KR20230072431A - Small-Molecule Modulators of MLL1-WDR5 Interactions and the use - Google Patents

Small-Molecule Modulators of MLL1-WDR5 Interactions and the use Download PDF

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KR20230072431A
KR20230072431A KR1020220152080A KR20220152080A KR20230072431A KR 20230072431 A KR20230072431 A KR 20230072431A KR 1020220152080 A KR1020220152080 A KR 1020220152080A KR 20220152080 A KR20220152080 A KR 20220152080A KR 20230072431 A KR20230072431 A KR 20230072431A
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methyl
compound
imidazol
dihydro
trifluoromethyl
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태현섭
이빛
김현주
이미진
양홍주
최종윤
김윤란
하형호
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엘젠테라퓨틱스 주식회사
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

본 발명은 이중고리 저분자 유도체를 유효성분으로 함유하는 항암용 약학적 조성물 및 이의 제조방법에 관한 것으로, 상기 이중고리 유도체를 유효성분으로 함유하는 조성물은 암 예방 또는 치료용 조성물로 유용하게 사용가능하다.The present invention relates to an anticancer pharmaceutical composition containing a bicyclic low-molecular derivative as an active ingredient and a method for preparing the same, and the composition containing the bicyclic derivative as an active ingredient can be usefully used as a composition for preventing or treating cancer. .

Description

MLL1-WDR5 상호작용을 조절하는 저분자 화합물 및 이의 용도 { Small-Molecule Modulators of MLL1-WDR5 Interactions and the use }Small molecule compounds modulating MLL1-WDR5 interactions and their uses { Small-Molecule Modulators of MLL1-WDR5 Interactions and the use }

본 발명은 이중고리 저분자 화합물을 유효성분으로 함유하는 항암용 약학적 조성물 및 이의 제조방법에 관한 것이다.The present invention relates to a pharmaceutical composition for anticancer containing a double-ringed low-molecular compound as an active ingredient and a method for preparing the same.

히스톤 (histone)의 메틸화 (methylation)는 다수의 생물학적 과정에서 중요한 역할을 하며 히스톤 변형은 후성유전학적 조절에 중요하다. 포유류에서, SET1a, SET1b와 MLL (mixed-lineage leukemia protein) 1-4로 구성되어있는 SET1을 포함하는 몇가지의 히스톤 메틸트렌스퍼레이즈 (histone methyltransferases)에 의해 H3K4는 메틸화 된다 (Guillermo, S. et al., 2013). 이들 효소는 조립과 활성을 위해 이펙터 단백질 (effector protein) WDR5 (WD40 repeat protein 5)를 필요로 하는 보존된 거대분자 복합체의 구성요소이다 (Trievel, R. C. et al., 2009). SET1 단백질의 가장 잘 특성화된 것은 MLL1으로 조혈계, 근형성, 신경발생을 포함하여 적절한 배아 발달에 필요한 선택된 타겟 Hox 유전자의 발현을 유지하는 핵심 단백질이다 (Argiropoulos, B. et al., 2007; Lim, D. A. et al., 2009).Histone methylation plays an important role in a number of biological processes, and histone modifications are important for epigenetic regulation. In mammals, H3K4 is methylated by several histone methyltransferases, including SET1a, SET1b, and SET1, which is composed of MLL (mixed-lineage leukemia protein) 1–4 (Guillermo, S. et al. ., 2013). These enzymes are components of a conserved macromolecular complex that requires the effector protein WDR5 (WD40 repeat protein 5) for assembly and activity (Trievel, RC et al ., 2009). The best characterized of the SET1 proteins is MLL1, which is a key protein that maintains the expression of selected target Hox genes required for proper embryonic development, including hematopoiesis, myogenesis, and neurogenesis (Argiropoulos, B. et al ., 2007; Lim , DA et al ., 2009).

야생형 MLL1은 H3K4 메틸화의 최대 효소 활성을 위해 필요로하는 4개의 구성요소인 MLL1, WDR5, RbBP5 및 ASH2L과 코어 다중 단백질 복합체를 형성하여 그 기능을 한다 (Dou, Y. et al., 2006). MLL1 단독으로는 H3K4 메틸트렌스퍼레이즈 활성이 약하지만 WDR5, RbBP5 및 ASH2L과 함께 코어 복합체를 이루었을 때 H3K4 메틸트렌스퍼레이즈 효소 활성은 매우 향상되며 WDR5와 RbBP5는 MLL1 활성을 위해 필수적이다.Wild-type MLL1 functions by forming a core multiprotein complex with four components required for maximal enzymatic activity of H3K4 methylation: MLL1, WDR5, RbBP5 and ASH2L (Dou, Y. et al. , 2006). MLL1 alone has weak H3K4 methyltransferase activity, but when it forms a core complex with WDR5, RbBP5 and ASH2L, H3K4 methyltransferase activity is greatly enhanced, and WDR5 and RbBP5 are essential for MLL1 activity.

MLL1 유전자 재배열 이상은 성인의 급성골수성 백혈병 (AML, acute myeloid leukemia)의 5-10%, 유아의 급성림프모구 백혈병 (ALL, acute lymphoblastic)의 70%를 차지한다 (Ayton, P. M. et al., 2001). 대부분의 경우, 하나의 MLL1 대립유전자에서 염색체 전위 (chromosome translocation)가 발생하여 MLL1-AF9, MLL1-AF4 및 MLL1-ENL 과 같은 발암성 MLL1 융합 단백질이 발현된다 (Dou, Y. et al., 2008). 카복실기 말단 SET 도메인이 결여되어있어 H3K4 히스톤 메틸트렌스퍼레이즈 (HMTs, histone methyltransferases) 활성이 없는 MLL1 융합 단백질은 단독으로는 백혈병을 유발할 수 없으며, 백혈병 발생을 위해 야생형 MLL1 (wild-type MLL1)의 효소 활성이 필요하다 (Thiel, A. T. et al., 2010). 야생형 MLL1은 아미노 말단 단편에서 Hox 유전자의 조절 영역에 결합하는 반면 촉매-카복실 말단 도메인은 WDR5와의 상호작용을 통해 H3K4 메틸화를 촉매하고 표적 유전자 전사를 상향 조절한다 (Thomas, A. M. et al., 2005; Akihiko, Y. et al., 2004). 발암성 MLL1 융합 단백질은 Hox 및 MEIS1을 비롯한 다수의 종양유전자의 전사를 조절한다고 알려져 있다.MLL1 gene rearrangement abnormalities account for 5-10% of acute myeloid leukemia (AML) in adults and 70% of acute lymphoblastic (ALL) cases in infants (Ayton, PM et al ., 2001). In most cases, one MLL1 allele results in chromosome translocation, resulting in the expression of oncogenic MLL1 fusion proteins such as MLL1-AF9, MLL1-AF4 and MLL1-ENL (Dou, Y. et al ., 2008 ). The MLL1 fusion protein, which lacks the carboxyl terminal SET domain and thus has no H3K4 histone methyltransferases (HMTs) activity, cannot induce leukemia by itself, and requires wild-type MLL1 to cause leukemia. enzymatic activity is required (Thiel, AT et al ., 2010). Wild-type MLL1 binds to the regulatory regions of Hox genes in its amino-terminal fragment, while its catalytic-carboxyl-terminal domain catalyzes H3K4 methylation through interaction with WDR5 and upregulates target gene transcription (Thomas, AM et al ., 2005; Akihiko, Y. et al ., 2004). Oncogenic MLL1 fusion proteins are known to regulate the transcription of multiple oncogenes including Hox and MEIS1.

WDR5는 질병의 시작, 발달, 유지와 관련 있으며 백혈병, 간세포암, 유방암 등 다양한 암종에서 과발현되어 있고, 임상에서 좋지 않은 예후와 관련되어 있다. WD40 반복은 7개의 날개가 있는 프로펠러 접힘을 형성하고 각 날개가 있는 프로펠러 접힘을 형성하고 각 날개는 4가닥의 역평행 시트로 구성되어 있다. 이러한 구조적인 특징은 WDR5가 노출된 표면이 많아 다른 단백질과 상호 작용하는데 유용한 어뎁터로서 작용할 수 있다 (Raymond, C. T. et al., 2009). WDR5는 WRAD 복합체의 필수적인 부분일 뿐만 아니라 Myc 종양 단백질 계열 (c-, L-, N- Myc)에 직접 결합하며 WDR5의 WBM site와 Myc 아미노 말단 부위의 Myc-box IIIb에서 결합한다고 알려져 있다 (Thomas, L. R. et al., 2020). WDR5와 상호 작용하는 다양한 단백질은 생식, 발달, 면역, 신경 및 체액 조절과 같은 다양한 생물학적 역할을 한다.WDR5 is related to the initiation, development, and maintenance of disease, and is overexpressed in various carcinomas such as leukemia, hepatocellular carcinoma, and breast cancer, and is associated with poor prognosis in clinical practice. WD40 iterations form a propeller fold with seven blades and each blade is composed of four anti-parallel sheets. This structural feature can act as a useful adapter for interacting with other proteins because WDR5 has many exposed surfaces (Raymond, CT et al ., 2009). It is known that WDR5 is not only an essential part of the WRAD complex, but also binds directly to the Myc oncoprotein family (c-, L-, N-Myc) and binds to the WBM site of WDR5 and Myc-box IIIb at the amino terminal site of Myc (Thomas , L R et al ., 2020). The various proteins that interact with WDR5 play a variety of biological roles, such as reproduction, development, immunity, neural and humoral regulation.

Myc은 세포의 증식과 사멸에 관여하는 대표적인 원발암 유전자 중 하나로 암 발생과 성장에 영향을 미치는 필수 전사 인자이며, 혈액암, 폐암, 유방암, 간암, 대장암, 췌장암 등 다양한 악성 종양에서 발현이 증가되어 있다고 알려져 있다 (Hessmann, E. et al., 2016). Myc과 WDR5 상호작용은 리보솜 (ribosome) 및 단백질 생산을 위한 구성요소의 Myc-매개 유도에 필요로 하고, 종양 형성을 유도하는데 광범위하게 연관되어 있다. Myc의 부분적인 유전적 억제는 폐 선암종과 같은 여러 종양 모델에서 종양 퇴행 및 생존 기간을 연장한다고 알려져 있음에도 불구하고 (Soucek, L. et al., 2013), Myc을 저해하는 물질의 개발은 기술적인 어려움으로 인해 상용화된 임상 억제제는 없다.Myc is one of the representative proto-oncogenes involved in cell proliferation and apoptosis, and is an essential transcription factor that affects cancer development and growth. It is known to be (Hessmann, E. et al ., 2016). Myc and WDR5 interactions are required for Myc-mediated induction of components for ribosome and protein production, and have been implicated extensively in inducing tumorigenesis. Although partial genetic inhibition of Myc is known to prolong tumor regression and survival in several tumor models such as lung adenocarcinoma (Soucek, L. et al ., 2013), the development of substances that inhibit Myc is technically challenging. Due to difficulties, there are no commercially available clinical inhibitors.

따라서, 저분자를 이용하여 MLL1-WDR5의 단백질-단백질 상호 작용을 방해하는 방법은 MLL 효소 활성을 억제하고 Hox 유전자 발현을 하향 조절하여 병의 진행을 차단하는데 효과적일 뿐만 아니라, 이를 통해 Myc을 저해함으로써 Myc 유발 종양을 치료하는데 좋은 치료제가 될 수 있다.Therefore, the method of disrupting the protein-protein interaction of MLL1-WDR5 using small molecules is not only effective in inhibiting MLL enzymatic activity and down-regulating Hox gene expression to block disease progression, but also by inhibiting Myc. It can be a good therapeutic agent for treating Myc-induced tumors.

Akihiko, Y.; Zhong, W.; Joanna, W.; Mrinmoy, S.; Deborah, J. A. Issay, K.; Winship, H.; Michael, L. C. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol. 2004 24(13), 5639-49.Akihiko, Y.; Zhong, W.; Joanna, W.; Mrinmoy, S.; Deborah, J. A. Issay, K.; Winship, H.; Michael, L. C. Leukemia proto-oncoprotein MLL forms a SET1-like histone methyltransferase complex with menin to regulate Hox gene expression. Mol Cell Biol. 2004 24(13), 5639-49. Argiropoulos, B.; Humphries, R. K. Hox genes in hematopoiesis and leukemogenesis. Oncogene 2007, 26, 6766-6776. Argiropoulos, B.; Humphries, R. K. Hox genes in hematopoiesis and leukemogenesis. Oncogene 2007, 26, 6766-6776. Ayton, P. M.; Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 2001, 20 (40), 5695-5707.Ayton, P. M.; Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. 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Inhibition of Myc Family Proteins eradicates KRas-driven Lung Cancer in Mice. Genes Dev. 2013, 27, 504- 513.Soucek, L.; Whitfield, J. R.; Sodir, N.M.; Masso-Valles, D.; Serrano, E.; Karnezis, A. N.; Swigart, L. B.; Evan, G. I. Inhibition of Myc Family Proteins eradicates KRas-driven Lung Cancer in Mice. Genes Dev. 2013, 27, 504-513. Thiel, A. T.; Blessington, P.; Zou, T.; Feather, D.; Wu, X.; Yan, J.; Zhang, H.; Liu, Z.; Ernst, P.; Koretzky, G. A.; Hua, X. MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 2010, 17(2), 148-159.Thiel, A. T.; Blessington, P.; Zou, T.; Feather, D.; Wu, X.; Yan, J.; Zhang, H.; Liu, Z.; Ernst, P.; Koretzky, G. A.; Hua, X. MLL-AF9-induced leukemogenesis requires coexpression of the wild-type Mll allele. Cancer Cell 2010, 17(2), 148-159. Thomas, A. M.; Mary, E. M.; Hugh, W. B.; Robert, K. S.; Jay, L. H. 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H.; Haiching, M. Assay Drug Dev Technol. 2013, 11(4), 227-36.Kurumi, Y. H.; Mia, M. E.; Joseph, J.F.; Jamie, L. P.; Colin, P. W.; Robert, F. S.;, Konrad, T. H.; Haiching, M. Assay Drug Dev Technol. 2013, 11(4), 227-36.

본 발명의 목적은 이중고리 저분자 화합물을 유효성분으로 함유하는 항암용 약학적 조성물 및 이의 제조방법을 제공하는 데 있다.An object of the present invention is to provide a pharmaceutical composition for anticancer containing a bicyclic low-molecular compound as an active ingredient and a method for preparing the same.

본 발명은 이중고리 저분자 화합물로 구성된 하기 화학식 1, 또는 이의 거울상 이성질체, 부분입체 이성질체, 입체 이성질체, 수화물, 용매화물, 프로드럭 또는 이의 약제학적으로 허용 가능한 염인 화합물에 관한 것이다.The present invention relates to a compound comprising a bicyclic low-molecular-weight compound of Formula 1 below, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

Figure pat00001
Figure pat00001

상기 식 중,In the above formula,

A는 -C(O)- 또는 -C(OH)-로 치환되며;A is substituted with -C(O)- or -C(OH)-;

R1은 치환 또는 비치환된 3~6각의 사이클로알킬, 치환 또는 비치환된 4~10각의 아릴, 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴로 이루어진 군에서 선택되는 치환기로 치환되고,R 1 is substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted 4-10 membered cycloalkyl It is substituted with a substituent selected from the group consisting of 10-membered heteroaryl,

여기서 상기 치환된 사이클로알킬, 아릴, 헤테로사이클로알킬, 또는 헤테로아릴은 독립적으로 수소, 할로겐, 아미노, 카르복실산, C1-C6 알콕시카보닐, -NH-tert-부톡시카보닐, -N(C1-C3 알킬)-tert-부톡시카보닐, 모노(또는 디)C1-C6 알킬아미노, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 할로 C1-C6 알콕시, (C1-C6 알콕시)카보닐(C1-C6 알콕시), -O[(CH2)1-4O]1-4CH3, -O[(CH2)1-4O]1-4CH2C(O)OH, -O[(CH2)1-4O]1-4CH2C(O)O(C1-C3 알킬), -O(CH2)1-4C(O)OH, -O(CH2)1-4C(O)O(C1-C3 알킬), C1-C3 알킬옥시카보닐, 치환 또는 비치환된 아제티딘, 치환 또는 비치환된 피페라진, 치환 또는 비치환된 피리딘, 또는 치환 또는 비치환된 피페리딘, 치환 또는 비치환된 피페리딘-2,5-디온으로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며,wherein said substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, amino, carboxylic acid, C 1 -C 6 alkoxycarbonyl, -NH-tert-butoxycarbonyl, -N (C 1 -C 3 alkyl)-tert-butoxycarbonyl, mono(or di)C 1 -C 6 alkylamino, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy , halo C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)carbonyl(C 1 -C 6 alkoxy), -O[(CH 2 ) 1-4 O] 1-4 CH 3 , -O[( CH 2 ) 1-4 O] 1-4 CH 2 C(O)OH, -O[(CH 2 ) 1-4 O] 1-4 CH 2 C(O)O(C 1 -C 3 alkyl), -O(CH 2 ) 1-4 C(O)OH, -O(CH 2 ) 1-4 C(O)O(C 1 -C 3 alkyl), C 1 -C 3 alkyloxycarbonyl, substituted or Selected from the group consisting of unsubstituted azetidine, substituted or unsubstituted piperazine, substituted or unsubstituted pyridine, or substituted or unsubstituted piperidine, or substituted or unsubstituted piperidine-2,5-dione It is substituted with one or more substituents that are,

여기서 상기 치환된 아제티딘, 피페라진, 피리딘, 피페리딘, 피페리딘-2,5-디온은 독립적으로 수소, 할로겐, 아미노, tert-부톡시카보닐, -NH-tert-부톡시카보닐, -N(C1-C3 알킬)-tert-부톡시카보닐, C1-C6 알킬 아미노, 벤질옥시로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;wherein the substituted azetidine, piperazine, pyridine, piperidine, piperidine-2,5-dione is independently hydrogen, halogen, amino, tert-butoxycarbonyl, -NH-tert-butoxycarbonyl , -N(C 1 -C 3 alkyl)-tert-butoxycarbonyl, C 1 -C 6 alkyl amino, substituted with one or more substituents selected from the group consisting of benzyloxy;

R2는 할로겐, 치환 또는 비치환된 3~6각의 사이클로알킬, 치환 또는 비치환된 4~10각의 아릴, 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴이고,R 2 is halogen, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted It is a 4-10-membered heteroaryl,

상기 치환된 사이클로알킬, 아릴, 헤테로사이클로알킬, 또는 헤테로아릴은 독립적으로 수소, 할로겐, C1-C6 알킬, 아세트아미도, 할로 C1-C6 알킬, C1-C6 알콕시, 할로 C1-C6 알콕시 또는 메톡시-(C1-C2 알콕시)1-5(C1-C2알킬)로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;The substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, C 1 -C 6 alkyl, acetamido, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C It is substituted with one or more substituents selected from the group consisting of 1 -C 6 alkoxy or methoxy-(C 1 -C 2 alkoxy) 1-5 (C 1 -C 2 alkyl);

R3는 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴이고,R 3 is a substituted or unsubstituted 3-6 membered heterocycloalkyl or a substituted or unsubstituted 4-10 membered heteroaryl;

상기 치환된 헤테로사이클로알킬 또는 헤테로아릴은 독립적으로 수소, 할로겐, =N-tert-부톡시카보닐, =NH, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시 또는 할로 C1-C6 알콕시로 치환되며;The substituted heterocycloalkyl or heteroaryl is independently hydrogen, halogen, =N-tert-butoxycarbonyl, =NH, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halo C 1 -C 6 alkoxy;

상기 화학식에서

Figure pat00002
는 단일결합 또는 이중결합을 의미한다.in the above formula
Figure pat00002
means a single bond or a double bond.

또한 본 발명은 이중고리 저분자 화합물로 구성된 하기 화학식 2, 또는 이의 거울상 이성질체, 부분입체 이성질체, 입체 이성질체, 수화물, 용매화물, 프로드럭 또는 이의 약제학적으로 허용 가능한 염인 화합물에 관한 것이다.In addition, the present invention relates to a compound comprising a bicyclic low-molecular-weight compound of Formula 2 below, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof.

[화학식 2][Formula 2]

Figure pat00003
Figure pat00003

상기 식 중,In the above formula,

A는 -C(O)- 또는 -C(OH)-로 치환되며;A is substituted with -C(O)- or -C(OH)-;

R1은 치환 또는 비치환된 3~6각의 사이클로알킬, 치환 또는 비치환된 4~10각의 아릴, 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴로 이루어진 군에서 선택되는 치환기로 치환되고,R 1 is substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted 4-10 membered cycloalkyl It is substituted with a substituent selected from the group consisting of 10-membered heteroaryl,

여기서 상기 치환된 사이클로알킬, 아릴, 헤테로사이클로알킬, 또는 헤테로아릴은 독립적으로 수소, 할로겐, 아미노, 카르복실산, C1-C6 알콕시카보닐, -NH-tert-부톡시카보닐, -N(C1-C3 알킬)-tert-부톡시카보닐, 모노(또는 디)C1-C6 알킬아미노, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 할로 C1-C6 알콕시, (C1-C6 알콕시)카보닐(C1-C6 알콕시), -O[(CH2)1-4O]1-4CH3, -O[(CH2)1-4O]1-4CH2C(O)OH, -O[(CH2)1-4O]1-4CH2C(O)O(C1-C3 알킬), -O(CH2)1-4C(O)OH, -O(CH2)1-4C(O)O(C1-C3 알킬), C1-C3 알킬옥시카보닐, 치환 또는 비치환된 아제티딘, 치환 또는 비치환된 피페라진, 치환 또는 비치환된 피리딘, 또는 치환 또는 비치환된 피페리딘, 치환 또는 비치환된 피페리딘-2,5-디온으로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며,wherein said substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, amino, carboxylic acid, C 1 -C 6 alkoxycarbonyl, -NH-tert-butoxycarbonyl, -N (C 1 -C 3 alkyl)-tert-butoxycarbonyl, mono(or di)C 1 -C 6 alkylamino, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy , halo C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)carbonyl(C 1 -C 6 alkoxy), -O[(CH 2 ) 1-4 O] 1-4 CH 3 , -O[( CH 2 ) 1-4 O] 1-4 CH 2 C(O)OH, -O[(CH 2 ) 1-4 O] 1-4 CH 2 C(O)O(C 1 -C 3 alkyl), -O(CH 2 ) 1-4 C(O)OH, -O(CH 2 ) 1-4 C(O)O(C 1 -C 3 alkyl), C 1 -C 3 alkyloxycarbonyl, substituted or Selected from the group consisting of unsubstituted azetidine, substituted or unsubstituted piperazine, substituted or unsubstituted pyridine, or substituted or unsubstituted piperidine, or substituted or unsubstituted piperidine-2,5-dione It is substituted with one or more substituents that are,

여기서 상기 치환된 아제티딘, 피페라진, 피리딘, 피페리딘, 피페리딘-2,5-디온은 독립적으로 수소, 할로겐, 아미노, tert-부톡시카보닐, -NH-tert-부톡시카보닐, -N(C1-C3 알킬)-tert-부톡시카보닐, C1-C6 알킬 아미노, 벤질옥시로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;wherein the substituted azetidine, piperazine, pyridine, piperidine, piperidine-2,5-dione is independently hydrogen, halogen, amino, tert-butoxycarbonyl, -NH-tert-butoxycarbonyl , -N(C 1 -C 3 alkyl)-tert-butoxycarbonyl, C 1 -C 6 alkyl amino, substituted with one or more substituents selected from the group consisting of benzyloxy;

R2는 할로겐, 치환 또는 비치환된 3~6각의 사이클로알킬, 치환 또는 비치환된 4~10각의 아릴, 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴이고,R 2 is halogen, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted It is a 4-10-membered heteroaryl,

상기 치환된 사이클로알킬, 아릴, 헤테로사이클로알킬, 또는 헤테로아릴은 독립적으로 수소, 할로겐, C1-C6 알킬, 아세트아미도, 할로 C1-C6 알킬, C1-C6 알콕시, 할로 C1-C6 알콕시 또는 메톡시-(C1-C2 알콕시)1-5(C1-C2알킬)로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;The substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, C 1 -C 6 alkyl, acetamido, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C It is substituted with one or more substituents selected from the group consisting of 1 -C 6 alkoxy or methoxy-(C 1 -C 2 alkoxy) 1-5 (C 1 -C 2 alkyl);

R3는 하기 화학식 2-1, 화학식 2-2, 또는 화학식 2-3으로 치환되며.R 3 is substituted with Formula 2-1, Formula 2-2, or Formula 2-3.

[화학식 2-1][Formula 2-1]

Figure pat00004
Figure pat00004

[화학식 2-2][Formula 2-2]

Figure pat00005
Figure pat00005

[화학식 2-3][Formula 2-3]

Figure pat00006
Figure pat00006

상기 화학시 2-1 내지 화학식 2-3의 식 중에서,In the formulas of Chemical Formulas 2-1 to 2-3,

R4는 수소, tert-부톡시카보닐, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시로 치환되며,R 4 is substituted with hydrogen, tert-butoxycarbonyl, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy;

R5는 수소, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시로 치환; 된다. R 5 is substituted with hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy; do.

또한 본 발명은 크로만-4-온 유도체로 화학식 2의 화합물에서 R2가 하기 화학식 3-1, 화학식 3-2로 치환된 화합물, 이의 거울상 이성질체, 부분입체 이성질체, 입체 이성질체, 수화물, 용매화물, 프로드럭 또는 이의 약제학적으로 허용 가능한 염인 화합물에 관한 것이다.In addition, the present invention is a chroman-4-one derivative, wherein R 2 in the compound of Formula 2 is substituted with Formula 3-1 or Formula 3-2, an enantiomer, a diastereomer, a stereoisomer, a hydrate, or a solvate thereof. , a prodrug or a pharmaceutically acceptable salt thereof.

R2는 하기 화학식 3-1 또는 화학식 3-2로 치환되며.R 2 is substituted with Formula 3-1 or Formula 3-2.

[화학식 3-1][Formula 3-1]

Figure pat00007
Figure pat00007

[화학식 3-2][Formula 3-2]

Figure pat00008
Figure pat00008

상기 화학시 3-1 또는 화학식 3-2의 식 중에서,In the formula of 3-1 or Formula 3-2,

R6는 수소, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시로 치환되며,R 6 is substituted with hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy;

R7는 수소, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시 또는 메틸-(C1-C2 알콕시)1-5로 치환되며,R 7 is hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy or methyl-(C 1 -C 2 alkoxy) 1-5 is replaced,

R8은 독립적으로 수소, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시, 또는 아세트아미도로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;R 8 is independently one or more selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy, or acetamido. substituted with a substituent;

X는 N, CH, 또는 C 이며,X is N, CH, or C;

m은 0 내지 2의 정수;이다m is an integer from 0 to 2;

본 발명의 크로만-4-온 유도체 화합물은 아래 Scheme 1 내지 22와 같은 방법으로 제조하였다.The chroman-4-one derivative compound of the present invention was prepared by the same method as Scheme 1 to 22 below.

[Scheme 1][Scheme 1]

Figure pat00009
Figure pat00009

출발물질인 8-브로모-6-메틸크로만-4-온 화합물에 상응하는 벤즈알데히드를 파라-톨루엔설폰산 촉매하에서 반응하여 벤질리덴 화합물을 합성하였고, 루테늄 촉매로 비대칭 수소화반응을 통하여 비대칭적인 알코올 화합물을 합성하였다. 이후 산화반응과 브롬화 반응을 통해 중간체 화합물을 합성하였고, 이후 상응하는 아민과의 알킬화반응, 상응하는 붕소산 화합물과 스즈키 커플링을 통하여 생성물 (화합물 1 내지 22)을 수득하였다.Benzaldehyde corresponding to the starting material 8-bromo-6-methylchroman-4-one compound was reacted under a para-toluenesulfonic acid catalyst to synthesize a benzylidene compound, and an asymmetric alcohol through an asymmetric hydrogenation reaction with a ruthenium catalyst. compound was synthesized. Subsequently, an intermediate compound was synthesized through an oxidation reaction and a bromination reaction, and then products (Compounds 1 to 22) were obtained through an alkylation reaction with a corresponding amine and a Suzuki coupling with a corresponding boronic acid compound.

[Scheme 2][Scheme 2]

Figure pat00010
Figure pat00010

출발물질인 8-브로모-6-메틸크로만-4-온 화합물에 터트-뷰틸 (4-포밀사이크로헥실)카바메이트를 피롤리딘 염기하에서 반응하여 벤질리덴 화합물을 합성하였고, 루테늄 촉매로 비대칭 수소화반응을 통하여 비대칭적인 케톤화합물을 합성하였다. 이어서 브롬화 반응을 통해 중간체 화합물을 합성하였고, 이후 상응하는 아민과의 알킬화반응, 상응하는 붕소산 화합물과 스즈키 커플링을 통하여 생성물 (화합물 23 내지 29)을 수득하였다.A benzylidene compound was synthesized by reacting tert-butyl (4-formylcyclohexyl) carbamate with 8-bromo-6-methylchroman-4-one compound as a starting material in the presence of a pyrrolidine base. An asymmetric ketone compound was synthesized through an asymmetric hydrogenation reaction. Intermediate compounds were then synthesized through bromination, and then products (Compounds 23 to 29) were obtained through alkylation with the corresponding amine and Suzuki coupling with the corresponding boronic acid compound.

[Scheme 3][Scheme 3]

Figure pat00011
Figure pat00011

출발물질인 8-브로모-6-메틸크로만-4-온 화합물에 (4-플로로페닐)붕소 산을 스즈키 커플링과 축합반응을 통해서 벤질리덴 화합물 합성후 팔라듐 촉매하에서 수소 치환하여 환원하고, 루테늄 촉매로 비대칭 수소화 반응을 통하여 비대칭적인 알코올 화합물을 합성하였다. 이후 산화반응과 브롬화 반응을 통해 중간체 화합물을 합성하였고, 이후 상응하는 아민과의 알킬화반응을 통해 생성물(화합물 30 내지 31)을 수득하였다.After synthesizing a benzylidene compound through Suzuki coupling and condensation reaction of (4-fluorophenyl)boronic acid with 8-bromo-6-methylchroman-4-one compound as a starting material, it is reduced by hydrogen substitution under a palladium catalyst. , synthesized an asymmetric alcohol compound through an asymmetric hydrogenation reaction with a ruthenium catalyst. Thereafter, an intermediate compound was synthesized through an oxidation reaction and a bromination reaction, and then products (Compounds 30 to 31) were obtained through an alkylation reaction with a corresponding amine.

[Scheme 4][Scheme 4]

Figure pat00012
Figure pat00012

출발물질인 8-브로모-6-메틸크로만-4-온 화합물에 브롬화 반응과 축합반응을 통해서 벤질리덴 화합물 합성 후 수소치환하여 환원하고, 이미다졸 아민과의 알킬화반응을 통한 생성물을 상응하는 붕소산과 스즈키 커플링하여 화합물 (32 내지 34)을 수득하였다.After synthesizing a benzylidene compound through bromination and condensation of 8-bromo-6-methylchroman-4-one compound as a starting material, reduction by hydrogen substitution, and alkylation with imidazole amine, the product is obtained as the corresponding product. Suzuki coupling with boronic acid gave compounds (32 to 34).

[Scheme 5][Scheme 5]

Figure pat00013
Figure pat00013

출발물질인 8-브로모-6-메틸크로만-4-온 화합물에 (4-플로로페닐)붕소 산을 팔라듐 촉매하에서 스즈키 커플링과 브롬화 반응을 통해서 중간체 화합물 합성후 이미다졸 아민과의 알킬화반응으로 중간체를 합성하였다. 이후 Boc으로 이민을 보호하고 벤즈알데히드와 축합반응을 통해 중간체 화합물을 합성하였고, 이후 탈보호 반응을 통해 생성물 (화합물 35)을 수득하였다.Synthesis of an intermediate compound through bromination and Suzuki coupling of (4-fluorophenyl)boronic acid to 8-bromo-6-methylchroman-4-one compound as a starting material under a palladium catalyst, followed by alkylation with imidazole amine An intermediate was synthesized by the reaction. Thereafter, the imine was protected with Boc, and an intermediate compound was synthesized through a condensation reaction with benzaldehyde, and then a product (Compound 35) was obtained through a deprotection reaction.

[Scheme 6][Scheme 6]

Figure pat00014
Figure pat00014

출발물질인 8-브로모-6-메틸크로만-4-온 화합물에 (4-플로로페닐)붕소 산을 팔라듐 촉매하에서 스즈키 커플링과 브롬화 반응을 통해서 중간체 화합물 합성후 벤즈알데히드와 축합반응, 수소화 반응을 진행하고, 다음으로 이미다졸 아민과의 알킬화반응을 통해 생성물 (화합물 36)을 수득하였다.8-bromo-6-methylchroman-4-one compound as a starting material, (4-fluorophenyl) boric acid was synthesized through Suzuki coupling and bromination reaction under a palladium catalyst, followed by condensation reaction with benzaldehyde and hydrogenation The reaction proceeded, and then a product (Compound 36) was obtained through an alkylation reaction with imidazole amine.

[Scheme 7][Scheme 7]

Figure pat00015
Figure pat00015

출발물질인 8-브로모-6-메틸크로만-4-온 화합물에 (4-플로로페닐)붕소 산을 팔라듐 촉매하에서 스즈키 커플링과 벤즈알데히드와 축합반응, 이후 수소 치환하여 환원하고, 루테늄 촉매로 비대칭 수소화 반응을 통하여 비대칭적인 알코올 화합물을 합성하였다. 이후 산화반응과 브롬화 반응을 통해서 중간체 화합물 합성 후 이미다졸 아민과의 알킬화반응을 통해 생성물 (화합물 37)을 수득하였다.The starting material, 8-bromo-6-methylchroman-4-one compound, (4-fluorophenyl)boronic acid was subjected to a condensation reaction with Suzuki coupling and benzaldehyde under a palladium catalyst, followed by hydrogen substitution and reduction, followed by a ruthenium catalyst. An asymmetric alcohol compound was synthesized through an asymmetric hydrogenation reaction. Subsequently, an intermediate compound was synthesized through an oxidation reaction and a bromination reaction, and then a product (Compound 37) was obtained through an alkylation reaction with imidazole amine.

[Scheme 8][Scheme 8]

Figure pat00016
Figure pat00016

출발물질인 4-클로로-3-히드록시벤즈알데히드에 메틸브로모아세테이트를 염기 하에서 치환하고, 상응하는 크로마논과 축합반응과 환원반응을 진행하여 중간체를 합성하였다. 이후 이미다졸 아민과의 알킬화반응을 통해 38번 화합물을 합성하였고, 이후 이민의 보호반응과 상응하는 붕소산과의 스즈키반응, 그리고 에스터의 가수분해 반응을 통해 생성물 (화합물 39 내지 43)을 수득 하였다.The starting material, 4-chloro-3-hydroxybenzaldehyde, was substituted with methyl bromoacetate in the presence of a base, and a condensation reaction and a reduction reaction were conducted with the corresponding chromanone to synthesize an intermediate. Thereafter, compound 38 was synthesized through an alkylation reaction with imidazole amine, and then products (compounds 39 to 43) were obtained through a protection reaction of imine, a Suzuki reaction with the corresponding boronic acid, and a hydrolysis reaction of esters.

[Scheme 9][Scheme 9]

Figure pat00017
Figure pat00017

출발물질인 트리에틸렌글리콜을 벤질로 선택적인 보호반응 후 메틸 브로모아세테이트와 알킬화 반응, 수소 환원반응 후 토실기를 치환하여, 상응하는 벤즈알데히드와 치환반응을 통해 중간체를 합성하였다. 상응하는 크로마논과 산 조건하에서 축합반응과 수소 환원 반응 이후 이미다졸아민과의 알킬화 반응을 진행하였다. 이후 이민을 boc으로 보호하고, 상응하는 붕소산과의 스즈키반응과 염기조건 하에서 가수분해 반응을 통해 원하는 생성물 (화합물 44 내지 45)을 수득 하였다.After a selective protection reaction of triethylene glycol as a starting material with benzyl, an alkylation reaction with methyl bromoacetate, a hydrogen reduction reaction, and then substitution of the tosyl group, an intermediate was synthesized through a substitution reaction with the corresponding benzaldehyde. After the condensation reaction and hydrogen reduction reaction under the corresponding chromanone and acid conditions, an alkylation reaction with imidazolamine was performed. Thereafter, the imine was protected with boc, and the desired products (Compounds 44 to 45) were obtained through a Suzuki reaction with the corresponding boronic acid and a hydrolysis reaction under basic conditions.

[Scheme 10][Scheme 10]

Figure pat00018
Figure pat00018

출발물질인 4-클로로-3-히드록시벤즈알데히드에 에틸브로모발러레이트를 염기하에서 치환하고, 상응하는 크로마논과 축합반응과 환원반응을 진행하여 중간체를 합성하였다. 상응하는 이미다졸 아민과의 알킬화반응을 통해 중간체를 합성하였고, 이후 이민의 보호반응과 상응하는 붕소산과의 스즈키반응 및 에스터의 가수분해 반응을 통해 생성물 (화합물 46 내지 51)을 수득 하였다. The starting material, 4-chloro-3-hydroxybenzaldehyde, was substituted with ethyl bromovalerate in the presence of a base, and a condensation reaction and a reduction reaction were conducted with the corresponding chromanone to synthesize an intermediate. An intermediate was synthesized through an alkylation reaction with the corresponding imidazole amine, followed by a protection reaction of imine, a Suzuki reaction with the corresponding boronic acid, and a hydrolysis reaction of esters to obtain products (Compounds 46 to 51).

[Scheme 11][Scheme 11]

Figure pat00019
Figure pat00019

출발물질인 4-플루오로-3-히드록시벤즈알데히드에 메틸브로모아세테이트를 염기하에서 치환하고, 상응하는 크로마논과 산 조건하에서 축합반응을 진행하여 중간체를 합성하였다. 루테늄 촉매로 비대칭 수소화 반응을 통하여 비대칭적인 알코올 화합물을 합성하였다. 이후 산화반응과 브롬화 반응을 통해 중간체 화합물을 합성하였고, 이후 상응하는 아민과의 알킬화반응을 진행 후 이민의 보호반응과 상응하는 붕소산과의 스즈키반응, 그리고 에스터의 가수분해 반응을 통해 생성물 52를 수득 하였다.The starting material, 4-fluoro-3-hydroxybenzaldehyde, was substituted with methyl bromoacetate under a base, and a condensation reaction was conducted with the corresponding chromanone under an acidic condition to synthesize an intermediate. An asymmetric alcohol compound was synthesized through an asymmetric hydrogenation reaction using a ruthenium catalyst. Then, an intermediate compound was synthesized through an oxidation reaction and a bromination reaction, followed by an alkylation reaction with the corresponding amine, followed by a protection reaction of imine, a Suzuki reaction with the corresponding boronic acid, and a hydrolysis reaction of ester to obtain product 52. did

[Scheme 12][Scheme 12]

Figure pat00020
Figure pat00020

먼저 합성된 벤질리덴 중간체를 출발물질로 하여 상응하는 붕소산과 스즈키반응 및 루테늄 촉매 비대칭 수소화 반응을 통해 생성물 53번을 수득 하였고, 합성된 중간체 메틸 2-(2-플루오로-5-포밀페녹시)아세테이트에 상응하는 크로마논과 축합반응 후 상응하는 붕소산과의 스즈키반응을 통해 생성물 54를 수득하였다.Using the benzylidene intermediate synthesized first as a starting material, product No. 53 was obtained through a Suzuki reaction with the corresponding boronic acid and a ruthenium-catalyzed asymmetric hydrogenation reaction, and the synthesized intermediate methyl 2-(2-fluoro-5-formylphenoxy) After a condensation reaction with chromanone corresponding to acetate, product 54 was obtained through Suzuki reaction with corresponding boronic acid.

[Scheme 13][Scheme 13]

Figure pat00021
Figure pat00021

출발물질인 메틸 2-플루오로-5-포밀벤조에이트와 상응하는 크로마논을 산 조건하에서 축합반응을 진행하여 중간체를 합성하였다. 루테늄 촉매로 비대칭 수소화 반응을 통하여 비대칭적인 알코올 화합물을 합성한 후 산화반응과 브롬화 반응을 통해 중간체 화합물을 합성하였고, 이후 상응하는 아민과의 알킬화반응을 진행 후 이민의 보호반응과 상응하는 붕소산과의 스즈키반응, 그리고 에스터의 가수분해 반응을 통해 생성물 (화합물 55 내지 58)을 수득 하였다.An intermediate was synthesized by condensation reaction between methyl 2-fluoro-5-formylbenzoate as a starting material and the corresponding chromanone under acidic conditions. An asymmetric alcohol compound was synthesized through an asymmetric hydrogenation reaction with a ruthenium catalyst, and then an intermediate compound was synthesized through an oxidation reaction and a bromination reaction. Products (Compounds 55 to 58) were obtained through Suzuki reaction and ester hydrolysis.

[Scheme 14][Scheme 14]

Figure pat00022
Figure pat00022

출발물질인 8-브로모-6-메틸크로만-4-온에 브롬화 반응 후 상응하는 아민과의 알킬화반응을 진행하고 이민의 보호반응과 상응하는 붕소산과의 스즈키반응을 통해 화합물 59를 수득하였다. 상응하는 벤즈알데히드와 염기조건 하에서 축합반응을 통해 벤질리덴 화합물을 합성하였고, 이후 루테늄 촉매 비대칭 수소화 반응과 산화반응 및 가수분해 반응을 통해 생성물 (화합물 60 내지 63)을 수득하였다.After bromination of the starting material 8-bromo-6-methylchroman-4-one, an alkylation reaction with the corresponding amine was carried out, and compound 59 was obtained through the protection reaction of imine and the Suzuki reaction with the corresponding boronic acid. . A benzylidene compound was synthesized through a condensation reaction with corresponding benzaldehyde under basic conditions, and then products (Compounds 60 to 63) were obtained through a ruthenium-catalyzed asymmetric hydrogenation reaction, oxidation reaction, and hydrolysis reaction.

[Scheme 15][Scheme 15]

Figure pat00023
Figure pat00023

출발물질 8-브로모-6-(브로모메틸)크로만-4-온 및 상응하는 이미다졸의 치환반응 이후 상응하는 붕소산과 스즈키 커플링을 통해 중간체를 합성하였다. 메틸 2-클로로-6-메틸피리미딘-4-카복실레이트에 상응하는 아제티딘과 알킬화반응후 환원반응을 통해 중간체를 합성하고 준비된 크로마논과 축합반응을 통해 생성물 64를 수득하였다.Intermediates were synthesized through a substitution reaction between the starting material 8-bromo-6-(bromomethyl)chroman-4-one and the corresponding imidazole, followed by Suzuki coupling with the corresponding boronic acid. After an alkylation reaction with azetidine corresponding to methyl 2-chloro-6-methylpyrimidine-4-carboxylate, an intermediate was synthesized through a reduction reaction, and a product 64 was obtained through a condensation reaction with prepared chromanone.

[Scheme 16][Scheme 16]

Figure pat00024
Figure pat00024

Figure pat00025
Figure pat00025

출발물질인 메틸 6-클로로-4-메틸피콜리네이트에 상응하는 아제티딘과 알킬화 반응 후 환원, 산화 반응을 통해 중간체를 합성하였다. 상응하는 크로마논과 축합반응과 루테늄 촉매 비대칭 수소화 반응과 산화 반응, 이후 산 조건하에서 탈 보호 반응을 통해 생성물을 (화합물 65 내지 72) 수득하였다.An intermediate was synthesized through an alkylation reaction with azetidine corresponding to the starting material, methyl 6-chloro-4-methylpicolinate, followed by a reduction and oxidation reaction. Products (Compounds 65 to 72) were obtained through a condensation reaction with the corresponding chromanone, a ruthenium-catalyzed asymmetric hydrogenation reaction and an oxidation reaction, followed by a deprotection reaction under an acidic condition.

[Scheme 17][Scheme 17]

Figure pat00026
Figure pat00026

출발물질인 4-메톡시피콜린알데히드에 상응하는 크로마논과 축합반응및 루테늄 촉매 비대칭 수소화 반응 그리고 산화반응을 통해 화합물 73을 수득하였다.Compound 73 was obtained through a condensation reaction with chromanone corresponding to 4-methoxypicolinaldehyde as a starting material, a ruthenium-catalyzed asymmetric hydrogenation reaction, and an oxidation reaction.

[Scheme 18][Scheme 18]

Figure pat00027
Figure pat00027

출발물질인 메틸 2-클로로-6-메틸피리미딘-4-카복실레이트에 상응하는 피페라진과 알킬화반응 후 환원, 산화 반응을 통해 중간체를 합성하였다. 이후 상응하는 크로마논과 축합반응및 루테늄 촉매 비대칭 수소화 반응과 산화 반응, 이후 산조건 하에서 탈 보호 반응을 통해 생성물 (화합물 74 내지 79)을 수득 하였다.An intermediate was synthesized through an alkylation reaction with piperazine corresponding to the starting material, methyl 2-chloro-6-methylpyrimidine-4-carboxylate, followed by reduction and oxidation reactions. Thereafter, products (Compounds 74 to 79) were obtained through a condensation reaction with the corresponding chromanone, a ruthenium-catalyzed asymmetric hydrogenation reaction and an oxidation reaction, and then a deprotection reaction under an acidic condition.

[Scheme 19][Scheme 19]

Figure pat00028
Figure pat00028

출발물질인 8-브로모-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온에 상응하는 붕소산과의 스즈키반응을 통하여 화합물 80을 수득한 후 상응하는 벤즈알데히드와 축합 반응과 루테늄 촉매 비대칭 수소화 반응을 진행하였다. 산화 반응 및 산조건 하에서 탈 보호 반응을 통해 생성물을(화합물 82) 수득 하였다. 6-클로로-4-메틸피콜리닉에시드와 히드록실아민과의 커플링을 통해 생성된 웨인렙아미드를 환원한후 상응하는 크로마논의 축합반응을 통하여 중간체를 합성하고 루테늄 촉매 비대칭 수소화 반응과 산화 반응을 통해 화합물 81을 수득하였다. Compound 80 was obtained through Suzuki reaction with boronic acid corresponding to the starting material 8-bromo-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one, and then the corresponding A condensation reaction with benzaldehyde and a ruthenium-catalyzed asymmetric hydrogenation reaction were performed. A product (Compound 82) was obtained through an oxidation reaction and a deprotection reaction under acidic conditions. Weinrebamide produced through coupling of 6-chloro-4-methylpicolinic acid with hydroxylamine is reduced, and then intermediates are synthesized through the corresponding chromanone condensation reaction, and ruthenium-catalyzed asymmetric hydrogenation and oxidation reactions Through this, compound 81 was obtained.

[Scheme 20][Scheme 20]

Figure pat00029
Figure pat00029

출발물질인 메틸 6-클로로-4-메틸피콜리네이트를 상응하는 아민과 팔라듐촉매 커플링 반응 후 산화 및 환원반응을 통해 중간체를 합성하였다. 이후 상응하는 크로마논과 축합반응, 루테늄 촉매 비대칭 수소화 반응및 산화 반응을 통해 케톤화합물을 합성한 후 산조건하에서 탈보호반응과 상응하는 할로겐과 알킬화 반응을 통해 생성물 (화합물 83 내지 85)을 수득 하였다.Intermediates were synthesized through oxidation and reduction reactions after a palladium-catalyzed coupling reaction of methyl 6-chloro-4-methyl picolinate as a starting material with the corresponding amine. Thereafter, a ketone compound was synthesized through a condensation reaction with the corresponding chromanone, a ruthenium-catalyzed asymmetric hydrogenation reaction, and an oxidation reaction, and then products (Compounds 83 to 85) were obtained through a deprotection reaction and an alkylation reaction with the corresponding halogen under an acidic condition.

[Scheme 21][Scheme 21]

Figure pat00030
Figure pat00030

출발물질인 8-브로모-6-메틸크로만-4-온을 상응하는 붕소산과 스즈키반응 후에 브롬화 반응 및 상응하는 아민과의 알킬화반응을 진행하고 이민의 보호반응을 통해 화합물 86을 수득하였다. 이후 상응하는 벤즈알데히드와 염기조건 하에서 축합반응을 통해 벤질리덴 화합물을 합성하였고, 이후 탈보호 반응 및 수소치환 반응을 통해 생성물 (화합물 86 내지 90)을 수득하였다.The starting material, 8-bromo-6-methylchroman-4-one, was subjected to Suzuki reaction with the corresponding boronic acid, followed by bromination and alkylation with the corresponding amine, and compound 86 was obtained through imine protection. Thereafter, a benzylidene compound was synthesized through a condensation reaction with corresponding benzaldehyde under basic conditions, and then products (Compounds 86 to 90) were obtained through a deprotection reaction and a hydrogen substitution reaction.

[Scheme 22][Scheme 22]

Figure pat00031
Figure pat00031

Figure pat00032
Figure pat00032

출발물질인 (6-브로모-5-플루오로피리딘-2-일)메탄올을 상응하는 아민과 팔라듐 촉매 커플링 반응을 진행한 후 산화 반응을 통하여 중간체를 합성하였다. 상응하는 크로마논과 축합반응 및 탈보호 반응을 통해 생성물을 수득하였다. 생성물 93을 루테늄 촉매 비대칭 수소화 반응과 산화 반응및 탈 보호 반응을 통해 생성물 (화합물 91 내지 100)을 수득하였다.The starting material, (6-bromo-5-fluoropyridin-2-yl)methanol, was subjected to a palladium-catalyzed coupling reaction with the corresponding amine, and then an intermediate was synthesized through an oxidation reaction. A product was obtained through a condensation reaction and a deprotection reaction with the corresponding chromanone. Product 93 was obtained through ruthenium-catalyzed asymmetric hydrogenation, oxidation, and deprotection to obtain products (Compounds 91 to 100).

또한, 본 발명에서 상기 화학식 1로 표시되는 화합물은 하기 화합물 군으로부터 선택되는 어느 하나인 것을 특징으로 하는 화합물 또는 이의 거울상 이성질체, 부분입체 이성질체 또는 입체 이성질체, 수화물, 용매화물, 프로드럭 또는 이의 약제학적으로 허용 가능한 염에 관한 것이다.In addition, in the present invention, the compound represented by Formula 1 is a compound characterized in that it is any one selected from the group of compounds or its enantiomer, diastereomer or stereoisomer, hydrate, solvate, prodrug or pharmaceutical thereof. It relates to acceptable salts.

(S)-3-(3,4-디클로로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 1);(S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino- 3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 1);

(S)-3-(3,4-디클로로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 2);(S)-3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3- dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 2);

(S)-N-(4-(3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-8-일)피리딘-2-일)아세트아미드(화합물 3);(S)-N-(4-(3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide (Compound 3);

(S)-8-(3,5-비스(트리플루오로메틸)페닐)-3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 4);(S)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-di hydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 4);

(S)-3-(3,4-디클로로벤질)-8-(3,4-디메톡시페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 5);(S)-3-(3,4-dichlorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imi dazol-1-yl)methyl)chroman-4-one (Compound 5);

(S)-3-(3,4-디클로로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노옥사졸-3(2H)-일)메틸)크로만-4-온(화합물 6);(S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-iminooxazole -3(2H)-yl)methyl)chroman-4-one (Compound 6);

(R)-3-(3,4-디클로로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 7);(R)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino- 3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 7);

(R)-3-(3,4-디클로로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 8);(R)-3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3- dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 8);

(R)-N-(4-(3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-8-일)피리딘-2-일)아세트아미드(화합물 9);(R)-N-(4-(3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide (Compound 9);

(R)-8-(3,5-비스(트리플루오로메틸)페닐)-3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 10);(R)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-di hydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 10);

(R)-3-(3,4-디클로로벤질)-8-(3,4-디메톡시페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 11);(R)-3-(3,4-dichlorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imine dazol-1-yl)methyl)chroman-4-one (Compound 11);

(R)-3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-8-(1-(2-(2-(2-메톡시에톡시)에톡시)에틸)-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온(화합물 12);(R)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-( 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one (Compound 12) ;

(S)-3-(2-클로로-4-플루오로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 13);(S)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2- imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 13);

(S)-3-(2-클로로-4-플루오로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 14);(S)-3-(2-chloro-4-fluorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2 ,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 14);

(S)-N-(4-(3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-8-일)피리딘-2-일)아세트아미드(화합물 15);(S)-N-(4-(3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide (Compound 15);

(S)-8-(3,5-비스(트리플루오로메틸)페닐)-3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 16);(S)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2, 3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 16);

(S)-3-(2-클로로-4-플루오로벤질)-8-(3,4-디메톡시페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 17);(S)-3-(2-chloro-4-fluorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)chroman-4-one (Compound 17);

(R)-3-(2-클로로-4-플루오로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 18);(R)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2- imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 18);

(R)-3-(2-클로로-4-플루오로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 19);(R)-3-(2-chloro-4-fluorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2 ,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 19);

(R)-N-(4-(3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-8-일)피리딘-2-일)아세트아미드(화합물 20);(R)-N-(4-(3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide (Compound 20);

(R)-8-(3,5-비스(트리플루오로메틸)페닐)-3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 21);(R)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2, 3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 21);

(R)-3-(2-클로로-4-플루오로벤질)-8-(3,4-디메톡시페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 22);(R)-3-(2-chloro-4-fluorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)chroman-4-one (Compound 22);

tert-부틸 (S)-(4-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트(화합물 23);tert-Butyl (S)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (Compound 23);

(S)-3-((4-아미노사이클로헥실)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 24);(S)-3-((4-aminocyclohexyl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imid no-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 24);

tert-부틸 (S)-(4-((8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트(화합물 25);tert-Butyl (S)-(4-((8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (Compound 25);

(S)-3-((4-아미노사이클로헥실)메틸)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 26);(S)-3-((4-aminocyclohexyl)methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2, 3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 26);

tert-부틸 (R)-(4-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트(화합물 27);tert-Butyl (R)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (Compound 27);

(R)-3-((4-아미노사이클로헥실)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 28);(R)-3-((4-aminocyclohexyl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imid no-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 28);

tert-부틸 (R)-(4-((8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트(화합물 29);tert-Butyl (R)-(4-((8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (Compound 29);

(R)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 30);(R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole- 1-yl)methyl)chroman-4-one (Compound 30);

(S)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 31);(S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole- 1-yl)methyl)chroman-4-one (Compound 31);

3-(3,4-디클로로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 32);3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl- 2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 32);

3-(3,4-디클로로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 33);3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H -imidazol-1-yl)methyl)chroman-4-one (Compound 33);

3-(3-(2-((2-(2-(l1-옥시다네일)에톡시)에틸)(메틸)-l3-옥시다네일)에톡시)-4-플루오로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 34);3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8- (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)chroman-4-one (Compound 34);

2,2,2-트리플루오로아세트알데히드-(E)-3-(3,5-디메톡시벤질리덴)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 35);2,2,2-trifluoroacetaldehyde-(E)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-6-((2-imino-3- methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 35);

3-(3,5-디메톡시벤질)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 36);3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)chroman-4-one (Compound 36);

(S)-3-(2,6-디브로모-3,5-디메톡시벤질)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 37);(S)-3-(2,6-dibromo-3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3 -dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 37);

메틸 2-(5-((8-브로모-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트(화합물 38);Methyl 2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman -3-yl)methyl)-2-chlorophenoxy)acetate (Compound 38);

메틸 (Z)-2-(5-((8-브로모-6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트(화합물 39);Methyl (Z)-2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imi dazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate (Compound 39);

메틸 (E)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트(화합물 40);Methyl (E)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate (Compound 40);

(E)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세틱 애시드(화합물 41);(E)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetic Acid (Compound 41);

메틸 2-(2-클로로-5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)페녹시)아세테이트(화합물 42);Methyl 2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)acetate (Compound No. 42);

2-(2-클로로-5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)페녹시)아세틱 애시드(화합물 43);2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl- 2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)acetic acid (Compound 43);

메틸 (Z)-2-(2-(2-(2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)에톡시)에톡시)에톡시)아세테이트(화합물 44);Methyl (Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro -1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl )-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate (Compound 44);

(Z)-2-(2-(2-(2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)에톡시)에톡시)에톡시)아세틱 애시드(화합물 45);(Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl) -2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetic acid (Compound 45);

에틸 5-(2-클로로-5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)페녹시)펜타노에이트(화합물 46);Ethyl 5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoate (Compound No. 46);

5-(2-클로로-5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)페녹시)펜타노익 애시드(화합물 47);5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl- 2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoic acid (Compound 47);

에틸 (Z)-5-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노에이트(화합물 48);Ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)penta Noate (Compound 48);

(Z)-5-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노익 애시드(화합물 49);(Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoic Acid (Compound 49);

에틸 (Z)-5-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(6-플루오로-2-메틸피리딘-3-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노에이트(화합물 50);Ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate (Compound 50);

(Z)-5-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(6-플루오로-2-메틸피리딘-3-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노익 애시드(화합물 51);(Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoic acid (Compound 51);

(S,Z)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세틱 애시드(화합물 52);(S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazole-1- yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy ) acetic acid (compound 52);

메틸 2-(2-클로로-5-(((3S,4S)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)메틸)-4-히드록시크로만-3-일)메틸)페녹시)아세테이트(화합물 53);Methyl 2-(2-chloro-5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1- ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-hydroxychroman-3-yl)methyl)phenoxy)acetate (Compound No. 53);

메틸 (E)-2-(5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)메틸)-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트(화합물 54);Methyl (E)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(tri Fluoromethyl)-1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate (Compound 54);

메틸 (S,E)-5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로벤조에이트(화합물 55);Methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) Methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate (compound 55);

(S,E)-5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로벤조익 애시드(화합물 56);(S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl )-8-(1-Ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoic acid (Compound 56 );

메틸 (S,E)-5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로벤조에이트(화합물 57);Methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate (Compound 57);

(S,E)-5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로벤조익 애시드(화합물 58);(S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl )-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoic acid (Compound 58);

tert-부틸 (1-((8-(4-플루오로-2-메틸페닐)-4-옥소크로만-6-일)메틸)-3-메틸-1,3-디히드로-2H-이미다졸-2-일리덴)카바메이트(화합물 59);tert-Butyl (1-((8-(4-fluoro-2-methylphenyl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazole- 2-ylidene)carbamate (Compound 59);

메틸 2-(5-(((3E)-6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트(화합물 60);Methyl 2-(5-(((3E)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate (Compound 60);

메틸 2-(5-(((3S,4S)-6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-히드록시크로만-3-일)메틸)-2-플루오로페녹시)아세테이트(화합물 61);Methyl 2-(5-(((3S,4S)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-hydroxychroman-3-yl)methyl)-2-fluorophenoxy)acetate (Compound 61);

메틸 (S,Z)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트(화합물 62);Methyl (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate (Compound 62);

(S,Z)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세틱 애시드(화합물 63);(S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazole-1- yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid (Compound 63);

tert-부틸 (E)-메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일리덴)메틸)피리미딘-2-일)아제티딘-3-일)카바메이트(화합물 64);tert-Butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)azetidin-3-yl)carbamate (Compound 64);

tert-부틸 (E)-메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일리덴)메틸)피리딘-2-일)아제티딘-3-일)카바메이트(화합물 65);tert-Butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyridin-2-yl)azetidin-3-yl)carbamate (Compound 65);

tert-부틸 (1-(6-(((3S,4S)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-3-일)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카바메이트(화합물 66);tert-butyl (1-(6-(((3S,4S)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(Trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate (compound 66);

tert-부틸 (S)-메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리딘-2-일)아제티딘-3-일)카바메이트(화합물 67);tert-Butyl (S)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamate (Compound 67);

(S)-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-3-((4-메틸-6-(3-(메틸아미노)아제티딘-1-일)피리딘-2-일)메틸)크로만-4-온 히드로클로라이드 (화합물 68);(S)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)- 3-((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochloride (Compound 68);

tert-부틸 메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리딘-2-일)아제티딘-3-일)카바메이트(화합물 69);tert-Butyl methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl )-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamate (Compound 69);

tert-부틸 (1-(6-(((3R,4R)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-3-일)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카바메이트(화합물 70); ;tert-butyl (1-(6-(((3R,4R)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(Trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate (compound 70); ;

tert-부틸 (R)-메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리딘-2-일)아제티딘-3-일)카바메이트(화합물 71);tert-Butyl (R)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamate (Compound 71);

(R)-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-3-((4-메틸-6-(3-(메틸아미노)아제티딘-1-일)피리딘-2-일)메틸)크로만-4-온 히드로클로라이드(화합물 72);(R)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)- 3-((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochloride (Compound 72);

(S)-3-((4-메톡시피리딘-2-일)메틸)-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온(화합물 73);(S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3- (Trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one (Compound 73);

tert-부틸 (E)-4-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일리덴)메틸)피리미딘-2-일)피페라진-1-카복실레이트(화합물 74);tert-Butyl (E)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoro) Romethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (Compound 74);

tert-부틸 4-(4-(((3S,4S)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-3-일)메틸)-6-메틸피리미딘-2-일)피페라진-1-카복실레이트(화합물 75);tert-Butyl 4-(4-(((3S,4S)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3- (Trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate (Compound 75);

tert-부틸 (S)-4-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리미딘-2-일)피페라진-1-카복실레이트(화합물 76);tert-Butyl (S)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoro) Romethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (Compound 76);

tert-부틸 4-(4-(((3R,4R)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-3-일)메틸)-6-메틸피리미딘-2-일)피페라진-1-카복실레이트(화합물 77);tert-Butyl 4-(4-(((3R,4R)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3- (Trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate (Compound 77);

tert-부틸 (R)-4-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리미딘-2-일)피페라진-1-카복실레이트(화합물 78);tert-Butyl (R)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoro Romethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (Compound 78);

(R)-6-((2-메틸-1H-이미다졸-1-일)메틸)-3-((6-메틸-2-(피페라진-1-일)피리미딘-4-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온 히드로클로라이드(화합물 79);(R)-6-((2-methyl-1H-imidazol-1-yl)methyl)-3-((6-methyl-2-(piperazin-1-yl)pyrimidin-4-yl)methyl )-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one hydrochloride (Compound 79);

8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 80);8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4- on (compound 80);

(R)-3-((6-클로로-4-메틸피리딘-2-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 81);(R)-3-((6-chloro-4-methylpyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)- 6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 81);

(S)-2-(5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세틱 애시드(화합물 82);(S)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazole- 1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid (Compound 82);

tert-부틸 (R)-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카바메이트(화합물 83);tert-Butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H -imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate (Compound 83);

(R)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-3-((4-메틸-6-(3-(메틸아미노)아제티딘-1-일)피리딘-2-일)메틸)크로만-4-온 히드로클로라이드(화합물 84);(R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)- 3-((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochloride (Compound 84);

tert-부틸 (R)-N-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)-N-메틸글리시네이트(화합물 85);tert-Butyl (R)-N-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl -1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)-N-methylglycinate ( compound 85);

tert-부틸 (Z)-(1-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-6-일)메틸)-3-메틸-1,3-디히드로-2H-이미다졸-2-일리덴)카바메이트(화합물 86);tert-butyl (Z)-(1-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl) -3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate (Compound 86);

tert-부틸 ((Z)-1-((3-((E)-3-브로모-4-플루오로벤질리덴)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-6-일)메틸)-3-메틸-1,3-디히드로-2H-이미다졸-2-일리덴)카바메이트(화합물 87);tert-Butyl ((Z)-1-((3-((E)-3-bromo-4-fluorobenzylidene)-8-(1-ethyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate (Compound 87);

tert-부틸 ((Z)-1-((3-((E)-3-(2,6-비스(벤질옥시)피리딘-3-일)-4-플루오로벤질리덴)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-6-일)메틸)-3-메틸-1,3-디히드로-2H-이미다졸-2-일리덴)카바메이트(화합물 88);tert-butyl ((Z)-1-((3-((E)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzylidene)-8-(1 -Ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazole -2-ylidene)carbamate (Compound 88);

(E)-3-(3-(2,6-비스(벤질옥시)피리딘-3-일)-4-플루오로벤질리덴)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)크로만-4-온 히드로클로라이드(화합물 89);(E)-3-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzylidene)-8-(1-ethyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride ( compound 89);

3-(5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((3-메틸이미다졸리딘-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페닐)피페리딘-2,6-디온(화합물 90);3-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((3-methylimidazolidin-1-yl)methyl )-4-oxochroman-3-yl)methyl)-2-fluorophenyl)piperidine-2,6-dione (Compound 90);

tert-부틸 (1-(3-플루오로-6-(히드록시메틸)피리딘-2-일)아제티딘-3-일)카바메이트(화합물 91);tert-butyl (1-(3-fluoro-6-(hydroxymethyl)pyridin-2-yl)azetidin-3-yl)carbamate (Compound 91);

tert-부틸 (1-(3-플루오로-6-포르밀피리딘-2-일)아제티딘-3-일)카바메이트(화합물 92);tert-butyl (1-(3-fluoro-6-formylpyridin-2-yl)azetidin-3-yl)carbamate (Compound 92);

tert-부틸 (E)-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일리덴)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 93);tert-Butyl (E)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H -imidazol-1-yl)methyl)-4-oxochroman-3-ylidene)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 93);

(E)-3-((6-(3-아미노아제티딘-1-일)-5-플루오로피리딘-2-일)메틸렌)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온 히드로클로라이드(화합물 94);(E)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methylene)-8-(1-ethyl-3-(trifluoromethyl) -1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride (Compound 94);

tert-부틸 (1-(6-(((3R,4R)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-3-일)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 95);tert-butyl (1-(6-(((3R,4R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6- ((2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 95) ;

tert-부틸 (R)-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 96);tert-Butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H -imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 96);

(R)-3-((6-(3-아미노아제티딘-1-일)-5-플루오로피리딘-2-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온 히드로클로라이드(화합물 97);(R)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl) -1H-Pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride (Compound 97);

tert-부틸 (1-(6-(((3S,4S)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-3-일)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 98);tert-butyl (1-(6-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6- ((2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 98) ;

tert-부틸 (S)-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 99); 및tert-Butyl (S)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H -imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 99); and

(S)-3-((6-(3-아미노아제티딘-1-일)-5-플루오로피리딘-2-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온 히드로클로라이드(화합물 100); (S)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl) -1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride (Compound 100);

또한, 본 발명에서의 하기 용어는 달리 지시되지 않으면 하기 의미를 가진다. 정의되지 않은 임의의 용어는 당해 분야에서 이해되는 의미를 가진다.In addition, the following terms in the present invention have the following meanings unless otherwise indicated. Any term not defined has an art-understood meaning.

상기 용어 “알킬”은 1 내지 20개의 탄소 원자 및 바람직하게는 1 내지 6개의 탄소 원자를 가지는 단일결합의 직쇄 또는 분지쇄의 탄화수소기를 의미하며, 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, tert-부틸, 1-메틸프로필, 펜틸 및 헥실 등이 있다. The term “alkyl” refers to a single-bonded straight or branched hydrocarbon group having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms, and includes methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, 1-methylpropyl, pentyl and hexyl.

상기 용어 “알콕시”는 1 내지 20개의 탄소 원자 및 바람직하게는 1 내지 6개의 탄소 원자를 가지는 단일결합의 직쇄 또는 분지쇄의 포화 탄화수소가 결합된 산소기를 의미하며 메톡시, 에톡시, 프로폭시, n-부톡시, tert-부톡시, 1-메틸프로폭시 등이 있다.The term “alkoxy” refers to an oxygen group to which a single bonded straight or branched saturated hydrocarbon having 1 to 20 carbon atoms and preferably 1 to 6 carbon atoms is bonded, and includes methoxy, ethoxy, propoxy, n-butoxy, tert-butoxy, and 1-methylpropoxy.

상기 용어 “Boc”은 tert-부톡시카보닐을 의미한다.The term “Boc” means tert-butoxycarbonyl.

상기 용어 "할로" 및 "할로겐"은 플루오로, 클로로, 브로모 또는 아이오도 치환기를 지칭하기 위해서 통상적인 의미로 사용된다.The terms “halo” and “halogen” are used in their conventional sense to refer to fluoro, chloro, bromo or iodo substituents.

상기 용어 "할로알킬"은 알킬기의 하나 이상의 수소 원자가 할로기로 대체된 알킬기를 나타내며, 알킬 및 할로기는 상기에서 개시된 바와 같다.The term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced with a halo group, and the alkyl and halo groups are as defined above.

상기 용어 "할로알콕시"는 알콕시기의 하나 이상의 수소 원자가 할로기로 대체된 알콕시기를 나타내며, 할로 및 알콕시는 상기에서 개시된 바와 같다.The term “haloalkoxy” refers to an alkoxy group in which one or more hydrogen atoms of the alkoxy group have been replaced with a halo group, and halo and alkoxy are as defined above.

나아가, 본 발명의 화합물은 하나 이상의 비대칭 탄소 원자를 함유할 수 있고, 라세미 형태 및 광학적인 활성 형태로 존재할 수 있다. 이러한 모든 화합물 및 부분입체이성질체는 본 발명의 범위에 포함된다.Furthermore, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.

본 발명에서 상기 약학적으로 허용 가능한 염이란 바람직한 생물학적 활성을 보유한 화학식 1의 염 또는 복합체를 의미한다. 그러한 염의 예는 이에 한정되지 않지만, 무기산(예. 염산, 브롬화수소산, 황산, 인산, 질산 등)으로 형성되는 산 부가 염, 및 아세트산, 옥살산, 타르타르산, 호박산, 말산, 푸마르산, 말레산, 아스코르브산, 벤조산, 타닌산, 파모산, 알긴산, 폴리글루타민산, 나프탈렌 술폰산, 나프탈렌 디술폰산, 및 폴리-갈락투론산과 같은 유기산으로 형성된 염을 포함한다. 상기 화합물은 또한 당업자에게 알려진 약학적으로 허용 가능한 사차 염으로 투여될 수 있는데, 특히, 클로라이드, 브로마이드, 요오다이드, -O-알킬, 톨루엔술포네이트, 메틸술포네이트, 술포네이트, 포스페이트, 또는 카복실레이트(예를 들어, 벤조에이트, 숙시네이트, 아세테이트, 글리코레이트, 말리에이트 (maleate), 말레이트 (malate), 푸마레이트, 시트레이트, 타르트레이트, 아스코르베이트, 시나모에이트, 만델로에이트 및 디페닐아세테이트)를 포함한다. 본 발명의 화학식 1의 화합물은 약학적으로 허용 가능한 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물, 용매화물 및 프로드럭을 모두 포함할 수 있다.In the present invention, the pharmaceutically acceptable salt means a salt or complex of Formula 1 having a desired biological activity. Examples of such salts include, but are not limited to, acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), and acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid , salts formed with organic acids such as benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, and poly-galacturonic acid. The compounds may also be administered as pharmaceutically acceptable quaternary salts known to those skilled in the art, in particular chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxyl esters (e.g., benzoates, succinates, acetates, glycolates, maleates, malates, fumarates, citrates, tartrates, ascorbates, cinnamoates, mandeloates and diphenylacetate). The compound of Formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods.

본 발명에 따른 산 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들면 화학식 1의 유도체를 메탄올, 에탄올, 아세톤, 디클로로메탄, 아세토니트릴 등과 같은 유기용매에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조시켜 제조하거나, 용매와 과량의 산을 감압 증류한 후 건조시켜 유기용매 하에서 결정화시켜서 제조할 수 있다.The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate formed by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile, etc., and adding an organic or inorganic acid thereto It may be prepared by filtering and drying, or by distilling the solvent and excess acid under reduced pressure, drying it, and crystallizing it in an organic solvent.

또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻는다.In addition, a pharmaceutically acceptable metal salt may be prepared using a base. An alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

본 발명은 크로만-4-온 유도체를 이용하여 암을 예방 또는 치료하는 것을 특징으로 하는 약학적 조성물에 관한 것이다.The present invention relates to a pharmaceutical composition for preventing or treating cancer using a chroman-4-one derivative.

상기 암은 고형암 또는 혈액암인 것을 의미하며, 상기 고형암은 뇌암, 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 신경교종, 교모세포종, 후두암, 구인두암, 비강암, 비인두암, 침샘암, 하인두암, 편도암, 갑상선암, 구강암, 식도암, 안암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 폐선암, 폐암, 폐편평상피세포암, 흉막암, 종격동 종양, 유방암, 남성유방암, 복부종양, 위암, 위유양종, 간암, 간모세포종, 담낭암, 담도암, 췌장암, 소장암, 대장암, 결장암, 직장암, 십이지장암, 항문암, 방광암, 신장암, 신우암, 심장암, 복막암, 부신암, 척수암, 골암, 성생식기종양, 음경암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암 또는 피부암으로 이루어진 군에서 선택될 수 있으나 특별히 이에 제한되지는 않는다. 또한 상기 혈액암은 급성골수성백혈병, 급성림프구성백혈병, 만성골수성백혈병, 만성림프구성백혈병, 소아림프종, 악성림프종, 다발성골수종 또는 재생불량성 빈혈로 이루어진 군에서 선택될 수 있으나 특별히 이에 제한되지는 않는다.The cancer means solid cancer or blood cancer, and the solid cancer means brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, brain lymphoma, oligodendroglioma, intracranial race, ependymoma, brainstem tumor, head and neck tumor, Glioma, glioblastoma, laryngeal cancer, oropharyngeal cancer, nasal cancer, nasopharyngeal cancer, salivary gland cancer, hypopharynx cancer, tonsil cancer, thyroid cancer, oral cancer, esophageal cancer, eye cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, lung adenocarcinoma , lung cancer, lung squamous cell carcinoma, pleural cancer, mediastinal tumor, breast cancer, male breast cancer, abdominal tumor, stomach cancer, gastric mastoid, liver cancer, hepatoblastoma, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, Duodenal cancer, anal cancer, bladder cancer, kidney cancer, renal pelvic cancer, heart cancer, peritoneal cancer, adrenal cancer, spinal cord cancer, bone cancer, sexual genital tumor, penile cancer, prostate cancer, female genital tract tumor, cervical cancer, endometrial cancer, ovarian cancer , uterine sarcoma, vaginal cancer, female external genital cancer, female urethral cancer, or skin cancer, but is not particularly limited thereto. In addition, the blood cancer may be selected from the group consisting of acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, childhood lymphoma, malignant lymphoma, multiple myeloma, or aplastic anemia, but is not particularly limited thereto.

본 발명에 따른 약학 조성물은 일반적으로 사용되는 약학적으로 허용 가능한 담체와 함께 적합한 형태로 제형화될 수 있다. “약학적으로 허용 가능”이란 생리학적으로 허용되고 인간에게 투여될 때, 통상적으로 위장 장애, 현기증 등과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 또한, 상기 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다.The pharmaceutical composition according to the present invention may be formulated in a suitable form together with a generally used pharmaceutically acceptable carrier. "Pharmaceutically acceptable" refers to a composition that is physiologically acceptable and does not usually cause allergic reactions such as gastrointestinal disorders, dizziness, etc., or similar reactions when administered to humans. In addition, the composition may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods.

상기 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토오스, 덱스트로즈, 수크로스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아라비아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미결정셀룰로오스, 폴리비닐 피롤리돈, 물, 파라옥시벤조산메틸, 파라옥시벤조산프로필, 탈크, 스테아르산마그네슘 및 광물유를 포함할 수 있으나, 이에 한정되는 것은 아니다. 제제화할 경우에는 보통 사용하는 충진제, 안정화제, 결합제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 화합물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 미결정셀룰로오스, 수크로스 또는 락토오스, 저치환히드록시프로필셀룰로오스, 히프로멜로오스 등을 섞어 조제된다. 또한 단순한 부형제 이외에 스테아르산마그네슘, 탈크 같은 활택제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 유동파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함된다. 비수성용제, 현탁용제로는 프로필렌글리콜, 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다. 비경구 투여용 제형으로 제제화하기 위하여 상기 화학식 1의 화합물 또는 이의 약학적으로 허용되는 염을 멸균되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질과 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다.Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl paraoxybenzoate, propyl paraoxybenzoate, talc, magnesium stearate, and mineral oil, but is not limited thereto. When formulated, it is prepared using diluents or excipients such as commonly used fillers, stabilizers, binders, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the compound of the present invention, for example, starch, microcrystalline cellulose, sucrose or lactose, It is prepared by mixing low-substituted hydroxypropyl cellulose, hypromellose, and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions for oral use, emulsions, syrups, etc. In addition to water and liquid paraffin, which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, aromatics, and preservatives may be included. . Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for suppositories, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerol, gelatin, and the like may be used. In order to formulate a formulation for parenteral administration, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is sterilized or preservatives, stabilizers, hydrating agents or emulsification accelerators, salts or buffers for osmotic pressure control, and other therapeutic agents. It can be mixed with water together with useful substances to prepare a solution or suspension, which can be prepared in an ampoule or vial unit dosage form.

본 발명에 개시된 화학식 1의 화합물을 유효성분으로 포함하는 약학 조성물은 쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사에 의해 투여될 수 있다. 투여량은 치료받을 대상의 연령, 성별, 체중, 치료할 특정 질환 또는 병리 상태, 질환 또는 병리 상태의 심각도, 투여시간, 투여경로, 약물의 흡수, 분포 및 배설률, 사용되는 다른 약물의 종류 및 처방자의 판단 등에 따라 달라질 것이다. 이러한 인자에 기초한 투여량 결정은 당업자의 수준 내에 있으며, 일반적으로 투여량은 0.01 ㎎/㎏/일 내지 대략 2000 ㎎/㎏/일의 범위이다. 더 바람직한 투여량은 1 ㎎/㎏/일 내지 500 ㎎/㎏/일이다. 투여는 하루에 한번 투여할 수도 있고, 수회 나누어 투여할 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다.A pharmaceutical composition comprising the compound of Formula 1 disclosed in the present invention as an active ingredient may be administered to mammals such as rats, livestock, and humans through various routes. All modes of administration are contemplated, eg oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine intrathecal or intracerebrovascular injection. The dose depends on the age, sex, and weight of the subject to be treated, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the time of administration, the route of administration, the absorption, distribution and excretion rate of the drug, the type of other drug used, and the prescription It will depend on judgment, etc. Determination of dosage based on these factors is within the level of those skilled in the art, and generally dosages range from 0.01 mg/kg/day to approximately 2000 mg/kg/day. A more preferred dosage is 1 mg/kg/day to 500 mg/kg/day. Administration may be administered once a day, or may be administered in several divided doses. The dosage is not intended to limit the scope of the present invention in any way.

또한 본 발명의 상기 약학 조성물은 암의 예방 또는 치료를 위하여 단독으로, 또는 수술, 호르몬 치료, 화학 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the prevention or treatment of cancer.

본 발명은 이중고리 저분자 화합물을 유효성분으로 함유하는 항암용 약학적 조성물 및 이의 제조방법에 관한 것으로, 상기 저분자 유도체를 유효성분으로 함유하는 조성물은 암 예방 또는 치료용 조성물로 유용하게 사용가능하다.The present invention relates to an anti-cancer pharmaceutical composition containing a low-molecular-weight bicyclic compound as an active ingredient and a method for preparing the same, and the composition containing the low-molecular-weight derivative as an active ingredient can be usefully used as a composition for preventing or treating cancer.

이하 본 발명의 바람직한 실시예를 상세히 설명하기로 한다. 그러나 본 발명은 여기서 설명되는 실시예에 한정되지 않고 다른 형태로 구체화될 수도 있다. 오히려, 여기서 소개되는 내용이 철저하고 완전해지고, 당업자에게 본 발명의 사상을 충분히 전달하기 위해 제공하는 것이다.Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the disclosure herein is provided so that it will be thorough and complete, and will fully convey the spirit of the invention to those skilled in the art.

<실시예 1. 화합물 합성 및 물리화학적 특성 확인><Example 1. Synthesis of compound and confirmation of physical and chemical properties>

본 발명 화합물 1 내지 100의 합성과정은 다음과 같다.The synthesis process of compounds 1 to 100 of the present invention is as follows.

Figure pat00033
Figure pat00033

화합물 1. (S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 1. (S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

Figure pat00034
Figure pat00034

단계 1) (E)-8-bromo-3-(3,4-dichlorobenzylidene)-6-methylchroman-4-one의 제조Step 1) Preparation of (E)-8-bromo-3-(3,4-dichlorobenzylidene)-6-methylchroman-4-one

8-브로모-6-메틸크로만-4-온 (1928 mg, 8 mmol), 3,4-디클로로 벤즈알데히드(1470 mg, 8.4 mmol) 및 p-톨루엔 설폰산 (140 mg, 0.8 mmol)을 톨루엔 (35 mL) 용매하에서 반응혼합물을 15시간 동안 환류시켰다. 상온으로 냉각한 후, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출한 후(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (디클로로메탄/n-헵탄 = 1:10 내지 1:1)로 정제하여 생성물 (2593 mg, 83%)을 얻었다.8-Bromo-6-methylchroman-4-one (1928 mg, 8 mmol), 3,4-dichlorobenzaldehyde (1470 mg, 8.4 mmol) and p-toluene sulfonic acid (140 mg, 0.8 mmol) were added to toluene (35 mL) under solvent, the reaction mixture was refluxed for 15 hours. After cooling to room temperature, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane/n-heptane = 1:10 to 1:1) to give the product (2593 mg, 83%).

1H NMR (400 MHz, CDCl3) δ 7.80 - 7.76 (m, 1H), 7.75 (s, 1H), 7.61 - 7.57 (m, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.16 (ddd, J = 8.3, 2.2, 0.7 Hz, 1H), 5.38 (d, J = 1.9 Hz, 2H), 2.34 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 - 7.76 (m, 1H), 7.75 (s, 1H), 7.61 - 7.57 (m, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.40 ( d, J = 2.1 Hz, 1H), 7.16 (ddd, J = 8.3, 2.2, 0.7 Hz, 1H), 5.38 (d, J = 1.9 Hz, 2H), 2.34 (s, 3H).

Figure pat00035
Figure pat00035

단계 2) (S,S)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-ol의 제조Step 2) Preparation of (S,S)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-ol

(E)-8-브로모-3-(3,4-디클로로벤질리덴)-6-메틸크로만-4-온(500 mg, 1.284 mmol), RuCl(p-시멘)[(S,S)-Ts-DPEN](4 mg, 6.42 μmol) 및 DBU (2.5 eq)/포름산 (5 eq)(480 μL : 240 μL)의 아세토니트릴(5 mL) 용액을 주변 온도에서 첨가했다. 50℃에서 17시간 동안 교반한 후, 반응을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. 디에틸에테르로 추출한 후, 유기층을 추가의 포화 NaHCO3수용액으로 세척하고, MgSO4로 건조시키고, 감압하에 농축시켰다. 잔류물을 MPLC (에틸 아세테이트/n-헵탄 = 1:5 내지 1:2)로 정제하여 생성물 (424 mg, 82%)을 수득하였다.(E)-8-bromo-3-(3,4-dichlorobenzylidene)-6-methylchroman-4-one (500 mg, 1.284 mmol), RuCl(p-cymene)[(S,S) -Ts-DPEN] (4 mg, 6.42 μmol) and DBU (2.5 eq)/formic acid (5 eq) (480 μL : 240 μL) in acetonitrile (5 mL) was added at ambient temperature. After stirring at 50° C. for 17 h, the reaction was quenched with saturated aqueous NH 4 Cl solution at room temperature. After extraction with diethylether, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate/n-heptane = 1:5 to 1:2) to give the product (424 mg, 82%).

1H NMR (400 MHz, CDCl3) δ 7.42 - 7.35 (m, 2H), 7.33 - 7.28 (m, 1H), 7.11 (dd, J = 8.2, 2.1 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 4.43 (s, 1H), 4.25 - 4.15 (m, 1H), 4.13 (d, J = 11.0 Hz, 1H), 2.85 (dd, J = 13.7, 8.8 Hz, 1H), 2.63 (dd, J = 13.7, 6.9 Hz, 1H), 2.26 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 - 7.35 (m, 2H), 7.33 - 7.28 (m, 1H), 7.11 (dd, J = 8.2, 2.1 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 4.43 (s, 1H), 4.25 - 4.15 (m, 1H), 4.13 (d, J = 11.0 Hz, 1H), 2.85 (dd, J = 13.7, 8.8 Hz, 1H), 2.63 (dd , J = 13.7, 6.9 Hz, 1H), 2.26 (m, 4H).

Figure pat00036
Figure pat00036

단계 3) (S)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-one의 제조Step 3) Preparation of (S)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-one

CH2Cl2 (7 mL) 중 (S,S)-8-브로모-3-(3,4-디클로로벤질)-6-메틸크로만-4-올(428 mg, 1.064 mmol) 및 분자체 4 Å (50 mg)의 용액을 10분 동안 교반하였다. 그 다음, N-메틸모르폴린 N-옥사이드 (NMO, 125 mg, 1.064 mmol), 테트라프로필암모늄 퍼루테네이트 (TPAP, 37 mg, 0.106 mmol)를 0℃에서 첨가하고, 상온에서 2시간 동안 교반하였다. 어두운 색의 혼합물에 용리제로서 디에틸 에테르를 사용하여 셀라이트 상에서 여과하였다. 진공에서 농축한 후, 잔류물을 MPLC (에틸 아세테이트:n-헵탄, 20%)로 정제하여 생성물 (257 mg, 60%, BORSM 88%)을 얻는다.(S,S)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-ol (428 mg, 1.064 mmol) and molecular sieves in CH 2 Cl 2 (7 mL) A solution of 4 Å (50 mg) was stirred for 10 minutes. Then, N-methylmorpholine N-oxide (NMO, 125 mg, 1.064 mmol) and tetrapropylammonium perruthenate (TPAP, 37 mg, 0.106 mmol) were added at 0°C and stirred at room temperature for 2 hours. . The dark colored mixture was filtered over celite using diethyl ether as an eluent. After concentration in vacuo, the residue is purified by MPLC (ethyl acetate:n-heptane, 20%) to give the product (257 mg, 60%, BORSM 88%).

1H NMR (400 MHz, CDCl3) δ 7.67 (dq, J = 2.3, 0.8 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 4.49 (dd, J = 11.5, 4.5 Hz, 1H), 4.23 (dd, J = 11.6, 9.1 Hz, 1H), 3.22 (dd, J = 14.2, 4.9 Hz, 1H), 2.95 (dt, J = 9.3, 4.7 Hz, 1H), 2.71 (dd, J = 14.2, 9.5 Hz, 1H), 2.31 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.67 (dq, J = 2.3, 0.8 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 4.49 (dd, J = 11.5, 4.5 Hz, 1H), 4.23 (dd, J = 11.6, 9.1 Hz, 1H), 3.22 (dd, J = 14.2, 4.9 Hz, 1H), 2.95 (dt, J = 9.3, 4.7 Hz, 1H), 2.71 (dd, J = 14.2, 9.5 Hz, 1H), 2.31 (s, 3H).

Figure pat00037
Figure pat00037

단계 4) (S)-8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzyl)chroman-4-one의 제조Step 4) Preparation of (S)-8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzyl)chroman-4-one

(S)8-브로모-3-(3,4-디클로로벤질)-6-메틸크로만-4-온 (255 mg, 0.634 mmol), NBS (135 mg, 0.760 mmol), AIBN (21 mg, 0.127 mmol) 및 MeOAc (10 mL)의 용액을 60℃에서 2시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트 및 물로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (에틸 아세테이트:n-헵탄 = 1:10 내지 1:2)로 정제하여 생성물 (130 mg, 43%)을 수득하였다.(S) 8-Bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-one (255 mg, 0.634 mmol), NBS (135 mg, 0.760 mmol), AIBN (21 mg, 0.127 mmol) and MeOAc (10 mL) was refluxed at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:n-heptane = 1:10 to 1:2) to give the product (130 mg, 43%).

1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.2 Hz, 1H), 4.54 (dd, J = 11.6, 4.6 Hz, 1H), 4.43 (s, 2H), 4.27 (dd, J = 11.6, 9.4 Hz, 1H), 3.24 (dd, J = 14.2, 4.9 Hz, 1H), 2.99 (dt, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 14.3, 9.5 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d , J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.2 Hz, 1H), 4.54 (dd, J = 11.6, 4.6 Hz, 1H), 4.43 (s, 2H), 4.27 (dd, J = 11.6, 9.4 Hz, 1H), 3.24 (dd, J = 14.2, 4.9 Hz, 1H), 2.99 (dt, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 14.3, 9.5 Hz, 1H).

Figure pat00038
Figure pat00038

단계 5) (S)-8-bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 5) (S)-8-bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman Preparation of 4-one

(S)-8-브로모-6-(브로모메틸)-3-(3,4-다이클로로벤질)크로만-4-온 (126 mg, 0.264 mmol), 1-메틸-1,3-다이하이드로-2H-이미다졸-2-이민 (106 mg, 0.792 mmol), DIEA (140 uL, 0.792 mmol), KI (44 mg, 0.264 mmol) 및 MeCN (3 mL)의 용액을 60℃에서 2시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2 = 1:50 내지 1:10)로 정제하여 생성물 (66 mg, 50%)을 얻었다.(S)-8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzyl)chroman-4-one (126 mg, 0.264 mmol), 1-methyl-1,3- A solution of dihydro-2H-imidazol-2-imine (106 mg, 0.792 mmol), DIEA (140 uL, 0.792 mmol), KI (44 mg, 0.264 mmol) and MeCN (3 mL) at 60 °C for 2 h. heated while After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 = 1:50 to 1:10) to give the product (66 mg, 50%).

1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.73 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 7.07 (dd, J = 8.3, 2.2 Hz, 1H), 6.59 (dd, J = 22.5, 2.5 Hz, 2H), 5.49 (s, 2H), 4.53 (dd, J = 11.6, 4.5 Hz, 1H), 4.27 (dd, J = 11.7, 9.4 Hz, 1H), 3.83 (s, 3H), 3.21 (dd, J = 14.2, 5.2 Hz, 1H), 3.00 (tt, J = 9.5, 4.9 Hz, 1H), 2.69 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 495.9 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.73 (s, 1H), 7.39 (d, J = 8.2 Hz , 1H), 7.33 (s, 1H), 7.07 (dd, J = 8.3, 2.2 Hz, 1H), 6.59 (dd, J = 22.5, 2.5 Hz, 2H), 5.49 (s, 2H), 4.53 (dd, J = 11.6, 4.5 Hz, 1H), 4.27 (dd, J = 11.7, 9.4 Hz, 1H), 3.83 (s, 3H), 3.21 (dd, J = 14.2, 5.2 Hz, 1H), 3.00 (tt, J = 9.5, 4.9 Hz, 1H), 2.69 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 495.9 (M+H) +

Figure pat00039
Figure pat00039

단계 6) (S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 6) (S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl Preparation of -2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

(S)-8-브로모-3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)크로만-4-온 (56.9 mg, 0.115 mmol), (1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)보론산 (48 mg, 0.230 mmol), K2CO3 (48 mg, 0.345mmol) 및 Pd(dppf)Cl2 (8.4 mg, 0.011 mmol)을 1,4-디옥산/H2O (3:1, 2 mL)에 첨가하였다. 혼합물을 탈기시킨 다음 17시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 1,4-디옥산을 감압하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸아세테이트로 추출하여 (x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 화합물 1 (4.8 mg, 7%)을 얻는다. (S)-8-Bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl )chroman-4-one (56.9 mg, 0.115 mmol), (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (48 mg, 0.230 mmol), K 2 CO 3 (48 mg, 0.345 mmol) and Pd(dppf)Cl 2 (8.4 mg, 0.011 mmol) were added to 1,4-dioxane/H 2 O (3:1, 2 mL). The mixture was degassed and then heated to 100° C. for 17 hours. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3) and dried over Na 2 SO 4 , concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give compound 1 (4.8 mg, 7%).

1H NMR (400 MHz, CDCl3) δ 8.86 (s, 3H), 7.82 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.47 (d, J = 13.9 Hz, 2H), 5.43 (s, 2H), 4.39 (s, 1H), 4.27 - 4.12 (m, 3H), 3.76 (s, 3H), 3.19 (d, J = 15.1 Hz, 1H), 2.92 (s, 1H), 2.71 (d, J = 11.6 Hz, 1H), 1.55 (d, J = 14.7 Hz, 3H). ESI-MS m/z 578.0 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, 3H), 7.82 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H) , 7.32 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.47 (d, J = 13.9 Hz, 2H), 5.43 (s, 2H), 4.39 (s, 1H), 4.27 - 4.12 ( m, 3H), 3.76 (s, 3H), 3.19 (d, J = 15.1 Hz, 1H), 2.92 (s, 1H), 2.71 (d, J = 11.6 Hz, 1H), 1.55 (d, J = 14.7 Hz, 3H). ESI-MS m/z 578.0 (M+H) +

Figure pat00040
Figure pat00040

화합물 2. (S)-3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 2. (S)-3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro -1H-imidazol-1-yl)methyl)chroman-4-one

(6-플루오로-2-메틸피리딘-3-일)보론산 (27 mg, 0.15 mmol)을 사용하여 화합물 2 (16.1 mg, 31% 수율)를 실시예 1, 단계 6에 기재된 절차로부터 제조하였다.Compound 2 (16.1 mg, 31% yield) was prepared from the procedure described in Example 1, Step 6 using (6-fluoro-2-methylpyridin-3-yl)boronic acid (27 mg, 0.15 mmol). .

1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.62 (t, J = 8.1 Hz, 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.04 (dd, J = 8.1, 2.1 Hz, 1H), 6.77 (dd, J = 8.1, 3.1 Hz, 1H), 6.51 (t, J = 2.2 Hz, 2H), 5.46 (s, 2H), 4.38 (dd, J = 11.6, 4.5 Hz, 1H), 4.19 - 4.09 (m, 1H), 3.74 (s, 3H), 3.22 (dd, J = 14.2, 4.9 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.69 (dd, J = 14.3, 9.3 Hz, 1H), 2.32 (s, 3H). ESI-MS m/z 525.1 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 8.91 (s, 1H), 7.86 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.62 (t, J = 8.1 Hz , 1H), 7.36 (d, J = 8.3 Hz, 1H), 7.32 - 7.26 (m, 1H), 7.04 (dd, J = 8.1, 2.1 Hz, 1H), 6.77 (dd, J = 8.1, 3.1 Hz, 1H), 6.51 (t, J = 2.2 Hz, 2H), 5.46 (s, 2H), 4.38 (dd, J = 11.6, 4.5 Hz, 1H), 4.19 - 4.09 (m, 1H), 3.74 (s, 3H) ), 3.22 (dd, J = 14.2, 4.9 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.69 (dd, J = 14.3, 9.3 Hz, 1H), 2.32 (s, 3H). ESI-MS m/z 525.1 (M+H) +

Figure pat00041
Figure pat00041

화합물 3. (S)-N-(4-(3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamideCompound 3. (S)-N-(4-(3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl )-4-oxochroman-8-yl)pyridin-2-yl)acetamide

N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (40 mg, 1.5 mmol)을 사용하여 화합물 3 (8.7 mg, 16% 수율)을 실시예 1, 단계 6에 기재된 절차로부터 제조하였다.Compound 3 (8.7 mg) with N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (40 mg, 1.5 mmol) , 16% yield) was prepared from the procedure described in Example 1, Step 6.

1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.33 (s, 1H), 7.27 (s, 1H), 7.22 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.49 (s, 2H), 5.46 (s, 2H), 4.42 (d, J = 12.1 Hz, 1H), 4.17 (t, J = 10.6 Hz, 1H), 3.75 (s, 3H), 3.21 (d, J = 14.7 Hz, 1H), 2.97 (s, 1H), 2.75 - 2.62 (m, 1H), 2.23 (s, 3H). ESI-MS m/z 550.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.91 (s, 1H), 8.39 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.33 (s, 1H), 7.27 (s, 1H), 7.22 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.49 (s, 2H), 5.46 ( s, 2H), 4.42 (d, J = 12.1 Hz, 1H), 4.17 (t, J = 10.6 Hz, 1H), 3.75 (s, 3H), 3.21 (d, J = 14.7 Hz, 1H), 2.97 ( s, 1H), 2.75 - 2.62 (m, 1H), 2.23 (s, 3H). ESI-MS m/z 550.1 (M+H) +

Figure pat00042
Figure pat00042

화합물 4. (S)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 4. (S)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H -imidazol-1-yl)methyl)chroman-4-one

(3,5-비스(트리플루오로메틸)페닐)보론산 (39 mg, 0.15 mmol)을 사용하여 화합물 4 (22 mg, 35% 수율)를 실시예 1, 단계 6에 기재된 절차로부터 제조하였다. Compound 4 (22 mg, 35% yield) was prepared from the procedure described in Example 1, Step 6 using (3,5-bis(trifluoromethyl)phenyl)boronic acid (39 mg, 0.15 mmol).

1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.06 (s, 2H), 8.00 (d, J = 2.4 Hz, 1H), 7.86 - 7.81 (m, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.06 (dd, J = 8.2, 2.1 Hz, 1H), 6.54 - 6.48 (m, 2H), 5.49 (s, 2H), 4.44 (dd, J = 11.6, 4.6 Hz, 1H), 4.28 - 4.15 (m, 1H), 3.76 (s, 3H), 3.26 (dd, J = 14.2, 5.0 Hz, 1H), 3.01 (dt, J = 9.5, 4.7 Hz, 1H), 2.71 (dd, J = 14.3, 9.3 Hz, 1H). ESI-MS m/z 628.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 9.00 (s, 1H), 8.06 (s, 2H), 8.00 (d, J = 2.4 Hz, 1H), 7.86 - 7.81 (m, 2H), 7.39 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.06 (dd, J = 8.2, 2.1 Hz, 1H), 6.54 - 6.48 (m, 2H), 5.49 (s, 2H), 4.44 (dd, J = 11.6, 4.6 Hz, 1H), 4.28 - 4.15 (m, 1H), 3.76 (s, 3H), 3.26 (dd, J = 14.2, 5.0 Hz, 1H), 3.01 (dt, J = 9.5, 4.7 Hz, 1H), 2.71 (dd, J = 14.3, 9.3 Hz, 1H). ESI-MS m/z 628.1 (M+H) +

Figure pat00043
Figure pat00043

화합물 5. (S)-3-(3,4-dichlorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 5. (S)-3-(3,4-dichlorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1 -yl)methyl)chroman-4-one

(3,4-디메톡시페닐)보론산 (32 mg, 0.174 mmol)을 사용하여 화합물 5 (22.7 mg, 35% 수율)를 실시예 1, 단계 6에 기재된 절차로부터 제조하였다.Compound 5 (22.7 mg, 35% yield) was prepared from the procedure described in Example 1, Step 6 using (3,4-dimethoxyphenyl)boronic acid (32 mg, 0.174 mmol).

1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.08 (ddd, J = 15.8, 8.0, 2.0 Hz, 3H), 6.87 (d, J = 8.3 Hz, 1H), 6.47 (s, 2H), 5.44 (s, 2H), 4.41 (dd, J = 11.6, 4.6 Hz, 1H), 4.15 (dd, J = 11.6, 9.5 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H), 3.24 (dd, J = 14.3, 4.9 Hz, 1H), 2.97 (dt, J = 9.5, 4.7 Hz, 1H), 2.69 (dd, J = 14.2, 9.4 Hz, 1H). ESI-MS m/z 552.1 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 8.95 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.2 Hz , 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.08 (ddd, J = 15.8, 8.0, 2.0 Hz, 3H), 6.87 (d, J = 8.3 Hz, 1H), 6.47 (s, 2H) , 5.44 (s, 2H), 4.41 (dd, J = 11.6, 4.6 Hz, 1H), 4.15 (dd, J = 11.6, 9.5 Hz, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H), 3.24 (dd, J = 14.3, 4.9 Hz, 1H), 2.97 (dt, J = 9.5, 4.7 Hz, 1H), 2.69 (dd, J = 14.2, 9.4 Hz, 1H). ESI-MS m/z 552.1 (M+H) +

Figure pat00044
Figure pat00044

화합물 6. (S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-iminooxazol-3(2H)-yl)methyl)chroman-4-oneCompound 6. (S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-iminooxazol-3(2H )-yl)methyl)chroman-4-one

Figure pat00045
Figure pat00045

단계 1) tert-butyl (S,E)-(3-((8-bromo-3-(3,4-dichlorobenzyl)-4-oxochroman-6-yl)methyl)oxazol-2(3H)-ylidene)carbamate의 제조Step 1) tert-butyl (S,E)-(3-((8-bromo-3-(3,4-dichlorobenzyl)-4-oxochroman-6-yl)methyl)oxazol-2(3H)-ylidene) Preparation of carbamate

tert-부틸 (Z)-옥사졸-2(3H)-일리덴카바메이트 (346.1 mg, 1.88 mmol)를 사용하여 생성물 (269.3 mg, 74.6% 수율)을 실시예 1, 단계 5에 기재된 절차로부터 제조하였다.The product (269.3 mg, 74.6% yield) was prepared from the procedure described in Example 1, step 5 using tert-butyl (Z)-oxazol-2(3H)-ylidenecarbamate (346.1 mg, 1.88 mmol) did

1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 1.0 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.09 - 7.04 (m, 1H), 7.02 (d, J = 1.0 Hz, 1H), 4.89 (s, 2H), 4.51 (dd, J = 11.6, 4.6 Hz, 1H), 4.24 (dd, J = 11.6, 9.4 Hz, 1H), 3.23 (dd, J = 14.2, 4.9 Hz, 1H), 2.96 (tt, J = 9.4, 4.7 Hz, 1H), 2.69 (dd, J = 14.3, 9.5 Hz, 1H), 1.50 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 1.0 Hz, 1H), 7.39 (d , J = 8.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.09 - 7.04 (m, 1H), 7.02 (d, J = 1.0 Hz, 1H), 4.89 (s, 2H), 4.51 (dd, J = 11.6, 4.6 Hz, 1H), 4.24 (dd, J = 11.6, 9.4 Hz, 1H), 3.23 (dd, J = 14.2, 4.9 Hz, 1H), 2.96 (tt, J = 9.4, 4.7 Hz, 1H), 2.69 (dd, J = 14.3, 9.5 Hz, 1H), 1.50 (s, 9H).

Figure pat00046
Figure pat00046

단계 2) tert-butyl (S,E)-(3-((3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)oxazol-2(3H)-ylidene)carbamate의 제조Step 2) tert-butyl (S,E)-(3-((3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4 Preparation of -oxochroman-6-yl)methyl)oxazol-2(3H)-ylidene)carbamate

tert-부틸 (S)-(3-((8-브로모-3-(3,4-디클로로벤질)-4-옥소크로만-6-일)메틸)옥사졸-2(3H)-일리덴)카바메이트 (100 mg, 0.171 mmol), (1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)보론산 (54 mg, 0.256 mmol), Cs2CO3(88 mg, 0.342 mmol) 및 Pd(amphos)Cl2 (12 mg, 0.017 mmol)을 1,4-디옥산/H2O (3:1, 2 mL)에 첨가하였다. 혼합물을 탈기한 다음, 1시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 1,4-디옥산을 감압 하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 생성물 (4.1 mg, 7%)을 얻는다.tert-butyl (S)-(3-((8-bromo-3-(3,4-dichlorobenzyl)-4-oxochroman-6-yl)methyl)oxazol-2(3H)-ylidene )carbamate (100 mg, 0.171 mmol), (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (54 mg, 0.256 mmol), Cs 2 CO 3 (88 mg, 0.342 mmol) and Pd(amphos)Cl 2 (12 mg, 0.017 mmol) were added to 1,4-dioxane/H 2 O (3:1, 2 mL). The mixture was degassed and then heated to 100 °C for 1 hour. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3) and dried over Na 2 SO 4 , concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give the product (4.1 mg, 7%).

1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J = 1.0 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.07 - 7.03 (m, 1H), 7.01 (d, J = 1.0 Hz, 1H), 4.94 (s, 2H), 4.36 (dd, J = 11.6, 4.4 Hz, 1H), 4.25 (q, J = 7.3 Hz, 2H), 4.19 - 4.10 (m, 1H), 3.23 (dd, J = 14.2, 4.7 Hz, 1H), 2.91 (tt, J = 9.2, 4.5 Hz, 1H), 2.67 (dd, J = 14.2, 9.8 Hz, 1H), 1.57 (t, J = 7.4 Hz, 3H), 1.48 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.90 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.48 (s, 1H), 7.45 (d, J = 1.0 Hz , 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.07 - 7.03 (m, 1H), 7.01 (d, J = 1.0 Hz, 1H), 4.94 (s, 2H), 4.36 (dd, J = 11.6, 4.4 Hz, 1H), 4.25 (q, J = 7.3 Hz, 2H), 4.19 - 4.10 (m, 1H), 3.23 (dd, J = 14.2, 4.7 Hz, 1H), 2.91 (tt, J = 9.2, 4.5 Hz, 1H), 2.67 (dd, J = 14.2, 9.8 Hz, 1H), 1.57 (t, J = 7.4 Hz, 3H), 1.48 (s, 9H) ).

Figure pat00047
Figure pat00047

단계 3) (S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-iminooxazol-3(2H)-yl)methyl)chroman-4-one의 제조Step 3) (S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-iminooxazol-3(2H Preparation of )-yl)methyl)chroman-4-one

tert-부틸 (S)-(4-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)시클로헥실)카르바메이트 (4.1 mg, 0.006 mmol)를 무수 CH2Cl2 (1 mL) 중 TFA (5 방울)를 0°C에서 적가하였다. 생성된 혼합물을 0℃에서 30분 동안 교반하고, 반응혼합물을 감압하에 농축하였다. 잔류물을 실리카겔 상에서 플래시칼럼크로마토그래피 (MeOH:CH2Cl2, 10%)로 정제하여 화합물 6 (1.5 mg, 36%)을 얻는다.tert-Butyl (S)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (4.1 mg, 0.006 mmol) was dissolved in anhydrous CH 2 Cl TFA (5 drops) in 2 (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0° C. for 30 min, and the reaction mixture was concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 10%) to give compound 6 (1.5 mg, 36%).

1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 1.0 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.29 (d, J = 1.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.1 Hz, 1H), 6.75 (d, J = 1.1 Hz, 1H), 4.43 (s, 2H), 4.39 (dd, J = 11.6, 4.4 Hz, 1H), 4.27 (q, J = 7.3 Hz, 2H), 4.20 (dd, J = 11.7, 8.3 Hz, 1H), 3.21 - 3.11 (m, 1H), 3.01 (tt, J = 9.2, 4.9 Hz, 2H), 2.77 (dd, J = 14.0, 8.9 Hz, 1H), 1.52 (t, J = 7.3 Hz, 3H). ESI-MS m/z 565.0 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 1.0 Hz, 1H), 7.52 (d, J = 2.4 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.29 (d, J = 1.1 Hz, 1H), 7.17 (dd, J = 8.3, 2.1 Hz, 1H), 6.75 (d, J = 1.1 Hz, 1H), 4.43 (s, 2H) ), 4.39 (dd, J = 11.6, 4.4 Hz, 1H), 4.27 (q, J = 7.3 Hz, 2H), 4.20 (dd, J = 11.7, 8.3 Hz, 1H), 3.21 - 3.11 (m, 1H) , 3.01 (tt, J = 9.2, 4.9 Hz, 2H), 2.77 (dd, J = 14.0, 8.9 Hz, 1H), 1.52 (t, J = 7.3 Hz, 3H). ESI-MS m/z 565.0 (M+H) +

Figure pat00048
Figure pat00048

화합물 7. (R)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 7. (R)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl) -2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

Figure pat00049
Figure pat00049

단계 1) (R,R)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-ol의 제조Step 1) Preparation of (R,R)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-ol

(E)-8-브로모-3-(3,4-디클로로벤질리덴)-6-메틸크로만-4-온(500 mg, 1.284 mmol), RuCl(p-시멘)[(R,R)-Ts-DPEN] (4 mg, 6.42 μmol) 및 DBU (2.5 eq)/포름산 (5 eq) (480 μL:240 μL)의 아세토니트릴 (5 mL) 용액을 주변 온도에서 첨가했습니다. 50 ℃에서 17시간 동안 교반한 후, 반응을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. 디에틸 에테르로 추출한 후, 유기층을 추가의 포화 NaHCO3 수용액으로 세척하고, MgSO4로 건조시키고, 감압하에 농축시켰다. 잔류물을 MPLC (에틸 아세테이트/n-헵탄 = 1:5 내지 1:2)로 정제하여 생성물 (420 mg, 81%)을 수득하였다.(E)-8-bromo-3-(3,4-dichlorobenzylidene)-6-methylchroman-4-one (500 mg, 1.284 mmol), RuCl(p-cymene)[(R,R) -Ts-DPEN] (4 mg, 6.42 μmol) and a solution of DBU (2.5 eq)/formic acid (5 eq) (480 μL:240 μL) in acetonitrile (5 mL) was added at ambient temperature. After stirring at 50 °C for 17 h, the reaction was quenched with saturated aqueous NH 4 Cl solution at ambient temperature. After extraction with diethyl ether, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate/n-heptane = 1:5 to 1:2) to give the product (420 mg, 81%).

1H NMR (400 MHz, CDCl3) δ 7.42 - 7.35 (m, 2H), 7.33 - 7.28 (m, 1H), 7.11 (dd, J = 8.2, 2.1 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 4.43 (s, 1H), 4.25 - 4.15 (m, 1H), 4.13 (d, J = 11.0 Hz, 1H), 2.85 (dd, J = 13.7, 8.8 Hz, 1H), 2.63 (dd, J = 13.7, 6.9 Hz, 1H), 2.26 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.42 - 7.35 (m, 2H), 7.33 - 7.28 (m, 1H), 7.11 (dd, J = 8.2, 2.1 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 4.43 (s, 1H), 4.25 - 4.15 (m, 1H), 4.13 (d, J = 11.0 Hz, 1H), 2.85 (dd, J = 13.7, 8.8 Hz, 1H), 2.63 (dd , J = 13.7, 6.9 Hz, 1H), 2.26 (m, 4H).

Figure pat00050
Figure pat00050

단계 2) (R)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-one의 제조Step 2) Preparation of (R)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-one

CH2Cl2 (7 mL) 중 (R,R)-8-브로모-3-(3,4-디클로로벤질)-6-메틸크로만-4-올 (477 mg, 1.186 mmol) 및 분자체 4 Å (50 mg)의 용액을 10분 동안 교반하였다. 이어서, N-메틸모르폴린 N-옥사이드 (NMO, 139 mg, 1.186 mmol), 테트라프로필암모늄 퍼루테네이트 (TPAP, 42 mg, 0.119 mmol)를 0℃에서 첨가하고, 상온에서 2시간 동안 교반하였다. 어두운 색의 혼합물을 용리제로서 디에틸 에테르를 사용하여 셀라이트 상에서 여과하였다. 진공에서 농축한 후, 잔류물을 MPLC (에틸 아세테이트:n-헵탄, 20%)로 정제하여 생성물 (415 mg, 87%)을 얻는다.(R,R)-8-bromo-3-(3,4-dichlorobenzyl)-6-methylchroman-4-ol (477 mg, 1.186 mmol) and molecular sieve in CH 2 Cl 2 (7 mL) A solution of 4 Å (50 mg) was stirred for 10 minutes. Then, N-methylmorpholine N-oxide (NMO, 139 mg, 1.186 mmol) and tetrapropylammonium perruthenate (TPAP, 42 mg, 0.119 mmol) were added at 0°C and stirred at room temperature for 2 hours. The dark colored mixture was filtered over celite using diethyl ether as eluent. After concentration in vacuo, the residue is purified by MPLC (ethyl acetate:n-heptane, 20%) to give the product (415 mg, 87%).

1H NMR (400 MHz, CDCl3) δ 7.67 (dq, J = 2.3, 0.8 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 4.49 (dd, J = 11.5, 4.5 Hz, 1H), 4.23 (dd, J = 11.6, 9.1 Hz, 1H), 3.22 (dd, J = 14.2, 4.9 Hz, 1H), 2.95 (dt, J = 9.3, 4.7 Hz, 1H), 2.71 (dd, J = 14.2, 9.5 Hz, 1H), 2.31 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.67 (dq, J = 2.3, 0.8 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 4.49 (dd, J = 11.5, 4.5 Hz, 1H), 4.23 (dd, J = 11.6, 9.1 Hz, 1H), 3.22 (dd, J = 14.2, 4.9 Hz, 1H), 2.95 (dt, J = 9.3, 4.7 Hz, 1H), 2.71 (dd, J = 14.2, 9.5 Hz, 1H), 2.31 (s, 3H).

Figure pat00051
Figure pat00051

단계 3) (R)8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzyl)chroman-4-one의 제조Step 3) Preparation of (R)8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzyl)chroman-4-one

(R)8-브로모-3-(3,4-디클로로벤질)-6-메틸크로만-4-온 (409 mg, 1.022 mmol), NBS (218 mg, 1.226 mmol), AIBN (34 mg, 0.204 mmol) 및 MeOAc (10 mL)의 용액 을 60℃에서 2시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트 및 물로 희석하고, 에틸 아세테이트로 추출하여(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (에틸아세테이트:n-헵탄 = 1:10 내지 1:2)로 정제하여 생성물 (248 mg, 51%)을 수득하였다.(R) 8-bromo-3- (3,4-dichlorobenzyl) -6-methylchroman-4-one (409 mg, 1.022 mmol), NBS (218 mg, 1.226 mmol), AIBN (34 mg, 0.204 mmol) and MeOAc (10 mL) was refluxed at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:n-heptane = 1:10 to 1:2) to give the product (248 mg, 51%).

1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.2 Hz, 1H), 4.54 (dd, J = 11.6, 4.6 Hz, 1H), 4.43 (s, 2H), 4.27 (dd, J = 11.6, 9.4 Hz, 1H), 3.24 (dd, J = 14.2, 4.9 Hz, 1H), 2.99 (dt, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 14.3, 9.5 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d , J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.2 Hz, 1H), 4.54 (dd, J = 11.6, 4.6 Hz, 1H), 4.43 (s, 2H), 4.27 (dd, J = 11.6, 9.4 Hz, 1H), 3.24 (dd, J = 14.2, 4.9 Hz, 1H), 2.99 (dt, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 14.3, 9.5 Hz, 1H).

Figure pat00052
Figure pat00052

단계 4) (R)-8-bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 4) (R)-8-bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman Preparation of 4-one

(R)8-브로모-6-(브로모메틸)-3-(3,4-다이클로로벤질)크로만-4-온 (177 mg, 0.369 mmol), 1-메틸-1,3-다이하이드로-2H-이미다졸-2-이민 (148 mg, 1.109 mmol), DIEA (194 uL, 1.109 mmol), KI (61 mg, 0.369 mmol) 및 MeCN (4 mL)의 용액을 60℃에서 2시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2=1:50 내지 1:10)로 정제하여 생성물 (94 mg, 51%)을 얻었다.(R) 8-bromo-6- (bromomethyl) -3- (3,4-dichlorobenzyl) chroman-4-one (177 mg, 0.369 mmol), 1-methyl-1,3-di A solution of hydro-2H-imidazol-2-imine (148 mg, 1.109 mmol), DIEA (194 uL, 1.109 mmol), KI (61 mg, 0.369 mmol) and MeCN (4 mL) at 60 °C for 2 h. heated. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 =1:50 to 1:10) to give the product (94 mg, 51%).

1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.73 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.33 (s, 1H), 7.07 (dd, J = 8.3, 2.2 Hz, 1H), 6.59 (dd, J = 22.5, 2.5 Hz, 2H), 5.49 (s, 2H), 4.53 (dd, J = 11.6, 4.5 Hz, 1H), 4.27 (dd, J = 11.7, 9.4 Hz, 1H), 3.83 (s, 3H), 3.21 (dd, J = 14.2, 5.2 Hz, 1H), 3.00 (tt, J = 9.5, 4.9 Hz, 1H), 2.69 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 495.9 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.73 (s, 1H), 7.39 (d, J = 8.2 Hz , 1H), 7.33 (s, 1H), 7.07 (dd, J = 8.3, 2.2 Hz, 1H), 6.59 (dd, J = 22.5, 2.5 Hz, 2H), 5.49 (s, 2H), 4.53 (dd, J = 11.6, 4.5 Hz, 1H), 4.27 (dd, J = 11.7, 9.4 Hz, 1H), 3.83 (s, 3H), 3.21 (dd, J = 14.2, 5.2 Hz, 1H), 3.00 (tt, J = 9.5, 4.9 Hz, 1H), 2.69 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 495.9 (M+H) +

Figure pat00053
Figure pat00053

단계 5) (R)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 5) (R)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl Preparation of -2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

(R)-8-브로모-3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)크로만-4-온 (84.7 mg, 0.171 mmol)에 보론산 (71 mg, 0.342mmol), K2CO3 (71 mg, 0.513 mmol) 및 Pd(dppf))Cl2 (12.4 mg, 0.017 mmol)을 1,4-디옥산/H2O (3:1, 2mL) 중 첨가했다. 혼합물을 탈기한 다음 15시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 1,4-디옥산을 감압 하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 화합물 7 (18.5 mg, 19%)을 얻는다.(R)-8-bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl ) Chroman-4-one (84.7 mg, 0.171 mmol) boronic acid (71 mg, 0.342 mmol), K 2 CO 3 (71 mg, 0.513 mmol) and Pd(dppf))Cl 2 (12.4 mg, 0.017 mmol) ) in 1,4-dioxane/H 2 O (3:1, 2 mL). The mixture was degassed and then heated to 100° C. for 15 hours. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3) and dried over Na 2 SO 4 , concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give compound 7 (18.5 mg, 19%).

1H NMR (400 MHz, CDCl3) δ 8.86 (s, 3H), 7.82 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.47 (d, J = 13.9 Hz, 2H), 5.43 (s, 2H), 4.39 (s, 1H), 4.27 - 4.12 (m, 3H), 3.76 (s, 3H), 3.19 (d, J = 15.1 Hz, 1H), 2.92 (s, 1H), 2.71 (d, J = 11.6 Hz, 1H), 1.55 (d, J = 14.7 Hz, 3H). ESI-MS m/z 578.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.86 (s, 3H), 7.82 (s, 1H), 7.66 (s, 1H), 7.62 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H) , 7.32 (s, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.47 (d, J = 13.9 Hz, 2H), 5.43 (s, 2H), 4.39 (s, 1H), 4.27 - 4.12 ( m, 3H), 3.76 (s, 3H), 3.19 (d, J = 15.1 Hz, 1H), 2.92 (s, 1H), 2.71 (d, J = 11.6 Hz, 1H), 1.55 (d, J = 14.7 Hz, 3H). ESI-MS m/z 578.1 (M+H) +

Figure pat00054
Figure pat00054

화합물 8. (R)-3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 8. (R)-3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro -1H-imidazol-1-yl)methyl)chroman-4-one

(6-플루오로-2-메틸피리딘-3-일)보론산 (27 mg, 0.151 mmol)을 사용하여 화합물 8 (4.2 mg, 8% 수율)을 실시예 7, 단계 5에 기재된 절차로부터 제조하였다. 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J = 2.4 Hz, 1H), 7.70 (t, J = 8.1 Hz, 1H), 7.45 - 7.35 (m, 3H), 7.14 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 - 6.88 (m, 3H), 5.10 (s, 2H)4.44 (dd, J = 11.7, 4.6 Hz, 1H), 4.23 (dd, J = 11.6, 8.9 Hz, 1H), 3.51 (s, 3H), 3.20 - 3.04 (m, 2H), 2.78 (dd, J = 13.7, 7.7 Hz, 1H), 2.26 (s, 3H). ESI-MS m/z 525.1 (M+H)+ Compound 8 (4.2 mg, 8% yield) was prepared from the procedure described in Example 7, Step 5 using (6-fluoro-2-methylpyridin-3-yl)boronic acid (27 mg, 0.151 mmol). . 1H NMR (400 MHz, CD 3 OD) δ 7.83 (d, J = 2.4 Hz, 1H), 7.70 (t, J = 8.1 Hz, 1H), 7.45 - 7.35 (m, 3H), 7.14 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 - 6.88 (m, 3H), 5.10 (s, 2H) 4.44 (dd, J = 11.7, 4.6 Hz, 1H), 4.23 (dd, J = 11.6, 8.9 Hz, 1H) ), 3.51 (s, 3H), 3.20 - 3.04 (m, 2H), 2.78 (dd, J = 13.7, 7.7 Hz, 1H), 2.26 (s, 3H). ESI-MS m/z 525.1 (M+H) +

Figure pat00055
Figure pat00055

화합물 9. (R)-N-(4-(3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamideCompound 9. (R)-N-(4-(3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl )-4-oxochroman-8-yl)pyridin-2-yl)acetamide

N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (40 mg, 0.151 mmol)을 사용하여 화합물 9 (8.2 mg, 15% 수율)를 실시예 7, 단계 5에 기재된 절차로부터 제조하였다.Compound 9 (8.2 mg) using N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (40 mg, 0.151 mmol) , 15% yield) was prepared from the procedure described in Example 7, Step 5.

1H NMR (400 MHz, CD3OD) δ 8.32 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 5.2, 1.6 Hz, 1H), 7.21 (dd, J = 8.3, 2.1 Hz, 1H), 6.98 (d, J = 2.6 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 5.13 (s, 2H), 4.52 - 4.47 (m, 1H), 4.31 - 4.25 (m, 1H), 3.55 (s, 3H), 3.20 (d, J = 5.2 Hz, 1H), 3.14 - 3.10 (m, 1H), 2.83 - 2.80 (m, 1H), 2.20 (s, 3H). ESI-MS m/z 550.1 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 8.32 (d, J = 5.2 Hz, 1H), 8.27 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 2.1 Hz, 1H), 7.43 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 5.2, 1.6 Hz, 1H), 7.21 (dd, J = 8.3 , 2.1 Hz, 1H), 6.98 (d, J = 2.6 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 5.13 (s, 2H), 4.52 - 4.47 (m, 1H), 4.31 - 4.25 (m, 1H), 3.55 (s, 3H), 3.20 (d, J = 5.2 Hz, 1H), 3.14 - 3.10 (m, 1H), 2.83 - 2.80 (m, 1H), 2.20 (s, 3H). ESI-MS m/z 550.1 (M+H) +

Figure pat00056
Figure pat00056

화합물 10. (R)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 10. (R)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H -imidazol-1-yl)methyl)chroman-4-one

(3,5-비스(트리플루오로메틸)페닐)보론산 (40 mg, 0.151 mmol)을 사용하여 화합물 10 (15.7 mg, 25% 수율)을 실시예 7, 단계 5에 기재된 절차로부터 제조하였다.Compound 10 (15.7 mg, 25% yield) was prepared from the procedure described in Example 7, Step 5 using (3,5-bis(trifluoromethyl)phenyl)boronic acid (40 mg, 0.151 mmol).

1H NMR (400 MHz, CD3OD) δ 8.12 (s, 2H), 8.00 (s, 2H), 7.87 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 5.14 (s, 2H), 4.54 (dd, J = 11.6, 4.5 Hz, 1H), 4.31 (dd, J = 11.6, 8.8 Hz, 1H), 3.54 (s, 3H), 3.24 - 3.15 (m, 2H), 2.90 - 2.80 (m, 1H). ESI-MS m/z 628.0 (M+H)+ 1 H NMR (400 MHz, CD 3 OD) δ 8.12 (s, 2H), 8.00 (s, 2H), 7.87 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 2.4 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 6.99 (d, J = 2.6 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 5.14 (s , 2H), 4.54 (dd, J = 11.6, 4.5 Hz, 1H), 4.31 (dd, J = 11.6, 8.8 Hz, 1H), 3.54 (s, 3H), 3.24 - 3.15 (m, 2H), 2.90 - 2.80 (m, 1H). ESI-MS m/z 628.0 (M+H) +

Figure pat00057
Figure pat00057

화합물 11. (R)-3-(3,4-dichlorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 11. (R)-3-(3,4-dichlorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1 -yl)methyl)chroman-4-one

(3,4-디메톡시페닐)보론산 (27 mg, 0.151 mmol)을 사용하여 화합물 11 (21 mg, 38% 수율)을 실시예 7, 단계 5에 기재된 절차로부터 제조하였다.Compound 11 (21 mg, 38% yield) was prepared from the procedure described in Example 7, step 5 using (3,4-dimethoxyphenyl)boronic acid (27 mg, 0.151 mmol).

1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.08 (ddd, J = 16.0, 8.0, 2.1 Hz, 3H), 6.87 (d, J = 8.3 Hz, 1H), 6.46 (s, 2H), 5.44 (s, 2H), 4.41 (dd, J = 11.6, 4.6 Hz, 1H), 4.15 (dd, J = 10.6, 8.5 Hz, 1H), 3.90 (d, J = 8.9 Hz, 6H), 3.75 (s, 3H), 3.24 (dd, J = 14.2, 4.9 Hz, 1H), 2.97 (dt, J = 9.5, 4.7 Hz, 1H), 2.69 (dd, J = 14.3, 9.4 Hz, 1H). ESI-MS m/z 552.1 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 8.97 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.37 (d, J = 8.2 Hz , 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.08 (ddd, J = 16.0, 8.0, 2.1 Hz, 3H), 6.87 (d, J = 8.3 Hz, 1H), 6.46 (s, 2H) , 5.44 (s, 2H), 4.41 (dd, J = 11.6, 4.6 Hz, 1H), 4.15 (dd, J = 10.6, 8.5 Hz, 1H), 3.90 (d, J = 8.9 Hz, 6H), 3.75 ( s, 3H), 3.24 (dd, J = 14.2, 4.9 Hz, 1H), 2.97 (dt, J = 9.5, 4.7 Hz, 1H), 2.69 (dd, J = 14.3, 9.4 Hz, 1H). ESI-MS m/z 552.1 (M+H) +

Figure pat00058
Figure pat00058

화합물 12. (R)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-oneCompound 12. (R)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1 -(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one

(1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (49 mg, 0.1 mmol)을 사용하여 화합물 12 (18 mg, 17% 수율)를 실시예 7, 단계 5에 기재된 절차로부터 제조하였다.Compound 12 (18 mg) was prepared using (1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (49 mg, 0.1 mmol). , 17% yield) was prepared from the procedure described in Example 7, step 5.

1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.83 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.57 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.2, 2.2 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 5.41 (s, 2H), 4.44 - 4.34 (m, 3H), 4.18 (dd, J = 11.7, 8.6 Hz, 1H), 3.92 (t, J = 5.2 Hz, 2H), 3.78 (s, 3H), 3.68 - 3.56 (m, 7H), 3.52 - 3.48 (m, 2H), 3.32 (s, 3H), 3.19 (dd, J = 14.1, 5.0 Hz, 1H), 2.93 (dq, J = 9.2, 4.6 Hz, 1H), 2.70 (dd, J = 14.2, 9.5 Hz, 1H). ESI-MS m/z 696.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (s, 1H), 7.83 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.57 (s, 1H), 7.38 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.2, 2.2 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.57 (d, J = 8.2, 2.2 Hz, 1H ). 2.5 Hz, 1H), 5.41 (s, 2H), 4.44 - 4.34 (m, 3H), 4.18 (dd, J = 11.7, 8.6 Hz, 1H), 3.92 (t, J = 5.2 Hz, 2H), 3.78 ( s, 3H), 3.68 - 3.56 (m, 7H), 3.52 - 3.48 (m, 2H), 3.32 (s, 3H), 3.19 (dd, J = 14.1, 5.0 Hz, 1H), 2.93 (dq, J = 9.2, 4.6 Hz, 1H), 2.70 (dd, J = 14.2, 9.5 Hz, 1H). ESI-MS m/z 696.1 (M+H) +

Figure pat00059
Figure pat00059

화합물 13. (S)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 13. (S)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3 -methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

Figure pat00060
Figure pat00060

단계 1) (E)-3-(2-chloro-4-fluorobenzylidene)-8-bromo-2,3-dihydro-6-methylchromen-4-one의 제조Step 1) Preparation of (E)-3-(2-chloro-4-fluorobenzylidene)-8-bromo-2,3-dihydro-6-methylchromen-4-one

톨루엔 (242 mL) 중 8-브로모-2,3-디하이드로-6-메틸크로멘-4-온 (13.48 g, 55.91 mmol)의 용액에 2-클로로-4-플루오로벤즈알데히드 (9.31 g, 58.82 mmol) 및 p-톨루엔 설폰산 (1.06 g, 5.59 mmol)를 첨가하고, 반응혼합물을 15시간 동안 환류시켰다. 상온으로 냉각한 후, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, EtOAc (X3)를 추출하고, MgSO4로 건조하고, 감압 하에 농축하였다. 잔류물을 톨루엔(90 ml) 및 EtOH (200 mL)로부터 결정화하여 생성물 (15.51 g, 72.7%)을 고체로서 수득하였다. To a solution of 8-bromo-2,3-dihydro-6-methylchromen-4-one (13.48 g, 55.91 mmol) in toluene (242 mL) was added 2-chloro-4-fluorobenzaldehyde (9.31 g, 58.82 mmol) and p-toluene sulfonic acid (1.06 g, 5.59 mmol) were added and the reaction mixture was refluxed for 15 hours. After cooling to room temperature, the resulting residue was diluted with EtOAc, brine and H 2 O, EtOAc (X3) was extracted, dried over MgSO 4 and concentrated under reduced pressure. The residue was crystallized from toluene (90 ml) and EtOH (200 mL) to give the product (15.51 g, 72.7%) as a solid.

1H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.22 (m, 1H), 7.14 - 7.07 (m, 1H), 7.04 (m, 1H), 5.21 (s, 2H), 2.32 (s, 3H). ESI-MS m/z 383.0 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 (s, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.22 (m, 1H), 7.14 - 7.07 (m, 1H), 7.04 ( m, 1H), 5.21 (s, 2H), 2.32 (s, 3H). ESI-MS m/z 383.0 (M+H) +

Figure pat00061
Figure pat00061

단계 2) (3S,4S)-3-(2-chloro-4-fluorobenzyl)-8-bromo-3,4-dihydro-6-methyl-2H-chromen-4-ol의 제조Step 2) Preparation of (3S,4S)-3-(2-chloro-4-fluorobenzyl)-8-bromo-3,4-dihydro-6-methyl-2H-chromen-4-ol

(E)-3-(2-클로로-4-플루오로벤질리덴)-8-브로모-2,3-디하이드로-6-메틸크로멘-4-온 (7.5 g, 19.65 mmol)에 RuCl(p-시멘)[(S,S)-Ts-DPEN] (62.5 mg, 0.098 mmol) 및 DBU (2.5 eq)/포름산 (5.0 eq)(7.35 mL/3.7 mL)의 아세토니트릴 (75 mL) 용액을 상온에서 첨가하였다. 50℃에서 15시간 동안 교반한 후, 반응물을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. 디에틸 에테르로 추출한 후, 유기층을 추가의 포화 NaHCO3수용액으로 세척하고, MgSO4로 건조시키고, 감압하에 농축시켰다. 잔류물을 컬럼 크로마토그래피 (EtOAc:헵탄=1:15 내지 1:2)로 정제하여 생성물 (6.06 g, 80.0%)을 수득하였다.(E)-3-(2-chloro-4-fluorobenzylidene)-8-bromo-2,3-dihydro-6-methylchromen-4-one (7.5 g, 19.65 mmol) in RuCl ( A solution of p-cymene)[(S,S)-Ts-DPEN] (62.5 mg, 0.098 mmol) and DBU (2.5 eq)/formic acid (5.0 eq) (7.35 mL/3.7 mL) in acetonitrile (75 mL) It was added at room temperature. After stirring at 50° C. for 15 h, the reaction was quenched with saturated aqueous NH 4 Cl solution at ambient temperature. After extraction with diethyl ether, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:heptane=1:15 to 1:2) to give the product (6.06 g, 80.0%).

1H NMR (400 MHz, CDCl3) δ 7.28 (t, J = 7.3 Hz, 2H), 7.11 (dd, J = 8.5, 2.6 Hz, 1H), 6.96 (m, 1H), 6.93 (m, 1H), 4.44 (s, 1H), 4.14 (m, 2H), 2.94 (dd, J = 13.7, 7.2 Hz, 1H), 2.76 (dd, J = 13.7, 7.2 Hz, 1H), 2.43 - 2.30 (m, 1H), 2.22 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (t, J = 7.3 Hz, 2H), 7.11 (dd, J = 8.5, 2.6 Hz, 1H), 6.96 (m, 1H), 6.93 (m, 1H) , 4.44 (s, 1H), 4.14 (m, 2H), 2.94 (dd, J = 13.7, 7.2 Hz, 1H), 2.76 (dd, J = 13.7, 7.2 Hz, 1H), 2.43 - 2.30 (m, 1H) ), 2.22 (s, 3H).

Figure pat00062
Figure pat00062

단계 3) (S)-3-(2-chloro-4-fluorobenzyl)-8-bromo-2,3-dihydro-6-methylchromen-4-one의 제조Step 3) Preparation of (S)-3-(2-chloro-4-fluorobenzyl)-8-bromo-2,3-dihydro-6-methylchromen-4-one

(3S,4S)-3-(2-클로로-4-플루오로벤질)-8-브로모-3,4-디히드로-6-메틸-2H-크로멘-4-올 (6.0 g, 15.56 mmol) 및 분자체 4Å (600 mg)를 CH2Cl2 (100 mL) 중에서 10분 동안 교반하였다. 이어서, N-메틸모르폴린 N-옥사이드 (NMO, 1.91 g, 16.34 mmol), 테트라프로필암모늄 퍼루테네이트 (TPAP, 601 mg, 1.71 mmol)를 0℃에서 첨가하고, 상온에서 3시간 동안 교반을 계속하였다. 어두운 혼합물을 용리제로서 디에틸 에테르를 사용하여 셀라이트 상에서 여과하였다. 진공에서 농축한 후, 잔류물을 컬럼 크로마토그래피 (EtOAc:heptane= 1:20)로 정제하여 생성물 (4.74 g, 79.4%)을 얻었다.(3S,4S)-3-(2-chloro-4-fluorobenzyl)-8-bromo-3,4-dihydro-6-methyl-2H-chromen-4-ol (6.0 g, 15.56 mmol ) and molecular sieve 4Å (600 mg) were stirred in CH 2 Cl 2 (100 mL) for 10 min. Subsequently, N-methylmorpholine N-oxide (NMO, 1.91 g, 16.34 mmol) and tetrapropylammonium perruthenate (TPAP, 601 mg, 1.71 mmol) were added at 0°C, and stirring was continued at room temperature for 3 hours. did The dark mixture was filtered over celite using diethyl ether as eluent. After concentration in vacuo, the residue was purified by column chromatography (EtOAc: heptane= 1:20) to give the product (4.74 g, 79.4%).

1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 2.2, 0.8 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.23 - 7.19 (m, 1H), 7.12 (dd, J = 8.5, 2.6 Hz, 1H), 6.93 (td, J = 8.3, 2.7 Hz, 1H), 4.49 (dd, J = 11.5, 4.6 Hz, 1H), 4.26 (dd, J = 11.5, 9.7 Hz, 1H), 3.39 (dd, J = 14.2, 5.3 Hz, 1H), 3.12 - 2.99 (m, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H), 2.29 (s, 3H). ESI-MS m/z 382.9 (M-H)- 1H NMR (400 MHz, CDCl 3 ) δ 7.65 (dd, J = 2.2, 0.8 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.23 - 7.19 (m, 1H), 7.12 (dd, J = 8.5 , 2.6 Hz, 1H), 6.93 (td, J = 8.3, 2.7 Hz, 1H), 4.49 (dd, J = 11.5, 4.6 Hz, 1H), 4.26 (dd, J = 11.5, 9.7 Hz, 1H), 3.39 (dd, J = 14.2, 5.3 Hz, 1H), 3.12 - 2.99 (m, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H), 2.29 (s, 3H). ESI-MS m/z 382.9 (MH) -

Figure pat00063
Figure pat00063

단계 4) (S)-3-(2-chloro-4-fluorobenzyl)-8-bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one의 제조Step 4) Preparation of (S)-3-(2-chloro-4-fluorobenzyl)-8-bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one

(S)-3-(2-클로로-4-플루오로벤질)-8-브로모-2,3-디하이드로-6-메틸크로멘-4-온(4.7 g, 12.25 mmol), NBS (2.62 g, 14.70 mmol), AIBN (0.40 g, 2.45 mmol)을 MeOAc (94 mL) 용액중 60℃에서 5시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 EtOAc 및 H2O로 희석하고, EtOAc (X2)로 추출하여, MgSO4로 건조하고, 감압 하에 농축하였다. 잔류물을 컬럼 크로마토그래피(EtOAc:헵탄 = 1:20 내지 1:4)로 정제하여 생성물 (2.5 g, 44.1%)을 얻었다.(S)-3-(2-chloro-4-fluorobenzyl)-8-bromo-2,3-dihydro-6-methylchromen-4-one (4.7 g, 12.25 mmol), NBS (2.62 g, 14.70 mmol), AIBN (0.40 g, 2.45 mmol) was refluxed in a solution of MeOAc (94 mL) at 60° C. for 5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and H 2 O, extracted with EtOAc (X2), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:heptanes = 1:20 to 1:4) to give the product (2.5 g, 44.1%).

1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.13 (dd, J = 8.5, 2.6 Hz, 1H), 6.94 (td, J = 8.3, 2.6 Hz, 1H), 4.53 (dd, J = 11.6, 4.7 Hz, 1H), 4.41 (s, 2H), 4.30 (dd, J = 11.6, 9.9 Hz, 1H), 3.40 (dd, J = 14.2, 5.3 Hz, 1H), 3.18 - 3.03 (m, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 2.3 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.23 - 7.19 (m, 1H), 7.13 (dd, J = 8.5, 2.6 Hz, 1H), 6.94 (td, J = 8.3, 2.6 Hz, 1H), 4.53 (dd, J = 11.6, 4.7 Hz, 1H), 4.41 (s, 2H), 4.30 (dd, J = 11.6 , 9.9 Hz, 1H), 3.40 (dd, J = 14.2, 5.3 Hz, 1H), 3.18 - 3.03 (m, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H).

Figure pat00064
Figure pat00064

단계 5) (S)-8-bromo-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 5) (S)-8-bromo-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl ) Preparation of chroman-4-one

(S)-3-(2-클로로-4-플루오로벤질)-8-브로모-6-(브로모메틸)-2,3-디히드로크로멘-4-온 (1.0 g, 2.162 mmol), 1-메틸- 1,3-디히드로-2H-이미다졸-2-이민 (630 mg, 6.486 mmol), DIEA (1130 uL, 6.486 mmol) 및 KI (359 mg, 2.162 mmol)를 MeCN (20 mL) 용매 중 2시간 동안 가열하였다. 60°C 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2=1:50 내지 1:10)로 정제하여 생성물 (547 mg, 53%)을 얻었다.(S)-3-(2-chloro-4-fluorobenzyl)-8-bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one (1.0 g, 2.162 mmol) , 1-methyl-1,3-dihydro-2H-imidazol-2-imine (630 mg, 6.486 mmol), DIEA (1130 uL, 6.486 mmol) and KI (359 mg, 2.162 mmol) were added to MeCN (20 mL). ) in solvent for 2 h. After cooling to room temperature at 60°C, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 =1:50 to 1:10) to give the product (547 mg, 53%).

1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.65 (s, 1H), 7.24 (dd, J = 8.6, 6.0 Hz, 1H), 7.13 (dd, J = 8.4, 2.6 Hz, 1H), 6.96 (td, J = 8.3, 2.7 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 5.49 (s, 2H), 4.54 (dd, J = 11.6, 4.7 Hz, 1H), 4.32 (dd, J = 11.7, 9.9 Hz, 1H), 3.83 (s, 3H), 3.39 (dd, J = 14.2, 5.3 Hz, 1H), 3.12 (dt, J = 9.5, 4.7 Hz, 1H), 2.77 (dd, J = 14.2, 9.1 Hz, 1H). ESI-MS m/z 479.9 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.65 (s, 1H), 7.24 (dd, J = 8.6, 6.0 Hz, 1H), 7.13 (dd, J = 8.4, 2.6 Hz, 1H), 6.96 (td, J = 8.3, 2.7 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 5.49 (s, 2H), 4.54 (dd, J = 11.6, 4.7 Hz, 1H), 4.32 (dd, J = 11.7, 9.9 Hz, 1H), 3.83 (s, 3H), 3.39 (dd, J = 14.2, 5.3 Hz, 1H), 3.12 (dt, J = 9.5, 4.7 Hz, 1H), 2.77 (dd, J = 14.2, 9.1 Hz, 1H). ESI-MS m/z 479.9 (M+H) +

Figure pat00065
Figure pat00065

단계 6) (S)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 6) (S)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3 Preparation of -methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

(S)-8-브로모-3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온 (50 mg, 0.109 mmol)에 (1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)보론산 (33.7 mg, 0.162 mmol), Cs2CO3 (71 mg, 0.218 mmol) 및 Pd(amphos)Cl2 (7.7 mg, 0.011 mmol)을 1,4-디옥산/H2O (3:1, 2 mL) 중 첨가하였다. 혼합물을 탈기한 다음, 1시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 1,4-디옥산을 감압 하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 화합물 13 (12.8 mg, 22.7%)을 얻는다.(S)-8-bromo-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole-1- yl)methylchroman-4-one (50 mg, 0.109 mmol) (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (33.7 mg, 0.162 mmol) , Cs 2 CO 3 (71 mg, 0.218 mmol) and Pd(amphos)Cl 2 (7.7 mg, 0.011 mmol) in 1,4-dioxane/H 2 O (3:1, 2 mL). The mixture was degassed and then heated to 100 °C for 1 hour. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3) and dried over Na 2 SO 4 , concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give compound 13 (12.8 mg, 22.7%).

1H NMR (400 MHz, CDCl3) δ 7.87 - 7.75 (m, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 13.0 Hz, 1H), 7.23 (dd, J = 8.6, 6.0 Hz, 1H), 7.12 (dd, J = 8.4, 2.6 Hz, 1H), 6.95 (td, J = 8.2, 2.7 Hz, 1H), 6.67 - 6.55 (m, 2H), 5.43 (s, 2H), 4.40 (dd, J = 11.7, 4.6 Hz, 1H), 4.33 - 4.19 (m, 3H), 3.79 (s, 3H), 3.38 (dd, J = 14.0, 5.3 Hz, 1H), 3.06 (dd, J = 9.2, 4.7 Hz, 1H), 2.77 (dd, J = 14.2, 9.3 Hz, 1H), 1.55 (t, J = 7.3 Hz, 3H). ESI-MS m/z 562.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 - 7.75 (m, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 13.0 Hz, 1H), 7.23 (dd, J = 8.6, 6.0 Hz, 1H), 7.12 (dd, J = 8.4, 2.6 Hz, 1H), 6.95 (td, J = 8.2, 2.7 Hz, 1H), 6.67 - 6.55 (m, 2H), 5.43 (s, 2H) ), 4.40 (dd, J = 11.7, 4.6 Hz, 1H), 4.33 - 4.19 (m, 3H), 3.79 (s, 3H), 3.38 (dd, J = 14.0, 5.3 Hz, 1H), 3.06 (dd, J = 9.2, 4.7 Hz, 1H), 2.77 (dd, J = 14.2, 9.3 Hz, 1H), 1.55 (t, J = 7.3 Hz, 3H). ESI-MS m/z 562.1 (M+H) +

Figure pat00066
Figure pat00066

화합물 14. (S)-3-(2-chloro-4-fluorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 14. (S)-3-(2-chloro-4-fluorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3 -dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

(6-플루오로-2-메틸피리딘-3-일)보론산 (25 mg, 0.162 mmol)을 사용하여 화합물 14 (13.2 mg, 21% 수율)를 실시예 13, 단계 6에 기재된 절차로부터 제조하였다.Compound 14 (13.2 mg, 21% yield) was prepared from the procedure described in Example 13, step 6 using (6-fluoro-2-methylpyridin-3-yl)boronic acid (25 mg, 0.162 mmol). .

1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.4 Hz, 1H), 7.73 - 7.64 (m, 3H), 7.21 (dd, J = 8.5, 6.0 Hz, 1H), 7.12 (dd, J = 8.4, 2.7 Hz, 1H), 6.96 - 6.91 (m, 1H), 6.79 (dd, J = 8.2, 3.2 Hz, 1H), 6.62 (q, J = 2.5 Hz, 2H), 5.50 (s, 2H), 4.40 (dd, J = 11.6, 4.6 Hz, 1H), 4.26 - 4.17 (m, 1H), 3.79 (s, 3H), 3.41 (dd, J = 14.2, 5.3 Hz, 1H), 3.09 (dt, J = 9.5, 4.7 Hz, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H), 2.33 (s, 3H); ESI-MS m/z 509.1 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.85 (d, J = 2.4 Hz, 1H), 7.73 - 7.64 (m, 3H), 7.21 (dd, J = 8.5, 6.0 Hz, 1H), 7.12 (dd, J = 8.4, 2.7 Hz, 1H), 6.96 - 6.91 (m, 1H), 6.79 (dd, J = 8.2, 3.2 Hz, 1H), 6.62 (q, J = 2.5 Hz, 2H), 5.50 (s, 2H) ), 4.40 (dd, J = 11.6, 4.6 Hz, 1H), 4.26 - 4.17 (m, 1H), 3.79 (s, 3H), 3.41 (dd, J = 14.2, 5.3 Hz, 1H), 3.09 (dt, J = 9.5, 4.7 Hz, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H), 2.33 (s, 3H); ESI-MS m/z 509.1 (M+H) +

Figure pat00067
Figure pat00067

화합물 15. (S)-N-(4-(3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamideCompound 15. (S)-N-(4-(3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide

N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (41 mg, 0.157 mmol)을 사용하여 화합물 15 (11.8 mg, 21% 수율)을 실시예 13, 단계 6에 기재된 절차로부터 제조하였다.Compound 15 (11.8 mg) using N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (41 mg, 0.157 mmol) , 21% yield) was prepared from the procedure described in Example 13, Step 6.

1H NMR (400 MHz, CD3OD) δ 8.32 (dd, J = 5.3, 0.8 Hz, 1H), 8.28 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.31 (dd, J = 5.2, 1.6 Hz, 1H), 7.23 (dd, J = 8.7, 2.7 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.47 (dd, J = 11.7, 4.5 Hz, 1H), 4.34 (dd, J = 11.7, 8.5 Hz, 1H), 3.55 (s, 3H), 3.47 - 3.40 (m, 1H), 3.19 - 3.10 (m, 1H), 2.92 - 2.81 (m, 1H), 2.20 (s, 3H). ESI-MS m/z 532.1 (M-H)- 1 H NMR (400 MHz, CD 3 OD) δ 8.32 (dd, J = 5.3, 0.8 Hz, 1H), 8.28 (s, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.31 (dd, J = 5.2, 1.6 Hz, 1H), 7.23 (dd, J = 8.7, 2.7 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H), 5.15 (s, 2H), 4.47 (dd, J = 11.7, 4.5 Hz, 1H), 4.34 ( dd, J = 11.7, 8.5 Hz, 1H), 3.55 (s, 3H), 3.47 - 3.40 (m, 1H), 3.19 - 3.10 (m, 1H), 2.92 - 2.81 (m, 1H), 2.20 (s, 3H). ESI-MS m/z 532.1 (MH) -

Figure pat00068
Figure pat00068

화합물 16. (S)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 16. (S)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro -1H-imidazol-1-yl)methyl)chroman-4-one

(3,5-비스(트리플루오로메틸)페닐)보론산 (41 mg, 0.157 mmol)을 사용하여 화합물 16 (8.7 mg, 14% 수율)을 실시예 13, 단계 6에 기재된 절차로부터 제조하였다.Compound 16 (8.7 mg, 14% yield) was prepared from the procedure described in Example 13, step 6 using (3,5-bis(trifluoromethyl)phenyl)boronic acid (41 mg, 0.157 mmol).

1H NMR (400 MHz, CDCl3) δ 8.07 (s, 2H), 7.92 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.4 Hz, 2H), 7.24 (dd, J = 8.6, 5.9 Hz, 1H), 7.14 (dd, J = 8.4, 2.6 Hz, 1H), 6.96 (td, J = 8.2, 2.7 Hz, 1H), 6.61 - 6.55 (m, 2H), 5.54 (s, 2H), 4.44 (dd, J = 11.6, 4.6 Hz, 1H), 4.24 (dd, J = 11.6, 9.6 Hz, 1H), 3.80 (s, 3H), 3.48 - 3.39 (m, 1H), 3.13 (dq, J = 10.1, 5.5, 5.1 Hz, 1H), 2.82 (dd, J = 14.2, 9.4 Hz, 1H). ESI-MS m/z 612.0 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 8.07 (s, 2H), 7.92 (d, J = 2.4 Hz, 1H), 7.85 (d, J = 2.4 Hz, 2H), 7.24 (dd, J = 8.6, 5.9 Hz, 1H), 7.14 (dd, J = 8.4, 2.6 Hz, 1H), 6.96 (td, J = 8.2, 2.7 Hz, 1H), 6.61 - 6.55 (m, 2H), 5.54 (s, 2H), 4.44 (dd, J = 11.6, 4.6 Hz, 1H), 4.24 (dd, J = 11.6, 9.6 Hz, 1H), 3.80 (s, 3H), 3.48 - 3.39 (m, 1H), 3.13 (dq, J = 10.1, 5.5, 5.1 Hz, 1H), 2.82 (dd, J = 14.2, 9.4 Hz, 1H). ESI-MS m/z 612.0 (M+H) +

Figure pat00069
Figure pat00069

화합물 17. (S)-3-(2-chloro-4-fluorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 17. (S)-3-(2-chloro-4-fluorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol -1-yl)methyl)chroman-4-one

(3,4-디메톡시페닐) 보론산 (28 mg, 0.156 mmol)을 사용하여 화합물 17 (27.4 mg, 49% 수율)을 실시예 13, 단계 6에 기재된 절차로부터 제조하였다.Compound 17 (27.4 mg, 49% yield) was prepared from the procedure described in Example 13, step 6 using (3,4-dimethoxyphenyl) boronic acid (28 mg, 0.156 mmol).

1H NMR (400 MHz, CDCl3) δ 8.96 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.6, 6.0 Hz, 1H), 7.15 - 7.07 (m, 3H), 6.94 (td, J = 8.2, 2.7 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.46 (s, 2H), 5.44 (s, 2H), 4.42 (dd, J = 11.5, 4.7 Hz, 1H), 4.21 (dd, J = 11.5, 10.0 Hz, 1H), 3.90 (d, J = 9.2 Hz, 6H), 3.75 (s, 3H), 3.42 (dd, J = 14.2, 5.2 Hz, 1H), 3.10 (tt, J = 9.8, 5.0 Hz, 1H), 2.80 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 536.1 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 8.96 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.6, 6.0 Hz, 1H), 7.15 - 7.07 (m, 3H), 6.94 (td, J = 8.2, 2.7 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.46 (s, 2H), 5.44 ( s, 2H), 4.42 (dd, J = 11.5, 4.7 Hz, 1H), 4.21 (dd, J = 11.5, 10.0 Hz, 1H), 3.90 (d, J = 9.2 Hz, 6H), 3.75 (s, 3H) ), 3.42 (dd, J = 14.2, 5.2 Hz, 1H), 3.10 (tt, J = 9.8, 5.0 Hz, 1H), 2.80 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 536.1 (M+H) +

Figure pat00070
Figure pat00070

화합물 18. (R)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 18. (R)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3 -methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

Figure pat00071
Figure pat00071

단계 1) (3R,4R)-3-(2-chloro-4-fluorobenzyl)-8-bromo-3,4-dihydro-6-methyl-2H-chromen-4-ol의 제조Step 1) Preparation of (3R,4R)-3-(2-chloro-4-fluorobenzyl)-8-bromo-3,4-dihydro-6-methyl-2H-chromen-4-ol

(E)-3-(2-클로로-4-플루오로벤질리덴)-8-브로모-2,3-디하이드로-6-메틸크로멘-4-온 (8.0 g, 20.96 mmol)에 RuCl(p-시멘)[(R,R)-Ts-DPEN] (66.7 mg, 0.105 mmol), DBU(2.5 eq)/포름산(5.0 eq)(7.84 mL/3.95 mL)을 아세토니트릴 (80 mL) 용액에 상온에서 첨가하였다. 50℃에서 16시간 동안 교반한 후, 반응물을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. 디에틸 에테르로 추출한 후, 유기층을 추가의 포화 NaHCO3 수용액으로 세척하고, MgSO4로 건조시키고, 감압하에 농축시켰다. 잔류물을 컬럼 크로마토그래피 (MC:헵탄=2:1)로 정제하여 생성물 (6.84 g, 84.6%)을 얻었다.(E)-3-(2-chloro-4-fluorobenzylidene)-8-bromo-2,3-dihydro-6-methylchromen-4-one (8.0 g, 20.96 mmol) in RuCl ( p-cymene)[(R,R)-Ts-DPEN] (66.7 mg, 0.105 mmol), DBU (2.5 eq)/formic acid (5.0 eq) (7.84 mL/3.95 mL) in acetonitrile (80 mL) solution. It was added at room temperature. After stirring at 50° C. for 16 h, the reaction was quenched with saturated aqueous NH 4 Cl solution at ambient temperature. After extraction with diethyl ether, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (MC:heptane=2:1) to give the product (6.84 g, 84.6%).

1H NMR (400 MHz, CDCl3) δ 7.28 (t, J = 7.2 Hz, 2H), 7.11 (dd, J = 8.5, 2.3 Hz, 1H), 6.96 (s, 1H), 6.93 (m, 1H), 4.43 (s, 1H), 4.18 (m, 1H), 2.94 (dd, J = 13.7, 8.0 Hz, 1H), 2.76 (dd, J = 13.7, 7.2 Hz, 1H), 2.44 - 2.30 (m, 1H), 2.23 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.28 (t, J = 7.2 Hz, 2H), 7.11 (dd, J = 8.5, 2.3 Hz, 1H), 6.96 (s, 1H), 6.93 (m, 1H) , 4.43 (s, 1H), 4.18 (m, 1H), 2.94 (dd, J = 13.7, 8.0 Hz, 1H), 2.76 (dd, J = 13.7, 7.2 Hz, 1H), 2.44 - 2.30 (m, 1H) ), 2.23 (s, 3H).

Figure pat00072
Figure pat00072

단계 2) (R)-3-(2-chloro-4-fluorobenzyl)-8-bromo-2,3-dihydro-6-methylchromen-4-one의 제조Step 2) Preparation of (R)-3-(2-chloro-4-fluorobenzyl)-8-bromo-2,3-dihydro-6-methylchromen-4-one

(3R,4R)-3-(2-클로로-4-플루오로벤질)-8-브로모-3,4-디하이드로-6-메틸-2H-크로멘-4-올 (6.65 g, 17.24 mmol) 및 분자체 4Å (800 mg)를 CH2Cl2 (110 mL) 중 10분 동안 교반하였다. 이어서, N-메틸모르폴린 N-옥사이드 (NMO, 2.12 g, 18.11 mmol), 테트라프로필암모늄 퍼루테네이트 (TPAP, 667 mg, 1.90 mmol)를 0℃에서 첨가하고, 상온에서 3.5시간 동안 계속 교반하였다. 어두운 혼합물을 용리제로서 디에틸 에테르를 사용하여 셀라이트 상에서 여과하였다. 진공에서 농축한 후, 잔류물을 컬럼 크로마토그래피 (EtOAC:헤파탄=1:20)로 정제하여 생성물 (5.85 g, 88.5%)을 얻었다.(3R,4R)-3-(2-chloro-4-fluorobenzyl)-8-bromo-3,4-dihydro-6-methyl-2H-chromen-4-ol (6.65 g, 17.24 mmol ) and molecular sieve 4Å (800 mg) were stirred in CH 2 Cl 2 (110 mL) for 10 min. N-methylmorpholine N-oxide (NMO, 2.12 g, 18.11 mmol), tetrapropylammonium perruthenate (TPAP, 667 mg, 1.90 mmol) were then added at 0°C and stirring was continued at room temperature for 3.5 hours. . The dark mixture was filtered over celite using diethyl ether as eluent. After concentration in vacuo, the residue was purified by column chromatography (EtOAC: Hepatan=1:20) to give the product (5.85 g, 88.5%).

1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 2.2, 0.8 Hz, 1H), 7.55 (dd, J = 2.2, 0.6 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.12 (dd, J = 8.5, 2.6 Hz, 1H), 6.93 (td, J = 8.2, 2.7 Hz, 1H), 4.49 (dd, J = 11.5, 4.6 Hz, 1H), 4.26 (dd, J = 11.5, 9.7 Hz, 1H), 3.39 (dd, J = 14.2, 5.3 Hz, 1H), 3.12 - 3.01 (m, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 385.0 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.65 (dd, J = 2.2, 0.8 Hz, 1H), 7.55 (dd, J = 2.2, 0.6 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.12 ( dd, J = 8.5, 2.6 Hz, 1H), 6.93 (td, J = 8.2, 2.7 Hz, 1H), 4.49 (dd, J = 11.5, 4.6 Hz, 1H), 4.26 (dd, J = 11.5, 9.7 Hz) , 1H), 3.39 (dd, J = 14.2, 5.3 Hz, 1H), 3.12 - 3.01 (m, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 385.0 (M+H) +

Figure pat00073
Figure pat00073

단계 3) (R)-3-(2-chloro-4-fluorobenzyl)-8-bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one의 제조Step 3) Preparation of (R)-3-(2-chloro-4-fluorobenzyl)-8-bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one

(R)-3-(2-클로로-4-플루오로벤질)-8-브로모-2,3-디하이드로-6-메틸크로멘-4-온(5.81 g, 15.14 mmol), NBS (3.23 g, 18.17 mmol), AIBN (0.50 g, 3.03 mmol)을 MeOAc (116 mL)용액 중 60℃에서 5시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 EtOAc 및 H2O로 희석하고, EtOAc (X2)로 추출하고, MgSO4로 건조하고, 감압 하에 농축하였다. 잔류물을 컬럼 크로마토그래피 (EtOAc:헵탄 = 1:20)로 정제하여 생성물 (4.8 g, 68.5%)을 얻었다.(R)-3-(2-chloro-4-fluorobenzyl)-8-bromo-2,3-dihydro-6-methylchromen-4-one (5.81 g, 15.14 mmol), NBS (3.23 g, 18.17 mmol), AIBN (0.50 g, 3.03 mmol) was refluxed in MeOAc (116 mL) at 60 °C for 5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and H 2 O, extracted with EtOAc (X2), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:heptane = 1:20) to give the product (4.8 g, 68.5%).

1H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.13 (dd, J = 8.5, 2.6 Hz, 1H), 6.94 (td, J = 8.3, 2.6 Hz, 1H), 4.53 (dd, J = 11.6, 4.7 Hz, 1H), 4.41 (s, 2H), 4.30 (dd, J = 11.5, 9.9 Hz, 1H), 3.40 (dd, J = 14.1, 5.4 Hz, 1H), 3.09 (m, 1H), 2.77 (dd, J = 14.3, 9.2 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.86 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.13 (dd, J = 8.5, 2.6 Hz, 1H), 6.94 (td, J = 8.3, 2.6 Hz, 1H), 4.53 (dd, J = 11.6, 4.7 Hz, 1H), 4.41 (s, 2H), 4.30 (dd, J = 11.5 , 9.9 Hz, 1H), 3.40 (dd, J = 14.1, 5.4 Hz, 1H), 3.09 (m, 1H), 2.77 (dd, J = 14.3, 9.2 Hz, 1H).

Figure pat00074
Figure pat00074

단계 4) (R)-8-bromo-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 4) (R)-8-bromo-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl ) Preparation of chroman-4-one

(R)-3-(2-클로로-4-플루오로벤질)-8-브로모-6-(브로모메틸)-2,3-디히드로크로멘-4-온 (1.0 g, 2.162 mmol), 1-메틸- 1,3-디히드로-2H-이미다졸-2-이민 (630 mg, 6.486 mmol), DIEA (1130 uL, 6.486 mmol)및 KI (359 mg, 2.162 mmol)를 MeCN (20 mL)중 2시간 동안 가열하였다. 60°C 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2=1:50 내지 1:10)로 정제하여 생성물 (469 mg, 45%)을 얻었다.(R)-3-(2-chloro-4-fluorobenzyl)-8-bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one (1.0 g, 2.162 mmol) , 1-methyl-1,3-dihydro-2H-imidazol-2-imine (630 mg, 6.486 mmol), DIEA (1130 uL, 6.486 mmol) and KI (359 mg, 2.162 mmol) were added to MeCN (20 mL). ) for 2 hours. After cooling to room temperature at 60°C, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 =1:50 to 1:10) to give the product (469 mg, 45%).

1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.66 (s, 1H), 7.23 (dd, J = 8.6, 6.0 Hz, 1H), 7.13 (dd, J = 8.4, 2.6 Hz, 1H), 7.00 - 6.91 (m, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 5.48 (d, J = 1.7 Hz, 2H), 4.54 (dd, J = 11.6, 4.7 Hz, 1H), 4.31 (dd, J = 11.7, 9.9 Hz, 1H), 3.83 (s, 3H), 3.38 (dd, J = 14.2, 5.3 Hz, 1H), 3.11 (tt, J = 9.8, 5.0 Hz, 1H), 2.76 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 479.9 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.66 (s, 1H), 7.23 (dd, J = 8.6, 6.0 Hz, 1H), 7.13 (dd, J = 8.4, 2.6 Hz, 1H), 7.00 - 6.91 (m, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 5.48 (d, J = 1.7 Hz, 2H), 4.54 (dd, J = 11.6, 4.7 Hz, 1H), 4.31 (dd, J = 11.7, 9.9 Hz, 1H), 3.83 (s, 3H), 3.38 (dd, J = 14.2, 5.3 Hz, 1H), 3.11 (tt, J = 9.8, 5.0 Hz, 1H), 2.76 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 479.9 (M+H) +

Figure pat00075
Figure pat00075

단계 5) (R)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 5) (R)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3 Preparation of -methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

(R)-8-브로모-3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-다이하이드로-1H-이미다졸-1-일)메틸)크로만-4-온 (50 mg, 0.10 mmol), (1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)보론산 (31 mg, 0.15 mmol), Cs2CO3 (65 mg, 0.2 mmol) 및 Pd(amphos)Cl2 (7 mg, 0.01 mmol)을 1,4-디옥산/H2O (3:1, 2 mL) 중 첨가하였다. 혼합물을 탈기한 다음, 1시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 1,4-디옥산을 감압 하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 화합물 18 (11.7 mg, 20%)을 얻는다.(R)-8-bromo-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole-1- yl) methyl) chroman-4-one (50 mg, 0.10 mmol), (1-ethyl-3- (trifluoromethyl) -1H-pyrazol-4-yl) boronic acid (31 mg, 0.15 mmol) , Cs 2 CO 3 (65 mg, 0.2 mmol) and Pd(amphos)Cl 2 (7 mg, 0.01 mmol) in 1,4-dioxane/H 2 O (3:1, 2 mL). The mixture was degassed and then heated to 100 °C for 1 hour. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3) and dried over Na 2 SO 4 , concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give compound 18 (11.7 mg, 20%).

1H NMR (300 MHz, CDCl3) δ 7.87 - 7.73 (m, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.6, 6.0 Hz, 1H), 7.11 (dd, J = 8.5, 2.6 Hz, 1H), 7.01 - 6.88 (m, 1H), 6.65 - 6.48 (m, 2H), 5.43 (s, 2H), 4.40 (dd, J = 11.7, 4.6 Hz, 1H), 4.32 - 4.15 (m, 3H), 3.79 (s, 3H), 3.37 (dd, J = 14.1, 5.3 Hz, 1H), 3.06 (tt, J = 9.4, 4.9 Hz, 1H), 2.76 (dd, J = 14.1, 9.2 Hz, 1H), 1.54 (t, J = 7.3 Hz, 3H). ESI-MS m/z 562.1 (M+H)+ 1 H NMR (300 MHz, CDCl 3 ) δ 7.87 - 7.73 (m, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.6, 6.0 Hz, 1H), 7.11 (dd, J = 8.5, 2.6 Hz, 1H), 7.01 - 6.88 (m, 1H), 6.65 - 6.48 (m, 2H), 5.43 (s, 2H), 4.40 (dd, J = 11.7, 4.6 Hz, 1H), 4.32 - 4.15 (m, 3H), 3.79 (s, 3H), 3.37 (dd, J = 14.1, 5.3 Hz, 1H), 3.06 (tt, J = 9.4, 4.9 Hz, 1H), 2.76 (dd, J = 14.1 , 9.2 Hz, 1H), 1.54 (t, J = 7.3 Hz, 3H). ESI-MS m/z 562.1 (M+H) +

Figure pat00076
Figure pat00076

화합물 19. (R)-3-(2-chloro-4-fluorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 19. (R)-3-(2-chloro-4-fluorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3 -dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

(6-플루오로-2-메틸피리딘-3-일)보론산 (23.2 mg, 0.15 mmol)을 사용하여 화합물 19 (10 mg, 19% 수율)를 실시예 18, 단계 5에 기재된 절차로부터 제조하였다.Compound 19 (10 mg, 19% yield) was prepared from the procedure described in Example 18, Step 5 using (6-fluoro-2-methylpyridin-3-yl)boronic acid (23.2 mg, 0.15 mmol). .

1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 2.4 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.21 (dd, J = 8.6, 6.0 Hz, 1H), 7.11 (dd, J = 8.4, 2.6 Hz, 1H), 6.94 (td, J = 8.2, 2.7 Hz, 1H), 6.79 (dd, J = 8.3, 3.2 Hz, 1H), 6.62 (d, J = 1.5 Hz, 2H), 5.51 (s, 2H), 4.40 (dd, J = 11.6, 4.7 Hz, 1H), 4.21 (dd, J = 11.6, 9.6 Hz, 1H), 3.79 (s, 3H), 3.41 (dd, J = 14.2, 5.2 Hz, 1H), 3.08 (dq, J = 9.7, 4.7 Hz, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H), 2.33 (s, 3H). ESI-MS m/z 509.2 (M+H)+ 1H NMR (300 MHz, CDCl 3 ) δ 7.86 (d, J = 2.4 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.21 (dd, J = 8.6, 6.0 Hz, 1H), 7.11 (dd, J = 8.4, 2.6 Hz, 1H), 6.94 (td, J = 8.2, 2.7 Hz, 1H), 6.79 (dd, J = 8.3, 3.2 Hz, 1H), 6.62 (d, J = 1.5 Hz, 2H), 5.51 (s, 2H), 4.40 (dd, J = 11.6, 4.7 Hz, 1H), 4.21 (dd, J = 11.6, 9.6 Hz, 1H), 3.79 (s, 3H), 3.41 (dd, J = 14.2, 5.2 Hz, 1H), 3.08 (dq, J = 9.7, 4.7 Hz, 1H), 2.77 (dd, J = 14.2, 9.2 Hz, 1H), 2.33 (s, 3H). ESI-MS m/z 509.2 (M+H) +

Figure pat00077
Figure pat00077

화합물 20. (R)-N-(4-(3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamideCompound 20. (R)-N-(4-(3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide

N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (39.3 mg, 0.15 mmol)을 사용하여 화합물 20 (12.8 mg, 23% 수율)을 실시예 18, 단계 5에 기재된 절차로부터 제조하였다.Compound 20 (12.8 mg) using N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide (39.3 mg, 0.15 mmol) , 23% yield) was prepared from the procedure described in Example 18, Step 5.

1H NMR (300 MHz, CDCl3) δ 8.32 (s, 2H), 8.26 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.79 (s, 1H), 7.30 (dd, J = 3.8, 2.2 Hz, 1H), 7.12 (dd, J = 8.4, 2.6 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.61 (s, 2H), 5.46 (s, 2H), 4.44 (dd, J = 11.6, 4.7 Hz, 1H), 4.29 - 4.19 (m, 1H), 3.78 (s, 3H), 3.47 - 3.40 (m, 1H), 3.11 (dd, J = 9.1, 4.2 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.23 (s, 3H). ESI-MS m/z 534.1 (M+H)+ 1 H NMR (300 MHz, CDCl 3 ) δ 8.32 (s, 2H), 8.26 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.79 (s, 1H), 7.30 (dd, J = 3.8, 2.2 Hz, 1H), 7.12 (dd, J = 8.4, 2.6 Hz, 1H), 7.00 - 6.93 (m, 1H), 6.61 (s, 2H), 5.46 (s, 2H), 4.44 (dd, J = 11.6, 4.7 Hz, 1H), 4.29 - 4.19 (m, 1H), 3.78 (s, 3H), 3.47 - 3.40 (m, 1H), 3.11 (dd, J = 9.1, 4.2 Hz, 1H), 2.82 - 2.73 (m, 1H), 2.23 (s, 3H). ESI-MS m/z 534.1 (M+H) +

Figure pat00078
Figure pat00078

화합물 21. (R)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 21. (R)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro -1H-imidazol-1-yl)methyl)chroman-4-one

(3,5-비스(트리플루오로메틸)페닐)보론산 (38.7 mg, 0.15 mmol)을 사용하여 화합물 21 (9.5 mg, 15% 수율)을 실시예 18, 단계 5에 기재된 절차로부터 제조하였다.Compound 21 (9.5 mg, 15% yield) was prepared from the procedure described in Example 18, step 5 using (3,5-bis(trifluoromethyl)phenyl)boronic acid (38.7 mg, 0.15 mmol).

1H NMR (300 MHz, CDCl3) δ 8.06 (s, 2H), 7.89 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 2.4 Hz, 3H), 7.24 - 7.20 (m, 1H), 7.14 (dd, J = 8.4, 2.6 Hz, 1H), 6.96 (td, J = 8.2, 2.7 Hz, 1H), 6.62 - 6.51 (m, 2H), 5.51 (s, 2H), 4.44 (dd, J = 11.6, 4.7 Hz, 1H), 4.24 (dd, J = 11.6, 9.5 Hz, 1H), 3.78 (s, 3H), 3.43 (dd, J = 14.1, 5.2 Hz, 1H), 3.13 (dd, J = 9.6, 4.9 Hz, 1H), 2.87 - 2.78 (m, 1H). ESI-MS m/z 612.1 (M+H)+ 1 H NMR (300 MHz, CDCl 3 ) δ 8.06 (s, 2H), 7.89 (d, J = 2.3 Hz, 1H), 7.85 (d, J = 2.4 Hz, 3H), 7.24 - 7.20 (m, 1H) , 7.14 (dd, J = 8.4, 2.6 Hz, 1H), 6.96 (td, J = 8.2, 2.7 Hz, 1H), 6.62 - 6.51 (m, 2H), 5.51 (s, 2H), 4.44 (dd, J = 11.6, 4.7 Hz, 1H), 4.24 (dd, J = 11.6, 9.5 Hz, 1H), 3.78 (s, 3H), 3.43 (dd, J = 14.1, 5.2 Hz, 1H), 3.13 (dd, J = 9.6, 4.9 Hz, 1H), 2.87 - 2.78 (m, 1H). ESI-MS m/z 612.1 (M+H) +

Figure pat00079
Figure pat00079

화합물 22. (R)-3-(2-chloro-4-fluorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 22. (R)-3-(2-chloro-4-fluorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol -1-yl)methyl)chroman-4-one

(3,4-디메톡시페닐)보론산 (28 mg, 0.156 mmol)을 사용하여 화합물 22 (8.1 mg, 15% 수율)를 실시예 18, 단계 5에 기재된 절차로부터 제조하였다.Compound 22 (8.1 mg, 15% yield) was prepared from the procedure described in Example 18, step 5 using (3,4-dimethoxyphenyl)boronic acid (28 mg, 0.156 mmol).

1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.6, 6.0 Hz, 1H), 7.16 - 7.06 (m, 3H), 6.94 (td, J = 8.2, 2.7 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.45 (s, 2H), 5.42 (s, 2H), 4.42 (dd, J = 11.5, 4.7 Hz, 1H), 4.25 - 4.18 (m, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H), 3.42 (dd, J = 14.2, 5.3 Hz, 1H), 3.10 (dt, J = 9.6, 4.8 Hz, 1H), 2.80 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 536.0 (M+H)+. 1H NMR (400 MHz, CDCl 3 ) δ 8.90 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.23 (dd, J = 8.6, 6.0 Hz, 1H), 7.16 - 7.06 (m, 3H), 6.94 (td, J = 8.2, 2.7 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.45 (s, 2H), 5.42 ( s, 2H), 4.42 (dd, J = 11.5, 4.7 Hz, 1H), 4.25 - 4.18 (m, 1H), 3.91 (s, 3H), 3.89 (s, 3H), 3.74 (s, 3H), 3.42 (dd, J = 14.2, 5.3 Hz, 1H), 3.10 (dt, J = 9.6, 4.8 Hz, 1H), 2.80 (dd, J = 14.2, 9.2 Hz, 1H). ESI-MS m/z 536.0 (M+H) + .

Figure pat00080
Figure pat00080

화합물 23. tert-butyl (S)-( (S)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6- ((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamateCompound 23. tert-butyl (S)-( (S)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino- 3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate

Figure pat00081
Figure pat00081

단계 1) tert-butyl 4-((E)-(8-bromo-6-methyl-4-oxo-2H-chromen-3(4H)- ylidene)methyl)cyclohexylcarbamate의 제조Step 1) Preparation of tert-butyl 4-((E)-(8-bromo-6-methyl-4-oxo-2H-chromen-3(4H)-ylidene)methyl)cyclohexylcarbamate

8-브로모-2,3-다이하이드로-6-메틸크로멘-4-온 (5.0 g, 20.74 mmol)의 MeOH (75 mL) 용액에 tert-부틸 4-포르밀사이클로헥실카바메이트 (9.51 g, 41.48 mmol) 및 피롤리딘 (1.77 g, 24.89 mmol)을 첨가하였다. 반응혼합물을 4시간 동안 환류시켰다. 상온으로 냉각한 후, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, EtOAc (X2)로 추출하여, MgSO4로 건조하고, 감압 하에 농축하였다. 잔류물을 컬럼 크로마토그래피 (EtOAc:헵탄 = 1:10 내지 1:8)로 정제하여 생성물 (7.41 g, 79.3%)을 얻었다.To a solution of 8-bromo-2,3-dihydro-6-methylchromen-4-one (5.0 g, 20.74 mmol) in MeOH (75 mL) was added tert-butyl 4-formylcyclohexylcarbamate (9.51 g , 41.48 mmol) and pyrrolidine (1.77 g, 24.89 mmol) were added. The reaction mixture was refluxed for 4 hours. After cooling to room temperature, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with EtOAc (X2), dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:heptanes = 1:10 to 1:8) to give the product (7.41 g, 79.3%).

1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.49 (s, 1H), 6.68 (d, J = 10.1 Hz, 1H), 5.04 (s, 2H), 3.36 (m, 1H), 2.26 (s, 3H), 2.01 (m, 2H), 1.76 - 1.60 (m, 3H), 1.38 (s, 9H), 1.24 - 1.17 (m, 1H), 1.11 (m, 2H), 0.82 (m, 1H). ESI-MS m/z 450.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.66 (s, 1H), 7.49 (s, 1H), 6.68 (d, J = 10.1 Hz, 1H), 5.04 (s, 2H), 3.36 (m, 1H) , 2.26 (s, 3 H), 2.01 (m, 2H), 1.76 - 1.60 (m, 3H), 1.38 (s, 9H), 1.24 - 1.17 (m, 1H), 1.11 (m, 2H), and m, 1H). ESI-MS m/z 450.1 (M+H) +

Figure pat00082
Figure pat00082

단계 2) tert-butyl 4-(((S)-8-bromo-3,4-dihydro-6-methyl-4-oxo-2H- chromen-3-yl)methyl)cyclohexylcarbamate의 제조Step 2) Preparation of tert-butyl 4-(((S)-8-bromo-3,4-dihydro-6-methyl-4-oxo-2H- chromen-3-yl)methyl)cyclohexylcarbamate

tert-부틸 4-((E)-(8-브로모-6-메틸-4-옥소-2H-크로멘-3(4H)-일리덴)메틸)사이클로헥실카바메이트 (7.41 g, 16.45 mmol)의 아세토니트릴 (150 mL) 용액에 RuCl(p-시멘)[(S,S)-Ts-DPEN] (62.3 mg, 0.10 mmol), DBU (2.5 eq)/포름산 (5.0 eq) (6.16 ml / 3.10 ml)의 아세토니트릴 (150 mL) 용액을 상온에서 첨가하였다. 상온에서 4시간 동안 교반한 후, 반응을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. 디에틸 에테르로 추출한 후, 유기층을 추가의 포화 NaHCO3수용액으로 세척하고, MgSO4로 건조시키고, 감압하에 농축시켰다. 잔류물을 컬럼 크로마토그래피 (EtOAc:헵탄 = 1:9)로 정제하여 생성물 (2.95 g, 39.6%)을 얻었다.tert-butyl 4-((E)-(8-bromo-6-methyl-4-oxo-2H-chromen-3(4H)-ylidene)methyl)cyclohexylcarbamate (7.41 g, 16.45 mmol) of RuCl(p-cymene)[(S,S)-Ts-DPEN] (62.3 mg, 0.10 mmol), DBU (2.5 eq)/formic acid (5.0 eq) (6.16 ml / 3.10 ml) of acetonitrile (150 mL) solution was added at room temperature. After stirring at room temperature for 4 hours, the reaction was quenched with saturated aqueous NH 4 Cl solution at room temperature. After extraction with diethyl ether, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:heptane = 1:9) to give the product (2.95 g, 39.6%).

1H NMR (400 MHz, CDCl3) δ 7.61 (s, 1H), 7.53 (s, 1H), 4.55 (dd, J = 11.5, 4.4 Hz, 1H), 4.27 (dd, J = 11.5, 8.4 Hz, 1H), 3.38 (m, 1H), 2.72 (m, 1H), 2.03 - 1.94 (m, 2H), 1.87 - 1.79 (m, 1H), 1.79 - 1.70 (m, 2H), 1.34 - 1.27 (m, 1H), 1.25 (m, 4H), 1.12 - 0.96 (m, 2H), 0.86 (m, 1H). ESI-MS m/z 450.1 (M-H)- 1H NMR (400 MHz, CDCl 3 ) δ 7.61 (s, 1H), 7.53 (s, 1H), 4.55 (dd, J = 11.5, 4.4 Hz, 1H), 4.27 (dd, J = 11.5, 8.4 Hz, 1H), 3.38 (m, 1H), 2.72 (m, 1H), 2.03 - 1.94 (m, 2H), 1.87 - 1.79 (m, 1H), 1.79 - 1.70 (m, 2H), 1.34 - 1.27 (m, 1H), 1.25 (m, 4H), 1.12 - 0.96 (m, 2H), 0.86 (m, 1H). ESI-MS m/z 450.1 (MH) -

Figure pat00083
Figure pat00083

단계 3) tert-butyl 4-(((S)-8-bromo-6-(bromomethyl)-3,4-dihydro-4-oxo-2H- chromen-3-yl)methyl)cyclohexylcarbamate의 제조Step 3) Preparation of tert-butyl 4-(((S)-8-bromo-6-(bromomethyl)-3,4-dihydro-4-oxo-2H- chromen-3-yl)methyl)cyclohexylcarbamate

tert-부틸 4-(((S)-8-브로모-3,4-디히드로-6-메틸-4-옥소-2H-크로멘-3-일)메틸)시클로헥실카르바메이트 (0.78 g, 1.724 mmol), NBS (0.37 g, 2.062 mmol) 및 AIBN (0.055 g, 0.335 mmol)을 DCM (35 mL)용액 중 60℃에서 5시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 DCM 및 H2O로 희석하고, DCM(X2)을 추출하고, MgSO4로 건조하고, 감압 하에 농축하였다. 잔류물을 컬럼 크로마토그래피 (EtOAc:헵탄 = 1:10)로 정제하여 생성물 (0.46 g, 50.2%)을 얻었다.tert-butyl 4-(((S)-8-bromo-3,4-dihydro-6-methyl-4-oxo-2H-chromen-3-yl)methyl)cyclohexylcarbamate (0.78 g , 1.724 mmol), NBS (0.37 g, 2.062 mmol) and AIBN (0.055 g, 0.335 mmol) were refluxed at 60° C. for 5 h in DCM (35 mL). After cooling to room temperature, the reaction mixture was diluted with DCM and H 2 O, DCM (X2) was extracted, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:heptane = 1:10) to give the product (0.46 g, 50.2%).

1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.76 (s, 1H), 4.59 (dd, J = 11.6, 4.4 Hz, 1H), 4.40 (s, 2H), 4.38 - 4.26 (m, 1H), 3.38 (m, 1H), 2.76 (m, 1H), 1.98 (m, 1H), 1.79 (m, 3H), 1.41 (s, 9H), 1.30 (m, 1H), 1.25 (m, 2H), 1.06 (m, 2H), 0.85 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (s, 1H), 7.76 (s, 1H), 4.59 (dd, J = 11.6, 4.4 Hz, 1H), 4.40 (s, 2H), 4.38 - 4.26 ( m, 1H), 3.38 (m, 1H), 2.76 (m, 1H), 1.98 (m, 1H), 1.79 (m, 3H), 1.41 (s, 9H), 1.30 (m, 1H), 1.25 (m , 2H), 1.06 (m, 2H), 0.85 (m, 1H).

Figure pat00084
Figure pat00084

단계 4) tert-butyl (S)-(4-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H- imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate의 제조Step 4) tert-butyl (S)-(4-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4- Preparation of oxochroman-3-yl)methyl)cyclohexyl)carbamate

tert-부틸 4-(((S)-8-브로모-6-(브로모메틸)-3,4-디히드로-4-옥소-2H-크로멘-3-일)메틸)시클로헥실카르바메이트 (500 mg, 0.94 mmol), 1-메틸-1,3-디하이드로-2H-이미다졸-2-이민 (273.8 mg, 2.82 mmol), DIEA (500 uL, 2.82 mmol) 및 KI (156 mg, 0.94 mmol)를 MeCN (10 mL) 용매 중 60℃에서 2시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2 = 1:50 내지 1:10)로 정제하여 생성물 (164.5 mg, 32%)을 얻었다.tert-Butyl 4-(((S)-8-bromo-6-(bromomethyl)-3,4-dihydro-4-oxo-2H-chromen-3-yl)methyl)cyclohexylcarba Mate (500 mg, 0.94 mmol), 1-methyl-1,3-dihydro-2H-imidazol-2-imine (273.8 mg, 2.82 mmol), DIEA (500 uL, 2.82 mmol) and KI (156 mg, 0.94 mmol) in MeCN (10 mL) solvent at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 = 1:50 to 1:10) to give the product (164.5 mg, 32%).

1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.72 (s, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 5.42 (s, 2H), 5.28 (s, 1H), 4.59 (dd, J = 11.7, 4.3 Hz, 1H), 4.42 - 4.24 (m, 2H), 3.80 (s, 3H), 3.31 (d, J = 26.2 Hz, 1H), 2.75 (dd, J = 8.3, 4.8 Hz, 1H), 1.98 (d, J = 11.1 Hz, 1H), 1.84 - 1.69 (m, 4H), 1.41 (s, 9H), 1.26 - 1.20 (m, 1H), 1.04 (p, J = 12.3 Hz, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.90 (s, 1H), 7.72 (s, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 5.42 (s, 2H), 5.28 (s, 1H), 4.59 (dd, J = 11.7, 4.3 Hz, 1H), 4.42 - 4.24 (m, 2H), 3.80 (s, 3H), 3.31 (d, J = 26.2 Hz, 1H), 2.75 (dd, J = 8.3, 4.8 Hz, 1H), 1.98 (d, J = 11.1 Hz, 1H), 1.84 - 1.69 (m, 4H), 1.41 (s, 9H), 1.26 - 1.20 (m, 1H), 1.04 (p, J = 12.3 Hz, 4H).

Figure pat00085
Figure pat00085

단계 5) tert-butyl (S)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl) -6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate의 제조Step 5) tert-butyl (S)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2 Preparation of ,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate

tert-부틸 (S)-(4-((8-브로모-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트 (50 mg, 0.09 mmol)에 (1-에틸-3-(트리플루오로메틸)-1H-피라졸-4 -일)붕소산 (28.6 mg, 0.13 mmol), Cs2CO3 (58.6 mg, 0.18 mmol) 및 Pd(amphos)Cl2 (6.3 mg, 0.009 mmol)를 1,4-디옥산/H2O (3:1, 2 mL) 중 첨가하였다. 혼합물을 탈기한 다음, 1시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 1,4-디옥산을 감압 하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 화합물 23 (11.8 mg, 20%)을 얻는다.tert-Butyl (S)-(4-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4 -Oxochroman-3-yl)methyl)cyclohexyl)carbamate (50 mg, 0.09 mmol) in (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid ( 28.6 mg, 0.13 mmol), Cs 2 CO 3 (58.6 mg, 0.18 mmol) and Pd(amphos)Cl 2 (6.3 mg, 0.009 mmol) in 1,4-dioxane/H 2 O (3:1, 2 mL). ) was added. The mixture was degassed and then heated to 100 °C for 1 hour. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3) and dried over Na 2 SO 4 , concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give compound 23 (11.8 mg, 20%).

1H NMR (400 MHz, CDCl3) δ 7.85 - 7.81 (m, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.56 (s, 1H), 6.60 (d, J = 2.5 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 5.40 (s, 2H), 4.49 (dd, J = 11.6, 4.2 Hz, 1H), 4.40 (d, J = 7.9 Hz, 1H), 4.30 - 4.19 (m, 3H), 3.79 (s, 3H), 3.37 (s, 1H), 2.79 - 2.67 (m, 1H), 2.00 (d, J = 11.2 Hz, 3H), 1.88 - 1.71 (m, 2H), 1.56 (t, J = 7.4 Hz, 3H), 1.43 (s, 9H), 1.37 - 1.21 (m, 2H), 1.06 (p, J = 12.1 Hz, 4H). ESI-MS m/z 631.4 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.85 - 7.81 (m, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.56 (s, 1H) , 6.60 (d, J = 2.5 Hz, 1H), 6.57 (d, J = 2.5 Hz, 1H), 5.40 (s, 2H), 4.49 (dd, J = 11.6, 4.2 Hz, 1H), 4.40 (d, J = 7.9 Hz, 1H), 4.30 - 4.19 (m, 3H), 3.79 (s, 3H), 3.37 (s, 1H), 2.79 - 2.67 (m, 1H), 2.00 (d, J = 11.2 Hz, 3H) ), 1.88 - 1.71 (m, 2H), 1.56 (t, J = 7.4 Hz, 3H), 1.43 (s, 9H), 1.37 - 1.21 (m, 2H), 1.06 (p, J = 12.1 Hz, 4H) . ESI-MS m/z 631.4 (M+H) +

Figure pat00086
Figure pat00086

화합물 24. (S)-3-((4-aminocyclohexyl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 24. (S)-3-((4-aminocyclohexyl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3- methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

tert-부틸 (S)-(4-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)시클로헥실)카르바메이트 (6.8 mg, 0.01 mmol)에 무수 CH2Cl2 (1 mL) 중 TFA (5방울)를 0°C에서 적가하고, 생성된 혼합물을 0℃에서 30분 동안 교반하였다. 반응혼합물을 감압하에 농축하고, 잔류물을 실리카겔상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 화합물 24 (5.9 mg, 91%)을 얻는다.tert-Butyl (S)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (6.8 mg, 0.01 mmol) in anhydrous CH 2 Cl TFA (5 drops) in 2 (1 mL) was added dropwise at 0 °C and the resulting mixture was stirred at 0 °C for 30 min. The reaction mixture is concentrated under reduced pressure, and the residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give compound 24 (5.9 mg, 91%).

1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 0.7 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 5.07 (s, 2H), 4.52 (dd, J = 11.6, 4.3 Hz, 1H), 4.27 (p, J = 7.7, 7.3 Hz, 3H), 3.51 (s, 3H), 3.04 - 2.93 (m, 1H), 2.83 - 2.72 (m, 1H), 2.01 (d, J = 11.9 Hz, 2H), 1.89 (q, J = 14.0 Hz, 2H), 1.70 (dt, J = 13.9, 6.9 Hz, 1H), 1.50 (t, J = 7.3 Hz, 3H), 1.43 - 1.23 (m, 6H), 1.06 (p, J = 12.0 Hz, 2H), 0.88 (t, J = 7.6 Hz, 1H). ESI-MS m/z 529.1 (M-H)- 1H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J = 0.7 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 6.91 ( d, J = 2.5 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 5.07 (s, 2H), 4.52 (dd, J = 11.6, 4.3 Hz, 1H), 4.27 (p, J = 7.7 , 7.3 Hz, 3H), 3.51 (s, 3H), 3.04 - 2.93 (m, 1H), 2.83 - 2.72 (m, 1H), 2.01 (d, J = 11.9 Hz, 2H), 1.89 (q, J = 14.0 Hz, 2H), 1.70 (dt, J = 13.9, 6.9 Hz, 1H), 1.50 (t, J = 7.3 Hz, 3H), 1.43 - 1.23 (m, 6H), 1.06 (p, J = 12.0 Hz, 2H), 0.88 (t, J = 7.6 Hz, 1H). ESI-MS m/z 529.1 (MH) -

Figure pat00087
Figure pat00087

화합물 25. tert-butyl (S)-(4-((8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamateCompound 25. tert-butyl (S)-(4-((8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H -imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate

(6-플루오로-2-메틸피리딘-3-일)보론산 (21.2 mg, 0.137 mmol)을 사용하여 화합물 25 (17.4 mg, 33.4%)를 실시예 23, 단계 5에 기재된 절차로부터 제조하였다.Compound 25 (17.4 mg, 33.4%) was prepared from the procedure described in Example 23, step 5 using (6-fluoro-2-methylpyridin-3-yl)boronic acid (21.2 mg, 0.137 mmol).

1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 2.4 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 6.81 (dd, J = 8.2, 3.1 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 5.47 (s, 2H), 4.47 (dd, J = 11.5, 4.3 Hz, 1H), 4.40 (d, J = 7.9 Hz, 1H), 4.27 - 4.16 (m, 1H), 3.78 (s, 3H), 3.37 (s, 1H), 2.76 (t, J = 6.1 Hz, 1H), 2.33 (s, 3H), 2.00 (d, J = 10.9 Hz, 2H), 1.88 - 1.72 (m, 2H), 1.44 (s, 9H), 1.36 - 1.22 (m, 2H), 1.06 (p, J = 11.9 Hz, 4H). ESI-MS m/z 578.3 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 2.4 Hz, 1H), 7.71 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.4 Hz, 1H), 6.81 (dd , J = 8.2, 3.1 Hz, 1H), 6.61 (d, J = 2.5 Hz, 1H), 6.60 (d, J = 2.5 Hz, 1H), 5.47 (s, 2H), 4.47 (dd, J = 11.5, 4.3 Hz, 1H), 4.40 (d, J = 7.9 Hz, 1H), 4.27 - 4.16 (m, 1H), 3.78 (s, 3H), 3.37 (s, 1H), 2.76 (t, J = 6.1 Hz, 1H), 2.33 (s, 3H), 2.00 (d, J = 10.9 Hz, 2H), 1.88 - 1.72 (m, 2H), 1.44 (s, 9H), 1.36 - 1.22 (m, 2H), 1.06 (p , J = 11.9 Hz, 4H). ESI-MS m/z 578.3 (M+H) +

Figure pat00088
Figure pat00088

화합물 26. (S)-3-((4-aminocyclohexyl)methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 26. (S)-3-((4-aminocyclohexyl)methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3- dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

tert-부틸 (S)-(4-((8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트 (12.4 mg, 0.02 mmol)를 무수 CH2Cl2 (1 mL) 중 0℃에서 TFA (5방울)로 적가하였다. 생성된 혼합물을 0℃에서 30분 동안 교반하고, 반응혼합물을 감압하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 화합물 26 (10.8 mg, 91%)을 얻는다.tert-Butyl (S)-(4-((8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (12.4 mg, 0.02 mmol) in anhydrous CH 2 Cl 2 (1 mL) at 0°C TFA (5 drops) was added dropwise. The resulting mixture was stirred at 0° C. for 30 min, and the reaction mixture was concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give compound 26 (10.8 mg, 91%).

1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 2.5 Hz, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 6.96 (ddd, J = 12.4, 7.7, 2.6 Hz, 3H), 5.12 (s, 2H), 4.55 (dd, J = 11.5, 4.5 Hz, 1H), 4.30 (dd, J = 11.6, 8.0 Hz, 1H), 3.54 (s, 3H), 3.13 - 2.98 (m, 1H), 2.89 - 2.76 (m, 1H), 2.29 (s, 3H), 2.09 - 1.98 (m, 2H), 1.92 (t, J = 16.5 Hz, 2H), 1.75 (dt, J = 13.9, 6.9 Hz, 2H), 1.51 - 1.28 (m, 2H), 1.09 (t, J = 12.4 Hz, 2H). ESI-MS m/z 476.2 (M-H)- 1H NMR (400 MHz, MeOD) δ 7.84 (d, J = 2.5 Hz, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 6.96 (ddd, J = 12.4, 7.7, 2.6 Hz, 3H), 5.12 (s, 2H), 4.55 (dd, J = 11.5, 4.5 Hz, 1H), 4.30 (dd, J = 11.6, 8.0 Hz, 1H), 3.54 (s , 3H), 3.13 - 2.98 (m, 1H), 2.89 - 2.76 (m, 1H), 2.29 (s, 3H), 2.09 - 1.98 (m, 2H), 1.92 (t, J = 16.5 Hz, 2H), 1.75 (dt, J = 13.9, 6.9 Hz, 2H), 1.51 - 1.28 (m, 2H), 1.09 (t, J = 12.4 Hz, 2H). ESI-MS m/z 476.2 (MH) -

Figure pat00089
Figure pat00089

화합물 27. tert-butyl (R)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6- ((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamateCompound 27. tert-butyl (R)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2 ,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate

Figure pat00090
Figure pat00090

단계 1) tert-butyl 4-(((R)-8-bromo-3,4-dihydro-6-methyl -4-oxo-2H-chromen-3-yl)methyl)cyclohexylcarbamate의 제조Step 1) Preparation of tert-butyl 4-(((R)-8-bromo-3,4-dihydro-6-methyl -4-oxo-2H-chromen-3-yl)methyl)cyclohexylcarbamate

tert-부틸 4-((E)-(8-브로모-6-메틸-4-옥소-2H-크로멘-3(4H)-일리덴)메틸)사이클로헥실카바메이트 (8.94 g, 19.85 mmol)의 아세토니트릴 (180 mL) 용액에 RuCl(p-시멘)[(R,R)-Ts-DPEN] (63 mg, 0.10 mmol), DBU(2.5 eq)/포름산 (5.0 eq)(7.41ml/ 3.75 mL)의 아세토니트릴 (180 mL) 용액을 상온에서 첨가하였다. 상온에서 4시간 동안 교반한 후, 반응을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. 디에틸 에테르로 추출한 후, 유기층을 추가의 포화 NaHCO3수용액으로 세척하고, MgSO4로 건조시키고, 감압하에 농축시켰다. 잔류물을 컬럼 크로마토그래피 (EtOAc:헵탄 = 1:10)로 정제하여 생성물 (2.82g, 31.4%)을 얻었다.tert-butyl 4-((E)-(8-bromo-6-methyl-4-oxo-2H-chromen-3(4H)-ylidene)methyl)cyclohexylcarbamate (8.94 g, 19.85 mmol) in acetonitrile (180 mL) solution of RuCl(p-cymene)[(R,R)-Ts-DPEN] (63 mg, 0.10 mmol), DBU (2.5 eq)/formic acid (5.0 eq) (7.41 ml/ 3.75 mL) of acetonitrile (180 mL) solution was added at room temperature. After stirring at room temperature for 4 hours, the reaction was quenched with saturated aqueous NH 4 Cl solution at room temperature. After extraction with diethyl ether, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:heptane = 1:10) to give the product (2.82g, 31.4%).

1H NMR (400 MHz, CDCl3) δ 7.60 (s, 1H), 7.52 (s, 1H), 4.55 (dd, J = 11.5, 4.3 Hz, 1H), 4.26 (dd, J = 11.5, 8.4 Hz, 1H), 3.38 (m, 1H), 2.72 (m, 1H), 2.27 (s, 3H), 1.98 (m, 2H), 1.84 - 1.71 (m, 3H), 1.41 (s, 9H), 1.34 - 1.28 (m, 1H), 1.23 (m, 2H), 1.04 (m, 2H), 0.85 (m, 1H). ESI-MS m/z 452.1 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.60 (s, 1H), 7.52 (s, 1H), 4.55 (dd, J = 11.5, 4.3 Hz, 1H), 4.26 (dd, J = 11.5, 8.4 Hz, 1H), 3.38 (m, 1H), 2.72 (m, 1H), 2.27 (s, 3H), 1.98 (m, 2H), 1.84 - 1.71 (m, 3H), 1.41 (s, 9H), 1.34 - 1.28 (m, 1H), 1.23 (m, 2H), 1.04 (m, 2H), 0.85 (m, 1H). ESI-MS m/z 452.1 (M+H) +

Figure pat00091
Figure pat00091

단계 2) tert-butyl 4-(((R)-8-bromo-6-(bromomethyl)-3,4- dihydro-4-oxo-2H-chromen-3-yl)methyl)cyclohexylcarbamate의 제조Step 2) Preparation of tert-butyl 4-(((R)-8-bromo-6-(bromomethyl)-3,4-dihydro-4-oxo-2H-chromen-3-yl)methyl)cyclohexylcarbamate

tert-부틸 4-(((R)-8-브로모-3,4-디히드로-6-메틸-4-옥소-2H-크로멘-3-일)메틸)시클로헥실카르바메이트 (2.8 g, 6.189 mmol)의 DCM (100 mL) 용액에 NBS (1.32 g, 7.427 mmol), AIBN (0.2 g, 0.124 mmol)을 60℃에서 2시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 DCM 및 H2O로 희석하고, DCM(X2)을 추출하고, MgSO4로 건조하고, 감압 하에 농축하였다. 잔류물을 컬럼 크로마토그래피 (EtOAc:헵탄 = 1:10)로 정제하여 생성물 (1.44g, 43.7%)을 얻었다.tert-butyl 4-(((R)-8-bromo-3,4-dihydro-6-methyl-4-oxo-2H-chromen-3-yl)methyl)cyclohexylcarbamate (2.8 g , 6.189 mmol) in DCM (100 mL), NBS (1.32 g, 7.427 mmol) and AIBN (0.2 g, 0.124 mmol) were refluxed at 60 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with DCM and H 2 O, DCM (X2) was extracted, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:heptane = 1:10) to give the product (1.44g, 43.7%).

1H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 4.60 (dd, J = 11.6, 4.4 Hz, 1H), 4.40 (s, 2H), 4.31 (dd, J = 11.6, 8.5 Hz, 1H), 3.35 (m, 1H), 2.76 (m, 1H), 1.98 (s, 2H), 1.85 - 1.71 (m, 3H), 1.42 (s, 9H), 1.33 - 1.28 (m, 1H), 1.25 (m, 5H), 1.05 (m, 2H), 0.86 (m, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.83 (d, J = 2.3 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 4.60 (dd, J = 11.6, 4.4 Hz, 1H), 4.40 (s, 2H), 4.31 (dd, J = 11.6, 8.5 Hz, 1H), 3.35 (m, 1H), 2.76 (m, 1H), 1.98 (s, 2H), 1.85 - 1.71 (m, 3H), 1.42 (s, 9H), 1.33 - 1.28 (m, 1H), 1.25 (m, 5H), 1.05 (m, 2H), 0.86 (m, 1H).

Figure pat00092
Figure pat00092

단계 3) tert-butyl (R)-(4-((8-bromo-6-((2-imino-3-methyl- 2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate의 제조Step 3) tert-butyl (R)-(4-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4- Preparation of oxochroman-3-yl)methyl)cyclohexyl)carbamate

tert-부틸 4-(((R)-8-브로모-6-(브로모메틸)-3,4-디하이드로-4-옥소-2H-크로멘-3-일)메틸)사이클로헥실카바메이트 (500 mg, 0.94 mmol)의 MeCN (10 mL) 용액에 1-메틸-1,3-디하이드로-2H-이미다졸-2-이민 (273.8 mg, 2.82 mmol), DIEA (500 uL, 2.82 mmol)및 KI (156 mg, 0.94 mmol)를 60℃에서 2시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2 = 1:50 내지 1:10)로 정제하여 생성물 (196 mg, 40%)을 얻었다.tert-Butyl 4-(((R)-8-bromo-6-(bromomethyl)-3,4-dihydro-4-oxo-2H-chromen-3-yl)methyl)cyclohexylcarbamate (500 mg, 0.94 mmol) of 1-methyl-1,3-dihydro-2H-imidazol-2-imine (273.8 mg, 2.82 mmol), DIEA (500 uL, 2.82 mmol) in a solution of MeCN (10 mL). and KI (156 mg, 0.94 mmol) at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 = 1:50 to 1:10) to give the product (196 mg, 40%).

1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 5.40 (s, 2H), 5.26 (s, 3H), 4.56 (dd, J = 11.7, 4.4 Hz, 1H), 4.43 (d, J = 8.1 Hz, 1H), 4.27 (dd, J = 11.6, 8.7 Hz, 1H), 3.31 (s, 1H), 2.73 (t, J = 6.5 Hz, 1H), 1.95 - 1.89 (m, 2H), 1.81 - 1.65 (m, 3H), 1.38 (s, 9H), 1.36 (s, 10H), 1.30 - 1.23 (m, 2H), 1.12 - 0.92 (m, 4H), 0.86 - 0.78 (m, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.87 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 6.65 (d, J = 2.5 Hz, 1H), 6.58 (d , J = 2.5 Hz, 1H), 5.40 (s, 2H), 5.26 (s, 3H), 4.56 (dd, J = 11.7, 4.4 Hz, 1H), 4.43 (d, J = 8.1 Hz, 1H), 4.27 (dd, J = 11.6, 8.7 Hz, 1H), 3.31 (s, 1H), 2.73 (t, J = 6.5 Hz, 1H), 1.95 - 1.89 (m, 2H), 1.81 - 1.65 (m, 3H), 1.38 (s, 9H), 1.36 (s, 10H), 1.30 - 1.23 (m, 2H), 1.12 - 0.92 (m, 4H), 0.86 - 0.78 (m, 1H).

Figure pat00093
Figure pat00093

단계 4) tert-butyl (R)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate의 제조Step 4) tert-butyl (R)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2 Preparation of ,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate

tert-부틸 (R)-(4-((8-브로모-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트 (50 mg, 0.09 mmol)에 (1-에틸-3-(트리플루오로메틸)-1H-피라졸-4 -일)붕소산 (28.6 mg, 0.13mmol), Cs2CO3 (58.6 mg, 0.18 mmol), 및 Pd(amphos)Cl2 (6.3 mg, 0.009 mmol)를 1,4-디옥산/H2O (3:1, 2 mL) 중 첨가하였다. 혼합물을 탈기한 다음, 1시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 1,4-디옥산을 감압 하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 화합물 27 (8.1mg, 14.2%)을 얻는다.tert-Butyl (R)-(4-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4 -Oxochroman-3-yl)methyl)cyclohexyl)carbamate (50 mg, 0.09 mmol) in (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid ( 28.6 mg, 0.13 mmol), Cs 2 CO 3 (58.6 mg, 0.18 mmol), and Pd(amphos)Cl 2 (6.3 mg, 0.009 mmol) in 1,4-dioxane/H 2 O (3:1, 2 mL) was added. The mixture was degassed and then heated to 100 °C for 1 hour. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3) and dried over Na 2 SO 4 , concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give compound 27 (8.1 mg, 14.2%).

1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 2.3 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 5.39 (s, 2H), 4.48 (dd, J = 11.6, 4.3 Hz, 1H), 4.39 (s, 1H), 4.25 (q, J = 7.3 Hz, 3H), 3.77 (s, 3H), 3.37 (s, 1H), 2.73 (q, J = 6.6, 5.6 Hz, 1H), 2.00 (d, J = 10.9 Hz, 2H), 1.89 - 1.65 (m, 7H), 1.56 (t, J = 7.3 Hz, 4H), 1.44 (s, 9H), 1.36 - 1.20 (m, 4H), 1.06 (p, J = 12.7 Hz, 4H). ESI-MS m/z 631.4 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 2.3 Hz, 1H), 7.72 (s, 1H), 7.62 (d, J = 2.4 Hz, 1H), 6.50 (d, J = 2.5 Hz) , 1H), 6.47 (d, J = 2.5 Hz, 1H), 5.39 (s, 2H), 4.48 (dd, J = 11.6, 4.3 Hz, 1H), 4.39 (s, 1H), 4.25 (q, J = 7.3 Hz, 3H), 3.77 (s, 3H), 3.37 (s, 1H), 2.73 (q, J = 6.6, 5.6 Hz, 1H), 2.00 (d, J = 10.9 Hz, 2H), 1.89 - 1.65 ( m, 7H), 1.56 (t, J = 7.3 Hz, 4H), 1.44 (s, 9H), 1.36 - 1.20 (m, 4H), 1.06 (p, J = 12.7 Hz, 4H). ESI-MS m/z 631.4 (M+H) +

Figure pat00094
Figure pat00094

화합물 28. (R)-3-((4-aminocyclohexyl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 28. (R)-3-((4-aminocyclohexyl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3- methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

tert-부틸 (R)-(4-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)시클로헥실)카르바메이트 (5.1 mg, 0.008 mmol)를 무수 CH2Cl2 (1 mL) 중 TFA (5방울)를 0°C에서 적가하고, 생성된 혼합물을 0℃에서 30분 동안 교반하였다. 반응혼합물을 감압하에 농축하고, 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% 내지 10%)로 정제하여 화합물 28 (3.8 mg, 74%)을 얻는다.tert-Butyl (R)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (5.1 mg, 0.008 mmol) was dissolved in anhydrous CH 2 Cl TFA (5 drops) in 2 (1 mL) was added dropwise at 0 °C and the resulting mixture was stirred at 0 °C for 30 min. The reaction mixture is concentrated under reduced pressure, and the residue is purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 , 2% to 10%) to give compound 28 (3.8 mg, 74%).

1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 1.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 5.07 (s, 2H), 4.52 (dd, J = 11.7, 4.3 Hz, 1H), 4.32 - 4.22 (m, 3H), 4.08 (q, J = 7.2 Hz, 1H), 3.51 (s, 3H), 3.05 - 2.96 (m, 1H), 2.83 - 2.74 (m, 1H), 2.03 (s, 1H), 1.90 (dd, J = 22.0, 15.4 Hz, 2H), 1.70 (dt, J = 13.7, 6.8 Hz, 1H), 1.50 (t, J = 7.3 Hz, 3H), 1.43 - 1.31 (m, 4H), 1.07 (t, J = 12.5 Hz, 2H). ESI-MS m/z 531.2 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J = 1.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 6.92 ( d, J = 2.5 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 5.07 (s, 2H), 4.52 (dd, J = 11.7, 4.3 Hz, 1H), 4.32 - 4.22 (m, 3H) ), 4.08 (q, J = 7.2 Hz, 1H), 3.51 (s, 3H), 3.05 - 2.96 (m, 1H), 2.83 - 2.74 (m, 1H), 2.03 (s, 1H), 1.90 (dd, J = 22.0, 15.4 Hz, 2H), 1.70 (dt, J = 13.7, 6.8 Hz, 1H), 1.50 (t, J = 7.3 Hz, 3H), 1.43 - 1.31 (m, 4H), 1.07 (t, J = 12.5 Hz, 2H). ESI-MS m/z 531.2 (M+H) +

Figure pat00095
Figure pat00095

화합물 29. tert-butyl (R)-(4-((8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamateCompound 29. tert-butyl (R)-(4-((8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H -imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate

(6-플루오로-2-메틸피리딘-3-일)보론산 (21.2 mg, 0.135 mmol)을 사용하여 실시예 27, 단계 4에 기재된 절차로부터 화합물 29 (4.8mg, 9%)를 제조하였다.Compound 29 (4.8mg, 9%) was prepared from the procedure described in Example 27, Step 4 using (6-fluoro-2-methylpyridin-3-yl)boronic acid (21.2 mg, 0.135 mmol).

1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 6.78 (dd, J = 8.2, 3.1 Hz, 1H), 6.50 (q, J = 2.5 Hz, 2H), 5.43 (s, 2H), 4.46 (dd, J = 11.5, 4.3 Hz, 1H), 4.38 (s, 1H), 4.20 (dd, J = 11.6, 8.2 Hz, 1H), 3.73 (s, 3H), 3.44 - 3.28 (m, 1H), 2.75 (d, J = 6.7 Hz, 1H), 2.32 (s, 3H), 2.00 (d, J = 10.4 Hz, 2H), 1.86 - 1.58 (m, 2H), 1.43 (s, 9H), 1.35 - 1.22 (m, 4H), 1.07 (q, J = 10.8, 9.4 Hz, 4H). ESI-MS m/z 578.2 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.64 (t, J = 8.1 Hz, 1H), 6.78 (dd , J = 8.2, 3.1 Hz, 1H), 6.50 (q, J = 2.5 Hz, 2H), 5.43 (s, 2H), 4.46 (dd, J = 11.5, 4.3 Hz, 1H), 4.38 (s, 1H) , 4.20 (dd, J = 11.6, 8.2 Hz, 1H), 3.73 (s, 3H), 3.44 - 3.28 (m, 1H), 2.75 (d, J = 6.7 Hz, 1H), 2.32 (s, 3H), 2.00 (d, J = 10.4 Hz, 2H), 1.86 - 1.58 (m, 2H), 1.43 (s, 9H), 1.35 - 1.22 (m, 4H), 1.07 (q, J = 10.8, 9.4 Hz, 4H) . ESI-MS m/z 578.2 (M+H) +

Figure pat00096
Figure pat00096

화합물 30. (R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 30. (R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)chroman-4-one

Figure pat00097
Figure pat00097

단계 1) 8-(4-fluorophenyl)-6-methylchroman-4-one의 제조Step 1) Preparation of 8-(4-fluorophenyl)-6-methylchroman-4-one

1,4-디옥산/H2O (3:1, 32 mL) 중 8-브로모-6-메틸크로만-4-온 (3857 mg, 16 mmol)에 (4-플루오로페닐)보론산 (2238 mg, 16 mmol), K2CO3 (6634 mg, 48 mmol) 및 Pd(dppf)Cl2 (117 mg, 016 mmol)을 첨가하였다. 혼합물을 탈기시킨 다음 11시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고 (x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (5% 에틸 아세테이트:n-헥산에서 10%로)로 정제하여 생성물 (3419 mg, 83%)을 얻는다.(4-fluorophenyl)boronic acid in 8-bromo-6-methylchroman-4-one (3857 mg, 16 mmol) in 1,4-dioxane/H 2 O (3:1, 32 mL) (2238 mg, 16 mmol), K 2 CO 3 (6634 mg, 48 mmol) and Pd(dppf)Cl 2 (117 mg, 016 mmol) were added. The mixture was degassed and then heated to 100° C. for 11 hours. After cooling to room temperature, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by MPLC (5% ethyl acetate:n-hexane to 10%) to give the product (3419 mg, 83%).

1H NMR (300 MHz, CDCl3) δ 7.73 (dt, J = 2.4, 0.8 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.16 - 7.05 (m, 2H), 4.51 (dd, J = 6.9, 5.9 Hz, 2H), 2.82 (dd, J = 6.9, 6.0 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H). ESI-MS m/z 257.1 (M+H)+ 1H NMR (300 MHz, CDCl 3 ) δ 7.73 (dt, J = 2.4, 0.8 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.16 - 7.05 ( m, 2H), 4.51 (dd, J = 6.9, 5.9 Hz, 2H), 2.82 (dd, J = 6.9, 6.0 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H). ESI-MS m/z 257.1 (M+H) +

Figure pat00098
Figure pat00098

단계 2) (E)-3-(3,4-dichlorobenzylidene)-8-(4-fluorophenyl)-6-methylchroman-4-one의 제조Step 2) Preparation of (E)-3-(3,4-dichlorobenzylidene)-8-(4-fluorophenyl)-6-methylchroman-4-one

8-(4-플루오로페닐)-6-메틸크로만-4-온 (2919 mg, 11.389 mmol)의 톨루엔 (20 mL) 용액에 3,4-디클로로 벤즈알데히드 (2990 mg, 17.085 mmol) 및 p- 톨루엔 설폰산 (196 mg, 1.139 mmol) 반응혼합물을 14시간 동안 환류시켰다. 상온으로 냉각한 후, 생성된 잔류물을 CH2Cl2, 염수 및 H2O로 희석하고, 에틸 아세테이트(x3)로 추출하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (디클로로메탄/n-헥산 = 1:5 내지 1:1)로 정제하여 생성물 (2665 mg, 57%, BORSM 72%)을 얻었다.To a solution of 8-(4-fluorophenyl)-6-methylchroman-4-one (2919 mg, 11.389 mmol) in toluene (20 mL) was added 3,4-dichlorobenzaldehyde (2990 mg, 17.085 mmol) and p- Toluene sulfonic acid (196 mg, 1.139 mmol) The reaction mixture was refluxed for 14 hours. After cooling to room temperature, the resulting residue was diluted with CH 2 Cl 2 , brine and H 2 O, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane/n-hexane = 1:5 to 1:1) to give the product (2665 mg, 57%, BORSM 72%).

1H NMR (400 MHz, CDCl3) δ 7.83 (dt, J = 2.3, 0.8 Hz, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.54 - 7.40 (m, 3H), 7.37 (ddd, J = 5.2, 2.2, 0.7 Hz, 2H), 7.18 - 7.05 (m, 3H), 5.26 (d, J = 1.9 Hz, 2H), 2.39 (s, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.83 (dt, J = 2.3, 0.8 Hz, 1H), 7.76 (t, J = 1.9 Hz, 1H), 7.54 - 7.40 (m, 3H), 7.37 (ddd, J = 5.2, 2.2, 0.7 Hz, 2H), 7.18 - 7.05 (m, 3H), 5.26 (d, J = 1.9 Hz, 2H), 2.39 (s, 3H).

Figure pat00099
Figure pat00099

단계 3) 3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methyl chroman-4-one의 제조Step 3) Preparation of 3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methyl chroman-4-one

(E)-3-(3,4-디클로로벤질리덴)-8-(4-플루오로페닐)-6-메틸크로만-4-온 (2665 mg, 6.467 mmol)의 EtOAc (35 mL) 중 PtO2 (147 mg, 0.65 mmol)를 실온에서 첨가하였다. 반응혼합물을 H2 분위기 (풍선 압력) 하에 실온에서 4시간 동안 교반하였다. 촉매를 셀라이트 패드를 통한 여과에 의해 제거하고 EtOAc로 세척하였다. 여액을 농축하고 MPLC (10% EA/헵탄)에 의해 정제하여 생성물 (365 mg, 14%)을 얻는다.(E)-3-(3,4-dichlorobenzylidene)-8-(4-fluorophenyl)-6-methylchroman-4-one (2665 mg, 6.467 mmol) of PtO in EtOAc (35 mL) 2 (147 mg, 0.65 mmol) was added at room temperature. The reaction mixture was stirred for 4 hours at room temperature under H2 atmosphere (balloon pressure). The catalyst was removed by filtration through a celite pad and washed with EtOAc. The filtrate is concentrated and purified by MPLC (10% EA/heptane) to give the product (365 mg, 14%).

1H NMR (400 MHz, CDCl3) δ 7.74 (dq, J = 2.4, 0.8 Hz, 1H), 7.50 - 7.29 (m, 5H), 7.15 - 7.02 (m, 3H), 4.38 (dd, J = 11.5, 4.5 Hz, 1H), 4.13 (dd, J = 11.5, 9.5 Hz, 1H), 3.27 (dd, J = 14.2, 4.8 Hz, 1H), 2.95 (dd, J = 9.5, 4.7 Hz, 1H), 2.70 (dd, J = 14.2, 9.5 Hz, 1H), 2.39 - 2.33 (m, 3H), 2.28 (dt, J = 5.3, 0.7 Hz, 1H). ESI-MS m/z 415.0 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.74 (dq, J = 2.4, 0.8 Hz, 1H), 7.50 - 7.29 (m, 5H), 7.15 - 7.02 (m, 3H), 4.38 (dd, J = 11.5 , 4.5 Hz, 1H), 4.13 (dd, J = 11.5, 9.5 Hz, 1H), 3.27 (dd, J = 14.2, 4.8 Hz, 1H), 2.95 (dd, J = 9.5, 4.7 Hz, 1H), 2.70 (dd, J = 14.2, 9.5 Hz, 1H), 2.39 - 2.33 (m, 3H), 2.28 (dt, J = 5.3, 0.7 Hz, 1H). ESI-MS m/z 415.0 (M+H) +

Figure pat00100
Figure pat00100

단계 4) (3R,4R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)- 6-methylchroman-4-ol의 제조Step 4) Preparation of (3R,4R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-ol

3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-메틸크로만-4-온 (190 mg, 0.458 mmol), RuCl(p-시멘)[(R,R)-Ts-DPEN](29 mg, 0.046 mmol)및 DBU/포름산 (300 μL:100 μL)의 아세토니트릴 (2 mL) 용액을 상온에서 첨가하였다. 50℃에서 1시간 동안 교반한 후, 반응을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. EtOAc로 추출한 후, 유기층을 추가의 포화 NaHCO3 수용액으로 세척하고, MgSO4로 건조하고, 감압하에 농축하였다. 잔류물을 MPLC(에틸 아세테이트/n-헥산 = 1:10 내지 1:2)로 정제하여 생성물 (131 mg, 69%)을 수득하였다.3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one (190 mg, 0.458 mmol), RuCl(p-cymene)[(R,R) -Ts-DPEN] (29 mg, 0.046 mmol) and a solution of DBU/formic acid (300 μL:100 μL) in acetonitrile (2 mL) was added at room temperature. After stirring at 50° C. for 1 hour, the reaction was quenched with saturated aqueous NH 4 Cl solution at room temperature. After extraction with EtOAc, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate/n-hexane = 1:10 to 1:2) to give the product (131 mg, 69%).

1H NMR (400 MHz, CDCl3) δ 7.49 - 7.34 (m, 4H), 7.14 - 7.00 (m, 5H), 4.49 (t, J = 3.7 Hz, 1H), 4.06 (d, J = 7.7 Hz, 2H), 2.86 (dd, J = 13.7, 8.7 Hz, 1H), 2.63 (dd, J = 13.7, 7.1 Hz, 1H), 2.29 (s, 3H), 2.30 - 2.23 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.49 - 7.34 (m, 4H), 7.14 - 7.00 (m, 5H), 4.49 (t, J = 3.7 Hz, 1H), 4.06 (d, J = 7.7 Hz, 2H), 2.86 (dd, J = 13.7, 8.7 Hz, 1H), 2.63 (dd, J = 13.7, 7.1 Hz, 1H), 2.29 (s, 3H), 2.30 - 2.23 (m, 1H).

Figure pat00101
Figure pat00101

단계 5) (R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6- methylchroman-4-one의 제조Step 5) Preparation of (R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one

(3R,4R)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-메틸크로만-4-올 (116 mg, 0.28 mmol)의 CH2Cl2 (5 mL) 중 분자체 (4 Å, 30 mg) 및 N-메틸모르폴린 N-옥사이드 (82 mg, 0.07 mmol)를 첨가하고, 혼합물을 15분 동안 교반하였다. 이어서, 테트라프로필암모늄 퍼루테네이트 (12 mg, 0.033 mmol)를 첨가하고, 상온에서 1시간 동안 계속 교반하였다. 어두운 혼합물을 용리제로서 디에틸 에테르를 사용하여 실리카 겔 상에서 여과하였다. 진공에서 농축 후. 잔류물을 MPLC (에틸 아세테이트/n-헥산 = 1:10)로 정제하여 생성물 (70.2 mg, 61%)을 얻었다.CH 2 Cl 2 (5 Molecular sieves (4 Å, 30 mg) and N-methylmorpholine N-oxide (82 mg, 0.07 mmol) in mL) were added and the mixture was stirred for 15 min. Tetrapropylammonium perruthenate (12 mg, 0.033 mmol) was then added and stirring was continued at room temperature for 1 hour. The dark mixture was filtered over silica gel using diethyl ether as eluent. After concentration in vacuo. The residue was purified by MPLC (ethyl acetate/n-hexane = 1:10) to give the product (70.2 mg, 61%).

1H NMR (400 MHz, CDCl3) δ 7.77 - 7.71 (m, 1H), 7.50 - 7.41 (m, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.15 - 7.03 (m, 3H), 4.39 (dd, J = 11.5, 4.6 Hz, 1H), 4.13 (dd, J = 11.5, 9.5 Hz, 1H), 3.27 (dd, J = 14.2, 4.9 Hz, 1H), 2.96 (dt, J = 9.5, 4.7 Hz, 1H), 2.71 (dd, J = 14.2, 9.5 Hz, 1H), 2.36 (d, J = 0.7 Hz, 3H). ESI-MS m/z 415.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 - 7.71 (m, 1H), 7.50 - 7.41 (m, 2H), 7.37 (d, J = 8.2 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.15 - 7.03 (m, 3H), 4.39 (dd, J = 11.5, 4.6 Hz, 1H), 4.13 (dd, J = 11.5, 9.5 Hz, 1H), 3.27 (dd, J = 14.2, 4.9 Hz, 1H) , 2.96 (dt, J = 9.5, 4.7 Hz, 1H), 2.71 (dd, J = 14.2, 9.5 Hz, 1H), 2.36 (d, J = 0.7 Hz, 3H). ESI-MS m/z 415.1 (M+H) +

Figure pat00102
Figure pat00102

단계 6) (R)-6-(bromomethyl)-3-(3,4-dichlorobenzyl)-8-(4-fluoro phenyl)chroman-4-one의 제조Step 6) Preparation of (R)-6-(bromomethyl)-3-(3,4-dichlorobenzyl)-8-(4-fluoro phenyl)chroman-4-one

(R)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-메틸크로만-4-온 (55mg, 0.132 mmol), NBS (28 mg, 0.159 mmol)및 AIBN (4.4 mg, 0.026 mmol)을 MeOAc의 용액 (3 mL)중 60℃에서 4시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트 및 물로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC(에틸 아세테이트 : n-헥산 = 1:10 ~ 1:2)로 정제하여 생성물 (34 mg, 53%)을 얻었다.(R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one (55 mg, 0.132 mmol), NBS (28 mg, 0.159 mmol) and AIBN (4.4 mg, 0.026 mmol) was refluxed in a solution of MeOAc (3 mL) at 60° C. for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate : n-hexane = 1:10 to 1:2) to give the product (34 mg, 53%).

1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 8.8, 5.4 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.17 - 7.02 (m, 3H), 4.52 (s, 2H), 4.43 (dd, J = 11.5, 4.6 Hz, 1H), 4.17 (dd, J = 11.6, 9.7 Hz, 1H), 3.29 (dd, J = 14.3, 4.8 Hz, 1H), 2.99 (dt, J = 9.6, 4.8 Hz, 1H), 2.71 (dd, J = 14.3, 9.4 Hz, 1H). ESI-MS m/z 492.9 (M-H)- 1H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.46 (dd, J = 8.8, 5.4 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.17 - 7.02 (m, 3H), 4.52 (s, 2H), 4.43 (dd, J = 11.5, 4.6 Hz, 1H), 4.17 (dd, J = 11.6, 9.7 Hz, 1H), 3.29 (dd, J = 14.3, 4.8 Hz, 1H), 2.99 (dt, J = 9.6, 4.8 Hz, 1H), 2.71 (dd, J = 14.3, 9.4 Hz, 1H). ESI-MS m/z 492.9 (MH) -

Figure pat00103
Figure pat00103

단계 7) (R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2- imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 7) (R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl Preparation of )methyl)chroman-4-one

(R)-6-(브로모메틸)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)크로만-4-온 (53 mg, 0.109 mmol), 1-메틸-1,3-디하이드로-2H-이미다졸-2-이민 (44 mg, 0.329 mmol), DIEA (57 uL, 0.329 mmol)및 KI (18 mg, 0.109 mmol)를 MeCN (2 mL)의 용액 중 60℃에서 4시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2=1:50 내지 1:10)로 정제하여 화합물 30 (5.2 mg, 17%)을 얻었다.(R)-6-(bromomethyl)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)chroman-4-one (53 mg, 0.109 mmol), 1-methyl- 1,3-dihydro-2H-imidazol-2-imine (44 mg, 0.329 mmol), DIEA (57 uL, 0.329 mmol) and KI (18 mg, 0.109 mmol) were dissolved in a solution of MeCN (2 mL) at 60 C. for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 =1:50 to 1:10) to give Compound 30 (5.2 mg, 17%).

1H NMR (400 MHz, CDCl3) δ 7.82 - 7.74 (m, 2H), 7.61 (s, 1H), 7.57 - 7.49 (m, 2H), 7.41 - 7.34 (m, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.12 - 7.02 (m, 3H), 6.62 - 6.55 (m, 2H), 5.49 (s, 2H), 4.43 (dd, J = 11.6, 4.6 Hz, 1H), 4.22 - 4.12 (m, 1H), 3.80 (s, 3H), 3.30 - 3.16 (m, 1H), 3.00 (dt, J = 9.6, 4.7 Hz, 1H), 2.70 (dd, J = 14.3, 9.2 Hz, 1H). ESI-MS m/z 510.0 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 - 7.74 (m, 2H), 7.61 (s, 1H), 7.57 - 7.49 (m, 2H), 7.41 - 7.34 (m, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.12 - 7.02 (m, 3H), 6.62 - 6.55 (m, 2H), 5.49 (s, 2H), 4.43 (dd, J = 11.6, 4.6 Hz, 1H), 4.22 - 4.12 ( m, 1H), 3.80 (s, 3H), 3.30 - 3.16 (m, 1H), 3.00 (dt, J = 9.6, 4.7 Hz, 1H), 2.70 (dd, J = 14.3, 9.2 Hz, 1H). ESI-MS m/z 510.0 (M+H) +

Figure pat00104
Figure pat00104

화합물 31. (S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 31. (S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)chroman-4-one

Figure pat00105
Figure pat00105

단계 1) (3S,4S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-ol의 제조Step 1) Preparation of (3S,4S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-ol

3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-메틸크로만-4-온 (174 mg, 0.42 mmol)에 RuCl(p-시멘)[(S,S)-Ts-DPEN] (27 mg, 0.042 mmol) 및 DBU/포름산(300 μL:100 μL)의 아세토니트릴 (2 mL) 용액을 상온에서 첨가하였다. 50℃에서 1시간 동안 교반한 후, 반응을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. EtOAc로 추출한 후, 유기층을 추가의 포화 NaHCO3수용액으로 세척하고, MgSO4로 건조하고, 감압하에 농축하였다. 잔류물을 MPLC (에틸 아세테이트/n-헥산 = 1:10 내지 1:2)로 정제하여 생성물 (135 mg, 79%)을 수득하였다.3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one (174 mg, 0.42 mmol) in RuCl(p-cymene)[(S,S) -Ts-DPEN] (27 mg, 0.042 mmol) and a solution of DBU/formic acid (300 μL:100 μL) in acetonitrile (2 mL) was added at room temperature. After stirring at 50° C. for 1 hour, the reaction was quenched with saturated aqueous NH 4 Cl solution at room temperature. After extraction with EtOAc, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate/n-hexane = 1:10 to 1:2) to give the product (135 mg, 79%).

1H NMR (400 MHz, CDCl3) δ 7.45 (dd, J = 8.7, 5.5 Hz, 2H), 7.41 - 7.35 (m, 2H), 7.14 - 7.00 (m, 5H), 4.49 (s, 1H), 4.09 - 4.02 (m, 2H), 2.85 (dd, J = 13.7, 8.7 Hz, 1H), 2.63 (dd, J = 13.7, 7.1 Hz, 1H), 2.34 - 2.25 (m, 4H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (dd, J = 8.7, 5.5 Hz, 2H), 7.41 - 7.35 (m, 2H), 7.14 - 7.00 (m, 5H), 4.49 (s, 1H), 4.09 - 4.02 (m, 2H), 2.85 (dd, J = 13.7, 8.7 Hz, 1H), 2.63 (dd, J = 13.7, 7.1 Hz, 1H), 2.34 - 2.25 (m, 4H).

Figure pat00106
Figure pat00106

단계 2) (S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one의 제조Step 2) Preparation of (S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one

(3S,4S)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-메틸크로만-4-올 (100 mg, 0.264 mmol)의 CH2Cl2 (5 mL) 중 분자체 (4 Å, 30 mg) 및 N-메틸모르폴린 N-옥사이드 (77 mg, 0.66 mmol)를 첨가하고, 혼합물을 15분 동안 교반하였다. 이어서, 테트라프로필암모늄 퍼루테네이트 (12 mg, 0.033 mmol)를 첨가하고, 상온에서 1시간 동안 계속 교반하였다. 어두운 혼합물을 용리제로서 디에틸 에테르를 사용하여 실리카 겔 상에서 여과하였다. 진공에서 농축 후. 잔류물을 MPLC (에틸 아세테이트/n-헥산 = 1:10)로 정제하여 생성물(80 mg, 73%)을 얻었다.CH 2 Cl 2 (5 Molecular sieves (4 Å, 30 mg) and N-methylmorpholine N-oxide (77 mg, 0.66 mmol) in mL) were added and the mixture was stirred for 15 min. Tetrapropylammonium perruthenate (12 mg, 0.033 mmol) was then added and stirring was continued at room temperature for 1 hour. The dark mixture was filtered over silica gel using diethyl ether as eluent. After concentration in vacuo. The residue was purified by MPLC (ethyl acetate/n-hexane = 1:10) to give the product (80 mg, 73%).

1H NMR (400 MHz, CDCl3) δ 7.77 - 7.71 (m, 1H), 7.50 - 7.41 (m, 2H), 7.41 - 7.32 (m, 1H), 7.36 - 7.30 (m, 2H), 7.15 - 7.03 (m, 3H), 4.39 (dd, J = 11.5, 4.5 Hz, 1H), 4.13 (dd, J = 11.5, 9.5 Hz, 1H), 3.27 (dd, J = 14.2, 4.8 Hz, 1H), 2.95 (dq, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 14.2, 9.5 Hz, 1H), 2.36 (d, J = 0.7 Hz, 3H). ESI-MS m/z 415.0 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.77 - 7.71 (m, 1H), 7.50 - 7.41 (m, 2H), 7.41 - 7.32 (m, 1H), 7.36 - 7.30 (m, 2H), 7.15 - 7.03 (m, 3H), 4.39 (dd, J = 11.5, 4.5 Hz, 1H), 4.13 (dd, J = 11.5, 9.5 Hz, 1H), 3.27 (dd, J = 14.2, 4.8 Hz, 1H), 2.95 ( dq, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 14.2, 9.5 Hz, 1H), 2.36 (d, J = 0.7 Hz, 3H). ESI-MS m/z 415.0 (M+H) +

Figure pat00107
Figure pat00107

단계 3) (S)-6-(bromomethyl)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)chroman-4-one의 제조Step 3) Preparation of (S)-6-(bromomethyl)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)chroman-4-one

(S)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-메틸크로만-4-온 (69 mg, 0.166 mmol), NBS (36 mg, 0.199 mmol), AIBN (5.5 mg, 0.033 mmol)을 MeOAc (3 mL)용액 중 60℃에서 4시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트 및 물로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (에틸 아세테이트:n-헥산 = 1:10 내지 1:2)로 정제하여 생성물 (31 mg, 38%)을 얻었다.(S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one (69 mg, 0.166 mmol), NBS (36 mg, 0.199 mmol) , AIBN (5.5 mg, 0.033 mmol) was refluxed in MeOAc (3 mL) at 60 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:n-hexane = 1:10 to 1:2) to give the product (31 mg, 38%).

1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 8.9, 5.4 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.17 - 7.02 (m, 3H), 4.52 (s, 2H), 4.43 (dd, J = 11.5, 4.6 Hz, 1H), 4.17 (dd, J = 11.5, 9.8 Hz, 1H), 3.29 (dd, J = 14.3, 4.8 Hz, 1H), 2.99 (dt, J = 9.6, 4.8 Hz, 1H), 2.71 (dd, J = 14.3, 9.5 Hz, 1H). ESI-MS m/z 492.9 (M-H)- 1H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 7.46 (dd, J = 8.9, 5.4 Hz, 2H), 7.38 (d, J = 8.2 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.17 - 7.02 (m, 3H), 4.52 (s, 2H), 4.43 (dd, J = 11.5, 4.6 Hz, 1H), 4.17 (dd, J = 11.5, 9.8 Hz, 1H), 3.29 (dd, J = 14.3, 4.8 Hz, 1H), 2.99 (dt, J = 9.6, 4.8 Hz, 1H), 2.71 (dd, J = 14.3, 9.5 Hz, 1H). ESI-MS m/z 492.9 (MH) -

Figure pat00108
Figure pat00108

단계 4) (S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 4) (S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl Preparation of )methyl)chroman-4-one

(S)-6-(브로모메틸)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)크로만-4-온 (53 mg, 0.109 mmol), 1-메틸-1,3-디하이드로-2H-이미다졸-2-이민 (44 mg, 0.329 mmol), DIEA (57 uL, 0.329 mmol), KI (18 mg, 0.109 mmol) 및 MeCN (2 mL)의 용액을 60℃에서 4시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2=1:50 내지 1:10)로 정제하여 화합물 31 (7.8 mg, 28%)을 얻었다.(S)-6-(bromomethyl)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)chroman-4-one (53 mg, 0.109 mmol), 1-methyl- A solution of 1,3-dihydro-2H-imidazol-2-imine (44 mg, 0.329 mmol), DIEA (57 uL, 0.329 mmol), KI (18 mg, 0.109 mmol) and MeCN (2 mL) was added to 60 C. for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 =1:50 to 1:10) to give compound 31 (7.8 mg, 28%).

1H NMR (400 MHz, CDCl3) δ 7.82 - 7.74 (m, 2H), 7.64 (s, 1H), 7.53 (s, 1H), 7.57 - 7.49 (m, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.11 - 7.02 (m, 3H), 6.58 (q, J = 2.5 Hz, 2H), 5.49 (s, 2H), 4.43 (dd, J = 11.6, 4.6 Hz, 1H), 4.22 - 4.07 (m, 1H), 3.80 (s, 3H), 3.25 (dd, J = 14.2, 5.1 Hz, 1H), 3.00 (dq, J = 9.5, 4.8 Hz, 1H), 2.69 (dd, J = 14.3, 9.3 Hz, 1H). ESI-MS m/z 510.0 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 - 7.74 (m, 2H), 7.64 (s, 1H), 7.53 (s, 1H), 7.57 - 7.49 (m, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 2.1 Hz, 1H), 7.11 - 7.02 (m, 3H), 6.58 (q, J = 2.5 Hz, 2H), 5.49 (s, 2H), 4.43 (dd, J = 11.6, 4.6 Hz, 1H), 4.22 - 4.07 (m, 1H), 3.80 (s, 3H), 3.25 (dd, J = 14.2, 5.1 Hz, 1H), 3.00 (dq, J = 9.5, 4.8 Hz, 1H), 2.69 (dd, J = 14.3, 9.3 Hz, 1H). ESI-MS m/z 510.0 (M+H) +

Figure pat00109
Figure pat00109

화합물 32. 3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 32. 3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3 -dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

Figure pat00110
Figure pat00110

단계 1) 8-bromo-6-(bromomethyl)chroman-4-one의 제조Step 1) Preparation of 8-bromo-6-(bromomethyl)chroman-4-one

8-브로모-6-메틸크로만-4-온 (3274 mg, 13.58 mmol), NBS (2417 mg, 13.58 mmol), AIBN (223 mg, 1.358 mmol)을 MeOAc (20 mL)의 용액을 15시간 동안 환류시켰다. 60 °C에서 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트 및 물로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (에틸 아세테이트:n-헥산 = 1:10)로 정제하여 생성물 (2454 mg, 56%)을 수득하였다.A solution of 8-bromo-6-methylchroman-4-one (3274 mg, 13.58 mmol), NBS (2417 mg, 13.58 mmol) and AIBN (223 mg, 1.358 mmol) in MeOAc (20 mL) was incubated for 15 hours. refluxed during After cooling from 60 °C to room temperature, the reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:10) to give the product (2454 mg, 56%).

1H NMR (400 MHz, CDCl3) δ 7.91 - 7.83 (m, 1H), 7.80 (d, J = 2.3 Hz, 1H), 4.67 (dd, J = 6.9, 6.1 Hz, 2H), 4.43 (s, 2H), 2.86 (dd, J = 6.8, 6.1 Hz, 2H). ESI-MS m/z 320.9 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.91 - 7.83 (m, 1H), 7.80 (d, J = 2.3 Hz, 1H), 4.67 (dd, J = 6.9, 6.1 Hz, 2H), 4.43 (s, 2H), 2.86 (dd, J = 6.8, 6.1 Hz, 2H). ESI-MS m/z 320.9 (M+H) +

Figure pat00111
Figure pat00111

단계 2) (E)-8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzylidene)chroman-4-one의 제조Step 2) Preparation of (E)-8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzylidene)chroman-4-one

8-브로모-6-(브로모메틸)크로만-4-온 (2456 mg, 7.675 mmol)의 톨루엔 (25 mL) 용액에 3,4-디클로로 벤즈알데히드 (1477 mg, 8.443 mmol) 및 para-톨루엔 술폰산 (132 mg, 0.767 mmol) 반응혼합물을 15시간 동안 환류시켰다. 상온으로 냉각한 후, 생성된 잔류물을 CH2Cl2, 염수 및 H2O로 희석하고, CH2Cl2(x3)로 추출하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (에틸아세테이트/n-헵탄 = 1:30 내지 1:1)로 정제하여 생성물 (2010 mg, 55%)을 수득하였다.To a solution of 8-bromo-6-(bromomethyl)chroman-4-one (2456 mg, 7.675 mmol) in toluene (25 mL) was added 3,4-dichlorobenzaldehyde (1477 mg, 8.443 mmol) and para-toluene. Sulfonic acid (132 mg, 0.767 mmol) The reaction mixture was refluxed for 15 hours. After cooling to room temperature, the resulting residue was diluted with CH 2 Cl 2 , brine and H 2 O, extracted with CH 2 Cl 2 (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate/n-heptane = 1:30 to 1:1) to give the product (2010 mg, 55%).

1H NMR (400 MHz, CDCl3) δ 8.01 - 7.96 (m, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.16 (ddd, J = 8.2, 2.1, 0.6 Hz, 1H), 5.43 (d, J = 1.9 Hz, 2H), 4.46 (s, 2H). ESI-MS m/z 477.3 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 8.01 - 7.96 (m, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 7.16 (ddd, J = 8.2, 2.1, 0.6 Hz, 1H), 5.43 (d, J = 1.9 Hz, 2H), 4.46 (s, 2H). ESI-MS m/z 477.3 (M+H) +

Figure pat00112
Figure pat00112

단계 3) 8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzyl)chroman-4-one의 제조Step 3) Preparation of 8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzyl)chroman-4-one

EtOAc(20 mL) 중 (E)-8-브로모-6-(브로모메틸)-3-(3,4-디클로로벤질리덴)크로만-4-온 (1585 mg, 3.323 mmol)과 PtO2 (76 mg, 0.332 mmol) 반응혼합물을 H2 분위기 (풍선 압력) 하에 실온에서 20시간 동안 실온에서 교반하였다. 촉매를 셀라이트 패드를 통한 여과에 의해 제거하고 EtOAc로 세척하였다. 여액을 농축하고 MPLC (10% EA/헵탄)로 정제하여 생성물 (486 mg, 31%)을 얻는다.(E)-8-bromo-6-(bromomethyl)-3-(3,4-dichlorobenzylidene)chroman-4-one (1585 mg, 3.323 mmol) and PtO 2 in EtOAc (20 mL). (76 mg, 0.332 mmol) The reaction mixture was stirred at room temperature for 20 hours under H 2 atmosphere (balloon pressure). The catalyst was removed by filtration through a celite pad and washed with EtOAc. The filtrate is concentrated and purified by MPLC (10% EA/heptane) to give the product (486 mg, 31%).

1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.2 Hz, 1H), 4.54 (dd, J = 11.6, 4.5 Hz, 1H), 4.43 (s, 2H), 4.27 (dd, J = 11.6, 9.4 Hz, 1H), 3.24 (dd, J = 14.2, 4.9 Hz, 1H), 2.99 (dt, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 14.3, 9.5 Hz, 1H). ESI-MS m/z 476.8 (M-H)- 1H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.33 (d , J = 2.1 Hz, 1H), 7.08 (dd, J = 8.2, 2.2 Hz, 1H), 4.54 (dd, J = 11.6, 4.5 Hz, 1H), 4.43 (s, 2H), 4.27 (dd, J = 11.6, 9.4 Hz, 1H), 3.24 (dd, J = 14.2, 4.9 Hz, 1H), 2.99 (dt, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 14.3, 9.5 Hz, 1H). ESI-MS m/z 476.8 (MH) -

Figure pat00113
Figure pat00113

단계 4) 8-bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 4) 8-bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one manufacture of

8-브로모-6-(브로모메틸)-3-(3,4-다이클로로벤질)크로만-4-온 (124 mg, 0.258 mmol), 1-메틸-1,3-다이하이드로-2H-이미다졸-2-이민 (104 mg, 0.776 mmol), DIEA (136 uL, 0.776 mmol), KI (43 mg, 0.258 mmol) 및 MeCN (3 mL)의 용액을 60℃에서 2시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2=1:50 내지 1:10)로 정제하여 생성물 (87.7 mg, 69%)을 얻었다.8-Bromo-6-(bromomethyl)-3-(3,4-dichlorobenzyl)chroman-4-one (124 mg, 0.258 mmol), 1-methyl-1,3-dihydro-2H A solution of -imidazol-2-imine (104 mg, 0.776 mmol), DIEA (136 uL, 0.776 mmol), KI (43 mg, 0.258 mmol) and MeCN (3 mL) was heated at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 =1:50 to 1:10) to give the product (87.7 mg, 69%).

1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.69 (s, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.2, 2.1 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 6.56 (d, J = 2.5 Hz, 1H), 5.49 (s, 2H), 4.54 (dd, J = 11.6, 4.6 Hz, 1H), 4.27 (dd, J = 11.7, 9.4 Hz, 1H), 3.83 (s, 3H), 3.26 - 3.16 (m, 1H), 3.00 (dt, J = 9.3, 4.6 Hz, 1H), 2.69 (dd, J = 14.3, 9.3 Hz, 1H). ESI-MS m/z 495.6 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J = 2.3 Hz, 1H), 7.80 (d, J = 2.2 Hz, 1H), 7.69 (s, 1H), 7.39 (d, J = 8.2 Hz , 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.2, 2.1 Hz, 1H), 6.62 (d, J = 2.5 Hz, 1H), 6.56 (d, J = 2.5 Hz) , 1H), 5.49 (s, 2H), 4.54 (dd, J = 11.6, 4.6 Hz, 1H), 4.27 (dd, J = 11.7, 9.4 Hz, 1H), 3.83 (s, 3H), 3.26 - 3.16 ( m, 1H), 3.00 (dt, J = 9.3, 4.6 Hz, 1H), 2.69 (dd, J = 14.3, 9.3 Hz, 1H). ESI-MS m/z 495.6 (M+H) +

Figure pat00114
Figure pat00114

단계 5) 3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 5) 3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3 Preparation of -dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

8-브로모-3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온 (28.2 mg, 0.057mmol), (1-에틸-3-(트리플루오로메틸)-1H-피라졸-4 -일)붕소산 (13 mg, 0.063 mmol), K2CO3 (24 mg, 0.171 mmol) 및 Pd(dppf)Cl2 (4.2 mg, 0.005 mmol)의 1,4-디옥산/H2O (3:1, 1.2mL)용매 혼합물을 탈기시킨 다음 17시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 1,4-디옥산을 감압 하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 칼럼크로마토그래피 (10% MeOH:CH2Cl2)로 정제하여 화합물 32 (3.0 mg, 9% 수율)을 얻는다.8-Bromo-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman- 4-one (28.2 mg, 0.057 mmol), (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (13 mg, 0.063 mmol), K 2 CO 3 (24 mg, 0.171 mmol) and Pd(dppf)Cl 2 (4.2 mg, 0.005 mmol) in 1,4-dioxane/H 2 O (3:1, 1.2 mL) solvent mixture was degassed and then heated to 100°C for 17 h. heated. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3) and dried over Na 2 SO 4 , concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (10% MeOH:CH 2 Cl 2 ) to give compound 32 (3.0 mg, 9% yield).

1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.41 - 7.32 (m, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.06 (dd, J = 8.2, 2.3 Hz, 1H), 6.51 - 6.42 (m, 2H), 5.42 (s, 2H), 4.38 (dd, J = 11.7, 4.3 Hz, 1H), 4.24 (q, J = 7.0 Hz, 3H), 3.77 (s,3H), 3.19 (dd, J = 14.1, 5.1 Hz, 1H), 2.90 (m, 1H), 2.69 (dd, J = 14.2, 9.6 Hz, 1H), 1.25 (s, 3H). ESI-MS m/z 578.1 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 8.81 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.69 - 7.60 (m, 2H), 7.41 - 7.32 (m, 1H), 7.32 ( d, J = 2.1 Hz, 1H), 7.06 (dd, J = 8.2, 2.3 Hz, 1H), 6.51 - 6.42 (m, 2H), 5.42 (s, 2H), 4.38 (dd, J = 11.7, 4.3 Hz) , 1H), 4.24 (q, J = 7.0 Hz, 3H), 3.77 (s, 3H), 3.19 (dd, J = 14.1, 5.1 Hz, 1H), 2.90 (m, 1H), 2.69 (dd, J = 14.2, 9.6 Hz, 1H), 1.25 (s, 3H). ESI-MS m/z 578.1 (M+H) +

Figure pat00115
Figure pat00115

화합물 33. 3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 33. 3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol -1-yl)methyl)chroman-4-one

(6-플루오로-2-메틸피리딘-3-일)보론산 (8 mg, 0.052 mmol)을 사용하여 화합물 33 (2.0 mg, 8% 수율)을 실시예 32, 단계 5에 기재된 절차로부터 제조하였다.Compound 33 (2.0 mg, 8% yield) was prepared from the procedure described in Example 32, Step 5 using (6-fluoro-2-methylpyridin-3-yl)boronic acid (8 mg, 0.052 mmol). .

1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.04 (dd, J = 8.2, 2.1 Hz, 1H), 6.82 (dd, J = 8.2, 3.2 Hz, 1H), 6.68 (s, 1H), 6.54 (s, 1H), 4.56 (d, J = 5.6 Hz, 2H), 4.37 (dd, J = 11.6, 4.6 Hz, 1H), 4.18 - 4.08 (m, 1H), 3.42 (s, 3H), 3.23 (dd, J = 14.2, 4.7 Hz, 1H), 2.98 - 2.91 (m, 1H), 2.70 (dd, J = 14.1, 9.4 Hz, 1H), 2.33 (s, 3H). ESI-MS m/z 525.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.37 (d, J = 8.2 Hz) , 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.04 (dd, J = 8.2, 2.1 Hz, 1H), 6.82 (dd, J = 8.2, 3.2 Hz, 1H), 6.68 (s, 1H) , 6.54 (s, 1H), 4.56 (d, J = 5.6 Hz, 2H), 4.37 (dd, J = 11.6, 4.6 Hz, 1H), 4.18 - 4.08 (m, 1H), 3.42 (s, 3H), 3.23 (dd, J = 14.2, 4.7 Hz, 1H), 2.98 - 2.91 (m, 1H), 2.70 (dd, J = 14.1, 9.4 Hz, 1H), 2.33 (s, 3H). ESI-MS m/z 525.1 (M+H) +

Figure pat00116
Figure pat00116

화합물 34. 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 34. 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-(1-ethyl- 3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

Figure pat00117
Figure pat00117

단계 1) (E)-3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzylidene)-8-bromo-6-(bromomethyl)chroman-4-one의 제조Step 1) (E)-3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzylidene)-8-bromo Preparation of -6-(bromomethyl)chroman-4-one

3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzaldehyde (325 mg, 1.135 mmol)을 사용하여 생성물 (128 mg, 19% 수율)을 실시예 32, 단계 2에 기재된 절차로부터 제조하였다.3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzaldehyde (325 mg, 1.135 mmol) was used to obtain the product (128 mg, 19% yield) was prepared from the procedure described in Example 32, Step 2.

1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.4 Hz, 2H), 7.15 (dd, J = 10.8, 8.3 Hz, 1H), 6.98 (dd, J = 7.9, 2.2 Hz, 1H), 6.86 (ddd, J = 8.4, 4.3, 2.1 Hz, 1H), 5.46 (d, J = 1.9 Hz, 2H), 4.46 (s, 2H), 4.27 - 4.22 (m, 2H), 3.95 - 3.88 (m, 2H), 3.79 - 3.72 (m, 2H), 3.70 - 3.64 (m, 4H), 3.58 - 3.51 (m, 2H), 3.36 (s, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.99 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.4 Hz, 2H), 7.15 (dd, J = 10.8, 8.3 Hz, 1H), 6.98 (dd, J = 7.9, 2.2 Hz, 1H), 6.86 (ddd, J = 8.4, 4.3, 2.1 Hz, 1H), 5.46 (d, J = 1.9 Hz, 2H), 4.46 (s, 2H), 4.27 - 4.22 (m, 2H), 3.95 - 3.88 (m, 2H), 3.79 - 3.72 (m, 2H), 3.70 - 3.64 (m, 4H), 3.58 - 3.51 (m, 2H), 3.36 (s, 3H).

Figure pat00118
Figure pat00118

단계 2) 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-bromo-6-(bromomethyl)chroman-4-one의 제조Step 2) 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-bromo-6-( Preparation of bromomethyl)chroman-4-one

(E)-3-(3-(2-((2-(2-(11-옥시다일)에톡시)에틸)(메틸)-13-옥시다일)에톡시)-4-플루오로벤질리덴)-8-브로모-6-(브로모메틸)크로만-4-온 (128 mg, 0.217 mmol)에 PtO2 (6 mg, 0.021 mmol)를 EtOAc (5 mL) 중 실온에서 첨가하였다. 반응혼합물을 H2 분위기(풍선 압력) 하에 실온에서 6시간 동안 교반하였다. 촉매를 셀라이트 패드를 통한 여과에 의해 제거하고 EtOAc로 세척하였다. 여액을 농축하고 MPLC (10% EA/헵탄)에 의해 정제하여 생성물 (97 mg, 96%)을 얻는다.(E)-3-(3-(2-((2-(2-(11-oxydyl)ethoxy)ethyl)(methyl)-13-oxydyl)ethoxy)-4-fluorobenzylidene) To -8-bromo-6-(bromomethyl)chroman-4-one (128 mg, 0.217 mmol) was added PtO 2 (6 mg, 0.021 mmol) in EtOAc (5 mL) at room temperature. The reaction mixture was stirred at room temperature under H 2 atmosphere (balloon pressure) for 6 hours. The catalyst was removed by filtration through a celite pad and washed with EtOAc. The filtrate is concentrated and purified by MPLC (10% EA/heptane) to give the product (97 mg, 96%).

1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.01 (dd, J = 11.1, 8.2 Hz, 1H), 6.86 (dd, J = 8.0, 2.1 Hz, 1H), 6.75 (m, 1H), 4.52 (dd, J = 11.6, 4.5 Hz, 1H), 4.43 (s, 2H), 4.30 - 4.22 (m, 1H), 4.19 (dd, J = 5.7, 4.0 Hz, 2H), 3.94 - 3.86 (m, 2H), 3.79 - 3.72 (m, 2H), 3.71 - 3.63 (m, 4H), 3.57 - 3.51 (m, 2H), 3.37 (s, 3H), 3.21 (dd, J = 14.1, 4.8 Hz, 1H), 2.95 (tt, J = 9.3, 4.6 Hz, 1H), 2.69 (dd, J = 14.2, 9.8 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.88 (s, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.01 (dd, J = 11.1, 8.2 Hz, 1H), 6.86 (dd, J = 8.0, 2.1 Hz, 1H), 6.75 (m, 1H), 4.52 (dd, J = 11.6, 4.5 Hz, 1H), 4.43 (s, 2H), 4.30 - 4.22 (m, 1H), 4.19 (dd, J = 5.7, 4.0 Hz, 2H), 3.94 - 3.86 (m, 2H), 3.79 - 3.72 (m, 2H), 3.71 - 3.63 (m, 4H), 3.57 - 3.51 (m, 2H), 3.37 (s, 3H) ), 3.21 (dd, J = 14.1, 4.8 Hz, 1H), 2.95 (tt, J = 9.3, 4.6 Hz, 1H), 2.69 (dd, J = 14.2, 9.8 Hz, 1H).

Figure pat00119
Figure pat00119

단계 3) 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 3) 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-bromo-6-( Preparation of (2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

3-(3-(2-((2-(2-(11-옥시다네일)에톡시)에틸)(메틸)-13-옥시다네일)에톡시)-4-플루오로벤질)-8-브로모-6-(브로모메틸)크로만-4-온 (165 mg, 0.28 mmol), 1-메틸-1,3-디하이드로-2H-이미다졸-2-이민 (81 mg, 0.83 mmol), DIEA (150 uL, 0.83mmol), KI (46 mg, 0.28 mmol) 및 MeCN (3 mL)을 60℃에서 2시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2 = 1:50 내지 1:10)로 정제하여 생성물 (31 mg, 18.3%)을 얻었다.3-(3-(2-((2-(2-(11-oxidaneyl)ethoxy)ethyl)(methyl)-13-oxidaneyl)ethoxy)-4-fluorobenzyl)-8- Bromo-6-(bromomethyl)chroman-4-one (165 mg, 0.28 mmol), 1-methyl-1,3-dihydro-2H-imidazol-2-imine (81 mg, 0.83 mmol) , DIEA (150 uL, 0.83 mmol), KI (46 mg, 0.28 mmol) and MeCN (3 mL) were heated at 60 °C for 2 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 = 1:50 to 1:10) to give the product (31 mg, 18.3%).

1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 6.97 (dd, J = 11.1, 8.2 Hz, 1H), 6.81 (dd, J = 8.0, 2.1 Hz, 1H), 6.70 (ddd, J = 8.2, 4.2, 2.1 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.43 (d, J = 2.4 Hz, 2H), 4.49 (dd, J = 11.7, 4.5 Hz, 1H), 4.25 (dd, J = 11.6, 8.9 Hz, 1H), 4.16 (t, J = 4.8 Hz, 2H), 3.87 - 3.84 (m, 2H), 3.79 (s, 2H), 3.74 - 3.70 (m, 2H), 3.68 - 3.61 (m, 4H), 3.54 - 3.50 (m, 2H), 3.34 (s, 3H), 3.15 (dd, J = 14.1, 4.9 Hz, 1H), 2.93 (tt, J = 9.2, 4.7 Hz, 1H), 2.66 (dd, J = 14.2, 9.5 Hz, 1H), 0.84 - 0.79 (m, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.90 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 6.97 (dd, J = 11.1, 8.2 Hz, 1H), 6.81 (dd, J = 8.0, 2.1 Hz, 1H), 6.70 (ddd, J = 8.2, 4.2, 2.1 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.52 (d, J = 2.5 Hz, 1H), 5.43 (d, J = 2.4 Hz, 2H), 4.49 (dd, J = 11.7, 4.5 Hz, 1H), 4.25 (dd, J = 11.6, 8.9 Hz, 1H), 4.16 (t, J = 4.8 Hz, 2H), 3.87 - 3.84 (m, 2H), 3.79 (s, 2H), 3.74 - 3.70 (m, 2H), 3.68 - 3.61 (m, 4H), 3.54 - 3.50 (m, 2H), 3.34 ( s, 3H), 3.15 (dd, J = 14.1, 4.9 Hz, 1H), 2.93 (tt, J = 9.2, 4.7 Hz, 1H), 2.66 (dd, J = 14.2, 9.5 Hz, 1H), 0.84 - 0.79 (m, 3H).

Figure pat00120
Figure pat00120

단계 4) 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 4) 3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8-(1-ethyl- Preparation of 3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

3-(3-(2-((2-(2-(11-옥시단일)에톡시)에틸)(메틸)-13-옥시단일)에톡시)-4-플루오로벤질)-8-브로모-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온 (36 mg, 0.059 mmol), (1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)보론산 (18 mg, 0.089 mmol), Cs2CO3 (38 mg, 0.118 mmol), 및 Pd(amphos)Cl2 (4.2 mg, 0.006mmol)를 1,4-디옥산/H2O (3:1, 1.2 mL) 용매하에 첨가하였다. 혼합물을 탈기한 다음, 1시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 1,4-디옥산을 감압 하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시칼럼크로마토그래피 (10% MeOH:CH2Cl2)로 정제하여 화합물 34 (13 mg, 31.7% 수율)를 얻는다.3-(3-(2-((2-(2-(11-oxymonoyl)ethoxy)ethyl)(methyl)-13-oxymonoyl)ethoxy)-4-fluorobenzyl)-8-bromo -6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (36 mg, 0.059 mmol), (1-ethyl -3-(trifluoromethyl)-1H-pyrazol-4-yl)boronic acid (18 mg, 0.089 mmol), Cs 2 CO 3 (38 mg, 0.118 mmol), and Pd(amphos)Cl 2 (4.2 mg, 0.006 mmol) was added under a solvent of 1,4-dioxane/H 2 O (3:1, 1.2 mL). The mixture was degassed and then heated to 100 °C for 1 hour. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3) and dried over Na 2 SO 4 , concentrated under reduced pressure. The residue is purified by flash column chromatography on silica gel (10% MeOH:CH 2 Cl 2 ) to give compound 34 (13 mg, 31.7% yield).

1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 14.3 Hz, 2H), 7.63 (s, 1H), 6.95 (t, J = 9.8 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.70 (s, 1H), 6.57 (dq, J = 4.7, 2.4 Hz, 2H), 5.38 (d, J = 7.3 Hz, 2H), 4.35 (d, J = 11.8 Hz, 1H), 4.20 (dd, J = 15.3, 8.0 Hz, 1H), 4.14 (s, 2H), 3.85 (d, J = 5.3 Hz, 2H), 3.77 - 3.69 (m, 4H), 3.67 - 3.58 (m, 4H), 3.55 - 3.49 (m, 2H), 3.33 (q, J = 2.9, 1.9 Hz, 3H), 3.12 (d, J = 14.4 Hz, 1H), 2.87 (s, 1H), 2.67 (t, J = 12.0 Hz, 1H), 1.52 (t, J = 7.1 Hz, 3H). ESI-MS m/z 690.6 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 14.3 Hz, 2H), 7.63 (s, 1H), 6.95 (t, J = 9.8 Hz, 1H), 6.80 (d, J = 7.8 Hz) , 1H), 6.70 (s, 1H), 6.57 (dq, J = 4.7, 2.4 Hz, 2H), 5.38 (d, J = 7.3 Hz, 2H), 4.35 (d, J = 11.8 Hz, 1H), 4.20 (dd, J = 15.3, 8.0 Hz, 1H), 4.14 (s, 2H), 3.85 (d, J = 5.3 Hz, 2H), 3.77 - 3.69 (m, 4H), 3.67 - 3.58 (m, 4H), 3.55 - 3.49 (m, 2H), 3.33 (q, J = 2.9, 1.9 Hz, 3H), 3.12 (d, J = 14.4 Hz, 1H), 2.87 (s, 1H), 2.67 (t, J = 12.0 Hz) , 1H), 1.52 (t, J = 7.1 Hz, 3H). ESI-MS m/z 690.6 (M+H) +

Figure pat00121
Figure pat00121

화합물 35. 2,2,2-trifluoroacetaldehyde-(E)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 35. 2,2,2-trifluoroacetaldehyde-(E)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro -1H-imidazol-1-yl)methyl)chroman-4-one

Figure pat00122
Figure pat00122

단계 1) 8-(4-fluorophenyl)-6-methylchroman-4-one의 제조Step 1) Preparation of 8-(4-fluorophenyl)-6-methylchroman-4-one

8-브로모-6-메틸크로만-4-온(723 mg, 3 mmol)에 (4-플루오로페닐)보론산 (462 mg, 3.3 mmol), K2CO3 (1.243 g, 9mmol) 및 Pd(dppf)Cl2 (110 mg, 0.15 mmol)의 1,4-디옥산/H2O (3:1, 16 mL) 용매 중 혼합물을 탈기시킨 다음 17시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 용매를 감압 하에 제거하고, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (10% 에틸 아세테이트:n-헥산)로 정제하여 생성물 (700 mg, 91% 수율)을 얻는다.To 8-bromo-6-methylchroman-4-one (723 mg, 3 mmol) (4-fluorophenyl)boronic acid (462 mg, 3.3 mmol), K 2 CO 3 (1.243 g, 9 mmol) and A mixture of Pd(dppf)Cl 2 (110 mg, 0.15 mmol) in 1,4-dioxane/H 2 O (3:1, 16 mL) solvent was degassed and then heated to 100° C. for 17 h. After cooling to room temperature, the solvent was removed under reduced pressure and the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. . The residue is purified by flash column chromatography on silica gel (10% ethyl acetate:n-hexane) to give the product (700 mg, 91% yield).

1H NMR (300 MHz, CDCl3) δ 7.73 (dt, J = 2.4, 0.8 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.16 - 7.05 (m, 2H), 4.51 (dd, J = 6.9, 5.9 Hz, 2H), 2.82 (dd, J = 6.9, 6.0 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H). ESI-MS m/z 257.1 (M+H)+ 1H NMR (300 MHz, CDCl 3 ) δ 7.73 (dt, J = 2.4, 0.8 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.16 - 7.05 ( m, 2H), 4.51 (dd, J = 6.9, 5.9 Hz, 2H), 2.82 (dd, J = 6.9, 6.0 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H). ESI-MS m/z 257.1 (M+H) +

Figure pat00123
Figure pat00123

단계 2) 6-(bromomethyl)-8-(4-fluorophenyl)chroman-4-one의 제조Step 2) Preparation of 6-(bromomethyl)-8-(4-fluorophenyl)chroman-4-one

8-(4-플루오로페닐)-6-메틸크로만-4-온 (347 mg, 1.353 mmol), NBS (265 mg, 1.489 mmol), AIBN (22 mg, 0.135 mmol) 및 MeOAc (5 mL)의 용액을 60 °C에서 4시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트 및 물로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 칼럼크로마토그래피 (에틸 아세테이트:n-헥산 = 1:10)로 정제하여 생성물 (172 mg, 38%)을 수득하였다.8-(4-fluorophenyl)-6-methylchroman-4-one (347 mg, 1.353 mmol), NBS (265 mg, 1.489 mmol), AIBN (22 mg, 0.135 mmol) and MeOAc (5 mL) The solution was refluxed at 60 °C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:10) to give the product (172 mg, 38%).

1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.13 (t, J = 8.7 Hz, 2H), 4.55 (dd, J = 6.9, 6.0 Hz, 2H), 4.51 (s, 2H), 2.90 - 2.81 (m, 2H). 1H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.13 (t, J = 8.7 Hz, 2H), 4.55 (dd, J = 6.9, 6.0 Hz, 2H), 4.51 (s, 2H), 2.90 - 2.81 (m, 2H).

Figure pat00124
Figure pat00124

단계 3) 8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 3) Preparation of 8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one

6-(브로모메틸)-8-(4-플루오로페닐)크로만-4-온 (172 mg, 0.484 mmol), 1-메틸-1H-이미다졸-2-아민 염산염 (194 mg, 1.452 mmol), DIEA (260 uL, 1.452 mmol), KI (8 mg, 0.05 mmol) 및 MeCN (3 mL)을 60℃에서 15시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (MeOH:CH2Cl2=1:30 내지 1:10)로 정제하여 생성물 (10 mg, 6%)을 수득하였다.6-(Bromomethyl)-8-(4-fluorophenyl)chroman-4-one (172 mg, 0.484 mmol), 1-methyl-1H-imidazol-2-amine hydrochloride (194 mg, 1.452 mmol) ), DIEA (260 uL, 1.452 mmol), KI (8 mg, 0.05 mmol) and MeCN (3 mL) were heated at 60 °C for 15 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (MeOH:CH 2 Cl 2 =1:30 to 1:10) to give the product (10 mg, 6%).

1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.08 - 7.03 (m, 2H), 6.66 (d, J = 2.0 Hz, 1H), 6.45 (d, J = 2.0 Hz, 1H), 4.61 (d, J = 5.2 Hz, 2H), 4.50 - 4.42 (m, 2H), 3.56 (s, 3H), 2.76 (t, J = 6.4 Hz, 2H). ESI-MS m/z 352.9 (M-H)- 1H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 2.3 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.52 - 7.47 (m, 2H), 7.08 - 7.03 (m, 2H), 6.66 (d, J = 2.0 Hz, 1H), 6.45 (d, J = 2.0 Hz, 1H), 4.61 (d, J = 5.2 Hz, 2H), 4.50 - 4.42 (m, 2H), 3.56 ( s, 3H), 2.76 (t, J = 6.4 Hz, 2H). ESI-MS m/z 352.9 (MH) -

Figure pat00125
Figure pat00125

단계 4) tert-butyl (Z)-(1-((8-(4-fluorophenyl)-4-oxochroman-6-yl)methyl)-3-methyl -1,3-dihydro-2H-imidazol-2-ylidene)carbamate의 제조Step 4) tert-butyl (Z)-(1-((8-(4-fluorophenyl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2- Manufacture of ylidene)carbamate

8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)크로만-4-온 (10 mg, 0.028 mmol), (Boc)2O (13 uL, 0.057 mmol), DMAP (1 mg, 0.006 mmol) 및 CH2Cl2 (1 mL)를 실온에서 15시간 동안 교반하였다. 반응혼합물을 CH2Cl2로 희석하고 유기상을 물로 세척하고 Na2SO4로 건조시키고 감압하에 농축시켰다. 잔류물을 실리카겔 상에서 플래시칼럼크로마토그래피 (에틸 아세테이트:n-헥산 = 1:2)로 정제하여 보호된 생성물 (5.9 mg, 47%)을 수득하였다.8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (10 mg , 0.028 mmol), (Boc) 2 O (13 uL, 0.057 mmol), DMAP (1 mg, 0.006 mmol) and CH 2 Cl 2 (1 mL) were stirred at room temperature for 15 hours. The reaction mixture was diluted with CH 2 Cl 2 and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate:n-hexane = 1:2) to give the protected product (5.9 mg, 47%).

1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.42 (qd, J = 4.7, 4.1, 2.2 Hz, 3H), 7.14 - 7.06 (m, 2H), 6.93 (d, J = 1.4 Hz, 1H), 6.71 (d, J = 1.5 Hz, 1H), 4.81 (s, 2H), 4.52 (t, J = 6.4 Hz, 2H), 3.26 (s, 3H), 2.82 (t, J = 6.4 Hz, 2H), 1.43 (s, 9H). ESI-MS m/z 452.2 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (s, 1H), 7.42 (qd, J = 4.7, 4.1, 2.2 Hz, 3H), 7.14 - 7.06 (m, 2H), 6.93 (d, J = 1.4 Hz, 1H), 6.71 (d, J = 1.5 Hz, 1H ), 4.81 (s, 2H), 4.52 (t, J = 6.4 Hz, 2H), 3.26 (s, 3H), 2.82 (t, J = 6.4 Hz, 2H), 1.43 (s, 9H). ESI-MS m/z 452.2 (M+H) +

Figure pat00126
Figure pat00126

단계 5) tert-butyl ((E)-1-((3-((E)-3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)- 4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate의 제조Step 5) tert-butyl ((E)-1-((3-((E)-3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-4-oxochroman-6-yl)methyl)-3- Preparation of methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate

tert-부틸 (Z)-(1-((8-(4-플루오로페닐)-4-옥소크로만-6-일)메틸)-3-메틸-1,3-디히드로-2H-이미다졸-2-일리덴)카바메이트 (5.9mg, 0.013mmol) 및 벤즈알데히드(3.4mg, 0.020mmol)에 1N-NaOH 용액 (13 uL, 0.013 mmol)을 EtOH (1 mL)중 0℃에서 첨가하였다. 반응 혼합물을 실온에서 밤새 교반하였다. 반응혼합물을 감압하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (에틸아세테이트; n-헥산 = 1:4 내지 1:2)로 정제하여 생성물 (8 mg, 정량적)을 수득하였다.tert-Butyl (Z)-(1-((8-(4-fluorophenyl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazole To -2-ylidene)carbamate (5.9 mg, 0.013 mmol) and benzaldehyde (3.4 mg, 0.020 mmol) was added 1N-NaOH solution (13 uL, 0.013 mmol) in EtOH (1 mL) at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate; n-hexane = 1:4 to 1:2) to give the product (8 mg, quant.).

1H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.81 (s, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.40 (dd, J = 8.6, 5.6 Hz, 2H), 7.08 (t, J = 8.7 Hz, 2H), 6.94 (d, J = 1.4 Hz, 1H), 6.71 (d, J = 1.3 Hz, 1H), 6.50 (s, 1H), 6.41 (d, J = 2.2 Hz, 2H), 5.33 (d, J = 1.8 Hz, 2H), 3.81 (s, 8H), 3.27 (s, 3H), 1.44 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.92 (s, 1H), 7.81 (s, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.40 (dd, J = 8.6, 5.6 Hz, 2H) , 7.08 (t, J = 8.7 Hz, 2H), 6.94 (d, J = 1.4 Hz, 1H), 6.71 (d, J = 1.3 Hz, 1H), 6.50 (s, 1H), 6.41 (d, J = 1H). 2.2 Hz, 2H), 5.33 (d, J = 1.8 Hz, 2H), 3.81 (s, 8H), 3.27 (s, 3H), 1.44 (s, 9H).

Figure pat00127
Figure pat00127

단계 6) (E)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 6) (E)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl Preparation of )methyl)chroman-4-one

tert-부틸 ((E)-1-((3-((E)-3,5-디메톡시벤질리덴)-8-(4-플루오로페닐)-4-옥소크로만-6-일)메틸)-3-메틸-1,3-디하이드로-2H-이미다졸-2-일리덴)카바메이트 (8 mg, 0.013 mmol)의 무수 CH2Cl2 (1 mL) 용액 중 0℃에서 TFA (5 방울)로 적가하였다. 생성된 혼합물을 실온에서 2시간 동안 교반하였다. 반응혼합물을 감압하에 농축하였다. 생성된 고체를 여과하고, 디에틸에테르(2 mL x 8)로 헹구고, 진공에서 농축하여 TFA 염 생성물 (화합물 35; 2.4 mg, 31%)를 얻었다.tert-butyl ((E)-1-((3-((E)-3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-4-oxochroman-6-yl)methyl )-3-methyl-1,3-dihydro-2H-imidazol- 2 -ylidene)carbamate (8 mg, 0.013 mmol) in TFA (5 drops) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting solid was filtered, rinsed with diethyl ether (2 mL x 8), and concentrated in vacuo to give the TFA salt product (compound 35; 2.4 mg, 31%).

1H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.45 (s, 2H), 7.05 (t, J = 8.4 Hz, 2H), 6.75 (s, 1H), 6.49 (s, 2H), 6.36 (s, 2H), 5.29 (s, 2H), 4.60 (s, 2H), 3.80 (s, 6H), 3.61 (s, 3H). ESI-MS m/z 500.2 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (s, 1H), 7.74 (s, 1H), 7.60 (s, 1H), 7.45 (s, 2H), 7.05 (t, J = 8.4 Hz, 2H) , 6.75 (s, 1H), 6.49 (s, 2H), 6.36 (s, 2H), 5.29 (s, 2H), 4.60 (s, 2H), 3.80 (s, 6H), 3.61 (s, 3H). ESI-MS m/z 500.2 (M+H) +

Figure pat00128
Figure pat00128

화합물 36. 3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 36. 3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman -4-one

Figure pat00129
Figure pat00129

단계 1) 8-(4-fluorophenyl)-6-methylchroman-4-one의 제조Step 1) Preparation of 8-(4-fluorophenyl)-6-methylchroman-4-one

8-브로모-6-메틸크로만-4-온 (964 mg, 4 mmol)의 1,4-디옥산/H2O (3:1, 16 mL) 중에 (4-플루오로페닐)보론산 (616 mg, 4.4 mmol), K2CO3 (1.66 g, 12 mmol) 및 Pd(dppf)Cl2 (146 mg, 0.2 mmol)을 첨가하였다. 혼합물을 탈기시킨 다음, 4시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (5%-10%, 에틸 아세테이트:n-헥산)로 정제하여 생성물 (717 mg, 70%)을 얻는다.8-Bromo-6-methylchroman-4-one (964 mg, 4 mmol) in 1,4-dioxane/H 2 O (3:1, 16 mL) (4-fluorophenyl)boronic acid (616 mg, 4.4 mmol), K 2 CO 3 (1.66 g, 12 mmol) and Pd(dppf)Cl 2 (146 mg, 0.2 mmol) were added. The mixture was degassed and then heated to 100° C. for 4 hours. After cooling to room temperature, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by MPLC (5%-10%, ethyl acetate:n-hexane) to give the product (717 mg, 70%).

1H NMR (300 MHz, CDCl3) δ 7.73 (dt, J = 2.4, 0.8 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.16 - 7.05 (m, 2H), 4.51 (dd, J = 6.9, 5.9 Hz, 2H), 2.82 (dd, J = 6.9, 6.0 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H). ESI-MS m/z 257.1 (M+H)+ 1H NMR (300 MHz, CDCl 3 ) δ 7.73 (dt, J = 2.4, 0.8 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.16 - 7.05 ( m, 2H), 4.51 (dd, J = 6.9, 5.9 Hz, 2H), 2.82 (dd, J = 6.9, 6.0 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H). ESI-MS m/z 257.1 (M+H) +

Figure pat00130
Figure pat00130

단계 2) 6-(bromomethyl)-8-(4-fluorophenyl)chroman-4-one의 제조Step 2) Preparation of 6-(bromomethyl)-8-(4-fluorophenyl)chroman-4-one

8-(4-플루오로페닐)-6-메틸크로만-4-온 (369 mg, 1.439 mmol), NBS (307 mg, 1.727 mmol), AIBN (24 mg, 0.144 mmol) 및 MeOAc (4.8 mL)의 용액을 60℃에서 20시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트 및 물로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (에틸아세테이트:n-헥산 = 1:20 ~ 1:10)로 정제하여 생성물 (357mg, 74%)을 얻었다.8-(4-fluorophenyl)-6-methylchroman-4-one (369 mg, 1.439 mmol), NBS (307 mg, 1.727 mmol), AIBN (24 mg, 0.144 mmol) and MeOAc (4.8 mL) The solution was refluxed at 60 °C for 20 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:n-hexane = 1:20 to 1:10) to give the product (357mg, 74%).

1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.13 (t, J = 8.7 Hz, 2H), 4.55 (dd, J = 6.9, 6.0 Hz, 2H), 4.51 (s, 2H), 2.90 - 2.81 (m, 2H). ESI-MS m/z 352.9 (M-H)- 1H NMR (400 MHz, CDCl 3 ) δ 7.94 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.13 (t, J = 8.7 Hz, 2H), 4.55 (dd, J = 6.9, 6.0 Hz, 2H), 4.51 (s, 2H), 2.90 - 2.81 (m, 2H). ESI-MS m/z 352.9 (MH) -

Figure pat00131
Figure pat00131

단계 3) (E)-6-(bromomethyl)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)chroman-4-one의 제조Step 3) Preparation of (E)-6-(bromomethyl)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)chroman-4-one

톨루엔 (5 mL) 중 6-(브로모메틸)-8-(4-플루오로페닐)크로만-4-온 (357 mg, 1.065 mmol)의 용액에 3,5-디메톡시 벤즈알데히드 (266 mg, 1.598 mmol)및 para-톨루엔 설폰산 (19 mg, 0.107 mmol)을 상온에서 첨가하였다. 반응혼합물을 17시간 동안 환류시켰다. 상온으로 냉각한 후, 혼합물을 감압 하에 농축하였다. 잔류물을 실리카겔 상에서 플래시 컬럼 크로마토그래피 (디클로로메탄/n-헥산 = 1:1)로 정제하여 생성물 (354 mg, 69%)을 수득하였다.3,5-dimethoxy benzaldehyde (266 mg, 1.598 mmol) and para-toluene sulfonic acid (19 mg, 0.107 mmol) were added at room temperature. The reaction mixture was refluxed for 17 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (dichloromethane/n-hexane = 1:1) to give the product (354 mg, 69%).

1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.15 - 7.06 (m, 2H), 6.50 (t, J = 2.2 Hz, 1H), 6.42 (d, J = 2.2 Hz, 2H), 5.35 (d, J = 1.9 Hz, 2H), 4.54 (s, 2H), 3.81 (s, 6H). ESI-MS m/z 485.1 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 8.05 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.15 - 7.06 (m, 2H), 6.50 (t, J = 2.2 Hz, 1H), 6.42 (d, J = 2.2 Hz, 2H), 5.35 (d, J = 1.9 Hz, 2H) , 4.54 (s, 2H), 3.81 (s, 6H). ESI-MS m/z 485.1 (M+H) +

Figure pat00132
Figure pat00132

단계 4) 6-(bromomethyl)-3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)chroman-4-one의 제조Step 4) Preparation of 6-(bromomethyl)-3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)chroman-4-one

EtOAc (4 mL) 중 (E)-6-(브로모메틸)-3-(3,5-디메톡시벤질리덴)-8-(4-플루오로페닐)크로만-4-온 (77 mg, 0.159 mmol)의 혼합물에 실온에서 PtO2 (3.6 mg, 0.016 mmol)를 첨가하였다. 반응혼합물을 H2 (풍선 압력) 존재하에 실온에서 6시간 동안 교반하였다. 촉매를 셀라이트 패드를 통한 여과에 의해 제거하고 EtOAc로 세척하였다. 여액을 농축하고 MPLC (50% MC/헵탄)에 의해 정제하여 생성물 (58 mg, 76%)을 얻는다.(E)-6-(bromomethyl)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)chroman-4-one (77 mg, 0.159 mmol) was added PtO 2 (3.6 mg, 0.016 mmol) at room temperature. The reaction mixture was stirred at room temperature in the presence of H 2 (balloon pressure) for 6 hours. The catalyst was removed by filtration through a celite pad and washed with EtOAc. The filtrate is concentrated and purified by MPLC (50% MC/heptane) to give the product (58 mg, 76%).

1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.11 (t, J = 8.6 Hz, 2H), 6.35 (dd, J = 7.8, 2.3 Hz, 4H), 4.52 (s, 2H), 4.42 (dd, J = 11.6, 4.6 Hz, 1H), 4.18 (dd, J = 11.6, 9.5 Hz, 1H), 3.77 (s, 6H), 3.30 (dd, J = 14.0, 4.4 Hz, 1H), 3.00 (dt, J = 9.8, 5.0 Hz, 1H), 2.64 (dd, J = 14.0, 10.2 Hz, 1H). ESI-MS m/z 487.0 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.11 (t, J = 8.6 Hz, 2H), 6.35 (dd, J = 7.8, 2.3 Hz, 4H), 4.52 (s, 2H), 4.42 (dd, J = 11.6, 4.6 Hz, 1H), 4.18 (dd, J = 11.6, 9.5 Hz, 1H), 3.77 (s, 6H), 3.30 (dd, J = 14.0, 4.4 Hz, 1H), 3.00 (dt, J = 9.8, 5.0 Hz, 1H), 2.64 (dd, J = 14.0, 10.2 Hz) , 1H). ESI-MS m/z 487.0 (M+H) +

Figure pat00133
Figure pat00133

단계 5) 3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 5) 3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman Preparation of 4-one

6-(브로모메틸)-3-(3,5-디메톡시벤질)-8-(4-플루오로페닐)크로만-4-온 (53 mg, 0.109 mmol), 1-메틸-1H-이미다졸-2-아민 염산염 (44 mg, 0.329 mmol), DIEA (57 uL, 0.329 mmol), KI (18 mg, 0.109 mmol) 및 MeCN (2 mL)의 용액을 60℃에서 4시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2=1:50 내지 1:10)로 정제하여 화합물 36 (32.7 mg, 60%)을 얻었다.6-(Bromomethyl)-3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)chroman-4-one (53 mg, 0.109 mmol), 1-methyl-1H-imi A solution of dazol-2-amine hydrochloride (44 mg, 0.329 mmol), DIEA (57 uL, 0.329 mmol), KI (18 mg, 0.109 mmol) and MeCN (2 mL) was heated at 60 °C for 4 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 =1:50 to 1:10) to give Compound 36 (32.7 mg, 60%).

1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.63 (s, 2H), 7.59 - 7.51 (m, 2H), 7.11 - 7.02 (m, 2H), 6.57 (q, J = 2.5 Hz, 2H), 6.41 - 6.30 (m, 3H), 5.46 (s, 2H), 4.42 (dd, J = 11.6, 4.6 Hz, 1H), 4.17 (dd, J = 11.6, 9.6 Hz, 1H), 3.79 (s, 3H), 3.76 (d, J = 9.6 Hz, 9H), 3.26 (dd, J = 14.0, 4.5 Hz, 1H), 3.00 (td, J = 9.7, 4.8 Hz, 1H), 2.60 (dd, J = 14.1, 10.2 Hz, 1H). ESI-MS m/z 502.2 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.81 (d, J = 2.4 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.63 (s, 2H), 7.59 - 7.51 (m, 2H) , 7.11 - 7.02 (m, 2H), 6.57 (q, J = 2.5 Hz, 2H), 6.41 - 6.30 (m, 3H), 5.46 (s, 2H), 4.42 (dd, J = 11.6, 4.6 Hz, 1H) ), 4.17 (dd, J = 11.6, 9.6 Hz, 1H), 3.79 (s, 3H), 3.76 (d, J = 9.6 Hz, 9H), 3.26 (dd, J = 14.0, 4.5 Hz, 1H), 3.00 (td, J = 9.7, 4.8 Hz, 1H), 2.60 (dd, J = 14.1, 10.2 Hz, 1H). ESI-MS m/z 502.2 (M+H) +

Figure pat00134
Figure pat00134

화합물 37. (S)-3-(2,6-dibromo-3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 37. (S)-3-(2,6-dibromo-3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H -imidazol-1-yl)methyl)chroman-4-one

Figure pat00135
Figure pat00135

단계 1) 8-(4-fluorophenyl)-6-methylchroman-4-one의 제조Step 1) Preparation of 8-(4-fluorophenyl)-6-methylchroman-4-one

1,4-디옥산/H2O (3:1, 32 mL) 중 8-브로모-6-메틸크로만-4-온 (1860 mg, 7.718 mmol)에 (4-플루오로페닐)보론산 (1080 mg, 7.718 mmol), K2CO3 (3200 mg, 23.15 mmol) 및 Pd(dppf)Cl2 (57 mg, 0.077 mmol)을 첨가하였다. 혼합물을 탈기한 다음 16시간 동안 100℃로 가열하였다. 실온으로 냉각한 후, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MC:헵탄/1:5 내지 1:1)로 정제하여 생성물 (1562 mg, 79%)을 얻는다.(4-fluorophenyl)boronic acid in 8-bromo-6-methylchroman-4-one (1860 mg, 7.718 mmol) in 1,4-dioxane/H 2 O (3:1, 32 mL) (1080 mg, 7.718 mmol), K 2 CO 3 (3200 mg, 23.15 mmol) and Pd(dppf)Cl 2 (57 mg, 0.077 mmol) were added. The mixture was degassed and then heated to 100° C. for 16 hours. After cooling to room temperature, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue is purified by MPLC (MC:heptane/1:5 to 1:1) to give the product (1562 mg, 79%).

1H NMR (300 MHz, CDCl3) δ 7.73 (dt, J = 2.4, 0.8 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.16 - 7.05 (m, 2H), 4.51 (dd, J = 6.9, 5.9 Hz, 2H), 2.82 (dd, J = 6.9, 6.0 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H). ESI-MS m/z 257 (M+H)+ 1H NMR (300 MHz, CDCl 3 ) δ 7.73 (dt, J = 2.4, 0.8 Hz, 1H), 7.55 - 7.42 (m, 2H), 7.32 (d, J = 2.4 Hz, 1H), 7.16 - 7.05 ( m, 2H), 4.51 (dd, J = 6.9, 5.9 Hz, 2H), 2.82 (dd, J = 6.9, 6.0 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H). ESI-MS m/z 257 (M+H) +

Figure pat00136
Figure pat00136

단계 2) (E)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-6-methylchroman-4-one의 제조Step 2) Preparation of (E)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-6-methylchroman-4-one

톨루엔 (15 mL) 중 8-(4-플루오로페닐)-6-메틸크로만-4-온 (1562 mg, 6.094 mmol), 3,5-디메톡시 벤즈알데히드 (1519 mg, 9.141 mmol) 및 p-톨루엔 설폰산 (105 mg, 0.61 mmol) 반응혼합물을 17시간 동안 환류시켰다. 상온으로 냉각한 후, 생성된 잔류물을 EtOAc, 염수 및 H2O로 희석하고, 에틸 아세테이트로 추출하고(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (디클로로메탄/n-헥산 = 1:5 내지 1:1)로 정제하여 생성물 (1843 mg, 75%)을 얻었다.8-(4-fluorophenyl)-6-methylchroman-4-one (1562 mg, 6.094 mmol), 3,5-dimethoxy benzaldehyde (1519 mg, 9.141 mmol) and p- Toluene sulfonic acid (105 mg, 0.61 mmol) The reaction mixture was refluxed for 17 hours. After cooling to ambient temperature, the resulting residue was diluted with EtOAc, brine and H 2 O, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (dichloromethane/n-hexane = 1:5 to 1:1) to give the product (1843 mg, 75%).

1H NMR (400 MHz, CDCl3) δ 7.87 - 7.78 (m, 2H), 7.46 (tdd, J = 6.1, 5.4, 2.7, 1.4 Hz, 2H), 7.38 - 7.32 (m, 1H), 7.15 - 7.06 (m, 2H), 6.49 (t, J = 2.3 Hz, 1H), 6.42 (d, J = 2.3 Hz, 2H), 5.31 (d, J = 1.9 Hz, 2H), 3.84 - 3.78 (m, 6H), 2.41 - 2.35 (m, 3H). ESI-MS m/z 405.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.87 - 7.78 (m, 2H), 7.46 (tdd, J = 6.1, 5.4, 2.7, 1.4 Hz, 2H), 7.38 - 7.32 (m, 1H), 7.15 - 7.06 (m, 2H), 6.49 (t, J = 2.3 Hz, 1H), 6.42 (d, J = 2.3 Hz, 2H), 5.31 (d, J = 1.9 Hz, 2H), 3.84 - 3.78 (m, 6H) , 2.41 - 2.35 (m, 3H). ESI-MS m/z 405.1 (M+H) +

Figure pat00137
Figure pat00137

단계 3) 3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one의 제조Step 3) Preparation of 3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one

EtOAc(10 mL) 중 (E)-3-(3,5-디메톡시벤질리덴)-8-(4-플루오로페닐)-6-메틸크로만-4-온 (1843 mg, 4.56 mmol)의 혼합물에 PtO2 (103 mg, 0.456 mmol)를 실온에서 첨가하였다. 반응혼합물을 H2 (풍선 압력) 존재하에 실온에서 4시간 동안 교반하였다. 촉매를 셀라이트 패드를 통한 여과에 의해 제거하고 EtOAc로 세척하였다. 여액을 농축하고 MPLC (10% MC/헥산)로 정제하여 생성물 (1338 mg, 72%)을 얻었다.( E )-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-6-methylchroman-4-one (1843 mg, 4.56 mmol) in EtOAc (10 mL) To the mixture was added PtO 2 (103 mg, 0.456 mmol) at room temperature. The reaction mixture was stirred at room temperature in the presence of H 2 (balloon pressure) for 4 hours. The catalyst was removed by filtration through a celite pad and washed with EtOAc. The filtrate was concentrated and purified by MPLC (10% MC/Hexanes) to give the product (1338 mg, 72%).

1H NMR (300 MHz, CDCl3) δ 7.75 (dd, J = 2.3, 1.0 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.33 (d, J = 2.3 Hz, 1H), 7.16 - 7.03 (m, 2H), 6.35 (dd, J = 10.1, 2.2 Hz, 3H), 4.38 (dd, J = 11.5, 4.5 Hz, 1H), 4.14 (dd, J = 11.5, 9.2 Hz, 1H), 3.77 (s, 6H), 3.29 (dd, J = 13.9, 4.3 Hz, 1H), 2.96 (ddt, J = 10.3, 9.0, 4.4 Hz, 1H), 2.63 (dd, J = 13.9, 10.4 Hz, 1H), 2.35 (s, 3H). 1H NMR (300 MHz, CDCl 3 ) δ 7.75 (dd, J = 2.3, 1.0 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.33 (d, J = 2.3 Hz, 1H), 7.16 - 7.03 ( m, 2H), 6.35 (dd, J = 10.1, 2.2 Hz, 3H), 4.38 (dd, J = 11.5, 4.5 Hz, 1H), 4.14 (dd, J = 11.5, 9.2 Hz, 1H), 3.77 (s , 6H), 3.29 (dd, J = 13.9, 4.3 Hz, 1H), 2.96 (ddt, J = 10.3, 9.0, 4.4 Hz, 1H), 2.63 (dd, J = 13.9, 10.4 Hz, 1H), 2.35 ( s, 3H).

Figure pat00138
Figure pat00138

단계 4) (3S,4S)-3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-ol의 제조Step 4) Preparation of (3S,4S)-3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-ol

3-(3,5-디메톡시벤질)-8-(4-플루오로페닐)-6-메틸크로만-4-온 (190 mg, 0.469 μmol)에 RuCl(p-시멘)[(S,S)-Ts-DPEN] (30 mg, 0.047 mmol), DBU/포름산 (300 μL:100 μL)의 아세토니트릴 (2 mL) 용액을 상온에서 첨가하였다. 50℃에서 14시간 동안 교반한 후, 반응을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. 디에틸 에테르로 추출한 후, 유기층을 추가의 포화 NaHCO3수용액으로 세척하고, MgSO4로 건조시키고, 감압하에 농축시켰다. 잔류물을 MPLC (에틸 아세테이트/n-헥산 = 1:10 내지 1:2)로 정제하여 생성물 (159 mg, 83%)을 수득하였다.RuCl(p-cymene)[(S,S )-Ts-DPEN] (30 mg, 0.047 mmol), and a solution of DBU/formic acid (300 μL:100 μL) in acetonitrile (2 mL) was added at room temperature. After stirring at 50° C. for 14 h, the reaction was quenched with saturated aqueous NH 4 Cl solution at ambient temperature. After extraction with diethyl ether, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate/n-hexane = 1:10 to 1:2) to give the product (159 mg, 83%).

1H NMR (400 MHz, CDCl3) δ 7.46 (dd, J = 8.9, 5.5 Hz, 2H), 7.11 - 7.02 (m, 4H), 6.41 (d, J = 2.2 Hz, 2H), 6.34 (t, J = 2.3 Hz, 1H), 4.57 (t, J = 3.8 Hz, 1H), 4.11 - 4.04 (m, 2H), 3.78 (s, 6H), 2.83 (dd, J = 13.6, 8.2 Hz, 1H), 2.63 (dd, J = 13.6, 7.6 Hz, 1H), 2.34 (d, J = 8.5 Hz, 1H), 2.30 (s, 3H), 1.74 (d, J = 4.4 Hz, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.46 (dd, J = 8.9, 5.5 Hz, 2H), 7.11 - 7.02 (m, 4H), 6.41 (d, J = 2.2 Hz, 2H), 6.34 (t, J = 2.3 Hz, 1H), 4.57 (t, J = 3.8 Hz, 1H), 4.11 - 4.04 (m, 2H), 3.78 (s, 6H), 2.83 (dd, J = 13.6, 8.2 Hz, 1H), 2.63 (dd, J = 13.6, 7.6 Hz, 1H), 2.34 (d, J = 8.5 Hz, 1H), 2.30 (s, 3H), 1.74 (d, J = 4.4 Hz, 1H).

Figure pat00139
Figure pat00139

단계 5) (S)-3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one의 제조Step 5) Preparation of (S)-3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one

CH2Cl2 (4 mL) 중 (3S,4S)-3-(3,5-디메톡시벤질)-8-(4-플루오로페닐)-6-메틸크로만-4-올 (152 mg, 0.372 mmol)에 N-메틸모르폴린 N-옥사이드 (65 mg, 0.186 mmol)를 첨가하고, 혼합물을 15분 동안 교반하였다. 이어서, 테트라프로필암모늄 퍼루테네이트 (65 mg, 0.559 mmol)를 첨가하고, 상온에서 1시간 동안 계속 교반하였다. 어두운 혼합물을 용리제로서 CH2Cl2를 사용하여 셀라이트 상에서 여과하였다. 진공에서 농축한 후, 잔류물을 MPLC (에틸아세테이트:n-헥산, 20%)로 정제하여 생성물 (140 mg, 93%)을 얻는다.(3S,4S)-3-(3,5 - dimethoxybenzyl )-8-(4-fluorophenyl)-6-methylchroman-4-ol (152 mg, 0.372 mmol) was added N-methylmorpholine N-oxide (65 mg, 0.186 mmol) and the mixture was stirred for 15 minutes. Tetrapropylammonium perruthenate (65 mg, 0.559 mmol) was then added and stirring was continued at room temperature for 1 hour. The dark mixture was filtered over celite using CH 2 Cl 2 as eluent. After concentration in vacuo, the residue is purified by MPLC (ethyl acetate:n-hexane, 20%) to give the product (140 mg, 93%).

1H NMR (300 MHz, CDCl3) δ 7.75 (dd, J = 2.4, 1.0 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.33 (d, J = 2.3 Hz, 1H), 7.15 - 7.03 (m, 2H), 6.35 (dd, J = 10.1, 2.3 Hz, 3H), 4.38 (dd, J = 11.4, 4.5 Hz, 1H), 4.14 (dd, J = 11.4, 9.3 Hz, 1H), 3.77 (s, 6H), 3.29 (dd, J = 13.9, 4.3 Hz, 1H), 2.96 (ddd, J = 9.3, 5.9, 4.6 Hz, 1H), 2.63 (dd, J = 13.9, 10.4 Hz, 1H), 2.36 (s, 3H). ESI-MS m/z 407.1 (M+H)+ 1H NMR (300 MHz, CDCl 3 ) δ 7.75 (dd, J = 2.4, 1.0 Hz, 1H), 7.52 - 7.41 (m, 2H), 7.33 (d, J = 2.3 Hz, 1H), 7.15 - 7.03 ( m, 2H), 6.35 (dd, J = 10.1, 2.3 Hz, 3H), 4.38 (dd, J = 11.4, 4.5 Hz, 1H), 4.14 (dd, J = 11.4, 9.3 Hz, 1H), 3.77 (s , 6H), 3.29 (dd, J = 13.9, 4.3 Hz, 1H), 2.96 (ddd, J = 9.3, 5.9, 4.6 Hz, 1H), 2.63 (dd, J = 13.9, 10.4 Hz, 1H), 2.36 ( s, 3H). ESI-MS m/z 407.1 (M+H) +

Figure pat00140
Figure pat00140

단계 6) (S)-6-(bromomethyl)-3-(2,6-dibromo-3,5-dimethoxybenzyl)-8-(4-fluorophenyl)chroman-4-one의 제조Step 6) Preparation of (S)-6-(bromomethyl)-3-(2,6-dibromo-3,5-dimethoxybenzyl)-8-(4-fluorophenyl)chroman-4-one

(S)-3-(3,5-디메톡시벤질)-8-(4-플루오로페닐)-6-메틸크로만-4-온 (10 mg, 0.026 mmol), NBS (9 mg, 0.052 mmol), 벤조일의 용액 과산화물 (13 mg, 0.052 mmol) 및 CHCl3 (1 mL)를 70℃에서 1시간 동안 환류시켰다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트 및 물로 희석하고, 에틸 아세테이트로 추출하여(x3), Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (에틸 아세테이트:n-헥산 = 1:20 ~ 1:10)로 정제하여 생성물 (9.3 mg, 56%)을 얻었다.(S)-3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-methylchroman-4-one (10 mg, 0.026 mmol), NBS (9 mg, 0.052 mmol) ), a solution of benzoyl peroxide (13 mg, 0.052 mmol) and CHCl 3 (1 mL) was refluxed at 70° C. for 1 hour. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (ethyl acetate:n-hexane = 1:20 to 1:10) to give the product (9.3 mg, 56%).

1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.15 - 7.04 (m, 2H), 6.46 (s, 1H), 4.53 (s, 2H), 4.48 - 4.31 (m, 2H), 3.92 (s, 6H), 3.96 - 3.85 (m, 1H), 3.40 (ddd, J = 15.8, 10.7, 4.7 Hz, 1H), 3.28 (dd, J = 13.9, 10.6 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.97 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.51 - 7.42 (m, 2H), 7.15 - 7.04 (m, 2H), 6.46 (s, 1H), 4.53 (s, 2H), 4.48 - 4.31 (m, 2H), 3.92 (s, 6H), 3.96 - 3.85 (m, 1H), 3.40 (ddd, J = 15.8, 10.7, 4.7 Hz, 1H), 3.28 (dd, J = 13.9, 10.6 Hz, 1H).

Figure pat00141
Figure pat00141

단계 7) (S)-3-(2,6-dibromo-3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 7) (S)-3-(2,6-dibromo-3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H Preparation of -imidazol-1-yl)methyl)chroman-4-one

(S)-6-(브로모메틸)-3-(2,6-디브로모-3,5-디메톡시벤질)-8-(4-플루오로페닐)크로만-4-온 (9.3 mg, 0.014 mmol), 1-메틸-1H-이미다졸-2-아민 염산염 (5.8 mg, 0.043 mmol), DIEA (7.5 uL, 0.043 mmol), KI (2.4 mg, 0.014 mmol) 및 Me CN(1 mL)을 50°에서 11시간 동안 가열하였다. 상온으로 냉각한 후, 반응혼합물을 에틸 아세테이트로 희석하고, 유기 상을 물로 세척하고, Na2SO4로 건조하고, 감압 하에 농축하였다. 잔류물을 MPLC (MeOH:CH2Cl2=1:50 내지 1:10)로 정제하여 화합물 37 (2.4 mg, 25%)을 얻었다.(S)-6-(Bromomethyl)-3-(2,6-dibromo-3,5-dimethoxybenzyl)-8-(4-fluorophenyl)chroman-4-one (9.3 mg , 0.014 mmol), 1-methyl-1H-imidazol-2-amine hydrochloride (5.8 mg, 0.043 mmol), DIEA (7.5 uL, 0.043 mmol), KI (2.4 mg, 0.014 mmol) and Me CN (1 mL) was heated at 50° for 11 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic phase was washed with water, dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH 2 Cl 2 =1:50 to 1:10) to give Compound 37 (2.4 mg, 25%).

1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.60 - 7.49 (m, 3H), 7.05 (s, 1H), 6.60 - 6.52 (m, 2H), 6.46 (s, 1H), 5.47 (s, 2H), 4.48 - 4.32 (m, 2H), 3.86 (d, J = 45.7 Hz, 10H), 3.37 (dd, J = 10.6, 5.5 Hz, 1H), 3.25 (dd, J = 13.9, 10.5 Hz, 1H). 1H NMR (400 MHz, CDCl 3 ) δ 7.82 (d, J = 2.3 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.60 - 7.49 (m, 3H), 7.05 (s, 1H) , 6.60 - 6.52 (m, 2H), 6.46 (s, 1H), 5.47 (s, 2H), 4.48 - 4.32 (m, 2H), 3.86 (d, J = 45.7 Hz, 10H), 3.37 (dd, J = 10.6, 5.5 Hz, 1H), 3.25 (dd, J = 13.9, 10.5 Hz, 1H).

Figure pat00142
Figure pat00142

화합물 38. methyl 2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetateCompound 38. methyl 2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3- yl)methyl)-2-chlorophenoxy)acetate

Figure pat00143
Figure pat00143

단계 1) methyl 2-(2-chloro-5-formylphenoxy)acetate의 제조Step 1) Preparation of methyl 2-(2-chloro-5-formylphenoxy)acetate

4-클로로-3-히드록시벤즈알데히드 (3000 mg, 19.160 mmol)의 DMF (25 mL) 용액에 K2CO3 (5296 mg, 38.320 mmol), 메틸 브로모아세테이트 (1.8 mL, 19.160 mmol)을 0°C에 넣는다. 반응혼합물을 60°C에서 2시간 교반한다. 상온으로 냉각한 후 반응혼합물을 ethyl acetate로 희석하고 유기층을 물로 세척 Na2SO4로 건조한후 감압농축한후 잔사를 MPLC (ethyl acetate : n-heptane = 1:5 to 1:2)로 정제하여 목적물 (4166 mg, 95%)을 얻는다.To a solution of 4-chloro-3-hydroxybenzaldehyde (3000 mg, 19.160 mmol) in DMF (25 mL) was added K 2 CO 3 (5296 mg, 38.320 mmol), methyl bromoacetate (1.8 mL, 19.160 mmol) at 0°. put in C The reaction mixture is stirred at 60 °C for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, the organic layer was washed with water, dried with Na 2 SO 4 , concentrated under reduced pressure, and the residue was purified by MPLC (ethyl acetate : n-heptane = 1:5 to 1:2). The target product (4166 mg, 95%) is obtained.

Figure pat00144
Figure pat00144

단계 2) methyl (E)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-chlorophenoxy)acetate의 제조Step 2) Preparation of methyl (E)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-chlorophenoxy)acetate

8-브로모-6-(브로모메틸)크로만-4-온 (2799 mg, 8.747 mmol)의 toluene (25 mL)용액에 메틸 2-(2-클로로-5-포밀페녹시)아세테이트 (3000 mg, 13.12 mmol)와 para-톨루엔 설폰산 (151 mg, 0.875 mmol)을 넣는다. 반응혼합물을 24시간 가열, 환류한다. 상온으로 냉각시킨 후 EtOAc, 소금물과 H2O로 희석하고, ethyl acetate (x3) 추출한다음 Na2SO4로 건조 및 감압, 농축한다. 잔사를 실리카겔 컬럼 크로마토그래피 (ethylacetate: n-heptane = 1:5)로 정제하여 목적물 (2500 mg, 54%)을 얻는다.Methyl 2-(2-chloro-5-formylphenoxy)acetate (3000 mg, 13.12 mmol) and para-toluene sulfonic acid (151 mg, 0.875 mmol). The reaction mixture is heated to reflux for 24 hours. After cooling to room temperature, dilute with EtOAc, brine and H 2 O, extract with ethyl acetate (x3), dry with Na 2 SO 4 and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (ethylacetate: n-heptane = 1:5) to obtain the target product (2500 mg, 54%).

Figure pat00145
Figure pat00145

단계 3) methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate의 제조Step 3) Preparation of methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate

메틸 (E)-2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일리덴)메틸)-2-크로로페녹시)아세테이트 (1957 mg, 3.688 mmol)의 EtOAc (50 mL) 용액에 PtO2 (84 mg, 0.369 mmol)를 상온에서 넣는다. 반응혼합물을 H2 기압(balloon pressure)하에 상온에서 15시간 교반한다. 촉매를 셀라이트 패드를 통해 여과 제거하고 EtOAc로 세척한다. 여액을 감압, 농축하고 MPLC (CH2Cl2 : n-heptane = 3:1 to 10:1)로 정제하여 목적물 (1316 mg, 68%)을 얻는다.Methyl (E)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-chlorophenoxy)acetate (1957 mg , 3.688 mmol) in EtOAc (50 mL) was added PtO 2 (84 mg, 0.369 mmol) at room temperature. The reaction mixture was stirred for 15 hours at room temperature under H2 atmosphere (balloon pressure). The catalyst is filtered off through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure and purified by MPLC (CH 2 Cl 2 : n-heptane = 3:1 to 10:1) to obtain the target product (1316 mg, 68%).

Figure pat00146
Figure pat00146

단계 4) methyl 2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate의 제조Step 4) methyl 2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3- Preparation of yl)methyl)-2-chlorophenoxy)acetate

메틸 2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트 (1316 mg, 2.473 mmol), 1-메틸-1,3-다이하이드로-2H-이미다졸-2-이민 (360 mg, 3.710 mmol), DIEA (1296 uL, 7.241 mmol), KI (410 mg, 2.473 mmol)와 MeCN (20 mL) 혼합물을 60°C에서 2시간 교반한다. 반응혼합물을 상온으로 냉각하고 ethyl acetate로 희석하고 유기층을 물로 세척 및 Na2SO4로 건조한다음 농축한 잔사를 실리카겔 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% to 10%)로 정제하여 화합물 38 (860 mg, 63%)을 얻는다.Methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate (1316 mg, 2.473 mmol), 1 A mixture of -methyl-1,3-dihydro-2H-imidazol-2-imine (360 mg, 3.710 mmol), DIEA (1296 uL, 7.241 mmol), KI (410 mg, 2.473 mmol) and MeCN (20 mL) is stirred at 60 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and the organic layer was washed with water and dried with Na 2 SO 4 . The concentrated residue was purified by silica gel column chromatography (MeOH:CH 2 Cl 2 , 2% to 10%) to obtain a compound. 38 (860 mg, 63%).

1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.62 (s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.81 (dd, J = 8.2, 1.8 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.63 (dd, J = 15.8, 2.5 Hz, 2H), 5.46 (s, 2H), 4.74 (s, 2H), 4.50 (dd, J = 11.7, 4.5 Hz, 1H), 4.26 (dd, J = 11.8, 9.0 Hz, 1H), 3.82 (d, J = 6.4 Hz, 6H), 3.16 (dd, J = 14.1, 5.1 Hz, 1H), 2.96 (tt, J = 9.4, 4.8 Hz, 1H), 2.69 (dd, J = 14.1, 9.4 Hz, 1H). ESI-MS m/z 550.1 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 2.2 Hz, 1H), 7.62 (s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.81 (dd, J = 8.2, 1.8 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.63 (dd, J = 15.8, 2.5 Hz, 2H), 5.46 (s, 2H), 4.74 (s, 2H), 4.50 (dd, J = 11.7, 4.5 Hz, 1H), 4.26 (dd, J = 11.8, 9.0 Hz, 1H), 3.82 (d, J = 6.4 Hz, 6H), 3.16 (dd , J = 14.1, 5.1 Hz, 1H), 2.96 (tt, J = 9.4, 4.8 Hz, 1H), 2.69 (dd, J = 14.1, 9.4 Hz, 1H). ESI-MS m/z 550.1 (M+H)+

Figure pat00147
Figure pat00147

화합물 39. methyl (Z)-2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetateCompound 39. methyl (Z)-2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1- yl)methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate

화합물 38 (860 mg, 1.568 mmol), (Boc)2O (2.4 mL, 3.136 mmol)와 THF (20 mL) 용액을 상온에서 10 분 교반한다음 DMAP (96 mg, 0.784 mmol)를 넣고 15h 교반한다. 반응혼합물을 CH2Cl2로 희석하고 유기층을 물로 세척 및 Na2SO4로 건조한다음 감압농축한다. 농축물을 실리카겔 컬럼 크로마토그래피 (MeOH : CH2Cl2 = 1:50 to 1:10)로 정제하여 화합물 39 (448 mg, 44%)을 얻는다.A solution of compound 38 (860 mg, 1.568 mmol), (Boc) 2 O (2.4 mL, 3.136 mmol) and THF (20 mL) was stirred at room temperature for 10 minutes, then DMAP (96 mg, 0.784 mmol) was added and stirred for 15 hours. The reaction mixture was diluted with CH 2 Cl 2 and the organic layer was washed with water, dried over Na 2 SO 4 and then concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (MeOH : CH 2 Cl 2 = 1:50 to 1:10) to give Compound 39 (448 mg, 44%).

1H NMR (400 MHz, CDCl3) δ 7.78 - 7.70 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 8.1, 1.9 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 5.04 (s, 2H), 4.74 (s, 2H), 4.51 (dd, J = 11.7, 4.4 Hz, 1H), 4.26 (dd, J = 11.7, 8.7 Hz, 1H), 3.85 (s, 3H), 3.51 (s, 3H), 3.20 (dd, J = 14.1, 4.8 Hz, 1H), 2.93 (dt, J = 9.1, 4.6 Hz, 1H), 2.72 (dd, J = 14.1, 9.6 Hz, 1H), 1.54 (s, 9H). ESI-MS m/z 650.1 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 7.78 - 7.70 (m, 2H), 7.34 (d, J = 8.1 Hz, 1H), 6.84 (dd, J = 8.1, 1.9 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 6.48 (d, J = 2.5 Hz, 1H), 5.04 (s, 2H), 4.74 (s, 2H), 4.51 (dd, J = 11.7, 4.4 Hz, 1H), 4.26 (dd, J = 11.7, 8.7 Hz, 1H), 3.85 (s, 3H), 3.51 (s, 3H), 3.20 (dd, J = 14.1, 4.8 Hz, 1H) , 2.93 (dt, J = 9.1, 4.6 Hz, 1H), 2.72 (dd, J = 14.1, 9.6 Hz, 1H), 1.54 (s, 9H). ESI-MS m/z 650.1 (M+H)+

Figure pat00148
Figure pat00148

화합물 40. methyl (E)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetateCompound 40. methyl (E)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl) -8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate

화합물 39 (269 mg, 0.414 mmol)의 1,4-dioxane/H2O (10:1, 5.5 mL) 용액에 세슘 카보네이트 (270 mg, 0.828 mmol)과 Pd(amphos)Cl2 (30 mg, 0.042 mmol)을 상온에서 넣고 교반 10분후에 (1-에틸-3-(트리플루오로)-1H-피라졸-4-일)보로닉 애시드 (129 mg, 0.621 mmol)을 넣고 100 °C에서 2시간 교반한다. 상온으로 냉각한다음 1,4-dioxane을 감압제거하고 잔사를 EtOAc로 희석, 소금물과 물로 세척, ethyl acetate (x3)로 추출 및 Na2SO4 건조한다음 감압농축한다. 잔사를 실리카겔 컬럼 크로마토그래피 (MeOH:CH2Cl2, 2% to 10%)로 정제하여 화합물 40 (237 mg, 78%)을 얻는다.Cesium carbonate (270 mg, 0.828 mmol) and Pd(amphos)Cl2 (30 mg, 0.042 mmol) were added to a 1,4-dioxane/H2O (10:1, 5.5 mL) solution of compound 39 (269 mg, 0.414 mmol). After stirring at room temperature for 10 minutes, add (1-ethyl-3-(trifluoro)-1H-pyrazol-4-yl)boronic acid (129 mg, 0.621 mmol) and stir at 100 °C for 2 hours. After cooling to room temperature, remove 1,4-dioxane under reduced pressure, dilute the residue with EtOAc, wash with brine and water, extract with ethyl acetate (x3), dry with Na 2 SO 4 and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (MeOH:CH 2 Cl 2 , 2% to 10%) to give Compound 40 (237 mg, 78%).

1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 2.3 Hz, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.83 (dd, J = 8.1, 1.9 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.58 (d, J = 29.7 Hz, 2H), 5.09 (s, 2H), 4.72 (s, 2H), 4.37 (dd, J = 11.7, 4.1 Hz, 1H), 4.26 (q, J = 7.4 Hz, 2H), 4.17 (dd, J = 11.5, 7.8 Hz, 1H), 3.81 (s, 3H), 3.54 (s, 3H), 3.19 (dd, J = 13.9, 4.4 Hz, 1H), 2.87 (d, J = 9.4 Hz, 1H), 2.73 (dd, J = 13.9, 10.0 Hz, 1H), 1.59 (d, J = 7.2 Hz, 3H), 1.51 (s, 9H). ESI-MS m/z 732.2 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 2.3 Hz, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.83 ( dd, J = 8.1, 1.9 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.58 (d, J = 29.7 Hz, 2H), 5.09 (s, 2H), 4.72 (s, 2H), 4.37 (dd, J = 11.7, 4.1 Hz, 1H), 4.26 (q, J = 7.4 Hz, 2H), 4.17 (dd, J = 11.5, 7.8 Hz, 1H), 3.81 (s, 3H), 3.54 (s , 3H), 3.19 (dd, J = 13.9, 4.4 Hz, 1H), 2.87 (d, J = 9.4 Hz, 1H), 2.73 (dd, J = 13.9, 10.0 Hz, 1H), 1.59 (d, J = 9.4 Hz, 1H). 7.2 Hz, 3H), 1.51 (s, 9H). ESI-MS m/z 732.2 (M+H)+

Figure pat00149
Figure pat00149

화합물 41. (E)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetic acidCompound 41. (E)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)- 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetic acid

화합물 40 (122 mg, 0.166 mmol)을 0°C에서 LiOH (6 mg, 0.249 mmol) MeOH/H2O (2/0.2 mL) 용액에 넣는다. 반응혼합물을 상온에서 2h 교반하고 용매를 증발시킨다. 반응혼합물을 0 °C로 냉각하고 1N HCl 용액으로 pH를 3-4로 조절한다. 반응혼합물을 ethyl acetate와 물로 희석하고, ethyl acetate (x3)로 추출 및 Na2SO4로 건조한다음 감압농축하여 화합물 41 (97 mg, 81%)을 얻는다.Compound 40 (122 mg, 0.166 mmol) is added to a solution of LiOH (6 mg, 0.249 mmol) MeOH/H 2 O (2/0.2 mL) at 0°C. The reaction mixture was stirred at room temperature for 2 h and the solvent was evaporated. Cool the reaction mixture to 0 °C and adjust the pH to 3-4 with 1N HCl solution. The reaction mixture was diluted with ethyl acetate and water, extracted with ethyl acetate (x3), dried with Na 2 SO 4 and concentrated under reduced pressure to obtain compound 41 (97 mg, 81%).

1H NMR (400 MHz, CD3OD) δ 7.91 - 7.83 (m, 2H), 7.57 (dd, J = 17.0, 2.4 Hz, 2H), 7.47 (d, J = 2.5 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.81 (dd, J = 8.1, 1.9 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 5.32 (s, 2H), 4.54 (s, 2H), 4.46 (dd, J = 11.7, 4.2 Hz, 1H), 4.28 (h, J = 8.2, 7.8 Hz, 3H), 3.74 (s, 3H), 3.12 (dd, J = 13.7, 5.7 Hz, 1H), 3.01 (q, J = 7.0, 5.3 Hz, 1H), 2.83 (dd, J = 13.7, 8.4 Hz, 1H), 1.53 (t, J = 7.4 Hz, 3H), 1.45 (s, 9H). ESI-MS m/z 718.3 (M+H)+ 1 H NMR (400 MHz, CD 3 OD) δ 7.91 - 7.83 (m, 2H), 7.57 (dd, J = 17.0, 2.4 Hz, 2H), 7.47 (d, J = 2.5 Hz, 1H), 7.27 (d , J = 8.1 Hz, 1H), 6.81 (dd, J = 8.1, 1.9 Hz, 1H), 6.76 (d, J = 2.0 Hz, 1H), 5.32 (s, 2H), 4.54 (s, 2H), 4.46 (dd, J = 11.7, 4.2 Hz, 1H), 4.28 (h, J = 8.2, 7.8 Hz, 3H), 3.74 (s, 3H), 3.12 (dd, J = 13.7, 5.7 Hz, 1H), 3.01 ( q, J = 7.0, 5.3 Hz, 1H), 2.83 (dd, J = 13.7, 8.4 Hz, 1H), 1.53 (t, J = 7.4 Hz, 3H), 1.45 (s, 9H). ESI-MS m/z 718.3 (M+H)+

Figure pat00150
Figure pat00150

화합물 42. methyl 2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)acetateCompound 42. methyl 2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2 ,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)acetate

화합물 40 합성과정에서 화합물 39 대신 화합물 38 (280 mg, 0.510 mmol)을 사용하여 화합물 42 (125 mg, 39% 수율)을 제조하였다.Compound 42 (125 mg, 39% yield) was prepared by using compound 38 (280 mg, 0.510 mmol) instead of compound 39 during the synthesis of compound 40.

1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 6.53 - 6.43 (m, 2H), 5.45 - 5.35 (m, 2H), 4.71 (s, 2H), 4.35 (dd, J = 11.6, 4.2 Hz, 1H), 4.24 (q, J = 7.4 Hz, 2H), 4.16 (dd, J = 11.5, 8.0 Hz, 1H), 3.82 - 3.70 (m, 7H), 3.15 (dd, J = 13.8, 4.6 Hz, 1H), 2.86 (s, 1H), 2.70 (dd, J = 14.0, 9.9 Hz, 1H), 1.57 - 1.51 (m, 3H). 1H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 7.81 (s, 1H), 7.68 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 6.53 - 6.43 (m, 2H), 5.45 - 5.35 (m, 2H), 4.71 (s, 2H), 4.35 (dd, J = 11.6, 4.2 Hz, 1H), 4.24 (q, J = 7.4 Hz, 2H), 4.16 (dd, J = 11.5, 8.0 Hz, 1H), 3.82 - 3.70 (m, 7H), 3.15 ( dd, J = 13.8, 4.6 Hz, 1H), 2.86 (s, 1H), 2.70 (dd, J = 14.0, 9.9 Hz, 1H), 1.57 - 1.51 (m, 3H).

Figure pat00151
Figure pat00151

화합물 43. 2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)acetic acidCompound 43. 2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2, 3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)acetic acid

화합물 41 합성과정에서 화합물 40 대신 화합물 42 (69 mg, 0.109 mmol)를 사용하여 화합물 43 (36.7 mg, 54% 수율)을 제조하였다.Compound 43 (36.7 mg, 54% yield) was prepared using Compound 42 (69 mg, 0.109 mmol) instead of Compound 40 during the synthesis of Compound 41.

1H NMR (400 MHz, CD3OD) δ 7.91 - 7.85 (m, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.91 (s, 2H), 6.75 (dd, J = 8.1, 1.9 Hz, 1H), 6.68 (d, J = 1.9 Hz, 1H), 5.09 (s, 2H), 4.40 (d, J = 3.8 Hz, 3H), 4.29 - 4.19 (m, 3H), 3.51 (s, 3H), 3.10 (dd, J = 13.8, 6.0 Hz, 1H), 2.98 - 2.93 (m, 1H), 2.74 (dd, J = 13.8, 8.4 Hz, 1H), 1.48 (t, J = 7.3 Hz, 3H). 1 H NMR (400 MHz, CD 3 OD) δ 7.91 - 7.85 (m, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.91 (s, 2H), 6.75 (dd, J = 8.1, 1.9 Hz, 1H), 6.68 (d, J = 1.9 Hz, 1H), 5.09 (s, 2H), 4.40 (d , J = 3.8 Hz, 3H), 4.29 - 4.19 (m, 3H), 3.51 (s, 3H), 3.10 (dd, J = 13.8, 6.0 Hz, 1H), 2.98 - 2.93 (m, 1H), 2.74 ( dd, J = 13.8, 8.4 Hz, 1H), 1.48 (t, J = 7.3 Hz, 3H).

Figure pat00152
Figure pat00152

화합물 44. methyl (Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetateCompound 44. methyl (Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H -imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy )ethoxy)acetate

Figure pat00153
Figure pat00153

단계 1) 4-(2-(benzyloxy)ethoxy)-1-(l1-oxidaneyl)butan-2-ol의 제조Step 1) Preparation of 4-(2-(benzyloxy)ethoxy)-1-(l1-oxidaneyl)butan-2-ol

4-(2-하이드록시에톡시)-1-(l1-옥시다네일)부탄-2-올 (2 g, 13.32 mmol), silver oxide (2.51 g, 14.65 mmol), potassium iodide (442 mg, 2.66 mmol)의 MC (50 mL) 용액에 benzyl bromide (2.51 g, 14.65 mmol)를 0 ℃에서 넣고 상온에서 2~3h 교반한다. 반응혼합물을 셀라이트 패드에서 여과한다음 여액을 감압농축한다. 농축물을 실리카겔 컬럼 크로마토그래피 (EtOAc:Hep = 1:1)으로 정제하여 목적물 (2.18 g, 68%)을 얻는다.4-(2-hydroxyethoxy)-1-(l1-oxidaneyl)butan-2-ol (2 g, 13.32 mmol), silver oxide (2.51 g, 14.65 mmol), potassium iodide (442 mg, 2.66 mmol) mmol) into a solution of MC (50 mL) at 0 °C and stirred for 2-3 hours at room temperature. The reaction mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc:Hep = 1:1) to give the desired product (2.18 g, 68%).

Figure pat00154
Figure pat00154

단계 2) methyl 1-phenyl-2,5,8,11-tetraoxatridecan-13-oate의 제조Step 2) Preparation of methyl 1-phenyl-2,5,8,11-tetraoxatridecan-13-oate

4-(2-(벤질옥시)에톡시)-1-(l1-옥시다네일)부탄-2-올 (2.2 g, 9.15 mmol)의 THF (50 mL) 용액에 sodium hydride-60% dispersion/mineral oil (550 mg, 13.72 mmol)을 0℃에서 넣어주고 상온에서 45 min 교반하고 메틸 브로모아세테이트 (1.89 g, 12.36 mmol)을 적가한다. 반응혼합물을 80 ℃에서 overnight 교반한후 반응혼합물을 0℃에서 물로 ??칭하고 ethyl acetate로 희석하여 소금물로 세척하고 유기층을 Na2SO4로 건조다음 감압농축한다. 농축물을 실리카겔 컬럼 크로마토그래피 (EtOAc:Hep = 1:1)로 정제하여 목적물 (1.5 g, 50%)을 얻는다.A solution of 4-(2-(benzyloxy)ethoxy)-1-(l1-oxidaneyl)butan-2-ol (2.2 g, 9.15 mmol) in THF (50 mL) in sodium hydride-60% dispersion/mineral oil (550 mg, 13.72 mmol) was added thereto at 0°C, stirred at room temperature for 45 min, and methyl bromoacetate (1.89 g, 12.36 mmol) was added dropwise. The reaction mixture was stirred overnight at 80 °C, then the reaction mixture was quenched with water at 0 °C, diluted with ethyl acetate, washed with brine, and the organic layer dried over Na 2 SO 4 and then concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc:Hep = 1:1) to give the desired product (1.5 g, 50%).

Figure pat00155
Figure pat00155

단계 3) methyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate의 제조Step 3) Preparation of methyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate

메틸 1-페닐-2,5,8,11-테트라옥사트리데칸-13-오에이트 (1.37 g, 4.20 mmol)의 EtOH (30 mL) 용액에 10% Palladium/carbon (45 mg, 10 mol%)을 상온에서 넣어주고 플라스크내 공기를 제거한다음 수소 풍선으로 연결하고 상온에서 2h 교반한후 반응혼합물을 셀라이트 패드를 통해 여과한다. 반응혼합물을 감압농축하고 농축물(950 mg, 96%)을 정제과정 없이 다음 단계에 사용한다.To a solution of methyl 1-phenyl-2,5,8,11-tetraoxatridecan-13-oate (1.37 g, 4.20 mmol) in EtOH (30 mL) in 10% Palladium/carbon (45 mg, 10 mol%) was added at room temperature, the air in the flask was removed, connected with a hydrogen balloon, stirred at room temperature for 2 h, and the reaction mixture was filtered through a celite pad. The reaction mixture was concentrated under reduced pressure, and the concentrate (950 mg, 96%) was used in the next step without purification.

Figure pat00156
Figure pat00156

단계 4) methyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate의 제조Step 4) Preparation of methyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate

메틸 2-(2-(2-(2-하이드록시에톡시)에톡시)에톡시)아세테이트 (50 mg, 0.212 mmol), DMAP (2.6 mg, 0.021 mmol), TEA (23 mg, 0.222 mmol) 의 methylene chloride (2 mL) 용액에 TsCl (42 mg, 0.216 mmol)를 0℃에서 넣어준다. 반응혼합물을 밤새 교반한다. 반응혼합물을 물로 ??칭하고 methylene chloride로 추출하고 소금물로 세척, Na2SO4로 건조한다음 감압농축한다. 농축물을 실리카겔 컬럼 크로마토그래피 (EtOAc:Hep = 1:1)로 정제하여 목적물 (28 mg, 32%)을 얻는다. of methyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate (50 mg, 0.212 mmol), DMAP (2.6 mg, 0.021 mmol), TEA (23 mg, 0.222 mmol) Add TsCl (42 mg, 0.216 mmol) to a methylene chloride (2 mL) solution at 0℃. The reaction mixture is stirred overnight. Quench the reaction mixture with water, extract with methylene chloride, wash with brine, dry with Na 2 SO 4 and concentrate under reduced pressure. The concentrate is purified by silica gel column chromatography (EtOAc:Hep = 1:1) to give the desired product (28 mg, 32%).

Figure pat00157
Figure pat00157

단계 5) methyl 2-(2-(2-(2-(2-fluoro-5-formylphenoxy)ethoxy)ethoxy)ethoxy)acetate의 제조Step 5) Preparation of methyl 2-(2-(2-(2-(2-fluoro-5-formylphenoxy)ethoxy)ethoxy)ethoxy)acetate

4-클로로-3-하이드록시벤즈알데히드 (2.678 g, 19.118 mmol)의 DMF (30 mL) 용엑에 K2CO3 (4.403 g, 31.862 mmol)와 메틸2-(2-(2-(2-(토실옥시)에톡시)에톡시)에톡시)아세테이트 (5.997 g, 15.931 mmol)를 0°C에서 넣는다. 반응혼합물을 50°C에서 17 h 교반한다. 상온으로 냉각한다음 반응혼합물을 에틸 아세테이트로 희석하고 유기층을 물로 세척하여 Na2SO4로 건조한다음 감압농축한다. 농축물을 MPLC (ethyl acetate : n-heptane = 1:5 to 1:1)로 정제하여 목적물 (4368 mg, 80%)을 얻는다.KCO 3 (4.403 g, 31.862 mmol) and methyl 2-(2-(2-(2-(tosyloxy) Ethoxy)ethoxy)ethoxy)acetate (5.997 g, 15.931 mmol) is added at 0°C. The reaction mixture is stirred at 50°C for 17 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and the organic layer was washed with water, dried over Na2SO4, and then concentrated under reduced pressure. The concentrate was purified by MPLC (ethyl acetate : n-heptane = 1:5 to 1:1) to obtain the target product (4368 mg, 80%).

Figure pat00158
Figure pat00158

단계 6) methyl (E)-2-(2-(2-(2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate의 제조Step 6) methyl (E)-2-(2-(2-(2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)ethoxy Preparation of )ethoxy)ethoxy)acetate

화합물 38 합성과정 단계 2에서 메틸 2-(2-클로로-5-포밀페녹시)아세테이트 대신 메틸 2-(2-(2-(2-(2-플루오로-5-포밀페녹시)에톡시)에톡시)에톡시)아세테이트 (4318 mg, 12.539 mmol)를 사용하여 생성물 (3475 mg, 43% 수율)을 제조하였다.Methyl 2-(2-(2-(2-(2-fluoro-5-formylphenoxy)ethoxy) instead of methyl 2-(2-chloro-5-formylphenoxy)acetate in step 2 of the synthesis of compound 38 The product (3475 mg, 43% yield) was prepared using ethoxy)ethoxy)acetate (4318 mg, 12.539 mmol).

Figure pat00159
Figure pat00159

단계 7) methyl 2-(2-(2-(2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate의 제조Step 7) methyl 2-(2-(2-(2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy )Manufacture of acetate

메틸 (E)-2-(2-(2-(2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)에톡시)에톡시)에톡시)아세테이트 (3317 mg, 5.132 mmol)의 EtOAc (20 mL) 용액에 PtO2 (116 mg, 0.513 mmol)를 상온에서 넣는다. 반응혼합물을 수소 기압 (balloon pressure)하에 17 h 교반한다. 촉매를 셀라이트 패드를 통해 여과 제거하고 EtOAc로 세척한다. 여액을 감압농축하고 농축물을 MPLC (ethyl acetate : n-heptane = 1:5 to 1:2)로 정제하여 목적물 (1303 mg, 39%)을 얻는다.Methyl (E)-2-(2-(2-(2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2- To a solution of fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate (3317 mg, 5.132 mmol) in EtOAc (20 mL) was added PtO 2 (116 mg, 0.513 mmol) at room temperature. The reaction mixture is stirred for 17 h under hydrogen pressure (balloon pressure). The catalyst is filtered off through a pad of celite and washed with EtOAc. The filtrate was concentrated under reduced pressure, and the concentrate was purified by MPLC (ethyl acetate : n-heptane = 1:5 to 1:2) to obtain the target product (1303 mg, 39%).

Figure pat00160
Figure pat00160

단계 8) methyl 2-(2-(2-(2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate의 제조Step 8) methyl 2-(2-(2-(2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl) Preparation of methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate

화합물 38의 단계 4 합성과정에서 메틸 2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트 대신 메틸 (E)-2-(2-(2-(2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)에톡시)에톡시)에톡시)아세테이트 (1291 mg, 1.991 mmol)를 사용하여 생성물 (453 mg, 34% 수율)을 제조하였다.In the step 4 synthesis of compound 38, instead of methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate Methyl (E)-2-(2-(2-(2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2- The product (453 mg, 34% yield) was prepared using fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate (1291 mg, 1.991 mmol).

Figure pat00161
Figure pat00161

단계 9) methyl (Z)-2-(2-(2-(2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate의 제조Step 9) methyl (Z)-2-(2-(2-(2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3 Preparation of -dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate

화합물 39 합성과정에서 화합물 38 대신 메틸 2-(2-(2-(2-(5-((8-브로모-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-y일)메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)에톡시)에톡시)에톡시)acetate (445 mg, 0.669 mmol)를 사용하여 생성물(310 mg, 61% 수율)을 제조하였다.During the synthesis of compound 39, methyl 2-(2-(2-(2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yyl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate (445 mg, 0.669 mmol) The product (310 mg, 61% yield) was prepared using

Figure pat00162
Figure pat00162

단계 10) methyl (Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate의 제조Step 10) methyl (Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H -imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy Preparation of )ethoxy)acetate

화합물 40의 합성과정에서 화합물 39 대신 메틸 (Z)-2-(2-(2-(2-(5-((8-브로모-6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)에톡시)에톡시)에톡시)아세테이트 (291 mg, 0.3805 mmol)를 사용하여 화합물 44 (241 mg, 75% 수율)를 제조하였다.In the synthesis of compound 40, methyl (Z)-2-(2-(2-(2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)) instead of compound 39 imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy) Compound 44 (241 mg, 75% yield) was prepared using ethoxy)ethoxy)acetate (291 mg, 0.3805 mmol).

1H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 2.3 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J = 2.3 Hz, 1H), 6.99 (dd, J = 11.1, 8.2 Hz, 1H), 6.85 (dd, J = 8.0, 2.0 Hz, 1H), 6.73 (ddd, J = 8.3, 4.1, 2.0 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.44 (d, J = 2.5 Hz, 1H), 5.01 (s, 2H), 4.35 (dd, J = 11.7, 4.4 Hz, 1H), 4.24 (q, J = 7.4 Hz, 2H), 4.17 (d, J = 5.1 Hz, 5H), 3.87 (t, J = 4.8 Hz, 2H), 3.78 - 3.63 (m, 13H), 3.46 (d, J = 1.7 Hz, 3H), 3.18 (dd, J = 14.0, 4.4 Hz, 1H), 2.88 (td, J = 8.9, 4.3 Hz, 1H), 2.68 (dd, J = 14.0, 10.1 Hz, 1H), 1.55 (t, J = 7.4 Hz, 3H), 1.49 (s, 9H). ESI-MS m/z 848.3 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.82 (d, J = 2.3 Hz, 1H), 7.52 (s, 1H), 7.39 (d, J = 2.3 Hz, 1H), 6.99 (dd, J = 11.1, 8.2 Hz, 1H), 6.85 (dd, J = 8.0, 2.0 Hz, 1H), 6.73 (ddd, J = 8.3, 4.1, 2.0 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H), 6.44 ( d, J = 2.5 Hz, 1H), 5.01 (s, 2H), 4.35 (dd, J = 11.7, 4.4 Hz, 1H), 4.24 (q, J = 7.4 Hz, 2H), 4.17 (d, J = 5.1 Hz, 5H), 3.87 (t, J = 4.8 Hz, 2H), 3.78 - 3.63 (m, 13H), 3.46 (d, J = 1.7 Hz, 3H), 3.18 (dd, J = 14.0, 4.4 Hz, 1H) ), 2.88 (td, J = 8.9, 4.3 Hz, 1H), 2.68 (dd, J = 14.0, 10.1 Hz, 1H), 1.55 (t, J = 7.4 Hz, 3H), 1.49 (s, 9H). ESI-MS m/z 848.3 (M+H)+

Figure pat00163
Figure pat00163

화합물 45. (Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetic acidCompound 45. (Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H- imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy) ethoxy)acetic acid

화합물 41의 합성과정에서 화합물 40 대신 메틸 (Z)-2-(2-(2-(2-(5-((6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸- 1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)에톡시)에톡시)에톡시) 아세테이트 (92.9 mg, 0.1095 mmol)를 사용하여 화합물 45 (36.6 mg, 40% 수율)를 제조하였다.In the synthesis of compound 41, methyl (Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3 instead of compound 40) -Methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4- Compound 45 (36.6 mg, 40% yield) was prepared using oxochroman-3-yl)methyl)-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate (92.9 mg, 0.1095 mmol) did

1H NMR (400 MHz, CD3OD) δ 7.97 - 7.83 (m, 2H), 7.57 (dd, J = 9.8, 2.4 Hz, 2H), 7.48 (d, J = 2.3 Hz, 1H), 7.05 - 6.96 (m, 2H), 6.79 (ddd, J = 8.3, 4.2, 2.0 Hz, 1H), 5.29 (d, J = 28.9 Hz, 2H), 4.45 (dd, J = 11.7, 4.4 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.17 (d, J = 4.6 Hz, 3H), 4.04 (d, J = 4.6 Hz, 2H), 3.85 (d, J = 4.4 Hz, 2H), 3.78 - 3.67 (m, 10H), 3.33 (s, 3H), 3.14 (dd, J = 13.9, 5.2 Hz, 1H), 3.03 (dt, J = 8.6, 4.1 Hz, 1H), 2.79 (dd, J = 13.9, 8.7 Hz, 1H), 1.53 (t, J = 7.3 Hz, 3H), 1.44 (d, J = 2.3 Hz, 9H). ESI-MS m/z 834.2 (M+H)+ 1 H NMR (400 MHz, CD 3 OD) δ 7.97 - 7.83 (m, 2H), 7.57 (dd, J = 9.8, 2.4 Hz, 2H), 7.48 (d, J = 2.3 Hz, 1H), 7.05 - 6.96 (m, 2H), 6.79 (ddd, J = 8.3, 4.2, 2.0 Hz, 1H), 5.29 (d, J = 28.9 Hz, 2H), 4.45 (dd, J = 11.7, 4.4 Hz, 1H), 4.29 ( q, J = 7.1 Hz, 2H), 4.17 (d, J = 4.6 Hz, 3H), 4.04 (d, J = 4.6 Hz, 2H), 3.85 (d, J = 4.4 Hz, 2H), 3.78 - 3.67 ( m, 10H), 3.33 (s, 3H), 3.14 (dd, J = 13.9, 5.2 Hz, 1H), 3.03 (dt, J = 8.6, 4.1 Hz, 1H), 2.79 (dd, J = 13.9, 8.7 Hz) , 1H), 1.53 (t, J = 7.3 Hz, 3H), 1.44 (d, J = 2.3 Hz, 9H). ESI-MS m/z 834.2 (M+H)+

Figure pat00164
Figure pat00164

화합물 46. ethyl 5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoateCompound 46. ethyl 5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2 ,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoate

Figure pat00165
Figure pat00165

단계 1) ethyl 5-(2-chloro-5-formylphenoxy)pentanoate의 제조Step 1) Preparation of ethyl 5-(2-chloro-5-formylphenoxy)pentanoate

화합물 38 합성과정 단계 1에서 메틸브로모아세테이트 대신 에틸브로모발러레이트 (0.6 mL, 3.832 mmol)를 사용하여 생성물 (920 mg, quant.)을 제조하였다.In step 1 of the synthesis of compound 38, ethyl bromovalerate (0.6 mL, 3.832 mmol) was used instead of methyl bromoacetate to prepare a product (920 mg, quant.).

Figure pat00166
Figure pat00166

단계 2) ethyl (E)-5-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-chlorophenoxy)pentanoate의 제조Step 2) Preparation of ethyl (E)-5-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-chlorophenoxy)pentanoate

화합물 38 합성과정 단계 2에서 메틸 2-(2-클로로-5-포르밀페녹시)아세테이트 대신 에틸 5-(2-클로로-5-포르밀페녹시)펜타노에이트 (1072 mg, 3.35 mmol)를 사용하여 생성물 (958 mg, 52% 수율)을 제조하였다.In step 2 of the synthesis of compound 38, ethyl 5-(2-chloro-5-formylphenoxy)pentanoate (1072 mg, 3.35 mmol) was added instead of methyl 2-(2-chloro-5-formylphenoxy)acetate. The product (958 mg, 52% yield) was prepared using

Figure pat00167
Figure pat00167

단계 3) ethyl 5-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate의 제조Step 3) Preparation of ethyl 5-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate

화합물 38 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일리덴)메틸)-2-클로로페녹시)아세테이트 대신 에틸 (E)-5-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일리덴)메틸)-2-클로로페녹시)펜타노에이트 (912 mg, 1.554 mmol)를 사용하여 생성물 (711 mg, 78% 수율)을 제조하였다.From step 3 of the synthesis of compound 38, methyl (E)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-chlorophenoxy cy)acetate instead of ethyl (E)-5-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-chlorophenoxy)penta The product (711 mg, 78% yield) was prepared using noate (912 mg, 1.554 mmol).

Figure pat00168
Figure pat00168

단계 4) ethyl 5-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate의 제조Step 4) ethyl 5-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3- Preparation of yl)methyl)-2-chlorophenoxy)pentanoate

화합물 38 합성과정 단계 4에서 메틸 2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트 대신 에틸 5-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노에이트 (691 mg, 1.173 mmol)를 사용하여 생성물 (217 mg, 45% 수율)을 제조하였다.Ethyl instead of methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate in step 4 of the synthesis of compound 38 5-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate (691 mg, 1.173 mmol) The product (217 mg, 45% yield) was prepared using

Figure pat00169
Figure pat00169

단계 5) ethyl 5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoate의 제조Step 5) ethyl 5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2 Preparation of ,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoate

화합물 40 합성과정에서 화합물 39 대신 에틸 5-(5-((8-브로모-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸 )-2-클로로페녹시)펜타노에이트 (246 mg, 0.407 mmol)를 사용하여 화합물 46 (116 mg, 42% 수율)을 제조하였다.In the synthesis of compound 40, ethyl 5-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl) instead of compound 39 Compound 46 (116 mg, 42% yield) was prepared using methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate (246 mg, 0.407 mmol).

1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.68 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 6.73 (dd, J = 8.0, 1.8 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 5.46 - 5.37 (m, 2H), 4.36 (dd, J = 11.6, 4.3 Hz, 1H), 4.28 - 4.22 (m, 2H), 4.19 (dd, J = 11.3, 3.1 Hz, 1H), 4.16 - 4.10 (m, 2H), 4.06 - 3.98 (m, 2H), 3.76 (s, 3H), 3.18 (dd, J = 14.0, 4.4 Hz, 1H), 2.92 - 2.86 (m, 1H), 2.68 (dd, J = 14.0, 10.1 Hz, 1H), 2.41 (t, J = 6.8 Hz, 2H), 1.92 - 1.85 (m, 4H), 1.53 (d, J = 7.4 Hz, 3H), 1.27 (s, 3H). ESI-MS m/z 688.5 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 8.82 (s, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.68 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.28 (d, J = 1.5 Hz, 1H), 6.78 (d, J = 1.9 Hz, 1H), 6.73 (dd, J = 8.0, 1.8 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 6.47 (d, J = 2.5 Hz, 1H), 5.46 - 5.37 (m, 2H), 4.36 (dd, J = 11.6, 4.3 Hz, 1H), 4.28 - 4.22 (m, 2H), 4.19 (dd, J = 11.3 , 3.1 Hz, 1H), 4.16 - 4.10 (m, 2H), 4.06 - 3.98 (m, 2H), 3.76 (s, 3H), 3.18 (dd, J = 14.0, 4.4 Hz, 1H), 2.92 - 2.86 ( m, 1H), 2.68 (dd, J = 14.0, 10.1 Hz, 1H), 2.41 (t, J = 6.8 Hz, 2H), 1.92 - 1.85 (m, 4H), 1.53 (d, J = 7.4 Hz, 3H) ), 1.27 (s, 3H). ESI-MS m/z 688.5 (M+H)+

Figure pat00170
Figure pat00170

화합물 47. 5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoic acidCompound 47. 5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2, 3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoic acid

화합물 41 합성과정에서 화합물 40 대신 화합물 46 (95.4 mg, 0.138 mmol)를 사용하여 생성물 47 (47 mg, 52% 수율)을 제조하였다.In the process of synthesizing compound 41, compound 46 (95.4 mg, 0.138 mmol) was used instead of compound 40 to prepare product 47 (47 mg, 52% yield).

1H NMR (400 MHz, CD3OD) δ 7.96 - 7.91 (m, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.91 (q, J = 3.8, 2.9 Hz, 2H), 6.78 - 6.74 (m, 1H), 6.71 (dd, J = 8.0, 1.8 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 4.24 (q, J = 7.5 Hz, 4H), 3.97 - 3.89 (m, 2H), 3.52 (s, 3H), 2.94 (d, J = 7.2 Hz, 2H), 2.30 (t, J = 6.9 Hz, 2H), 1.76 - 1.67 (m, 4H), 1.14 - 1.11 (m, 3H). ESI-MS m/z 660.2 (M+H)+1H NMR (400 MHz, CD 3 OD) δ 7.96 - 7.91 (m, 1H), 7.80 (d, J = 2.1 Hz, 1H), 7.32 (d, J = 2.1 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 6.91 (q, J = 3.8, 2.9 Hz, 2H), 6.78 - 6.74 (m, 1H), 6.71 (dd, J = 8.0, 1.8 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 4.24 (q, J = 7.5 Hz, 4H), 3.97 - 3.89 (m, 2H), 3.52 (s, 3H), 2.94 (d, J = 7.2 Hz, 2H), 2.30 (t, J = 6.9 Hz, 2H), 1.76 - 1.67 (m, 4H), 1.14 - 1.11 (m, 3H). ESI-MS m/z 660.2 (M+H)+

Figure pat00171
Figure pat00171

화합물 48. ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoateCompound 48. ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl) -8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate

Figure pat00172
Figure pat00172

단계 1) ethyl (Z)-5-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate의 제조Step 1) ethyl (Z)-5-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1- Preparation of yl) methyl) -4-oxochroman-3-yl) methyl) -2-chlorophenoxy) pentanoate

화합물 39 합성과정에서 화합물 38 대신 에틸 5-(5-((8-브로모-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸 )-2-클로로페녹시)펜타노에이트 (690 mg, 1.15 mmol)를 사용하여 생성물 (523 mg, 65% 수율)을 제조하였다.In the synthesis of compound 39, ethyl 5-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl) instead of compound 38 The product (523 mg, 65% yield) was prepared using methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate (690 mg, 1.15 mmol).

1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 2.6 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 4.99 (s, 2H), 4.50 (dd, J = 11.6, 4.3 Hz, 1H), 4.25 (dd, J = 11.7, 9.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.03 (d, J = 5.9 Hz, 2H), 3.46 (s, 3H), 3.21 (dd, J = 14.1, 4.6 Hz, 1H), 2.94 (dq, J = 9.4, 4.8 Hz, 1H), 2.68 (dd, J = 14.1, 9.9 Hz, 1H), 2.42 (t, J = 6.8 Hz, 2H), 1.85 (s, 4H), 1.58 (s, 3H), 1.53 (s, 9H), 1.26 (d, J = 2.8 Hz, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.74 (d, J = 2.2 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 6.77 (d , J = 2.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.52 (d, J = 2.6 Hz, 1H), 6.41 (d, J = 2.5 Hz, 1H), 4.99 (s, 2H) ), 4.50 (dd, J = 11.6, 4.3 Hz, 1H), 4.25 (dd, J = 11.7, 9.0 Hz, 1H), 4.13 (q, J = 7.2 Hz, 2H), 4.03 (d, J = 5.9 Hz). , 2H), 3.46 (s, 3H), 3.21 (dd, J = 14.1, 4.6 Hz, 1H), 2.94 (dq, J = 9.4, 4.8 Hz, 1H), 2.68 (dd, J = 14.1, 9.9 Hz, 1H), 2.42 (t, J = 6.8 Hz, 2H), 1.85 (s, 4H), 1.58 (s, 3H), 1.53 (s, 9H), 1.26 (d, J = 2.8 Hz, 3H).

Figure pat00173
Figure pat00173

단계 2) ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate의 제조Step 2) ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl) Preparation of -8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate

화합물 40 합성과정에서 화합물 39 대신 에틸 (Z)-5-(5-((8-브로모-6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸 )-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노에이트 (520 mg, 0.74 mmol)를 사용하여 화합물 48 (198 mg, 34% 수율)을 제조하였다.Ethyl (Z)-5-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2, Compound using 3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate (520 mg, 0.74 mmol) 48 (198 mg, 34% yield) was prepared.

1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 2.3 Hz, 1H), 7.60 (s, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.80 (d, J = 1.9 Hz, 1H), 6.74 (dd, J = 8.0, 1.9 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 6.58 (d, J = 2.5 Hz, 1H), 5.06 (s, 2H), 4.37 (dd, J = 11.7, 4.3 Hz, 1H), 4.24 (q, J = 7.3 Hz, 2H), 4.22 - 4.17 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.05 - 4.00 (m, 2H), 3.51 (s, 3H), 3.19 (dd, J = 13.9, 4.6 Hz, 1H), 2.91 (dp, J = 12.8, 4.4 Hz, 1H), 2.70 (dd, J = 14.0, 10.0 Hz, 1H), 2.44 - 2.38 (m, 2H), 1.93 - 1.81 (m, 4H), 1.55 (t, J = 7.3 Hz, 3H), 1.48 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 2.3 Hz, 1H), 7.60 (s, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.0 Hz , 1H), 6.80 (d, J = 1.9 Hz, 1H), 6.74 (dd, J = 8.0, 1.9 Hz, 1H), 6.66 (d, J = 2.6 Hz, 1H), 6.58 (d, J = 2.5 Hz) , 1H), 5.06 (s, 2H), 4.37 (dd, J = 11.7, 4.3 Hz, 1H), 4.24 (q, J = 7.3 Hz, 2H), 4.22 - 4.17 (m, 1H), 4.13 (q, J = 7.1 Hz, 2H), 4.05 - 4.00 (m, 2H), 3.51 (s, 3H), 3.19 (dd, J = 13.9, 4.6 Hz, 1H), 2.91 (dp, J = 12.8, 4.4 Hz, 1H) ), 2.70 (dd, J = 14.0, 10.0 Hz, 1H), 2.44 - 2.38 (m, 2H), 1.93 - 1.81 (m, 4H), 1.55 (t, J = 7.3 Hz, 3H), 1.48 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H).

Figure pat00174
Figure pat00174

화합물 49. (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoic acidCompound 49. (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)- 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoic acid

화합물 41 합성과정에서 화합물 40 대신 에틸 (Z)-5-(5-((6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8- (1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노에이트(130 mg, 0.164 mmol)를 사용하여 화합물 49 (57 mg, 44 % 수율)을 제조하였다.Ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl) Compound 49 (57 mg, 44 % yield) was prepared using -2-chlorophenoxy)pentanoate (130 mg, 0.164 mmol).

1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 2.2 Hz, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 6.90 (s, 1H), 6.78 (s, 2H), 6.72 (t, J = 10.8 Hz, 2H), 5.30 (s, 2H), 4.43 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.4 Hz, 1H), 4.24 (td, J = 7.3, 3.5 Hz, 4H), 4.02 (s, 2H), 3.73 (s, 3H), 3.15 (d, J = 13.5 Hz, 1H), 3.04 (t, J = 8.9 Hz, 1H), 2.93 (d, J = 9.0 Hz, 3H), 2.77 - 2.67 (m, 1H), 1.90 (s, 2H), 1.82 (s, 4H), 1.48 (s, 9H). ESI-MS m/z 760.8 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 2.2 Hz, 1H), 7.72 (s, 1H), 7.55 (s, 1H), 6.90 (s, 1H), 6.78 (s, 2H) , 6.72 (t, J = 10.8 Hz, 2H), 5.30 (s, 2H), 4.43 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.4 Hz, 1H), 4.24 (td, J = 7.3, 3.5 Hz, 4H), 4.02 (s, 2H), 3.73 (s, 3H), 3.15 (d, J = 13.5 Hz, 1H), 3.04 (t, J = 8.9 Hz, 1H), 2.93 (d, J = 9.0 Hz, 3H), 2.77 - 2.67 (m, 1H), 1.90 (s, 2H), 1.82 (s, 4H), 1.48 (s, 9H). ESI-MS m/z 760.8 (M+H)+

Figure pat00175
Figure pat00175

화합물 50. ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoateCompound 50. ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl) -8-(6-fluoro-2-methylpyridin-3-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate

화합물 48 합성과정에서 (1-에틸-3-(트리플루오로)-1H-피라졸-4-일)보로닉 애시드 대신 (6-플루오로-2-메틸피리딘-3-일)보론산 (600 mg, 0.85 mmol), 를 사용하여 화합물 50 (557 mg, 89% 수율)을 제조하였다.(6-fluoro-2-methylpyridin-3-yl) boronic acid (600 mg, 0.85 mmol), to prepare compound 50 (557 mg, 89% yield).

1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 2.4 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.26 (s, 1H), 6.79 (dd, J = 8.3, 3.1 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 8.1, 1.9 Hz, 1H), 6.53 (d, J = 2.5 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 5.04 (s, 2H), 4.36 (dd, J = 11.7, 4.3 Hz, 1H), 4.18 - 4.08 (m, 3H), 3.99 (d, J = 5.7 Hz, 2H), 3.45 (s, 3H), 3.22 (dd, J = 14.1, 4.5 Hz, 1H), 2.93 (tt, J = 9.3, 4.6 Hz, 1H), 2.69 (dd, J = 14.0, 9.7 Hz, 1H), 2.45 - 2.36 (m, 2H), 2.30 (s, 3H), 1.87 (qd, J = 7.2, 4.5, 3.9 Hz, 4H), 1.46 (s, 9H), 1.25 (t, J = 7.2 Hz, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.87 (d, J = 2.4 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.26 (s , 1H), 6.79 (dd, J = 8.3, 3.1 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.69 (dd, J = 8.1, 1.9 Hz, 1H), 6.53 (d, J = 2.0 Hz, 1H). 2.5 Hz, 1H), 6.49 (d, J = 2.6 Hz, 1H), 5.04 (s, 2H), 4.36 (dd, J = 11.7, 4.3 Hz, 1H), 4.18 - 4.08 (m, 3H), 3.99 ( d, J = 5.7 Hz, 2H), 3.45 (s, 3H), 3.22 (dd, J = 14.1, 4.5 Hz, 1H), 2.93 (tt, J = 9.3, 4.6 Hz, 1H), 2.69 (dd, J = 14.0, 9.7 Hz, 1H), 2.45 - 2.36 (m, 2H), 2.30 (s, 3H), 1.87 (qd, J = 7.2, 4.5, 3.9 Hz, 4H), 1.46 (s, 9H), 1.25 ( t, J = 7.2 Hz, 3H).

Figure pat00176
Figure pat00176

화합물 51. (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoic acidCompound 51. (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)- 8-(6-fluoro-2-methylpyridin-3-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoic acid

화합물 41 합성과정에서 화합물 40 대신 에틸 (Z)-5-(5-((6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8- (6-플루오로-2-메틸피리딘-3-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노에이트 (80 mg, 0.109 mmol)를 사용하여 화합물 51 (62 mg, 89% 수율)을 제조하였다. Ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)penta Compound 51 (62 mg, 89% yield) was prepared using noate (80 mg, 0.109 mmol).

1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 13.9 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 30.6 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.89 (s, 1H), 6.86 - 6.74 (m, 3H), 6.69 (d, J = 8.7 Hz, 1H), 5.32 (d, J = 3.6 Hz, 2H), 4.43 (t, J = 13.7 Hz, 1H), 4.18 (q, J = 11.8, 10.7 Hz, 1H), 4.03 (s, 2H), 3.69 (s, 3H), 3.27 - 2.87 (m, 4H), 2.68 (d, J = 54.2 Hz, 1H), 2.32 (s, 3H), 1.83 (s, 4H), 1.50 - 1.43 (m, 9H). ESI-MS m/z 707.8 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.95 (d, J = 13.9 Hz, 1H), 7.59 (t, J = 8.1 Hz, 1H), 7.44 (d, J = 30.6 Hz, 1H), 7.24 (d , J = 8.2 Hz, 1H), 6.89 (s, 1H), 6.86 - 6.74 (m, 3H), 6.69 (d, J = 8.7 Hz, 1H), 5.32 (d, J = 3.6 Hz, 2H), 4.43 (t, J = 13.7 Hz, 1H), 4.18 (q, J = 11.8, 10.7 Hz, 1H), 4.03 (s, 2H), 3.69 (s, 3H), 3.27 - 2.87 (m, 4H), 2.68 ( d, J = 54.2 Hz, 1H), 2.32 (s, 3H), 1.83 (s, 4H), 1.50 - 1.43 (m, 9H). ESI-MS m/z 707.8 (M+H)+

Figure pat00177
Figure pat00177

화합물 52. (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acidCompound 52. (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl )-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid

Figure pat00178
Figure pat00178

단계 1) methyl 2-(2-fluoro-5-formylphenoxy)acetate의 제조Step 1) Preparation of methyl 2-(2-fluoro-5-formylphenoxy)acetate

화합물 38 합성과정에서 단계 1에서 4-클로로-3-히드록시벤즈알데히드 대신 4-플루오로-3-히드록시벤즈알데히드 (8 g, 57.1 mmol)를 사용하여 생성물 (11.651 g, 96% 수율)을 제조하였다.In the synthesis of compound 38, a product (11.651 g, 96% yield) was prepared using 4-fluoro-3-hydroxybenzaldehyde (8 g, 57.1 mmol) instead of 4-chloro-3-hydroxybenzaldehyde in step 1. .

Figure pat00179
Figure pat00179

단계 2) methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate의 제조Step 2) Preparation of methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate

8-브로모-6-메틸크로만-4-온 (15.276 g, 63.45 mmol)의 toluene (110 mL) 용액에 메틸 2-(2-플루오로-5-포르밀페녹시)아세테이트 (11.219 g, 52.875 mmol)와 p-톨루엔 설폰산 (910 mg, 5.287 mmol)를 넣고 20 h 환류한다음 상온으로 냉각하고 반응혼합물을 CH2Cl2로 희석하고 소금물과 물로 세척하고, CH2Cl2 (x3) 추출한다음 sodium sulfate로 건조 및 감압농축한다. 농축액을 컬럼 크로마토그래피 (CH2Cl2: n-heptane = 1:10 to 1:1)으로 정제하여 목적물 (8.491 g, 37%, BORSM 64%)을 얻는다.Methyl 2-(2-fluoro-5-formylphenoxy)acetate (11.219 g, 11.219 g, 52.875 mmol) and p-toluenesulfonic acid (910 mg, 5.287 mmol), refluxed for 20 h, cooled to room temperature, and the reaction mixture was diluted with CH 2 Cl 2 , washed with brine and water, and CH 2 Cl 2 (x3) After extraction, it is dried with sodium sulfate and concentrated under reduced pressure. The concentrate was purified by column chromatography (CH 2 Cl 2 : n-heptane = 1:10 to 1:1) to obtain the target product (8.491 g, 37%, 64% BORSM).

Figure pat00180
Figure pat00180

단계 3) methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy)acetate의 제조Step 3) Preparation of methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy)acetate

메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 (4.23 g, 9.713 mmol)의 아세토니트릴 (10 mL)용액에 DBU/formic acid (3.6 mL:1.8 mL)의 아세토니트릴 (50 mL) 용액을 상온에서 넣어주고 20 분 교반한다음 RuCl(p-cymene)[(S,S)-Ts-DPEN] (32 mg, 48 umol)을 넣고 50 °C에서 16시간 교반한다. 상온에서 포화 NaHCO3 수용액으로 ??칭한다. 반응혼합물을 CH2Cl2로 추출하고 NH4Cl로 세척하고 MgSO4로 건조 및 감압농축한다. 농축물을 MPLC (ethyl acetate/n-hexane = 1:4 to 1:1)로 정제하여 목적물 (3.75 g, 91%)을 얻는다. Methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate (4.23 g, 9.713 mmol) A solution of DBU/formic acid (3.6 mL: 1.8 mL) in acetonitrile (50 mL) was added to the acetonitrile (10 mL) solution at room temperature, stirred for 20 minutes, and RuCl (p-cymene) [(S, S -Ts-DPEN] (32 mg, 48 umol) was added and stirred at 50 °C for 16 hours. Quench with saturated NaHCO 3 aqueous solution at room temperature. The reaction mixture was extracted with CH 2 Cl 2 , washed with NH 4 Cl, dried over MgSO 4 and concentrated under reduced pressure. The concentrate was purified by MPLC (ethyl acetate/n-hexane = 1:4 to 1:1) to obtain the target product (3.75 g, 91%).

Figure pat00181
Figure pat00181

단계 4) methyl (S)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate의 제조Step 4) Preparation of methyl (S)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate

메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 (3385 mg, 7.705 mmol)와 Molecular sieves 4 Å (300 mg)의 CH2Cl2 (60 mL) 용액을 10분 교반한 다음 N-메틸모르폴린 N-옥사이드 (NMO, 903 mg, 7.705 mmol)와 테트라프로필암모늄 퍼루테네이트 (TPAP, 271 mg, 0.771 mmol)를 0°C에서 넣어주고 상온에서 3 h 교반한다. 검은색 반응혼합물을 diethyl ether 용매로 셀라이트 여과한다음 여액을 감압농축한다. 농축액을 MPLC (ethyl acetate:n-heptane, 20%)로 정제하여 목적물 (2828 mg, 84%)을 얻는다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy)acetate (3385 mg, 7.705 mmol) and Molecular sieves 4 Å (300 mg) in CH 2 Cl 2 (60 mL) was stirred for 10 minutes, and then N-methylmorpholine N-oxide (NMO, 903 mg, 7.705 mmol) and tetrapropylammonium perute Nate (TPAP, 271 mg, 0.771 mmol) was added at 0°C and stirred at room temperature for 3 h. The black reaction mixture was filtered through celite with a diethyl ether solvent, and the filtrate was concentrated under reduced pressure. The concentrate was purified by MPLC (ethyl acetate:n-heptane, 20%) to obtain the target product (2828 mg, 84%).

Figure pat00182
Figure pat00182

단계 5) methyl (S)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate의 제조Step 5) Preparation of methyl (S)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate

메틸 (S)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 (2828 mg, 6.467 mmol), NBS (1266 mg, 7.114 mmol), AIBN (319 mg, 1.94 mmol)의 에틸아세테이트 (50 mL) 용액을 70 °C에서 4 h 교반하고 상온으로 냉각한다음 반응혼합물을 ethyl acetate로 희석, 물을 넣고, ethyl acetate (x3)로 추출하고 유기층을 Na2SO4로 건조 및 감압농축한다. 농축물을 컬럼 크로마토그래피 (ethyl acetate : n-hexane = 1:10)으로 정제하여 목적물 (1459 mg, 44%)을 얻는다.methyl (S)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate (2828 mg, 6.467 mmol), A solution of NBS (1266 mg, 7.114 mmol) and AIBN (319 mg, 1.94 mmol) in ethyl acetate (50 mL) was stirred at 70 °C for 4 h, cooled to room temperature, and the reaction mixture was diluted with ethyl acetate and added with water. , Extract with ethyl acetate (x3), dry the organic layer with Na 2 SO 4 and concentrate under reduced pressure. The concentrate was purified by column chromatography (ethyl acetate : n-hexane = 1:10) to obtain the target product (1459 mg, 44%).

Figure pat00183
Figure pat00183

단계 6) methyl (S)-2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate의 제조Step 6) methyl (S)-2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4- Preparation of oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate

화합물 38 합성과정 단계 4에서 메틸 2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트 대신 메틸 (S)-2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 (1459 mg, 1.991 mmol)를 사용하여 생성물 (448 mg, 30% 수율)을 제조하였다.methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate in step 4 of the synthesis of compound 38 (S)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate (1459 mg, 1.991 mmol) was used to prepare the product (448 mg, 30% yield).

Figure pat00184
Figure pat00184

단계 7) methyl (S,Z)-2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate의 제조Step 7) methyl (S,Z)-2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol- Preparation of 1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate

화합물 39 합성과정에서 화합물 38 대신 메틸 (S)-2-(5-((8-브로모-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3 -일)메틸)-2-플루오로페녹시)아세테이트 (445 mg, 0.835 mmol)를 사용하여 생성물 (350 mg, 66% 수율)을 제조하였다.During the synthesis of compound 39, methyl (S)-2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole- The product (350 mg, 66% yield) was prepared using 1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate (445 mg, 0.835 mmol) .

Figure pat00185
Figure pat00185

단계 8) methyl (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate의 제조Step 8) methyl (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) Preparation of methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate

화합물 40 합성과정에서 화합물 39 대신 메틸 (S,Z)-2-(5-((8-브로모-6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일 )메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 (82.2 mg, 0.1299 mmol)를 사용하여 생성물 (37 mg, 40% 수율)을 제조하였다.Methyl (S,Z)-2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl- 2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate (82.2 mg, 0.1299 mmol) The product (37 mg, 40% yield) was prepared.

Figure pat00186
Figure pat00186

단계 9) (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid의 제조Step 9) (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl Preparation of )-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid

화합물 41 합성과정에서 화합물 40 대신 메틸 (S,Z)-2-(5-((6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)- 8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 (33.6 mg, 0.0469 mmol)를 사용하여 화합물 52 (31.4 mg, 95% 수율)을 제조하였다. During the synthesis of compound 41, methyl (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-di instead of compound 40 Hydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl) Compound 52 (31.4 mg, 95% yield) was prepared using methyl)-2-fluorophenoxy)acetate (33.6 mg, 0.0469 mmol).

1H NMR (400 MHz, CD3OD) δ 7.91 - 7.84 (m, 2H), 7.61 (dd, J = 13.5, 2.4 Hz, 2H), 7.48 (d, J = 2.3 Hz, 1H), 7.03 (dd, J = 11.3, 8.2 Hz, 1H), 6.88 (dd, J = 8.1, 2.1 Hz, 1H), 6.82 (ddd, J = 8.3, 4.2, 2.0 Hz, 1H), 5.34 (s, 2H), 4.63 (s, 2H), 4.44 (dd, J = 11.7, 4.4 Hz, 1H), 4.34 - 4.27 (m, 2H), 4.27 - 4.21 (m, 1H), 3.76 (s, 3H), 3.13 (dd, J = 13.9, 5.5 Hz, 1H), 3.00 (tt, J = 8.6, 4.8 Hz, 1H), 2.85 - 2.75 (m, 1H), 1.53 (t, J = 7.3 Hz, 3H), 1.45 (s, 9H). 1 H NMR (400 MHz, CD 3 OD) δ 7.91 - 7.84 (m, 2H), 7.61 (dd, J = 13.5, 2.4 Hz, 2H), 7.48 (d, J = 2.3 Hz, 1H), 7.03 (dd , J = 11.3, 8.2 Hz, 1H), 6.88 (dd, J = 8.1, 2.1 Hz, 1H), 6.82 (ddd, J = 8.3, 4.2, 2.0 Hz, 1H), 5.34 (s, 2H), 4.63 ( s, 2H), 4.44 (dd, J = 11.7, 4.4 Hz, 1H), 4.34 - 4.27 (m, 2H), 4.27 - 4.21 (m, 1H), 3.76 (s, 3H), 3.13 (dd, J = 13.9, 5.5 Hz, 1H), 3.00 (tt, J = 8.6, 4.8 Hz, 1H), 2.85 - 2.75 (m, 1H), 1.53 (t, J = 7.3 Hz, 3H), 1.45 (s, 9H).

Figure pat00187
Figure pat00187

화합물 53. methyl 2-(2-chloro-5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-hydroxychroman-3-yl)methyl)phenoxy)acetateCompound 53. methyl 2-(2-chloro-5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl -3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-hydroxychroman-3-yl)methyl)phenoxy)acetate

Figure pat00188
Figure pat00188

단계 1) methyl (E)-2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)phenoxy)acetate의 제조Step 1) methyl (E)-2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3 Preparation of -(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)phenoxy)acetate

화합물 40 합성과정에서 화합물 39 대신 메틸 (E)-2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일리덴)메틸)-2-클로로페녹시)아세테이트 (19.6 mg, 0.037 mmol)를 사용하여 생성물 (16 mg, 58% 수율)을 제조하였다.In the synthesis of compound 40, methyl (E)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-chloro instead of compound 39 The product (16 mg, 58% yield) was prepared using phenoxy)acetate (19.6 mg, 0.037 mmol).

Figure pat00189
Figure pat00189

단계 2) methyl 2-(2-chloro-5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-hydroxychroman-3-yl)methyl)phenoxy)acetate의 제조Step 2) methyl 2-(2-chloro-5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl Preparation of -3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-hydroxychroman-3-yl)methyl)phenoxy)acetate

화합물 52 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 대신 메틸 (E)-2-(2-클로로-5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((1-에틸-3-(트리플루오로메틸) )-1H-피라졸-4-일)메틸)-4-옥소크로만-3-일리덴)메틸)페녹시)아세테이트 (16 mg, 0.0216 mmol)를 사용하여 화합물 53 (7.3 mg, 45% 수율)을 제조하였다. Methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate from step 3 of the synthesis of compound 52 Instead of methyl (E)-2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl -3-(trifluoromethyl))-1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)phenoxy)acetate (16 mg, 0.0216 mmol) Compound 53 (7.3 mg, 45% yield) was prepared.

1H NMR (400 MHz, CDCl3) δ 7.55 (d, J = 1.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.15 - 7.08 (m, 2H), 7.05 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.1, 1.8 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 4.75 (s, 2H), 4.48 (d, J = 3.1 Hz, 1H), 4.25 (q, J = 7.3 Hz, 2H), 4.15 (q, J = 7.4 Hz, 2H), 4.08 (d, J = 7.6 Hz, 2H), 3.82 (d, J = 8.0 Hz, 5H), 2.86 (dd, J = 13.6, 8.7 Hz, 1H), 2.64 (dd, J = 13.6, 7.1 Hz, 1H), 2.25 (ddd, J = 12.8, 8.9, 5.2 Hz, 1H), 1.58 (d, J = 7.3 Hz, 3H), 1.48 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.55 (d, J = 1.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.15 - 7.08 (m, 2H), 7.05 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.1, 1.8 Hz, 1H), 6.81 (d, J = 1.9 Hz, 1H), 4.75 (s, 2H), 4.48 (d, J = 3.1 Hz, 1H) , 4.25 (q, J = 7.3 Hz, 2H), 4.15 (q, J = 7.4 Hz, 2H), 4.08 (d, J = 7.6 Hz, 2H), 3.82 (d, J = 8.0 Hz, 5H), 2.86 (dd, J = 13.6, 8.7 Hz, 1H), 2.64 (dd, J = 13.6, 7.1 Hz, 1H), 2.25 (ddd, J = 12.8, 8.9, 5.2 Hz, 1H), 1.58 (d, J = 7.3 Hz, 3H), 1.48 (t, J = 7.3 Hz, 3H).

Figure pat00190
Figure pat00190

화합물 54. methyl (E)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetateCompound 54. methyl (E)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(trifluoromethyl) -1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate

Figure pat00191
Figure pat00191

단계 1) methyl (E)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate의 제조Step 1) Preparation of methyl (E)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate

화합물 38 합성과정 단계 2에서 메틸 2-(2-클로로-5-포르밀페녹시)아세테이트 대신 메틸 2-(2-플루오로-5-포르밀페녹시)아세테이트 (2088 mg, 9.840 mmol)를 사용하여 생성물 (1.572 g, 31% 수율)을 제조하였다.Methyl 2-(2-chloro-5-formylphenoxy)acetate (2088 mg, 9.840 mmol) was used instead of methyl 2-(2-chloro-5-formylphenoxy)acetate in step 2 of the synthesis of compound 38 to prepare the product (1.572 g, 31% yield).

Figure pat00192
Figure pat00192

단계 2) methyl (E)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate의 제조Step 2) methyl (E)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(trifluoromethyl) Preparation of -1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate

화합물 40 합성과정에서 화합물 39 대신 메틸 (E)-2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 (100 mg, 0.194 mmol)를 사용하여 화합물 54 (30 mg, 23% 수율)를 제조하였다.In the synthesis of compound 40, methyl (E)-2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-ylidene)methyl)-2-fluoro instead of compound 39 Compound 54 (30 mg, 23% yield) was prepared using lophenoxy)acetate (100 mg, 0.194 mmol).

1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 7.22 - 7.14 (m, 2H), 6.94 - 6.89 (m, 2H), 5.30 (d, J = 1.9 Hz, 2H), 4.75 (s, 2H), 4.26 (q, J = 7.4 Hz, 2H), 4.19 - 4.14 (m, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 1.56 (d, J = 7.3 Hz, 3H), 1.50 (t, J = 7.3 Hz, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 2.4 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H), 7.36 (d , J = 2.3 Hz, 1H), 7.22 - 7.14 (m, 2H), 6.94 - 6.89 (m, 2H), 5.30 (d, J = 1.9 Hz, 2H), 4.75 (s, 2H), 4.26 (q, J = 7.4 Hz, 2H), 4.19 - 4.14 (m, 2H), 3.93 (s, 2H), 3.83 (s, 3H), 1.56 (d, J = 7.3 Hz, 3H), 1.50 (t, J = 7.3 Hz, 3H).

Figure pat00193
Figure pat00193

화합물 55. methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoateCompound 55. methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)- 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate

Figure pat00194
Figure pat00194

단계 1) methyl (E)-5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorobenzoate의 제조Step 1) Preparation of methyl (E)-5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorobenzoate

화합물 52 합성과정 단계 2에서 메틸 2-(2-클로로-5-포르밀페녹시)아세테이트대신 메틸 2-플루오로-5-포르밀벤조에이트 (17 g, 93.3 mmol)를 사용하여 생성물(10.23 g, 55% 수율)을 제조하였다.In step 2 of the synthesis of compound 52, methyl 2-(2-chloro-5-formylphenoxy)acetate was replaced with methyl 2-fluoro-5-formylbenzoate (17 g, 93.3 mmol) to obtain the product (10.23 g). , 55% yield) was prepared.

Figure pat00195
Figure pat00195

단계 2) methyl 5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorobenzoate의 제조Step 2) Preparation of methyl 5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorobenzoate

화합물 52 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 대신 메틸 (E)-5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로벤조에이트 (2.47 g, 6.0 mmol )를 사용하여 생성물 (1.65 g, 67% 수율)을 제조하였다.Methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate from step 3 of the synthesis of compound 52 Product using methyl (E)-5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorobenzoate (2.47 g, 6.0 mmol) instead (1.65 g, 67% yield).

Figure pat00196
Figure pat00196

단계 3) methyl (S)-5-((8-bromo-6-methyl-4-oxochroman-3-yl)methyl)-2-fluorobenzoate의 제조Step 3) Preparation of methyl (S)-5-((8-bromo-6-methyl-4-oxochroman-3-yl)methyl)-2-fluorobenzoate

화합물 52 합성과정 단계 4에서 메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 메틸 5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로벤조에이트 (1.6 g, 4.0 mmol)를 사용하여 생성물 (1.3 g, 80% 수율)을 제조하였다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy from synthesis step 4 of compound 52 )methyl 5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorobenzoate (1.6 g, 4.0 mmol) instead of acetate The product (1.3 g, 80% yield) was prepared using

Figure pat00197
Figure pat00197

단계 4) methyl (S)-5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate의 제조Step 4) Preparation of methyl (S)-5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate

화합물 52 합성과정 단계 5에서 메틸 (S)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 메틸 (S)-5-((8-브로모-6-메틸-4-옥소크로만-3-일)메틸)-2-플루오로벤조에이트 (2.6 g, 6.38 mmol)를 사용하여 생성물(2.48 g, 80% 수율)을 제조하였다.Instead of methyl (S)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate in step 5 of the synthesis of compound 52 The product (2.48 g, 80% yield) was prepared.

Figure pat00198
Figure pat00198

단계 5) methyl (S)-5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate의 제조Step 5) methyl (S)-5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3 Preparation of -yl)methyl)-2-fluorobenzoate

화합물 38 합성과정 단계 4에서 메틸 2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트 대신 메틸 (S)-5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-플루오로벤조에이트 (3.8 g, 6.38 mmol)를 사용하여 생성물 (2.08 g, 64% 수율)을 제조하였다.methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate in step 4 of the synthesis of compound 38 (S)-5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate (3.8 g, 6.38 mmol) The product (2.08 g, 64% yield) was prepared.

Figure pat00199
Figure pat00199

단계 6) methyl (S,E)-5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate의 제조Step 6) methyl (S,E)-5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl Preparation of )methyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate

화합물 39 합성과정에서 화합물 38 대신 메틸 (S)-5-((8-브로모-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일) 메틸)-2-플루오로벤조에이트 (2.0 g, 4.1 mmol)를 사용하여 생성물 (1.14 g, 46% 수율)을 제조하였다.In the synthesis of compound 39, methyl (S)-5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl instead of compound 38) )methyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate (2.0 g, 4.1 mmol) was used to give the product (1.14 g, 46% yield).

Figure pat00200
Figure pat00200

단계 7) methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate의 제조Step 7) methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)- Preparation of 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate

화합물 40 합성과정에서 화합물 39 대신 메틸 (S,E)-5-((8-브로모-6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸) -4-옥소크로만-3-일)메틸)-2-플루오로벤조에이트 (500 mg, 0.827 mmol) 를 사용하여 화합물 55 (470 mg, 83% 수율)을 제조하였다.Methyl (S,E)-5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3 instead of compound 39 during the synthesis of compound 40 Compound 55 (470 mg) using -dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate (500 mg, 0.827 mmol) , 83% yield) was prepared.

Figure pat00201
Figure pat00201

화합물 56. (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoic acidCompound 56. (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8 -(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoic acid

화합물 41 합성과정에서 화합물 40 대신 메틸 (S,E)-5-((6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로벤조에이트 (470 mg, 0.69 mmol), 소듐바이카보네이트 (290 mg, 3.4 mmol)를 사용하여 화합물 56 (93 mg, 20% 수율)을 제조하였다. ESI-MS m/z 672.2 (M+H)+In the synthesis of compound 41, methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H instead of compound 40 -imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)- Compound 56 (93 mg, 20% yield) was prepared using 2-fluorobenzoate (470 mg, 0.69 mmol) and sodium bicarbonate (290 mg, 3.4 mmol). ESI-MS m/z 672.2 (M+H)+

Figure pat00202
Figure pat00202

화합물 57. methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoateCompound 57. methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)- 8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate

화합물 55 합성과정 단계 7에서 (1-에틸-3-(트리플루오로)-1H-피라졸-4-일)보론산 대신 (6-플루오로-2-메틸피리딘-3-일)보론산 (114 mg, 0.744 mmol)을 사용하여 화합물 57 (143 mg, 45% 수율)을 제조하였다.(6-fluoro-2-methylpyridin-3-yl)boronic acid instead of (1-ethyl-3-(trifluoro)-1H-pyrazol-4-yl)boronic acid in step 7 of the synthesis of compound 55 ( Compound 57 (143 mg, 45% yield) was prepared using 114 mg, 0.744 mmol).

1H NMR (400 MHz, CDCl3) δ 7.85 - 7.27 (m, 5H), 7.12 - 6.85 (m, 3H), 6.52 (t, J = 2.1 Hz, 1H), 6.44 (dd, J = 14.8, 2.6 Hz, 1H), 5.00 (d, J = 17.8 Hz, 2H), 4.55 - 4.30 (m, 1H), 4.16 (ddd, J = 54.1, 11.6, 9.2 Hz, 1H), 3.90 (d, J = 6.6 Hz, 3H), 3.44 (d, J = 3.3 Hz, 3H), 3.25 (dt, J = 14.4, 4.3 Hz, 1H), 2.95 (ddd, J = 20.7, 9.2, 4.4 Hz, 1H), 2.71 (ddd, J = 14.2, 9.4, 6.9 Hz, 1H), 2.22 - 1.94 (m, 2H), 1.47 (d, J = 21.9 Hz, 9H), 1.27 - 1.20 (m, 1H). ESI-MS m/z 632.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.85 - 7.27 (m, 5H), 7.12 - 6.85 (m, 3H), 6.52 (t, J = 2.1 Hz, 1H), 6.44 (dd, J = 14.8, 2.6 Hz, 1H), 5.00 (d, J = 17.8 Hz, 2H), 4.55 - 4.30 (m, 1H), 4.16 (ddd, J = 54.1, 11.6, 9.2 Hz, 1H), 3.90 (d, J = 6.6 Hz) , 3H), 3.44 (d, J = 3.3 Hz, 3H), 3.25 (dt, J = 14.4, 4.3 Hz, 1H), 2.95 (ddd, J = 20.7, 9.2, 4.4 Hz, 1H), 2.71 (ddd, J = 14.2, 9.4, 6.9 Hz, 1H), 2.22 - 1.94 (m, 2H), 1.47 (d, J = 21.9 Hz, 9H), 1.27 - 1.20 (m, 1H). ESI-MS m/z 632.1 (M+H)+

Figure pat00203
Figure pat00203

화합물 58. (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoic acidCompound 58. (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8 -(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoic acid

화합물 56 합성과정에서 화합물 55 대신 메틸 (S,E)-5-((6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로벤조에이트 (143 mg, 0.22 mmol) 를 사용하여 화합물 58(74 mg, 55% 수율)을 제조하였다.During the synthesis of compound 56, methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H instead of compound 55 -imidazol-1-yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate (143 mg, 0.22 mmol) was used to prepare compound 58 (74 mg, 55% yield).

1H NMR (400 MHz, CD3OD) δ 7.88 (d, J = 2.4 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.14 - 7.09 (m, 1H), 7.08 - 6.97 (m, 3H), 6.93 (td, J = 8.4, 2.8 Hz, 1H), 5.25 (s, 2H), 4.20 (dd, J = 11.6, 8.3 Hz, 1H), 3.66 (s, 3H), 3.16 (dd, J = 13.9, 5.5 Hz, 1H), 3.07 (q, J = 6.6 Hz, 1H), 3.04 - 2.96 (m, 1H), 2.81 (dd, J = 14.4, 8.7 Hz, 1H), 2.12 (d, J = 4.7 Hz, 3H), 1.41 (s, 9H). ESI-MS m/z 618.7 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 7.88 (d, J = 2.4 Hz, 1H), 7.58 - 7.53 (m, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.14 - 7.09 (m, 1H), 7.08 - 6.97 (m, 3H), 6.93 (td, J = 8.4, 2.8 Hz, 1H) , 5.25 (s, 2H), 4.20 (dd, J = 11.6, 8.3 Hz, 1H), 3.66 (s, 3H), 3.16 (dd, J = 13.9, 5.5 Hz, 1H), 3.07 (q, J = 6.6 Hz, 1H), 3.04 - 2.96 (m, 1H), 2.81 (dd, J = 14.4, 8.7 Hz, 1H), 2.12 (d, J = 4.7 Hz, 3H), 1.41 (s, 9H). ESI-MS m/z 618.7 (M+H)+

Figure pat00204
Figure pat00204

화합물 59. tert-butyl (1-((8-(4-fluoro-2-methylphenyl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamateCompound 59. tert-butyl (1-((8-(4-fluoro-2-methylphenyl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2- ylidene)carbamate

Figure pat00205
Figure pat00205

단계 1) 8-bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one의 제조Step 1) Preparation of 8-bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one

8-브로모-2,3-디하이드로-6-메틸크로멘-4-온 (32 g, 0.133 mol, 1 eq.)의 methyl acetate (640 mL) 용액을 상온에서 NBS (28.35 g, 0.159 mol, 1.2 eq.)와 AIBN (4.36 g, 26.54 mmol, 0.2 eq.)을 넣고 70 °C에서 3h 교반한다음 ice-bath에서 H2O로 ??칭하고 ethyl acetate 희석, 소금물로 세척, MgSO4 건조 및 감압농축한다. 농축물을 MC/MeOH/Heptane 용매에서 결정화하여 목적물 (30.85g, 70.4%)을 얻는다.A solution of 8-bromo-2,3-dihydro-6-methylchromen-4-one (32 g, 0.133 mol, 1 eq.) in methyl acetate (640 mL) was mixed with NBS (28.35 g, 0.159 mol) at room temperature. , 1.2 eq.) and AIBN (4.36 g, 26.54 mmol, 0.2 eq.), stirred at 70 °C for 3 h, then quenched with H2O in an ice-bath, diluted with ethyl acetate, washed with brine, dried with MgSO 4 and reduced pressure. Concentrate. The concentrate was crystallized in MC/MeOH/Heptane solvent to obtain the desired product (30.85 g, 70.4%).

Figure pat00206
Figure pat00206

단계 2) 8-bromo-2,3-dihydro-6-((2,3-dihydro-2-imino-3-methylimidazol-1-yl)methyl)chromen-4-one의 제조Step 2) Preparation of 8-bromo-2,3-dihydro-6-((2,3-dihydro-2-imino-3-methylimidazol-1-yl)methyl)chromen-4-one

화합물 38 합성과정 단계 4에서 메틸 2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트 대신 8-브로모-6-(브로모메틸)-2,3-디히드로크로멘-4-온 (15.5 g, 48.44 mmol)를 사용하여 생성물 (13.33 g, 81.8% 수율)을 제조하였다.In step 4 of the synthesis of compound 38, methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate was replaced by 8 -Bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one (15.5 g, 48.44 mmol) was used to prepare the product (13.33 g, 81.8% yield).

Figure pat00207
Figure pat00207

단계 3) tert-butyl (Z)-(1-((8-bromo-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate의 제조Step 3) tert-butyl (Z)-(1-((8-bromo-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate manufacturing

화합물 39 합성과정에서 화합물 38 대신 8-브로모-2,3-디히드로-6-((2,3-디히드로-2-이미노-3-메틸이미다졸-1-일)메틸)크로멘-4-온 (3.8 g, 11.30 mmol, 1 eq.)를 사용하여 생성물 (3.68 g, 74.6% 수율)을 제조하였다.During the synthesis of compound 39, 8-bromo-2,3-dihydro-6-((2,3-dihydro-2-imino-3-methylimidazol-1-yl)methyl)chrome instead of compound 38 The product (3.68 g, 74.6% yield) was prepared using men-4-one (3.8 g, 11.30 mmol, 1 eq.).

Figure pat00208
Figure pat00208

단계 4) tert-butyl (1-((8-(4-fluoro-2-methylphenyl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate의 제조Step 4) tert-butyl (1-((8-(4-fluoro-2-methylphenyl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2- Manufacture of ylidene)carbamate

화합물 57 합성과정에서 메틸 (S,Z)-2-(5-((8-브로모-6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 1-((8-브로모-3,4-디히드로-4-옥소-2H-크로멘-6-일)메틸)-3-메틸-1H-이미다졸-2(3H)-일리덴카르바메이트 (0.5 g, 1.15mmol, 1 eq.)를 사용하여 화합물 59 (0.41 g, 76.9% 수율)을 제조하였다.During the synthesis of compound 57, methyl (S,Z)-2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3 1-((8-bromo-3,4 instead of -dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate -dihydro-4-oxo-2H-chromen-6-yl)methyl)-3-methyl-1H-imidazol-2(3H)-ylidenecarbamate (0.5 g, 1.15 mmol, 1 eq.) was used to prepare compound 59 (0.41 g, 76.9% yield).

1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.4, 5.9 Hz, 1H), 6.97 (m, 2H), 6.52 (d, J = 2.6 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 5.03 (s, 2H), 4.51 (t, J = 6.4 Hz, 2H), 3.47 (s, 3H), 2.82 (t, J = 6.4 Hz, 2H), 2.14 (s, 3H), 1.49 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.11 (dd, J = 8.4, 5.9 Hz, 1H), 6.97 (m, 2H), 6.52 (d, J = 2.6 Hz, 1H), 6.46 (d, J = 2.6 Hz, 1H), 5.03 (s, 2H), 4.51 (t, J = 6.4 Hz, 2H), 3.47 (s, 3H), 2.82 (t, J = 6.4 Hz, 2H), 2.14 (s, 3H), 1.49 (s, 9H).

Figure pat00209
Figure pat00209

화합물 60. methyl 2-(5-(((3E)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetateCompound 60. methyl 2-(5-(((3E)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl) -8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate

화합물 59 (2340 mg, 5.02 mmol) 의 MeOH (20 mL) 용액에 피롤리딘 (820 uL, 10.04 mmol)을 적가후 혼합물을 한시간동안 상온에서 교반한다. 메틸 2-(2-플루오오-5-포밀페녹시)아세테이트 (1600 mg, 7.54 mmol)를 넣고 17시간동안 상온에서 교반후 용매를 제거하고 여액을 에틸아세테이트 용매에 희석한후 소금물과 물로 세척하고 에틸아세테이트로 세 번 추출후 Na2SO4 건조 및 감압농축한다. 농축물을 MPLC (ethyl acetate : n-heptane = 1:10 to 1:2)로 정제하여 화합물 60 (2880 mg, 87%)을 얻는다.After adding pyrrolidine (820 uL, 10.04 mmol) dropwise to a solution of compound 59 (2340 mg, 5.02 mmol) in MeOH (20 mL), the mixture was stirred at room temperature for one hour. After adding methyl 2-(2-fluoro-5-formylphenoxy)acetate (1600 mg, 7.54 mmol) and stirring at room temperature for 17 hours, the solvent was removed, the filtrate was diluted in ethyl acetate solvent, washed with brine and water, After extraction with ethyl acetate three times, Na 2 SO 4 was dried and concentrated under reduced pressure. The concentrate was purified by MPLC (ethyl acetate : n-heptane = 1:10 to 1:2) to obtain compound 60 (2880 mg, 87%).

1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.19 - 7.13 (m, 1H), 7.10 (dd, J = 8.4, 5.9 Hz, 1H), 6.95 (ddd, J = 11.3, 8.9, 2.7 Hz, 2H), 6.92 - 6.86 (m, 2H), 6.59 (d, J = 18.2 Hz, 2H), 5.27 (d, J = 1.9 Hz, 2H), 5.14 (s, 2H), 4.74 (s, 2H), 3.80 (s, 3H), 3.53 (s, 3H), 2.14 (s, 3H), 1.50 (s, 9H). ESI-MS m/z 660.3 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.96 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.19 - 7.13 (m, 1H), 7.10 (dd, J = 8.4, 5.9 Hz, 1H), 6.95 (ddd, J = 11.3, 8.9, 2.7 Hz, 2H), 6.92 - 6.86 (m, 2H), 6.59 (d, J = 18.2 Hz, 2H), 5.27 (d, J = 1.9 Hz, 2H), 5.14 (s, 2H), 4.74 (s, 2H), 3.80 (s, 3H), 3.53 (s, 3H), 2.14 (s , 3H), 1.50 (s, 9H). ESI-MS m/z 660.3 (M+H)+

Figure pat00210
Figure pat00210

화합물 61. methyl 2-(5-(((3S,4S)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-hydroxychroman-3-yl)methyl)-2-fluorophenoxy)acetateCompound 61. methyl 2-(5-(((3S,4S)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(4-fluoro-2-methylphenyl)-4-hydroxychroman-3-yl)methyl)-2-fluorophenoxy)acetate

화합물 52 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 대신 메틸 2-(5-(((3E)-6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8- (4-플루오로-2-메틸페닐)-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 (1000 mg, 1.515 mmol)를 사용하여 화합물 61 (435 mg, 43% 수율)을 제조하였다.Methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate from step 3 of the synthesis of compound 52 Methyl 2-(5-(((3E)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazole-1- yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate (1000 mg, 1.515 mmol) Compound 61 (435 mg, 43% yield) was prepared.

1H NMR (400 MHz, CDCl3) δ 7.15 (dd, J = 6.0, 2.3 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.98 - 6.92 (m, 3H), 6.91 - 6.84 (m, 2H), 6.55 (dd, J = 18.4, 2.5 Hz, 2H), 4.97 (d, J = 2.7 Hz, 2H), 4.71 (s, 2H), 4.54 - 4.47 (m, 1H), 4.07 - 3.94 (m, 2H), 3.81 (s, 3H), 3.49 (d, J = 3.0 Hz, 3H), 2.97 (s, 1H), 2.84 (dd, J = 13.4, 8.8 Hz, 1H), 2.57 (dd, J = 13.7, 7.2 Hz, 1H), 2.19 (s, 1H), 2.12 (s, 3H), 1.49 (s, 9H). ESI-MS m/z 664.3 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 7.15 (dd, J = 6.0, 2.3 Hz, 1H), 7.08 - 7.01 (m, 2H), 6.98 - 6.92 (m, 3H), 6.91 - 6.84 (m, 2H) , 6.55 (dd, J = 18.4, 2.5 Hz, 2H), 4.97 (d, J = 2.7 Hz, 2H), 4.71 (s, 2H), 4.54 - 4.47 (m, 1H), 4.07 - 3.94 (m, 2H) ), 3.81 (s, 3H), 3.49 (d, J = 3.0 Hz, 3H), 2.97 (s, 1H), 2.84 (dd, J = 13.4, 8.8 Hz, 1H), 2.57 (dd, J = 13.7, 7.2 Hz, 1H), 2.19 (s, 1H), 2.12 (s, 3H), 1.49 (s, 9H). ESI-MS m/z 664.3 (M+H)+

Figure pat00211
Figure pat00211

화합물 62. methyl (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetateCompound 62. methyl (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate

화합물 52 합성과정 단계 4에서 메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 메틸 2-(5-(((3S,4S)-6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-히드록시크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 (390 mg, 0.587 mmol)를 사용하여 화합물 62 (170 mg, 44% 수율)을 제조하였다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy from synthesis step 4 of compound 52 )Methyl 2-(5-(((3S,4S)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imino instead of acetate dazol-1-yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-hydroxychroman-3-yl)methyl)-2-fluorophenoxy)acetate (390 mg, 0.587 mmol ) was used to prepare compound 62 (170 mg, 44% yield).

1H NMR (400 MHz, CDCl3) δ 7.85 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.11 - 7.07 (m, 1H), 7.07 - 6.91 (m, 3H), 6.82 - 6.76 (m, 2H), 6.64 - 6.45 (m, 2H), 5.10 (s, 2H), 4.69 (s, 2H), 4.35 (dd, J = 11.6, 4.4 Hz, 1H), 4.18 - 4.08 (m, 1H), 3.79 (s, 3H), 3.51 (s, 3H), 3.20 (dd, J = 14.1, 4.7 Hz, 1H), 2.89 (dt, J = 9.1, 4.5 Hz, 1H), 2.70 (dd, J = 14.1, 9.7 Hz, 1H), 2.13 (s, 3H), 1.49 (s, 9H). ESI-MS m/z 662.8 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.85 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.11 - 7.07 (m, 1H), 7.07 - 6.91 (m, 3H), 6.82 - 6.76 (m, 2H), 6.64 - 6.45 (m, 2H), 5.10 (s, 2H), 4.69 (s, 2H), 4.35 (dd, J = 11.6, 4.4 Hz, 1H), 4.18 - 4.08 (m, 1H), 3.79 (s, 3H), 3.51 (s, 3H), 3.20 (dd, J = 14.1, 4.7 Hz, 1H), 2.89 (dt, J = 9.1, 4.5 Hz, 1H), 2.70 (dd, J = 14.1, 9.7 Hz, 1H), 2.13 (s, 3H), 1.49 (s, 9H). ESI-MS m/z 662.8 (M+H)+

Figure pat00212
Figure pat00212

화합물 63. (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acidCompound 63. (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl )-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid

화합물 41 합성과정에서 화합물 40 대신 메틸 (S,Z)-2-(5-((6-((2-((tert-부톡시카르보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)- 8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 (164 mg, 0.247 mmol)를 사용하여 화합물 63 (144 mg, 90% 수율)을 제조하였다. During the synthesis of compound 41, methyl (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-di instead of compound 40 Hydro-1H-imidazol-1-yl) methyl) -8- (4-fluoro-2-methylphenyl) -4-oxochroman-3-yl) methyl) -2-fluorophenoxy) acetate (164 mg, 0.247 mmol) to prepare compound 63 (144 mg, 90% yield).

1H NMR (400 MHz, CD3OD) δ 7.91 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 8.4, 5.9 Hz, 1H), 7.07 - 7.01 (m, 2H), 6.96 (dd, J = 8.5, 2.8 Hz, 1H), 6.87 (dd, J = 8.1, 2.0 Hz, 1H), 6.80 (ddd, J = 8.5, 4.3, 2.1 Hz, 1H), 5.35 (s, 2H), 4.62 (s, 2H), 4.42 (dd, J = 11.8, 4.5 Hz, 1H), 4.20 (dd, J = 11.7, 8.7 Hz, 1H), 3.76 (s, 3H), 3.13 (dd, J = 13.8, 5.3 Hz, 1H), 3.02 (td, J = 8.8, 4.4 Hz, 1H), 2.80 (dd, J = 13.9, 8.5 Hz, 1H), 2.14 (s, 3H), 1.44 (s, 9H). ESI-MS m/z 648.8 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 7.91 (d, J = 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.33 ( d, J = 2.4 Hz, 1H), 7.13 (dd, J = 8.4, 5.9 Hz, 1H), 7.07 - 7.01 (m, 2H), 6.96 (dd, J = 8.5, 2.8 Hz, 1H), 6.87 (dd , J = 8.1, 2.0 Hz, 1H), 6.80 (ddd, J = 8.5, 4.3, 2.1 Hz, 1H), 5.35 (s, 2H), 4.62 (s, 2H), 4.42 (dd, J = 11.8, 4.5 Hz, 1H), 4.20 (dd, J = 11.7, 8.7 Hz, 1H), 3.76 (s, 3H), 3.13 (dd, J = 13.8, 5.3 Hz, 1H), 3.02 (td, J = 8.8, 4.4 Hz) , 1H), 2.80 (dd, J = 13.9, 8.5 Hz, 1H), 2.14 (s, 3H), 1.44 (s, 9H). ESI-MS m/z 648.8 (M+H)+

Figure pat00213
Figure pat00213

화합물 64. tert-butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)azetidin-3-yl)carbamateCompound 64. tert-butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)azetidin-3-yl)carbamate

Figure pat00214
Figure pat00214

단계 1) 8-bromo-2,3-dihydro-6-((2-methyl-1H-imidazol-1-yl)methyl)chromen-4-one의 제조Step 1) Preparation of 8-bromo-2,3-dihydro-6-((2-methyl-1H-imidazol-1-yl)methyl)chromen-4-one

8-브로모-6-(브로모메틸)-2,3-디히드로크로멘-4-온 (20 g, 62.5 mmol, 1 eq.) 의 DMF (100 mL) 용액에 2-메틸이미다졸 (10.26 g, 125.0 mmol, 2 eq.)을 넣고 50 °C에서 3.5 h 교반하고 상온으로 냉각한다. 반응혼합물에 CH2Cl2 (700 mL)을 넣고 물로 세척, MgSO4 건조 및 감압농축한다. 농축액을 컬럼 크로마토그래피 ( MC:MeOH=20:1)로 정제하여 목적물 (12.42 g, 61.9%)을 얻는다.To a solution of 8-bromo-6-(bromomethyl)-2,3-dihydrochromen-4-one (20 g, 62.5 mmol, 1 eq.) in DMF (100 mL) 2-methylimidazole (10.26 g, 125.0 mmol, 2 eq.) was stirred at 50 °C for 3.5 h and cooled to room temperature. Add CH 2 Cl 2 (700 mL) to the reaction mixture, wash with water, dry MgSO 4 and concentrate under reduced pressure. The concentrate was purified by column chromatography (MC:MeOH=20:1) to obtain the target product (12.42 g, 61.9%).

Figure pat00215
Figure pat00215

단계 2) 8-(3-(trifluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 2) Preparation of 8-(3-(trifluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one

화합물 40 합성과정에서 화합물 39 대신 8-브로모-2,3-디하이드로-6-((2-메틸-1H-이미다졸-1-일)메틸)크로멘-4-온 (5 g, 15.57 mmol, 1 eq.), 3-(트리플루오로메틸)-1-메틸-1H-피라졸-4-일-4-보론산 (3.6 g, 18.68 mmol, 1.2 eq.)를 사용하여 생성물 (4.13 g, 68% 수율)을 제조하였다.8-bromo-2,3-dihydro-6-((2-methyl-1H-imidazol-1-yl)methyl)chromen-4-one (5 g, 15.57 mmol, 1 eq.), product (4.13 g, 68% yield) was prepared.

Figure pat00216
Figure pat00216

단계 3) methyl 2-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-6-methylpyrimidine-4-carboxylate의 제조Step 3) Preparation of methyl 2-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-6-methylpyrimidine-4-carboxylate

화합물 65 합성과정 단계 1에서 메틸 6-클로로-4-메틸피콜리네이트 대신 메틸 2-클로로-6-메틸피리미딘-4-카르복실레이트 (5000 mg, 26.938 mmol) 와 tert-부틸 아제티딘-3-일(메틸)카바메이트 (5519 mg, 29.632 mmol)를 사용하여 생성물 (4.13 g, 68% 수율)을 제조하였다.In step 1 of the synthesis of compound 65, methyl 2-chloro-6-methylpyrimidine-4-carboxylate (5000 mg, 26.938 mmol) and tert-butyl azetidine-3 were used instead of methyl 6-chloro-4-methylpicolinate. The product (4.13 g, 68% yield) was prepared using -yl(methyl)carbamate (5519 mg, 29.632 mmol).

Figure pat00217
Figure pat00217

단계 4) tert-butyl (1-(4-formyl-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamate의 제조Step 4) Preparation of tert-butyl (1-(4-formyl-6-methylpyrimidin-2-yl)azetidin-3-yl)(methyl)carbamate

메틸 2-(3-((tert-부톡시카르보닐)(메틸)아미노)아제티딘-1-일)-6-메틸피리미딘-4-카르복실레이트 (2 g, 8.4 mmol)의 건조 CH2Cl2 (17 mL) 용액을 -78 °C로 냉각한다. DIBAL-H을 적가하고 0 °C에서 3 h 교반한다. 반응혼합물을 -78 °C에서 K·Na·tartrate/H2O로 ??칭하고 슬러리를 상온에서 1 h 교반한다. 반응혼합물을 ethyl acetate (x3)로 세척, Na2SO4로 건조, 감압농축한다. 농축물을 컬럼 크로마토그래피 (ethyl acetate : n-hexane = 1:2)로 정제하여 목적물 (1.2 g, 66%)을 얻는다. 1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 6.93 (s, 1H), 4.40 (t, J = 8.9 Hz, 2H), 4.22 (dd, J = 9.9, 5.6 Hz, 2H), 2.97 (s, 3H), 2.47 (s, 3H), 1.48 (s, 9H).dry CH 2 of methyl 2-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-6-methylpyrimidine-4-carboxylate (2 g, 8.4 mmol) Cool the Cl 2 (17 mL) solution to -78 °C. Add DIBAL-H dropwise and stir for 3 h at 0 °C. The reaction mixture is quenched with K·Na·tartrate/H 2 O at -78 °C and the slurry is stirred at room temperature for 1 h. The reaction mixture was washed with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The concentrate was purified by column chromatography (ethyl acetate : n-hexane = 1:2) to obtain the target product (1.2 g, 66%). 1H NMR (400 MHz, CDCl 3 ) δ 9.84 (s, 1H), 6.93 (s, 1H), 4.40 (t, J = 8.9 Hz, 2H), 4.22 (dd, J = 9.9, 5.6 Hz, 2H) , 2.97 (s, 3H), 2.47 (s, 3H), 1.48 (s, 9H).

Figure pat00218
Figure pat00218

단계 5) tert-butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)azetidin-3-yl)carbamate의 제조Step 5) tert-butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 Preparation of -(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)azetidin-3-yl)carbamate

화합물 60 합성과정에서 화합물 59 대신 8-(3-(트리플루오로메틸)-1-메틸-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온 (300 mg, 0.768 mmol), tert-부틸 tert-부틸 (1-(4-포르밀-6-메틸피리미딘-2-일)아제티딘-3-일)(메틸)카바메이트 (237 mg, 0.774 mmol)를 사용하여 화합물 64 (105 mg, 15% 수율)을 제조하였다.8-(3-(trifluoromethyl)-1-methyl-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl) instead of compound 59 during the synthesis of compound 60 )methyl)chroman-4-one (300 mg, 0.768 mmol), tert-butyl tert-butyl (1-(4-formyl-6-methylpyrimidin-2-yl)azetidin-3-yl)( Compound 64 (105 mg, 15% yield) was prepared using methyl)carbamate (237 mg, 0.774 mmol).

1H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 1.0 Hz, 1H), 7.53 (s, 1H), 7.23 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 1.4 Hz, 1H), 6.87 (d, J = 1.4 Hz, 1H), 6.48 (s, 1H), 5.15 (s, 2H), 5.10 - 4.88 (m, 1H), 4.26 (t, J = 8.8 Hz, 2H), 4.09 - 4.04 (m, 2H), 4.02 (s, 3H), 3.71 (s, 2H), 2.93 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H), 1.44 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J = 2.3 Hz, 1H), 7.92 (d, J = 1.0 Hz, 1H), 7.53 (s, 1H), 7.23 (d, J = 2.3 Hz , 1H), 6.98 (d, J = 1.4 Hz, 1H), 6.87 (d, J = 1.4 Hz, 1H), 6.48 (s, 1H), 5.15 (s, 2H), 5.10 - 4.88 (m, 1H) , 4.26 (t, J = 8.8 Hz, 2H), 4.09 - 4.04 (m, 2H), 4.02 (s, 3H), 3.71 (s, 2H), 2.93 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H), 1.44 (s, 9H).

Figure pat00219
Figure pat00219

화합물 65. tert-butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyridin-2-yl)azetidin-3-yl)carbamateCompound 65. tert-butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyridin-2-yl)azetidin-3-yl)carbamate

Figure pat00220
Figure pat00220

단계 1) methyl 6-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-4-methylpicolinate의 제조Step 1) Preparation of methyl 6-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-4-methylpicolinate

메틸 6-클로로-4-메틸피콜리네이트 (5000 mg, 26.938 mmol)와 tert-부틸 아제티딘-3-일(메틸)카바메이트 (5519 mg, 29.632 mmol)의 NMP (70 mL) 용액에 K2CO3 (11.169 g, 80.814 mmol)를 넣고 100°C에서 1일 교반한다. 반응혼합물을 EtOAc (100 mL)를 넣고 물 (5x10 mL)로 세척한다음 유기층을 Na2SO4 건조 및 감압농축한다. 농축물을 컬럼 크로마토그래피 (n-heptane : EtOAc/ 10% to 40%)을 정제하고 목적물 (980 mg, 7.7%)을 얻는다.K2CO3 ( 11.169 g, 80.814 mmol) and stirred at 100 ° C for 1 day. EtOAc (100 mL) was added to the reaction mixture, washed with water (5x10 mL), and the organic layer was dried with Na 2 SO 4 and concentrated under reduced pressure. The concentrate was purified by column chromatography (n-heptane : EtOAc/ 10% to 40%) to obtain the target product (980 mg, 7.7%).

Figure pat00221
Figure pat00221

단계 2) tert-butyl (1-(6-(hydroxymethyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate의 제조Step 2) Preparation of tert-butyl (1-(6-(hydroxymethyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate

Methyl 6-(3-((tert-부톡시카르보닐)(메틸)아미노)아제티딘-1-일)-4-메틸피콜리네이트 (980 mg, 2.92 mmol)의 건조 CH2Cl2 (10 mL) 용액을 -78 °C로 냉각한다. DIBAL-H을 적가하고 0 °C에서 3 h 교반한다. 반응혼합물을 -78 °C에서 K·Na·tartrate/H2O로 ??칭하고 슬러리를 상온에서 1 h 교반한다. 반응혼합물을 ethyl acetate (x3)로 세척, Na2SO4로 건조, 감압농축한다. 농축물을 컬럼 크로마토그래피 (ethyl acetate : n-hexane = 1:2)로 정제하여 목적물 (800 mg, 89%)을 얻는다.Methyl 6-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-4-methylpicolinate (980 mg, 2.92 mmol) in dry CH 2 Cl 2 (10 mL) ) to cool the solution to -78 °C. Add DIBAL-H dropwise and stir for 3 h at 0 °C. The reaction mixture is quenched with K·Na·tartrate/H 2 O at -78 °C and the slurry is stirred at room temperature for 1 h. The reaction mixture was washed with ethyl acetate (x3), dried over Na 2 SO 4 and concentrated under reduced pressure. The concentrate was purified by column chromatography (ethyl acetate : n-hexane = 1:2) to obtain the target product (800 mg, 89%).

Figure pat00222
Figure pat00222

단계 3) tert-butyl (1-(6-formyl-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate의 제조Step 3) Preparation of tert-butyl (1-(6-formyl-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate

tert-부틸 (1-(6-(히드록시메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카르바메이트 (800 mg, 2.602 mmol)와 Molecular sieves 4 Å (100 mg)의 CH2Cl2 (10 mL) 용액을 10 min 동안 교반한다. 그리고 N-메틸모르폴린 N-옥사이드 (NMO, 362 mg, 3.903 mmol)와 테트라프로필암모늄 퍼루테네이트 (TPAP, 91 mg, 0.26 mmol)를 0°C에서 넣고 상온에서 3 h 교반한다. 검은색 혼합물을 셀라이트에서 여과하고 diethyl ether로 세척한다. 감압농축한다음 농축물을 MPLC (ethyl acetate:n-heptane, 20%)로 정제하여 목적물 (386 mg, 49%)을 얻는다.tert-butyl (1-(6-(hydroxymethyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate (800 mg, 2.602 mmol) and 100 mg) of CH 2 Cl 2 (10 mL) solution is stirred for 10 min. Then, N-methylmorpholine N-oxide (NMO, 362 mg, 3.903 mmol) and tetrapropylammonium perruthenate (TPAP, 91 mg, 0.26 mmol) were added at 0 °C and stirred at room temperature for 3 h. The black mixture was filtered through celite and washed with diethyl ether. After concentration under reduced pressure, the concentrate was purified by MPLC (ethyl acetate:n-heptane, 20%) to obtain the target product (386 mg, 49%).

Figure pat00223
Figure pat00223

단계 4) tert-butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyridin-2-yl)azetidin-3-yl)carbamate의 제조Step 4) tert-butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 Preparation of -(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyridin-2-yl)azetidin-3-yl)carbamate

화합물 60 합성과정에서 화합물 59 대신 6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온 (12 mg, 0.030 mmol)과 tert-부틸 (1-(6-포르밀-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카르바메이트 (9.4 mg, 0.030 mmol) 를 사용하여 생성물 65 (16 mg, 80% 수율)을 제조하였다.6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4 instead of compound 59 during the synthesis of compound 60 -yl)chroman-4-one (12 mg, 0.030 mmol) and tert-butyl (1-(6-formyl-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carba Mate (9.4 mg, 0.030 mmol) was used to prepare product 65 (16 mg, 80% yield).

1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 2.1 Hz, 1H), 7.48 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.98 (d, J = 1.4 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 6.76 (d, J = 1.1 Hz, 1H), 6.15 (t, J = 1.1 Hz, 1H), 5.98 (d, J = 2.1 Hz, 2H), 5.06 (s, 3H), 4.26 (q, J = 8.1 Hz, 2H), 4.04 (dd, J = 8.7, 5.7 Hz, 2H), 4.01 (s, 3H), 2.97 (d, J = 1.4 Hz, 3H), 2.41 (s, 3H), 2.30 (s, 3H), 1.49 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 2.1 Hz, 1H), 7.48 (s, 1H), 7.12 (d, J = 2.4 Hz , 1H), 6.98 (d, J = 1.4 Hz, 1H), 6.89 (d, J = 1.4 Hz, 1H), 6.76 (d, J = 1.1 Hz, 1H), 6.15 (t, J = 1.1 Hz, 1H) ), 5.98 (d, J = 2.1 Hz, 2H), 5.06 (s, 3H), 4.26 (q, J = 8.1 Hz, 2H), 4.04 (dd, J = 8.7, 5.7 Hz, 2H), 4.01 (s , 3H), 2.97 (d, J = 1.4 Hz, 3H), 2.41 (s, 3H), 2.30 (s, 3H), 1.49 (s, 9H).

Figure pat00224
Figure pat00224

화합물 66. tert-butyl (1-(6-(((3S,4S)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamateCompound 66. tert-butyl (1-(6-(((3S,4S)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl- 3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate

화합물 52 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 대신 화합물 65 (100 mg, 0.14 mmol)를 사용하여 화합물 66 (86 mg, 90% 수율)을 제조하였다.Methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate from step 3 of the synthesis of compound 52 Instead, compound 66 (86 mg, 90% yield) was prepared using compound 65 (100 mg, 0.14 mmol).

1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.89 (t, J = 1.8 Hz, 2H), 6.41 (s, 1H), 6.06 (s, 1H), 5.21 - 4.89 (m, 3H), 4.50 (d, J = 3.8 Hz, 1H), 4.28 (t, J = 8.2 Hz, 2H), 4.13 - 4.03 (m, 4H), 4.00 (s, 3H), 3.00 (s, 3H), 2.82 - 2.66 (m, 3H), 2.50 (s, 3H), 2.33 (s, 1H), 2.26 (s, 3H), 1.51 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.49 (s, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.03 (d, J = 1.6 Hz, 1H), 6.89 (t, J = 1.8 Hz , 2H), 6.41 (s, 1H), 6.06 (s, 1H), 5.21 - 4.89 (m, 3H), 4.50 (d, J = 3.8 Hz, 1H), 4.28 (t, J = 8.2 Hz, 2H) , 4.13 - 4.03 (m, 4H), 4.00 (s, 3H), 3.00 (s, 3H), 2.82 - 2.66 (m, 3H), 2.50 (s, 3H), 2.33 (s, 1H), 2.26 (s , 3H), 1.51 (s, 9H).

Figure pat00225
Figure pat00225

화합물 67. tert-butyl (S)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamateCompound 67. tert-butyl (S)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamate

화합물 52 합성과정 단계 4에서 메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 화합물 66 (86 mg, 0.126 mmol)을 사용하여 화합물 67 (5.2 mg, 6% 수율)을 제조하였다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy from synthesis step 4 of compound 52 ) Compound 67 (5.2 mg, 6% yield) was prepared using compound 66 (86 mg, 0.126 mmol) instead of acetate.

1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 2.3 Hz, 1H), 7.59 (s, 1H), 7.24 - 7.15 (m, 2H), 6.99 (s, 1H), 6.43 (s, 1H), 6.03 (s, 1H), 5.14 (s, 2H), 4.92 (s, 1H), 4.71 (dd, J = 11.6, 5.1 Hz, 1H), 4.35 (t, J = 11.2 Hz, 1H), 4.25 (d, J = 7.8 Hz, 2H), 4.02 (s, 5H), 3.48 (ddd, J = 15.8, 8.5, 3.4 Hz, 1H), 3.30 (dd, J = 14.6, 4.9 Hz, 1H), 2.95 (s, 3H), 2.84 (s, 1H), 2.68 (s, 3H), 2.26 (s, 3H), 1.48 (s, 9H). 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 2.3 Hz, 1H), 7.59 (s, 1H), 7.24 - 7.15 (m, 2H), 6.99 (s, 1H), 6.43 (s, 1H), 6.03 (s, 1H), 5.14 (s, 2H), 4.92 (s, 1H), 4.71 (dd, J = 11.6, 5.1 Hz, 1H), 4.35 (t, J = 11.2 Hz, 1H), 4.25 (d, J = 7.8 Hz, 2H), 4.02 (s, 5H), 3.48 (ddd, J = 15.8, 8.5, 3.4 Hz, 1H), 3.30 (dd, J = 14.6, 4.9 Hz, 1H), 2.95 (s, 3H), 2.84 (s, 1H), 2.68 (s, 3H), 2.26 (s, 3H), 1.48 (s, 9H).

Figure pat00226
Figure pat00226

화합물 68. (S)-6-((2-methyl-1H-imidazol-1-yl)methyl)-3-((6-methyl-2-(3-(methylamino)azetidin-1-yl)pyrimidin-4-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one hydrochlorideCompound 68. (S)-6-((2-methyl-1H-imidazol-1-yl)methyl)-3-((6-methyl-2-(3-(methylamino)azetidin-1-yl)pyrimidin- 4-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one hydrochloride

화합물 67 (5.2 mg, 7.6 umol)의 CH2Cl2 (3 mL) 용액에 0℃에서 4N-HCl in dioxane (excess)을 넣고 상온에서 교반한다. 반응이 종료되면 용매를 제거하고 염으로서 화합물 68 (4.5 mg, 95%)을 얻는다. Add 4N-HCl in dioxane (excess) to a solution of Compound 67 (5.2 mg, 7.6 umol) in CH 2 Cl 2 (3 mL) at 0°C and stir at room temperature. Upon completion of the reaction, the solvent was removed to obtain compound 68 (4.5 mg, 95%) as a salt.

1H NMR (400 MHz, CD3OD) δ 7.95 - 7.85 (m, 2H), 7.57 - 7.46 (m, 3H), 7.01 - 6.64 (m, 2H), 5.42 (s, 2H), 4.74 - 4.58 (m, 2H), 4.50 (d, J = 9.6 Hz, 1H), 4.35 (dd, J = 23.3, 12.0 Hz, 2H), 4.17 (t, J = 8.7 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.99 (s, 3H), 3.80 - 3.71 (m, 2H), 3.16 (td, J = 12.1, 3.6 Hz, 1H), 2.91 (s, 3H), 2.65 (d, J = 2.1 Hz, 3H), 2.43 (d, J = 4.7 Hz, 3H). 1 H NMR (400 MHz, CD 3 OD) δ 7.95 - 7.85 (m, 2H), 7.57 - 7.46 (m, 3H), 7.01 - 6.64 (m, 2H), 5.42 (s, 2H), 4.74 - 4.58 ( m, 2H), 4.50 (d, J = 9.6 Hz, 1H), 4.35 (dd, J = 23.3, 12.0 Hz, 2H), 4.17 (t, J = 8.7 Hz, 1H), 4.12 - 4.01 (m, 2H) ), 3.99 (s, 3H), 3.80 - 3.71 (m, 2H), 3.16 (td, J = 12.1, 3.6 Hz, 1H), 2.91 (s, 3H), 2.65 (d, J = 2.1 Hz, 3H) , 2.43 (d, J = 4.7 Hz, 3H).

Figure pat00227
Figure pat00227

화합물 69. tert-butyl methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamateCompound 69. tert-butyl methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl) -1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamate

화합물 64(50 mg, 0.07 mmol)의 ACN용액에 DBU (2 eq)와 HCO2H (5 eq)의 MeCN 용액을 0℃에서 넣고 가스제거한 다음 상온에서 1h 교반한다. 반응혼합물에 RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.1 eq)을 넣고 50℃에서 17시간 교반한후 반응을 상온에서 포화 수성 NH4Cl 용액으로 ??칭하였다. 디에틸 에테르로 추출한 후, 유기층을 추가의 포화 NaHCO3수용액으로 세척하고, MgSO4로 건조시키고, 감압하에 농축시켰다. 잔류물을 컬럼 크로마토그래피로 정제하여 화합물 69 (5.0 mg, 10%)을 얻었다.A MeCN solution of DBU (2 eq) and HCO 2 H (5 eq) was added to an ACN solution of compound 64 (50 mg, 0.07 mmol) at 0 °C, degassed, and stirred at room temperature for 1 h. After adding RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.1 eq) to the reaction mixture and stirring at 50°C for 17 hours, the reaction was quenched with a saturated aqueous NH 4 Cl solution at room temperature. After extraction with diethyl ether, the organic layer was washed with more saturated aqueous NaHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. The residue was purified by column chromatography to give compound 69 (5.0 mg, 10%).

1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 1.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 6.41 (s, 1H), 6.09 (s, 1H), 5.33 (s, 2H), 4.78 (s, 1H), 4.50 (dd, J = 11.4, 5.1 Hz, 1H), 4.37 (t, J = 10.9 Hz, 1H), 4.07 - 3.99 (m, 2H), 3.84 (ddd, J = 9.3, 5.9, 3.8 Hz, 2H), 3.41 (d, J = 7.0 Hz, 1H), 3.06 (dd, J = 14.8, 4.2 Hz, 1H), 2.82 (s, 3H), 2.71 (dd, J = 14.9, 8.9 Hz, 1H), 2.18 (s, 3H), 1.24 (s, 3H). ESI-MS m/z 680.2 (M+H)+ 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 1.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 1.8 Hz, 1H), 7.43 ( d, J = 2.4 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 6.41 (s, 1H), 6.09 (s, 1H), 5.33 (s, 2H), 4.78 (s, 1H), 4.50 (dd, J = 11.4, 5.1 Hz, 1H), 4.37 (t, J = 10.9 Hz, 1H), 4.07 - 3.99 (m, 2H), 3.84 (ddd, J = 9.3, 5.9, 3.8 Hz, 2H) , 3.41 (d, J = 7.0 Hz, 1H), 3.06 (dd, J = 14.8, 4.2 Hz, 1H), 2.82 (s, 3H), 2.71 (dd, J = 14.9, 8.9 Hz, 1H), 2.18 ( s, 3H), 1.24 (s, 3H). ESI-MS m/z 680.2 (M+H)+

Figure pat00228
Figure pat00228

화합물 70. tert-butyl (1-(6-(((3R,4R)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamateCompound 70. tert-butyl (1-(6-(((3R,4R)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl- 3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate

화합물 52 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 대신 화합물 65 및 RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.1 eq)를 사용하여 화합물 70 (210 mg, 78% 수율)을 제조하였다.Methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate from step 3 of the synthesis of compound 52 Instead, compound 70 (210 mg, 78% yield) was prepared using compound 65 and RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.1 eq).

1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 1.0 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 1.5 Hz, 1H), 6.86 (t, J = 1.8 Hz, 2H), 6.38 (d, J = 1.2 Hz, 1H), 6.03 (t, J = 1.0 Hz, 1H), 4.99 (d, J = 41.0 Hz, 3H), 4.47 (d, J = 3.8 Hz, 1H), 4.26 (t, J = 8.2 Hz, 2H), 4.10 - 3.99 (m, 4H), 3.97 (s, 3H), 2.97 (s, 3H), 2.79 - 2.64 (m, 2H), 2.46 (s, 3H), 2.31 (td, J = 11.0, 10.1, 4.1 Hz, 1H), 2.24 (s, 3H), 1.48 (s, 9H). ESI-MS m/z 682 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J = 1.0 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 1.5 Hz, 1H), 6.86 (t , J = 1.8 Hz, 2H), 6.38 (d, J = 1.2 Hz, 1H), 6.03 (t, J = 1.0 Hz, 1H), 4.99 (d, J = 41.0 Hz, 3H), 4.47 (d, J = 3.8 Hz, 1H), 4.26 (t, J = 8.2 Hz, 2H), 4.10 - 3.99 (m, 4H), 3.97 (s, 3H), 2.97 (s, 3H), 2.79 - 2.64 (m, 2H) , 2.46 (s, 3H), 2.31 (td, J = 11.0, 10.1, 4.1 Hz, 1H), 2.24 (s, 3H), 1.48 (s, 9H). ESI-MS m/z 682 (M+H)+

Figure pat00229
Figure pat00229

화합물 71. tert-butyl (R)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamateCompound 71. tert-butyl (R)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamate

화합물 52 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 대신 화합물 70 (164 mg, 0.4 mmol) 사용하여 화합물 71 (35 mg, 13% 수율)을 제조하였다.Methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate from step 3 of the synthesis of compound 52 Compound 71 (35 mg, 13% yield) was prepared using compound 70 (164 mg, 0.4 mmol) instead.

1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 1.1 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.01 (d, J = 1.5 Hz, 1H), 6.87 (d, J = 1.5 Hz, 1H), 6.38 (s, 1H), 5.98 (s, 1H), 5.04 (s, 3H), 4.59 (dd, J = 11.4, 5.1 Hz, 1H), 4.29 (t, J = 11.2 Hz, 1H), 4.17 - 4.11 (m, 2H), 3.98 (s, 3H), 3.92 (ddd, J = 8.4, 5.8, 2.0 Hz, 2H), 3.45 - 3.35 (m, 1H), 3.29 (dd, J = 14.7, 4.2 Hz, 1H), 2.92 (s, 3H), 2.69 (dd, J = 14.8, 9.1 Hz, 1H), 2.44 (s, 3H), 2.21 (s, 3H), 1.45 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.77 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 1.1 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.01 (d , J = 1.5 Hz, 1H), 6.87 (d, J = 1.5 Hz, 1H), 6.38 (s, 1H), 5.98 (s, 1H), 5.04 (s, 3H), 4.59 (dd, J = 11.4, 5.1 Hz, 1H), 4.29 (t, J = 11.2 Hz, 1H), 4.17 - 4.11 (m, 2H), 3.98 (s, 3H), 3.92 (ddd, J = 8.4, 5.8, 2.0 Hz, 2H), 3.45 - 3.35 (m, 1H), 3.29 (dd, J = 14.7, 4.2 Hz, 1H), 2.92 (s, 3H), 2.69 (dd, J = 14.8, 9.1 Hz, 1H), 2.44 (s, 3H) , 2.21 (s, 3H), 1.45 (s, 9H).

Figure pat00230
Figure pat00230

화합물 72. (R)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3-((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochlorideCompound 72. (R)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-3- ((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochloride

화합물 68 합성과정에서 화합물 67 대신 화합물 71 (27 mg, 0.039 mmol)을 사용하여 화합물 72 (24 mg, 99% 수율)을 제조하였다.Compound 72 (24 mg, 99% yield) was prepared by using compound 71 (27 mg, 0.039 mmol) instead of compound 67 during the synthesis of compound 68.

1H NMR (400 MHz, CD3OD) δ 7.95 - 7.85 (m, 2H), 7.57 - 7.46 (m, 3H), 7.01 - 6.64 (m, 2H), 5.42 (s, 2H), 4.74 - 4.58 (m, 2H), 4.50 (d, J = 9.6 Hz, 1H), 4.35 (dd, J = 23.3, 12.0 Hz, 2H), 4.17 (t, J = 8.7 Hz, 1H), 4.12 - 4.01 (m, 2H), 3.99 (s, 3H), 3.80 - 3.71 (m, 2H), 3.16 (td, J = 12.1, 3.6 Hz, 1H), 2.91 (s, 3H), 2.65 (d, J = 2.1 Hz, 3H), 2.43 (d, J = 4.7 Hz, 3H). 1 H NMR (400 MHz, CD 3 OD) δ 7.95 - 7.85 (m, 2H), 7.57 - 7.46 (m, 3H), 7.01 - 6.64 (m, 2H), 5.42 (s, 2H), 4.74 - 4.58 ( m, 2H), 4.50 (d, J = 9.6 Hz, 1H), 4.35 (dd, J = 23.3, 12.0 Hz, 2H), 4.17 (t, J = 8.7 Hz, 1H), 4.12 - 4.01 (m, 2H) ), 3.99 (s, 3H), 3.80 - 3.71 (m, 2H), 3.16 (td, J = 12.1, 3.6 Hz, 1H), 2.91 (s, 3H), 2.65 (d, J = 2.1 Hz, 3H) , 2.43 (d, J = 4.7 Hz, 3H).

Figure pat00231
Figure pat00231

화합물 73. (S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-oneCompound 73. (S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3- (trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one

Figure pat00232
Figure pat00232

단계 1) (E)-3-((4-methoxypyridin-2-yl)methylene)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one의 제조Step 1) (E)-3-((4-methoxypyridin-2-yl)methylene)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3- Preparation of (trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one

화합물 60 합성과정에서 화합물 59 대신 6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온 (500 mg, 1.28 mmol), 4-메톡시피콜린알데히드 (210 mg, 1.53 mmol) 사용하여 생성물 (142 mg, 22% 수율)을 제조하였다.6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazole-4 instead of compound 59 during the synthesis of compound 60 The product (142 mg, 22% yield) was prepared using -yl)chroman-4-one (500 mg, 1.28 mmol) and 4-methoxypicolinaldehyde (210 mg, 1.53 mmol).

Figure pat00233
Figure pat00233

단계 2) (3S,4S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-ol의 제조Step 2) (3S,4S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl- Preparation of 3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-ol

화합물 52 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 대신 (E)-3-((4-메톡시피리딘-2-일)메틸렌)-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온 (137 mg, 0.268 mmol)을 사용하여 생성물 (35 mg, 25% 수율)을 제조하였다.Methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate from step 3 of the synthesis of compound 52 Instead of (E)-3-((4-methoxypyridin-2-yl)methylene)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 The product (35 mg, 25% yield) was prepared using -(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one (137 mg, 0.268 mmol).

Figure pat00234
Figure pat00234

단계 3) (S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one의 제조Step 3) (S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3- Preparation of (trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one

화합물 52 합성과정 단계 4에서 메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 (3S,4S)-3-((4-메톡시피리딘-2-일)메틸)-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-올 (35 mg, 0.068 mmol)를 사용하여 화합물 73 (18.5 mg, 53% 수율)을 제조하였다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy from synthesis step 4 of compound 52 )acetate instead of (3S,4S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1 Compound 73 (18.5 mg, 53% yield) was prepared using -methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-ol (35 mg, 0.068 mmol) .

1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 5.8 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.49 (s, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 1.5 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 5.8, 2.5 Hz, 1H), 5.02 (s, 2H), 4.56 (dd, J = 11.5, 4.7 Hz, 1H), 4.24 (dd, J = 11.5, 10.2 Hz, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 3.45 - 3.35 (m, 2H), 2.85 - 2.73 (m, 1H), 2.39 (s, 3H). ESI-MS m/z 512.1 (M+H)+ 1H NMR (400 MHz, CDCl3) δ 8.32 (d, J = 5.8 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.49 (s, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 1.5 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 6.74 (d, J = 2.5 Hz, 1H), 6.68 (dd, J = 5.8, 2.5 Hz, 1H), 5.02 (s, 2H), 4.56 (dd, J = 11.5, 4.7 Hz, 1H), 4.24 (dd, J = 11.5, 10.2 Hz, 1H), 3.96 (s, 3H), 3.83 (s, 3H) ), 3.45 - 3.35 (m, 2H), 2.85 - 2.73 (m, 1H), 2.39 (s, 3H). ESI-MS m/z 512.1 (M+H)+

Figure pat00235
Figure pat00235

화합물 74. tert-butyl (E)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)piperazine-1-carboxylateCompound 74. tert-butyl (E)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)piperazine-1-carboxylate

Figure pat00236
Figure pat00236

단계 1) methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpyrimidine-4-carboxylate의 제조Step 1) Preparation of methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-methylpyrimidine-4-carboxylate

메틸 2-클로로-6-메틸피리미딘-4-카르복실레이트 (5 g, 26.80 mmol), 1-Boc 피페라진 (4.75 g, 25.52 mmol)의 NMP (30 mL) 용액에 탄산 칼륨 (7 g, 51.04 mmol)을 넣어주고 80 ℃에서 overnight 교반한다음 상온으로 냉각하고 생성된 침전물을 여과하고 침전물을 헵탄에 교반하고 여과하여 목적물 (8 g, 89%)을 얻는다.To a solution of methyl 2-chloro-6-methylpyrimidine-4-carboxylate (5 g, 26.80 mmol), 1-Boc piperazine (4.75 g, 25.52 mmol) in NMP (30 mL) was added potassium carbonate (7 g, 51.04 mmol) was added thereto, stirred overnight at 80 °C, cooled to room temperature, and the resulting precipitate was filtered, and the precipitate was stirred in heptane and filtered to obtain the target product (8 g, 89%).

Figure pat00237
Figure pat00237

단계 2) tert-butyl 4-(4-(hydroxymethyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate의 제조Step 2) Preparation of tert-butyl 4-(4-(hydroxymethyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate

화합물 65 합성과정 단계 2에서 메틸 6-(3-((tert-부톡시카르보닐)(메틸)아미노)아제티딘-1-일)-4-메틸피콜리네이트 대신 메틸 2-(4-(tert-부톡시카르보닐)피페라진-1-일)-6-메틸피리미딘-4-카르복실레이트 (7 g, 22.89 mmol)를 사용하여 생성물 (4.6 g, 66% 수율)을 제조하였다.In step 2 of the synthesis of compound 65, methyl 2-(4-(tert The product (4.6 g, 66% yield) was prepared using -butoxycarbonyl)piperazin-1-yl)-6-methylpyrimidine-4-carboxylate (7 g, 22.89 mmol).

Figure pat00238
Figure pat00238

단계 3) tert-butyl 4-(4-formyl-6-methylpyrimidin-2-yl)piperazine-1-carboxylate의 제조Step 3) Preparation of tert-butyl 4-(4-formyl-6-methylpyrimidin-2-yl)piperazine-1-carboxylate

화합물 65 합성과정 단계 3에서 tert-부틸 (1-(6-(히드록시메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카르바메이트 대신 tert-부틸 4-(4-(히드록시메틸)-6-메틸피리미딘-2-일)피페라진-1-카르복실레이트 (4 g, 12.98 mmol)를 사용하여 생성물 (2 g, 50% 수율)을 제조하였다.In step 3 of the synthesis of compound 65, tert-butyl (1-(6-(hydroxymethyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate was replaced with tert-butyl 4- The product (2 g, 50% yield) was prepared using (4-(hydroxymethyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate (4 g, 12.98 mmol).

Figure pat00239
Figure pat00239

단계 4) tert-butyl (E)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)piperazine-1-carboxylate의 제조Step 4) tert-butyl (E)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( Preparation of trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)piperazine-1-carboxylate

화합물 73 합성과정 단계 1에서 4-메톡시피콜린알데히드 대신 tert-부틸 4-(4-포르밀-6-메틸피리미딘-2-일)피페라진-1-카르복실레이트 (600 mg, 1.959 mmol)를 사용하여 화합물 74 (400 mg, 45% 수율)을 제조하였다.tert-butyl 4-(4-formyl-6-methylpyrimidin-2-yl)piperazine-1-carboxylate (600 mg, 1.959 mmol) instead of 4-methoxypicolinaldehyde in step 1 of the synthesis of compound 73 was used to prepare compound 74 (400 mg, 45% yield).

1H NMR (400 MHz, CDCl3) δ 8.09 (dd, J = 2.0, 1.1 Hz, 1H), 7.92 (d, J = 1.0 Hz, 1H), 7.56 (d, J = 1.1 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.02 (d, J = 1.4 Hz, 1H), 6.90 (d, J = 1.4 Hz, 1H), 6.47 (s, 1H), 5.19 (s, 2H), 4.05 (s, 3H), 3.77 (t, J = 5.3 Hz, 4H), 3.72 (s, 2H), 3.46 (dd, J = 6.5, 4.0 Hz, 4H), 2.42 (s, 3H), 2.31 (s, 3H), 1.49 (s, 9H). ESI-MS m/z 679.3 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 8.09 (dd, J = 2.0, 1.1 Hz, 1H), 7.92 (d, J = 1.0 Hz, 1H), 7.56 (d, J = 1.1 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.02 (d, J = 1.4 Hz, 1H), 6.90 (d, J = 1.4 Hz, 1H), 6.47 (s, 1H), 5.19 (s, 2H), 4.05 (s, 3H), 3.77 (t, J = 5.3 Hz, 4H), 3.72 (s, 2H), 3.46 (dd, J = 6.5, 4.0 Hz, 4H), 2.42 (s, 3H), 2.31 (s, 3H), 1.49 (s, 9H). ESI-MS m/z 679.3 (M+H)+

Figure pat00240
Figure pat00240

화합물 75. tert-butyl 4-(4-(((3S,4S)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylateCompound 75. tert-butyl 4-(4-(((3S,4S)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate

화합물 52 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 대신 화합물 74 (200 mg, 0.294 mmol)를 사용하여 화합물 75 (38.5 mg, 19% 수율)을 제조하였다.Methyl (E)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate from step 3 of the synthesis of compound 52 Compound 75 (38.5 mg, 19% yield) was prepared using compound 74 (200 mg, 0.294 mmol) instead.

1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.18 - 7.13 (m, 1H), 7.08 (d, J = 1.6 Hz, 1H), 6.93 (dd, J = 5.3, 1.9 Hz, 2H), 6.39 (s, 1H), 5.04 (d, J = 6.6 Hz, 2H), 4.52 (d, J = 3.7 Hz, 1H), 4.15 (dd, J = 10.9, 3.7 Hz, 1H), 4.08 (t, J = 10.5 Hz, 1H), 4.00 (s, 3H), 3.83 (s, 4H), 3.55 (t, J = 5.2 Hz, 4H), 2.74 - 2.64 (m, 2H), 2.56 (s, 3H), 2.42 (dd, J = 10.6, 5.9 Hz, 1H), 2.35 (s, 3H), 1.52 (s, 9H). ESI-MS m/z 683.3 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (s, 1H), 7.18 - 7.13 (m, 1H), 7.08 (d, J = 1.6 Hz, 1H), 6.93 (dd, J = 5.3, 1.9 Hz, 2H), 6.39 (s, 1H), 5.04 (d, J = 6.6 Hz, 2H), 4.52 (d, J = 3.7 Hz, 1H), 4.15 (dd, J = 10.9, 3.7 Hz, 1H), 4.08 ( t, J = 10.5 Hz, 1H), 4.00 (s, 3H), 3.83 (s, 4H), 3.55 (t, J = 5.2 Hz, 4H), 2.74 - 2.64 (m, 2H), 2.56 (s, 3H) ), 2.42 (dd, J = 10.6, 5.9 Hz, 1H), 2.35 (s, 3H), 1.52 (s, 9H). ESI-MS m/z 683.3 (M+H)+

Figure pat00241
Figure pat00241

화합물 76. tert-butyl (S)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyrimidin-2-yl)piperazine-1-carboxylateCompound 76. tert-butyl (S)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate

화합물 52 합성과정 단계 4에서 메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 화합물 75 (35 mg, 0.051 mmol)를 사용하여 화합물 76 (7.0 mg, 20% 수율)을 제조하였다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy from synthesis step 4 of compound 52 ) Compound 76 (7.0 mg, 20% yield) was prepared using compound 75 (35 mg, 0.051 mmol) instead of acetate.

1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 2.3 Hz, 1H), 7.55 (s, 1H), 7.20 (d, J = 2.5 Hz, 2H), 7.01 (s, 1H), 6.35 (s, 1H), 5.16 (s, 2H), 4.61 (dd, J = 11.4, 5.2 Hz, 1H), 4.35 (t, J = 11.4 Hz, 1H), 4.02 (s, 3H), 3.76 (t, J = 5.4 Hz, 4H), 3.45 (t, J = 5.4 Hz, 5H), 3.24 (dd, J = 15.3, 4.0 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.66 (s, 3H), 2.32 (d, J = 1.9 Hz, 3H), 1.49 (s, 9H). ESI-MS m/z 681.2 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J = 2.3 Hz, 1H), 7.55 (s, 1H), 7.20 (d, J = 2.5 Hz, 2H), 7.01 (s, 1H), 6.35 (s, 1H), 5.16 (s, 2H), 4.61 (dd, J = 11.4, 5.2 Hz, 1H), 4.35 (t, J = 11.4 Hz, 1H), 4.02 (s, 3H), 3.76 (t, J = 5.4 Hz, 4H), 3.45 (t, J = 5.4 Hz, 5H), 3.24 (dd, J = 15.3, 4.0 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.66 (s, 3H), 2.32 (d, J = 1.9 Hz, 3H), 1.49 (s, 9H). ESI-MS m/z 681.2 (M+H)+

Figure pat00242
Figure pat00242

화합물 77. tert-butyl 4-(4-(((3R,4R)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylateCompound 77. tert-butyl 4-(4-(((3R,4R)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate

화합물 75 합성과정에서 RuCl(p-cymene)[(S,S)-Ts-DPEN] 대신 RuCl(p-cymene)[(R,R)-Ts-DPEN]를 사용하여 화합물 77 (19.8 mg, 11% 수율)을 제조하였다.Compound 77 (19.8 mg, 11 % yield) was prepared.

1H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.18 - 7.12 (m, 2H), 6.95 (s, 2H), 6.39 (s, 1H), 5.06 (d, J = 7.8 Hz, 2H), 4.53 (d, J = 3.7 Hz, 1H), 4.19 - 4.07 (m, 2H), 4.01 (s, 3H), 3.84 (s, 4H), 3.57 - 3.53 (m, 4H), 2.73 - 2.67 (m, 2H), 2.64 (s, 3H), 2.41 (s, 1H), 2.35 (s, 3H), 1.52 (s, 9H). ESI-MS m/z 683.2 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.51 (s, 1H), 7.18 - 7.12 (m, 2H), 6.95 (s, 2H), 6.39 (s, 1H), 5.06 (d, J = 7.8 Hz, 2H), 4.53 (d, J = 3.7 Hz, 1H), 4.19 - 4.07 (m, 2H), 4.01 (s, 3H), 3.84 (s, 4H), 3.57 - 3.53 (m, 4H), 2.73 - 2.67 (m, 2H), 2.64 (s, 3H), 2.41 (s, 1H), 2.35 (s, 3H), 1.52 (s, 9H). ESI-MS m/z 683.2 (M+H)+

Figure pat00243
Figure pat00243

화합물 78. tert-butyl (R)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyrimidin-2-yl)piperazine-1-carboxylateCompound 78. tert-butyl (R)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate

화합물 52 합성과정 단계 4에서 메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 화합물 77 (15 mg, 0.022 mmol)을 사용하여 화합물 78 (6.6 mg, 44% 수율)을 제조하였다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy from synthesis step 4 of compound 52 ) Compound 78 (6.6 mg, 44% yield) was prepared using compound 77 (15 mg, 0.022 mmol) instead of acetate.

1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 2.4 Hz, 1H), 7.51 (s, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.07 (s, 1H), 6.92 (d, J = 1.5 Hz, 1H), 6.35 (s, 1H), 5.09 (s, 2H), 4.59 (dd, J = 11.4, 5.2 Hz, 1H), 4.33 (t, J = 11.4 Hz, 1H), 4.01 (s, 3H), 3.81 - 3.73 (m, 4H), 3.50 - 3.41 (m, 5H), 3.24 (dd, J = 15.3, 4.0 Hz, 1H), 2.67 (dd, J = 15.3, 9.0 Hz, 1H), 2.51 (s, 3H), 2.32 (s, 3H), 1.50 (s, 9H). ESI-MS m/z 681.2 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J = 2.4 Hz, 1H), 7.51 (s, 1H), 7.15 (d, J = 2.4 Hz, 1H), 7.07 (s, 1H), 6.92 (d, J = 1.5 Hz, 1H), 6.35 (s, 1H), 5.09 (s, 2H), 4.59 (dd, J = 11.4, 5.2 Hz, 1H), 4.33 (t, J = 11.4 Hz, 1H) , 4.01 (s, 3H), 3.81 - 3.73 (m, 4H), 3.50 - 3.41 (m, 5H), 3.24 (dd, J = 15.3, 4.0 Hz, 1H), 2.67 (dd, J = 15.3, 9.0 Hz) , 1H), 2.51 (s, 3H), 2.32 (s, 3H), 1.50 (s, 9H). ESI-MS m/z 681.2 (M+H)+

Figure pat00244
Figure pat00244

화합물 79. (R)-6-((2-methyl-1H-imidazol-1-yl)methyl)-3-((6-methyl-2-(piperazin-1-yl)pyrimidin-4-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one hydrochlorideCompound 79. (R)-6-((2-methyl-1H-imidazol-1-yl)methyl)-3-((6-methyl-2-(piperazin-1-yl)pyrimidin-4-yl)methyl )-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one hydrochloride

화합물 72 합성과정에서 화합물 71 대신 화합물 78 (4.6 mg, 0.006 mmol)을 사용하여 화합물 79 (3.3 mg, 79% 수율)을 제조하였다.During the synthesis of compound 72, compound 79 (3.3 mg, 79% yield) was prepared using compound 78 (4.6 mg, 0.006 mmol) instead of compound 71.

1H NMR (400 MHz, CD3OD) δ 7.89 (d, J = 13.1 Hz, 2H), 7.60 - 7.47 (m, 3H), 6.71 (s, 1H), 5.44 (s, 2H), 4.61 (d, J = 10.7 Hz, 1H), 4.38 (t, J = 10.4 Hz, 1H), 4.11 (s, 4H), 4.01 (s, 4H), 3.53 (s, 1H), 3.30 (s, 3H), 3.25 (s, 1H), 2.82 (dd, J = 15.5, 7.2 Hz, 1H), 2.67 (s, 3H), 2.42 (s, 3H). ESI-MS m/z 581.1 (M+H)+ 1 H NMR (400 MHz, CD 3 OD) δ 7.89 (d, J = 13.1 Hz, 2H), 7.60 - 7.47 (m, 3H), 6.71 (s, 1H), 5.44 (s, 2H), 4.61 (d , J = 10.7 Hz, 1H), 4.38 (t, J = 10.4 Hz, 1H), 4.11 (s, 4H), 4.01 (s, 4H), 3.53 (s, 1H), 3.30 (s, 3H), 3.25 (s, 1H), 2.82 (dd, J = 15.5, 7.2 Hz, 1H), 2.67 (s, 3H), 2.42 (s, 3H). ESI-MS m/z 581.1 (M+H)+

Figure pat00245
Figure pat00245

화합물 80. 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 80. 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one

화합물 40 합성과정에서 화합물 39 대신 8-브로모-2,3-디하이드로-6-((2-메틸-1H-이미다졸-1-일)메틸)크로멘-4-온 (5.5 g, 16.41 mmol, 1 eq)을 사용하여 화합물 80 (6.18 g, 76.2% 수율)을 제조하였다.8-Bromo-2,3-dihydro-6-((2-methyl-1H-imidazol-1-yl)methyl)chromen-4-one (5.5 g, 16.41 mmol, 1 eq) was used to prepare compound 80 (6.18 g, 76.2% yield).

1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 0.8 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 5.02 (s, 2H), 4.55 (m, 2H), 4.26 (q, J = 7.4 Hz, 2H), 2.84 (m, 2H), 2.36 (s, 3H), 1.57 (t, J = 7.4 Hz, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 2.4 Hz, 1H), 7.52 (d, J = 0.8 Hz, 1H), 7.15 (d, J = 2.4 Hz, 1H), 6.95 (d , J = 1.4 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 5.02 (s, 2H), 4.55 (m, 2H), 4.26 (q, J = 7.4 Hz, 2H), 2.84 (m , 2H), 2.36 (s, 3H), 1.57 (t, J = 7.4 Hz, 3H).

Figure pat00246
Figure pat00246

화합물 81. (R)-3-((6-chloro-4-methylpyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-oneCompound 81. (R)-3-((6-chloro-4-methylpyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6- ((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one

Figure pat00247
Figure pat00247

단계 1) 6-chloro-N-methoxy-N,4-dimethylpicolinamide의 제조Step 1) Preparation of 6-chloro-N-methoxy-N,4-dimethylpicolinamide

N,O-디메틸히드록실아민염산염 (1250 mg, 12.82 mmol)의 CH2Cl2 (30 mL)용액에 6-클로로-4-메틸피콜린산 (2000 mg, 11.656 mmol ), EDCI (1809 mg, 11.656 mmol), DMAP (142 mg, 1.16 mmol)와 TEA (3.25 mL, 23.3 mmol)을 상온에서 넣고 20 h 교반한다. 반응혼합물을 EtOAc, 소금물, 물로 세척한 다음, 에틸아세테이트 (x3)로 추출하고 유기층을 Na2SO4로 건조하고 감압농축한다. 농축물을 MPLC (EtOAc : n-heptane = 1:10 to 1:2)로 정제하여 목적물 (1589 mg, 64%)을 얻는다.6- chloro - 4 -methylpicolinic acid (2000 mg, 11.656 mmol), EDCI (1809 mg, 11.656 mmol), DMAP (142 mg, 1.16 mmol) and TEA (3.25 mL, 23.3 mmol) were added at room temperature and stirred for 20 h. The reaction mixture was washed with EtOAc, brine and water, extracted with ethyl acetate (x3), and the organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure. The concentrate was purified by MPLC (EtOAc : n-heptane = 1:10 to 1:2) to obtain the target product (1589 mg, 64%).

Figure pat00248
Figure pat00248

단계 2) 6-chloro-4-methylpicolinaldehyde의 제조Step 2) Preparation of 6-chloro-4-methylpicolinaldehyde

6-클로로-N-메톡시-N,4-디메틸피콜린아미드 (1589 mg, 7.402 mmol)의 무수 THF (100 mL)용액을 -78 °C로 냉각한다음 DIBAL-H (22.2 mL, 22.2 mmol) 적가하고 -78 °C에서 3 h 교반한다. 반응혼합물을 -78 °C에서 K·Na·tartrate 용액으로 ??칭하다음 슬러리를 상온에서 1 h 교반한다. 반응혼합물을 에틸아세테이트 (x3)로 추출하고 Na2SO4 건조 및 감압농축하여 목적물 (1.15 g, 99%)을 얻는다. A solution of 6-chloro-N-methoxy-N,4-dimethylpicolinamide (1589 mg, 7.402 mmol) in anhydrous THF (100 mL) was cooled to -78 °C and then added with DIBAL-H (22.2 mL, 22.2 mmol). ) and stir for 3 h at -78 °C. The reaction mixture is quenched with a K·Na·tartrate solution at -78 °C and then the slurry is stirred at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate (x3), dried with Na2SO4 and concentrated under reduced pressure to obtain the desired product (1.15 g, 99%).

Figure pat00249
Figure pat00249

단계 3) (E)-3-((6-chloro-4-methylpyridin-2-yl)methylene)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 3) (E)-3-((6-chloro-4-methylpyridin-2-yl)methylene)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6- Preparation of ((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one

화합물 38 합성과정 단계 2에서 메틸 2-(2-클로로-5-포르밀페녹시)아세테이트 대신 화합물 80 (2.078 g, 5.14 mmol), 6-클로로-4-메틸피콜린알데히드 (1.60 g, 10.28 mmol)를 사용하여 생성물 (1.91 g, 69% 수율)을 제조하였다.Compound 80 (2.078 g, 5.14 mmol), 6-chloro-4-methylpicolinaldehyde (1.60 g, 10.28 mmol) instead of methyl 2-(2-chloro-5-formylphenoxy)acetate in step 2 of the synthesis of compound 38 ) was used to prepare the product (1.91 g, 69% yield).

Figure pat00250
Figure pat00250

단계 4) (3R,4R)-3-((6-chloro-4-methylpyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-ol의 제조Step 4) (3R,4R)-3-((6-chloro-4-methylpyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)- Preparation of 6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-ol

화합물 77 합성과정에서 화합물 74 대신 (E)-3-((6-클로로-4-메틸피리딘-2-일)메틸렌)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온 (1.560 g, 2.878 mmol) 를 사용하여 생성물 (450 mg, 29% 수율)을 제조하였다.In the synthesis of compound 77, instead of compound 74, (E)-3-((6-chloro-4-methylpyridin-2-yl)methylene)-8-(1-ethyl-3-(trifluoromethyl)-1H- Product (450 mg, 29% yield) was prepared.

Figure pat00251
Figure pat00251

단계 5) (R)-3-((6-chloro-4-methylpyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 5) (R)-3-((6-chloro-4-methylpyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6- Preparation of ((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one

화합물 52 합성과정 단계 4에서 메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 (3R,4R)-3-((6-클로로-4-메틸피리딘-2-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-( (2-메틸-1H-이미다졸-1-일)메틸)크로만-4-올 (446 mg, 0.816 mmol)를 사용하여 화합물 81 (240 mg, 54% 수율)을 제조하였다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy from synthesis step 4 of compound 52 )acetate instead of (3R,4R)-3-((6-chloro-4-methylpyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazole- Compound 81 (240 mg, 54% yield) using 4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-ol (446 mg, 0.816 mmol) was manufactured.

1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.04 (s, 1H), 7.00 (s, 1H), 6.96 (d, J = 1.4 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 5.03 (s, 2H), 4.59 (dd, J = 11.4, 4.7 Hz, 1H), 4.26 (dd, J = 8.4, 6.3 Hz, 3H), 3.47 - 3.37 (m, 2H), 2.83 - 2.73 (m, 1H), 2.37 (s, 3H), 2.34 (s, 3H), 1.58 (d, J = 7.4 Hz, 3H). 1H NMR (400 MHz, CDCl 3 ) δ 7.75 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 7.04 (s , 1H), 7.00 (s, 1H), 6.96 (d, J = 1.4 Hz, 1H), 6.86 (d, J = 1.4 Hz, 1H), 5.03 (s, 2H), 4.59 (dd, J = 11.4, 4.7 Hz, 1H), 4.26 (dd, J = 8.4, 6.3 Hz, 3H), 3.47 - 3.37 (m, 2H), 2.83 - 2.73 (m, 1H), 2.37 (s, 3H), 2.34 (s, 3H) ), 1.58 (d, J = 7.4 Hz, 3H).

Figure pat00252
Figure pat00252

화합물 82. (S)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acidCompound 82. (S)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1- yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid

Figure pat00253
Figure pat00253

단계 1) methyl (E)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate의 제조Step 1) methyl (E)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1 Preparation of -yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate

화합물 60 합성과정에서 화합물 59 대신 화합물 80 (500 mg, 1.236 mmol)을 사용하여 생성물 (248 mg, 34% 수율)을 제조하였다.A product (248 mg, 34% yield) was prepared using compound 80 (500 mg, 1.236 mmol) instead of compound 59 during the synthesis of compound 60.

Figure pat00254
Figure pat00254

단계 2) methyl 2-(5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-2-fluorophenoxy)acetate의 제조Step 2) methyl 2-(5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6-((2-methyl Preparation of -1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-2-fluorophenoxy)acetate

화합물 52 합성과정 단계 3에서 메틸 (E)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 대신 메틸 (E)-2-(5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트 (245 mg, 0.409 mmol)를 사용하여 생성물 (99 mg, 40% 수율)을 제조하였다.Methyl ( E )-2-(5-((8-bromo-6-methyl-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate from synthesis step 3 of compound 52 Instead of methyl ( E )-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-already Product (99 mg, 40% yield) using dazol-1-yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate (245 mg, 0.409 mmol) was manufactured.

Figure pat00255
Figure pat00255

단계 3) methyl (S)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate의 제조Step 3) methyl (S)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1 Preparation of -yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate

화합물 52 합성과정 단계 4에서 메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 메틸 2-(5-(((3S,4S)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-히드록시-6-((2-메틸-1H- 이미다졸-1-일)메틸)크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 (95 mg, 0.158 mmol)를 사용하여 생성물 (44 mg, 46% 수율)을 제조하였다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy from synthesis step 4 of compound 52 )methyl 2-(5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6- instead of acetate Product (44 mg, 46% yield) was prepared.

Figure pat00256
Figure pat00256

단계 4) (S)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid의 제조Step 4) (S)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1- Preparation of yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid

화합물 41 합성과정에서 화합물 40 대신 메틸 (S)-2-(5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일) 메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 (39 mg, 0.065 mmol)를 사용하여 화합물 82 (26 mg, 68% 수율)을 제조하였다.During the synthesis of compound 41, methyl (S)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(( Compound 82 (2-methyl-1H-imidazol-1-yl) methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate (39 mg, 0.065 mmol) 26 mg, 68% yield) was prepared.

1H NMR (400 MHz, CD3OD) δ 7.93 (d, J = 1.1 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.01 - 6.95 (m, 1H), 6.87 (dd, J = 8.1, 2.1 Hz, 1H), 6.78 (ddd, J = 8.3, 4.2, 2.1 Hz, 1H), 5.39 (s, 2H), 4.55 (s, 2H), 4.44 (dd, J = 11.7, 4.5 Hz, 1H), 4.31 - 4.24 (m, 3H), 3.19 - 3.11 (m, 1H), 3.01 (dt, J = 8.7, 4.4 Hz, 1H), 2.73 (dd, J = 13.9, 9.1 Hz, 1H), 2.61 (d, J = 1.1 Hz, 3H), 1.53 (d, J = 7.3 Hz, 3H). ESI-MS m/z 587.2 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 7.93 (d, J = 1.1 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.01 - 6.95 (m, 1H), 6.87 (dd, J = 8.1, 2.1 Hz, 1H), 6.78 (ddd, J = 8.3, 4.2, 2.1 Hz, 1H), 5.39 (s, 2H), 4.55 (s, 2H), 4.44 (dd, J = 11.7, 4.5 Hz, 1H), 4.31 - 4.24 (m, 3H), 3.19 - 3.11 (m, 1H) , 3.01 (dt, J = 8.7, 4.4 Hz, 1H), 2.73 (dd, J = 13.9, 9.1 Hz, 1H), 2.61 (d, J = 1.1 Hz, 3H), 1.53 (d, J = 7.3 Hz, 3H). ESI-MS m/z 587.2 (M+H)+

Figure pat00257
Figure pat00257

화합물 83. tert-butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamateCompound 83. tert-butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H- imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate

Figure pat00258
Figure pat00258

단계 1) methyl 6-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-4-methylpicolinate의 제조Step 1) Preparation of methyl 6-(3-((tert-butoxycarbonyl)(methyl)amino)azetidin-1-yl)-4-methylpicolinate

메틸 6-클로로-4-메틸피콜리네이트 (1.25 g, 6.7 mmol), N-메틸아제티딘-3-아민 염산염 (1 eq), Cs2CO3 (3 eq), Pd2(dba)3 (5 mol%)과 Xantphos (10 mol%)의 Dioxane 용액을 90℃에서 17시간 교반하고 상온으로 냉각한다. 반응혼합물을 셀라이트 패드를 통해 EA로 여과하고 잔류용매를 제거한후 잔사를 MPLC로 정제하여 목적물 (1.123 g, 71%)을 얻는다.Methyl 6-chloro-4-methylpicolinate (1.25 g, 6.7 mmol), N-methylazetidin-3-amine hydrochloride (1 eq), Cs 2 CO 3 (3 eq), Pd 2 (dba) 3 ( A dioxane solution of 5 mol%) and Xantphos (10 mol%) was stirred at 90°C for 17 hours and then cooled to room temperature. The reaction mixture was filtered with EA through a celite pad to remove the residual solvent, and the residue was purified by MPLC to obtain the target product (1.123 g, 71%).

Figure pat00259
Figure pat00259

단계 2) (4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methanol의 제조Step 2) Preparation of (4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methanol

화합물 65 합성과정 단계 2와 같다.Same as step 2 of compound 65 synthesis process.

Figure pat00260
Figure pat00260

단계 3) 4-methyl-6-(3-(methylamino)azetidin-1-yl)picolinaldehyde의 제조Step 3) Preparation of 4-methyl-6-(3-(methylamino)azetidin-1-yl)picolinaldehyde

화합물 65 합성과정 단계 3과 같다.Same as step 3 of compound 65 synthesis process.

Figure pat00261
Figure pat00261

단계 4) tert-butyl (E)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-ylidene)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate의 제조Step 4) tert-butyl (E)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H- Preparation of imidazol-1-yl)methyl)-4-oxochroman-3-ylidene)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate

화합물 65 합성과정에서 6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온 대신 8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온 (565 mg, 1.39 mmol)를 사용하여 생성물 (486 mg, 75% 수율)을 제조하였다.During the synthesis of compound 65, 6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl) 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl) instead of chroman-4-one The product (486 mg, 75% yield) was prepared using methyl)chroman-4-one (565 mg, 1.39 mmol).

Figure pat00262
Figure pat00262

단계 5) tert-butyl (1-(6-(((3R,4R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate의 제조Step 5) tert-butyl (1-(6-(((3R,4R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6-(( Preparation of 2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate

화합물 70 합성과정에서 화합물 65 대신 tert-부틸 (E)-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1)-일)메틸)-4-옥소크로만-3-일리덴)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카바메이트 (486 mg, 0.7 mmol)를 사용하여 생성물 (361 mg, 74% 수율)을 제조하였다.In the synthesis of compound 70, tert-butyl (E)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6 instead of compound 65 -((2-methyl-1H-imidazol-1)-yl)methyl)-4-oxochroman-3-ylidene)methyl)-4-methylpyridin-2-yl)azetidin-3-yl) The product (361 mg, 74% yield) was prepared using (methyl)carbamate (486 mg, 0.7 mmol).

Figure pat00263
Figure pat00263

단계 6) tert-butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate의 제조Step 6) tert-butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H- Preparation of imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate

화합물 52 합성과정 단계 4에서 메틸 2-(5-(((3S,4S)-8-브로모-4-하이드록시-6-메틸크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 tert-부틸 (1-(6-(((3R,4R)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-히드록시-6-((2-메틸)-1H-이미다졸-1-일)메틸)크로만-3-일)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카바메이트 (361 mg, 0.51 mmol)를 사용하여 화합물 83 (162 mg, 46% 수율)을 제조하였다.Methyl 2-(5-(((3S,4S)-8-bromo-4-hydroxy-6-methylchroman-3-yl)methyl)-2-fluorophenoxy from synthesis step 4 of compound 52 )tert-butyl (1-(6-(((3R,4R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy instead of acetate -6-((2-methyl)-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl) Compound 83 (162 mg, 46% yield) was prepared using carbamate (361 mg, 0.51 mmol).

1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 2.4 Hz, 1H), 7.49 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 1.4 Hz, 1H), 6.84 (d, J = 1.4 Hz, 1H), 6.38 (s, 1H), 5.97 (s, 1H), 5.01 (s, 2H), 4.83 (s, 1H), 4.57 (dd, J = 11.4, 5.1 Hz, 1H), 4.32 - 4.26 (m, 1H), 4.26 - 4.19 (m, 2H), 4.13 (td, J = 8.4, 3.0 Hz, 2H), 3.91 (ddd, J = 8.7, 5.9, 3.0 Hz, 2H), 3.39 (tt, J = 9.5, 4.6 Hz, 1H), 3.29 (dd, J = 14.7, 4.1 Hz, 1H), 2.93 (s, 3H), 2.66 (dd, J = 14.7, 9.4 Hz, 1H), 2.36 (s, 3H), 2.21 (s, 3H), 1.55 (t, J = 7.4 Hz, 3H), 1.46 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.76 (d, J = 2.4 Hz, 1H), 7.49 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 1.4 Hz) , 1H), 6.84 (d, J = 1.4 Hz, 1H), 6.38 (s, 1H), 5.97 (s, 1H), 5.01 (s, 2H), 4.83 (s, 1H), 4.57 (dd, J = 11.4, 5.1 Hz, 1H), 4.32 - 4.26 (m, 1H), 4.26 - 4.19 (m, 2H), 4.13 (td, J = 8.4, 3.0 Hz, 2H), 3.91 (ddd, J = 8.7, 5.9, 3.0 Hz, 2H), 3.39 (tt, J = 9.5, 4.6 Hz, 1H), 3.29 (dd, J = 14.7, 4.1 Hz, 1H), 2.93 (s, 3H), 2.66 (dd, J = 14.7, 9.4 Hz, 1H), 2.36 (s, 3H), 2.21 (s, 3H), 1.55 (t, J = 7.4 Hz, 3H), 1.46 (s, 9H).

Figure pat00264
Figure pat00264

화합물 84. (R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-3-((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochlorideCompound 84. (R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-3- ((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochloride

화합물 72 합성과정에서 화합물 71 대신 화합물 83 (139 mg, 0.2 mmol)을 사용하여 화합물 84 (126 mg, 99% 수율)을 제조하였다.Compound 84 (126 mg, 99% yield) was prepared using Compound 83 (139 mg, 0.2 mmol) instead of Compound 71 during the synthesis of Compound 72.

1H NMR (400 MHz, CD3OD) δ 7.97 (d, J = 1.0 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.51 (q, J = 3.1, 2.7 Hz, 2H), 6.83 (d, J = 1.3 Hz, 1H), 6.67 (s, 1H), 5.44 (s, 2H), 4.71 (dd, J = 10.5, 7.7 Hz, 2H), 4.65 (dd, J = 11.5, 4.8 Hz, 1H), 4.52 (d, J = 10.7 Hz, 2H), 4.42 - 4.33 (m, 2H), 4.30 (q, J = 7.4 Hz, 2H), 3.52 - 3.37 (m, 2H), 2.93 (dd, J = 14.3, 6.7 Hz, 1H), 2.81 (s, 3H), 2.67 (s, 3H), 2.50 - 2.39 (m, 3H), 1.53 (t, J = 7.3 Hz, 3H). ESI-MS m/z 631 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 7.97 (d, J = 1.0 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 2.1 Hz, 1H), 7.51 ( q, J = 3.1, 2.7 Hz, 2H), 6.83 (d, J = 1.3 Hz, 1H), 6.67 (s, 1H), 5.44 (s, 2H), 4.71 (dd, J = 10.5, 7.7 Hz, 2H) ), 4.65 (dd, J = 11.5, 4.8 Hz, 1H), 4.52 (d, J = 10.7 Hz, 2H), 4.42 - 4.33 (m, 2H), 4.30 (q, J = 7.4 Hz, 2H), 3.52 - 3.37 (m, 2H), 2.93 (dd, J = 14.3, 6.7 Hz, 1H), 2.81 (s, 3H), 2.67 (s, 3H), 2.50 - 2.39 (m, 3H), 1.53 (t, J = 7.3 Hz, 3H). ESI-MS m/z 631 (M+H)+

Figure pat00265
Figure pat00265

화합물 85. tert-butyl (R)-N-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)-N-methylglycinateCompound 85. tert-butyl (R)-N-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl- 1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)-N-methylglycinate

화합물 84 (100 mg, 0.15 mmol)와 Cs2CO3 (3 eq)의 DMF (2 mL)용액에 tert-부틸 브로모 아세테이트 (1.5 eq)을 넣어주고 반응혼합물을 60℃에서 3h 교반한다. 반응이 종료되면 용매를 증발시키고 EA로 희석한다. 잔사를 H2O로 2회 세척하고 EA로 추출한다. 유기층을 Na2SO4로 건조하고 감압농축한다. 농축물을 MPLC로 정제하여 화합물 85 (9 mg, 8.4%)을 얻는다.To a solution of compound 84 (100 mg, 0.15 mmol) and Cs2CO3 (3 eq) in DMF (2 mL) was added tert-butyl bromo acetate (1.5 eq), and the reaction mixture was stirred at 60°C for 3 h. After the reaction is complete, the solvent is evaporated and diluted with EA. The residue is washed twice with H 2 O and extracted with EA. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The concentrate is purified by MPLC to give compound 85 (9 mg, 8.4%).

1H NMR (400 MHz, CDCl3) δ 7.78 (dd, J = 11.6, 2.4 Hz, 1H), 7.49 (d, J = 16.2 Hz, 1H), 7.11 (dd, J = 12.3, 2.4 Hz, 1H), 6.94 (t, J = 1.6 Hz, 1H), 6.84 (t, J = 1.2 Hz, 1H), 6.31 (d, J = 26.0 Hz, 1H), 5.99 (d, J = 22.0 Hz, 1H), 5.01 (d, J = 2.8 Hz, 2H), 4.54 (dt, J = 9.4, 4.7 Hz, 1H), 4.27 - 4.22 (m, 2H), 4.20 (d, J = 6.1 Hz, 1H), 4.07 - 3.96 (m, 2H), 3.90 - 3.76 (m, 2H), 3.68 (dt, J = 19.5, 6.2 Hz, 1H), 3.39 (d, J = 10.2 Hz, 1H), 3.29 (dd, J = 14.5, 4.0 Hz, 1H), 2.63 (dd, J = 14.6, 9.5 Hz, 1H), 2.36 (t, J = 2.8 Hz, 6H), 2.20 (d, J = 3.3 Hz, 3H), 1.55 (td, J = 7.3, 3.7 Hz, 3H), 1.46 (d, J = 3.4 Hz, 9H). ESI-MS m/z 708 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.78 (dd, J = 11.6, 2.4 Hz, 1H), 7.49 (d, J = 16.2 Hz, 1H), 7.11 (dd, J = 12.3, 2.4 Hz, 1H) , 6.94 (t, J = 1.6 Hz, 1H), 6.84 (t, J = 1.2 Hz, 1H), 6.31 (d, J = 26.0 Hz, 1H), 5.99 (d, J = 22.0 Hz, 1H), 5.01 (d, J = 2.8 Hz, 2H), 4.54 (dt, J = 9.4, 4.7 Hz, 1H), 4.27 - 4.22 (m, 2H), 4.20 (d, J = 6.1 Hz, 1H), 4.07 - 3.96 ( m, 2H), 3.90 - 3.76 (m, 2H), 3.68 (dt, J = 19.5, 6.2 Hz, 1H), 3.39 (d, J = 10.2 Hz, 1H), 3.29 (dd, J = 14.5, 4.0 Hz) , 1H), 2.63 (dd, J = 14.6, 9.5 Hz, 1H), 2.36 (t, J = 2.8 Hz, 6H), 2.20 (d, J = 3.3 Hz, 3H), 1.55 (td, J = 7.3, 3.7 Hz, 3H), 1.46 (d, J = 3.4 Hz, 9H). ESI-MS m/z 708 (M+H)+

Figure pat00266
Figure pat00266

화합물 86. tert-butyl (Z)-(1-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamateCompound 86. tert-butyl (Z)-(1-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3- methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate

Figure pat00267
Figure pat00267

단계 1) 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-methylchroman-4-one의 제조Step 1) Preparation of 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-methylchroman-4-one

화합물 40 합성과정에서 화합물 39 대신 8-브로모-6-메틸크로만-4-온 (1.5 g, 6.222 mmol)를 사용하여 생성물 (1.069 g, 53% 수율)을 제조하였다.In the synthesis of compound 40, a product (1.069 g, 53% yield) was prepared using 8-bromo-6-methylchroman-4-one (1.5 g, 6.222 mmol) instead of compound 39.

Figure pat00268
Figure pat00268

단계 2) 6-(bromomethyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one의 제조Step 2) Preparation of 6-(bromomethyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one

화합물 52 합성과정 단계 5에서 메틸 (S)-2-(5-((8-브로모-6-메틸-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트 대신 8-(1-에틸-3-(트리플루오로메틸)- 1H-피라졸-4-일)-6-메틸크로만-4-온 (1.07 g, 3.3 mmol)을 사용하여 생성물 (512 mg, 44% 수율)을 제조하였다.Instead of methyl (S)-2-(5-((8-bromo-6-methyl-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate in step 5 of the synthesis of compound 52 Product (512 mg, 44% yield) was prepared.

Figure pat00269
Figure pat00269

단계 3) 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one의 제조Step 3) 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl Preparation of )methyl)chroman-4-one

화합물 38 합성과정 단계 4에서 메틸 2-(5-((8-브로모-6-(브로모메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트대신 6-(브로모메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온 (4.62 g, 13.24 mmol) 사용하여 생성물(2.426 g, 43.7% 수율)을 제조하였다.In step 4 of the synthesis of compound 38, methyl 2-(5-((8-bromo-6-(bromomethyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate was replaced by 6 -(Bromomethyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one (4.62 g, 13.24 mmol) using product (2.426 g, 43.7% yield) was prepared.

Figure pat00270
Figure pat00270

단계 4) tert-butyl (Z)-(1-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate의 제조Step 4) tert-butyl (Z)-(1-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3- Preparation of methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate

화합물 39 합성과정에서 화합물 38 대신 8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸) 크로만-4-온 (2 g, 4.7 mmol)을 사용하여 화합물 86 (1.870 g, 77.8% 수율)을 제조하였다.In the synthesis of compound 39, 8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3 -Dihydro-1H-imidazol-1-yl)methyl) chroman-4-one (2 g, 4.7 mmol) was used to prepare compound 86 (1.870 g, 77.8% yield).

1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 6.79 (d, J = 2.5 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 5.08 (s, 2H), 4.54 - 4.46 (m, 2H), 4.21 (q, J = 7.3 Hz, 2H), 3.55 (s, 3H), 2.82 - 2.71 (m, 2H), 1.52 (t, J = 7.4 Hz, 3H), 1.43 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 1.2 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 6.79 (d , J = 2.5 Hz, 1H), 6.68 (d, J = 2.5 Hz, 1H), 5.08 (s, 2H), 4.54 - 4.46 (m, 2H), 4.21 (q, J = 7.3 Hz, 2H), 3.55 (s, 3H), 2.82 - 2.71 (m, 2H), 1.52 (t, J = 7.4 Hz, 3H), 1.43 (s, 9H).

Figure pat00271
Figure pat00271

화합물 87. tert-butyl ((Z)-1-((3-((E)-3-bromo-4-fluorobenzylidene)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamateCompound 87. tert-butyl ((Z)-1-((3-((E)-3-bromo-4-fluorobenzylidene)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4- yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate

화합물 60 합성과정에서 화합물 59 대신 화합물 86 (52 mg, 0.1 mmol), 3-브로모-4-플루오로벤즈알데히드 (31 mg ,0.15 mmol)를 사용하여 화합물 87 (14.9 mg, 21% 수율)을 제조하였다.During the synthesis of compound 60, compound 87 (14.9 mg, 21% yield) was prepared using compound 86 (52 mg, 0.1 mmol) and 3-bromo-4-fluorobenzaldehyde (31 mg, 0.15 mmol) instead of compound 59. did

1H NMR (400 MHz, CDCl3) δ 7.95 (t, J = 1.8 Hz, 1H), 7.78 (s, 1H), 7.52 (dd, J = 22.4, 15.8 Hz, 3H), 7.27 - 7.17 (m, 2H), 6.58 (d, J = 27.8 Hz, 2H), 5.30 (s, 2H), 5.11 (s, 2H), 4.25 (q, J = 7.4 Hz, 2H), 3.54 (s, 3H), 1.57 (td, J = 7.3, 1.5 Hz, 3H), 1.52 (d, J = 1.5 Hz, 9H). ESI-MS m/z 706.0 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.95 (t, J = 1.8 Hz, 1H), 7.78 (s, 1H), 7.52 (dd, J = 22.4, 15.8 Hz, 3H), 7.27 - 7.17 (m, 2H), 6.58 (d, J = 27.8 Hz, 2H), 5.30 (s, 2H), 5.11 (s, 2H), 4.25 (q, J = 7.4 Hz, 2H), 3.54 (s, 3H), 1.57 ( td, J = 7.3, 1.5 Hz, 3H), 1.52 (d, J = 1.5 Hz, 9H). ESI-MS m/z 706.0 (M+H)+

Figure pat00272
Figure pat00272

화합물 88. tert-butyl ((Z)-1-((3-((E)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzylidene)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamateCompound 88. tert-butyl ((Z)-1-((3-((E)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzylidene)-8-(1- ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate

화합물 87 합성과정에서 3-브로모-4-플루오로벤즈알데히드 대신 3-(2,6-비스(벤질옥시)피리딘-3-일)-4-플루오로벤즈알데히드 (73 mg, 0.175 mmol)를 사용하여 화합물 88 (73.5 mg, 80% 수율)을 제조하였다.In the synthesis of compound 87, 3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzaldehyde (73 mg, 0.175 mmol) was used instead of 3-bromo-4-fluorobenzaldehyde. Compound 88 (73.5 mg, 80% yield) was prepared.

1H NMR (400 MHz, CDCl3) δ 7.98 - 7.92 (m, 1H), 7.86 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J = 8.0 Hz, 3H), 7.42 - 7.37 (m, 2H), 7.37 - 7.31 (m, 4H), 7.28 - 7.18 (m, 5H), 6.58 - 6.46 (m, 3H), 5.42 (s, 2H), 5.38 (s, 2H), 5.28 (s, 2H), 5.07 (d, J = 5.1 Hz, 2H), 4.23 (q, J = 7.4 Hz, 2H), 3.50 (d, J = 5.2 Hz, 3H), 1.55 (dd, J = 7.4, 1.2 Hz, 3H), 1.52 (s, 9H). ESI-MS m/z 915.3(M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 7.98 - 7.92 (m, 1H), 7.86 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.45 (d, J = 8.0 Hz, 3H), 7.42 - 7.37 (m, 2H), 7.37 - 7.31 (m, 4H), 7.28 - 7.18 (m, 5H), 6.58 - 6.46 (m, 3H), 5.42 (s, 2H) , 5.38 (s, 2H), 5.28 (s, 2H), 5.07 (d, J = 5.1 Hz, 2H), 4.23 (q, J = 7.4 Hz, 2H), 3.50 (d, J = 5.2 Hz, 3H) , 1.55 (dd, J = 7.4, 1.2 Hz, 3H), 1.52 (s, 9H). ESI-MS m/z 915.3 (M+H)+

Figure pat00273
Figure pat00273

화합물 89. (E)-3-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzylidene)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one hydrochlorideCompound 89. (E)-3-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzylidene)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol- 4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride

화합물 72 합성과정에서 화합물 71 대신 화합물 88 (100 mg, 0.1 mmol)을 사용하여 화합물 89 (36 mg, 47% 수율)을 제조하였다.Compound 89 (36 mg, 47% yield) was prepared using Compound 88 (100 mg, 0.1 mmol) instead of Compound 71 during the synthesis of Compound 72.

1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.01 - 7.78 (m, 2H), 7.65 (s, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.49 - 7.15 (m, 14H), 6.49 (t, J = 8.2 Hz, 2H), 5.49 (s, 2H), 5.40 (d, J = 15.3 Hz, 4H), 5.28 (s, 2H), 4.22 (q, J = 7.3 Hz, 2H), 3.80 (s, 3H), 1.53 (t, J = 7.1 Hz, 3H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.98 (s, 1H), 8.01 - 7.78 (m, 2H), 7.65 (s, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.49 - 7.15 ( m, 14H), 6.49 (t, J = 8.2 Hz, 2H), 5.49 (s, 2H), 5.40 (d, J = 15.3 Hz, 4H), 5.28 (s, 2H), 4.22 (q, J = 7.3 Hz, 2H), 3.80 (s, 3H), 1.53 (t, J = 7.1 Hz, 3H).

Figure pat00274
Figure pat00274

화합물 90. 3-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((3-methylimidazolidin-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenyl)piperidine-2,6-dioneCompound 90. 3-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((3-methylimidazolidin-1-yl)methyl)-4-oxochroman -3-yl)methyl)-2-fluorophenyl)piperidine-2,6-dione

화합물 89 (20 mg, 0.023 mmol)와 10% Pd/C의 메탄올 용액을 hydrogen 기압하에서 2 days 교반한다. 반응혼합물을 셀라이트 패드를 통해 에틸아세테이트로 여과하고 여액을 감압농축하여 화합물 90 (10.8 mg, 75%)을 얻는다. A solution of compound 89 (20 mg, 0.023 mmol) and 10% Pd/C in methanol was stirred for 2 days under hydrogen pressure. The reaction mixture was filtered with ethyl acetate through a celite pad, and the filtrate was concentrated under reduced pressure to obtain compound 90 (10.8 mg, 75%).

ESI-MS m/z 628.1 (M+H)+ ESI-MS m/z 628.1 (M+H) +

1H NMR (400 MHz, CD3OD) δ 7.82 (d, J = 9.2 Hz, 1H), 7.16 (dd, J = 12.1, 6.7 Hz, 2H), 7.05 (t, J = 9.1 Hz, 1H), 7.00 (d, J = 5.7 Hz, 2H), 4.44 (d, J = 4.2 Hz, 2H), 4.25 (q, J = 7.4 Hz, 2H), 4.17 (d, J = 10.6 Hz, 1H), 4.06 - 3.88 (m, 1H), 3.82 (dd, J = 10.9, 8.0 Hz, 1H), 3.60 (t, J = 9.1 Hz, 2H), 3.53 - 3.43 (m, 3H), 2.98 (s, 3H), 2.90 - 2.73 (m, 2H), 2.69 (d, J = 6.1 Hz, 1H), 2.60 (td, J = 16.8, 15.6, 8.2 Hz, 2H), 2.40 - 2.05 (m, 4H), 1.50 (t, J = 7.3 Hz, 3H). ESI-MS m/z 628.1 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 7.82 (d, J = 9.2 Hz, 1H), 7.16 (dd, J = 12.1, 6.7 Hz, 2H), 7.05 (t, J = 9.1 Hz, 1H), 7.00 (d, J = 5.7 Hz, 2H), 4.44 (d, J = 4.2 Hz, 2H), 4.25 (q, J = 7.4 Hz, 2H), 4.17 (d, J = 10.6 Hz, 1H), 4.06 - 3.88 (m, 1H), 3.82 (dd, J = 10.9, 8.0 Hz, 1H), 3.60 (t, J = 9.1 Hz, 2H), 3.53 - 3.43 (m, 3H), 2.98 (s, 3H), 2.90 - 2.73 (m, 2H), 2.69 (d, J = 6.1 Hz, 1H), 2.60 (td, J = 16.8, 15.6, 8.2 Hz, 2H), 2.40 - 2.05 (m, 4H), 1.50 (t, J = 7.3 Hz, 3H). ESI-MS m/z 628.1 (M+H) +

Figure pat00275
Figure pat00275

화합물 91. tert-butyl (1-(3-fluoro-6-(hydroxymethyl)pyridin-2-yl)azetidin-3-yl)carbamateCompound 91. tert-butyl (1-(3-fluoro-6-(hydroxymethyl)pyridin-2-yl)azetidin-3-yl)carbamate

(6-브로모-5-플루오로피리딘-2-일)메탄올 (50 mg, 0.24 mmol, 1 eq), tert-부틸 아제티딘-3-일카르바메이트 (1 eq), Cs2CO3 (3 eq), Pd2(dba)3 (5 mol%)와 Xantphos (10 mol%)의 Dioxane 용액을 90 ℃에서 overnight 교반하고 상온으로 냉각한다. 반응혼합액을 셀라이트 패드를 통해 EA로 여과하고 여액을 감압농축하여 얻은 농축물을 MPLC로 정제하여 화합물 91 (45 mg, 63%)을 얻는다.(6-bromo-5-fluoropyridin-2-yl)methanol (50 mg, 0.24 mmol, 1 eq), tert-butyl azetidin-3-ylcarbamate (1 eq), Cs 2 CO 3 ( 3 eq), a dioxane solution of Pd 2 (dba) 3 (5 mol%) and Xantphos (10 mol%) was stirred overnight at 90 °C and cooled to room temperature. The reaction mixture was filtered with EA through a celite pad, and the filtrate was concentrated under reduced pressure. The concentrate was purified by MPLC to obtain compound 91 (45 mg, 63%).

1H NMR (400 MHz, CDCl3) δ 7.14 (dd, J = 11.5, 8.0 Hz, 1H), 6.50 (ddt, J = 8.0, 2.8, 0.8 Hz, 1H), 4.45 (t, J = 8.2 Hz, 2H), 3.97 - 3.87 (m, 2H), 3.43 (s, 1H), 1.45 (s, 9H). ESI-MS m/z 298.1 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.14 (dd, J = 11.5, 8.0 Hz, 1H), 6.50 (ddt, J = 8.0, 2.8, 0.8 Hz, 1H), 4.45 (t, J = 8.2 Hz, 2H), 3.97 - 3.87 (m, 2H), 3.43 (s, 1H), 1.45 (s, 9H). ESI-MS m/z 298.1 (M+H) +

Figure pat00276
Figure pat00276

화합물 92. tert-butyl (1-(3-fluoro-6-formylpyridin-2-yl)azetidin-3-yl)carbamateCompound 92. tert-butyl (1-(3-fluoro-6-formylpyridin-2-yl)azetidin-3-yl)carbamate

tert-부틸 (1-(3-플루오로-6-(히드록시메틸)피리딘-2-일)아제티딘-3-일)카르바메이트 (2900 mg, 1eq)과 Molecular sieves 4 Å (300 mg)의 CH2Cl2 (60 mL)용액을 30분 교반한다. N-메틸모르폴린 N-옥사이드 (NMO, 2 eq), 테트라프로필암모늄 퍼루테네이트 (TPAP, 0.2 eq)을 0°C에서 넣어주고 상온에서 3 h 교반한다. 검은색 반응혼합물을 셀라이트에서 diethyl ether 용매로 여과한다. 감압농축한다음 잔사를 MPLC로 정제하여 화합물 92 (1.612 g, 56%)을 얻는다.Molecular sieves 4 Å (300 mg) with tert-butyl (1-(3-fluoro-6-(hydroxymethyl)pyridin-2-yl)azetidin-3-yl)carbamate (2900 mg, 1eq) A solution of CH 2 Cl 2 (60 mL) was stirred for 30 minutes. N-methylmorpholine N-oxide (NMO, 2 eq) and tetrapropylammonium perruthenate (TPAP, 0.2 eq) were added at 0°C and stirred at room temperature for 3 h. The black reaction mixture was filtered through celite with diethyl ether solvent. After concentration under reduced pressure, the residue was purified by MPLC to obtain compound 92 (1.612 g, 56%).

1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.32 (dd, J = 8.0, 3.5 Hz, 1H), 7.29 - 7.23 (m, 1H), 5.04 (s, 1H), 4.63 (s, 1H), 4.57 - 4.44 (m, 2H), 4.01 (ddd, J = 9.5, 5.4, 1.6 Hz, 2H), 1.45 (s, 9H). ESI-MS m/z 296.1 (M+H)+ 1 H NMR (400 MHz, CDCl 3 ) δ 9.84 (s, 1H), 7.32 (dd, J = 8.0, 3.5 Hz, 1H), 7.29 - 7.23 (m, 1H), 5.04 (s, 1H), 4.63 ( s, 1H), 4.57 - 4.44 (m, 2H), 4.01 (ddd, J = 9.5, 5.4, 1.6 Hz, 2H), 1.45 (s, 9H). ESI-MS m/z 296.1 (M+H) +

Figure pat00277
Figure pat00277

화합물 93. tert-butyl (E)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-ylidene)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamateCompound 93. tert-butyl (E)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H- imidazol-1-yl)methyl)-4-oxochroman-3-ylidene)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate

화합물 80 (1000 mg, 2.58 mmol)의 MeOH 용액을 tert-부틸 (1-(3-플루오로-6-포르밀피리딘-2-일)아제티딘-3-일)카바메이트 (1 eq)과 피롤리딘 (1.5 eq)에 넣고 23h 교반한다. MeOH을 감압증류 제거하고 잔사를 에틸아세테이트로 희석하고 소금물과 물로 세척, EA로 추출한다음 Na2SO4로 건조하고 감압농축한다. 농축물을 MPLC로 정제하여 화합물 93 (1.87 g, 85%)을 얻는다.A solution of compound 80 (1000 mg, 2.58 mmol) in MeOH was mixed with tert-butyl (1-(3-fluoro-6-formylpyridin-2-yl)azetidin-3-yl)carbamate (1 eq) and Put in Rolidin (1.5 eq) and stir for 23h. MeOH was distilled off under reduced pressure, the residue was diluted with ethyl acetate, washed with brine and water, extracted with EA, dried over Na 2 SO 4 and concentrated under reduced pressure. The concentrate is purified by MPLC to give compound 93 (1.87 g, 85%).

1H NMR (400 MHz, CDCl3) δ 7.84 (d, J = 2.3 Hz, 1H), 7.52 (t, J = 2.1 Hz, 1H), 7.47 (s, 1H), 7.16 (dd, J = 11.3, 8.0 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 1.4 Hz, 1H), 6.89 - 6.84 (m, 2H), 5.87 (d, J = 2.2 Hz, 2H), 5.13 (s, 1H), 4.62 (s, 1H), 4.47 (t, J = 8.3 Hz, 2H), 4.25 (q, J = 7.3 Hz, 2H), 3.96 (ddd, J = 9.5, 5.6, 1.5 Hz, 2H), 2.36 (s, 3H), 1.94 (d, J = 15.9 Hz, 1H), 1.55 (t, J = 7.4 Hz, 3H), 1.45 (s, 9H). ESI-MS m/z 682.2 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 2.3 Hz, 1H), 7.52 (t, J = 2.1 Hz, 1H), 7.47 (s, 1H), 7.16 (dd, J = 11.3, 8.0 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 1.4 Hz, 1H), 6.89 - 6.84 (m, 2H), 5.87 (d, J = 2.2 Hz, 2H) , 5.13 (s, 1H), 4.62 (s, 1H), 4.47 (t, J = 8.3 Hz, 2H), 4.25 (q, J = 7.3 Hz, 2H), 3.96 (ddd, J = 9.5, 5.6, 1.5 Hz, 2H), 2.36 (s, 3H), 1.94 (d, J = 15.9 Hz, 1H), 1.55 (t, J = 7.4 Hz, 3H), 1.45 (s, 9H). ESI-MS m/z 682.2 (M+H) +

Figure pat00278
Figure pat00278

화합물 94. (E)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methylene)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochlorideCompound 94. (E)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methylene)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol -4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride

화합물 93 (15 mg, 1 eq)의 DCM 용액에 0℃에서 4N-HCl in dioxane (excess)을 넣고 상온에서 2h 교반한다. 반응이 종료되면 용매를 제거하여 화합물 94 (12 mg, 99%)를 얻는다. 4N-HCl in dioxane (excess) was added to a DCM solution of compound 93 (15 mg, 1 eq) at 0°C and stirred at room temperature for 2 h. When the reaction is complete, the solvent is removed to obtain compound 94 (12 mg, 99%).

1H NMR (400 MHz, CD3OD) δ 7.90 (d, J = 16.4 Hz, 1H), 7.79 (dd, J = 6.7, 2.3 Hz, 1H), 7.55 (s, 1H), 7.41 - 7.32 (m, 2H), 7.14 (d, J = 1.5 Hz, 1H), 6.95 (s, 1H), 6.00 - 5.94 (m, 1H), 5.29 - 5.20 (m, 2H), 4.48 (t, J = 7.8 Hz, 1H), 4.30 (q, J = 7.3 Hz, 3H), 4.13 - 4.02 (m, 1H), 3.85 - 3.68 (m, 2H), 3.61 - 3.52 (m, 1H), 2.37 (s, 3H), 1.55 (td, J = 7.4, 1.0 Hz, 3H). ESI-MS m/z 582.4 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 7.90 (d, J = 16.4 Hz, 1H), 7.79 (dd, J = 6.7, 2.3 Hz, 1H), 7.55 (s, 1H), 7.41 - 7.32 (m , 2H), 7.14 (d, J = 1.5 Hz, 1H), 6.95 (s, 1H), 6.00 - 5.94 (m, 1H), 5.29 - 5.20 (m, 2H), 4.48 (t, J = 7.8 Hz, 1H), 4.30 (q, J = 7.3 Hz, 3H), 4.13 - 4.02 (m, 1H), 3.85 - 3.68 (m, 2H), 3.61 - 3.52 (m, 1H), 2.37 (s, 3H), 1.55 (td, J = 7.4, 1.0 Hz, 3H). ESI-MS m/z 582.4 (M+H) +

Figure pat00279
Figure pat00279

화합물 95. tert-butyl (1-(6-(((3R,4R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamateCompound 95. tert-butyl (1-(6-(((3R,4R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6-(( 2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate

화합물 93 (1650mg, 1 eq)의 아세토니트릴 (10 mL) 용액에 DBU/formic acid (2 eq:5 eq)의 아세토니트릴 (50 mL) 용액을 상온에서 넣고 for 20 min 교반한다. 반응혼합물에 RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.1 eq)을 넣어주고 70 °C에서 2 h 교반하고 상온에서 포화 NaHCO3 수용액을 넣어 ??칭한다. 반응홍합물을 CH2Cl2로 추출하고 유기층을 NH4Cl 수용액으로 세척하고 MgSO4로 건조한 다음 감압농축한다. 농축물을 MPLC로 정제하여 화합물 95 (1.05 g, 57%)을 얻는다. An acetonitrile (50 mL) solution of DBU/formic acid (2 eq: 5 eq) was added to a solution of compound 93 (1650 mg, 1 eq) in acetonitrile (10 mL) at room temperature and stirred for 20 min. Add RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.1 eq) to the reaction mixture, stir at 70 °C for 2 h, and quench by adding saturated NaHCO 3 aqueous solution at room temperature. The reaction mussel was extracted with CH 2 Cl 2 , and the organic layer was washed with aqueous NH 4 Cl solution, dried over MgSO 4 and then concentrated under reduced pressure. The concentrate is purified by MPLC to give compound 95 (1.05 g, 57%).

1H NMR (400 MHz, CDCl3) δ 7.46 (d, J = 1.0 Hz, 1H), 7.09 - 7.04 (m, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 6.44 (dd, J = 7.9, 2.7 Hz, 1H), 5.44 (s, 1H), 4.91 (d, J = 6.2 Hz, 2H), 4.60 (s, 1H), 4.43 (t, J = 7.2 Hz, 3H), 4.19 (q, J = 7.4 Hz, 2H), 4.05 - 3.99 (m, 2H), 3.99 - 3.91 (m, 2H), 2.74 - 2.62 (m, 2H), 2.30 - 2.26 (m, 4H), 1.50 (t, J = 7.4 Hz, 3H), 1.43 (s, 9H). ESI-MS m/z 686.4 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.46 (d, J = 1.0 Hz, 1H), 7.09 - 7.04 (m, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6.85 (d, J = 1.4 Hz, 1H), 6.79 (d, J = 1.4 Hz, 1H), 6.44 (dd, J = 7.9, 2.7 Hz, 1H), 5.44 (s, 1H) , 4.91 (d, J = 6.2 Hz, 2H), 4.60 (s, 1H), 4.43 (t, J = 7.2 Hz, 3H), 4.19 (q, J = 7.4 Hz, 2H), 4.05 - 3.99 (m, 2H), 3.99 - 3.91 (m, 2H), 2.74 - 2.62 (m, 2H), 2.30 - 2.26 (m, 4H), 1.50 (t, J = 7.4 Hz, 3H), 1.43 (s, 9H). ESI-MS m/z 686.4 (M+H) +

Figure pat00280
Figure pat00280

화합물 96. tert-butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamateCompound 96. tert-butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H- imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate

화합물 95 (960mg, 1 eq)와 Molecular sieves 4 Å (100 mg)의 CH2Cl2 (60 mL) 용액을 30 min 교반하고. N-메틸모르폴린 N-옥사이드 (NMO, 2 eq)과 테트라프로필암모늄 퍼루테네이트 (TPAP, 0.2 eq)을 0°C에서 넣어주고, 상온에서 3 h 교반한다. 검은색 반응혼합물을 celite에서 diethyl ether 용매로 여과하고 여액을 감압농축한다. 농축물을 MPLC로 정제하여 화합물 96 (500 mg, 52%)을 얻는다.A solution of Compound 95 (960mg, 1 eq) and Molecular sieves 4 Å (100 mg) in CH 2 Cl 2 (60 mL) was stirred for 30 min. Add N-methylmorpholine N-oxide (NMO, 2 eq) and tetrapropylammonium perruthenate (TPAP, 0.2 eq) at 0°C, and stir at room temperature for 3 h. The black reaction mixture was filtered through celite with a diethyl ether solvent, and the filtrate was concentrated under reduced pressure. The concentrate is purified by MPLC to give compound 96 (500 mg, 52%).

1H NMR (400 MHz, CDCl3) δ 7.79 - 7.72 (m, 1H), 7.49 (d, J = 1.1 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 11.6, 7.9 Hz, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.84 (d, J = 1.4 Hz, 1H), 6.48 (dd, J = 8.0, 2.7 Hz, 1H), 5.01 (s, 3H), 4.54 (dd, J = 11.4, 5.0 Hz, 2H), 4.36 (d, J = 8.9 Hz, 2H), 4.31 - 4.21 (m, 3H), 3.83 (ddd, J = 9.3, 5.6, 1.5 Hz, 2H), 3.34 (ddt, J = 10.6, 9.0, 4.7 Hz, 1H), 3.26 (dd, J = 14.7, 4.3 Hz, 1H), 2.72 (dd, J = 14.6, 8.9 Hz, 1H), 2.36 (s, 3H), 1.55 (t, J = 7.4 Hz, 3H), 1.44 (s, 9H). ESI-MS m/z 684.2 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.79 - 7.72 (m, 1H), 7.49 (d, J = 1.1 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.05 (dd, J = 11.6, 7.9 Hz, 1H), 6.95 (d, J = 1.4 Hz, 1H), 6.84 (d, J = 1.4 Hz, 1H), 6.48 (dd, J = 8.0, 2.7 Hz, 1H), 5.01 (s, 3H), 4.54 (dd, J = 11.4, 5.0 Hz, 2H), 4.36 (d, J = 8.9 Hz, 2H), 4.31 - 4.21 (m, 3H), 3.83 (ddd, J = 9.3, 5.6, 1.5 Hz) , 2H), 3.34 (ddt, J = 10.6, 9.0, 4.7 Hz, 1H), 3.26 (dd, J = 14.7, 4.3 Hz, 1H), 2.72 (dd, J = 14.6, 8.9 Hz, 1H), 2.36 ( s, 3H), 1.55 (t, J = 7.4 Hz, 3H), 1.44 (s, 9H). ESI-MS m/z 684.2 (M+H) +

Figure pat00281
Figure pat00281

화합물 97. (R)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochlorideCompound 97. (R)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol -4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride

화합물 96 (488 mg, 1 eq)의 CH2Cl2 용액을 0℃에서 4N-HCl/dioxane (excess)에 넣고 상온에서 2h 교반하고 용매를 제거하여 화합물 97 (440 mg, 99%)을 얻는다.A CH 2 Cl 2 solution of compound 96 (488 mg, 1 eq) was added to 4N-HCl/dioxane (excess) at 0°C, stirred at room temperature for 2 h, and the solvent was removed to obtain compound 97 (440 mg, 99%).

1H NMR (400 MHz, CD3OD) δ 8.02 (s, 1H), 7.91 (dd, J = 7.0, 2.0 Hz, 1H), 7.73 (dd, J = 11.6, 8.0 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.52 (d, J = 3.5 Hz, 2H), 6.89 - 6.77 (m, 1H), 5.47 (s, 2H), 4.80 - 4.57 (m, 3H), 4.48 - 4.34 (m, 2H), 4.29 (q, J = 7.2 Hz, 2H), 4.14 - 3.93 (m, 2H), 3.57 - 3.37 (m, 2H), 3.12 - 2.92 (m, 1H), 2.69 (d, J = 1.4 Hz, 3H), 1.52 (t, J = 7.2 Hz, 3H). ESI-MS m/z 584.2 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 8.02 (s, 1H), 7.91 (dd, J = 7.0, 2.0 Hz, 1H), 7.73 (dd, J = 11.6, 8.0 Hz, 1H), 7.60 - 7.56 (m, 1H), 7.52 (d, J = 3.5 Hz, 2H), 6.89 - 6.77 (m, 1H), 5.47 (s, 2H), 4.80 - 4.57 (m, 3H), 4.48 - 4.34 (m, 2H) ), 4.29 (q, J = 7.2 Hz, 2H), 4.14 - 3.93 (m, 2H), 3.57 - 3.37 (m, 2H), 3.12 - 2.92 (m, 1H), 2.69 (d, J = 1.4 Hz, 3H), 1.52 (t, J = 7.2 Hz, 3H). ESI-MS m/z 584.2 (M+H) +

Figure pat00282
Figure pat00282

화합물 98. tert-butyl (1-(6-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamateCompound 98. tert-butyl (1-(6-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6-(( 2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate

화합물 95 합성과정에서 RuCl(p-cymene)[(R,R)-Ts-DPEN] 대신 RuCl(p-cymene)[(S,S)-Ts-DPEN]을 사용하여 화합물 98 (110 mg, 73%)을 제조하였다.In the synthesis of compound 95, compound 98 (110 mg, 73 %) was prepared.

1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 1.0 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.91 - 6.85 (m, 2H), 6.82 (d, J = 1.4 Hz, 1H), 6.46 (dd, J = 7.9, 2.8 Hz, 1H), 5.01 - 4.88 (m, 2H), 4.62 (s, 1H), 4.51 - 4.40 (m, 3H), 4.21 (q, J = 7.3 Hz, 2H), 4.13 - 4.01 (m, 2H), 3.97 (dq, J = 9.5, 5.8, 5.2 Hz, 2H), 2.77 - 2.64 (m, 2H), 2.32 (s, 3H), 2.29 - 2.23 (m, 1H), 1.53 (t, J = 7.3 Hz, 3H), 1.46 (s, 9H). ESI-MS m/z 686.4 (M+H)+ 1H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J = 1.0 Hz, 1H), 7.11 - 7.03 (m, 2H), 6.91 - 6.85 (m, 2H), 6.82 (d, J = 1.4 Hz, 1H), 6.46 (dd, J = 7.9, 2.8 Hz, 1H), 5.01 - 4.88 (m, 2H), 4.62 (s, 1H), 4.51 - 4.40 (m, 3H), 4.21 (q, J = 7.3 Hz) , 2H), 4.13 - 4.01 (m, 2H), 3.97 (dq, J = 9.5, 5.8, 5.2 Hz, 2H), 2.77 - 2.64 (m, 2H), 2.32 (s, 3H), 2.29 - 2.23 (m , 1H), 1.53 (t, J = 7.3 Hz, 3H), 1.46 (s, 9H). ESI-MS m/z 686.4 (M+H) +

Figure pat00283
Figure pat00283

화합물 99. tert-butyl (S)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamateCompound 99. tert-butyl (S)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H- imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate

화합물 96 합성과정에서 화합물 95 대신 화합물 98 (110 mg, 1eq)을 사용하여 화합물 99 (67 mg, 61%)을 제조하였다.Compound 99 (67 mg, 61%) was prepared using Compound 98 (110 mg, 1 eq) instead of Compound 95 during the synthesis of Compound 96.

1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 2.4 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 11.6, 7.9 Hz, 1H), 6.93 (d, J = 1.4 Hz, 1H), 6.83 (d, J = 1.4 Hz, 1H), 6.46 (dd, J = 7.9, 2.7 Hz, 1H), 5.14 (d, J = 16.8 Hz, 1H), 5.00 (s, 2H), 4.52 (dd, J = 11.4, 5.0 Hz, 2H), 4.37 - 4.30 (m, 2H), 4.28 - 4.19 (m, 3H), 3.82 (ddd, J = 9.6, 5.5, 1.6 Hz, 2H), 3.38 - 3.28 (m, 1H), 3.24 (dd, J = 14.7, 4.3 Hz, 1H), 2.70 (dd, J = 14.7, 8.9 Hz, 1H), 2.34 (s, 3H), 1.53 (t, J = 7.4 Hz, 3H), 1.42 (s, 9H). 1H NMR (400 MHz, CDCl 3 ) δ 7.73 (d, J = 2.4 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.02 (dd, J = 11.6, 7.9 Hz, 1H), 6.93 (d, J = 1.4 Hz, 1H), 6.83 (d, J = 1.4 Hz, 1H), 6.46 (dd, J = 7.9, 2.7 Hz, 1H), 5.14 (d, J = 16.8 Hz, 1H), 5.00 (s, 2H), 4.52 (dd, J = 11.4, 5.0 Hz, 2H), 4.37 - 4.30 (m, 2H), 4.28 - 4.19 (m, 3H), 3.82 (ddd , J = 9.6, 5.5, 1.6 Hz, 2H), 3.38 - 3.28 (m, 1H), 3.24 (dd, J = 14.7, 4.3 Hz, 1H), 2.70 (dd, J = 14.7, 8.9 Hz, 1H), 2.34 (s, 3H), 1.53 (t, J = 7.4 Hz, 3H), 1.42 (s, 9H).

Figure pat00284
Figure pat00284

화합물 100. (S)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochlorideCompound 100. (S)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol -4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride

화합물 97 합성과정에서 화합물 96 대신 화합물 99 (67 mg, 1eq)를 사용하여 화합물 100 (11.5 mg, 19%)을 제조하였다.Compound 100 (11.5 mg, 19%) was prepared using Compound 99 (67 mg, 1 eq) instead of Compound 96 during the synthesis of Compound 97.

1H NMR (400 MHz, CD3OD) δ 7.87 (dd, J = 2.0, 1.0 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.16 (dd, J = 11.1, 7.9 Hz, 1H), 7.10 (t, J = 1.5 Hz, 1H), 6.91 (s, 1H), 6.48 (dd, J = 7.9, 3.0 Hz, 1H), 5.20 (s, 2H), 4.50 (ddd, J = 11.7, 7.0, 4.8 Hz, 1H), 4.32 - 4.22 (m, 3H), 3.77 (ddd, J = 11.6, 4.1, 2.7 Hz, 1H), 3.72 - 3.50 (m, 5H), 3.24 - 3.14 (m, 1H), 2.85 - 2.74 (m, 1H), 2.33 (s, 3H), 1.51 (td, J = 7.3, 0.5 Hz, 3H). ESI-MS m/z 620.1 (M+H)+ 1H NMR (400 MHz, CD 3 OD) δ 7.87 (dd, J = 2.0, 1.0 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 2.2 Hz, 1H), 7.16 (dd, J = 11.1, 7.9 Hz, 1H), 7.10 (t, J = 1.5 Hz, 1H), 6.91 (s, 1H), 6.48 (dd, J = 7.9, 3.0 Hz, 1H), 5.20 (s , 2H), 4.50 (ddd, J = 11.7, 7.0, 4.8 Hz, 1H), 4.32 - 4.22 (m, 3H), 3.77 (ddd, J = 11.6, 4.1, 2.7 Hz, 1H), 3.72 - 3.50 (m , 5H), 3.24 - 3.14 (m, 1H), 2.85 - 2.74 (m, 1H), 2.33 (s, 3H), 1.51 (td, J = 7.3, 0.5 Hz, 3H). ESI-MS m/z 620.1 (M+H) +

<실험예 1: MLL1 HMT IC<Experimental Example 1: MLL1 HMT IC 5050 값 분석> Value analysis>

<MLL1 메틸전달효소 IC50 측정 방법><Method for measuring MLL1 methyltransferase IC50>

MLL1 메틸전달효소 측정 실험은 Reaction Biology Corporation (www.reactionbiology.com, Malvern, PA, USA)에서 수행하였으며, 실험 재료 및 방법은 아래와 같다 (Kurumi, Y. et al., 2013).MLL1 methyltransferase measurement experiments were performed at Reaction Biology Corporation (www.reactionbiology.com, Malvern, PA, USA), and the experimental materials and methods are as follows (Kurumi, Y. et al., 2013).

MLL1 코어 단백복합체는 인간 MLL1 (아미노산 3745-3969, 등록번호 #NM_005933), WDR5 (아미노산 22-334; #NM_017588), RbBP5 (아미노산 1-538, NM_005057), Ash2L (아미노산2-534, NM_001105214), 그리고 DPY-30 (아미노산 1-99, #NM_0325742)는 대장균 (E. coli)에 발현하여 N-말단 히스티딘-표지자 (histidine-tags)로 분리하였고 20 mM 트리스-하이드로콜로라이드 (pH 7.5), 300mM 염화칼슘, 1 mM 트리(크로로에틸)인산염, 10% (w/v) 글리세롤, 그리고 1μM 염화아연으로 보존하였다.The MLL1 core protein complex includes human MLL1 (amino acids 3745-3969, accession number #NM_005933), WDR5 (amino acids 22-334; #NM_017588), RbBP5 (amino acids 1-538, NM_005057), Ash2L (amino acids 2-534, NM_001105214), And DPY-30 (amino acid 1-99, #NM_0325742) was expressed in E. coli and isolated with N-terminal histidine-tags, and 20 mM Tris-hydrochloride (pH 7.5), 300 mM It was preserved with calcium chloride, 1 mM tri(chloroethyl)phosphate, 10% (w/v) glycerol, and 1 μM zinc chloride.

본 실험에 사용된 뉴클레오좀은 HeLa 세포에서 분리하였고, 히스톤 H3 단백질과 히스톤 H3 펩타이드 아미노산 1-21, S-아데노실-l-[메틸-3H]메타이오닌 (3H-SAM), 스트렙타비틴이 코팅되어있는 플레쉬플레이트 (FlashPlate)는 구매하여 사용하였다. 메틸전달효소를 측정하기 위해 동위원소 기반의 HotSpot 포멧을 사용하였으며 히스톤 메틸전달효소를 위한 반응 용액으로 50mM 트리스-하이드로콜로라이드 (pH 8.5), 50mM 염화칼슘, 1mM 염화마그네슘, 1mM 디티오트레이톨(DTT), 1mM 페닐메탄설포닐플루오라이드(PMSF)를 사용하였다.Nucleosomes used in this experiment were isolated from HeLa cells, histone H3 protein and histone H3 peptide amino acids 1-21, S-adenosyl-l-[methyl-3H]methionine (3H-SAM), streptavidin A tin-coated FlashPlate was purchased and used. To measure methyltransferase, an isotope-based HotSpot format was used. As a reaction solution for histone methyltransferase, 50mM Tris-hydrochloride (pH 8.5), 50mM calcium chloride, 1mM magnesium chloride, 1mM dithiothreitol (DTT ), 1 mM phenylmethanesulfonylfluoride (PMSF) was used.

표준 기질로 5μM의 히스티딘이 표지되어있는 MLL1 코어 단백 복합체와 50μg/ml 뉴클레오좀, 1μM S-아데노실-l-[메틸-3H]메타이오닌 (3H-SAM)과 테스트 화합물을 반응 용액과 함께 30℃에서 1시간 동안 반응하였다. 반응 혼합물은 필터-결합 방법으로 필터 페이퍼에 스팟팅한 다음 이를 세척하여 미반응 SAM을 제거하고 검출을 위해 결합된 방사성 표지된 생성물은 0.1% 디메틸설폭사이드 반응과 비교하여 테스트 화합물에서 남은 MLL1 메틸전달효소 활성을 백분율로 계산하였다. IC50 측정을 위해 테스트 화합물은 0.1%의 최종 농도 디메틸설폭사이드로 희석 (1:3의 비율로 희석, 9개 농도, 출발 농도 100 μM 또는 10μM)하여 실험하였으며, Echo550 (Labcyte)을 사용하여 나노리터 양의 효소/기질 혼합물에 첨가하였다. 양성대조 화합물로서 S-아데노실-l-호모시스테인(SAH)을 사용하였다. 저해 프로필 및 IC50는 GraphPad Prism 소프트웨어를 이용하여 계산하였다. 곡선 적합(curve fit)을 위한 삼항 복소 방정식을 사용한 GraFit (Erithacus)을 사용하여 통계분석하였고, 그 방정식은 아래와 같다. As standard substrates, 5 μM histidine-labeled MLL1 core protein complex, 50 μg/ml nucleosomes, 1 μM S-adenosyl-l-[methyl-3H]methionine (3H-SAM) and test compounds were mixed with the reaction solution. They were reacted together at 30° C. for 1 hour. The reaction mixture was spotted on filter paper by the filter-binding method and washed to remove unreacted SAM, and the bound radiolabeled product for detection was compared with the 0.1% dimethylsulfoxide reaction to determine the MLL1 methyl transfer remaining in the test compound. Enzyme activity was calculated as a percentage. For IC50 determination, test compounds were diluted in dimethylsulfoxide to a final concentration of 0.1% (1:3 dilution, 9 concentrations, starting concentration 100 μM or 10 μM) and tested using Echo550 (Labcyte) in nanoliters. An amount was added to the enzyme/substrate mixture. As a positive control compound, S-adenosyl-l-homocysteine (SAH) was used. Inhibition profiles and IC50 were calculated using GraphPad Prism software. Statistical analysis was performed using GraFit (Erithacus) using a ternary complex equation for curve fit, and the equation is as follows.

Figure pat00285
Figure pat00285

[A는 S-아데노실-메타이오닌 (SAM); B는 단백질 기질; KA 및 KB는 각 기질에 대한 미하엘리스 상수; KA’는 SAM의 해리 상수][A is S-adenosyl-methionine (SAM); B is a protein substrate; KA and KB are the Michaelis constants for each substrate; KA' is the dissociation constant of SAM]

본 발명에 따른 화합물을 이용하여 하기 표 1, 표 2에 나타난 바와 같이 MLL1 HMT IC50 값을 측정하여 활성 결과를 확인하였다.As shown in Tables 1 and 2 below, the MLL1 HMT IC 50 value was measured using the compound according to the present invention, and the activity result was confirmed.

Figure pat00286
Figure pat00286

Figure pat00287
Figure pat00287

Figure pat00288
Figure pat00288

Figure pat00289
Figure pat00289

Figure pat00290
Figure pat00290

Figure pat00291
Figure pat00291

Figure pat00292
Figure pat00292

Figure pat00293
Figure pat00293

Figure pat00294
Figure pat00294

Figure pat00295
Figure pat00295

Figure pat00296
Figure pat00296

Figure pat00297
Figure pat00297

Figure pat00298
Figure pat00298

Figure pat00299
Figure pat00299

Figure pat00300
Figure pat00300

표 1, 표 2에서 보듯이, 본 발명 실시예 화합물들은 우수한 MLL1 HMT IC50 값을 갖는다. 특히 본 발명 화합물들의 구조-활성 비교를 통해, 본 발명 화학식 1에서 R1은 아릴, 헤테로시클로알킬, 사이클로알킬, 또는 헤테로아릴로 치환되면서, R2가 [화학식 3-1] 또는 [화학식 3-2]로 치환되고, 동시에 R3가 [화학식 2-1], [화학식 2-2], 또는 [화학식 2-3]으로 치환된 화합물들에서 우수한 MLL1 HMT IC50 값을 보여주었으며, in vivo 동물모델에서도 우수한 항암효과를 확인하였다. As shown in Tables 1 and 2, the compounds of the Examples of the present invention have excellent MLL1 HMT IC 50 values. In particular, through structure-activity comparison of the compounds of the present invention, in Formula 1 of the present invention, R 1 is substituted with aryl, heterocycloalkyl, cycloalkyl, or heteroaryl, while R 2 is [Formula 3-1] or [Formula 3- 2] and at the same time R 3 was substituted with [Formula 2-1], [Formula 2-2], or [Formula 2-3] showed excellent MLL1 HMT IC 50 values, and in vivo animals Excellent anticancer effect was also confirmed in the model.

<제제예 1. 산제의 제조><Formulation Example 1. Preparation of Powder>

본 발명 화합물 13 2 g, 유당 1 g을 혼합하고 기밀포에 충진하여 산제를 제조하였다.2 g of the compound 13 of the present invention and 1 g of lactose were mixed and filled in an airtight bag to prepare a powder.

<제제예 2. 정제의 제조><Formulation Example 2. Preparation of tablets>

본 발명 화합물 13 100 ㎎, 미결정셀룰로오스 100 ㎎, 유당수화물 60 ㎎, 저치환도히드록시프로필셀룰로오스 20 ㎎ 및 스테아르산마그네슘 2 ㎎을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.Tablets were prepared by mixing 100 mg of the compound 13 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, and then tableting according to a conventional tablet manufacturing method. .

<제제예 3. 캡슐제의 제조><Formulation Example 3. Preparation of capsules>

본 발명 화합물 13 100 ㎎, 미결정셀룰로오스 100 ㎎, 유당수화물 60 ㎎, 저치환도히드록시프로필셀룰로오스 20 ㎎ 및 스테아르산마그네슘 2 ㎎을 혼합한 후 통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing 100 mg of the compound 13 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, the above ingredients were mixed according to a conventional capsule preparation method, Capsules were prepared by filling gelatin capsules.

<제제예 4. 환제의 제조><Formulation Example 4. Preparation of pills>

본 발명 화합물 13 90 ㎎, 찹쌀전분 5 ㎎ 및 정제수 5 ㎎ 및 흡습성을 저해하는 첨가제로서 덱스트린, 말토덱스트린, 옥수수전분, 미결정셀룰로오스(MCC)를 소량 혼합한 후, 통상의 방법에 따라 100 ㎎의 환제를 만들었다.After mixing 90 mg of the compound 13 of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water, and dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives that inhibit hygroscopicity, 100 mg of pills according to a conventional method made

<제제예 5. 주사제의 제조><Formulation Example 5. Preparation of Injections>

본 발명 화합물 13 10 ㎎, 주사용 멸균 증류수 적량 및 pH 조절제 적량을 혼합한 후 통상의 주사제의 제조방법에 따라 1 앰플당(2 ㎖) 상기의 성분 함량으로 제조하였다.After mixing 10 mg of the compound 13 of the present invention, an appropriate amount of sterilized distilled water for injection, and an appropriate amount of a pH adjusting agent, the above ingredients were prepared per ampoule (2 ml) according to a conventional method for preparing an injection.

Claims (9)

하기 화학식 1, 또는 이의 거울상 이성질체, 부분입체 이성질체, 입체 이성질체, 수화물, 용매화물, 프로드럭 또는 이의 약제학적으로 허용 가능한 염인 화합물;
[화학식 1]
Figure pat00301

상기 식 중,
A는 -C(O)- 또는 -C(OH)-로 치환되며;
R1은 치환 또는 비치환된 3~6각의 사이클로알킬, 치환 또는 비치환된 4~10각의 아릴, 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴로 이루어진 군에서 선택되는 치환기로 치환되고,
여기서 상기 치환된 사이클로알킬, 아릴, 헤테로사이클로알킬, 또는 헤테로아릴은 독립적으로 수소, 할로겐, 아미노, 카르복실산, C1-C6 알콕시카보닐, -NH-tert-부톡시카보닐, -N(C1-C3 알킬)-tert-부톡시카보닐아미노, 모노(또는 디)C1-C6 알킬아미노, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 할로 C1-C6 알콕시, (C1-C6 알콕시)카보닐(C1-C6 알콕시), -O[(CH2)1-4O]1-4CH3, -O[(CH2)1-4O]1-4CH2C(O)OH, -O[(CH2)1-4O]1-4CH2C(O)O(C1-C3 알킬), -O(CH2)1-4C(O)OH, -O(CH2)1-4C(O)O(C1-C3 알킬), C1-C3 알킬옥시카보닐, 치환 또는 비치환된 아제티딘, 치환 또는 비치환된 피페라진, 치환 또는 비치환된 피리딘, 또는 치환 또는 비치환된 피페리딘, 치환 또는 비치환된 피페리딘-2,5-디온으로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며,
여기서 상기 치환된 아제티딘, 피페라진, 피리딘, 피페리딘, 피페리딘-2,5-디온은 독립적으로 수소, 할로겐, 아미노, tert-부톡시카보닐, -NH-tert-부톡시카보닐, -N(C1-C3 알킬)-tert-부톡시카보닐, C1-C6 알킬 아미노, 벤질옥시로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;
R2는 할로겐, 치환 또는 비치환된 3~6각의 사이클로알킬, 치환 또는 비치환된 4~10각의 아릴, 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴이고,
상기 치환된 사이클로알킬, 아릴, 헤테로사이클로알킬, 또는 헤테로아릴은 독립적으로 수소, 할로겐, C1-C6 알킬, 아세트아미도, 할로 C1-C6 알킬, C1-C6 알콕시, 할로 C1-C6 알콕시 또는 메톡시-(C1-C2 알콕시)1-5(C1-C2 알킬)로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;
R3는 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴이고,
상기 치환된 헤테로사이클로알킬 또는 헤테로아릴은 독립적으로 수소, 할로겐, =N-tert-부톡시카보닐, =NH, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시 또는 할로 C1-C6 알콕시로 치환되며;
상기 화학식에서
Figure pat00302
는 단일결합 또는 이중결합을 의미한다.Compounds of Formula 1 below, or enantiomers, diastereomers, stereoisomers, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof;
[Formula 1]
Figure pat00301

In the above formula,
A is substituted with -C(O)- or -C(OH)-;
R 1 is substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted 4-10 membered cycloalkyl It is substituted with a substituent selected from the group consisting of 10-membered heteroaryl,
wherein said substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, amino, carboxylic acid, C 1 -C 6 alkoxycarbonyl, -NH-tert-butoxycarbonyl, -N (C 1 -C 3 alkyl)-tert-butoxycarbonylamino, mono(or di)C 1 -C 6 alkylamino, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 Alkoxy, halo C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)carbonyl(C 1 -C 6 alkoxy), -O[(CH 2 ) 1-4 O] 1-4 CH 3 , -O[ (CH 2 ) 1-4 O] 1-4 CH 2 C(O)OH, -O[(CH 2 ) 1-4 O] 1-4 CH 2 C(O)O(C 1 -C 3 alkyl) , -O(CH 2 ) 1-4 C(O)OH, -O(CH 2 ) 1-4 C(O)O(C 1 -C 3 alkyl), C 1 -C 3 alkyloxycarbonyl, substituted or from the group consisting of unsubstituted azetidine, substituted or unsubstituted piperazine, substituted or unsubstituted pyridine, or substituted or unsubstituted piperidine, or substituted or unsubstituted piperidine-2,5-dione Substituted with one or more substituents selected,
wherein the substituted azetidine, piperazine, pyridine, piperidine, piperidine-2,5-dione is independently hydrogen, halogen, amino, tert-butoxycarbonyl, -NH-tert-butoxycarbonyl , -N(C 1 -C 3 alkyl)-tert-butoxycarbonyl, C 1 -C 6 alkyl amino, substituted with one or more substituents selected from the group consisting of benzyloxy;
R 2 is halogen, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted It is a 4-10-membered heteroaryl,
The substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, C 1 -C 6 alkyl, acetamido, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C It is substituted with one or more substituents selected from the group consisting of 1 -C 6 alkoxy or methoxy-(C 1 -C 2 alkoxy) 1-5 (C 1 -C 2 alkyl);
R 3 is a substituted or unsubstituted 3-6 membered heterocycloalkyl or a substituted or unsubstituted 4-10 membered heteroaryl;
The substituted heterocycloalkyl or heteroaryl is independently hydrogen, halogen, =N-tert-butoxycarbonyl, =NH, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halo C 1 -C 6 alkoxy;
in the above formula
Figure pat00302
means a single bond or a double bond. 하기 화학식 2, 또는 이의 거울상 이성질체, 부분입체 이성질체, 입체 이성질체, 수화물, 용매화물, 프로드럭 또는 이의 약제학적으로 허용 가능한 염인 화합물;
[화학식 2]
Figure pat00303

상기 식 중,
A는 -C(O)- 또는 -C(OH)-로 치환되며;
R1은 치환 또는 비치환된 3~6각의 사이클로알킬, 치환 또는 비치환된 4~10각의 아릴, 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴로 이루어진 군에서 선택되는 치환기로 치환되고,
여기서 상기 치환된 사이클로알킬, 아릴, 헤테로사이클로알킬, 또는 헤테로아릴은 독립적으로 수소, 할로겐, 아미노, 카르복실산, C1-C6 알콕시카보닐, -NH-tert-부톡시카보닐, -N(C1-C3 알킬)-tert-부톡시카보닐, 모노(또는 디)C1-C6 알킬아미노, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 할로 C1-C6 알콕시, (C1-C6 알콕시)카보닐(C1-C6 알콕시), -O[(CH2)1-4O]1-4CH3, -O[(CH2)1-4O]1-4CH2C(O)OH, -O[(CH2)1-4O]1-4CH2C(O)O(C1-C3 알킬), -O(CH2)1-4C(O)OH, -O(CH2)1-4C(O)O(C1-C3 알킬), C1-C3 알킬옥시카보닐, 치환 또는 비치환된 아제티딘, 치환 또는 비치환된 피페라진, 치환 또는 비치환된 피리딘, 또는 치환 또는 비치환된 피페리딘, 치환 또는 비치환된 피페리딘-2,5-디온으로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며,
여기서 상기 치환된 아제티딘, 피페라진, 피리딘, 피페리딘, 피페리딘-2,5-디온은 독립적으로 수소, 할로겐, 아미노, tert-부톡시카보닐, -NH-tert-부톡시카보닐, -N(C1-C3 알킬)-tert-부톡시카보닐, C1-C6 알킬 아미노, 벤질옥시로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;
R2는 할로겐, 치환 또는 비치환된 3~6각의 사이클로알킬, 치환 또는 비치환된 4~10각의 아릴, 치환 또는 비치환된 3~6각의 헤테로사이클로알킬, 또는 치환 또는 비치환된 4~10각의 헤테로아릴이고,
상기 치환된 사이클로알킬, 아릴, 헤테로사이클로알킬, 또는 헤테로아릴은 독립적으로 수소, 할로겐, C1-C6 알킬, 아세트아미도, 할로 C1-C6 알킬, C1-C6 알콕시, 할로 C1-C6 알콕시 또는 메톡시-(C1-C2 알콕시)1-5(C1-C2알킬)로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;
R3는 하기 화학식 2-1, 화학식 2-2, 또는 화학식 2-3으로 치환되며.
[화학식 2-1]
Figure pat00304

[화학식 2-2]
Figure pat00305

[화학식 2-3]
Figure pat00306

상기 화학시 2-1 내지 화학식 2-3의 식 중에서,
R4는 수소, tert-부톡시카보닐, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시로 치환되며,
R5는 수소, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시로 치환; 된다. Compounds of Formula 2 below, or enantiomers, diastereomers, stereoisomers, hydrates, solvates, prodrugs, or pharmaceutically acceptable salts thereof;
[Formula 2]
Figure pat00303

In the above formula,
A is substituted with -C(O)- or -C(OH)-;
R 1 is substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted 4-10 membered cycloalkyl It is substituted with a substituent selected from the group consisting of 10-membered heteroaryl,
wherein said substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, amino, carboxylic acid, C 1 -C 6 alkoxycarbonyl, -NH-tert-butoxycarbonyl, -N (C 1 -C 3 alkyl)-tert-butoxycarbonyl, mono(or di)C 1 -C 6 alkylamino, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy , halo C 1 -C 6 alkoxy, (C 1 -C 6 alkoxy)carbonyl(C 1 -C 6 alkoxy), -O[(CH 2 ) 1-4 O] 1-4 CH 3 , -O[( CH 2 ) 1-4 O] 1-4 CH 2 C(O)OH, -O[(CH 2 ) 1-4 O] 1-4 CH 2 C(O)O(C 1 -C 3 alkyl), -O(CH 2 ) 1-4 C(O)OH, -O(CH 2 ) 1-4 C(O)O(C 1 -C 3 alkyl), C 1 -C 3 alkyloxycarbonyl, substituted or Selected from the group consisting of unsubstituted azetidine, substituted or unsubstituted piperazine, substituted or unsubstituted pyridine, or substituted or unsubstituted piperidine, or substituted or unsubstituted piperidine-2,5-dione It is substituted with one or more substituents that are,
wherein the substituted azetidine, piperazine, pyridine, piperidine, piperidine-2,5-dione is independently hydrogen, halogen, amino, tert-butoxycarbonyl, -NH-tert-butoxycarbonyl , -N(C 1 -C 3 alkyl)-tert-butoxycarbonyl, C 1 -C 6 alkyl amino, substituted with one or more substituents selected from the group consisting of benzyloxy;
R 2 is halogen, substituted or unsubstituted 3-6 membered cycloalkyl, substituted or unsubstituted 4-10 membered aryl, substituted or unsubstituted 3-6 membered heterocycloalkyl, or substituted or unsubstituted It is a 4-10-membered heteroaryl,
The substituted cycloalkyl, aryl, heterocycloalkyl, or heteroaryl is independently hydrogen, halogen, C 1 -C 6 alkyl, acetamido, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C It is substituted with one or more substituents selected from the group consisting of 1 -C 6 alkoxy or methoxy-(C 1 -C 2 alkoxy) 1-5 (C 1 -C 2 alkyl);
R 3 is substituted with Formula 2-1, Formula 2-2, or Formula 2-3.
[Formula 2-1]
Figure pat00304

[Formula 2-2]
Figure pat00305

[Formula 2-3]
Figure pat00306

In the formulas of Chemical Formulas 2-1 to 2-3,
R 4 is substituted with hydrogen, tert-butoxycarbonyl, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy;
R 5 is substituted with hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy; do. 제2항에 있어서,
상기 식 중,
R2는 하기 화학식 3-1 또는 화학식 3-2로 치환되며.
[화학식 3-1]
Figure pat00307

[화학식 3-2]
Figure pat00308

상기 화학시 3-1 또는 화학식 3-2의 식 중에서,
R6는 수소, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시로 치환되며,
R7는 수소, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시 또는 메틸-(C1-C2 알콕시)1-5로 치환되며,
R8은 독립적으로 수소, C1-C6 알킬, 할로 C1-C6 알킬, C1-C6 알콕시, 또는 할로 C1-C6 알콕시, 또는 아세트아미도로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;
X는 N, CH, 또는 C 이며, m은 0 내지 2의 정수;이다According to claim 2,
In the above formula,
R 2 is substituted with Formula 3-1 or Formula 3-2.
[Formula 3-1]
Figure pat00307

[Formula 3-2]
Figure pat00308

In the formula of 3-1 or Formula 3-2,
R 6 is substituted with hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy;
R 7 is hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy or methyl-(C 1 -C 2 alkoxy) 1-5 is replaced,
R 8 is independently one or more selected from the group consisting of hydrogen, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or halo C 1 -C 6 alkoxy, or acetamido. substituted with a substituent;
X is N, CH, or C, m is an integer from 0 to 2; 제1항에 있어서,
상기 화학식 1로 표시되는 화합물은,
(S)-3-(3,4-디클로로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 1);
(S)-3-(3,4-디클로로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 2);
(S)-N-(4-(3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-8-일)피리딘-2-일)아세트아미드(화합물 3);
(S)-8-(3,5-비스(트리플루오로메틸)페닐)-3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 4);
(S)-3-(3,4-디클로로벤질)-8-(3,4-디메톡시페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 5);
(S)-3-(3,4-디클로로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노옥사졸-3(2H)-일)메틸)크로만-4-온(화합물 6);
(R)-3-(3,4-디클로로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 7);
(R)-3-(3,4-디클로로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 8);
(R)-N-(4-(3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-8-일)피리딘-2-일)아세트아미드(화합물 9);
(R)-8-(3,5-비스(트리플루오로메틸)페닐)-3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 10);
(R)-3-(3,4-디클로로벤질)-8-(3,4-디메톡시페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 11);
(R)-3-(3,4-디클로로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-8-(1-(2-(2-(2-메톡시에톡시)에톡시)에틸)-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온(화합물 12);
(S)-3-(2-클로로-4-플루오로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 13);
(S)-3-(2-클로로-4-플루오로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 14);
(S)-N-(4-(3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-8-일)피리딘-2-일)아세트아미드(화합물 15);
(S)-8-(3,5-비스(트리플루오로메틸)페닐)-3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 16);
(S)-3-(2-클로로-4-플루오로벤질)-8-(3,4-디메톡시페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 17);
(R)-3-(2-클로로-4-플루오로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 18);
(R)-3-(2-클로로-4-플루오로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 19);
(R)-N-(4-(3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-8-일)피리딘-2-일)아세트아미드(화합물 20);
(R)-8-(3,5-비스(트리플루오로메틸)페닐)-3-(2-클로로-4-플루오로벤질)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 21);
(R)-3-(2-클로로-4-플루오로벤질)-8-(3,4-디메톡시페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 22);
tert-부틸 (S)-(4-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트(화합물 23);
(S)-3-((4-아미노사이클로헥실)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 24);
tert-부틸 (S)-(4-((8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트(화합물 25);
(S)-3-((4-아미노사이클로헥실)메틸)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 26);
tert-부틸 (R)-(4-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트(화합물 27);
(R)-3-((4-아미노사이클로헥실)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 28);
tert-부틸 (R)-(4-((8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)사이클로헥실)카바메이트(화합물 29);
(R)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 30);
(S)-3-(3,4-디클로로벤질)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 31);
3-(3,4-디클로로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 32);
3-(3,4-디클로로벤질)-8-(6-플루오로-2-메틸피리딘-3-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 33);
3-(3-(2-((2-(2-(l1-옥시다네일)에톡시)에틸)(메틸)-l3-옥시다네일)에톡시)-4-플루오로벤질)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 34);
2,2,2-트리플루오로아세트알데히드-(E)-3-(3,5-디메톡시벤질리덴)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 35);
3-(3,5-디메톡시벤질)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 36);
(S)-3-(2,6-디브로모-3,5-디메톡시벤질)-8-(4-플루오로페닐)-6-((2-이미노-3-메틸-2,3-디하이드로-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 37);
메틸 2-(5-((8-브로모-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트(화합물 38);
메틸 (Z)-2-(5-((8-브로모-6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트(화합물 39);
메틸 (E)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세테이트(화합물 40);
(E)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)아세틱 애시드(화합물 41);
메틸 2-(2-클로로-5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)페녹시)아세테이트(화합물 42);
2-(2-클로로-5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)페녹시)아세틱 애시드(화합물 43);
메틸 (Z)-2-(2-(2-(2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)에톡시)에톡시)에톡시)아세테이트(화합물 44);
(Z)-2-(2-(2-(2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)에톡시)에톡시)에톡시)아세틱 애시드(화합물 45);
에틸 5-(2-클로로-5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)페녹시)펜타노에이트(화합물 46);
5-(2-클로로-5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)페녹시)펜타노익 애시드(화합물 47);
에틸 (Z)-5-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노에이트(화합물 48);
(Z)-5-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노익 애시드(화합물 49);
에틸 (Z)-5-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(6-플루오로-2-메틸피리딘-3-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노에이트(화합물 50);
(Z)-5-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(6-플루오로-2-메틸피리딘-3-일)-4-옥소크로만-3-일)메틸)-2-클로로페녹시)펜타노익 애시드(화합물 51);
(S,Z)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세틱 애시드(화합물 52);
메틸 2-(2-클로로-5-(((3S,4S)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)메틸)-4-히드록시크로만-3-일)메틸)페녹시)아세테이트(화합물 53);
메틸 (E)-2-(5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)메틸)-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트(화합물 54);
메틸 (S,E)-5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로벤조에이트(화합물 55);
(S,E)-5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)-2-플루오로벤조익 애시드(화합물 56);
메틸 (S,E)-5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로벤조에이트(화합물 57);
(S,E)-5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로벤조익 애시드(화합물 58);
메틸 2-(5-(((3E)-6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일리덴)메틸)-2-플루오로페녹시)아세테이트(화합물 60);
메틸 2-(5-(((3S,4S)-6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-히드록시크로만-3-일)메틸)-2-플루오로페녹시)아세테이트(화합물 61);
메틸 (S,Z)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세테이트(화합물 62);
(S,Z)-2-(5-((6-((2-((tert-부톡시카보닐)이미노)-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)-8-(4-플루오로-2-메틸페닐)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세틱 애시드(화합물 63);
tert-부틸 (E)-메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일리덴)메틸)피리미딘-2-일)아제티딘-3-일)카바메이트(화합물 64);
tert-부틸 (E)-메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일리덴)메틸)피리딘-2-일)아제티딘-3-일)카바메이트(화합물 65);
tert-부틸 (1-(6-(((3S,4S)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-3-일)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카바메이트(화합물 66);
tert-부틸 (S)-메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리딘-2-일)아제티딘-3-일)카바메이트(화합물 67);
(S)-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-3-((4-메틸-6-(3-(메틸아미노)아제티딘-1-일)피리딘-2-일)메틸)크로만-4-온 히드로클로라이드 (화합물 68);
tert-부틸 메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리딘-2-일)아제티딘-3-일)카바메이트(화합물 69);
tert-부틸 (1-(6-(((3R,4R)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-3-일)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카바메이트(화합물 70); ;
tert-부틸 (R)-메틸(1-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리딘-2-일)아제티딘-3-일)카바메이트(화합물 71);
(R)-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-3-((4-메틸-6-(3-(메틸아미노)아제티딘-1-일)피리딘-2-일)메틸)크로만-4-온 히드로클로라이드(화합물 72);
(S)-3-((4-메톡시피리딘-2-일)메틸)-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온(화합물 73);
tert-부틸 (E)-4-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일리덴)메틸)피리미딘-2-일)피페라진-1-카복실레이트(화합물 74);
tert-부틸 4-(4-(((3S,4S)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-3-일)메틸)-6-메틸피리미딘-2-일)피페라진-1-카복실레이트(화합물 75);
tert-부틸 (S)-4-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리미딘-2-일)피페라진-1-카복실레이트(화합물 76);
tert-부틸 4-(4-(((3R,4R)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-3-일)메틸)-6-메틸피리미딘-2-일)피페라진-1-카복실레이트(화합물 77);
tert-부틸 (R)-4-(4-메틸-6-((6-((2-메틸-1H-이미다졸-1-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-3-일)메틸)피리미딘-2-일)피페라진-1-카복실레이트(화합물 78);
(R)-6-((2-메틸-1H-이미다졸-1-일)메틸)-3-((6-메틸-2-(피페라진-1-일)피리미딘-4-일)메틸)-8-(1-메틸-3-(트리플루오로메틸)-1H-피라졸-4-일)크로만-4-온 히드로클로라이드(화합물 79);
(R)-3-((6-클로로-4-메틸피리딘-2-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온(화합물 81);
(S)-2-(5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페녹시)아세틱 애시드(화합물 82);
tert-부틸 (R)-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)(메틸)카바메이트(화합물 83);
(R)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-3-((4-메틸-6-(3-(메틸아미노)아제티딘-1-일)피리딘-2-일)메틸)크로만-4-온 히드로클로라이드(화합물 84);
tert-부틸 (R)-N-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-4-메틸피리딘-2-일)아제티딘-3-일)-N-메틸글리시네이트(화합물 85);
tert-부틸 ((Z)-1-((3-((E)-3-브로모-4-플루오로벤질리덴)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-6-일)메틸)-3-메틸-1,3-디히드로-2H-이미다졸-2-일리덴)카바메이트(화합물 87);
tert-부틸 ((Z)-1-((3-((E)-3-(2,6-비스(벤질옥시)피리딘-3-일)-4-플루오로벤질리덴)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-옥소크로만-6-일)메틸)-3-메틸-1,3-디히드로-2H-이미다졸-2-일리덴)카바메이트(화합물 88);
(E)-3-(3-(2,6-비스(벤질옥시)피리딘-3-일)-4-플루오로벤질리덴)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-이미노-3-메틸-2,3-디히드로-1H-이미다졸-1-일)메틸)크로만-4-온 히드로클로라이드(화합물 89);
3-(5-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((3-메틸이미다졸리딘-1-일)메틸)-4-옥소크로만-3-일)메틸)-2-플루오로페닐)피페리딘-2,6-디온(화합물 90);
tert-부틸 (E)-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일리덴)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 93);
(E)-3-((6-(3-아미노아제티딘-1-일)-5-플루오로피리딘-2-일)메틸렌)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온 히드로클로라이드(화합물 94);
tert-부틸 (1-(6-(((3R,4R)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-3-일)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 95);
tert-부틸 (R)-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 96);
(R)-3-((6-(3-아미노아제티딘-1-일)-5-플루오로피리딘-2-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온 히드로클로라이드(화합물 97);
tert-부틸 (1-(6-(((3S,4S)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-4-히드록시-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-3-일)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 98);
tert-부틸 (S)-(1-(6-((8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)-4-옥소크로만-3-일)메틸)-3-플루오로피리딘-2-일)아제티딘-3-일)카바메이트(화합물 99); 및
(S)-3-((6-(3-아미노아제티딘-1-일)-5-플루오로피리딘-2-일)메틸)-8-(1-에틸-3-(트리플루오로메틸)-1H-피라졸-4-일)-6-((2-메틸-1H-이미다졸-1-일)메틸)크로만-4-온 히드로클로라이드(화합물 100);
으로 이루어진 군에서 선택되는 것을 특징으로 하는 화합물, 또는 이의 광학이성질체, 이의 거울상 이성질체, 부분입체 이성질체, 입체 이성질체, 수화물, 용매화물, 프로드럭, 또는 이들의 약학적으로 허용가능한 염.According to claim 1,
The compound represented by Formula 1,
(S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino- 3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 1);
(S)-3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3- dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 2);
(S)-N-(4-(3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide (Compound 3);
(S)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-di hydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 4);
(S)-3-(3,4-dichlorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imi dazol-1-yl)methyl)chroman-4-one (Compound 5);
(S)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-iminooxazole -3(2H)-yl)methyl)chroman-4-one (Compound 6);
(R)-3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino- 3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 7);
(R)-3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3- dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 8);
(R)-N-(4-(3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide (Compound 9);
(R)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-di hydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 10);
(R)-3-(3,4-dichlorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imine dazol-1-yl)methyl)chroman-4-one (Compound 11);
(R)-3-(3,4-dichlorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-8-( 1-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one (Compound 12) ;
(S)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2- imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 13);
(S)-3-(2-chloro-4-fluorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2 ,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 14);
(S)-N-(4-(3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide (Compound 15);
(S)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2, 3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 16);
(S)-3-(2-chloro-4-fluorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)chroman-4-one (Compound 17);
(R)-3-(2-chloro-4-fluorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2- imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 18);
(R)-3-(2-chloro-4-fluorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2 ,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 19);
(R)-N-(4-(3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)-4-oxochroman-8-yl)pyridin-2-yl)acetamide (Compound 20);
(R)-8-(3,5-bis(trifluoromethyl)phenyl)-3-(2-chloro-4-fluorobenzyl)-6-((2-imino-3-methyl-2, 3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 21);
(R)-3-(2-chloro-4-fluorobenzyl)-8-(3,4-dimethoxyphenyl)-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)chroman-4-one (Compound 22);
tert-Butyl (S)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (Compound 23);
(S)-3-((4-aminocyclohexyl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imid no-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 24);
tert-Butyl (S)-(4-((8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (Compound 25);
(S)-3-((4-aminocyclohexyl)methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2, 3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 26);
tert-Butyl (R)-(4-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (Compound 27);
(R)-3-((4-aminocyclohexyl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imid no-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 28);
tert-Butyl (R)-(4-((8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)cyclohexyl)carbamate (Compound 29);
(R)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole- 1-yl)methyl)chroman-4-one (Compound 30);
(S)-3-(3,4-dichlorobenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole- 1-yl)methyl)chroman-4-one (Compound 31);
3-(3,4-dichlorobenzyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl- 2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 32);
3-(3,4-dichlorobenzyl)-8-(6-fluoro-2-methylpyridin-3-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H -imidazol-1-yl)methyl)chroman-4-one (Compound 33);
3-(3-(2-((2-(2-(l1-oxidaneyl)ethoxy)ethyl)(methyl)-l3-oxidaneyl)ethoxy)-4-fluorobenzyl)-8- (1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)chroman-4-one (Compound 34);
2,2,2-trifluoroacetaldehyde-(E)-3-(3,5-dimethoxybenzylidene)-8-(4-fluorophenyl)-6-((2-imino-3- methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 35);
3-(3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)chroman-4-one (Compound 36);
(S)-3-(2,6-dibromo-3,5-dimethoxybenzyl)-8-(4-fluorophenyl)-6-((2-imino-3-methyl-2,3 -dihydro-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 37);
Methyl 2-(5-((8-bromo-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman -3-yl)methyl)-2-chlorophenoxy)acetate (Compound 38);
Methyl (Z)-2-(5-((8-bromo-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imi dazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate (Compound 39);
Methyl (E)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetate (Compound 40);
(E)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)acetic Acid (Compound 41);
Methyl 2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)acetate (Compound No. 42);
2-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl- 2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)acetic acid (Compound 43);
Methyl (Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro -1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl )-2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetate (Compound 44);
(Z)-2-(2-(2-(2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro- 1H-imidazol-1-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl) -2-fluorophenoxy)ethoxy)ethoxy)ethoxy)acetic acid (Compound 45);
Ethyl 5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl -2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoate (Compound No. 46);
5-(2-chloro-5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-imino-3-methyl- 2,3-dihydro-1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)phenoxy)pentanoic acid (Compound 47);
Ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)penta Noate (Compound 48);
(Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoic Acid (Compound 49);
Ethyl (Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoate (Compound 50);
(Z)-5-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(6-fluoro-2-methylpyridin-3-yl)-4-oxochroman-3-yl)methyl)-2-chlorophenoxy)pentanoic acid (Compound 51);
(S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazole-1- yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy ) acetic acid (compound 52);
Methyl 2-(2-chloro-5-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1- ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methyl)-4-hydroxychroman-3-yl)methyl)phenoxy)acetate (Compound No. 53);
Methyl (E)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((1-ethyl-3-(tri Fluoromethyl)-1H-pyrazol-4-yl)methyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate (Compound 54);
Methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) Methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate (compound 55);
(S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl )-8-(1-Ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoic acid (Compound 56 );
Methyl (S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl) methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoate (Compound 57);
(S,E)-5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl )-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorobenzoic acid (Compound 58);
Methyl 2-(5-(((3E)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazol-1-yl )methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-ylidene)methyl)-2-fluorophenoxy)acetate (Compound 60);
Methyl 2-(5-(((3S,4S)-6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-hydroxychroman-3-yl)methyl)-2-fluorophenoxy)acetate (Compound 61);
Methyl (S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazole-1 -yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetate (Compound 62);
(S,Z)-2-(5-((6-((2-((tert-butoxycarbonyl)imino)-3-methyl-2,3-dihydro-1H-imidazole-1- yl)methyl)-8-(4-fluoro-2-methylphenyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid (Compound 63);
tert-Butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)azetidin-3-yl)carbamate (Compound 64);
tert-Butyl (E)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyridin-2-yl)azetidin-3-yl)carbamate (Compound 65);
tert-butyl (1-(6-(((3S,4S)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(Trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate (compound 66);
tert-Butyl (S)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamate (Compound 67);
(S)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)- 3-((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochloride (Compound 68);
tert-Butyl methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl )-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamate (Compound 69);
tert-butyl (1-(6-(((3R,4R)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3 -(Trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate (compound 70); ;
tert-Butyl (R)-methyl(1-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-( trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyridin-2-yl)azetidin-3-yl)carbamate (Compound 71);
(R)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)- 3-((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochloride (Compound 72);
(S)-3-((4-methoxypyridin-2-yl)methyl)-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3- (Trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one (Compound 73);
tert-Butyl (E)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoro) Romethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-ylidene)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (Compound 74);
tert-Butyl 4-(4-(((3S,4S)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3- (Trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate (Compound 75);
tert-Butyl (S)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoro) Romethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (Compound 76);
tert-Butyl 4-(4-(((3R,4R)-4-hydroxy-6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3- (Trifluoromethyl)-1H-pyrazol-4-yl)chroman-3-yl)methyl)-6-methylpyrimidin-2-yl)piperazine-1-carboxylate (Compound 77);
tert-Butyl (R)-4-(4-methyl-6-((6-((2-methyl-1H-imidazol-1-yl)methyl)-8-(1-methyl-3-(trifluoro Romethyl)-1H-pyrazol-4-yl)-4-oxochroman-3-yl)methyl)pyrimidin-2-yl)piperazine-1-carboxylate (Compound 78);
(R)-6-((2-methyl-1H-imidazol-1-yl)methyl)-3-((6-methyl-2-(piperazin-1-yl)pyrimidin-4-yl)methyl )-8-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)chroman-4-one hydrochloride (Compound 79);
(R)-3-((6-chloro-4-methylpyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)- 6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one (Compound 81);
(S)-2-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazole- 1-yl)methyl)-4-oxochroman-3-yl)methyl)-2-fluorophenoxy)acetic acid (Compound 82);
tert-Butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H -imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)(methyl)carbamate (Compound 83);
(R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)- 3-((4-methyl-6-(3-(methylamino)azetidin-1-yl)pyridin-2-yl)methyl)chroman-4-one hydrochloride (Compound 84);
tert-Butyl (R)-N-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl -1H-imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-4-methylpyridin-2-yl)azetidin-3-yl)-N-methylglycinate ( compound 85);
tert-Butyl ((Z)-1-((3-((E)-3-bromo-4-fluorobenzylidene)-8-(1-ethyl-3-(trifluoromethyl)-1H- pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazol-2-ylidene)carbamate (Compound 87);
tert-butyl ((Z)-1-((3-((E)-3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzylidene)-8-(1 -Ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-oxochroman-6-yl)methyl)-3-methyl-1,3-dihydro-2H-imidazole -2-ylidene)carbamate (Compound 88);
(E)-3-(3-(2,6-bis(benzyloxy)pyridin-3-yl)-4-fluorobenzylidene)-8-(1-ethyl-3-(trifluoromethyl)- 1H-pyrazol-4-yl)-6-((2-imino-3-methyl-2,3-dihydro-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride ( compound 89);
3-(5-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((3-methylimidazolidin-1-yl)methyl )-4-oxochroman-3-yl)methyl)-2-fluorophenyl)piperidine-2,6-dione (Compound 90);
tert-Butyl (E)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H -imidazol-1-yl)methyl)-4-oxochroman-3-ylidene)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 93);
(E)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methylene)-8-(1-ethyl-3-(trifluoromethyl) -1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride (Compound 94);
tert-butyl (1-(6-(((3R,4R)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6- ((2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 95) ;
tert-Butyl (R)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H -imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 96);
(R)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl) -1H-Pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride (Compound 97);
tert-butyl (1-(6-(((3S,4S)-8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-4-hydroxy-6- ((2-methyl-1H-imidazol-1-yl)methyl)chroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 98) ;
tert-Butyl (S)-(1-(6-((8-(1-ethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)-6-((2-methyl-1H -imidazol-1-yl)methyl)-4-oxochroman-3-yl)methyl)-3-fluoropyridin-2-yl)azetidin-3-yl)carbamate (Compound 99); and
(S)-3-((6-(3-aminoazetidin-1-yl)-5-fluoropyridin-2-yl)methyl)-8-(1-ethyl-3-(trifluoromethyl) -1H-pyrazol-4-yl)-6-((2-methyl-1H-imidazol-1-yl)methyl)chroman-4-one hydrochloride (Compound 100);
A compound characterized in that it is selected from the group consisting of, or an optical isomer thereof, an enantiomer thereof, a diastereomer, a stereoisomer, a hydrate, a solvate, a prodrug thereof, or a pharmaceutically acceptable salt thereof. 치료적 유효량의 제1항 내지 제4항 중 어느 한 항의 화합물, 또는 이의 거울상 이성질체, 부분입체 이성질체, 입체 이성질체, 수화물, 용매화물, 프로드럭 또는 이의 약제학적으로 허용 가능한 염, 및 약제학적으로 허용가능한 담체를 포함하는 암의 예방 또는 치료용 약학적 조성물.A therapeutically effective amount of a compound of any one of claims 1 to 4, or an enantiomer, diastereomer, stereoisomer, hydrate, solvate, prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable salt thereof. A pharmaceutical composition for preventing or treating cancer comprising a possible carrier. 제5항에 있어서,
상기 화합물은 크로만-4-온 유도체를 이용하여 암을 예방 또는 치료하는 것을 특징으로 하는 약학적 조성물.According to claim 5,
The compound is a pharmaceutical composition characterized in that for preventing or treating cancer using a chroman-4-one derivative. 제5항에 있어서,
상기 암은 고형암 또는 혈액암인 것을 특징으로 하는 약학적 조성물.According to claim 5,
The pharmaceutical composition, characterized in that the cancer is solid cancer or hematological cancer. 제7항에 있어서,
상기 고형암은 뇌암, 뇌종양, 양성성상세포종, 악성성상세포종, 뇌하수체 선종, 뇌수막종, 뇌림프종, 핍지교종, 두개내인종, 상의세포종, 뇌간종양, 두경부 종양, 신경교종, 교모세포종, 후두암, 구인두암, 비강암, 비인두암, 침샘암, 하인두암, 편도암, 갑상선암, 구강암, 식도암, 안암, 흉부종양, 소세포성 폐암, 비소세포성 폐암, 흉선암, 폐선암, 폐암, 폐편평상피세포암, 흉막암, 종격동 종양, 유방암, 남성유방암, 복부종양, 위암, 위유양종, 간암, 간모세포종, 담낭암, 담도암, 췌장암, 소장암, 대장암, 결장암, 직장암, 십이지장암, 항문암, 방광암, 신장암, 신우암, 심장암, 복막암, 부신암, 척수암, 골암, 성생식기종양, 음경암, 전립선암, 여성생식기종양, 자궁경부암, 자궁내막암, 난소암, 자궁육종, 질암, 여성외부생식기암, 여성요도암 또는 피부암인 것을 특징으로 하는 약학적 조성물.According to claim 7,
The solid cancers include brain cancer, brain tumor, benign astrocytoma, malignant astrocytoma, pituitary adenoma, meningioma, cerebral lymphoma, oligodendroma, intracranial race, ependymoma, brainstem tumor, head and neck tumor, glioma, glioblastoma, laryngeal cancer, oropharyngeal cancer, nasal cavity Cancer, nasopharyngeal cancer, salivary gland cancer, hypopharyngeal cancer, tonsil cancer, thyroid cancer, oral cancer, esophageal cancer, eye cancer, chest tumor, small cell lung cancer, non-small cell lung cancer, thymus cancer, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, pleural cancer, Mediastinum tumor, breast cancer, male breast cancer, abdominal tumor, stomach cancer, gastric mastoid tumor, liver cancer, hepatoblastoma, gallbladder cancer, biliary tract cancer, pancreatic cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, duodenal cancer, anal cancer, bladder cancer, kidney cancer, renal pelvis cancer , heart cancer, peritoneal cancer, adrenal cancer, spinal cord cancer, bone cancer, sexual genital tumor, penile cancer, prostate cancer, female genital tumor, cervical cancer, endometrial cancer, ovarian cancer, uterine sarcoma, vaginal cancer, female external genital cancer, female A pharmaceutical composition, characterized in that urethral cancer or skin cancer. 제7항에 있어서,
상기 혈액암은 급성골수성백혈병, 급성림프구성백혈병, 만성골수성백혈병, 만성림프구성백혈병, 소아림프종, 악성림프종, 다발성골수종 또는 재생불량성 빈혈인 것을 특징으로 하는 약학적 조성물.According to claim 7,
The pharmaceutical composition, characterized in that the blood cancer is acute myelogenous leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, childhood lymphoma, malignant lymphoma, multiple myeloma or aplastic anemia.
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