료는 회복 치료(restorative treatment)이다.
본 명세서에서 사용되는, 용어 "예방" 또는 "예방하는"은 질환, 병태 또는 장애의 증상 또는 합병증의 시작을 막는 것을 기술한다.
1. 질병 또는 상태(Condition)
본 개시의 화합물들은 다양한 치료학적 또는 예방학적 용도 (예를 들어, 암)에 유용하다. 이러한 화합물들은 SHP2을 분해하여 SHP2 활성을 낮추기 위해 사용될 수 있으며, 또 SHP2 관련 질환의 치료를 위해서 또는 이러한 질병의 악화를 방지하기 위하여 사용될 수 있다. 따라서 본 개시의 일 측면은 세포 내 SHP2을 분해하는 방법을 제공한다. 이러한 방법에서 상기 세포는 본 개시의 화합물의 유효한 양과 접촉할 수 있다. 일 실시예에서, 상기 세포는 개체 내에 존재한다. 본 개시의 방법은 치료 또는 예방이 필요한 개체에게 치료적으로 또는 예방학적으로 유효한 양의 본 개시에 따른 화합물을 포함하는 약학 조성물을 투여하는 것을 포함한다.
일 양태에서, 본 발명의 일 측면은 SHP2 관련 질환의 세포 내에서 SHP2을 분해하는 방법을 제공한다. 예를 들어, 본 발명의 일 구체예는 후술하는 SHP2 관련 질환을 가진 개체의 세포 내에서 SHP2을 분해하여 결과적으로 SHP2 활성을 낮추는 방법을 제공할 수 있다. 본 발명의 다른 양태에서, 본 개시의 화합물은 암, 특히 백혈병, 림프종, 폐암, 두경부암, 식도암, 위암, 대장암, 췌장암, 간암, 유방암, 난소암, 자궁경부암, 방광암, 흑색종, 신경모세포종, 신경교종, 육종 등의 세포 내에서 SHP2를 분해하기 위하여 이용될 수 있다.
다른 양태에서, 본 개시의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물 또는 이들의 약학적으로 허용 가능한 염의 치료적으로 유효한 양을 개체에게 투여하는 단계를 포함하는 SHP2 관련 질환을 치료하는 방법을 제공한다. 이러한 방법은 SHP2를 분해하기 위해 충분한 양, 즉, 치료학적으로 유효한 양의 본 개시의 화합물을 치료가 필요한 개체에게 투여하는 단계를 포함한다. 이러한 방법에 있어, 본 개시의 화합물은 본 명세서에서 설명되는 약학 조성물의 형태로 상기 개체에 투여될 수 있다.
본 발명의 일 구체예에서, SHP2 관련 질환은 암, 암 전이 (metastasis), 심혈관 질환, 면역 장애 또는 안구 장애일 수 있다.
본 발명의 일 구체예에 있어, SHP2 관련 질환은 암이다. 예를 들어, 국제특허출원 공개공보 WO 2021/236775의 표 2에 기재된 암들 중 어느 하나 일 수 있지만 이에 제한되지 않는다. 구체적으로는 혈액암, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 급성 골수성 백혈병, 단핵구 백혈병, 만성 골수성 백혈병, 만성 림프구성 백혈병, 혼합 계통 백혈병, NUT-중간선 암, 다발성 골수종, 소세포 폐암, 비소세포 폐암, 신경모세포종, 림프종, 자궁경부암, 두경부암, 두부암, 식도암, 위암, 췌장암, 간암, 흑색종, 대장암, 결장암, 전립선암, 유방암, 난소암, 방광암, 신경교종, 또는 육종, 유두 갑성선 암종 및 이들의 조합으로부터 선택되는 하나 이상인 것일 수 있다. WO 2021/236775의 표 2의 기재는 인용에 의해 본 명세서에 모두 포함된다. 또 다른 양태에서, 암은 고형 종양이다. 또 다른 양태에서, 암은 혈액암이다. 예시적인 혈액암은 WO 2021/236775의 표 3에 열거된 암을 포함하지만 이에 제한되지 않는다. WO 2021/236775의 표 3의 기재는 인용에 의해 본 명세서에 모두 포함된다. 또 다른 양태에서, 혈액암은 급성 림프구성 백혈병, 만성 림프구성 백혈병(B-세포 만성 림프구성 백혈병 포함), 또는 급성 골수성 백혈병이다. 또 다른 양태에서, 암은 백혈병, 예를 들어 급성 단핵구 백혈병, 급성 골수성 백혈병, 만성 골수성 백혈병, 만성 림프구성 백혈병 및 혼합 계통 백혈병(MLL)으로부터 선택된 백혈병이다. 또 다른 양태에서, 암은 NUT-정중선 암종이다. 또 다른 양태에서, 암은 다발성 골수종이다. 또 다른 양태에서, 암은 소세포 폐암(SCLC)과 같은 폐암이다. 또 다른 양태에서, 암은 신경모세포종이다. 또 다른 양태에서, 암은 버킷 림프종이다. 또 다른 양태에서, 암은 자궁경부암이다. 또 다른 양태에서, 암은 두경부암이다. 또 다른 양태에서, 암은 식도암이다. 또 다른 양태에서, 암은 위암이다. 또 다른 양태에서, 암은 췌장암이다. 또 다른 양태에서, 암은 간암이다. 또 다른 양태에서, 암은 흑색종이다. 또 다른 양태에서, 암은 난소암이다. 또 다른 양태에서, 암은 대장암이다. 또 다른 양태에서, 암은 전립선암이다. 또 다른 양태에서, 암은 유방암이다.
또 다른 양태에서, 본 발명에 따른 암은 급성 단핵구성 백혈병, 급성 골수성 백혈병, 만성 골수성 백혈병, 만성 림프구성 백혈병, 혼합 계통 백혈병, 림프종, NUT-중간선 암종, 다발성 골수종, 소세포 폐암, 비소세포 폐암, 신경모세포종, 버킷 림프종, 자궁경부암, 두경부암, 식도암, 위암, 췌장암, 간암, 흑색종, 난소암, 대장암, 전립선암, 유방암, 방광암, 신경교종, 육종, 식도 편평 세포 암종 및 유두 갑상선 암종으로 이루어진 군으로부터 선택된다.
즉, 본 발명의 일 측면은 화학식 1의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물 또는 이들의 약학적으로 허용 가능한 염의 상기 질병을 치료 또는 예방하기 위한 의약 용도를 제공한다.
2. 개체(Subjects)
본 발명에 따라 치료될 적합한 개체는 포유동물 개체를 포함한다. 본 발명에 따른 포유동물은, 이에 한정되는 것은 아니지만, 인간, 개(canine), 고양잇과동물(feline), 소(bovine), 염소(caprine), 말(equine), 양(ovine), 돼지(porcine), 설치류(rodents), 토끼목(lagomorphs), 영장류(primates) 등을 포함하고, 자궁 내의(in utero) 포유동물을 포함한다.
일 양태에서, 본 발명에 따른 치료될 적합한 개체는 인간이다.
3. 투여 및 투여량(Administration and Dosing)
본 개시의 화합물은 일반적으로 치료적으로 유효한 양이 투여된다.
본 명세서에서 사용된 "유효량"은 SHP2 관련 질환의 진행을 늦추거나 또는 최소화하거나, SHP2 관련 질환의 치료 또는 관리에서 치료상 이점을 제공하기에 충분한 본 개시의 화합물의 양을 말한다. "유효량"은 또한 생체외(in vitro) 또는 생체내(in vivo) 어떤 쪽이든 SHP2 활성을 억제 또는 줄이기에 충분한 양을 말한다.
본 개시의 화합물은 임의의 적합한 경로에 의하여 이러한 경로에 적당한 약학 조성물의 형태, 그리고 의도된 치료를 위하여 효과적인 투여량으로 투여될 수 있다. 효과적인 투여량은 단일 또는 분할 투여로 일반적으로 약 0.001 내지 약 100 mg/체중kg/일이고, 바람직하게는 약 0.01 내지 약 50 mg/kg/일이다. 나이, 종, 및 치료될 질병 또는 상태(condition)에 따라 이 범위의 하한 미만의 투여량 수준이 적합할 수 있다. 다른 경우에는, 여전히 더 큰 투여량이 해로운 부작용없이 사용될 수 있다. 더 큰 투여량은 하루 동안 투여를 위하여, 여러 작은 투여량으로 분할될 수 있다.
본 개시 화합물의 약학 조성물
다른 양태에서, 본 발명은 화학식 1의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물 또는 이들의 약학적으로 허용 가능한 염, 및 약학적으로 허용 가능한 담체 또는 첨가제를 포함하는 약학 조성물이 제공한다. 본 발명의 일 양태에 있어, 상기 약학 조성물의 용도는 후술하는 SHP2 관련 질환, 구체적으로는 암의 치료 또는 예방 용도이다.
용어 "약학적으로 허용 가능한"은 약학적 제제로 사용하기에 적합한 것을 의미하며, 일반적으로 이러한 사용을 위하여 안전한 것으로 간주되며, 이러한 사용을 위하여 국가의 관리 기관에 의하여 공식적으로 승인되거나 한국 약전 또는 미국 약전의 명단에 있는 것을 의미한다.
약학 조성물, 제형 및 투여 경로
상기 설명된 질병 또는 상태(condition)의 치료를 위하여, 본 명세서에서 설명된 상기 화합물은 다음과 같이 투여될 수 있다.
1. 구강 투여(Oral administration)
본 개시의 화합물은 구강으로 투여될 수 있으며, 구강은 연하(swallowing)를 포함하는 개념이다. 구강 투여에 의하여 본 발명의 화합물이 위장관(gastrointestinal tract)에 들어가거나, 예를 들어, 구강(buccal) 또는 설하(sublingual) 투여와 같이, 입으로부터 혈류로 직접적으로 흡수될 수 있다.
구강 투여를 위한 적합한 조성물은 고형상, 액상, 겔(gel), 또는 파우더 형상일 수 있으며, 정제(tablet), 로젠지(lozenge), 캡슐(capsule), 과립제, 산제 등의 제형을 가질 수 있다.
구강 투여를 위한 조성물은 선택적으로 장용 코팅(enteric coating)될 수 있으며, 장용 코팅을 통하여 지연된(delayed) 또는 지속된(sustained) 방출을 나타낼 수 있다. 즉, 본 발명에 따른 구강 투여를 위한 조성물은 즉시 또는 변형된(modified) 방출 패턴을 가진 제형일 수 있다.
액체 제형은 용액, 시럽 및 현탁액을 포함할 수 있으며, 이러한 액상 조성물은 연질 또는 경질 캡슐 내에 함유된 형태일 수 있다. 이러한 제형은 약학적으로 허용 가능한 담체, 예를 들어, 물, 에탄올, 폴리에틸렌글리콜, 셀룰로오스, 또는 오일(oil)을 포함할 수 있다. 상기 제형은 또한 하나 이상의 유화제 및/또는 현탁제를 포함할 수 있다.
정제(tablet) 제형에서, 활성 성분인 약물의 양은 정제 총 중량 대비 약 0.05 중량% 내지 약 95 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 50 중량%로 존재할 수 있다. 또한, 정제는 약 0.5 중량% 내지 약 35 중량%, 더욱 일반적으로 제형의 약 2 중량% 내지 약 25 중량%를 포함하는 붕해제를 함유할 수 있다. 붕해제의 예로는 유당, 전분, 소디움스타치글리콜레이트, 크로스포비돈, 크로스카멜로스소디움(croscarmellose sodium), 말토덱스트린 또는 이들의 혼합물이 사용될 수 있으나 이에 한정되는 것은 아니다.
정제로 제조하기 위해 포함되는 적합한 활택제는 약 0.1 중량% 내지 약 5 중량% 양으로 존재할 수 있고, 탈크(talc), 이산화규소, 스테아린산, 칼슘, 아연 또는 마그네슘 스테아레이트, 소듐 스테아릴 푸마레이트 등이 활택제로 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다.
정제로 제조하기 위한 결합제(binder)로는 젤라틴, 폴리에틸렌글리콜, 당(sugar), 검(gum), 녹말(starch), 폴리비닐피롤리돈, 하이드록시프로필셀룰로오스, 하이드록시프로필메틸셀룰로오스 등이 사용될 수 있으며, 정제로 제조하기 위한 적합한 희석제로는 만니톨, 자일리톨, 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 녹말(starch), 미결정셀룰로오스 등이 사용될 수 있으나, 본 발명은 이러한 첨가제들의 종류에 한정되는 것은 아니다.
선택적으로 정제에 포함될 수 있는 가용화제는 정제 총 중량 대비 약 0.1 중량% 내지 약 3 중량% 양이 사용될 수 있고, 예를 들어, 폴리소르베이트, 소디움 라우릴설페이트, 소디움 도데실설페이트, 프로필렌 카보네이트, 디에틸렌글리콜모노에틸에테르, 디메틸이소소르비드, 폴리옥시에틸렌글리콜화된 천연 또는 수소화 피마자유, HCORTM(Nikkol), 올레일에스테르, 젤루시어(GelucireTM), 카프릴릭/카프릴산 모노/디글리세리드, 소르비탄지방산에스테르, 솔루톨HSTM 등이 본 발명에 따른 약학 조성물에 사용될 수 있으나, 본 발명은 이러한 가용화제의 구체적 종류에 한정되는 것은 아니다.
2. 비경구 투여(Parenteral Administration)
본 개시의 화합물은 혈류, 근육, 또는 내장 내로 직접 투여될 수 있다. 비경구 투여를 위한 적합한 방법은 정맥내(intravenous), 근육내(intra-muscular), 피하 동맥내(subcutaneous intraarterial), 복강내(intraperitoneal), 척추강내(intrathecal), 두개내(intracranial) 주사 등을 포함한다. 비경구 투여를 위한 적합한 장치는 (바늘 및 바늘 없는 주사기를 포함하는) 주사기(injector) 및 주입 방법(infusion method)을 포함한다.
비경구 투여를 위한 조성물은 즉시 또는 변형된 방출 패턴을 가진 제형일 수 있으며, 변형된 방출 패턴은 지연된(delayed) 또는 지속된(sustained) 방출 패턴일 수 있다.
대부분의 비경구 제형은 액상 조성물이며, 이러한 액상 조성물은 본 발명에 따른 약효 성분, 염, 완충제, 등장화제 등을 포함하는 수용액이다.
비경구 제형은 또한 건조된 형태(예를 들어, 동결 건조) 또는 멸균 비-수용액으로서 제조될 수 있다. 이들 제형은 멸균수(sterile water)와 같은 적합한 비히클(vehicle)과 함께 사용될 수 있다. 용해도 증강제(solubility-enhancing agents) 또한 비경구 용액의 제조에 사용될 수 있다.
3. 국소 투여(Topical Administration)
본 개시의 화합물은 피부 또는 경피로 국소적으로 투여될 수 있다. 이 국소 투여를 위한 제형은 로션, 용액, 크림, 젤, 하이드로젤, 연고, 폼(foam), 임플란트(implant), 패치 등을 포함한다. 국소 투여 제형을 위한 약학적으로 허용 가능한 담체는 물, 알코올, 미네랄 오일, 글리세린, 폴리에틸렌글리콜 등을 포함할 수 있다. 국소 투여는 또한 전기천공법(electroporation), 이온도입법(iontophoresis), 음파영동(phonophoresis) 등에 의하여 수행될 수 있다.
국소 투여를 위한 조성물은 즉시 또는 변형된 방출 패턴을 가진 제형일 수 있으며, 변형된 방출 패턴은 지연된(delayed) 또는 지속된(sustained) 방출 패턴일 수 있다.
치료제가 환자 체내에 어느 정도, 바람직하게는 효과적인 양으로 동시에 존재하는 한, 용어 "병용 투여" 및 "병용 투여하는 단계" 또는 "병용 요법"은 동시 투여(동시에 2개 이상의 치료제의 투여) 및 시간차를 둔 투여(추가 치료제 또는 제제의 투여와 상이한 시간에 한 번에 하나 이상의 치료제의 투여) 모두를 지칭한다. 특정 바람직한 양태에서, 본 명세서에서 기술된 하나 이상의 본 개시의 화합물은 특히 항암제를 포함하는 적어도 하나의 추가적인 생리활성제와 조합되어 병용 투여된다. 특정 바람직한 양태에서, 화합물의 병용 투여는 항암 요법을 포함하는 상승 활성 및/또는 치료로 결부된다.
본 개시는 SHP2 분해활성이 매우 우수하여 다양한 약리 활성을 나타낼 수 있는 화합물, 이들을 유효 성분으로 포함하는 약학 조성물, 이들의 의약 용도(특히, 암 또는 종양) 및 이들을 치료 또는 예방이 필요한 개체에게 투여하는 것을 포함하는 치료 방법을 제공한다. 본 개시에 따른 화합물은 SHP2 결합 리간드를 본 개시의 링커를 통해 VHL 리간드에 도입함에 따라 SHP2 분해 활성이 우수한 화합물을 제공할 수 있고, 이에 따라 종양 세포 특히 KRAS-돌연변이를 갖는 암에 대한 효과적인 치료 옵션을 제공할 수 있다. 또한 본 개시에 따른 화합물은 SHP2 분해활성, 혈장안정성, 대사안정성, 약물성, 물리화학적 성질 등의 다양한 측면에서 우수하다.
이하, 본 발명의 이해를 돕기 위하여 실시예 등을 들어 상세하게 설명하기로 한다. 그러나, 본 발명에 따른 실시예들은 여러 가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 하기 실시예들에 한정되는 것으로 해석되어서는 안 된다. 본 발명의 실시예들은 본 발명이 속한 분야에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.
본 발명 화합물들의 제조
이하, 본 개시 화합물의 일부 화합물들의 합성 과정을 기재하며, 하기 언급되지 않은 화합물들의 경우 출발 물질, 중간체 및/또는 반응 물질을 대체하여 유사한 방법으로 제조될 수 있다.
중간체 1. tert-butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate
단계 1: 3-(tert-butylthio)-2-chloroaniline의 합성
2-Chloro-3-fluoroaniline (5 g, 34.34 mmol), 2-methylpropane-2-thiol (11.6 ml, 103.02 mmol), 및 Cs2CO3 (22 g, 68.68 mmol)를 DMF (60 ml)에 현탁 시킨 후 120 ℃에서 16시간 동안 교반 하였다. 반응액을 EtOAc (400 ml)로 희석한 뒤 증류수 (150 ml x 3), brine (150 ml x 3)으로 씻고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 갈색 오일 7.8 g (quant.)을 수득하였다.
단계 2: 3-amino-2-chlorobenzenethiol의 합성
3-(tert-Butylthio)-2-chloroaniline (7.8 g, 34.34 mmol)을 conc. HCl (126 ml)에 현탁 시킨 후 90 ℃에서 6시간 동안 교반 하였다. 반응액을 냉각시킨 후 생성된 고체를 여과, 건조하여 상아색 고체 5.3 g (97%)을 수득하였다.
단계 3: 2-chloro-3-((5-chloropyrazin-2-yl)thio)aniline의 합성
3-Amino-2-chlorobenzenethiol (5.3 g, 33.20 mmol), 2-bromo-5-chloropyrazine (6.4 g, 33.20 mmol), Pd2(dba)3 (304 mg, 0.33 mmol), Xantphos (384 mg, 0.66 mmol), DIPEA (11.6 ml, 66.40 mmol)를 1,4-dioxane (60 ml)에 현탁 시킨 후 95 ℃에서 1시간 동안 교반 하였다. 반응액을 여과한 후 여과액을 감압 농축하여 얻어진 잔사를 MPLC (3-15% EtOAc/Hexane)하여 상아색 고체 5.93 g (66%)을 수득하였다.
단계 4: tert-butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
2-Chloro-3-((5-chloropyrazin-2-yl)thio)aniline (2.5 g, 9.19 mmol), tert-butyl ((4-methylpiperidin-4-yl)methyl)carbamate (2.3 g, 10.11 mmol), DIPEA (7.2 ml, 41.34 mmol)를 NMP (9 ml)에 현탁 시킨 후 130 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (150 ml)를 가한 뒤 EtOAc (150 ml)로 추출하였다. 유기층을 brine (150 ml)으로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (3-30% EtOAc/Hexane)하여 상아색 고체 3.84 g (90%)를 수득하였다.
중간체 2. tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate
단계 1: (9H-fluoren-9-yl)methyl 3-hydroxyazetidine-1-carboxylate의 합성
3-Hydroxyazetidine hydrochloride (1 g, 9.13 mmol), 및 Na2CO3 (2.9 g, 27.38 mmol)를 water : 1,4-dioxane = 1 : 1 (80 ml)에 현탁 시킨 후 0 ℃에서 10분 동안 교반 하였다. Fmoc-Cl (2.36 g, 9.13 mmol)를 가한 후 상온에서 2시간 동안 교반 하였다. 반응액에 증류수 (30 ml)를 가한 뒤 EtOAc (30 ml)로 추출하였다. 유기층을 brine (30 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (1-60% EtOAc/Hexane)하여 흰색 고체 2.52 g (93%)을 수득하였다.
단계 2: (9H-fluoren-9-yl)methyl 3-oxoazetidine-1-carboxylate의 합성
(9H-Fluoren-9-yl)methyl 3-hydroxyazetidine-1-carboxylate (1.11 g, 3.76 mmol), DMP (1.75 g, 4.13 mmol)를 DCM (17 ml)에 현탁 시킨 후 상온에서 2시간 동안 교반 하였다. 반응액에 Na2S2O3 포화수용액 (40 ml)를 가한 뒤 DCM (50 ml)으로 추출하였다. 유기층을 증류수 (40 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (1-25% EtOAc/Hexane)하여 흰색 고체 1.1 g (100%)을 수득하였다.
단계 3: (9H-fluoren-9-yl)methyl 3-((3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carboxylate의 합성
tert-Butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 1, 1.50 g, 3.23 mmol), (9H-fluoren-9-yl)methyl 3-oxoazetidine-1-carboxylate (2.37 g, 8.08 mmol), 및 Ti(Oi-Pr)4 (1.9 ml, 6.47 mmol)를 THF (12 ml)에 현탁 시킨 후 70 ℃에서 16시간 동안 교반 하였다. NaBH4 (306 mg, 8.08 mmol), MeOH (4 ml)를 가한 후 상온에서 1시간 동안 교반 하였다. 반응액에 증류수 (50 ml)를 가한 뒤 DCM (50 ml)으로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-15% EtOAc/DCM)하여 상아색 고체 1.62 g (68%)을 수득하였다.
단계 4: tert-butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
(9H-Fluoren-9-yl)methyl 3-((3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carboxylate (900 mg, 1.21 mmol), Et2NH (6.3 ml, 60.70 mmol)을 DCM (6.3 ml)에 현탁 시킨 후 상온에서 3시간 동안 교반 하였다. 반응액에 증류수 (20 ml)를 가한 뒤 DCM (30 ml)으로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 상아색 고체 739 mg (crude)을 수득하였다.
중간체 3. tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate
단계 1: (9H-fluoren-9-yl)methyl 4-hydroxypiperidine-1-carboxylate의 합성
4-Hydroxypiperidine (1 g, 9.89 mmol), 및 Na2CO3 (3.14 g, 29.66 mmol)를 water : 1,4-dioxane = 1 : 1 (82 ml)에 현탁 시킨 후 0 ℃에서 10분 동안 교반 하였다. Fmoc-Cl (2.56 g, 9.89 mmol)를 가한 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (30 ml)를 가한 뒤 EtOAc (30 ml)로 추출하였다. 유기층을 brine (30 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (20-70% EtOAc/Hexane)하여 흰색 고체 2.95 g (92%)을 수득하였다.
단계 2: (9H-fluoren-9-yl)methyl 4-oxopiperidine-1-carboxylate의 합성
(9H-Fluoren-9-yl)methyl 4-hydroxypiperidine-1-carboxylate (2.71 g, 8.38 mmol), DMP (3.90 g, 9.22 mmol)를 DCM (38 ml)에 현탁 시킨 후 상온에서 3시간 동안 교반 하였다. 반응액에 Na2S2O3 포화수용액 (40 ml)를 가한 뒤 DCM (50 ml)으로 추출하였다. 유기층을 증류수 (40 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-35% EtOAc/Hexane)하여 흰색 고체 2.76 g (quant.)을 수득하였다.
단계 3: (9H-fluoren-9-yl)methyl 4-((3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidine-1-carboxylate의 합성
tert-Butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 1, 150 mg, 0.32 mmol), (9H-fluoren-9-yl)methyl 4-oxopiperidine-1-carboxylate (260 mg, 0.81 mmol), NaBH(OAc)3 (206 mg, 0.97 mmol), 및 acetic acid (0.3 ml)를 ACN : DCM = 1 : 1 (2.1 ml)에 현탁 시킨 후 상온에서 4시간 동안 교반 하였다. 반응액에 NaHCO3 포화수용액 (10 ml)를 가한 뒤 DCM (10 ml x 2)으로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (1-40% EtOAc/Hexane)하여 상아색 고체 334 mg (crude)을 수득하였다.
단계 4: tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
(9H-Fluoren-9-yl)methyl 4-((3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidine-1-carboxylate (334 mg, crude), 및 piperidine (0.64 ml, 6.47 mmol)을 DCM (1.5 ml)에 현탁 시킨 후 상온에서 2시간 동안 교반 하였다. 반응액에 증류수 (10 ml)를 가한 뒤 DCM (10 ml)으로 추출하였다. 유기층을 brine (10 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-3% MeOH/DCM)하여 상아색 고체 80.1 mg (45%, 2 steps)을 수득하였다.
중간체 3의 합성법과 동일한 방법으로 중간체 4 내지 중간체 7을 합성하였다.
중간체 8. tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate
단계 1: tert-butyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate의 합성
3-Chloro-2-fluoro-4-iodopyridine (500 mg, 1.94 mmol), 1-Boc-3-aminoazetidine (669 mg, 3.88 mmol), 및 DIPEA (0.68 ml, 3.88 mmol)를 DMSO (7.5 ml)에 현탁 시킨 후 100 ℃에서 2시간 동안 교반 하였다. 반응액에 증류수 (30 ml)를 가한 뒤 EtOAc (30 ml)로 추출하였다. 유기층을 brine (30 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (1-15% EtOAc/Hexane)하여 흰색 고체 540 mg (68%)을 수득하였다.
단계 2: N-(azetidin-3-yl)-3-chloro-4-iodopyridin-2-amine의 합성
tert-Butyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate (440 mg, 1.07 mmol)를 DCM (10.6 ml)에 현탁 시키고 TFA (2.6 ml)를 가한 후 상온에서 1시간 동안 교반 하였다. 반응액을 감압 농축하여 갈색 오일 800 mg (quant.)을 수득하였다.
단계 3: 2-(trimethylsilyl)ethyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate의 합성
N-(Azetidin-3-yl)-3-chloro-4-iodopyridin-2-amine (800 mg, 1.07 mmol), TEA (0.60 ml, 4.30 mmol)를 DCM (3.8 ml)에 현탁 시키고 Teoc-Osu (279 mg, 1.07 mmol)를 0 ℃에서 가한 후 상온에서 1시간 동안 교반 하였다. 반응액에 증류수 (15 ml)를 가한 뒤 DCM (20 ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (1-15% EtOAc/Hexane)하여 무색 오일 468 mg (96%)을 수득하였다.
단계 4: tert-butyl ((1-(5-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
tert-Butyl ((4-methylpiperidin-4-yl)methyl)carbamate (504 mg, 2.21 mmol), 2,5-dibromopyrazine (500 mg, 2.10 mmol), DIPEA (1.1 ml, 6.31 mmol)를 NMP (2 ml)에 현탁 시킨 후 130 ℃에서 1시간 동안 교반 하였다. 반응액에 증류수 (20 ml)를 가한 뒤 EtOAc (30 ml)로 추출하였다. 유기층을 brine (20 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (1-15% EtOAc/Hexane)하여 노란색 고체 705 mg (87%)을 수득하였다.
단계 5: methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanoate의 합성
tert-Butyl ((1-(5-bromopyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (705 mg, 1.83 mmol), methyl 3-mercaptopropionate (0.22 ml, 2.01 mmol), Pd2(dba)3 (84 mg, 0.09 mmol), Xantphos (106 mg, 0.18 mmol), DIPEA (0.64 ml, 3.66 mmol)를 1,4-dioxane (3.6 ml)에 현탁 시킨 후 90 ℃에서 3시간 동안 교반 하였다. 반응액을 여과한 후 여과액을 감압 농축하여 얻어진 잔사를 MPLC (1-35% EtOAc/Hexane)하여 노란색 오일 680 mg (88%)을 수득하였다.
단계 6: sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate의 합성
Methyl 3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)propanoate (243 mg, 0.57 mmol)를 THF (1.28 ml)에 현탁 시키고 NaOEt (ca. 20% in Ethanol, 0.21 ml, 0.63 mmol)를 가한 후 상온에서 2시간 동안 교반 하였다. 반응액을 감압 농축하여 노란색 고체 278 mg (crude)을 수득하였다.
단계 7: 2-(trimethylsilyl)ethyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carboxylate의 합성
2-(Trimethylsilyl)ethyl 3-((3-chloro-4-iodopyridin-2-yl)amino)azetidine-1-carboxylate (200 mg, 0.44 mmol), sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate (278 mg, crude, 0.57 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), Xantphos (25 mg, 0.04 mmol), DIPEA (0.15 ml, 0.88 mmol)를 1,4-dioxane (1 ml)에 현탁 시킨 후 90 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (15 ml)를 가한 뒤 EtOAc (20 ml)로 추출하였다. 유기층을 brine (15 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (1-40% EtOAc/Hexane)하여 노란색 고체 278 mg (95%)을 수득하였다.
단계 8: tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
2-(Trimethylsilyl)ethyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carboxylate (37.8 mg, 0.06 mmol), TBAF (1.0 M in THF, 0.17 ml, 0.17 mmol)를 THF (0.43 ml)에 현탁 시킨 후 50 ℃에서 2시간 동안 교반 하였다. 반응액에 증류수 (5 ml)를 가한 뒤 DCM (5 ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 상아색 고체 28.5 mg (96%)을 수득하였다.
중간체 8의 합성법과 동일한 방법으로 중간체 9 내지 중간체 10을 합성하였다.
중간체 11. (1S,3S)-3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarboxylic acid
단계 1: (1S,3S)-methyl 3-((3-chloro-4-iodopyridin-2-yl)amino)cyclobutanecarboxylate의 합성
3-Chloro-2-fluoro-4-iodopyridine (1 g, 3.88 mmol), methyl (1S,3S)-3-aminocyclobutane-1-carboxylate hydrochloride (644 mg, 3.88 mmol), 및 DIPEA (2 ml, 11.65 mmol)를 DMSO (12 ml)에 현탁 시킨 후 100 ℃에서 4시간 동안 교반 하였다. 반응액에 증류수 (30 ml)를 가한 뒤 EtOAc (30 ml x 2)로 추출하였다. 유기층을 brine (30 ml x 2)으로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-10% EtOAc/Hex)하여 노란색 고체 600 mg (42%)을 수득하였다.
단계 2: (1S,3S)-methyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarboxylate의 합성
Sodium 5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazine-2-thiolate (905 mg, 2.51 mmol), (1S,3S)-methyl 3-((3-chloro-4-iodopyridin-2-yl)amino)cyclobutanecarboxylate (460 mg, 1.25 mmol), Pd2(dba)3 (14 mg, 0.06 mmol), Xantphos (73 mg, 0.13 mmol), 및 DIPEA (0.43 ml, 2.51 mmol)를 1,4-dioxane (4 ml)에 현탁 시킨 후 90 ℃에서 16시간 동안 교반 하였다. 반응액을 여과한 후 여과액을 감압 농축하여 얻어진 잔사를 MPLC (0-50% EtOAc/Hexane)하여 상아색 고체 680 mg (94%)을 수득하였다.
단계 3: (1S,3S)-3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarboxylic acid의 합성
(1S,3S)-Methyl 3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarboxylate (377 mg, 0.65 mmol), LiOH (41 mg, 0.98 mmol)를 THF : H2O : MeOH = 4 : 1 : 1 (2 ml)에 현탁 시킨 후 상온에서 2 시간 동안 교반 하였다. 반응액을 1N HCl 수용액을 이용하여 pH = 1~2로 조정한 뒤 EtOAc (15 ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-66% EtOAc/Hexane)하여 주황색 고체 241 mg (66%)를 수득하였다.
중간체 11의 합성법과 동일한 방법으로 중간체 12 내지 중간체 15를 합성하였다.
중간체 16.
(2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
단계 1: (2S,4R)-methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate의 합성
(2S,4R)-Methyl 4-hydroxypyrrolidine-2-carboxylate hydrochloride (7.85 g, 43.23 mmol), (S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (10 g, 43.23 mmol), EDCI (16.57 g, 86.46 mmol), HOBt (7 g, 86.46 mmol), DIPEA (45 ml, 259.38 mmol)를 DMF (216 ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액을 NH4Cl 포화수용액 (300 ml), NaHCO3 포화수용액 (300 ml)로 씻은 후 EtOAc (150 ml x 2)로 추출하였다. 유기층을 brine (150 ml x 2)으로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-5% MeOH/DCM)하여 상아색 고체 11 g (71%)을 수득하였다.
단계 2: (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid의 합성
(2S,4R)-Methyl 1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylate (781 mg, 2.18 mmol), lithium hydroxide (366 mg, 8.72 mmol)를 water : THF = 1 : 1 (10 ml)에 현탁 시킨 후 상온에서 3 시간 동안 교반 하였다. 반응액을 1 M HCl 수용액을 이용하여 pH = 1~2로 조정한 뒤 EtOAc (15 ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 흰색 고체 680 mg (91%)를 수득하였다.
단계 3: 2-hydroxy-4-(4-methylthiazol-5-yl)benzonitrile의 합성
4-Bromo-2-hydroxybenzonitrile (2 g, 10.15 mmol), 4-methylthiazole (1.83 ml, 20.20 mmol)을 DMAC (40 ml)에 현탁 시킨 후 KOAc (1.98 g, 20.20 mmol), Pd(OAc)2 (45 mg, 0.20 mmol)을 가하고 16시간 동안 가열 환류 하였다. 반응액에 증류수 (100 ml)를 가한 뒤 EtOAc (50 ml x 2)로 추출하였다. 유기층을 brine (50 ml x 2)로 씻고 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-50% EtOAc/Hexane)하여 상아색 고체 980 mg (45%)을 수득하였다.
단계 4: 2-(aminomethyl)-5-(4-methylthiazol-5-yl)phenol의 합성
2-Hydroxy-4-(4-methylthiazol-5-yl)benzonitrile (864 mg, 3.99 mmol)를 THF (22 ml)에 현탁 시킨 후 LAH (2.0 M in THF, 8 ml, 15.98 mmol)를 0 ℃에서 서서히 가하고 3 시간 동안 가열 환류 하였다. 반응액의 온도를 0 ℃로 낮춘 후 증류수 (0.5 ml)를 천천히 가하고 Rochelle salt solution (20 ml)로 중화한 뒤 celite filter로 여과하였다. 여과액을 MPLC (DCM : MeOH : NH4OH = 15 : 1 : 0.1)하여 노란색 고체 416 mg (47%)을 수득하였다.
단계 5: tert-butyl ((S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate의 합성
2-(Aminomethyl)-5-(4-methylthiazol-5-yl)phenol (416 mg, 1.89 mmol), (2S,4R)-1-((S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxylic acid (650 mg, 1.89 mmol), HATU (789 mg, 2.08 mmol), DIPEA (0.98 ml, 5.66 mmol)를 DMF (6 ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (25 ml)를 가한 후 EtOAc (15 ml x 2)로 추출하였다. 유기층을 brine (15 ml x 2)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-20% MeOH/DCM)하여 연한 노란색 고체 898 mg (87%)을 수득하였다.
단계 6: (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide의 합성
tert-Butyl ((S)-1-((2S,4R)-4-hydroxy-2-((2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (885 mg, 1.62 mmol)를 DCM (30 ml)에 현탁 시킨 후 4 M HCl in dioxane (8 ml)를 가하고 상온에서 2 시간 동안 교반 하였다. 반응액에 NaHCO3 포화수용액 (20 ml)을 가하여 중화한 뒤 DCM (10 ml x 2)로 추출하였다. 유기층을 brine (10 ml x 2)로 씻고 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-10% MeOH/DCM)하여 노란색 고체 522 mg (72%)을 수득하였다.
단계 7: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide의 합성
(2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (399 mg, 0.89 mmol), 1-fluorocyclopropane-1-carboxylic acid (92.6 mg, 0.89 mmol), HATU (381 mg, 0.89 mmol), DIPEA (0.8 ml, 4.47 mmol)를 DMF (4 ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (10 ml)를 가하고 EtOAc (11 ml x 2)로 추출하였다. 유기층을 brine (10 ml x 2)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-10% MeOH/DCM)하여 흰색 고체 377 mg (79%)을 수득하였다.
중간체 17. (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid
단계 1: (1S,4S)-methyl 4-(((2-nitrophenyl)sulfonyl)oxy)cyclohexanecarboxylate의 합성
Methyl (1S,4S)-4-hydroxycyclohexane-1-carboxylate (4 g, 25.29 mmol), TEA (7 ml, 50.57 mmol), DMAP (309 mg, 2.52 mmol)를 DCM (120 ml)에 현탁 시킨 후 2-nitrobenzenesulfonyl chloride (22.4 g, 101.14 mmol)를 DCM (25 ml)에 녹여 0 ℃에서 서서히 가하고 2 시간 동안 상온에서 교반 하였다. 반응액에 증류수 (200 ml)를 가한 뒤 DCM (50 ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-20% EtOAc/Hexane)하여 무색 오일 7.14 g (82%)을 수득하였다.
단계 2: (1S,4R)-methyl 4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylate의 합성
(1S,4S)-Methyl 4-(((2-nitrophenyl)sulfonyl)oxy)cyclohexanecarboxylate (3.9 g, 11.26 mmol), (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (중간체 16, 1.5 g, 2.82 mmol), Cs2CO3 (1.8 g, 5.63 mmol)를 DMF (60 ml)에 현탁 시킨 후 50 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (100 ml)를 가하고 EtOAc (100 ml x 2)로 추출하였다. 유기층을 brine (100 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-5% MeOH/DCM)하여 상아색 고체 1.3 g (70%)을 수득하였다.
단계 3: (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid의 합성
(1S,4R)-Methyl 4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylate (1.8 g, 2.75 mmol), lithium hydroxide (231 mg, 5.51 mmol)를 THF : H2O : MeOH = 4 : 1 : 1 (12 ml)에 현탁 시킨 후 상온에서 4 시간 동안 교반 하였다. 반응액을 1 M HCl 수용액을 이용하여 pH = 1~2로 조정한 뒤 EtOAc (20 ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-20% MeOH/DCM)하여 상아색 고체 896 mg (49%)를 수득하였다.
중간체 18. (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid
(2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (중간체 16) 대신 (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide를 사용하여 중간체 17의 합성법과 동일한 방법으로 중간체 18을 합성하였다.
중간체 19. (2S,4R)-N-(2-(2-chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
(2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (중간체 16, 350 mg, 0.657 mmol), 1-bromo-2-chloroethane (0.2 ml, 2.628 mmol)을 DMF (2 ml)에 현탁 시킨 후 K2CO3 (272 mg, 1.971 mmol), KI (218 mg, 1.314 mmol)을 가하고 70 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (20 ml)를 가한 뒤 EtOAc (20 ml x 2)로 추출하였다. 유기층을 brine (20 ml x 2)로 씻고 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-5% MeOH/DCM)하여 상아색 고체 234 mg (60%)을 수득하였다.
중간체 20. (2S,4R)-N-(2-((6-chlorohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1-bromo-2-chloroethane 대신 1-bromo-6-chlorohexane을 사용하여 중간체 19의 합성법과 동일한 방법으로 중간체 20을 합성하였다.
중간체 21. 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid
단계 1: ethyl 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylate의 합성
(2S,4R)-N-(2-(2-Chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (중간체 19, 100 mg, 0.15 mmol), ethyl piperidine-4-carboxylate (17.6 mg, 0.11 mmol), K2CO3 (46 mg, 0.37 mmol)를 DMF (0.15 ml)에 현탁 시킨 후 70 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (10 ml)를 가한 뒤 EtOAc (10 ml)로 추출하였다. 유기층을 brine (10 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-5% MeOH/DCM)하여 상아색 고체 67 mg (84%)을 수득하였다.
단계 2: 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid의 합성
Ethyl 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylate (67 mg, 0.09 mmol), lithium hydroxide (7.9 mg, 0.19 mmol)를 THF : MeOH : H2O = 3 : 2 : 1 (0.26 ml)에 현탁 시킨 후 상온에서 2시간 동안 교반 하였다. 반응액을 1 M HCl 수용액을 이용하여 pH = 2로 조정한 뒤 감압 농축하여 상아색 고체 87 mg (crude)를 수득하였다.
중간체 22. (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide
단계 1: tert-butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate의 합성
1-(2-Hydroxyethyl)piperazine (2.8 ml, 23.04 mmol)을 THF (23 ml)에 현탁 시킨 후 0 oC에서 Boc2O (5.8 ml, 25.35 mmol)를 가하고 상온에서 1시간 동안 교반 하였다. 반응액에 NH4Cl 포화수용액 (50 ml)를 가하여 중화한 뒤 DCM (50 ml)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 무색 오일 5.6 g (quant.)을 수득하였다.
단계 2: tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate의 합성
tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.6 g, 24.66 mmol), TEA (6.8 ml, 49.33 mmol), DMAP (120 mg, 0.99 mmol)를 DCM (123 ml)에 현탁 시킨 후 2-nitrobenzenesulfonyl chloride (5.4 g, 24.66 mmol)를 DCM (25 ml)에 녹여 0 oC에서 서서히 가하고 2 시간 동안 상온에서 교반 하였다. 반응액에 증류수 (200 ml)를 가한 뒤 DCM (50 ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-50% EtOAc/Hexane)하여 노란색 고체 2.9 g (49%)을 수득하였다.
단계 3: tert-butyl 4-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperazine-1-carboxylate의 합성
tert-Butyl 4-(2-chloroethyl)piperazine-1-carboxylate (1.4 g, 5.91 mmol), (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-hydroxy-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (중간체 16, 1.1 g, 1.97 mmol), Cs2CO3 (1.3 g, 3.94 mmol)를 DMF (44 ml)에 현탁 시킨 후 50 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (100 ml)를 가하고 EtOAc (100 ml x 2)로 추출하였다. 유기층을 brine (100 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-5% MeOH/DCM)하여 상아색 고체 833 mg (57%)을 수득하였다.
단계 4: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide의 합성
tert-Butyl 4-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperazine-1-carboxylate (819 mg, 1.10 mmol)를 DCM (9 ml)에 현탁 시킨 후 4 M HCl in dioxane (2 ml)를 가하고 상온에서 1 시간 동안 교반 하였다. 반응액에 NaHCO3 포화수용액 (30 ml)를 가하여 중화한 뒤 DCM (3 ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-5% MeOH/DCM)하여 상아색 고체 739 mg (quant.)을 수득하였다.
중간체 22의 합성법과 동일한 방법으로 중간체 23 내지 중간체 27을 합성하였다. (중간체 23 내지 중간체 27의 경우, 단계 2를 통해 O-nosylate를 결과물로 수득하였다.)
실시예 1. (2S,4R)-N-(2-((6-(4-(((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)methyl)piperidin-1-yl)hexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
단계 1: tert-butyl ((1-(5-((2-chloro-3-(((1-(6-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)hexyl)piperidin-4-yl)methyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
tert-Butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 5, 33 mg, 0.06 mmol), (2S,4R)-N-(2-((6-chlorohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (중간체 20, 46 mg, 0.07 mmol)을 DMF (0.1 ml)에 현탁 시킨 후 KI (13 mg, 0.12 mmol), K2CO3 (24 mg, 0.17 mmol)을 가하고 70 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (10 ml)를 가한 뒤 EtOAc (10 ml x 2)로 추출하였다. 유기층을 brine (10 ml x 2)로 씻고 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-2% MeOH/DCM)하여 상아색 고체 49 mg (72%)을 수득하였다.
단계 2: (2S,4R)-N-(2-((6-(4-(((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)methyl)piperidin-1-yl)hexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide의 합성
tert-Butyl ((1-(5-((2-chloro-3-(((1-(6-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)hexyl)piperidin-4-yl)methyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (43 mg, 0.04 mmol)를 DCM (1.0 ml)에 현탁 시킨 후 4 M HCl in dioxane (0.1 ml)를 가하고 상온에서 1 시간 동안 교반 하였다. 반응액에 NaHCO3 포화수용액 (10 ml)를 가하여 중화한 뒤 DCM (10 ml x 2)로 추출하였다. 유기층을 brine (10 ml x 2)로 씻고 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-5% MeOH/DCM)하여 상아색 고체 30 mg (78%)을 수득하였다.
1H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 8.16 (dd, J = 4.2, 1.4 Hz, 1H), 8.14 (d, J = 1.4 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.09 - 7.05 (m, 1H), 7.03 (dd, J = 8.9, 3.3 Hz, 1H), 6.99 - 6.97 (m, 1H), 6.95 (dd, J = 7.6, 1.6 Hz, 1H), 6.86 (d, J = 1.5 Hz, 1H), 6.48 (dd, J = 8.2, 1.2 Hz, 1H), 6.33 (dd, J = 7.9, 1.3 Hz, 1H), 4.70 - 4.65 (m, 1H), 4.57 - 4.52 (m, 3H), 4.49 - 4.42 (m, 2H), 4.39 (dd, J = 14.5, 5.1 Hz, 1H), 4.05 - 3.96 (m, 2H), 3.92 - 3.86 (m, 2H), 3.68 - 3.63 (m, 1H), 3.39 - 3.34 (m, 2H), 3.09 - 3.05 (m, 2H), 2.99 - 2.94 (m, 2H), 2.58 (s, 2H), 2.56 - 2.46 (m, 4H), 2.37 - 2.29 (m, 2H), 2.03 - 1.99 (m, 2H), 1.95 - 1.83 (m, 4H), 1.80 - 1.77 (m, 2H), 1.57 - 1.53 (m, 6H), 1.47 - 1.43 (m, 2H), 1.41 - 1.33 (m, 4H), 1.32 - 1.25 (m, 4H), 1.02 (s, 3H), 0.93 (s, 9H). m/z 1075.52 [M+H]+
실시예 2. (2S,4R)-N-(2-(2-(4-(2-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)ethyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 5) 대신 tert-butyl ((1-(5-((2-chloro-3-((2-(piperazin-1-yl)ethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 6)을 사용하고, (2S,4R)-N-(2-((6-chlorohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (중간체 20) 대신 (2S,4R)-N-(2-(2-chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (중간체 19)를 사용하여 실시예 1의 합성법과 동일한 방법으로 실시예 2를 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.17 (d, J = 1.4 Hz, 1H), 8.14 (d, J = 1.4 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.30 (t, J = 6.0 Hz, 1H), 7.03 - 6.96 (m, 3H), 6.89 (d, J = 1.4 Hz, 1H), 6.48 (dd, J = 8.2, 1.1 Hz, 1H), 6.33 (dd, J = 7.9, 1.2 Hz, 1H), 5.18 (t, J = 4.5 Hz, 1H), 4.71 (t, J = 7.7 Hz, 1H), 4.53 - 4.43 (m, 4H), 4.22 - 4.14 (m, 2H), 4.00 - 3.93 (m, 1H), 3.93 - 3.84 (m, 2H), 3.62 (dd, J = 11.2, 3.9 Hz, 1H), 3.40 - 3.33 (m, 2H), 3.19 - 3.16 (m, 2H), 2.94 - 2.89 (m, 2H), 2.70 - 2.67 (m, 4H), 2.58 (s, 3H), 2.56 - 2.48 (m, 8H), 2.09 - 2.02 (m, 1H), 1.72 - 1.52 (m, 1H), 1.58 - 1.52 (m, 2H), 1.48 - 1.42 (m, 2H), 1.32 - 1.26 (m, 4H), 1.03 (s, 3H), 0.93 (s, 9H). m/z 1034.54 [M+H]+
실시예 3. (2S,4R)-N-(2-(2-(4-(2-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)ethyl)-3-oxopiperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 5) 대신 tert-butyl ((1-(5-((2-chloro-3-((2-(2-oxopiperazin-1-yl)ethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 7)을 사용하고, (2S,4R)-N-(2-((6-chlorohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (중간체 20) 대신 (2S,4R)-N-(2-(2-chloroethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (중간체 19)를 사용하여 실시예 1의 합성법과 동일한 방법으로 실시예 3을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 8.15 (d, J = 1.2 Hz, 1H), 7.40 (t, J = 6.0 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.06 (dd, J = 8.7, 3.3 Hz, 1H), 7.02 - 6.93 (m, 2H), 6.87 (d, J = 1.4 Hz, 1H), 6.49 (d, J = 7.4 Hz, 1H), 6.30 (dd, J = 7.9, 1.0 Hz, 1H), 4.90 (t, J = 5.2 Hz, 1H), 4.57 - 4.52 (m, 2H), 4.51 - 4.46 (m, 3H), 4.22 - 4.10 (m, 2H), 3.97 - 3.88 (m, 3H), 3.79 - 3.72 (m, 1H), 3.63 (dd, J = 11.1, 3.7 Hz, 1H), 3.56 - 3.46 (m. 2H), 3.40 - 3.33 (m, 6H), 3.00 - 2.87 (m, 3H), 2.78 - 2.72 (m, 1H), 2.59 (s, 2H), 2.53 (s, 3H), 2.41 - 2.34 (m, 1H), 2.09 - 2.03 (m, 2H), 1.59 - 1.52 (m, 2H), 1.48 - 1.42 (m, 2H), 1.38 - 1.25 (m, 4H), 1.03 (s, 3H), 0.96 (s, 9H). m/z 1048.48 [M+H]+
실시예 4. (2S,4R)-N-(2-(2-(4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
단계 1: methyl (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycinate의 합성
tert-Butyl ((1-(5-((3-amino-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 1, 30 mg, 0.06 mmol), methyl bromoacetate (33 mg, 0.21 mmol), K2CO3 (27 mg, 0.19 mmol), KI (21 mg, 0.13 mmol)를 DMF (0.4 ml)에 현탁 시킨 후 70 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (10 ml)를 가한 뒤 EtOAc (10 ml)로 추출하였다. 유기층을 brine (10 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (1-30% EtOAc/Hexane)하여 상아색 고체 28.6 mg (82%)을 수득하였다.
단계 2: (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycine의 합성
Methyl (3-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycinate (28.6 mg, 0.05 mmol), lithium hydroxide (4.5 mg, 0.11 mmol)를 water : THF = 2 : 1 (0.4 ml)에 현탁 시킨 후 상온에서 2시간 동안 교반 하였다. 반응액을 1 M HCl 수용액을 이용하여 pH = 2로 조정한 뒤 DCM (10 ml x 2)로 추출하였다. 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-12% MeOH/DCM)하여 상아색 고체 20.3 mg (73%)을 수득하였다.
단계 3: tert-butyl ((1-(5-((2-chloro-3-((2-(4-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
(3-((5-(4-(((tert-Butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycine (19 mg 0.04 mmol), (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (중간체 22, 24.5 mg, 0.04 mmol), EDCI (8.4 mg, 0.04 mmol), HOBt (5.9 mg, 0.04 mmol), DIPEA (0.02 ml, 0.11 mmol)를 DMF (0.12 ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (7 ml)를 가한 뒤 EtOAc (10 ml)로 추출하였다. 유기층을 brine (7 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-7% MeOH/DCM)하여 상아색 고체 24 mg (57%)을 수득하였다.
단계 4: (2S,4R)-N-(2-(2-(4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)glycyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide의 합성
tert-Butyl ((1-(5-((2-chloro-3-((2-(4-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperazin-1-yl)-2-oxoethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (24 mg, 0.02 mmol)를 DCM (2.1 ml)에 현탁 시킨 후 4 M HCl in dioxane (0.052 ml)를 가하고 상온에서 2 시간 동안 교반 하였다. 반응액에 NaHCO3 포화수용액 (5 ml)을 가한 뒤 DCM (10 ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-3% MeOH/DCM)하여 상아색 고체 17.3 mg (79%)을 수득하였다.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.18 (d, J = 1.4 Hz, 1H), 8.14 (d, J = 1.4 Hz, 1H), 7.35 (m, 2H), 7.06 - 6.94 (m, 3H), 6.88 (d, J = 1.5 Hz, 1H), 6.37 (dd, J = 8.0, 1.9 Hz, 2H), 5.69 (t, J = 4.0 Hz, 1H), 4.69 (t, J = 7.7 Hz, 1H), 4.56 - 4.38 (m, 4H), 4.18 (t, J = 5.4 Hz, 2H), 4.01 - 3.84 (m, 5H), 3.73 (m, 2H), 3.61 (dd, J = 11.2, 3.8 Hz, 1H), 3.49 (m, 2H), 3.36 (ddd, J = 13.5, 10.0, 3.6 Hz, 2H), 3.04 - 2.86 (m, 2H), 2.66 (dt, J = 18.0, 4.9 Hz, 4H), 2.58 (s, 2H), 2.57 - 2.50 (m, 4H), 2.08 - 2.00 (m, 1H), 1.58 - 1.42 (m, 4H), 1.36 - 1.24 (m, 4H), 1.03 (s, 3H), 0.92 (s, 9H). m/z 1048.49 [M+H]+
실시예 5. (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
단계 1: tert-butyl ((1-(5-((2-chloro-3-((1-((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carbonyl)azetidin-3-yl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2, 278 mg, crude), (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (중간체 17, 205 mg, 0.31 mmol), EDCI (72 mg, 0.37 mmol), HOBt (54 mg, 0.37 mmol), DIPEA (0.16 ml, 0.93 mmol)를 DMF (1 ml)에 현탁 시킨 후 상온에서 16시간 동안 교반 하였다. 반응액에 증류수 (20 ml)를 가한 뒤 EtOAc (30 ml)로 추출하였다. 유기층을 brine (20 ml)로 씻고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-7% MeOH/DCM)하여 상아색 고체 144 mg (40%)을 수득하였다.
단계 2: (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide의 합성
tert-Butyl ((1-(5-((2-chloro-3-((1-((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carbonyl)azetidin-3-yl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (100 mg, 0.09 mmol)를 DCM (8.6 ml)에 현탁 시킨 후 4 M HCl in dioxane (0.22 ml)를 가하고 상온에서 1 시간 동안 교반 하였다. 반응액에 NaHCO3 포화수용액 (5 ml)을 가한 뒤 DCM (10 ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-3% MeOH/DCM)하여 상아색 고체 80.7 mg (88%)을 수득하였다.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.19 (d, J = 1.2 Hz, 1H), 8.15 (s, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.25 - 7.22 (m, 1H), 7.03 - 6.96 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.89 (s, 1H), 6.44 (d, J = 7.8 Hz, 1H), 6.24 (d, J = 8.0 Hz, 1H), 4.76 - 4.70 (m, 2H), 4.59 - 4.22 (m, 8H), 4.05 - 3.84 (m, 5H), 3.60 (dd, J = 11.3, 3.8 Hz, 1H), 3.38 (t, J = 9.7 Hz, 2H), 2.62 - 2.50 (m, 6H), 2.35 - 2.20 (m, 3H), 2.10 - 1.98 (m, 1H), 1.76 - 1.41 (m, 10H), 1.37 - 1.28 (m, 4H), 1.04 (s, 3H), 0.93 (s, 9H). m/z 1059.52 [M+H]+
실시예 6. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
(1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (중간체 17) 대신 (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (중간체 18)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 6을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.18 (d, J = 1.3 Hz, 1H), 8.14 (d, J = 1.3 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.14 (t, J = 5.9 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 6.93 (dd, J = 7.7, 1.4 Hz, 1H), 6.89 (s, 1H), 6.45 (d, J = 7.9 Hz, 1H), 6.24 (d, J = 7.4 Hz, 1H), 6.04 (d, J = 8.7 Hz, 1H), 4.74 - 4.66 (m, 2H), 4.57 - 4.34 (m, 6H), 4.33 - 4.22 (m, 2H), 4.08 (d, J = 11.4 Hz, 1H), 3.97 (dd, J = 8.5, 4.5 Hz, 1H), 3.94 - 3.84 (m, 3H), 3.57 (dd, J = 11.4, 3.7 Hz, 1H), 3.38 (ddd, J = 13.4, 9.9, 3.5 Hz, 2H), 2.61 - 2.54 (m, 3H), 2.52 (s, 3H), 2.35 - 2.19 (m, 3H), 2.13 - 2.01 (m, 1H), 1.99 (s, 3H), 1.94 - 1.84 (m, 2H), 1.60 - 1.40 (m, 8H), 1.03 (s, 3H), 0.89 (s, 9H). m/z 1015.55 [M+H]+
실시예 7.
(2S,4R)-N-(2-(2-(4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)piperidin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
(1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid (중간체 17) 대신 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid (중간체 21)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 7을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.17 (d, J = 1.4 Hz, 1H), 8.15 (s, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.24 (s, 1H), 7.13 - 7.09 (m, 1H), 7.00 - 6.95 (m, 2H), 6.87 (s, 1H), 6.40 (t, J = 7.6 Hz, 1H), 6.20 (d, J = 7.9 Hz, 1H), 4.74 - 4.64 (m, 2H), 4.60 (d, J = 8.8 Hz, 1H), 4.57 - 4.44 (m, 4H), 4.42 - 4.33 (m, 1H), 4.33 - 4.21 (m, 1H), 4.21 - 4.05 (m, 2H), 3.98 - 3.81 (m, 5H), 3.66 (dd, J = 10.8, 3.2 Hz, 1H), 3.41 - 3.35 (m, 2H), 3.16 - 3.07 (m, 2H), 2.93 - 2.87 (m, 1H), 2.79 - 2.74 (m, 1H), 2.54 (s, 3H), 2.38 - 2.16 (m, 3H), 2.07 - 2.00 (m, 2H), 1.93 - 1.79 (m, 3H), 1.73 - 1.65 (m, 3H), 1.47 - 1.43 (m, 3H), 1.36 - 1.21 (m, 4H), 1.03 (s, 3H), 0.97 (s, 9H). m/z 1088.41 [M+H]+
실시예 8.
(2S,4R)-N-(2-(((1R,4S)-4-(3-(((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)methyl)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 tert-butyl ((1-(5-((3-((azetidin-3-ylmethyl)amino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 4)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 8을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 8.14 (d, J = 1.4 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.23 (t, J = 5.9 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.94 (dd, J = 7.7, 1.5 Hz, 1H), 6.89 (s, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.42 (dd, J = 7.9, 1.2 Hz, 1H), 4.73 (t, J = 7.7 Hz, 1H), 4.54 - 4.38 (m, 5H), 4.33 - 4.28 (m, 1H), 4.17 - 4.12 (m, 1H), 4.03 (d, J = 11.3 Hz, 1H), 3.94 - 3.87 (m, 3H), 3.75 (dd, J = 10.0, 5.1 Hz, 1H), 3.60 (dd, J = 11.3, 3.8 Hz, 1H), 3.46 - 3.34 (m, 3H), 3.02 - 2.89 (m, 1H), 2.62 - 2.55 (m, 3H), 2.53 (s, 3H), 2.33 - 2.21 (m, 3H), 2.09 - 2.20 (m, 1H), 1.89 - 1.83 (m, 2H), 1.74 - 1.67 (m, 2H), 1.57 - 1.42 (m, 8H), 1.33 - 1.29 (m, 4H), 1.03 (s, 3H), 0.93 (s, 9H). m/z 1073.49 [M+H]+
실시예 9. (2S,4R)-N-(2-(((1R,4S)-4-(4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 3)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 9를 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.17 (d, J = 1.2Hz, 1H), 8.15 (d, J = 1.2Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.03 - 6.88 (m, 4H), 6.53 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 7.8 Hz, 1H), 4.74 (t, J = 7.7 Hz, 1H), 4.60 - 4.36 (m, 5H), 4.35 - 4.24 (m, 2H), 4.04 (d, J = 11.6 Hz, 1H), 3.96 - 3.84 (m, 3H), 3.63 - 3.51 (m, 2H), 3.42 - 3.32 (m, 2H), 3.29 - 3.19 (m, 1H), 2.98 - 2.87 (m, 1H), 2.68 - 2.49 (m, 7H), 2.37 - 2.24 (m, 2H), 2.15 - 2.00 (m, 3H), 1.95 - 1.85 (m, 2H), 1.54 - 1.37 (m, 10H), 1.37 - 1.20 (m, 4H), 1.03 (s, 3H), 0.93 (s, 9H). m/z 1087.51 [M+H]+
실시예 10.
(2S,4R)-N-(2-(2-(4-(4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidine-1-carbonyl)piperidin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 3)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid (중간체 17) 대신 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid (중간체 21)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 10을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.17 (s, 1H), 8.15 (s, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 5.8 Hz, 1H), 7.15 - 7.06 (m, 1H), 7.02 - 6.93 (m, 2H), 6.88 (d, J = 1.1 Hz, 1H), 6.50 (dd, J = 7.8, 2.3 Hz, 1H), 6.33 (t, J = 7.3 Hz, 1H), 4.71 - 4.65 (m, 1H), 4.61 (d, J = 8.8 Hz, 1H), 4.58 - 4.38 (m, 4H), 4.34 - 4.29 (m, 1H), 4.20 - 4.07 (m, 2H), 3.97 - 3.83 (m, 4H), 3.67 (dd, J = 11.1, 3.7 Hz, 1H), 3.57 - 3.53 (m, 1H), 3.45 - 3.32 (m, 2H), 3.26 - 3.21 (m, 1H), 3.17 - 3.05 (m, 2H), 2.99 - 2.83 (m, 2H), 2.80 - 2.76 (m, 1H), 2.54 (s, 4H), 2.38 - 2.22 (m, 2H), 2.14 - 2.05 (m, 4H), 1.98 - 1.84 (m, 2H), 1.74 - 1.67 (m. 4H), 1.66 - 1.62 (m, 4H), 1.44 - 1.37 (m, 2H), 1.33 - 1.28 (m, 4H), 1.05 (d, J = 12.7 Hz, 3H), 0.97 (s, 9H). m/z 1116.42 [M+H]+
실시예 11. (2S,4R)-N-(2-(((1R,4S)-4-(4-(((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)methyl)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 tert-butyl ((1-(5-((2-chloro-3-((piperidin-4-ylmethyl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 5)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 11을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.2 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.25 - 7.21 (s, 1H), 7.04 - 6.87 (m, 4H), 6.49 (d, J = 8.1 Hz, 1H), 6.38 (d, J = 8.1 Hz, 1H), 4.76 - 4.65 (m, 2H), 4.57 - 4.35 (m, 5H), 4.32 - 4.24 (m, 1H), 4.07 - 3.84 (m, 4H), 3.60 (dd, J = 11.4, 3.6 Hz, 1H), 3.41 - 3.31 (m, 2H), 3.18 - 2.98 (m, 3H), 2.64 - 2.50 (m, 7H), 2.37 - 2.23 (m, 2H), 2.11 - 2.01 (m, 2H), 1.91 - 1.82 (m, 2H), 1.59 - 1.40 (m, 13H), 1.36 - 1.15 (m, 4H), 1.03 (m, 3H), 0.93 (s, 9H). m/z 1101.57 [M+H]+
실시예 12.
(2S,4R)-N-(2-(((1R,4S)-4-(3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 tert-butyl ((1-(5-((2-(azetidin-3-ylamino)-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 8)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 12를 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.74 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.24 - 7.22 (m, 1H), 7.01 (dd, J = 8.3, 3.6 Hz, 1H), 6.94 (dd, J = 7.7, 1.5 Hz, 1H), 6.89 (s, 1H), 6.04 (d, J = 5.5 Hz, 1H), 5.29 - 5.28 (m, 1H), 4.78 - 4.69 (m, 2H), 4.57 - 4.36 (m, 6H), 4.30 - 4.25 (m, 1H), 4.04 - 3.89 (m, 4H), 3.60 (dd, J = 11.3, 3.8 Hz, 1H), 3.47 - 3.39 (m, 2H), 2.62 - 2.53 (m, 3H), 2.52 (s, 3H), 2.31 - 2.21 (m, 3H), 2.09 - 2.03 (m, 1H), 1.91 - 1.87 (m, 2H), 1.75 - 1.65 (m, 6H), 1.50 - 1.45 (m, 4H), 1.37 - 1.23 (m, 4H), 1.05 (s, 3H), 0.93 (s, 9H). m/z 1060.53 [M+H]+
실시예 13. (2S,4R)-N-(2-(((1R,4S)-4-(4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 tert-butyl ((1-(5-((3-chloro-2-(piperidin-4-ylamino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 9)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 13을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.19 (d, J = 1.3 Hz, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 6.0 Hz, 1H), 7.03 - 6.89 (m, 3H), 5.97 (d, J = 5.5 Hz, 1H), 4.87 (d, J = 7.6 Hz, 1H), 4.74 (t, J = 7.7 Hz, 1H), 4.61 - 4.35 (m, 4H), 4.34 - 4.25 (m, 1H), 4.23 - 4.13 (m, 1H), 4.03 (d, J = 11.4 Hz, 1H), 3.99 - 3.87 (m, 3H), 3.60 (dd, J = 11.4, 3.8 Hz, 1H), 3.42 (ddd, J = 13.5, 9.8, 3.5 Hz, 2H), 3.30 - 3.18 (m, 1H), 2.85 (t, J = 11.7 Hz, 1H), 2.65 - 2.55 (m, 4H), 2.53 (s, 3H), 2.37 - 2.24 (m, 2H), 2.24 - 2.15 (m, 1H), 2.12 - 2.02 (m, 1H), 1.95 - 1.85 (m, 2H), 1.79 - 1.68 (m, 2H), 1.55 - 1.37 (m, 10H), 1.36 - 1.23 (m, 4H), 1.04 (s, 3H), 0.93 (s, 9H). m/z 1088.63 [M+H]+
실시예 14. (2S,4R)-N-(2-(((1R,4S)-4-(4-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperazine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 tert-butyl ((1-(5-((3-chloro-2-(piperazin-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 10)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 14를 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.27 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.90 (d, J = 5.3 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.03 - 6.98 (m, 1H), 6.96 - 6.90 (m, 2H), 6.31 (d, J = 5.3 Hz, 1H), 4.74 (t, J = 7.7 Hz, 1H), 4.59 - 4.37 (m, 4H), 4.35 - 4.26 (m, 1H), 4.06 - 3.92 (m, 3H), 3.82 - 3.65 (m, 4H), 3.60 (dd, J = 11.3, 3.8 Hz, 1H), 3.43 (ddd, J = 13.4, 9.9, 3.6 Hz, 2H), 3.36 - 3.25 (m, 4H), 2.70 - 2.57 (m, 3H), 2.53 (s, 3H), 2.31 (t, J = 15.3 Hz, 2H), 2.07 (dd, J = 13.9, 8.7 Hz, 1H), 1.98 - 1.87 (m, 3H), 1.86 - 1.71 (m, 2H), 1.54 - 1.41 (m, 6H), 1.37 - 1.22 (m, 4H), 1.06 (s, 3H), 0.93 (s, 9H). m/z 1074.62 [M+H]+
실시예 15. (2S,4R)-N-(2-(2-(4-(4-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperazine-1-carbonyl)piperidin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 tert-butyl ((1-(5-((3-chloro-2-(piperazin-1-yl)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 10)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (중간체 17) 대신 1-(2-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)ethyl)piperidine-4-carboxylic acid (중간체 21)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 15를 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.08 (dd, J = 8.8, 3.4 Hz, 1H), 6.96 (dd, J = 7.6, 1.4 Hz, 1H), 6.89 (s, 1H), 6.30 (d, J = 5.4 Hz, 1H), 4.70 (t, J = 8.2 Hz, 1H), 4.60 (d, J = 8.5 Hz, 1H), 4.56 - 4.42 (m, 3H), 4.19 - 4.10 (m, 2H), 4.02 - 3.89 (m, 3H), 3.84 - 3.75 (m, 1H), 3.71 - 3.59 (m, 5H), 3.43 (ddd, J = 13.4, 9.9, 3.6 Hz, 2H), 3.38 - 3.19 (m, 5H), 3.19 - 3.06 (m, 2H), 2.96 - 2.86 (m, 1H), 2.86 - 2.74 (m, 1H), 2.63 - 2.50 (m, 6H), 2.41 - 3.32 (m, 1H), 2.28 - 2.19 (m, 1H), 2.12 (dd, J = 24.6, 12.0 Hz, 2H), 2.05 - 1.83 (m, 2H), 1.72 (t, J = 12.5 Hz, 2H), 1.52 - 1.38 (m, 2H), 1.36 - 1.17 (m, 4H), 1.05 (s, 3H), 0.96 (s, 9H). m/z 1103.82 [M+H]+
실시예 16.
(2S,4R)-N-(2-((1-((1s,3R)-3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 (1S,3S)-3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarboxylic acid (중간체 11)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid (중간체 17) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (중간체 26)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 16을 합성하였다.
1H NMR (400 MHz, DMSO-d6) 8.98 (s, 1H), 8.47 - 8.44 (m, 1H), 8.42 (d, J = 1.2 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.72 (d, J = 5.4 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.27 (dd, J = 9.2, 2.5 Hz, 1H), 7.08 (s, 1H), 6.95 (dd, J = 7.8, 1.2 Hz, 1H), 6.60 (d, J = 7.2 Hz, 1H), 5.83 (d, J = 5.4 Hz, 1H), 5.16 (d, J = 3.5 Hz, 1H), 4.78 (s, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.50 (t, J = 8.2 Hz, 1H), 4.41 - 4.34 (m, 2H), 4.27 (t, J = 5.8 Hz, 2H), 3.92 - 3.84 (m, 2H), 3.67 - 3.58 (m, 4H), 3.50 - 3.35 (m, 6H), 3.07 - 3.00 (m, 2H), 2.45 (s, 3H), 2.27 - 2.21 (m, 2H), 2.10 - 2.04 (m, 1H), 1.92 - 1.87 (m, 4H), 1.67 - 1.59 (m, 2H), 1.52 - 1.42 (m, 2H), 1.40 - 1.30 (m, 4H), 1.23 - 1.20 (m, 2H), 0.95 (s, 12H). m/z 1060.50 [M+H]+
실시예 17.
(2S,4R)-N-(2-((1-((1r,3S)-3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 (1R,3R)-3-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarboxylic acid (중간체 12)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid (중간체 17) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (중간체 26)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 17을 합성하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.49 - 8.44 (brs, 1H), 8.47 (d, J = 0.8 Hz, 1H), 8.29 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 5.4 Hz, 1H), 7.42 (dd, J = 7.8, 3.8 Hz, 1H), 7.27 (dd, J = 9.2, 2.6 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 6.9 Hz, 1H), 5.83 (d, J = 5.4 Hz, 1H), 5.17 (d, J = 3.6 Hz, 1H), 4.80 - 4.75 (m, 1H), 4.59 (d, J = 9.3 Hz, 1H), 4.50 (t, J = 8.2 Hz, 1H), 4.42 (dd, J = 14.8, 7.7 Hz, 1H), 4.35 - 4.31 (m, 1H), 4.27 (t, J = 6.2 Hz, 2H), 3.97 - 3.89 (m, 2H), 3.73 - 3.58 (m, 4H), 3.53 - 3.43 (m, 6H), 2.79 (s, 2H), 2.45 (s, 3H), 2.34 - 2.25 (m, 2H), 2.10 - 2.01 (m, 1H), 1.93 - 1.84 (m, 2H), 1.70 - 1.65 (m, 2H), 1.58 - 1.52 (m, 2H), 1.47 - 1.44 (m, 2H), 1.40 - 1.33 (m, 2H), 1.23 - 1.20 (m, 4H), 1.09 (s, 3H), 0.95 (s, 9H). m/z 1060.51 [M+H]+
실시예 18.
(2S,4R)-N-(2-((1-((1R,4S)-4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 (1R,4R)-4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexanecarboxylic acid (중간체 13)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid (중간체 17) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (중간체 26)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 18을 합성하였다.
1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.48 - 8.45 (m, 2H), 8.29 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 5.4 Hz, 1H), 7.46 - 7.41 (m, 2H), 7.27 (dd, J = 9.1, 2.7 Hz, 1H), 7.09 (d, J = 0.9 Hz, 1H), 6.96 (dd, J = 7.8, 1.1 Hz, 1H), 5.99 (d, J = 7.9 Hz, 1H), 5.80 (d, J = 5.4 Hz, 1H), 5.17 (d, J = 3.6 Hz, 1H), 4.81 - 4.76 (m, 1H), 4.59 (d, J = 9.2 Hz, 1H), 4.51 (t, J = 8.2 Hz, 1H), 4.37 - 4.32 (m, 1H), 4.27 (t, J = 6.0 Hz, 2H), 3.97 - 3.91 (m, 2H), 3.88 - 3.80 (m, 1H), 3.76 - 3.57 (m, 3H), 3.50 - 3.43 (m, 6H), 2.78 (s, 2H), 2.68 - 2.54 (m, 2H), 2.46 (s, 3H), 2.10 - 2.05 (m, 1H), 1.99 - 1.82 (m, 6H), 1.75 - 1.70 (m, 2H), 1.58 - 1.53 (m, 2H), 1.47 - 1.44 (m, 6H), 1.38 - 1.33 (m, 2H), 1.21 - 1.19 (m, 2H), 1.09 (s, 3H), 0.96 (s, 9H). m/z 1088.51 [M+H]+
실시예 19.
(2S,4R)-N-(2-(2-(4-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carbonyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carboxylic acid (중간체 14)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid (중간체 17) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (중간체 22)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 19를 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.75 (d, J = 5.4 Hz, 1H), 7.34 - 7.30 (m, 2H), 7.02 - 6.97 (m, 2H), 6.88 (s, 1H), 6.04 - 6.02 (m, 1H), 4.70 (t, J = 7.7 Hz, 1H), 4.54 - 4.49 (m, 4H), 4.41 - 4.36 (m, 4H), 4.17 (t, J = 5.3 Hz, 2H), 3.99 - 3.94 (m, 3H), 3.67 - 3.56 (m, 4H), 3.49 - 3.37 (m, 4H), 2.98 - 2.87 (m, 2H), 2.65 - 2.57 (m, 6H), 2.56 - 2.51 (m, 4H), 2.11 - 2.04 (m, 1H), 1.63 - 1.45 (m, 4H), 1.29 - 1.25 (m, 4H), 1.08 (s, 3H), 0.92 (s, 9H). m/z 1075.54 [M+H]+
실시예 20. (2S,4R)-N-(2-(2-(1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carbonyl)piperidin-4-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carboxylic acid (중간체 14)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (중간체 17) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperidin-4-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (중간체 23)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 20을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.76 (d, J = 5.4 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.02 - 6.93 (m, 2H), 6.87 (s, 1H), 6.03 (dd, J = 5.4, 2.3 Hz, 1H), 4.73 (t, J = 6.3 Hz, 1H), 4.62 (d, J = 13.6 Hz, 1H), 4.57 - 4.35 (m, 8H), 4.13 - 3.89 (m, 5H), 3.67 - 3.54 (m, 3H), 3.50 - 3.37 (m, 2H), 3.10 - 3.01 (m, 1H), 2.69 - 2.54 (m, 4H), 2.53 (s, 3H), 2.12 - 2.03 (m, 1H), 1.77 - 1.64 (m, 6H), 1.64 - 1.43 (m, 5H), 1.37 - 1.16 (m, 4H), 1.08 (s, 3H), 0.91 (s, 9H). m/z 1074.62 [M+H]+
실시예 21. (2S,4R)-N-(2-(2-(4-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (중간체 15)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid (중간체 17) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (중간체 22)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 21을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 7.86 (d, J = 5.3 Hz, 1H), 7.35 - 7.30 (m, 2H), 7.02 - 6.97 (m, 2H), 6.89 (s, 1H), 6.24 (d, J = 5.4 Hz, 1H), 4.72 (t, J = 7.7 Hz, 1H), 4.60 - 4.37 (m, 4H), 4.19 (t, J = 5.3 Hz, 2H), 4.00 - 3.95 (m, 2H), 3.81 (d, J = 12.3 Hz, 2H), 3.73 - 3.53 (m, 5H), 3.48 - 3.42 (m, 2H), 3.09 (s, 1H), 2.99 - 2.89 (m, 2H), 2.86 - 2.79 (m, 2H), 2.68 - 2.57 (m, 4H), 2.55 - 2.51 (m, 4H), 2.10 - 2.02 (m, 3H), 1.80 - 1.77 (m, 2H), 1.74 - 1.69 (m, 2H), 1.62 - 1.45 (m, 5H), 1.35 - 1.26 (m, 4H), 1.08 (s, 3H), 0.93 (s, 9H). m/z 1103.54 [M+H]+
실시예 22. (2S,4R)-N-(2-(2-(1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (중간체 15)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (중간체 17) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperidin-4-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (중간체 23)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 22를 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.35 - 7.29 (m, 2H), 7.03 - 6.94 (m, 2H), 6.87 (d, J = 1.3 Hz, 1H), 6.23 (d, J = 5.4 Hz, 1H), 4.77 - 4.63 (m, 2H), 4.58 - 4.38 (m, 4H), 4.12 - 3.91 (m, 6H), 3.81 (d, J = 11.9 Hz, 2H), 3.61 (dd, J = 11.2, 3.6 Hz, 1H), 3.43 (ddd, J = 13.5, 10.0, 3.6 Hz, 2H), 3.15 - 3.03 (m, 1H), 2.83 (t, J = 11.7 Hz, 2H), 2.72 - 2.55 (m, 5H), 2.53 (s, 3H), 2.14 - 1.97 (m, 3H), 1.93 - 1.73 (m, 7H), 1.53 - 1.42 (m, 6H), 1.38 - 1.17 (m, 4H), 1.05 (s, 3H), 0.92 (s, 9H). m/z 1102.57 [M+H]+
실시예 23. (2S,4R)-N-(2-((7-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)-7-azaspiro[3.5]nonan-2-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (중간체 15)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (중간체 17) 대신 (2S,4R)-N-(2-((7-azaspiro[3.5]nonan-2-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (중간체 24)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 23을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.03 - 6.93 (m, 2H), 6.67 (s, 1H), 6.23 (d, J = 5.4 Hz, 1H), 4.79 - 4.72 (m, 2H), 4.57 - 4.40 (m, 4H), 4.05 - 3.91 (m, 3H), 3.82 (d, J = 11.8 Hz, 2H), 3.66 - 3.38 (m, 7H), 2.88 - 2.76 (s, 2H), 2.69 - 2.55 (m, 4H), 2.54 - 2.43 (m, 5H), 2.20 - 2.14 (m, 1H), 2.11 - 1.97 (m, 4H), 1.81 - 1.71 (m, 2H), 1.61 - 1.43 (m, 8H), 1.37 - 1.23 (m, 4H), 1.05 (s, 3H), 0.94 (s, 9H). m/z 1114.58 [M+H]+
실시예 24. (2S,4R)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)methoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (중간체 15)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylic acid (중간체 17) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-ylmethoxy)benzyl)pyrrolidine-2-carboxamide (중간체 25)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 24를 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.22 - 7.16 (m, 1H), 7.02 - 6.95 (m, 2H), 6.85 (d, J = 1.3 Hz, 1H), 6.24 (d, J = 5.4 Hz, 1H), 4.80 - 4.68 (m, 2H), 4.61 - 4.49 (m, 3H), 4.45 - 4.33 (m, 1H), 4.09 - 3.79 (m, 8H), 3.62 (dd, J = 11.0, 3.9 Hz, 1H), 3.43 (ddd, J = 13.5, 9.9, 3.6 Hz, 2H), 3.20 - 3.07 (m, 1H), 2.86 (t, J = 12.2 Hz, 2H), 2.77 - 2.54 (m, 5H), 2.52 (s, 3H), 2.23 - 1.99 (m, 6H), 1.94 - 1.75 (m, 4H), 1.60 - 1.43 (m, 4H), 1.37 - 1.23 (m, 4H), 1.05 (s, 3H), 0.91 (s, 9H). m/z 1088.60 [M+H]+
실시예 25.
(2S,4R)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (중간체 15)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid (중간체 17) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (중간체 26)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 25를 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 5.3 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.30 - 7.19 (m, 1H), 7.00 - 6.97 (m, 2H), 6.89 (s, 1H), 6.24 (d, J = 5.4 Hz, 1H), 4.78 - 4.70 (m, 1H), 4.70 - 4.62 (m, 1H), 4.63 - 4.36 (m, 5H), 4.07 - 3.99 (m, 1H), 3.98 - 3.93 (m, 2H), 3.85 - 3.82 (m, 3H), 3.78 - 3.66 (m, 3H), 3.66 - 3.49 (m, 2H), 3.46 - 3.40 (m, 2H), 2.88 - 2.82 (m, 2H), 2.74 - 2.66 (m, 1H), 2.61 - 2.56 (m, 3H), 2.53 (s, 3H), 2.10 - 2.07 (m, 4H), 1.99 - 1.90 (m, 2H), 1.84 - 1.77 (m, 2H), 1.51 - 1.43 (m, 2H), 1.36 - 1.31 (m, 2H), 1.29 - 1.24 (m, 4H), 1.05 (s, 3H), 0.96 - 0.91 (m, 9H). m/z 1074.57 [M+H]+
실시예 26.
(2S,4R)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)azetidin-3-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (중간체 15)를 사용하고, (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexanecarboxylic acid (중간체 17) 대신 (2S,4R)-N-(2-(azetidin-3-yloxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide (중간체 27)를 사용하여 실시예 5의 합성법과 동일한 방법으로 실시예 26을 합성하였다.
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 5.4 Hz, 1H), 7.39 (t, J = 7.5 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.09 - 7.00 (m, 2H), 6.54 (s, 1H), 6.23 (d, J = 5.4 Hz, 1H), 5.07 - 5.01 (m, 1H), 4.72 (t, J = 7.7 Hz, 1H), 4.64 - 4.59 (m, 1H), 4.55 - 4.53 (m, 2H), 4.52 - 4.49 (m, 2H), 4.48 - 4.42 (m, 1H), 4.41 - 4.31 (m, 1H), 4.19 - 4.10 (m, 1H), 4.04 - 3.93 (m, 3H), 3.81 (d, J = 12.4 Hz, 2H), 3.64 (dd, J = 11.2, 3.7 Hz, 1H), 3.46 - 3.39 (m, 2H), 2.85 - 2.77 (m, 2H), 2.62 (s, 2H), 2.56 - 2.50 (m, 4H), 2.42 - 2.34 (m, 1H), 2.13 - 2.08 (m, 1H), 2.05 - 2.02 (m, 3H), 1.82 - 1.77 (m, 2H), 1.62 - 1.55 (m, 2H), 1.50 - 1.46 (m, 2H), 1.33 - 1.26 (m, 4H), 1.06 (s, 3H), 0.96 (d, J = 13.5 Hz, 9H). m/z 1046.46 [M+H]+
실시예 27. (2S,4R)-N-(2-(((1R,4S)-4-((3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidin-1-yl)methyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
단계 1: (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(((1R,4S)-4-(hydroxymethyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide의 합성
Methyl (1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexane-1-carboxylate (100 mg, 0.15 mmol)를 THF (2 ml)에 현탁 시키고 0 ℃에서 LAH (2.0 M in THF, 82 μl, 0.16 mmol)를 가한 후 상온에서 30분 동안 교반 하였다. 반응액에 10% NaOH 수용액 (5 ml)을 가한 뒤 EtOAc (15 ml)로 추출하였다. 유기층을 증류수 (10 ml), brine (10 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-5% MeOH/DCM)하여 상아색 고체 72.5 mg (76%)을 수득하였다.
단계 2: ((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexyl)methyl 4-methylbenzenesulfonate의 합성
(2S,4R)-1-((S)-2-(1-Fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(2-(((1R,4S)-4-(hydroxymethyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide (72.5 mg, 0.11 mmol)을 DCM (0.48 ml)에 현탁 시키고 0 ℃에서 TEA (23 μl, 0.17 mmol), DMAP (1.4 mg, 0.01 mmol), 4-toluenesulfonyl chloride (25.7 mg, 0.13 mmol)를 가한 후 상온에서 3시간 동안 교반 하였다. 반응액에 증류수 (10 ml)를 가한 뒤 DCM (10 ml)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-5% MeOH/DCM)하여 상아색 고체 55.8 mg (62%)을 수득하였다
단계 3: tert-butyl ((1-(5-((2-chloro-3-((1-(((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexyl)methyl)azetidin-3-yl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2, 26.4 mg, crude), ((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexyl)methyl 4-methylbenzenesulfonate (25 mg, 0.3 mmol), K2CO3 (13 mg, 0.09 mmol), KI (10 mg, 0.06 mmol)를 DMF (0.1 ml)에 현탁 시킨 후 70 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (7 ml)를 가한 뒤 EtOAc (10 ml)로 추출하였다. 유기층을 brine (7 ml)로 씻고 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-7% MeOH/DCM)하여 상아색 고체 11.6 mg (32%)을 수득하였다.
단계 4: (2S,4R)-N-(2-(((1R,4S)-4-((3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidin-1-yl)methyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide의 합성
tert-Butyl ((1-(5-((2-chloro-3-((1-(((1S,4R)-4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)cyclohexyl)methyl)azetidin-3-yl)amino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (11.6 mg, 0.01 mmol)를 DCM (1 ml)에 현탁 시킨 후 4 M HCl in dioxane (25 μl)를 가하고 상온에서 1 시간 동안 교반 하였다. 반응액에 NaHCO3 포화수용액 (3 ml)을 가한 뒤 DCM (5 ml x 2)로 추출하고 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-3% MeOH/DCM)하여 상아색 고체 7.6 mg (72%)을 수득하였다.
1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.16 (d, J = 1.2 Hz, 1H), 8.13 (d, J = 1.2 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.05 - 6.86 (m, 4H), 6.40 (d, J = 6.6 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 4.73 (t, J = 7.6 Hz, 1H), 4.61 (d, J = 6.6 Hz, 1H), 4.57 - 4.38 (m, 4H), 4.25 - 4.08 (m, 2H), 4.03 (d, J = 11.6 Hz, 1H), 3.93 - 3.77 (m, 4H), 3.61 (dd, J = 11.3, 3.8 Hz, 1H), 3.41 - 3.33 (m, 2H), 2.90 (t, J = 6.9 Hz, 2H), 2.63 - 2.55 (m, 3H), 2.52 (s, 3H), 2.39 (d, J = 6.7 Hz, 2H), 2.27 - 2.15 (m, 2H), 2.11 - 2.03 (m, 1H), 1.96 - 1.86 (m, 2H), 1.61 - 1.41 (m, 9H), 1.36 - 1.22 (m, 4H), 1.03 (s, 3H), 0.94 (s, 9H). m/z 1045.64 [M+H]+
실시예 28. (2S,4R)-N-(2-(((1R,4S)-4-((4-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)piperidin-1-yl)methyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
tert-Butyl ((1-(5-((3-(azetidin-3-ylamino)-2-chlorophenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 2) 대신 tert-butyl ((1-(5-((2-chloro-3-(piperidin-4-ylamino)phenyl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (중간체 3)를 사용하여 실시예 27의 합성법과 동일한 방법으로 실시예 28을 합성하였다.
1NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.17 - 8.15 (m, 1H), 8.14 - 8.12 (m, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.20 - 7.17 (m, 1H), 7.02 - 6.97 (m, 2H), 6.95 - 6.89 (m, 2H), 6.51 - 6.49 (m, 1H), 6.36 - 6.32 (m, 1H), 4.73 (t, J = 7.7 Hz, 1H), 4.56 - 4.50 (m, 2H), 4.47 - 4.43 (m, 2H), 4.37 - 4.31 (m, 1H), 4.25 - 4.17 (m, 1H), 4.05 - 4.02 (m, 1H), 3.92 - 3.86 (m, 2H), 3.61 (dd, J = 11.4, 3.9 Hz, 2H), 3.46 - 3.32 (m, 5H), 3.08 (s, 1H), 2.88 - 2.77 (m, 2H), 2.64 - 2.55 (m, 3H), 2.53 (s, 3H), 2.26 - 2.18 (m, 5H), 2.09 - 2.03 (m, 4H), 2.00 - 1.93 (m, 3H), 1.52 - 1.43 (m, 6H), 1.37 - 1.29 (m, 4H), 1.03 (s, 3H), 0.95 (s, 9H). m/z 1073.64 [M+H]+
실시예 29. (2S,4R)-N-(2-((1-(((1R,4S)-4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexyl)methyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
단계 1: tert-butyl ((1-(5-((3-chloro-2-(((1R,4R)-4-(hydroxymethyl)cyclohexyl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
(1R,4R)-4-((4-((5-(4-(((tert-Butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexanecarboxylic acid (중간체 13, 42 mg, 0.07 mmol)를 THF (0.24 ml)에 현탁 시키고 0 oC에서 LAH (2.0 M in THF, 0.03 ml, 0.07 mmol)를 가한 후 상온에서 1시간 동안 교반 하였다. 반응액에 증류수 (0.01 ml)를 가한 뒤 상온에서 5분 동안 교반하고 DCM (10 ml)로 추출하였다. 유기층을 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-5% MeOH/DCM)하여 상아색 고체 14 mg (34%)을 수득하였다.
단계 2: ((1R,4R)-4-((4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexyl)methyl 2-nitrobenzenesulfonate의 합성
tert-Butyl ((1-(5-((3-chloro-2-(((1R,4R)-4-(hydroxymethyl)cyclohexyl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (16 mg, 0.03 mmol), TEA (0.007 ml, 0.06 mmol), DMAP (0.13 mg, 0.001 mmol)을 DCM (0.14 ml)에 현탁 시킨 후 0 oC에서 10분 동안 교반하고 2-nitrobenzenesulfonyl chloride (20 mg, 0.09 mmol)를 가한 후 상온에서 4시간 동안 교반 하였다. 반응액에 증류수 (10 ml)를 가한 뒤 DCM (10 ml x 2)로 추출하고 유기층을 무수 황산 나트륨으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-5% MeOH/DCM)하여 상아색 고체 15 mg (quant.)를 수득하였다.
단계 3: tert-butyl ((1-(5-((3-chloro-2-(((1S,4R)-4-((4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidin-1-yl)methyl)cyclohexyl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate의 합성
((1R,4R)-4-((4-((5-(4-(((tert-Butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexyl)methyl 2-nitrobenzenesulfonate (14 mg, 0.02 mmol)을 DMF (0.2 ml)에 현탁 시킨 후 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (중간체 26, 14 mg, 0.02 mmol), Cs2CO3 (12 mg, 0.04 mmol)을 가하고 50 ℃에서 16시간 동안 교반 하였다. 반응액에 증류수 (10 ml)를 가한 뒤 EtOAc (10 ml x 2)로 추출하였다. 유기층을 brine (10 ml x 2)로 씻고 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (0-10% MeOH/DCM)하여 상아색 고체 6.8 mg (32%)을 수득하였다.
단계 4: (2S,4R)-N-(2-((1-(((1R,4S)-4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexyl)methyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide의 합성
tert-Butyl ((1-(5-((3-chloro-2-(((1S,4R)-4-((4-(2-(((2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamido)methyl)-5-(4-methylthiazol-5-yl)phenoxy)piperidin-1-yl)methyl)cyclohexyl)amino)pyridin-4-yl)thio)pyrazin-2-yl)-4-methylpiperidin-4-yl)methyl)carbamate (6 mg, 0.005 mmol)를 DCM (1.0 ml)에 현탁 시킨 후 4 M HCl in dioxane (0.01 ml)를 가하고 상온에서 1 시간 동안 교반 하였다. 반응액에 NaHCO3 포화수용액 (5 ml)를 가하여 중화한 뒤 DCM (5 ml x 2)로 추출하였다. 유기층을 brine (5 ml x 2)로 씻고 무수 황산 마그네슘으로 건조한 후 여과, 감압 농축하여 얻어진 잔사를 MPLC (amine-silica, 0-5% MeOH/DCM)하여 상아색 고체 3.5 mg (65%)을 수득하였다.
1NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.25 (d, J = 1.2 Hz, 1H), 8.19 (d, J = 1.2 Hz, 1H), 7.74 (d, J = 5.5 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.00 - 6.94 (m, 2H), 6.87 (d, J = 1.2 Hz, 1H), 5.91 (d, J = 5.5 Hz, 1H), 4.84 (d, J = 7.8 H, 1Hz), 4.74 (t, J = 7.7 Hz, 1H), 4.54 - 4.42 (m, 5H), 4.04 (d, J = 11.3 Hz, 1H), 3.96 - 3.86 (m, 3H), 3.60 (dd, J = 11.4, 3.7 Hz, 1H), 3.45 - 3.38 (m, 2H), 2.62 (s, 2H), 2.60 - 2.50 (m, 2H), 2.52 (s, 3H), 2.17 - 2.08 (m, 2H), 2.10 - 2.05 (m, 1H), 1.96 - 1.88 (m, 4H), 1.59 - 1.53 (m, 8H), 1.51 - 1.45 (m, 4H), 1.37 - 1.31 (m, 5H), 1.22 - 1.17 (m, 3H), 1.05 (s, 3H), 0.93 (s, 9H). m/z 1074.57 [M+H]+
실시예 30. (2S,4R)-N-(2-(2-(4-((1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)ethoxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
(1R,4R)-4-((4-((5-(4-(((tert-Butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclohexanecarboxylic acid (중간체 13) 대신 1-(4-((5-(4-(((tert-butoxycarbonyl)amino)methyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carboxylic acid (중간체 15)를 사용하고, (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(piperidin-4-yloxy)benzyl)pyrrolidine-2-carboxamide (중간체 26) 대신 (2S,4R)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)-2-(2-(piperazin-1-yl)ethoxy)benzyl)pyrrolidine-2-carboxamide (중간체 22)를 사용하여 실시예 29의 합성법과 동일한 방법으로 실시예 30을 합성하였다.
1NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.88 - 7.73 (m, 1H), 7.37 - 7.32 (m, 2H), 7.01 (dd, J = 8.3, 3.1 Hz, 1H), 6.96 (dd, J = 7.7, 1.4 Hz, 1H), 6.89 (s, 1H), 6.22 - 5.96 (m, 1H), 4.75 - 4.69 (m, 1H), 4.55 - 4.40 (m, 4H), 4.19 - 4.15 (m, 2H), 4.03 - 3.93 (m, 3H), 3.74 (d, J = 12.2 Hz, 2H), 3.62 (dd, J = 11.2, 3.6 Hz, 2H), 3.45 - 3.33 (m, 2H), 2.94 - 2.88 (m, 2H), 2.77 (t, J = 11.7 Hz, 2H), 2.80 - 2.64 (m, 2H), 2.60 - 2.55 (m, 3H), 2.53 - 2.38 (m, 7H), 2.25 (d, J = 7.2 Hz, 2H), 2.11 - 2.06 (m, 1H), 1.87 - 1.82 (m, 2H), 1.56 - 1.54 (m, 4H), 1.52 - 1.42 (m, 3H), 1.40 - 1.34 (m, 2H), 1.32 - 1.25 (m, 4H), 1.05 (s, 3H), 0.93 (s, 9H). m/z 1089.60 [M+H]+
실시예 1 내지 실시예 30의 합성법과 유사한 방법으로 아래의 실시예 31 내지 실시예 72를 합성하였다.
실시예 31.
(2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-((1S,3R)-3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.19 (d, J = 1.3 Hz, 1H), 7.72 (d, J = 5.5 Hz, 1H), 7.36 - 7.33 (m, 1H), 7.31 - 7.22 (m, 1H), 6.99 - 6.95 (m, 1H), 6.86 (s, 1H), 6.18 (dd, J = 39.9, 8.8 Hz, 1H), 5.95 (dd, J = 5.5, 1.6 Hz, 1H), 5.23 (d, J = 7.6 Hz, 1H), 4.71 - 4.65 (m, 1H), 4.63 - 4.59 (m, 1H), 4.54 - 4.40 (m, 5H), 4.05 (t, J = 11.5 Hz, 1H), 3.98 - 3.92 (m, 2H), 3.81 - 3.72 (m, 2H), 3.67 - 3.59 (m, 1H), 3.58 - 3.53 (m, 1H), 3.45 - 3.38 (m, 3H), 3.03 - 2.97 (m, 1H), 2.75 - 2.67 (m, 2H), 2.60 (s, 2H), 2.58 - 2.54 (m, 1H), 2.52 (s, 3H), 2.30 - 2.21 (m, 2H), 2.09 - 2.06 (m, 1H), 2.04 - 2.01 (m, 3H), 1.97 - 1.84 (m, 4H), 1.58 - 1.54 (m, 2H), 1.50 - 1.44 (m, 2H), 1.04 (s, 3H), 0.90 (d, J = 4.7 Hz, 9H). m/z 1016.52 [M+H]+
실시예 32. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(4-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.18 (t, J = 5.8 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H), 6.08 (d, J = 8.6 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 4.88 (d, J = 7.6 Hz, 1H), 4.72 (t, J = 7.8 Hz, 1H), 4.60 - 4.53 (m, 2H), 4.49 - 4.45 (m, 2H), 4.39 (dd, J = 14.6, 5.1 Hz, 1H), 4.31 - 4.24 (m, 1H), 4.22 - 4.15 (m, 1H), 4.11 - 4.07 (m, 1H), 3.99 - 3.91 (m, 3H), 3.58 (dd, J = 11.4, 3.6 Hz, 1H), 3.49 - 3.39 (m, 2H), 3.28 - 3.22 (m, 1H), 2.87 - 2.82 (m, 1H), 2.64 - 2.56 (m, 4H), 2.53 (s, 3H), 2.33 - 2.20 (m, 4H), 2.12 - 2.07 (m, 2H), 2.00 (s, 3H), 1.93 - 1.84 (m, 2H), 1.80 - 1.68 (m, 2H), 1.63 - 1.47 (m, 5H), 1.43 - 1.37 (d, 2H), 1.07 (s, 3H), 0.89 (s, 9H). m/z 1044.63 [M+H]+
실시예 33. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.74 (d, J = 5.5 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 5.8 Hz, 1H), 6.96 - 6.91 (m, 1H), 6.88 (s, 1H), 6.11 (d, J = 8.8 Hz, 1H), 6.04 (d, J = 5.5 Hz, 1H), 5.29 (m, 1H), 4.77 - 4.66 (m, 2H), 4.60 - 4.33 (m, 6H), 4.33 - 4.20 (m, 1H), 4.08 (d, J = 11.4 Hz, 1H), 4.05 - 3.87 (m, 4H), 3.57 (dd, J = 11.3, 3.6 Hz, 1H), 3.52 - 3.35 (m, 2H), 2.63 - 2.51 (m, 6H), 2.34 - 2.20 (m, 3H), 2.13 - 2.05 (m, 1H), 2.00 (s, 3H), 1.94 - 1.85 (m, 2H), 1.63 - 1.40 (m, 8H), 1.05 (s, 3H), 0.89 (s, 9H). m/z 1016.56 [M+H]+
실시예 34. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 0.9 Hz, 1H), 8.21 (d, J = 1.1 Hz, 1H), 7.87 (d, J = 5.3 Hz, 1H), 7.37 - 7.34 (m, 2H), 6.97 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.26 - 6.07 (m, 2H), 4.74 - 4.63 (m, 2H), 4.57 - 4.41 (m, 4H), 4.08 (d, J = 11.3 Hz, 1H), 3.98 - 3.95 (m, 2H), 3.85 - 3.73 (m, 4H), 3.60 - 3.52 (m, 2H), 3.50 - 3.39 (m, 2H), 3.08 (s, 2H), 2.90 - 2.80 (m, 3H), 2.73 - 2.67 (m, 1H), 2.62 - 2.56 (m, 1H), 2.53 (s, 3H), 2.14 - 1.94 (m, 9H), 1.81 - 1.69 (m, 5H), 1.55 - 1.47 (m, 2H), 1.08 (s, 3H), 0.91 (d, J = 12.0 Hz, 9H). m/z 1030.56 [M+H]+
실시예 35. (2S,4R)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-methylpiperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.85 (d, J = 5.4 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.21 (t, J = 5.9 Hz, 1H), 7.01 - 6.96 (m, 2H), 6.87 (d, J = 1.3 Hz, 1H), 6.21 (d, J = 5.4 Hz, 1H), 4.71 (t, J = 7.6 Hz, 1H), 4.68 - 4.61 (m, 1H), 4.57 - 4.41 (m, 4H), 4.02 - 3.91 (m, 3H), 3.91 - 3.81 (m, 1H), 3.79 - 3.73 (m, 3H), 3.63 (dd, J = 11.2, 4.1 Hz, 1H), 3.46 - 3.40 (m, 4H), 3.25 - 3.18 (m, 2H), 2.60 (s, 2H), 2.57 - 2.54 (m, 1H), 2.53 (s, 3H), 2.39 - 2.30 (m, 2H), 2.10 - 2.03 (m, 1H), 2.01 - 1.85 (m, 4H), 1.74 - 1.68 (m, 2H), 1.52 - 1.42 (m, 2H), 1.37 (s, 3H), 1.35 - 1.23 (m, 6H), 1.05 (s, 3H), 0.93 (s, 9H). m/z 1088.57 [M+H]+
실시예 36. (2S,4R)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-fluoropiperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.27 (d, J = 1.3 Hz, 1H), 8.22 (d, J = 1.3 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.03 - 6.95 (m, 2H), 6.88 (s, 1H), 6.25 (d, J = 5.3 Hz, 1H), 4.79 - 4.63 (m, 2H), 4.59 - 4.37 (m, 4H), 4.06 - 3.78 (m, 6H), 3.77 - 3.57 (m, 4H), 3.48 - 3.38 (m, 2H), 3.22 (t, J = 11.7 Hz, 2H), 2.68 - 2.40 (m, 8H), 2.16 - 1.88 (m, 7H), 1.72 - 1.43 (m, 4H), 1.38 - 1.24 (m, 4H), 1.05 (s, 3H), 0.93 (s, 9H). m/z 1092.52 [M+H]+
실시예 37. (2S,4R)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.26 - 7.19 (m, 1H), 7.03 - 6.95 (m, 2H), 6.88 (s, 1H), 6.22 (d, J = 5.4 Hz, 1H), 4.75 - 4.65 (m, 2H), 4.57 - 4.42 (m, 4H), 4.05 - 3.82 (m, 7H), 3.74 - 3.57 (m, 3H), 3.47 - 3.38 (m, 2H), 3.33 (t, J = 12.0 Hz, 2H), 2.62 - 2.49 (m, 6H), 2.42 - 2.29 (m, 2H), 2.11 - 1.92 (m, 5H), 1.75 (d, J = 13.5 Hz, 2H), 1.60 - 1.43 (m 4H), 1.34 - 1.24 (m, 4H), 1.05 (s, 3H), 0.95 (s, 9H). m/z 1090.60 [M+H]+
실시예 38. (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)oxy)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.00 (s, 1H), 7.68 (s, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.29 -7.24 (m, 1H), 7.13 (t, J = 8.2 Hz, 1H), 7.05 - 6.99 (m, 1H), 6.94 (d, J = 7.7 Hz, 1H), 6.89 (s, 1H), 6.51 (d, J = 8.2 Hz, 1H), 6.24 (d, J = 8.2 Hz, 1H), 4.77 - 4.69 (m, 2H), 4.61 - 4.24 (m, 8H), 4.07 - 3.97 (m, 2H), 3.90 (dd, J = 10.2, 4.4 Hz, 1H), 3.77 - 3.69 (m, 2H), 3.60 (dd, J = 11.2, 3.8 Hz, 1H), 3.31 - 3.21 (m, 2H), 2.68 - 2.54 (m, 3H), 2.53 (s, 3H), 2.37 - 2.21 (m, 3H), 2.12 - 2.02 (m, 1H), 1.75 - 1.63 (m, 6H), 1.62 - 1.42 (m, 4H), 1.36 - 1.27 (m, 4H), 1.03 (s, 3H), 0.93 (s, 9H). m/z 1043.54 [M+H]+
실시예 39. (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.18 (s, 1H), 8.16 (s, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.24 (t, J = 6.0 Hz, 1H), 7.06 - 6.96 (m, 2H), 6.94 (d, J = 7.7 Hz, 1H), 6.89 (s, 1H), 6.50 - 6.42 (m, 1H), 6.25 (d, J = 8.0 Hz, 1H), 4.77 - 4.69 (m, 2H), 4.59 - 4.36 (m, 6H), 4.34 - 4.22 (m, 2H), 4.22 - 4.14 (m, 1H), 4.05 - 3.85 (m, 5H), 3.81 (d, J = 8.8 Hz, 1H), 3.69 (d, J = 8.8 Hz, 1H), 3.64 - 3.55 (m, 1H), 3.51 - 3.40 (m, 1H), 3.39 - 3.31 (m, 1H), 2.99 (d, J = 4.5 Hz, 1H), 2.63 - 2.49 (m, 4H), 2.36 - 2.22 (m, 3H), 2.12 - 2.02 (m, 1H), 1.94 - 1.82 (m, 4H), 1.63 - 1.43 (m, 6H), 1.37 - 1.22 (m, 7H), 0.93 (s, 9H). m/z 1101.53 [M+H]+
실시예 40. (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.19 - 8.17 (m, 2H), 7.34 - 7.30 (m, 2H), 7.24 - 7.22 (m, 4H), 7.03 - 6.99 (m, 2H), 6.94 (dd, J = 7.7, 1.5 Hz, 1H), 6.89 (s, 1H), 6.46 (dd, J = 7.4, 3.7 Hz, 1H), 6.25 (d, J = 8.1 Hz, 1H), 4.75 - 4.71 (m, 2H), 4.54 - 4.41 (m, 7H), 4.31 - 4.26 (m, 2H), 4.23 - 4.19 (m, 2H), 4.05 - 3.96 (m, 3H), 3.88 (dd, J = 10.3, 4.7 Hz, 1H), 3.59 (dd, J = 11.4, 3.7 Hz, 1H), 3.28 - 3.19 (m, 2H), 3.10 (d, J = 15.6 Hz, 1H), 2.75 (d, J = 15.6 Hz, 1H), 2.64 - 2.55 (m, 1H), 2.53 (s, 3H), 2.29 - 2.22 (m, 2H), 2.11 - 2.04 (m, 1H), 1.89 - 1.83 (m, 4H), 1.81 - 1.75 (m, 4H), 1.42 - 1.39 (m, 2H), 1.36 - 1.22 (m, 4H), 0.93 (s, 9H). m/z 1133.30 [M+H]+
실시예 41. (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.18 (d, J = 1.4 Hz 1H), 8.16 (d, J = 1.3 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.25 - 7.23 (m, 1H), 7.02 - 6.98 (m, 2H), 6.94 (dd, J = 7.7, 1.5 Hz, 1H), 6.89 (d, J = 1.3 Hz, 1H) 6.45 (dd, J = 7.9, 1.1 Hz, 1H), 6.24 (dd, J = 8.1, 1.0 Hz, 1H), 4.73 (t, J = 7.3 Hz, 2H), 4.56 - 4.52 (m, 2H), 4.50 - 4.45 (m, 2H), 4.42 - 4.37 (m, 2H), 4.33 - 4.25 (m, 2H), 4.03 (d, J = 11.4 Hz, 1H), 4.00 - 3.96 (m, 1H), 3.88 (dd, J = 10.2, 4.7 Hz, 1H), 3.77 - 3.71 (m, 2H), 3.68 - 3.64 (m, 2H), 3.62 - 3.58 (m, 1H), 2.62 - 2.56 (m, 1H), 2.53 (s, 3H), 2.33 - 2.20 (m, 3H), 2.09 - 2.04 (m, 1H), 1.94 - 1.84 (m, 2H), 1.76 - 1.51 (m, 10H), 1.35 - 1.25 (m, 5H), 0.94 (s, 9H). m/z 1045.55 [M+H]+
실시예 42. (2S,4R)-N-(2-((1-((1S,3R)-3-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)cyclobutanecarbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.25 (d, J = 1.4 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.73 (d, J = 5.5 Hz, 1H), 7.35 (dd, J = 7.7, 4.6 Hz, 1H), 7.30 - 7.20 (m, 1H), 7.02 - 6.96 (m, 2H), 6.86 (s, 1H), 5.94 (d, J = 5.5 Hz, 1H), 5.23 (d, J = 7.7 Hz, 1H), 4.71 (dd, J = 13.6, 7.6 Hz, 1H), 4.65 - 4.61 (m, 1H), 4.57 - 4.38 (m, 4H), 4.01 (d, J = 10.4 Hz, 1H), 3.84 - 3.72 (m, 4H), 3.71 - 3.61 (m, 4H), 3.60 - 3.57 (m, 1H), 3.43 - 3.40 (m, 1H), 3.03 - 2.97 (m, 1H), 2.74 - 2.68 (m, 2H), 2.61 - 2.52 (m, 1H), 2.52 (s, 3H), 2.29 - 2.21 (m, 2H), 2.09 - 2.03 (m, 1H), 1.95 - 1.84 (m, 4H), 1.70 - 1.64 (m, 2H), 1.37 - 1.25 (m, 6H), 1.24 (s, 3H), 0.93 (d, J = 13.4 Hz, 9H). m/z 1046.54 [M+H]+
실시예 43. (2S,4R)-N-(2-(((1R,4S)-4-(4-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.24 (t, J = 6.1 Hz, 1H), 7.05 - 6.97 (m, 1H), 6.96 - 6.89 (m, 2H), 5.96 (d, J = 5.5 Hz, 1H), 4.87 (d, J = 7.6 Hz, 1H), 4.73 (t, J = 7.7 Hz, 1H), 4.60 - 4.36 (m, 4H), 4.34 - 4.24 (m, 1H), 4.24 - 4.12 (m, 1H), 4.03 (d, J = 11.5 Hz, 1H), 3.92 (d, J = 13.6 Hz, 1H), 3.86 - 3.77 (m, 2H), 3.72 - 3.57 (m, 3H), 3.24 (t, J = 11.4 Hz, 1H), 2.85 (t, J = 12.0 Hz, 1H), 2.67 - 2.55 (m, 2H), 2.53 (s, 3H), 2.37 - 2.24 (m, 2H), 2.24 - 2.15 (m, 1H), 2.14 - 2.03 (m, 3H), 1.96 - 1.85 (m, 2H), 1.83 - 1.68 (m, 4H), 1.57 - 1.47 (m, 4H), 1.47 - 1.38 (m, 2H), 1.36 - 1.26 (m, 4H), 1.24 (s, 3H), 0.93 (s, 9H). m/z 1074.50 [M+H]+
실시예 44. (2S,4R)-N-(2-(((1R,4S)-4-(3-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.74 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.01 (dd, J = 8.4, 3.3 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 6.89 (s, 1H), 6.04 (d, J = 5.5 Hz, 1H), 5.29 (d, J = 5.8 Hz, 1H), 4.77 - 4.69 (m, 2H), 4.57 - 4.36 (m, 6H), 4.33 - 4.23 (m, 1H), 4.06 - 3.88 (m, 3H), 3.87 - 3.76 (m, 2H), 3.73 - 3.56 (m, 3H), 2.65 - 2.54 (m, 1H), 2.53 (s, 3H), 2.35 - 2.20 (m, 3H), 2.11 - 2.01 (m, 1H), 1.94 - 1.83 (m, 2H), 1.74 - 1.65 (m, 8H), 1.38 - 1.26 (m, 4H), 1.24 (s, 3H), 0.93 (s, 9H). m/z 1046.52 [M+H]+
실시예 45. (2S,4R)-N-(2-((1-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.23 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.37 - 7.34 (m, 1H), 7.32 - 7.21 (m, 1H), 7.03 - 6.97 (m, 2H), 6.88 (s, 1H), 6.24 (d, J = 5.4 Hz, 1H), 4.76 - 4.70 (m, 1H), 4.66 (brs, 1H), 4.62 - 4.39 (m, 4H), 4.03 (t, J = 9.2 Hz, 1H), 3.84 - 3.78 (m, 7H), 3.72 - 3.66 (m, 3H), 3.65 - 3.52 (m, 2H), 2.85 (t, J = 11.6 Hz, 2H), 2.72 - 2.68 (m, 1H), 2.60 - 2.57 (m, 1H), 2.53 (s, 3H), 2.11 - 2.05 (m , 5H), 1.97 - 1.94 (m, 2H), 1.88 - 1.75 (m, 4H), 1.35 - 1.26 (m, 6H), 1.24 (s, 3H), 0.94 (d, J = 22.7 Hz, 9H). m/z 1060.51 [M+H]+
실시예 46. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1r,4S)-4-(3-((3-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.18 (d, J = 1.3 Hz, 1H), 8.16 (d, J = 1.1 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.15 (t, J = 5.9 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.94 (dd, J = 7.7, 1.5 Hz, 1H), 6.88 (s, 1H), 6.45 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 8.1 Hz, 1H), 6.09 (d, J = 8.8 Hz, 1H), 4.78 - 4.65 (m, 2H), 4.63 - 4.24 (m, 8H), 4.24 - 4.14 (m, 1H), 4.09 (d, J = 11.5 Hz, 1H), 3.99 - 3.85 (m, 4H), 3.81 (d, J = 8.8 Hz, 1H), 3.69 (d, J = 8.8 Hz, 1H), 3.57 (dd, J = 11.4, 3.6 Hz, 1H), 3.52 - 3.40 (m, 1H), 3.40 - 3.25 (m, 1H), 2.99 (d, J = 4.5 Hz, 1H), 2.59 - 2.47 (m, 4H), 2.34 - 2.19 (m, 3H), 2.14 - 2.03 (m, 1H), 2.00 (s, 3H), 1.97 - 1.80 (m, 3H), 1.79 - 1.67 (m, 5H), 1.56 - 1.41 (m, 2H), 1.24 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H). m/z 1057.55 [M+H]+
실시예 47.
(2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((3-((5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.21 - 8.15 (m, 2H), 7.35 - 7.33 (m, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.25 - 7.21 (m, 3H), 7.16 - 7.13 (m, 1H), 7.02 (t, J = 8.1 Hz, 1H), 6.96 - 6.91 (m, 1H), 6.88 (s, 1H), 6.45 (d, J = 7.9 Hz, 1H), 6.25 (d, J = 7.9 Hz, 1H), 6.12 (d, J = 8.6 Hz, 1H), 4.71 (dd, J = 17.9, 6.8 Hz, 2H), 4.57 - 4.37 (m, 6H), 4.32 - 4.18 (m, 4H), 4.08 (d, J = 11.7 Hz, 1H), 4.00 (s, 2H), 3.88 (dd, J = 10.4, 4.7 Hz, 1H), 3.57 (dd, J = 11.5, 3.6 Hz, 1H), 3.28 - 3.20 (m, 2H), 3.10 (d, J = 15.6 Hz, 1H), 2.75 (d, J = 15.5 Hz, 1H), 2.57 - 2.52 (s, 4H), 2.31 - 2.22 (m, 3H), 2.11 - 2.03 (m, 1H), 2.00 (S, 3H), 1.91 - 1.83 (m, 4H), 1.62 - 1.44 (m, 4H), 1.45 - 1.36 (m, 2H), 0.89 (s, 9H). m/z 1089.54 [M+H]+
실시예 48. (2S,4R)-N-((S)-1-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)phenyl)ethyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.87 (d, J = 5.3 Hz, 1H), 7.49 (dd, J = 33.9, 8.5 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 7.09 (s, 1H), 7.02 (d, J = 9.1 Hz, 1H), 6.90 (s, 1H), 6.23 (d, J = 5.4 Hz, 1H), 5.41 - 5.37 (m, 1H), 4.75 - 4.69 (m, 2H), 4.59 (d, J = 5.3 Hz, 1H), 4.53 (s, 1H), 4.05 (t, J = 12.6 Hz, 1H), 3.99 - 3.94 (m, 2H), 3.84 - 3.69 (m, 5H), 3.65 - 3.49 (m, 2H), 3.46 - 3.39 (m, 2H), 2.85 (t, J = 11.7 Hz, 2H), 2.74 - 2.66 (m, 1H), 2.60 (s, 2H), 2.58 - 2.50 (m, 4H), 2.09 - 1.92 (m, 5H), 1.86 - 1.76 (m, 2H), 1.58 - 1.55 (m, 3H), 1.51 - 1.45 (m, 6H), 1.39 - 1.23 (m, 4H), 1.09 (s, 9H), 1.05 (s, 3H). m/z 1088.44 [M+H]+
실시예 49. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.86 (d, J = 4.8 Hz, 1H), 7.69 - 7.52 (m, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.00 (t, J = 8.1 Hz, 1H), 6.91 (s, 1H), 6.43 - 6.14 (m, 2H), 5.39 - 5.32 (m, 1H), 4.75 - 4.67 (m, 2H), 4.64 - 4.52 (m, 2H), 4.09 (dd, J = 22.3, 12.1 Hz, 1H), 3.99 - 3.93 (m, 3H), 3.88 - 3.78 (m, 4H), 3.64 - 3.49 (m, 3H), 3.47 - 3.39 (m, 2H), 2.87 - 2.82 (m, 2H), 2.76 - 2.68 (m, 1H), 2.61 (s, 2H), 2.58 - 2.56 (m, 1H), 2.53 (s, 3H), 2.10 - 1.97 (m, 8H), 1.80 - 1.44 (m, 10H), 1.05 (m, 12H). m/z 1044.59 [M+H]+
실시예 50. (2S,4R)-N-(2-((1-(2-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-yl)acetyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.87 (d, J = 5.3 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.25 - 7.21 (m, 1H), 7.03 - 6.95 (m, 2H), 6.88 (s, 1H), 6.21 (d, J = 5.3 Hz, 1H), 4.77 - 4.61 (m, 2H), 4.60 - 4.36 (m, 4H), 4.05 - 3.92 (m, 3H), 3.86 - 3.67 (m, 5H), 3.67 - 3.58 (m, 1H), 3.58 - 3.47 (m, 1H), 3.47 - 3.35 (m, 2H), 2.84 (t, J = 11.5 Hz, 2H), 2.63 - 2.54 (m, 3H), 2.53 (s, 3H), 2.40 - 2.31 (m, 2H), 2.13 - 1.91 (m, 6H), 1.87 (d, J = 13.1 Hz, 2H), 1.63 - 1.42 (m, 6H), 1.38 - 1.22 (m, 4H), 1.05 (s, 3H), 0.93 (d, J = 18.0 Hz, 9H). m/z 1088.52 [M+H]+
실시예 51. (2S,4R)-N-(2-((1-(2-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.88 (d, J = 5.3 Hz, 1H), 7.36 (dd, J = 7.8, 3.2 Hz, 1H), 7.30 (t, J = 5.9 Hz, 1H), 7.04 - 6.97 (m, 2H), 6.87 (s, 1H), 6.21 (d, J = 5.3 Hz, 1H), 4.75 - 4.65 (m, 2H), 4.57 - 4.41 (m, 4H), 4.04 - 3.94 (m, 3H), 3.91 - 3.63 (m, 4H), 3.62 - 3.56 (m, 1H), 3.54 - 3.50 (m, 2H), 3.46 - 3.39 (m, 2H), 3.35 - 3.30 (m, 2H), 2.63 (s, 2H), 2.63 - 2.52 (m, 1H), 2.53 (s, 3H), 2.10 - 2.05 (m, 1H), 1.97 - 1.90 (m, 6H), 1.63 - 1.47 (m, 8H), 1.36 - 1.29 (m, 4H), 1.07 (s, 3H), 0.94 (d, J = 15.5 Hz, 9H). m/z 1104.49 [M+H]+
실시예 52. (2S,4R)-N-(2-((1-((1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidin-4-yl)methyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.23 (t, J = 6.0 Hz, 1H), 7.03 (dd, J = 8.5, 3.3 Hz, 1H), 6.94 (dd, J = 7.7, 1.5 Hz, 1H), 6.88 (d, J = 1.3 Hz, 1H), 6.22 (d, J = 5.4 Hz, 1H), 4.74 (t, J = 7.8 Hz, 1H), 4.55 - 4.42 (m, 5H), 4.06 - 4.03 (m, 1H), 3.99 - 3.93 (m, 2H), 3.77 - 3.74 (m, 2H), 3.63 - 3.59 (m, 1H), 3.46 - 3.39 (m, 2H), 2.82 - 2.66 (m, 4H), 2.62 - 2.58 (m, 2H), 2.57 - 2.55 (m, 1H), 2.53 (s, 3H), 2.41 - 2.22 (m, 4H), 2.12 - 2.03 (m, 3H), 1.92 - 1.84 (m, 3H), 1.58 - 1.55 (m, 4H), 1.51 - 1.45 (m, 2H), 1.42 - 1.39 (m, 2H), 1.35 - 1.25 (m, 4H), 1.05 (s, 3H), 0.95 (s, 9H). m/z 1060.48 [M+H]+
실시예 53. (2S,4R)-N-(2-((1-((1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)-4-hydroxypiperidin-4-yl)methyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.26 - 7.20 (m, 1H), 7.04 (dd, J = 8.7, 3.4 Hz, 1H), 6.95 (dd, J = 7.7, 1.4 Hz, 1H), 6.87 (s, 1H), 6.21 (d, J = 5.4 Hz, 1H), 4.74 (t, J = 7.7 Hz, 1H), 4.59 - 4.39 (m, 5H), 4.04 (d, J = 11.5 Hz, 1H), 4.00 - 3.90 (m, 2H), 3.64 - 3.38 (m, 5H), 3.31 - 3.21 (m, 2H), 2.98 - 2.87 (m, 2H), 2.67 - 2.56 (m, 5H), 2.52 (s, 3H), 2.44 (s, 2H), 2.12 - 1.87 (m, 7H), 1.58 - 1.40 (m, 6H), 1.38 - 1.26 (m, 4H), 1.05 (s, 3H), 0.95 (s, 9H). m/z 1076.62 [M+H]+
실시예 54. (2S,4R)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidine-3-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.25 (d, J = 1.2 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 7.77 (dd, J = 5.4, 1.3 Hz, 1H), 7.37 - 7.30 (m, 1H), 7.24 - 7.22 (m, 1H), 7.02 - 6.97 (m, 2H), 6.87 (s, 1H), 6.04 (dd, J = 5.4, 1.2 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.68 - 4.64 (m, 1H), 4.55 - 4.41 (m, 8H), 4.02 - 3.93 (m, 3H), 3.89 - 3.80 (m, 1H), 3.75 - 3.57 (m, 4H), 3.42 - 3.39 (m, 2H), 3.37 - 3.30 (m, 1H), 2.61 (s, 2H), 2.58 - 2.55 (m, 1H), 2.53 (s, 3H), 2.09 - 2.04 (m, 1H), 2.02 - 1.89 (m, 4H), 1.50 - 1.46 (m, 4H), 1.37 - 1.25 (m, 4H), 1.05 (s, 3H), 0.93 (d, J = 14.7 Hz, 9H). m/z 1046.50 [M+H]+
실시예 55. (2S,4R)-N-(2-((1-(2-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)azetidin-3-yl)acetyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.20 (d, J = 1.3 Hz, 1H), 7.75 (d, J = 5.4 Hz, 1H), 7.35 (dd, J = 7.7, 3.5 Hz, 1H), 7.33 - 7.30 (m, 1H), 7.03 - 6.97 (m, 2H), 6.87 (s, 1H), 5.99 (d, J = 5.4 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.66 - 4.62 (m, 1H), 4.56 - 4.44 (m, 6H), 4.05 - 3.89 (m, 5H), 3.83 - 3.58 (m, 4H), 3.54 - 3.48 (m, 1H), 3.45 - 3.39 (m, 2H), 3.10 - 3.03 (m, 1H), 2.76 (d, J = 7.3 Hz, 2H), 2.63 (s, 2H), 2.61 - 2.56 (m, 1H), 2.52 (s, 3H), 2.10 - 1.83 (m, 5H), 1.63 - 1.55 (m, 2H), 1.52 - 1.47 (m, 2H), 1.34 - 1.31 (m, 3H), 1.28 - 1.24 (m, 1H), 1.07 (s, 3H), 0.93 (d, J = 16.8 Hz, 9H). m/z 1060.54 [M+H]+
실시예 56. (2S,4R)-N-(2-(((1R,4S)-4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.24 - 7.22 (m, 1H), 7.01 - 6.99 (m, 1H), 6.94 (dd, J = 7.7, 1.5 Hz, 1H), 6.91 (s, 1H), 5.96 (d, J = 5.5 Hz, 1H), 4.88 (d, J = 7.7 Hz, 1H), 4.74 (t, J = 7.7 Hz, 1H), 4.58 - 4.54 (m, 2H), 4.51 - 4.46 (m, 2H), 4.40 (dd, J = 14.6, 5.4 Hz, 1H), 4.33 - 4.26 (m, 1H), 4.22 - 4.16 (m, 2H), 4.03 (d, J = 11.5 Hz, 1H), 4.00 - 3.91 (m, 3H), 3.82 (d, J = 8.8 Hz, 1H), 3.70 (d, J = 8.8 Hz, 1H), 3.60 (dd, J = 11.3, 3.8 Hz, 1H), 3.54 - 3.48 (m, 1H), 3.44 - 3.37 (m, 1H), 3.24 (t, J = 11.9 Hz, 1H), 3.01 (d, J = 4.6 Hz, 1H), 2.84 (t, J = 11.6 Hz, 1H), 2.64 - 2.57 (m, 3H), 2.53 (s, 3H), 2.37 - 2.27 (m, 2H), 2.22 - 2.17 (m, 1H), 2.10 - 2.04 (m, 2H), 1.94 - 1.87 (m, 4H), 1.81 - 1.73 (m, 4H), 1.72 - 1.67 (m, 3H), 1.43 - 1.28 (m, 4H), 1.25 (d, J = 6.4 Hz, 3H), 0.93 (s, 9H). m/z 1130.44 [M+H]+
실시예 57. (2S,4R)-N-(2-(((1R,4S)-4-(3-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.26 (s, 1H), 8.22 (s, 1H), 7.74 (d, J = 5.5 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 5.9 Hz, 1H), 7.01 (dd, J = 8.3, 3.3 Hz, 1H), 6.93 (d, J = 7.7 Hz, 1H), 6.89 (s, 1H), 6.04 (dd, J = 5.5, 0.9 Hz, 1H), 5.30 - 5.27 (m ,1H), 4.79 - 4.64 (m, 2H), 4.58 - 4.35 (m, 6H), 4.32 - 4.23 (m, 1H), 4.23 - 4.14 (m, 1H), 4.05 - 3.86 (m, 5H), 3.82 (d, J = 8.8 Hz, 1H), 3.70 (d, J = 8.9 Hz, 1H), 3.60 (dd, J = 11.3, 3.5 Hz, 1H), 3.56 - 3.45 (m, 1H), 3.45 - 3.34 (m, 1H), 3.00 (d, J = 4.3 Hz, 1H), 2.63 - 2.54 (m, 1H), 2.53 (s, 3H), 2.34 - 2.18 (m, 3H), 2.11 - 2.02 (m, 1H), 1.96 - 1.82 (m, 3H), 1.80 - 1.70 (m, 7H), 1.36 - 1.21 (m, 7H), 0.93 (s, 9H). m/z 1102.57 [M+H]+
실시예 58. (2S,4R)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.27 (d, J = 1.4 Hz, 1H), 8.23 (d, J = 1.4 Hz, 1H), 7.88 (d, J = 5.4 Hz, 1H), 7.36 - 7.33 (m, 1H), 7.32 - 7.20 (m, 1H), 7.02 - 6.97 (m, 2H), 6.88 (s, 1H), 6.23 (d, J = 5.3 Hz 1H), 4.76 - 4.70 (m, 1H), 4.69 - 4.63 (m, 1H), 4.60 - 4.38 (m, 4H), 4.23 - 4.17 (m, 1H), 4.05 - 3.91 (m, 3H), 3.85 - 3.77 (m, 6H), 3.71 - 3.69 (m, 2H), 3.63 - 3.56 (m, 2H), 3.54 - 3.48 (m, 1H), 3.44 - 3.38 (m, 1H), 3.02 - 3.01 (m, 1H), 2.88 - 2.82 (m, 2H), 2.74 - 2.68 (m, 1H), 2.64 - 2.55 (m, 1H), 2.53 (s, 3H), 2.10 - 2.05 (m, 4H), 1.98 - 1.87 (m, 2H), 1.82 - 1.76 (m, 4H), 1.72 - 1.67 (m, 2H), 1.37 - 1.31 (m, 4H), 1.28 - 1.24 (m, 3H), 0.93 (d, J = 22.5 Hz, 9H). m/z 1116.43 [M+H]+
실시예 59. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(4-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.3 Hz, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 5.8 Hz, 1H), 6.94 (dd, J = 7.7, 1.4 Hz, 1H), 6.90 (s, 1H), 6.06 (d, J = 8.6 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 4.88 (d, J = 7.6 Hz, 1H), 4.72 (t, J = 7.8 Hz, 1H), 4.58 - 4.51 (m, , 2H), 4.47 (dd, J = 11.9, 7.7 Hz, 2H), 4.39 (dd, J = 14.7, 5.2 Hz, 1H), 4.31 - 4.24 (m, 1H), 4.19 - 4.17 (m, 2H), 4.13 - 4.08 (m, 1H), 4.01 - 3.91 (m, 3H), 3.82 (d, J = 8.8 Hz, 1H), 3.70 (d, J = 8.8 Hz, 1H), 3.58 (dd, J = 11.4, 3.6 Hz, 1H), 3.55 - 3.51 (dd, J = 8.9, 4.4 Hz, 1H), 3.44 - 3.38 (m, 1H), 3.25 (t, J = 11.9 Hz, 1H), 3.01 (d, J = 4.5 Hz, 1H), 2.85 (t, J = 11.5 Hz, 1H), 2.63 - 2.55 (m, 2H), 2.53 (s, 3H) 2.34 - 2.20 (m, 4H), 2.12 - 2.07 (m, 2H), 2.00 (s, 3H), 1.94 - 1.87 (m, 4H), 1.79 - 1.67 (m, 5H), 1.42 (d, J = 11.2 Hz, 2H), 1.25 (d, J = 6.4 Hz, 3H), 0.89 (s, 9H). m/z 1086.57 [M+H]+
실시예 60. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.1 Hz, 1H), 7.74 (d, J = 5.5 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.18 (t, J = 5.6 Hz, 1H), 6.95 - 6.91 (m, 1H), 6.88 (s, 1H), 6.10 (d, J = 7.1 Hz, 1H), 6.04 (d, J = 5.5 Hz, 1H), 5.32 - 5.29 (m, 1H), 4.77 - 4.67 (m, 2H), 4.58 - 4.35 (m, 6H), 4.31 - 4.17 (m, 2H), 4.08 (d, J = 11.4 Hz, 1H), 4.05 - 3.88 (m, 4H), 3.85 (d, J = 8.8 Hz, 1H), 3.71 (d, J = 8.8 Hz, 1H), 3.57 (dd, J = 11.3, 3.7 Hz, 1H), 3.53 - 3.45 (m, 1H), 3.44 - 3.34 (m, 1H), 3.04 (d, J = 4.0 Hz, 1H), 2.61 - 2.49 (m, 4H), 2.35 - 2.18 (m, 3H), 2.12 - 2.03 (m, 1H), 2.00 (s, 3H), 1.97 - 1.83 (m, 3H), 1.80 - 1.64 (m, 7H), 1.30 - 1.26 (m, 3H), 0.89 (s, 9H). m/z 1058.58 [M+H]+
실시예 61. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.27 (d, J = 1.2 Hz, 1H), 8.23 (d, J = 1.2 Hz, 1H), 7.88 (d, J = 5.3 Hz, 1H), 7.37 - 7.34 (m, 2H), 6.97 (d, J = 7.8 Hz, 1H), 6.88 (s, 1H), 6.26 - 6.08 (m, 2H), 4.74 - 4.66 (m, 2H), 4.57 - 4.40 (m, 4H), 4.22 - 4.17 (m, 1H), 4.08 - 4.06 (m, 1H), 4.01 - 3.91 (m, 2H), 3.85 - 3.75 (m, 5H), 3.74 - 3.67 (m, 2H), 3.60 - 3.48 (m, 3H), 3.44 - 3.38 (m, 1H), 3.01 (d, J = 4.6 Hz, 1H), 2.88 - 2.82 (m, 2H), 2.73 - 2.67 (m, 1H), 2.61 - 2.55 (m, 1H), 2.52 (s, 3H), 2.13 - 2.04 (m, 5H), 2.01 - 1.95 (m, 5H), 1.94 - 1.87 (m, 2H), 1.81 - 1.69 (m, 4H), 1.25 - 1.23 (m, 3H), 0.91 (d, J = 11.9 Hz, 9H). m/z 1072.36 [M+H]+
실시예 62. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.18 (d, J = 1.3 Hz, 1H), 8.16 (d, J = 1.3 Hz, 1H), 7.33 - 7.28 (m, 1H), 7.15 (t, J = 5.9 Hz, 1H), 7.02 - 6.98 (m, 1H), 6.93 (dd, J = 7.7, 1.5 Hz, 1H), 6.88 (d, J = 1.3 Hz, 1H), 6.44 (dd, J = 8.0, 1.2 Hz, 1H), 6.24 (d, J = 7.1 Hz, 1H), 6.07 (d, J = 8.7 Hz, 1H), 4.73 - 4.69 (m, 2H), 4.57 - 4.46 (m, 4H), 4.43 - 4.35 (m, 2H), 4.32 - 4.24 (m, 2H), 4.10 - 4.08 (m, 1H), 3.98 (dd, J = 8.5, 4.6 Hz, 1H), 3.88 (dd, J = 10.2, 4.7 Hz, 1H), 3.78 - 3.71 (m, 2H), 3.68 - 3.61 (m, 2H), 3.57 (dd, J = 11.4, 3.6 Hz, 1H), 2.59 - 2.54 (m, 1H), 2.52 (s, 3H), 2.32 - 2.22 (m, 3H), 2.12 - 2.06 (m, 1H), 2.00 (s, 3H), 1.93 - 1.87 (m, 2H), 1.58 - 1.42 (m, 8H), 1.23 (s, 3H), 0.89 (s, 9H). m/z 1001.55 [M+H]+
실시예 63. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(4-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)piperidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.25 (d, J = 1.3 Hz, 1H), 8.21 (d, J = 1.3 Hz, 1H), 7.75 (d, J = 5.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 5.9 Hz, 1H), 6.94 (dd, J = 7.7, 1.5 Hz, 1H), 6.90 (d, J = 1.3 Hz, 1H), 6.08 (d, J = 8.7 Hz, 1H), 5.96 (d, J = 5.5 Hz, 1H), 4.88 (d, J = 7.6 Hz, 1H), 4.71 (t, J = 7.8 Hz, 1H), 4.58 - 4.53 (m, 2H), 4.51 - 4.45 (m, 2H), 4.39 (dd, J = 14.7, 5.2 Hz, 1H), 4.31 - 4.24 (m, 1H), 4.24 - 4.18 (m, 1H), 4.11 (d, J = 11.5 Hz, 1H), 3.92 (d, J = 14.4 Hz, 1H), 3.83 - 3.77 (m, 2H), 3.72 - 3.66 (m, 2H), 3.58 (dd, J = 11.4, 3.7 Hz, 1H), 3.25 (t, J = 11.8 Hz, 1H), 2.85 (t, J = 11.5 Hz, 1H), 2.61 - 2.54 (m, 1H), 2.53 (s, 3H), 2.33 - 2.17 (m, 3H), 2.12 - 2.07 (m, 2H), 2.00 (s, 3H), 1.93 - 1.87 (m, 2H), 1.71 - 1.58 (m, 8H), 1.46 - 1.40 (m, 2H), 1.25 (s, 3H), 0.89 (s, 9H). m/z 1030.58 [M+H]+
실시예 64. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.22 (d, J = 1.2 Hz, 1H), 7.74 (d, J = 5.5 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 5.8 Hz, 1H), 6.93 (dd, J = 7.7, 1.4 Hz, 1H), 6.88 (s, 1H), 6.08 (d, J = 8.6 Hz, 1H), 6.04 (d, J = 5.5 Hz, 1H), 5.29 - 5.28 (m, 1H), 4.76 - 4.67 (m, 2H), 4.60 - 4.33 (m, 6H), 4.31 - 4.21 (m, 1H), 4.08 (d, J = 11.5 Hz, 1H), 4.04 - 3.95 (m, 1H), 3.95 - 3.88 (m, 1H), 3.87 - 3.77 (m, 2H), 3.75 - 3.63 (m, 2H), 3.58 (dd, J = 11.3, 3.6 Hz, 1H), 2.61 - 2.48 (m, 4H), 2.37 - 2.19 (m, 3H), 2.12 - 2.04 (m, 1H), 2.00 (s, 3H), 1.95 - 1.84 (m, 2H), 1.64 - 1.42 (m, 8H), 1.24 (s, 3H), 0.89 (s, 9H). m/z 1002.60 [M+H]+
실시예 65. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-((1-(1-(4-((5-(4-amino-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (d, J = 1.1 Hz, 1H), 8.23 (d, J = 1.1 Hz, 1H), 7.87 (d, J = 5.3 Hz, 1H), 7.37 - 7.34 (m, 2H), 6.97 (d, J = 7.9 Hz, 1H), 6.88 (s, 1H), 6.24 - 6.08 (m, 2H), 4.74 - 4.62 (m, 2H), 4.56 - 4.41 (m, 4H), 4.08 - 4.05 (m, 1H), 3.84 - 3.78 (m, 7H), 3.72 - 3.65 (m, 2H), 3.60 - 3.56 (m, 2H), 2.87 - 2.82 (m, 2H), 2.73 - 2.67 (m, 1H), 2.61 - 2.52 (m, 1H), 2.52 (s, 3H), 2.09 - 2.05 (m, 5H), 2.01 - 1.94 (m, 5H), 1.85 - 1.77 (m, 2H), 1.70 - 1.63 (m, 4H), 1.24 (s, 3H), 0.91 (d, J = 11.6 Hz, 9H). m/z 1016.43 [M+H]+
실시예 66. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.19 (s, 1H), 8.16 (s, 1H), 7.43 - 7.38 (m, 1H), 7.25 (s, 1H), 7.01 - 6.96 (m, 2H), 6.91 (s, 1H), 6.45 - 6.40 (m, 1H), 6.23 (d, J = 8.5 Hz, 1H), 6.13 (d, J = 8.9 Hz, 1H), 5.32 - 5.28 (m, 1H), 4.72 - 4.65 (m, 2H), 4.54 - 4.50 (m, 3H), 4.42 - 4.39 (m, 1H), 4.33 - 4.28 (m, 2H), 4.11 - 4.09 (m, 1H), 4.00 - 3.90 (m, 4H), 3.62 - 3.59 (m, 1H), 3.42 - 3.36 (m, 2H), 3.07 - 2.58 (m, 2H), 2.54 - 2.46 (m, 4H), 2.33 - 2.20 (m, 4H), 2.08 - 2.01 (m, 4H), 1.92 - 1.85 (m, 2H), 1.74 - 1.67 (m, 6H), 1.44 - 1.42 (m, 3H), 1.06 - 1.03 (m, 12H). m/z 1029.55 [M+H]+
실시예 67. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-((S)-1-(2-(((1R,4S)-4-(3-((4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)phenyl)ethyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.73 (d, J = 5.5 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 6.97 (d, J = 7.8 Hz, 1H), 6.92 (s, 1H), 6.15 (d, J = 8.5 Hz, 1H), 6.04 (d, J = 5.5 Hz, 1H), 5.30 - 5.27 (m, 1H), 4.75 - 4.65 (m, 2H), 4.57 - 4.51 (m, 3H), 4.43 - 4.34 (m, 1H), 4.36 - 4.29 (m, 1H), 4.11 - 4.08 (m, 1H), 4.01 - 3.90 (m, 5H), 3.63 - 3.60 (m, 1H), 3.46 - 3.39 (m, 2H), 2.60 (s, 2H), 2.54 - 2.41 (m, 4H), 2.33 - 2.17 (m, 4H), 2.07 - 2.01 (m, 4H), 1.92 - 1.85 (m, 2H), 1.76 - 1.68 (m, 2H), 1.51 - 1.45 (m, 4H), 1.43 (d, J = 6.9 Hz, 3H), 1.05 (s, 12H). m/z 1030.56 [M+H]+
실시예 68. (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-1-((S)-2-(1-fluorocyclopropane-1-carboxamido)-3,3-dimethylbutanoyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.68 - 8.67 (m, 1H), 8.43 (d, J = 4.8 Hz, 1H), 8.20 - 8.16 (m, 2H), 7.64 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 7.25 - 7.22 (m, 1H), 7.17 - 7.14 (m, 1H), 7.04 - 6.86 (m, 5H), 6.49 - 6.46 (m, 1H), 6.25 (d, J = 8.0 Hz, 1H), 4.75 - 4.72 (m, 2H), 4.55 - 4.42 (m, 6H), 4.29 - 4.26 (m, 4H), 4.03 - 3.97 (m, 3H), 3.90 - 3.86 (m, 1H), 3.62 - 3.58 (m, 1H), 3.27 - 3.19 (m, 3H), 2.91 - 2.85 (m, 1H), 2.64 - 2.59 (m, 1H), 2.57 - 2.52 (m, 3H), 2.37 - 2.20 (m, 5H), 2.09 - 2.04 (m, 2H), 1.89 - 1.86 (m, 3H), 1.81 - 1.65 (m, 3H), 1.42 - 1.37 (m, 4H), 0.93 (s, 9H). m/z 1134.40 [M+H]+
실시예 69. (2S,4R)-1-((S)-2-acetamido-3,3-dimethylbutanoyl)-N-(2-(((1R,4S)-4-(3-((3-((5-((S)-5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.43 (d, J = 4.9 Hz, 1H), 8.19 - 8.16 (m, 2H), 7.64 (d, J = 7.5 Hz, 1H), 7.31 - 7.29 (m, 1H), 7.17 - 7.14 (m, 2H), 7.04 - 7.00 (m, 1H), 6.93 (dd, J = 7.7, 1.4 Hz, 1H), 6.88 (s, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.25 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 8.7 Hz, 1H), 4.73 - 4.69 (m, 2H), 4.55 - 4.40 (m, 6H), 4.29 - 4.26 (m, 4H), 4.10 (d, J = 11.6 Hz, 1H), 4.03 (s, 1H), 4.00 - 3.96 (m, 1H), 3.90 - 3.86 (m, 1H), 3.57 (dd, J = 11.5, 3.6 Hz, 1H), 3.28 - 3.19 (m, 3H), 2.88 (d, J = 16.4 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.53 (s, 3H), 2.36 - 2.20 (m, 4H), 2.12 - 2.02 (m, 1H), 2.00 (s, 3H), 1.92 - 1.83 (m, 4H), 1.80 - 1.69 (m, 2H), 1.42 - 1.29 (m, 3H), 0.88 (s, 9H). m/z 1090.42 [M+H]+
실시예 70. (2S,4R)-N-(2-(((1R,4S)-4-(3-((3-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-2-chlorophenyl)amino)azetidine-1-carbonyl)cyclohexyl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3, diastereomer mixture) δ 8.68 (s, 1H), 8.19 (d, J = 1.3 Hz, 1H), 8.15 (d, J = 1.3 Hz, 1H), 7.30 - 7.14 (m, 2H), 7.00 (t, J = 8.0 Hz, 1H), 6.97 - 6.92 (m, 1H), 6.90 (s, 1H), 6.43 (d, J = 7.9 Hz, 1H), 6.24 (d, J = 8.1 Hz, 1H), 5.99 (d, J = 58.6 Hz, 1H), 4.77 - 4.59 (m, 3H), 4.59 - 4.52 (m, 1H), 4.52 - 4.36 (m, 3H), 4.36 - 4.22 (m, 2H), 4.04 - 3.95 (m, 1H), 3.95 - 3.85 (m, 3H), 3.81 - 3.51 (m, 3H), 3.43 - 3.33 (m, 2H), 2.65 - 2.55 (m, 3H), 2.53 (s, 3H), 2.45 - 2.33 (m, 1H), 2.34 - 2.20 (m, 6H), 2.02 - 1.83 (m, 3H), 1.77 - 1.64 (m, 2H), 1.55 - 1.40 (m, 6H), 1.06 - 0.99 (m, 4H), 0.93 - 0.80 (m, 5H). m/z 1025.58 [M+H]+
실시예 71. (2S,4R)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxy-1-(3-methyl-2-(3-methylisoxazol-5-yl)butanoyl)pyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3, diastereomer mixture) δ 8.69 (s, 1H), 8.26 (d, J = 1.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.87 (d, J = 5.4 Hz, 1H), 7.42 - 7.16 (m, 2H), 7.01 - 6.93 (m, 1H), 6.88 (s, 1H), 6.24 (d, J = 5.4 Hz, 1H), 6.08 - 5.89 (m, 1H), 4.78 - 4.34 (m, 5H), 4.04 - 3.93 (m, 2H), 3.91 - 3.49 (m, 9H), 3.49 - 3.37 (m, 2H), 2.85 (t, J = 11.9 Hz, 2H), 2.76 - 2.67 (m, 1H), 2.64 - 2.57 (m, 3H), 2.53 (s, 3H), 2.44 - 2.30 (m, 1H), 2.29 - 2.14 (m, 3H), 2.10 - 1.91 (m, 7H), 1.88 - 1.71 (m, 2H), 1.62 - 1.53 (m, 2H), 1.53 - 1.43 (m, 2H), 1.09 - 1.00 (m, 4H), 0.94 - 0.80 (m, 5H). m/z 1040.40 [M+H]+
실시예 72. (2S,4R)-1-((S)-2-acetamido-3-methylbutanoyl)-N-(2-((1-(1-(4-((5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3-chloropyridin-2-yl)piperidine-4-carbonyl)piperidin-4-yl)oxy)-4-(4-methylthiazol-5-yl)benzyl)-4-hydroxypyrrolidine-2-carboxamide
1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.87 (d, J = 4.8 Hz, 1H), 7.52 - 7.31 (m, 2H), 7.00 - 6.95 (m, 1H), 6.89 (s, 1H), 6.43 - 6.05 (m, 2H), 4.74 - 4.67 (m, 2H), 4.55 - 4.54 (m, 1H), 4.49 - 4.34 (m, 2H), 4.17 - 4.10 (m, 1H), 3.99 - 3.91 (m, 2H), 3.85 - 3.66 (m, 5H), 3.62 - 3.49 (m, 2H), 3.47 - 3.39 (m, 2H), 3.08 - 2.81 (m, 3H), 2.75 - 2.68 (m, 1H), 2.65 - 2.56 (m, 3H), 2.53 (s, 3H), 2.12 - 2.06 (m, 4H), 2.01 - 1.91 (m, 7H), 1.84 - 1.78 (m, 2H), 1.61 - 1.55 (m, 2H), 1.51 - 1.42 (m, 2H), 1.05 (s, 3H), 0.96 - 0.88 (m, 3H), 0.84 (d, J = 6.7 Hz, 3H). m/z 1016.65 [M+H]+
본 개시 화합물들의 평가
실험예 1: MV-4-11 세포에서 SHP2 단백질 분해능 측정
합성된 실시예 화합물을 MV-4-11 세포에 처리하고 세포내에 존재하는 SHP2 단백질의 양을 western blotting 검출법을 사용하여 측정하였다. MV-4-11 세포를 사용하여 진행된 실험의 protocol은 다음과 같다.
[배양] MV-4-11 세포를 IMDM MEDIUM (Hyclone, SH30228.01, 5% FBS (Hyclone, SV30207.02), 1% Penicillin-streptomycin (Welgene, LS 202-02) media에 resuspend 하여 1 x 106/mL로 12-well plate에 1 mL씩 seeding 하였다.
[화합물 처리] 12-well plate에 다음과 같이 처리하였다. DMSO에 녹여진 10 mM stock을 media로 1/100 또는 1/10로 serial dilution하여 최종 농도 0.01, 0.1, 1 μM 또는 0.001, 0.01, 0.1 μM로 화합물을 세포에 처리하고 24 시간 후 harvest 하였다. 음성대조군에는 media에 1/100 또는 1/1000로 희석한 DMSO를 넣어주었다 (3 μL DMSO + 297 μL media 또는 1 μL DMSO + 999 μL media).
[Harvest] 각 well을 1 mL pipette으로 pipetting 하여 1.5 mL microtube에 모아 원심분리 하였다 (500 g, 5 min, 4 ℃). 상층액을 제거하고 PBS washing하여 다시 원심분리 하였다 (500 g, 5 min, 4 ℃). 이후 상층액을 제거하여 pellet을 준비하였다.
[Cell lysis 및 Sample 준비] Lysis buffer는 다음과 같이 준비하였다. RIPA buffer (Biosesang, RC2038-050-00) + 0.5 mM PMSF (SIGMA, P7626) + 1x Protease/Phosphatase Inhibitor (Cell signaling, 5872S)를 tube 당 50 μL씩 넣고 30분간 얼음에서 incubation하였다 (0, 30분에 각각 vortexing). 이후 sonication 과정을 (10초 pulse, 30초 rest, 5 cycles, 70% amplification) 진행하고 원심분리 (15,000 g, 15 min, 4 ℃)한 후 상층액만 취하여 microtube로 옮겼다. 96-well plate에 RIPA buffer 7.5 μL와 샘플 2.5 μL를 넣어 1/4로 희석한 후 BCA Protein Assay Kit (iNtRON, 21071)의 A와 B를 50:1 비율로 섞어 200 μL씩 넣었다. 그 후 plate를 37 ℃에서 30분 동안 incubation하고 상온에서 10분간 두었다. 이후 BioTek 사의 SYNERGY H1 microplate reader로 10초간 shaking 후 562 nm에서 absorbance를 측정하였다. 측정값으로 단백질을 정량하여 샘플을 만든 후 70 ℃에서 10분간 incubation하였다. 이때 사용되는 Sample buffer는 사용할 gel에 맞추어 NuPAGE 혹은 Bolt 4x sample buffer (Invitrogen)와 각각의 10x sample reducing agent를 섞어서 사용하며 단백질 희석은 RIPA buffer를 이용하였다.
[Western blotting 검출법] NuPAGE 혹은 Bolt Bis-tris 4-12% gradient gel에 같은 양의 샘플을 loading하여 running하였다 (200 V, 35분). Trans-blot Turbo (BIO-RAD)로 0.2 mm NC membrane에 transfer하였다 (1.3 A constant, 25 V limit, 15분). Skim milk 혹은 Intercept Blocking Buffer (LI-COR, 927-60001):0.1% TBST = 1:1 로 1시간 동안 상온에서 blocking하였다. Anti-SHPTP2 Mouse (1:500 in 2% BSA/0.2% TBST, size: 70 kDa, Santacruz sc-7384)은 4 ℃에서 overnight incubation 하고, Anti-GAPDH Rabbit (1:2,000 in 2% BSA/0.2% TBST, size: 37 kDa, CST #2118)은 상온에서 1시간 30분 혹은 3시간 동안 incubation하였다. 0.2% TBST washing buffer로 각 5분씩 3회 세척해주고 2차 antibody인 Anti-Mouse IgG (1:5,000 in 2% BSA/0.2% TBST, CST), IRDye® 680RD Goat anti-Rabbit IgG Secondary Antibody (1:10,000 in 2% BSA/0.2% TBST, LI-COR 926-68071)를 넣어준 후 상온의 rocker 위에서 45분간 incubation하였다. 0.2% TBST washing buffer로 각 5분씩 5회 세척해주고 LI-COR사의 Odyssey로 detection하였다. 이때 GAPDH는 700 nm channel로 detection하였고 SHPTP2은 SuperSignal West Pico PLUS Chemiluminescent Substrate를 이용해 detection 하였다.
본 실시예 화합물들의 SHP2 단백질 분해능 평가 결과를 표 1에 나타냈다. 본 개시의 화합물들은 SHP2 단백질 분해에 있어 우수한 활성을 나타냈다. 하기 표 1에서 "+"는 0초과 내지 50% 억제, "++"는 50초과 내지 90% 억제, "+++"는 90초과 내지 100% 억제를 의미한다.
실시예 | SHP2 %degradation at 100 nM | 실시예 | SHP2 %degradation at 100 nM |
1 | + | 27 | ++ |
2 | +++ | 28 | ++ |
3 | +++ | 29 | ++ |
4 | +++ | 30 | +++ |
5 | +++ | 31 | +++ |
6 | +++ | 32 | +++ |
7 | +++ | 33 | +++ |
8 | +++ | 34 | +++ |
9 | +++ | 35 | +++ |
10 | +++ | 36 | +++ |
11 | +++ | 37 | +++ |
12 | +++ | 38 | +++ |
13 | +++ | 39 | +++ |
14 | +++ | 40 | ++ |
15 | +++ | 41 | +++ |
16 | +++ | 42 | +++ |
17 | +++ | 43 | +++ |
18 | +++ | 44 | +++ |
19 | +++ | 45 | +++ |
20 | +++ | 46 | +++ |
21 | +++ | 47 | +++ |
22 | +++ | 48 | +++ |
23 | +++ | 49 | +++ |
24 | +++ | 50 | +++ |
25 | +++ | 51 | +++ |
26 | +++ | 52 | ++ |
실험예 2: NCI-H358 세포에서 SHP2 단백질 분해능 측정
합성된 실시예 화합물을 H358 세포에 처리하고 세포내에 존재하는 SHP2 단백질의 양을 western blotting 검출법을 사용하여 측정하였다. H358 세포를 사용하여 진행된 실험의 protocol은 다음과 같다.
[배양] H358 세포를 RPMI1640 with 25 mM HEPES (Hyclone, SH30255.01), 10% FBS (Hyclone, SV30207.02), 1% Penicillin-streptomycin (Welgene, LS 202-02) media에 resuspend 하여 3 x 105/mL로 12-well plate에 1 mL씩 seeding 한 후 24시간 배양하였다.
[화합물 처리] 화합물 처리 전에 1 mL media로 media change 한 후 12-well plate에 다음과 같이 처리하였다. DMSO에 녹여진 10 mM stock을 media로 1/100 또는 1/10로 serial dilution하여 최종 농도 0.001, 0.01, 0.1 μM로 화합물을 세포에 처리하고 24 시간 후 harvest하였다. 음성대조군에는 media에 1/1000로 희석한 DMSO를 넣어주었다 (1 μL DMSO + 999 μL media).
[Harvest] 화합물 처리 후 24시간 뒤 각 well을 cell lifter (SPL, 90040)로 긁고 1 mL pipette으로 pipetting 하여 1.5 mL microtube에 모아 원심분리 하였다 (500 g, 5 min, 4 ℃). 상층액을 제거하고 PBS washing하여 다시 원심분리 하였다 (500 g, 5 min, 4 ℃). 이후 상층액을 제거하여 pellet을 준비하였다.
[Cell lysis 및 Sample 준비] Lysis buffer는 다음과 같이 준비하였다. RIPA buffer (Biosesang, RC2038-050-00) + 0.5 mM PMSF (SIGMA, P7626) + 1x Protease/Phosphatase Inhibitor (Cell signaling, 5872S)를 tube 당 30 μL씩 넣고 vortexing 후 30분간 얼음에서 incubation하였다. 이후 sonication 과정을 (10초 pulse, 30초 rest, 5 cycles, 70% amplification) 진행하고 원심분리 (15,000 g, 15 min, 4 ℃)한 후 상층액만 취하여 microtube로 옮겼다. 96-well plate에 RIPA buffer 7.5 μL와 샘플 2.5 μL를 넣어 1/4로 희석한 후 BCA Protein Assay Kit (iNtRON, 21071)의 A와 B를 50:1 비율로 섞어 200 μL씩 넣었다. 그 후 plate를 37 ℃에서 30분 동안 incubation하고 상온에서 10분간 두었다. 이후 BioTek 사의 SYNERGY H1 microplate reader로 10초간 shaking 후 562 nm에서 absorbance를 측정하였다. 측정값으로 단백질을 정량하여 샘플을 만든 후 70 ℃에서 10분간 incubation 하였다. 이때 사용되는 Sample buffer는 사용할 gel에 맞추어 NuPAGE 혹은 Bolt 4x sample buffer (Invitrogen)와 각각의 10x sample reducing agent를 섞어서 사용하며 단백질 희석은 RIPA buffer를 이용하였다.
[Western blotting 검출법] NuPAGE 혹은 Bolt Bis-tris 4-12% gradient gel에 같은 양의 샘플을 loading하여 running하였다 (200 V, 35분). Trans-blot Turbo (BIO-RAD)로 0.2 mm NC membrane에 transfer하였다 (1.3 A constant, 25 V limit, 15분). 5% Skim milk/0.2% TBST으로 45분간 상온에서 blocking하였다. Anti-SHPTP2 Mouse (1:1,000 in 5% skim milk/0.2% TBST, size: 70 kDa, Santa cruz sc-7384)와 Anti-GAPDH Rabbit (1:2,000 in 5% skim milk or 5% BSA/0.2% TBST, size: 37 kDa, CST #2118)을 넣고 4 ℃에서 overnight incubation하였다. 0.2% TBST washing buffer로 각 5분씩 3회 세척해주고 2차 antibody인 Anti-Mouse IgG (1:5,000 in 5% skim milk/0.2% TBST, CST), IRDye® 680RD Goat anti-Rabbit IgG Secondary Antibody (1:10,000 in 5% skim milk/0.2% TBST, LI-COR 926-68071)를 넣어준 후 상온의 rocker 위에서 45분간 incubation하였다. 0.2% TBST washing buffer로 각 5분씩 5회 세척해주고 LI-COR사의 Odyssey로 detection하였다. 이때 GAPDH는 700 nm channel로 detection하였고 SHPTP2은 SuperSignal West Pico PLUS Chemiluminescent Substrate를 이용해 detection 하였다.
본 실시예 화합물들의 SHP2 단백질 분해능 평가 결과를 표 2에 나타냈다. 하기 표 2에서 보여지는 바와 같이, 본 개시의 화합물들은 SHP2 단백질 분해에 있어 우수한 활성을 나타냈다. 하기 표 2에서 "+"는 0초과 내지 50% 억제, "++"는 50초과 내지 90% 억제, "+++"는 90초과 내지 100% 억제를 의미한다.
실시예 | SHP2 %degradation at 100 nM | 실시예 | SHP2 %degradation at 100 nM |
53 | +++ | 63 | +++ |
54 | +++ | 64 | +++ |
55 | +++ | 65 | +++ |
56 | +++ | 66 | +++ |
57 | +++ | 67 | +++ |
58 | +++ | 68 | +++ |
59 | +++ | 69 | +++ |
60 | +++ | 70 | +++ |
61 | +++ | 71 | +++ |
62 | +++ | 72 | +++ |
Claims (8)
- 하기 화학식 1의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물 또는 이들의 약학적으로 허용 가능한 염
[화학식 1]
상기 화학식 1에서,
R1은 , , 또는 이고,
R11은 H, C1-6alkyl, hydroxy, halogen, C1-6hydroxyalkyl, C1-6haloalkyl, C3-10cycloalkyl, heterocycle, aryl, 또는 heteroaryl이고, 여기에서 aryl 및 heteroaryl은 서로 독립적이면서 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, hydroxy, halogen, C1-3hydroxyalkyl, C1-3haloalkyl, 또는 C1-3alkoxy로 치환되며,
R12는 amino, C1-6aminoalkyl, 또는 C1-6alkylamino이고,
R13a 및 R13b는 서로 독립적으로 H, C1-6alkyl, hydroxy, halogen, C1-6hydroxyalkyl, C1-6haloalkyl, 또는 C1-6alkoxy이고,
R14는 서로 독립적으로 H, C1-6alkyl, hydroxyl, halogen, 또는 CN이고,
Z는 -O-, -S-, -NH-, 또는 -CH2-이고,
고리(ring) C는 aryl 또는 heteroaryl이고,
n은 0 내지 5의 정수이고,
R2는 H, C1-6alkyl, 또는 -NH2이고,
R3는 H, C1-6alkyl, C1-6hydroxyalkyl, C1-6haloalkyl, -C(O)R9a, -C(O)OR9a, -C(O)NR9aR9b, 또는 CN이고,
R4는 H, C1-6alkyl, halogen, 또는 C1-6haloalkyl이고,
R5는 H, C1-6alkyl, C2-6alkynyl, halogen, -CN, 또는 heteroaryl이고, 여기에서 heteroaryl은 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, halogen, 또는 C1-3haloalkyl로 치환되며,
R6는 -NHC(O)R7 또는 heteroaryl이고, 여기에서 heteroaryl은 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, halogen, 또는 C1-3haloalkyl로 치환되며,
R7은 C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, 또는 heterocycle이고, 여기에서 cycloalkyl 및 heterocycle은 서로 독립적이면서 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, halogen, 또는 -CN로 치환되며,
R8a 및 R8b는 서로 독립적으로 H 또는 C1-6alkyl이고,
X는 -S-, -O-, -N(R9a)-, -CH2-, -CHCH-, -CC-, -CH2O-, 또는 -OCH2-이고,
Y는 CH 또는 N이고,
W는 직접 결합, -O-, 또는 -N(R9a)-이고,
R9a 및 R9b는 서로 독립적으로 H, C1-6alkyl, 또는 C1-6haloalkyl이고,
L은 하기 화학식 2이며,
[화학식 2]
화학식 2에서,
A1 및 A2는 서로 독립적으로 직접 결합, C3-10cycloalkyl, heterocycle, aryl, 또는 heteroaryl이며, 여기에서 cycloalkyl, heterocycle, aryl, 또는 heteroaryl은 임의로 고리 내 하나 이상의 수소가 C1-6alkyl, halogen, C1-3haloalkyl, -OH, 또는 =O로 치환되며,
B1 및 B2는 서로 독립적으로 직접 결합, -O-, -N(R10)- -C(O)-, -C(O)N(R10)-, 또는 -N(R10)C(O)-이고,
R10은 서로 독립적으로 H 또는 C1-6alkyl이고,
q1, q2, q3, q4, 및 q5는 서로 독립적으로 0 내지 10의 정수임. - 제1항의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 약학적으로 허용 가능한 염 및 약학적으로 허용 가능한 담체를 포함하는 조성물.
- 유효 성분으로 제1항의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 약학적으로 허용 가능한 염을 포함하는, Src 상동성 2 도메인-함유 포스파타제 (Src homology 2 domain-containing phosphatase, SHP2)의 억제 또는 분해를 위한 약학 조성물.
- 제3항에 있어서, 상기 Src 상동성 2 도메인-함유 포스파타제 (SHP2)의 억제 또는 분해를 위한 약학 조성물은 암, 암 전이 (metastasis), 심혈관 질환, 면역 장애, 안구 장애, 누난 (noonan) 증후군, 또는 레오파드 (leopard) 증후군의 치료 또는 예방용인, 약학 조성물.
- 제4항에 있어서, 상기 암은 혈액암, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 급성 골수성 백혈병, 단핵구 백혈병, 만성 골수성 백혈병, 만성 림프구성 백혈병, 혼합 계통 백혈병, NUT-중간선 암, 다발성 골수종, 소세포 폐암, 비소세포 폐암, 신경모세포종, 림프종, 자궁경부암, 두경부암, 두부암, 식도암, 위암, 췌장암, 간암, 흑색종, 대장암, 결장암, 전립선암, 유방암, 난소암, 방광암, 신경교종, 또는 육종, 유두 갑성선 암종 및 이들의 조합으로부터 선택되는 하나 이상인 것인, 약학 조성물.
- 제1항의 화합물, 이의 광학 이성질체, 입체 이성질체, 동위원소 변형체, 수화물, 용매화물, 또는 이들의 약학적으로 허용 가능한 염의 치료적으로 유효한 양을 이를 필요로 하는 개체에게 투여하는 단계를 포함하는, Src 상동성 2 도메인-함유 포스파타제 (SHP2) 관련 질환의 치료 또는 예방 방법.
- 제6항에 있어서, 상기 Src 상동성 2 도메인-함유 포스파타제 (SHP2) 관련 질환은 암, 암 전이 (metastasis), 심혈관 질환, 면역 장애, 안구 장애, 누난 (noonan) 증후군, 또는 레오파드 (leopard) 증후군인 치료 또는 예방 방법.
- 제7항에 있어서, 상기 암은 혈액암, 급성 림프구성 백혈병, 만성 림프구성 백혈병, 급성 골수성 백혈병, 단핵구 백혈병, 만성 골수성 백혈병, 만성 림프구성 백혈병, 혼합 계통 백혈병, NUT-중간선 암, 다발성 골수종, 소세포 폐암, 비소세포 폐암, 신경모세포종, 림프종, 자궁경부암, 두경부암, 두부암, 식도암, 위암, 췌장암, 간암, 흑색종, 대장암, 결장암, 전립선암, 유방암, 난소암, 방광암, 신경교종, 또는 육종, 유두 갑성선 암종 및 이들의 조합으로부터 선택되는 하나 이상인 것인, 치료 또는 예방 방법.
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