KR20150028130A - Indolizine derivatives, pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient - Google Patents

Indolizine derivatives, pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient Download PDF

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KR20150028130A
KR20150028130A KR20130106832A KR20130106832A KR20150028130A KR 20150028130 A KR20150028130 A KR 20150028130A KR 20130106832 A KR20130106832 A KR 20130106832A KR 20130106832 A KR20130106832 A KR 20130106832A KR 20150028130 A KR20150028130 A KR 20150028130A
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compound
formula
cancer
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김성환
김익연
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연세대학교 산학협력단
한국화학연구원
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    • 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
    • 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

Abstract

The present invention relates to indolizine derivatives, pharmaceutically acceptable salt thereof, a preparation method thereof, and a pharmaceutical composition for preventing or treating bone diseases or cancer comprising the same as an active ingredient. The indolizine derivatives of the present invention inhibit differentiation of osteoclasts, thereby showing treatment effect of bone diseases related to the osteoclast such as osteoporosis, and anticancer activity by inducing death of cancer cells. Accordingly, the derivatives can be used as a medicine for preventing or treating bone diseases or cancer.

Description

인돌리진 유도체, 이의 약학적으로 허용 가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 약학적 조성물{Indolizine derivatives, pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition containing the same as an active ingredient}TECHNICAL FIELD The present invention relates to an indolizine derivative, a pharmaceutically acceptable salt thereof, a process for preparing the same, and a pharmaceutical composition containing the same as an active ingredient.

본 발명은 인돌리진 유도체, 이의 약학적으로 허용 가능한 염, 이의 제조방법 및 이를 유효성분으로 포함하는 골 질환 또는 암의 예방 또는 치료용 약학적 조성물에 관한 것이다.
The present invention relates to an indolizine derivative, a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating bone diseases or cancers containing the same as an active ingredient.

인돌리진(indolizine) 유도체는 질소를 함유하는 이중고리 화합물로 심장혈관 치료제 등의 의약품 합성에 사용되며, 천연물의 합성에 기본골격으로 많이 이용된다. 또한, 광학적 특성을 가지고 있어 정밀과학이나 소재과학분야에도 사용된다. 이에 따라, 다양한 인돌리진 유도체에 관한 합성이 이루어지고 있다. 인돌리진 유도체에 관하여 개시하는 특허문헌으로는 대한민국 공개특허 제10-2008-0072000호, 대한민국 등록특허 제10-1125531호, 대한민국 공개특허 제10-2004-0053125호 등이 있다.Indolizine derivatives are nitrogen-containing bicyclic compounds that are used in the synthesis of drugs such as cardiovascular drugs and are used as a basic framework for the synthesis of natural products. It also has optical properties and is used in precision science and materials science. Thus, various indolizine derivatives have been synthesized. Patent documents disclosed in Korean Patent Laid-Open Nos. 10-2008-0072000, 10-1125531 and 10-2004-0053125 disclose indolizine derivatives.

한편, 암은 생체로부터 영양을 공급받지만, 생체와는 독립적으로 과잉 증식하며, 생체를 파괴하는 생체조직에서 발생한 비정상적인 조직의 덩어리이다. 신체의 모든 장기는 수많은 세포로 구성되어 있는데 신체의 정상적인 세포가 비정상적인 세포로 되면서 무질서하게 분열 증식하여 많은 세포를 만들므로 암이 발생하게 된다. 암의 발병에는 유전적 소인도 깊이 관여하지만 환경적 요인 또한 큰 영향을 미치며 선진국일수록 암의 발병이 증가하는 경향을 보이는 것으로 알려져 있다.On the other hand, cancer is an abnormally formed mass of tissue that is supplied from a living body, but is excessively proliferated independently of the living body, and is generated in a living tissue destroying the living body. All organs of the body are made up of a number of cells. The normal cells of the body become abnormal cells, and cancer cells develop because of disorder and proliferation. Although genetic predisposition is deeply involved in the onset of cancer, environmental factors also have a great influence. It is known that the developed countries tend to have an increased incidence of cancer.

현재 암을 치료하기 위한 다양한 방법이 개발되고 있으며, 암을 치료하는 대표적인 방법으로는 외과적 치료, 화학적 치료 및 방사선 치료가 있다. 이러한 치료방법 중에서 암의 화학적 치료를 위한 다양한 항암제에 대한 연구 개발이 활발히 이루어지고 있다.Currently, various methods for treating cancer are being developed, and surgical treatment, chemotherapy, and radiation therapy are representative methods of treating cancer. Among these treatments, various anti-cancer drugs have been actively developed for the chemical treatment of cancer.

한편, 골 질환의 대표적인 예인 골다공증은 골의 재흡수와 재형성 사이의 균형이 깨어져서 골 재흡수 속도가 빨라짐에 따라 골의 칼슘이 빠져 일어나게 되는 골소실로 인한 골절에 의해 급격히 초래되는 질병이다. 선행 연구보고에 의하면 65세 이상에서 잘 오는 노인성 골다공증과 성 호르몬 부족에서 오는 폐경 후 골다공증뿐만 아니라, 요즘은 젊은 학생에게도 편식 등으로 칼슘 섭취가 부족하게 되어 골다공증이 초래되는 것으로 알려져 있다. 그리고, 고혈압, 고지혈증, 당뇨병, 간질환, 신부전증, 갑상선 질환, 암, 성기능 감퇴, 스테로이드나 위장약을 장기 복용하는자, 술, 담배, 커피가 심한 자, 고기 많이 먹는 사람, 운동 잘 안하는 사람, 왜소한 사람, 앉아 일하는 사람, 위 수술 받은 사람, 요통, 관절염, 근육통이 있는 사람, 오래 누워 있는 사람, 피로를 잘 느끼는 사람 등은 골다공증 발생의 위험이 높아진다.On the other hand, osteoporosis, which is a typical example of bone disease, is a disease rapidly caused by fracture due to bone loss which is caused by loss of bone calcium due to breakage of balance between reabsorption and reshaping of bone. According to previous research reports, it is known that not only osteoporosis and osteoporosis coming from osteoporosis and sex hormone deficiency coming from well over 65 years old but also young students nowadays osteoporosis due to lack of calcium intake due to unilateralism. People who take long-term medication such as hypertension, hyperlipidemia, diabetes, liver disease, renal failure, thyroid disease, cancer, sexual dysfunction, steroids or gastrointestinal drug, alcohol, tobacco, heavy coffee, The risk of developing osteoporosis is increased by people, people who are sitting, those who have surgery, people with back pain, arthritis, people with muscle aches, people who are lying long, and people who feel well.

골다공증의 원인은 다양하게 생각할 수 있지만, 가장 많은 것이 나이가 드는 것(노화) 또는 여성의 폐경 후의 호르몬 불균형이기 때문에, 현재의 치료는 주로 에스트로겐, 비타민 D나 칼시토닌의 투여가 행해지고 있다. 그러나, 호르몬의 투여는 암(특히, 유방암, 자궁암 등)을 유발할 위험이 있어 안전한 치료 방법이라고는 할 수 없다. 또한, 제2 세대 치료제로서, 비스포스포네이트의 투여도 행해지고 있지만, 투여를 중단하면 리바운드가 발생하는 문제점을 가지고 있다. 따라서, 골다공증을 효과적으로 치료할 수 있는 새로운 약물에 대한 연구 개발이 필요한 실정이다.
Osteoporosis can be thought of as a variety of causes, but the most common treatment is estrogen, vitamin D, and calcitonin, since the majority are older (aging) or hormone imbalance after menopause in women. However, administration of hormones is not a safe treatment because of the risk of inducing cancer (especially breast cancer, uterine cancer, etc.). In addition, although bisphosphonate is administered as a second-generation therapeutic agent, there is a problem that rebound occurs when administration is discontinued. Therefore, it is necessary to research and develop new drugs that can effectively treat osteoporosis.

본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

대한민국 등록특허 제10-1125531호Korean Patent No. 10-1125531 대한민국 공개특허 제10-2004-0053125호Korean Patent Publication No. 10-2004-0053125 대한민국 공개특허 제10-2008-0072000호Korean Patent Publication No. 10-2008-0072000

본 발명자들은 다양한 치환기를 갖는 새로운 구조의 인돌리진 유도체 및 이의 효율적인 합성법을 개발하기 위하여 연구 노력하였다. 그 결과, 도미노 크뇌베나겔 축합 및 분자 내 알돌 고리화 반응(domino Knoevenagel condensation/intramolecular aldol cyclization)을 통하여 다양한 치환기를 갖는 신규한 인돌리진 유도체를 합성하고, 이들 유도체가 골 질환(파골세포 분화 억제) 및 암에 대하여 치료효과를 보임을 확인함으로써, 본 발명을 완성하게 되었다.The present inventors have made efforts to develop new structures of indolizine derivatives having various substituents and an efficient synthesis method thereof. As a result, novel indolizine derivatives having various substituents were synthesized through domino-kernobenzene condensation and intramolecular aldol cyclization (domino Knoevenagel condensation / intramolecular aldol cyclization), and these derivatives were used for bone diseases (osteoclast differentiation inhibition) And cancer, the present invention has been completed.

따라서, 본 발명의 목적은 화학식 1의 인돌리진 유도체 또는 이의 약학적으로 허용 가능한 염을 제공하는 데 있다.Accordingly, an object of the present invention is to provide an indolizine derivative of the formula (I) or a pharmaceutically acceptable salt thereof.

본 발명의 다른 목적은 상기 인돌리진 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 골 질환의 예방 또는 치료용 약학적 조성물을 제공하는 데 있다.It is another object of the present invention to provide a pharmaceutical composition for preventing or treating bone diseases comprising the indolizine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 또 다른 목적은 상기 인돌리진 유도체 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공하는 데 있다.Still another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer comprising the indolizine derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 또 다른 목적은 상기 인돌리진 유도체의 제조방법을 제공하는 데 있다.
It is still another object of the present invention to provide a process for preparing the indolizine derivative.

본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

본 발명의 일 양태에 따르면, 본 발명은 하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염을 제공한다:According to one aspect of the present invention, the present invention provides a compound of the formula 1: < EMI ID = 2.1 > or a pharmaceutically acceptable salt thereof,

화학식 1Formula 1

Figure pat00001
Figure pat00001

상기 화학식에서,In the above formulas,

R1은

Figure pat00002
, 또는 시아노이고;R 1 is
Figure pat00002
, Or cyano;

상기 A는 C1-C6 알킬, C1-C6 알콕시, 하이드록시, 또는 비치환되거나 할로겐 또는 C1-C6 알콕시로 치환된 페닐로 치환된 C2-C6 알케닐이거나, 또는 R2와 함께 고리를 이루어 5각-6각의 환형구조를 이루고, 이때

Figure pat00003
는 이중결합이며;Wherein A is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, or C 2 -C 6 alkenyl unsubstituted or substituted by phenyl substituted by halogen or C 1 -C 6 alkoxy, or R 2 to form a ring and form a pentagonal-pentagonal annular structure,
Figure pat00003
Is a double bond;

R2는 C1-C6 알킬, 아민 또는 하이드록시이거나, 또는 A와 함께 고리를 이루어 5각-6각의 환형구조를 이루고, 이때

Figure pat00004
는 이중결합이고;R 2 is C 1 -C 6 alkyl, amine or hydroxy, or forms a ring together with A to form a pentane-6-angled cyclic structure,
Figure pat00004
Is a double bond;

R3은

Figure pat00005
가 단일결합인 경우 하이드록시, C1-C6 알킬, 또는 아민이고,
Figure pat00006
가 이중결합인 경우에는 존재하지 않으며;R 3 is
Figure pat00005
Is a single bond when the hydroxy, C 1 -C 6 alkyl, or an amine,
Figure pat00006
Lt; / RTI > is not a double bond;

R4는 비치환되거나 할로겐, C1-C6 알콕시, C1-C6 알킬 및 페닐C1-C3 알콕시로 구성된 군으로부터 선택된 1 이상의 치환기로 치환된 5각-10각 고리의 아릴 또는 헤테로아릴, 또는 C1-C6 알콕시이고;R 4 is unsubstituted or substituted by halogen, C 1 -C 6 alkoxy, C 1 -C 6 -10 5 each aryl or heteroaryl each ring optionally substituted with one or more substituents selected from the group consisting of alkyl and phenyl C 1 -C 3 alkoxy Aryl, or C 1 -C 6 alkoxy;

R5는 수소,

Figure pat00007
(B는 C1-C6 알킬) 또는 -CHO이거나, 또는 R6과 함께 페닐을 형성하며;R 5 is hydrogen,
Figure pat00007
(B is C 1 -C 6 alkyl) or -CHO, or forms together with R 6 a phenyl;

R6은 수소 또는 C1-C6 알킬이거나, 또는 R5와 함께 페닐을 형성하고;R 6 is to form a phenyl together with hydrogen or C 1 -C 6 alkyl, or R 5;

R7은 수소, 또는

Figure pat00008
(B는 C1-C6 알킬)이다.
R 7 is hydrogen, or
Figure pat00008
(B is C 1 -C 6 alkyl).

본 발명자들은 다양한 치환기를 갖는 새로운 구조의 인돌리진 유도체 및 이의 효율적인 합성법을 개발하기 위하여 연구 노력하였다. 그 결과, 도미노 크뇌베나겔 축합 및 분자 내 알돌 고리화 반응을 통하여 다양한 치환기를 갖는 신규한 인돌리진 유도체를 합성하고, 이들 유도체가 골 질환(파골세포 분화 억제) 및 암에 대하여 치료효과를 보임을 확인하였다. 따라서, 본 발명의 화합물은 골 질환 및 암에 대한 효율적인 예방 및 치료제로서 활용이 가능하다.The present inventors have made efforts to develop new structures of indolizine derivatives having various substituents and an efficient synthesis method thereof. As a result, novel indolizine derivatives having various substituents were synthesized through domino-kerbene-enegna condensation and intramolecular aldol cyclization, and these derivatives showed therapeutic effects on bone diseases (osteoclast differentiation inhibition) and cancer Respectively. Therefore, the compound of the present invention can be utilized as an effective preventive and therapeutic agent for bone diseases and cancer.

본 명세서에서 사용된 용어,"알킬"은 직쇄 또는 분쇄의 포화 탄화수소기를 의미하며, 예를 들어, 메틸, 에틸, 프로필, 이소부틸, 펜틸 또는 헥실 등을 포함한다. C1-C6 알킬은 탄소수 1 내지 6의 알킬 유니트를 가지는 알킬기를 의미하며, C1-C6 알킬이 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다.As used herein, the term "alkyl" means a straight or branched saturated hydrocarbon group, including, for example, methyl, ethyl, propyl, isobutyl, pentyl or hexyl. C 1 -C 6 alkyl means an alkyl group having an alkyl unit having 1 to 6 carbon atoms, and when C 1 -C 6 alkyl is substituted, the number of carbon atoms of the substituent is not included.

본 발명의 일구현예에 따르면, 상기 화학식 1에서 C1-C6 알킬은 C1-C4 알킬이고, 다른 특정예에서는 C1-C3 알킬이다.According to one embodiment of the present invention, in Formula 1 C 1 -C 6 alkyl is a C 1 -C 4 alkyl, and in another specific example, a C 1 -C 3 alkyl.

본 명세서에서 사용된 용어, "알콕시"는 알코올에서 수소가 제거되어 형성된 라디칼을 의미하며, C1-C6 알콕시가 치환된 경우 치환체의 탄소수는 포함되지 않은 것이다. 알콕시의 예는 다음을 포함한다: 메톡시, 에톡시, 프로폭시, 이소프로폭시, 부톡시, 이소부톡시, sec-부톡시, tert-부톡시, 펜틸옥시, 이소펜틸옥시, 네오펜틸옥시, tert-펜틸옥시, 헥실옥시 및 이소헥실옥시.As used herein, the term "alkoxy" means a radical formed by removal of hydrogen from an alcohol, and when C 1 -C 6 alkoxy is substituted, the number of carbon atoms of the substituent is not included. Examples of alkoxy include: methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec -butoxy, tert -butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert - pentyloxy, hexyloxy and isohexyloxy.

본 발명의 일구현예에 따르면, 상기 화학식 1에서 C1-C6 알콕시는 C1-C3 알콕시이다.According to one embodiment of the present invention, in the above formula (1), C 1 -C 6 alkoxy is C 1 -C 3 alkoxy.

본 명세서에서 사용된 용어, "할로겐"은 할로겐족 원소를 나타내며, 예컨대, 플루오로, 클로로, 브로모 및 요오도를 포함한다.As used herein, the term "halogen" refers to a halogen group element and includes, for example, fluoro, chloro, bromo and iodo.

본 명세서에서 사용된 용어, "아릴"은 전체적으로 또는 부분적으로 불포화되고 방향성(aromaticity)을 가지는 치환 또는 비치환된 모노사이클릭 또는 폴리사이클릭 탄소 고리를 의미한다.As used herein, the term "aryl" means a substituted or unsubstituted monocyclic or polycyclic carbon ring that is totally or partially unsaturated and has aromaticity.

본 명세서에서 사용된 용어, "헤테로아릴"은 헤테로원자로서 고리 내에 산소, 황 또는 질소를 포함하는 헤테로사이클릭 방향족기를 의미한다. 고리 내 헤테로원자의 개수는 1-4 이다.As used herein, the term "heteroaryl" means a heterocyclic aromatic group containing a hetero atom, oxygen, sulfur or nitrogen, in the ring. The number of heteroatoms in the ring is 1-4.

본 발명의 일구현예에 따르면, 상기 R4의 헤테로아릴은 티오펜이다.According to one embodiment of the present invention, said heteroaryl of R < 4 > is thiophene.

본 발명의 일구현예에 따르면, 상기 R1의 A에서 비치환되거나 할로겐 또는 C1-C6 알콕시로 치환된 페닐로 치환된 C2-C6 알케닐은, 할로겐 또는 C1-C3 알콕시로 치환된 페닐로 치환된 C2-C3 알케닐이다.According to one embodiment of the present invention, C 2 -C 6 alkenyl unsubstituted or substituted by phenyl substituted by halogen or C 1 -C 6 alkoxy in R 1 is halogen or C 1 -C 3 alkoxy a is C 2 -C 3 alkenyl substituted with phenyl substituted with.

본 발명의 일구현예에 따르면, 상기 R1의 A에서 R2와 함께 고리를 이루어 형성한 환형구조는, 6각의 환형구조이며, 비치환되거나 C1-C6 알킬로 치환될 수 있다.According to an embodiment of the present invention, the cyclic structure formed by ringing together with R 2 of R 1 in the above R 1 is a hexagonal cyclic structure and may be unsubstituted or substituted with C 1 -C 6 alkyl.

본 발명의 일구현예에 따르면, 상기 R2는 C1-C3 알킬 또는 아민이거나, 또는 A와 함께 고리를 이루어 6각의 환형구조를 이룰 수 있다.According to one embodiment of the present invention, R 2 may be C 1 -C 3 alkyl or amine, or may form a ring with A to form a hexagonal ring structure.

본 발명의 일구현예에 따르면, 상기 R3은

Figure pat00009
가 단일결합인 경우 하이드록시이다.According to an embodiment of the present invention, R < 3 >
Figure pat00009
Lt; / RTI > is a single bond.

본 발명의 일구현예에 따르면, 본 발명의 화학식 1의 화합물은 하기의 화학식 2 내지 57로 표시되는 화합물로 구성된 군으로부터 선택된다.
According to one embodiment of the present invention, the compound of formula (I) of the present invention is selected from the group consisting of the compounds represented by the following formulas (2) to (57).

화학식 2(2)

Figure pat00010
Figure pat00010

화학식 3(3)

Figure pat00011
Figure pat00011

화학식 4Formula 4

Figure pat00012
Figure pat00012

화학식 5Formula 5

Figure pat00013
Figure pat00013

화학식 66

Figure pat00014
Figure pat00014

화학식 7Formula 7

Figure pat00015
Figure pat00015

화학식 88

Figure pat00016
Figure pat00016

화학식 9Formula 9

Figure pat00017
Figure pat00017

화학식 1010

Figure pat00018
Figure pat00018

화학식 11Formula 11

Figure pat00019
Figure pat00019

화학식 12Formula 12

Figure pat00020
Figure pat00020

화학식 13Formula 13

Figure pat00021
Figure pat00021

화학식 14Formula 14

Figure pat00022
Figure pat00022

화학식 15Formula 15

Figure pat00023
Figure pat00023

화학식 16Formula 16

Figure pat00024
Figure pat00024

화학식 17Formula 17

Figure pat00025
Figure pat00025

화학식 1818

Figure pat00026
Figure pat00026

화학식 19Formula 19

Figure pat00027
Figure pat00027

화학식 2020

Figure pat00028
Figure pat00028

화학식 21Formula 21

Figure pat00029
Figure pat00029

화학식 22Formula 22

Figure pat00030
Figure pat00030

화학식 23Formula 23

화학식 2424

Figure pat00032
Figure pat00032

화학식 2525

Figure pat00033
Figure pat00033

화학식 2626

Figure pat00034
Figure pat00034

화학식 2727

Figure pat00035
Figure pat00035

화학식 2828

Figure pat00036
Figure pat00036

화학식 29Formula 29

Figure pat00037
Figure pat00037

화학식 30Formula 30

Figure pat00038
Figure pat00038

화학식 3131

Figure pat00039
Figure pat00039

화학식 32(32)

Figure pat00040
Figure pat00040

화학식 33Formula 33

Figure pat00041
Figure pat00041

화학식 34(34)

Figure pat00042
Figure pat00042

화학식 35(35)

Figure pat00043
Figure pat00043

화학식 36Formula 36

Figure pat00044
Figure pat00044

화학식 3737

Figure pat00045

Figure pat00045

화학식 38Formula 38

Figure pat00046
Figure pat00046

화학식 3939

Figure pat00047
Figure pat00047

화학식 4040

Figure pat00048
Figure pat00048

화학식 41Formula 41

Figure pat00049

Figure pat00049

화학식 42Formula 42

Figure pat00050
Figure pat00050

화학식 43Formula 43

Figure pat00051
Figure pat00051

화학식 4444

Figure pat00052
Figure pat00052

화학식 45Formula 45

Figure pat00053
Figure pat00053

화학식 46Formula 46

Figure pat00054
Figure pat00054

화학식 47Formula 47

Figure pat00055
Figure pat00055

화학식 4848

Figure pat00056
Figure pat00056

화학식 49Formula 49

Figure pat00057
Figure pat00057

화학식 5050

Figure pat00058
Figure pat00058

화학식 51Formula 51

Figure pat00059
Figure pat00059

화학식 52Formula 52

Figure pat00060

Figure pat00060

본 발명의 일구현예에 따르면, 본 발명의 화학식 1로 표시되는 화합물은 상기 화학식 3-5, 9, 10, 13-15, 18, 19, 22-24, 27, 34, 35, 37, 38 및 41-48로 표시되는 화합물로 구성된 군으로부터 선택된다. 이들 화합물은 하기 표 4에 나타난 바와 같이 골 질환과 암에 대한 치료효과를 나타내는 화합물들이다(표 4 참조).According to one embodiment of the present invention, the compound represented by the general formula (1) of the present invention is a compound represented by the general formula (3-5, 9, 10, 13-15, 18, 19, 22-24, 27, 34, 35, 37, 38 And compounds represented by 41-48. These compounds are compounds showing the therapeutic effect on bone diseases and cancer as shown in Table 4 (see Table 4).

본 발명은 화학식 1의 화합물뿐만 아니라, 이의 약학적으로 허용 가능한 염도 포함한다.The present invention includes not only the compounds of formula (I) but also their pharmaceutically acceptable salts.

본 명세서에서 사용된 용어, "약학적으로 허용 가능한 염"은, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는, 화합물의 제형을 의미한다. 상기 약학적 염은, 본 발명의 화합물을, 염산, 브롬산, 황산, 질산, 인산 등의 무기산, 메탄술폰산, 에탄술폰산, p-톨루엔술폰산 등의 술폰산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플루오로아세트산, 카프릭산, 이소부탄산, 말론산, 숙신산, 프탈산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리실산 등과 같은 유기 카본산과 반응시켜 얻어질 수 있다. 본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 화학식 1의 화합물을 유기용매, 예를 들면 메탄올, 에탄올, 아세톤, 메틸렌클로라이드, 아세토니트릴 등에 녹이고 유기산 또는 무기산을 가하여 생성된 침전물을 여과, 건조하여 제조되거나, 용매와 과량의 산을 감압 증류한 후 건조하거나 유기용매 하에서 결정화시켜 제조할 수 있다.As used herein, the term "pharmaceutically acceptable salt" means a formulation of a compound that does not cause serious irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound. The pharmaceutical salt may be prepared by dissolving the compound of the present invention in an organic solvent such as mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, sulfonic acid such as methanesulfonic acid, ethanesulfonic acid or p- toluenesulfonic acid, tartaric acid, formic acid, With an organic carboxylic acid such as acetic acid, acetic acid, benzenesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, rosacetic acid, trifluoroacetic acid, capric acid, isobutanoic acid, malonic acid, succinic acid, phthalic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like. The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving the compound of the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, , Or may be prepared by drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying or crystallization in an organic solvent.

또한, 본 발명의 화합물을 염기와 반응시켜, 암모니움 염, 나트륨 또는 칼륨염 등의 알칼리 금속염, 칼슘 또는 마그네슘염 등의 알칼리 토금속염 등의 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸) 메틸아민 등의 유기염기들의 염, 및 아르기닌, 리신 등의 아미노산 염을 형성함으로써 얻어질 수도 있다.Also, by reacting the compound of the present invention with a base, an alkali metal salt such as an ammonium salt, a sodium or potassium salt, a salt such as an alkaline earth metal salt such as a calcium salt or a magnesium salt, a dicyclohexylamine, Carmine, tris (hydroxymethyl) methylamine and the like, and amino acid salts such as arginine, lysine and the like.

본 발명은 상기 화학식 1로 표시되는 인돌리진 유도체 및 이의 약학적으로 허용되는 염뿐만 아니라, 이로부터 제조될 수 있는 용매화물, 수화물 및 입체이성질체 등을 모두 포함한다.
The present invention includes not only the indolizine derivatives represented by the above formula (1) and pharmaceutically acceptable salts thereof, but also solvates, hydrates and stereoisomers thereof which can be prepared therefrom.

본 발명의 다른 양태에 따르면, 본 발명은 (a) 본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 약학적 유효량; 및 (b) 약학적으로 허용 가능한 담체를 포함하는 골 질환의 예방 또는 치료용 약학적 조성물을 제공한다.According to another aspect of the present invention, there is provided a pharmaceutical composition comprising (a) a pharmaceutically effective amount of a compound represented by formula (1) of the present invention or a pharmaceutically acceptable salt thereof; And (b) a pharmaceutically acceptable carrier. The present invention also provides a pharmaceutical composition for preventing or treating bone diseases.

본 발명의 또 다른 양태에 따르면, 본 발명은 (a) 본 발명의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염의 약학적 유효량; 및 (b) 약학적으로 허용 가능한 담체를 포함하는 암의 예방 또는 치료용 약학적 조성물을 제공한다.According to another aspect of the present invention, there is provided a pharmaceutical composition comprising (a) a pharmaceutically effective amount of a compound represented by formula (1) of the present invention or a pharmaceutically acceptable salt thereof; And (b) a pharmaceutically acceptable carrier. The present invention also provides a pharmaceutical composition for preventing or treating cancer.

본 명세서에서 사용된 용어, "예방"은 본 발명의 조성물의 투여로 상기 질환을 억제시키거나 진행을 지연시키는 모든 행위를 의미하며, 용어 "치료"는 상기 질환의 (i) 발전의 억제, (ii) 질환의 경감, 및 (iii) 질환의 제거를 의미한다.As used herein, the term "prophylactic " means any action that inhibits or delays progression of the disease by administration of a composition of the present invention, and the term" treatment " ii) alleviation of the disease, and (iii) elimination of the disease.

본 발명의 일구현예에 따르면, 상기 골 질환은 파골세포 관련 골 질환이다. 본 발명의 화합물은 파골세포의 분화 또는 골 흡수를 억제할 수 있어 파골세포와 관련된 질환의 예방 및 치료를 위하여 활용될 수 있다.According to one embodiment of the present invention, the bone disease is osteoclast-related bone disease. The compound of the present invention can inhibit osteoclast differentiation or bone resorption and thus can be utilized for prevention and treatment of osteoclast-related diseases.

상기 골 질환은 골 질환은 골다공증, 파제트병, 골절, 치주염, 골 성장 장애, 원발성 골종양, 암의 골전이, 골 전이암 및 류마티스 관절염으로 구성된 군으로부터 선택될 수 있으며, 이에 의하여 제한되는 것은 아니다.The bone disease can be selected from the group consisting of osteoporosis, Paget's disease, fracture, periodontitis, bone growth disorder, primary bone tumor, bone metastasis of cancer, bone metastatic cancer and rheumatoid arthritis, but is not limited thereto .

상기 암은 폐암, 전립선암, 위암, 대장암, 유방암, 간암, 결장암 및 자궁경부암으로 구성된 군으로부터 선택될 수 있으며, 이에 의하여 제한되는 것은 아니다.The cancer may be selected from the group consisting of lung cancer, prostate cancer, stomach cancer, colon cancer, breast cancer, liver cancer, colon cancer and cervical cancer, but is not limited thereto.

본 발명의 조성물은 약학적으로 허용되는 담체를 포함한다. 본 발명의 조성물에 포함되는 약학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences(19th ed., 1995)에 상세히 기재되어 있다.The composition of the present invention comprises a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be included in the composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, calcium silicate , Microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, no. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc., in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).

본 발명의 약학적 조성물은 경구 또는 비경구 투여할 수 있으며, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다.The pharmaceutical composition of the present invention can be administered orally or parenterally. In the case of parenteral administration, the composition can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration, or the like.

본 발명의 약학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약학적 조성물의 1일 투여량은 예컨대 0.0001-100 ㎎/㎏이다.The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on such factors as formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, route of administration, excretion rate, . The daily dose of the pharmaceutical composition of the present invention is, for example, 0.0001-100 mg / kg.

본 발명의 약학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.
The pharmaceutical composition of the present invention may be formulated into a unit dosage form by using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by those having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.

본 발명의 또 다른 양태에 따르면, 본 발명은 하기 반응식 1에 나타난 바와 같이, 하기 화학식 58의 피롤-2-카복스알데하이드 유도체를 화합물 A 내지 F로 구성된 군으로부터 선택된 화합물과 반응시켜 도미노 크뇌베나겔 축합 및 분자 내 알돌 고리화 반응을 통하여 화학식 1의 화합물을 제조하는 방법을 제공한다:According to another aspect of the present invention, the present invention relates to a process for the preparation of a compound of formula (I), which comprises reacting a pyrrole-2-carboxaldehyde derivative of the following formula (58) with a compound selected from the group consisting of compounds A to F, Lt; RTI ID = 0.0 > (I) < / RTI > through condensation and intramolecular aldol cyclization reactions:

반응식 1Scheme 1

Figure pat00061
Figure pat00061

상기 반응식에서,In the above reaction formula,

상기 R1 내지 R7은 제 1 항에서 정의한 바와 같으며;Wherein R 1 to R 7 are as defined in claim 1;

화합물 A는

Figure pat00062
이고;Compound A
Figure pat00062
ego;

화합물 B는

Figure pat00063
이며;Compound B is
Figure pat00063
;

화합물 C는

Figure pat00064
이고;Compound C is
Figure pat00064
ego;

화합물 D는

Figure pat00065
이며;Compound D is
Figure pat00065
;

화합물 E는

Figure pat00066
이고;Compound E is
Figure pat00066
ego;

화합물 F는

Figure pat00067
이다.Compound F is
Figure pat00067
to be.

본 발명의 제조방법은 출발물질인 화학식 58의 피롤-2-카복스알데하이드 유도체와 상기 화합물 A-F 중 하나의 화합물을 촉매 및 유기용매 하에서 반응시켜 인돌리진 유도체를 높은 수율로 제조할 수 있다. 상기 반응은 도미노 크뇌베나겔 축합 및 분자 내 알돌 고리화 반응으로 통상적으로 알려진 반응이다.The production method of the present invention can produce the indolizine derivative in high yield by reacting the pyrrole-2-carboxaldehyde derivative of the formula (58), which is the starting material, with one of the compounds A-F in a catalyst and an organic solvent. This reaction is a reaction commonly known as dominoquineben gel condensation and intramolecular aldol cyclization.

본 발명의 일구현예에 따르면, 상기 피롤-2-카복스알데하이드 유도체는 하기 화합물 a-k로부터 선택된다.According to one embodiment of the present invention, the pyrrole-2-carboxaldehyde derivative is selected from the following compounds a-k.

화합물 aThe compound a

Figure pat00068

Figure pat00068

화합물 bCompound b

Figure pat00069
Figure pat00069

화합물 cCompound c

Figure pat00070
Figure pat00070

화합물 dCompound d

Figure pat00071
Figure pat00071

화합물 eCompound e

Figure pat00072

Figure pat00072

화합물 fCompound f

Figure pat00073
Figure pat00073

화합물 gCompound g

Figure pat00074
Figure pat00074

화합물 hCompound h

Figure pat00075
Figure pat00075

화합물 iCompound i

Figure pat00076

Figure pat00076

화합물 jCompound j

Figure pat00077
Figure pat00077

화합물 kCompound k

Figure pat00078
Figure pat00078

상기 화합물 A-F는 일반식

Figure pat00079
(E는 전자 끄는 기)로 표현될 수 있으며, 상기 피롤-2-카복스알데하이드 유도체 1당량에 대하여 1-2 당량의 양으로 사용할 수 있다.The compound AF is a compound represented by the general formula
Figure pat00079
(E is an electron withdrawing group) and can be used in an amount of 1 to 2 equivalents based on 1 equivalent of the pyrrole-2-carboxaldehyde derivative.

본 발명의 일구현예에 따르면, 상기 반응의 촉매로 피페리디늄 아세테이트, 트리에틸아민, 모포린, 피페리딘, 탄산칼륨 또는 프롤린을 사용할 수 있으며, 피페리디늄 아세테이트가 바람직하다. 상기 촉매는 상기 피롤-2-카복스알데하이드 유도체 1당량에 대하여 0.3-0.7 당량의 양으로 사용할 수 있다.According to an embodiment of the present invention, as a catalyst for the reaction, piperidinium acetate, triethylamine, morpholine, piperidine, potassium carbonate or proline can be used, and piperidinium acetate is preferable. The catalyst may be used in an amount of 0.3-0.7 equivalents based on 1 equivalent of the pyrrole-2-carboxaldehyde derivative.

본 발명의 일구현예에 따르면, 상기 반응의 용매로 에탄올, 톨루엔, 아세토니트릴, 디클로로에탄 또는 테트라하이드로퓨란을 사용할 수 있으며, 에탄올이 바람직하다.According to an embodiment of the present invention, ethanol, toluene, acetonitrile, dichloroethane or tetrahydrofuran may be used as a solvent for the reaction, and ethanol is preferable.

본 발명의 일구현예에 따르면, 상기 반응의 온도는 110-130℃이고, 반응시간은 12-24시간이다.
According to an embodiment of the present invention, the temperature of the reaction is 110-130 占 폚 and the reaction time is 12-24 hours.

본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:

(i) 본 발명은 신규한 인돌리진 유도체, 이의 약학적으로 허용 가능한 염, 이의 제조방법 및 이을 포함하는 골 질환 또는 암의 예방 또는 치료용 약학적 조성물을 제공한다.(i) The present invention provides a novel indolizine derivative, a pharmaceutically acceptable salt thereof, a process for producing the same, and a pharmaceutical composition for preventing or treating bone diseases or cancer comprising the same.

(ii) 본 발명의 인돌리진 유도체는 파골세포의 분화를 억제하여 골다공증과 같은 파골세포 관련 골 질환에 대한 치료 효과를 나타내며, 암세포의 사멸을 유도하여 항암 활성을 나타내므로, 골 질환과 암에 대한 예방 및 치료제로서 유용하게 이용될 수 있다.
(ii) The indolizine derivative of the present invention inhibits the osteoclast differentiation and shows a therapeutic effect on osteoclast-related bone diseases such as osteoporosis, induces cancer cell death and induces anticancer activity, And can be usefully used as a preventive and therapeutic agent.

이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

실시예Example

제조예Manufacturing example

1. 화합물 a-k의 합성1. Synthesis of compound a-k

<1-1> 1-(2-옥소-2-페닐에틸)-1H-피롤-2-카브알데하이드(화합물 a) 합성<1-1> 1- (2-oxo-2-phenylethyl) -1H-pyrrole-2-carbaldehyde (Compound a) Synthesis

피롤-2-카복스알데하이드(500 mg, 5.258 mmol)를 CH3CN(18 ㎖)에 녹이고, K2CO3(1.09 g, 1.5 당량) 및 2-브로모아세토페논(1.26 g, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(30 ㎖)로 희석한 다음 H2O(30 ㎖)로 세척하였다. 에틸아세테이트(30 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(952.9 mg, 85%)을 수득하였다.
A pyrrole-2-carboxaldehyde (500 mg, 5.258 mmol) was dissolved in CH 3 CN (18 ㎖), K 2 CO 3 (1.09 g, 1.5 eq) and 2-bromo collected Seto benzophenone (1.26 g, 1.2 eq.) And the mixture was stirred at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (30 mL), and then washed with H 2 O (30 mL). The aqueous layer was extracted once more with ethyl acetate (30 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the title compound (952.9 mg, 85%).

<1-2> 1-(2-(4-플루로페닐)-2-옥소에틸)-1H-피롤-2-카브알데하이드(화합물 b) 합성<1-2> 1- (2- (4-Fluorophenyl) -2-oxoethyl) -1H-pyrrole-2-carbaldehyde (Compound b) Synthesis

피롤-2-카복스알데하이드(200 mg, 2.103 mmol)를 CH3CN(7 ㎖)에 녹이고, K2CO3(436.0 mg, 1.5 당량) 및 2-브로모-4′-플루오로아세토페논(547.7 mg, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(12 ㎖)로 희석한 다음 H2O(12 ㎖)로 세척하였다. 에틸아세테이트(12 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(286.9 mg, 59%)을 수득하였다.
Dissolving the pyrrole-2-carboxaldehyde (200 mg, 2.103 mmol) in CH 3 CN (7 ㎖), acetophenone with K 2 CO 3 (436.0 mg, 1.5 eq) and 2-bromo-4'-fluoro ( 547.7 mg, 1.2 eq.) Was added thereto, followed by stirring at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (12 mL) and washed with H 2 O (12 mL). The aqueous layer was extracted once more with ethyl acetate (12 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the title compound (286.9 mg, 59%).

<1-3> 1-(2-(4-클로로페닐)-2-옥소에틸)-1H-피롤-2-카브알데하이드(화합물 c) 합성<1-3> Synthesis of 1- (2- (4-chlorophenyl) -2-oxoethyl) -1H-pyrrole-2-carbaldehyde (Compound c)

피롤-2-카복스알데하이드(500 mg, 5.258 mmol)를 CH3CN(18 ㎖)에 녹이고, K2CO3(1.09 g, 1.5 당량) 및 2-브로모-4′-클로로아세토페논(1.47 g, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(30 ㎖)로 희석한 다음 H2O(30 ㎖)로 세척하였다. 에틸아세테이트(30 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(703.2 mg, 54%)을 수득하였다.
Dissolving the pyrrole-2-carboxaldehyde (500 mg, 5.258 mmol) in CH 3 CN (18 ㎖), K 2 CO 3 (1.09 g, 1.5 eq) and 2-bromo-4'-chloro-acetophenone (1.47 g, 1.2 eq.) and stirred at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (30 mL), and then washed with H 2 O (30 mL). The aqueous layer was extracted once more with ethyl acetate (30 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the target compound (703.2 mg, 54%).

<1-4> 1-(2-(4-브로모페닐)-2-옥소에틸)-1H-피롤-2-카브알데하이드(화합물 d) 합성<1-4> 1- (2- (4-Bromophenyl) -2-oxoethyl) -1H-pyrrole-2-carbaldehyde (Compound d) Synthesis

피롤-2-카복스알데하이드(1 g, 10.52 mmol)를 CH3CN(35 ㎖)에 녹이고, K2CO3(2.18 g, 1.5 당량) 및 2,4-디브로모아세토페논(2.88 g, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(60 ㎖)로 희석한 다음 H2O(60 ㎖)로 세척하였다. 에틸아세테이트(60 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(1.94 g, 63%)을 수득하였다.
Pyrrole-2-carboxaldehyde (1 g, 10.52 mmol) was dissolved in a CH 3 CN (35 ㎖), K 2 CO 3 (2.18 g, 1.5 eq.) And 2,4-bromo collected Seto benzophenone (2.88 g, 1.2 equivalent) was added and stirred at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (60 mL) and washed with H 2 O (60 mL). The aqueous layer was extracted once again with ethyl acetate (60 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the desired compound (1.94 g, 63%).

<1-5> 1-(2-(4-메톡시페닐)-2-옥소에틸)-1H-피롤-2-카브알데하이드(화합물 e) 합성<1-5> Synthesis of 1- (2- (4-methoxyphenyl) -2-oxoethyl) -1H-pyrrole-2-carbaldehyde (Compound e)

피롤-2-카복스알데하이드(300 mg, 3.155 mmol)를 CH3CN(10 ㎖)에 녹이고, K2CO3(654 mg, 1.5 당량) 및 2-브로모-4′-메톡시아세토페논(867.1 mg, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(18 ㎖)로 희석한 다음 H2O(18 ㎖)로 세척하였다. 에틸아세테이트(18 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(629.3 mg, 82%)을 수득하였다.
Pyrrole-2-carboxaldehyde is dissolved in (300 mg, 3.155 mmol) to CH 3 CN (10 ㎖), K 2 CO 3 (654 mg, 1.5 eq) and 2-bromo-4'-methoxy acetophenone ( 867.1 mg, 1.2 eq.) Were added and stirred at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (18 mL), and then washed with H 2 O (18 mL). The aqueous layer was extracted once more with ethyl acetate (18 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the target compound (629.3 mg, 82%).

<1-6> 1-(2-(4-(벤질옥시)페닐)-2-옥소에틸)-1H-피롤-2-카브알데하이드(화합물 f) 합성<1-6> Synthesis of 1- (2- (4- (benzyloxy) phenyl) -2-oxoethyl) -1H-pyrrole-2-carbaldehyde

피롤-2-카복스알데하이드(300 mg, 3.155 mmol)를 CH3CN(10 ㎖)에 녹이고, K2CO3(654 mg, 1.5 당량) 및 1-(4-(벤질옥시)페닐)-2-브로모에탄온(1.16 g, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(18 ㎖)로 희석한 다음 H2O(18 ㎖)로 세척하였다. 에틸아세테이트(18 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(785.8 mg, 78%)을 수득하였다.
Dissolving the pyrrole-2-carboxaldehyde (300 mg, 3.155 mmol) in CH 3 CN (10 ㎖), K 2 CO 3 (654 mg, 1.5 equiv.) And 1- (4- (benzyloxy) phenyl) -2 - Bromoethane (1.16 g, 1.2 eq.) Was added and stirred at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (18 mL), and then washed with H 2 O (18 mL). The aqueous layer was extracted once more with ethyl acetate (18 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the desired compound (785.8 mg, 78%).

<1-7> 1-(2-(3-메톡시페닐)-2-옥소에틸)-1H-피롤-2-카브알데하이드(화합물 g) 합성<1-7> Synthesis of 1- (2- (3-methoxyphenyl) -2-oxoethyl) -1H-pyrrole-2-carbaldehyde (Compound g)

피롤-2-카복스알데하이드(300 mg, 3.155 mmol)를 CH3CN(10 ㎖)에 녹이고, K2CO3(654 mg, 1.5 당량) 및 2-브로모-3′-메톡시아세토페논(867.1 mg, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(18 ㎖)로 희석한 다음 H2O(18 ㎖)로 세척하였다. 에틸아세테이트(18 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(606.2 mg, 79%)을 수득하였다.
Pyrrole-2-carboxaldehyde is dissolved in (300 mg, 3.155 mmol) to CH 3 CN (10 ㎖), K 2 CO 3 (654 mg, 1.5 eq) and 2-bromo-3'-methoxy-acetophenone ( 867.1 mg, 1.2 eq.) Were added and stirred at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (18 mL), and then washed with H 2 O (18 mL). The aqueous layer was extracted once more with ethyl acetate (18 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the title compound (606.2 mg, 79%).

<1-8> 1-(2-(5-브로모티오펜-2-일)-2-옥소에틸)-1H-피로로-2-카브알데하이드(화합물 h) 합성<1-8> Synthesis of 1- (2- (5-bromothiophen-2-yl) -2-oxoethyl) -1H-pyrrolo 2-carbaldehyde (Compound h)

피롤-2-카복스알데하이드(500 mg, 5.258 mmol)를 CH3CN(18 ㎖)에 녹이고, K2CO3(1.09 g, 1.5 당량) 및 2-브로모-1-(5-브로모티오펜-2-일)에탄온(1.79 g, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(30 ㎖)로 희석한 다음 H2O(30 ㎖)로 세척하였다. 에틸아세테이트(30 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(987.6 mg, 63%)을 수득하였다.
Pyrrole-2-carboxaldehyde (500 mg, 5.258 mmol) was dissolved in a CH 3 CN (18 ㎖), K 2 CO 3 (1.09 g, 1.5 eq) and 2-bromo-1- (5-bromothiophene -2-yl) ethanone (1.79 g, 1.2 eq.) And stirred at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (30 mL), and then washed with H 2 O (30 mL). The aqueous layer was extracted once more with ethyl acetate (30 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the title compound (987.6 mg, 63%).

<1-9> 1-(2-(5-(터트-부틸)-3-요오도-2,4-디메톡시페닐)-2-옥소에틸)-1H-피롤-2-카브알데하이드(화합물 i) 합성<1-9> 1- (2- (5- (tert-Butyl) -3-iodo-2,4-dimethoxyphenyl) -2-oxoethyl) -1H- pyrrole-2-carbaldehyde ) synthesis

피롤-2-카복스알데하이드(300 mg, 3.155 mmol)를 CH3CN(10 ㎖)에 녹이고, K2CO3(654 mg, 1.5 당량) 및 2-브로모-1-(5-(터트-부틸)-3-요오도-2,4-디메톡시페닐)에탄온(1.67 g, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(18 ㎖)로 희석한 다음 H2O(18 ㎖)로 세척하였다. 에틸아세테이트(18 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(1.11 g, 77%)을 수득하였다.
Pyrrole-2-carboxaldehyde (300 mg, 3.155 mmol) was dissolved in a CH 3 CN (10 ㎖), K 2 CO 3 (654 mg, 1.5 eq) and 2-bromo-1- (5- (tert- Butyl) -3-iodo-2,4-dimethoxyphenyl) ethanone (1.67 g, 1.2 eq.) Was added thereto and stirred at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (18 mL), and then washed with H 2 O (18 mL). The aqueous layer was extracted once more with ethyl acetate (18 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the desired compound (1.11 g, 77%).

<1-10> 디에틸 5-포르밀-3-메틸-1-(2-옥소-2-페닐에틸)-1H-피롤-2,4-디카르복실레이트(화합물 j) 합성<1-10> Synthesis of diethyl 5-formyl-3-methyl-1- (2-oxo-2-phenylethyl) -1H-pyrrole-2,4-dicarboxylate

디에틸 5-포르밀-3-메틸-1H-피롤-2,4-디카르복실레이트(500 mg, 1.974 mmol)를 CH3CN(9.6 ㎖)에 녹이고, K2CO3(409.3 mg, 1.5 당량) 및 2-브로모아세토페논(471.5 mg, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(12 ㎖)로 희석한 다음 H2O(12 ㎖)로 세척하였다. 에틸아세테이트(12 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(313.1 mg, 42.7%)을 수득하였다.
It was dissolved in diethyl 5-formyl-3-methyl -1H- pyrrole-2,4-dicarboxylate (500 mg, 1.974 mmol) to CH 3 CN (9.6 ㎖), K 2 CO 3 (409.3 mg, 1.5 And 2-bromoacetophenone (471.5 mg, 1.2 eq.) Were added thereto, followed by stirring at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (12 mL) and washed with H 2 O (12 mL). The aqueous layer was extracted once more with ethyl acetate (12 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the title compound (313.1 mg, 42.7%).

<1-11> 에틸 5-포르밀-1-(2-(4-메톡시페닐)-2-옥소에틸)-1H-피롤-2-카르복실레이트(화합물 k) 합성<1-11> Synthesis of ethyl 5-formyl-1- (2- (4-methoxyphenyl) -2-oxoethyl) -1H-pyrrole-2-carboxylate

에틸 5-포르밀-1H-피롤-2-카르복실레이트(500 mg, 2.991 mmol)를 CH3CN(10 ㎖)에 녹이고, K2CO3(620.1 mg, 1.5 당량) 및 2-브로모-4′-메톡시아세토페논(822.2 mg, 1.2 당량)을 넣은 뒤 상온에서 저어주었다. 24시간 동안 저어준 후, 반응 혼합액을 감압 농축하고, 에틸아세테이트(17 ㎖)로 희석한 다음 H2O(17 ㎖)로 세척하였다. 에틸아세테이트(17 ㎖)를 사용하여 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 혼합 용매(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2 또는 10 : 1 : 2)로 마쇄(trituration)하여 정제함으로써 목적 화합물(754.5 mg, 80%)을 수득하였다.
(500 mg, 2.991 mmol) was dissolved in CH 3 CN (10 mL), K 2 CO 3 (620.1 mg, 1.5 eq.) And 2-bromo- 4'-methoxyacetophenone (822.2 mg, 1.2 eq.) Was added and stirred at room temperature. After stirring for 24 h, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (17 mL) and washed with H 2 O (17 mL). The aqueous layer was extracted once more with ethyl acetate (17 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The obtained residue was purified by trituration with a mixed solvent (hexane: ethyl acetate: dichloromethane = 30: 1: 2 or 10: 1: 2) to obtain the title compound (754.5 mg, 80%).

합성한 화합물 a-k의 화학구조 및 NMR 데이터는 다음과 같다(표 1).The chemical structure and NMR data of the synthesized compound a-k are as follows (Table 1).

Figure pat00080
Figure pat00080

Figure pat00081

Figure pat00081

2. 인돌리진 유도체의 합성2. Synthesis of indolizine derivatives

<2-1> 에틸 5-벤조일-6-메틸인돌리진-7-카르복실레이트 합성 <2-1> Synthesis of ethyl 5-benzoyl-6-methylindolizine-7-carboxylate (5a)(5a)

화합물 a(50 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 50 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound a (50 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and ethyl acetoacetate (Compound A; 44.5 μL, 1.5 equivalent) Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 50: 1: 2) to obtain the target compound.

화학식The 22

Figure pat00082
Figure pat00082

노랑 고형물, mp: 71.5~72.3℃ (70.6 mg, 98.0%); 1 H NMR (400 MHz CDCl3) δ 8.30 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.02 (s, 1H), 6.81~6.72 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 2.32 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 193.1, 166.6, 135.6, 135.0, 131.0, 130.4, 129.7, 129.5, 124.9, 119.5, 117.7, 115.6, 114.4, 104.8, 60.9, 16.9, 14.5; HRMS (ESI-QTOF) calcd for C19H17NO3 308.1281 ([M+H]+), found 308.1285.
Yellow solid, mp: 71.5-72.3 DEG C (70.6 mg, 98.0%); 1 H NMR (400 MHz CDCl 3 ) δ 8.30 (s, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.65 (t, J = 7.2 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.02 (s, 1H), 6.81-6.72 (m, 2H), 4.36 (q, J = 7.2 Hz, 2H), 2.32 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 193.1, 166.6, 135.6, 135.0, 131.0, 130.4, 129.7, 129.5, 124.9, 119.5, 117.7, 115.6, 114.4, 104.8, 60.9, 16.9, 14.5; HRMS (ESI-QTOF) calcd for C 19 H 17 NO 3 308.1281 ([M + H] + ), found 308.1285.

<2-2> 1-(5-벤조일-6-메틸인돌리진-7-일)에탄온 합성 <2-2> Synthesis of 1- (5-benzoyl-6-methylindolizin-7-yl) ethanone (5b)(5b)

화합물 a(50 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 2,4-펜테인다이온(화합물 B; 35.2 μL, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound a (50 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and 2,4-pentanedione (compound B; 35.2 μL, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 3 (Y-001)(Y-001)

Figure pat00083
Figure pat00083

갈색 고형물, mp: 96.0~96.5℃ (56.1 mg, 88%); 1 H NMR (400 MHz, CDCl3) δ8.09 (s, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 8.0 Hz, 2H), 7.03 (s, 1H), 6.79 (s, 1H), 6.78 (s, 1H), 2.63 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 198.6, 193.3, 135.5, 135.1, 130.7, 130.6, 129.7, 129.5, 127.2, 124.6, 117.3, 115.8, 114.8, 105.4, 28.6, 17.0; HRMS (ESI-QTOF) calcd for C18H15NO2 278.1176 ([M+H]+), found 278.1181.
Brown solid, mp: 96.0-96.5 DEG C (56.1 mg, 88%); 1 H NMR (400 MHz, CDCl 3) δ8.09 (s, 1H), 7.89 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 8.0 2H), 7.03 (s, 1H), 6.79 (s, 1H), 6.78 (s, 1H), 2.63 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 198.6, 193.3, 135.5, 135.1, 130.7, 130.6, 129.7, 129.5, 127.2, 124.6, 117.3, 115.8, 114.8, 105.4, 28.6, 17.0; HRMS (ESI-QTOF) calcd for C 18 H 15 NO 2 278.1176 ([M + H] + ), found 278.1181.

<2-3> 6-아미노-5-벤조일인돌리진-7-카보니트릴 합성 &Lt; 2-3 > Synthesis of 6-amino-5-benzoylindolizine-7-carbonitrile (5c)(5c)

화합물 a(50 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound a (50 mg, 0.23 mmol) was dissolved in 2 mL of EtOH and piperidinium acetate (17 mg, 0.5 eq.) And malononitrile (compound C; 22.8 mg, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 4 (Y-002)(Y-002)

Figure pat00084
Figure pat00084

오렌지색 고형물, mp: 155.2~155.6 ℃(57.1 mg, 95%); 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.57~7.49 (m, 3H), 7.42 (t, J = 7.2 Hz, 2H), 6.87 (s, 1H), 6.73 (d, J = 4.0 Hz, 1H), 6.48 (dd, J = 2.8, 3.6 Hz, 1H), 6.26 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 189.5, 141.2, 138.2, 132.5, 131.6, 129.3, 128.3, 128.2, 123.5, 116.6, 114.3, 113.0, 108.9, 93.4; HRMS (ESI-QTOF) calcd for C16H11N3O 262.0975 ([M+H]+), found 262.0974.
Orange solid, mp: 155.2-155.6 &lt; 0 &gt; C (57.1 mg, 95%); 1 H NMR (400 MHz, CDCl 3) δ 7.85 (s, 1H), 7.57 ~ 7.49 (m, 3H), 7.42 (t, J = 7.2 Hz, 2H), 6.87 (s, 1H), 6.73 (d, J = 4.0 Hz, 1H), 6.48 (dd, J = 2.8,3.6 Hz, 1H), 6.26 (s, 2H); 13 C NMR (100 MHz, CDCl 3) δ 189.5, 141.2, 138.2, 132.5, 131.6, 129.3, 128.3, 128.2, 123.5, 116.6, 114.3, 113.0, 108.9, 93.4; HRMS (ESI-QTOF) calcd for C 16 H 11 N 3 O 262.0975 ([M + H] + ), found 262.0974.

<2-4> 5-벤조일-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-4> 5-Benzoyl-7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (6H) (5d)(5d)

화합물 a(50 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound a (50 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (Compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 5 (Y-003)(Y-003)

Figure pat00085
Figure pat00085

갈색 고형물, mp: 92.2~92.6℃ (55.2 mg, 83%); 1 H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.15 (s, 1H), 6.89 (d, J = 3.2 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 2.71~2.61 (m, 4H), 2.09~1.95 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 196.4, 192.4, 135.9, 135.0, 132.4, 129.62, 129.58, 128.0, 122.4, 122.3, 122.2, 116.5, 115.7, 107.3, 39.3, 26.2, 22.9; HRMS (ESI-QTOF) calcd for C19H15NO2 290.1176 ([M+H]+), found 290.1178.
Brown solid, mp 92.2-92.6 [deg.] C (55.2 mg, 83%); 1 H NMR (400 MHz, CDCl 3) δ 8.41 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.51 (t, J = 7.6 Hz 2H), 7.15 (s, 1H), 6.89 (d, J = 3.2 Hz, 1H), 6.83 (d, J = 2.0 Hz, 1H), 2.71-2.61 (m, 4H), 2.09-1.95 2H); 13 C NMR (100 MHz, CDCl 3) δ 196.4, 192.4, 135.9, 135.0, 132.4, 129.62, 129.58, 128.0, 122.4, 122.3, 122.2, 116.5, 115.7, 107.3, 39.3, 26.2, 22.9; HRMS (ESI-QTOF) calcd for C 19 H 15 NO 2 290.1176 ([M + H] +), found 290.1178.

<2-5> 5-벤조일-7,7-디메틸-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-5> Synthesis of 5-benzoyl-7,7-dimethyl-7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (6H) (5e)(5e)

화합물 a(50 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 5,5-디메틸-1,3-사이클로헥산다이온(화합물 E; 48.4 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound a (50 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidineacetate (17 mg, 0.5 equivalent) and 5,5-dimethyl-1,3-cyclohexanedione (compound E; 48.4 mg, 1.5 Equivalent), and the mixture was reacted at 120 DEG C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 66

Figure pat00086
Figure pat00086

노란색 검 (38.0 mg, 52%); 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 7.08 (s, 1H), 6.89 (d, J = 3.6 Hz, 1H), 6.82 (dd, J = 2.8, 4.0 Hz, 1H), 2.53 (s, 2H), 2.49 (s, 2H), 0.99 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 196.4, 192.4, 135.6, 135.1, 132.3, 129.65, 129.60, 121.8, 121.4, 120.6, 116.5, 115.7, 107.2, 52.5, 39.2, 33.1, 28.3; HRMS (ESI-QTOF) calcd for C21H19NO2 318.1489 ([M+H]+), found 318.1490.
Yellow gum (38.0 mg, 52%); 1 H NMR (400 MHz, CDCl 3) δ 8.40 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz 2H), 2.49 (s, 2H), 7.08 (s, 1H), 6.89 (d, J = 3.6 Hz, 1H), 6.82 (dd, J = , 0.99 (s, 6H); 13 C NMR (100 MHz, CDCl 3) δ 196.4, 192.4, 135.6, 135.1, 132.3, 129.65, 129.60, 121.8, 121.4, 120.6, 116.5, 115.7, 107.2, 52.5, 39.2, 33.1, 28.3; HRMS (ESI-QTOF) calcd for C 21 H 19 NO 2 318.1489 ([M + H] + ), found 318.1490.

상기 화학식 2 내지 6으로 표시되는 화합물의 합성을 요약하면 다음과 같다(표 2).The synthesis of the compounds represented by the above Formulas 2 to 6 is summarized as follows (Table 2).

Figure pat00087
Figure pat00087

<2-6> 에틸 5-(4-플루오르벤조일)-6-메틸인돌리진-7-카르복실레이트 합성 <2-6> Synthesis of ethyl 5- (4-fluorobenzoyl) -6-methylindolizine-7-carboxylate (5f)(5f)

화합물 b(53.2 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound b (53.2 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and ethyl acetoacetate (Compound A; 44.5 μL, 1.5 equivalent) Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 7Formula 7

Figure pat00088
Figure pat00088

갈색 검(44.9 mg, 60%); 1 H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.97~7.86 (m, 2H), 7.21~7.09 (m, 2H), 7.00 (s, 1H), 6.78 (s, 1H), 6.76 (s, 1H), 4.36 (q, J = 6.8 Hz, 2H), 2.32 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 191.5, 166.6, 165.7, 132.6, 132.5, 131.1, 125.1, 119.5, 117.8, 117.0, 116.7, 115.8, 114.4, 105.0, 61.0, 16.8, 14.5; HRMS (ESI-QTOF) calcd for C19H16FNO3 326.1187 ([M+H]+), found 326.1187.
Brown gum (44.9 mg, 60%); 1 H NMR (400 MHz, CDCl 3) δ 8.29 (s, 1H), 7.97 ~ 7.86 (m, 2H), 7.21 ~ 7.09 (m, 2H), 7.00 (s, 1H), 6.78 (s, 1H), 6.76 (s, 1H), 4.36 (q, J = 6.8 Hz, 2H), 2.32 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 191.5, 166.6, 165.7, 132.6, 132.5, 131.1, 125.1, 119.5, 117.8, 117.0, 116.7, 115.8, 114.4, 105.0, 61.0, 16.8, 14.5; HRMS (ESI-QTOF) calcd for C 19 H 16 FNO 3 326.1187 ([M + H] +), found 326.1187.

<2-7> 1-(5-(4-플루오르벤조일)-6-메틸인돌리진-7-일)에탄온 합성 <2-7> 1- (5- (4-Fluorobenzoyl) -6-methylindolizin-7-yl) ethanone Synthesis (5g)(5g)

화합물 b(53.2 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 2,4-펜테인다이온(화합물 B; 35.2 μL, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Compound b (53.2 mg, 0.23 mmol) was dissolved in EtOH (2 mL), and piperidinium acetate (17 mg, 0.5 equivalent) and 2,4-pentanedione (compound B; 35.2 μL, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 88

Figure pat00089
Figure pat00089

노란색 검 (44.1 mg, 65%); 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.98~7.86 (m, 2H), 7.22~7.09 (m, 2H), 7.02 (s, 1H), 6.80 (s, 2H), 2.64 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 198.6, 191.6, 132.6, 132.5, 130.6, 127.3, 124.7, 117.4, 117.0, 116.8, 115.9, 114.8, 105.5, 28.6, 17.0; HRMS (ESI-QTOF) calcd for C18H14FNO2 296.1081 ([M+H]+), found 296.1064.
Yellow gum (44.1 mg, 65%); 1 H NMR (400 MHz, CDCl 3) δ 8.09 (s, 1H), 7.98 ~ 7.86 (m, 2H), 7.22 ~ 7.09 (m, 2H), 7.02 (s, 1H), 6.80 (s, 2H), 2.64 (s, 3 H), 2.28 (s, 3 H); 13 C NMR (100 MHz, CDCl 3) δ 198.6, 191.6, 132.6, 132.5, 130.6, 127.3, 124.7, 117.4, 117.0, 116.8, 115.9, 114.8, 105.5, 28.6, 17.0; HRMS (ESI-QTOF) calcd for C 18 H 14 FNO 2 296.1081 ([M + H] + ), found 296.1064.

<2-8> 6-아미노-5-(4-플루로벤조일)인돌리진-7-카보니트릴 합성 <2-8> Synthesis of 6-amino-5- (4-fluorobenzoyl) indolizine-7-carbonitrile (5h)(5h)

화합물 b(53.2 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 10 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound b (53.2 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 eq.) And malononitrile (compound C; 22.8 mg, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 10: 1: 2) to obtain the desired compound.

화학식 9 (Y-014)(Y-014)

Figure pat00090
Figure pat00090

빨강 고형물, mp: 135.6~135.8℃ (59.1 mg, 92%); 1 H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.60~7.49 (m, 2H), 7.15~7.04 (m, 2H), 6.88 (s, 1H), 6.75 (d, J = 4.0 Hz, 1H), 6.51 (s, 1H), 6.24 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 187.9, 141.1, 134.2, 131.6, 131.05, 130.96, 128.4, 123.4, 116.6, 116.4, 114.5, 109.0; HRMS (ESI-QTOF) calcd for C16H10FN3O 280.0881 ([M+H]+), found 280.0882.
Red solid, mp: 135.6-135.8 [deg.] C (59.1 mg, 92%); 1 H NMR (400 MHz, CDCl 3) δ 7.86 (s, 1H), 7.60 ~ 7.49 (m, 2H), 7.15 ~ 7.04 (m, 2H), 6.88 (s, 1H), 6.75 (d, J = 4.0 Hz, 1 H), 6.51 (s, 1 H), 6.24 (s, 2 H); 13 C NMR (100 MHz, CDCl 3 ) 隆 187.9, 141.1, 134.2, 131.6, 131.05, 130.96, 128.4, 123.4, 116.6, 116.4, 114.5, 109.0; HRMS (ESI-QTOF) calcd for C 16 H 10 FN 3 O 280.0881 ([M + H] +), found 280.0882.

<2-9> 5-(4-플루로벤조일)-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-9> Synthesis of 5- (4-fluorobenzoyl) -7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (6H) (5i)(5i)

화합물 b(53.2 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 10 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound b (53.2 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 10: 1: 2) to obtain the desired compound.

화학식 10 (Y-015)(Y-015)

Figure pat00091
Figure pat00091

노랑 고형물, mp: 109.8~110.5℃ (41.0 mg, 58%); 1 H NMR (400 MHz, CDCl3) δ8.42 (s, 1H), 7.97~7.86 (m, 2H), 7.24~7.15 (m, 2H), 7.14 (s, 1H), 6.91 (d, J = 3.2 Hz, 1H), 6.85 (t, J = 2.8 Hz, 1H), 2.73~2.59 (m, 4H), 2.12~1.96 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 196.3, 190.8, 132.5, 132.44, 132.42, 127.6, 122.5, 122.3, 122.2, 117.1, 116.8, 116.7, 115.6, 107.4, 39.2, 26.2, 22.8; HRMS (ESI-QTOF) calcd for C19H14FNO2 308.1081 ([M+H]+), found 308.1084.
Yellow solid, mp: 109.8-110.5 C (41.0 mg, 58%); 1 H NMR (400 MHz, CDCl 3) δ8.42 (s, 1H), 7.97 ~ 7.86 (m, 2H), 7.24 ~ 7.15 (m, 2H), 7.14 (s, 1H), 6.91 (d, J = 3.2 Hz, 1H), 6.85 (t, J = 2.8 Hz, 1H), 2.73 ~ 2.59 (m, 4H), 2.12 ~ 1.96 (m, 2H); 13 C NMR (100 MHz, CDCl 3) δ 196.3, 190.8, 132.5, 132.44, 132.42, 127.6, 122.5, 122.3, 122.2, 117.1, 116.8, 116.7, 115.6, 107.4, 39.2, 26.2, 22.8; HRMS (ESI-QTOF) calcd for C 19 H 14 FNO 2 308.1081 ([M + H] +), found 308.1084.

<2-10> 5-(4-플루오르벤조일)-7,7-디메틸-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-10> Synthesis of 5- (4-fluorobenzoyl) -7,7-dimethyl-7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (5j)(5j)

화합물 b(53.2 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 5,5-디메틸-1,3-사이클로헥산다이온(화합물 E; 48.4 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Compound b (53.2 mg, 0.23 mmol) was dissolved in 2 mL of EtOH and piperidineacetate (17 mg, 0.5 eq.) And 5,5-dimethyl-1,3-cyclohexanedione (compound E; 48.4 mg, 1.5 Equivalent), and the mixture was reacted at 120 DEG C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 11Formula 11

Figure pat00092
Figure pat00092

오렌지 검 (45.5 mg, 59%); 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.97~7.85 (m, 2H), 7.22~7.13 (m, 2H), 7.07 (s, 1H), 6.90 (d, J = 4.4 Hz, 1H), 6.83 (t, J = 3.2 Hz, 1H), 2.52 (s, 2H), 2.49 (s, 2H), 1.00 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 132.6, 132.5, 132.3, 121.9, 121.3, 120.6, 117.1, 116.9, 116.6, 115.6, 107.4, 52.5, 39.3, 33.2, 28.3; HRMS (ESI-QTOF) calcd for C21H18FNO2 336.1394 ([M+H]+), found 336.1401.
Orange gum (45.5 mg, 59%); 1 H NMR (400 MHz, CDCl 3) δ 8.40 (s, 1H), 7.97 ~ 7.85 (m, 2H), 7.22 ~ 7.13 (m, 2H), 7.07 (s, 1H), 6.90 (d, J = 4.4 1H), 6.83 (t, J = 3.2 Hz, 1H), 2.52 (s, 2H), 2.49 (s, 2H), 1.00 (s, 6H); 13 C NMR (100 MHz, CDCl 3) δ 132.6, 132.5, 132.3, 121.9, 121.3, 120.6, 117.1, 116.9, 116.6, 115.6, 107.4, 52.5, 39.3, 33.2, 28.3; HRMS (ESI-QTOF) calcd for C 21 H 18 FNO 2 336.1394 ([M + H] + ), found 336.1401.

<2-11> 에틸 5-(4-클로로벤조일)-6-메틸인돌리진-7-카르복실레이트 합성 <2-11> Synthesis of ethyl 5- (4-chlorobenzoyl) -6-methylindolizine-7-carboxylate (5k)(5k)

화합물 c(57 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 50 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.To a solution of the compound c (57 mg, 0.23 mmol) in 2 mL of EtOH, piperidinium acetate (17 mg, 0.5 eq.) And ethylacetoacetate (Compound A; 44.5 μL, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 50: 1: 2) to obtain the target compound.

화학식 12Formula 12

Figure pat00093
Figure pat00093

오렌지 검 (69.2 mg, 88%); 1 H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 6.82~6.77 (m, 1H), 6.77~6.73 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 191.9, 166.6, 141.7, 134.0, 131.1, 129.9, 125.1, 119.4, 118.0, 115.8, 114.4, 105.0, 61.0, 16.9, 14.5; HRMS (ESI-QTOF) calcd for C19H16ClNO3 342.0891 ([M+H]+), found 342.0897.
Orange gum (69.2 mg, 88%); 1 H NMR (400 MHz, CDCl 3) δ 8.30 (s, 1H), 7.82 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.00 (s, 1H), 6.82 1H), 6.77 (m, 1H), 6.77-6.73 (m, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 191.9, 166.6, 141.7, 134.0, 131.1, 129.9, 125.1, 119.4, 118.0, 115.8, 114.4, 105.0, 61.0, 16.9, 14.5; HRMS (ESI-QTOF) calcd for C 19 H 16 ClNO 3 342.0891 ([M + H] + ), found 342.0897.

<2-12> 1-(5-(4-클로로벤조일)-6-메틸인돌리진-7-일)에탄온 합성 <2-12> 1- (5- (4-Chlorobenzoyl) -6-methylindolizin-7-yl) ethanone Synthesis (5l)(5l)

화합물 c(57 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 2,4-펜테인다이온(화합물 B; 35.2 μL, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound c (57 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and 2,4-pentanedione (compound B; 35.2 μL, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 13 (Y-004)(Y-004)

Figure pat00094
Figure pat00094

갈색 고형물, mp: 114.9~115.4℃ (43.7 mg, 61%); 1 H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.01 (s, 1H), 6.80 (s, 2H), 2.64 (s, 3H), 2.27 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 198.6, 192.1, 141.8, 133.9, 131.1, 130.6, 130.2, 130.0, 127.2, 124.8, 117.6, 116.0, 114.8, 105.6, 28.6, 17.1; HRMS (ESI-QTOF) calcd for C18H14ClNO2 312.0786 ([M+H]+), found 312.0784.
Brown solid, mp 114.9-115.4 占 폚 (43.7 mg, 61%); 1 H NMR (400 MHz, CDCl 3) δ 8.09 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.01 (s, 1H), 6.80 (s, 2 H), 2.64 (s, 3 H), 2.27 (s, 3 H); 13 C NMR (100 MHz, CDCl 3) δ 198.6, 192.1, 141.8, 133.9, 131.1, 130.6, 130.2, 130.0, 127.2, 124.8, 117.6, 116.0, 114.8, 105.6, 28.6, 17.1; HRMS (ESI-QTOF) calcd for C 18 H 14 ClNO 2 312.0786 ([M + H] + ), found 312.0784.

<2-13> 6-아미노-5-(4-클로로벤조일)인돌리진-7-카보니트릴 합성 <2-13> Synthesis of 6-amino-5- (4-chlorobenzoyl) indolizine-7-carbonitrile (5m)(5m)

화합물 c(57 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound c (57 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and malononitrile (Compound C; 22.8 mg, 1.5 equivalent) Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 14 (Y-005)14 (Y-005)

Figure pat00095
Figure pat00095

오렌지색 고형물, mp: 142.9~143.4℃ (46.3 mg, 68%); 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 6.86 (s, 1H), 6.75 (d, J = 4.4 Hz, 1H), 6.50 (dd, J = 2.4, 4.2 Hz, 1H), 6.33 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ187.8, 141.6, 138.6, 136.4, 131.8, 129.8, 129.6, 128.3, 123.7, 116.4, 114.4, 112.7, 109.2, 93.4; HRMS (ESI-QTOF) calcd for C16H10ClN3O 296.0585 ([M+H]+), found 296.0582.
Orange solid, mp: 142.9-143.4 &lt; 0 &gt; C (46.3 mg, 68%); 1 H NMR (400 MHz, CDCl 3) δ 7.85 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 6.86 (s, 1H), 6.75 (d, J = 4.4 Hz, 1H), 6.50 (dd, J = 2.4, 4.2 Hz, 1H), 6.33 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 187.8, 141.6, 138.6, 136.4, 131.8, 129.8, 129.6, 128.3, 123.7, 116.4, 114.4, 112.7, 109.2, 93.4; HRMS (ESI-QTOF) calcd for C 16 H 10 ClN 3 O 296.0585 ([M + H] + ), found 296.0582.

<2-14> 5-(4-클로로벤조일)-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-14> 5- (4-Chlorobenzoyl) -7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (6H) (5n)(5n)

화합물 c(57 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound c (57 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 15 (Y-022)(Y-022)

Figure pat00096
Figure pat00096

갈색 고형물, mp: 99.2~100.1℃ (50.6 mg, 68%); 1 H NMR (400 MHz, CDCl3) δ8.42 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.14 (t, J = 0.8 Hz, 1H), 6.91 (d, J = 4.4 Hz, 1H), 6.84 (dd, J = 2.4, 4.2 Hz, 1H), 2.69~2.61 (m, 4H), 2.07~1.97 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 196.3, 191.2, 141.7, 134.2, 132.4, 131.0, 130.0, 127.4, 122.7, 122.6, 122.1, 116.7, 115.7, 107.5, 39.2, 26.2, 22.8; HRMS (ESI-QTOF) calcd for C19H14ClNO2 324.0786 ([M+H]+), found 324.0778.
Brown solid, mp 99.2-100.1 C (50.6 mg, 68%); 1 H NMR (400 MHz, CDCl 3) δ8.42 (s, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.14 (t, J = 0.8 2H), 6.91 (d, J = 4.4 Hz, 1H), 6.84 (dd, J = 2.4, 4.2 Hz, 1H), 2.69-2.61 (m, 4H), 2.07-1.97 (m, 2H). 13 C NMR (100 MHz, CDCl 3) δ 196.3, 191.2, 141.7, 134.2, 132.4, 131.0, 130.0, 127.4, 122.7, 122.6, 122.1, 116.7, 115.7, 107.5, 39.2, 26.2, 22.8; HRMS (ESI-QTOF) calcd for C 19 H 14 ClNO 2 324.0786 ([M + H] + ), found 324.0778.

<2-15> 5-(4-클로로벤조일)-7,7-디메틸-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-15> Synthesis of 5- (4-chlorobenzoyl) -7,7-dimethyl-7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (5o)(5o)

화합물 c(57 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 5,5-디메틸-1,3-사이클로헥산다이온(화합물 E; 48.4 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound c (57 mg, 0.23 mmol) was dissolved in 2 ml of EtOH, and piperidineacetate (17 mg, 0.5 equivalent) and 5,5-dimethyl-1,3-cyclohexanedione (compound E; 48.4 mg, 1.5 Equivalent), and the mixture was reacted at 120 DEG C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 16Formula 16

Figure pat00097
Figure pat00097

갈색 검 (54.2 mg, 67%); 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.82 (dd, J = 2.4, 3.4 Hz, 1H), 2.52 (s, 2H), 2.49 (s, 2H), 1.00 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 196.3, 191.2, 141.8, 134.0, 132.3, 131.0, 130.0, 128.4, 122.05, 120.8, 116.6, 115.6, 107.5, 52.5, 46.1, 39.3, 33.2, 28.3; HRMS (ESI-QTOF) calcd for C21H18ClNO2 352.1099 ([M+H]+), found 352.1095.
Brown gum (54.2 mg, 67%); 1 H NMR (400 MHz, CDCl 3) δ 8.40 (s, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.06 (s, 1H), 6.90 (d, J = 3.6 Hz, 1H), 6.82 (dd, J = 2.4, 3.4 Hz, 1H), 2.52 (s, 2H), 2.49 (s, 2H), 1.00 13 C NMR (100 MHz, CDCl 3 ) δ 196.3, 191.2, 141.8, 134.0, 132.3, 131.0, 130.0, 128.4, 122.05, 120.8, 116.6, 115.6, 107.5, 52.5, 46.1, 39.3, 33.2, 28.3; HRMS (ESI-QTOF) calcd for C 21 H 18 ClNO 2 352.1099 ([M + H] + ), found 352.1095.

<2-16> 에틸 5-(4-브로모벤조일)-6-메틸인돌리진-7-카르복실레이트의 합성 (5p)<2-16> Synthesis of ethyl 5- (4-bromobenzoyl) -6-methylindolizine-7-carboxylate (5p)

화합물 d(67.2 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound d (67.2 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and ethyl acetoacetate (Compound A; 44.5 μL, 1.5 equivalent) Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 17Formula 17

Figure pat00098
Figure pat00098

갈색 검 (69.3 mg, 78%); 1 H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.00 (s, 1H), 6.81~6.77 (m, 1H), 6.77~6.74 (m, 1H), 4.36 (q, J = 6.8 Hz, 2H), 2.31 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 192.1, 166.6, 134.5, 132.9, 131.1, 131.1, 130.6, 129.9, 125.2, 119.5, 118.1, 115.8, 114.4, 105.0, 61.0, 16.9, 14.5; HRMS (ESI-QTOF) calcd for C19H16BrNO3 386.0386 ([M+H]+), found 386.0385.
Brown gum (69.3 mg, 78%); 1 H NMR (400 MHz, CDCl 3) δ 8.29 (s, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H), 7.00 (s, 1H), 6.81 J = 6.8 Hz, 2H), 2.31 (s, 3H), 1.41 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 192.1, 166.6, 134.5, 132.9, 131.1, 131.1, 130.6, 129.9, 125.2, 119.5, 118.1, 115.8, 114.4, 105.0, 61.0, 16.9, 14.5; HRMS (ESI-QTOF) calcd for C 19 H 16 BrNO 3 386.0386 ([M + H] +), found 386.0385.

<2-17> 1-(5-(4-브로모벤조일)-6-메틸인돌리진-7-일)에탄온 합성 <2-17> 1- (5- (4-Bromobenzoyl) -6-methylindolizin-7-yl) ethanone Synthesis (5q)(5q)

화합물 d(67.2 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 2,4-펜테인다이온(화합물 B; 35.2 μL, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound d (67.2 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and 2,4-pentanedione (compound B; 35.2 μL, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 18 (Y-033)(Y-033)

Figure pat00099
Figure pat00099

노랑 고형물, mp: 108.7~109.2℃ (59.0 mg, 72%); 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.80 (s, 2H), 2.63 (s, 3H), 2.27 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ198.5, 192.3, 134.4, 132.9, 131.1, 130.7, 130.6, 130.2, 127.2, 124.8, 117.7, 116.0, 114.8, 105.6, 28.6, 17.0; HRMS (ESI-QTOF) calcd for C18H14BrNO2 356.0281 ([M+H]+), found 356.0282.
Yellow solid, mp: 108.7-109.2 &lt; 0 &gt; C (59.0 mg, 72%); 1 H NMR (400 MHz, CDCl 3) δ 8.08 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.80 (s, 2 H), 2.63 (s, 3 H), 2.27 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 198.5, 192.3, 134.4, 132.9, 131.1, 130.7, 130.6, 130.2, 127.2, 124.8, 117.7, 116.0, 114.8, 105.6, 28.6, 17.0; HRMS (ESI-QTOF) calcd for C 18 H 14 BrNO 2 356.0281 ([M + H] +), found 356.0282.

<2-18> 6-아미노-5-(4-브로모벤조일)인돌리진-7-카보니트릴 합성 <2-18> Synthesis of 6-amino-5- (4-bromobenzoyl) indolizine-7-carbonitrile (5r)(5r)

화합물 d(67.2 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 10 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Compound D (67.2 mg, 0.23 mmol) was dissolved in 2 mL of EtOH and piperidinium acetate (17 mg, 0.5 eq.) And malononitrile (compound C; 22.8 mg, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 10: 1: 2) to obtain the desired compound.

화학식 19 (Y-032)(Y-032)

Figure pat00100
Figure pat00100

오렌지색 고형물, mp: 161.3~161.7℃ (60.2 mg, 77%); 1 H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 6.86 (s, 1H), 6.75 (dd, J = 0.8, 4.0 Hz, 1H), 6.51 (dd, J = 2.4, 4.4 Hz, 1H), 6.33 (s, 2H); 13 C NMR (100 MHz, CDCl3)δ 187.8, 141.6, 136.9, 132.5, 131.8, 129.9, 128.3, 127.2, 123.7, 116.4, 114.4, 112.7, 109.2, 93.4; HRMS (ESI-QTOF) calcd for C16H10BrN3O 340.0080 ([M+H]+), found 342.0072.
Orange solid, mp: 161.3-161.7 ° C (60.2 mg, 77%); 1 H NMR (400 MHz, CDCl 3) δ 7.85 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 6.86 (s, 1H), 6.75 (dd, J = 0.8, 4.0 Hz, 1H), 6.51 (dd, J = 2.4, 4.4 Hz, 1H), 6.33 (s, 2H); 13 C NMR (100 MHz, CDCl 3) δ 187.8, 141.6, 136.9, 132.5, 131.8, 129.9, 128.3, 127.2, 123.7, 116.4, 114.4, 112.7, 109.2, 93.4; HRMS (ESI-QTOF) calcd for C 16 H 10 BrN 3 O 340.0080 ([M + H] + ), found 342.0072.

<2-19> 에틸 5-(4-메톡시벤조일)-6-메틸인돌리진-7-카르복실레이트 합성 <2-19> Synthesis of ethyl 5- (4-methoxybenzoyl) -6-methylindolizine-7-carboxylate (5s)(5s)

화합물 e(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.To a solution of Compound e (56 mg, 0.23 mmol) in EtOH (2 mL), piperidinium acetate (17 mg, 0.5 eq.) And ethylacetoacetate (Compound A, 44.5 μL, 1.5 eq.) Were added, Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 2020

Figure pat00101
Figure pat00101

갈색 검 (56.6 mg, 73%); 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.82~6.75 (m, 1H), 6.75~6.70 (m, 1H), 4.36 (q, J = 6.8 Hz, 2H), 3.88 (s, 3H), 2.32 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 191.5, 166.7, 165.1, 132.3, 131.0, 130.7, 128.6, 124.7, 119.5, 117.1, 115.6, 114.7, 114.3, 104.6, 60.9, 55.8, 16.8, 14.5; HRMS (ESI-QTOF) calcd for C20H19NO4 338.1387 ([M+H]+), found 338.1384.
Brown gum (56.6 mg, 73%); 1 H NMR (400 MHz, CDCl 3) δ 8.28 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.03 (s, 1H), 6.94 (d, J = 8.8 Hz, 2H), 6.82 3H), 1.41 (t, J = 7.2 Hz, 2H), 6.75 (s, 3H) Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 191.5, 166.7, 165.1, 132.3, 131.0, 130.7, 128.6, 124.7, 119.5, 117.1, 115.6, 114.7, 114.3, 104.6, 60.9, 55.8, 16.8, 14.5; HRMS (ESI-QTOF) calcd for C 20 H 19 NO 4 338.1387 ([M + H] + ), found 338.1384.

<2-20> 1-(5-(4-메톡시벤조일)-6-메틸인돌리진-7-일)에탄온 합성 <2-20> Synthesis of 1- (5- (4-methoxybenzoyl) -6-methylindolizin-7-yl) ethanone (5t)(5t)

화합물 e(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 2,4-펜테인다이온(화합물 B; 35.2 μL, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound e (56 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and 2,4-pentanedione (compound B; 35.2 μL, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 21Formula 21

Figure pat00102
Figure pat00102

노란색 검 (48.1 mg, 68%); 1 H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.04 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.78 (s, 2H), 3.88 (s, 3H), 2.64 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 198.8, 191.6, 165.2, 132.3, 131.1, 130.5, 128.5, 127.3, 124.3, 116.8, 115.7, 114.7, 105.2, 55.8, 28.6, 16.9; HRMS (ESI-QTOF) calcd for C19H17NO3 308.1281 ([M+H]+), found 308.1285.
Yellow gum (48.1 mg, 68%); 1 H NMR (400 MHz, CDCl 3) δ 8.07 (s, 1H), 7.87 (d, J = 7.6 Hz, 2H), 7.04 (s, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.78 (s, 2H), 3.88 (s, 3H), 2.64 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 198.8, 191.6, 165.2, 132.3, 131.1, 130.5, 128.5, 127.3, 124.3, 116.8, 115.7, 114.7, 105.2, 55.8, 28.6, 16.9; HRMS (ESI-QTOF) calcd for C 19 H 17 NO 3 308.1281 ([M + H] + ), found 308.1285.

<2-21> 6-아미노-5-(4-메톡시벤조일)인돌리진-7-카보니트릴 합성 <2-21> Synthesis of 6-amino-5- (4-methoxybenzoyl) indolizine-7-carbonitrile (5u)(5u)

화합물 e(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 10 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Compound e (56 mg, 0.23 mmol) was dissolved in EtOH (2 mL), and piperidinium acetate (17 mg, 0.5 equivalent) and malononitrile (Compound C; 22.8 mg, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 10: 1: 2) to obtain the desired compound.

화학식 22 (Y-006)Formula 22 (Y-006)

Figure pat00103
Figure pat00103

오렌지색 고형물, mp: 131.4~132.2℃ (64.3 mg, 96%); 1 H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 4.0 Hz, 1H), 6.53 (dd, J = 2.4, 3.8 Hz, 1H), 5.83 (s, 2H), 3.87 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 188.5, 163.5, 139.3, 131.0, 130.8, 130.1, 128.4, 122.6, 116.7, 114.5, 114.4, 113.5, 108.2, 93.8, 55.6; HRMS (ESI-QTOF) calcd for C17H13N3O 2292.1081 ([M+H]+), found 292.1076.
Orange solid, mp: 131.4-132.2 占 (64.3 mg, 96%); 1 H NMR (400 MHz, CDCl 3) δ 7.83 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.89 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 4.0 Hz, 1H), 6.53 (dd, J = 2.4, 3.8 Hz, 1H), 5.83 (s, 2H), 3.87 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 188.5, 163.5, 139.3, 131.0, 130.8, 130.1, 128.4, 122.6, 116.7, 114.5, 114.4, 113.5, 108.2, 93.8, 55.6; HRMS (ESI-QTOF) calcd for C 17 H 13 N 3 O 2292.1081 ([M + H] + ), found 292.1076.

<2-22> 5-(4-메톡시벤조일)-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-22> 5- (4-Methoxybenzoyl) -7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (6H) (5v)(5v)

화합물 e(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound e (56 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 23 (Y-023)(Y-023)

Figure pat00104
Figure pat00104

노랑 고형물, mp: 112.2~112.8℃ (41.1 mg, 56%); 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.88 (s, 1H), 6.84 (s, 1H), 3.89 (s, 3H), 2.75~2.59 (m, 4H), 2.09~1.96 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 196.7, 190.8, 165.2, 132.3, 128.6, 122.2, 122.0, 121.4, 116.5, 115.5, 114.8, 107.1, 55.8, 39.3, 26.0, 22.9; HRMS (ESI-QTOF) calcd for C20H17NO3 320.1281 ([M+H]+), found 320.1278.
Yellow solid, mp: 112.2-112.8 [deg.] C (41.1 mg, 56%); 1 H NMR (400 MHz, CDCl 3) δ 8.40 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.15 (s, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.88 (s, 1H), 6.84 (s, 1H), 3.89 (s, 3H), 2.75 ~ 2.59 (m, 4H), 2.09 ~ 1.96 (m, 2H); 13 C NMR (100 MHz, CDCl 3) δ 196.7, 190.8, 165.2, 132.3, 128.6, 122.2, 122.0, 121.4, 116.5, 115.5, 114.8, 107.1, 55.8, 39.3, 26.0, 22.9; HRMS (ESI-QTOF) calcd for C 20 H 17 NO 3 320.1281 ([M + H] +), found 320.1278.

<2-23> 5-(4-메톡시벤조일)-7,7-디메틸-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-23> Synthesis of 5- (4-methoxybenzoyl) -7,7-dimethyl-7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (6H) (5w)(5w)

화합물 e(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 5,5-디메틸-1,3-사이클로헥산다이온(화합물 E; 48.4 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Compound e (56 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidineacetate (17 mg, 0.5 eq.) And 5,5-dimethyl-1,3-cyclohexanedione Equivalent), and the mixture was reacted at 120 DEG C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 24 (Y-030)24 (Y-030)

Figure pat00105
Figure pat00105

갈색 고형물, mp: 116.9~117.6℃ (41.5 mg, 52%); 1 H NMR (400 MHz, CDCl3) δ 8.38(s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.09 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 3.6 Hz, 1H), 6.81 (s, 1H), 3.89 (s, 3H), 2.54 (s, 2H), 2.48 (s, 2H), 1.00 (s, 6H); 13 C NMR (100 MHz, CDCl3) δ 196.5, 190.7, 165.3, 132.3, 129.3, 128.6, 121.4, 119.8, 116.4, 115.4, 114.9, 107.0, 55.8, 52.6, 39.2, 33.1, 28.3; HRMS (ESI-QTOF) calcd for C22H21NO3 348.1594 ([M+H]+), found 348.1612.
Brown solid, mp: 116.9-117.6 &lt; 0 &gt; C (41.5 mg, 52%); 1 H NMR (400 MHz, CDCl 3) δ 8.38 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.09 (s, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 3.6 Hz, 1H), 6.81 (s, 1H), 3.89 (s, 3H), 2.54 (s, 2H), 2.48 (s, 2H), 1.00 13 C NMR (100 MHz, CDCl 3) δ 196.5, 190.7, 165.3, 132.3, 129.3, 128.6, 121.4, 119.8, 116.4, 115.4, 114.9, 107.0, 55.8, 52.6, 39.2, 33.1, 28.3; HRMS (ESI-QTOF) calcd for C 22 H 21 NO 3 348.1594 ([M + H] + ), found 348.1612.

<2-24> 에틸 5-(4-(벤질옥시)벤조일)-6-메틸인돌리진-7-카르복실레이트 합성 <2-24> Synthesis of ethyl 5- (4- (benzyloxy) benzoyl) -6-methylindolizine-7-carboxylate (5x)(5x)

화합물 f(73.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound f (73.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and ethyl acetoacetate (Compound A; 44.5 μL, 1.5 equivalent) Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 2525

Figure pat00106
Figure pat00106

노란색 검 (66.6 mg, 70%); 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.45~7.33 (m, 5H), 7.01 (d, J = 8.8 Hz, 3H), 6.77 (dd, J = 2.4, 4.0 Hz, 1H), 6.73 (dd, J = 0.8, 3.6 Hz, 1H), 5.13 (s, 2H), 4.35 (q, J = 7.2 Hz, 2H), 2.32 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 191.5, 166.8, 164.3, 135.9, 132.3, 131.1, 130.8, 128.9, 128.8, 128.5, 127.7, 124.7, 119.6, 117.2, 115.6, 115.5, 114.4, 104.6, 70.5, 60.9, 16.8, 14.5; HRMS (ESI-QTOF) calcd for C26H23NO4 414.1700 ([M+H]+), found 414.1706.
Yellow gum (66.6 mg, 70%); 1 H NMR (400 MHz, CDCl 3) δ 8.27 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.45 ~ 7.33 (m, 5H), 7.01 (d, J = 8.8 Hz, 3H) , 6.77 (dd, J = 2.4,4.0 Hz, 1H), 6.73 (dd, J = 0.8,3.6 Hz, 1H), 5.13 (s, 2H), 4.35 s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 191.5, 166.8, 164.3, 135.9, 132.3, 131.1, 130.8, 128.9, 128.8, 128.5, 127.7, 124.7, 119.6, 117.2, 115.6, 115.5, 114.4, 104.6, , 16.8, 14.5; HRMS (ESI-QTOF) calcd for C 26 H 23 NO 4 414.1700 ([M + H] + ), found 414.1706.

<2-25> 1-(5-(4-(벤질옥시)벤조일)-6-메틸인돌리진-7-일)에탄온 합성 <2-25> Synthesis of 1- (5- (4- (benzyloxy) benzoyl) -6-methylindolizin-7-yl) ethanone (5y)(5y)

화합물 f(73.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 2,4-펜테인다이온(화합물 B; 35.2 μL, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound f (73.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and 2,4-pentanedione (compound B; 35.2 μL, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 2626

Figure pat00107
Figure pat00107

노란색 검 (52.9 mg, 60%); 1 H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.45~7.33 (m, 5H), 7.03 (d, J = 5.2 Hz, 2H), 7.00 (s, 1H), 6.77 (s, 2H), 5.13 (s, 2H), 2.63 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 198.7, 191.6, 164.4, 135.9, 132.3, 131.1, 130.6, 128.9, 128.8, 128.5, 127.6, 127.4, 124.3, 116.8, 115.75, 115.6, 114.8, 105.2, 70.5, 28.6, 16.9; HRMS (ESI-QTOF) calcd for C25H21NO3 384.1594 ([M+H]+), found 384.1609.
Yellow gum (52.9 mg, 60%); 1 H NMR (400 MHz, CDCl 3) δ 8.06 (s, 1H), 7.86 (d, J = 7.2 Hz, 2H), 7.45 ~ 7.33 (m, 5H), 7.03 (d, J = 5.2 Hz, 2H) , 7.00 (s, 1 H), 6.77 (s, 2 H), 5.13 (s, 2 H), 2.63 (s, 3 H), 2.28 (s, 3 H); 13 C NMR (100 MHz, CDCl 3) δ 198.7, 191.6, 164.4, 135.9, 132.3, 131.1, 130.6, 128.9, 128.8, 128.5, 127.6, 127.4, 124.3, 116.8, 115.75, 115.6, 114.8, 105.2, 70.5, 28.6 , 16.9; HRMS (ESI-QTOF) calcd for C 25 H 21 NO 3 384.1594 ([M + H] + ), found 384.1609.

<2-26> 6-아미노-5-(4-(벤질옥시)벤조일)인돌리진-7-카보니트릴 합성 <2-26> Synthesis of 6-amino-5- (4- (benzyloxy) benzoyl) indolizine-7-carbonitrile (5z)(5z)

화합물 f(73.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound f (73.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and malononitrile (compound C; 22.8 mg, 1.5 equivalent) Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 27 (Y-020)(Y-020)

Figure pat00108
Figure pat00108

오렌지색 고형물, mp: 169.4~169.8℃ (61.7 mg, 73%); 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.46~7.31 (m, 5H), 7.02 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 6.71 (d, J = 3.6 Hz, 1H), 6.53 (s, 1H), 5.80 (s, 2H), 5.11 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 188.5, 162.6, 139.3, 136.2, 131.0, 130.8, 130.4, 128.8, 128.5, 127.7, 122.6, 116.7, 115.4, 114.45, 113.5, 108.2, 93.7, 70.4; HRMS (ESI-QTOF) calcd for C23H17N3O2 368.1394 ([M+H]+), found 368.1392.
Orange solid, mp: 169.4-169.8 캜 (61.7 mg, 73%); 1 H NMR (400 MHz, CDCl 3) δ 7.82 (s, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.46 ~ 7.31 (m, 5H), 7.02 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 6.71 (d, J = 3.6 Hz, 1H), 6.53 (s, 1H), 5.80 (s, 2H), 5.11 13 C NMR (100 MHz, CDCl 3) δ 188.5, 162.6, 139.3, 136.2, 131.0, 130.8, 130.4, 128.8, 128.5, 127.7, 122.6, 116.7, 115.4, 114.45, 113.5, 108.2, 93.7, 70.4; HRMS (ESI-QTOF) calcd for C 23 H 17 N 3 O 2 368.1394 ([M + H] + ), found 368.1392.

<2-27> 5-(4-(벤질옥시)벤조일)-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-27> Synthesis of 5- (4- (benzyloxy) benzoyl) -7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (6H) (5aa)(5aa)

화합물 f(73.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound f (73.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 2828

Figure pat00109
Figure pat00109

오렌지색 검 (47.3 mg, 52%); 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.45~7.32 (m, 5H), 7.14 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 4.0 Hz, 1H), 6.83 (dd, J = 2.4, 3.6 Hz, 1H), 5.14 (s, 2H), 2.73~2.59 (m, 4H), 2.09~1.96 (m, 2H); 13 C NMR (100 MHz, CDCl) δ 190.8, 164.4, 135.9, 132.35, 132.26, 128.9, 128.6, 127.6, 122.3, 122.0, 121.5, 116.5, 115.7, 115.5, 107.1, 70.5, 39.3, 26.0, 22.9; HRMS (ESI-QTOF) calcd for C26H21NO3 396.1594 ([M+H]+), found 396.1609.
Orange gum (47.3 mg, 52%); 1 H NMR (400 MHz, CDCl 3) δ 8.39 (s, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.45 ~ 7.32 (m, 5H), 7.14 (s, 1H), 7.03 (d, 2H), 6.88 (d, J = 4.0 Hz, 1H), 6.83 (dd, J = 2.4, 3.6 Hz, 2.09 ~ 1.96 (m, 2H); 13 C NMR (100 MHz, CDCl 3) δ 190.8, 164.4, 135.9, 132.35, 132.26, 128.9, 128.6, 127.6, 122.3, 122.0, 121.5, 116.5, 115.7, 115.5, 107.1, 70.5, 39.3, 26.0, 22.9; HRMS (ESI-QTOF) calcd for C 26 H 21 NO 3 396.1594 ([M + H] + ), found 396.1609.

<2-28> 에틸 5-(3-메톡시벤조일)-6-메틸인돌리진-7-카르복실레이트 합성 <2-28> Synthesis of ethyl 5- (3-methoxybenzoyl) -6-methylindolizine-7-carboxylate (5ab)(5ab)

화합물 g(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound g (56 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and ethyl acetoacetate (Compound A, 44.5 μL, 1.5 equivalent) Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 29Formula 29

Figure pat00110
Figure pat00110

노란색 검 (77.6 mg, 100%); 1 H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.53 (s, 1H), 7.39~7.30 (m, 2H), 7.24~7.15 (m, 1H), 7.02 (s, 1H), 6.81~6.76 (m, 1H), 6.76~6.72 (m, 1H), 4.36 (q, J = 6.8 Hz, 2H), 3.86 (s, 3H), 2.32 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 193.0, 166.7, 160.5, 137.0, 131.1, 130.5, 124.9, 122.7, 121.7, 119.5, 117.7, 115.7, 114.4, 113.0, 104.8, 60.9, 55.7, 16.9, 14.5; HRMS (ESI-QTOF) calcd for C20H19NO4 338.1387 ([M+H]+), found 338.1382.
Yellow gum (77.6 mg, 100%); 1 H NMR (400 MHz, CDCl 3) δ 8.29 (s, 1H), 7.53 (s, 1H), 7.39 ~ 7.30 (m, 2H), 7.24 ~ 7.15 (m, 1H), 7.02 (s, 1H), J = 6.8 Hz, 2H), 3.86 (s, 3H), 2.32 (s, 3H), 1.41 (t, J = 7.2 Hz, 3 H); 13 C NMR (100 MHz, CDCl 3) δ 193.0, 166.7, 160.5, 137.0, 131.1, 130.5, 124.9, 122.7, 121.7, 119.5, 117.7, 115.7, 114.4, 113.0, 104.8, 60.9, 55.7, 16.9, 14.5; HRMS (ESI-QTOF) calcd for C 20 H 19 NO 4 338.1387 ([M + H] + ), found 338.1382.

<2-29> 1-(5-(3-메톡시벤조일)-6-메틸인돌리진-7-일)에탄온 합성 <2-29> 1- (5- (3-Methoxybenzoyl) -6-methylindolizin-7-yl) ethanone Synthesis (5ac)(5ac)

화합물 g(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 2,4-펜테인다이온(화합물 B; 35.2 μL, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Compound g (56 mg, 0.23 mmol) was dissolved in EtOH (2 mL), and piperidinium acetate (17 mg, 0.5 equivalent) and 2,4-pentanedione (compound B; 35.2 μL, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 30Formula 30

Figure pat00111
Figure pat00111

노랑 고형물, mp: 128.1~128.8℃ (45.9 mg, 65%); 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.53 (s, 1H), 7.39~7.30 (m, 2H), 7.23~7.17 (m, 1H), 7.03 (s, 1H), 6.79 (s, 2H), 3.86 (s, 3H), 2.64 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 198.6, 193.2, 160.5, 136.9, 130.8, 130.6, 130.5, 127.2, 124.6, 122.7, 121.8, 117.3, 115.8, 114.8, 113.0, 105.4, 55.7, 28.6, 17.0; HRMS (ESI-QTOF) calcd for C19H17NO3 308.1281 ([M+H]+), found 308.1287.
Yellow solid, mp: 128.1- 128.8 [deg.] C (45.9 mg, 65%); 1 H NMR (400 MHz, CDCl 3) δ 8.08 (s, 1H), 7.53 (s, 1H), 7.39 ~ 7.30 (m, 2H), 7.23 ~ 7.17 (m, 1H), 7.03 (s, 1H), 6.79 (s, 2H), 3.86 (s, 3H), 2.64 (s, 3H), 2.28 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 198.6, 193.2, 160.5, 136.9, 130.8, 130.6, 130.5, 127.2, 124.6, 122.7, 121.8, 117.3, 115.8, 114.8, 113.0, 105.4, 55.7, 28.6, 17.0; HRMS (ESI-QTOF) calcd for C 19 H 17 NO 3 308.1281 ([M + H] + ), found 308.1287.

<2-30> 6-아미노-5-(3-메톡시벤조일)인돌리진-7-카보니트릴 합성 <2-30> Synthesis of 6-amino-5- (3-methoxybenzoyl) indolizine-7-carbonitrile (5ad)(5ad)

화합물 g(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Compound g (56 mg, 0.23 mmol) was dissolved in EtOH (2 mL), and piperidinium acetate (17 mg, 0.5 eq.) And malononitrile (compound C; 22.8 mg, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 3131

Figure pat00112
Figure pat00112

오렌지색 고형물, mp: 123.4~123.8℃ (57.6 mg, 86%); 1 H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.07~7.04 (m, 3H), 6.91 (s, 1H), 6.72 (d, J = 3.6 Hz, 1H), 6.48 (s, 1H), 6.26 (s, 2H), 3.77 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 189.2, 160.4, 141.3, 139.6, 131.6, 130.4, 128.3, 123.5, 120.3, 118.7, 116.6, 114.3, 113.1, 112.6, 109.0, 93.3, 55.6; HRMS (ESI-QTOF) calcd for C17H13N3O2 292.1081 ([M+H]+), found 292.1085.
Orange solid, mp: 123.4-123.8 캜 (57.6 mg, 86%); 1 H NMR (400 MHz, CDCl 3) δ 7.83 (s, 1H), 7.29 (t, J = 7.6 Hz, 1H), 7.07 ~ 7.04 (m, 3H), 6.91 (s, 1H), 6.72 (d, J = 3.6 Hz, 1 H), 6.48 (s, 1 H), 6.26 (s, 2 H), 3.77 (s, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 189.2, 160.4, 141.3, 139.6, 131.6, 130.4, 128.3, 123.5, 120.3, 118.7, 116.6, 114.3, 113.1, 112.6, 109.0, 93.3, 55.6; HRMS (ESI-QTOF) calcd for C 17 H 13 N 3 O 2 292.1081 ([M + H] +), found 292.1085.

<2-31> 5-(3-메톡시벤조일)-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-31> Synthesis of 5- (3-methoxybenzoyl) -7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (6H) (5ae)(5ae)

화합물 g(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound g (56 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 32(32)

Figure pat00113
Figure pat00113

오렌지색 고형물, mp: 149.3~149.6℃ (52.9 mg, 72%); 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 7.50 (s, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 6.8 Hz, 1H), 7.16 (s, 1H), 6.88 (s, 1H), 6.83 (s, 1H), 3.86 (s, 3H), 2.73~2.58 (m, 4H), 2.09~1.95 (m, 2H); 13 C NMR (100 MHz, CDCl3) δ 196.4, 192.3, 160.6, 137.2, 132.4, 130.6, 128.0, 122.5, 122.4, 122.21, 122.17, 121.7, 116.5, 115.7, 113.1, 107.3, 55.7, 39.3, 26.1, 22.8; HRMS (ESI-QTOF) calcd for C20H17NO3 320.1281 ([M+H]+), found 320.1294.
Orange solid, mp: 149.3-149.6 &lt; 0 &gt; C (52.9 mg, 72%); 1 H NMR (400 MHz, CDCl 3) δ 8.40 (s, 1H), 7.50 (s, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.21 (d, J = 6.8 Hz, 1H), 7.16 (s, 1H), 6.88 (s, 1H), 6.83 (s, 1H), 3.86 (s, 3H), 2.73 ~ 2.58 (m, 4H), 2.09 ~ 1.95 (m, 2H); 13 C NMR (100 MHz, CDCl 3 ) δ 196.4, 192.3, 160.6, 137.2, 132.4, 130.6, 128.0, 122.5, 122.4, 122.21, 122.17, 121.7, 116.5, 115.7, 113.1, 107.3, 55.7, 39.3, 26.1, 22.8 ; HRMS (ESI-QTOF) calcd for C 20 H 17 NO 3 320.1281 ([M + H] +), found 320.1294.

<2-32> 에틸 5-(5-브로모티오펜-2-카보닐)-6-메틸인돌리진-7-카르복실레이트 합성 <2-32> Synthesis of ethyl 5- (5-bromothiophene-2-carbonyl) -6-methylindolizine-7-carboxylate (5af)(5af)

화합물 h(68.6 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound h (68.6 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 eq.) And ethyl acetoacetate (Compound A; 44.5 μL, 1.5 eq.) Were added thereto. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 33Formula 33

Figure pat00114
Figure pat00114

오렌지색 검 (45.1 mg, 50%); 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.25 (d, J = 4.0 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J = 4.0 Hz, 1H), 6.81 (dd, J = 2.8, 3.8 Hz, 1H), 6.75 (d, J = 4.0 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H), 2.39 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 183.8, 166.5, 144.4, 135.9, 132.2, 131.1, 129.6, 126.2, 125.4, 119.4, 118.1, 115.8, 114.4, 105.1, 61.0, 17.2, 14.5; HRMS (ESI-QTOF) calcd for C17H14BrNO3S 391.9951 ([M+H]+), found 391.9952.
Orange gum (45.1 mg, 50%); 1 H NMR (400 MHz, CDCl 3) δ 8.27 (s, 1H), 7.25 (d, J = 4.0 Hz, 1H), 7.15 (s, 1H), 7.09 (d, J = 4.0 Hz, 1H), 6.81 (d, J = 2.8,3.8 Hz, 1H), 6.75 (d, J = 4.0 Hz, 1H), 4.36 (q, J = 7.2 Hz, 2H) 7.2 Hz, 3 H); 13 C NMR (100 MHz, CDCl 3 ) δ 183.8, 166.5, 144.4, 135.9, 132.2, 131.1, 129.6, 126.2, 125.4, 119.4, 118.1, 115.8, 114.4, 105.1, 61.0, 17.2, 14.5; HRMS (ESI-QTOF) calcd for C 17 H 14 BrNO 3 S 391.9951 ([M + H] +), found 391.9952.

<2-33> 6-아미노-5-(5-브로모티오펜-2-카보닐)인돌리진-7-카보니트릴 합성 2-33 Synthesis of 6-amino-5- (5-bromothiophene-2-carbonyl) indolizine-7-carbonitrile (5ag)(5ag)

화합물 h(68.6 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound h (68.6 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 eq.) And malononitrile (Compound C; 22.8 mg, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 34 (Y-009)(Y-009)

Figure pat00115
Figure pat00115

빨강 고형물, mp: 177.4~178.0℃ (59.7 mg, 75%); 1 H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.43 (s, 1H), 7.12 (d, J = 4.0 Hz, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.75 (d, J = 4.0 Hz, 1H), 6.61 (dd, J = 2.8, 4.0 Hz, 1H), 5.76 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 179.3, 143.7, 139.2, 132.2, 131.4, 131.3, 128.6, 122.8, 122.4, 116.4, 114.5, 113.0, 108.7, 93.9; HRMS (ESI-QTOF) calcd for C14H8BrN3OS 345.9644 ([M+H]+), found 345.9622.
Red solid, mp: 177.4-178.0 [deg.] C (59.7 mg, 75%); 1 H NMR (400 MHz, CDCl 3) δ 7.82 (s, 1H), 7.43 (s, 1H), 7.12 (d, J = 4.0 Hz, 1H), 6.98 (d, J = 4.0 Hz, 1H), 6.75 (d, J = 4.0 Hz, 1H), 6.61 (dd, J = 2.8, 4.0 Hz, 1H), 5.76 (s, 2H); 13 C NMR (100 MHz, CDCl 3) δ 179.3, 143.7, 139.2, 132.2, 131.4, 131.3, 128.6, 122.8, 122.4, 116.4, 114.5, 113.0, 108.7, 93.9; HRMS (ESI-QTOF) calcd for C 14 H 8 BrN 3 OS 345.9644 ([M + H] + ), found 345.9622.

<2-34> 5-(5-브로모티오펜-2-카보닐)-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-34> Synthesis of 5- (5-bromothiophene-2-carbonyl) -7,8-dihydropyrrolo [1,2-b] isoquinolin-9 (6H) (5ah)(5ah)

화합물 h(68.6 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound h (68.6 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (Compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 35 (Y-010)35 (Y-010)

Figure pat00116
Figure pat00116

오렌지색 고형물, mp: 134.4~134.8℃ (62.0 mg, 72%); 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.26 (s, 2H), 7.11 (d, J = 3.6 Hz, 1H), 6.92~6.88 (m, 1H), 6.88~6.84 (m, 1H), 2.75 (t, J = 5.6 Hz, 2H), 2.66 (t, J = 6.0 Hz, 2H), 2.05 (t, J = 6.4 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 196.2, 183.0, 144.2, 135.8, 132.4, 132.3, 127.0, 126.5, 122.7, 122.1, 116.7, 115.5, 107.6, 39.2, 26.3, 22.8; HRMS (ESI-QTOF) calcd for C17H12BrNO2S 373.9845 ([M+H]+), found 373.9831.
Orange solid, mp: 134.4-134.8 [deg.] C (62.0 mg, 72%); 1 H NMR (400 MHz, CDCl 3) δ 8.39 (s, 1H), 7.26 (s, 2H), 7.11 (d, J = 3.6 Hz, 1H), 6.92 ~ 6.88 (m, 1H), 6.88 ~ 6.84 ( (t, J = 6.4 Hz, 2H), 2.66 (t, J = 6.0 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ 196.2, 183.0, 144.2, 135.8, 132.4, 132.3, 127.0, 126.5, 122.7, 122.1, 116.7, 115.5, 107.6, 39.2, 26.3, 22.8; HRMS (ESI-QTOF) calcd for C 17 H 12 BrNO 2 S 373.9845 ([M + H] +), found 373.9831.

<2-35> 에틸 5-(5-(터트-부틸)-3-요오도-2,4-디메톡시벤조일)-6-메틸인돌리진-7-카르복실레이트 합성 <2-35> Synthesis of ethyl 5- (5- (tert-butyl) -3-iodo-2,4-dimethoxybenzoyl) -6-methylindolizine-7- (5ai)(5ai)

화합물 i(105 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Compound I (105 mg, 0.23 mmol) was dissolved in EtOH (2 mL), and piperidinium acetate (17 mg, 0.5 eq.) And ethyl acetoacetate (Compound A; 44.5 μL, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 36Formula 36

Figure pat00117
Figure pat00117

갈색 검 (83.4 mg, 66%); 1 H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 7.80 (s, 1H), 7.11 (s, 1H), 6.78 (s, 1H), 6.74 (d, J = 3.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.96 (s, 3H), 3.52 (s, 3H), 2.35 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H), 1.33 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 190.4, 166.7, 166.3, 160.8, 141.7, 132.4, 131.3, 131.1, 126.5, 124.9, 119.6, 117.6, 115.6, 114.5, 104.9, 93.2, 62.4, 62.4, 60.9, 35.4, 30.9, 16.7, 14.5; HRMS (ESI-QTOF) calcd for C25H28INO5 550.1085 ([M+H]+), found 550.1089.
Brown gum (83.4 mg, 66%); 1 H NMR (400 MHz, CDCl 3) δ 8.26 (s, 1H), 7.80 (s, 1H), 7.11 (s, 1H), 6.78 (s, 1H), 6.74 (d, J = 3.6 Hz, 1H) (S, 3H), 2.35 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H), 1.33 9H); 13 C NMR (100 MHz, CDCl 3 ) δ 190.4, 166.7, 166.3, 160.8, 141.7, 132.4, 131.3, 131.1, 126.5, 124.9, 119.6, 117.6, 115.6, 114.5, 104.9, 93.2, 62.4, 62.4, 60.9, 35.4 , 30.9, 16.7, 14.5; HRMS (ESI-QTOF) calcd for C 25 H 28 INO 5 550.1085 ([M + H] + ), found 550.1089.

<2-36> 6-아미노-5-(5-(터트-부틸)-3-요오도-2,4-디메톡시벤조일)인돌리진-7-카보니트릴 합성 2-36 Synthesis of 6-amino-5- (5-tert-butyl) -3-iodo-2,4-dimethoxybenzoyl) indolizine-7-carbonitrile (5aj)(5aj)

화합물 i(105 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound i (105 mg, 0.23 mmol) was dissolved in 2 mL of EtOH and piperidinium acetate (17 mg, 0.5 eq.) And malononitrile (compound C; 22.8 mg, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 37 (Y-016)37 (Y-016)

Figure pat00118
Figure pat00118

오렌지색 고형물, mp: 138.4~140.2℃ (94.9 mg, 82%); 1 H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.33 (s, 1H), 6.85 (s, 2H), 6.74 (d, J = 1.6 Hz, 1H), 6.73 (s, 1H), 6.47 (t, J = 3.2 Hz, 1H), 3.9 (s, 3H), 3.60 (s, 3H), 1.34 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 186.5, 163.5, 157.1, 142.8, 142.1, 132.3, 128.5, 128.4, 128.4, 122.9, 116.6, 114.5, 113.9, 109.9, 92.6, 92.4, 62.8, 62.5, 35.3, 31.0; HRMS (ESI-QTOF) calcd for C22H22IN3O3 504.0779 ([M+H]+), found 504.0780.
Orange solid, mp: 138.4-140.2 ° C (94.9 mg, 82%); 1 H NMR (400 MHz, CDCl 3) δ 7.84 (s, 1H), 7.33 (s, 1H), 6.85 (s, 2H), 6.74 (d, J = 1.6 Hz, 1H), 6.73 (s, 1H) , 6.47 (t, J = 3.2 Hz, 1H), 3.9 (s, 3H), 3.60 (s, 3H), 1.34 (s, 9H); 13 C NMR (100 MHz, CDCl 3) δ 186.5, 163.5, 157.1, 142.8, 142.1, 132.3, 128.5, 128.4, 128.4, 122.9, 116.6, 114.5, 113.9, 109.9, 92.6, 92.4, 62.8, 62.5, 35.3, 31.0 ; HRMS (ESI-QTOF) calcd for C 22 H 22 IN 3 O 3 504.0779 ([M + H] + ), found 504.0780.

<2-37> 5-(5-(터트-부틸)-3-요오도-2,4-디메톡시벤조일)-7,8-디하이드로피로로[1,2-b]이소퀴놀린-9(6H)-온 합성 <2-37> Synthesis of 5- (5-tert-butyl) -3-iodo-2,4-dimethoxybenzoyl) -7,8-dihydropyrrolo [ 6H) -one Synthesis (5ak)(5ak)

화합물 i(105 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound i (105 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (Compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 38 (Y-021)38 (Y-021)

Figure pat00119
Figure pat00119

노랑 고형물, mp: 158.4~159.3℃ (66.0 mg, 54%); 1 H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.76 (s, 1H), 7.32 (s, 1H), 6.89 (d, J = 3.6 Hz, 1H), 6.85 (t, J = 4.0 Hz, 1H), 3.98 (s, 3H), 3.49 (s, 3H), 2.69 (t, J = 6.0 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.08~1.96 (m, 2H), 1.35 (s, 9H); 13 C NMR (100 MHz, CDCl3) δ 196.5, 189.7, 166.1, 160.3, 141.9, 132.5, 130.8, 129.5, 127.0, 123.2, 122.8, 122.1, 116.6, 116.0, 107.6, 93.1, 62.7, 62.5, 39.2, 35.4, 30.9, 26.3, 22.9; HRMS (ESI-QTOF) calcd for C25H26INO4 532.0979 ([M+H]+), found 532.1008.
Yellow solid, mp: 158.4-159.3 [deg.] C (66.0 mg, 54%); 1 H NMR (400 MHz, CDCl 3) δ 8.41 (s, 1H), 7.76 (s, 1H), 7.32 (s, 1H), 6.89 (d, J = 3.6 Hz, 1H), 6.85 (t, J = 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.08-1.96 (m, 2H), 1.35 (s, 9H); 13 C NMR (100 MHz, CDCl 3) δ 196.5, 189.7, 166.1, 160.3, 141.9, 132.5, 130.8, 129.5, 127.0, 123.2, 122.8, 122.1, 116.6, 116.0, 107.6, 93.1, 62.7, 62.5, 39.2, 35.4 , 30.9, 26.3, 22.9; HRMS (ESI-QTOF) calcd for C 25 H 26 INO 4 532.0979 ([M + H] + ), found 532.1008.

<2-38> 디에틸 7-아세틸-5-벤조일-2,6-디메틸인돌리진-1,3-디카르복실레이트 합성 2-38 Synthesis of diethyl 7-acetyl-5-benzoyl-2,6-dimethylindolizine-1,3-dicarboxylate (5al)(5al)

화합물 j(85.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 2,4-펜테인다이온(화합물 B; 35.2 μL, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound j (85.5 mg, 0.23 mmol) was dissolved in EtOH (2 mL), and piperidinium acetate (17 mg, 0.5 equivalent) and 2,4-pentanedione (compound B; 35.2 μL, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 3939

Figure pat00120
Figure pat00120

옅은 노랑 고형물, mp: 83.8~84.4℃ (51.1 mg, 51%); 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 4.45 (q, J = 7.2 Hz, 2H), 3.99 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 2.66 (s, 3H), 2.15 (s, 3H), 1.47 (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 194.7, 167.8, 137.2, 133.3, 129.2, 128.7, 128.5, 127.9, 124.9, 121.0, 114.6, 111.8, 74.0, 66.2, 60.9, 30.4, 14.3; HRMS (ESI-QTOF) calcd for C25H25NO6 436.1755 ([M+H]+), found 436.1790.
Pale yellow solid, mp: 83.8-84.4 DEG C (51.1 mg, 51%); 1 H NMR (400 MHz, CDCl 3) δ 8.90 (s, 1H), 7.85 (d, J = 7.6 Hz, 2H), 7.61 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz 3H), 2.15 (s, 3H), 1.47 (q, J = 7.2 Hz, 2H) (t, J = 7.2 Hz, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 194.7, 167.8, 137.2, 133.3, 129.2, 128.7, 128.5, 127.9, 124.9, 121.0, 114.6, 111.8, 74.0, 66.2, 60.9, 30.4, 14.3; HRMS (ESI-QTOF) calcd for C 25 H 25 NO 6 436.1755 ([M + H] + ), found 436.1790.

<2-39> 디에틸 6-아미노-5-벤조일-7-시아노-2-메틸인돌리진-1,3-디카르복실레이트 합성 2-39 Synthesis of diethyl 6-amino-5-benzoyl-7-cyano-2-methylindolizine-1,3-dicarboxylate (5am)(5am)

화합물 j(85.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound j (85.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH and piperidinium acetate (17 mg, 0.5 eq.) And malononitrile (compound C; 22.8 mg, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 4040

Figure pat00121
Figure pat00121

노란색 검 (80.1 mg, 83%); 1 H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 8.0 Hz, 2H), 7.19 (d, J = 7.6 Hz, 2H), 6.01 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 4.02 (q, J = 7.2 Hz, 2H), 2.53 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 187.8, 164.2, 161.5, 139.6, 135.8, 135.6, 132.8, 130.9, 129.5, 128.7, 128.4, 123.1, 115.5, 114.7, 110.3, 101.5, 61.1, 60.7, 14.6, 14.2, 12.5; HRMS (ESI-QTOF) calcd for C23H21N3O5 420.1554 ([M+H]+), found 420.1582.
Yellow gum (80.1 mg, 83%); 1 H NMR (400 MHz, CDCl 3) δ 8.76 (s, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.28 (t, J = 8.0 Hz, 2H), 7.19 (d, J = 7.6 Hz J = 7.2 Hz, 2 H), 2.53 (s, 3 H), 1.46 (t, J = 7.2 Hz, 2H) , 3H), 1.15 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 187.8, 164.2, 161.5, 139.6, 135.8, 135.6, 132.8, 130.9, 129.5, 128.7, 128.4, 123.1, 115.5, 114.7, 110.3, 101.5, 61.1, 60.7, 14.6, 14.2 , 12.5; HRMS (ESI-QTOF) calcd for C 23 H 21 N 3 O 5 420.1554 ([M + H] + ), found 420.1582.

<2-40> 디에틸 5-벤조일-2-메틸-9-옥소-6,7,8,9-테트라하이드로피로로[1,2-b]이소퀴놀린-1,3-디카르복실레이트 합성 <2-40> Diethyl 5-benzoyl-2-methyl-9-oxo-6,7,8,9-tetrahydropyrrolo [1,2-b] isoquinoline-1,3-dicarboxylate Synthesis (5an)(5an)

화합물 j(85.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 10 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound j (85.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (Compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 10: 1: 2) to obtain the desired compound.

화학식 41 (Y-008)41 (Y-008)

Figure pat00122
Figure pat00122

노랑 고형물, mp: 169.6~169.9℃ (102.9 mg, 100%); 1 H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 4.47 (q, J = 7.2 Hz, 2H), 4.03 (q, J = 6.8 Hz, 2H), 2.72 (t, J = 6.4 Hz, 2H), 2.68 (s, 3H), 2.00 (t, J = 6.0 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 196.0, 189.5, 164.4, 161.9, 137.1, 136.8, 136.7, 134.0, 131.3, 129.14, 129.08, 128.4, 127.1, 122.0, 119.8, 109.9, 61.0, 60.5, 39.0, 27.2, 22.6, 14.65, 14.3, 12.6; HRMS (ESI-QTOF) calcd for C26H25NO6 448.1755 ([M+H]+), found 448.1799.
Yellow solid, mp: 169.6-169.9 ° C (102.9 mg, 100%); 1 H NMR (400 MHz, CDCl 3) δ 9.18 (s, 1H), 7.71 (d, J = 7.2 Hz, 2H), 7.61 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 7.6 Hz 2H), 2.47 (q, J = 7.2 Hz, 2H), 4.47 (q, J = 7.2 Hz, 2H), 4.03 , J = 6.0 Hz, 2H), 1.49 (t, J = 7.2 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 196.0, 189.5, 164.4, 161.9, 137.1, 136.8, 136.7, 134.0, 131.3, 129.14, 129.08, 128.4, 127.1, 122.0, 119.8, 109.9, 61.0, 60.5, 39.0, 27.2 , 22.6, 14.65, 14.3, 12.6; HRMS (ESI-QTOF) calcd for C 26 H 25 NO 6 448.1755 ([M + H] + ), found 448.1799.

<2-41> 에틸 6-아미노-7-시아노-5-(4-메톡시벤조일)인돌리진-3-카르복실레이트 합성 2-41 Synthesis of ethyl 6-amino-7-cyano-5- (4-methoxybenzoyl) indolizine-3-carboxylate (5ao)(5ao)

화합물 k(72.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 10 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound k (72.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH and piperidinium acetate (17 mg, 0.5 eq.) And malononitrile (compound C; 22.8 mg, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 10: 1: 2) to obtain the desired compound.

화학식 42 (Y-031)(Y-031)

Figure pat00123
Figure pat00123

오렌지색 고형물, mp: 156.4~156.8℃ (74.4 mg, 89%); 1 H NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.16 (s, 1H), 7.14 (d, J = 4.0 Hz, 2H), 6.78 (d, J = 4.0 Hz, 1H), 6.74 (s, 1H), 6.72 (s, 1H), 5.82 (s, 2H), 4.03 (q, J = 7.2 Hz, 2H), 3.79 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 187.2, 162.8, 160.9, 138.9, 131.4, 130.5, 129.2, 129.0, 124.4, 121.3, 115.9, 114.7, 113.8, 108.7, 98.7, 60.8, 55.5, 14.3; HRMS (ESI-QTOF) calcd for C20H17N3O4 364.1292 ([M+H]+), found 364.1314.
Orange solid, mp: 156.4 ~ 156.8 캜 (74.4 mg, 89%); 1 H NMR (400 MHz, CDCl 3) δ 7.92 (s, 1H), 7.16 (s, 1H), 7.14 (d, J = 4.0 Hz, 2H), 6.78 (d, J = 4.0 Hz, 1H), 6.74 (s, 1H), 6.72 (s, 1H), 5.82 (s, 2H), 4.03 (q, J = 7.2 Hz, 2H) ; 13 C NMR (100 MHz, CDCl 3) δ 187.2, 162.8, 160.9, 138.9, 131.4, 130.5, 129.2, 129.0, 124.4, 121.3, 115.9, 114.7, 113.8, 108.7, 98.7, 60.8, 55.5, 14.3; HRMS (ESI-QTOF) calcd for C 20 H 17 N 3 O 4 364.1292 ([M + H] +), found 364.1314.

<2-42> 에틸 5-(4-메톡시벤조일)-9-옥소-6,7,8,9-테트라하이드로피로로[1,2-b]이소퀴놀린-3-카르복실레이트 합성 <2-42> Synthesis of ethyl 5- (4-methoxybenzoyl) -9-oxo-6,7,8,9-tetrahydropyrrolo [1,2-b] isoquinoline- (5ap)(5ap)

화합물 k(72.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 1,3-사이클로헥산다이온(화합물 D; 38.7 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 10 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound k (72.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and 1,3-cyclohexanedione (Compound D; 38.7 mg, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 10: 1: 2) to obtain the desired compound.

화학식 43 (Y-013)43 (Y-013)

Figure pat00124
Figure pat00124

노랑 고형물, mp: 162.1~162.6℃ (87.3 mg, 97%); 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.68 (d, J = 6.4 Hz, 2H), 7.47 (s, 1H), 6.92 (s, 2H), 6.90 (s, 1H), 4.09 (q, J = 6.8 Hz, 2H), 3.87 (s, 3H), 2.75 (br s, 2H), 2.66 (t, J = 5.2 Hz, 2H), 2.00 (t, J = 5.6 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 196.6, 188.3, 163.8, 160.8, 137.0, 131.5, 131.2, 130.4, 125.9, 125.8, 123.5, 121.8, 120.3, 114.2, 108.2, 60.7, 55.6, 39.0, 27.0, 22.7, 14.4; HRMS (ESI-QTOF) calcd for C23H21NO5 392.1492 ([M+H]+), found 392.1496.
Yellow solid, mp: 162.1 to 162.6 캜 (87.3 mg, 97%); 1 H NMR (400 MHz, CDCl 3) δ 8.45 (s, 1H), 7.68 (d, J = 6.4 Hz, 2H), 7.47 (s, 1H), 6.92 (s, 2H), 6.90 (s, 1H) 2H), 2.00 (t, J = 5.6 Hz, 2H), 4.09 (q, J = 6.8 Hz, 2H), 3.87 ), 1.17 (t, J = 7.2 Hz, 3 H); 13 C NMR (100 MHz, CDCl 3) δ 196.6, 188.3, 163.8, 160.8, 137.0, 131.5, 131.2, 130.4, 125.9, 125.8, 123.5, 121.8, 120.3, 114.2, 108.2, 60.7, 55.6, 39.0, 27.0, 22.7 , 14.4; HRMS (ESI-QTOF) calcd for C 23 H 21 NO 5 392.1492 ([M + H] + ), found 392.1496.

상기 화학식 7 내지 43으로 표시되는 화합물의 합성을 요약하면 다음과 같다(표 3).The synthesis of the compounds represented by the above formulas (7) to (43) is summarized as follows (Table 3).

Figure pat00125
Figure pat00125

<2-43> 트리에틸 5-벤조일-6-하이드록시-2,6-디메틸-5,6-디하이드로인돌리진-1,3,7-트리카르복실레이트 합성<2-43> Synthesis of triethyl 5-benzoyl-6-hydroxy-2,6-dimethyl-5,6-dihydroindolizine-1,3,7-tricarboxylate

화합물 j(85.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 아세토아세테이트(화합물 A; 44.5 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.To a solution of compound j (85.5 mg, 0.23 mmol) in 2 mL of EtOH, piperidinium acetate (17 mg, 0.5 eq.) And ethylacetoacetate (Compound A, 44.5 μL, 1.5 eq.) Were added, Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 44 (Y-007)(Y-007)

Figure pat00126
Figure pat00126

옅은 노란색 고형물, mp: 154.8~155.7℃ (90.9%); 1 H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.10 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 2H), 6.99 (s, 1H), 5.40 (s, 1H), 4.45~4.29 (m, 2H), 4.29~4.07 (m, 4H), 2.59 (s, 3H), 1.67 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 194.6, 167.0, 164.3, 161.6, 137.5, 135.5, 133.7, 133.2, 129.4, 128.4, 127.3, 126.7, 122.7, 116.1, 73.6, 64.4, 61.5, 60.9, 60.4, 30.2, 14.4, 14.3, 14.2, 12.6.
Pale yellow solid, mp: 154.8-155.7 C (90.9%); 1 H NMR (400 MHz, CDCl 3) δ 8.24 (s, 1H), 8.10 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz 2H), 6.99 (s, 1H), 5.40 (s, 1H), 4.45-4.29 (m, 2H), 4.29-4. 1.43 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 194.6, 167.0, 164.3, 161.6, 137.5, 135.5, 133.7, 133.2, 129.4, 128.4, 127.3, 126.7, 122.7, 116.1, 73.6, 64.4, 61.5, 60.9, 60.4, , 14.4, 14.3, 14.2, 12.6.

<2-44> 에틸 6-아미노-7-시아노인돌리진-5-카르복실레이트 합성<2-44> Synthesis of ethyl 6-amino-7-cyanoindolizine-5-carboxylate

에틸 2-(2-포르밀-1H-피롤-1-일)아세테이트(41.7 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.(41.7 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 eq.) And malononitrile (compound C; 22.8 mg, 1.5 eq.) Was added thereto, followed by reaction at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the desired compound.

화학식 45 (Y-011)(Y-011)

Figure pat00127
Figure pat00127

암록색 고형물, mp: 159.6~161.4℃ (33.5%); 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.82 (s, 1H), 6.79 (s, 1H), 6.78 (s, 1H), 6.39 (s, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 164.5, 142.8, 131.1, 128.6, 123.8, 116.9, 115.1, 109.2, 92.3, 61.6, 14.6; HRMS (ESI-QTOF) calcd for C12H11N3O 230.0924 ([M+H]+), found 230.0923.
Dark green solid, mp: 159.6-161.4 占 폚 (33.5%); 1 H NMR (400 MHz, CDCl 3) δ 8.53 (s, 1H), 7.82 (s, 1H), 6.79 (s, 1H), 6.78 (s, 1H), 6.39 (s, 2H), 4.51 (q, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3) δ 164.5, 142.8, 131.1, 128.6, 123.8, 116.9, 115.1, 109.2, 92.3, 61.6, 14.6; HRMS (ESI-QTOF) calcd for C 12 H 11 N 3 O 230.0924 ([M + H] + ), found 230.0923.

<2-45> 에틸 7-아세틸-6-하이드록시-5-(4-메톡시벤조일)-6-메틸-5,6-디하이드로인돌리진-3-카르복실레이트 합성<2-45> Synthesis of ethyl 7-acetyl-6-hydroxy-5- (4-methoxybenzoyl) -6-methyl-5,6-dihydroindolizine-

화합물 k(72.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 2,4-펜테인다이온(화합물 B; 35.2 μL, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Compound (k) (72.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH. Piperidinium acetate (17 mg, 0.5 equivalent) and 2,4- pentanedione (compound B; 35.2 μL, 1.5 equivalent) And reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 46 (Y-012)(Y-012)

Figure pat00128
Figure pat00128

옅은 노란색 고형물, mp: 177.5~178.3℃ (87.5%); 1 H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.85 (s, 1H), 6.56 (d, J = 3.6 Hz, 1H), 5.84 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.40 (s, 3H), 1.62 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 200.9, 193.4, 163.7, 160.7, 133.8, 132.2, 131.7, 130.6, 128.9, 126.1, 119.6, 114.1, 113.6, 77.5, 77.2, 76.8, 74.9, 63.9, 60.6, 55.5, 30.3, 26.0, 14.3.
Pale yellow solid, mp: 177.5-178.3 캜 (87.5%); 1 H NMR (400 MHz, CDCl 3) δ 8.09 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.03 (d, J = 3.6 Hz, 1H), 6.95 (d, J = 8.4 Hz 2H), 6.85 (s, 1H), 6.56 (d, J = 3.6 Hz, 1H), 5.84 (s, 3H), 1.62 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ) δ 200.9, 193.4, 163.7, 160.7, 133.8, 132.2, 131.7, 130.6, 128.9, 126.1, 119.6, 114.1, 113.6, 77.5, 77.2, 76.8, 74.9, 63.9, 60.6, 55.5 , 30.3, 26.0, 14.3.

<2-46> 5-벤조일-6-메틸인돌리진-7-카르복실산 합성<2-46> Synthesis of 5-benzoyl-6-methylindolizine-7-carboxylic acid

화합물 5a(600 mg, 1.95 mmol)를 MeOH 7 ㎖에 녹이고, NaOH(780.9 mg, 10 당량)을 녹인 H2O 7㎖를 0℃에서 넣은 뒤, 실온에서 3시간 동안 반응시켰다. 반응 종결 후 반응물을 10% HCl로 산성화시킨 후 반응물의 MeOH를 감압제거하였다. 잔류물을 감압여과하고 물로 한두 번 여과지 위의 고체를 세척하였다. 건조하여 원하는 화합물을 얻었다.Compound 5a (600 mg, 1.95 mmol) was dissolved in 7 mL of MeOH, and 7 mL of H 2 O in which NaOH (780.9 mg, 10 eq.) Was dissolved was added at 0 ° C., followed by reaction at room temperature for 3 hours. After completion of the reaction, the reaction product was acidified with 10% HCl, and the MeOH of the reaction product was removed under reduced pressure. The residue was filtered under reduced pressure and the solids on the filter paper washed once or twice with water. The desired compound was obtained by drying.

화학식 47 (Y-028)(Y-028)

Figure pat00129
Figure pat00129

노랑 고형물(100%); 1 H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.07 (s, 1H), 6.82 (s, 1H) 6.81 (s, 1H), 2.37 (s, 3H).
Yellow solid (100%); 1 H NMR (400 MHz, CDCl 3) δ 8.48 (s, 1H), 7.91 (d, J = 7.2 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz 2H), 7.07 (s, IH), 6.82 (s, IH) 6.81 (s, IH), 2.37 (s, 3H).

<2-47> 에틸 6-아미노-5-(4-메톡시벤조일)인돌리진-7-카르복실레이트 합성2-47 Synthesis of ethyl 6-amino-5- (4-methoxybenzoyl) indolizine-7-carboxylate

화합물 e(56 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 에틸 시아노아세테이트(화합물 F; 36.7 μL, 1.5 당량)를 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 10 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.The compound e (56 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.5 equivalent) and ethyl cyanoacetate (Compound F; 36.7 μL, 1.5 eq.) Were added. Lt; / RTI &gt; After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 10: 1: 2) to obtain the desired compound.

화학식 48 (Y-029)48 (Y-029)

Figure pat00130
Figure pat00130

옅은 오렌지색 고형물, mp: 153.2~153.9℃ (52.0%); 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 4.4 Hz, 1H), 7.81 (s, 1H), 7.02 (s, 2H), 6.99 (s, 1H), 6.50 (s, 1H), 5.47 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 3.91 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 190.0, 164.7, 164.1, 139.3, 131.6, 130.6, 127.8, 127.0, 120.1, 117.0, 114.5, 112.7, 94.1, 62.2, 55.8, 52.6, 14.3; HRMS (ESI-QTOF) calcd for C19H18N2O4 339.1339 ([M+H]+), found 339.1348.
Pale orange solid, mp: 153.2 ~ 153.9 캜 (52.0%); 1 H NMR (400 MHz, CDCl 3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 4.4 Hz, 1H), 7.81 (s, 1H), 7.02 (s, 2H), 6.99 (s, 1H), 6.50 (s, 1H), 5.47 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H) ; 13 C NMR (100 MHz, CDCl 3) δ 190.0, 164.7, 164.1, 139.3, 131.6, 130.6, 127.8, 127.0, 120.1, 117.0, 114.5, 112.7, 94.1, 62.2, 55.8, 52.6, 14.3; HRMS (ESI-QTOF) calcd for C 19 H 18 N 2 O 4 339.1339 ([M + H] +), found 339.1348.

<2-48><2-48> 7-아미노-6-(4-메톡시벤조일)피리도[1,2-a]인돌-8-카보니트릴 합성Synthesis of 7-amino-6- (4-methoxybenzoyl) pyrido [1,2-a] indole-8-carbonitrile

1-(2-(4-메톡시페닐)-2-옥소에틸)-1H-인돌-2-카르발데히드(67.5 mg, 0.23 mmol)를 EtOH 2 ㎖에 녹이고, 피페리디늄 아세테이트(17 mg, 0.5 당량)와 말로노나이트릴(화합물 C; 22.8 mg, 1.5 당량)을 넣은 뒤, 120℃에서 24시간 동안 반응시켰다. 반응 종결 후 반응물을 감압농축 하여 얻은 잔사물을 실리카 겔 컬럼 크로마토그래피(헥산 : 에틸 아세테이트 : 디클로로메테인 = 20 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.Indole-2-carbaldehyde (67.5 mg, 0.23 mmol) was dissolved in 2 mL of EtOH, and piperidinium acetate (17 mg, 0.58 eq.) And malononitrile (22.8 mg, 1.5 eq. Of compound C) were placed in a flask and reacted at 120 ° C for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: dichloromethane = 20: 1: 2) to obtain the target compound.

화학식 49Formula 49

Figure pat00131
Figure pat00131

빨강 고형물, mp: 120.7~121.3℃ (60.5 mg, 77%); 1 H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.40 (s, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.14~7.07 (m, 2H), 6.97 (t, J = 8.4 Hz, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 5.48 (s, 2H), 3.74 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 196.3, 187.3, 163.6, 132.2, 131.0, 130.8, 129.7, 129.1, 123.6, 122.4, 122.0, 116.1, 114.6, 114.3, 101.2, 100.0, 55.5; HRMS (ESI-QTOF) calcd for C21H15N3O2 342.1237 ([M+H]+), found 342.1240.
Red solid, mp: 120.7-121.3 [deg.] C (60.5 mg, 77%); 1 H NMR (400 MHz, CDCl 3) δ 8.08 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.40 (s, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.14 2H), 6.74 (s, 1H), 6.74 (s, 1H), 6.74 (s, 1H), 7.07 (m, 2H), 6.97 (t, J = 8.4 Hz, 13 C NMR (100 MHz, CDCl 3) δ 196.3, 187.3, 163.6, 132.2, 131.0, 130.8, 129.7, 129.1, 123.6, 122.4, 122.0, 116.1, 114.6, 114.3, 101.2, 100.0, 55.5; HRMS (ESI-QTOF) calcd for C 21 H 15 N 3 O 2 342.1237 ([M + H] +), found 342.1240.

<2-49> 에틸 5-벤조일-3-포르밀-6-메틸인돌리진-7-카르복실레이트 합성<2-49> Synthesis of ethyl 5-benzoyl-3-formyl-6-methylindolizine-7-carboxylate

DMF(0.5 ㎖)에 POCl3(75.8 ㅅL, 0.81 mmol, 5 당량)를 넣고 0℃에서 1시간 동안 저어주었다. 건조된 CH2Cl2(2 ㎖)에 화학식 2의 화합물(50 mg, 0.163 mmol)을 혼합한 후 POCl3와 DMF 혼합물에 첨가하였다. 0℃에서 1시간 동안 저어준 후, 반응 혼합물을 포화 NaHCO3(3 ㎖) 용액으로 반응 종결시키고, CH2Cl2(5 ㎖)로 희석한 다음 H2O(2 ㎖)로 세척하였다. 에틸아세테이트(5 ㎖)로 수층을 다시 한 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 실리카 겔 크로마토그래피(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.POCl 3 (75.8 mmol, 0.81 mmol, 5 eq.) Was added to DMF (0.5 mL) and stirred at 0 ° C for 1 hour. The compound of formula 2 (50 mg, 0.163 mmol) was mixed with dried CH 2 Cl 2 (2 mL) and added to the mixture of POCl 3 and DMF. After stirring at 0 ° C for 1 hour, the reaction mixture was quenched with saturated NaHCO 3 (3 mL) solution, diluted with CH 2 Cl 2 (5 mL) and washed with H 2 O (2 mL). The aqueous layer was extracted once more with ethyl acetate (5 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the target compound.

화학식 5050

Figure pat00132
Figure pat00132

흰색 고형물, mp: 168.6~169.4℃ (34.6 mg, 63%); 1 H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.28 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.52~7.43 (m, 3H), 6.88 (d, J = 4.8 Hz, 1H), 4.40 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 189.5, 176.0, 165.7, 138.2, 137.9, 134.6, 133.6, 129.0, 129.0, 127.6, 127.5, 127.4, 123.4, 122.2, 107.4, 61.7, 17.2, 14.3; HRMS (ESI-QTOF) calcd for C20H17NO4 336.1230 ([M+H]+), found 336.1242.
White solid, mp: 168.6-169.4 &lt; 0 &gt; C (34.6 mg, 63%); 1 H NMR (400 MHz, CDCl 3) δ 9.42 (s, 1H), 8.28 (s, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.52 J = 7.2 Hz, 3H), 7.43 (m, 3H), 6.88 (d, J = 4.8 Hz, ; 13 C NMR (100 MHz, CDCl 3) δ 189.5, 176.0, 165.7, 138.2, 137.9, 134.6, 133.6, 129.0, 129.0, 127.6, 127.5, 127.4, 123.4, 122.2, 107.4, 61.7, 17.2, 14.3; HRMS (ESI-QTOF) calcd for C 20 H 17 NO 4 336.1230 ([M + H] + ), found 336.1242.

<2-50> (E)-1-(5-벤조일-6-메틸인돌리진-7-일)-3-(4-메톡시페닐)프로프-2-엔-1-온 합성2- Synthesis of (E) -1- (5-benzoyl-6-methylindolizin-7-yl) -3- (4-methoxyphenyl) prop-

화학식 3의 화합물(50 mg, 0.18 mmol)과 P-아니스알데하이드(25.8 mg, 1.05 당량)를 EtOH(1 ㎖)에 녹이고 NaOH(7.2 mg, 1 당량)와 H2O(1 ㎖)의 용액에 상온에서 첨가하였다. 상온에서 24시간 동안 저어준 후, 반응 혼합물을 10% HCl으로 산성화하고, 진공에서 농축한 다음 디클로로메탄(5 ㎖)으로 두 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 실리카 겔 크로마토그래피(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.To a solution of the compound of formula 3 (50 mg, 0.18 mmol) and P -anisaldehyde (25.8 mg, 1.05 eq.) In EtOH (1 mL) and NaOH (7.2 mg, 1 eq.) And H 2 O (1 mL) Was added at room temperature. After stirring at room temperature for 24 h, the reaction mixture was acidified with 10% HCl, concentrated in vacuo and extracted twice with dichloromethane (5 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the target compound.

화학식 51Formula 51

Figure pat00133
Figure pat00133

노랑 고형물, mp: 139.0~139.7℃ (55.3 mg, 78%); 1 H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.89 (s, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 16.0 Hz, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.15 (d, J = 16.0 Hz, 1H), 7.04 (s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.78 (dd, J = 2.4, 4.0 Hz, 1H), 6.73 (d, J = 3.2 Hz, 1H), 3.87 (s, 3H), 2.22 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 193.2, 161.9, 145.5, 135.7, 135.1, 131.0, 130.8, 130.4, 129.8, 129.54, 129.48, 127.5, 123.7, 122.5, 117.1, 115.5, 114.6, 114.3, 104.2, 55.6, 16.1; HRMS (ESI) calcd for C26H22NO3 396.1594 ([M+H]+), found 396.1605.
Yellow solid, mp: 139.0-139.7 [deg.] C (55.3 mg, 78%); 1 H NMR (400 MHz, CDCl 3) δ 7.93 (d, J = 8.0 Hz, 2H), 7.89 (s, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.62 (d, J = 16.0 Hz , 7.58 (d, J = 8.8 Hz, 2H), 7.50 (t, J = 7.6 Hz, 2H), 7.15 2H), 6.78 (dd, J = 2.4, 4.0 Hz, 1H), 6.73 (d, J = 3.2 Hz, 1H), 3.87 (s, 3H), 2.22 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 193.2, 161.9, 145.5, 135.7, 135.1, 131.0, 130.8, 130.4, 129.8, 129.54, 129.48, 127.5, 123.7, 122.5, 117.1, 115.5, 114.6, 114.3, 104.2, 55.6 , 16.1; HRMS (ESI) calcd for C 26 H 22 NO 3 396.1594 ([M + H] + ), found 396.1605.

<2-51> (E)-1-(5-벤조일-6-메틸인돌리진-7-일)-3-(4-브로모페닐)프로프-2-엔-1-온 합성<2-51> Synthesis of (E) -1- (5-benzoyl-6-methylindolizin-7-yl) -3- (4-bromophenyl) prop-

화학식 3의 화합물(50 mg, 0.18 mmol)과 4-브로모벤즈알데하이드(35.0 mg, 1.05 당량)를 EtOH(1 ㎖)에 녹이고 NaOH(7.2 mg, 1 당량)와 H2O(1 ㎖)의 용액에 상온에서 첨가하였다. 상온에서 24시간 동안 저어준 후, 반응 혼합물을 10% HCl으로 산성화하고, 진공에서 농축한 다음 디클로로메탄(5 ㎖)으로 두 번 추출하였다. MgSO4로 유기물 층을 건조시키고, 감압 농축하였다. 얻은 잔사물을 실리카 겔 크로마토그래피(헥산 : 에틸아세테이트 : 디클로로메탄 = 30 : 1 : 2)로 정제하여 목적 화합물을 수득하였다.To a solution of the compound of formula 3 (50 mg, 0.18 mmol) and 4-bromobenzaldehyde (35.0 mg, 1.05 eq.) In EtOH (1 mL) was added NaOH (7.2 mg, 1 eq.) And H 2 O (1 mL) At room temperature. After stirring at room temperature for 24 h, the reaction mixture was acidified with 10% HCl, concentrated in vacuo and extracted twice with dichloromethane (5 mL). The organic layer was dried over MgSO 4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane: ethyl acetate: dichloromethane = 30: 1: 2) to obtain the target compound.

화학식 52Formula 52

Figure pat00134
Figure pat00134

노랑 고형물, mp: 148.3~148.9℃ (42.2 mg, 52.7%); 1 H NMR (400 MHz, CDCl3)δ 7.94 (s, 1H), δ 7.92 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 16.0 Hz, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.54~7.44 (m, 4H), 7.29 (d, J = 16.0 Hz, 1H), 7.06 (s, 1H), 6.79 (dd, J = 2.4, 3.6 Hz, 1H), 6.76 (d, J = 3.6 Hz, 1H), 2.24 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 193.1, 192.2, 143.7, 135.6, 135.1, 133.8, 132.4, 131.1, 130.6, 129.9, 129.8, 129.6, 128.9, 126.1, 125.0, 123.1, 117.1, 115.7, 114.7, 104.9, 16.2; HRMS (ESI) calcd for C25H19BrNO2 444.0594 ([M+H]+), found 444.0599.
Yellow solid, mp: 148.3- 148.9 캜 (42.2 mg, 52.7%); 1 H NMR (400 MHz, CDCl 3) δ 7.94 (s, 1H), δ 7.92 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 16.0 1H), 7.06 (s, 1H), 6.79 (dd, J = 8.8 Hz, 2H), 7.54 (d, J = = 2.4, 3.6 Hz, 1 H), 6.76 (d, J = 3.6 Hz, 1 H), 2.24 (s, 3H); 13 C NMR (100 MHz, CDCl 3) δ 193.1, 192.2, 143.7, 135.6, 135.1, 133.8, 132.4, 131.1, 130.6, 129.9, 129.8, 129.6, 128.9, 126.1, 125.0, 123.1, 117.1, 115.7, 114.7, 104.9 , 16.2; HRMS (ESI) calcd for C 25 H 19 BrNO 2 444.0594 ([M + H] +), found 444.0599.

실험예Experimental Example

1. 실험방법1. Experimental Method

파골세포 분화Osteoclast differentiation

ICR 5주령 생쥐의 대퇴골과 경골을 분리하고 뼈속질 공간을 1 cc 주사기로 수세하여 골수세포를 얻었다. 분리된 골수세포는 10% FBS(Gibco, Paisley, UK), 항생제, M-CSF(30 ng/㎖)가 포함된 α-MEM(Gibco, Paisley, UK) 배지에서 3일간 배양하였다. 3일 후, 부착된 세포를 대식세포(bone marrow macrophage, BMM)로 사용하였다. 파골세포로 분화를 유도하기 위하여, M-CSF(30 ng/㎖)와 RANKL(10 ng/㎖)을 첨가하여 대식세포(1 X 104 세포/웰)를 4일간 배양하였다. 3일마다 배지를 교체하였다.
Bone marrow cells were obtained by dissociating the femur and tibia of ICR 5 - week old mice and washing the subcortical space with 1 cc syringe. Separated bone marrow cells were cultured in α-MEM (Gibco, Paisley, UK) medium containing 10% FBS (Gibco, Paisley, UK), antibiotics and M-CSF (30 ng / ml) for 3 days. Three days later, adherent cells were used as bone marrow macrophages (BMM). M-CSF (30 ng / ml) and RANKL (10 ng / ml) were added to induce differentiation into osteoclasts, and macrophages (1 × 10 4 cells / well) were cultured for 4 days. The medium was changed every 3 days.

TRAP(Tartrate-resistant acid phosphatase) 염색 및 활성Tartrate-resistant acid phosphatase (TRAP) staining and activity

대식세포를 96-웰 플레이트에 1 X 104 세포/웰로 분주하여 M-CSF(30 ng/㎖), RANKL(10 ng/㎖) 및 샘플을 첨가하여 배양하였다. 4일 후, 배양한 세포를 3.7% 포름알데하이드로 10분간 고정한 뒤, 0.1% Triton X-100으로 10분간 처리하여 어두운 곳에서 TRAP 용액(Sigma, MO)으로 염색하고 붉은색으로 염색된 세포를 파골세포로 간주하였다. TRAP 활성을 측정하기 위하여, 세포를 3.7% 포름알데하이드로 10분간 고정한 뒤, 0.1% Triton X-100으로 10분간 처리하여 구연산염 버퍼(50 mM 주석산나트륨, 3 mM p-니트로페닐포스페이트, Sigma)를 100 μl 분주하였다. 1시간 동안 효소 반응 시킨 뒤, 동량의 0.1 N NaOH가 들어있는 플레이트로 옮긴 다음 405 nm에서 파장을 측정하였다.
Macrophages were cultured in 96-well plates at 1 × 10 4 cells / well and M-CSF (30 ng / ml), RANKL (10 ng / ml) and samples were added. After 4 days, the cultured cells were fixed with 3.7% formaldehyde for 10 minutes, treated with 0.1% Triton X-100 for 10 minutes, stained with TRAP solution (Sigma, MO) in the dark, Cells. To measure TRAP activity, the cells were fixed with 3.7% formaldehyde for 10 minutes and then treated with 0.1% Triton X-100 for 10 minutes to give a citrate buffer (50 mM sodium tartrate, 3 mM p-nitrophenylphosphate, Sigma) mu] l. After enzymatic reaction for 1 hour, the plate was transferred to a plate containing the same amount of 0.1 N NaOH and the wavelength was measured at 405 nm.

세포 독성 검사Cytotoxicity test

A549, PC-3 세포주를 1.5 X 105 세포/웰로, LNCap 세포주를 2 X 105 세포/웰로 96-웰에 분주하여 1일 배양하였다. 각 세포주에 샘플을 처리하여 1일과 3일 동안 배양하여 세포독성을 검사하기 위해 Cell Counting Kit-8(Dojindo Moleculer Technologies, MD)을 이용하여 450 nm에서 흡광도를 측정하였다.
A549 and PC-3 cells were plated at 1.5 × 10 5 cells / well and LNCap cell line was seeded at 96 × 10 5 cells / well for 1 day. Each cell line was treated with a sample for 1 and 3 days, and the absorbance was measured at 450 nm using Cell Counting Kit-8 (Dojindo Molecular Technologies, MD) to examine cytotoxicity.

루시페라아제(luciferase) 활성 검사Luciferase activity test

A549(β-catenin, NF-kB) 세포주를 1.5 X 105 세포/웰로, LNCap(Androgen receptor, AR) 세포주를 2 X 105 세포/웰로 96-웰에 분주하여 1일 배양하였다. 각 세포주에 샘플을 처리한뒤 배양하고, 1일 후 세포 분쇄 후 각 보고유전자에 대한 루시페라아제 활성을 측정하기 위하여 dual-luciferase assay system(Promega)을 이용하였다.
The A549 (β-catenin, NF- kB) cell line 1.5 X 10 5 cells / well, by dividing the (Androgen receptor, AR) LNCap cell lines to 2 X 10 5 cells / well 96-well and incubated one day. Each cell line was treated with a sample and cultured. After 1 day, cell lysis was performed and a dual-luciferase assay system (Promega) was used to measure the luciferase activity of each reported gene.

2. 실험결과2. Experimental results

실험결과를 하기 표 4에 나타내었다.The experimental results are shown in Table 4 below.

Figure pat00135
Figure pat00135

Figure pat00136
Figure pat00136

상기 표 4에 나타난 바와 같이, 본 발명의 인돌리진 유도체는 파골세포의 분화를 효과적으로 억제하였을 뿐만 아니라, 암세포의 사멸도 유도하였다(표 4). 이러한 결과는, 본 발명의 인돌리진 유도체를 골다공증과 같은 파골세포 관련 골 질환 및 암의 치료를 위하여 활용할 수 있음을 보여준다.
As shown in Table 4, the indolizine derivatives of the present invention not only effectively inhibited osteoclast differentiation but also induced the death of cancer cells (Table 4). These results show that the indolizine derivatives of the present invention can be utilized for the treatment of osteoclast-related bone diseases and cancers such as osteoporosis.

한편, 본 발명에 따른 상기 화학식 1의 화합물은 목적에 따라 여러 형태로 제제화가 가능하다. 하기는 본 발명의 화합물을 활성성분으로 함유시킨 몇몇 제제화 방법을 예시한 것으로, 본 발명이 이에 한정되는 것은 아니다.Meanwhile, the compound of Formula 1 according to the present invention can be formulated into various forms according to the purpose. The following examples illustrate some formulations containing the compound of the present invention as an active ingredient, but the present invention is not limited thereto.

<제제예 1> 산제의 제조&Lt; Formulation Example 1 > Preparation of powders

화학식 1의 화합물 2 g2 g &lt; RTI ID = 0.0 &gt;

유당 1 gLactose 1 g

목적 성분을 혼합하고 기밀포에 충진하여 산제를 제조하였다.
The objective components were mixed and filled in airtight bags to prepare powders.

<제제예 2> 정제의 제조&Lt; Formulation Example 2 > Preparation of tablet

화학식 1의 화합물 100 ㎎100 mg of the compound of formula (1)

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

목적 성분을 혼합한 후, 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.
After the desired components were mixed, tablets were prepared by tableting according to a conventional method for producing tablets.

<제제예 3> 캡슐제의 제조&Lt; Formulation Example 3 > Preparation of capsules

화학식 1의 화합물 100 ㎎100 mg of the compound of formula (1)

옥수수전분 100 ㎎Corn starch 100 mg

유당 100 ㎎Lactose 100 mg

스테아린산 마그네슘 2 ㎎2 mg of magnesium stearate

목적 성분을 혼합한 후, 통상의 캡슐제의 제조방법에 따라서 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.
After the objective components were mixed, they were filled in gelatin capsules according to the conventional preparation method of capsules to prepare capsules.

<제제예 4> 주사제의 제조&Lt; Formulation Example 4 > Preparation of injection

화학식 1의 화합물 100 ㎎100 mg of the compound of formula (1)

만니톨 180 ㎎180 mg mannitol

Na2HPO4ㆍ2H2O 26 ㎎Na 2 HPO 4 .2H 2 O 26 mg

증류수 2974 ㎎2974 mg of distilled water

통상적인 주사제의 제조방법에 따라, 상기 성분들을 제시된 함량으로 함유시켜 주사제를 제조하였다.
According to the conventional method for preparing an injectable preparation, an injectable preparation was prepared by incorporating the aforementioned components in the amounts indicated.

이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (13)

하기 화학식 1의 화합물 또는 이의 약학적으로 허용 가능한 염:
화학식 1
Figure pat00137

상기 화학식에서,
R1은
Figure pat00138
, 또는 시아노이고;
상기 A는 C1-C6 알킬, C1-C6 알콕시, 하이드록시, 또는 비치환되거나 할로겐 또는 C1-C6 알콕시로 치환된 페닐로 치환된 C2-C6 알케닐이거나, 또는 R2와 함께 고리를 이루어 5각-6각의 환형구조를 이루고, 이때
Figure pat00139
는 이중결합이며;
R2는 C1-C6 알킬, 아민 또는 하이드록시이거나, 또는 A와 함께 고리를 이루어 5각-6각의 환형구조를 이루고, 이때
Figure pat00140
는 이중결합이고;
R3은
Figure pat00141
가 단일결합인 경우 하이드록시, C1-C6 알킬, 또는 아민이고,
Figure pat00142
가 이중결합인 경우에는 존재하지 않으며;
R4는 비치환되거나 할로겐, C1-C6 알콕시, C1-C6 알킬 및 페닐C1-C3 알콕시로 구성된 군으로부터 선택된 1 이상의 치환기로 치환된 5각-10각 고리의 아릴 또는 헤테로아릴, 또는 C1-C6 알콕시이고;
R5는 수소,
Figure pat00143
(B는 C1-C6 알킬) 또는 -CHO이거나, 또는 R6과 함께 페닐을 형성하며;
R6은 수소 또는 C1-C6 알킬이거나, 또는 R5와 함께 페닐을 형성하고;
R7은 수소, 또는
Figure pat00144
(B는 C1-C6 알킬)이다.
Claims 1. Compounds of the general formula &lt; RTI ID = 0.0 &gt; (1) &lt; / RTI &
Formula 1
Figure pat00137

In the above formulas,
R 1 is
Figure pat00138
, Or cyano;
Wherein A is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxy, or C 2 -C 6 alkenyl unsubstituted or substituted by phenyl substituted by halogen or C 1 -C 6 alkoxy, or R 2 to form a ring and form a pentagonal-pentagonal annular structure,
Figure pat00139
Is a double bond;
R 2 is C 1 -C 6 alkyl, amine or hydroxy, or forms a ring together with A to form a pentane-6-angled cyclic structure,
Figure pat00140
Is a double bond;
R 3 is
Figure pat00141
Is a single bond when the hydroxy, C 1 -C 6 alkyl, or an amine,
Figure pat00142
Lt; / RTI &gt; is not a double bond;
R 4 is unsubstituted or substituted by halogen, C 1 -C 6 alkoxy, C 1 -C 6 -10 5 each aryl or heteroaryl each ring optionally substituted with one or more substituents selected from the group consisting of alkyl and phenyl C 1 -C 3 alkoxy Aryl, or C 1 -C 6 alkoxy;
R 5 is hydrogen,
Figure pat00143
(B is C 1 -C 6 alkyl) or -CHO, or forms together with R 6 a phenyl;
R 6 is to form a phenyl together with hydrogen or C 1 -C 6 alkyl, or R 5;
R 7 is hydrogen, or
Figure pat00144
(B is C 1 -C 6 alkyl).
제 1 항에 있어서, 상기 R2는 C1-C3 알킬 또는 아민이거나, 또는 A와 함께 고리를 이루어 6각의 환형구조를 이루고, 이때
Figure pat00145
는 이중결합이며; R3은
Figure pat00146
가 단일결합인 경우 하이드록시인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용 가능한 염.
2. The method of claim 1, wherein R 2 forms a cyclic structure is made of a hexagonal or a ring together with the C 1 -C 3 alkyl, or an amine, or A, wherein
Figure pat00145
Is a double bond; R 3 is
Figure pat00146
Lt; / RTI &gt; is hydroxy, or &lt; RTI ID = 0.0 &gt; pharmaceutically &lt; / RTI &gt; acceptable salts thereof.
제 1 항에 있어서, 상기 R4의 헤테로아릴은 티오펜인 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용 가능한 염.
2. A compound according to claim 1, wherein said heteroaryl of R &lt; 4 &gt; is thiophene or a pharmaceutically acceptable salt thereof.
제 1 항에 있어서, 상기 화학식 1의 화합물은 하기의 화학식 2 내지 57로 표시되는 화합물로 구성된 군으로부터 선택되는 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용 가능한 염.
화학식 2
Figure pat00147

화학식 3
Figure pat00148

화학식 4
Figure pat00149

화학식 5
Figure pat00150

화학식 6
Figure pat00151

화학식 7
Figure pat00152

화학식 8
Figure pat00153


화학식 9
Figure pat00154

화학식 10
Figure pat00155

화학식 11
Figure pat00156

화학식 12
Figure pat00157


화학식 13
Figure pat00158

화학식 14
Figure pat00159

화학식 15
Figure pat00160

화학식 16
Figure pat00161


화학식 17
Figure pat00162

화학식 18
Figure pat00163

화학식 19
Figure pat00164

화학식 20
Figure pat00165


화학식 21
Figure pat00166

화학식 22
Figure pat00167

화학식 23
Figure pat00168

화학식 24
Figure pat00169


화학식 25
Figure pat00170

화학식 26
Figure pat00171

화학식 27
Figure pat00172

화학식 28
Figure pat00173

화학식 29
Figure pat00174

화학식 30
Figure pat00175

화학식 31
Figure pat00176

화학식 32
Figure pat00177

화학식 33
Figure pat00178

화학식 34
Figure pat00179

화학식 35
Figure pat00180

화학식 36
Figure pat00181


화학식 37
Figure pat00182

화학식 38
Figure pat00183

화학식 39
Figure pat00184

화학식 40
Figure pat00185


화학식 41
Figure pat00186

화학식 42
Figure pat00187

화학식 43
Figure pat00188

화학식 44
Figure pat00189



화학식 45
Figure pat00190

화학식 46
Figure pat00191

화학식 47
Figure pat00192

화학식 48
Figure pat00193



화학식 49
Figure pat00194

화학식 50
Figure pat00195

화학식 51
Figure pat00196

화학식 52
Figure pat00197

The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula (1) is selected from the group consisting of compounds represented by the following formulas (2) to (57).
(2)
Figure pat00147

(3)
Figure pat00148

Formula 4
Figure pat00149

Formula 5
Figure pat00150

6
Figure pat00151

Formula 7
Figure pat00152

8
Figure pat00153


Formula 9
Figure pat00154

10
Figure pat00155

Formula 11
Figure pat00156

Formula 12
Figure pat00157


Formula 13
Figure pat00158

Formula 14
Figure pat00159

Formula 15
Figure pat00160

Formula 16
Figure pat00161


Formula 17
Figure pat00162

18
Figure pat00163

Formula 19
Figure pat00164

20
Figure pat00165


Formula 21
Figure pat00166

Formula 22
Figure pat00167

Formula 23
Figure pat00168

24
Figure pat00169


25
Figure pat00170

26
Figure pat00171

27
Figure pat00172

28
Figure pat00173

Formula 29
Figure pat00174

Formula 30
Figure pat00175

31
Figure pat00176

(32)
Figure pat00177

Formula 33
Figure pat00178

(34)
Figure pat00179

(35)
Figure pat00180

Formula 36
Figure pat00181


37
Figure pat00182

Formula 38
Figure pat00183

39
Figure pat00184

40
Figure pat00185


Formula 41
Figure pat00186

Formula 42
Figure pat00187

Formula 43
Figure pat00188

44
Figure pat00189



Formula 45
Figure pat00190

Formula 46
Figure pat00191

Formula 47
Figure pat00192

48
Figure pat00193



Formula 49
Figure pat00194

50
Figure pat00195

Formula 51
Figure pat00196

Formula 52
Figure pat00197

 제 4 항에 있어서, 상기 화학식 1의 화합물은 화학식 3-5, 9, 10, 13-15, 18, 19, 22-24, 27, 34, 35, 37, 38 및 41-48로 표시되는 화합물로 구성된 군으로부터 선택되는 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용 가능한 염.
The compound according to claim 4, wherein the compound represented by Formula 1 is a compound represented by Formula 3-5, 9, 10, 13-15, 18, 19, 22-24, 27, 34, 35, 37, 38, &Lt; / RTI &gt; or a pharmaceutically acceptable salt thereof.
(a) 제 1 항 내지 제 5 항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염의 약학적 유효량; 및 (b) 약학적으로 허용 가능한 담체를 포함하는 골 질환의 예방 또는 치료용 약학적 조성물.
(a) a pharmaceutically effective amount of a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof; And (b) a pharmaceutically acceptable carrier.
제 6 항에 있어서, 상기 골 질환은 골다공증, 파제트병, 골절, 치주염, 골 성장 장애, 원발성 골종양, 암의 골전이, 골 전이암 및 류마티스 관절염으로 구성된 군으로부터 선택되는 것을 특징으로 하는 약학적 조성물.
The pharmaceutical composition according to claim 6, wherein the bone disease is selected from the group consisting of osteoporosis, Paget's disease, fracture, periodontitis, bone growth disorder, primary bone tumor, bone metastasis of cancer, bone metastatic cancer and rheumatoid arthritis Composition.
(a) 제 1 항 내지 제 5 항 중 어느 한 항의 화합물 또는 이의 약학적으로 허용 가능한 염의 약학적 유효량; 및 (b) 약학적으로 허용 가능한 담체를 포함하는 암의 예방 또는 치료용 약학적 조성물.
(a) a pharmaceutically effective amount of a compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof; And (b) a pharmaceutically acceptable carrier.
제 8 항에 있어서, 상기 암은 폐암, 전립선암, 위암, 대장암, 유방암, 간암, 결장암 및 자궁경부암으로 구성된 군으로부터 선택되는 것을 특징으로 하는 약제학적 조성물.
9. The pharmaceutical composition according to claim 8, wherein the cancer is selected from the group consisting of lung cancer, prostate cancer, stomach cancer, colon cancer, breast cancer, liver cancer, colon cancer and cervical cancer.
하기 반응식 1에 나타난 바와 같이, 하기 화학식 58의 피롤-2-카복스알데하이드 유도체를 화합물 A 내지 F로 구성된 군으로부터 선택된 화합물과 반응시켜 도미노 크뇌베나겔 축합 및 분자 내 알돌 고리화 반응을 통하여 화학식 1의 화합물을 제조하는 방법:
반응식 1
Figure pat00198

상기 반응식에서,
상기 R1 내지 R7은 제 1 항에서 정의한 바와 같으며;
화합물 A는
Figure pat00199
이고;
화합물 B는
Figure pat00200
이며;
화합물 C는
Figure pat00201
이고;
화합물 D는
Figure pat00202
이며;
화합물 E는
Figure pat00203
이고;
화합물 F는
Figure pat00204
이다.
Reacting a pyrrole-2-carboxaldehyde derivative of the following formula (58) with a compound selected from the group consisting of Compounds A to F as shown in Reaction Scheme 1 below to produce a compound of formula (1) through dominoquinbenergic condensation and intramolecular aldol condensation, Lt; RTI ID = 0.0 &gt; of:
Scheme 1
Figure pat00198

In the above reaction formula,
Wherein R 1 to R 7 are as defined in claim 1;
Compound A
Figure pat00199
ego;
Compound B is
Figure pat00200
;
Compound C is
Figure pat00201
ego;
Compound D is
Figure pat00202
;
Compound E is
Figure pat00203
ego;
Compound F is
Figure pat00204
to be.
제 10 항에 있어서, 상기 화학식 58의 화합물은 하기 화학물 a 내지 k로 구성된 군으로부터 선택되는 화합물인 것을 특징으로 하는 제조방법.
화합물 a
Figure pat00205

화합물 b
Figure pat00206

화합물 c
Figure pat00207

화합물 d
Figure pat00208

화합물 e
Figure pat00209

화합물 f
Figure pat00210

화합물 g
Figure pat00211

화합물 h
Figure pat00212

화합물 i
Figure pat00213

화합물 j
Figure pat00214

화합물 k
Figure pat00215

11. The process according to claim 10, wherein the compound of formula (58) is a compound selected from the group consisting of the following compounds a to k.
The compound a
Figure pat00205

Compound b
Figure pat00206

Compound c
Figure pat00207

Compound d
Figure pat00208

Compound e
Figure pat00209

Compound f
Figure pat00210

Compound g
Figure pat00211

Compound h
Figure pat00212

Compound i
Figure pat00213

Compound j
Figure pat00214

Compound k
Figure pat00215

 제 10 항에 있어서, 상기 반응의 촉매는 피페리디늄 아세테이트(piperidinium acetate)인 것을 특징으로 하는 제조방법.
11. The process according to claim 10, wherein the catalyst of the reaction is piperidinium acetate.
제 10 항에 있어서, 상기 반응의 용매는 에탄올인 것을 특징으로 하는 제조방법.11. The process according to claim 10, wherein the solvent of the reaction is ethanol.
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WO2022188876A1 (en) * 2021-03-11 2022-09-15 浙江大学 Fused ring heterocyclic compound and application thereof, and pharmaceutical composition containing same and application thereof
WO2022191656A1 (en) * 2021-03-11 2022-09-15 연세대학교 산학협력단 Novel indolizine derivative and composition for prevention or treatment of cancer comprising same
WO2022216101A1 (en) * 2021-04-09 2022-10-13 연세대학교 산학협력단 Novel indolizine derivative, and composition for preventing or treating fibrosis, comprising same

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Publication number Priority date Publication date Assignee Title
WO2022188876A1 (en) * 2021-03-11 2022-09-15 浙江大学 Fused ring heterocyclic compound and application thereof, and pharmaceutical composition containing same and application thereof
WO2022191656A1 (en) * 2021-03-11 2022-09-15 연세대학교 산학협력단 Novel indolizine derivative and composition for prevention or treatment of cancer comprising same
KR20220127570A (en) * 2021-03-11 2022-09-20 연세대학교 산학협력단 Novel Indolizine Derivatives and A Composition for Treating or Preventing Cancer Comprising the Same
WO2022216101A1 (en) * 2021-04-09 2022-10-13 연세대학교 산학협력단 Novel indolizine derivative, and composition for preventing or treating fibrosis, comprising same
KR20220140268A (en) * 2021-04-09 2022-10-18 연세대학교 산학협력단 Novel Indolizine Derivatives and A Composition for Treating or Preventing Fibrosis Comprising the Same

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