KR20150037207A - Pyrimidine compounds having inhibitory activity on fms kinase - Google Patents

Pyrimidine compounds having inhibitory activity on fms kinase Download PDF

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KR20150037207A
KR20150037207A KR20130116609A KR20130116609A KR20150037207A KR 20150037207 A KR20150037207 A KR 20150037207A KR 20130116609 A KR20130116609 A KR 20130116609A KR 20130116609 A KR20130116609 A KR 20130116609A KR 20150037207 A KR20150037207 A KR 20150037207A
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methyl
alkyl
pyrimidin
indazol
cancer
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방극찬
박창희
김서희
함영진
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한미약품 주식회사
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Abstract

A compound selected from a pyrimidine compound represented by chemical formula 1, pharmaceutically acceptable salt thereof, an optical isomer, a hydrate, and a solvate has enhanced inhibitory activities on FMS kinase, therefore a pharmaceutical composition comprising the same has enhanced preventing or treating effects on immune disorders, metabolic diseases, and inflammatory diseases, and cancer which are caused by the FMS kinase. In the chemical formula 1, A, Z, R_1, R_2, R_3, and R_11 are defined as in the specification.

Description

FMS 키나아제 저해 활성을 갖는 피리미딘 화합물{PYRIMIDINE COMPOUNDS HAVING INHIBITORY ACTIVITY ON FMS KINASE}PYRIMIDINE COMPOUNDS HAVING INHIBITORY ACTIVITY ON FMS KINASE}

본 발명은 FMS 키나아제 저해 활성을 갖는 신규한 피리미딘 화합물 및 FMS 키나아제에 기인하는 질환의 예방 및 치료용 약학적 조성물에 관한 것이다.
The present invention relates to a novel pyrimidine compound having FMS kinase inhibitory activity and a pharmaceutical composition for the prophylaxis and treatment of diseases caused by FMS kinase.

단백질 키나아제(protein kinase)는 단백질의 타이로신(tyrosine), 세린(serine) 또는 트레오닌(threonine) 잔기에 존재하는 하이드록시(hydroxy)기의 인산화(phosphorylation) 반응을 통한 세포내 신호전달 과정에서 중요한 역할을 담당 하는 효소로서, 세포의 성장, 분화 및 증식 등에 깊숙이 관여한다. Protein kinases play an important role in intracellular signaling through the phosphorylation of the hydroxy group present in the tyrosine, serine or threonine residues of proteins As an enzyme responsible, it is deeply involved in the growth, differentiation and proliferation of cells.

세포가 항상성을 유지하기 위해서는 세포 내 신호전달 과정의 켜짐과 꺼짐이 균형을 이루어야 한다. 그러나 특정 단백질 키나아제의 과발현 또는 돌연변이에 의해 정상적인 세포 내 신호전달 과정이 붕괴(주로 세포내 신호 전달이 계속되는 상태)되면 각종 암, 염증성 질환, 대사성 질환 또는 뇌질환 등 다양한 질병을 유발한다. 단백질 키나아제는 인간 전체 유전자의 약 1.7%에 해당하는 518종이 존재하는 것으로 추정되는데, 크게 타이로신 단백질 키나아제(90종 이상)와 세린/트레오닌 단백질 키나아제로 양분된다. 타이로신 단백질 키나아제는 20개의 아과(subtype)로 구분되는 58종의 수용체 타이로신 키나아제와 10개의 아과로 구분되는 32종의 세포질성/비수용체 타이로신 키나아제로 나눌 수 있다. 수용체 타이로신 키나아제는 세포 표면에 성장 인자(growth factor)를 수용할 수 있는 도메인과 세포질에 타이로신 잔기를 인산화시킬 수 있는 활성부위를 갖고 있다. 성장 인자가 세포 표면의 성장인자 수용체 자리에 결합되면, 수용체 타이로신 키나아제는 중합체를 형성하고, 세포질 내 활성부위 타이로신 잔기는 자가인산화 된다. 이후 하위 계열의 세포질성 단백질 키나아제들이 순차적으로 인산화 되면서 세포외 신호가 핵 안으로 전달되어 성장, 분화 및 증식 등에 관여하는 다양한 유전자들이 전사되고 합성된다. 이때 단백질 키나아제가 비정상적으로 과발현되거나 또는 돌연변이 등을 통해 비정상적으로 활성화되면 암과 같은 다양한 질병이 유발되는 것으로 알려져 있다. In order for cells to maintain homeostasis, the on and off of intracellular signaling processes must be balanced. However, the overexpression or mutation of a specific protein kinase leads to a variety of diseases such as various cancers, inflammatory diseases, metabolic diseases or brain diseases when the normal intracellular signal transduction process is collapsed (mainly intracellular signal transduction is continued). Protein kinase is presumed to contain 518 species, which accounts for about 1.7% of total human genes, and is largely divided into tyrosine protein kinases (over 90 species) and serine / threonine protein kinases. Tyrosine protein kinases can be divided into 20 subtypes, 58 receptor tyrosine kinases, and 10 subfamilies, 32 cytoplasmic / nonreceptor tyrosine kinases. Receptor tyrosine kinase has a domain capable of accepting a growth factor on the cell surface and an active site capable of phosphorylating a tyrosine residue in the cytoplasm. When the growth factor is bound to the growth factor receptor site on the cell surface, the receptor tyrosine kinase forms a polymer and the cytoplasmic active site tyrosine residue is autophosphorylated. Subsequently, the cytoplasmic protein kinases of the lower lineage are sequentially phosphorylated, and the extracellular signal is transferred into the nucleus to transcribe and synthesize various genes involved in growth, differentiation and proliferation. It is known that when protein kinase is overexpressed or abnormally activated through mutation, various diseases such as cancer are induced.

단백질 키나아제의 일종인 FMS(c-fms; cellular feline McDonough sarcoma)는 CSF-1R(colony-stimulating factor-1 receptor; 콜로니 자극 인자-1 수용체)라고도 하며, 고양이 육종 바이러스의 수잔 맥도너(Susan McDonough) 균주로부터 최초로 단리된 유전자 군의 일원이다. FMS는 M-CSF(macrophage-colony-stimulating factor; 대식세포 콜로니 자극 인자)에 대한 수용체로서, Kit, Flt-3 및 PDGFR와 함께 타입 III 수용체 타이로신 키나아제(class III RTK)로 분류되며, FMS 원발암유전자(c-fms proto-oncogene)에 의해 코딩된다. M-CSF는 CSF-1라고도 하며 쥐 동맥혈관 내피세포(RACE; RA endothelial cell)에서 활발히 발현될 수 있고 쥐 동맥혈관의 생물지표(biomarker)로도 유용하게 사용되는 물질이다.FMS (c-fms; cellular feline McDonough sarcoma), a protein kinase, is also known as CSF-1R (Colony-Stimulating Factor-1 Receptor), and Susan McDonough, It is a member of the first group of genes isolated from the strain. FMS is a receptor for macrophage-colony-stimulating factor (M-CSF) and is classified as a type III receptor tyrosine kinase (class III RTK) with Kit, Flt-3 and PDGFR, (C-fms proto-oncogene). M-CSF is also referred to as CSF-1 and can be actively expressed in rat endothelial cells (RACE) and is also useful as a biomarker of rat arterial blood vessels.

FMS 는 대식세포 및 파골세포의 확산, 생존, 분화 및 이동을 제어하는 단백질로서 다른 단백질과 함께 시너지 작용을 통해 대식 세포의 사이토카인(Cytokine)의 분비를 조절하며 선천성 면역(innate immunity)과 조직 성장 및 기능에 중요한 역할을 한다. FMS 는 특히 단핵백혈구(monocyte)가 대식세포로 활성화되고 파골세포로 분화하는 과정에 관여함으로써, 염증(inflammation) 및 골침식(bone erosion)에 중요한 역할을 한다. 구체적으로, 초기에 단핵백혈구의 FMS에 M-CSF가 결합되면 RANK(NF-κB의수용체활성인자)를 발현시킴으로써 양쪽성 분화가 가능한 전구체(bipotential precursor) 상태가 되고 확산이 이루어진다. 전구체는 발현된 RANK에 RANKL(RANK ligand)이 결합되지 않은 상태에서는 대식세포로서 활성화되어 TNF-α 및 IL-1β와 같은 염증성 사이토킨(inflammatory cytokine) 분비에 관여하고, M-CSF가 관여하여 RANKL이 결합되면 파골세포로 분화되어 골침식에 관여한다. 일반적으로 FMS는 관절 중의 활막(synovium) 내에서 발현이 제한되는 것으로 알려져 있다.FMS is a protein that controls the proliferation, survival, differentiation and migration of macrophages and osteoclasts. It regulates the secretion of macrophage cytokines through synergistic action with other proteins and regulates innate immunity and tissue growth And functions. FMS plays an important role in inflammation and bone erosion, in particular, by participating in monocyte-activated macrophage-activated and osteoclast differentiation processes. Specifically, when M-CSF is initially bound to the FMS of mononuclear leukocytes, RANK (a receptor activator of NF-κB) is expressed to become a bipotential precursor and diffuse. The precursor is activated as a macrophage when the RANKL (RANK ligand) is not bound to the expressed RANK and is involved in the inflammatory cytokine secretion such as TNF-α and IL-1β, and the M-CSF is involved and RANKL When combined, they are differentiated into osteoclasts and are involved in bone erosion. In general, FMS is known to be restricted in synovium within the joints.

이와 같은 FMS 키나아제는 면역성 질환, 대사성 질환, 염증성 질환, 또는 암에 관련되어 있으며, 구체적으로 류마티스 관절염(rheumatoid arthritis), 골다공증(osteoporosis), 크론병(Crohn's disease), 동맥경화증, 고지혈증, 폐암, 유방암, 전립선암 등이 이에 해당한다. Such FMS kinases are related to immune diseases, metabolic diseases, inflammatory diseases or cancers and specifically include rheumatoid arthritis, osteoporosis, Crohn's disease, arteriosclerosis, hyperlipidemia, lung cancer, breast cancer , And prostate cancer.

이 중 류마티스 관절염(rheumatoid arthritis)은 다발성 관절염을 특징으로 하는 원인 불명의 만성 염증성 질환으로서, 초기에는 관절을 싸고 있는 활막에 염증이 발생하지만 점차 주위의 연골과 뼈로 염증이 퍼져 관절의 파괴와 변형을 초래하게 된다. 손가락을 예로 들자면, 류마티스 관절염의 말기에는 엄지손가락의 일명 단추구멍 변형(boutonniere deformity of thumb), 중수지절 관절의 척골편향(ulnar deviation of metacarpophalangeal joint), 손가락의 백조 목 형태 변형(swan-neck deformity of fingers) 등이 발생하게 된다. Rheumatoid arthritis is a chronic inflammatory disease characterized by multiple arthritis. Initially, the synovial membrane surrounding the joint is inflamed, but inflammation spreads to surrounding cartilage and bones, causing destruction and deformation of joints. . For example, in the late phase of rheumatoid arthritis, a finger deformity of the thumb, a ulnar deviation of the metacarpophalangeal joint, and a swan-neck deformity of the finger fingers and so on.

류마티스 관절염 환자는 현재 전세계적 인구의 약 1%에 달하는 3천만명 정도인 것으로 파악되고, 20세에서 45세 성인 중 여성이 더욱 많은 것으로 알려져 있다. 류마티스 관절염 치료제 시장은 매년 성장세에 있으며, 예를 들어 TNF(tumor necrosis factor; 종양 괴사인자) 억제제, 비스테로이드성 진통소염제(NSAID), 급성염증유발인자(COX-2) 억제제, 항류마티스 제제(DMARD; disease-modifying antirheumatic drugs), 스테로이드성 제제 등으로 크게 구분된다. 이들 중 특히 TNF 억제제(anti-TNF) 시장은 2007년 137억 달러에서 2008년에 180억 달러로 급성장했고, DMARD 제제 시장은 2007년 25억 달러에서 2008년에 30억 달러로 성장세에 있다.Patients with rheumatoid arthritis are estimated to be about 30 million people, or about 1% of the world's population, and more women are among the 20 to 45 year olds. The market for the treatment of rheumatoid arthritis is growing annually. For example, it is known that TNF (tumor necrosis factor) inhibitors, nonsteroidal anti-inflammatory drugs (NSAID), acute inflammatory inducers (COX-2) disease-modifying antirheumatic drugs, and steroids. In particular, the market for TNF inhibitors (anti-TNF) has grown rapidly from $ 13.7 billion in 2007 to $ 18 billion in 2008 and the market for DMARDs is growing from $ 2.5 billion in 2007 to $ 3 billion in 2008.

류마티스 관절염의 치료에는 기본적으로 증세를 개선시켜 주는 항류마티스 제제(DMARD; disease-modifying antirheumatic drugs)가 처방된다. 류마티스 관절염의 치료에 사용되는 생물학적 제제로서는 1차적으로 TNF 억제제(anti-TNF)가 처방되는데, 현재 시판되는 것으로는 엔브렐(EnbrelTM; etanercept), 휴미라(HumiraTM; adalimumab), 레미케이드(RemicadeTM; infliximab), 및 심지아(CimziaTM; certolizumab)가 있고 이들은 MTX(methotrexate; 메소트렉세이트)와 병용 처방된다. 이와 같은 1차 처방이 실패할 경우, 영국 국립보건임상연구소(NICE)에서 추천하는 치료법에 따르면 2차적으로 리툭시맙(rituximab)이 MTX와 병용 처방된다. 이와 같은 2차 처방이 실패하거나 리툭시맙에 대한 부작용이 예상될 경우, TNF 억제제를 재처방하거나 3차적으로 아바타셉트(abatacept) 또는 토실리주맙(tocilizumab)을 MTX와 병용 처방하는 것이 고려된다.In the treatment of rheumatoid arthritis, disease-modifying antirheumatic drugs (DMARDs) are prescribed to improve symptoms. TNF inhibitors (anti-TNF) are prescribed primarily as biological agents used in the treatment of rheumatoid arthritis. Enbrel ( TM ), Humira ( TM ), adalimumab, Remicade TM infliximab), and the core O (Cimzia TM; is certolizumab) and these MTX (methotrexate; is prescribed methotrexate) and combined. If such a primary prescription fails, the recommended treatment in the National Institute of Health and Clinical Nutrition (NICE) is that rituximab is secondarily prescribed in combination with MTX. If such secondary regimens fail or are expected to have adverse effects on rituximab, it may be considered to prescribe TNF inhibitors or, in the third, to administer abatacept or tocilizumab in combination with MTX.

그러나, 상기와 같이 다양한 DMARD 제제와 생물학적 제제들이 존재함에도 불구하고 경구용 제제는 아직 개발되지 않은 상황이다. 따라서, 경구용 제제의 개발을 통해 약효의 증진이 필요한 실정이다.However, despite the existence of various DMARD and biological agents as described above, oral preparations have not yet been developed. Therefore, it is necessary to improve the drug efficacy through development of oral preparations.

D'Aura swanson, C. et al., tyrosine kinases as targets for the treatment of rheumatoid arthritis, Nat. Rev. Rheumatol. 5, pp.317-324 (2009) D'Aura swanson, C. et al., Tyrosine kinases as targets for treatment of rheumatoid arthritis, Nat. Rev. Rheumatol. 5, pp. 317-324 (2009) Fiona J. Pixley and E. Richard Stanley, CSF-1 regulation of the wandering macrophage: complexity in action, Trend in Cell Bio. 14(11) pp.628-638 (2004) Fiona J. Pixley and E. Richard Stanley, CSF-1 regulation of the wandering macrophage: complexity in action, Trend in Cell Bio. 14 (11) pp.628-638 (2004)

본 발명의 목적은 FMS 키나아제에 대한 저해 활성이 우수한 신규의 피리미딘 화합물을 제공하는 것이다.It is an object of the present invention to provide novel pyrimidine compounds having excellent inhibitory activity against FMS kinase.

본 발명의 다른 목적은 FMS 키나아제에 기인하는 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.It is another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of diseases caused by FMS kinase.

상기 목적에 따라, 본 발명은 하기 화학식 1의 피리미딘 화합물, 이의 약학적으로 허용가능한 염, 광학이성질체, 수화물 및 용매화물로부터 선택되는 화합물을 제공한다: To this end, the present invention provides a compound selected from the group consisting of pyrimidine compounds of formula (I), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:

화학식 1Formula 1

Figure pat00001
Figure pat00001

상기 식에서, In this formula,

A 는 =CH- 또는 =N-이고;A is = CH- or = N-;

Z 는 C6-12아릴, 5-12원의 헤테로아릴, 또는 5-12원의 헤테로사이클로알킬이고, 이때 상기 Z 는 할로겐, 하이드록시, 나이트로, 사이아노, 아미노, C1-6알킬, C1-6알콕시, C1-6알킬아미노C1-6알콕시, 다이C1-6알킬아미노C1-6알콕시, C1-6알킬아미노, C1-6알킬카보닐아미노, C1-6알킬아미노카보닐, C1-6알킬설피닐, C1-6알킬설포닐, C1-6알킬설포닐아미노, C1-6알킬아미노설포닐, R, -O-R, -(CH2)1-6-R, -(CH2)1-6-O-R 및 -C(=O)-R로 이루어진 군으로부터 선택된 1 내지 3개의 치환기로 치환될 수 있고; Z is C 6-12 aryl, 5-12 membered heteroaryl, or 5-12 membered heterocycloalkyl wherein Z is selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxy, di-C 1-6 alkylamino-C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl amino, C 1- 6-alkyl-amino-carbonyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl amino, C 1-6 alkyl aminosulfonyl, R, -OR, - (CH 2) 1-6- R, - (CH 2 ) 1-6 -OR, and -C (= O) -R;

R 은 5-12원의 헤테로사이클로알킬, 5-12원의 헤테로사이클로알켄일, C6-12아릴, 또는 5-12원의 헤테로아릴이고, 이때 상기 R 은 할로겐, 하이드록시, 아세틸, C1-6알킬, 하이드록시C1-6알킬, C1-6알콕시, C3-8사이클로알킬C1-6알킬, C1-6알킬아미노, 다이C1-6알킬아미노, t-부톡시카보닐, 및 5-6원의 헤테로사이클로알킬로 이루어진 군으로부터 선택된 1 내지 3개의 치환기로 치환될 수 있고;R is a 5-12 membered heterocycloalkyl, alkenyl heterocycloalkyl of 5-12 W, C 6-12 aryl, or a heteroaryl group of 5-12 W, wherein the R is a halogen, hydroxy, acetyl, C 1 -6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkylamino, di-C 1-6 alkylamino, t- butoxycarbonyl- ≪ RTI ID = 0.0 > 5-6 < / RTI > membered heterocycloalkyl;

R1 은 H, 할로겐, 또는 C1-10알킬이고;R 1 is H, halogen, or C 1-10 alkyl;

R2 는 H, 할로겐, C1-10알킬, C2-10알켄일, 또는 C3-10사이클로알킬이고;R 2 is H, halogen, C 1-10 alkyl, C 2-10 alkenyl, or C 3-10 cycloalkyl;

R3 는 H, C1-10알킬 또는 -(CH2)1-6-R4이고, 여기서 R4 는 C1-6알킬아미노, 다이C1-6알킬아미노, C1-6알콕시, C2-5알카인일, C3-10사이클로알킬, 5-12원의 헤테로사이클로알킬, C6-12아릴, 또는 5-12원의 헤테로아릴이며, 이때 상기 사이클로알킬, 헤테로사이클로알킬, 아릴 및 헤테로아릴은 각각 독립적으로 할로겐, 할로C1-6알킬, 나이트로, 사이아노, 카보닐아미노, 아미노카보닐, 설피닐, C1-6알킬, C1-6알킬아미노, C1-6알콕시, C1-6알킬설포닐, C1-6알킬설포닐아미노, C1-6알킬아미노설포닐, 페닐, C3-10사이클로알킬 및 5-6원의 헤테로사이클로알킬로 이루어진 군으로부터 선택된 1 내지 3개의 치환기로 치환될 수 있으며; R 3 is H, C 1-10 alkyl or - (CH 2 ) 1-6 -R 4 wherein R 4 is C 1-6 alkylamino, di C 1-6 alkylamino, C 1-6 alkoxy, C 2-5 alkynyl, C 3-10 cycloalkyl, and heteroaryl of 5-12 source of heterocycloalkyl, C 6-12 aryl, or 5-12 source, wherein said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each a halogen, halo C 1-6 alkyl, independently nitro, cyano, amino-carbonyl, aminocarbonyl, sulfinyl, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy , C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl amino, C 1-6 alkyl aminosulfonyl, phenyl, C 3-10 cycloalkyl, and 5-6 selected from the group consisting of alkyl heterocycloalkyl of circle 1 Lt; / RTI > to 3 substituents;

R11 은 H, C1-10알킬, C3-10사이클로알킬, 또는 -(CH2)1-6-N(R')2이고, 여기서 R'는 C1-10알킬 또는 C3-10사이클로알킬이고;R 11 is H, C 1-10 alkyl, C 3-10 cycloalkyl, or - (CH 2 ) 1-6 -N (R ') 2 wherein R' is C 1-10 alkyl or C 3-10 Cycloalkyl;

상기 헤테로아릴, 헤테로사이클로알킬 및 헤테로사이클로알켄일은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택된 1개 이상의 헤테로 원자를 포함한다.Wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl each independently comprise one or more heteroatoms selected from the group consisting of N, O, and S.

상기 다른 목적에 따라, 본 발명은 상기 화합물을 활성 성분으로 함유하는 약학적 조성물을 제공한다.According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the compound as an active ingredient.

본 발명의 화학식 1의 피리미딘 화합물, 이의 약학적으로 허용가능한 염, 광학이성질체, 수화물 또는 용매화물은 FMS 키나아제에 대한 저해 활성이 우수하므로, 이들 화합물 및 이를 포함하는 약학적 조성물은 FMS 키나아제에 기인하는 면역성 질환, 대사성 질환, 염증성 질환, 또는 암의 예방 또는 치료 효과가 우수하다.
Since the pyrimidine compound of the present invention, its pharmaceutically acceptable salt, optical isomer, hydrate or solvate thereof is excellent in inhibitory activity against FMS kinase, these compounds and the pharmaceutical composition containing the same are effective for inhibiting An immune disease, a metabolic disease, an inflammatory disease, or cancer.

이하, 본 발명을 보다 상세히 설명한다.
Hereinafter, the present invention will be described in more detail.

본 명세서에 사용되는 용어 '할로겐'은 다른 언급이 없으면, 불소, 염소, 브롬 또는 요오드를 의미한다. The term " halogen ", as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine.

본 명세서에 사용되는 용어 '알킬'은 다른 언급이 없으면, 직쇄형 또는 분지형의 탄화수소 잔기를 의미한다.The term " alkyl ", as used herein, unless otherwise indicated, refers to straight or branched hydrocarbon residues.

본 명세서에 사용되는 용어 '할로알킬'은 다른 언급이 없으면, 하나 이상의 할로겐으로 치환된 알킬을 의미한다. The term haloalkyl, as used herein, unless otherwise indicated, means alkyl substituted with one or more halogens.

본 명세서에 사용되는 용어 '사이클로알킬'은 다른 언급이 없으면 사이클로프로필, 사이클로부틸, 사이클로펜틸, 사이클로헥실 등을 포함한 환상 알킬을 나타내며, 모노사이클릭 또는 바이사이클릭 이상의 환상 알킬도 가능하다. The term " cycloalkyl ", as used herein, unless otherwise indicated, refers to cyclic alkyl including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and cyclic alkyls over monocyclic or bicyclic are possible.

본 명세서에 사용되는 용어 '아릴'은 다른 언급이 없으면 페닐, 나프틸 등을 포함하는 방향족 그룹을 나타낸다.The term " aryl ", as used herein, unless otherwise indicated, refers to an aromatic group including phenyl, naphthyl, and the like.

본 명세서에 사용되는 용어 '헤테로사이클로알킬'은 다른 언급이 없으면 O, N 및 S 중에서 선택된 1개 이상의 헤테로 원자를 함유하는 모노사이클릭 또는 바이사이클릭 이상의 환상 알킬을 나타낸다. 모노사이클릭 헤테로사이클로알킬의 예로는 피페리딘일, 모폴린일, 싸이아모폴린일, 피롤리딘일, 이미다졸리딘일, 테트라하이드로퓨란일, 피페라진일 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.The term " heterocycloalkyl ", as used herein, unless otherwise indicated, refers to a monocyclic or bicyclic cyclic alkyl containing one or more heteroatoms selected from O, N, and S. Examples of monocyclic heterocycloalkyl include, but are not limited to, piperidinyl, morpholinyl, thiamorpholinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, piperazinyl and similar groups. It is not.

본 명세서에 사용되는 용어 '헤테로사이클로알켄일'은 다른 언급이 없으면 헤테로사이클로알킬의 고리를 이루는 하나 이상의 결합이 이중결합을 형성하되 비방향성인 것을 나타내며, 예를 들어 테트라하이드로피리딘일을 들 수 있다.The term " heterocycloalkenyl ", as used herein, unless otherwise indicated, indicates that at least one bond forming a ring of heterocycloalkyl forms a double bond but is non-aromatic, such as tetrahydropyridinyl .

본 명세서에 사용되는 용어 '헤테로아릴'은 다른 언급이 없으면 O, N 및 S 중에서 선택된 1개 이상의 헤테로원자를 함유하는 모노사이클릭 또는 바이사이클릭 이상의 방향족 그룹을 의미한다. 모노사이클릭 헤테로아릴의 예로는 싸이아졸릴, 옥사졸릴, 싸이오펜일, 퓨란일, 피롤릴, 이미다졸릴, 아이소옥사졸릴, 피라졸릴, 트라이아졸릴, 싸이아다이아졸릴, 테트라졸릴, 옥사다이아졸릴, 피리딘일, 피리다진일, 피리미딘일, 피라진일 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다. 바이사이클릭 헤테로아릴의 예로는 인돌릴, 벤조싸이오펜일, 벤조퓨란일, 벤즈이미다졸릴, 벤즈옥사졸릴, 벤즈이속사졸릴, 벤즈싸이아졸릴, 벤즈싸이아다이아졸릴, 벤즈트라이아졸릴, 퀴놀린일, 아이소퀴놀린일, 퓨린일, 퓨로피리딘일 및 이와 유사한 그룹을 들 수 있으나 이들로 제한되는 것은 아니다.
The term " heteroaryl ", as used herein, unless otherwise indicated, refers to a monocyclic or bicyclic or higher aromatic group containing one or more heteroatoms selected from O, N and S. Examples of monocyclic heteroaryl include thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, imidazolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, But are not limited to, pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, and similar groups. Examples of bicyclic heteroaryl include indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiazolyl, benzthiazolyl, quinolyl Pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl, pyrimidinyl,

이하, 본 발명의 화학식 1의 화합물에 대해 구체적으로 설명한다.
Hereinafter, the compound of formula (I) of the present invention will be described in detail.

상기 화학식 1의 화합물의 일례에 있어서, 상기 A 가 =N-일 수 있다.
In one example of the compound of Formula 1, A may be = N-.

상기 화학식 1의 화합물의 다른 예에 있어서, In another example of the compound of Formula 1,

상기 A 가 =N-이고;Wherein A is = N-;

상기 Z 가 C6-10아릴, 5-10원의 헤테로아릴, 또는 5-10원의 헤테로사이클로알킬이고, 이때 상기 Z 는 할로겐, 하이드록시, 나이트로, 사이아노, 아미노, C1-6알킬, C1-3알콕시, C1-6알킬아미노, C1-6알킬설피닐, C1-6알킬설포닐, R, -O-R, -(CH2)1-6-O-R 및 -C(=O)-R로 이루어진 군으로부터 선택된 1 또는 2개의 치환기로 치환될 수 있고; Wherein Z is C 6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl wherein Z is selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C 1-6 alkyl , C 1-3 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, R, -OR, - (CH 2) 1-6 -OR and -C (= O) -R < / RTI >;

상기 R 이 5-10원의 헤테로사이클로알킬, 5-10원의 헤테로사이클로알켄일, C6-10아릴, 또는 5-10원의 헤테로아릴이고, 이때 상기 R 은 할로겐, 하이드록시, 아세틸, C1-6알킬, 하이드록시C1-6알킬, C1-6알콕시, C3-8사이클로알킬C1-6알킬, C1-6알킬아미노, 다이C1-6알킬아미노, t-부톡시카보닐, 및 5-6원의 헤테로사이클로알킬로 이루어진 군으로부터 선택된 1 또는 2개의 치환기로 치환될 수 있고;Wherein R is 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein R is selected from the group consisting of halogen, hydroxy, acetyl, C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkylamino, di-C 1-6 alkylamino, t- butoxycarbonyl Carbonyl, and 5-6 membered heterocycloalkyl; < RTI ID = 0.0 > R < / RTI >

상기 R1 이 H, 할로겐, 또는 C1-6알킬이고; Wherein R 1 is H, halogen, or C 1-6 alkyl;

상기 R2 가 C1-8알킬, C2-8알켄일, 또는 C3-8사이클로알킬이고; Wherein R 2 is C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl;

상기 R3 이 C1-8알킬 또는 -(CH2)1-6-R4이고, 여기서 R4 는 C3-8사이클로알킬, 5-10원의 헤테로사이클로알킬, C6-10아릴, 또는 5-10원의 헤테로아릴이고, 상기 R4 는 할로겐, C1-6알킬, 또는 C1-6알콕시로 치환될 수 있으며; Wherein R 3 is C 1-8 alkyl or - (CH 2 ) 1-6 -R 4 wherein R 4 is C 3-8 cycloalkyl, 5-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, and R < 4 > may be substituted with halogen, C1-6 alkyl, or C1-6 alkoxy;

상기 R11 이 H, C1-8알킬 또는 C3-8사이클로알킬이고; Wherein R 11 is H, C 1-8 alkyl or C 3-8 cycloalkyl;

상기 헤테로아릴, 헤테로사이클로알킬 및 헤테로사이클로알켄일은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택된 1 내지 3개의 헤테로 원자를 포함할 수 있다.
The heteroaryl, heterocycloalkyl and heterocycloalkenyl may each independently comprise 1 to 3 heteroatoms selected from the group consisting of N, O,

상기 화학식 1의 화합물의 또 다른 예에 있어서,In another example of the compound of Formula 1,

상기 A 가 =N-이고;Wherein A is = N-;

상기 Z 가 C6-12아릴 또는 5-6원의 헤테로아릴이고, 이때 상기 Z 는 할로겐, 하이드록시, 나이트로, 사이아노, 아미노, C1-6알킬, C1-3알콕시, R, -O-R, -(CH2)1-3-O-R 및 -C(=O)-R로 이루어진 군으로부터 선택된 1 또는 2개의 치환기로 치환되고; Wherein Z is C 6-12 aryl or 5-6 membered heteroaryl wherein Z is selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C 1-6 alkyl, C 1-3 alkoxy, oR, - substituted with (CH 2) 1-3 -OR and -C (= O) 1 or 2 substituents selected from the group consisting of -R and;

상기 R 이 5-6원의 헤테로사이클로알킬, 5-6원의 헤테로사이클로알켄일, 또는 5-6원의 헤테로아릴이고, 이때 상기 R 은 하이드록시, 아세틸, C1-6알킬, 하이드록시C1-6알킬, C3-8사이클로알킬C1-6알킬, 다이C1-6알킬아미노, t-부톡시카보닐, 또는 5-6원의 헤테로사이클로알킬로 치환될 수 있고;Wherein R is 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl, wherein R is hydroxy, acetyl, C1-6alkyl , hydroxyC C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl, di C 1-6 alkylamino, t-butoxycarbonyl, or 5-6 membered heterocycloalkyl;

상기 R1 이 H 또는 C1-3알킬이고; Wherein R 1 is H or C 1-3 alkyl;

상기 R2 가 C1-6알킬 또는 C3-8사이클로알킬이고; Wherein R 2 is C 1-6 alkyl or C 3-8 cycloalkyl;

상기 R3 이 C1-8알킬 또는 -(CH2)1-3-R4이고, 여기서 R4 는 C3-8사이클로알킬, C6-10아릴, 또는 5-6원의 헤테로아릴이고, 상기 R4 는 할로겐, C1-6알킬, 또는 C1-6알콕시로 치환될 수 있으며; Wherein R 3 is C 1-8 alkyl or - (CH 2 ) 1-3 -R 4 wherein R 4 is C 3-8 cycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl, R 4 may be substituted with halogen, C 1-6 alkyl, or C 1-6 alkoxy;

상기 R11 이 H, C1-6알킬, 또는 C3-6사이클로알킬이고; Wherein R 11 is H, C 1-6 alkyl, or C 3-6 cycloalkyl;

상기 헤테로아릴, 헤테로사이클로알킬 및 헤테로사이클로알켄일은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택된 1 또는 2개의 헤테로 원자를 포함할 수 있다.
The heteroaryl, heterocycloalkyl and heterocycloalkenyl may each independently comprise one or two heteroatoms selected from the group consisting of N, O and S.

상기 화학식 1의 화합물의 또 다른 예에 있어서,In another example of the compound of Formula 1,

상기 A 가 =N-이고;Wherein A is = N-;

상기 Z 가 페닐 또는 피라졸릴이고, 이때 상기 Z 는 할로겐, C1-3알콕시, R, -O-R, -(CH2)1-3-O-R 및 -C(=O)-R로 이루어진 군으로부터 선택된 1 또는 2개의 치환기로 치환되고; Wherein Z is phenyl or pyrazolyl, wherein Z is selected from the group consisting of halogen, C 1-3 alkoxy, R, -OR, - (CH 2 ) 1-3 -OR and -C (= O) -R 1 or 2 substituents;

상기 R 이 N 및 O 중에서 선택된 1 또는 2개의 헤테로원자를 함유하는 5-6원의 헤테로사이클로알킬 또는 헤테로사이클로알켄일이고, 이때 상기 R 은 하이드록시, 아세틸, C1-6알킬, 하이드록시C1-6알킬, C3-8사이클로알킬C1-3알킬, 다이C1-3알킬아미노, t-부톡시카보닐, 또는 피롤리딘일로 치환될 수 있고; Wherein R is 5-6 membered heterocycloalkyl or heterocycloalkenyl containing 1 or 2 heteroatoms selected from N and O, wherein R is selected from the group consisting of hydroxy, acetyl, C1-6alkyl , hydroxyC C 1-6 alkyl, C 3-8 cycloalkyl C 1-3 alkyl, di C 1-3 alkylamino, t-butoxycarbonyl, or pyrrolidinyl;

상기 R1 이 H이고; Wherein R < 1 > is H;

상기 R2 가 C1-3알킬 또는 C3-6사이클로알킬이고; Wherein R < 2 > is C 1-3 alkyl or C 3-6 cycloalkyl;

상기 R3 이 C1-6알킬 또는 -(CH2)1-3-R4이고, 여기서 R4 는 C3-8사이클로알킬, 페닐, 또는 S 및 N 중 적어도 하나를 함유하는 5-6원의 헤테로아릴이고, 상기 R4는 할로겐, C1-3알킬, 또는 C1-3알콕시로 치환될 수 있으며; Wherein R 3 is C 1-6 alkyl or - (CH 2 ) 1-3 -R 4 wherein R 4 is C 3-8 cycloalkyl, phenyl, or a 5-6 membered ring containing at least one of S and N And R < 4 > may be substituted with halogen, C1-3 alkyl, or C1-3 alkoxy;

상기 R11 이 H 또는 C1-3알킬일 수 있다.
The R 11 may be H or C 1-3 alkyl.

본 발명에 따르는 피리미딘 화합물의 바람직한 예는 다음과 같으며, 이의 약학적으로 허용 가능한 염, 광학이성질체, 수화물 및 용매화물도 본 발명의 범주에 포함된다: Preferred examples of pyrimidine compounds according to the present invention are as follows, and pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof are also included in the scope of the present invention:

1) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;1) Methyl-3- (3-methyl-1 - ((6-methylpiperazin-1 -yl) Pyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

2) 3-(1-((6-에톡시피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-일)-1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸유레아;2) Synthesis of 3- (1 - ((6-ethoxypyridin-2-yl) methyl) -3-methyl-1H-indazol- -1-yl) phenylamino) pyrimidin-4-yl) -1-methylurea;

3) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-(3-메톡시벤질)-3-메틸-1H-인다졸-4-일)-1-메틸유레아;3) Preparation of 1- (6- (4- (4-ethylpiperazin-1-yl) phenylamino) pyrimidin- -Indazol-4-yl) -1-methylurea;

4) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(1-메틸피페리딘-4-일)페닐아미노)피리미딘-4-일)유레아;4) Synthesis of 1-methyl-3- (3-methyl-1- (6-methylpyridin- Methylpiperidin-4-yl) phenylamino) pyrimidin-4-yl) urea;

5) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-((6-플루오로피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-일)-1-메틸유레아;5) Preparation of 1- (6- (4- (4-ethylpiperazin-1-yl) phenylamino) pyrimidin- ) -3-methyl-1H-indazol-4-yl) -1-methylurea;

6) 1-(6-(4-(4-아이소프로필피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;6) 1- (6- (4- (4-Isopropylpiperazin-1-yl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

7) 1-(6-(4-(4-(사이클로프로필메틸)피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;7) Preparation of 1- (6- (4- (4- (cyclopropylmethyl) piperazin-1-yl) phenylamino) pyrimidin- (6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

8) 1-(6-(4-(4-(다이메틸아미노)피페리딘-1-일)-2-메톡시페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;8) Preparation of 1- (6- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenylamino) pyrimidin- Methyl-1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

9) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;9) 1- (6- (4- (4-Ethylpiperazin-1-yl) phenylamino) pyrimidin- Yl) methyl) -1H-indazol-4-yl) urea;

10) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-((6-메톡시피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-일)-1-메틸유레아;10) 1- (6- (4- (4-Ethylpiperazin-1-yl) phenylamino) pyrimidin- ) -3-methyl-1H-indazol-4-yl) -1-methylurea;

11) 3-(1-(사이클로헥실메틸)-3-메틸-1H-인다졸-4-일)-1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸유레아;11) Preparation of 3- (1- (cyclohexylmethyl) -3-methyl-1H-indazol-4-yl) 4-yl) -1-methylurea;

12) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-((2-아이소프로필싸이아졸-4-일)메틸)-3-메틸-1H-인다졸-4-일)-1-메틸유레아;12) 1- (6- (4- (4-Ethylpiperazin-1-yl) phenylamino) pyrimidin- Methyl) -3-methyl-1H-indazol-4-yl) -1-methylurea;

13) tert-부틸 4-(4-(6-(1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레이도)피리미딘-4-일아미노)페닐)피페라진-1-카복실레이트;13) tert-Butyl 4- (4- (6- (1 -methyl-3- (3-methyl- Yurido) pyrimidin-4-ylamino) phenyl) piperazine-1-carboxylate;

14) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(피페라진-1-일)페닐아미노)피리미딘-4-일)유레아;14) Preparation of l-methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) Yl) phenylamino) pyrimidin-4-yl) urea;

15) 1-(6-(4-(4-(2-하이드록시에틸)피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;15) 1- (6- (4- (4- (2-Hydroxyethyl) piperazin-1-yl) phenylamino) pyrimidin- - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

16) 3-(3-사이클로프로필-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸유레아;16) 3- (3-Cyclopropyl-l- (6-methylpyridin-2-yl) methyl) -lH-indazol- -1-yl) phenylamino) pyrimidin-4-yl) -1-methylurea;

17) 1-(6-(4-(4-아세틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;17) 1- (6- (4- (4-Acetylpiperazin-1-yl) phenylamino) pyrimidin- Pyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

18) 1-(6-(4-(4-에틸피페라진-1-카보닐)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;18) 1- (6- (4- (4-Ethylpiperazine-1-carbonyl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

19) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(4-메틸피페라진-1-카보닐)페닐아미노)피리미딘-4-일)유레아;19) 1-Methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) Methylpiperazine-1-carbonyl) phenylamino) pyrimidin-4-yl) urea;

20) 1-(6-(4-(4-(다이메틸아미노)피페리딘-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;20) 1- (6- (4- (4- (dimethylamino) piperidin-l-yl) phenylamino) pyrimidin- ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

21) 1-(6-(2-메톡시-4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;21) Preparation of 1- (6- (2-methoxy-4- (4- (pyrrolidin- 1 -yl) piperidin- 1- yl) phenylamino) pyrimidin- 3- (3-Methyl-1 - ((6-methylpyridin-2-yl) methyl) -1 H-indazol-4-yl) urea;

22) 1-(6-(2-메톡시-4-모폴리노페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;22) 1- (6- (2-Methoxy-4-morpholinophenylamino) pyrimidin- Yl) methyl) -lH-indazol-4-yl) urea;

23) 1-(6-(2-메톡시-4-(1-메틸피페리딘-4-일옥시)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;23) 1- (6- (2-Methoxy-4- (1- methylpiperidin-4-yloxy) phenylamino) pyrimidin- 1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

24) 1-(6-(4-(4-에틸피페라진-1-일)-3-플루오로페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;24) 1- (6- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenylamino) pyrimidin- ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

25) 1-에틸-1-(6-(4-(4-에틸피페라진-1-일)-3-플루오로페닐아미노)피리미딘-4-일)-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;25) A mixture of 1-ethyl-1- (6- (4- (4-ethylpiperazin-1-yl) -3-fluorophenylamino) pyrimidin- ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

26) 4-(6-(3-(1-아이소부틸-3-메틸-1H-인다졸-4-일)-1-메틸유레이도)피리미딘-4-일아미노)-3-메톡시-N-(1-메틸피페리딘-4-일)벤즈아마이드;26) 4- (6- (3- (1-isobutyl-3-methyl-1H-indazol- N- (1-methylpiperidin-4-yl) benzamide;

27) 3-메톡시-4-(6-(1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레이도)피리미딘-4-일아미노)-N-(1-메틸피페리딘-4-일)벤즈아마이드; 27) 3-Methoxy-4- (6- (1-methyl-3- (3- methyl- Yl) pyrimidin-4-ylamino) -N- (1-methylpiperidin-4-yl) benzamide;

28) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일아미노)피리미딘-4-일)유레아;28) l-Methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) Methylpiperidin-4-yl) -1H-pyrazol-4-ylamino) pyrimidin-4-yl) urea;

29) 1-메틸-1-(6-(4-(1-메틸-1,2,3,6-테트라하이드로피리딘-4-일)페닐아미노)피리미딘-4-일)-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;29) 1-Methyl-1- (6- (4- (1-methyl-1,2,3,6-tetrahydropyridin-4- yl) phenylamino) pyrimidin- Methyl-1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;

30) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(2-모폴리노에톡시)페닐아미노)피리미딘-4-일)유레아; 및30) 1-Methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) Morpholinoethoxy) phenylamino) pyrimidin-4-yl) urea; And

31) 1-(6-(4-(4-하이드록시피페리딘-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아.
31) 1- (6- (4- (4-Hydroxypiperidin-1-yl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea.

본 발명은 또한 상기 화학식 1로 표시되는 피리미딘 화합물의 약학적으로 허용 가능한 염을 제공한다. 약학적으로 허용된 염은 인체에 독성이 낮고 모화합물의 생물학적 활성과 물리화학적 성질에 악영향을 주지 않아야 한다. 약학적으로 허용된 염은 약학적으로 사용 가능한 유리산과 화학식 1의 염기 화합물의 산부가염, 알칼리 금속염(나트륨염 등)과 알칼리 토금속염(칼슘염 등), 유기염기와 화학식 1의 카복실산의 유기염기부가염, 아미노산부가염 등이 가능하다. The present invention also provides a pharmaceutically acceptable salt of the pyrimidine compound represented by the formula (1). Pharmacologically acceptable salts should be low in toxicity to humans and should not adversely affect the biological activity and physicochemical properties of the parent compound. Pharmaceutically acceptable salts include salts of acid addition salts, alkali metal salts (such as sodium salts) and alkaline earth metal salts (such as calcium salts) of pharmaceutically acceptable free acids and base compounds of formula (I), organic bases of carboxylic acids of formula Addition salts, amino acid addition salts, and the like.

본 발명에 따르는 화합물의 바람직한 염의 형태로는 무기산 또는 유기산과의 염을 들 수 있다. 이 때, 무기산은 염산, 황산, 질산, 인산, 과염소산, 브롬산 등이 사용될 수 있다. 또한, 유기산은 초산, 메탄설폰산, 에탄설폰산, p-톨루엔설폰산, 푸마린산, 말레산, 말론산, 프탈산, 숙신산, 젖산, 구연산, 시트르산, 글루콘산, 타타르산, 살리실산, 말산, 옥살산, 벤조산, 엠본산, 아스파르트산, 글루탐산 등이 사용될 수 있다. 유기염기부가염 제조에 사용될 수 있는 유기염기는 트리스(하이드록시메틸)메틸아민, 다이사이클로헥실아민 등이다. 아미노산부가염기 제조에 사용될 수 있는 아미노산은 알라닌, 글라이신 등의 천연아미노산이다.Preferred salts of the compounds according to the invention include salts with inorganic or organic acids. The inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, or the like. In addition, the organic acid may be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, citric acid, gluconic acid, Oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, and the like. Organic bases that can be used to prepare organic base addition salts include tris (hydroxymethyl) methylamine, dicyclohexylamine, and the like. Amino acids that can be used in the production of amino acid addition bases are natural amino acids such as alanine and glycine.

이와 같은 염은 통상적인 방법으로 제조될 수 있다. 예를 들어 상기한 화학식 1의 화합물을 메탄올, 에탄올, 아세톤, 1,4-다이옥산과 같은 물과 섞일 수 있는 용매에 녹인 다음에 유리산 또는 유리염기를 가한 후에 결정화시켜 제조할 수 있다. Such salts may be prepared by conventional methods. For example, the compound of formula (1) can be prepared by dissolving the compound of formula (1) in a solvent which can be mixed with water such as methanol, ethanol, acetone, or 1,4-dioxane, and then adding a free acid or a free base.

또한, 본 발명에 따른 화합물들은 비대칭 탄소중심을 가질 수 있으므로 R 또는 S 이성질체, 라세믹 화합물, 개개의 거울상이성질체(enantiomer) 또는 혼합물, 개개의 부분입체이성질체(diastereomer) 또는 혼합물로서 존재할 수 있으며, 이들 모든 입체이성질체(stereoisomer) 및 혼합물은 본 발명의 범위에 포함된다.In addition, the compounds according to the invention may have asymmetric carbon centers and therefore may exist as R or S isomers, racemic compounds, individual enantiomers or mixtures, individual diastereomers or mixtures thereof, All stereoisomers and mixtures are included within the scope of the present invention.

그 외에도, 화학식 1의 화합물의 용매화물 및 수화물 형태도 본 발명의 범위에 포함된다. 이러한 수화물 또는 용매화물은 공지의 방법으로 제조될 수 있으며, 비독성 및 수용성인 것이 바람직하고, 물 또는 알코올계 용매 (특히, 에탄올 등)의 분자가 1개 내지 5개 결합된 수화물 또는 용매화물인 것이 바람직하다.
In addition, solvates and hydrate forms of the compounds of formula (I) are also included within the scope of the present invention. Such a hydrate or solvate may be prepared by a known method and is preferably non-toxic and water-soluble, and may be a hydrate or a solvate in which one to five molecules of water or an alcohol-based solvent (particularly, ethanol etc.) .

상기 화학식 1의 화합물, 이의 약학적으로 허용가능한 염, 광학이성질체, 수화물 또는 용매화물은 FMS 키나아제의 활성에 기인하는 질환을 예방 또는 치료하기 위한 용도로 사용될 수 있다.The compound of Formula 1, a pharmaceutically acceptable salt, an optical isomer, a hydrate or a solvate thereof may be used for the purpose of preventing or treating a disease caused by the activity of FMS kinase.

또한, 상기 화학식 1의 화합물, 이의 약학적으로 허용가능한 염, 광학이성질체, 수화물 또는 용매화물은 FMS 키나아제의 활성에 기인하는 질환을 예방 또는 치료하는 방법에 사용될 수 있다.In addition, the compound of Formula 1, a pharmaceutically acceptable salt, an optical isomer, a hydrate or a solvate thereof may be used in a method for preventing or treating a disease caused by the activity of FMS kinase.

또한, 상기 화학식 1의 화합물, 이의 약학적으로 허용가능한 염, 광학이성질체, 수화물 또는 용매화물은 FMS 키나아제의 활성에 기인하는 질환을 예방 또는 치료하는 약제의 제조에 사용될 수 있다.
In addition, the compound of Formula 1, a pharmaceutically acceptable salt, an optical isomer, a hydrate or a solvate thereof may be used for the preparation of a medicament for preventing or treating a disease caused by the activity of FMS kinase.

상기 FMS 키나아제의 활성에 기인하는 질환의 예로는, 면역성 질환, 대사성 질환, 염증성 질환, 암 등이 있다.Examples of the disease caused by the activity of the FMS kinase include an immune disease, a metabolic disease, an inflammatory disease, a cancer and the like.

상기 FMS 키나아제의 활성에 기인하는 면역성 질환, 대사성 질환 및 염증성 질환의 구체적인 예로는, 류마티스 관절염(rheumatoid arthritis), 골다공증(osteoporosis), 크론병(Crohn's disease), 동맥경화증, 고지혈증 등이 있다.Specific examples of the immune diseases, metabolic diseases and inflammatory diseases caused by the activity of the FMS kinase include rheumatoid arthritis, osteoporosis, Crohn's disease, arteriosclerosis, hyperlipemia and the like.

또한, 상기 FMS 키나아제의 활성에 기인하는 암 및 종양의 구체적인 예로는 간암(liver cancer), 간세포암(hepatocellular carcinoma), 갑상선암(thyroid cancer), 결장암(colon cancer), 고환암(testicular cancer), 골암(bone cancer), 구강암(oral cancer), 기저세포암(basal cell carcinoma), 난소암(ovarian cancer), 뇌종양(brain tumor), 담낭암(gallbladder carcinoma), 담도암(biliary tract cancer), 두경부암(head and neck cancer), 직장암(rectal cancer), 방광암(vesical carcinoma), 설암(tongue cancer), 식도암(esophageal cancer), 신경교종(glioma), 신경교아종(glioblastoma), 신장암(renal cancer), 악성흑색종(malignant melanoma), 위암(gastric cancer), 유방암(breast cancer), 육종(sarcoma), 인두암(pharynx carcinoma), 자궁암(uterine cancer), 자궁경부암(cervical cancer), 전립선암(prostate cancer), 직장암(rectal cancer), 췌장암(pancreatic cancer), 폐암(lung cancer), 피부암(skin cancer), 기타 고형암 등을 들 수 있으나, 이에 제한되지 않는다.
Specific examples of the cancer and tumor caused by the activity of the FMS kinase include liver cancer, hepatocellular carcinoma, thyroid cancer, colon cancer, testicular cancer, bone cancer bone cancer, oral cancer, basal cell carcinoma, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer cancer of the esophagus, glioma, glioblastoma, renal cancer, malignant melanoma, renal cancer, malignant melanoma, malignant melanoma, malignant melanoma, Cancer, gastric cancer, breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, ovarian cancer, Rectal cancer, pancreatic cancer, lung cancer, skin cancer, However other include solid tumors including, but not limited thereto.

상기 화학식 1의 화합물, 이의 약학적으로 허용가능한 염, 광학이성질체, 수화물 또는 용매화물의 인체에 대한 투여용량은 일반적으로 몸무게가 70kg인 성인환자를 기준으로 할 때 1 mg/일 내지 1,000 mg/일의 범위인 것이 바람직하다. 본 발명에 따른 화합물은 1일 1회 내지 수회로 분할 투여할 수 있다. 상기 투여용량은 환자의 건강상태, 나이, 몸무게 및 성별, 투여형태 및 질환 정도에 따라 달라질 수 있으며, 이에 따라 본 발명의 범주는 상기 제시한 투여용량에 국한되지는 않는다.
The dosage of the compound of formula 1, its pharmaceutically acceptable salt, optical isomer, hydrate or solvate for the human body is generally from 1 mg / day to 1,000 mg / day, based on adult patients weighing 70 kg . The compounds according to the present invention may be administered once to several times per day. The dosage may vary depending on the patient's health condition, age, weight and sex, dosage form and disease severity, and accordingly, the scope of the present invention is not limited to the above-mentioned dosage.

본 발명에 따른 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은, 염증성 질환, 자가면역 질환 또는 면역학적으로 매개된 질환을 치료하기 위한 다른 약제와 함께 병용 투여함으로써 치료효과를 강화시킬 수 있다. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect by co-administration with an inflammatory disease, an autoimmune disease, or another medicament for treating an immunologically mediated disease.

염증성 질환, 자가면역 질환 또는 면역학적으로 매개된 질환을 치료하기 위한 다른 약제의 예로는 스테로이드 약제(프레드니손, 프레드니솔론, 메틸프레드니솔론, 코르티손, 하이드록시코르티손, 베타메타손 및 덱사메타손 등), 메소트렉세이트, 레플루노마이드, 항-TNFα 약제(에타너셉트, 인플릭시맙 및 아달리무맙 등), 칼시네우린 저해제(타크로리무스 및 피메크로리무스 등) 및 항히스타민 약제(다이펜하이드라민, 하이드록시진, 로라타딘, 에바스틴, 케토티펜, 세티리진, 레보세티리진 및 펙소페나딘 등) 등의 약물을 들 수 있으나, 이에 제한되지 않으며, 이들 중에서 선택된 1개 이상의 약제가 병용 처방될 수 있다.
Examples of other medicaments for treating inflammatory diseases, autoimmune diseases or immunologically mediated diseases include steroid drugs (prednisone, prednisolone, methylprednisolone, cortisone, hydroxycortisone, betamethasone and dexamethasone etc.), methotrexate, (Norepinephrine, norepinephrine, norepinephrine, nomade, anti-TNFa agents such as etanercept, infliximab and adalimumab), calcineurin inhibitors (such as tacrolimus and pimecrolimus) and antihistamines (diphenhydramine, hydroxygene, loratadine, But are not limited thereto, and one or more medicines selected therefrom may be used in combination. In addition, the medicament may be used in combination with other medicines such as corticosteroids, corticosteroids, corticosteroids, corticosteroids,

본 발명에 따른 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은, 암 또는 종양을 치료하기 위한 다른 항암제와 함께 병용 투여함으로써 항암제의 치료효과를 강화시킬 수 있다. The compound of the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention can enhance the therapeutic effect of the anticancer drug by co-administration with other anticancer drugs for treating cancer or tumors.

암 또는 종양을 치료하기 위한 다른 항암제의 예로는 세포 신호 전달 억제제(이매티닙, 게피티닙, 볼테조밉, 얼로티닙, 소라페닙, 수니티닙, 다사티닙, 보리노스타트, 라파티닙, 템시로리무스, 닐로티닙, 에버롤리무스, 파조파닙, 트라스투주맵, 베바시주맵, 세툭시맵, 라니비주맵, 페갑타닙 및 파니투무맵 등), 유사분열 억제제(파클리탁셀, 빈크리스틴 및 빈블라스틴 등), 알킬화제(시스플라틴, 싸이클로포스파마이드, 크로마부실 및 카무스틴 등), 항-대사제(메쏘트렉세이트 및 5-FU 등), 삽입 항암제(액티노마이신, 안트라싸이클린, 블레오마이신 및 마이토마이신-C 등), 토포아이소머라제 억제제(이리노테칸, 토포테간 및 테니포사이드 등), 면역요법제(인터루킨 및 인터페론 등) 및 항-호르몬제(타목시펜 및 랄록시펜 등) 계열의 약물을 들 수 있으나, 이에 제한되지 않으며, 이들 중에서 선택된 1개 이상의 약제가 병용 처방될 수 있다.
Examples of other anti-cancer agents for treating cancer or tumors include cell signaling inhibitors (imatinib, gefitinib, bortezomib, allotinib, sorafenib, sunitinib, dasatinib, borinostat, lapatinib, Paclitaxel, paclitaxel, vincristine, and vinblastine), paclitaxel, paclitaxel, paclitaxel, paclitaxel, paclitaxel, paclitaxel, Antimetabolites such as cisplatin, cyclophosphamide, and chromostin, antimetabolites such as methotrexate and 5-FU, and anticancer agents such as actinomycin, anthracycline, bleomycin, and mitomycin Such as topoisomerase inhibitors (irinotecan, topotecan and teniposide), immunotherapeutic agents (interleukin and interferon), and anti-hormonal agents (tamoxifen and raloxifene, etc.) Therefore And one or more agents selected therefrom may be used in combination.

본 발명은 상기 화학식 1의 피리미딘 화합물, 이의 약학적으로 허용가능한 염, 광학이성질체, 수화물 또는 용매화물을 활성 성분으로 함유하는 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition comprising the pyrimidine compound of Formula 1, a pharmaceutically acceptable salt, optical isomer, hydrate or solvate thereof as an active ingredient.

상기 약학적 조성물은 FMS 키나아제의 활성에 기인하는 질환을 예방 또는 치료하기 위한 것이다. 상기 FMS 키나아제의 활성에 기인하는 질환의 예로는 면역성 질환, 대사성 질환, 염증성 질환, 암 등을 들 수 있으며, 이들의 구체적인 예는 앞서 서술한 바와 같다.The pharmaceutical composition is for preventing or treating diseases caused by the activity of FMS kinase. Examples of the disease caused by the activity of the FMS kinase include an immune disease, a metabolic disease, an inflammatory disease, cancer and the like, and specific examples thereof are as described above.

또한, 상기 약학적 조성물에는 염증성 질환, 자가면역 질환, 또는 면역학적으로 매개된 질환, 암, 또는 종양을 치료하기 위한 다른 항암제를 추가적인 활성 성분으로 첨가시킴으로써 치료효과를 강화시킬 수 있다. 상기 추가적인 활성 성분의 구체적인 예는 앞서 서술한 바와 같으며, 이들 중 1종 이상이 상기 약학적 조성물에 포함되어 복합 제제화되거나 병용 처방될 수 있다.In addition, the pharmaceutical composition can further enhance the therapeutic effect by adding an additional anti-cancer agent as an additional active ingredient to treat an inflammatory disease, an autoimmune disease, or an immunologically mediated disease, cancer, or tumor. Specific examples of the above-mentioned additional active ingredients are as described above, and at least one of them may be contained in the pharmaceutical composition to form a combined preparation or a combined preparation.

또한, 본 발명의 약학적 조성물은 활성 성분 외에 통상의 약학적으로 허용 가능한 첨가제, 예를 들어 담체, 부형제, 희석제 및 보강제가 첨가되어 통상적인 방법에 따라 제제화될 수 있다. In addition, the pharmaceutical composition of the present invention may be formulated according to a conventional method in addition to the active ingredient with conventional pharmaceutically acceptable additives such as carriers, excipients, diluents, and a reinforcing agent.

본 발명의 약학적 조성물은 정제, 환제, 산제, 캅셀제, 시럽 또는 에멀젼 등의 다양한 경구 투여 형태 또는 근육내, 정맥내 또는 피하 투여와 같은 비경구 투여 형태로 제조될 수 있으며, 바람직하게는 경구 투여 형태로 제제화되는 것이 좋다.The pharmaceutical compositions of the present invention may be prepared in various oral dosage forms such as tablets, pills, powders, capsules, syrups or emulsions or in parenteral dosage forms such as intramuscular, intravenous or subcutaneous administration, Formulations.

본 발명의 약학적 조성물에 사용될 수 있는 첨가제로는 감미제, 결합제, 용해제, 용해보조제, 습윤제, 유화제, 등장화제, 흡착제, 붕해제, 산화방지제, 방부제, 활택제, 충진제, 방향제 등이 포함될 수 있다. 상기 첨가제의 예로서 락토스, 덱스트로스, 수크로스, 만니톨, 솔비톨, 셀룰로오스, 글라이신, 실리카, 탈크, 스테아린산, 스테린, 마그네슘 스테아린산염, 마그네슘 알루미늄 규산염, 녹말, 젤라틴, 트라가칸트 고무, 알지닌산, 소듐 알진산염, 메틸셀룰로오스, 소듐 카복실메틸셀룰로오스, 아가, 물, 에탄올, 폴리에틸렌글리콜, 폴리비닐피롤리돈, 염화나트륨, 염화칼슘, 오렌지 엣센스, 딸기 엣센스, 바닐라 향 등을 들 수 있다.Additives that may be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, . Examples of the additives include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, tragacanth gum, , Sodium alginate, methylcellulose, sodium carboxylmethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor and the like.

본 발명의 약학적 조성물이 경구 투여 형태로 제제화되는 경우, 사용되는 첨가제의 예로는 셀룰로오스, 규산칼슘, 옥수수전분, 락토오스, 수크로스, 덱스트로스, 인산칼슘, 스테아르산, 스테아르산 마그네슘, 스테아르산 칼슘, 젤라틴, 탈크, 계면활성제, 현탁제, 유화제, 희석제 등을 들 수 있다. When the pharmaceutical composition of the present invention is formulated into an oral dosage form, examples of the additives to be used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate , Gelatin, talc, a surfactant, a suspending agent, an emulsifier, and a diluent.

본 발명의 약학적 조성물이 주사제 형태로 제제화되는 경우, 사용되는 첨가제의 예로는 물, 식염수, 포도당 수용액, 유사 당수용액, 알콜, 글리콜, 에테르, 오일, 지방산, 지방산에스테르, 글리세라이드, 계면활성제, 현탁제, 유화제 등을 들 수 있다.
When the pharmaceutical composition of the present invention is formulated into an injectable form, examples of the additives to be used include water, saline solution, aqueous glucose solution, pseudosugar solution, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, A suspending agent, and an emulsifying agent.

본 발명의 화학식 1의 화합물의 제조방법의 일례는 아래 반응식 1과 같다.An example of the process for preparing the compound of formula (1) of the present invention is shown in the following reaction formula (1).

반응식 1Scheme 1

Figure pat00002
Figure pat00002

상기 반응식 1에서, A, Z, R1, R2, R3 및 R11은 상기 화학식 1에서 정의한 바와 같다.In the above Reaction Scheme 1, A, Z, R 1 , R 2 , R 3, and R 11 are as defined in Formula 1.

상기 반응식 1에서 보듯이, 화학식 a1의 화합물을 포스겐(phosgene), 다이포스겐(diphosgene), 또는 트리포스겐(triphosgen)과 반응시켜 화학식 a2의 화합물을 제조할 수 있다. 이때 트리에틸아민, 다이아이소프로필 아민 등의 유기염기 또는 탄산수소나트륨, 탄산나트륨 등의 무기염기를 첨가할 수 있다. 화학식 a2 의 화합물은 반응 용액으로부터 분리하여 사용하거나 분리하지 않고 반응 용액 자체로 다음 단계에 사용될 수 있다. As shown in Scheme 1, the compound of formula (a2) can be prepared by reacting the compound of formula (a1) with phosgene, diphosgene, or triphosgene. In this case, an organic base such as triethylamine or diisopropylamine, or an inorganic base such as sodium hydrogencarbonate or sodium carbonate may be added. The compound of formula (a2) can be used in the next step as the reaction solution itself, with or without separation from the reaction solution.

이후, 화학식 a2의 화합물을 유기용매 하에서 화학식 b1의 화합물과 반응시키는 단계를 포함하여 화학식 1의 화합물을 제조할 수 있다. 이때 유기용매는 벤젠, 톨루엔, 염화메틸렌, 이염화에탄, 다이메틸포름아마이드 등을 사용할 수 있고, 반응온도는 0℃ 내지 150℃, 바람직하게는 50℃ 내지 100℃이다.
Thereafter, the compound of formula (1) may be prepared by reacting the compound of formula (a2) with a compound of formula (b1) in an organic solvent. The organic solvent may be benzene, toluene, methylene chloride, ethane dichloride, dimethylformamide or the like, and the reaction temperature is 0 ° C to 150 ° C, preferably 50 ° C to 100 ° C.

이하 본 발명을 하기 제조예 및 실시예에 의거하여 더욱 상세히 설명하지만, 이는 본 발명을 예시하는 것일 뿐 본 발명의 범위가 이에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in more detail with reference to the following Preparation Examples and Examples, but the present invention is not limited thereto.

실시예 1: 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 1: Preparation of 1- (6- (4- (4-ethylpiperazin-1-yl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea

3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민(100mg, 0.396mmol)에 1,2-다이클로로에탄을 가한 후, 트리포스젠(59mg, 0.198mmol)을 첨가하고 상온에서 1시간 동안 교반하였다. 상기 반응 용액에 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민(62mg, 0.198mmol; Journal of Medicinal Chemistry, 54(20), 7066-7083, 2011) 및 다이아이소프로필에틸아민(0.137mL, 0.79mmol)을 첨가하고 70℃에서 12시간 동안 교반하였다. 용매를 감압하여 제거하고 잔류물을 실리카겔 컬럼 크로마토그래피(DCE/MeOH=10:1)로 정제하여 표제 화합물(40mg, 34%)을 수득하였다.
1,2-dichloroethane was added to 3-methyl-1- ((6-methylpyridin-2-yl) methyl) -1 H- indazol- 59mg, 0.198mmol) was added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added N 4 - (4- (4-ethylpiperazin-1-yl) phenyl) -N 6 -methylpyrimidine-4,6-diamine (62 mg, 0.198 mmol; Journal of Medicinal Chemistry, 54 20), 7066-7083, 2011) and diisopropylethylamine (0.137 mL, 0.79 mmol) were added, and the mixture was stirred at 70 DEG C for 12 hours. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (DCE / MeOH = 10: 1) to give the title compound (40 mg, 34%).

실시예 2: 3-(1-((6-에톡시피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-일)-1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸유레아의 제조Example 2: 3- (l- (6-Ethoxypyridin-2-yl) methyl) -3-methyl- Piperazin-1-yl) phenylamino) pyrimidin-4-yl) -1-methylurea

실시예 1에서 3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민 대신 1-((6-에톡시피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
Except that 1 - ((6-ethoxypyridin-2-yl) methyl) - (3-methylpyrrolidin- The same procedure was repeated as in Example 1, except that 3-methyl-1H-indazol-4-amine was used to give the title compound.

실시예 3: 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-(3-메톡시벤질)-3-메틸-1H-인다졸-4-일)-1-메틸유레아의 제조Example 3: Preparation of 1- (6- (4- (4-ethylpiperazin-1-yl) phenylamino) pyrimidin- -1H-indazol-4-yl) -1-methylurea

실시예 1에서 3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민 대신 1-(3-메톡시벤질)-3-메틸-1H-인다졸-4-아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(3-methoxybenzyl) -3-methyl-1H-indole instead of 3-methyl-1 - ((6- methylpyridin- The same procedure as in Example 1 was repeated except that the sol-4-amine was used to obtain the title compound.

실시예 4: 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(1-메틸피페리딘-4-일)페닐아미노)피리미딘-4-일)유레아의 제조Example 4: 1-Methyl-3- (3-methyl-1- (6- (methylpyridin- Methylpiperidin-4-yl) phenylamino) pyrimidin-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-메틸-N6-(4-(1-메틸피페리딘-4-일)페닐)피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - methyl -N 6 - (4- ( 1-methylpiperidin-4-yl) phenyl) pyrimidine-4,6-diamine, the same procedure as in Example 1 was repeated to give the title compound.

실시예 5: 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-((6-플루오로피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-일)-1-메틸유레아의 제조Example 5: Preparation of 1- (6- (4- (4-ethylpiperazin-1-yl) phenylamino) pyrimidin- ) Methyl) -3-methyl-1H-indazol-4-yl) -1-methylurea

실시예 1에서 3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민 대신 1-((6-플루오로피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
Except that 1 - ((6-fluoropyridin-2-yl) methyl) - (3-methylpyridin-2-yl) The same procedure was repeated as in Example 1, except that 3-methyl-1H-indazol-4-amine was used to give the title compound.

실시예 6: 1-(6-(4-(4-아이소프로필피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 6: Preparation of l- (6- (4- (4-isopropylpiperazin-l-yl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-(4-(4-아이소프로필피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - (4- (4- isopropyl-piperazin- L-yl) phenyl) -N 6 -methylpyrimidine-4,6-diamine as starting materials, the title compound was obtained.

실시예 7: 1-(6-(4-(4-(사이클로프로필메틸)피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 7: Preparation of l- (6- (4- (4- (cyclopropylmethyl) piperazin-l-yl) phenylamino) pyrimidin- - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-(4-(4-(사이클로프로필메틸)피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - (4- (4- (cyclopropyl Methyl) piperazin-1-yl) phenyl) -N 6 -methylpyrimidine-4,6-diamine was used in place of the compound obtained in Example 1, the title compound was obtained.

실시예 8: 1-(6-(4-(4-(다이메틸아미노)피페리딘-1-일)-2-메톡시페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 8: Preparation of l- (6- (4- (4- (dimethylamino) piperidin-l-yl) -2-methoxyphenylamino) pyrimidin- (3-methyl-1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-(4-(4-(다이메틸아미노)피페리딘-1-일)-2-메톡시페닐)-N6-메틸피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - - methylpyrimidine-4,6-diamine instead of N 4 - (4- (4- (N-Dimethyl-4 in Example 1, Amino) piperidin-1-yl) -2-methoxyphenyl) -N 6 -methylpyrimidine-4,6-diamine as starting materials, the title compound ≪ / RTI >

실시예 9: 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 9: Preparation of 1- (6- (4- (4-ethylpiperazin-l-yl) phenylamino) pyrimidin- Yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-(4-(4-에틸피페라진-1-일)페닐)피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - (4- (4- ethylpiperazine -1-yl) phenyl) pyrimidine-4,6-diamine, the same procedure as in Example 1 was repeated to give the title compound.

실시예 10: 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-((6-메톡시피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-일)-1-메틸유레아의 제조Example 10: 1- (6- (4- (4-Ethylpiperazin-1-yl) phenylamino) pyrimidin- ) Methyl) -3-methyl-1H-indazol-4-yl) -1-methylurea

실시예 1에서 3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민 대신 1-((6-메톡시피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
1 - ((6-methoxypyridin-2-yl) methyl) - (3-methylpyridin-2-yl) The same procedure was repeated as in Example 1, except that 3-methyl-1H-indazol-4-amine was used to give the title compound.

실시예 11: 3-(1-(사이클로헥실메틸)-3-메틸-1H-인다졸-4-일)-1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸유레아의 제조Example 11: Preparation of 3- (1- (cyclohexylmethyl) -3-methyl-1H-indazol-4-yl) ) Pyrimidin-4-yl) -1-methylurea

실시예 1에서 3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민 대신 1-(사이클로헥실메틸)-3-메틸-1H-인다졸-4-아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(Cyclohexylmethyl) -3-methyl-1H-indazole-1-carboxylic acid in place of 3-methyl-1 - ((6- methylpyridin- The title compound was obtained by repeating the procedure of Example 1, except that 4-amine was used.

실시예 12: 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-((2-아이소프로필싸이아졸-4-일)메틸)-3-메틸-1H-인다졸-4-일)-1-메틸유레아의 제조Example 12: 1- (6- (4- (4-Ethylpiperazin-1-yl) phenylamino) pyrimidin- Yl) methyl) -3-methyl-1H-indazol-4-yl) -1-methylurea

실시예 1에서 3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민 대신 1-((2-아이소프로필싸이아졸-4-일)메틸)-3-메틸-1H-인다졸-4-아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(2-isopropylthiazol-4-yl) methyl) -1H-indazol-4-amine instead of 3-methyl- -3-methyl-1H-indazol-4-amine, the same procedure as in Example 1 was repeated to give the title compound.

실시예 13: tert-부틸 4-(4-(6-(1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레이도)피리미딘-4-일아미노)페닐)피페라진-1-카복실레이트의 제조Example 13: tert-Butyl 4- (4- (6- (1 -methyl-3- (3-methyl- Yl) ureido) pyrimidin-4-ylamino) phenyl) piperazine-1-carboxylate

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 tert-부틸 4-(4-(6-(메틸아미노)피리미딘-4-일아미노)페닐)피페라진-1-카복실레이트을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - - Example 1 N 4-methylpyrimidine-4,6-diamine in place of tert- butyl 4- (4- (6- ( Methylamino) pyrimidin-4-ylamino) phenyl) piperazine-1-carboxylate was used as the starting material to obtain the title compound.

실시예 14: 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(피페라진-1-일)페닐아미노)피리미딘-4-일)유레아의 제조Example 14: 1-Methyl-3- (3-methyl-1- (6- (methylpyridin- Piperazin-1-yl) phenylamino) pyrimidin-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-메틸-N6-(4-(피페라진-1-일)페닐)피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - methyl -N 6 - (4- ( Piperazin-1-yl) phenyl) pyrimidine-4,6-diamine was used, the same procedure as in Example 1 was repeated to give the title compound.

실시예 15: 1-(6-(4-(4-(2-하이드록시에틸)피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 15: Preparation of l- (6- (4- (4- (2-hydroxyethyl) piperazin-l-yl) phenylamino) pyrimidin- -1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 2-(4-(4-(6-(메틸아미노)피리미딘-4-일아미노)페닐)피페라진-1-일)에탄올을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - - Example 1 N 4-methylpyrimidine-4,6-diamine in place of 2- (4- (4- (6- ( Methylamino) pyrimidin-4-ylamino) phenyl) piperazin-1-yl) ethanol was used as the starting material.

실시예 16: 3-(3-사이클로프로필-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸유레아의 제조Example 16: 3- (3-Cyclopropyl-l- (6-methylpyridin-2-yl) methyl) -lH-indazol- Piperazin-1-yl) phenylamino) pyrimidin-4-yl) -1-methylurea

실시예 1에서 3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민 대신 3-사이클로프로필-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
Cyclopropyl-1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol- ) Methyl) -1H-indazol-4-amine was used as the starting material, the same procedure as in Example 1 was repeated to give the title compound.

실시예 17: 1-(6-(4-(4-아세틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 17: Preparation of 1- (6- (4- (4-acetylpiperazin-1-yl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 1-(4-(4-(6-(메틸아미노)피리미딘-4-일아미노)페닐)피페라진-1-일)에탄온을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - - Example 1 N 4-methylpyrimidine-4,6-diamine in place of 1- (4- (4- (6- ( Methylamino) pyrimidin-4-ylamino) phenyl) piperazin-1-yl) ethanone was used as the starting material.

실시예 18: 1-(6-(4-(4-에틸피페라진-1-카보닐)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 18: 1- (6- (4- (4-Ethylpiperazine-1-carbonyl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 (4-에틸피페라진-1-일)(4-(6-(메틸아미노)피리미딘-4-일아미노)페닐)메탄온을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - - Example 1 N 4-methylpyrimidine-4,6-diamine in place of (4-ethyl-piperazin-1-yl) ( The same procedure was repeated as in Example 1, except that 4- (6- (methylamino) pyrimidin-4-ylamino) phenyl) methanone was used to yield the title compound.

실시예 19: 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(4-메틸피페라진-1-카보닐)페닐아미노)피리미딘-4-일)유레아의 제조Example 19: l-Methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) 4-methylpiperazine-1-carbonyl) phenylamino) pyrimidin-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 (4-(6-(메틸아미노)피리미딘-4-일아미노)페닐)(4-메틸피페라진-1-일)메탄온을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of (4- (6- (methylamino) pyrimidine -4-ylamino) phenyl) (4-methylpiperazin-1-yl) methanone was used in place of the title compound.

실시예 20: 1-(6-(4-(4-(다이메틸아미노)피페리딘-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 20: Preparation of l- (6- (4- (4- (dimethylamino) piperidin-l-yl) phenylamino) pyrimidin- Preparation of 1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-(4-(4-(다이메틸아미노)피페리딘-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - - methylpyrimidine-4,6-diamine instead of N 4 - (4- (4- (N-Dimethyl-4 in Example 1, Amino) piperidin-1-yl) phenyl) -N 6 -methylpyrimidine-4,6-diamine as starting materials.

실시예 21: 1-(6-(2-메톡시-4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 21: 1- (6- (2-Methoxy-4- (4- (pyrrolidin- 1 -yl) piperidin- 1 -yl) phenylamino) pyrimidin- Preparation of methyl-3- (3-methyl-1 - ((6-methylpyridin-2- yl) methyl) -1H-indazol-

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-(2-메톡시-4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
N 4 in Example 1 - (4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - (2- methoxy-4- ( The same procedure as in Example 1 was performed except that 4- (pyrrolidin-1-yl) piperidin-1-yl) phenyl) -N 6 -methylpyrimidine-4,6- Lt; / RTI > to yield the title compound.

실시예 22: 1-(6-(2-메톡시-4-모폴리노페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 22: 1- (6- (2-Methoxy-4 -morpholinophenylamino) pyrimidin-4- Yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-(2-메톡시-4-모폴리노페닐)-N6-메틸피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - (2- methoxy-4-all Polynophenyl) -N 6 -methylpyrimidine-4,6-diamine, the same procedure as in Example 1 was repeated to give the title compound.

실시예 23:Example 23: 1-(6-(2-메톡시-4-(1-메틸피페리딘-4-일옥시)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조4-yl) -1-methyl-3- (3-methyl-l- ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-(2-메톡시-4-(1-메틸피페리딘-4-일옥시)페닐)-N6-메틸피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
N 4 in Example 1 - (4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - (2- methoxy-4- ( 1-methylpiperidin-4-yloxy) phenyl) -N 6 -methylpyrimidine-4,6-diamine as starting materials, the same procedure as in Example 1 was repeated to give the title compound .

실시예 24: 1-(6-(4-(4-에틸피페라진-1-일)-3-플루오로페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 24: 1- (6- (4- (4-Ethylpiperazin-l-yl) -3-fluorophenylamino) pyrimidin- Preparation of 1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-(4-(4-에틸피페라진-1-일)-3-플루오로페닐)-N6-메틸피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - (4- (4- ethylpiperazine -1-yl) -3-fluorophenyl) -N 6 -methylpyrimidine-4,6-diamine was used in place of the compound obtained in Example 1, the title compound was obtained.

실시예 25:Example 25: 1-에틸-1-(6-(4-(4-에틸피페라진-1-일)-3-플루오로페닐아미노)피리미딘-4-일)-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Yl) -3- (3-methyl-1 - (((4-methylpiperazin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-에틸-N6-(4-(4-에틸피페라진-1-일)-3-플루오로페닐)피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - ethyl -N 6 - (4- ( 4-ethylpiperazin-1-yl) -3-fluorophenyl) pyrimidine-4,6-diamine was used in place of the compound obtained in Example 1, the title compound was obtained.

실시예 26: 4-(6-(3-(1-아이소부틸-3-메틸-1H-인다졸-4-일)-1-메틸유레이도)피리미딘-4-일아미노)-3-메톡시-N-(1-메틸피페리딘-4-일)벤즈아마이드의 제조Example 26: 4- (6- (3- (1-isobutyl-3-methyl-1H-indazol- (1-methylpiperidin-4-yl) benzamide < / RTI >

실시예 1에서 3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-아민 대신 1-아이소부틸-3-메틸-1H-인다졸-4-아민을 사용하고, N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 3-메톡시-4-(6-(메틸아미노)피리미딘-4-일아미노)-N-(1-메틸피페리딘-4-일)벤즈아마이드를 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
Except that 1-isobutyl-3-methyl-1 H-indazol-4-amine (2-methyl- use and, N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of 4- (6- (methyl Amino) pyrimidin-4-ylamino) -N- (1-methylpiperidin-4-yl) benzamide was used.

실시예 27: 3-메톡시-4-(6-(1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레이도)피리미딘-4-일아미노)-N-(1-메틸피페리딘-4-일)벤즈아마이드의 제조Example 27: Preparation of 3-methoxy-4- (6- (1-methyl-3- (3-methyl- ) Ureido) pyrimidin-4-ylamino) -N- (1-methylpiperidin-4-yl) benzamide

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 3-메톡시-4-(6-(메틸아미노)피리미딘-4-일아미노)-N-(1-메틸피페리딘-4-일)벤즈아마이드를 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
(4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - - methylpyrimidine-4,6-diamine instead of 4- (6- (methyl Example 1 N 4 in Amino) pyrimidin-4-ylamino) -N- (1-methylpiperidin-4-yl) benzamide was used.

실시예 28: 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일아미노)피리미딘-4-일)유레아의 제조Example 28: 1-Methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) 1-methylpiperidin-4-yl) -1H-pyrazol-4-ylamino) pyrimidin-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-메틸-N6-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일)피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - methyl -N 6 - (1- ( 1-methylpiperidin-4-yl) -1H-pyrazol-4-yl) pyrimidine-4,6-diamine was used as the starting material to obtain the title compound .

실시예 29: 1-메틸-1-(6-(4-(1-메틸-1,2,3,6-테트라하이드로피리딘-4-일)페닐아미노)피리미딘-4-일)-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Example 29: 1-Methyl-1- (6- (4- (1 -methyl-1,2,3,6-tetrahydropyridin-4-yl) phenylamino) pyrimidin- (3-methyl-1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-메틸-N6-(4-(1-메틸-1,2,3,6-테트라하이드로피리딘-4-일)페닐)피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일한 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - methyl -N 6 - (4- ( 4-yl) phenyl) pyrimidine-4,6-diamine, the same procedure as in Example 1 was repeated to obtain the title compound ≪ / RTI >

실시예 30: 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(2-모폴리노에톡시)페닐아미노)피리미딘-4-일)유레아의 제조Example 30: 1-Methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) 2-morpholinoethoxy) phenylamino) pyrimidin-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 N4-메틸-N6-(4-(2-모폴리노에톡시)페닐)피리미딘-4,6-다이아민을 사용하는 것을 제외하고, 상기 실시예 1과 동일 절차를 반복하여 표제 화합물을 수득하였다.
In Example 1 N 4 - (4- (4- ethyl-piperazin-1-yl) phenyl) -N 6 - methylpyrimidine-4,6-diamine instead of N 4 - methyl -N 6 - (4- ( 2-morpholinoethoxy) phenyl) pyrimidine-4,6-diamine, the same procedure as in Example 1 was repeated to give the title compound.

실시예 31: Example 31: 1-(6-(4-(4-하이드록시피페리딘-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아의 제조Methyl-3- (3-methyl-1 - ((6-methylpiperazin-1 -yl) Pyridin-2-yl) methyl) -1H-indazol-4-yl) urea

실시예 1에서 N4-(4-(4-에틸피페라진-1-일)페닐)-N6-메틸피리미딘-4,6-다이아민 대신 1-(4-(6-(메틸아미노)피리미딘-4-일아미노)페닐)피페리딘-4-올을 사용하는 것을 제외하고, 상기 실시예 1과 동일 절차를 반복하여 표제 화합물을 수득하였다.
(4- (4-ethyl-piperazin-1-yl) phenyl) -N 6 - - methylpyrimidine-4,6-diamine instead of 1- (4- (6- (methylamino) 4 in Example 1 N Pyrimidin-4-ylamino) phenyl) piperidin-4-ol was used as the starting material, the same procedure as in Example 1 was repeated to give the title compound.

이상 실시예 화합물들의 1H-NMR 및 MS 데이터를 하기 표 1에 정리하였다. 1 H-NMR and MS data of the compounds of the above Examples are summarized in Table 1 below.

No.No. 화합물 구조Compound structure 데이터 (NMR, MS)Data (NMR, MS) 1One

Figure pat00003
Figure pat00003
MS (ESI+, m/z): 553.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.95 (s, 1H), 8.36 (s, 1H), 7.65 (d, 1H), 7.39-7.38 (m, 1H), 7.30-7.18 (m, 3H), 7.05-6.96 (m, 5H), 6.44 (t, 1H), 6.11 (s, 1H), 5.70 (s, 2H), 3.33 (s, 3H), 3.27-3.24 (m, 4H), 2.82 (s, 3H), 2.65-2.62 (m, 4H), 2.57 (s, 3H), 2.50 (q, 2H), 1.15 (t, 3H).MS (ESI +, m / z): 553.3 [M + H] <
1 H-NMR (300 MHz, CDCl 3 ):? 12.95 (s, IH), 8.36 (s, IH), 7.65 (d, IH), 7.39-7. 3H), 3.27-3.24 (m, 4H), 2.82 (s, 2H), 7.05-6.96 (m, 5H) , 3H), 2.65-2.62 (m, 4H), 2.57 (s, 3H), 2.50 (q, 2H), 1.15 (t, 3H). 22
Figure pat00004
Figure pat00004
 MS (ESI+, m/z): 621.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.94 (s, 1H), 8.34 (s, 1H), 7.64 (d, 1H), 7.38-7.13 (m, 6H), 6.98-6.95 (m, 2H), 6.54 (d, 1H), 6.33 (d, 1H), 6.10 (s, 1H), 5.49 (s, 1H), 4.30 (q, 2H), 3.32 (s, 3H), 3.27-3.24 (m, 4H), 2.81 (s, 3H), 2.65-2.61 (m, 4H), 2.49 (q, 2H), 1.34 (t, 3H), 1.14 (t, 3H).MS (ESI +, m / z): 621.3 [M + H] <
1 H-NMR (300MHz, CDCl 3): δ 12.94 (s, 1H), 8.34 (s, 1H), 7.64 (d, 1H), 7.38-7.13 (m, 6H), 6.98-6.95 (m, 2H) , 6.54 (d, IH), 6.33 (d, IH), 6.10 (s, IH), 5.49 (s, IH), 4.30 (q, 2H), 3.32 (s, 3H), 3.27-3.24 ), 2.81 (s, 3H), 2.65-2.61 (m, 4H), 2.49 (q, 2H), 1.34 (t, 3H), 1.14 (t, 3H). 33
Figure pat00005
Figure pat00005
 MS (ESI+, m/z): 606.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.93 (s, 1H), 8.49 (s, 1H), 7.64 (d, 1H), 7.27-7.14 (m, 3H), 7.03-6.96 (m, 4H), 6.78-6.72 (m, 4H), 6.09 (s, 1H), 5.46 (s, 2H), 3.73 (s, 3H), 3.32 (s, 3H), 3.27-3.24 (m, 4H), 2.80 (s, 3H), 2.65-2.62 (m, 4H), 2.51 (q, 2H), 1.14 (t, 3H).MS (ESI +, m / z): 606.3 [M + H] <
1 H-NMR (300 MHz, CDCl 3 ):? 12.93 (s, IH), 8.49 (s, IH), 7.64 (d, IH), 7.27-7.14 (m, 3H), 7.03-6.96 3H), 3.27-3.24 (m, 4H), 2.80 (s, 2H), 3.73 (s, , 3H), 2.65-2.62 (m, 4H), 2.51 (q, 2H), 1.14 (t, 3H). 44
Figure pat00006
Figure pat00006
 MS (ESI+, m/z): 576.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.92 (s, 1H), 8.42 (s, 1H), 7.67 (d, 1H), 7.43-7.27 (m, 6H), 7.05-7.00 (m, 3H), 6.47-6.39 (m, 2H), 5.62 (s, 2H), 3.66 (t, 2H), 3.41 (s, 3H), 3.10-3.05 (m, 2H), 2.88 (s, 3H), 2.72 (m, 5H), 2.57 (s, 3H), 2.39-2.35 (m, 2H).MS (ESI +, m / z): 576.3 [M + H] <
1 H-NMR (300 MHz, CDCl 3 ):? 12.92 (s, IH), 8.42 (s, IH), 7.67 (d, IH), 7.43-7.27 (m, 6H), 7.05-7.00 2H), 2.67 (s, 3H), 2.72 (m, 2H) , 5H), 2.57 (s, 3H), 2.39-2. 35 (m, 2H). 55
Figure pat00007
Figure pat00007
 MS (ESI+, m/z): 595.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.95 (s, 1H), 8.34 (s, 1H), 7.66-7.59 (m, 2H), 7.43 (s, 1H), 7.31-7.19 (m, 3H), 7.02-6.94 (m, 3H), 6.77 (d, 1H), 6.55 (d, 1H), 5.54 (s, 2H), 3.31 (s, 3H), 3.26-3.23 (m, 4H), 2.80 (s, 3H), 2.64-2.61 (m, 4H), 2.48 (q, 2H), 1.13 (t, 3H).MS (ESI +, m / z): 595.3 [M + H] <
1 H-NMR (300MHz, CDCl 3): δ 12.95 (s, 1H), 8.34 (s, 1H), 7.66-7.59 (m, 2H), 7.43 (s, 1H), 7.31-7.19 (m, 3H) 2H), 3.31 (s, 3H), 3.26-3.23 (m, 4H), 2.80 (s, 2H) , 3H), 2.64-2.61 (m, 4H), 2.48 (q, 2H), 1.13 (t, 3H). 66
Figure pat00008
Figure pat00008
 MS (ESI+, m/z): 605.3 [M+H]MS (ESI +, m / z): 605.3 [M + H] < 77
Figure pat00009
Figure pat00009
 MS (ESI+, m/z): 617.3 [M+H]MS (ESI +, m / z): 617.3 [M + H] < 88
Figure pat00010
Figure pat00010
 MS (ESI+, m/z): 635.4 [M+H]MS (ESI +, m / z): 635.4 [M + H] < 99
Figure pat00011
Figure pat00011
 MS (ESI+, m/z): 577.3 [M+H]
1H-NMR (300MHz, DMSO-d6): δ 11.01 (s,1H), 9.88 (s, 1H), 9.31 (s, 1H), 8.34 (s, 1H), 7.58-7.53 (m, 2H), 7.36-7.22 (m, 3H), 7.14-7.11 (m, 2H), 6.92-6.90 (m, 2H), 6.57-6.54 (m, 2H), 5.57 (s, 2H), 3.08 (m, 4H), 2.72 (s, 3H), 2.49 (m, 4H), 2.44 (s, 3H), 2.37 (q, 2H), 1.02 (t, 3H).MS (ESI +, m / z): 577.3 [M + H] <
1 H-NMR (300MHz, DMSO -d 6): δ 11.01 (s, 1H), 9.88 (s, 1H), 9.31 (s, 1H), 8.34 (s, 1H), 7.58-7.53 (m, 2H) 2H), 7.08 (m, 2H), 7.36-7.22 (m, 3H), 7.14-7.11 (m, 2H), 6.92-6.90 , 2.72 (s, 3H), 2.49 (m, 4H), 2.44 (s, 3H), 2.37 (q, 2H), 1.02 1010
Figure pat00012
Figure pat00012
 MS (ESI+, m/z): 607.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.94 (s, 1H), 8.35 (s, 1H), 7.66 (d, 1H), 7.43-7.21 (m, 7H), 7.14 (d, 2H), 6.98 (d, 1H), 6.37 (d, 1H), 5.52 (s, 2H), 3.88 (s, 3H), 3.33 (s, 3H), 3.28-3.25 (m, 4H), 2.82 (s, 3H), 2.66-2.63 (m, 4H), 2.50 (q, 2H), 1.15 (t, 3H).MS (ESI +, m / z): 607.3 [M + H] <
1 H-NMR (300MHz, CDCl 3): δ 12.94 (s, 1H), 8.35 (s, 1H), 7.66 (d, 1H), 7.43-7.21 (m, 7H), 7.14 (d, 2H), 6.98 (d, 1H), 6.37 (d, 1H), 5.52 (s, 2H), 3.88 (s, 3H), 3.33 (s, 3H), 3.28-3.25 2.66 - 2.63 (m, 4H), 2.50 (q, 2H), 1.15 (t, 3H). 1111
Figure pat00013
Figure pat00013
 MS (ESI+, m/z): 582.4 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.90 (s, 1H), 8.36 (s, 1H), 7.63 (d, 1H), 7.35-7.18 (m, 3H), 7.11 (s, 1H), 7.07 (d, 1H), 6.98 (d, 2H), 6.11 (s, 1H), 4.17-4.09 (m, 2H), 3.34 (s, 3H), 3.29-3.26 (m, 4H), 2.80 (s, 3H), 2.67-2.64 (m, 4H), 2.51 (q, 2H), 2.05 (m, 1H), 1.68-1.59 (m, 6H), 1.19-1.03 (m, 7H).MS (ESI +, m / z): 582.4 [M + H] <
1 H-NMR (300MHz, CDCl 3): δ 12.90 (s, 1H), 8.36 (s, 1H), 7.63 (d, 1H), 7.35-7.18 (m, 3H), 7.11 (s, 1H), 7.07 (d, IH), 6.98 (d, 2H), 6.11 (s, IH), 4.17-4. 09 (m, 2H), 3.34 (s, 3H), 3.29-3.26 ), 2.67-2.64 (m, 4H), 2.51 (q, 2H), 2.05 (m, 1H), 1.68-1.59 (m, 6H), 1.19-1.03 (m, 7H). 1212
Figure pat00014
Figure pat00014
 MS (ESI+, m/z): 625.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.93 (s, 1H), 8.35 (s, 1H), 7.64 (d, 1H), 7.32-7.10 (m, 5H), 6.97 (d, 2H), 6.50 (s, 1H), 6.09 (s, 1H), 5.61 (s, 2H), 3.32 (s, 3H), 3.30-3.23 (m, 5H), 2.80 (s, 3H), 2.65-2.62 (m, 4H), 2.49 (q, 2H), 1.38 (s, 3H), 1.35 (s, 3H), 1.14 (t, 3H).MS (ESI +, m / z): 625.3 [M + H] <
1 H-NMR (300MHz, CDCl 3): δ 12.93 (s, 1H), 8.35 (s, 1H), 7.64 (d, 1H), 7.32-7.10 (m, 5H), 6.97 (d, 2H), 6.50 (s, 3H), 2.65 (s, 3H), 2.65-2.62 (m, 4H) ), 2.49 (q, 2H), 1.38 (s, 3H), 1.35 (s, 3H), 1.14 (t, 3H). 1313
Figure pat00015
Figure pat00015
 MS(ESI+, m/z): 663.4 [M+H]
1H-NMR (300MHz, DMSO-d6): δ 12.76 (s, 1H), 9.52 (s, 1H), 8.47 (s, 1H), 7.56 (t, 2H), 7.45 (d, 2H), 7.29 (d, 2H), 7.12 (d, 1H), 6.94 (d, 2H), 6.57 (d, 1H), 6.36 (s, 1H), 5.58 (s, 2H), 3.46 (t, 4H), 3.34 (s, 3H), 3.04 (t, 4H), 2.70 (s, 3H), 2.45 (s, 3H), 1.42 (s, 9H)MS (ESI +, m / z): 663.4 [M + H] <
1 H-NMR (300MHz, DMSO -d 6): δ 12.76 (s, 1H), 9.52 (s, 1H), 8.47 (s, 1H), 7.56 (t, 2H), 7.45 (d, 2H), 7.29 (d, 2H), 7.12 (d, 1H), 6.94 (d, 2H), 6.57 (d, 1H), 6.36 (s, 3H), 2.45 (s, 3H), 1.42 (s, 9H) 1414
Figure pat00016
Figure pat00016
 MS(ESI+, m/z): 563.3 [M+H]
1H-NMR (300MHz, DMSO-d6): δ 12.66 (s, 1H), 9.79 (s, 1H), 9.25 (s, 1H), 8.49 (s, 1H), 8.14 (t, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 7.50 (m, 2H), 7.37 (d, 1H), 7.00 (d, 3H), 6.46 (s, 1H), 5.93 (s, 2H), 3.69 (m, 4H), 3.34 (s, 3H), 3.22 (m, 4H), 2.72 (s, 3H), 2.70 (s, 3H), 1.22 (s, 1H)MS (ESI +, m / z): 563.3 [M + H] <
1 H-NMR (300 MHz, DMSO-d 6 ):? 12.66 (s, IH), 9.79 (s, IH), 9.25 (d, IH), 7.58 (d, IH), 7.50 (m, 2H), 7.37 (d, IH), 7.00 3H), 1.22 (s, 3H), 2.32 (s, 3H) 1515
Figure pat00017
Figure pat00017
 MS(ESI+, m/z): 607.3 [M+H]
1H-NMR (300MHz, DMSO-d6): δ 12.77 (s, 1H), 9.49 (s, 1H), 8.46 (s, 1H), 7.56 (t, 2H), 7.41 (d, 2H), 7.29 (d, 2H), 7.12 (d, 1H), 6.91 (d, 2H), 6.57(d, 1H), 6.35(s, 1H), 5.58 (s, 2H), 4.41 (bs, 1H), 3.53 (t, 2H), 3.33 (s, 3H), 3.06 (t, 4H), 2.70 (s, 3H), 2.56 (t, 4H), 2.45 (s, 3H), 2.43 (d, 2H)MS (ESI +, m / z): 607.3 [M + H] <
1 H-NMR (300MHz, DMSO -d 6): δ 12.77 (s, 1H), 9.49 (s, 1H), 8.46 (s, 1H), 7.56 (t, 2H), 7.41 (d, 2H), 7.29 (s, 2H), 4.41 (d, 2H), 6.91 (d, 2H), 6.57 2H), 3.33 (s, 3H), 3.06 (t, 4H), 2.70 (s, 3H), 2.56 (t, 1616
Figure pat00018
Figure pat00018
 MS (ESI+, m/z): 617.3 [M+H]MS (ESI +, m / z): 617.3 [M + H] < 1717
Figure pat00019
Figure pat00019
 MS(ESI+, m/z): 605.3 [M+H]
1H-NMR (300MHz, DMSO-d6): δ 12.76 (s, 1H), 9.53 (s, 1H), 8.48 (s, 1H), 7.56 (t, 2H), 7.45 (d, 2H), 7.30 (d, 2H), 7.12 (d, 1H), 6.95 (d, 2H), 6.56 (d, 1H), 6.36 (s, 1H), 5.58 (s, 2H), 4.09 (q, 4H), 3.15 (s, 3H), 3.07 (m, 4H), 2.70 (s, 3H), 2.44 (s, 3H), 1.76 (s, 3H)MS (ESI +, m / z): 605.3 [M + H] <
1 H-NMR (300MHz, DMSO -d 6): δ 12.76 (s, 1H), 9.53 (s, 1H), 8.48 (s, 1H), 7.56 (t, 2H), 7.45 (d, 2H), 7.30 (d, 2H), 7.12 (d, 1H), 6.95 (d, 2H), 6.56 (d, 1H), 6.36 (s, 3H), 3.07 (m, 4H), 2.70 (s, 3H) 1818
Figure pat00020
Figure pat00020
 MS (ESI+, m/z): 619.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.81 (s, 1H), 8.38 (s, 1H), 7.63-7.59 (m, 2H), 7.50-7.20 (m, 5H), 7.08 (s, 1H), 6.99-6.93 (m, 2H), 6.40 (d, 1H), 6.21 (s, 1H), 5.56 (s, 2H), 3.78 (m, 2H), 3.45 (m, 2H), 3.33 (s, 3H), 2.76 (s, 3H), 2.51-2.37 (m, 9H), 1.04 (t, 3H).MS (ESI +, m / z): 619.3 [M + H] <
1 H-NMR (300MHz, CDCl 3): δ 12.81 (s, 1H), 8.38 (s, 1H), 7.63-7.59 (m, 2H), 7.50-7.20 (m, 5H), 7.08 (s, 1H) 2H), 6.99 (m, 2H), 6.40 (d, 1H), 6.21 (s, ), 2.76 (s, 3H), 2.51-2.37 (m, 9H), 1.04 (t, 3H). 1919
Figure pat00021
Figure pat00021
 MS (ESI+, m/z): 605.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.93 (s, 1H), 8.51 (s, 1H), 7.72 (d, 1H), 7.60-7.32 (m, 6H), 7.24 (d, 1H), 7.11-7.05 (m, 2H), 6.50 (d, 1H), 6.34 (s, 1H), 5.68 (s, 2H), 3.88 (m, 2H), 3.57 (m, 2H), 3.47 (s, 3H), 2.89 (s, 3H), 2.63-2.37 (m, 10H).MS (ESI +, m / z): 605.3 [M + H] <
1 H-NMR (300 MHz, CDCl 3 ):? 12.93 (s, IH), 8.51 (s, IH), 7.72 (d, IH), 7.60-7.32 2H), 3.57 (m, 2H), 3.47 (s, 3H), 3.58 (m, 2.89 (s, 3H), 2.63-2.37 (m, 10H). 2020
Figure pat00022
Figure pat00022
 MS(ESI+, m/z): 605.3 [M+H]
1H-NMR (300MHz, DMSO-d6): δ 12.79 (s, 1H), 9.56 (s, 1H), 8.47 (s, 1H), 7.54 (t, 2H), 7.42 (d, 2H), 7.29 (d, 2H), 7.13 (d, 2H), 6.94 (d, 1H), 6.57 (d, 1H), 6.37 (s, 1H), 5.58 (s, 2H), 3.70 (d, 4H), 3.34 (s, 3H), 2.70 (s, 3H), 2.62 (m, 1H), 2.49 (s, 3H), 2.44 (s, 6H), 1.97 (m, 2H), 1.59 (m, 2H)MS (ESI +, m / z): 605.3 [M + H] <
1 H-NMR (300MHz, DMSO -d 6): δ 12.79 (s, 1H), 9.56 (s, 1H), 8.47 (s, 1H), 7.54 (t, 2H), 7.42 (d, 2H), 7.29 (d, 2H), 7.13 (d, 2H), 6.94 (d, IH), 6.57 (d, IH), 6.37 2H), 1.59 (m, 2H), 2.49 (s, 3H), 2.70 2121
Figure pat00023
Figure pat00023
 MS (ESI+, m/z): 661.4 [M+H]MS (ESI +, m / z): 661.4 [M + H] < 2222
Figure pat00024
Figure pat00024
 MS (ESI+, m/z): 593.3 [M+H]MS (ESI +, m / z): 593.3 [M + H] < 2323
Figure pat00025
Figure pat00025
 MS (ESI+, m/z): 622.3 [M+H]MS (ESI +, m / z): 622.3 [M + H] < 2424
Figure pat00026
Figure pat00026
 MS (ESI+, m/z): 609.3 [M+H]MS (ESI +, m / z): 609.3 [M + H] < 2525
Figure pat00027
Figure pat00027
 MS (ESI+, m/z): 623.3 [M+H]MS (ESI +, m / z): 623.3 [M + H] < 2626
Figure pat00028
Figure pat00028
 MS (ESI+, m/z): 600.3 [M+H]MS (ESI +, m / z): 600.3 [M + H] < 2727
Figure pat00029
Figure pat00029
 MS (ESI+, m/z): 649.3 [M+H]MS (ESI +, m / z): 649.3 [M + H] < 2828
Figure pat00030
Figure pat00030
 MS (ESI+, m/z): 566.3 [M+H]MS (ESI +, m / z): 566.3 [M + H] < 2929
Figure pat00031
Figure pat00031
 MS (ESI+, m/z): 574.3 [M+H]
1H-NMR (300MHz, CDCl3): δ 12.90 (s, 1H), 8.44 (s, 1H), 7.67 (d, 1H), 7.47-7.30 (m, 6H), 7.07-7.00 (m, 3H), 6.47 (d, 1H), 6.29 (s, 1H), 6.11 (m, 1H), 5.63 (s, 2H), 3.40 (s, 3H), 3.17-3.16 (m, 2H), 2.84 (s, 3H), 2.77-2.74 (m, 2H), 2.72 (m, 2H), 2.70 (s, 3H), 2.44 (s, 3H).MS (ESI +, m / z): 574.3 [M + H] <
1 H-NMR (300 MHz, CDCl 3 ):? 12.90 (s, IH), 8.44 (s, IH), 7.67 (d, IH), 7.47-7.30 (m, 6H), 7.07-7.00 , 6.47 (d, IH), 6.29 (s, IH), 6.11 (m, IH), 5.63 (s, 2H), 3.40 ), 2.77-2.74 (m, 2H), 2.72 (m, 2H), 2.70 (s, 3H), 2.44 (s, 3H). 3030
Figure pat00032
Figure pat00032
 MS (ESI+, m/z): 608.3 [M+H]MS (ESI +, m / z): 608.3 [M + H] < 3131
Figure pat00033
Figure pat00033
 MS (ESI+, m/z): 578.3 [M+H]MS (ESI +, m / z): 578.3 [M + H] <

상기 실시예에서 제조한 화합물들에 대해 다음과 같이 효능을 평가하였다.
The compounds prepared in the above examples were evaluated for efficacy as follows.

시험예 1: FMS 키나아제 저해활성 평가Test Example 1: Evaluation of FMS Kinase Inhibitory Activity

본 시험예는 FMS 키나아제의 활성 억제 약효 평가를 위한 시험으로서, FRET 원리를 이용한 분석 키트(Z'-Lyte™ kinase assay-Tyr 1 peptide kit, Cat. pv3190, Invitrogen사) 및 재조합 인간 FMS 키나아제(Cat. pv3249, Invitrogen사)를 사용하였다. This test example is a test for evaluating the inhibitory effect of FMS kinase on the activity of inhibiting the activity of the FMS kinase, using an assay kit (Z'-Lyte ™ kinase assay-Tyr 1 peptide kit, Cat. Pv3190, Invitrogen) using FRET principle and recombinant human FMS kinase pv3249, Invitrogen) was used.

시험 화합물을 4% DMSO에 1㎕, 100nM, 50nM, 10nM, 및 1nM로 각각 희석한 후, 검은색 바닥 384-웰판(NUNC, 넝크)에 넣은 후 FMS 키나아제를 0.3㎍/mL의 농도로 Tyr 1 펩타이드와 키나아제 반응액(kinase buffer)과 함께 혼합물 형식으로 웰당 10㎕씩 넣어주고 ATP를 150μM의 농도로 넣어주었다. 빛을 차단시킨 상태로 실온에서 1시간 동안 반응시키고, 전개 시약을 첨가한 후 다시 빛을 차단시킨 상태로 실온에서 1시간 동안 반응시켰다. 종결 시약을 넣어 반응을 종결하고 미세판 판독기에서 들뜸 파장 400nm 및 방출 파장 445nm로 형광을 측정하였다. The test compounds were diluted with 1 μl, 100 nM, 50 nM, 10 nM and 1 nM in 4% DMSO, respectively. The test compounds were then placed in a black bottom 384-well plate (NUNC) and FMS kinase was diluted with Tyr 1 Peptides and kinase buffer were added to each well in the form of a mixture of 10 μl per well and ATP was added at a concentration of 150 μM. The mixture was allowed to react at room temperature for 1 hour in the state of blocking light, and the reaction solution was reacted at room temperature for 1 hour in the state that the developing reagent was added and the light was blocked again. The reaction was terminated by adding a terminating reagent and the fluorescence was measured at 400 nm excitation wavelength and 445 nm emission wavelength in a microplate reader.

아울러, 100% 저해군으로서 시험 화합물 대신 4% DMSO을 사용하고 ATP 대신 키나아제 반응액을 사용하여 상기와 동일하게 반응시켜 형광을 측정하였다. 또한, 0% 저해군으로서 시험 화합물 대신 4% DMSO를 사용하여 상기와 동일하게 반응시켜 형광을 측정하였다. 또한, 100% 인산화군으로서 시험 화합물 대신 4% DMSO을 사용하고 Tyr 1 펩타이드 혼합물 대신 포스포-펩타이드(phospho-peptide) 용액을 사용하고 ATP 대신 키나아제 반응액을 사용하여 상기와 동일하게 반응시켜 형광을 측정하였다.In addition, fluorescence was measured by using 4% DMSO instead of the test compound as a 100% low-navy group and reacting in the same manner as above using a kinase reaction solution instead of ATP. In addition, fluorescence was measured by reacting in the same manner as above using 4% DMSO instead of the test compound as a 0% lower navy group. In addition, as a 100% phosphorylation group, 4% DMSO was used instead of the test compound, phospho-peptide solution was used in place of the Tyr 1 peptide mixture, and a kinase reaction solution was used instead of ATP to perform fluorescence Respectively.

측정된 각각의 형광값을 바탕으로 마이크로소프트사의 엑셀(Excel™) 프로그램을 이용하여 IC50 농도값을 계산하였다.
Based on the measured fluorescence values, IC 50 concentration values were calculated using Microsoft's Excel ™ program.

시험예 2: M-NFS-60 세포주Test Example 2: M-NFS-60 cell line 평가evaluation

ATCC(American Type Culture Collection, USA)에서 구입한 M-NFS-60 세포주를 RPMI 배양액[10% FBS, 1% 페니실린/스트렙토마이신(penicillin/streptomycin), 및 재조합 M-CSF 20ng/mL 함유]으로 5% CO2 존재하에서 37℃에서 배양하였다. 배양된 M-NFS-60 세포주를 플레이트에 넣기 전 24시간 동안 무혈청 배지 상태로 배양한 후 웰당 2.5x104개의 세포를 50㎕로 준비하여 96-웰 플레이트에 넣었다. 이후 5% FBS 배양액에 재조합 M-CSF 20ng/mL을 넣은 후 시험 화합물을 10μM부터 0.1nM까지 각각 1/10 비율의 농도로 계단식 희석하여 처리하였다. The M-NFS-60 cell line purchased from the ATCC (American Type Culture Collection, USA) was cultured in RPMI medium (containing 10% FBS, 1% penicillin / streptomycin, and recombinant M-CSF at 20 ng / % CO 2 at 37 ° C. The cultured M-NFS-60 cell line was cultured in a serum-free medium for 24 hours before being added to the plate. Then, 2.5x10 4 cells per well were prepared as 50 μl and placed in a 96-well plate. Subsequently, 20 ng / mL of recombinant M-CSF was added to the 5% FBS culture, and the test compound was treated by diluting stepwise at a concentration of 1/10 from 10 μM to 0.1 nM.

세포의 생존 능력을 측정하기 위해서 MTT[3-(4,5-다이메틸싸이아졸-2-일)-2,5-다이페닐테트라졸리움 브로마이드] 활성 검색법(CellTiter 96 Assay, Promega Cat. G3581)을 사용하였다. 한 개의 웰당 16㎕의 염료를 넣고 2시간 동안 배양한 다음 흡광도를 측정하였으며, 미세판 판독기를 사용해 590nm 파장에서 측정하여 분석 소프트웨어(GraphPad Prism 4.0)로 IC50값을 산출하였다.
(CellTiter 96 Assay, Promega Cat. G3581) was used to measure the viability of the cells. MTT [3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide] Were used. After incubation for 2 hours with 16 μl of dye per well, the absorbance was measured and the IC 50 value was measured with a software (GraphPad Prism 4.0) at 590 nm wavelength using a microplate reader Respectively.

상기 시험예 1 및 2로부터 얻은 결과를 하기 표 2에 나타내었다.The results obtained from Test Examples 1 and 2 are shown in Table 2 below.

화합물compound FMS (ICFMS (IC 5050 )) M-NFS-60 (ICM-NFS-60 (IC 5050 )) 실시예 1Example 1 77 8787 실시예 2Example 2 1717 <50<50

상기 표 2에서 보듯이, 본 발명에 따른 실시예의 화합물은 FMS 키나아제 및 M-NFS-60 세포주에 대한 저해 활성이 우수함을 알 수 있다.
As shown in Table 2, the compounds of the examples according to the present invention have excellent inhibitory activity against FMS kinase and M-NFS-60 cell lines.

이상, 본 발명을 상기 실시예를 중심으로 하여 설명하였으나 이는 예시에 지나지 아니하며, 본 발명은 본 발명의 기술분야에서 통상의 지식을 가진 자에게 자명한 다양한 변형 및 균등한 기타의 실시예를 이하에 첨부한 청구범위 내에서 수행할 수 있다는 사실을 이해하여야 한다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.

Claims (12)

하기 화학식 1의 피리미딘 화합물, 이의 약학적으로 허용가능한 염, 광학이성질체, 수화물 및 용매화물로부터 선택되는 화합물:
화학식 1
Figure pat00034

상기 식에서,
A 는 =CH- 또는 =N-이고;
Z 는 C6-12아릴, 5-12원의 헤테로아릴, 또는 5-12원의 헤테로사이클로알킬이고, 이때 상기 Z 는 할로겐, 하이드록시, 나이트로, 사이아노, 아미노, C1-6알킬, C1-6알콕시, C1-6알킬아미노C1-6알콕시, 다이C1-6알킬아미노C1-6알콕시, C1-6알킬아미노, C1-6알킬카보닐아미노, C1-6알킬아미노카보닐, C1-6알킬설피닐, C1-6알킬설포닐, C1-6알킬설포닐아미노, C1-6알킬아미노설포닐, R, -O-R, -(CH2)1-6-R, -(CH2)1-6-O-R 및 -C(=O)-R로 이루어진 군으로부터 선택된 1 내지 3개의 치환기로 치환될 수 있고;
R 은 5-12원의 헤테로사이클로알킬, 5-12원의 헤테로사이클로알켄일, C6-12아릴, 또는 5-12원의 헤테로아릴이고, 이때 상기 R 은 할로겐, 하이드록시, 아세틸, C1-6알킬, 하이드록시C1-6알킬, C1-6알콕시, C3-8사이클로알킬C1-6알킬, C1-6알킬아미노, 다이C1-6알킬아미노, t-부톡시카보닐, 및 5-6원의 헤테로사이클로알킬로 이루어진 군으로부터 선택된 1 내지 3개의 치환기로 치환될 수 있고;
R1 은 H, 할로겐, 또는 C1-10알킬이고;
R2 는 H, 할로겐, C1-10알킬, C2-10알켄일, 또는 C3-10사이클로알킬이고;
R3 는 H, C1-10알킬 또는 -(CH2)1-6-R4이고, 여기서 R4 는 C1-6알킬아미노, 다이C1-6알킬아미노, C1-6알콕시, C2-5알카인일, C3-10사이클로알킬, 5-12원의 헤테로사이클로알킬, C6-12아릴, 또는 5-12원의 헤테로아릴이며, 이때 상기 사이클로알킬, 헤테로사이클로알킬, 아릴 및 헤테로아릴은 각각 독립적으로 할로겐, 할로C1-6알킬, 나이트로, 사이아노, 카보닐아미노, 아미노카보닐, 설피닐, C1-6알킬, C1-6알킬아미노, C1-6알콕시, C1-6알킬설포닐, C1-6알킬설포닐아미노, C1-6알킬아미노설포닐, 페닐, C3-10사이클로알킬 및 5-6원의 헤테로사이클로알킬로 이루어진 군으로부터 선택된 1 내지 3개의 치환기로 치환될 수 있으며;
R11 은 H, C1-10알킬, C3-10사이클로알킬, 또는 -(CH2)1-6-N(R')2이고, 여기서 R'는 C1-10알킬 또는 C3-10사이클로알킬이고;
상기 헤테로아릴, 헤테로사이클로알킬 및 헤테로사이클로알켄일은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택된 1개 이상의 헤테로 원자를 포함한다.
Claims 1. A compound selected from the group consisting of pyrimidine compounds of formula (I), pharmaceutically acceptable salts, optical isomers, hydrates and solvates thereof:
Formula 1
Figure pat00034

In this formula,
A is = CH- or = N-;
Z is C 6-12 aryl, 5-12 membered heteroaryl, or 5-12 membered heterocycloalkyl wherein Z is selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkoxy, di-C 1-6 alkylamino-C 1-6 alkoxy, C 1-6 alkylamino, C 1-6 alkylcarbonyl amino, C 1- 6-alkyl-amino-carbonyl, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl amino, C 1-6 alkyl aminosulfonyl, R, -OR, - (CH 2) 1-6- R, - (CH 2 ) 1-6 -OR, and -C (= O) -R;
R is a 5-12 membered heterocycloalkyl, alkenyl heterocycloalkyl of 5-12 W, C 6-12 aryl, or a heteroaryl group of 5-12 W, wherein the R is a halogen, hydroxy, acetyl, C 1 -6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkylamino, di-C 1-6 alkylamino, t- butoxycarbonyl- &Lt; RTI ID = 0.0 &gt; 5-6 &lt; / RTI &gt; membered heterocycloalkyl;
R 1 is H, halogen, or C 1-10 alkyl;
R 2 is H, halogen, C 1-10 alkyl, C 2-10 alkenyl, or C 3-10 cycloalkyl;
R 3 is H, C 1-10 alkyl or - (CH 2 ) 1-6 -R 4 wherein R 4 is C 1-6 alkylamino, di C 1-6 alkylamino, C 1-6 alkoxy, C 2-5 alkynyl, C 3-10 cycloalkyl, and heteroaryl of 5-12 source of heterocycloalkyl, C 6-12 aryl, or 5-12 source, wherein said cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each a halogen, halo C 1-6 alkyl, independently nitro, cyano, amino-carbonyl, aminocarbonyl, sulfinyl, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy , C 1-6 alkylsulfonyl, C 1-6 alkylsulfonyl amino, C 1-6 alkyl aminosulfonyl, phenyl, C 3-10 cycloalkyl, and 5-6 selected from the group consisting of alkyl heterocycloalkyl of circle 1 Lt; / RTI &gt; to 3 substituents;
R 11 is H, C 1-10 alkyl, C 3-10 cycloalkyl, or - (CH 2 ) 1-6 -N (R ') 2 wherein R' is C 1-10 alkyl or C 3-10 Cycloalkyl;
Wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl each independently comprise one or more heteroatoms selected from the group consisting of N, O, and S.
제 1 항에 있어서,
상기 A 가 =N-인 것을 특징으로 하는 화합물.
The method according to claim 1,
Wherein A is = N-.
제 1 항에 있어서,
상기 A 가 =N-이고;
상기 Z 가 C6-10아릴, 5-10원의 헤테로아릴, 또는 5-10원의 헤테로사이클로알킬이고, 이때 상기 Z 는 할로겐, 하이드록시, 나이트로, 사이아노, 아미노, C1-6알킬, C1-3알콕시, C1-6알킬아미노, C1-6알킬설피닐, C1-6알킬설포닐, R, -O-R, -(CH2)1-6-O-R 및 -C(=O)-R로 이루어진 군으로부터 선택된 1 또는 2개의 치환기로 치환될 수 있고;
상기 R 이 5-10원의 헤테로사이클로알킬, 5-10원의 헤테로사이클로알켄일, C6-10아릴, 또는 5-10원의 헤테로아릴이고, 이때 상기 R 은 할로겐, 하이드록시, 아세틸, C1-6알킬, 하이드록시C1-6알킬, C1-6알콕시, C3-8사이클로알킬C1-6알킬, C1-6알킬아미노, 다이C1-6알킬아미노, t-부톡시카보닐, 및 5-6원의 헤테로사이클로알킬로 이루어진 군으로부터 선택된 1 또는 2개의 치환기로 치환될 수 있고;
상기 R1 이 H, 할로겐, 또는 C1-6알킬이고;
상기 R2 가 C1-8알킬, C2-8알켄일, 또는 C3-8사이클로알킬이고;
상기 R3 이 C1-8알킬 또는 -(CH2)1-6-R4이고, 여기서 R4 는 C3-8사이클로알킬, 5-10원의 헤테로사이클로알킬, C6-10아릴, 또는 5-10원의 헤테로아릴이고, 상기 R4 는 할로겐, C1-6알킬, 또는 C1-6알콕시로 치환될 수 있으며;
상기 R11 이 H, C1-8알킬 또는 C3-8사이클로알킬이고;
상기 헤테로아릴, 헤테로사이클로알킬 및 헤테로사이클로알켄일은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택된 1 내지 3개의 헤테로 원자를 포함하는 것을 특징으로 하는, 화합물.
The method according to claim 1,
Wherein A is = N-;
Wherein Z is C 6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocycloalkyl wherein Z is selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C 1-6 alkyl , C 1-3 alkoxy, C 1-6 alkylamino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, R, -OR, - (CH 2) 1-6 -OR and -C (= O) -R &lt; / RTI &gt;;
Wherein R is 5-10 membered heterocycloalkyl, 5-10 membered heterocycloalkenyl, C6-10 aryl, or 5-10 membered heteroaryl, wherein R is selected from the group consisting of halogen, hydroxy, acetyl, C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, C 3-8 cycloalkyl C 1-6 alkyl, C 1-6 alkylamino, di-C 1-6 alkylamino, t- butoxycarbonyl Carbonyl, and 5-6 membered heterocycloalkyl; &lt; RTI ID = 0.0 &gt; R &lt; / RTI &gt;
Wherein R 1 is H, halogen, or C 1-6 alkyl;
Wherein R 2 is C 1-8 alkyl, C 2-8 alkenyl, or C 3-8 cycloalkyl;
Wherein R 3 is C 1-8 alkyl or - (CH 2 ) 1-6 -R 4 wherein R 4 is C 3-8 cycloalkyl, 5-10 membered heterocycloalkyl, C 6-10 aryl, or 5-10 membered heteroaryl, and R &lt; 4 &gt; may be substituted with halogen, C1-6 alkyl, or C1-6 alkoxy;
Wherein R 11 is H, C 1-8 alkyl or C 3-8 cycloalkyl;
Wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl each independently comprise 1 to 3 heteroatoms selected from the group consisting of N, O, and S;
제 1 항에 있어서,
상기 A 가 =N-이고;
상기 Z 가 C6-12아릴 또는 5-6원의 헤테로아릴이고, 이때 상기 Z 는 할로겐, 하이드록시, 나이트로, 사이아노, 아미노, C1-6알킬, C1-3알콕시, R, -O-R, -(CH2)1-3-O-R 및 -C(=O)-R로 이루어진 군으로부터 선택된 1 또는 2개의 치환기로 치환되고;
상기 R 이 5-6원의 헤테로사이클로알킬, 5-6원의 헤테로사이클로알켄일, 또는 5-6원의 헤테로아릴이고, 이때 상기 R 은 하이드록시, 아세틸, C1-6알킬, 하이드록시C1-6알킬, C3-8사이클로알킬C1-6알킬, 다이C1-6알킬아미노, t-부톡시카보닐, 또는 5-6원의 헤테로사이클로알킬로 치환될 수 있고;
상기 R1 이 H 또는 C1-3알킬이고;
상기 R2 가 C1-6알킬 또는 C3-8사이클로알킬이고;
상기 R3 이 C1-8알킬 또는 -(CH2)1-3-R4이고, 여기서 R4 는 C3-8사이클로알킬, C6-10아릴, 또는 5-6원의 헤테로아릴이고, 상기 R4 는 할로겐, C1-6알킬, 또는 C1-6알콕시로 치환될 수 있으며;
상기 R11 이 H, C1-6알킬, 또는 C3-6사이클로알킬이고;
상기 헤테로아릴, 헤테로사이클로알킬 및 헤테로사이클로알켄일은 각각 독립적으로 N, O 및 S로 이루어진 군으로부터 선택된 1 또는 2개의 헤테로 원자를 포함하는 것을 특징으로 하는, 화합물.
The method according to claim 1,
Wherein A is = N-;
Wherein Z is C 6-12 aryl or 5-6 membered heteroaryl wherein Z is selected from the group consisting of halogen, hydroxy, nitro, cyano, amino, C 1-6 alkyl, C 1-3 alkoxy, oR, - substituted with (CH 2) 1-3 -OR and -C (= O) 1 or 2 substituents selected from the group consisting of -R and;
Wherein R is 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl, or 5-6 membered heteroaryl, wherein R is hydroxy, acetyl, C1-6alkyl , hydroxyC C 1-6 alkyl, C 3-8 cycloalkyl C 1-6 alkyl, di C 1-6 alkylamino, t-butoxycarbonyl, or 5-6 membered heterocycloalkyl;
Wherein R 1 is H or C 1-3 alkyl;
Wherein R 2 is C 1-6 alkyl or C 3-8 cycloalkyl;
Wherein R 3 is C 1-8 alkyl or - (CH 2 ) 1-3 -R 4 wherein R 4 is C 3-8 cycloalkyl, C 6-10 aryl, or 5-6 membered heteroaryl, R 4 may be substituted with halogen, C 1-6 alkyl, or C 1-6 alkoxy;
Wherein R 11 is H, C 1-6 alkyl, or C 3-6 cycloalkyl;
Wherein said heteroaryl, heterocycloalkyl and heterocycloalkenyl each independently comprise one or two heteroatoms selected from the group consisting of N, O, and S;
제 1 항에 있어서,
상기 A 가 =N-이고;
상기 Z 가 페닐 또는 피라졸릴이고, 이때 상기 Z 는 할로겐, C1-3알콕시, R, -O-R, -(CH2)1-3-O-R 및 -C(=O)-R로 이루어진 군으로부터 선택된 1 또는 2개의 치환기로 치환되고;
상기 R 이 N 및 O 중에서 선택된 1 또는 2개의 헤테로원자를 함유하는 5-6원의 헤테로사이클로알킬 또는 헤테로사이클로알켄일이고, 이때 상기 R 은 하이드록시, 아세틸, C1-6알킬, 하이드록시C1-6알킬, C3-8사이클로알킬C1-3알킬, 다이C1-3알킬아미노, t-부톡시카보닐, 또는 피롤리딘일로 치환될 수 있고;
상기 R1 이 H이고;
상기 R2 가 C1-3알킬 또는 C3-6사이클로알킬이고;
상기 R3 이 C1-6알킬 또는 -(CH2)1-3-R4이고, 여기서 R4 는 C3-8사이클로알킬, 페닐, 또는 S 및 N 중 적어도 하나를 함유하는 5-6원의 헤테로아릴이고, 상기 R4는 할로겐, C1-3알킬, 또는 C1-3알콕시로 치환될 수 있으며;
상기 R11 이 H 또는 C1-3알킬인 것을 특징으로 하는, 화합물.
The method according to claim 1,
Wherein A is = N-;
Wherein Z is phenyl or pyrazolyl, wherein Z is selected from the group consisting of halogen, C 1-3 alkoxy, R, -OR, - (CH 2 ) 1-3 -OR and -C (= O) -R 1 or 2 substituents;
Wherein R is 5-6 membered heterocycloalkyl or heterocycloalkenyl containing 1 or 2 heteroatoms selected from N and O, wherein R is selected from the group consisting of hydroxy, acetyl, C1-6alkyl , hydroxyC C 1-6 alkyl, C 3-8 cycloalkyl C 1-3 alkyl, di C 1-3 alkylamino, t-butoxycarbonyl, or pyrrolidinyl;
Wherein R &lt; 1 &gt; is H;
Wherein R &lt; 2 &gt; is C 1-3 alkyl or C 3-6 cycloalkyl;
Wherein R 3 is C 1-6 alkyl or - (CH 2 ) 1-3 -R 4 wherein R 4 is C 3-8 cycloalkyl, phenyl, or a 5-6 membered ring containing at least one of S and N And R &lt; 4 &gt; may be substituted with halogen, C1-3 alkyl, or C1-3 alkoxy;
Wherein R &lt; 11 &gt; is H or C1-3 alkyl.
제 1 항에 있어서,
상기 화학식 1의 피리미딘 화합물이 하기 화합물 중 어느 하나인 것을 특징으로 하는 화합물:
1) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
2) 3-(1-((6-에톡시피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-일)-1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸유레아;
3) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-(3-메톡시벤질)-3-메틸-1H-인다졸-4-일)-1-메틸유레아;
4) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(1-메틸피페리딘-4-일)페닐아미노)피리미딘-4-일)유레아;
5) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-((6-플루오로피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-일)-1-메틸유레아;
6) 1-(6-(4-(4-아이소프로필피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
7) 1-(6-(4-(4-(사이클로프로필메틸)피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
8) 1-(6-(4-(4-(다이메틸아미노)피페리딘-1-일)-2-메톡시페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
9) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
10) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-((6-메톡시피리딘-2-일)메틸)-3-메틸-1H-인다졸-4-일)-1-메틸유레아;
11) 3-(1-(사이클로헥실메틸)-3-메틸-1H-인다졸-4-일)-1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸유레아;
12) 1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-3-(1-((2-아이소프로필싸이아졸-4-일)메틸)-3-메틸-1H-인다졸-4-일)-1-메틸유레아;
13) tert-부틸 4-(4-(6-(1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레이도)피리미딘-4-일아미노)페닐)피페라진-1-카복실레이트;
14) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(피페라진-1-일)페닐아미노)피리미딘-4-일)유레아;
15) 1-(6-(4-(4-(2-하이드록시에틸)피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
16) 3-(3-사이클로프로필-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(4-에틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸유레아;
17) 1-(6-(4-(4-아세틸피페라진-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
18) 1-(6-(4-(4-에틸피페라진-1-카보닐)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
19) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(4-메틸피페라진-1-카보닐)페닐아미노)피리미딘-4-일)유레아;
20) 1-(6-(4-(4-(다이메틸아미노)피페리딘-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
21) 1-(6-(2-메톡시-4-(4-(피롤리딘-1-일)피페리딘-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
22) 1-(6-(2-메톡시-4-모폴리노페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
23) 1-(6-(2-메톡시-4-(1-메틸피페리딘-4-일옥시)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
24) 1-(6-(4-(4-에틸피페라진-1-일)-3-플루오로페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
25) 1-에틸-1-(6-(4-(4-에틸피페라진-1-일)-3-플루오로페닐아미노)피리미딘-4-일)-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
26) 4-(6-(3-(1-아이소부틸-3-메틸-1H-인다졸-4-일)-1-메틸유레이도)피리미딘-4-일아미노)-3-메톡시-N-(1-메틸피페리딘-4-일)벤즈아마이드;
27) 3-메톡시-4-(6-(1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레이도)피리미딘-4-일아미노)-N-(1-메틸피페리딘-4-일)벤즈아마이드;
28) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(1-(1-메틸피페리딘-4-일)-1H-피라졸-4-일아미노)피리미딘-4-일)유레아;
29) 1-메틸-1-(6-(4-(1-메틸-1,2,3,6-테트라하이드로피리딘-4-일)페닐아미노)피리미딘-4-일)-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아;
30) 1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)-1-(6-(4-(2-모폴리노에톡시)페닐아미노)피리미딘-4-일)유레아; 및
31) 1-(6-(4-(4-하이드록시피페리딘-1-일)페닐아미노)피리미딘-4-일)-1-메틸-3-(3-메틸-1-((6-메틸피리딘-2-일)메틸)-1H-인다졸-4-일)유레아.
The method according to claim 1,
Wherein the pyrimidine compound of Formula 1 is any one of the following compounds:
1) Methyl-3- (3-methyl-1 - ((6-methylpiperazin-1 -yl) Pyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
2) Synthesis of 3- (1 - ((6-ethoxypyridin-2-yl) methyl) -3-methyl-1H-indazol- -1-yl) phenylamino) pyrimidin-4-yl) -1-methylurea;
3) Preparation of 1- (6- (4- (4-ethylpiperazin-1-yl) phenylamino) pyrimidin- -Indazol-4-yl) -1-methylurea;
4) Synthesis of 1-methyl-3- (3-methyl-1- (6-methylpyridin- Methylpiperidin-4-yl) phenylamino) pyrimidin-4-yl) urea;
5) Preparation of 1- (6- (4- (4-ethylpiperazin-1-yl) phenylamino) pyrimidin- ) -3-methyl-1H-indazol-4-yl) -1-methylurea;
6) 1- (6- (4- (4-Isopropylpiperazin-1-yl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
7) Preparation of 1- (6- (4- (4- (cyclopropylmethyl) piperazin-1-yl) phenylamino) pyrimidin- (6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
8) Preparation of 1- (6- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenylamino) pyrimidin- Methyl-1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
9) 1- (6- (4- (4-Ethylpiperazin-1-yl) phenylamino) pyrimidin- Yl) methyl) -1H-indazol-4-yl) urea;
10) 1- (6- (4- (4-Ethylpiperazin-1-yl) phenylamino) pyrimidin- ) -3-methyl-1H-indazol-4-yl) -1-methylurea;
11) Preparation of 3- (1- (cyclohexylmethyl) -3-methyl-1H-indazol-4-yl) 4-yl) -1-methylurea;
12) 1- (6- (4- (4-Ethylpiperazin-1-yl) phenylamino) pyrimidin- Methyl) -3-methyl-1H-indazol-4-yl) -1-methylurea;
13) tert-Butyl 4- (4- (6- (1 -methyl-3- (3-methyl- Yurido) pyrimidin-4-ylamino) phenyl) piperazine-1-carboxylate;
14) Preparation of l-methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) Yl) phenylamino) pyrimidin-4-yl) urea;
15) 1- (6- (4- (4- (2-Hydroxyethyl) piperazin-1-yl) phenylamino) pyrimidin- - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
16) 3- (3-Cyclopropyl-l- (6-methylpyridin-2-yl) methyl) -lH-indazol- -1-yl) phenylamino) pyrimidin-4-yl) -1-methylurea;
17) 1- (6- (4- (4-Acetylpiperazin-1-yl) phenylamino) pyrimidin- Pyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
18) 1- (6- (4- (4-Ethylpiperazine-1-carbonyl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
19) 1-Methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) Methylpiperazine-1-carbonyl) phenylamino) pyrimidin-4-yl) urea;
20) 1- (6- (4- (4- (dimethylamino) piperidin-l-yl) phenylamino) pyrimidin- ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
21) Preparation of 1- (6- (2-methoxy-4- (4- (pyrrolidin- 1 -yl) piperidin- 1- yl) phenylamino) pyrimidin- 3- (3-Methyl-1 - ((6-methylpyridin-2-yl) methyl) -1 H-indazol-4-yl) urea;
22) 1- (6- (2-Methoxy-4-morpholinophenylamino) pyrimidin- Yl) methyl) -lH-indazol-4-yl) urea;
23) 1- (6- (2-Methoxy-4- (1- methylpiperidin-4-yloxy) phenylamino) pyrimidin- 1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
24) 1- (6- (4- (4-Ethylpiperazin-1-yl) -3-fluorophenylamino) pyrimidin- ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
25) A mixture of 1-ethyl-1- (6- (4- (4-ethylpiperazin-1-yl) -3-fluorophenylamino) pyrimidin- ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
26) 4- (6- (3- (1-isobutyl-3-methyl-1H-indazol- N- (1-methylpiperidin-4-yl) benzamide;
27) 3-Methoxy-4- (6- (1-methyl-3- (3- methyl- Yl) pyrimidin-4-ylamino) -N- (1-methylpiperidin-4-yl) benzamide;
28) l-Methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) Methylpiperidin-4-yl) -1H-pyrazol-4-ylamino) pyrimidin-4-yl) urea;
29) 1-Methyl-1- (6- (4- (1-methyl-1,2,3,6-tetrahydropyridin-4- yl) phenylamino) pyrimidin- Methyl-1 - ((6-methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea;
30) 1-Methyl-3- (3-methyl-l- (6-methylpyridin- 2- yl) methyl) Morpholinoethoxy) phenylamino) pyrimidin-4-yl) urea; And
31) 1- (6- (4- (4-Hydroxypiperidin-1-yl) phenylamino) pyrimidin- Methylpyridin-2-yl) methyl) -1H-indazol-4-yl) urea.
제 1 항 내지 제 6 항 중 어느 한 항에 따르는 화합물을 활성 성분으로 함유하는, FMS 키나아제의 활성에 기인하는 질환을 예방 또는 치료하기 위한 약학적 조성물.
A pharmaceutical composition for preventing or treating a disease caused by the activity of FMS kinase, which comprises the compound according to any one of claims 1 to 6 as an active ingredient.
제 7 항에 있어서,
상기 FMS 키나아제의 활성에 기인하는 질환이, 면역성 질환, 대사성 질환, 염증성 질환, 암, 또는 종양인 것을 특징으로 하는, 약학적 조성물.
8. The method of claim 7,
Wherein the disease caused by the activity of the FMS kinase is an immune disease, a metabolic disease, an inflammatory disease, a cancer, or a tumor.
제 8 항에 있어서,
상기 면역성 질환, 대사성 질환, 또는 염증성 질환이 류마티스 관절염(rheumatoid arthritis), 골다공증(osteoporosis), 크론병(Crohn's disease), 동맥경화증, 또는 고지혈증인 것을 특징으로 하는, 약학적 조성물.
9. The method of claim 8,
Wherein said immune, metabolic, or inflammatory disease is rheumatoid arthritis, osteoporosis, Crohn's disease, arteriosclerosis, or hyperlipidemia.
제 8 항에 있어서,
상기 암 또는 종양이 간암(liver cancer), 간세포암(hepatocellular carcinoma), 갑상선암(thyroid cancer), 결장암(colon cancer), 고환암(testicular cancer), 골암(bone cancer), 구강암(oral cancer), 기저세포암(basal cell carcinoma), 난소암(ovarian cancer), 뇌종양(brain tumor), 담낭암(gallbladder carcinoma), 담도암(biliary tract cancer), 두경부암(head and neck cancer), 직장암(rectal cancer), 방광암(vesical carcinoma), 설암(tongue cancer), 식도암(esophageal cancer), 신경교종(glioma), 신경교아종(glioblastoma), 신장암(renal cancer), 악성흑색종(malignant melanoma), 위암(gastric cancer), 유방암(breast cancer), 육종(sarcoma), 인두암(pharynx carcinoma), 자궁암(uterine cancer), 자궁경부암(cervical cancer), 전립선암(prostate cancer), 직장암(rectal cancer), 췌장암(pancreatic cancer), 폐암(lung cancer), 또는 피부암(skin cancer)인 것을 특징으로 하는, 약학적 조성물.
9. The method of claim 8,
The cancer or the tumor may be a liver cancer, a hepatocellular carcinoma, a thyroid cancer, a colon cancer, a testicular cancer, a bone cancer, an oral cancer, a basal cell Cancer, ovarian cancer, brain tumor, gallbladder carcinoma, biliary tract cancer, head and neck cancer, rectal cancer, bladder cancer, ovarian cancer, esophageal cancer, glioma, glioblastoma, renal cancer, malignant melanoma, gastric cancer, pancreatic cancer, gastric cancer, Breast cancer, sarcoma, pharynx carcinoma, uterine cancer, cervical cancer, prostate cancer, rectal cancer, pancreatic cancer, A lung cancer, or a skin cancer.
제 7 항에 있어서,
상기 약학적 조성물이 스테로이드 약제, 메소트렉세이트, 레플루노마이드, 항-TNFα 약제, 칼시네우린 저해제, 항히스타민 약제, 세포 신호전달 억제제, 유사분열 억제제, 알킬화제, 항-대사제, 삽입 항암제, 토포아이소머라제 억제제, 면역요법제, 항-호르몬제 및 이들의 혼합물로 이루어진 군으로부터 선택된 약제와 복합 제제화되거나 또는 병용 처방되는 것을 특징으로 하는, 약학적 조성물.
8. The method of claim 7,
Wherein said pharmaceutical composition is selected from the group consisting of a steroid agent, mesotrexate, re flunomide, an anti-TNFa agent, a calcineurin inhibitor, an antihistamine agent, a cell signaling inhibitor, a mitotic inhibitor, an alkylating agent, Or a combination thereof with a medicament selected from the group consisting of an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent, an antiinflammatory agent,
제 7 항에 있어서,
상기 약학적 조성물이 정제, 환제, 산제, 캅셀제, 시럽 또는 에멀젼 형태의 경구용 제제인 것을 특징으로 하는, 약학적 조성물.8. The method of claim 7,
Wherein the pharmaceutical composition is an oral preparation in the form of tablets, pills, powders, capsules, syrups or emulsions.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019519512A (en) * 2016-05-20 2019-07-11 浙江海正薬業股▲ふん▼有限公司Ｚｈｅｊｉａｎｇ Ｈｉｓｕｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ ＣＯ．，ＬＴＤ． Pyrimidine derivatives, process for their preparation and use in medicine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2019519512A (en) * 2016-05-20 2019-07-11 浙江海正薬業股▲ふん▼有限公司Ｚｈｅｊｉａｎｇ Ｈｉｓｕｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌ ＣＯ．，ＬＴＤ． Pyrimidine derivatives, process for their preparation and use in medicine

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