KR20220085735A

KR20220085735A - Isoxazolidine derivative compounds, and uses thereof

Info

Publication number: KR20220085735A
Application number: KR1020210179109A
Authority: KR
Inventors: 류희선; 김다미; 김승수; 조서현; 손정범; 김성환; 김남두
Original assignee: 보로노이바이오 주식회사; 보로노이 주식회사
Priority date: 2020-12-14
Filing date: 2021-12-14
Publication date: 2022-06-22
Also published as: WO2022131741A1

Abstract

본 발명은 아이소옥사졸리딘 유도체 화합물 및 이의 용도에 관한 것이다. 본 발명의 아이소옥사졸리딘 유도체 화합물은 CDK2, CDK4, CDK6 및/또는 HPK1에 대해 우수한 억제 활성을 나타내므로, 상기 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방에 유용하게 사용될 수 있다.The present invention relates to isoxazolidine derivative compounds and uses thereof. Since the isoxazolidine derivative compound of the present invention exhibits excellent inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1, it can be usefully used for the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases. .

Description

아이소옥사졸리딘 유도체 화합물 및 이의 용도 {Isoxazolidine derivative compounds, and uses thereof}Isoxazolidine derivative compounds, and uses thereof

본 발명은 아이소옥사졸리딘 유도체 화합물 및 이의 의약적 용도에 관한 것이다. 구체적으로, 본 발명은 CDK2, CDK4, CDK6 및/또는 HPK1 억제 활성을 갖는 아이소옥사졸리딘 유도체 화합물에 관한 것이다.The present invention relates to isoxazolidine derivative compounds and medicinal uses thereof. Specifically, the present invention relates to isoxazolidine derivative compounds having CDK2, CDK4, CDK6 and/or HPK1 inhibitory activity.

단백질 키나아제는 ATP의 감마-인산기를 단백질의 타이로신, 세린 또는 트레오닌의 하이드록시 그룹에 전달하는 인산화 반응을 촉매하는 효소로서, 세포의 대사, 유전자 발현, 세포 성장, 분화, 세포 분열 작용을 담당하며 세포 신호 전달 등에서 중요한 역할을 한다(Thomas A. Hamilton, in Encyclopedia of Immunology(Second Edition), 1998, 2028-2033). Protein kinase is an enzyme that catalyzes the phosphorylation reaction that transfers the gamma-phosphate group of ATP to the hydroxyl group of tyrosine, serine, or threonine of a protein. It is responsible for cell metabolism, gene expression, cell growth, differentiation, and cell division. It plays an important role in signal transduction, etc. (Thomas A. Hamilton, in Encyclopedia of Immunology (Second Edition), 1998, 2028-2033).

단백질 키나아제는 분자 스위치로 작용하여 신호전달경로에 관여하는데, 세포 내에서 키나아제에 의한 표적 단백질의 활성과 비활성 상태 사이의 전환은 원활하게 조절되어야 한다. 만약, 상기 활성과 비활성 상태 사이의 전환이 비정상적으로 조절되면 세포 내 신호 전달을 과도하게 활성화하거나 비활성화시켜 통제불능의 세포 분열 및 증식을 유도하게 된다. 특히, 단백질 키나아제 유전자의 변이, 증폭 및/또는 과발현에 의한 비정상적인 활성화는 다양한 종양의 발생 및 진행을 유발하거나 염증성 질환, 퇴행성 뇌질환, 자가면역 질환 등 다양한 질병의 발병에 결정적인 역할을 하게 된다. 이와 관련된 키나아제의 예를 들면 ABL1, ABL2, BRAF, CDK2, CDK4, CDK6, CDK8, CDK11, CDKL2, CIT, CSF1R, DDR1, DDR2, FLT3, HPK1, KIT, LOK, LTK, MUSK, PAK3, PDGFRA, PDGFRB, RAF1, RIPK1 등이 있다. Protein kinases are involved in signaling pathways by acting as molecular switches, and the switching between the active and inactive states of the target protein by the kinase in the cell must be smoothly regulated. If the transition between the active and inactive states is abnormally regulated, intracellular signal transduction is excessively activated or inactivated to induce uncontrolled cell division and proliferation. In particular, abnormal activation by mutation, amplification and/or overexpression of protein kinase genes causes the development and progression of various tumors or plays a decisive role in the onset of various diseases such as inflammatory diseases, degenerative brain diseases, and autoimmune diseases. Examples of kinases related thereto include ABL1, ABL2, BRAF, CDK2, CDK4, CDK6, CDK8, CDK11, CDKL2, CIT, CSF1R, DDR1, DDR2, FLT3, HPK1, KIT, LOK, LTK, MUSK, PAK3, PDGFRA, PDGFRB , RAF1, RIPK1, and the like.

특히, 사이클린-의존성 키나아제(Cyclin-Dependent Kinase, CDK)는 세포 분열 및 증식을 조절하는 필수적인 기능을 수행하는 효소이다. CDK는 조절 서브유닛인 사이클린에 의해 활성화되며, 사이클린 B/CDK1, 사이클린 A/CDK2, 사이클린 E/CDK2, 사이클린 D/CDK4, 사이클린 D/CDK6 등의 헤테로다인은 세포 주기 진행의 중요한 조절자이고, 추가적으로 전사, DNA 수선, 분화 및 세포자멸 조절 기능을 갖는 것으로 알려져 있다(Morgan DO. et al, Annu. Rev. Cell. Dev. Biol. 1997, 13, 261-291).In particular, cyclin-dependent kinase (Cyclin-Dependent Kinase, CDK) is an enzyme that performs essential functions regulating cell division and proliferation. CDK is activated by the regulatory subunit cyclin, and heterodynes such as cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 are important regulators of cell cycle progression, It is additionally known to have transcriptional, DNA repair, differentiation and apoptosis regulatory functions (Morgan DO. et al, Annu. Rev. Cell. Dev. Biol. 1997, 13, 261-291).

CDK4/6 억제제인 팔보시클립, 리보시클립 및 아베마시클립은 단일 약품 또는 다른 치료제와 병용으로 암에 대한 임상 시험이 진행되고 있다. 팔보시클립 및 리보시클립은 폐경 후 여성에서 아로마타제 억제제와 병용으로 호르몬 수용체 (HR)-양성, 인간 표피 성장인자 수용체 2(HER2)-음성 진행성 또는 전이성 유방암의 치료에 대해 승인되었다(O'Leary et al., Nature Reviews, 2016, 13, 417-430). 또한 CDK4/6 억제제는 ER-양성 전이성 유방암에서 유의한 임상 효능을 나타내었다.The CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib are being tested for cancer as a single drug or in combination with other therapeutic agents. Palbociclib and ribociclib are approved for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with aromatase inhibitors in postmenopausal women (O') Leary et al., Nature Reviews, 2016, 13, 417-430). In addition, CDK4/6 inhibitors showed significant clinical efficacy in ER-positive metastatic breast cancer.

CDK2의 과발현은 세포 주기의 비정상적인 조절과 연관되며, 사이클린 E/CDK2 복합체는 G1/S 전환, 히스톤 생합성 및 중심체 복제의 조절에서 중요한 역할을 한다. 사이클린 D/CDK4/6 및 사이클린 E/CDK2에 의한 Rb의 진행성 인산화는 G1 전사인자인 E2F를 방출하고 S기로의 진입을 촉진한다. 초기 S기 중 사이클린 A/CDK2의 활성화는 S기 완료를 위해 E2F의 DNA 복제 및 불활성화를 가능하게 하는 내인성 기질의 인산화를 촉진한다(Asghar et al., Nat. Rev. Drug. Discov., 2015, 14(2), 130-146). Overexpression of CDK2 is associated with aberrant regulation of the cell cycle, and the cyclin E/CDK2 complex plays an important role in the regulation of G1/S conversion, histone biosynthesis and centrosome replication. Progressive phosphorylation of Rb by cyclin D/CDK4/6 and cyclin E/CDK2 releases the G1 transcription factor E2F and promotes entry into S phase. Activation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates that enable DNA replication and inactivation of E2F for S phase completion (Asghar et al., Nat. Rev. Drug. Discov., 2015 , 14(2), 130-146).

한편, 조혈 전구 키나아제(Hematopoietic Progenitor Kinase 1, HPK1)는 조혈 세포에 제한된 세린/트레오닌 키나아제로서, HPK1 활성은 리간드 결합시 조혈 세포에서 발견되는 다양한 세포 표면 수용체에 의해 생성된 활성화 신호에 의해 유도될 수 있다(Liou et al., Immunity, 2000, 12, 399; Wang et al., J. Biol. Chem., 1997, 272, 22771; Zhou et al., J. Biol. Chem., 1999, 274, 13133; Nagata et al., Blood, 1999, 93, 3347; Chen et al., Oncogene, 1999, 18, 7370). HPK1은 암 면역치료를 위한 신규 표적이 될 수 있다고 보고되고 있다. 구체적으로, HPK1^-/- T 세포는 TCR 결합에 반응하여 Th1 사이토카인 생성이 증가되고, 빠르게 증식하며, PGE2-매개 억제에 저항성을 가지고, HPK1^-/- T 세포를 이식받은 마우스는 폐 종양 성장에 저항성을 갖는다. 수지상 세포에서 HPK1을 제거한 경우 항원 제시 능력이 현저히 증가되어, 암 백신으로 사용할 경우 더욱 우수한 항종양 면역 반응을 보일 수 있다(Sawasdikosol et al., Immunol Res., 2012, 54(1-3), 262-265). 또한, 전장 HPK1은 IKK베타(IKappaB kinase beta) 인산화를 증가시키는 반면, HPK1 발현을 억제시킬 경우 TCR-매개 NF-카파B 활성을 둔화시키고 세포 사멸을 증가시킨다(Brenner et al., EMBO J. 2005, 24, 4279).On the other hand, hematopoietic progenitor kinase (Hematopoietic Progenitor Kinase 1, HPK1) is a serine/threonine kinase restricted to hematopoietic cells, and HPK1 activity can be induced by activation signals generated by various cell surface receptors found in hematopoietic cells upon ligand binding. (Liou et al., Immunity, 2000, 12, 399; Wang et al., J. Biol. Chem., 1997, 272, 22771; Zhou et al., J. Biol. Chem., 1999, 274, 13133 ; Nagata et al., Blood, 1999, 93, 3347; Chen et al., Oncogene, 1999, 18, 7370). It has been reported that HPK1 can be a novel target for cancer immunotherapy. Specifically, HPK1 ^-/- T cells have increased Th1 cytokine production in response to TCR binding, proliferate rapidly, and are resistant to PGE2-mediated inhibition, and mice transplanted with HPK1 ^-/- T cells can grow lung tumors have resistance to When HPK1 is removed from dendritic cells, antigen-presenting ability is significantly increased, and when used as a cancer vaccine, a better anti-tumor immune response may be exhibited (Sawasdikosol et al., Immunol Res., 2012, 54(1-3), 262). -265). In addition, while full-length HPK1 increases IKKbeta (IKappaB kinase beta) phosphorylation, inhibition of HPK1 expression slows TCR-mediated NF-kappaB activity and increases apoptosis (Brenner et al., EMBO J. 2005) , 24, 4279).

상술한 바와 같이, CDK2, CDK4, CDK6 및/또는 HPK1에 대해 억제 활성을 가지는 화합물은 항암제로서 우수한 효과를 기대할 수 있는바, 이들을 억제하는 신규 화합물에 대한 개발이 지속적으로 요구되고 있다.As described above, compounds having inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1 can be expected to have excellent effects as anticancer agents, and development of novel compounds for inhibiting them is continuously required.

Thomas A. Hamilton, in Encyclopedia of Immunology(Second Edition), 1998, 2028-2033Thomas A. Hamilton, in Encyclopedia of Immunology (Second Edition), 1998, 2028-2033 Morgan DO. et al, Annu. Rev. Cell. Dev. Biol. 1997, 13, 261-291Morgan DO. et al, Annu. Rev. Cell. Dev. Biol. 1997, 13, 261-291 O'Leary et al., Nature Reviews, 2016, 13, 417-430O'Leary et al., Nature Reviews, 2016, 13, 417-430 Asghar et al., Nat. Rev. Drug. Discov., 2015, 14(2), 130-146Asghar et al., Nat. Rev. Drug. Discov., 2015, 14(2), 130-146 Liou et al., Immunity, 2000, 12, 399Liou et al., Immunity, 2000, 12, 399 Wang et al., J. Biol. Chem., 1997, 272, 22771Wang et al., J. Biol. Chem., 1997, 272, 22771 Zhou et al., J. Biol. Chem., 1999, 274, 13133Zhou et al., J. Biol. Chem., 1999, 274, 13133 Nagata et al., Blood, 1999, 93, 3347Nagata et al., Blood, 1999, 93, 3347 Chen et al., Oncogene, 1999, 18, 7370Chen et al., Oncogene, 1999, 18, 7370 Sawasdikosol et al., Immunol Res., 2012, 54(1-3), 262-265Sawasdikosol et al., Immunol Res., 2012, 54(1-3), 262-265 Brenner et al., EMBO J. 2005, 24, 4279Brenner et al., EMBO J. 2005, 24, 4279

본 발명의 목적은 신규한 구조의 아이소옥사졸리딘 유도체, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.An object of the present invention is to provide an isoxazolidine derivative having a novel structure, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

본 발명의 다른 목적은 상기 아이소옥사졸리딘 유도체 화합물의 제조방법을 제공하는 것이다.Another object of the present invention is to provide a method for preparing the isoxazolidine derivative compound.

본 발명의 다른 목적은 상기 아이소옥사졸리딘 유도체 화합물의 의약용도를 제공하는 것으로서, 구체적으로 상기 아이소옥사졸리딘 유도체 화합물을 유효성분으로 포함하는 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방용 약학적 조성물, 상기 화합물을 이용한 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방 용도 또는 상기 화합물을 투여하는 단계를 포함하는 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방방법을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical use of the isoxazolidine derivative compound, specifically for the treatment or treatment of CDK2, CDK4, CDK6 and/or HPK1-related diseases comprising the isoxazolidine derivative compound as an active ingredient. A pharmaceutical composition for prophylaxis, the use of the compound for the treatment or prophylaxis of a CDK2, CDK4, CDK6 and/or HPK1-related disease, or the treatment or prevention of a CDK2, CDK4, CDK6 and/or HPK1-related disease comprising administering the compound to provide preventive measures.

상기 목적을 달성하기 위하여, 본 발명자들이 연구 노력한 결과, 아래에서 언급하는 화학식 1로 표시되는 아이소옥사졸리딘 유도체 화합물들이 CDK2, CDK4, CDK6 및/또는 HPK1이 활성화된 세포의 증식을 저해하는 것을 확인함으로써 본 발명을 완성하였다.In order to achieve the above object, as a result of research efforts of the present inventors, it was confirmed that the isoxazolidine derivative compounds represented by Formula 1 mentioned below inhibit the proliferation of cells in which CDK2, CDK4, CDK6 and/or HPK1 are activated. Thus, the present invention was completed.

아이소옥사졸리딘 유도체 화합물Isooxazolidine Derivative Compounds

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염을 제공한다:The present invention provides a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

상기 화학식 1에서,In Formula 1,

고리 A₁은 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6아미노알킬, -C_1-6하이드록시알킬, -C_1-6할로알킬, -C_1-6알킬-O-C_1-6알킬, -CN, -(C=O)NR₃R₄, -(C=O)OR₅, -NR₆R₇, -OR₈, -할로, 아릴 또는 헤테로아릴로 치환될 수 있음}; Ring A ₁ is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _{1 -6} Haloalkyl, -C _1-6 Alkyl-OC _1-6 Alkyl, -CN, -(C=O)NR ₃ R ₄ , -(C=O)OR ₅ , -NR ₆ R ₇ , -OR ₈ , which may be substituted with halo, aryl or heteroaryl};

고리 A₂는 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고 Ring A ₂ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl

{여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -C_1-6아미노알킬, -C_1-6할로알킬, -C_1-6알킬-CN, -CN, -C_1-6알킬-O-C_1-6알킬, -C_1-6알킬NR₉R₁₀, -(C=O)NR₉R₁₀, -C_1-6알킬-(C=O)NR₉R₁₀, -(C=O)-C_1-6알킬, -(C=O)OR₁₁, -C_1-6알킬-(C=O)OR₁₁, -NR₁₂R₁₃, -OR₁₄, -할로, -S-C_1-6알킬, -SO₂-C_1-6알킬, -SO₂-NR₁₂R₁₃, -SO₂-할로, -(S=O)NH-C_1-6알킬, -S(=O)(=NH)-C_1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)NR₁₅R₁₆, -(C=O)OR₁₇, -NR₁₈R₁₉, -할로, -SO₂-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -C_1-6아미노알킬, -C_1-6할로알킬, -NR₂₀R₂₁, 또는 사이클로알킬로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, -NR₂₂R₂₃, -O-C_1-6알킬,할로, -SO₂-C_1-6알킬, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있음]; {Wherein, at least one H of the aryl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 aminoalkyl, -C _1-6 haloalkyl, -C _{1 6} alkyl-CN, -CN, -C _1-6 alkyl-OC _1-6 alkyl, -C _1-6 alkylNR ₉ R ₁₀ , -(C=O)NR ₉ R ₁₀ , -C _1-6 alkyl- (C=O)NR ₉ R ₁₀ , -(C=O)-C _1-6 alkyl, -(C=O)OR ₁₁ , -C _1-6 alkyl-(C=O)OR ₁₁ , -NR ₁₂ R ₁₃ , -OR ₁₄ , -halo, -SC _1-6 alkyl, -SO ₂ -C _1-6 alkyl, -SO ₂ -NR ₁₂ R ₁₃ , -SO ₂ -halo, -(S=O)NH- C _1-6 alkyl, -S(=O)(=NH)-C _1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _1-6 alkyl-cycloalkyl, -C _1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)-heterocycloalkyl, may be substituted with aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _1-6 alkyl-cycloalkyl, -C _1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)-heterocycloalkyl, At least one H of an aryl, -(C=O)-aryl, or heteroaryl ring is -C _1-6 alkyl, -(=O)-, -(C=O)-C _1-6 alkyl, -(C =O)NR ₁₅ R ₁₆ , -(C=O)OR ₁₇ , -NR ₁₈ R ₁₉ , -halo, -SO ₂ -, cycloalkyl, heterocycloalkyl, or heterobicycloalkyl (supra At least one H of a cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 aminoalkyl, -C _1-6 haloalkyl, -NR ₂₀ R ₂₁ , or may be substituted with cycloalkyl)], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is —C _1-6 alkyl; -(=O)-, -(C=O)-C _1-6 alkyl, -(C=O)OC _1-6 alkyl, -NR ₂₂ R ₂₃ , -OC _1-6 alkyl,halo, -SO ₂ -C _1-6 alkyl, cycloalkyl, or heterocycloalkyl];

상기 사이클로알킬 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, 또는 -SO₂-C_1-6알킬로 치환될 수 있음}; at least one H of said cycloalkyl or heterocycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -(C=O)-C _1-6 alkyl, -(C=O)OC _{1 -6} alkyl, or —SO ₂ —C _1-6 alkyl};

R₁은 -H 또는 -C_1-6알킬이고;R ₁ is —H or —C _1-6 alkyl;

R₂는 -H, -C_1-6알킬, -C_1-6아미노알킬, -C_1-6하이드록시알킬, -C_1-6할로알킬, -CN, -할로, 또는 5-7원 고리이고 {여기서, 상기 5-7원 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6할로알킬, 또는 할로로 치환될 수 있음};R ₂ is -H, -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -halo, or 5-7 membered ring and {wherein, one or more H of the 5-7 membered ring may be substituted with -C _1-6 alkyl, -C _1-6 haloalkyl, or halo};

R₃ 내지 R₇은 각각 독립적으로 -H 또는 -C_1-6알킬이고;R ₃ to R ₇ are each independently —H or —C _1-6 alkyl;

R₈은 -H, -C_1-6알킬, 페닐 또는 벤질이고; R ₈ is —H, —C _1-6 alkyl, phenyl or benzyl;

R₉ 및 R₁₀은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6히드록시알킬, -C_1-6알킬-NR₂₄R₂₅, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬로 치환될 수 있음};R ₉ and R ₁₀ are each independently —H, —C _1-6 alkyl, —C _1-6 hydroxyalkyl, —C _1-6 alkyl-NR ₂₄ R ₂₅ , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C _1-6 alkyl};

R₁₁은 -H 또는 -C_1-6알킬이고;R ₁₁ is —H or —C _1-6 alkyl;

R₁₂ 및 R₁₃은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6알킬-NR₂₄R₂₅, 또는 -(C=O)O-C_1-6알킬이고;R ₁₂ and R ₁₃ are each independently —H, —C _1-6 alkyl, —C _1-6 alkyl-NR ₂₄ R ₂₅ , or —(C=O)OC _1-6 alkyl;

R₁₄은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6알킬-NR₂₆R₂₇, 헤테로사이클로알킬, 또는 -C_1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C_1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬로 치환될 수 있음};each R ₁₄ is independently —H, —C _1-6 alkyl, —C _1-6 alkyl-NR ₂₆ R ₂₇ , heterocycloalkyl, or —C _1-6 alkyl-heterocycloalkyl {wherein the heterocyclo one or more H of an alkyl or —C _1-6 alkyl-heterocycloalkyl ring may be substituted with —C _1-6 alkyl;

R₁₅ 내지 R₁₇은 각각 독립적으로 -H 또는 -C_1-6알킬이고;R ₁₅ to R ₁₇ are each independently —H or —C _1-6 alkyl;

R₁₈ 및 R₁₉은 각각 독립적으로 -C_1-6알킬 또는 -C_1-6알킬-NR₂₈R₂₉이고;R ₁₈ and R ₁₉ are each independently —C _1-6 alkyl or —C _1-6 alkyl-NR ₂₈ R ₂₉ ;

R₂₀ 내지 R₂₉은 각각 독립적으로 -H 또는 -C_1-6알킬이다.R ₂₀ to R ₂₉ are each independently —H or —C _1-6 alkyl.

본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 아래 범위일 수 있다:According to an embodiment of the present invention, the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof may be in the following ranges:

고리 A₁은 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6할로알킬, -CN, -NR₆R₇, -OR₈, 또는 -할로 로 치환될 수 있음}; Ring A ₁ is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 haloalkyl, -CN, -NR ₆ R ₇ , -OR ₈ , or - may be substituted with halo};

고리 A₂는 아릴, 헤테로아릴, 또는 헤테로사이클로알킬이고Ring A ₂ is aryl, heteroaryl, or heterocycloalkyl

{여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6할로알킬, -C_1-6알킬-CN, -CN, -C_1-6알킬-O-C_1-6알킬, -C_1-6알킬NR₉R₁₀, -(C=O)NR₉R₁₀, -C_1-6알킬-(C=O)NR₉R₁₀, -(C=O)-C_1-6알킬, -(C=O)OR₁₁, -NR₁₂R₁₃, -OR₁₄, -할로, -S-C_1-6알킬, -SO₂-C_1-6알킬, -SO₂-NR₁₂R₁₃, -SO₂-할로, -S(=O)(=NH)-C_1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)NR₁₅R₁₆, -(C=O)OR₁₇, -NR₁₈R₁₉, -할로, -SO₂-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, 또는 -NR₂₀R₂₁ 로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, -NR₂₂R₂₃, -O-C_1-6알킬,할로, -SO₂-C_1-6알킬, 또는 사이클로알킬 로 치환될 수 있음]; {wherein at least one H of the aryl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-CN, -CN, -C _1-6 alkyl-OC _{1 -6} alkyl, -C _1-6 alkylNR ₉ R ₁₀ , -(C=O)NR ₉ R ₁₀ , -C _1-6 alkyl-(C=O)NR ₉ R ₁₀ , -(C=O)- C _1-6 alkyl, -(C=O)OR ₁₁ , -NR ₁₂ R ₁₃ , -OR ₁₄ , -halo, -SC _1-6 alkyl, -SO ₂ -C _1-6 alkyl, -SO ₂ -NR ₁₂ R ₁₃ , —SO ₂ -halo, —S(=O)(=NH)—C _1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, —C _1-6 alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _{1 -} At least one H of a ₆ alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl ring is -C _1-6 alkyl, -(=O) -, -(C=O)-C _1-6 alkyl, -(C=O)NR ₁₅ R ₁₆ , -(C=O)OR ₁₇ , -NR ₁₈ R ₁₉ , -halo, -SO ₂ -, cyclo may be substituted with alkyl, heterocycloalkyl, or heterobicycloalkyl (one or more H of the cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxy alkyl, or -NR ₂₀ R ₂₁ )], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is -C _1-6 alkyl, -(=O)-, -(C=O)-C _1-6 alkyl, -(C=O)OC _1-6 alkyl, -NR ₂₂ R ₂₃ , -OC _1-6 alkyl, may be substituted with halo, —SO ₂ —C _1-6 alkyl, or cycloalkyl ];

상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, 또는 -SO₂-C_1-6알킬로 치환될 수 있음}; at least one H of the heterocycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -(C=O)-C _1-6 alkyl, -(C=O)OC _1-6 alkyl , or —SO ₂ —C _1-6 alkyl};

R₁은 -H이고;R ₁ is —H;

R₂는 -H, -C_1-6알킬, -C_1-6할로알킬, -CN, -할로, 또는 5-7원 고리이고 {여기서, 상기 5-7원 고리의 하나 이상의 H는 -C_1-6알킬 또는 할로로 치환될 수 있음};R ₂ is -H, -C _1-6 alkyl, -C _1-6 haloalkyl, -CN, -halo, or a 5-7 membered ring {wherein at least one H of the 5-7 membered ring is -C may be substituted with _1-6 alkyl or halo};

R₆ 및 R₇은 각각 독립적으로 -C_1-6알킬이고;R ₆ and R ₇ are each independently —C _1-6 alkyl;

R₈은 -H, -C_1-6알킬, 또는 페닐이고; R ₈ is —H, —C _1-6 alkyl, or phenyl;

R₁₁은 -C_1-6알킬이고;R ₁₁ is —C _1-6 alkyl;

R₁₂ 및 R₁₃은 각각 독립적으로 -H, -C_1-6알킬, 또는 -(C=O)O-C_1-6알킬이고;R ₁₂ and R ₁₃ are each independently —H, —C _1-6 alkyl, or —(C=O)OC _1-6 alkyl;

R₁₄은 각각 독립적으로 -C_1-6알킬, -C_1-6알킬-NR₂₆R₂₇, 헤테로사이클로알킬, 또는 -C_1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C_1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬로 치환될 수 있음};each R ₁₄ is independently —C _1-6 alkyl, —C _1-6 alkyl-NR ₂₆ R ₂₇ , heterocycloalkyl, or —C _1-6 alkyl-heterocycloalkyl {wherein said heterocycloalkyl or — one or more H of a C _1-6 alkyl-heterocycloalkyl ring may be substituted with —C _1-6 alkyl};

R₁₅ 내지 R₁₇은 각각 독립적으로 -C_1-6알킬이고;R ₁₅ to R ₁₇ are each independently —C _1-6 alkyl;

R₂₀ 내지 R₂₃, R₂₆ 내지 R₂₉은 각각 독립적으로 -H 또는 -C_1-6알킬이다. R ₂₀ to R ₂₃ , R ₂₆ to R ₂₉ are each independently —H or —C _1-6 alkyl.

고리 A₁은 페닐 또는 피리디닐이고 {여기서, 상기 페닐 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6아미노알킬, -C_1-6하이드록시알킬, -C_1-6할로알킬, -C_1-6알킬-O-C_1-6알킬, -CN, -(C=O)NR₃R₄, -(C=O)OR₅, -NR₆R₇, -OR₈, -할로, 아릴 또는 헤테로아릴로 치환될 수 있음}; Ring A ₁ is phenyl or pyridinyl {wherein at least one H of said phenyl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _{1 -6} Haloalkyl, -C _1-6 Alkyl-OC _1-6 Alkyl, -CN, -(C=O)NR ₃ R ₄ , -(C=O)OR ₅ , -NR ₆ R ₇ , -OR ₈ , which may be substituted with halo, aryl or heteroaryl};

R₈은 -H, -C_1-6알킬, 페닐 또는 벤질이다. R ₈ is -H, -C _1-6 alkyl, phenyl or benzyl.

고리 A₂는 페닐, 5-6원 헤테로아릴, 3-7원 사이클로알킬, 또는 3-7원 헤테로사이클로알킬이고 Ring A ₂ is phenyl, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl

{여기서, 상기 페닐 또는 5-6원 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -C_1-6아미노알킬, -C_1-6할로알킬, -C_1-6알킬-CN, -CN, -C_1-6알킬-O-C_1-6알킬, -C_1-6알킬NR₉R₁₀, -(C=O)NR₉R₁₀, -C_1-6알킬-(C=O)NR₉R₁₀, -(C=O)-C_1-6알킬, -(C=O)OR₁₁, -C_1-6알킬-(C=O)OR₁₁, -NR₁₂R₁₃, -OR₁₄, -할로, -S-C_1-6알킬, -SO₂-C_1-6알킬, -SO₂-NR₁₂R₁₃, -SO₂-할로, -(S=O)NH-C_1-6알킬, -S(=O)(=NH)-C_1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)NR₁₅R₁₆, -(C=O)OR₁₇, -NR₁₈R₁₉, -할로, -SO₂-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -C_1-6아미노알킬, -C_1-6할로알킬, -NR₂₀R₂₁, 또는 사이클로알킬로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, -NR₂₂R₂₃, -O-C_1-6알킬,할로, -SO₂-C_1-6알킬, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있음]; {Wherein, at least one H of the phenyl or 5-6 membered heteroaryl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 aminoalkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-CN, -CN, -C _1-6 alkyl-OC _1-6 alkyl, -C _1-6 alkylNR ₉ R ₁₀ , -(C=O)NR ₉ R ₁₀ , -C _{1 -6} alkyl-(C=O)NR ₉ R ₁₀ , -(C=O)-C _1-6 alkyl, -(C=O)OR ₁₁ , -C _1-6 alkyl-(C=O)OR ₁₁ , -NR ₁₂ R ₁₃ , -OR ₁₄ , -halo, -SC _1-6 alkyl, -SO ₂ -C _1-6 alkyl, -SO ₂ -NR ₁₂ R ₁₃ , -SO ₂ -halo, -(S= O)NH-C _1-6 alkyl, -S(=O)(=NH)-C _1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _1-6 alkyl-cycloalkyl, - C _1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)- which may be substituted with heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _1-6 alkyl-cycloalkyl, - C _1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)- At least one H of a heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl ring is -C _1-6 alkyl, -(=O)-, -(C=O)-C _1-6 alkyl to be substituted with , -(C=O)NR ₁₅ R ₁₆ , -(C=O)OR ₁₇ , -NR ₁₈ R ₁₉ , -halo, -SO ₂ -, cycloalkyl, heterocycloalkyl, or heterobicycloalkyl can be (at least one H of the cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 aminoalkyl, -C _{1 6} haloalkyl, -NR ₂₀ R ₂₁ , or may be substituted with cycloalkyl)], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is —C _1-6 alkyl, -(=O)-, -(C=O)-C _1-6 alkyl, -(C=O)OC _1-6 alkyl, -NR ₂₂ R ₂₃ , -OC _1-6 alkyl,halo, - SO ₂ -C _1-6 alkyl, cycloalkyl, or heterocycloalkyl];

R₁₁은 -H 또는 -C_1-6알킬이고;R ₁₁ is —H or —C _1-6 alkyl;

R₂₀ 내지 R₂₉은 각각 독립적으로 -H 또는 -C_1-6알킬이다. R ₂₀ to R ₂₉ are each independently —H or —C _1-6 alkyl.

R₁은 -H이다. R ₁ is -H.

R₂는 -H, -C_1-6알킬, -C_1-6할로알킬, -CN, -할로, 또는 5-6원 고리이다 {여기서, 상기 5-6원 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6할로알킬, 또는 할로로 치환될 수 있음}.R ₂ is -H, -C _1-6 alkyl, -C _1-6 haloalkyl, -CN, -halo, or a 5-6 membered ring {wherein at least one H of the 5-6 membered ring is -C may be substituted with _1-6 alkyl, —C _1-6 haloalkyl, or halo}.

본 발명의 구체예에 따르면, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염이 하기 [표 1], [표 2], 및 [표 3] 에 기재된 실시예 1 내지 240의 화합물 또는 이의 약학적으로 허용가능한 염으로 이루어진 군으로부터 선택된 것일 수 있다.According to an embodiment of the present invention, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is the compound of Examples 1 to 240 described in [Table 1], [Table 2], and [Table 3], or It may be selected from the group consisting of pharmaceutically acceptable salts thereof.

본 발명에 있어서, "알킬"은, 다른 기재가 없는 한, 직쇄 또는 분지쇄의 비고리형, 고리형 또는 이들이 결합된 포화 탄화수소를 의미할 수 있다. 예를 들어, "C_1-6알킬"은 탄소 원자를 1 내지 6개 포함하는 알킬을 의미할 수 있다. 비고리형 알킬은, 일 예로서, 메틸, 에틸, n-프로필, n-부틸, 아이소프로필, 2급(sec)-부틸, 아이소부틸, 또는 3급(tert)-부틸 등을 포함할 수 있으나, 이에 제한되지 않는다. 고리형 알킬은 본 명세서에서 "사이클로알킬"과 교환적으로 사용될 수 있으며, 일 예로서, 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실, 사이클로헵틸, 또는 사이클로옥틸 등을 포함할 수 있으나, 이에 제한되지 않는다. In the present invention, unless otherwise stated, "alkyl" may mean a straight or branched acyclic, cyclic, or saturated hydrocarbon to which they are bonded. For example, "C _1-6 alkyl" can mean an alkyl containing 1 to 6 carbon atoms. Acyclic alkyl may include, as an example, methyl, ethyl, n -propyl, n -butyl, isopropyl, sec -butyl, isobutyl, or tert -butyl, etc., It is not limited thereto. Cyclic alkyl may be used interchangeably with “cycloalkyl” herein, and may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl. doesn't happen

본 발명에 있어서, "알콕시"는 알킬 에터기로 -(O-알킬)을 의미할 수 있고, 여기서, 알킬은 상기에서 정의된 바와 같다. 예를 들어, "C_1-6의 알콕시"는 C_1-6의 알킬을 함유하는 알콕시, 즉, -(O-C_1-6알킬)을 의미할 수 있으며, 일 예로서, 알콕시는 메톡시(methoxy), 에톡시(ethoxy), n-프로폭시(n-propoxy), 아이소프로폭시(isopropoxy), n-부톡시(n-butoxy), 아이소부톡시(isobutoxy), sec-부톡시(sec-butoxy), 또는 tert-부톡시(tert-butoxy) 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "alkoxy" may mean -(O-alkyl) as an alkyl ether group, wherein alkyl is as defined above. For example, "C _1-6 alkoxy" may mean alkoxy containing C _1-6 alkyl, that is, -(OC _1-6 alkyl). For example, alkoxy is methoxy ), ethoxy, n -propoxy, isopropoxy, n -butoxy , isobutoxy , sec -butoxy ), or tert - butoxy , etc., but is not limited thereto.

본 발명에 있어서, "할로"는 F, Cl, Br, 또는 I일 수 있다.In the present invention, "halo" may be F, Cl, Br, or I.

본 발명에 있어서, "할로알킬"은 본원에 정의된 바와 같은 하나 이상의 할로로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 상기 할로알킬의 예로는 하나 이상의 할로겐, 예를 들어 F, Cl, Br, 또는 I로 독립적으로 치환된 메틸, 에틸, 프로필, 아이소프로필, 아이소부틸 또는 n-부틸을 포함하나, 이에 한정되는 것은 아니다.In the present invention, "haloalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having one or more halo substituted carbon atoms as defined herein. Examples of such haloalkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl or n-butyl independently substituted with one or more halogens, such as F, Cl, Br, or I. .

본 명세서에서, "아미노알킬"은 아미노-(NR'R")로 치환된 탄소 원자를 갖는 직쇄 또는 분지쇄 알킬(탄화수소)을 의미할 수 있다. 여기서, R' 및 R"은 각각 독립적으로 수소, 및 C_1-6알킬로 이루어진 군으로부터 선택될 수 있으며, 상기 선택된 R'및 R"은 각각 독립적으로 치환되거나 비치환될 수 있다. As used herein, "aminoalkyl" may mean a straight or branched chain alkyl (hydrocarbon) having a carbon atom substituted with amino-(NR'R"), wherein R' and R" are each independently hydrogen. , and may be selected from the group consisting of C _1-6 alkyl, wherein the selected R′ and R″ may each independently be substituted or unsubstituted.

본 발명에 있어서, "헤테로사이클로알킬"은 고리를 형성하는 원자로 N, O 및 S로부터 선택된 1 내지 5 개의 헤테로 원자를 함유하는 고리를 의미할 수 있고, 포화 또는 부분적으로 불포화될 수 있다. 여기서, 불포화된 경우, 헤테로사이클로알켄으로 지칭될 수 있다. 달리 언급하지 않는 한, 헤테로사이클로알킬은 단일 고리이거나, 스파이로(spiro) 고리, 다리(bridged) 고리 또는 융합(fused) 고리와 같은 다중 고리일 수 있다. 또한, "3 내지 12 원자의 헤테로사이클로알킬"은 고리를 형성하는 원자를 3 내지 12 개 포함하는 헤테로사이클로알킬을 의미할 수 있으며, 일 예로서, 헤테로사이클로알킬은 피롤리딘, 피페리딘, 이미다졸리딘, 피라졸리딘, 부티로락탐, 발레로락탐, 이미다졸리딘온, 하이단토인, 다이옥솔란, 프탈이미드, 피페리딘, 피리미딘-2,4(1H,3H)-다이온, 1,4-다이옥산, 모르폴린, 싸이오모르폴린, 싸이오모르폴린-S-옥사이드, 싸이오모르폴린-S,S-옥사이드, 피페라진, 피란, 피리돈, 3-피롤린, 싸이오피란, 피론, 테트라하이드로퓨란, 테트라하이드로싸이오펜, 퀴누클리딘, 트로판, 2-아자스파이로[3.3]헵탄, (1R,5S)-3-아자바이사이클로[3.2.1]옥탄, (1s,4s)-2-아자바이사이클로[2.2.2]옥탄, 또는 (1R,4R)-2-옥사-5-아자바이사이클로[2.2.2]옥탄 등을 포함할 수 있으나, 이에 제한되는 것은 아니다.In the present invention, "heterocycloalkyl" may mean a ring containing 1 to 5 heteroatoms selected from N, O and S as atoms forming the ring, and may be saturated or partially unsaturated. Here, when unsaturated, it may be referred to as a heterocycloalkene. Unless otherwise stated, heterocycloalkyl may be a single ring or multiple rings such as a spiro ring, a bridged ring or a fused ring. In addition, "3 to 12 membered heterocycloalkyl" may mean a heterocycloalkyl containing 3 to 12 atoms forming a ring, for example, heterocycloalkyl is pyrrolidine, piperidine, Imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, pyrimidine-2,4( 1H , 3H ) -Dione, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine- S -oxide, thiomorpholine- S , S -oxide, piperazine, pyran, pyridone, 3-pyrroline , thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane, ( 1R , 5S )-3-azabicyclo[3.2.1 ]octane, (1 s ,4 s )-2-azabicyclo[2.2.2]octane, or ( 1R , 4R )-2-oxa-5-azabicyclo[2.2.2]octane, and the like. can, but is not limited thereto.

본 발명에 있어서, "아렌"은 방향족 탄화수소 고리를 의미할 수 있다. 아렌은 단환식 아렌 또는 다환식 아렌일 수 있다. 아렌의 고리 형성 탄소수는 5 이상 30 이하, 5 이상 20 이하, 또는 5 이상 15 이하일 수 있다. 아렌의 예로는 벤젠, 나프탈렌, 플루오렌, 안트라센, 페난트렌, 바이벤젠, 터벤젠, 쿼터벤젠, 퀸크벤젠, 섹시벤젠, 트라이페닐렌, 피렌, 벤조 플루오란텐, 크리센 등을 예시할 수 있지만, 이들에 한정되지 않는다. 본 명세서에서 상기 "아렌"에서 수소 원자 하나를 제거한 잔기를 "아릴"로 지칭한다.In the present invention, "arene" may mean an aromatic hydrocarbon ring. The arene may be a monocyclic arene or a polycyclic arene. The ring carbon number of arene may be 5 or more and 30 or less, 5 or more and 20 or less, or 5 or more and 15 or less. Examples of arenes include benzene, naphthalene, fluorene, anthracene, phenanthrene, bibenzene, terbenzene, quaterbenzene, quinkbenzene, sexbenzene, triphenylene, pyrene, benzofluoranthene, chrysene, etc. , but not limited to these. In the present specification, the residue obtained by removing one hydrogen atom from "arene" is referred to as "aryl".

본 발명에 있어서, "헤테로아렌"은 이종 원소로 O, N, P, Si, 및 S 중 1 개 이상을 포함하는 고리일 수 있다. 헤테로아렌의 고리 형성 탄소수는 2 이상 30 이하 또는 2 이상 20 이하일 수 있다. 헤테로 아렌은 단환식 헤테로 아렌 또는 다환식 헤테로 아렌일 수 있다. 다환식 헤테로아렌은 예를 들어, 2 환 또는 3 환 구조를 갖는 것일 수 있다. 헤테로아렌의 예로는 싸이오펜, 퓨린, 피롤, 피라졸, 이미다졸, 싸이아졸, 옥사졸, 아이소싸이아졸, 옥사다이아졸, 트라이아졸, 피리딘, 비피리딜, 트리아진, 아크리딜, 피리다진, 피라진, 퀴놀린, 퀴나졸린, 퀴녹살린, 페녹사진, 프탈라진, 피리미딘, 피리도 피리미딘, 피리도 피라진, 피라지노 피라진, 아이소퀴놀린, 인돌, 카바졸, 이미다조피리다진, 이미다조피리딘, 이미다조피리미딘, 피라졸로피리미딘, 이미다조피라진 또는 피라졸로피리딘, N-아릴카바졸, N-헤테로아릴카바졸, N-알킬카바졸, 벤조옥사졸, 벤조이미다졸, 벤조싸이아졸, 벤조카바졸, 벤조싸이오펜, 다이벤조싸이오펜, 싸이에노싸이오펜, 벤조퓨란, 페난트롤린, 아이소옥사졸, 옥사다이아졸, 싸이아다이아졸, 벤조싸이아졸, 테트라졸, 페노싸이아진, 다이벤조실롤 및 다이벤조퓨란 등이 있으나, 이들에 한정되지 않는다. 본 발명의 일 실시 태양에서 헤테로아렌은 또한 헤테로사이클로알킬 고리에 융합된 아렌 고리 또는 사이클로알킬 고리에 융합된 헤테로아렌을 포함하는 바이사이클릭 헤테로사이클로-아렌을 포함할 수 있다. 본 명세서에서 상기 "헤테로아렌"에서 수소 원자 하나를 제거한 잔기를 "헤테로아릴"로 지칭한다.In the present invention, "heteroarene" may be a ring including at least one of O, N, P, Si, and S as a heterogeneous element. The number of ring carbon atoms in the heteroarene may be 2 or more and 30 or less, or 2 or more and 20 or less. The hetero arene may be a monocyclic hetero arene or a polycyclic hetero arene. The polycyclic heteroarene may have, for example, a two- or three-ring structure. Examples of heteroarenes include thiophene, purine, pyrrole, pyrazole, imidazole, thiazole, oxazole, isothiazole, oxadiazole, triazole, pyridine, bipyridyl, triazine, acridyl, pyridazine , pyrazine, quinoline, quinazoline, quinoxaline, phenoxazine, phthalazine, pyrimidine, pyridopyrimidine, pyridopyrazine, pyrazinopyrazine, isoquinoline, indole, carbazole, imidazopyridazine, imidazopyridine , imidazopyrimidine, pyrazolopyrimidine, imidazopyrazine or pyrazolopyridine, N -arylcarbazole, N -heteroarylcarbazole, N -alkylcarbazole, benzoxazole, benzoimidazole, benzothiazole , benzocarbazole, benzothiophene, dibenzothiophene, thienothiophene, benzofuran, phenanthroline, isoxazole, oxadiazole, thiadiazole, benzothiazole, tetrazole, phenothiazine , dibenzosilol and dibenzofuran, but are not limited thereto. In one embodiment of the invention heteroarenes may also include bicyclic heterocyclo-arenes, including arene rings fused to heterocycloalkyl rings or heteroarenes fused to cycloalkyl rings. In the present specification, the residue obtained by removing one hydrogen atom from the "heteroarene" is referred to as "heteroaryl".

상기 언급된 동종 또는 이종의 치환기는 동일한 위치 또는 상이한 위치에 하나 이상 치환될 수 있고, 순차적으로도 치환될 수 있다. 상기 "순차적"으로의 의미는 화학식에서 하나의 치환기가 치환된 후 상기 치환기에 또 다른 치환기가 연속하여 치환되는 것을 의미하며, 예를 들면, 알킬기가 치환된 후 상기 알킬기에 사이클로알킬기가 치환되고 상기 사이클로알킬기에 카보닐기가 순차적으로 치환되는 경우에, 카보닐사이클로알킬알킬로 명명함으로써 순차적으로 치환된 것임을 나타낼 수 있다.The above-mentioned homologous or heterogeneous substituents may be substituted one or more at the same position or different positions, and may also be substituted sequentially. The term "sequentially" means that in the formula, one substituent is substituted and then another substituent is successively substituted in the substituent, for example, after the alkyl group is substituted, a cycloalkyl group is substituted in the alkyl group and the When a carbonyl group is sequentially substituted with a cycloalkyl group, it can be indicated that the sequential substitution is made by naming the cycloalkyl group as carbonylcycloalkylalkyl.

또한, 상기 나열된 연결 라디칼은 결합 방향을 명시하지 않았으며 결합방향은 임의적이다. 예를 들어

에서 연결된 라디칼 L은 -M-W-이고, 이 때, -M-W-는 고리 A와 고리 B를 왼쪽에서 오른쪽으로 읽기 순서와 같은 방향으로 연결하여

를 형성할 수 있고, 고리 A와 고리 B를 왼쪽에서 오른쪽으로 읽기 순서와 반대 방향으로 연결하여

를 형성할 수 있다.In addition, the above-listed linking radicals do not specify the bonding direction, and the bonding direction is arbitrary. for example

The connected radical L is -MW-, where -MW- connects Ring A and Ring B in the same direction as the reading order from left to right.

can be formed, and by connecting Ring A and Ring B in the reverse reading order from left to right,

can form.

본 발명에 있어서, 용어 "광학 이성질체(enantiomer)"는 동일한 화학식 또는 분자식을 가지지만 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 각각의 광학 이성질체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다. 다른 설명이 없는 한, 비대칭 탄소 원자와 연결되는 실선 결합 (-)은 입체 중심의 절대적 배열을 나타내는 쐐기형 실선 결합

또는 쐐기형 점선 결합

을 포함할 수 있다.In the present invention, the term "enantiomer" means a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but sterically different. Each of these optical isomers and mixtures thereof are also included within the scope of the present invention. Unless otherwise noted, a solid line bond (-) connecting an asymmetric carbon atom is a wedge-shaped solid line bond indicating the absolute configuration of the stereocenter.

or wedge-dotted join

may include

본 발명의 화학식 1의 화합물은 "약학적으로 허용가능한 염"의 형태로 존재할 수 있다. 염으로는 약학적으로 허용가능한 유리산(free acid)에 의해 형성된 산부가염이 유용하다. 본 발명의 용어 "약학적으로 허용가능한 염"이란 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 화학식 1로 표시되는 화합물의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기산 또는 무기산 부가염을 의미한다.The compound of Formula 1 of the present invention may exist in the form of a "pharmaceutically acceptable salt". As the salt, an acid addition salt formed with a pharmaceutically acceptable free acid is useful. As used herein, the term "pharmaceutically acceptable salt" refers to any of the compounds at a concentration having an effective action that is relatively non-toxic and harmless to a patient, and the side effects due to the salt do not reduce the beneficial efficacy of the compound represented by the formula (1). Any organic or inorganic acid addition salt of

산부가염은 통상의 방법, 예를 들어 화합물을 과량의 산 수용액에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들어 메탄올, 에탄올, 아세톤 또는 아세토나이트릴을 사용하여 침전시켜서 제조한다. 동 몰량의 화합물 및 물 중의 산 또는 알코올을 가열하고, 이어서 상기 혼합물을 증발시켜 건조시키거나, 또는 석출된 염을 흡인 여과시킬 수 있다.Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of an excess of acid and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of compound and acid or alcohol in water may be heated, and then the mixture may be evaporated to dryness, or the precipitated salt may be filtered off with suction.

이때, 유리산으로는 유기산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 인산, 황산, 또는 질산 등을 사용할 수 있고 유기산으로는 메테인설폰산, p-톨루엔설폰산, 아세트산, 트라이플루오로아세트산, 말레인산(maleic acid), 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산(fumaric acid), 만데르산, 프로피온산(propionic acid), 구연산(citric acid), 젖산(lactic acid), 글리콜산(glycollic acid), 글루콘산(gluconic acid), 갈락투론산, 글루탐산, 글루타르산(glutaric acid), 글루쿠론산(glucuronic acid), 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 또는 아이오딘화수소산(hydroiodic acid) 등을 사용할 수 있다. 다만, 이들에 제한되지 않는다.In this case, an organic acid and an inorganic acid may be used as the free acid, and hydrochloric acid, phosphoric acid, sulfuric acid, or nitric acid may be used as the inorganic acid. As the organic acid, methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, glycolic acid, glue Conic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, or hydroiodic acid, etc. can be used However, the present invention is not limited thereto.

또한, 염기를 사용하여 약학적으로 허용가능한 금속염을 만들 수 있다. 알칼리 금속염 또는 알칼리 토금속염은, 예를 들어 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해시키고, 비용해 화합물 염을 여과한 후 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 특히 나트륨, 칼륨, 또는 칼슘염을 제조하는 것이 제약상 적합하나 이들에 제한되는 것은 아니다. 또한 이에 대응하는 은염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 은염(예, 질산은)과 반응시켜 얻을 수 있다.In addition, a pharmaceutically acceptable metal salt can be prepared using a base. The alkali metal salt 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 then evaporating and drying the filtrate. In this case, it is pharmaceutically suitable to prepare a sodium, potassium, or calcium salt as the metal salt, but is not limited thereto. Also, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

본 발명의 약학적으로 허용가능한 염은, 달리 지시되지 않는 한, 상기 화학식 1의 화합물에 존재할 수 있는 산성 또는 염기성 기의 염을 포함한다. 예를 들어, 약학적으로 허용가능한 염으로는 하이드록시기의 나트륨, 칼슘 및 칼륨염 등이 포함될 수 있고, 아미노기의 기타 약학적으로 허용가능한 염으로는 하이드로브롬화물, 황산염, 수소 황산염, 인산염, 수소 인산염, 이수소 인산염, 아세테이트, 숙시네이트, 시트레이트, 타르트레이트, 락테이트, 만델레이트, 메테인설포네이트(메실레이트), 및 p-톨루엔설포네이트(토실레이트) 염 등이 있으며, 당업계에 알려진 염의 제조방법을 통하여 제조될 수 있다.The pharmaceutically acceptable salts of the present invention include salts of acidic or basic groups that may be present in the compound of Formula 1, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of a hydroxyl group, and other pharmaceutically acceptable salts of an amino group include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), and p-toluenesulfonate (tosylate) salts; It can be prepared through a method for preparing a known salt.

아이소옥사졸리딘 유도체 화합물의 용도Uses of isoxazolidine derivative compounds

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염의 용도를 제공한다.The present invention provides the use of a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[화학식 1][Formula 1]

본 발명의 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염은 다양한 키나아제에 대하여 억제 활성을 나타낸다(실험예 1). The compound represented by Formula 1 of the present invention, an optical isomer thereof, or a pharmaceutically acceptable salt thereof exhibits inhibitory activity against various kinases (Experimental Example 1).

본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 아이소옥사졸리딘 유도체 화합물은 여러 키나아제 중에서 CDK2, CDK4, CDK6 및/또는 HPK1에 대해 우수한 억제 활성을 나타내므로, CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환, 특히, 암에 대하여 치료 또는 예방에 유용하게 사용될 수 있다. According to one embodiment of the present invention, since the isoxazolidine derivative compound represented by Formula 1 exhibits excellent inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1 among various kinases, CDK2, CDK4, CDK6 and/or Alternatively, it may be usefully used for treatment or prevention of HPK1-related diseases, particularly cancer.

본 발명에 있어서, 상기 암은 CDK2, CDK4, CDK6 및/또는 HPK1 활성 억제로 인해 치료 또는 예방 효능을 나타낼 수 있는 모든　암을 포함하며, 고형암　또는 혈액암일 수 있다. 예컨대, 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인 것일 수 있으나, 이에 제한되지 않는다. 또한, 상기　암은 원발성　암뿐 아니라 전이성　암도 포함한다.In the present invention, the cancer includes all cancers capable of exhibiting therapeutic or prophylactic efficacy due to inhibition of CDK2, CDK4, CDK6 and/or HPK1 activity, and may be solid cancer or blood cancer. For example, pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell cancer, ovarian cancer Epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer, Parathyroid cancer, adrenal cancer, nasal sinus cancer, non-small cell lung cancer, tongue cancer, astrocytoma, small cell lung cancer, juvenile brain cancer, juvenile lymphoma, juvenile leukemia, small intestine cancer, meningioma, esophageal cancer, glioma, renal pelvic cancer, kidney cancer, heart cancer, duodenum Cancer, malignant soft tissue cancer, malignant bone cancer, malignant lymphoma, malignant mesothelioma, malignant melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilms cancer , breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational villous disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, auditory schwannoma, Pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, blood cancer, and thymus cancer It may be one or more selected from the group consisting of, but is not limited thereto. In addition, the above cancers include not only primary cancers but also metastatic cancers.

본 발명의 일 구체예에 따르면, 본 발명은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방용 약학적 조성물을 제공한다. 구체적으로, 상기 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환은 암일 수 있다. 상기 암의 종류는 위에서 언급한 바와 같다. According to one embodiment of the present invention, the present invention provides a CDK2, CDK4, CDK6 and/or HPK1-related disease containing the compound represented by Formula 1, an optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for treatment or prevention is provided. Specifically, the CDK2, CDK4, CDK6 and/or HPK1-related disease may be cancer. The types of cancer are as described above.

본 발명의 약학적 조성물은 투여를 위해서 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 추가로 약학적으로 허용가능한 담체를 1 종 이상 더 포함할 수 있다. 약학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 따라서, 본 발명의 조성물은 패치제, 액제, 환약, 캡슐, 과립, 정제, 좌제 등일 수 있다. 이들 제제는 당 분야에서 제제화에 사용되는 통상의 방법 또는 문헌 [Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA]에 개시되어 있는 방법으로 제조될 수 있으며 각 질환에 따라 또는 성분에 따라 다양한 제제로 제제화될 수 있다. For administration, the pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable carrier may be used in a mixture of saline, sterile water, Ringer's solution, buffered saline, dextrose solution, maltodextrin solution, glycerol, ethanol, and one or more of these components. , and other conventional additives such as a bacteriostatic agent may be added. In addition, diluents, dispersants, surfactants, binders and lubricants may be additionally added to form an injectable formulation such as an aqueous solution, suspension, emulsion, etc., pills, capsules, granules or tablets. Accordingly, the composition of the present invention may be a patch, solution, pill, capsule, granule, tablet, suppository, and the like. These formulations may be prepared by a conventional method used for formulation in the art or a method disclosed in Remington's Pharmaceutical Science, Mack Publishing Company, Easton PA, and may be formulated into various formulations according to each disease or component. can

본 발명의 상기 약학적 조성물은 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이들의 약학적으로 허용가능한 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상을 더 포함할 수 있다. The pharmaceutical composition of the present invention may further include one or more active ingredients exhibiting the same or similar efficacy in addition to the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

또한 본 발명의 일 구체예에 따르면, 상기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 치료학적으로 유효한 양을, 이를 필요로 하는 대상(subject)에게 투여하는 단계를 포함하는, CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환을 치료 또는 예방하는 방법을 제공한다. 상기 대상(subject)은 인간을 포함하는 포유류일 수 있다.Also, according to one embodiment of the present invention, the step of administering to a subject in need thereof a therapeutically effective amount of the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof Provided is a method for treating or preventing a CDK2, CDK4, CDK6 and/or HPK1 related disease, comprising: The subject may be a mammal including a human.

본 발명에서 사용되는 "치료학적으로 유효한 양"이라는 용어는 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방에 유효한 상기 화학식 1로 표시되는 화합물의 양을 나타낸다. 구체적으로, "치료학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 개체 종류 및 중증도, 연령, 성별, 질병의 종류, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 시판되는 치료제와는 순차적으로 또는 동시에 투여될 수 있다. 그리고 단일 또는 다중 투여될 수 있다. 상기 요소를 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 당업자에 의해 용이하게 결정될 수 있다. 본 발명의 약학적 조성물의 투여 용량은, 환자의 상태, 연령, 성별 및 합병증 등의 다양한 요인에 따라 전문가에 의해 결정될 수 있다. 본 발명의 약학적 조성물의 유효성분은 안전성이 우수하므로, 결정된 투여 용량 이상으로도 사용될 수 있다.As used herein, the term "therapeutically effective amount" refers to an amount of the compound represented by Formula 1 effective for the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases. Specifically, "therapeutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit/risk ratio applicable to medical treatment, and effective dose level includes the subject type and severity, age, sex, type of disease, The activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and the rate of excretion, the duration of treatment, factors including concurrently used drugs, and other factors well known in the medical field may be determined according to factors. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or may be administered in combination with other therapeutic agents, and may be administered sequentially or simultaneously with commercially available therapeutic agents. and may be administered single or multiple. Taking all of the above factors into consideration, it is important to administer an amount that can obtain the maximum effect with a minimum amount without side effects, and can be easily determined by those skilled in the art. The dosage of the pharmaceutical composition of the present invention may be determined by an expert according to various factors such as the patient's condition, age, sex, and complications. Since the active ingredient of the pharmaceutical composition of the present invention is excellent in safety, it may be used at a dose higher than the determined dosage.

또한 본 발명의 일 구체예에 따르면, 본 발명은 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방에 사용하기 위한 약제(medicament)의 제조에 사용하기 위한, 상기 화학식 1 로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염의 용도(use)를 제공한다. 약제의 제조를 위한 상기 화학식 1로 표시되는 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다. Also, according to one embodiment of the present invention, the present invention provides a compound represented by Formula 1 for use in the manufacture of a medicament for use in the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases , an optical isomer thereof, or a pharmaceutically acceptable salt thereof. The compound represented by Formula 1 for the manufacture of a drug may be mixed with an acceptable adjuvant, diluent, carrier, etc., and may have a synergistic action of the active ingredients by being prepared as a complex formulation together with other active agents.

본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.Matters mentioned in the uses, compositions, and treatment methods of the present invention are equally applicable as long as they do not contradict each other.

본 발명의 실시 형태는 여러가지 다른 형태로 변형될 수 있으며, 본 발명의 범위가 이하 설명하는 실시 형태로 한정되는 것은 아니다. 또한 본 발명의 실시 형태는 당해 기술분야에서 평균적인 지식을 가진 자에게 본 발명을 더욱 완전하게 설명하기 위해서 제공되는 것이다. 나아가, 명세서 전체에서 어떤 구성요소를 "포함"한다는 것은 특별히 반대되는 기재가 없는 한 다른 구성요소를 제외하는 것이 아니라 다른 구성요소를 더 포함할 수 있다는 것을 의미한다.Embodiments of the present invention may be modified in various other forms, and the scope of the present invention is not limited to the embodiments described below. In addition, the embodiment of the present invention is provided in order to more completely explain the present invention to those of ordinary skill in the art. Furthermore, in the entire specification, "including" a certain element means that other elements may be further included, rather than excluding other elements, unless otherwise stated.

본 발명의 아이소옥사졸리딘 유도체 화합물은 CDK2, CDK4, CDK6 및/또는 HPK1에 대해 우수한 억제 활성을 나타내므로, 상기 CDK2, CDK4, CDK6 및/또는 HPK1 관련 질환의 치료 또는 예방에 유용하게 사용될 수 있다.Since the isoxazolidine derivative compound of the present invention exhibits excellent inhibitory activity against CDK2, CDK4, CDK6 and/or HPK1, it can be usefully used for the treatment or prevention of CDK2, CDK4, CDK6 and/or HPK1-related diseases. .

이하, 본 발명을 실시예 및 실험예에 의하여 상세히 설명한다. 단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 범위가 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by way of Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, and the scope of the present invention is not limited thereto.

본 발명의 실시예에서 합성된 화합물은 다음의 HPLC 조건에 의해 정제하거나 또는 구조 분석을 실시한 것이다: The compound synthesized in the Examples of the present invention is purified by the following HPLC conditions or subjected to structural analysis:

정제용 중압액체크로마토그래피(Medium pressure liquid chromatography; MPLC)Medium pressure liquid chromatography (MPLC) for purification

중압액체크로마토그래피는 TELEDYNE ISCO사의 CombiFlash Rf +UV을 사용하였다.Medium pressure liquid chromatography was performed using TELEDYNE ISCO's CombiFlash Rf +UV.

분석용 HPLC 조건(ACQUITY UPLC H-Class Core System)Analytical HPLC conditions (ACQUITY UPLC H-Class Core System)

Waters사 제조 UPLC system(ACQUITY UPLC PDA Detector)에 Waters사 제조 mass QDA Detector가 장착된 장비를 사용하였다. 사용 컬럼은 Waters사의 ACQUITY UPLC^®BEH C18(1.7　㎛, 2.1 X 50 mm)였으며 컬럼온도는 30 ℃에서 진행하였다.An equipment equipped with a mass QDA Detector manufactured by Waters was used in the UPLC system (ACQUITY UPLC PDA Detector) manufactured by Waters. The column used was Waters' ACQUITY UPLC ^® BEH C18 (1.7 ㎛, 2.1 X 50 mm), and the column temperature was 30 ℃.

이동상 A는 0.1 % 개미산이 포함된 물, 이동상 B는 0.1 %의 개미산이 포함된 아세토나이트릴을 사용하였다.Mobile phase A used water containing 0.1% formic acid, and mobile phase B used acetonitrile containing 0.1% formic acid.

Gradient condition(10 - 100 % B로 3 분, 이동속도 = 0.6 ml/min)Gradient condition (10 - 100 % B for 3 minutes, movement speed = 0.6 ml/min)

정제용 Prep-LCMS(Preparative-Liquid chromatography mass spectrometry)Preparative-Liquid chromatography mass spectrometry (Prep-LCMS) for purification

Waters사 제조 Autopurification HPLC system(2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector)에 Waters사 제조 mass QDA Detector가 장착된 장비를 사용하였다. 사용 컬럼은 Waters사의 SunFire^®Prep C18 OBD^TM(5　㎛, 19 X 50 mm)였으며 컬럼온도는 실온에서 진행하였다.The Autopurification HPLC system manufactured by Waters (2767 sample manger, 2545 binary gradient module, 2998 Photodiode Array Detector) was equipped with a mass QDA Detector manufactured by Waters was used. The column used was Waters' SunFire ^® Prep C18 OBD ^TM (5 ㎛, 19 X 50 mm), and the column temperature was performed at room temperature.

이동상 A는 0.035 % 트라이플루오로아세트산이 포함된 물, 이동상 B는 0.035 %의 트라이플루오로아세트산이 포함된 메탄올을 사용하였다.Water containing 0.035% trifluoroacetic acid was used for mobile phase A, and methanol containing 0.035% trifluoroacetic acid was used for mobile phase B.

Gradient condition(15 - 100 % B로 10 분, 이동속도 = 25 ml/min)Gradient condition (15 - 10 minutes with 100 % B, movement speed = 25 ml/min)

정제용 Prep-150 LC System(Preparative-Liquid chromatography UV spectrometry)Prep-150 LC System for purification (Preparative-Liquid chromatography UV spectrometry)

Waters사 제조 Prep 150 LC system(2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III)에 Waters사 제조 장비를 사용하였다. 사용 컬럼은 Waters사의 XTERRA^®Prep RP18 OBD^TM(10　㎛, 30 X 300 mm)였으며 컬럼온도는 실온에서 진행하였다.The equipment manufactured by Waters was used for the Prep 150 LC system manufactured by Waters (2545 Quaternary gradient module, 2998 Photodiode Array Detector, Fraction collector III). The column used was Waters' XTERRA ^® Prep RP18 OBD ^TM (10 μm, 30 X 300 mm), and the column temperature was performed at room temperature.

Gradient condition(3 - 100 % B로 120 분, 이동속도 = 40 ml/min)Gradient condition (3 - 120 min with 100 % B, movement speed = 40 ml/min)

사용된 시판 시약은 추가 정제 없이 사용하였다. 본 발명에서 실온은 1 ~ 35 ℃ 정도의 온도를 말한다. 감압하 농축 또는 용매 증류 제거는, 회전식 증발기(rotary evaporator)를 사용하였다.Commercial reagents used were used without further purification. In the present invention, room temperature refers to a temperature of about 1 ~ 35 ℃. For concentration under reduced pressure or solvent distillation, a rotary evaporator was used.

<제조예 1> (S)-3-페닐아이소옥사졸리딘의 제조<Preparation Example 1> Preparation of (S)-3-phenylisoxazolidine

단계 1: Step 1: terttert -부틸 (-Butyl ( RR )-(3-하이드록시-3-페닐프로폭시)카바메이트의 제조Preparation of )-(3-hydroxy-3-phenylpropoxy)carbamate

tert-부틸 하이드록시카바메이트(7.8 g, 58.6 mmol)를 다이메틸포름아마이드(140 mL)에 녹인 후 0 ℃에서 수소화나트륨(2.58 g, 64.5 mmol)을 첨가하고 30 분 동안 반응하였다. 그리고 다이메틸포름아마이드(10 mL)에 녹인 (R)-3-클로로-1-페닐프로판-1-올(5 g, 29.3 mmol)을 0 ℃에서 10 분간 천천히 적가하고 실온에서 72 시간 동안 교반하였다. 반응 혼합물에 염화암모늄 수용액을 넣어 반응을 종결시키고, 아세트산에틸 및 소금물로 추출하여 유기층을 합하였다. 유기층을 황산나트륨으로 건조한 후 감압하여 농축 후 중압액체크로마토그래피(아세트산에틸/n-헥산)로 정제하여 목적 화합물(2.8 g, 68 %)을 수득하였다. tert -Butyl hydroxycarbamate (7.8 g, 58.6 mmol) was dissolved in dimethylformamide (140 mL), and sodium hydride (2.58 g, 64.5 mmol) was added at 0 °C, followed by reaction for 30 minutes. Then, ( R )-3-chloro-1-phenylpropan-1-ol (5 g, 29.3 mmol) dissolved in dimethylformamide (10 mL) was slowly added dropwise at 0° C. for 10 minutes, followed by stirring at room temperature for 72 hours. . The reaction was terminated by adding an aqueous ammonium chloride solution to the reaction mixture, followed by extraction with ethyl acetate and brine to combine the organic layers. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (ethyl acetate/n-hexane) to obtain the target compound (2.8 g, 68%).

MS (m/z): 150.17 [M+1]⁺ MS (m/z): 150.17 [M+1] ⁺

¹H NMR (400 MHz, CDCl₃) δ = 7.43 - 7.39 (m, 2H), 7.38 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 5.05 - 4.97 (m, 1H), 4.15 - 4.08 (m, 1H), 4.07 - 4.00 (m, 1H), 2.10 - 1.93 (m, 2H), 1.54 - 1.48 (m, 9H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.43 - 7.39 (m, 2H), 7.38 - 7.32 (m, 2H), 7.27 - 7.24 (m, 1H), 5.05 - 4.97 (m, 1H), 4.15 - 4.08 (m, 1H), 4.07 - 4.00 (m, 1H), 2.10 - 1.93 (m, 2H), 1.54 - 1.48 (m, 9H)

단계 2: Step 2: terttert -부틸 (-Butyl ( SS )-3-페닐아이소옥사졸리딘-2-카복실레이트의 제조) Preparation of -3-phenylisoxazolidine-2-carboxylate

단계 1에서 제조한 tert-부틸 (R)-(3-하이드록시-3-페닐프로폭시)카바메이트(2.55 g, 9.54 mmol)와 트라이에틸아민(3.13 mL, 22.44 mmol)을 염화메틸렌(250 mL)에 녹인 후 0 ℃로 냉각하였다. 그리고 MsCl(1 mL, 13 mmol)를 적가하고 0 ℃에서 2 시간 동안 반응하였다. 반응 혼합물을 소금물 및 염화메틸렌으로 추출하여 유기층을 합하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 목적 화합물(2.3 g, crude)을 얻어 정제 없이 다음 반응에 사용하였다. tert -Butyl ( R )-(3-hydroxy-3-phenylpropoxy)carbamate (2.55 g, 9.54 mmol) prepared in step 1 and triethylamine (3.13 mL, 22.44 mmol) were mixed with methylene chloride (250 mL) ) and then cooled to 0 °C. Then, MsCl (1 mL, 13 mmol) was added dropwise and reacted at 0 °C for 2 hours. The reaction mixture was extracted with brine and methylene chloride, and the organic layers were combined. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (2.3 g, crude), which was used in the next reaction without purification.

MS (m/z): 194.13 [M+1]⁺ MS (m/z): 194.13 [M+1] ⁺

¹H NMR (400 MHz, CDCl₃) δ = 7.29 - 7.23 (m, 4H), 7.18 - 7.17 (m, 1H), 5.12 - 5.11 (m, 1H), 4.10 - 4.03 (m, 1H), 3.82- 3.80 (m, 1H), 2.75 - 2.65 (m, 1H), 2.29 - 2.15 (m, 1H), 1.37 (s, 9H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.29 - 7.23 (m, 4H), 7.18 - 7.17 (m, 1H), 5.12 - 5.11 (m, 1H), 4.10 - 4.03 (m, 1H), 3.82 3.80 (m, 1H), 2.75 - 2.65 (m, 1H), 2.29 - 2.15 (m, 1H), 1.37 (s, 9H)

단계 3: (Step 3: ( SS )-3-페닐아이소옥사졸리딘의 제조) Preparation of -3-phenylisoxazolidine

단계 2에서 제조한 tert-부틸 (S)-3-페닐아이소옥사졸리딘-2-카복실레이트(2.3 g)를 염화메틸렌(90 mL)에 녹인 후 TFA(14 mL)를 첨가하고 실온에서 1 시간 동안 반응하였다. 반응 혼합물을 중탄산나트륨 수용액으로 중화시킨 뒤 유기층을 합하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 중압액체크로마토그래피(THF/n-헥산)로 정제하여 목적 화합물(1.3 g, 94 %)을 수득하였다. tert -Butyl ( S )-3-phenylisoxazolidine-2-carboxylate (2.3 g) prepared in step 2 was dissolved in methylene chloride (90 mL), TFA (14 mL) was added, and 1 hour at room temperature reacted while The reaction mixture was neutralized with aqueous sodium bicarbonate solution, and then the organic layers were combined. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by medium pressure liquid chromatography (THF/n - hexane) to obtain the target compound (1.3 g, 94 %).

MS (m/z): 150.08 [M+1]⁺ MS (m/z): 150.08 [M+1] ⁺

¹H NMR (400 MHz, DMSO-d ₆) δ = 7.59 - 7.52 (m, 2H), 7.50 - 7.39 (m, 3H), 5.01 - 4.93 (m, 1H), 2.93 - 2.82 (m, 1H), 2.62 - 2.53 (m, 2H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.59 - 7.52 (m, 2H), 7.50 - 7.39 (m, 3H), 5.01 - 4.93 (m, 1H), 2.93 - 2.82 (m, 1H), 2.62 - 2.53 (m, 2H)

<제조예2> (R)-3-페닐아이소옥사졸리딘의 제조<Preparation Example 2> Preparation of (R)-3-phenylisooxazolidine

상기 제조예 1과 유사한 방법으로 제조예 2를 제조하였으며, 이하 실시예의 제조시 사용하였다.Preparation Example 2 was prepared in a manner similar to Preparation Example 1, and was used in the preparation of Examples below.

MS (m/z) : 150.08 [M+1]⁺ MS (m/z): 150.08 [M+1] ⁺

<제조예 3> (<Preparation Example 3> ( SS )-3-(3-플루오로페닐)아이소옥사졸리딘)-3-(3-fluorophenyl)isoxazolidine

단계 1: 3-플루오로-Step 1: 3-Fluoro- N-N- 메톡시-methoxy- N-N- 메틸벤즈아마이드의 제조Preparation of methylbenzamide

3-플루오로벤조산(90 g, 642.3 mmol)을 피리딘(150 mL)에 녹인 후, N,O-다이메틸하이드록실아민 염산염(75.19 g, 770.81 mmol)을 첨가하였다. 그 후 15 ℃에서 EDCI(147.77 g, 770.8 mmol)를 첨가하였다. 반응 혼합물을 50 ℃에서 30 분 동안 교반하였다. TLC 분석결과(석유에터:아세트산에틸 = 3:1), 출발 물질이 모두 사라졌으며 낮은 극성을 가지는 새로운 스팟이 검출되었다. 감압 농축하여 용매를 제거하고, 염화메틸렌(500 mL)과 HCl(500 mL, 2 N), 소금물(200 mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 황색 오일의 목적 화합물(110 g, 94 %)을 수득하였다.3-fluorobenzoic acid (90 g, 642.3 mmol) was dissolved in pyridine (150 mL), and N,O -dimethylhydroxylamine hydrochloride (75.19 g, 770.81 mmol) was added thereto. EDCI (147.77 g, 770.8 mmol) was then added at 15 °C. The reaction mixture was stirred at 50 °C for 30 min. As a result of TLC analysis (petroleum ether:ethyl acetate = 3:1), all starting materials disappeared and a new spot with low polarity was detected. The solvent was removed by concentration under reduced pressure, and the organic layer was extracted using methylene chloride (500 mL), HCl (500 mL, 2 N), and brine (200 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (110 g, 94 %) as a yellow oil.

단계 2: 1-(3-플루오로페닐)프로프-2-엔-1-온의 제조Step 2: Preparation of 1-(3-fluorophenyl)prop-2-en-1-one

단계 1에서 제조한 3-플루오로-N-메톡시-N-메틸벤즈아마이드(110 g, 600.5 mmol)를 THF(1 L)에 녹인 후, -78 ℃에서 브로모(비닐)마그네슘(1M, 630.53 mL)을 한 방울씩 적가하였다. 그 후, 반응 혼합물을 0 ℃에서 30 분 동안 교반하였다. TLC 분석 결과(석유에터:아세트산에틸 = 4:1), 출발 물질이 모두 사라졌으며, 낮은 극성을 가지는 새로운 스팟이 검출되었다. HCl(4 N, 500 mL)을 첨가하여 반응을 종결한 후, MTBE(2 L)와 소금물(500 mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후, 감압 농축하였다. 농축한 화합물을 중압크로마토그래피(석유에터/아세트산에틸 = 30/1)를 이용해 정제하여 황색 오일 상태의 목적 화합물(80 g, 89 %)을 수득하였다.After dissolving 3-fluoro- N -methoxy- N -methylbenzamide (110 g, 600.5 mmol) prepared in step 1 in THF (1 L), bromo(vinyl)magnesium (1M, 630.53 mL) was added dropwise. After that, the reaction mixture was stirred at 0 °C for 30 min. As a result of TLC analysis (petroleum ether:ethyl acetate = 4:1), all starting materials disappeared, and a new spot with low polarity was detected. After the reaction was terminated by addition of HCl (4 N, 500 mL), the organic layer was extracted using MTBE (2 L) and brine (500 mL). The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The concentrated compound was purified by medium pressure chromatography (petroleum ether/ethyl acetate = 30/1) to obtain the target compound as a yellow oil (80 g, 89%).

단계 3: 3-클로로-1-(3-플루오로페닐)프로판-1-온의 제조Step 3: Preparation of 3-chloro-1-(3-fluorophenyl)propan-1-one

단계 2에서 제조한 1-(3-플루오로페닐)프로프-2-엔-1-온(71 g, 472.86 mmol)을 염화메틸렌(71 mL)에 녹인 후, 0 ℃에서 HCl(4 M, 295.54 mL)을 첨가하였다. 그 후, 반응 혼합물을 15 ℃에서 1.5 시간 동안 교반하였다. TLC 분석 결과(석유에터:아세트산에틸 = 10:1), 출발 물질은 모두 사라졌으며, 목적 화합물이 검출되었다. 반응 혼합물을 감압 하에 농축한 후, 염화메틸렌(450 mL)과 물(200 mL * 5 회)을 첨가하여 유기층을 추출하였고, 황산나트륨으로 건조한 후 감압 농축하여 황색 고체의 목적 화합물 (73 g, 83 %)을 수득하였다.After dissolving 1-(3-fluorophenyl)prop-2-en-1-one (71 g, 472.86 mmol) prepared in step 2 in methylene chloride (71 mL), HCl (4 M, 295.54 mL) was added. Then, the reaction mixture was stirred at 15 °C for 1.5 hours. As a result of TLC analysis (petroleum ether:ethyl acetate = 10:1), all starting materials disappeared, and the target compound was detected. After the reaction mixture was concentrated under reduced pressure, methylene chloride (450 mL) and water (200 mL * 5 times) were added to extract the organic layer, dried over sodium sulfate, and then concentrated under reduced pressure to give the title compound as a yellow solid (73 g, 83 %) ) was obtained.

¹H NMR (400 MHz, CDCl₃) δ = 7.78 - 7.72 (m, 1H), 7.69 - 7.60 (m, 1H), 7.53 - 7.44 (m, 1H), 7.37 - 7.24 (m, 1H), 3.93 (t, J = 6.8 Hz, 2H), 3.46 (t, J = 6.8 Hz, 2H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.78 - 7.72 (m, 1H), 7.69 - 7.60 (m, 1H), 7.53 - 7.44 (m, 1H), 7.37 - 7.24 (m, 1H), 3.93 ( t, J = 6.8 Hz, 2H), 3.46 (t, J = 6.8 Hz, 2H)

단계 4: (Step 4: ( RR )-3-클로로-1-(3-플루오로페닐)프로판-1-올의 제조Preparation of -3-chloro-1- (3-fluorophenyl) propan-1-ol

(S)-1-메틸-3,3-다이페닐테트라하이드로-1H,3H-피롤로[1,2-c][1,3,2]옥사자보롤(9.27 mL, 31.08 mmol)을 THF(380 mL)에 녹인 후, BH₃.THF(1M, 186.48 mL)를 0 ℃에서 질소기류 하에 한 방울씩 첨가하였다. 반응 혼합물을 0 ℃에서 30 분간 교반하였다. 그 후, 반응 혼합물에 THF(390 mL)에 희석한 상기 단계 3에서 얻어진 3-클로로-1-(3-플루오로페닐)프로판-1-온(70 g, 375.11 mmol)을 0 ℃에서 한 방울씩 적가하였다. 반응 혼합물을 0 ℃에서 30 분 동안 교반하였다. TLC 분석 결과(석유에터:아세트산에틸 = 5:1), 출발 물질이 모두 사라졌으며, 목적 화합물 스팟이 검출되었다. 0 ℃에서 메탄올(100 mL)을 첨가하여 반응을 종결한 후, 용매를 감압 하에 날려주었다. 농축한 화합물을 염화메틸렌(100 mL * 3 회)과 염화암모늄 수용액(300 mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하였다. 농축한 화합물을 중압액체크로마토그래피(석유에터:아세트산에틸 = 50:1 내지 5:1)를 사용해 정제하여 무색의 오일(55 g, 92 %, 98.2 % purity, 54.1 % e.e.)을 수득하였다.( S )-1-methyl-3,3-diphenyltetrahydro- 1H , 3H -pyrrolo[1,2- c ][1,3,2]oxazaborol (9.27 mL, 31.08 mmol) After dissolving in THF (380 mL), BH ₃ .THF (1M, 186.48 mL) was added dropwise at 0 °C under a nitrogen stream. The reaction mixture was stirred at 0 °C for 30 min. Thereafter, 3-chloro-1-(3-fluorophenyl)propan-1-one (70 g, 375.11 mmol) obtained in step 3 above diluted in THF (390 mL) was added to the reaction mixture at 0 ° C. dropwise. were added dropwise. The reaction mixture was stirred at 0 °C for 30 min. As a result of TLC analysis (petroleum ether:ethyl acetate = 5:1), all the starting materials disappeared, and a target compound spot was detected. After the reaction was terminated by adding methanol (100 mL) at 0 °C, the solvent was blown away under reduced pressure. The organic layer was extracted from the concentrated compound using methylene chloride (100 mL * 3 times) and ammonium chloride aqueous solution (300 mL). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified using medium pressure liquid chromatography (petroleum ether:ethyl acetate = 50:1 to 5:1) to give a colorless oil (55 g, 92 %, 98.2 % purity, 54.1 % ee).

MS (m/z): 135.2 [M-56+H]^＋ MS (m/z): 135.2 [M-56+H] ⁺

¹H NMR (400 MHz, CDCl₃) δ = 7.35 - 7.28 (m, 1H), 7.19 - 7.04 (m, 2H), 7.01 - 6.91 (m, 1H), 5.00 - 4.88 (m, 1H), 3.76 - 3.70 (m, 1H), 3.60 - 3.51 (m, 1H), 2.24 - 2.13 (m, 1H), 2.12 - 1.98 (m, 2H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.35 - 7.28 (m, 1H), 7.19 - 7.04 (m, 2H), 7.01 - 6.91 (m, 1H), 5.00 - 4.88 (m, 1H), 3.76 - 3.70 (m, 1H), 3.60 - 3.51 (m, 1H), 2.24 - 2.13 (m, 1H), 2.12 - 1.98 (m, 2H)

단계 5: Step 5: terttert -부틸 (-Butyl ( RR )-(3-(3-플루오로페닐)-3-하이드록시프로폭시)카바메이트의 제조Preparation of )-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate

tert-부틸 하이드록시카바메이트(40.76 g, 306.16 mmol)를 다이메틸포름아마이드(400 mL)에 녹인 후, 0 ℃에서 질소 기류 하에 수소화나트륨(12.83 g, 320.74 mmol, 60 % purity)을 첨가하였다. 반응 혼합물을 10 ℃에서 1 시간 동안 교반하고, 다이메틸포름아마이드(150 mL)에 단계 4에서 제조한 (R)-3-클로로-1-(3-플루오로페닐)프로판-1-올(55 g, 291.58 mmol)을 0 ℃에서 한 방울씩 첨가하고 10 ℃에서 16 시간 동안 교반하였다. TLC 분석 결과, 출발 물질은 모두 사라졌으며, 목적 화합물이 검출되었다. 물(800 mL)을 첨가하여 반응을 종결한 후, 생성된 고체를 필터하였다. 회수한 고체를 아세트산에틸(800 mL)과 물(100 mL), 소금물(100 mL)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 밝은 황색 고체의 목적 화합물(72 g, 65 %, 75.12 % purity)을 수득하였다. tert -Butyl hydroxycarbamate (40.76 g, 306.16 mmol) was dissolved in dimethylformamide (400 mL), and then sodium hydride (12.83 g, 320.74 mmol, 60 % purity) was added at 0° C. under a nitrogen stream. The reaction mixture was stirred at 10 °C for 1 hour, and ( R )-3-chloro-1-(3-fluorophenyl)propan-1-ol (55) prepared in step 4 was added to dimethylformamide (150 mL). g, 291.58 mmol) was added dropwise at 0 °C and stirred at 10 °C for 16 hours. As a result of TLC analysis, all the starting materials disappeared, and the target compound was detected. After the reaction was terminated by addition of water (800 mL), the resulting solid was filtered. The organic layer was extracted from the recovered solid using ethyl acetate (800 mL), water (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (72 g, 65 %, 75.12 % purity) as a light yellow solid.

MS (m/z) : 167.9 [M-118]^＋ MS (m/z): 167.9 [M-118] ⁺

¹H NMR (400 MHz, CDCl₃) δ = 7.17 - 7.06 (m, 1H), 7.01 - 6.93 (m, 2H), 6.80 - 6.73 (m, 1H), 4.89 - 4.79 (m, 1H), 3.95 - 3.89 (m, 1H), 3.88 - 3.82 (m, 1H), 1.89 - 1.81 (m, 1H), 1.80 - 1.69 (m, 1H), 1.32 (s, 9H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.17 - 7.06 (m, 1H), 7.01 - 6.93 (m, 2H), 6.80 - 6.73 (m, 1H), 4.89 - 4.79 (m, 1H), 3.95 - 3.89 (m, 1H), 3.88 - 3.82 (m, 1H), 1.89 - 1.81 (m, 1H), 1.80 - 1.69 (m, 1H), 1.32 (s, 9H)

단계 6: Step 6: terttert -부틸 (-Butyl ( SS )-3-(3-플루오로페닐)아이소옥사졸리딘-2-카복실레이트의 제조Preparation of )-3-(3-fluorophenyl)isoxazolidine-2-carboxylate

단계 5에서 제조한 tert-부틸 (R)-(3-(3-플루오로페닐)-3-하이드록시프로폭시)카바메이트(72 g, 252.36 mmol)와 트라이에틸아민(105.38 mL, 757.07 mmol)을 염화메틸렌(700 mL)에 녹인 후, 0 ℃에서 메테인설폰산 무수물(65.94 g, 378.53 mmol)을 천천히 첨가하였다. 반응 혼합물을 20 ℃에서 12 시간 동안 교반하였다. TLC 분석 결과(석유에터:아세트산에틸 = 3:1), 출발 물질은 모두 사라졌으며, 새로운 스팟이 검출되었다. 물(1000 mL)을 첨가하여 반응을 종결한 후, 염화메틸렌(200 mL * 3 회)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하였다. 농축한 화합물을 중압액체크로마토그래피(석유에터:아세트산에틸 = 50:1 내지 5:1)로 정제하여 57.7 % e.e 값을 가지는 목적 화합물 35 g을 추출하였다. 목적 화합물을 SFC(column : DAICEL CHIRALPAK AD-H (250 mm X 30 mm, 5 ㎛); mobile phase: [Neu-메탄올]; B % : 15 %, 2.9 min; 760 min)을 통해 정제하여 밝은 황색 고체의 tert-부틸 (S)-3-(3-플루오로페닐)아이소옥사졸리딘-2-카복실레이트(25 g, 36 %, 98.37 % purity, 100 % e.e.)와 tert-부틸 (R)-3-(3-플루오로페닐)아이소옥사졸리딘-2-카복실레이트(6.5 g, 8.7 %, 91.13 % purity, 100 % e.e.)를 수득하였다. tert -Butyl ( R )-(3-(3-fluorophenyl)-3-hydroxypropoxy)carbamate (72 g, 252.36 mmol) prepared in step 5 and triethylamine (105.38 mL, 757.07 mmol) was dissolved in methylene chloride (700 mL), and methanesulfonic anhydride (65.94 g, 378.53 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 20 °C for 12 h. As a result of TLC analysis (petroleum ether:ethyl acetate = 3:1), all starting materials disappeared and a new spot was detected. After the reaction was terminated by adding water (1000 mL), the organic layer was extracted using methylene chloride (200 mL * 3 times). The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The concentrated compound was purified by medium pressure liquid chromatography (petroleum ether: ethyl acetate = 50:1 to 5:1) to extract 35 g of the target compound having a 57.7% ee value. The target compound was purified through SFC (column: DAICEL CHIRALPAK AD-H (250 mm X 30 mm, 5 μm); mobile phase: [Neu-methanol]; B %: 15 %, 2.9 min; 760 min) to light yellow Solid tert -butyl ( S )-3-(3-fluorophenyl)isoxazolidine-2-carboxylate (25 g, 36 %, 98.37 % purity, 100 % ee) and tert -butyl ( R )- 3-(3-fluorophenyl)isoxazolidine-2-carboxylate (6.5 g, 8.7 %, 91.13 % purity, 100 % ee) was obtained.

MS (m/z): 212.2 [M-56+H]^＋ MS (m/z): 212.2 [M-56+H] ⁺

¹H NMR (400 MHz, CDCl₃) δ = 7.34 - 7.27 (m, 1H), 7.17 - 7.05 (m, 2H), 6.99 - 6.91 (m, 1H), 5.20 (dd, J = 5.6, 8.8 Hz, 1H), 4.22 - 4.14 (m, 1H), 3.94 - 3.84 (m, 1H), 2.84 - 2.73 (m, 1H), 2.34 - 2.22 (m, 1H), 1.47 (s, 9H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.34 - 7.27 (m, 1H), 7.17 - 7.05 (m, 2H), 6.99 - 6.91 (m, 1H), 5.20 (dd, J = 5.6, 8.8 Hz, 1H), 4.22 - 4.14 (m, 1H), 3.94 - 3.84 (m, 1H), 2.84 - 2.73 (m, 1H), 2.34 - 2.22 (m, 1H), 1.47 (s, 9H)

단계 7: (Step 7: ( SS )-3-(3-플루오로페닐)아이소옥사졸리딘의 제조Preparation of )-3-(3-fluorophenyl)isoxazolidine

단계 6에서 제조한 tert-부틸 (S)-3-(3-플루오로페닐)아이소옥사졸리딘-2-카복실레이트(25 g, 93.53 mmol)를 아세트산에틸(50 mL)에 녹인 후, 0 ℃에서 HCl/아세트산에틸(4M, 250 mL)을 첨가하였다. 그 후, 반응 혼합물을 10 ℃에서 1 시간 동안 교반하였다. LCMS 분석 결과, 출발 물질이 모두 사라졌고 목적 스팟이 검출되었다. 고체를 얻기 위해 감압 농축하여 백색 고체의 목적 화합물(19.12 g, 93 %, 92.35 % purity, HCl, 99.91 % e.e.)을 수득하였다.After dissolving tert -butyl ( S )-3-(3-fluorophenyl)isoxazolidine-2-carboxylate (25 g, 93.53 mmol) prepared in step 6 in ethyl acetate (50 mL), 0 °C HCl/ethyl acetate (4M, 250 mL) was added. After that, the reaction mixture was stirred at 10 °C for 1 hour. As a result of LCMS analysis, all of the starting material disappeared and the target spot was detected. The target compound (19.12 g, 93 %, 92.35 % purity, HCl, 99.91 % ee) was obtained as a white solid by concentration under reduced pressure to obtain a solid.

MS (m/z): 168.3 [M+H]^＋ MS (m/z): 168.3 [M+H] ⁺

¹H NMR (400 MHz, DMSO-d ₆) δ = 12.51 (br s, 1H), 7.55 - 7.44 (m, 2H), 7.44 - 7.37 (m, 1H), 7.32 - 7.22 (m, 1H), 5.03 (t, J = 8.0 Hz, 1H), 4.54 - 4.43 (m, 1H), 4.34 - 4.24 (m, 1H), 2.95 - 2.83 (m, 1H), 2.64 - 2.52 (m, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 12.51 (br s, 1H), 7.55 - 7.44 (m, 2H), 7.44 - 7.37 (m, 1H), 7.32 - 7.22 (m, 1H), 5.03 (t, J = 8.0 Hz, 1H), 4.54 - 4.43 (m, 1H), 4.34 - 4.24 (m, 1H), 2.95 - 2.83 (m, 1H), 2.64 - 2.52 (m, 1H)

상기 제조예 1 내지 3과 유사한 방법으로 제조예 4 내지 25를 제조하였으며, 제조예 4 내지 25의 화합물명, 화학구조식, NMR분석 결과를 아래에 나타내었고 이하 실시예의 제조시 사용하였다.Preparation Examples 4 to 25 were prepared in a manner similar to Preparation Examples 1 to 3, and the compound names, chemical structural formulas, and NMR analysis results of Preparation Examples 4 to 25 were shown below and were used in the preparation of Examples below.

<제조예 4> (<Preparation Example 4> ( SS )-3-(4-플루오로페닐)아이소옥사졸리딘)-3-(4-fluorophenyl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ 7.66 - 7.60 (m, 2H), 7.34 - 7.26 (m, 2H), 5.00 (t, J = 8.0 Hz, 1H), 4.49 (td, J = 8.1, 4.0 Hz, 1H), 4.29 (q, J = 7.7 Hz, 1H), 2.87 (dtd, J = 12.6, 7.5, 4.0 Hz, 1H), 2.62 - 2.52 (m, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.66 - 7.60 (m, 2H), 7.34 - 7.26 (m, 2H), 5.00 (t, J = 8.0 Hz, 1H), 4.49 (td, J = 8.1) , 4.0 Hz, 1H), 4.29 (q, J = 7.7 Hz, 1H), 2.87 (dtd, J = 12.6, 7.5, 4.0 Hz, 1H), 2.62 - 2.52 (m, 1H)

<제조예 5> (<Preparation Example 5> ( SS )-3-(3,5-다이플루오로페닐)아이소옥사졸리딘)-3-(3,5-difluorophenyl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ = 7.36 - 7.28 (m, 3H), 5.04 - 4.98 (t, J = 7.6 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.25 - 4.19 (dd, J = 7.6, 15.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.36 - 7.28 (m, 3H), 5.04 - 4.98 (t, J = 7.6 Hz, 1H), 4.47 - 4.38 (m, 1H), 4.25 - 4.19 ( dd, J = 7.6, 15.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H)

<제조예 6> (<Preparation Example 6> ( RR )-3-(3,5-다이플루오로페닐)아이소옥사졸리딘)-3-(3,5-difluorophenyl)isoxazolidine

<제조예 7> (<Preparation Example 7> ( SS )-3-(2,6-다이플루오로페닐)아이소옥사졸리딘)-3-(2,6-difluorophenyl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ 7.55 (tt, J = 8.5, 6.5 Hz, 1H), 7.27 - 7.15 (m, 2H), 5.19 (t, J = 8.2 Hz, 1H), 4.47 (td, J = 8.0, 3.9 Hz, 1H), 4.19 (q, J = 8.0 Hz, 1H), 2.95 - 2.77 (m, 1H), 2.57 (dq, J = 12.3, 8.0 Hz, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.55 (tt, J = 8.5, 6.5 Hz, 1H), 7.27 - 7.15 (m, 2H), 5.19 (t, J = 8.2 Hz, 1H), 4.47 ( td, J = 8.0, 3.9 Hz, 1H), 4.19 (q, J = 8.0 Hz, 1H), 2.95 - 2.77 (m, 1H), 2.57 (dq, J = 12.3, 8.0 Hz, 1H)

<제조예 8> (<Preparation Example 8> ( SS )-3-(2,3,4-트라이플루오로페닐)아이소옥사졸리딘)-3-(2,3,4-trifluorophenyl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ 7.37 - 7.21 (m, 2H), 6.59 (s, 1H), 4.70 - 4.57 (m, 1H), 3.95 (td, J = 8.0, 4.8 Hz, 1H), 3.74 - 3.57 (m, 1H), 2.65 (dtd, J = 12.0, 8.7, 4.8 Hz, 1H), 2.13 - 2.01 (m, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.37 - 7.21 (m, 2H), 6.59 (s, 1H), 4.70 - 4.57 (m, 1H), 3.95 (td, J = 8.0, 4.8 Hz, 1H) ), 3.74 - 3.57 (m, 1H), 2.65 (dtd, J = 12.0, 8.7, 4.8 Hz, 1H), 2.13 - 2.01 (m, 1H)

<제조예 9> (<Preparation Example 9> ( SS )-3-(2-플루오로-3-메틸페닐)아이소옥사졸리딘)-3-(2-fluoro-3-methylphenyl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ 7.32 (td, J = 7.4, 1.8 Hz, 1H), 7.14 (td, J = 7.5, 1.9 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.59 (dd, J = 8.6, 4.7 Hz, 1H), 3.92 (td, J = 8.0, 5.0 Hz, 1H), 3.75 - 3.67 (m, 1H), 2.62 (dtd, J = 12.1, 8.6, 5.1 Hz, 1H), 2.22 (d, J = 2.2 Hz, 3H), 2.03 (ttd, J = 10.8, 5.9, 5.3, 2.4 Hz, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.32 (td, J = 7.4, 1.8 Hz, 1H), 7.14 (td, J = 7.5, 1.9 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 4.59 (dd, J = 8.6, 4.7 Hz, 1H), 3.92 (td, J = 8.0, 5.0 Hz, 1H), 3.75 - 3.67 (m, 1H), 2.62 (dtd, J = 12.1, 8.6, 5.1 Hz, 1H), 2.22 (d, J = 2.2 Hz, 3H), 2.03 (ttd, J = 10.8, 5.9, 5.3, 2.4 Hz, 1H)

<제조예 10> (<Preparation Example 10> ( SS )-3-(아이소옥사졸리딘-3-일)-)-3-(isoxazolidin-3-yl)- NN ,, NN -다이메틸아닐린-dimethylaniline

¹H NMR (400 MHz, CDCl₃) δ 7.23 - 7.17 (m, 1H), 6.81 - 6.60 (m, 3H), 4.46 - 4.34 (m, 1H), 4.02 (dq, J = 14.0, 7.5, 7.1 Hz, 2H), 2.94 (s, 6H), 2.63 (dtd, J = 12.2, 8.1, 6.7 Hz, 1H), 2.36 - 2.20 (m, 1H) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.23 - 7.17 (m, 1H), 6.81 - 6.60 (m, 3H), 4.46 - 4.34 (m, 1H), 4.02 (dq, J = 14.0, 7.5, 7.1 Hz) , 2H), 2.94 (s, 6H), 2.63 (dtd, J = 12.2, 8.1, 6.7 Hz, 1H), 2.36 - 2.20 (m, 1H)

<제조예 11> (<Preparation Example 11> ( SS )-3-(아이소옥사졸리딘-3-일)-)-3-(isoxazolidin-3-yl)- N,NN, N -다이메틸벤즈아마이드-Dimethylbenzamide

¹H NMR (400 MHz, DMSO-d ₆) δ = 7.96 (t, J = 2.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.46 (t, J = 7.7 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.15 - 4.05 (m, 1H), 3.97 - 3.86 (m, 1H), 2.70 - 2.58 (m, 1H), 2.14 - 2.01 (m, 1H), 1.32 (d, J = 6.3 Hz, 6H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.96 (t, J = 2.8 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.67 - 7.58 (m, 1H), 7.46 (t) , J = 7.7 Hz, 1H), 5.19 - 5.07 (m, 1H), 4.15 - 4.05 (m, 1H), 3.97 - 3.86 (m, 1H), 2.70 - 2.58 (m, 1H), 2.14 - 2.01 (m) , 1H), 1.32 (d, J = 6.3 Hz, 6H)

<제조예 12> (<Preparation Example 12> ( SS )-3-(3-(트라이플루오로메틸)페닐)아이소옥사졸리딘)-3-(3-(trifluoromethyl)phenyl)isoxazolidine

¹H NMR (400 MHz, CDCl₃) δ 7.70 - 7.40 (m, 4H), 4.57 (dd, J = 8.4, 5.4 Hz, 1H), 4.10 (td, J = 8.3, 5.2 Hz, 1H), 3.99 - 3.86 (m, 1H), 2.82 - 2.59 (m, 1H), 2.28 (dddd, J = 12.4, 8.5, 7.1, 5.3 Hz, 1H) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70 - 7.40 (m, 4H), 4.57 (dd, J = 8.4, 5.4 Hz, 1H), 4.10 (td, J = 8.3, 5.2 Hz, 1H), 3.99 - 3.86 (m, 1H), 2.82 - 2.59 (m, 1H), 2.28 (dddd, J = 12.4, 8.5, 7.1, 5.3 Hz, 1H)

<제조예 13> (<Preparation Example 13> ( SS )-3-(아이소옥사졸리딘-3-일)벤조나이트릴)-3-(isoxazolidin-3-yl)benzonitrile

¹H NMR (400 MHz, DMSO-d ₆) δ = 7.89 (m, 1H), 7.79 (s, 1H), 7.64 (m, 1H), 4.61 - 4.43 (m, 1H), 3.92 (td, J = 8.0, 4.8 Hz, 1H), 3.77 - 3.56 (m, 1H), 2.66 (dtd, J = 12.0, 8.6, 4.9 Hz, 1H), 2.06 (m, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.89 (m, 1H), 7.79 (s, 1H), 7.64 (m, 1H), 4.61 - 4.43 (m, 1H), 3.92 (td, J = 8.0, 4.8 Hz, 1H), 3.77 - 3.56 (m, 1H), 2.66 (dtd, J = 12.0, 8.6, 4.9 Hz, 1H), 2.06 (m, 1H)

<제조예 14> (<Preparation Example 14> ( SS )-4-(아이소옥사졸리딘-3-일)벤조나이트릴)-4-(isoxazolidin-3-yl)benzonitrile

¹H NMR (400 MHz, DMSO-d ₆) δ 7.81 - 7.74 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H), 6.55 (s, 1H), 4.61 - 4.43 (m, 1H), 3.92 (td, J = 8.0, 4.8 Hz, 1H), 3.77 - 3.56 (m, 1H), 2.66 (dtd, J = 12.0, 8.6, 4.9 Hz, 1H), 2.06 (dddd, J = 11.9, 8.5, 7.2, 4.6 Hz, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.81 - 7.74 (m, 2H), 7.57 (d, J = 8.2 Hz, 2H), 6.55 (s, 1H), 4.61 - 4.43 (m, 1H), 3.92 (td, J = 8.0, 4.8 Hz, 1H), 3.77 - 3.56 (m, 1H), 2.66 (dtd, J = 12.0, 8.6, 4.9 Hz, 1H), 2.06 (dddd, J = 11.9, 8.5, 7.2) , 4.6 Hz, 1H)

<제조예 15> (<Production Example 15> ( SS )-3-(3-메톡시페닐)아이소옥사졸리딘)-3-(3-methoxyphenyl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ = 7.37 (t, J = 8.0 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 8.3, 2.5 Hz, 1H), 4.96 (t, J = 8.1 Hz, 1H), 4.49 (td, J = 8.1, 4.0 Hz, 1H), 4.30 (q, J = 7.7 Hz, 1H), 3.79 (s, 3H), 2.88 (dtd, J = 11.5, 7.4, 4.0 Hz, 1H), 2.58 (dq, J = 12.5, 8.5 Hz, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.37 (t, J = 8.0 Hz, 1H), 7.23 - 7.20 (m, 1H), 7.13 (d, J = 7.7 Hz, 1H), 7.01 (dd , J = 8.3, 2.5 Hz, 1H), 4.96 (t, J = 8.1 Hz, 1H), 4.49 (td, J = 8.1, 4.0 Hz, 1H), 4.30 (q, J = 7.7 Hz, 1H), 3.79 (s, 3H), 2.88 (dtd, J = 11.5, 7.4, 4.0 Hz, 1H), 2.58 (dq, J = 12.5, 8.5 Hz, 1H)

<제조예 16> (<Preparation Example 16> ( SS )-3-(피리딘-3-일)아이소옥사졸리딘)-3-(pyridin-3-yl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ = 9.09 - 9.08 (d, J = 1.6 Hz, 1H), 8.96 - 8.95 (d, J = 5.2 Hz 1H), 8.76 - 8.74 (m, 1H), 8.15 - 8.12 (dd, J = 5.6 Hz, 8.0 Hz, 1H), 5.34 - 5.30 (m, 1H), 4.52 - 4.48 (m, 1H), 4.29 - 4.25 (m, 1H), 2.94 - 2.91 (m, 1H), 2.69 - 2.66 (m, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.09 - 9.08 (d, J = 1.6 Hz, 1H), 8.96 - 8.95 (d, J = 5.2 Hz 1H), 8.76 - 8.74 (m, 1H), 8.15 - 8.12 (dd, J = 5.6 Hz, 8.0 Hz, 1H), 5.34 - 5.30 (m, 1H), 4.52 - 4.48 (m, 1H), 4.29 - 4.25 (m, 1H), 2.94 - 2.91 (m, 1H), 2.69 - 2.66 (m, 1H)

<제조예 17><Production Example 17> (( SS )-3-(6-메틸피리딘-3-일)아이소옥사졸리딘)-3-(6-methylpyridin-3-yl)isoxazolidine

¹H NMR (400 MHz, MeOD) δ = 8.98 (d, J = 2.0 Hz, 1H), 8.71 - 8.68 (dd, J = 2.0, 8.4 Hz, 1H), 8.09 - 8.07 (d, J = 8.4 Hz, 1H), 5.53 - 5.49 (dd, J = 6.8, 8.0 Hz, 1H), 4.79-4.75 (m, 1H), 4.49 - 4.43 (m, 1H), 3.17 - 3.11 (m, 1H), 2.94 - 2.78 (m, 4H) ¹ H NMR (400 MHz, MeOD) δ = 8.98 (d, J = 2.0 Hz, 1H), 8.71 - 8.68 (dd, J = 2.0, 8.4 Hz, 1H), 8.09 - 8.07 (d, J = 8.4 Hz, 1H), 5.53 - 5.49 (dd, J = 6.8, 8.0 Hz, 1H), 4.79-4.75 (m, 1H), 4.49 - 4.43 (m, 1H), 3.17 - 3.11 (m, 1H), 2.94 - 2.78 ( m, 4H)

<제조예 18> (<Preparation Example 18> ( SS )-5-(아이소옥사졸리딘-3-일)니코티노나이트릴)-5-(isooxazolidin-3-yl)nicotinonitrile

¹H NMR (400 MHz, CDCl₃) δ = 8.79 - 8.76 (dd, J = 2.0, 12.4 Hz, 2H), 8.09 (s, 1H), 5.58 (br s, 1H), 4.67 - 4.66 (m, 1H), 4.19 - 4.14 (m, 1H), 3.84 - 3.82 (m, 1H), 2.82 - 2.77 (m, 1H), 2.29 - 2.25 (m, 1H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 8.79 - 8.76 (dd, J = 2.0, 12.4 Hz, 2H), 8.09 (s, 1H), 5.58 (br s, 1H), 4.67 - 4.66 (m, 1H) ), 4.19 - 4.14 (m, 1H), 3.84 - 3.82 (m, 1H), 2.82 - 2.77 (m, 1H), 2.29 - 2.25 (m, 1H)

<제조예 19> (<Production Example 19> ( SS )-3-(싸이오펜-2-일)아이소옥사졸리딘)-3-(thiophen-2-yl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ = 7.38 (m, 1H), 6.97 (m, 1H), 6.87 (m, 1H), 4.67 - 4.66 (m, 1H), 4.19 - 4.14 (m, 1H), 3.84 - 3.82 (m, 1H), 2.82 - 2.77 (m, 1H), 2.29 - 2.25 (m, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.38 (m, 1H), 6.97 (m, 1H), 6.87 (m, 1H), 4.67 - 4.66 (m, 1H), 4.19 - 4.14 (m, 1H), 3.84 - 3.82 (m, 1H), 2.82 - 2.77 (m, 1H), 2.29 - 2.25 (m, 1H)

<제조예 20> (<Preparation Example 20> ( SS )-3-(나프탈렌-1-일)아이소옥사졸리딘)-3-(naphthalen-1-yl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ 8.13 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 7.6, 1.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.47 (dd, J = 8.2, 7.2 Hz, 1H), 6.61 (s, 1H), 5.08 (s, 1H), 3.94 (td, J = 8.0, 4.8 Hz, 1H), 3.76 (s, 1H), 2.93 - 2.76 (m, 1H), 2.07 (d, J = 11.5 Hz, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.13 (d, J = 8.2 Hz, 1H), 7.93 (dd, J = 7.6, 1.7 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H) , 7.70 (d, J = 7.2 Hz, 1H), 7.59 - 7.49 (m, 2H), 7.47 (dd, J = 8.2, 7.2 Hz, 1H), 6.61 (s, 1H), 5.08 (s, 1H), 3.94 (td, J = 8.0, 4.8 Hz, 1H), 3.76 (s, 1H), 2.93 - 2.76 (m, 1H), 2.07 (d, J = 11.5 Hz, 1H)

<제조예 21> (<Preparation Example 21> ( SS )-3-(4-(트라이플루오로메틸)싸이아졸-2-일)아이소옥사졸리딘)-3-(4-(trifluoromethyl)thiazol-2-yl)isoxazolidine

¹H NMR (400 MHz, CDCl₃) δ = 7.71 (s, 1H), 5.76 (br d, J = 4.4 Hz, 1H), 4.91 - 4.88 (m, 1H), 4.20 - 4.15 (m, 1H), 3.80 (m, 1H), 2.81 - 2.76 (m, 2H) ¹ H NMR (400 MHz, CDCl ₃ ) δ = 7.71 (s, 1H), 5.76 (br d, J = 4.4 Hz, 1H), 4.91 - 4.88 (m, 1H), 4.20 - 4.15 (m, 1H), 3.80 (m, 1H), 2.81 - 2.76 (m, 2H)

<제조예 22> (<Preparation Example 22> ( SS )-3-(나프탈렌-2-일)아이소옥사졸리딘)-3-(naphthalen-2-yl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ 7.93 - 7.82 (m, 4H), 7.60 - 7.40 (m, 3H), 6.47 (s, 1H), 4.49 (d, J = 36.8 Hz, 1H), 4.02 - 3.90 (m, 1H), 3.88 - 3.70 (m, 1H), 2.67 (dtd, J = 11.9, 8.4, 5.2 Hz, 1H), 2.19 (dddd, J = 12.1, 8.5, 6.9, 5.4 Hz, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.93 - 7.82 (m, 4H), 7.60 - 7.40 (m, 3H), 6.47 (s, 1H), 4.49 (d, J = 36.8 Hz, 1H), 4.02 - 3.90 (m, 1H), 3.88 - 3.70 (m, 1H), 2.67 (dtd, J = 11.9, 8.4, 5.2 Hz, 1H), 2.19 (dddd, J = 12.1, 8.5, 6.9, 5.4 Hz, 1H )

<제조예 23> (<Preparation Example 23> ( SS )-3-([1,1'-바이페닐]-3-일)아이소옥사졸리딘)-3-([1,1'-biphenyl]-3-yl)isoxazolidine

¹H NMR (400 MHz, CDCl₃) δ 7.59 (dt, J = 8.1, 1.6 Hz, 3H), 7.54 - 7.48 (m, 1H), 7.43 (dt, J = 7.5, 6.5 Hz, 3H), 7.39 - 7.31 (m, 2H), 4.53 (d, J = 14.4 Hz, 1H), 4.09 (s, 2H), 2.71 (dtd, J = 12.2, 8.1, 5.9 Hz, 1H), 2.35 (ddt, J = 12.5, 8.1, 6.4 Hz, 1H) ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 (dt, J = 8.1, 1.6 Hz, 3H), 7.54 - 7.48 (m, 1H), 7.43 (dt, J = 7.5, 6.5 Hz, 3H), 7.39 - 7.31 (m, 2H), 4.53 (d, J = 14.4 Hz, 1H), 4.09 (s, 2H), 2.71 (dtd, J = 12.2, 8.1, 5.9 Hz, 1H), 2.35 (ddt, J = 12.5, 8.1, 6.4 Hz, 1H)

<제조예 24> (<Production Example 24> ( SS )-3-(3-페녹시페닐)아이소옥사졸리딘)-3-(3-phenoxyphenyl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ = 7.42 (m, 2H), 7.18 (m, 2H), 7.06 (m, 5H), 4.25 - 4.19 (dd, J = 7.6, 15.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 7.42 (m, 2H), 7.18 (m, 2H), 7.06 (m, 5H), 4.25 - 4.19 (dd, J = 7.6, 15.2 Hz, 1H) , 2.89 - 2.81 (m, 1H), 2.58 - 2.51 (m, 1H)

<제조예 25> (<Preparation Example 25> ( SS )-3-(3-(벤질옥시)페닐)아이소옥사졸리딘)-3-(3-(benzyloxy)phenyl)isoxazolidine

¹H NMR (400 MHz, DMSO-d ₆) δ 7.50 - 7.28 (m, 5H), 7.22 (t, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.91 - 6.83 (m, 1H), 5.08 (s, 2H), 4.36 (q, J = 20.5, 15.3 Hz, 1H), 3.89 (td, J = 8.0, 5.4 Hz, 1H), 3.37 (d, J = 10.2 Hz, 1H), 2.57 (tt, J = 8.1, 4.4 Hz, 1H), 2.06 (ddt, J = 12.2, 7.9, 6.0 Hz, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.50 - 7.28 (m, 5H), 7.22 (t, J = 7.9 Hz, 1H), 7.05 (s, 1H), 6.95 (d, J = 7.6 Hz, 1H), 6.91 - 6.83 (m, 1H), 5.08 (s, 2H), 4.36 (q, J = 20.5, 15.3 Hz, 1H), 3.89 (td, J = 8.0, 5.4 Hz, 1H), 3.37 (d) , J = 10.2 Hz, 1H), 2.57 (tt, J = 8.1, 4.4 Hz, 1H), 2.06 (ddt, J = 12.2, 7.9, 6.0 Hz, 1H)

실시예 1. (Example 1. ( SS )-)- NN -(4-(4-메틸피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine

단계 1: (Step 1: ( SS )-2-(2-클로로피리미딘-4-일)-3-페닐아이소옥사졸리딘의 제조Preparation of )-2-(2-chloropyrimidin-4-yl)-3-phenylisoxazolidine

2,4-다이클로로피리미딘(1 g, 6.7 mmol), (S)-3-페닐아이소옥사졸리딘(1 g, 6.7 mmol)과 DIPEA(2.3 mL, 13.4 mmol)를 넣고 DMSO(20 mL)를 첨가하여 60 ℃에서 2 시간 동안 교반하였다. 반응 종결 후 반응 혼합물을 과량의 물에 넣고 생성된 고체를 필터하여 목적 화합물(1.2 g, 68 %)을 수득하였다.Add 2,4-dichloropyrimidine (1 g, 6.7 mmol), ( S )-3-phenylisoxazolidine (1 g, 6.7 mmol) and DIPEA (2.3 mL, 13.4 mmol), and DMSO (20 mL) was added and stirred at 60 °C for 2 hours. After completion of the reaction, the reaction mixture was added to excess water, and the resulting solid was filtered to obtain the target compound (1.2 g, 68%).

MS (m/z): 262.8 [M+1]⁺ MS (m/z): 262.8 [M+1] ⁺

단계 2: (Step 2: ( SS )-)- NN -(4-(4-메틸피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine

단계 1에서 제조한 (S)-2-(2-클로로피리미딘-4-일)-3-페닐아이소옥사졸리딘(100 mg, 0.38 mmol), 4-(4-메틸피페라진-1-일)아닐린(110 mg, 0.57 mmol) 및 탄산칼륨(158 mg, 1.152 mmol)을 sec-BuOH(1 mL)에 녹인 후 질소를 흘리면서 5 분 동안 초음파 처리하였다. 반응 혼합물에 Pd₂(dba)₃(35 mg, 0.140 mmol), XPhos(36 mg, 0.04 mmol)를 첨가한 후 100 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 Celite로 여과하고, 아세트산에틸로 씻어 주었다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 감압 하에 농축한 후 중압액체크로마토그래피(메탄올/염화메틸렌 0 ~ 10 %)로 정제하여 목적 화합물(0.1 g, 63 %)을 수득하였다.Prepared in Step 1 ( S )-2-(2-chloropyrimidin-4-yl)-3-phenylisoxazolidin (100 mg, 0.38 mmol), 4-(4-methylpiperazin-1-yl) ) Aniline (110 mg, 0.57 mmol) and potassium carbonate (158 mg, 1.152 mmol) were dissolved in sec -BuOH (1 mL) and then sonicated for 5 minutes while flowing nitrogen. Pd ₂ (dba) ₃ (35 mg, 0.140 mmol) and XPhos (36 mg, 0.04 mmol) were added to the reaction mixture, followed by stirring at 100° C. for 2 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure, it was purified by medium pressure liquid chromatography (methanol/methylene chloride 0 to 10%) to obtain the target compound (0.1 g, 63%).

MS (m/z): 417.4 [M+1]⁺ MS (m/z): 417.4 [M+1] ⁺

¹H NMR (400 MHz, DMSO-d₆) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m, 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m) , 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H)

실시예 2 내지 44Examples 2 to 44

상기 실시예 1과 유사한 방법으로 실시예 2 내지 44를 제조하였으며, 실시예 1 내지 44의 화합물명, 화학구조식, NMR 및 LC-MS 분석 결과를 하기 표 1에 정리하여 나타내었다.Examples 2-44 were prepared in a manner similar to Example 1, and the compound names, chemical structural formulas, NMR and LC-MS analysis results of Examples 1-44 are summarized and shown in Table 1 below.

실시예 45. (Example 45. ( SS )-)- NN -(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine

단계 1: (Step 1: ( SS )-2-(2-클로로-5-아이오도피리미딘-4-일)-3-페닐아이소옥사졸리딘의 제조Preparation of )-2-(2-chloro-5-iodopyrimidin-4-yl)-3-phenylisoxazolidine

2,4-다이클로로-5-아이오도피리미딘(10 g, 36.4 mmol), (S)-3-페닐아이소옥사졸리딘(5.9 g, 40.0 mmol)과 DIPEA(12.71 mL, 72.8 mmol)를 넣고 DMSO(75 mL)를 첨가하여 50 ℃에서 2 시간 동안 교반하였다. 물(1000 mL)을 첨가하여 반응을 종결한 후, 아세트산에틸(200 mL * 3 회)을 이용해 유기층을 추출하였다. 유기층을 황산나트륨으로 건조한 후 감압 농축하여 목적 화합물(13 g, 92 %)을 수득하였다.Add 2,4-dichloro-5-iodopyrimidine (10 g, 36.4 mmol), ( S )-3-phenylisoxazolidine (5.9 g, 40.0 mmol) and DIPEA (12.71 mL, 72.8 mmol) DMSO (75 mL) was added and stirred at 50 °C for 2 hours. After the reaction was terminated by adding water (1000 mL), the organic layer was extracted using ethyl acetate (200 mL * 3 times). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the target compound (13 g, 92%).

MS (m/z): 388.6 [M+1]⁺ MS (m/z): 388.6 [M+1] ⁺

단계 2: (Step 2: ( SS )-2-(2-클로로-5-(트라이플루오로메틸)피리미딘-4-일)-3-페닐아이소옥사졸리딘의 제조Preparation of )-2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-3-phenylisoxazolidine

반응 용기에 아이오딘화구리(3 g, 15.48 mmol), 플루오린화칼륨(0.9 g, 15.48 mmol)을 넣은 후, 감압 하에 120 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 상온으로 식힌 후에 질소 기류 하에 단계 1에서 제조한 (S)-2-(2-클로로-5-아이오도피리미딘-4-일)-3-페닐아이소옥사졸리딘(3 g, 7.74 mmol), TMS-CF₃(2.3 mL, 15.48 mmol)를 NMP(50 mL)에 녹여 첨가한 후 50

에서 2 시간 동안 교반하였다. 반응 혼합물에 과량의 물을 첨가한 후 아세트산에틸로 추출하였다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 감압 하에 농축한 후 중압액체크로마토그래피(아세트산에틸/n-헥산 0 ~ 60%)로 정제하여 목적 화합물(1.15 g, 45 %)을 수득하였다.Copper iodide (3 g, 15.48 mmol) and potassium fluoride (0.9 g, 15.48 mmol) were placed in a reaction vessel, and the mixture was stirred at 120° C. under reduced pressure for 2 hours. After the reaction mixture was cooled to room temperature, ( S )-2-(2-chloro-5-iodopyrimidin-4-yl)-3-phenylisoxazolidine prepared in step 1 under a nitrogen stream (3 g, 7.74) mmol), TMS-CF ₃ (2.3 mL, 15.48 mmol) was dissolved in NMP (50 mL) and added to 50

was stirred for 2 hours. An excess of water was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure, the mixture was purified by medium pressure liquid chromatography (ethyl acetate/n-hexane 0 to 60%) to obtain the target compound (1.15 g, 45%).

MS (m/z): 417.5 [M+1]⁺ MS (m/z): 417.5 [M+1] ⁺

단계 3: (Step 3: ( SS )-)- NN -(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine

단계 2에서 제조한 (S)-2-(2-클로로-5-(트라이플루오로메틸)피리미딘-4-일)-3-페닐아이소옥사졸리딘(50 mg, 0.15 mmol), PTSA(58 mg, 0.30 mmol)를 sec-BuOH(1.5 mL)에 녹인 후 100 ℃에서 2 시간 교반하였다. 반응 혼합물을 아세트산에틸로 씻어 주었다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 감압 하에 농축한 후 중압액체크로마토그래피(메탄올/염화메틸렌 0 ~ 10 %)로 정제하여 목적 화합물(50 mg, 68 %)을 수득하였다.( S )-2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-3-phenylisoxazolidine (50 mg, 0.15 mmol) prepared in step 2, PTSA (58 mg, 0.30 mmol) was dissolved in sec-BuOH (1.5 mL) and stirred at 100 °C for 2 hours. The reaction mixture was washed with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure, it was purified by medium pressure liquid chromatography (methanol/methylene chloride 0 to 10%) to obtain the target compound (50 mg, 68%).

MS (m/z): 485.5 [M+1]⁺ MS (m/z): 485.5 [M+1] ⁺

¹H NMR (400 MHz, DMSO-d ₆) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m, 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ = 9.87 (s, 1H), 9.54 (s, 1H), 8.59 (s, 2H), 7.92 - 7.88 (m, 2H), 7.65 (ddd, J = 8.3, 2.2, 1.1 Hz, 1H), 7.50 (d, J = 0.9 Hz, 1H), 7.38 (dd, J = 7.2, 1.2 Hz, 4H), 7.35 - 7.32 (m, 1H), 7.31 - 7.25 (m) , 1H), 7.18 (dt, J = 7.7, 1.3 Hz, 1H), 5.41 (dd, J = 8.6, 5.9 Hz, 1H), 4.26 (d, J = 3.1 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.81 (s, 3H), 2.86 (dddd, J = 12.0, 8.7, 7.0, 3.0 Hz, 1H), 2.28 - 2.19 (m, 1H)

실시예 46 내지 234Examples 46-234

상기 실시예 45과 유사한 방법으로 실시예 46 내지 234를 제조하였으며, 실시예 45 내지 234의 화합물명, 화학구조식, NMR 및 LC-MS 분석 결과를 하기 표 2에 정리하여 나타내었다.Examples 46 to 234 were prepared in a manner similar to that of Example 45, and the compound names, chemical structural formulas, NMR and LC-MS analysis results of Examples 45 to 234 are summarized and shown in Table 2 below.

실시예 235. (Example 235. ( SS )-5-(3,6-다이하이드로-2)-5-(3,6-dihydro-2 HH -피란-4-일)--pyran-4-yl)- NN -(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine

단계 1: (Step 1: ( SS )-2-(2-클로로-5-(3,6-다이하이드로-2)-2-(2-Chloro-5-(3,6-dihydro-2) HH -피란-4-일)피리미딘-4-일)-3-페닐아이소옥사졸리딘의 제조-Pyran-4-yl) pyrimidin-4-yl) -3-phenylisooxazolidine preparation

(S)-2-(5-브로모-2-클로로피리미딘-4-일)-3-페닐아이소옥사졸리딘(190 mg, 0.056 mmol), 탄산나트륨(177 mg, 1.7 mmol) 및 2-(3,6-다이하이드로-2H-피란-4-일)-4,4,5,5-테트라메틸-1,3,2-다이옥사보로란(141 mg, 0.67 mmol)을 1,4-다이옥세인(4 mL)와 물(1 mL)에 녹인 후 질소를 흘리면서 5 분 동안 초음파 처리하였다. 반응 혼합물에 Pd(PPh₃)₄(65 mg, 0.056 mmol)을 첨가한 후 100 ℃에서 2 시간 동안 교반하였다. 반응 혼합물을 Celite로 여과하고, 아세트산에틸로 씻어 주었다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 농축한 후 중압액체크로마토그래피(아세트산에틸/n-헥산 0 ~ 50 %)로 정제하여 목적 화합물(78 mg, 41 %)을 수득하였다.( S )-2-(5-bromo-2-chloropyrimidin-4-yl)-3-phenylisoxazolidine (190 mg, 0.056 mmol), sodium carbonate (177 mg, 1.7 mmol) and 2-( 3,6-dihydro- 2H -pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (141 mg, 0.67 mmol) was mixed with 1,4- After dissolving in dioxane (4 mL) and water (1 mL), it was sonicated for 5 minutes while flowing nitrogen. After adding Pd(PPh ₃ ) ₄ (65 mg, 0.056 mmol) to the reaction mixture, the mixture was stirred at 100° C. for 2 hours. The reaction mixture was filtered through Celite and washed with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration, it was purified by medium pressure liquid chromatography (ethyl acetate/n-hexane 0 to 50%) to obtain the target compound (78 mg, 41%).

MS (m/z): 388.6 [M+1]⁺ MS (m/z): 388.6 [M+1] ⁺

단계 2: (Step 2: ( SS )-5-(3,6-다이하이드로-2)-5-(3,6-dihydro-2 HH -피란-4-일)--pyran-4-yl)- NN -(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민의 제조Preparation of -(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine

단계 1에서 제조한 (S)-2-(2-클로로-5-(3,6-다이하이드로-2H-피란-4-일)피리미딘-4-일)-3-페닐아이소옥사졸리딘(78 mg, 0.23 mmol), PTSA(86 mg, 0.45 mmol)를 sec-BuOH(3 mL)에 녹인 후 80 ℃에서 12 시간 동안 교반하였다. 반응 혼합물을 아세트산에틸로 씻어 주었다. 얻어진 여과액을 소금물로 씻어 유기층을 모아 황산나트륨으로 건조하였다. 회전식 증발기를 이용하여 감압 하에 농축한 후 중압액체크로마토그래피(메탄올/염화메틸렌 0 ~ 10 %)로 정제하여 목적 화합물(35 mg, 31 %)을 수득하였다.( S )-2-(2-chloro-5-(3,6-dihydro- 2H -pyran-4-yl)pyrimidin-4-yl)-3-phenylisoxazolidine prepared in step 1 (78 mg, 0.23 mmol) and PTSA (86 mg, 0.45 mmol) were dissolved in sec -BuOH (3 mL) and stirred at 80 °C for 12 hours. The reaction mixture was washed with ethyl acetate. The obtained filtrate was washed with brine, and the organic layers were collected and dried over sodium sulfate. After concentration under reduced pressure using a rotary evaporator, the target compound (35 mg, 31%) was obtained by purification by medium pressure liquid chromatography (methanol/methylene chloride 0 to 10%).

MS (m/z): 499.4 [M+1]⁺ MS (m/z): 499.4 [M+1] ⁺

¹H NMR (400 MHz, DMSO-d₆) δ = 9.16 (s, 1H), 7.87 (s, 1H), 7.45 - 7.36 (m, 6H), 7.30 - 7.25 (m, 1H), 6.80 - 6.74 (m, 2H), 5.63 (d, J = 8.4 Hz, 2H), 4.11 (td, J = 7.7, 7.1, 3.3 Hz, 3H), 3.76 - 3.69 (m, 1H), 3.65 (h, J = 5.2, 4.5 Hz, 2H), 3.03 (t, J = 5.0 Hz, 4H), 2.83 - 2.74 (m, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.21 - 2.07 (m, 3H) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 9.16 (s, 1H), 7.87 (s, 1H), 7.45 - 7.36 (m, 6H), 7.30 - 7.25 (m, 1H), 6.80 - 6.74 ( m, 2H), 5.63 (d, J = 8.4 Hz, 2H), 4.11 (td, J = 7.7, 7.1, 3.3 Hz, 3H), 3.76 - 3.69 (m, 1H), 3.65 (h, J = 5.2, 4.5 Hz, 2H), 3.03 (t, J = 5.0 Hz, 4H), 2.83 - 2.74 (m, 1H), 2.45 (t, J = 5.0 Hz, 4H), 2.22 (s, 3H), 2.21 - 2.07 ( m, 3H)

실시예 236 내지 240Examples 236 to 240

상기 실시예 235와 유사한 방법으로 실시예 236 내지 240을 제조하였으며, 실시예 235 내지 240의 화합물명, 화학구조식, NMR 및 LC-MS 분석 결과를 하기 표 3에 정리하여 나타내었다.Examples 236 to 240 were prepared in a manner similar to that of Example 235, and the compound names, chemical structural formulas, NMR and LC-MS analysis results of Examples 235 to 240 are summarized in Table 3 below.

실험예 1. 본 발명에 따른 화합물의 키나아제 저해 활성 평가Experimental Example 1. Evaluation of the kinase inhibitory activity of the compound according to the present invention

본 발명에 따른 화합물의 키나아제 저해 활성을 평가하기 위해 하기와 같은 실험을 수행하였다. 구체적으로, 본 발명의 실시예 화합물 중, 선별된 실시예 45 및 46에 대하여, DiscoverX 사에 의뢰하여 효소(kinase) 선택성을 측정하기로 하고, scanMAX^TM Kinase 분석용 패널을 사용하여 실험을 진행하였다. 이때, 효소에 처리되는 약물의 농도는 DMSO에 1 μM로 하였고, 하기 식 1과 같은 방법으로 조절 백분율(% control)을 정하였고, 그 결과를 하기 표 4 및 표 5에 나타내었다.In order to evaluate the kinase inhibitory activity of the compound according to the present invention, the following experiment was performed. Specifically, among the example compounds of the present invention, selected Examples 45 and 46 were commissioned by DiscoverX to measure enzyme (kinase) selectivity, and experiments were conducted using a scanMAX ^TM Kinase analysis panel. . At this time, the concentration of the drug treated with the enzyme was 1 μM in DMSO, and the control percentage (% control) was determined in the same way as in Equation 1 below, and the results are shown in Tables 4 and 5 below.

[식 1][Equation 1]

(실시예 화합물 - 양성 대조군) / (음성 대조군- 양성 대조군) x 100(Example compound - positive control) / (negative control - positive control) x 100

여기서, 상기 양성 대조군은 0 %의 조절 백분율을 나타내는 화합물을 말하며, 음성 대조군은 DMSO로 100 %의 조절 백분율을 나타낸다. 또한, 본 발명의 효소 선택성은 효소에 대하여 조절 백분율이 < 20 % (즉 20 % 미만)이면 해당 효소에 대하여 활성을 갖는 것으로 판단하였다.Here, the positive control refers to a compound showing a percentage control of 0%, and the negative control indicates a percentage control of 100% with DMSO. In addition, the enzyme selectivity of the present invention was determined to have activity for the enzyme when the control percentage for the enzyme is <20% (ie, less than 20%).

상기 표 4 및 표 5에서 확인할 수 있듯이, 본 발명에 따른 실시예 화합물은 ALK, ALK(C1156Y), ALK(L1196M), AMPK-alpha1, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BIKE, CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK7, CDKL2, CLK1, CSNK2A2, DCAMKL1, DCAMKL3, DMPK, DRAK2, DYRK2, ERK5, ERK8, FAK, FER, FES, FGFR1, FGFR3(G697C), FGFR4, FLT1, FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q), FLT4, HIPK4, HPK1, IKK-epsilon, IRAK3, JAK1(JH2domain-pseudokinase), JAK2(JH1domain-catalytic), JAK3(JH1domain-catalytic), KIT, KIT(A829P), KIT(D816H), KIT(L576P), KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LATS2, LRRK2, LRRK2(G2019S), MAP3K2, MAP3K3, MARK4, MERTK, MKNK2, MLCK, MLK1, MLK2, MLK3, MUSK, NEK10, PCTK1, PCTK2, PIK3CA(C420R), PIK3CA(E545A), PDGFRB, PKN1, PKN2, PKNB(M.tuberculosis), PLK4, PRKCE, PRKCQ, PRKD2, PRKD3, PYK2, RET, RET(M918T), RET(V804L), RET(V804M), RIOK3, ROS1, RPS6KA4(Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK1(Kin.Dom.1-N-terminal), RSK2(Kin.Dom.1-N-terminal), RSK3(Kin.Dom.1-N-terminal), RSK4(Kin.Dom.1-N-terminal), S6K1, SBK1, SGK, SGK3, SIK2, SLK, SNARK, SRPK1, STK16, TAK1, TAOK3, TIE1, TNK1, TRKA, TRKB, TTK, TYK2(JH1domain-catalytic), ULK1, ULK2, ULK3, VEGFR2, VPS34, YSK4에 대하여 조절 백분율 20 %보다 작은 값을 가지므로, 상기 나열된 효소에 대하여 활성을 가짐을 알 수 있다. 이는 본 발명에 따른 실시예 화합물을 상기 나열된 효소에 관련된 질환에 사용할 경우 유용한 효과가 있음을 암시하는 것이며, 따라서, 상기 나열된 효소 관련 질환의 치료 또는 예방용 조성물로 유용하게 사용할 수 있다.As can be seen in Tables 4 and 5, the example compounds according to the present invention are ALK, ALK (C1156Y), ALK (L1196M), AMPK-alpha1, AMPK-alpha2, ARK5, AURKA, AURKB, AURKC, AXL, BIKE , CDK4, CDK4-cyclinD1, CDK4-cyclinD3, CDK7, CDKL2, CLK1, CSNK2A2, DCAMKL1, DCAMKL3, DMPK, DRAK2, DYRK2, ERK5, ERK8, FAK, FER, FES, FGFR1, FGFR3 (G697C), FGFR3 (G697C) FLT3, FLT3(D835H), FLT3(D835V), FLT3(D835Y), FLT3(ITD), FLT3(ITD,D835V), FLT3(ITD,F691L), FLT3(K663Q), FLT3(N841I), FLT3(R834Q) , FLT4, HIPK4, HPK1, IKK-epsilon, IRAK3, JAK1 (JH2domain-pseudokinase), JAK2 (JH1domain-catalytic), JAK3 (JH1domain-catalytic), KIT, KIT (A829P), KIT (D816H), KIT (L576P) , KIT(V559D), KIT(V559D,T670I), KIT(V559D,V654A), LATS2, LRRK2, LRRK2(G2019S), MAP3K2, MAP3K3, MARK4, MERTK, MKNK2, MLCK, MLK1, MLK2, MLK10 , PCTK1, PCTK2, PIK3CA(C420R), PIK3CA(E545A), PDGFRB, PKN1, PKN2, PKNB(M.tuberculosis), PLK4, PRKCE, PRKCQ, PRKD2, PRKD3, PYK2, RET, RET(M918T), RET(M918T) ), RET(V804M), RIOK3, ROS1, RPS6KA4(Kin.Dom.2-C-terminal), RPS6KA5(Kin.Dom.2-C-terminal), RSK1(Kin.Dom) .1-N-terminal), RSK2 (Kin.Dom.1-N-terminal), RSK3 (Kin.Dom.1-N-terminal), RSK4 (Kin.Dom.1-N-terminal), S6K1, SBK1 Regulates against , SGK, SGK3, SIK2, SLK, SNARK, SRPK1, STK16, TAK1, TAOK3, TIE1, TNK1, TRKA, TRKB, TTK, TYK2 (JH1domain-catalytic), ULK1, ULK2, ULK3, VEGFR2, V Since it has a value less than the percentage 20%, it can be seen that it has activity against the enzymes listed above. This suggests that the example compound according to the present invention has a useful effect when used in the diseases related to the enzymes listed above, and thus can be usefully used as a composition for treating or preventing the diseases related to the enzymes listed above.

실험예 2. CDK4(Cyclin-Dependent protein Kinase, CDK4) 효소 저해능 평가 Experimental Example 2. CDK4 (Cyclin-Dependent Protein Kinase, CDK4) enzyme inhibitory ability evaluation

본 발명에 따른 실시예 화합물의 CDK4(Cyclin-Dependent protein Kinase, CDK4)효소에 대한 저해능을 평가하기 위해 하기와 같은 실험을 수행하였다.In order to evaluate the inhibitory ability of the Example compound according to the present invention to the CDK4 (Cyclin-Dependent Protein Kinase, CDK4) enzyme, the following experiment was performed.

실시예 화합물을 정제된 human GST-CDK4/CyclinD3 (full-length human CDK4 and CyclinD3 were co-expressed protein, Signalchem) 효소와 반응하여, 하기와 같은 방법으로 효소 저해능을 평가하였다. 반응 버퍼는 40 mM Tris-HCl pH 7.4, 20 mM MgCl₂, 0.5 mg/mL BSA, 및 50 μM DTT 조성을 사용하였으며 모든 시험물은 반응 버퍼상에서 반응을 수행하였다. 시험 시 human GST-CDK4/CyclinD3(10 ng) 효소와 정제된 ATP(200 μM), 특이적인 기질용액을 30 ℃ 상에서 4 시간 동안 반응시킨 후, in vitro ADP-Glo^TM kinase assay(promega)를 이용하여 효소활성을 확인하였다. 2:2:1 비율로 효소활성 반응액과 ADP-Glo 반응액, 효소능 검출용액을 반응시켜서 형광도를 측정하였다. 화합물을 처리하지 않은 용매 대조군 효소활성의 형광도를 기준으로 각 화합물들의 처리 농도에 따른 효소활성 저해 정도를 산출하였으며, 이때 효소활성을 50 % 억제하는 각 화합물의 농도를 IC₅₀(nM) 값으로 결정하였다. 각 화합물의 IC₅₀는 GraphPad Prism 8.3.0(GraphPad software Inc., San Diego) 소프트웨어를 이용하여 구하였다. 그 결과는 하기 표 6에 나타내었다.The example compound was reacted with purified human GST-CDK4/CyclinD3 (full-length human CDK4 and CyclinD3 were co-expressed protein, Signalchem) enzymes, and the enzyme inhibitory ability was evaluated as follows. The reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl ₂ , 0.5 mg/mL BSA, and 50 μM DTT composition. All test materials were reacted in the reaction buffer. For testing, human GST-CDK4/CyclinD3 (10 ng) enzyme, purified ATP (200 μM), and a specific substrate solution were reacted at 30 ° C for 4 hours, followed by in vitro ADP-Glo ^TM kinase assay (promega). Thus, the enzyme activity was confirmed. The fluorescence was measured by reacting the enzyme activity reaction solution with the ADP-Glo reaction solution and the enzyme activity detection solution in a 2:2:1 ratio. The degree of _inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control that was not treated with the compound. It was decided. IC ₅₀ of each compound was obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) software. The results are shown in Table 6 below.

실험예 3. CDK2(Cyclin-Dependent protein Kinase, CDK2) 효소 저해능 평가Experimental Example 3. CDK2 (Cyclin-Dependent Protein Kinase, CDK2) enzyme inhibitory ability evaluation

본 발명에 따른 실시예 화합물의 CDK2(Cyclin-Dependent protein Kinase, CDK2) 효소 저해능을 평가하기 위해 하기와 같은 실험을 수행하였다.In order to evaluate the CDK2 (Cyclin-Dependent Protein Kinase, CDK2) enzyme inhibitory ability of the Example compound according to the present invention, the following experiment was performed.

실시예 화합물을 정제된 human GST-CDK2/CyclinE1(full-length human CDK2 and CyclinE1 were co-expressed protein, SignalChem) 효소와 반응하여, 하기와 같은 방법으로 효소 저해능을 평가하였다. 반응 버퍼는 40 mM Tris-HCl pH 7.4, 20 mM MgCl₂, 0.5 mg/mL BSA, 및 50 μM DTT 조성을 사용하였으며 모든 시험물은 반응 버퍼상에서 반응을 수행하였다. 시험 시 human GST-CDK2/CyclinE1(1.5 ng) 효소와 정제된 ATP(50 μM), 특이적인 기질용액을 30 ℃ 상에서 4 시간 동안 반응시킨 후, in vitro ADP-Glo^TM kinase assay (promega)를 이용하여 효소활성을 확인하였다. 2:2:1 비율로 효소활성 반응액과 ADP-Glo 반응액, 효소능 검출용액을 반응시켜서 형광도를 측정하였다. 화합물을 처리하지 않은 용매 대조군 효소활성의 형광도를 기준으로 각 화합물들의 처리 농도에 따른 효소활성 저해 정도를 산출하였으며, 이때 효소활성을 50 % 억제하는 각 화합물의 농도를 IC₅₀(nM) 값으로 결정하였다. 각 화합물의 IC₅₀는 GraphPad Prism 8.3.0(GraphPad software Inc., San Diego) 소프트웨어를 이용하여 구하였다. 그 결과는 하기 표 7에 나타내었다.Example compounds were reacted with purified human GST-CDK2/CyclinE1 (full-length human CDK2 and CyclinE1 were co-expressed protein, SignalChem) enzymes, and the enzyme inhibitory ability was evaluated as follows. The reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl ₂ , 0.5 mg/mL BSA, and 50 μM DTT composition. All test materials were reacted in the reaction buffer. For testing, human GST-CDK2/CyclinE1 (1.5 ng) enzyme, purified ATP (50 μM), and a specific substrate solution were reacted at 30 °C for 4 hours, followed by in vitro ADP-Glo ^TM kinase assay (promega) Thus, the enzyme activity was confirmed. The fluorescence was measured by reacting the enzyme activity reaction solution with the ADP-Glo reaction solution and the enzyme activity detection solution in a 2:2:1 ratio. The degree of _inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control that was not treated with the compound. It was decided. IC ₅₀ of each compound was obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) software. The results are shown in Table 7 below.

실험예 4. HPK1(Hematopoietic Progenitor Kinase 1) 효소 저해능 평가Experimental Example 4. HPK1 (Hematopoietic Progenitor Kinase 1) enzyme inhibitory ability evaluation

본 발명에 따른 실시예 화합물의 HPK1 효소 저해능을 평가하기 위하여 다음과 같은 방법으로 수행하였다.In order to evaluate the HPK1 enzyme inhibitory ability of the example compounds according to the present invention, the following method was performed.

실시예 화합물을 정제된 human HPK1(1-346, SignalChem) 효소와 반응하여, 하기와 같은 방법으로 효소 저해능을 평가하였다. 반응 버퍼는 40 mM Tris-HCl pH 7.4, 20 mM MgCl₂, 0.5 mg/ml BSA, 50 μM DTT 조성으로 사용하였으며, 모든 시험물의 반응은 반응 버퍼상에서 이루어졌다. 화합물은 10 mM DMSO 스톡을 계열 희석법으로 12 단계로 희석하였으며, 최종 화합물의 농도 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, 0.00003 μM에서 효소 활성을 측정하였다. 시험 시 human HPK1(3 ng) 효소와 정제된 ATP(3 μM), 효소 기질(0.1 μg)과 25 ℃에서 2 시간 동안 반응시킨 후, in vitro ADP-Glo^TM kinase assay(promega)을 이용하여 효소활성을 확인하였다. 2:2:1 비율로 효소활성 반응액과 ADP-Glo 반응액, 효소활성 검출용액을 반응시켜서 효소의 활성 저해도를 형광도로 측정하였다. 화합물을 처리하지 않은 용매 대조군 효소활성의 형광도를 기준으로 각 화합물들의 처리 농도에 따른 효소활성 저해 정도를 산출하였으며, 이때 효소활성을 50 % 억제하는 각 화합물의 농도를 IC₅₀(nM) 값으로 결정하였고, GraphPad Prism 8.3.0(GraphPad software Inc., San Diego)을 이용하여 구하였다. 그 결과를 하기 표 8에 정리하여 나타내었다.The example compound was reacted with purified human HPK1 (1-346, SignalChem) enzyme, and the enzyme inhibitory ability was evaluated as follows. The reaction buffer was 40 mM Tris-HCl pH 7.4, 20 mM MgCl ₂ , 0.5 mg/ml BSA, and 50 μM DTT composition, and all test materials were reacted in the reaction buffer. Compounds were diluted in 12 steps from a 10 mM DMSO stock by serial dilution, and enzyme activity was measured at concentrations of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001, 0.0003, 0.0001, 0.00003 μM of the final compound. . In the test, the enzyme was reacted with human HPK1 (3 ng) enzyme, purified ATP (3 μM), and enzyme substrate (0.1 μg) at 25 °C for 2 hours, and then the enzyme was used in vitro ADP-Glo ^TM kinase assay (promega). Activity was confirmed. By reacting the enzyme activity reaction solution with the ADP-Glo reaction solution and the enzyme activity detection solution in a 2:2:1 ratio, the degree of inhibition of enzyme activity was measured by fluorescence. The degree of _inhibition of enzyme activity according to the treatment concentration of each compound was calculated based on the fluorescence of the enzyme activity of the solvent control that was not treated with the compound. It was determined and obtained using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego). The results are summarized in Table 8 below.

실험예 5. MCF-7 세포 성장 저해능 평가Experimental Example 5. MCF-7 cell growth inhibitory ability evaluation

MCF-7 유방암세포(한국세포주은행)를 clear bottom white 96-웰 플레이트(Corning)에 3 Х 10³/ 150 μl/웰이 되도록 심었다. 그 다음, 3 배수로 연속 희석된 12 가지 농도(0.00001 - 2 mM)의 화합물 또는 DMSO 대조군이 포함된 배양액을 0.5 μl/웰씩 첨가하여 최종농도가 0.00005 - 10 μM이 되도록 처리한 뒤 37 ℃ CO₂ 배양기에서 120 시간 동안 배양하였다. 120 시간 후, 화합물을 처리한 플레이트를 꺼내어, CellTiter-Glo® 2.0 Assay(Promega) 용액을 150 μl/웰씩 처리한 후, 잘 섞어 주었다. 상온에서 10 분 정도 잘 섞어 주고, 마이크로플레이트 판독기로 형광도를 측정하였다. 데이터는 비히클 기준 처리된 세포에 비례하여 백분율로 나타내었고, GraphPad Prism 8.3.0(GraphPad software Inc., San Diego)을 이용하여 GI₅₀(nM) 값을 산출하였다. 그 결과를 표 9에 정리하여 나타내었다.MCF-7 breast cancer cells (Korea Cell Line Bank) were planted in a clear bottom white 96-well plate (Corning) to 3 Х 10 ³ / 150 μl/well. Then, 0.5 μl/well of a culture solution containing 12 concentrations (0.00001 - 2 mM) of a compound or DMSO control serially diluted in 3 folds was added at a time to a final concentration of 0.00005 - 10 μM, followed by a 37 ° C CO ₂ incubator incubated for 120 hours. After 120 hours, the plate treated with the compound was taken out, 150 μl/well of CellTiter-Glo® 2.0 Assay (Promega) solution was treated, and then mixed well. After mixing well for about 10 minutes at room temperature, the fluorescence was measured with a microplate reader. The data were expressed as a percentage relative to the treated cells relative to the vehicle standard, and GI ₅₀ (nM) values were calculated using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego). The results are summarized in Table 9 and shown.

실험예 6. CCNE 과발현 세포 성장 저해능 평가Experimental Example 6. Evaluation of CCNE overexpression cell growth inhibitory ability

OVCAR-3 난소암 세포(한국세포주은행)를 clear bottom white 96-웰 플레이트(Corning)에 5 Х 10³/200 μl/웰이 되도록 심었다. 그 다음, 3 배수로 연속 희석된 11 가지 농도(0.00003 - 2 mM)의 화합물 또는 DMSO 대조군이 포함된 배양액을 0.5 μl/웰씩 첨가하여 최종농도가 0.0002 - 10 μM이 되도록 처리한 뒤 37 ℃, CO₂ 배양기에서 120 시간 동안 배양하였다. 120 시간 후, 화합물을 처리한 플레이트를 꺼내어, 각 well에 CellTiter-Glo® 2.0 Assay (Promega) 용액을 100 μl씩 처리한 후, 잘 섞어 주었다. 상온에서 10 분 정도 잘 섞어 주고, 마이크로플레이트 판독기로 형광도를 측정하였다. GI₅₀(nM)는 측정된 luminescence 값을 토대로 GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego)을 이용하여 산출하였다. 그 결과를 표 10에 정리하여 나타내었다.OVCAR-3 ovarian cancer cells (Korea Cell Line Bank) were planted in a clear bottom white 96-well plate (Corning) at a volume of 5 Х 10 ³ /200 μl/well. Then, 0.5 μl/well of a culture solution containing 11 different concentrations (0.00003 - 2 mM) of the compound or DMSO control, serially diluted in 3 folds, was added at a time to a final concentration of 0.0002 - 10 μM, and then treated at 37 ° C, CO ₂ Incubated for 120 hours in an incubator. After 120 hours, the plate treated with the compound was taken out, and 100 μl of CellTiter-Glo® 2.0 Assay (Promega) solution was treated in each well, and then mixed well. After mixing well for about 10 minutes at room temperature, the fluorescence was measured with a microplate reader. GI ₅₀ (nM) was calculated using GraphPad Prism 8.3.0 (GraphPad software Inc., San Diego) based on the measured luminescence value. The results are summarized in Table 10 and shown.

Claims

하기 화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염:
[화학식 1]

상기 화학식 1에서,
고리 A₁은 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6아미노알킬, -C_1-6하이드록시알킬, -C_1-6할로알킬, -C_1-6알킬-O-C_1-6알킬, -CN, -(C=O)NR₃R₄, -(C=O)OR₅, -NR₆R₇, -OR₈, -할로, 아릴 또는 헤테로아릴로 치환될 수 있음};
고리 A₂는 아릴, 헤테로아릴, 사이클로알킬, 또는 헤테로사이클로알킬이고
{여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -C_1-6아미노알킬, -C_1-6할로알킬, -C_1-6알킬-CN, -CN, -C_1-6알킬-O-C_1-6알킬, -C_1-6알킬NR₉R₁₀, -(C=O)NR₉R₁₀, -C_1-6알킬-(C=O)NR₉R₁₀, -(C=O)-C_1-6알킬, -(C=O)OR₁₁, -C_1-6알킬-(C=O)OR₁₁, -NR₁₂R₁₃, -OR₁₄, -할로, -S-C_1-6알킬, -SO₂-C_1-6알킬, -SO₂-NR₁₂R₁₃, -SO₂-할로, -(S=O)NH-C_1-6알킬, -S(=O)(=NH)-C_1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)NR₁₅R₁₆, -(C=O)OR₁₇, -NR₁₈R₁₉, -할로, -SO₂-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -C_1-6아미노알킬, -C_1-6할로알킬, -NR₂₀R₂₁, 또는 사이클로알킬로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, -NR₂₂R₂₃, -O-C_1-6알킬,할로, -SO₂-C_1-6알킬, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있음];
상기 사이클로알킬 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, 또는 -SO₂-C_1-6알킬로 치환될 수 있음};
R₁은 -H 또는 -C_1-6알킬이고;
R₂는 -H, -C_1-6알킬, -C_1-6아미노알킬, -C_1-6하이드록시알킬, -C_1-6할로알킬, -CN, -할로, 또는 5-7원 고리이고 {여기서, 상기 5-7원 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6할로알킬, 또는 할로로 치환될 수 있음};
R₃ 내지 R₇은 각각 독립적으로 -H 또는 -C_1-6알킬이고;
R₈은 -H, -C_1-6알킬, 페닐 또는 벤질이고;
R₉ 및 R₁₀은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6히드록시알킬, -C_1-6알킬-NR₂₄R₂₅, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬로 치환될 수 있음};
R₁₁은 -H 또는 -C_1-6알킬이고;
R₁₂ 및 R₁₃은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6알킬-NR₂₄R₂₅, 또는 -(C=O)O-C_1-6알킬이고;
R₁₄은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6알킬-NR₂₆R₂₇, 헤테로사이클로알킬, 또는 -C_1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C_1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬로 치환될 수 있음};
R₁₅ 내지 R₁₇은 각각 독립적으로 -H 또는 -C_1-6알킬이고;
R₁₈ 및 R₁₉은 각각 독립적으로 -C_1-6알킬 또는 -C_1-6알킬-NR₂₈R₂₉이고;
R₂₀ 내지 R₂₉은 각각 독립적으로 -H 또는 -C_1-6알킬이다.A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]

In Formula 1,
Ring A ₁ is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _{1 -6} Haloalkyl, -C _1-6 Alkyl-OC _1-6 Alkyl, -CN, -(C=O)NR ₃ R ₄ , -(C=O)OR ₅ , -NR ₆ R ₇ , -OR ₈ , which may be substituted with halo, aryl or heteroaryl};
Ring A ₂ is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl
{Wherein, at least one H of the aryl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 aminoalkyl, -C _1-6 haloalkyl, -C _{1 6} alkyl-CN, -CN, -C _1-6 alkyl-OC _1-6 alkyl, -C _1-6 alkylNR ₉ R ₁₀ , -(C=O)NR ₉ R ₁₀ , -C _1-6 alkyl- (C=O)NR ₉ R ₁₀ , -(C=O)-C _1-6 alkyl, -(C=O)OR ₁₁ , -C _1-6 alkyl-(C=O)OR ₁₁ , -NR ₁₂ R ₁₃ , -OR ₁₄ , -halo, -SC _1-6 alkyl, -SO ₂ -C _1-6 alkyl, -SO ₂ -NR ₁₂ R ₁₃ , -SO ₂ -halo, -(S=O)NH- C _1-6 alkyl, -S(=O)(=NH)-C _1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _1-6 alkyl-cycloalkyl, -C _1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)-heterocycloalkyl, may be substituted with aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _1-6 alkyl-cycloalkyl, -C _1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)-heterocycloalkyl, At least one H of an aryl, -(C=O)-aryl, or heteroaryl ring is -C _1-6 alkyl, -(=O)-, -(C=O)-C _1-6 alkyl, -(C =O)NR ₁₅ R ₁₆ , -(C=O)OR ₁₇ , -NR ₁₈ R ₁₉ , -halo, -SO ₂ -, cycloalkyl, heterocycloalkyl, or heterobicycloalkyl (supra At least one H of a cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 aminoalkyl, -C _1-6 haloalkyl, -NR ₂₀ R ₂₁ , or may be substituted with cycloalkyl)], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is —C _1-6 alkyl; -(=O)-, -(C=O)-C _1-6 alkyl, -(C=O)OC _1-6 alkyl, -NR ₂₂ R ₂₃ , -OC _1-6 alkyl,halo, -SO ₂ -C _1-6 alkyl, cycloalkyl, or heterocycloalkyl];
at least one H of said cycloalkyl or heterocycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -(C=O)-C _1-6 alkyl, -(C=O)OC _{1 -6} alkyl, or —SO ₂ —C _1-6 alkyl};
R ₁ is —H or —C _1-6 alkyl;
R ₂ is -H, -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _1-6 haloalkyl, -CN, -halo, or 5-7 membered ring and {wherein, one or more H of the 5-7 membered ring may be substituted with -C _1-6 alkyl, -C _1-6 haloalkyl, or halo};
R ₃ to R ₇ are each independently —H or —C _1-6 alkyl;
R ₈ is —H, —C _1-6 alkyl, phenyl or benzyl;
R ₉ and R ₁₀ are each independently —H, —C _1-6 alkyl, —C _1-6 hydroxyalkyl, —C _1-6 alkyl-NR ₂₄ R ₂₅ , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C _1-6 alkyl};
R ₁₁ is —H or —C _1-6 alkyl;
R ₁₂ and R ₁₃ are each independently —H, —C _1-6 alkyl, —C _1-6 alkyl-NR ₂₄ R ₂₅ , or —(C=O)OC _1-6 alkyl;
each R ₁₄ is independently —H, —C _1-6 alkyl, —C _1-6 alkyl-NR ₂₆ R ₂₇ , heterocycloalkyl, or —C _1-6 alkyl-heterocycloalkyl {wherein the heterocyclo one or more H of an alkyl or —C _1-6 alkyl-heterocycloalkyl ring may be substituted with —C _1-6 alkyl;
R ₁₅ to R ₁₇ are each independently —H or —C _1-6 alkyl;
R ₁₈ and R ₁₉ are each independently —C _1-6 alkyl or —C _1-6 alkyl-NR ₂₈ R ₂₉ ;
R ₂₀ to R ₂₉ are each independently —H or —C _1-6 alkyl.

제 1 항에 있어서,
고리 A₁은 아릴 또는 헤테로아릴이고 {여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6할로알킬, -CN, -NR₆R₇, -OR₈, 또는 -할로로 치환될 수 있음};
고리 A₂는 아릴, 헤테로아릴, 또는 헤테로사이클로알킬이고
{여기서, 상기 아릴 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6할로알킬, -C_1-6알킬-CN, -CN, -C_1-6알킬-O-C_1-6알킬, -C_1-6알킬NR₉R₁₀, -(C=O)NR₉R₁₀, -C_1-6알킬-(C=O)NR₉R₁₀, -(C=O)-C_1-6알킬, -(C=O)OR₁₁, -NR₁₂R₁₃, -OR₁₄, -할로, -S-C_1-6알킬, -SO₂-C_1-6알킬, -SO₂-NR₁₂R₁₃, -SO₂-할로, -S(=O)(=NH)-C_1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)NR₁₅R₁₆, -(C=O)OR₁₇, -NR₁₈R₁₉, -할로, -SO₂-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, 또는 -NR₂₀R₂₁로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, -NR₂₂R₂₃, -O-C_1-6알킬,할로, -SO₂-C_1-6알킬, 또는 사이클로알킬로 치환될 수 있음];
상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, 또는 -SO₂-C_1-6알킬로 치환될 수 있음};
R₁은 -H이고;
R₂는 -H, -C_1-6알킬, -C_1-6할로알킬, -CN, -할로, 또는 5-7원 고리이고 {여기서, 상기 5-7원 고리의 하나 이상의 H는 -C_1-6알킬 또는 할로로 치환될 수 있음};
R₆ 및 R₇은 각각 독립적으로 -C_1-6알킬이고;
R₈은 -H, -C_1-6알킬, 또는 페닐이고;
R₉ 및 R₁₀은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6히드록시알킬, -C_1-6알킬-NR₂₄R₂₅, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬로 치환될 수 있음};
R₁₁은 -C_1-6알킬이고;
R₁₂ 및 R₁₃은 각각 독립적으로 -H, -C_1-6알킬, 또는 -(C=O)O-C_1-6알킬이고;
R₁₄은 각각 독립적으로 -C_1-6알킬, -C_1-6알킬-NR₂₆R₂₇, 헤테로사이클로알킬, 또는 -C_1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C_1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬로 치환될 수 있음};
R₁₅ 내지 R₁₇은 각각 독립적으로 -C_1-6알킬이고;
R₁₈ 및 R₁₉은 각각 독립적으로 -C_1-6알킬 또는 -C_1-6알킬-NR₂₈R₂₉이고;
R₂₀ 내지 R₂₃, R₂₆ 내지 R₂₉은 각각 독립적으로 -H 또는 -C_1-6알킬인;
화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.The method of claim 1,
Ring A ₁ is aryl or heteroaryl {wherein at least one H of said aryl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 haloalkyl, -CN, -NR ₆ R ₇ , -OR ₈ , or - may be substituted with halo};
Ring A ₂ is aryl, heteroaryl, or heterocycloalkyl
{wherein at least one H of the aryl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-CN, -CN, -C _1-6 alkyl-OC _{1 -6} alkyl, -C _1-6 alkylNR ₉ R ₁₀ , -(C=O)NR ₉ R ₁₀ , -C _1-6 alkyl-(C=O)NR ₉ R ₁₀ , -(C=O)- C _1-6 alkyl, -(C=O)OR ₁₁ , -NR ₁₂ R ₁₃ , -OR ₁₄ , -halo, -SC _1-6 alkyl, -SO ₂ -C _1-6 alkyl, -SO ₂ -NR ₁₂ R ₁₃ , —SO ₂ -halo, —S(=O)(=NH)—C _1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, —C _1-6 alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _{1 -} At least one H of a ₆ alkyl-heterocycloalkyl, -(C=O)-heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl ring is -C _1-6 alkyl, -(=O) -, -(C=O)-C _1-6 alkyl, -(C=O)NR ₁₅ R ₁₆ , -(C=O)OR ₁₇ , -NR ₁₈ R ₁₉ , -halo, -SO ₂ -, cyclo may be substituted with alkyl, heterocycloalkyl, or heterobicycloalkyl (one or more H of the cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxy alkyl, or -NR ₂₀ R ₂₁ )], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is -C _1-6 alkyl, -(=O)-, -(C=O)-C _1-6 alkyl, -(C=O)OC _1-6 alkyl, -NR ₂₂ R ₂₃ , -OC _1-6 alkyl, may be substituted with halo, —SO ₂ —C _1-6 alkyl, or cycloalkyl];
at least one H of the heterocycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -(C=O)-C _1-6 alkyl, -(C=O)OC _1-6 alkyl , or —SO ₂ —C _1-6 alkyl};
R ₁ is —H;
R ₂ is -H, -C _1-6 alkyl, -C _1-6 haloalkyl, -CN, -halo, or a 5-7 membered ring {wherein at least one H of the 5-7 membered ring is -C may be substituted with _1-6 alkyl or halo};
R ₆ and R ₇ are each independently —C _1-6 alkyl;
R ₈ is —H, —C _1-6 alkyl, or phenyl;
R ₉ and R ₁₀ are each independently —H, —C _1-6 alkyl, —C _1-6 hydroxyalkyl, —C _1-6 alkyl-NR ₂₄ R ₂₅ , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C _1-6 alkyl};
R ₁₁ is —C _1-6 alkyl;
R ₁₂ and R ₁₃ are each independently —H, —C _1-6 alkyl, or —(C=O)OC _1-6 alkyl;
each R ₁₄ is independently —C _1-6 alkyl, —C _1-6 alkyl-NR ₂₆ R ₂₇ , heterocycloalkyl, or —C _1-6 alkyl-heterocycloalkyl {wherein said heterocycloalkyl or — one or more H of a C _1-6 alkyl-heterocycloalkyl ring may be substituted with —C _1-6 alkyl};
R ₁₅ to R ₁₇ are each independently —C _1-6 alkyl;
R ₁₈ and R ₁₉ are each independently —C _1-6 alkyl or —C _1-6 alkyl-NR ₂₈ R ₂₉ ;
R ₂₀ to R ₂₃ , R ₂₆ to R ₂₉ are each independently —H or —C _1-6 alkyl;
A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

제 1 항에 있어서,
고리 A₁은 페닐 또는 피리디닐이고 {여기서, 상기 페닐 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6아미노알킬, -C_1-6하이드록시알킬, -C_1-6할로알킬, -C_1-6알킬-O-C_1-6알킬, -CN, -(C=O)NR₃R₄, -(C=O)OR₅, -NR₆R₇, -OR₈, -할로, 아릴 또는 헤테로아릴로 치환될 수 있음};
R₃ 내지 R₇은 각각 독립적으로 -H 또는 -C_1-6알킬이고;
R₈은 -H, -C_1-6알킬, 페닐 또는 벤질인;
화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.The method of claim 1,
Ring A ₁ is phenyl or pyridinyl {wherein at least one H of said phenyl or heteroaryl ring is -C _1-6 alkyl, -C _1-6 aminoalkyl, -C _1-6 hydroxyalkyl, -C _{1 -6} Haloalkyl, -C _1-6 Alkyl-OC _1-6 Alkyl, -CN, -(C=O)NR ₃ R ₄ , -(C=O)OR ₅ , -NR ₆ R ₇ , -OR ₈ , which may be substituted with halo, aryl or heteroaryl};
R ₃ to R ₇ are each independently —H or —C _1-6 alkyl;
R ₈ is -H, -C _1-6 alkyl, phenyl or benzyl;
A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

제 1 항에 있어서,
고리 A₂는 페닐, 5-6원 헤테로아릴, 3-7원 사이클로알킬, 또는 3-7원 헤테로사이클로알킬이고
{여기서, 상기 페닐 또는 5-6원 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -C_1-6아미노알킬, -C_1-6할로알킬, -C_1-6알킬-CN, -CN, -C_1-6알킬-O-C_1-6알킬, -C_1-6알킬NR₉R₁₀, -(C=O)NR₉R₁₀, -C_1-6알킬-(C=O)NR₉R₁₀, -(C=O)-C_1-6알킬, -(C=O)OR₁₁, -C_1-6알킬-(C=O)OR₁₁, -NR₁₂R₁₃, -OR₁₄, -할로, -S-C_1-6알킬, -SO₂-C_1-6알킬, -SO₂-NR₁₂R₁₃, -SO₂-할로, -(S=O)NH-C_1-6알킬, -S(=O)(=NH)-C_1-6알킬, 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴로 치환될 수 있고 [이때, 상기 사이클로알킬, 헤테로사이클로알킬, 헤테로바이사이클로알킬, -C_1-6알킬-사이클로알킬, -C_1-6알킬-헤테로사이클로알킬, -(C=O)-사이클로알킬, -(C=O)-헤테로사이클로알킬, -NH(C=O)-사이클로알킬, -NH(C=O)-헤테로사이클로알킬, 아릴, -(C=O)-아릴, 또는 헤테로아릴 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)NR₁₅R₁₆, -(C=O)OR₁₇, -NR₁₈R₁₉, -할로, -SO₂-, 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬로 치환될 수 있음 (상기 사이클로알킬, 헤테로사이클로알킬, 또는 헤테로바이사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -C_1-6아미노알킬, -C_1-6할로알킬, -NR₂₀R₂₁, 또는 사이클로알킬로 치환될 수 있음)], 또는 상기 아릴 또는 헤테로아릴의 2 이상의 치환기가 서로 연결되어 융합 고리를 형성할 수 있고 [여기서, 상기 융합 고리의 하나 이상의 H는 -C_1-6알킬, -(=O)-, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, -NR₂₂R₂₃, -O-C_1-6알킬,할로, -SO₂-C_1-6알킬, 사이클로알킬, 또는 헤테로사이클로알킬로 치환될 수 있음];
상기 사이클로알킬 또는 헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6하이드록시알킬, -(C=O)-C_1-6알킬, -(C=O)O-C_1-6알킬, 또는 -SO₂-C_1-6알킬로 치환될 수 있음};
R₉ 및 R₁₀은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6히드록시알킬, -C_1-6알킬-NR₂₄R₂₅, 또는 헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬로 치환될 수 있음};
R₁₁은 -H 또는 -C_1-6알킬이고;
R₁₂ 및 R₁₃은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6알킬-NR₂₄R₂₅, 또는 -(C=O)O-C_1-6알킬이고;
R₁₄은 각각 독립적으로 -H, -C_1-6알킬, -C_1-6알킬-NR₂₆R₂₇, 헤테로사이클로알킬, 또는 -C_1-6알킬-헤테로사이클로알킬이고 {여기서, 상기 헤테로사이클로알킬 또는 -C_1-6알킬-헤테로사이클로알킬 고리의 하나 이상의 H는 -C_1-6알킬로 치환될 수 있음};
R₁₅ 내지 R₁₇은 각각 독립적으로 -H 또는 -C_1-6알킬이고;
R₁₈ 및 R₁₉은 각각 독립적으로 -C_1-6알킬 또는 -C_1-6알킬-NR₂₈R₂₉이고;
R₂₀ 내지 R₂₉은 각각 독립적으로 -H 또는 -C_1-6알킬인;
화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.The method of claim 1,
Ring A ₂ is phenyl, 5-6 membered heteroaryl, 3-7 membered cycloalkyl, or 3-7 membered heterocycloalkyl
{Wherein, at least one H of the phenyl or 5-6 membered heteroaryl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 aminoalkyl, -C _1-6 haloalkyl, -C _1-6 alkyl-CN, -CN, -C _1-6 alkyl-OC _1-6 alkyl, -C _1-6 alkylNR ₉ R ₁₀ , -(C=O)NR ₉ R ₁₀ , -C _{1 -6} alkyl-(C=O)NR ₉ R ₁₀ , -(C=O)-C _1-6 alkyl, -(C=O)OR ₁₁ , -C _1-6 alkyl-(C=O)OR ₁₁ , -NR ₁₂ R ₁₃ , -OR ₁₄ , -halo, -SC _1-6 alkyl, -SO ₂ -C _1-6 alkyl, -SO ₂ -NR ₁₂ R ₁₃ , -SO ₂ -halo, -(S= O)NH-C _1-6 alkyl, -S(=O)(=NH)-C _1-6 alkyl, cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _1-6 alkyl-cycloalkyl, - C _1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)- which may be substituted with heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl [wherein said cycloalkyl, heterocycloalkyl, heterobicycloalkyl, -C _1-6 alkyl-cycloalkyl, - C _1-6 Alkyl-heterocycloalkyl, -(C=O)-cycloalkyl, -(C=O)-heterocycloalkyl, -NH(C=O)-cycloalkyl, -NH(C=O)- At least one H of a heterocycloalkyl, aryl, -(C=O)-aryl, or heteroaryl ring is -C _1-6 alkyl, -(=O)-, -(C=O)-C _1-6 alkyl to be substituted with , -(C=O)NR ₁₅ R ₁₆ , -(C=O)OR ₁₇ , -NR ₁₈ R ₁₉ , -halo, -SO ₂ -, cycloalkyl, heterocycloalkyl, or heterobicycloalkyl can be (at least one H of the cycloalkyl, heterocycloalkyl, or heterobicycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -C _1-6 aminoalkyl, -C _{1 6} haloalkyl, -NR ₂₀ R ₂₁ , or may be substituted with cycloalkyl)], or two or more substituents of the aryl or heteroaryl may be linked to each other to form a fused ring, wherein at least one H of the fused ring is —C _1-6 alkyl, -(=O)-, -(C=O)-C _1-6 alkyl, -(C=O)OC _1-6 alkyl, -NR ₂₂ R ₂₃ , -OC _1-6 alkyl,halo, - SO ₂ -C _1-6 alkyl, cycloalkyl, or heterocycloalkyl];
at least one H of said cycloalkyl or heterocycloalkyl ring is -C _1-6 alkyl, -C _1-6 hydroxyalkyl, -(C=O)-C _1-6 alkyl, -(C=O)OC _{1 -6} alkyl, or —SO ₂ —C _1-6 alkyl};
R ₉ and R ₁₀ are each independently —H, —C _1-6 alkyl, —C _1-6 hydroxyalkyl, —C _1-6 alkyl-NR ₂₄ R ₂₅ , or heterocycloalkyl {wherein the hetero one or more H of the cycloalkyl ring may be substituted with —C _1-6 alkyl};
R ₁₁ is —H or —C _1-6 alkyl;
R ₁₂ and R ₁₃ are each independently —H, —C _1-6 alkyl, —C _1-6 alkyl-NR ₂₄ R ₂₅ , or —(C=O)OC _1-6 alkyl;
each R ₁₄ is independently —H, —C _1-6 alkyl, —C _1-6 alkyl-NR ₂₆ R ₂₇ , heterocycloalkyl, or —C _1-6 alkyl-heterocycloalkyl {wherein the heterocyclo one or more H of an alkyl or —C _1-6 alkyl-heterocycloalkyl ring may be substituted with —C _1-6 alkyl;
R ₁₅ to R ₁₇ are each independently —H or —C _1-6 alkyl;
R ₁₈ and R ₁₉ are each independently —C _1-6 alkyl or —C _1-6 alkyl-NR ₂₈ R ₂₉ ;
R ₂₀ to R ₂₉ are each independently —H or —C _1-6 alkyl;
A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

제 1 항에 있어서,
R₁은 -H인;
화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.The method of claim 1,
R ₁ is -H;
A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

제 1 항에 있어서,
R₂는 -H, -C_1-6알킬, -C_1-6할로알킬, -CN, -할로, 또는 5-6원 고리인 {여기서, 상기 5-6원 고리의 하나 이상의 H는 -C_1-6알킬, -C_1-6할로알킬, 또는 할로로 치환될 수 있음};
화학식 1로 표시되는 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용가능한 염.The method of claim 1,
R ₂ is -H, -C _1-6 alkyl, -C _1-6 haloalkyl, -CN, -halo, or a 5-6 membered ring {wherein at least one H of the 5-6 membered ring is -C may be substituted with _1-6 alkyl, —C _1-6 haloalkyl, or halo};
A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

제 1 항에 있어서,
상기 화학식 1로 표시되는 화합물이 하기 화합물로 이루어진 군으로부터 선택된 것인, 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염:
(1) (S)-N-(4-(4-메틸피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(2) (R)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(3) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;
(4) (S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(5) (S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(6) (S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(7) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(8) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;
(9) (R)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-(3-페녹시페닐)아이소옥사졸리딘-2-일)피리미딘-2-아민;
(10) (S)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;
(11) (S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(12) (S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(13) (S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(14) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-5-메틸-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(15) (S)-5-메틸-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(16) (R)-5-메틸-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(17) (S)-5-메틸-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(18) (S)-5-클로로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(19) (R)-5-클로로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(20) (R)-5-클로로-N-(1-(2-메톡시에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(21) (R)-2-(4-((5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)아미노)-1H-피라졸-1-일)-N,N-다이메틸아세트아마이드;
(22) (S)-5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;
(23) (S)-5-클로로-N-(4-(2-(다이에틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(24) (S)-5-클로로-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(25) (S)-5-클로로-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(26) (S)-5-클로로-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(27) (S)-5-클로로-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(28) 5-클로로-N-(3-사이클로프로필-5-(((3S,5R)-3,5-다이메틸피페라진-1-일)메틸)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(29) (S)-5-클로로-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(30) 5-클로로-N-(3-메톡시-4-(4-((1S,4S)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피페리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(31) (S)-5-클로로-N-(3-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(32) (S)-N-(5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;
(33) (S)-N-(5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-2-메틸-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;
(34) (S)-N-(5-클로로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;
(35) (S)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;
(36) (S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(37) (S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(38) (S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(39) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(40) (S)-5-플루오로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(41) (R)-5-플루오로-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(42) (S)-5-플루오로-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(43) N-(3-사이클로프로필-5-(((3S,5R)-3,5-다이메틸피페라진-1-일)메틸)페닐)-5-플루오로-4-((S)-3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(44) (S)-N-(5-플루오로-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;
(45) (S)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(46) (R)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(47) (S)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤조나이트릴;
(48) (S)-N1,N1-다이메틸-N4-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)벤젠-1,4-다이아민;
(49) (S)-N-(4-플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(50) (S)-N-(4-메톡시페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(51) (S)-N-(4-(메틸싸이오)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(52) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)-N-(4-(트라이플루오로메틸)페닐)피리미딘-2-아민;
(53) tert-부틸 (S)-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)카바메이트;
(54) (S)-N1-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)벤젠-1,4-다이아민;
(55) (S)-N-(4-(4-에틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(56) (S)-1-(4-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페라진-1-일)에탄-1-온;
(57) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)-N-(4-((3S,5R)-3,4,5-트라이메틸피페라진-1-일)페닐)피리미딘-2-아민;
(58) (S)-N1-(2-(다이메틸아미노)에틸)-N1-메틸-N4-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)벤젠-1,4-다이아민;
(59) (S)-N-(4-(2-(다이메틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(60) (S)-N-(4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(61) N-(4-((2S,6R)-2,6-다이메틸몰포리노)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(62) N-(4-((1R,4R)-2-옥사-5-아자바이사이클로[2.2.1]헵탄-5-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(63) (S)-N-(4-(3-(다이메틸아미노)아제티딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(64) (S)-N-(4-(4-메틸피페라진-1-일)-3-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(65) (S)-N-(2-메톡시-4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(66) (S)-N-(3-메톡시-4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(67) (S)-N-(4-(4-사이클로프로필피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(68) (S)-N-(3-메톡시-4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(69) (R)-3-메틸-N-(4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-아민;
(70) (S)-3-메틸-N-(4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4,4a,5-헥사하이드로벤조[b]피라지노[1,2-d][1,4]옥사진-8-아민;
(71) 메틸 (S)-8-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-2,3-다이하이드로벤조[b][1,4]다이옥신-5-카복실레이트;
(72) 메틸 (S)-7-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-2,3-다이하이드로벤조퓨란-4-카복실레이트;
(73) N-(4-((R)-3-(다이메틸아미노)피롤리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(74) N-(4-((S)-3-(다이메틸아미노)피롤리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(75) (S)-1-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피롤리딘-2-온;
(76) (S)-2-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)아이소싸이아졸리딘 1,1-다이옥사이드;
(77) (S)-N-(3-메톡시-4-(1-메틸-1H-피라졸-5-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(78) (S)-N-(4-(4-(다이메틸아미노)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(79) (S)-N-(4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(80) (S)-N-(2-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(81) (S)-N-(3-플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(82) (S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(83) (S)-N-(3-메틸-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(84) (S)-N-(3-메톡시-4-(4-몰포리노피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(85) (S)-N1-(1-(2-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-4-일)-N1,N2,N2-트라이메틸에탄-1,2-다이아민;
(86) N-(3-메톡시-4-(4-((1S,4S)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피페리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(87) N-(3-메톡시-4-(4-((1R,4R)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피페리딘-1-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(88) (S)-2-(4-(1-(2-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-4-일)피페라진-1-일)에탄-1-올;
(89) (S)-1'-(2-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)-N,N-다이메틸-[1,4'-바이피페리딘]-4-아민;
(90) (S)-N-(4-(4-(3-(다이메틸아미노)아제티딘-1-일)피페리딘-1-일)-3-메톡시페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(91) (S)-2-(4-(1-(2-플루오로-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-4-일)피페라진-1-일)에탄-1-올;
(92) (S)-N-(4-(4-(1-메틸피페리딘-4-일)피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(93) (S)-N-(3-메톡시-4-(4-(1-메틸피페리딘-4-일)피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(94) (S)-N-(4-(3-(4-메틸피페라진-1-일)아제티딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(95) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)-N-(3,4,5-트라이메톡시페닐)피리미딘-2-아민;
(96) (S)-N-(4-(2-(다이에틸아미노)에톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(97) (S)-N-(4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(98) (S)-N-(4-(3-(다이에틸아미노)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(99) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(100) (R)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(101) (S)-N-(3,5-다이메틸-4-(3-(4-메틸피페라진-1-일)프로폭시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(102) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(103) (S)-N-(3-플루오로-4-((1-메틸피페리딘-4-일)옥시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(104) tert-부틸 (S)-4-(2-플루오로-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피페리딘-1-카복실레이트;
(105) (S)-N-(3-플루오로-4-(피페리딘-4-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(106) (S)-N-(4-(4-에틸피페라진-1-일)-3,5-다이플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(107) (S)-N-(3,5-다이플루오로-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(108) (S)-N-(4-(4-(다이메틸아미노)피페리딘-1-일)-3,5-다이플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(109) N-(4-((R)-3-(다이메틸아미노)피롤리딘-1-일)-3,5-다이플루오로페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(110) N-(4-((S)-3-(다이메틸아미노)피롤리딘-1-일)-3,5-다이플루오로페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(111) (S)-1-(2,6-다이플루오로-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)피롤리딘-2-온;
(112) (S)-N-(3,5-다이플루오로-4-(4-메틸-1,4-다이아제판-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(113) (S)-N-(3,5-다이플루오로-4-((1-메틸피페리딘-4-일)옥시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(114) (S)-N-(3,5-다이플루오로-4-((1-메틸피페리딘-4-일)메톡시)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(115) (S)-N-(4-(3-(다이에틸아미노)프로폭시)-3,5-다이플루오로페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(116) (S)-N-(3,5-다이플루오로-4-(4-메틸-1H-이미다졸-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(117) (S)-N-(5-(4-메틸피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(118) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(5-(피페라진-1-일)피리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(119) (S)-N-(5-몰포리노피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(120) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(5-(테트라하이드로-2H-피란-4-일)피리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(121) (S)-N-(5-(4-아이소프로필피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(122) (S)-N-(5-(4-사이클로프로필피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(123) (S)-N-(5-(4-(옥세탄-3-일)피페라진-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(124) (S)-N-(5-((4-에틸피페라진-1-일)메틸)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(125) (S)-N-(5-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-2-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(126) (S)-N-(6-(4-(4-메틸피페라진-1-일)피페리딘-1-일)피리딘-3-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(127) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;
(128) (S)-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;
(129) (S)-1-(6-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-3,4-다이하이드로아이소퀴놀린-2(1H)-일)에탄-1-온;
(130) (S)-2-(메틸설포닐)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;
(131) (S)-2-사이클로프로필-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-6-아민;
(132) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;
(133) (S)-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;
(134) (S)-6-메톡시-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;
(135) (S)-6-메톡시-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;
(136) (S)-6-플루오로-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;
(137) (S)-6-플루오로-7-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-3,4-다이하이드로아이소퀴놀린-1(2H)-온;
(138) (S)-6-플루오로-2-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-1,2,3,4-테트라하이드로아이소퀴놀린-7-아민;
(139) 6-메톡시-N2,N2-다이메틸-N5-(4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-2,3-다이하이드로-1H-인덴-2,5-다이아민;
(140) (S)-5-메톡시-2-메틸-6-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)아이소인돌린-1-온;
(141) (S)-5'-메톡시-6'-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)스파이로[사이클로프로판-1,3'-인돌린]-2'-온;
(142) (S)-3,3-다이메틸-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)아이소벤조퓨란-1(3H)-온;
(143) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(1H-피라졸-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(144) (S)-N-(1-메틸-1H-피라졸-3-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(145) (S)-N-(1-메틸-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(146) (S)-N-(1-아이소프로필-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(147) (S)-N-(1-사이클로프로필-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(148) (S)-N-(1-(2,2-다이플루오로에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(149) (S)-N-메틸-2-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-1H-피라졸-1-일)아세트아마이드;
(150) (S)-N-(1-(2-메톡시에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(151) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(1-(피페리딘-4-일)-1H-피라졸-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(152) (S)-N-(1-(2-몰포리노에틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(153) (S)-N-(1-(3-(다이에틸아미노)프로필)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(154) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-(1-(((R)-테트라하이드로퓨란-2-일)메틸)-1H-피라졸-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(155) tert-부틸 (S)-3-((4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-1H-피라졸-1-일)메틸)아제티딘-1-카복실레이트;
(156) (S)-N-(1-(아제티딘-3-일메틸)-1H-피라졸-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(157) (S)-6-메틸-2-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-5,6-다이하이드로-4H-피라졸로[1,5-d][1,4]다이아제핀-7(8H)-온;
(158) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-4-(피페리딘-4-일)싸이아졸-2-아민;
(159) tert-부틸 (S)-2-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)-6,7-다이하이드로싸이아졸로[5,4-c]피리딘-5(4H)-카복실레이트;
(160) (S)-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-4,5,6,7-테트라하이드로싸이아졸로[5,4-c]피리딘-2-아민;
(161) (S)-5-메틸-N-(4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)-4,5,6,7-테트라하이드로싸이아졸로[5,4-c]피리딘-2-아민;
(162) 메틸 (S)-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)싸이오펜-2-카복실레이트;
(163) (S)-1-(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)에탄-1-온;
(164) (S)-페닐(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)메탄온;
(165) (S)-N,N-다이메틸-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;
(166) (S)-(4-메틸피페라진-1-일)(4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)메탄온;
(167) (S)-N-(2-하이드록시에틸)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;
(168) (S)-N-(3-하이드록시프로필)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;
(169) (S)-N-(2-(메틸아미노)에틸)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;
(170) 이미노(메틸)(4-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)-λ⁶-설판온;
(171) 1-(4-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)-4,5-다이하이드로-3H-아이소싸이아졸 1-옥사이드;
(172) (S)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤젠설포닐 플로라이드;
(173) (S)-N,N-다이메틸-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤젠설폰아마이드;
(174) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(3-(피리딘-3-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;
(175) (S)-N-(3-메톡시-5-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(176) (S)-N-(3-(4-메틸피페라진-1-일)-5-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(177) (S)-N-(3-((4-메틸피페라진-1-일)메틸)-5-(트라이플루오로메틸)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(178) (S)-2-메틸-2-(3-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)프로판나이트릴;
(179) (S)-2-메틸-2-(3-(4-메틸피페라진-1-일)-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)프로판나이트릴;
(180) (S)-2-메틸-2-(3-((4-메틸피페라진-1-일)메틸)-5-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)페닐)프로판나이트릴;
(181) N-(3-((1R,4R)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)-5-(메틸설포닐)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(182) N-(3-((1S,4S)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)-5-(메틸설포닐)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(183) (S)-N-(3-(4-(4-메틸피페라진-1-일)피페리딘-1-일)-5-(메틸설포닐)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(184) N-(2-플루오로-5-((1R,4R)-5-메틸-2,5-다이아자바이사이클로[2.2.1]헵탄-2-일)피리딘-3-일)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(185) N-(3-(3,3-다이플루오로피롤리딘-1-일)-5-((R)-피롤리딘-3-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(186) N-(3-(3,3-다이플루오로피롤리딘-1-일)-5-((S)-피롤리딘-3-일)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(187) (S)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(188) (S)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(189) (R)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-몰포리노페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(190) (R)-N-(2-메톡시-5-(1-메틸-1H-피라졸-4-일)-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(191) (S)-2-플루오로-N-(1-아이소프로필피페리딘-4-일)-5-메톡시-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)벤즈아마이드;
(192) N-(3-사이클로프로필-5-(((3S,5R)-3,5-다이메틸피페라진-1-일)메틸)페닐)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(193) (S)-N-(1-(메틸설포닐)피페리딘-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(194) (S)-N-(1-아이소프로필피페리딘-4-일)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(195) (3S,4S)-1-(메틸설포닐)-4-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-3-올;
(196) (3R,4R)-1-(메틸설포닐)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-4-올;
(197) tert-부틸 (S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-카복실레이트;
(198) tert-부틸 (S)-4-((4-(3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-카복실레이트;
(199) tert-부틸 (S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피롤리딘-1-카복실레이트;
(200) tert-부틸 (R)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피롤리딘-1-카복실레이트;
(201) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((S)-피페리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(202) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-N-(피페리딘-4-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(203) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((S)-피롤리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(204) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((R)-피롤리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(205) 3-((S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피롤리딘-1-일)프로판-1-올;
(206) tert-부틸 (R)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-카복실레이트;
(207) 1-((S)-3-((4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-일)아미노)피페리딘-1-일)에탄-1-온;
(208) 4-((S)-3-페닐아이소옥사졸리딘-2-일)-N-((R)-피페리딘-3-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(209) N-((S)-1-메틸피페리딘-3-일)-4-((S)-3-페닐아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(210) (S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-(3-메톡시페닐)아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(211) (S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-(피리딘-3-일)아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(212) (S)-4-(3-(3-플루오로페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;
(213) (S)-4-(3-(4-플루오로페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;
(214) (S)-4-(3-(2,6-다이플루오로페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;
(215) (S)-4-(3-(3-(다이메틸아미노)페닐)아이소옥사졸리딘-2-일)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-5-(트라이플루오로메틸)피리미딘-2-아민;
(216) (S)-3-(2-(2-((3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-5-(트라이플루오로메틸)피리미딘-4-일)아이소옥사졸리딘-3-일)벤조나이트릴;
(217) (S)-N-(3-메톡시-4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)-4-(3-(3-페녹시페닐)아이소옥사졸리딘-2-일)-5-(트라이플루오로메틸)피리미딘-2-아민;
(218) (S)-3-(2-(2-((1,2,3,4-테트라하이드로아이소퀴놀린-7-일)아미노)-5-(트라이플루오로메틸)피리미딘-4-일)아이소옥사졸리딘-3-일)벤조나이트릴;
(219) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-2-((3,4,5-트라이메톡시페닐)아미노)피리미딘-5-카보나이트릴;
(220) (S)-2-((4-(2-(다이에틸아미노)에톡시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(221) (S)-2-((4-(2-(다이에틸아미노)에톡시)-3,5-다이메틸페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(222) (S)-2-((4-(3-(다이에틸아미노)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(223) (S)-2-((4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(224) (S)-2-((4-(3-(다이에틸아미노)프로폭시)-3,5-다이플루오로페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(225) (R)-2-((4-(4-메틸피페라진-1-일)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(226) (R)-2-((4-(3-(다이에틸아미노)프로폭시)-3,5-다이메틸페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(227) (S)-2-((4-(4-(4-메틸피페라진-1-일)피페리딘-1-일)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(228) (S)-2-((3,5-다이메틸-4-(3-(피롤리딘-1-일)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(229) (S)-2-((3,5-다이메틸-4-(3-(피페리딘-1-일)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(230) (S)-2-((3,5-다이메틸-4-(3-몰포리노프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(231) (S)-2-((3,5-다이메틸-4-(3-(4-메틸피페라진-1-일)프로폭시)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(232) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-2-((4-(피페라진-1-일)-3-(트라이플루오로메틸)페닐)아미노)피리미딘-5-카보나이트릴;
(233) (S)-2-((4-(4-메틸피페라진-1-일)페닐)아미노)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-5-카보나이트릴;
(234) (S)-4-(3-페닐아이소옥사졸리딘-2-일)-2-((1,2,3,4-테트라하이드로아이소퀴놀린-6-일)아미노)피리미딘-5-카보나이트릴;
(235) (S)-5-(3,6-다이하이드로-2H-피란-4-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(236) (S)-5-(사이클로헥산-1-엔-1-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(237) (S)-5-(1-메틸-1H-피라졸-4-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(238) (S)-5-(퓨란-3-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민;
(239) (S)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)-5-(피리딘-3-일)피리미딘-2-아민; 및
(240) (S)-5-(6-플루오로피리딘-3-일)-N-(4-(4-메틸피페라진-1-일)페닐)-4-(3-페닐아이소옥사졸리딘-2-일)피리미딘-2-아민.The method of claim 1,
The compound represented by Formula 1 is selected from the group consisting of the following compounds, a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
(1) ( S )-N-(4-(4- methylpiperidin -1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine;
(2) ( R )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine;
(3) ( S )-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine;
(4) ( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-amine;
(5) ( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidin-2-amine;
(6) ( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)pyrimidine- 2-amine;
(7) ( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)pyrimidine- 2-amine;
(8) ( S )-N-(4-(3- phenylisooxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinolin-6-amine;
(9) ( R )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-(3-phenoxyphenyl)isoxazolidin-2-yl)pyrimidine- 2-amine;
(10) ( S )-5-methyl-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine;
(11) ( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-5-methyl-4-(3-phenylisooxazolidin-2-yl)pyrimidine-2- amines;
(12) ( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-5-methyl-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
(13) ( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-5-methyl-4-(3-phenylisooxazolidin-2-yl)pyrimidine-2- amines;
(14) ( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-5-methyl-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
(15) ( S )-5-methyl- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
(16) ( R )-5-methyl- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
(17) ( S )-5-methyl- N- (4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazoli din-2-yl)pyrimidin-2-amine;
(18) ( S )-5-chloro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
(19) ( R )-5-chloro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
(20) ( R )-5-chloro- N- (1-(2-methoxyethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl) pyrimidin-2-amine;
(21) ( R )-2-(4-((5-chloro-4-(3-phenylisooxazolidin-2-yl)pyrimidin-2-yl)amino) -1H -pyrazole-1 -yl) -N , N -dimethylacetamide;
(22) ( S )-5-chloro-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine;
(23) ( S )-5-chloro- N- (4-(2-(diethylamino)ethoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
(24) ( S )-5-chloro- N- (4-(3-(diethylamino)propoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2- amines;
(25) ( S )-5-chloro- N- (4-(2-(diethylamino)ethoxy)-3,5-dimethylphenyl)-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
(26) ( S )-5-chloro- N- (4-(3-(diethylamino)propoxy)-3,5-dimethylphenyl)-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
(27) ( S )-5-chloro- N- (4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazoli din-2-yl)pyrimidin-2-amine;
(28) 5-chloro- N- (3-cyclopropyl-5-((( 3S , 5R )-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)pyrimidin-2-amine;
(29) ( S )-5-chloro- N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3 -phenylisoxazolidin-2-yl)pyrimidin-2-amine;
(30) 5-chloro- N -(3-methoxy-4-(4-(( 1S , 4S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl) )piperidin-1-yl)phenyl)-4-(( S )-3-phenylisooxazolidin-2-yl)pyrimidin-2-amine;
(31) ( S )-5-chloro- N- (3-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3- phenylisooxazolidin-2-yl)pyrimidin-2-amine;
(32) ( S )-N-(5-chloro-4-(3- phenylisooxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline- 7-amine;
(33) ( S )-N-(5-chloro-4-(3- phenylisoxazolidin -2-yl)pyrimidin-2-yl)-2-methyl-1,2,3,4-tetra hydroisoquinolin-7-amine;
(34) ( S )-N-(5-chloro-4-(3- phenylisooxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline- 6-amine;
(35) ( S )-5-fluoro-4-(3- phenylisooxazolidin -2-yl)-N-(3,4,5-trimethoxyphenyl)pyrimidin-2-amine;
(36) ( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-5-fluoro-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2 -amines;
(37) ( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-5-fluoro-4-(3-phenylisooxazolidin-2-yl)pyrimidine-2 -amines;
(38) ( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-5-fluoro-4-(3-phenylisoxazolidine-2- yl) pyrimidin-2-amine;
(39) ( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-5-fluoro-4-(3-phenylisoxazolidine-2- yl) pyrimidin-2-amine;
(40) ( S )-5-fluoro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2 -amines;
(41) ( R )-5-fluoro- N- (4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-2 -amines;
(42) ( S )-5-fluoro- N- (4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)pyrimidin-2-amine;
(43) N- (3-cyclopropyl-5-((( 3S , 5R )-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-5-fluoro-4-(( S )-3-phenylisoxazolidin-2-yl)pyrimidin-2-amine;
(44) ( S )-N-(5-fluoro-4-(3- phenylisooxazolidin -2-yl)pyrimidin-2-yl)-1,2,3,4-tetrahydroisoquinoline -6-amine;
(45) ( S )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(46) ( R )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(47) ( S )-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzonitrile;
(48) ( S ) -N 1, N 1-dimethyl- N 4-(4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl )benzene-1,4-diamine;
(49) ( S ) -N- (4-fluorophenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(50) ( S ) -N- (4-methoxyphenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(51) ( S ) -N- (4-(methylthio)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine ;
(52) ( S )-4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)pyrimidine-2- amines;
(53) tert -butyl ( S )-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl) carbamate;
(54) ( S ) -N 1-(4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)benzene-1,4-diamine ;
(55) ( S )-N-(4-(4-ethylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(56) ( S )-1-(4-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)piperazin-1-yl)ethan-1-one;
(57) 4-(( S )-3- phenylisoxazolidin - 2 -yl)-5-(trifluoromethyl)-N-(4-((3S,5R)-3,4,5 -trimethylpiperazin-1-yl)phenyl)pyrimidin-2-amine;
(58) ( S ) -N 1-(2-(dimethylamino)ethyl) -N 1-methyl- N 4-(4-(3-phenylisoxazolidin-2-yl)-5-(tri fluoromethyl)pyrimidin-2-yl)benzene-1,4-diamine;
(59) ( S ) -N- (4-(2-(dimethylamino)ethoxy)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(60) ( S ) -N- (4-morpholinophenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(61) N- (4-(( 2S ,6R)-2,6-dimethylmorpholino)phenyl)-4-(( S )-3- phenylisoxazolidin -2-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
(62) N- (4-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)phenyl)-4-(( S )-3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(63) ( S )-N-(4-(3-( dimethylamino )azetidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(tri fluoromethyl)pyrimidin-2-amine;
(64) ( S )-N-(4-(4-methylpiperazin- 1 -yl)-3-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
(65) ( S )-N-(2-methoxy-4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
(66) ( S )-N-(3-methoxy-4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
(67) ( S )-N-(4-(4-cyclopropylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl ) pyrimidin-2-amine;
(68) ( S ) -N- (3-methoxy-4-morpholinophenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2 -amines;
(69) ( R )-3-methyl- N- (4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)- 1,2,3,4,4a,5-hexahydrobenzo[ b ]pyrazino[1,2- d ][1,4]oxazin-8-amine;
(70) ( S )-3-methyl- N- (4-(( S )-3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)- 1,2,3,4,4a,5-hexahydrobenzo[ b ]pyrazino[1,2- d ][1,4]oxazin-8-amine;
(71) methyl ( S )-8-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3- dihydrobenzo[ b ][1,4]dioxine-5-carboxylate;
(72) methyl ( S )-7-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,3- dihydrobenzofuran-4-carboxylate;
(73) N- (4-(( R )-3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
(74) N- (4-(( S )-3-(dimethylamino)pyrrolidin-1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
(75) ( S )-1-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)p rollidin-2-one;
(76) ( S )-2-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)iso thiazolidine 1,1-dioxide;
(77) ( S ) -N- (3-methoxy-4-(1-methyl- 1H -pyrazol-5-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
(78) ( S )-N-(4-(4-( dimethylamino )piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
(79) ( S ) -N-(4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazolidine-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(80) ( S ) -N- (2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(81) ( S ) -N- (3-fluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(82) ( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(83) ( S ) -N-(3-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-phenylisoxazoli din-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(84) ( S ) -N- (3-methoxy-4-(4-morpholinopiperidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
(85) ( S ) -N 1-(1-(2-methoxy-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)phenyl)piperidin-4-yl) -N 1, N 2, N 2-trimethylethane-1,2-diamine;
(86) N -(3-methoxy-4-(4-(( 1S , 4S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine -1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(87) N -(3-methoxy-4-(4-((1 R ,4 R )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)piperidine -1-yl)phenyl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(88) ( S )-2-(4-(1-(2-methoxy-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyri) midin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol;
(89) ( S )-1'-(2-methoxy-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)phenyl) -N , N -dimethyl-[1,4′-bipiperidin]-4-amine;
(90) ( S )-N-(4-(4-(3-( dimethylamino )azetidin-1-yl)piperidin-1-yl)-3-methoxyphenyl)-4-(3 -phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(91) ( S )-2-(4-(1-(2-fluoro-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyri) midin-2-yl)amino)phenyl)piperidin-4-yl)piperazin-1-yl)ethan-1-ol;
(92) ( S ) -N- (4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)-4-(3-phenylisoxazolidine-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(93) ( S ) -N- (3-methoxy-4-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)phenyl)-4-(3-phenylisooxa zolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(94) ( S )-N-(4-(3-(4-methylpiperazin- 1 -yl)azetidin-1-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl )-5-(trifluoromethyl)pyrimidin-2-amine;
(95) ( S )-4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)-N-(3,4,5-trimethoxyphenyl)pyrimidine-2 -amines;
(96) ( S )-N-(4-(2-( diethylamino )ethoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(97) ( S )-N-(4-(2-(diethylamino)ethoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine;
(98) ( S )-N-(4-(3-( diethylamino )propoxy)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(99) ( S )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine;
(100) ( R )-N-(4-(3-(diethylamino)propoxy)-3,5- dimethylphenyl )-4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine;
(101) ( S )-N-(3,5- dimethyl -4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(102) ( S )-N-(4-(3-( diethylamino )propoxy)-3-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
(103) ( S ) -N- (3-fluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
(104) tert -Butyl ( S )-4-(2-fluoro-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2 -yl)amino)phenyl)piperidine-1-carboxylate;
(105) ( S ) -N- (3-fluoro-4-(piperidin-4-yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoro romethyl)pyrimidin-2-amine;
(106) ( S )-N-(4-(4-ethylpiperazin- 1 -yl)-3,5-difluorophenyl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine;
(107) ( S ) -N- (3,5-difluoro-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3- phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(108) ( S )-N-(4-(4-( dimethylamino )piperidin-1-yl)-3,5-difluorophenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(109) N- (4-(( R )-3-(dimethylamino)pyrrolidin-1-yl)-3,5-difluorophenyl)-4-(( S )-3-phenyliso oxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(110) N- (4-(( S )-3-(dimethylamino)pyrrolidin-1-yl)-3,5-difluorophenyl)-4-(( S )-3-phenyliso oxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(111) ( S )-1-(2,6-difluoro-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2 -yl)amino)phenyl)pyrrolidin-2-one;
(112) ( S ) -N- (3,5-difluoro-4-(4-methyl-1,4-diazepan-1-yl)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(113) ( S ) -N- (3,5-difluoro-4-((1-methylpiperidin-4-yl)oxy)phenyl)-4-(3-phenylisoxazolidine-2 -yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(114) ( S ) -N- (3,5-difluoro-4-((1-methylpiperidin-4-yl)methoxy)phenyl)-4-(3-phenylisoxazolidine- 2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(115) ( S )-N-(4-(3-( diethylamino )propoxy)-3,5-difluorophenyl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine;
(116) ( S ) -N- (3,5-difluoro-4-(4-methyl-1 H -imidazol-1-yl)phenyl)-4-(3-phenylisoxazolidine-2 -yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(117) ( S )-N-(5-(4-methylpiperazin- 1 -yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(tri fluoromethyl)pyrimidin-2-amine;
(118) ( S )-4-(3- phenylisoxazolidin -2-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)-5-(trifluoromethyl ) pyrimidin-2-amine;
(119) ( S ) -N- (5-morpholinopyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2- amines;
(120) ( S )-4-(3-phenylisooxazolidin-2-yl) -N- (5-(tetrahydro- 2H -pyran-4-yl)pyridin-2-yl)-5- (trifluoromethyl)pyrimidin-2-amine;
(121) ( S )-N-(5-(4-isopropylpiperazin- 1 -yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
(122) ( S )-N-(5-(4-cyclopropylpiperazin- 1 -yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
(123) ( S )-N-(5-(4-( oxetan -3-yl)piperazin-1-yl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2- yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(124) ( S )-N-(5-((4-ethylpiperazin- 1 -yl)methyl)pyridin-2-yl)-4-(3-phenylisoxazolidin-2-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
(125) ( S ) -N-(5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)-4-(3-phenylisoxazoli din-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(126) ( S ) -N-(6-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-3-yl)-4-(3-phenylisoxazoli din-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(127) ( S )-N-(4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-6-amine;
(128) ( S )-2-methyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2, 3,4-tetrahydroisoquinolin-6-amine;
(129) ( S )-1-(6-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3, 4-dihydroisoquinolin-2(1 H )-yl)ethan-1-one;
(130) ( S )-2-(methylsulfonyl)-N-(4-(3- phenylisooxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)- 1,2,3,4-tetrahydroisoquinolin-6-amine;
(131) ( S )-2-cyclopropyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2 ,3,4-tetrahydroisoquinolin-6-amine;
(132) ( S )-N-(4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4- tetrahydroisoquinolin-7-amine;
(133) ( S )-2-methyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2, 3,4-tetrahydroisoquinolin-7-amine;
(134) ( S )-6-methoxy- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2 ,3,4-tetrahydroisoquinolin-7-amine;
(135) ( S )-6-methoxy-2-methyl- N- (4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinolin-7-amine;
(136) ( S )-6-fluoro- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-1,2 ,3,4-tetrahydroisoquinolin-7-amine;
(137) ( S )-6-fluoro-7-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)- 3,4-dihydroisoquinolin-1( 2H )-one;
(138) ( S )-6-fluoro-2-methyl- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl) -1,2,3,4-tetrahydroisoquinolin-7-amine;
(139) 6-methoxy- N 2, N 2-dimethyl- N 5-(4-(( S )-3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyri midin-2-yl)-2,3-dihydro-1 H -indene-2,5-diamine;
(140) ( S )-5-methoxy-2-methyl-6-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl )amino)isoindolin-1-one;
(141) ( S )-5'-methoxy-6'-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) spiro[cyclopropane-1,3'-indolin]-2'-one;
(142) ( S )-3,3-dimethyl-5-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) isobenzofuran-1(3 H )-one;
(143) ( S )-4-(3- phenylisoxazolidin -2-yl)-N-( 1H -pyrazol-4-yl)-5-(trifluoromethyl)pyrimidine-2- amines;
(144) ( S ) -N-(1-methyl- 1H -pyrazol-3-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyri midin-2-amine;
(145) ( S ) -N- (1-methyl- 1H -pyrazol-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyri midin-2-amine;
(146) ( S ) -N- (1-isopropyl- 1H -pyrazol-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(147) ( S ) -N- (1-cyclopropyl- 1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(148) ( S ) -N-(1-(2,2-difluoroethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine;
(149) ( S ) -N -methyl-2-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )-1 H -pyrazol-1-yl)acetamide;
(150) ( S ) -N-(1-(2-methoxyethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
(151) ( S )-4-(3-phenylisoxazolidin-2-yl) -N- (1-(piperidin-4-yl) -1H -pyrazol-4-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
(152) ( S ) -N-(1-(2-morpholinoethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
(153) ( S )-N-(1-(3-( diethylamino )propyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)- 5-(trifluoromethyl)pyrimidin-2-amine;
(154) 4-(( S )-3- phenylisoxazolidin -2-yl)-N-(1-((( R )-tetrahydrofuran-2-yl)methyl) -1H -pyrazole -4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(155) tert -butyl ( S )-3-((4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )-1 H -pyrazol-1-yl)methyl)azetidine-1-carboxylate;
(156) ( S ) -N-(1-(azetidin-3-ylmethyl) -1H -pyrazol-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5 -(trifluoromethyl)pyrimidin-2-amine;
(157) ( S )-6-methyl-2-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-5 ,6-dihydro- 4H -pyrazolo[1,5- d ][1,4]diazepin-7( 8H )-one;
(158) ( S )-N-(4-(3- phenylisooxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4-(piperidin-4 -yl) thiazol-2-amine;
(159) tert -butyl ( S )-2-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-6, 7-dihydrothiazolo[5,4-c]pyridine-5( 4H )-carboxylate;
(160) ( S )-N-(4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4,5,6,7- tetrahydrothiazolo[5,4-c]pyridin-2-amine;
(161) ( S )-5-methyl- N- (4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)-4,5, 6,7-tetrahydrothiazolo[5,4-c]pyridin-2-amine;
(162) methyl ( S )-5-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)thiophene-2- carboxylate;
(163) ( S )-1-(4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)ethane -1-one;
(164) ( S )-phenyl(4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)methanone ;
(165) ( S ) -N , N -dimethyl-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )benzamide;
(166) ( S )-(4-methylpiperazin-1-yl)(4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)phenyl)methanone;
(167) ( S ) -N-(2-hydroxyethyl)-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2- yl)amino)benzamide;
(168) ( S ) -N- (3-hydroxypropyl)-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine-2- yl)amino)benzamide;
(169) ( S )-N-(2-(methylamino)ethyl)-4-((4-(3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl)pyrimidine- 2-yl)amino)benzamide;
(170) imino(methyl)(4-((4-(( S )-3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino) phenyl)-λ ⁶ -sulfanone;
(171) 1-(4-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)- 4,5-dihydro-3 H -isothiazole 1-oxide;
(172) ( S )-4-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonyl fluoride;
(173) ( S ) -N , N -dimethyl-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) benzenesulfonamide;
(174) ( S )-4-(3- phenylisooxazolidin -2-yl)-N-(3-(pyridin-3-yl)phenyl)-5-(trifluoromethyl)pyrimidine-2 -amines;
(175) ( S )-N-(3-methoxy-5-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-( trifluoromethyl)pyrimidin-2-amine;
(176) ( S )-N-(3-(4-methylpiperazin- 1 -yl)-5-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-amine;
(177) ( S )-N-(3-((4-methylpiperazin- 1 -yl)methyl)-5-(trifluoromethyl)phenyl)-4-(3-phenylisoxazolidine-2 -yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(178) ( S )-2-methyl-2-(3-((4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )phenyl)propanenitrile;
(179) ( S )-2-methyl-2-(3-(4-methylpiperazin-1-yl)-5-((4-(3-phenylisoxazolidin-2-yl)-5- (trifluoromethyl)pyrimidin-2-yl)amino)phenyl)propanenitrile;
(180) ( S )-2-methyl-2-(3-((4-methylpiperazin-1-yl)methyl)-5-((4-(3-phenylisoxazolidin-2-yl) -5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)propanenitrile;
(181) N -(3-(( 1R , 4R )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(methylsulfonyl)phenyl)- 4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(182) N -(3-(( 1S , 4S )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-5-(methylsulfonyl)phenyl)- 4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(183) ( S ) -N-(3-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-(methylsulfonyl)phenyl)-4-(3- phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(184) N -(2-fluoro-5-((1 R ,4 R )-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-yl) -4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(185) N -(3-(3,3-difluoropyrrolidin-1-yl)-5-(( R )-pyrrolidin-3-yl)phenyl)-4-(( S )- 3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(186) N -(3-(3,3-difluoropyrrolidin-1-yl)-5-(( S )-pyrrolidin-3-yl)phenyl)-4-(( S )- 3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(187) ( S ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-morpholinophenyl)-4-(3-phenylisoxazolidine -2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(188) ( S ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)p peridin-1-yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(189) ( R ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-morpholinophenyl)-4-(3-phenylisoxazolidine -2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(190) ( R ) -N- (2-methoxy-5-(1-methyl-1 H -pyrazol-4-yl)-4-(4-(4-methylpiperazin-1-yl)pi peridin-1-yl)phenyl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(191) ( S )-2-fluoro- N- (1-isopropylpiperidin-4-yl)-5-methoxy-4-((4-(3-phenylisoxazolidine-2- yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide;
(192) N- (3-cyclopropyl-5-((( 3S,5R)-3,5-dimethylpiperazin-1-yl)methyl)phenyl)-4-((S ) -3- phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(193) ( S ) -N- (1-(methylsulfonyl)piperidin-4-yl)-4-(3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(194) ( S ) -N- (1-isopropylpiperidin-4-yl)-4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
(195) (3S, 4S )-1-(methylsulfonyl)-4-((4-(( S )-3- phenylisoxazolidin -2-yl)-5-(trifluoromethyl) )pyrimidin-2-yl)amino)piperidin-3-ol;
(196) ( 3R , 4R )-1-(methylsulfonyl)-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) )pyrimidin-2-yl)amino)piperidin-4-ol;
(197) tert -butyl ( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) piperidine-1-carboxylate;
(198) tert -butyl ( S )-4-((4-(3-phenylisooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine -1-carboxylate;
(199) tert -butyl ( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) pyrrolidine-1-carboxylate;
(200) tert -butyl ( R )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) pyrrolidine-1-carboxylate;
(201) 4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( S )-piperidin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
(202) ( S )-4-(3- phenylisooxazolidin -2-yl)-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(203) 4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( S )-pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
(204) 4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( R )-pyrrolidin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
(205) 3-(( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )pyrrolidin-1-yl)propan-1-ol;
(206) tert -butyl ( R )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino ) piperidine-1-carboxylate;
(207) 1-(( S )-3-((4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )piperidin-1-yl)ethan-1-one;
(208) 4-(( S )-3-phenylisoxazolidin-2-yl) -N -(( R )-piperidin-3-yl)-5-(trifluoromethyl)pyrimidine- 2-amine;
(209) N -(( S )-1-methylpiperidin-3-yl)-4-(( S )-3-phenylisoxazolidin-2-yl)-5-(trifluoromethyl) pyrimidin-2-amine;
(210) ( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-(3- methoxyphenyl)isooxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(211) ( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-(pyridine- 3-yl)isoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(212) ( S )-4-(3-(3-fluorophenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpiperazine-1) -yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine;
(213) ( S )-4-(3-(4-fluorophenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpiperazine-1) -yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine;
(214) ( S )-4-(3-(2,6-difluorophenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpipette) Razin-1-yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine;
(215) ( S )-4-(3-(3-(dimethylamino)phenyl)isoxazolidin-2-yl) -N- (3-methoxy-4-(4-(4-methylpipette) Razin-1-yl)piperidin-1-yl)phenyl)-5-(trifluoromethyl)pyrimidin-2-amine;
(216) ( S )-3-(2-(2-((3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino) -5-(trifluoromethyl)pyrimidin-4-yl)isooxazolidin-3-yl)benzonitrile;
(217) ( S ) -N- (3-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)-4-(3-(3- phenoxyphenyl)isoxazolidin-2-yl)-5-(trifluoromethyl)pyrimidin-2-amine;
(218) ( S )-3-(2-(2-((1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-5-(trifluoromethyl)pyrimidin-4- day) isoxazolidin-3-yl) benzonitrile;
(219) ( S )-4-(3-phenylisooxazolidin-2-yl)-2-((3,4,5-trimethoxyphenyl)amino)pyrimidine-5-carbonitrile;
(220) ( S )-2-((4-(2-(diethylamino)ethoxy)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-5-carbonite reel;
(221) ( S )-2-((4-(2-(diethylamino)ethoxy)-3,5-dimethylphenyl)amino)-4-(3-phenylisoxazolidin-2-yl) pyrimidine-5-carbonitrile;
(222) ( S )-2-((4-(3-(diethylamino)propoxy)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-5-carbonite reel;
(223) ( S )-2-((4-(3-(diethylamino)propoxy)-3,5-dimethylphenyl)amino)-4-(3-phenylisoxazolidin-2-yl) pyrimidine-5-carbonitrile;
(224) ( S )-2-((4-(3-(diethylamino)propoxy)-3,5-difluorophenyl)amino)-4-(3-phenylisoxazolidine-2- I) pyrimidine-5-carbonitrile;
(225) ( R )-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-5-carbonite reel;
(226) ( R )-2-((4-(3-(diethylamino)propoxy)-3,5-dimethylphenyl)amino)-4-(3-phenylisoxazolidin-2-yl) pyrimidine-5-carbonitrile;
(227) ( S )-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-4-(3-phenylisoxazolidine -2-yl)pyrimidine-5-carbonitrile;
(228) ( S )-2-((3,5-dimethyl-4-(3-(pyrrolidin-1-yl)propoxy)phenyl)amino)-4-(3-phenylisoxazolidine -2-yl)pyrimidine-5-carbonitrile;
(229) ( S )-2-((3,5-dimethyl-4-(3-(piperidin-1-yl)propoxy)phenyl)amino)-4-(3-phenylisoxazolidine -2-yl)pyrimidine-5-carbonitrile;
(230) ( S )-2-((3,5-dimethyl-4-(3-morpholinopropoxy)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine -5-carbonitrile;
(231) ( S )-2-((3,5-dimethyl-4-(3-(4-methylpiperazin-1-yl)propoxy)phenyl)amino)-4-(3-phenylisooxa zolidin-2-yl)pyrimidine-5-carbonitrile;
(232) ( S )-4-(3-phenylisoxazolidin-2-yl)-2-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino) pyrimidine-5-carbonitrile;
(233) ( S )-2-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4-(3-phenylisoxazolidin-2-yl)pyrimidine-5-carbonite reel;
(234) ( S )-4-(3-phenylisooxazolidin-2-yl)-2-((1,2,3,4-tetrahydroisoquinolin-6-yl)amino)pyrimidine-5 -carbonitrile;
(235) ( S )-5-(3,6-dihydro-2H-pyran-4-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3- phenylisooxazolidin-2-yl)pyrimidin-2-amine;
(236) ( S )-5-(cyclohexane-1- en -1-yl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-4-(3-phenylisoxazoli din-2-yl)pyrimidin-2-amine;
(237) ( S )-5-(1-methyl- 1H -pyrazol-4-yl)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenyl) isoxazolidin-2-yl)pyrimidin-2-amine;
(238) ( S )-5-(furan-3-yl)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl ) pyrimidin-2-amine;
(239) ( S )-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidin-2-yl)-5-(pyridin-3-yl) ) pyrimidin-2-amine; and
(240) ( S )-5-(6-fluoropyridin-3-yl)-N-(4-(4-methylpiperazin- 1 -yl)phenyl)-4-(3-phenylisoxazolidine -2-yl)pyrimidin-2-amine.

제 1 항 내지 제 7 항 중 어느 하나의 항에 따른 화합물, 이의 광학 이성질체, 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는, 암의 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating cancer, comprising the compound according to any one of claims 1 to 7, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

제 8 항에 있어서,
CDK2, CDK4, CDK6, 및/또는 HKP1을 억제하는 것인, 약학적 조성물.9. The method of claim 8,
A pharmaceutical composition that inhibits CDK2, CDK4, CDK6, and/or HKP1.

제 8 항에 있어서,
상기 암은 가성점액종, 간내 담도암, 간모세포종, 간암, 갑상선암, 결장암, 고환암, 골수이형성증후군, 교모세포종, 구강암, 구순암, 균상식육종, 급성골수성백혈병, 급성림프구성백혈병, 기저세포암, 난소상피암, 난소생식세포암, 남성유방암, 뇌암, 뇌하수체선종, 다발성골수종, 담낭암, 담도암, 대장암, 만성골수성백혈병, 만성림프구백혈병, 망막모세포종, 맥락막흑색종, 바터팽대부암, 방광암, 복막암, 부갑상선암, 부신암, 비부비동암, 비소세포폐암, 설암, 성상세포종, 소세포폐암, 소아뇌암, 소아림프종, 소아백혈병, 소장암, 수막종, 식도암, 신경교종, 신우암, 신장암, 심장암, 십이지장암, 악성 연부조직 암, 악성골암, 악성림프종, 악성중피종, 악성흑색종, 안암, 외음부암, 요관암, 요도암, 원발부위불명암, 위림프종, 위암, 위유암종, 위장관간질암, 윌름스암, 유방암, 육종, 음경암, 인두암, 임신융모질환, 자궁경부암, 자궁내막암, 자궁육종, 전립선암, 전이성 골암, 전이성뇌암, 종격동암, 직장암, 직장유암종, 질암, 척수암, 청신경초종, 췌장암, 침샘암, 카포시 육종, 파제트병, 편도암, 편평상피세포암, 폐선암, 폐암, 폐편평상피세포암, 피부암, 항문암, 횡문근육종, 후두암, 흉막암, 혈액암, 및 흉선암으로 이루어진 군으로부터 선택되는 1종 이상인, 약학적 조성물.
9. The method of claim 8,
The cancer is pseudomyxoma, intrahepatic biliary tract cancer, hepatoblastoma, liver cancer, thyroid cancer, colon cancer, testicular cancer, myelodysplastic syndrome, glioblastoma, oral cancer, labial cancer, mycosis fungoides, acute myeloid leukemia, acute lymphoblastic leukemia, basal cell carcinoma, Ovarian epithelial cancer, ovarian germ cell cancer, male breast cancer, brain cancer, pituitary adenoma, multiple myeloma, gallbladder cancer, biliary tract cancer, colorectal cancer, chronic myelogenous leukemia, chronic lymphocytic leukemia, retinoblastoma, choroidal melanoma, ampulla Barter cancer, bladder cancer, peritoneal cancer ; Duodenal cancer, malignant soft tissue cancer, malignant bone cancer, lymphoma malignant, mesothelioma malignant, melanoma, eye cancer, vulvar cancer, ureter cancer, urethral cancer, cancer of unknown primary site, gastric lymphoma, gastric cancer, gastric carcinoma, gastrointestinal stromal cancer, Wilm Cancer, breast cancer, sarcoma, penile cancer, pharyngeal cancer, gestational chorionic disease, cervical cancer, endometrial cancer, uterine sarcoma, prostate cancer, metastatic bone cancer, metastatic brain cancer, mediastinal cancer, rectal cancer, rectal carcinoma, vaginal cancer, spinal cord cancer, acoustic schwannoma , pancreatic cancer, salivary gland cancer, Kaposi's sarcoma, Paget's disease, tonsil cancer, squamous cell carcinoma, lung adenocarcinoma, lung cancer, lung squamous cell carcinoma, skin cancer, anal cancer, rhabdomyosarcoma, laryngeal cancer, pleural cancer, hematological cancer, and thymus At least one selected from the group consisting of cancer, a pharmaceutical composition.