WO2019107943A1 - Jak inhibitor compound and preparation method therefor - Google Patents

Jak inhibitor compound and preparation method therefor Download PDF

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WO2019107943A1
WO2019107943A1 PCT/KR2018/014884 KR2018014884W WO2019107943A1 WO 2019107943 A1 WO2019107943 A1 WO 2019107943A1 KR 2018014884 W KR2018014884 W KR 2018014884W WO 2019107943 A1 WO2019107943 A1 WO 2019107943A1
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cancer
nmr
mhz
disease
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PCT/KR2018/014884
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강수성
김신애
박은희
박재돈
이광석
전현호
한승희
홍기범
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주식회사한국파마
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to JAK inhibitor compounds, and methods for their preparation.
  • Protein kinases are a class of enzymes that regulate a variety of important biological processes, including cell growth, survival and differentiation, organogenesis and development, neovascularization, tissue repair and regeneration. Protein kinases exert their biological functions by catalyzing the phosphorylation of the protein (or substrate), thereby modulating the cellular activity of the substrate in a variety of biological contexts. In addition to functioning in normal tissues / organs, many protein kinases also play a more specific role in the host of human disease, including cancer. A subpopulation of protein kinases (also referred to as tumor protein kinase), when not regulated, induces tumor formation and growth, and also contributes to tumor progression and progression. Thus, tumor protein kinases are one of the largest and most interested groups of protein targets for cancer regulation and drug development.
  • JAK Janus Kinase
  • JAK1 Janus kinase-1
  • JAK-2 Janus kinase-2
  • JAK3 Janus kinase-3)
  • TYK2 Protein-Tyrosine Kinase 2
  • JAK protein ranges from 120 kDa to 140 kDa and includes seven conserved JAK homology (JH) domains, one of which is a functional catalytic kinase domain and the other is potentially regulatory and / or STAT Is a pseudokinase domain capable of functioning as a docking site for < Desc / Clms Page number 2 >
  • JH JAK homology
  • Blocking signal transduction at the level of JAK kinase has the potential for the development of therapies for, for example, inflammatory diseases, autoimmune diseases, myeloproliferative disorders, and cancer of the human body, Will have a therapeutically beneficial effect on the patient suffering from.
  • Patent Document 1 As a result, all of the contents disclosed in Patent Document 1 are cited by the prior art in this specification.
  • Patent Document 1 US 2007/0135461 A1 (Jun. 14, 2007)
  • R 1 is a hydrogen group, a C 1 -C 3 alkyl group, or a C 3 -C 8 cycloalkyl group;
  • R 2 is a hydrogen group, or a C 1 -C 3 alkyl group
  • R 3 represents a hydrogen group, , or ego
  • R 4 and R 5 are each independently a hydrogen group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;
  • R 1 is not a hydrogen group.
  • R 1 is a methyl group, or a pharmaceutically acceptable salt thereof.
  • R 2 is a hydrogen group or a methyl group, or a pharmaceutically acceptable salt thereof.
  • R 4 and R 5 each independently represent a hydrogen group, a methyl group, a methoxy group, a halogen group, a hydroxy group, or a cyano group, or a pharmaceutically acceptable salt thereof.
  • compositions for the treatment or prevention of an autoimmune disease, an inflammatory disease, or cancer comprising a compound of any one of the present invention or a pharmaceutically acceptable salt thereof.
  • the present invention can modulate signal transduction at the level of JAK kinase, for example, to show therapeutic effects on inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and cancer of the human body.
  • An aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 is a hydrogen group, a C 1 -C 3 alkyl group, or a C 3 -C 8 cycloalkyl group;
  • R 2 is a hydrogen group, or a C 1 -C 3 alkyl group
  • R 3 represents a hydrogen group, , or ego
  • R 4 and R 5 are each independently a hydrogen group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;
  • R 1 is not a hydrogen group.
  • the compounds represented by the above formula (I) can control the activity of Janus kinase (JAK).
  • the term "modulate" refers to the ability to increase or decrease the activity of one or more of the JAK kinases.
  • the compounds of the present invention can be used in a method of modulating JAK by contacting JAK with at least one compound or composition of the invention.
  • a compound of the invention may act as an inhibitor of one or more JAKs.
  • JAKs that the compounds of the invention bind and / or modulate include any member of the JAK family.
  • the JAK is JAK1, JAK2, JAK3, or TYK2.
  • the JAK is JAK1 or JAK2.
  • the JAK is JAK2.
  • JAK is JAK3.
  • Another aspect of the present invention relates to a pharmaceutical composition for the treatment or prevention of an autoimmune disease, an inflammatory disease, or cancer comprising the compound represented by the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof.
  • JAK-related diseases include diseases or diseases or conditions that are directly or indirectly related to the expression or activity of JAK, such as hyperplasia and / or abnormal activity.
  • JAK-related diseases include diseases, diseases or conditions that can be prevented, alleviated or cured by controlling JAK activity.
  • JAK-related diseases include, but are not limited to, immune system related diseases such as organ transplant rejection (e.g., transplant rejection and graft versus host response), multiple sclerosis, rheumatoid arthritis, inflammatory arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis Inflammatory bowel disease, ulcerative colitis, Crohn's disease, severe myasthenia gravis, immunoglobulin nephritis, autoimmune thyroid disease, asthma, food allergy, atopic dermatitis, psoriasis, autoimmune, (PV) or water-repellent oil pumice window (BP).
  • organ transplant rejection e.g., transplant rejection and graft versus host response
  • multiple sclerosis rheumatoid arthritis
  • inflammatory arthritis e.g., psoriatic arthritis
  • type I diabetes lupus
  • psoriasis Inflammatory bowel disease ulcerative colitis
  • JAK-related diseases include inflammatory and inflammatory diseases.
  • inflammatory diseases include inflammatory diseases of the eye such as blinking, uveitis, scleritis, conjunctivitis or related diseases, inflammatory diseases of the respiratory tract such as upper respiratory tract including nose and sinus such as rhinitis or sinusitis, Obstructive pulmonary disease, and the like), inflammatory myopathies such as myocarditis and other inflammatory diseases.
  • Other inflammatory diseases include, for example, systemic inflammatory response syndrome (SIRS) and sepsis shock, and may also be used to treat them.
  • SIRS systemic inflammatory response syndrome
  • sepsis shock and may also be used to treat them.
  • JAK-related diseases include cancer characterized by solid tumors such as prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, (AML) or multiple myeloma), and skin cancers such as skin T-cell lymphoma (CTCL) and skin B-cell lymphoma are administered to a mammal in need of such treatment, .
  • skin T-cell lymphomas include Sezary syndrome and bacterial sarcoma.
  • it can be used to treat diseases or conditions related to ischemic reperfusion injury or inflammatory ischemic cases such as stroke or cardiac arrest, and can also be used to treat stenosis, percutaneous dermatitis or fibrosis.
  • the JAK inhibitors of the present invention may also be used to treat conditions associated with hypoxia or astrocytosis, such as diabetic retinopathy, cancer or neurodegeneration. See, for example, Dudley, A.C. et al. Biochem. J. 2005, 390 (Pt 2): 427-36) and [Sriram, K. et al. J. Biol. Chem. 2004, 279 (19): 19936-47. Epub 2004 Mar 2].
  • the JAK inhibitors of the present invention can also be used to treat Alzheimer's disease.
  • JAK inhibitors of the present invention can also be used to treat gout and prostatic enlargement due to, for example, benign prostatic hyperplasia or benign prostatic hyperplasia.
  • compositions of the present invention may be administered orally in dosage forms such as tablets, capsules (each of which includes a sustained release or time release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions . They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all of which are well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
  • composition of the present invention can be administered intranasally via topical use of suitable intranasal vehicles, or via the transdermal route using a transdermal patch.
  • administration of the dose will, of course, be continuous rather than intermittent throughout the course of the administration.
  • the compounds may specifically illustrate the compounds of Tables 1 and 2.
  • the values of JAK1, JAK2, and JAK3 are shown by testing the IC50 concentration of each compound.
  • the compounds of the present invention represented by formula (I) including the exemplified compounds of Tables 1 and 2 above can be prepared by the methods specifically described in the general synthesis procedures described below. As a person skilled in the art, it will be understood from the description of this general synthesis procedure that the synthesis method for the specific exemplified compounds or the example compounds will also be understood from the description of the individual synthesis methods for each compound.
  • tert-butyl (1-aryl piperidin-4-yl) carbamate (2 mmol) was added to a 10% HCl methanol solution and mixed at room temperature for about 18 hours. After the reaction, the mixture was concentrated under reduced pressure. The yield ( ⁇ 100% yield) was used without further purification.
  • Reagents and conditions (a) Amines, CDI, DMF, room temperature; (b) Amines, TEA, NMP, microwave, 180 ° C
  • CDI (1.07 g, 6.61 mmol) was added dropwise to a solution of 4-chloro- 1H- pyrrolo [2,3- b ] pyridine-5-carboxylic acid (1.00 g, 5.09 mmol) in DMF , And the reaction mixture was stirred at room temperature for about 1 hour. To this mixture was slowly added dropwise 2.0 mmol of various amines (30 mmol, solvent THF), followed by stirring at room temperature for about 1 hour. The resulting mixture was poured into ethyl acetate and a white solid was obtained as a precipitate.

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Abstract

The present invention relates to a JAK inhibitor compound and a preparation method therefor and, more specifically, to a compound of chemical formula I below and a pharmaceutically acceptable salt thereof. The present invention controls signal transduction at the JAK kinase level, thereby enabling treatment effects on inflammatory diseases, autoimmune diseases, myeloproliferative disorders, cancer of the human body and the like to be exhibited.

Description

JAK 저해제 화합물, 및 이의 제조방법JAK inhibitor compounds, and methods for their preparation
본 발명은 JAK 저해제 화합물, 및 이의 제조방법에 관한 것이다.The present invention relates to JAK inhibitor compounds, and methods for their preparation.
단백질 키나제(PK)는 특히 세포 성장, 생존 및 분화, 기관 형성 및 발생, 신혈관형성, 조직 보수 및 재생을 비롯한 다양하고 중요한 생물학적 과정을 조절하는 일단의 효소이다. 단백질 키나제는 단백질(또는 기질)의 포스포릴화에 촉매 작용을 함으로써 그 생물학적 기능을 발휘하고, 이로써 다양한 생물학적 맥락에서 기질의 세포활성을 조정한다. 정상의 조직/기관에서의 기능 이외에도, 많은 단백질 키나제는 암을 비롯한 인체 질병의 숙주에서 보다 특수한 역할도 한다. 단백질 키나제의 하위집단(종양 단백질 키나제로도 언급함)은, 조절되지 않을 경우에, 종양 형성 및 성장을 유발하고, 또한 종양의 지속 및 진행에도 기여한다. 따라서, 종양 단백질 키나제는 암 조정 및 약물 개발에 대한 가장 크고 가장 관심이 가는 단백질 표적의 군 중의 대표적인 하나이다.Protein kinases (PKs) are a class of enzymes that regulate a variety of important biological processes, including cell growth, survival and differentiation, organogenesis and development, neovascularization, tissue repair and regeneration. Protein kinases exert their biological functions by catalyzing the phosphorylation of the protein (or substrate), thereby modulating the cellular activity of the substrate in a variety of biological contexts. In addition to functioning in normal tissues / organs, many protein kinases also play a more specific role in the host of human disease, including cancer. A subpopulation of protein kinases (also referred to as tumor protein kinase), when not regulated, induces tumor formation and growth, and also contributes to tumor progression and progression. Thus, tumor protein kinases are one of the largest and most interested groups of protein targets for cancer regulation and drug development.
야누스 키나제(Janus Kinase, JAK) 부류는 면역 반응에 관여하는 세포의 증식 및 작용의 시토킨 의존적 조절에 있어서 중요한 역할을 한다. 현재, 다음과 같은 4종의 포유류 JAK 부류 구성원이 알려져 있다: JAK1(야누스 키나제-1), JAK-2(야누스 키나제-2), JAK3(야누스 키나제-3) 및 TYK2(단백질-티로신 키나제 2). JAK 단백질의 크기는 120 kDa 내지 140 kDa 범위이며, 7개의 보존된 JAK 상동성(JH) 도메인을 포함하며, 이중 하나는 기능성 촉매 키나제 도메인이고, 다른 하나는 잠재적으로 조절 기능을 하고/하거나 STAT에 대한 도킹(docking) 부위로서 기능할 수 있는 슈도키나제 도메인이다.The Janus Kinase (JAK) class plays an important role in the cytokine-dependent regulation of cell proliferation and action involved in the immune response. At present, the following four members of the mammalian JAK class are known: JAK1 (Janus kinase-1), JAK-2 (Janus kinase-2), JAK3 (Janus kinase-3) and TYK2 (Protein-Tyrosine Kinase 2) . The size of the JAK protein ranges from 120 kDa to 140 kDa and includes seven conserved JAK homology (JH) domains, one of which is a functional catalytic kinase domain and the other is potentially regulatory and / or STAT Is a pseudokinase domain capable of functioning as a docking site for < Desc / Clms Page number 2 >
JAK 키나제의 수준에서 신호 형질도입을 차단하는 것은, 예컨대 염증성 질환, 자가면역 질환, 골수증식성 질환, 및 인체의 암에 대한 치료법의 개발에 대한 가능성을 갖고, 건선 및 피부 감작과 같은 피부 면역 질환에 걸린 환자에서 치료학적으로 유리한 효과를 가질 것이다.Blocking signal transduction at the level of JAK kinase has the potential for the development of therapies for, for example, inflammatory diseases, autoimmune diseases, myeloproliferative disorders, and cancer of the human body, Will have a therapeutically beneficial effect on the patient suffering from.
따라서, 야누스 키나제 또는 관련 키나제에 대한 억제제들을 광범위하게 찾고 있으며, 몇가지 특허 공보들은 유효한 부류의 화합물들을 보고하고 있다. 예를 들면, 피롤로피리딘 및 피롤로피리미딘이 일부의 JAK 억제제로서 작용할 수 있음이 미국출원공개공보 US2007/0135461 A1 등에 개시되어 있다(특허문헌 1). 이로써, 특허문헌 1에 개시된 내용 전부는 본 명세서 상의 종래기술로 모두 인용·합체된다.Therefore, inhibitors against Janus kinase or related kinases are extensively sought, and several patent publications report effective classes of compounds. For example, pyrrolopyridines and pyrrolopyrimidines may act as some JAK inhibitors, as disclosed in US Patent Application Publication No. US2007 / 0135461 A1 (Patent Document 1). As a result, all of the contents disclosed in Patent Document 1 are cited by the prior art in this specification.
[선행기술문헌][Prior Art Literature]
(특허문헌 1) US 2007/0135461 A1 (2007.06.14.)(Patent Document 1) US 2007/0135461 A1 (Jun. 14, 2007)
야누스 키나제 억제 활성을 갖는 신규화합물 제공하는 것을 본 발명의 목적으로 한다.It is an object of the present invention to provide a novel compound having Janus kinase inhibitory activity.
본 발명은 상기한 종래기술의 문제점을 해결하기 위해 안출된 것으로서,SUMMARY OF THE INVENTION The present invention has been made to solve the above-mentioned problems of the prior art,
하기 화학식 I의 화합물 또는 그의 약제학적으로 허용되는 염을 제공한다.Claims 1. A compound of formula (I): < EMI ID = 32.1 >
[화학식 I](I)
Figure PCTKR2018014884-appb-I000001
Figure PCTKR2018014884-appb-I000001
상기 식에서,In this formula,
R1은 수소기, C1-C3 알킬기, 또는 C3-C8 시클로알킬기이고;R 1 is a hydrogen group, a C 1 -C 3 alkyl group, or a C 3 -C 8 cycloalkyl group;
R2는 수소기, 또는 C1-C3 알킬기이고;R 2 is a hydrogen group, or a C 1 -C 3 alkyl group;
R3는 수소기,
Figure PCTKR2018014884-appb-I000002
, 또는
Figure PCTKR2018014884-appb-I000003
이고;R 3 represents a hydrogen group,
Figure PCTKR2018014884-appb-I000002
, or
Figure PCTKR2018014884-appb-I000003
ego;
R4, 및 R5는, 각각 독립적으로, 수소기, C1-C3 알킬기, C1-C3 알콕시기, 할로겐기, 히드록시기, 또는 시아노기이며; n은 0, 또는 1의 정수이다.R 4 and R 5 are each independently a hydrogen group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;
단, R4, 및 R5가 동시에 수소기인 경우, R1은 수소기가 아니다.Provided that when R 4 and R 5 are simultaneously a hydrogen group, R 1 is not a hydrogen group.
본 발명에 있어서, R1은 메틸기인 것인 화합물 또는 그의 약제학적으로 허용되는 염을 제공한다.In the present invention, R 1 is a methyl group, or a pharmaceutically acceptable salt thereof.
본 발명에 있어서, R2는 수소기, 또는 메틸기인 것인 화합물 또는 약제학적으로 허용되는 염을 제공한다.In the present invention, R 2 is a hydrogen group or a methyl group, or a pharmaceutically acceptable salt thereof.
본 발명에 있어서, R4, R5는, 각각 독립적으로, 수소기, 메틸기, 메톡시기, 할로겐기, 히드록시기, 또는 시아노기인 것인 화합물 또는 그의 약제학적으로 허용되는 염을 제공한다.In the present invention, R 4 and R 5 each independently represent a hydrogen group, a methyl group, a methoxy group, a halogen group, a hydroxy group, or a cyano group, or a pharmaceutically acceptable salt thereof.
또한, 본 발명의 어느 한 한 항의 화합물 또는 그의 약제학적으로 허용되는 염을 포함하는 자가면역 질병, 염증성 질병, 또는 암을 치료 또는 예방에 사용하기 위한 의약 조성물을 제공한다.Also provided is a pharmaceutical composition for the treatment or prevention of an autoimmune disease, an inflammatory disease, or cancer comprising a compound of any one of the present invention or a pharmaceutically acceptable salt thereof.
본 발명은, JAK 키나제의 수준에서 신호 형질도입을 조절하여, 예컨대 염증성 질환, 자가면역 질환, 골수증식성 질환, 및 인체의 암 등에 대한 치료 효과를 나타낼 수 있다.The present invention can modulate signal transduction at the level of JAK kinase, for example, to show therapeutic effects on inflammatory diseases, autoimmune diseases, myeloproliferative diseases, and cancer of the human body.
이하, 본 발명에 대해서 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명의 일측면은 하기 화학식 I의 화합물 또는 그의 약제학적으로 허용되는 염에 관한 것이다.An aspect of the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:
[화학식 I](I)
Figure PCTKR2018014884-appb-I000004
Figure PCTKR2018014884-appb-I000004
상기 식에서,In this formula,
R1은 수소기, C1-C3 알킬기, 또는 C3-C8 시클로알킬기이고;R 1 is a hydrogen group, a C 1 -C 3 alkyl group, or a C 3 -C 8 cycloalkyl group;
R2는 수소기, 또는 C1-C3 알킬기이고;R 2 is a hydrogen group, or a C 1 -C 3 alkyl group;
R3는 수소기,
Figure PCTKR2018014884-appb-I000005
, 또는
Figure PCTKR2018014884-appb-I000006
이고;R 3 represents a hydrogen group,
Figure PCTKR2018014884-appb-I000005
, or
Figure PCTKR2018014884-appb-I000006
ego;
R4, 및 R5는, 각각 독립적으로, 수소기, C1-C3 알킬기, C1-C3 알콕시기, 할로겐기, 히드록시기, 또는 시아노기이며; n은 0, 또는 1의 정수이다.R 4 and R 5 are each independently a hydrogen group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;
단, R4, 및 R5가 동시에 수소기인 경우, R1은 수소기가 아니다.Provided that when R 4 and R 5 are simultaneously a hydrogen group, R 1 is not a hydrogen group.
상기 본 발명의 화합물은 하나 이상의 비대칭 중심을 가질 수 있다. 달리 나타내지 않는 한, 본 발명의 화합물의 모든 키랄 (거울상이성질체 및 부분입체이성질체) 및 라세미 형태는 본 발명에 포함된다. 또한 올레핀, C=N 이중결합 등의 다수의 기하이성질체가 화합물 중에 존재할 수 있고, 그 모든 안정한 이성질체가 본 발명에서 고려된다. 본 발명의 화합물의 시스 및 트랜스 기하 이성질체가 기재되어 있고, 이들은 이성질체의 혼합물로서 또는 분리된 이성질체 형태로서 단리될 수 있다. 본 발명의 화합물은 광학 활성 형태 또는 라세미 형태로 단리될 수 있다. 광학적으로 활성인 형태를 제조하는 방법 (예를 들어, 라세미 형태의 분할에 의해 또는 광학적으로 활성인 출발 물질로부터의 합성에 의해)은 당업계에 널리 공지되어 있다. 특정 입체화학 또는 이성질체 형태가 구체적으로 표시되지 않는다면, 구조의 모든 키랄 (거울상이성질체 및 부분입체이성질체) 및 라세미 형태, 및 모든 기하이성질체 형태가 의도된다.The compounds of the present invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of the compounds of this invention are included in the present invention. Also, a number of geometric isomers such as olefins, C = N double bonds, etc., can be present in the compounds, and all the stable isomers thereof are contemplated by the present invention. The cis and trans geometric isomers of the compounds of the invention are described, which can be isolated as a mixture of isomers or in isolated isomeric forms. The compounds of the present invention may be isolated in optically active form or in racemic form. Methods for preparing optically active forms (e. G., By resolution in racemic form or by synthesis from optically active starting materials) are well known in the art. Unless specific stereochemistry or isomeric forms are specifically indicated, all chiral (enantiomeric and diasteriomeric) and racemic forms of the structure, and all geometric isomeric forms are contemplated.
상기 화학식 I로 표시되는 화합물들은 야누스 키나제(JAK)의 활성을 조절할 수 있다. 여기서, 용어 "조절한다"의 의미는 1종 이상의 JAK 부류의 키나제의 활성을 증가 또는 감소시킬 수 있는 능력을 언급한 것이다. 따라서, 본 발명의 화합물은, JAK와 본 발명의 화합물 또는 조성물 1종 이상을 접촉시킴으로써 JAK를 조절하는 방법에 사용될 수 있다. 특히, 일부의 실시양태에서, 본 발명의 화합물은 1종 이상의 JAK의 억제제로서 작용할 수 있다.The compounds represented by the above formula (I) can control the activity of Janus kinase (JAK). As used herein, the term " modulate " refers to the ability to increase or decrease the activity of one or more of the JAK kinases. Thus, the compounds of the present invention can be used in a method of modulating JAK by contacting JAK with at least one compound or composition of the invention. In particular, in some embodiments, a compound of the invention may act as an inhibitor of one or more JAKs.
본 발명의 화합물이 결합 및/또는 조절하는 JAK는 JAK 부류중 임의의 구성원을 포함한다. 일부의 실시양태에서, JAK는 JAK1, JAK2, JAK3 또는 TYK2이다. 일부의 실시양태에서, JAK는 JAK1 또는 JAK2이다. 일부의 실시양태에서, JAK는 JAK2이다. 일부의 실시양태에서, JAK는 JAK3이다.JAKs that the compounds of the invention bind and / or modulate include any member of the JAK family. In some embodiments, the JAK is JAK1, JAK2, JAK3, or TYK2. In some embodiments, the JAK is JAK1 or JAK2. In some embodiments, the JAK is JAK2. In some embodiments, JAK is JAK3.
본 발명의 다른 측면은 상기 화학식 I로 표시되는 화합물 또는 그의 약제학적으로 허용되는 염을 포함하는 자가면역 질병, 염증성 질병, 또는 암을 치료 또는 예방에 사용하기 위한 의약 조성물에 관한 것이다.Another aspect of the present invention relates to a pharmaceutical composition for the treatment or prevention of an autoimmune disease, an inflammatory disease, or cancer comprising the compound represented by the above-mentioned formula (I) or a pharmaceutically acceptable salt thereof.
JAK 관련 질병으로서는, JAK의 형질발현 또는 활성, 예를 들면 과형질발현 및/또는 비정상적인 활성도와 직접 또는 간접적으로 연관된 질병, 질환 또는 증상을 들 수 있다. 또한, JAK 관련 질병으로는, JAK 활성을 조절함으로써 예방, 경감 또는 치유될 수 있는 질병, 질환 또는 증상을 들 수 있다.JAK-related diseases include diseases or diseases or conditions that are directly or indirectly related to the expression or activity of JAK, such as hyperplasia and / or abnormal activity. In addition, JAK-related diseases include diseases, diseases or conditions that can be prevented, alleviated or cured by controlling JAK activity.
JAK 관련 질병의 예로서는, 면역계 관련 질병, 예를 들면 기관 이식 거부반응(예: 이식거절반응 및 이식편대숙주반응), 다발성 경화증, 류마티스 관절염, 연소성 관절염, 건선성 관절염, I형 당뇨병, 루푸스, 건선, 염증성 장 질환, 궤양성 대장염, 크론병(Crohn's disease), 중증근 무력증, 면역글로불린 신증, 자가면역 갑상선 질환, 천식, 음식 알레르기, 아토피 피부염, 건선, 자가면역 수포성 피부 질환, 예컨대 심상성천포창(PV) 또는 수포성 유천포창(BP) 등을 들 수 있다.Examples of JAK-related diseases include, but are not limited to, immune system related diseases such as organ transplant rejection (e.g., transplant rejection and graft versus host response), multiple sclerosis, rheumatoid arthritis, inflammatory arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis Inflammatory bowel disease, ulcerative colitis, Crohn's disease, severe myasthenia gravis, immunoglobulin nephritis, autoimmune thyroid disease, asthma, food allergy, atopic dermatitis, psoriasis, autoimmune, (PV) or water-repellent oil pumice window (BP).
JAK 관련 질병의 다른 예로서는, 염증 및 염증성 질병을 들 수 있다. 염증성 질병의 예로서는, 눈의 염증성 질병(예: 홍채염, 포도막염, 공막염, 결막염 또는 관련 질병), 호흡관의 염증성 질병(예: 코 및 부비동을 포함한 상부 호흡관, 예컨대 비염 또는 부비동염, 또는 기관지, 만성 폐색성 폐 질환 등을 비롯한 하부 호흡관의 질병), 염증성 근병증, 예컨대 심근염 및 기타 염증성 질병을 들 수 있다. 다른 염증성 질환으로는, 예컨대 전신성 염증성 반응 증후군(SIRS) 및 패혈증 쇼크를 들 수 있고, 이들을 치료하는 데에도 사용될 수도 있다.Other examples of JAK-related diseases include inflammatory and inflammatory diseases. Examples of inflammatory diseases include inflammatory diseases of the eye such as iritis, uveitis, scleritis, conjunctivitis or related diseases, inflammatory diseases of the respiratory tract such as upper respiratory tract including nose and sinus such as rhinitis or sinusitis, Obstructive pulmonary disease, and the like), inflammatory myopathies such as myocarditis and other inflammatory diseases. Other inflammatory diseases include, for example, systemic inflammatory response syndrome (SIRS) and sepsis shock, and may also be used to treat them.
JAK 관련 질병의 또 다른 예로서는, 고형 종양을 특징으로 하는 암(예: 전립선암, 신장암, 간암, 췌장암, 위암, 유방암, 폐암, 두경부암, 갑상선암, 교아종, 카포시 육종, 캐슬만(Castleman)병, 흑색종), 혈액암(예: 림프종, 백혈병, 예컨대 급성 림프성 백혈병, 급성 골수성 백혈병(AML) 또는 다발성 골수종), 및 피부암, 예컨대 피부 T세포 림프종(CTCL) 및 피부 B세포 림프종을 들 수 있다. 피부 T세포 림프종의 예로서는 세저리(Sezary) 증후군 및 균상식육종을 들 수 있다.Other examples of JAK-related diseases include cancer characterized by solid tumors such as prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, (AML) or multiple myeloma), and skin cancers such as skin T-cell lymphoma (CTCL) and skin B-cell lymphoma are administered to a mammal in need of such treatment, . Examples of skin T-cell lymphomas include Sezary syndrome and bacterial sarcoma.
이외에도, 허혈 재관류 손상 또는 졸중 또는 심장 정지와 같은 염증성 허혈 사례와 관련된 질병 또는 증상을 치료하는 데에도 사용될 수 있고, 협착증, 경피성 피부염 또는 섬유증을 치료하는 데에도 사용될 수 있다.In addition, it can be used to treat diseases or conditions related to ischemic reperfusion injury or inflammatory ischemic cases such as stroke or cardiac arrest, and can also be used to treat stenosis, percutaneous dermatitis or fibrosis.
또한, 본 발명의 JAK 억제제는 저산소증 또는 성상교세포증, 예컨대 당뇨병성 망막증, 암 또는 신경퇴화와 관련된 증상을 치료하는 데에도 사용될 수 있다. 이에 관해서는 문헌 [Dudley, A.C. et al. Biochem. J. 2005, 390(Pt 2):427-36] 및 [Sriram, K. et al. J. Biol. Chem. 2004, 279(19): 19936-47. Epub 2004 Mar 2]을 참조할 수 있다. 본 발명의 JAK 억제제는 알츠하이머병을 치료하는 데에도 사용될 수 있다.In addition, the JAK inhibitors of the present invention may also be used to treat conditions associated with hypoxia or astrocytosis, such as diabetic retinopathy, cancer or neurodegeneration. See, for example, Dudley, A.C. et al. Biochem. J. 2005, 390 (Pt 2): 427-36) and [Sriram, K. et al. J. Biol. Chem. 2004, 279 (19): 19936-47. Epub 2004 Mar 2]. The JAK inhibitors of the present invention can also be used to treat Alzheimer's disease.
나아가, 본 발명의 JAK 억제제는 통풍 및 예를 들면 양성 전립선 비대증 또는 전립선 비대증에 기인한 전립선 크기 증가를 치료하는 데에도 사용될 수 있다.Furthermore, the JAK inhibitors of the present invention can also be used to treat gout and prostatic enlargement due to, for example, benign prostatic hyperplasia or benign prostatic hyperplasia.
본 발명의 의약 조성물은 정제, 캡슐 (이들 각각은 지속 방출형 또는 시간 방출형 제제를 포함함), 환제, 분말, 과립, 엘릭시르, 팅크제, 현탁액, 시럽 및 에멀젼과 같은 경구 투여 형태로 투여될 수 있다. 이들은 또한 정맥 내 (볼루스 또는 주입), 복강내, 피하 또는 근육내 형태로 투여될 수 있고, 모든 사용되는 투여 형태는 제약 업계의 통상의 기술자에게 널리 공지되어 있다. 이들은 단독으로 투여될 수 있지만, 일반적으로 선택된 투여 경로 및 표준 제약 실무를 기초로 하여 선택되는 제약 담체와 함께 투여될 것이다.The pharmaceutical compositions of the present invention may be administered orally in dosage forms such as tablets, capsules (each of which includes a sustained release or time release formulation), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions . They can also be administered intravenously (bolus or infusion), intraperitoneally, subcutaneously or intramuscularly, all of which are well known to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.
또한, 본 발명의 의약 조성물은 적합한 비내 비히클의 국소 사용을 통해 비내 형태로, 또는 경피 피부 패치를 사용하여 경피 경로를 통해 투여될 수 있다. 경피 전달 시스템의 형태로 투여되는 경우에, 투여량의 투여는 물론 투여 요법 전반에 걸쳐 간헐적이기보다는 연속적일 것이다.In addition, the pharmaceutical composition of the present invention can be administered intranasally via topical use of suitable intranasal vehicles, or via the transdermal route using a transdermal patch. When administered in the form of a transdermal delivery system, administration of the dose will, of course, be continuous rather than intermittent throughout the course of the administration.
상기의 화학식 I으로 표현되는 화합물들의 각종 실시형태에서, 당해 화합물은 표 1 및 2의 화합물들을 구체적으로 예시할 수 있다. JAK1, JAK2, JAK3의 수치는 각 화합물의 IC50 농도를 시험하여 나타낸 것이다.In various embodiments of the compounds represented by formula (I) above, the compounds may specifically illustrate the compounds of Tables 1 and 2. The values of JAK1, JAK2, and JAK3 are shown by testing the IC50 concentration of each compound.
Figure PCTKR2018014884-appb-T000001
Figure PCTKR2018014884-appb-T000001
Figure PCTKR2018014884-appb-T000002
Figure PCTKR2018014884-appb-T000002
상기 표 1, 및 2의 예시된 화합물을 포함하는 화학식 I로 표시되는 본 발명의 화합물들은, 후술할 일반적인 합성 절차에서 구체적으로 기재된 방법을 포함하여 제조될 수 있다. 해당 분야 통상의 기술자로서는, 이러한 일반적 합성 절차 설명을 통해서, 구체적인 예시 화합물들이나 실시예 화합물들에 대한 합성방법에 대해서도 미루어 보아 이해할 수 있으므로, 각각의 화합물에 대한 개별적인 제조방법 설명은 생략하기로 한다.The compounds of the present invention represented by formula (I) including the exemplified compounds of Tables 1 and 2 above can be prepared by the methods specifically described in the general synthesis procedures described below. As a person skilled in the art, it will be understood from the description of this general synthesis procedure that the synthesis method for the specific exemplified compounds or the example compounds will also be understood from the description of the individual synthesis methods for each compound.
스킴 1. 1-benzylpiperidin-4-amine 또는 그의 유도체 화합물 합성의 일반적 절차Scheme 1. General procedure for the synthesis of 1-benzylpiperidin-4-amine or its derivative compounds
[일반적 반응식 Ⅰ][General Scheme I]
Figure PCTKR2018014884-appb-I000007
Figure PCTKR2018014884-appb-I000007
시약 및 조건: (a) t-butyl piperidin-4-yl carbamate, K2CO3, DMF, 실온; (b) 10% HCl in MeOH, 실온Reagents and conditions: (a) t- butyl piperidin-4-yl carbamate, K 2 CO 3 , DMF, room temperature; (b) 10% HCl in MeOH, room temperature
일반적 절차 AGeneral Procedure A
용액(용매 DMF(5ml), t-butyl piperidin-4-yl carbamate (0.50 g, 2.5 mmol))에 K2CO3 (0.83 g, 5.99 mmol) 및 aryl halide(ex.bromide) (2.75 mmol)를 실온에서 적가하였다. 상기 반응 혼합물은 실온에서 약 8시간 동안 혼합되어졌다. 반응 이후, 결과물을 Et2O (40 ml)에 붓고, H2O (40 ml), 브라인 (40 ml)으로 세척, MgSO4으로 건조하였다. 조화합물들은 실리카겔 속성 크로마토그래피 (30% Ethyl acetate in n-Hexane elution) 로 정제하였다(0.61 g, 수율 78%).K 2 CO 3 (0.83 g, 5.99 mmol) and aryl halide (ex.bromide) (2.75 mmol) were added to a solution (solvent DMF (5 ml), t -butyl piperidin-4-yl carbamate (0.50 g, 2.5 mmol) Dropwise at room temperature. The reaction mixture was mixed at room temperature for about 8 hours. After the reaction, the resultant was poured into Et 2 O (40 ml), washed with H 2 O (40 ml), brine (40 ml) and dried over MgSO 4 . The crude compounds were purified by silica gel chromatography (30% Ethyl acetate in n-Hexane elution) (0.61 g, yield 78%).
일반적 절차 BGeneral Procedure B
tert-butyl (1-aryl piperidin-4-yl)carbamate (2 mmol)를 10% HCl 메탄올 용액에 넣고 약 18시간 동안 실온에서 혼합하였다. 반응 후, 혼합물은 감압 농축되었다. 수득물(수율~100%)은 추가적인 정제없이 사용되었다.tert-butyl (1-aryl piperidin-4-yl) carbamate (2 mmol) was added to a 10% HCl methanol solution and mixed at room temperature for about 18 hours. After the reaction, the mixture was concentrated under reduced pressure. The yield (~ 100% yield) was used without further purification.
terttert -Butyl (1-(3-cyanobenzyl)piperidin-4-yl)carbamate-Butyl (1- (3-cyanobenzyl) piperidin-4-yl) carbamate
Figure PCTKR2018014884-appb-I000008
Figure PCTKR2018014884-appb-I000008
일반적 절차 A에 따라 합성하였다(수율: 78%); 1H NMR (400 MHz, CD3OD) δ 7.73 (br. s, 1 H), 7.68-7.63 (m, 1 H), 7.53 (t, J=7.6 Hz, 1 H), 3.58 (s, 2 H), 3.40-3.32 (m, 1 H), 2.87-2.80 (m, 2 H), 2.19-2.10 (m, 2 H), 1.89-1.91 (m, 2 H), 1.55-1.46 (m, 2 H), 1.45 (s, 9 H). MS (ESI, m/z) calculated for C18H25N3O2 [M+H]+ 315.19, found 316.10.Was synthesized according to general procedure A (Yield: 78%); 1 H NMR (400 MHz, CD 3 OD)? 7.73 (br.s, 1H), 7.68-7.63 (m, 1H), 7.53 (t, J = 7.6 Hz, 1H) 2 H), 1.89-1.91 (m, 2 H), 1.55-1.46 (m, 2 H), 3.40-3.32 H), 1.45 (s, 9 H). MS (ESI, m / z) calculated for C 18 H 25 N 3 O 2 [M + H] + 315.19, found 316.10.
terttert -Butyl (1-(3-methoxy)piperidin-4-yl)carbamate-Butyl (1- (3-methoxy) piperidin-4-yl) carbamate
Figure PCTKR2018014884-appb-I000009
Figure PCTKR2018014884-appb-I000009
일반적 절차 A에 따라 합성하였다(수율: 74%); 1H NMR (400 MHz, CD3OD) δ 7.24 (t, J=7.6 Hz, 1 H), 6.94-6.88 (m, 2 H), 6.84 (dd, J=2.4, 8.4 Hz, 1 H), 3.80 (S, 3 H), 3.50 (s, 2 H), 3.39-3.32 (m, 1 H), 2.90-2.83 (m, 2 H), 2.16-2.07 (m, 2 H), 1.88-1.81 (m, 2 H), 1.55-1.46 (m, 2 H), 1.45 (s, 9 H). MS (ESI, m/z) calculated for C18H28N2O3 [M+H]+ 320.21, found 321.25.Was synthesized according to general procedure A (Yield: 74%); 1 H NMR (400 MHz, CD 3 OD) δ 7.24 (t, J = 7.6 Hz, 1 H), 6.94-6.88 (m, 2 H), 6.84 (dd, J = 2.4, 8.4 Hz, 1 H), (M, 2H), 3.80-3.32 (m, 1H), 2.90-2.83 (m, 2H), 2.16-2.07 (m, 2H), 1.88-1.81 m, 2 H), 1.55-1.46 (m, 2 H), 1.45 (s, 9 H). MS (ESI, m / z) calculated for C 18 H 28 N 2 O 3 [M + H] + 320.21, found 321.25.
terttert -Butyl (1-(pyridine-4-ylmethyl)piperidin-4-yl)carbamate-Butyl (1- (pyridin-4-ylmethyl) piperidin-4-yl) carbamate
Figure PCTKR2018014884-appb-I000010
Figure PCTKR2018014884-appb-I000010
일반적 절차 A에 따라 합성하였다(수율: 54%); 1H NMR (400 MHz, CD3OD) δ 8.49 (d, J=6.0 Hz, 2 H), 7.44 (d, J=6.0 Hz, 2 H), 3.58 (s, 2 H), 3.41-3.31 (m, 1 H), 2.87-2.81 (m, 2 H), 2.20-2.12 (m, 2 H), 1.89-1.83 (m, 2 H), 1.57-1.49 (m, 2 H), 1.45 (s, 9 H). MS (ESI, m/z) calculated for C16H25N3O2 [M+H]+ 291.19, found 292.30.Was synthesized according to general procedure A (Yield: 54%); 1 H NMR (400 MHz, CD 3 OD) δ 8.49 (d, J = 6.0 Hz, 2 H), 7.44 (d, J = 6.0 Hz, 2 H), 3.58 (s, 2 H), 3.41-3.31 ( (m, 2H), 1.45 (s, 1H), 2.87-2.81 (m, 2H), 2.20-2.12 9 H). MS (ESI, m / z ) calculated for C 16 H 25 N 3 O 2 [M + H] + 291.19, found 292.30.
terttert -Butyl (1-(3,4-dimethoxybenzyl)piperidin-4-yl)carbamate-Butyl (1- (3,4-dimethoxybenzyl) piperidin-4-yl) carbamate
Figure PCTKR2018014884-appb-I000011
Figure PCTKR2018014884-appb-I000011
일반적 절차 A에 따라 합성하였다(수율: 55%); 1H NMR (400 MHz, CDCl3) δ 6.87 (br. s, 1 H), 6.84-6.77 (m, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.53-3.42 (m, 1 H), 3.42 (s, 2 H), 2.83-2.74 (m, 2 H), 2.11-2.00 (m, 2 H), 1.94-1.86 (m, 2 H), 1.45-1.34 (m, 2 H), 1.44 (s, 9 H). MS (ESI, m/z) calculated for C19H30N2O4 [M+H]+ 350.22, found 351.30.Was synthesized according to general procedure A (Yield: 55%); 1 H NMR (400 MHz, CDCl 3) δ 6.87 (br. S, 1 H), 6.84-6.77 (m, 2 H), 3.89 (s, 3 H), 3.87 (s, 3 H), 3.53-3.42 (m, 1H), 3.42 (s, 2H), 2.83-2.74 (m, 2H), 2.11-2.00 (m, 2H), 1.94-1.86 , 2 H), 1.44 (s, 9 H). MS (ESI, m / z) calculated for C 19 H 30 N 2 O 4 [M + H] + 350.22, found 351.30.
terttert -Butyl (1-(2-methoxybenzyl)piperidin-4-yl)carbamate-Butyl (1- (2-methoxybenzyl) piperidin-4-yl) carbamate
Figure PCTKR2018014884-appb-I000012
Figure PCTKR2018014884-appb-I000012
일반적 절차 A에 따라 합성하였다(수율: 93%); 1H NMR (400 MHz, CD3OD) δ 7.31-7.25 (m, 2 H), 6.98 (d, J=8.2 Hz, 1 H), 6.93 (t, J=7.5 Hz, 1 H), 3.84 (s, 3 H), 3.59 (s, 2 H), 3.33-3.27 (m, 1 H), 2.95-2.88 (m, 2 H), 2.23-2.13 (m, 2 H), 1.87-.179 (m, 2 H), 1.55-1.45 (m, 2 H), 1.44 (s, 9 H). MS (ESI, m/z) calculated for C18H28N2O3 [M+H]+ 320.21, found 321.10.Was synthesized according to general procedure A (yield: 93%); 1 H NMR (400 MHz, CD 3 OD) δ 7.31-7.25 (m, 2 H), 6.98 (d, J = 8.2 Hz, 1 H), 6.93 (t, J = 7.5 Hz, 1 H), 3.84 ( (m, 2H), 2.29-2.13 (m, 2H), 1.87-1.79 (m, 2H), 3.59 , 2 H), 1.55-1.45 (m, 2 H), 1.44 (s, 9 H). MS (ESI, m / z) calculated for C 18 H 28 N 2 O 3 [M + H] + 320.21, found 321.10.
terttert -Butyl (1-(4-methoxybenzyl)piperidin-4-yl)carbamate-Butyl (1- (4-methoxybenzyl) piperidin-4-yl) carbamate
Figure PCTKR2018014884-appb-I000013
Figure PCTKR2018014884-appb-I000013
일반적 절차 A에 따라 합성하였다(수율: 81%); 1H NMR (400 MHz, CD3OD) δ 7.24 (d, J=8.6 Hz, 2 H), 6.89 (d, J=8.6 Hz, 2 H), 3.80 (s, 3 H), 3.47 (s, 2 H), 3.38-3.28 (m, 1 H), 2.90-2.82 (m, 2 H), 2.14-2.05 (m, 2 H), 1.88-1.80 (m, 2 H), 1.53-1.44 (m, 2 H), 1.44 (s, 9 H). MS (ESI, m/z) calculated for C18H28N2O3 [M+H]+ 320.21, found 321.30.Was synthesized according to general procedure A (Yield: 81%); 1 H NMR (400 MHz, CD 3 OD) δ 7.24 (d, J = 8.6 Hz, 2 H), 6.89 (d, J = 8.6 Hz, 2 H), 3.80 (s, 3 H), 3.47 (s, (M, 2H), 1.38-1.80 (m, 2H), 1.53-1.44 (m, 2H), 2.38-2.22 2 H), 1.44 (s, 9 H). MS (ESI, m / z ) calculated for C 18 H 28 N 2 O 3 [M + H] + 320.21, found 321.30.
terttert -Butyl (1-(3-hydroxybenzyl)piperidin-4-yl)carbamate-Butyl (1- (3-hydroxybenzyl) piperidin-4-yl) carbamate
Figure PCTKR2018014884-appb-I000014
Figure PCTKR2018014884-appb-I000014
일반적 절차 A에 따라 합성하였다(수율: 87%); 1H NMR (400 MHz, CD3OD) δ 7.15 (t, J=8.4 Hz, 1 H), 6.82-6.77 (m, 2 H), 6.73-6.69 (m, 1 H), 3.48 (s, 2 H), 3.40-3.33 (m, 1 H), 2.93-2.85 (m, 2 H), 2.19-2.09 (m, 2 H), 1.89-1.81 (m, 2 H), 1.55-1.45 (m, 2 H), 1.44 (s, 9 H). MS (ESI, m/z) calculated for C17H26N2O3 [M+H]+ 306.19, found 307.20.Was synthesized according to general procedure A (yield: 87%); 1 H NMR (400 MHz, CD 3 OD)? 7.15 (t, J = 8.4 Hz, 1H), 6.82-6.77 (m, 2H), 6.73-6.69 2 H), 1.89-1.81 (m, 2 H), 1.55-1.45 (m, 2 H), 2.93-2.85 H), 1.44 (s, 9 H). MS (ESI, m / z) calculated for C 17 H 26 N 2 O 3 [M + H] + 306.19, found 307.20.
terttert -Butyl (1-(3-bromobenzyl)piperidin-4-yl)carbamate-Butyl (1- (3-bromobenzyl) piperidin-4-yl) carbamate
Figure PCTKR2018014884-appb-I000015
Figure PCTKR2018014884-appb-I000015
일반적 절차 A에 따라 합성하였다(수율: 81%); 1H NMR (400 MHz, CDCl3) δ 7.47 (br. s, 1 H), 7.37 (d, J=8.0 Hz, 1 H), 7.22 (d, J=8.0 Hz, 1 H), 7.16 (t, J=7.6 Hz, 1 H), 3.53-3.40 (m, 1 H), 3.43 (s, 2 H), 2.82-2.72 (m, 2 H), 2.12-2.02 (m, 2 H), 1.94-1.86 (m, 2 H), 1.48-1.38 (m, 2 H), 1.44 (s, 9 H). MS (ESI, m/z) calculated for C17H25BrN2O2 [M+H]+ 368.11, found 371.25.Was synthesized according to general procedure A (Yield: 81%); 1 H NMR (400 MHz, CDCl 3) δ 7.47 (br. S, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 1 H), 7.16 (t , J = 7.6 Hz, 1 H ), 3.53-3.40 (m, 1 H), 3.43 (s, 2 H), 2.82-2.72 (m, 2 H), 2.12-2.02 (m, 2 H), 1.94- 1.86 (m, 2H), 1.48-1.38 (m, 2H), 1.44 (s, 9H). MS (ESI, m / z ) calculated for C 17 H 25 BrN 2 O 2 [M + H] + 368.11, found 371.25.
terttert -Butyl (1-(3-methylbenzyl)piperidin-4-yl)carbamate-Butyl (1- (3-methylbenzyl) piperidin-4-yl) carbamate
Figure PCTKR2018014884-appb-I000016
Figure PCTKR2018014884-appb-I000016
일반적 절차 A에 따라 합성하였다(수율: 57%); 1H NMR (400 MHz, CD3OD) δ 7.21 (t, J=7.6 Hz, 1 H), 7.16 (br. s, 1 H), 7.13-7.08 (m, 2 H), 3.49 (s, 2 H), 3.39-3.31 (m, 1 H), 2.90-2.82 (m, 2 H), 2.35 (s, 3 H), 2.16-2.06 (m, 2 H), 1.88-1.80 (m, 2 H), 1.55-1.45 (m, 2 H), 1.45 (s, 9 H). MS (ESI, m/z) calculated for C18H28N2O2 [M+H]+ 304.22, found 305.00.Was synthesized according to general procedure A (Yield: 57%); 1 H NMR (400 MHz, CD 3 OD)? 7.21 (t, J = 7.6 Hz, 1H), 7.16 (br.s, 1H), 7.13-7.08 (M, 2H), 2.35 (s, 3H), 2.16-2.06 (m, 2H), 1.88-1.80 (m, 2H), 3.39-3.31 , 1.55-1.45 (m, 2H), 1.45 (s, 9H). MS (ESI, m / z) calculated for C 18 H 28 N 2 O 2 [M + H] + 304.22, found 305.00.
3-((4-aminopiperidin-1-yl)methyl)benzonitrile hydrochloride3 - ((4-aminopiperidin-1-yl) methyl) benzonitrile hydrochloride
Figure PCTKR2018014884-appb-I000017
Figure PCTKR2018014884-appb-I000017
일반적 절차 B에 따라 합성하였다; 1H NMR (400 MHz, CD3OD) δ 8.07 (br. s, 1 H), 7.98 (d, J=7.8 Hz, 1 H), 7.90 (d, J=7.8 Hz, 1 H), 7.71 (t, J=7.8 Hz, 1 H), 4.47 (s, 2 H), 3.67-3.58 (m, 2 H), 3.58-3.48 (m, 1 H), 3.32-3.22 (m, 2 H), 2.35-2.26 (m, 2 H), 2.17-2.03 (m, 2 H). MS (ESI, m/z) calculated for C13H17N3 [M+H]+ 215.14, found 216.10.Was synthesized according to general procedure B; 1 H NMR (400 MHz, CD 3 OD) δ 8.07 (br. S, 1 H), 7.98 (d, J = 7.8 Hz, 1 H), 7.90 (d, J = 7.8 Hz, 1 H), 7.71 ( t, J = 7.8 Hz, 1 H), 4.47 (s, 2 H), 3.67-3.58 (m, 2 H), 3.58-3.48 (m, 1 H), 3.32-3.22 (m, 2 H), 2.35 -2.26 (m, 2H), 2.17-2.03 (m, 2H). MS (ESI, m / z) calculated for C 13 H 17 N 3 [M + H] + 215.14, found 216.10.
1-(3-Methoxybenzyl)piperidin-4-amine hydrochloride1- (3-Methoxybenzyl) piperidin-4-amine hydrochloride
Figure PCTKR2018014884-appb-I000018
Figure PCTKR2018014884-appb-I000018
일반적 절차 B에 따라 합성하였다; 1H NMR (400 MHz, CD3OD) δ 7.42 (t, J=7.9 Hz, 1 H), 7.23 (br. s, 1 H), 7.14 (d, J=7.4 Hz, 1 H), 7.06 (d, J=8.2 Hz, 1 H), 4. 34 (s, 2 H), 3.86 (s, 3 H), 3.63-3.55 (m, 2 H), 3.57-3.44 (m, 1 H), 3.28-3.17 (m, 2 H), 2.31-2.23 (m, 2 H), 2.15-2.01 (m, 2 H). MS (ESI, m/z) calculated for C13H20N2O [M+H]+ 220.16, found 221.15.Was synthesized according to general procedure B; 1 H NMR (400 MHz, CD 3 OD) δ 7.42 (t, J = 7.9 Hz, 1 H), 7.23 (br. S, 1 H), 7.14 (d, J = 7.4 Hz, 1 H), 7.06 ( 3H), 3.63-3.55 (m, 2H), 3.57-3.44 (m, 1H), 3.28 (d, J = 8.2 Hz, 1H) -3.17 (m, 2H), 2.31-2.23 (m, 2H), 2.15-2.01 (m, 2H). MS (ESI, m / z) calculated for C 13 H 20 N 2 O [M + H] + 220.16, found 221.15.
1-(Pyridin-4-ylmethyl)piperidin-4-amine hydrochloride1- (Pyridin-4-ylmethyl) piperidin-4-amine hydrochloride
Figure PCTKR2018014884-appb-I000019
Figure PCTKR2018014884-appb-I000019
일반적 절차 B에 따라 합성하였다; 1H NMR (400 MHz, DMSO-d 6) δ 8.86 (d, J = 6.3 Hz, 2 H), 8.32 (br. s, 2 H), 7.82 (d, J = 6.4 Hz, 2 H), 4.45 (s, 2 H), 3.45 (d, J = 12.3 Hz, 2 H), 3.37-3.25 (m, 1 H), 3.20-3.00 (m, 2 H), 2.17-1.99 (m, 2 H), 1.94-1.68 (m, 2 H). MS (ESI, m/z) calculated for C11H17N3 [M+H]+ 191.14, found 192.10.Was synthesized according to general procedure B; 1 H NMR (400 MHz, DMSO- d 6) δ 8.86 (d, J = 6.3 Hz, 2 H), 8.32 (br. S, 2 H), 7.82 (d, J = 6.4 Hz, 2 H), 4.45 (m, 2H), 3.45 (d, J = 12.3 Hz, 2H), 3.37-3.25 (m, 1H), 3.20-3.00 1.94-1.68 (m, 2 H). MS (ESI, m / z) calculated for C 11 H 17 N 3 [M + H] + 191.14, found 192.10.
1-(3,4-diMethoxybenzyl)piperidin-4-amine hydrochloride1- (3,4-Dimethoxybenzyl) piperidin-4-amine hydrochloride
Figure PCTKR2018014884-appb-I000020
Figure PCTKR2018014884-appb-I000020
일반적 절차 B에 따라 합성하였다; 1H NMR (400 MHz, DMSO-d 6) δ 8.51 (br. s, 3 H), 7.41 (d, J=1.6 Hz, 1 H), 7.06 (dd, J=1.5, 8.2 Hz, 1 H), 6.99 (d, J=8.3 Hz, 1 H), 4.17 (d, J=4.7 Hz, 2 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.38-3.30 (m, 2 H), 3.31-3.14 (m, 1 H), 3.06-2.94 (m, 2 H), 2.18-2.09 (m, 2 H), 2.09-1.96 (m, 2 H). MS (ESI, m/z) calculated for C14H22N2O2 [M+H]+ 250.17, found 251.15.Was synthesized according to general procedure B; 1 H NMR (400 MHz, DMSO- d 6) δ 8.51 (br. S, 3 H), 7.41 (d, J = 1.6 Hz, 1 H), 7.06 (dd, J = 1.5, 8.2 Hz, 1 H) , 6.99 (d, J = 8.3 Hz, 1 H), 4.17 (d, J = 4.7 Hz, 2 H), 3.80 (s, 3 H), 3.77 (s, 3 H), 3.38-3.30 (m, 2 H), 3.31-3.14 (m, 1H), 3.06-2.94 (m, 2H), 2.18-2.09 (m, 2H), 2.09-1.96 (m, 2H). MS (ESI, m / z) calculated for C 14 H 22 N 2 O 2 [M + H] + 250.17, found 251.15.
1-(2-Methoxybenzyl)piperidin-4-amine hydrochloride1- (2-Methoxybenzyl) piperidin-4-amine hydrochloride
Figure PCTKR2018014884-appb-I000021
Figure PCTKR2018014884-appb-I000021
일반적 절차 B에 따라 합성하였다; 1H NMR (400 MHz, DMSO-d 6) δ 8.61 (br. s, 3 H), 7.64 (d, J=7.5 Hz, 1 H), 7.45 (t, J=7.5 Hz, 1 H), 7.12 (d, J=8.2 Hz, 1 H), 7.02 (t, J=7.4 Hz, 1 H), 4.19 (d, J=4.6 Hz, 2 H), 3.85 (s, 3 H), 3.43-3.34 (m, 2 H), 3.33-3.19 (m, 1 H), 3.10-2.98 (m, 2 H), 2.17-2.09 (m, 2 H), 2.08-1.95 (m, 2 H). MS (ESI, m/z) calculated for C13H20N2O [M+H]+ 220.16, found 221.25.Was synthesized according to general procedure B; 1 H NMR (400 MHz, DMSO- d 6) δ 8.61 (br. S, 3 H), 7.64 (d, J = 7.5 Hz, 1 H), 7.45 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 8.2 Hz, 1H), 7.02 (t, J = 7.4 Hz, 1H), 4.19 (d, J = 4.6 Hz, 2H), 3.85 m, 2 H), 3.33-3.19 (m, 1H), 3.10-2.98 (m, 2H), 2.17-2.09 (m, 2H), 2.08-1.95 (m, 2H). MS (ESI, m / z) calculated for C 13 H 20 N 2 O [M + H] + 220.16, found 221.25.
1-(4-Methoxybenzyl)piperidin-4-amine hydrochloride1- (4-Methoxybenzyl) piperidin-4-amine hydrochloride
Figure PCTKR2018014884-appb-I000022
Figure PCTKR2018014884-appb-I000022
일반적 절차 B에 따라 합성하였다; 1H NMR (400 MHz, DMSO-d 6) δ 8.50 (br. s, 3 H), 7.53 (d, J=8.6 Hz, 2 H), 6.99 (d, J=8.7 Hz, 2 H), 4.17 (d, J=4.8 Hz, 2 H), 3.78 (s, 3 H), 3.39-3.31 (m, 2 H), 3.28-3.13 (m, 1 H), 3.03-2.92 (m, 2 H), 2.16-2.07 (m, 2 H), 2.04-1.92 (m, 2 H). MS (ESI, m/z) calculated for C13H20N2O [M+H]+ 220.16, found 221.25.Was synthesized according to general procedure B; 1 H NMR (400 MHz, DMSO- d 6) δ 8.50 (br. S, 3 H), 7.53 (d, J = 8.6 Hz, 2 H), 6.99 (d, J = 8.7 Hz, 2 H), 4.17 (d, J = 4.8 Hz, 2H), 3.78 (s, 3H), 3.39-3.31 (m, 2H), 3.28-3.13 (m, 1H), 3.03-2.92 2.16-2.07 (m, 2H), 2.04-1.92 (m, 2H). MS (ESI, m / z) calculated for C 13 H 20 N 2 O [M + H] + 220.16, found 221.25.
3-((4-Aminopiperidin-1-yl)methyl)phenol hydrochloride3 - ((4-Aminopiperidin-1-yl) methyl) phenol hydrochloride
Figure PCTKR2018014884-appb-I000023
Figure PCTKR2018014884-appb-I000023
일반적 절차 B에 따라 합성하였다; 1H NMR (400 MHz, DMSO-d 6) δ 8.34 (br. s, 3 H), 7.24 (t, J=7.8 Hz, 1 H), 6.99 (d, J=7.7 Hz, 1 H), 6.96 (br. s, 1 H), 6.86 (d, J=8.0 Hz, 1 H), 4.14 (d, J=4.8 Hz, 2 H), 3.40-3.30 (m, 2 H), 3.27-3.17 (m, 1 H), 3.03-2.91 (m, 2 H), 2.14-2.04 (m, 2 H), 2.01-1.89 (m, 2 H). MS (ESI, m/z) calculated for C12H18N2O [M+H]+ 206.14, found 207.25.Was synthesized according to general procedure B; 1 H NMR (400 MHz, DMSO- d 6) δ 8.34 (br. S, 3 H), 7.24 (t, J = 7.8 Hz, 1 H), 6.99 (d, J = 7.7 Hz, 1 H), 6.96 (m, 2H), 3.27-3.17 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 4.14 (d, J = 4.8 Hz, 2H) , 1H), 3.03-2.91 (m, 2H), 2.14-2.04 (m, 2H), 2.01-1.89 (m, 2H). MS (ESI, m / z ) calculated for C 12 H 18 N 2 O [M + H] + 206.14, found 207.25.
1-(3-Bromobenzyl)piperidin-4-amine hydrochloride1- (3-Bromobenzyl) piperidin-4-amine hydrochloride
Figure PCTKR2018014884-appb-I000024
Figure PCTKR2018014884-appb-I000024
일반적 절차 B에 따라 합성하였다; 1H NMR (400 MHz, DMSO-d 6) δ 8.50 (br. s, 3 H), 7.92 (br. s, 1 H), 7.68-7.62 (m, 2 H), 7.42 (t, J=7.8 Hz, 1 H), 4.27 (d, J=4.6 Hz, 2 H), 3.43-3.32 (m, 2 H), 3.29-3.18 (m, 1 H), 3.08-2.97 (m, 2 H), 2.18-2.08 (m, 2 H), 2.06-1.95 (m, 2 H). MS (ESI, m/z) calculated for C12H17BrN2 [M+H]+ 268.06, found 271.10.Was synthesized according to general procedure B; 1 H NMR (400 MHz, DMSO- d 6) δ 8.50 (br. S, 3 H), 7.92 (br. S, 1 H), 7.68-7.62 (m, 2 H), 7.42 (t, J = 7.8 Hz), 4.27 (d, J = 4.6 Hz, 2H), 3.43-3.32 (m, 2H), 3.29-3.18 (m, 1H), 3.08-2.97 -2.08 (m, 2 H), 2.06-1.95 (m, 2 H). MS (ESI, m / z ) calculated for C 12 H 17 BrN 2 [M + H] + 268.06, found 271.10.
1-(3-Methylbenzyl)piperidin-4-amine hydrochloride1- (3-Methylbenzyl) piperidin-4-amine hydrochloride
Figure PCTKR2018014884-appb-I000025
Figure PCTKR2018014884-appb-I000025
일반적 절차 B에 따라 합성하였다; 1H NMR (400 MHz, DMSO-d 6) δ 8.44 (br. s, 3 H), 7.43-7.38 (m, 2 H), 7.34 (t, J=7.4 Hz, 1 H), 7.27 (d, J=7.5 Hz, 1 H), 4.19 (d, J=4.8 Hz, 2 H), 3.39-3.31 (m, 2 H), 3.28-3.16 (m, 1 H), 3.05-2.94 (m, 2 H), 2.33 (s, 3 H), 2.15-2.06 (m, 2 H), 2.04-1.93 (m, 2 H). MS (ESI, m/z) calculated for C13H20N2 [M+H]+ 204.16, found 205.25.Was synthesized according to general procedure B; 1 H NMR (400 MHz, DMSO- d 6) δ 8.44 (br. S, 3 H), 7.43-7.38 (m, 2 H), 7.34 (t, J = 7.4 Hz, 1 H), 7.27 (d, J = 7.5 Hz, 1H), 4.19 (d, J = 4.8 Hz, 2H), 3.39-3.31 (m, 2H), 3.28-3.16 (m, 1H), 3.05-2.94 ), 2.33 (s, 3 H), 2.15-2.06 (m, 2 H), 2.04-1.93 (m, 2 H). MS (ESI, m / z) calculated for C 13 H 20 N 2 [M + H] + 204.16, found 205.25.
스킴 2. 화합물의 합성Scheme 2. Synthesis of compounds
[일반적인 반응식 Ⅱ][General Scheme II]
Figure PCTKR2018014884-appb-I000026
Figure PCTKR2018014884-appb-I000026
시약 및 조건: (a) Amines, CDI, DMF, 실온; (b) Amines, TEA, NMP, microwave, 180℃Reagents and conditions: (a) Amines, CDI, DMF, room temperature; (b) Amines, TEA, NMP, microwave, 180 ° C
일반적 절차 CGeneral procedure C
DMF (10 ml) 중의 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (1.00 g, 5.09 mmol) 용액에 CDI (1.07 g, 6.61 mmol)를 실온에서 적가한 후, 반응 혼합물을 실온에서 약 1시간 정도 교반하였다. 상기 혼합물에 다양한 아민 30 mmol(용매 THF) 2.0M을 천천히 적가한 후, 약 1시간 동안 실온에서 교반하였다. 수득 혼합물을 에틸 아세테이트에 부었고, 백색 고체물이 침전물로 얻어졌다.CDI (1.07 g, 6.61 mmol) was added dropwise to a solution of 4-chloro- 1H- pyrrolo [2,3- b ] pyridine-5-carboxylic acid (1.00 g, 5.09 mmol) in DMF , And the reaction mixture was stirred at room temperature for about 1 hour. To this mixture was slowly added dropwise 2.0 mmol of various amines (30 mmol, solvent THF), followed by stirring at room temperature for about 1 hour. The resulting mixture was poured into ethyl acetate and a white solid was obtained as a precipitate.
일반적 절차 DGeneral procedure D
NMP (2 ml) 중의 1-(benzyl)piperidin-4-amine hydrogen chloride salt (0.36 g, 1.43 mmol) 용액에 TEA (0.40 ml, 2.86 mmol) 및 4-chloro-N-alkyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (0.286 mmol)를 적가한 후, 마이크로웨이브 조사 하 약 180℃에서 약 3시간 동안 교반하였다. 결과물은 실온으로 냉각되었고, 에틸 아세테이트로 증류된 이후, H2O, 브라인으로 세척, MgSO4으로 건조되었다. 조화합물들은 실리카겔 속성 크로마토그래피(20% Methaol in dichloromethane elution)로 정제되어 표제의 생성물을 얻었다.NMP (2 ml) of 1- (benzyl) piperidin-4- amine hydrogen chloride salt (0.36 g, 1.43 mmol) in TEA (0.40 ml, 2.86 mmol) and 4-chloro- N -alkyl-1 H -pyrrolo solution [ 2,3- b ] pyridine-5-carboxamide (0.286 mmol) was added dropwise thereto, followed by stirring at about 180 ° C for about 3 hours under microwave irradiation. The resultant was cooled to room temperature, distilled with ethyl acetate, washed with H 2 O, brine, and dried over MgSO 4 . The crude compounds were purified by silica gel property chromatography (20% Methaol in dichloromethane elution) to give the title product.
4-Chloro-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide4-Chloro-N-methyl-1H-pyrrolo [2,3-b] pyridine-5-carboxamide
Figure PCTKR2018014884-appb-I000027
Figure PCTKR2018014884-appb-I000027
일반적 절차 C에 따라 합성하였다(수율 76%); 1H NMR (400 MHz, DMSO-d 6) δ 12.19 (br. s, 1 H), 8.45-8.38 (m, 1 H), 7.66 (d, J=3.5 Hz, 1 H), 6.57 (d, J=3.5 Hz, 1 H), 2.80 (d, J=4.6 Hz, 3 H). 13C NMR (100 MHz, DMSO-d 6) δ 166.24, 148.98, 142.77, 132.01, 128.82, 124.87, 118.97, 99.31, 26.66. MS (ESI, m/z) calculated for C9H8ClN3O [M+H]+ 209.04, found 210.00.Was synthesized according to general procedure C (Yield 76%); 1 H NMR (400 MHz, DMSO- d 6) δ 12.19 (br. S, 1 H), 8.45-8.38 (m, 1 H), 7.66 (d, J = 3.5 Hz, 1 H), 6.57 (d, J = 3.5 Hz, 1H), 2.80 (d, J = 4.6 Hz, 3 H). 13 C NMR (100 MHz, DMSO- d 6 ) 隆 166.24, 148.98, 142.77, 132.01, 128.82, 124.87, 118.97, 99.31, 26.66. MS (ESI, m / z ) calculated for C 9 H 8 ClN 3 O [M + H] + 209.04, found 210.00.
4-Chloro-N-cyclopropyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide4-Chloro-N-cyclopropyl-1H-pyrrolo [2,3-b] pyridine-5-carboxamide
Figure PCTKR2018014884-appb-I000028
Figure PCTKR2018014884-appb-I000028
일반적 절차 C에 따라 합성하였다(수율 62%); 1H NMR (400 MHz, DMSO-d 6) δ 12.18 (s, 1 H), 8.53 (d, J=4.4 Hz, 1 H), 8.21 (s, 1 H), 7.65 (d, J=3.5 Hz, 1 H), 6.56 (d, J=3.5 Hz, 1 H), 2.91-2.80 (m, 1 H), 0.76-0.66 (m, 2 H), 0.60-0.51 (m, 2 H). 13C NMR (100 MHz, DMSO-d 6) δ 167.01, 148.94, 142.63, 132.06, 128.81, 124.79, 118.93, 99.29, 23.39, 6.25. MS (ESI, m/z) calculated for C11H10ClN3O [M+H]+ 235.05, found 235.95.Was synthesized according to general procedure C (62% yield); 1 H NMR (400 MHz, DMSO- d 6) δ 12.18 (s, 1 H), 8.53 (d, J = 4.4 Hz, 1 H), 8.21 (s, 1 H), 7.65 (d, J = 3.5 Hz , 1H), 6.56 (d, J = 3.5 Hz, 1H), 2.91-2.80 (m, 1H), 0.76-0.66 (m, 2H), 0.60-0.51 (m, 2H). 13 C NMR (100 MHz, DMSO- d 6 )? 167.01, 148.94, 142.63, 132.06, 128.81, 124.79, 118.93, 99.29, 23.39, 6.25. MS (ESI, m / z ) calculated for C 11 H 10 ClN 3 O [M + H] + 235.05, found 235.95.
4-Chloro-1H-pyrrolo[2,3-b]pyridine-5-carboxamide4-Chloro-1H-pyrrolo [2,3-b] pyridine-5-carboxamide
Figure PCTKR2018014884-appb-I000029
Figure PCTKR2018014884-appb-I000029
일반적 절차 C에 따라 합성하였다(수율 71%); 1H NMR (400 MHz, DMSO-d 6) δ 8.44 (s, 1 H), 7.49 (d, J=3.4 Hz, 1 H), 6.47 (d, J=3.4 Hz, 1 H). 13C NMR (100 MHz, DMSO-d 6) δ 168.76, 148.24, 145.29, 132.33, 128.10, 127.23, 119.13, 99.24. MS (ESI, m/z) calculated for C8H6ClN3O [M+H]+ 195.02, found 196.90.Was synthesized according to general procedure C (71% yield); 1 H NMR (400 MHz, DMSO- d 6 )? 8.44 (s, 1H), 7.49 (d, J = 3.4 Hz, 1H), 6.47 (d, J = 3.4 Hz, 1H). 13 C NMR (100 MHz, DMSO- d 6) δ 168.76, 148.24, 145.29, 132.33, 128.10, 127.23, 119.13, 99.24. MS (ESI, m / z ) calculated for C 8 H 6 ClN 3 O [M + H] + 195.02, found 196.90.
4-Chloro-N-cyclopentyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide4-Chloro-N-cyclopentyl-1H-pyrrolo [2,3-b] pyridine-5-carboxamide
Figure PCTKR2018014884-appb-I000030
Figure PCTKR2018014884-appb-I000030
일반적 절차 C에 따라 합성하였다(수율 32%); 1H NMR (400 MHz, DMSO-d 6) δ 8.44 (d, J=7.2 Hz, 1 H), 8.20 (s, 1 H), 7.65 (d, J=3.4 Hz, 1 H), 6.56 (d, J=3.4 Hz, 1 H), 4.27-4.17 (m, 1 H), 1.96-1.82 (m, 2 H), 1.78-1.61 (m, 3 H), 1.59-1.42 (m, 5 H). 13C NMR (100 MHz, DMSO-d 6) δ 165.27, 148.90, 142.64, 131.96, 128.74, 125.29, 118.89, 99.19, 51.43, 32.64, 24.03. MS (ESI, m/z) calculated for C13H14ClN3O [M+H]+ 263.08, found 263.95.Was synthesized according to general procedure C (yield 32%); 1 H NMR (400 MHz, DMSO- d 6) δ 8.44 (d, J = 7.2 Hz, 1 H), 8.20 (s, 1 H), 7.65 (d, J = 3.4 Hz, 1 H), 6.56 (d , J = 3.4 Hz, 1H), 4.27-4.17 (m, 1H), 1.96-1.82 (m, 2H), 1.78-1.61 (m, 3H), 1.59-1.42 (m, 5H). 13 C NMR (100 MHz, DMSO- d 6 )? 165.27, 148.90, 142.64, 131.96, 128.74, 125.29, 118.89, 99.19, 51.43, 32.64, 24.03. MS (ESI, m / z) calculated for C 13 H 14 ClN 3 O [M + H] + 263.08, found 263.95.
실시예 1Example 1
Figure PCTKR2018014884-appb-I000031
Figure PCTKR2018014884-appb-I000031
4-((1-(3-Cyanobenzyl)piperidin-4-yl)amino)-4 - ((1- (3-Cyanobenzyl) piperidin-4-yl) amino) - NN -methyl-1-methyl-1 HH -pyrrolo[2,3-b]pyridine-5-carboxamidepyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 17%); 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1 H), 7.99 (br. s, 1 H), 7.93-7.89 (m, 8.1 Hz, 2 H), 7.73 (t, J=8.0 Hz, 1 H), 7.38 (d, J=4.0 Hz, 1 H), 6.96 (d, J=4.0 Hz, 1 H), 4.62-4.52 (m, 1 H), 4.50 (s, 2 H), 3.67-3.50 (m, 2 H), 3.50-3.38 (m, 2 H), 2.93 (s, 3 H), 2.52-2.40 (m, 2 H), 2.18-1.90 (m, 2 H). 13C NMR (100 MHz, CD3OD) δ 168.08, 152.04, 138.93, 135.68, 135.68, 134.79, 134.68, 133.53, 130.63, 123.83, 117.49, 113.22, 106.50, 104.86, 103.67, 58.85, 48.44, 29.26, 25.37. MS (ESI, m/z) calculated for C22H24N6O [M+H]+ 388.20, found 389.10.Was synthesized according to general procedure D (yield 17%); 1 H NMR (400 MHz, CD 3 OD) δ 8.38 (s, 1 H), 7.99 (br. S, 1 H), 7.93-7.89 (m, 8.1 Hz, 2 H), 7.73 (t, J = 8.0 Hz, 1H), 7.38 (d, J = 4.0 Hz, 1H), 6.96 (d, J = 4.0 Hz, 1H), 4.62-4.52 (m, 1H), 4.50 3.67-3.50 (m, 2H), 3.50-3.38 (m, 2H), 2.93 (s, 3H), 2.52-2.40 (m, 2H), 2.18-1.90 (m, 2H). 13 C NMR (100 MHz, CD 3 OD)? 168.08, 152.04, 138.93, 135.68, 135.68, 134.79, 134.68, 133.53, 130.63, 123.83, 117.49, 113.22, 106.50, 104.86, 103.67, 58.85, 48.44, 29.26, 25.37. MS (ESI, m / z) calculated for C 22 H 24 N 6 O [M + H] + 388.20, found 389.10.
실시예 2Example 2
Figure PCTKR2018014884-appb-I000032
Figure PCTKR2018014884-appb-I000032
4-((1-(3-Methoxybenzyl)piperidin-4-yl)amino)-4 - ((1- (3-Methoxybenzyl) piperidin-4-yl) amino) - NN -methyl-1-methyl-1 HH -pyrrolo[2,3-b]pyridine-5-carboxamidepyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 27%); 1H NMR (400 MHz, DMSO-d 6) δ 9.44 (d, J=7.9 Hz, 1 H), 8.28 (s, 1 H), 8.22 (d, J=4.4 Hz, 1 H), 7.23 (t, J=8.0 Hz, 1 H), 7.15-7.12 (m, 1 H), 6.92-6.87 (m, 2 H), 6.81 (d, J=7.1 Hz, 1 H), 6.48 (br. s, 1 H), 4.02-3.92 (m., 1 H), 3.75 (s, 3 H), 3.47 (s, 2 H), 2.78-2.66 (m, 2 H), 2.74 (d, J=4.3 Hz, 3 H), 2.30-2.22 (m, 2 H), 2.05-1.97 (m, 2 H), 1.58-1.47 (m, 2 H). 13C NMR (100 MHz, CD3OD) δ 167.96, 160.40, 152.11, 138.61, 134.49, 130.17, 130.14, 130.09, 123.85, 122.87, 121.45, 116.21, 115.47, 104.88, 103.74, 60.26, 54.46, 50.67, 29.58, 25.36. MS (ESI, m/z) calculated for C22H27N5O2 [M+H]+ 393.22, found 394.10.Was synthesized according to general procedure D (27% yield); 1 H NMR (400 MHz, DMSO- d 6) δ 9.44 (d, J = 7.9 Hz, 1 H), 8.28 (s, 1 H), 8.22 (d, J = 4.4 Hz, 1 H), 7.23 (t , J = 8.0 Hz, 1 H ), 7.15-7.12 (m, 1 H), 6.92-6.87 (m, 2 H), 6.81 (d, J = 7.1 Hz, 1 H), 6.48 (br. s, 1 2 H), 2.74 (d, J = 4.3 Hz, 3 H), 4.02-3.92 (m, 1H), 3.75 H), 2.30-2.22 (m, 2H), 2.05-1.97 (m, 2H), 1.58-1.47 (m, 2H). 13 C NMR (100 MHz, CD 3 OD) δ 167.96, 160.40, 152.11, 138.61, 134.49, 130.17, 130.14, 130.09, 123.85, 122.87, 121.45, 116.21, 115.47, 104.88, 103.74, 60.26, 54.46, 50.67, 29.58, 25.36. MS (ESI, m / z) calculated for C 22 H 27 N 5 O 2 [M + H] + 393.22, found 394.10.
실시예 3Example 3
Figure PCTKR2018014884-appb-I000033
Figure PCTKR2018014884-appb-I000033
NN -Methyl-4-((1-(pyridin-4-ylmethyl)piperidin-4-yl)amino)-1-Methyl-4 - ((1- (pyridin-4-ylmethyl) piperidin-4- yl) amino) -1 HH -pyrrolo[2,3-pyrrolo [2,3- bb ]pyridine-5-carboxamide] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 20%); 1H NMR (400 MHz, DMSO-d 6) δ 9.45 (d, J=7.8 Hz, 1 H), 8.51 (d, J=5.6 Hz, 2 H), 8.29 (s, 1 H), 8.23 (d, J=4.3 Hz, 1 H), 7.35 (d, J=5.5 Hz, 2 H), 7.14 (br. s, 1 H), 6.49 (br. s, 1 H), 4.04-3.95 (m, 1 H), 3.54 (s, 2 H), 2.78-2.67 (m, 2 H), 2.74 (d, J=4.2 Hz, 2 H), 2.35-2.26 (m, 2 H), 2.06-1.98 (m, 2 H), 1.60-1.49 (m, 2 H). 13C NMR (100 MHz, DMSO-d 6) δ 170.61, 150.71, 150.00, 149.31, 148.21, 144.98, 124.15, 122.29, 104.97, 103.09, 102.18, 61.16, 51.51, 49.29, 33.19, 26.54. MS (ESI, m/z) calculated for C20H24N6O [M+H]+ 364.20, found 365.20.Was synthesized according to general procedure D (20% yield); 1 H NMR (400 MHz, DMSO- d 6 )? 9.45 (d, J = 7.8 Hz, 1H), 8.51 (d, J = 5.6 Hz, 2H), 8.29 , J = 4.3 Hz, 1 H ), 7.35 (d, J = 5.5 Hz, 2 H), 7.14 (br. s, 1 H), 6.49 (br. s, 1 H), 4.04-3.95 (m, 1 H), 3.54 (s, 2 H), 2.78-2.67 (m, 2 H), 2.74 (d, J = 4.2 Hz, 2 H), 2.35-2.26 (m, 2 H), 2.06-1.98 (m, 2 H), 1.60-1.49 (m, 2 H). 13 C NMR (100 MHz, DMSO- d 6 )? 170.61, 150.71, 150.00, 149.31, 148.21, 144.98, 124.15, 122.29, 104.97, 103.09, 102.18, 61.16, 51.51, 49.29, 33.19, 26.54. MS (ESI, m / z) calculated for C 20 H 24 N 6 O [M + H] + 364.20, found 365.20.
실시예 4Example 4
Figure PCTKR2018014884-appb-I000034
Figure PCTKR2018014884-appb-I000034
4-((1-(3,4-Dimethoxybenzyl)piperidin-4-yl)amino)-4 - ((1- (3,4-Dimethoxybenzyl) piperidin-4-yl) amino) NN -methyl-1-methyl-1 HH -pyrrolo[2,3-b]pyridine-5-carboxamidepyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 36%); 1H NMR (400 MHz, CD3OD) δ 8.36 (br. s, 1 H), 7.40-7.35 (m, 1 H), 7.19-7.05 (m, 4 H), 6.99-6.92 (m, 1 H), 4.58-4.47 (m, 1 H), 4.33 (br. s, 2 H), 3.90 (s, 3 H), 3.87 (s, 3 H), 3.69-3.61 (m, 2 H), 3.38-3.27 (m, 2 H), 2.91 (s, 3 H), 2.53-2.44 (m, 2 H), 2.02-1.87 (m, 2 H). 13C NMR (100 MHz, CD3OD) δ 167.90, 150.68, 149.54, 138.54, 134.44, 124.08, 123.85, 121.05, 117.91, 115.01, 113.88, 111.50, 106.41, 104.90, 103.74, 60.22, 55.07, 55.02, 50.39, 29.61, 25.35. MS (ESI, m/z) calculated for C23H29N5O3 [M+H]+ 423.23, found 424.20.Was synthesized according to general procedure D (yield 36%); 1 H NMR (400 MHz, CD 3 OD)? 8.36 (br.s, 1H), 7.40-7.35 (m, 1H), 7.19-7.05 (m, 4H), 6.99-6.92 3H), 3.87 (s, 3H), 3.69-3.61 (m, 2H), 3.38 (s, 3.27 (m, 2H), 2.91 (s, 3H), 2.53-2.44 (m, 2H), 2.02-1.87 (m, 2H). 13 C NMR (100 MHz, CD 3 OD) δ 167.90, 150.68, 149.54, 138.54, 134.44, 124.08, 123.85, 121.05, 117.91, 115.01, 113.88, 111.50, 106.41, 104.90, 103.74, 60.22, 55.07, 55.02, 50.39, 29.61, 25.35. MS (ESI, m / z ) calculated for C 23 H 29 N 5 O 3 [M + H] + 423.23, found 424.20.
실시예 5Example 5
Figure PCTKR2018014884-appb-I000035
Figure PCTKR2018014884-appb-I000035
4-((1-(2-Methoxybenzyl)piperidin-4-yl)amino)-4 - ((1- (2-Methoxybenzyl) piperidin-4-yl) amino) NN -methyl-1-methyl-1 HH -pyrrolo[2,3-b]pyridine-5-carboxamidepyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 20%); 1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1 H), 7.38-7.28 (m, 2 H), 7.13 (d, J=3.4 Hz, 1 H), 7.04-6.93 (m, 2 H), 6.61 (d, J=3.6 Hz, 1 H), 4.20-4.08 (m, 1 H), 3.87 (s, 3 H), 3.75 (s, 2 H), 3.05-2.94 (m, 2 H), 2.89 (s, 3 H), 2.62-2.50 (m, 2 H), 2.22-2.12 (m, 2 H), 1.80-1.69 (m, 2 H). 13C NMR (100 MHz, CD3OD) δ 171.29, 158.20, 149.39, 149.35, 143.63, 131.39, 129.02, 123.65, 121.60, 119.96, 110.36, 105.24, 103.49, 101.85, 55.63, 54.44, 50.95, 31.78, 31.35, 25.23. MS (ESI, m/z) calculated for C22H27N5O2 [M+H]+ 393.22, found 394.00.Was synthesized according to general procedure D (20% yield); 1 H NMR (400 MHz, CD 3 OD)? 8.21 (s, 1H), 7.38-7.28 (m, 2H), 7.13 (d, J = 3.4 Hz, 1H), 7.04-6.93 3H), 3.75 (s, 2H), 3.05-2.94 (m, 2H), 6.61 (d, J = 3.6 Hz, 1H), 4.20-4.08 ), 2.89 (s, 3H), 2.62-2.50 (m, 2H), 2.22-2.12 ( m , 2H), 1.80-1.69 (m, 2H). 13 C NMR (100 MHz, CD 3 OD) δ 171.29, 158.20, 149.39, 149.35, 143.63, 131.39, 129.02, 123.65, 121.60, 119.96, 110.36, 105.24, 103.49, 101.85, 55.63, 54.44, 50.95, 31.78, 31.35, 25.23. MS (ESI, m / z) calculated for C 22 H 27 N 5 O 2 [M + H] + 393.22, found 394.00.
실시예 6Example 6
Figure PCTKR2018014884-appb-I000036
Figure PCTKR2018014884-appb-I000036
4-((1-(4-Methoxybenzyl)piperidin-4-yl)amino)-4 - ((1- (4-Methoxybenzyl) piperidin-4-yl) amino) - NN -methyl-1-methyl-1 HH -pyrrolo[2,3-b]pyridine-5-carboxamidepyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 21%); 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1 H), 7.27-7.23 (m, 3 H), 7.03 (d, J=3.5 Hz, 1 H), 6.87(d, J=8.6 Hz, 2 H), 6.53 (d, J=3.5 Hz, 1 H), 4.05-3.95 (m, 1 H), 3.81 (s, 3 H), 3.50 (s, 2 H), 2.98 (s, 3 H), 2.89-2.77 (m, 2 H), 2.32-2.22 (m, 2 H), 2.15-2.08 (m, 2 H), 1.83-1.68 (m, 2 H). 13C NMR (100 MHz, CDCl3) δ 170.66, 158.71, 149.89, 149.76, 143.37, 130.33, 120.96, 113.59, 105.12, 103.51, 102.75, 62.44, 55.27, 51.63, 32.83, 32.10, 26.65, 26.51. MS (ESI, m/z) calculated for C22H27N5O2 [M+H]+ 393.22, found 394.05.Was synthesized according to general procedure D (Yield 21%); 1 H NMR (400 MHz, CDCl 3) δ 8.23 (s, 1 H), 7.27-7.23 (m, 3 H), 7.03 (d, J = 3.5 Hz, 1 H), 6.87 (d, J = 8.6 Hz , 2 H), 6.53 (d , J = 3.5 Hz, 1 H), 4.05-3.95 (m, 1 H), 3.81 (s, 3 H), 3.50 (s, 2 H), 2.98 (s, 3 H ), 2.89-2.77 (m, 2H), 2.32-2.22 (m, 2H), 2.15-2.08 (m, 2H), 1.83-1.68 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ) 隆 170.66, 158.71, 149.89, 149.76, 143.37, 130.33, 120.96, 113.59, 105.12, 103.51, 102.75, 62.44, 55.27, 51.63, 32.83, 32.10, 26.65, 26.51. MS (ESI, m / z) calculated for C 22 H 27 N 5 O 2 [M + H] + 393.22, found 394.05.
실시예 7Example 7
Figure PCTKR2018014884-appb-I000037
Figure PCTKR2018014884-appb-I000037
NN -Methyl-4-((1-phenylpiperidin-4-yl)amino)-1-Methyl-4 - ((1-phenylpiperidin-4-yl) amino) -1 HH -pyrrolo[2,3-pyrrolo [2,3- bb ]pyridine-5-carboxamide] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 30%); 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1 H), 7.26 (t, J=8.7 Hz, 2 H), 7.15 (d, J=3.7 Hz, 1 H), 7.05 (d, J=7.9 Hz, 2 H), 6.86 (t, J=7.3 Hz, 1 H), 6.69 (d, J=3.7 Hz, 1 H), 4.30-4.21 (m, 1 H), 3.67-3.58 (m, 2 H), 3.37 (s, 2 H), 3.13-3.05 (m, 2 H), 2.89 (s, 3 H), 2.32-2.24 (m, 2 H), 1.88-1.77 (m, 2 H). 13C NMR (100 MHz, CD3OD) δ 171.33, 151.51, 149.46, 149.38, 143.64, 128.65, 121.56, 119.74, 116.82, 105.30, 103.51, 102.01, 60.14, 49.48, 32.44, 25.24. MS (ESI, m/z) calculated for C20H23N5O [M+H]+ 349.19, found 350.05.Was synthesized according to general procedure D (30% yield); 1 H NMR (400 MHz, CD 3 OD) δ 8.28 (s, 1 H), 7.26 (t, J = 8.7 Hz, 2 H), 7.15 (d, J = 3.7 Hz, 1 H), 7.05 (d, J = 7.9 Hz, 2H), 6.86 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 3.7 Hz, 1H), 4.30-4.21 (m, 1H), 3.67-3.58 (M, 2H), 3.37 (s, 2H), 3.13-3.05 (m, 2H), 2.89 . 13 C NMR (100 MHz, CD 3 OD)? 171.33, 151.51, 149.46, 149.38, 143.64, 128.65, 121.56, 119.74, 116.82, 105.30, 103.51, 102.01, 60.14, 49.48, 32.44, 25.24. MS (ESI, m / z) calculated for C 20 H 23 N 5 O [M + H] + 349.19, found 350.05.
실시예 8Example 8
Figure PCTKR2018014884-appb-I000038
Figure PCTKR2018014884-appb-I000038
4-((1-(3-Hydroxybenzyl)piperidin-4-yl)amino)-4 - ((1- (3-Hydroxybenzyl) piperidin-4-yl) amino) - NN -methyl-1-methyl-1 HH -pyrrolo[2,3-b]pyridine-5-carboxamidepyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 22%); 1H NMR (400 MHz, CD3OD) δ 8.24 (br. s, 1 H), 7.23 (br. s, 1 H), 7.21 (d, J=7.8 Hz, 1 H), 6.90-6.78 (m, 4 H), 4.48-4.30 (m, 1 H), 4.21 (br. s, 2 H), 3.58-3.43 (m, 2 H), 2.80 (s, 3 H), 2.40-2.35 (m, 2 H), 1.90-1.73 (m, 2 H), 1.29-1.15 (m, 2 H). 13C NMR (100 MHz, CD3OD) δ 167.99, 158.13, 152.07, 138.70, 134.56, 130.12, 130.07, 123.84, 121.61, 117.60, 116.72, 116.69, 104.86, 103.72, 65.50, 50.64, 41.49, 29.58, 25.37. MS (ESI, m/z) calculated for C21H25N5O2 [M+H]+ 379.20, found 379.80.Was synthesized according to general procedure D (yield: 22%); 1 H NMR (400 MHz, CD 3 OD) δ 8.24 (br. S, 1 H), 7.23 (br. S, 1 H), 7.21 (d, J = 7.8 Hz, 1 H), 6.90-6.78 (m , 4H), 4.48-4.30 (m, 1H), 4.21 (br.s, 2H), 3.58-3.43 (m, 2H), 2.80 H), 1.90-1.73 (m, 2H), 1.29-1.15 (m, 2H). 13 C NMR (100 MHz, CD 3 OD)? 167.99, 158.13, 152.07, 138.70, 134.56, 130.12, 130.07, 123.84, 121.61, 117.60, 116.72, 116.69, 104.86, 103.72, 65.50, 50.64, 41.49, 29.58, 25.37. MS (ESI, m / z ) calculated for C 21 H 25 N 5 O 2 [M + H] + 379.20, found 379.80.
실시예 9Example 9
Figure PCTKR2018014884-appb-I000039
Figure PCTKR2018014884-appb-I000039
4-((1-(3-Bromobenzyl)piperidin-4-yl)amino)-4 - ((1- (3-Bromobenzyl) piperidin-4-yl) amino) - NN -methyl-1-methyl-1 HH -pyrrolo[2,3-b]pyridine-5-carboxamidepyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 36%); 1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1 H), 7.51 (br. s, 1 H), 7.40 (d, J=7.8 Hz, 1 H), 7.28 (d, J=7.6 Hz, 1 H), 7.21 (t, J=7.6 Hz, 1 H), 7.04 (d, J=3.7 Hz, 1 H), 6.52 (d, J=3.6 Hz, 1 H), 4.09-3.99 (m, 1 H), 3.53 (s, 2 H), 2.95 (s, 3 H), 2.88-2.78 (m, 2 H), 2.37-2.27 (m, 2 H), 2.17-2.08 (m, 2 H), 1.82-1.71 (m, 2 H). 13C NMR (100 MHz, CD3OD) δ 170.78, 149.75, 149.24, 143.47, 140.42, 132.08, 130.24, 129.84, 127.77, 122.38, 121.13, 77.28, 62.38, 51.53, 32.51, 26.38. MS (ESI, m/z) calculated for C21H24BrN5O [M+H]+ 441.12, found 443.50.Was synthesized according to general procedure D (yield 36%); 1 H NMR (400 MHz, CDCl 3) δ 8.13 (s, 1 H), 7.51 (br. S, 1 H), 7.40 (d, J = 7.8 Hz, 1 H), 7.28 (d, J = 7.6 Hz , 1 H), 7.21 (t , J = 7.6 Hz, 1 H), 7.04 (d, J = 3.7 Hz, 1 H), 6.52 (d, J = 3.6 Hz, 1 H), 4.09-3.99 (m, 2 H), 2.37-2.27 (m, 2 H), 2.17-2.08 (m, 2 H), 3.52 (s, 1.82-1.71 (m, 2H). 13 C NMR (100 MHz, CD 3 OD)? 170.78, 149.75, 149.24, 143.47, 140.42, 132.08, 130.24, 129.84, 127.77, 122.38, 121.13, 77.28, 62.38, 51.53, 32.51, 26.38. MS (ESI, m / z ) calculated for C 21 H 24 BrN 5 O [M + H] + 441.12, found 443.50.
실시예 10Example 10
Figure PCTKR2018014884-appb-I000040
Figure PCTKR2018014884-appb-I000040
N-Methyl-4-((1-(3-methylbenzyl)piperidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine-5-carboxamideN-Methyl-4 - ((1- (3-methylbenzyl) piperidin-4-yl) amino) -1H-pyrrolo [2,3- b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 21%); 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1 H), 7.23 (t, J=7.5 Hz, 1 H), 7.19-7.13 (m, 2 H), 7.10 (d, J=7.4 Hz, 1 H), 7.04 (d, J=3.6 Hz, 1 H), 6.52 (d, J=3.6 Hz, 1 H), 4.10-4.00 (m, 1 H), 3.57 (s, 2 H), 2.94 (s, 3 H), 2.92-2.82 (m, 2 H), 2.43-2.32 (m, 2 H), 2.36 (s, 3 H), 2.20-2.10 (m, 2 H), 1.83-1.72 (m, 2 H). 13C NMR (100 MHz, CD3OD) δ 170.75, 149.77, 148.93, 143.23, 137.92, 136.87, 130.26, 128.16, 128.10, 126.58, 121.23, 105.23, 103.56, 102.64, 77.29, 35.94, 51.34, 32.19, 26.35, 21.28. MS (ESI, m/z) calculated for C22H27N5O [M+H]+ 377.22, found 378.60.Was synthesized according to general procedure D (Yield 21%); 1 H NMR (400 MHz, CDCl 3) δ 8.14 (s, 1 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.19-7.13 (m, 2 H), 7.10 (d, J = 7.4 Hz (M, 1H), 7.07 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H) (s, 3H), 2.92-2.82 (m, 2H), 2.43-2.32 (m, 2H), 2.36 , 2 H). 13 C NMR (100 MHz, CD 3 OD) δ 170.75, 149.77, 148.93, 143.23, 137.92, 136.87, 130.26, 128.16, 128.10, 126.58, 121.23, 105.23, 103.56, 102.64, 77.29, 35.94, 51.34, 32.19, 26.35, 21.28. MS (ESI, m / z) calculated for C 22 H 27 N 5 O [M + H] + 377.22, found 378.60.
실시예 11Example 11
Figure PCTKR2018014884-appb-I000041
Figure PCTKR2018014884-appb-I000041
4-((1-(3-Cyanobenzyl)piperidin-4-yl)amino)-4 - ((1- (3-Cyanobenzyl) piperidin-4-yl) amino) - NN -cyclopropyl-1-cyclopropyl-1 HH -pyrrolo[2,3-b]pyridine-5-carboxamidepyrrolo [2,3-b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 16%); 1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1 H), 8.01 (s, 1 H), 7.95-7.89 (m, 2 H), 7.39 (d, J=4.0 Hz, 1 H), 6.98 (d, J=4.0 Hz, 1 H), 4.63-4.53 (m, 1 H), 4.51 (s, 2 H), 3.71-3.55 (m, 2 H), 3.51-3.39 (m, 2 H), 2.93-2.81 (m, 1 H), 2.54-2.38 (m, 2 H), 2.10-1.97 (m, 2 H), 0.89-0.82 (m, 2 H), 0.71-0.64 (m, 2 H). MS (ESI, m/z) calculated for C24H26N6O [M+H]+ 414.22, found 415.15.Was synthesized according to general procedure D (yield 16%); 1 H NMR (400 MHz, CD 3 OD) δ 8.37 (s, 1 H), 8.01 (s, 1 H), 7.95-7.89 (m, 2 H), 7.39 (d, J = 4.0 Hz, 1 H) , 6.98 (d, J = 4.0 Hz, 1H), 4.63-4.53 (m, 1H), 4.51 (s, 2H), 3.71-3.55 ), 2.93-2.81 (m, 1H), 2.54-2.38 (m, 2H), 2.10-1.97 (m, 2H), 0.89-0.82 ). MS (ESI, m / z ) calculated for C 24 H 26 N 6 O [M + H] + 414.22, found 415.15.
실시예 12Example 12
Figure PCTKR2018014884-appb-I000042
Figure PCTKR2018014884-appb-I000042
N-cyclopropyl-4-((1-(3-methoxybenzyl)piperidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine -5-carboxamideN-cyclopropyl-4 - ((1- (3-methoxybenzyl) piperidin-4-yl) amino) -1H pyrrolo [2,3- b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 20%); 1H NMR (400 MHz, CD3OD) δ 8.23 (br. s, 1 H), 7.37-7.29 (m, 1 H), 7.05-6.93 (m, 3 H), 6.82 (br. s, 1 H), 4.48-4.31 (m, 1 H), 4.25 (br. s, 2 H), 3.60-3.48 (m, 2 H), 3.30-3.20 (m, 2 H), 2.84-2.70 (m, 1 H), 2.43-2.31 (m, 2 H), 1.90-1.73 (m, 2 H), 0.80-0.69 (m, 2 H), 0.60-0.49 (m, 2 H). MS (ESI, m/z) calculated for C24H29N5O2 [M+H]+ 419.23, found 420.15.Was synthesized according to general procedure D (20% yield); 1 H NMR (400 MHz, CD 3 OD)? 8.23 (br.s, 1H), 7.37-7.29 (m, 1H), 7.05-6.93 ), 4.48-4.31 (m, 1H), 4.25 (br.s, 2H), 3.60-3.48 (m, 2H), 3.30-3.20 (m, 2H), 2.84-2.70 ), 2.43-2.31 (m, 2H), 1.90-1.73 (m, 2H), 0.80-0.69 (m, 2H), 0.60-0.49 (m, 2H). MS (ESI, m / z ) calculated for C 24 H 29 N 5 O 2 [M + H] + 419.23, found 420.15.
실시예 13Example 13
Figure PCTKR2018014884-appb-I000043
Figure PCTKR2018014884-appb-I000043
4-((1-(3-Methoxybenzyl)piperidin-4-yl)amino)-14 - ((1- (3-Methoxybenzyl) piperidin-4-yl) amino) -1 HH -pyrrolo[2,3-pyrrolo [2,3- bb ]pyridine-5-carboxamide] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 14%); 1H NMR (400 MHz, CD3OD) δ 8.49 (br. s, 1 H), 7.50-7.42 (m, 1 H), 7.37 (br. s, 1 H), 7.18-7.09 (m, 3 H), 6.95 (br. s, 1 H), 4.59-4.43 (m, 1 H), 4.37 (br. s, 2 H), 3.70-3.59 (m, 2 H), 3.42-3.32 (m, 2 H), 2.57-2.49 (m, 2 H), 1.99-1.84 (m, 2 H); MS (ESI, m/z) calculated for C21H25N5O2 [M+H]+ 379.20, found 380.15.Was synthesized according to general procedure D (14% yield); 1 H NMR (400 MHz, CD 3 OD)? 8.49 (br.s, 1H), 7.50-7.42 (m, 1H), 7.37 (br.s, 1H), 7.18-7.09 ), 6.95 (br.s, 1H), 4.59-4.43 (m, 1H), 4.37 (br.s, 2H), 3.70-3.59 (m, 2H), 3.42-3.32 ), 2.57-2.49 (m, 2H), 1.99-1.84 (m, 2H); MS (ESI, m / z) calculated for C 21 H 25 N 5 O 2 [M + H] + 379.20, found 380.15.
실시예 14Example 14
Figure PCTKR2018014884-appb-I000044
Figure PCTKR2018014884-appb-I000044
N-cyclopentyl-4-((1-(3-methoxybenzyl)piperidin-4-yl)amino)-1H-pyrrolo[2,3-b]pyridine -5-carboxamideN-cyclopentyl-4 - ((1- (3-methoxybenzyl) piperidin-4-yl) amino) -1H pyrrolo [2,3- b] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 11%); 1H NMR (400 MHz, CD3OD) δ 8.40 (br. s, 1 H), 7.49-7.40 (m, 1 H), 7.38 (d, J=4.0 Hz, 1 H), 7.18-7.09 (m, 3 H), 6.95 (br. s, 1 H), 4.58-4.45 (m, 1 H), 4.37 (s, 2 H), 4.34-4.26 (m, 1 H), 3.70-3.60 (m, 2 H), 3.40-3.30 (m, 2 H), 2.57-2.41 (m, 2 H), 2.11-2.00 (m, 4 H), 2.00-1.88 (m, 2 H), 1.74-1.56 (m, 4 H); MS (ESI, m/z) calculated for C26H33N5O2 [M+H]+ 447.26, found 448.20.Was synthesized according to general procedure D (11% yield); 1 H NMR (400 MHz, CD 3 OD)? 8.40 (br s, 1H), 7.49-7.40 (m, 1H), 7.38 (d, J = 4.0 Hz, 1H), 7.18-7.09 , 3 H), 6.95 (br s, 1H), 4.58-4.45 (m, 1H), 4.37 (s, 2H), 4.34-4.26 (m, 1H), 3.70-3.60 (M, 2H), 3.40-3.30 (m, 2H), 2.57-2.41 (m, 2H), 2.11-2.00 H); MS (ESI, m / z ) calculated for C 26 H 33 N 5 O 2 [M + H] + 447.26, found 448.20.
실시예 15Example 15
Figure PCTKR2018014884-appb-I000045
Figure PCTKR2018014884-appb-I000045
4-((1-(3-Cyanobenzyl)piperidin-4-yl)amino)-4 - ((1- (3-Cyanobenzyl) piperidin-4-yl) amino) - NN -cyclopentyl-1-cyclopentyl-1 HH -pyrrolo[2,3-pyrrolo [2,3- bb ]pyridine-5-carboxamide] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 22%); 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1 H), 7.98 (s, 1 H), 7.96-7.88 (m, 2 H), 7.78-7.70 (m, 1 H), 7.39 (d, J=4.0 Hz, 1 H), 6.96 (d, J=4.0 Hz, 1 H), 4.61-4.53 (m, 1 H), 4.32 (s, 2 H), 4.40-4.29 (m, 1 H), 3.72-3.54 (m, 2 H), 3.54-3.38 (m, 2 H), 2.55-2.40 (m, 2 H), 2.12-2.00 (m, 4 H), 1.88-1.75 (m, 2 H), 1.75-1.57 (m, 4 H); MS (ESI, m/z) calculated for C26H30N6O [M+H]+ 442.25, found 443.15.Was synthesized according to general procedure D (yield: 22%); 1 H NMR (400 MHz, CD 3 OD) δ 8.41 (s, 1 H), 7.98 (s, 1 H), 7.96-7.88 (m, 2 H), 7.78-7.70 (m, 1 H), 7.39 ( d, J = 4.0 Hz, 1 H), 6.96 (d, J = 4.0 Hz, 1 H), 4.61-4.53 (m, 1 H), 4.32 (s, 2 H), 4.40-4.29 (m, 1 H ), 3.72-3.54 (m, 2H), 3.54-3.38 (m, 2H), 2.55-2.40 (m, 2H), 2.12-2.00 ), 1.75-1.57 (m, 4 H); MS (ESI, m / z ) calculated for C 26 H 30 N 6 O [M + H] + 442.25, found 443.15.
실시예 16Example 16
Figure PCTKR2018014884-appb-I000046
Figure PCTKR2018014884-appb-I000046
4-((1-Benzylpiperidin-4-yl)amino)-4 - ((1-Benzylpiperidin-4-yl) amino) - NN -methyl-1-methyl-1 HH -pyrrolo[2,3-pyrrolo [2,3- bb ]pyridine-5-carboxamide] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 6%); 1H NMR (400 MHz, CDCl3) δ 9.21 (d, J=7.8 Hz, 1 H), 8.19 (s, 1 H), 7.38-7.23 (m, 5 H), 7.04 (d, J=3.7 Hz, 1 H), 6.56 (d, J=3.7 Hz, 1 H), 6.04 (s, 1 H), 4.07-3.96 (m, 1 H), 3.56 (s, 2 H), 2.99 (d, J=4.8 Hz, 3 H), 2.91-2.80 (m, 2 H), 2.35-2.22 (m, 2 H), 2.17-2.08 (m, 2 H), 1.82-1.73 (m, 2 H); MS (ESI, m/z) calculated for C21H25N5O [M+H]+ 363.21, found 363.90.Was synthesized according to general procedure D (yield 6%); 1 H NMR (400 MHz, CDCl 3) δ 9.21 (d, J = 7.8 Hz, 1 H), 8.19 (s, 1 H), 7.38-7.23 (m, 5 H), 7.04 (d, J = 3.7 Hz , 1 H), 6.56 (d , J = 3.7 Hz, 1 H), 6.04 (s, 1 H), 4.07-3.96 (m, 1 H), 3.56 (s, 2 H), 2.99 (d, J = 4.8 Hz, 3 H), 2.91-2.80 (m, 2 H), 2.35-2.22 (m, 2 H), 2.17-2.08 (m, 2 H), 1.82-1.73 (m, 2 H); MS (ESI, m / z) calculated for C 21 H 25 N 5 O [M + H] + 363.21, found 363.90.
실시예 17Example 17
Figure PCTKR2018014884-appb-I000047
Figure PCTKR2018014884-appb-I000047
4-((1-Benzylpiperidin-4-yl)(methyl)amino)-4 - ((1-Benzylpiperidin-4-yl) (methyl) amino) - NN -methyl-1-methyl-1 HH -pyrrolo[2,3-pyrrolo [2,3- bb ]pyridine-5-carboxamide] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 12%); 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1 H), 9.36 (d, J=4.6 Hz, 1 H), 9.05 (s, 1 H), 7.38-7.21 (m, 5 H), 6.61 (d, J=3.3 Hz, 1 H), 3.48 (s, 2 H), 3.32-3.27 (m, 1 H), 3.10-2.95 (m, 8 H), 2.90-2.82 (m, 2 H), 2.00-1.91 (m, 2 H), 1.78-1.70 (m, 2 H). MS (ESI, m/z) calculated for C22H27N5O [M+H]+ 377.22, found 378.00.Was synthesized according to general procedure D (12% yield); 1 H NMR (400 MHz, CDCl 3 )? 10.50 (s, 1H), 9.36 (d, J = 4.6 Hz, 1H), 9.05 (s, 1H), 7.38-7.21 6.61 (d, J = 3.3 Hz , 1 H), 3.48 (s, 2 H), 3.32-3.27 (m, 1 H), 3.10-2.95 (m, 8 H), 2.90-2.82 (m, 2 H) , 2.00-1.91 (m, 2 H), 1.78-1.70 (m, 2 H). MS (ESI, m / z) calculated for C 22 H 27 N 5 O [M + H] + 377.22, found 378.00.
실시예 18Example 18
Figure PCTKR2018014884-appb-I000048
Figure PCTKR2018014884-appb-I000048
4-((1-Benzylpiperidin-4-yl)amino)-14 - ((1-Benzylpiperidin-4-yl) amino) -1 HH -pyrrolo[2,3-pyrrolo [2,3- bb ]pyridine-5-carboxylic acid] pyridine-5-carboxylic acid
일반적 절차 D에 따라 합성하였다(수율 12%); 1H NMR (400 MHz, CD3OD) δ 7.96 (s, 1 H), 7.67-7.44 (m, 5 H), 7.35-7.23 (m, 1 H), 6.90 (d, J=3.6 Hz, 1 H), 6.74 (s, 1 H), 4.39 (s, 2 H), 4.19-4.02 (m, 1 H), 3.73-3.56 (m, 2 H), 3.29-3.15 (m, 2 H), 2.41-2.23 (m, 2 H), 2.10-1.91 (m, 2 H). MS (ESI, m/z) calculated for C20H22N4O2 [M+H]+ 350.17, found 348.15.Was synthesized according to general procedure D (12% yield); 1 H NMR (400 MHz, CD 3 OD) δ 7.96 (s, 1 H), 7.67-7.44 (m, 5 H), 7.35-7.23 (m, 1 H), 6.90 (d, J = 3.6 Hz, 1 (M, 2H), 3.27-3.15 (m, 2H), 2.41 (s, 2H) -2.23 (m, 2 H), 2.10-1.91 (m, 2 H). MS (ESI, m / z) calculated for C 20 H 22 N 4 O 2 [M + H] + 350.17, found 348.15.
실시예 19Example 19
Figure PCTKR2018014884-appb-I000049
Figure PCTKR2018014884-appb-I000049
4-((1-Benzylpiperidin-4-yl)amino)-4 - ((1-Benzylpiperidin-4-yl) amino) - NN -cyclopropyl-1-cyclopropyl-1 HH -pyrrolo[2,3-pyrrolo [2,3- bb ]pyridine-5-carboxamide] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 11%); 1H NMR (400 MHz, CDCl3) δ 9.34 (br. s, 1 H), 9.28 (d, J=7.8 Hz, 1 H), 8.12 (s, 1 H), 7.38-7.30 (m, 4 H), 7.30-7.27 (m, 1 H), 7.03 (d, J=3.6 Hz, 1 H), 6.55 (d, J=3.7 Hz, 1 H), 6.18 (s, 1 H), 4.08-3.91 (m, 1 H), 3.56 (s, 2 H), 2.94-2.77 (m, 2 H), 2.34-2.20 (m, 2 H), 2.16-2.06 (m, 2 H), 2.08-1.97 (m, 1 H), 1.81-1.71 (m, 2 H), 0.92-0.85 (m, 2 H), 0.67-0.59 (m, 2 H). MS (ESI, m/z) calculated for C23H27N5O [M+H]+ 389.22, found 389.75.Was synthesized according to general procedure D (11% yield); 1 H NMR (400 MHz, CDCl 3 )? 9.34 (br.s, 1H), 9.28 (d, J = 7.8 Hz, 1H), 8.12 (s, 1H), 7.38-7.30 ), 7.30-7.27 (m, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.55 (d, J = 3.7 Hz, 1H), 6.18 (s, 1H), 4.08-3.91 (m, 2H), 2.16-2.06 (m, 2H), 2.08-1.97 (m, 2H) 1 H), 1.81-1.71 (m, 2 H), 0.92-0.85 (m, 2 H), 0.67-0.59 (m, 2 H). MS (ESI, m / z ) calculated for C 23 H 27 N 5 O [M + H] + 389.22, found 389.75.
실시예 20Example 20
Figure PCTKR2018014884-appb-I000050
Figure PCTKR2018014884-appb-I000050
4-((1-Benzylpiperidin-4-yl)amino)-4 - ((1-Benzylpiperidin-4-yl) amino) - NN -cyclopentyl-1-cyclopentyl-1 HH -pyrrolo[2,3-pyrrolo [2,3- bb ]pyridine-5-carboxamide] pyridine-5-carboxamide
일반적 절차 D에 따라 합성하였다(수율 23%); 1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1 H), 7.61-7.52 (m, 5 H), 7.40 (d, J=4.0 Hz, 1 H), 6.97 (d, J=4.0 Hz, 1 H), 4.57-4.48 (m, 1 H), 4.34 (s, 2 H), 4.34-4.26 (m, 1 H), 3.72-3.62 (m, 2 H), 3.50-3.40 (m, 2 H), 2.56-2.44 (m, 2 H), 2.11-2.02 (m, 2 H), 1.99-1.89 (m, 2 H), 1.88-1.76 (m, 2 H), 1.76-1.54 (m, 4 H). MS (ESI, m/z) calculated for C25H29N5O2 [M+H]+ 417.25, found 418.15.Was synthesized according to general procedure D (yield: 23%); 1 H NMR (400 MHz, CD 3 OD) δ 8.39 (s, 1 H), 7.61-7.52 (m, 5 H), 7.40 (d, J = 4.0 Hz, 1 H), 6.97 (d, J = 4.0 (M, 2H), 3.50-3.40 (m, 2H), 4.34-4.26 (m, 1H) (M, 2 H), 1.76-1.46 (m, 2 H), 2.16-2.44 (m, 4 H). MS (ESI, m / z ) calculated for C 25 H 29 N 5 O 2 [M + H] + 417.25, found 418.15.

Claims (8)

  1. 하기 화학식 I의 화합물 또는 그의 약제학적으로 허용되는 염.Claims 1. Compounds of the general formula < RTI ID = 0.0 > (I) < / RTI >
    [화학식 I](I)
    Figure PCTKR2018014884-appb-I000051
    Figure PCTKR2018014884-appb-I000051
    상기 식에서,In this formula,
    R1은 수소기, C1-C3 알킬기, 또는 C3-C8 시클로알킬기이고;R 1 is a hydrogen group, a C 1 -C 3 alkyl group, or a C 3 -C 8 cycloalkyl group;
    R2는 수소기, 또는 C1-C3 알킬기이고;R 2 is a hydrogen group, or a C 1 -C 3 alkyl group;
    R3는 수소기,
    Figure PCTKR2018014884-appb-I000052
    , 또는
    Figure PCTKR2018014884-appb-I000053
    이고;    R 3 represents a hydrogen group,
    Figure PCTKR2018014884-appb-I000052
    , or
    Figure PCTKR2018014884-appb-I000053
    ego;
    R4, 및 R5는, 각각 독립적으로, 수소기, C1-C3 알킬기, C1-C3 알콕시기, 할로겐기, 히드록시기, 또는 시아노기이며; n은 0, 또는 1의 정수이다.R 4 and R 5 are each independently a hydrogen group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a halogen group, a hydroxy group, or a cyano group; n is an integer of 0 or 1;
    단, R4, 및 R5가 동시에 수소기인 경우, R1은 수소기가 아니다.Provided that when R 4 and R 5 are simultaneously a hydrogen group, R 1 is not a hydrogen group.
  2. 청구항 1에 있어서, R1은 메틸기인 것인 화합물 또는 그의 약제학적으로 허용되는 염.2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R < 1 > is a methyl group.
  3. 청구항 1에 있어서, R2는 수소기, 또는 메틸기인 것인 화합물 또는 약제학적으로 허용되는 염.The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is a hydrogen group or a methyl group.
  4. 청구항 1에 있어서, R4, R5는, 각각 독립적으로, 수소기, 메틸기, 메톡시기, 할로겐기, 히드록시기, 또는 시아노기인 것인 화합물 또는 그의 약제학적으로 허용되는 염.The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 4 and R 5 are each independently a hydrogen group, a methyl group, a methoxy group, a halogen group, a hydroxy group, or a cyano group.
  5. 청구항 1 내지 4의 어느 한 한 항의 화합물 또는 그의 약제학적으로 허용되는 염을 포함하는 자가면역 질병, 염증성 질병, 또는 암을 치료 또는 예방에 사용하기 위한 의약 조성물.A pharmaceutical composition for use in the treatment or prophylaxis of an autoimmune disease, inflammatory disease, or cancer comprising the compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
  6. 청구항 5에 있어서, 상기 자가면역 질병이, 피부 질환, 다발성 경화증, 류마티스 관절염, 건선성 관절염, 연소성 관절염, I형 당뇨병, 루푸스, 염증성 장 질병, 크론병, 중증근무력증, 면역글로불린 신증, 심근염 또는 자가면역 갑상선 질환인 의약 조성물.The method of claim 5, wherein the autoimmune disease is selected from the group consisting of skin diseases, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn's disease, myasthenia gravis, A pharmaceutical composition which is an immune thyroid disease.
  7. 청구항 6에 있어서, 상기 피부 질환이 아토피 피부염, 건선, 피부 감작, 피부 자극, 피부 발진, 접촉성 피부염 또는 알레르기 접촉 감작인 의약 조성물.[Claim 7] The pharmaceutical composition according to claim 6, wherein the skin disease is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
  8. 청구항 5에 있어서, 췌장암, 전립선암, 폐암, 두경부암, 유방암, 결장암, 난소암, 위암, 간암, 캐슬만병, 다발성 골수종, 림프종, 흑색종, 신경모세포종, 교모세포종, 전신 비만세포증, 또는 백혈병인 의약 조성물.6. The method of claim 5, wherein the cancer is selected from the group consisting of pancreatic cancer, prostate cancer, lung cancer, head and neck cancer, breast cancer, colon cancer, ovarian cancer, gastric cancer, hepatoma, castellae, multiple myeloma, lymphoma, melanoma, neuroblastoma, ≪ / RTI >
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