KR20230068335A - Glutarimide moiety based isoindolinone derivatives and use thereof - Google Patents

Glutarimide moiety based isoindolinone derivatives and use thereof Download PDF

Info

Publication number
KR20230068335A
KR20230068335A KR1020220148244A KR20220148244A KR20230068335A KR 20230068335 A KR20230068335 A KR 20230068335A KR 1020220148244 A KR1020220148244 A KR 1020220148244A KR 20220148244 A KR20220148244 A KR 20220148244A KR 20230068335 A KR20230068335 A KR 20230068335A
Authority
KR
South Korea
Prior art keywords
compound
methyl
oxoisoindolin
dioxopiperidin
carboxamide
Prior art date
Application number
KR1020220148244A
Other languages
Korean (ko)
Inventor
황종연
조성윤
하재두
김필호
박지훈
김현진
조용희
듀우 악셰이
Original Assignee
한국화학연구원
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한국화학연구원 filed Critical 한국화학연구원
Priority to EP22893205.9A priority Critical patent/EP4431505A1/en
Priority to CN202280074437.2A priority patent/CN118234721A/en
Priority to PCT/KR2022/017592 priority patent/WO2023085785A1/en
Publication of KR20230068335A publication Critical patent/KR20230068335A/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Transplantation (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to an isoindolinone derivative compound having a glutarimide mother nucleus, and the application thereof and, more specifically, to an isoindolinone derivative compound having a glutarimide mother nucleus having a thalidomide analog. The compound of chemical formula 1 according to the present invention specifically binds to the CRBN protein and is involved in functions thereof. Thus, the compound of the present invention can be beneficially used in the prevention or treatment of leprosy, chronic graft versus host disease, inflammatory diseases, or cancer that are caused by actions of the CRBN protein.

Description

글루타이미드 모핵을 갖는 이소인돌리논 유도체 및 이의 용도 {Glutarimide moiety based isoindolinone derivatives and use thereof}Isoindolinone derivatives having glutimide moiety and use thereof

글루타이미드 모핵을 갖는 이소인돌리논 유도체 및 이의 용도에 관한 것으로, 보다 상세하게는 나병, 만성 이식편대숙주병, 염증성 질환 또는 암의 예방 또는 치료효과를 나타내는 글루타이미드 모핵을 갖는 이소인돌리논 유도체 화합물에 관한 것이다.It relates to an isoindolinone derivative having a glutimide parent nucleus and uses thereof, and more particularly, an isoindole having a glutimide parent nucleus that exhibits an effect of preventing or treating leprosy, chronic graft versus host disease, inflammatory disease or cancer. It relates to a paddy derivative compound.

탈리도마이드는 상표명 탈로미드(THALOMID (등록상표)) 및 α-(N-프탈이미도)글루타리미드 또는 2-(2,6-디옥소3-피페리디닐)-lH-이소인돌-1,3(2H)-디온의 화학명으로 판매되는 라세미 화합물이다. 탈리도마이드는 원래 아침병(morning sickness, 입덧)을 치료하기 위하여 개발되었으나, 기형발생 효과로 인하여 사용 중단되었다. 탈리도마이드는 현재 인간의 나병 결절 홍반 치료에 있어서 미국에서 승인되었다(한국등록특허 제10-0671366호).Thalidomide has the trade name THALOMID (registered trademark) and α-(N-phthalimido)glutarimide or 2-(2,6-dioxo3-piperidinyl)-lH-isoindole-1,3 It is a racemic compound sold under the chemical name of (2H)-dione. Thalidomide was originally developed to treat morning sickness, but was discontinued due to teratogenic effects. Thalidomide is currently approved in the United States for the treatment of erythema leprosy nodosum in humans (Korean Patent Registration No. 10-0671366).

또한, 탈리도마이드는 나병, 만성 이식편대숙주병, 류마티스 관절염, 사르코이드증, 몇몇 염증성 피부 질환 및 염증성 장질환 환자에게 사용된다고 보고된 바 있으며, 탈리도마이드는 심장 및 뇌동맥 폐쇄 관련 허혈/재관류를 치료하기 위하여 다른 약물과 조합할 수 있다고 보고된 바 있다(미국등록특허 제05643915호).In addition, thalidomide has been reported to be used in patients with leprosy, chronic graft-versus-host disease, rheumatoid arthritis, sarcoidosis, some inflammatory skin diseases and inflammatory bowel diseases, and thalidomide is used to treat ischemia/reperfusion associated with heart and cerebral artery occlusion. It has been reported that it can be combined with other drugs (US Patent No. 05643915).

보다 최근에, 탈리도마이드는 특정 유형의 암 치료에 사용되었다. 이는 불응성 다발성 골수종, 뇌, 흑색종, 유방, 결장, 중피종 및 신세포 암종을 포함한다. 탈리도마이드는 추가로 래트에서 독소루비신에 의하여 유발된 만성 심근병증의 발현을 예방하는데 사용된다고 보고되었다. 특정 암의 치료에서의 탈리도마이드의 용도에 관한 다른 보고는 다형성 교모세포증의 치료시 카르보플라틴과의 병용을 포함한다. 탈리도마이드는 또한 성상세포종 치료 시의 진통제로서 사용된다고 보고되었다(Costa, P. T. et al., Blood, 92(Suppl 1, Pt 2), 235b, 1998; Marx, G. M. et al., Proc Am Soc Clin Oncol., 454a, 1999; Singhal, S. et al., N Engl J Med., 341(21), 1565-1571, 1999; Zwart, D., Arzneimittelforschung, 16(12), 1688-1689, 1966). More recently, thalidomide has been used to treat certain types of cancer. These include refractory multiple myeloma, brain, melanoma, breast, colon, mesothelioma and renal cell carcinoma. It has been further reported that thalidomide is used to prevent the development of doxorubicin-induced chronic cardiomyopathy in rats. Other reports of the use of thalidomide in the treatment of certain cancers include its use with carboplatin in the treatment of glioblastosis multiforme. Thalidomide has also been reported to be used as an analgesic in the treatment of astrocytoma (Costa, P. T. et al., Blood, 92 (Suppl 1, Pt 2), 235b, 1998; Marx, G. M. et al., Proc Am Soc Clin Oncol. , 454a, 1999; Singhal, S. et al., N Engl J Med., 341(21), 1565-1571, 1999; Zwart, D., Arzneimittelforschung, 16(12), 1688-1689, 1966).

이외에도, 탈리도마이드는 루프스 신염, 섬유근육통, 정신분열증, 중추신경계 질환, 당뇨병, 염증성 질환 등의 예방 또는 치료 목적으로 다양하게 활용이 되고 있으나, 이를 복용한 임산부에게서 기형아가 유발되는 치명적인 부작용으로 인해 1961년 말 시장에서 철수된 이력을 갖고 있다.In addition, thalidomide is widely used for the prevention or treatment of lupus nephritis, fibromyalgia, schizophrenia, central nervous system diseases, diabetes, inflammatory diseases, etc. It has a history of being withdrawn from the horse market.

탈리도마이드의 다양한 생리학적 유용성은 그대로 보유하면서, 심각한 부작용의 문제가 해소된 유도체를 개발하기 위한 연구가 활발하게 진행되고 있다.Research is being actively conducted to develop derivatives of thalidomide that have various physiological usefulness intact and have no serious side effects.

세포내 단백질의 분해는 주로 유비퀴틴-프로테아좀 시스템 (Ubiquitin-proteasome system, UPS)을 통해서 일어난다. E1, E2, E3 리가아제라 불리는 단백질이 76개의 아미노산으로 이루어진 유비퀴틴 (Ub)을 분해하고자 하는 단백질 (substrate)에 전달하여 polyubiquitination 시키면, 26S 프로테아좀 (proteasome)이 이를 인지하여 단백질을 분해한다.Degradation of intracellular proteins occurs mainly through the ubiquitin-proteasome system (UPS). When proteins called E1, E2, and E3 ligases deliver ubiquitin (Ub) consisting of 76 amino acids to a protein to be degraded (substrate) for polyubiquitination, the 26S proteasome recognizes it and degrades the protein.

Immunomodulatory drug (IMiDs)로 알려진 탈리도마이드 (thalidomide)의 유도체인 레날리도마이드 (lenalidomide), 포말리도마이드 (pomalidomide)는 세레브론 (cerebron, CRBN)이라는 E3 리가아제에 결합하여 zinc finger transcription factor 인 ikaros (IKZF1), aiolos (IKZF3)의 분해를 유도하여 다발성 골수종 (multiple myeloma) 치료제로 사용된다. 특히 레날리도마이드는 CK-1a를 분해시켜 5q-del-MDS 환자 치료제로도 사용되며 전 세계적으로 많이 팔리는 항암제 중에 하나이다.Lenalidomide and pomalidomide, derivatives of thalidomide known as Immunomodulatory drugs (IMiDs), bind to the E3 ligase called cerebron (CRBN) to produce the zinc finger transcription factor ikaros ( IKZF1) and aiolos (IKZF3), which are used as a treatment for multiple myeloma. In particular, lenalidomide decomposes CK-1a and is also used as a treatment for 5q-del-MDS patients, and is one of the world's most popular anticancer drugs.

GSPT1은 GTPase로써 GTP 결합 하에 eRF1과 복합체를 형성하여 mRNA의 stop codon에 결합하며, GTP가 GDP로 바뀌면 eRF1으로부터 분리됨으로서 eRF1에 의한 단백질 절단에 관여한다(Cell Reports, 2014, 8, 59-65).GSPT1 is a GTPase that forms a complex with eRF1 under GTP binding and binds to the stop codon of mRNA. When GTP is changed to GDP, it is separated from eRF1 and is involved in protein cleavage by eRF1 (Cell Reports, 2014, 8, 59-65) .

GSPT1 knockdown 시, 4E-BP1과 kinase S6K1의 인산화 (phosphorylation)을 감소시켜 mTOR의 활성이 억제되고 G1 arrest를 유도하는 것으로 알려져있다(Molecular and cellular biology, 2007, 27, 5619).Upon GSPT1 knockdown, phosphorylation of 4E-BP1 and kinase S6K1 is reduced, mTOR activity is suppressed, and G1 arrest is known to be induced (Molecular and cellular biology, 2007, 27, 5619).

GSPT1은 대장암 세포주 (HCT116)에 과발현, 세포 성장과 이동에 관여, GSPT1 knockdown시켰을 때 c-myc, survivin과 Bcl2L15의 발현을 억제하여 세포 사멸을 유도함을 확인하였다(Biomed. Pharmacother. 2015, 74, 138-144).GSPT1 was overexpressed in the colorectal cancer cell line (HCT116), involved in cell growth and migration, and when GSPT1 was knocked down, it was confirmed that c-myc, survivin, and Bcl2L15 expression were suppressed to induce apoptosis (Biomed. Pharmacother. 2015, 74, 2015). 138-144).

또한 셀진사는 레날리도마이드로부터 유래된 CC-885 화합물이 새로운 단백질인 GSPT1를 분해하여 다양한 혈액암 세포에서 높은 세포독성 보임을 보고하였고, 최적화 연구를 통해 CC-90009 물질을 도출하여 R,R-AML 환자를 대상으로 임상 1상을 진행중이다(Nature, 2016, 14, 252; Blood, 2021).In addition, Celjin reported that the CC-885 compound derived from lenalidomide degraded GSPT1, a new protein, and showed high cytotoxicity in various hematological cancer cells. -Phase 1 clinical trials for AML patients are underway (Nature, 2016, 14, 252; Blood, 2021).

탈리도마이드가 나타내는 생리학적 활성은 그대로 보유하면서 탈리도마이드가 나타내는 부작용이 없는 피페리딘-2,6-디온 기반의 신규한 탈리도마이드 유도체를 개발하고, 이 화합물이 GSPT1 단백질 및 Aiolos에 대한 단백질 분해를 촉진하는 것을 확인하였다. 또한 상기 개발된 화합물들은 암세포에서 충분한 세포독성을 가지며, 특히 유레아 유도체가 치환된 화합물과 트리아진 유도체 화합물의 경우 암세포에 대한 세포독성활성이 보다 더 우수함을 확인할 수 있었다(한국공개특허 제10-2020-0054046호).Developing a novel thalidomide derivative based on piperidine-2,6-dione that retains the physiological activity of thalidomide and has no side effects of thalidomide, and demonstrates that this compound promotes proteolysis of GSPT1 and Aiolos. Confirmed. In addition, the developed compounds have sufficient cytotoxicity in cancer cells, and in particular, in the case of urea derivative-substituted compounds and triazine derivative compounds, it was confirmed that the cytotoxic activity against cancer cells was more excellent (Korean Patent Publication No. 10-2020 -0054046).

또한, 5-치환된 이소인돌린 화합물이 TNF-α 억제 효과, IL-2 생성 효과 뿐만 아니라 전립선, 결장, 췌장 및 유방 종양을 포함한 다양한 암 세포에 대한 항증식성 효과를 나타낸다고 보고되었으며(한국공개특허 제10-2011-0019761호), 이소인돌린 화합물이 혈관신생 제어, TNF-α 등 특정 시토카인의 생성 억제, IL-10 등 특정 시토카인의 생성 자극을 통해 암을 포함한 다양한 질환에 효과를 나타낸다고 보고되었다(한국등록특허 제10-1696938호).In addition, it has been reported that 5-substituted isoindoline compounds exhibit antiproliferative effects on various cancer cells including prostate, colon, pancreatic and breast tumors as well as TNF-α inhibitory effect and IL-2 production effect (Korean Publication). Patent No. 10-2011-0019761) reported that isoindoline compounds exert effects on various diseases including cancer by controlling angiogenesis, inhibiting the production of specific cytokines such as TNF-α, and stimulating the production of specific cytokines such as IL-10 (Korean Patent Registration No. 10-1696938).

또한, 이소인돌리논과 글루타이미드를 가지는 화합물을 투여하여 암을 포함한 다양한 질환을 예측 및 치료하는 방법이 보고되었으며(한국공개특허 10-2018-0095094호), 아미노 아미드 링커를 갖는 화합물이 사이토카인, TNF-α, GSPT1 등 다양한 단백질 활성의 조절제로 작용하여 염증성 질환 및 암과 같은 다양한 질환 치료에 효과를 나타낸다고 보고된 바 있다(호주공개특허 제 2019284608호).In addition, a method for predicting and treating various diseases including cancer by administering a compound having isoindolinone and glutimide has been reported (Korean Patent Publication No. 10-2018-0095094), and a compound having an amino amide linker is a cytokine , TNF-α, it has been reported to act as a modulator of various protein activities such as GSPT1 to show effects in the treatment of various diseases such as inflammatory diseases and cancer (Australian Patent Publication No. 2019284608).

본 발명자들은 이러한 기존 선행특허의 개발된 화합물과 대비하여 글루타이미드기와 이소인돌리논 구조를 가지는 본 발명의 화학식 1로 나타내는 화합물은 헤테로아릴에 아릴 치환체가 존재할 때 활성이 우수했으며, 특히 단고리형태의 헤테로아릴일 때 보다 이중고리 형태의 헤테로아릴일 때와 아릴기가 치환된 단고리형태의 헤테로아릴인 경우에 암세포에 대한 우수한 생리활성을 보임을 확인함으로써 본 발명을 완성할 수 있었다.Compared to the compounds developed in these existing prior patents, the present inventors found that the compound represented by Formula 1 of the present invention having a glutimide group and an isoindolinone structure was excellent in activity when an aryl substituent was present in the heteroaryl, especially in a monocyclic form The present invention could be completed by confirming that the heteroaryl of a double ring type heteroaryl and the case of a monocyclic heteroaryl in which an aryl group is substituted showed excellent physiological activity against cancer cells.

한국등록특허 제10-0671366호, 탈리도마이드의 제약 조성물 및 투여 형태, 2007년 01월 12일, 등록.Korean Patent Registration No. 10-0671366, Pharmaceutical composition and dosage form of thalidomide, registered on January 12, 2007. 미국등록특허 제05643915호, Treatment of ischemia/reperfusion injury with thalidomide alone or in combination with other therapies, 1997년 07월 01일, 등록.US Patent No. 05643915, Treatment of ischemia/reperfusion injury with thalidomide alone or in combination with other therapies, registered on July 01, 1997. 한국공개특허 제10-2020-0054046호, 신규한 피페리딘-2,6-디온 유도체 및 이의 용도, 2020년 05월 19일, 공개.Korean Patent Publication No. 10-2020-0054046, Novel piperidine-2,6-dione derivative and use thereof, published on May 19, 2020. 한국공개특허 제10-2011-0019761호, 5-치환된 이소인돌린 화합물, 2011년 02월 28일, 공개.Korean Patent Publication No. 10-2011-0019761, 5-substituted isoindoline compound, published on February 28, 2011. 한국등록특허 제10-1696938호, 암의 치료에 사용하기 위한 이소인돌린 화합물, 2017년 01월 10일, 등록.Korean Patent Registration No. 10-1696938, Isoindoline compound for use in the treatment of cancer, registered on January 10, 2017. 한국공개특허 10-2018-0095094호, 암을 치료하기 위한 방법 및 치료요법에 대한 임상 감수성의 예측변수로서 바이오마커의 용도, 2018년 08월 24일, 공개.Korean Patent Publication No. 10-2018-0095094, method for treating cancer and use of biomarkers as predictors of clinical sensitivity to therapy, published on August 24, 2018. 호주공개특허 제 2019284608호, Aminoamide compounds, 2019년 12월 19일, 공개.Australian Patent Publication No. 2019284608, Aminoamide compounds, published on December 19, 2019.

Chamberlain, P. P. et al., Nat Struct Mol Biol., 21(9), 803-809, 2014 Chamberlain, P. P. et al., Nat Struct Mol Biol., 21(9), 803-809, 2014 Chamberlain, P. P. et al., Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs, Nat Struct Mol Biol., 21(9), 803-809, 2014. Chamberlain, P. P. et al., Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs, Nat Struct Mol Biol., 21(9), 803-809, 2014. Costa, P. T. et al., Thalidomide and pentoxifylline prevent the development of chronic cardiomyopathy provoked by doxorubicin in rats without inhibiting its antitumoral effect, Blood, 92(Suppl 1, Pt 2), 235b, 1998. Costa, P. T. et al., Thalidomide and pentoxifylline prevent the development of chronic cardiomyopathy provoked by doxorubicin in rats without inhibiting its antitumoral effect, Blood, 92(Suppl 1, Pt 2), 235b, 1998. Marx, G. M. et al., A phase I/II trial of thalidomide as an antiangiogenic agent in the treatment of advanced cancer, Proc Am Soc Clin Oncol., 454a, 1999.Marx, G. M. et al., A phase I/II trial of thalidomide as an antiangiogenic agent in the treatment of advanced cancer, Proc Am Soc Clin Oncol., 454a, 1999. Matyskiela, M. E. et al., A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase, Nature, 535(7611), 252-257, 2016. Matyskiela, M. E. et al., A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase, Nature, 535(7611), 252-257, 2016. Singhal, S. et al., Antitumor activity of thalidomide in refractory multiple myeloma, N Engl J Med., 341(21), 1565-1571, 1999.Singhal, S. et al., Antitumor activity of thalidomide in refractory multiple myeloma, N Engl J Med., 341(21), 1565-1571, 1999. Zwart, D., Clinical observations in the influence of thalidomide in the treatment of a leiomyoma in a dog, Arzneimittelforschung, 16(12), 1688-1689, 1966.Zwart, D., Clinical observations in the influence of thalidomide in the treatment of a leiomyoma in a dog, Arzneimittelforschung, 16(12), 1688-1689, 1966. Preis, Anne, et al. Cryoelectron microscopic structures of eukaryotic translation termination complexes containing eRF1-eRF3 or eRF1-ABCE1, Cell reports, 8(1), 59-65, 2014.Preis, Anne, et al. Cryoelectron microscopic structures of eukaryotic translation termination complexes containing eRF1-eRF3 or eRF1-ABCE1, Cell reports, 8(1), 59-65, 2014. Chauvin, Celine, et al. Human eukaryotic release factor 3a depletion causes cell cycle arrest at G1 phase through inhibition of the mTOR pathway, Molecular and cellular biology, 27(16), 5619-5629, 2007.Chauvin, Celine, et al. Human eukaryotic release factor 3a depletion causes cell cycle arrest at G1 phase through inhibition of the mTOR pathway, Molecular and cellular biology, 27(16), 5619-5629, 2007. Xiao, Ruilin, et al. miRNA-144 suppresses proliferation and migration of colorectal cancer cells through GSPT1, Biomedicine & Pharmacotherapy 74, 138-144, 2015.Xiao, Ruilin, et al. miRNA-144 suppresses proliferation and migration of colorectal cancer cells through GSPT1, Biomedicine & Pharmacotherapy 74, 138-144, 2015. Surka, Christine, et al. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells, Blood, The Journal of the American Society of Hematology 137.5, 661-677, 2021.Surka, Christine, et al. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells, Blood, The Journal of the American Society of Hematology 137.5, 661-677, 2021.

본 발명자들은 나병, 만성 이식편대숙주병, 염증성 질환 또는 암의 예방 또는 치료효과를 나타내는 글루타이미드 모핵을 갖는 이소인돌리논 유도체 화합물을 개발하고 이의 활성을 평가함으로써 본 발명을 완성하게 되었다.The present inventors have completed the present invention by developing an isoindolinone derivative compound having a glutimide moiety that exhibits preventive or therapeutic effects on leprosy, chronic graft-versus-host disease, inflammatory disease or cancer, and evaluating its activity.

따라서, 본 발명의 목적은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.Accordingly, an object of the present invention is to provide a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.

본 발명은 하기 화학식 1로 표시되는 화합물, 이의 광학이성질체, 또는 이의 약학적으로 허용 가능한 염에 관한 것이다:The present invention relates to a compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

[화학식 1][Formula 1]

Figure pat00001
Figure pat00001

상기 식에서,In the above formula,

l은 0 내지 3의 정수이며;l is an integer from 0 to 3;

n은 0 또는 1의 정수이며;n is an integer of 0 or 1;

p는 1 또는 2의 정수이며;p is an integer of 1 or 2;

R1은 C5-13 헤테로아릴, C6-10 아릴, C4-10 시클로알킬, C4-10 헤테로시클로알킬이며;R 1 is C 5-13 heteroaryl, C 6-10 aryl, C 4-10 cycloalkyl, C 4-10 heterocycloalkyl;

R2는 독립적으로 수소, 할로겐, 케톤, C1-5알킬, C1-3알콕시, 할로C1-3알킬, 할로C1-3알콕시, C3-6사이클로알킬, 치환 또는 비치환된 페닐 및 치환 또는 비치환된 벤질로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되고,R 2 is independently hydrogen, halogen, ketone, C 1-5 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl, haloC 1-3 alkoxy, C 3-6 cycloalkyl, substituted or unsubstituted phenyl And substituted with one or more substituents selected from the group consisting of substituted or unsubstituted benzyl,

여기서 상기 치환된 페닐 또는 벤질은 할로겐 또는 C1-5알킬로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;wherein the substituted phenyl or benzyl is substituted with one or more substituents selected from the group consisting of halogen or C 1-5 alkyl;

R3는 수소 또는 중수소(D; deuterium)로 치환;된다.R 3 is substituted with hydrogen or deuterium (D);

또한, 본 발명은 바람직하게는 상기 화학식 1에 있어서,In addition, the present invention is preferably in the formula (1),

l은 0 내지 3의 정수이며;l is an integer from 0 to 3;

n은 0 또는 1의 정수이며;n is an integer of 0 or 1;

p는 1 또는 2의 정수이며;p is an integer of 1 or 2;

R1은 피롤일, 피라졸일, 이미다졸일, 이속사졸일, 트리아졸일, 피리딘일, 피라진일, 피리미딘일, 인돌일, 인다졸일, 벤조이미다졸일, 벤조푸란일, 벤조피리딘일, 벤조피란일, 벤조피리다진일, 벤조이속사졸일, 벤조옥사졸일, 벤조티아졸일, 벤조티오펜일 및 나프토푸란일로 이루어진 군에서 선택되는 1종의 치환기로 치환되며;R 1 is pyrroleyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl; pyrimidinyl, indolyl, indazolyl, benzoimidazolyl, benzofuranyl, benzopyridinyl, benzopyranyl, benzopyridazinyl, benzoisoxazolyl, benzooxazolyl, benzothiazolyl, benzothiophenyl and It is substituted with one substituent selected from the group consisting of naphthofuranyl;

R2는 독립적으로 수소, 할로겐, 케톤, C1-5알킬, 치환 또는 비치환된 페닐, 치환 또는 비치환된 벤질, C1-3알콕시, 할로C1-3알킬 및 할로C1-3알콕시로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되고,R 2 is independently hydrogen, halogen, ketone, C 1-5 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, C 1-3 alkoxy, haloC 1-3 alkyl and haloC 1-3 alkoxy Substituted with one or more substituents selected from the group consisting of

여기서 상기 치환된 페닐 또는 벤질은 할로겐 또는 C1-5알킬로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며; wherein the substituted phenyl or benzyl is substituted with one or more substituents selected from the group consisting of halogen or C 1-5 alkyl;

R3는 수소 또는 중수소(D; deuterium)로 치환;R 3 is substituted with hydrogen or deuterium;

되는 것을 특징으로 하는 화합물, 이의 광학이성질체 또는 이의 약학적으로 허용 가능한 염에 관한 것이다.It relates to a compound characterized in that it is, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

또한 본 발명은 바람직하게는 상기 화학식 1에 있어서,In addition, the present invention is preferably in the formula (1),

l은 0 내지 3의 정수이며;l is an integer from 0 to 3;

n은 0 또는 1의 정수이며;n is an integer of 0 or 1;

p는 1 또는 2의 정수이며;p is an integer of 1 or 2;

R1은 C5-10 헤테로아릴이며;R 1 is C 5-10 heteroaryl;

R2는 치환 또는 비치환된 페닐 및 치환 또는 비치환된 벤질로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되고,R 2 is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted benzyl;

여기서 상기 치환된 페닐 또는 벤질은 할로겐 또는 C1-5알킬로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며:wherein the substituted phenyl or benzyl is substituted with one or more substituents selected from the group consisting of halogen or C 1-5 alkyl:

R3는 수소 또는 중수소(D; deuterium)로 치환; R 3 is substituted with hydrogen or deuterium;

되는 것을 특징으로 하는 화합물, 이의 광학이성질체 또는 이의 약학적으로 허용 가능한 염에 관한 것이다.It relates to a compound characterized in that it is, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

또한, 본 발명은 바람직하게는 상기 화학식 1에 있어서,In addition, the present invention is preferably in the formula (1),

l은 0 내지 3의 정수이며;l is an integer from 0 to 3;

n은 0 또는 1의 정수이며;n is an integer of 0 or 1;

p는 1 또는 2의 정수이며;p is an integer of 1 or 2;

R1은 피롤일, 피라졸일, 이미다졸일, 이속사졸일, 트리아졸일, 피리딘일, 피라진일, 피리미딘일, 인돌일, 인다졸일, 벤조이미다졸일, 벤조푸란일, 벤조피리딘일, 벤조피란일, 벤조피리다진일, 벤조이속사졸일, 벤조옥사졸일, 벤조티아졸일, 벤조티오펜일 및 나프토푸란일로 이루어진 군에서 선택되는 1종의 치환기로 치환되며:R 1 is pyrroleyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl; pyrimidinyl, indolyl, indazolyl, benzoimidazolyl, benzofuranyl, benzopyridinyl, benzopyranyl, benzopyridazinyl, benzoisoxazolyl, benzooxazolyl, benzothiazolyl, benzothiophenyl and It is substituted with one substituent selected from the group consisting of naphthofuranyl:

R2는 치환 또는 비치환된 페닐 및 치환 또는 비치환된 벤질로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되고,R 2 is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted benzyl;

여기서 상기 치환된 페닐 또는 벤질은 할로겐 또는 C1-5알킬로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며:wherein the substituted phenyl or benzyl is substituted with one or more substituents selected from the group consisting of halogen or C 1-5 alkyl:

R3는 수소 또는 중수소(D; deuterium)로 치환; R 3 is substituted with hydrogen or deuterium;

되는 것을 특징으로 하는 화합물, 이의 광학이성질체 또는 이의 약학적으로 허용 가능한 염에 관한 것이다.It relates to a compound characterized in that it is, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

본 발명의 상기 화학식 1의 화합물을 보다 구체적으로 예시하면, When the compound of Formula 1 of the present invention is more specifically exemplified,

6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드(화합물 1);6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxamide (compound One);

3-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드(화합물 2);3-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol-5- carboxamide (Compound 2);

5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-벤조[d]이미다졸-2-카르복사미드(화합물 3);5-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-benzo[d]imidazole-2-carb copy mid (compound 3);

5,6-디클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드(화합물 4);5,6-Dichloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxamide (Compound 4);

3-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드(화합물 5);3-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol-5- carboxamide (Compound 5);

6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인돌-3-카르복사미드(화합물 6);6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indole-3-carboxamide (Compound 6 );

5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인돌-3-카르복사미드(화합물 7);5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indole-3-carboxamide (Compound 7 );

5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드(화합물 8);5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxamide (compound 8);

6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인돌-2-카르복사미드(화합물 9);6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indole-2-carboxamide (Compound 9 );

6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]이속사졸-3-카르복사미드(화합물 10);6-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]isoxazole-3-carboxamide ( compound 10);

5-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)이속사졸-3-카르복사미드(화합물 11);5-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)isoxazole-3-carboxamide (Compound 11);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-페닐피콜린아미드(화합물 12);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-phenylpicolinamide (Compound 12);

3-(3,4-디클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드(화합물 13);3-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol- 5-carboxamide (Compound 13);

4-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피롤-2-카르복사미드(화합물 14);4-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrrole-2-carb copymid (Compound 14);

1-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-1,2,3-트리아졸-4-카르복사미드(화합물 15);1-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-1,2,3 -Triazole-4-carboxamide (Compound 15);

5,6-디클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-벤조[d]이미다졸-2-카르복사미드(화합물 16);5,6-Dichloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-benzo[d]imidazole-2 -carboxamide (compound 16);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-5-페닐-1H-피라졸-3-카르복사미드(화합물 17);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl-5-phenyl-1H-pyrazole-3-carb copymid (Compound 17);

4-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)피콜린아미드(화합물 18);4-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)picolinamide (Compound 18);

5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)이속사졸-3-카르복사미드(화합물 19);5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)isoxazole-3-carboxamide (Compound 19);

5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)피리미딘-2-카르복사미드(화합물 20);5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)pyrimidine-2-carboxamide (Compound 20);

1-벤질-5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1H-피라졸-3-카르복사미드(화합물 21);1-benzyl-5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl -1H-pyrazole-3-carboxamide (Compound 21);

4-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)피콜린아미드(화합물 22);4-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)picolinamide (Compound 22);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-5-페닐-1H-피라졸-3-카르복사미드(화합물 23);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-5-phenyl-1H-pyrazole-3-carb copymid (Compound 23);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-3-페닐-1H-피라졸-5-카르복사미드(화합물 24);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-3-phenyl-1H-pyrazole-5-carb copymid (Compound 24);

5-(2,4-디클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-3-카르복사미드(화합물 25);5-(2,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol- 3-carboxamide (Compound 25);

6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]티아졸-2-카르복사미드(화합물 26);6-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]thiazole-2-carboxamide ( compound 26);

4-브로모-3-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드(화합물 27);4-Bromo-3-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H- pyrazole-5-carboxamide (Compound 27);

5-(2,5-디클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-3-카르복사미드(화합물 28);5-(2,5-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol- 3-carboxamide (Compound 28);

5-(2,4-디메틸페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 29);5-(2,4-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol- 3-carboxamide (Compound 29);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-[1,1'-비페닐]-3-카르복사미드 (화합물 30);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-[1,1'-biphenyl]-3-carboxamide ( compound 30);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸피콜린아미드 (화합물 31);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methylpicolinamide (Compound 31);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-페닐피콜린아미드 (화합물 32);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-phenylpicolinamide (Compound 32);

6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]옥사졸-2-카르복사미드 (화합물 33);6-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]oxazole-2-carboxamide ( compound 33);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드 (화합물 34);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxamide (Compound 34);

3-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-피라졸-5-카르복사미드 (화합물 35);3-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (compound 35);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-인다졸-3-카르복사미드 (화합물 36);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-indazole-3-carboxamide (compound 36);

4-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-이미다졸-2-카르복사미드 (화합물 37);4-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-imidazole-2- carboxamide (compound 37);

4-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-피롤-2-카르복사미드 (화합물 38);4-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-pyrrole-2-carb copymid (Compound 38);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-4-페닐-1H-피롤-2-카르복사미드 (화합물 39);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-4-phenyl-1H-pyrrole-2-carboxyl Mead (Compound 39);

4-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-피롤-2-카르복사미드 (화합물 40);4-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-pyrrole -2-carboxamide (Compound 40);

5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-이소부틸-4-메틸-1H-피라졸-3-카르복사미드 (화합물 41);5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-isobutyl-4- methyl-1H-pyrazole-3-carboxamide (Compound 41);

5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 42);5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl-1-phenyl -1H-pyrazole-3-carboxamide (Compound 42);

5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-(4-플루오로페닐)-4-메틸-1H-피라졸-3-카르복사미드 (화합물 43);5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-(4-fluoro phenyl)-4-methyl-1H-pyrazole-3-carboxamide (Compound 43);

5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]티아졸-2-카르복사미드 (화합물 44);5-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]thiazole-2-carboxamide ( compound 44);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메틸-4-페닐피콜린아미드 (화합물 45);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methyl-4-phenylpicolinamide (Compound 45);

5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-페닐피콜린아미드 (화합물 46);5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-phenylpicolinamide (Compound No. 46);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-페닐피라진-2-카르복사미드 (화합물 47);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-phenylpyrazine-2-carboxamide (Compound 47);

3-(2-클로로-6-플루오로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메틸이속사졸-4-카르복사미드 (화합물 48);3-(2-chloro-6-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5- methylisoxazole-4-carboxamide (Compound 48);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-페닐-1H-피라졸-5-카르복사미드 (화합물 49);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-phenyl-1H-pyrazole-5-carboxamide (compound 49);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-페닐-5-(트리플루오로메틸)-1H-피라졸-4-카르복사미드 (화합물 50);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-phenyl-5-(trifluoromethyl)-1H-pyra sol-4-carboxamide (Compound 50);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-[1,1'-비페닐]-4-카르복사미드 (화합물 51);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-[1,1'-biphenyl]-4-carboxamide ( compound 51);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-[1,1'-비페닐]-2-카르복사미드 (화합물 52);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-[1,1'-biphenyl]-2-carboxamide ( compound 52);

1-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)시클로펜탄-1-카르복사미드 (화합물 53);1-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)cyclopentane-1-carboxamide (Compound 53);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-페닐시클로펜탄-1-카르복사미드 (화합물 54);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-phenylcyclopentane-1-carboxamide (Compound 54);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-2-옥소-1-페닐피롤리딘-3-카르복사미드 (화합물 55);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-1-phenylpyrrolidine-3-carboxamide (Compound 55);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조푸란-2-카르복사미드 (화합물 56);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzofuran-2-carboxamide (Compound 56);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메톡시-1H-인돌-2-카르복사미드 (화합물 57);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methoxy-1H-indole-2-carboxamide (compound 57);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[b]티오펜-2-카르복사미드 (화합물 58);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[b]thiophene-2-carboxamide (Compound 58);

7-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-히드록시퀴놀린-3-카르복사미드 (화합물 59);7-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-hydroxyquinoline-3-carboxamide ( compound 59);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-2-옥소-2H-크로멘-3-카르복사미드 (화합물 60);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2H-chromene-3-carboxamide (compound 60);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)신놀린-4-카르복사미드 (화합물 61);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)cinnoline-4-carboxamide (Compound 61);

5-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-이소부틸-4-메틸-1H-피라졸-3 -카르복사미드 (화합물 62);5-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-isobutyl-4- methyl-1H-pyrazole-3-carboxamide (Compound 62);

5-(3-클로로페닐)-1-시클로프로필-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1H-피라졸-3 -카르복사미드 (화합물 63);5-(3-chlorophenyl)-1-cyclopropyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4- methyl-1H-pyrazole-3-carboxamide (Compound 63);

5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1-(2,2,2-트리플루오로에틸)-1H-피라졸-3-카르복사미드 (화합물 64);5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl-1-( 2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide (Compound 64);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메톡시벤조[b]티오펜-2-카르복사미드 (화합물 65);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methoxybenzo[b]thiophene-2-carboxamide (Compound 65);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메틸벤조[b]티오펜-2-카르복사미드 (화합물 66);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methylbenzo[b]thiophene-2-carboxamide ( compound 66);

3-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메틸벤조[b]티오펜-2-카르복사미드 (화합물 67);3-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methylbenzo[b]thiophene-2- carboxamide (compound 67);

3-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메톡시벤조[b]티오펜-2-카르복사미드 (화합물 68);3-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methoxybenzo[b]thiophene-2 -carboxamide (compound 68);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5,6-디메톡시벤조[b]티오펜-2-카르복사미드 (화합물 69);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5,6-dimethoxybenzo[b]thiophene-2-carb duxamide (Compound 69);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드 (화합물 70);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-(trifluoromethyl)benzo[b]thiophene-2 -carboxamide (compound 70);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-7-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드 (화합물 71);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-7-(trifluoromethyl)benzo[b]thiophene-2 -carboxamide (compound 71);

3-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드 (화합물 72);3-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-(trifluoromethyl)benzo[b] thiophene-2-carboxamide (Compound 72);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드 (화합물 73);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-(trifluoromethyl)benzo[b]thiophene-2 -carboxamide (compound 73);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메톡시벤조[b]티오펜-2-카르복사미드 (화합물 74);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methoxybenzo[b]thiophene-2-carboxamide (Compound 74);

5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 75);5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene-2- carboxamide (compound 75);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 76);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene-2-carboxamide ( compound 76);

4-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 77);4-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene-2- carboxamide (compound 77);

7-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 78);7-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene-2- carboxamide (compound 78);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-플루오로-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 79);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-fluoro-3-methylbenzo[b]thiophene-2 -carboxamide (compound 79);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조푸란-2-카르복사미드 (화합물 80);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzofuran-2-carboxamide (Compound 80);

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메톡시벤조푸란-2-카르복사미드 (화합물 81);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methoxybenzofuran-2-carboxamide (Compound 81) ;

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-7-메톡시벤조푸란-2-카르복사미드 (화합물 82);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-7-methoxybenzofuran-2-carboxamide (Compound 82) ;

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메톡시벤조푸란-2-카르복사미드 (화합물 83);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methoxybenzofuran-2-carboxamide (Compound 83) ;

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3,6-디메틸벤조푸란-2-카르복사미드 (화합물 84);N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3,6-dimethylbenzofuran-2-carboxamide (Compound 84 );

5-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조푸란-2-카르복사미드 (화합물 85); 및5-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzofuran-2-carboxamide (Compound 85); and

N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)나프토[2,1-b]푸란-2-카르복사미드 (화합물 86); 으로 이루어진 군에서 선택된다.N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)naphtho[2,1-b]furan-2-carboxamide ( compound 86); is selected from the group consisting of

또한, 본 발명의 상기 화학식 1로 표시되는 화합물은 하기 반응식 1 및 2의 방법으로 제조된다.In addition, the compound represented by Formula 1 of the present invention is prepared by the methods of Reaction Schemes 1 and 2 below.

[반응식 1][Scheme 1]

Figure pat00002
Figure pat00002

[반응식 2][Scheme 2]

Figure pat00003
Figure pat00003

상기 반응식 1에서, 각 중간체 2 내지 중간체 5의 제조방법은 아래와 같다.In Reaction Scheme 1, the preparation method of each intermediate 2 to intermediate 5 is as follows.

1) 메틸 4-시아노-2-메틸벤조에이트의 합성 (중간체 2)1) Synthesis of methyl 4-cyano-2-methylbenzoate (intermediate 2)

메틸 4-브로모-2-메틸벤조에이트 (3 g, 13.10 mmol)를 DMF (40 ㎖)에 녹인 후, Pd2(dba)3 (0.480 g, 0.524 mmol), dppf (0.436 g, 0.786 mmol), Zinc cyanide (1.692 g, 14.41 mmol)를 넣고 30분 동안 질소가스 하에서 교반한다. 그 후, 온도를 130 ℃로 올려 3시간 동안 교반한다. 반응 종결 후, 혼합물을 celite로 필터하고, DMF를 이용해 여러 번 씻어준다. 여과액을 EtOAc (50 ㎖×2)로 추출하고 물과 brine을 이용해 씻어준다. 모은 유기층은 무수황산마그네슘으로 물을 제거한 뒤 감압농축하여 용매를 제거한다. 혼합물을 컬럼 크로마토그래피 (Hexane:EtOAc = 9:1)로 정제하여 85%의 수득률로 밝은 노란색 고체의 중간체 2 (1.96 g, 11.19 mmol, 85%)를 얻었다.After dissolving methyl 4-bromo-2-methylbenzoate (3 g, 13.10 mmol) in DMF (40 mL), Pd 2 (dba) 3 (0.480 g, 0.524 mmol), dppf (0.436 g, 0.786 mmol) , Zinc cyanide (1.692 g, 14.41 mmol) was added and stirred for 30 minutes under nitrogen gas. Thereafter, the temperature was raised to 130 °C and stirred for 3 hours. After completion of the reaction, the mixture was filtered through celite and washed several times with DMF. Extract the filtrate with EtOAc (50 ㎖ × 2) and wash with water and brine. The collected organic layers were dried with anhydrous magnesium sulfate and then concentrated under reduced pressure to remove the solvent. The mixture was purified by column chromatography (Hexane:EtOAc = 9:1) to give Intermediate 2 (1.96 g, 11.19 mmol, 85%) as a bright yellow solid in 85% yield.

2) 메틸 2-(브로모메틸)-4-시아노벤조에이트의 합성 (중간체 3)2) Synthesis of methyl 2-(bromomethyl)-4-cyanobenzoate (intermediate 3)

중간체 2 (1.96 g, 11.19 mmol)를 DCE (30 ㎖)에 녹이고 N-bromosuccinimide (2.64 g, 22.38 mmol)와 bezoyl peroxide (0.271 g, 1.119 mmol)를 가한 후 8시간 동안 가열 환류 교반한다. 반응 종결 후, 실온으로 온도를 내려준다. 혼합물을 감압농축하여 용매를 제거하고 컬럼 크로마토그래피 (Hexane:EtOAc = 9:1)로 정제하여 81%의 수득률로 노란색 고체의 중간체 3 (2.29 g, 9.03 mmol, 81%)을 얻었다.Intermediate 2 (1.96 g, 11.19 mmol) was dissolved in DCE (30 mL) and N-bromosuccinimide (2.64 g, 22.38 mmol) and bezoyl peroxide (0.271 g, 1.119 mmol) were added, and the mixture was stirred under reflux for 8 hours. After completion of the reaction, the temperature is lowered to room temperature. The mixture was concentrated under reduced pressure to remove the solvent and purified by column chromatography (Hexane:EtOAc = 9:1) to obtain Intermediate 3 (2.29 g, 9.03 mmol, 81%) as a yellow solid in a yield of 81%.

3) 2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-카르보니트릴의 합성 (중간체 4)3) Synthesis of 2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-carbonitrile (Intermediate 4)

중간체 3 (7.34 g, 28.9 mmol)을 DMF (50 ㎖)에 녹이고 3-아미노피페리딘-2,6-디온 염산염 (4.75 g, 28.9 mmol)과 TEA (12.07 ㎖, 87 mmol)를 실온에서 첨가하고, 80 ℃에서 overnight 교반한다. 반응 종결 후, 실온으로 온도를 내려준 뒤 감압농축하여 용매를 제거한다. 혼합물에 물을 넣고 생기는 고체를 필터하고 과량의 물로 씻어준다. 고체를 감압하여 물을 완전히 제거하여 81%의 수득률로 어두운 남색 고체의 중간체 4 (6.28 g, 23.32 mmol, 81%)를 얻었다.Intermediate 3 (7.34 g, 28.9 mmol) was dissolved in DMF (50 mL) and 3-aminopiperidine-2,6-dione hydrochloride (4.75 g, 28.9 mmol) and TEA (12.07 mL, 87 mmol) were added at room temperature and stirred at 80 °C overnight. After completion of the reaction, the temperature was lowered to room temperature and concentrated under reduced pressure to remove the solvent. Add water to the mixture, filter the resulting solid, and wash with excess water. Water was completely removed from the solid under reduced pressure to obtain Intermediate 4 (6.28 g, 23.32 mmol, 81%) as a dark blue solid in a yield of 81%.

4) 3-(5-(아미노메틸)-1-옥소이소인돌린-2-일)피페리딘-2,6-디온의 합성 (중간체 5)4) Synthesis of 3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Intermediate 5)

중간체 4 (1.7 g, 6.31 mmol)을 DMA (20 ㎖)에 녹이고 10% Pd/C (2.32 g, 6.31 mmol)와 메탄술폰산 (0.451 ㎖, 6.94 mmol)를 첨가한 뒤 수소가스 하에서 40 ℃로 밤새 교반한다. 반응 종결 후, celite로 여과하고 50 ㎖의 DMA를 이용해 씻어준다. 여과액을 감압농축시키고 혼합물에 메탄올/에틸에테르 (5 ㎖/30 ㎖) 혼합용액을 이용하여 침전시킨다. 생성된 침전물을 필터하고 43%의 수득률로 회색 고체의 중간체 5 (0.99 g, 2.69 mmol, 43%)를 얻었다.Intermediate 4 (1.7 g, 6.31 mmol) was dissolved in DMA (20 mL), 10% Pd/C (2.32 g, 6.31 mmol) and methanesulfonic acid (0.451 mL, 6.94 mmol) were added, followed by overnight at 40 °C under hydrogen gas. Stir. After completion of the reaction, filter with celite and wash with 50 ml of DMA. The filtrate was concentrated under reduced pressure, and the mixture was precipitated using a mixed solution of methanol/ethyl ether (5 ml/30 ml). The resulting precipitate was filtered to obtain Intermediate 5 (0.99 g, 2.69 mmol, 43%) as a gray solid in a yield of 43%.

1H NMR (500 MHz, DMSO-d 6) δ 11.00 (s, 1H), 8.27 (s, 3H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.4 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 4.17 (q, J = 5.9 Hz, 2H), 2.97-2.87 (m, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.45-2.38 (m, 1H), 2.34 (s, 6H), 2.06-1.97 (m, 1H). 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.00 (s, 1H), 8.27 (s, 3H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 17.4 Hz, 1H), 4.35 (d, J = 17.4 Hz, 1H), 4.17 (q, J = 5.9 Hz, 2H), 2.97–2.87 (m, 1H), 2.60 (d, J = 17.4 Hz, 1H), 2.45–2.38 (m, 1H), 2.34 (s, 6H), 2.06–1.97 (m) , 1H).

또한, 반응식 2는 한국특허공개번호 제10-2011-0019761호에 개시된 방법으로 제조된다.In addition, Scheme 2 is prepared by the method disclosed in Korean Patent Publication No. 10-2011-0019761.

상기 제조방법에서 보이고 있는 본 발명에 따른 화학식 1로 표시되는 화합물의 제조방법은 본 발명의 화합물을 제조하기 위한 방법의 일 예로 이해되어야 하고, 본 발명이 제조하고 있는 화학식 1로 표시되는 화합물을 제조할 수 있는 방법이라면, 제한 없이 본 발명에 포함된다. 또한, 본 발명 명세서에 제시되어 있는 방법 및 이로부터 통상의 기술자가 용이하게 변경 및 수정하여 시도할 수 있는 제조방법 또한 본 발명의 범주에 포함되는 것으로 이해되어야 하고, 이는 해당 분야의 기술자에게 자명한 것으로 이해될 수 있다.The preparation method of the compound represented by Formula 1 according to the present invention shown in the above preparation method should be understood as an example of a method for preparing the compound of the present invention, and the preparation of the compound represented by Formula 1 prepared by the present invention. Any way that can be done is included in the present invention without limitation. In addition, it should be understood that the methods presented in the specification of the present invention and the manufacturing methods that can be easily changed and modified by those skilled in the art therefrom are also included in the scope of the present invention, which is obvious to those skilled in the art. can be understood as

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

본 발명에서의 “할로겐” 또는 “할로”는 플루오르(F), 염소(Cl), 브롬(Br), 요오드(I)를 의미한다.“Halogen” or “halo” in the present invention means fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

본 발명에서 사용한 용어 “알킬”은 단일결합의 직쇄 또는 분지쇄의 탄화수소기를 의미한다. 예를 들어 메틸, 에틸, 프로필 등을 포함하고 이로 제한되지 않는다.As used herein, the term "alkyl" refers to a single-bond straight-chain or branched-chain hydrocarbon group. Examples include, but are not limited to, methyl, ethyl, propyl, and the like.

본 발명에서 사용한 용어 “알콕시”는 단일결합의 직쇄 또는 분지쇄의 포화 탄화수소가 결합된 산소기를 의미한다. 예를 들어 메톡시, 에톡시, 프로폭시 등을 포함하고 이로 제한되지 않는다.The term "alkoxy" used in the present invention refers to an oxygen group to which a single-bond straight-chain or branched-chain saturated hydrocarbon is bonded. Examples include, but are not limited to, methoxy, ethoxy, propoxy, and the like.

본 발명에서 사용한 용어 "할로겐알킬"은 상기된 바와 같은 치환된 알킬 그룹을 언급하고, 여기서, 알킬 그룹 상의 하나 이상의 수소 원자는 할로겐 그룹으로 치환되었다. 예를 들어, 트리플루오로메틸, 디플루오로메틸, 트리플루오로에틸 등을 포함하고 이로 제한되지 않는다.As used herein, the term "halogenalkyl" refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been replaced with a halogen group. Examples include, but are not limited to, trifluoromethyl, difluoromethyl, trifluoroethyl, and the like.

본 발명에서 사용한 용어 "할로겐알콕시"는 그룹 알킬-O-를 언급하고, 여기서, 알킬 그룹 상의 하나 이상의 수소 원자는 할로겐 그룹으로 치환되고, 예를 들어, 트리플루오로메톡시 등을 포함하고 이로 제한되지 않는다.The term "halogenalkoxy" as used herein refers to the group alkyl-O-, wherein one or more hydrogen atoms on the alkyl group are substituted with a halogen group, including but not limited to, for example, trifluoromethoxy and the like. don't

상기 용어 “헤테로시클로알킬” 은 N, O, 또는 S와 같은 헤테로원자를 하나 이상 포함하는 고리모양의 단일결합의 포화탄화수소기를 말하며, 고리에 포함된 헤테로원자의 수 및 종류, 및 탄소수에 따라 피페리디닐, 모르폴리닐, 테트라히드로푸란일, 피페라지닐 등을 포함하고 이로 제한되지 않는다.The term "heterocycloalkyl" refers to a ring-shaped single-bond saturated hydrocarbon group containing one or more heteroatoms such as N, O, or S, and according to the number and type of heteroatoms included in the ring and the number of carbon atoms, pipette include, but are not limited to, ridinyl, morpholinyl, tetrahydrofuranyl, piperazinyl, and the like.

상기 용어 “헤테로아릴”은 N, O, 또는 S와 같은 헤테로원자를 하나 이상 포함하는 방향족 고리화합물을 말하며, 고리에 포함된 헤테로원자의 수 및 종류, 및 탄소수에 따라 피롤일, 피라졸일, 이미다졸일, 이속사졸일, 트리아졸일, 피리딘일, 피라진일, 피리미딘일, 인돌일, 인다졸일, 벤조이미다졸일, 벤조이속사졸일, 벤조옥사졸일, 벤조티아졸일, 벤조티오펜일, 나프토푸란일, 퀴놀린일, 이소퀴놀린일, 퀴녹살린일 등을 포함하고 이로 제한되지 않는다.The term "heteroaryl" refers to an aromatic ring compound containing one or more heteroatoms such as N, O, or S, and depending on the number and type of heteroatoms included in the ring and the number of carbon atoms, pyrroleyl, pyrazolyl, Dazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, indolyl, indazolyl, benzoimidazolyl, benzoisoxazolyl, benzooxazolyl, benzothiazolyl, benzothiophenyl, naph tofuranyl, quinolinyl, isoquinolinyl, quinoxalinyl, and the like, but are not limited thereto.

본 발명의 화학식 1의 화합물은 약학적으로 허용 가능한 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물, 용매화물 및 프로드럭을 모두 포함할 수 있다. 또한, 본 발명의 화합물은 하나 이상의 비대칭 탄소 원자를 함유할 수 있고, 라세미 형태 및 광학적인 활성 형태로 존재할 수 있다. 이러한 모든 화합물 및 부분입체이성질체는 본 발명의 범위에 포함된다.The compound of Formula 1 of the present invention may include not only pharmaceutically acceptable salts, but also all salts, hydrates, solvates, and prodrugs that can be prepared by conventional methods. In addition, the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All such compounds and diastereomers are included within the scope of the present invention.

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

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

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

또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 나병, 만성 이식편대숙주병, 염증성 질환 또는 암 예방 또는 치료용 약학적 조성물에 관한 것이다.In addition, the present invention relates to a pharmaceutical composition for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory disease or cancer, comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

본 발명의 일시험예에 따르면, CRBN(celebron) 단백질에 결합하여 Ikaros/Aiolos, GSPT1의 분해하는 것으로 확인되었다. CRBN 단백질은 E3 유비퀴틴 연결효소(E3 ubiquitin ligase)의 일종으로 탈리도마이드 및 이의 유사체인 포말리도마이드, 레날리도마이드 등과 결합하여 Ikaros/Aiolos 단백질, GSPT1 단백질 등의 기질 단백질에 대해서 유비퀴틴을 부착하는 활성을 가지는 것으로 알려져 있다.According to one test example of the present invention, it was confirmed that Ikaros/Aiolos and GSPT1 were degraded by binding to CRBN (celebron) protein. CRBN protein, a type of E3 ubiquitin ligase, binds to thalidomide and its analogs, such as pomalidomide and lenalidomide, and has the activity of attaching ubiquitin to substrate proteins such as Ikaros/Aiolos proteins and GSPT1 proteins. It is known to have

상기 암은 유방암, 대장암, 폐암, 소세포폐암, 위암, 간암, 혈액암, 골암, 췌장암, 피부암, 두부 또는 경부암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암, 질암, 음문암종, 호지킨병, 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, CNS 종양, 1차 CNS 림프종, 척수 종양, 뇌간신경교종 및 뇌하수체 선종으로 이루어진 군에서 선택될 수 있으나 특별히 이에 제한되는 것은 아니다.The cancer is breast cancer, colon cancer, lung cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, proximal anal cancer, colon cancer, Breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma may be selected from the group consisting of, but are not particularly limited thereto it is not going to be

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

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

상기 약학 조성물은 상기 화학식 1의 화합물 및 부형제를 포함하는 약학 조성물을 제공한다. 상기 화합물은 전체 조성물 총 중량에 대하여 바람직하게는 0.001 중량% 내지 50 중량%, 더 바람직하게는 0.001 중량% 내지 40 중량%, 가장 바람직하게는 0.001 중량% 내지 30 중량%로 하여 첨가될 수 있다.The pharmaceutical composition provides a pharmaceutical composition comprising the compound of Formula 1 and an excipient. The compound may be added in an amount of preferably 0.001% to 50% by weight, more preferably 0.001% to 40% by weight, and most preferably 0.001% to 30% by weight based on the total weight of the total composition.

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

본 발명에 따른 화학식 1의 화합물은 CRBN 단백질과 특이적으로 결합하며, 이의 기능에 관여한다. 따라서, 본 발명의 화합물은 CRBN 단백질의 작용에 의한 나병, 만성 이식편대숙주병, 염증성 질환 또는 암의 예방 또는 치료에 유용하게 이용될 수 있다.The compound represented by Formula 1 according to the present invention specifically binds to CRBN protein and is involved in its function. Accordingly, the compounds of the present invention can be usefully used for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory diseases, or cancer caused by the action of CRBN protein.

도 1은 본 발명 화합물 10을 6시간 처리한 GSPT1, IKZF1 및 GAPDH에 대한 분해 활성을 측정한 것이다.Figure 1 is a measurement of the degradation activity of GSPT1, IKZF1 and GAPDH treated with compound 10 of the present invention for 6 hours.

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

<실시예 1. 글루타이미드 모핵을 갖는 이소인돌리논 유도체 화합물의 합성 및 물리화학적 특성 확인><Example 1. Synthesis of isoindolinone derivative compound having glutimide mother nucleus and confirmation of physicochemical properties>

본 발명 화합물 1 내지 86은 한국특허공개번호 제10-2011-0019761호에 개시된 방법을 참고하여 제조하였으며, 이의 물리화학적 특성은 하기와 같다.Compounds 1 to 86 of the present invention were prepared by referring to the method disclosed in Korean Patent Publication No. 10-2011-0019761, and their physicochemical properties are as follows.

화합물 1. 6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드Compound 1. 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxa mid

Figure pat00004
Figure pat00004

3-(5-(아미노메틸)-1-옥소이소인돌린-2-일)피페리딘-2,6-디온메탄설포네이트 (15 ㎎, 0.00406 mmol)을 DMF (1 ㎖)에 녹이고 6-클로로-1H-인다졸-3-카복실산 (9.5 ㎎, 0.0487 mmol), EDCl·HCl (8.5 ㎎, 0.0446 mmol), HOBt·H2O (6.0 ㎎, 0.0446 mmol), DIPEA (28 ㎕, 0.162 mmol)를 가한 후 상온에서 12시간 교반하였다. 반응 혼합물은 물로 희석시키고 에틸아세테이트로 추출하였다. 유기층은 소금물로 씻고, 무수 황산나트륨으로 잔류물을 건조하고 여과하였다. 여과액은 감압 농축하고 컬럼크로마토그래피를 이용하여 분리 정제하여 목적하는 화합물 1(5.0 ㎎, 28%)을 흰색 고체로 얻었다.3-(5-(aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dionemethanesulfonate (15 mg, 0.00406 mmol) was dissolved in DMF (1 mL) and 6-chloro -1H-indazole-3-carboxylic acid (9.5 mg, 0.0487 mmol), EDCl HCl (8.5 mg, 0.0446 mmol), HOBt H 2 O (6.0 mg, 0.0446 mmol), DIPEA (28 μl, 0.162 mmol) After adding, the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, and the residue was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and separated and purified using column chromatography to obtain the desired compound 1 (5.0 mg, 28%) as a white solid.

1H NMR (500 MHz, DMSO-d6) δ 13.76 (s, 1H), 10.98 (s, 1H), 9.18 (t, J = 6.3 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H), 7.72 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.27 (dd, J = 8.7, 1.8 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.63 - 2.57 (m, 1H), 2.41 - 2.32 (m, 1H), 2.03 - 1.94 (m, 2H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.76 (s, 1H), 10.98 (s, 1H), 9.18 (t, J = 6.3 Hz, 1H), 8.15 (d, J = 8.6 Hz, 1H) , 7.72 (d, J = 1.8 Hz, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.27 (dd, J = 8.7, 1.8 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.63 - 2.57 (m, 1H), 2.41 - 2.32 (m, 1H), 2.03 - 1.94 (m, 2H).

화합물 2. 3-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드Compound 2. 3-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazole -5-carboxamide

Figure pat00005
Figure pat00005

6-클로로-1H-인다졸-3-카복실산 대신 3-(4-클로로페닐)-1H-피라졸-5-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 2를 합성하였다. Compound 2 was synthesized in the same manner as in the synthesis method of Compound 1, using 3-(4-chlorophenyl)-1H-pyrazole-5-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 13.75 (s, 1H), 10.98 (s, 1H), 8.99 (s, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.53 (m, 3H), 7.47 (d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.61 (m, 1H), 2.38 (m, 1H), 2.05 - 1.94 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.75 (s, 1H), 10.98 (s, 1H), 8.99 (s, 1H), 7.82 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.53 (m, 3H), 7.47 (d, J = 7.9 Hz, 1H), 7.20 (s, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 ( d, J = 6.1 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.61 (m, 1H), 2.38 ( m, 1H), 2.05 - 1.94 (m, 1H).

화합물 3. 5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-벤조[d]이미다졸-2-카르복사미드Compound 3. 5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-benzo[d]imidazole- 2-Carboxamide

Figure pat00006
Figure pat00006

6-클로로-1H-인다졸-3-카복실산 대신 5-클로로-1H-벤조[d]이미다졸-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 3을 합성하였다. Compound 3 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-chloro-1H-benzo[d]imidazole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 13.46 (s, 1H), 10.98 (s, 1H), 9.71 (t, J = 6.4 Hz, 1H), 7.79 - 7.54 (m, 4H), 7.49 (d, J = 7.9 Hz, 1H), 7.33 (dd, J = 8.7, 2.0 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.65 - 2.55 (m, 1H), 2.37 (m, 1H), 1.99 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.46 (s, 1H), 10.98 (s, 1H), 9.71 (t, J = 6.4 Hz, 1H), 7.79 - 7.54 (m, 4H), 7.49 ( d, J = 7.9 Hz, 1H), 7.33 (dd, J = 8.7, 2.0 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.65 - 2.55 (m, 1H), 2.37 (m, 1H), 1.99 (m , 1H).

화합물 4. 5,6-디클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드Compound 4. 5,6-Dichloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazol-3- carboxamide

Figure pat00007
Figure pat00007

6-클로로-1H-인다졸-3-카복실산 대신 5,6-디클로로-1H-인다졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 4를 합성하였다. Compound 4 was synthesized in the same manner as in the synthesis method of Compound 1, using 5,6-dichloro-1H-indazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.25 (t, J = 6.3 Hz, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.59 (m, 1H), 2.37 (m, 1H), 2.03 - 1.97 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 9.25 (t, J = 6.3 Hz, 1H), 8.32 (s, 1H), 7.99 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.59 (m, 1H), 2.37 (m, 1H), 2.03 - 1.97 (m, 1H).

화합물 5. 3-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드Compound 5. 3-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazole -5-carboxamide

Figure pat00008
Figure pat00008

6-클로로-1H-인다졸-3-카복실산 대신 5-(3-클로로페닐)-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 5를 합성하였다. Compound 5 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-(3-chlorophenyl)-1H-pyrazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 13.80 (s, 1H), 10.98 (s, 1H), 9.01 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.51 - 7.45 (m, 2H), 7.42 (d, J = 9.1 Hz, 1H), 7.26 (s, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.65 - 2.55 (m, 1H), 2.38 (m, 1H), 2.04 - 1.96 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.80 (s, 1H), 10.98 (s, 1H), 9.01 (s, 1H), 7.87 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.54 (s, 1H), 7.51 - 7.45 (m, 2H), 7.42 (d, J = 9.1 Hz, 1H), 7.26 (s, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.65 - 2.55 (m, 1H), 2.38 (m, 1H), 2.04 - 1.96 (m, 1H).

화합물 6. 6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인돌-3-카르복사미드Compound 6. 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indole-3-carboxamide

Figure pat00009
Figure pat00009

6-클로로-1H-인다졸-3-카복실산 대신 6-클로로-1H-인돌-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 6을 합성하였다. Compound 6 was synthesized in the same manner as in the synthesis method of Compound 1, using 6-chloro-1H-indole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 10.97 (s, 1H), 8.62 (t, J = 6.0 Hz, 1H), 8.18 - 8.08 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.51 - 7.46 (m, 2H), 7.12 (dd, J = 8.6, 2.0 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.88 (m, 1H), 2.68 - 2.55 (m, 1H), 2.42 - 2.29 (m, 1H), 2.02 - 1.90 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H), 10.97 (s, 1H), 8.62 (t, J = 6.0 Hz, 1H), 8.18 - 8.08 (m, 2H), 7.69 ( d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.51 - 7.46 (m, 2H), 7.12 (dd, J = 8.6, 2.0 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz) , 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.88 (m, 1H), 2.68 - 2.55 (m, 1H), 2.42 - 2.29 (m, 1H), 2.02 - 1.90 (m, 1H).

화합물 7. 5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인돌-3-카르복사미드Compound 7. 5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indole-3-carboxamide

Figure pat00010
Figure pat00010

6-클로로-1H-인다졸-3-카복실산 대신 5-클로로-1H-인돌-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 7을 합성하였다. Compound 7 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-chloro-1H-indole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.98 (s, 1H), 8.64 (t, J = 6.0 Hz, 1H), 8.18 - 8.12 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.47 (dd, J = 11.4, 8.4 Hz, 2H), 7.17 (dd, J = 8.6, 2.2 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.61 (m, 1H), 2.37 (m, 1H), 2.03 - 1.96 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.78 (s, 1H), 10.98 (s, 1H), 8.64 (t, J = 6.0 Hz, 1H), 8.18 - 8.12 (m, 2H), 7.69 ( d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.47 (dd, J = 11.4, 8.4 Hz, 2H), 7.17 (dd, J = 8.6, 2.2 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H) ), 2.61 (m, 1H), 2.37 (m, 1H), and 2.03 - 1.96 (m, 1H).

화합물 8. 5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드Compound 8. 5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxa mid

Figure pat00011
Figure pat00011

6-클로로-1H-인다졸-3-카복실산 대신 5-클로로-1H-인다졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 8을 합성하였다. Compound 8 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-chloro-1H-indazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 13.85 (s, 1H), 10.98 (s, 1H), 9.19 (t, J = 6.3 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 7.68 (dd, J = 8.4, 5.0 Hz, 2H), 7.56 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 8.9, 2.0 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.59 (m, 1H), 2.37 (m, 1H), 1.99 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.85 (s, 1H), 10.98 (s, 1H), 9.19 (t, J = 6.3 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H) , 7.68 (dd, J = 8.4, 5.0 Hz, 2H), 7.56 (s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.44 (dd, J = 8.9, 2.0 Hz, 1H), 5.10 ( dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.90 ( m, 1H), 2.59 (m, 1H), 2.37 (m, 1H), 1.99 (m, 1H).

화합물 9. 6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인돌-2-카르복사미드Compound 9. 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indole-2-carboxamide

Figure pat00012
Figure pat00012

6-클로로-1H-인다졸-3-카복실산 대신 6-클로로-1H-인돌-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 9를 합성하였다. Compound 9 was synthesized in the same manner as in the synthesis method of Compound 1, using 6-chloro-1H-indole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.78 (s, 1H), 10.98 (s, 1H), 9.22 (t, J = 6.1 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.51 - 7.47 (m, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.22 (s, 1H), 7.06 (dd, J = 8.6, 2.0 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.62 - 2.55 (m, 1H), 2.37 (m, 1H), 2.06 - 1.93 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.78 (s, 1H), 10.98 (s, 1H), 9.22 (t, J = 6.1 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H) , 7.66 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.51 - 7.47 (m, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.22 (s, 1H), 7.06 ( dd, J = 8.6, 2.0 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.62 - 2.55 (m, 1H), 2.37 (m, 1H), 2.06 - 1.93 (m, 1H).

화합물 10. 6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]이속사졸-3-카르복사미드Compound 10. 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]isoxazole-3-carb copy mid

Figure pat00013
Figure pat00013

6-클로로-1H-인다졸-3-카복실산 대신 5-클로로벤조[d]이속사졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 10을 합성하였다. Compound 10 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-chlorobenzo[d]isoxazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.80 (t, J = 6.2 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.57 (dd, J = 8.5, 1.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.96 - 2.89 (m, 1H), 2.61 (m, 1H), 2.38 (dd, J = 13.1, 4.4 Hz, 1H), 1.99 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 9.80 (t, J = 6.2 Hz, 1H), 8.15 (d, J = 1.7 Hz, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.57 (dd, J = 8.5, 1.8 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H) , 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H) , 2.96 - 2.89 (m, 1H), 2.61 (m, 1H), 2.38 (dd, J = 13.1, 4.4 Hz, 1H), 1.99 (m, 1H).

화합물 11. 5-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)이속사졸-3-카르복사미드Compound 11. 5-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)isoxazole-3- carboxamide

Figure pat00014
Figure pat00014

6-클로로-1H-인다졸-3-카복실산 대신 5-(4-클로로페닐)이속사졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 11을 합성하였다. Compound 11 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-(4-chlorophenyl)isoxazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.53 (t, J = 6.2 Hz, 1H), 8.00 - 7.94 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.56 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.46 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.61 (m, 1H), 2.38 (m, 1H), 1.99 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 9.53 (t, J = 6.2 Hz, 1H), 8.00 - 7.94 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.67 - 7.62 (m, 2H), 7.56 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.46 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H) ), 4.59 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.61 (m, 1H) ), 2.38 (m, 1H), 1.99 (m, 1H).

화합물 12. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-페닐피콜린아미드Compound 12. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-phenylpicolinamide

Figure pat00015
Figure pat00015

6-클로로-1H-인다졸-3-카복실산 대신 4-페닐피콜린산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 12를 합성하였다. Compound 12 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-phenylpicolinic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.57 (t, J = 6.4 Hz, 1H), 8.73 (d, J = 5.1 Hz, 1H), 8.34 - 8.25 (m, 1H), 7.96 (dd, J = 5.1, 1.9 Hz, 1H), 7.86 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.59 - 7.47 (m, 5H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.61 (m, 1H), 2.37 (m, 1H), 2.08 - 1.93 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 9.57 (t, J = 6.4 Hz, 1H), 8.73 (d, J = 5.1 Hz, 1H), 8.34 - 8.25 (m, 1H), 7.96 (dd, J = 5.1, 1.9 Hz, 1H), 7.86 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.59 - 7.47 (m, 5H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H) ), 2.61 (m, 1H), 2.37 (m, 1H), and 2.08 - 1.93 (m, 1H).

화합물 13. 3-(3,4-디클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드Compound 13. 3-(3,4-Dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H- Pyrazole-5-carboxamide

Figure pat00016
Figure pat00016

6-클로로-1H-인다졸-3-카복실산 대신 3-(3,4-디클로로페닐)-1H-피라졸-5-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 13을 합성하였다. Compound 13 was synthesized in the same manner as in the synthesis method of Compound 1, using 3-(3,4-dichlorophenyl)-1H-pyrazole-5-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 13.85 (m, 1H), 10.98 (s, 1H), 9.05 (m, 1H), 8.05 (m, 1H), 7.88 - 7.66 (m, 3H), 7.61 - 7.44 (m, 2H), 7.31 (m, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (d, J = 14.5 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.59 (d, J = 17.0 Hz, 1H), 2.38 (m, 1H), 2.05 - 1.92 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.85 (m, 1H), 10.98 (s, 1H), 9.05 (m, 1H), 8.05 (m, 1H), 7.88 - 7.66 (m, 3H), 7.61 - 7.44 (m, 2H), 7.31 (m, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (d, J = 14.5 Hz, 2H), 4.45 (d, J = 17.4 Hz) , 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.59 (d, J = 17.0 Hz, 1H), 2.38 (m, 1H), 2.05 - 1.92 (m, 1H) .

화합물 14. 4-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피롤-2-카르복사미드Compound 14. 4-(3-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrrole- 2-Carboxamide

Figure pat00017
Figure pat00017

6-클로로-1H-인다졸-3-카복실산 대신 4-(3-클로로페닐)-1H-피롤-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 14를 합성하였다. Compound 14 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-(3-chlorophenyl)-1H-pyrrole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 11.80 (s, 1H), 10.98 (s, 1H), 8.82 - 8.65 (m, 1H), 7.70 (dd, J = 7.9, 2.7 Hz, 1H), 7.62 - 7.45 (m, 6H), 7.35 (m, 1H), 7.28 (s, 1H), 7.22 - 7.13 (m, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 4.45 (d, J = 17.5 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 2.98 - 2.84 (m, 1H), 2.63 (m,1H), 2.40 - 2.32 (m, 1H), 2.04 - 1.96 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.80 (s, 1H), 10.98 (s, 1H), 8.82 - 8.65 (m, 1H), 7.70 (dd, J = 7.9, 2.7 Hz, 1H), 7.62 - 7.45 (m, 6H), 7.35 (m, 1H), 7.28 (s, 1H), 7.22 - 7.13 (m, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 4.45 (d, J = 17.5 Hz, 1H), 4.31 (d, J = 17.0 Hz, 1H), 2.98 - 2.84 (m, 1H), 2.63 (m, 1H), 2.40 - 2.32 (m, 1H), 2.04 - 1.96 (m, 1H).

화합물 15. 1-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-1,2,3-트리아졸-4-카르복사미드Compound 15. 1-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-1; 2,3-triazole-4-carboxamide

Figure pat00018
Figure pat00018

6-클로로-1H-인다졸-3-카복실산 대신 1-(3-클로로페닐)-1H-1,2,3-트리아졸-4-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 15를 합성하였다. Compound 15 was prepared in the same manner as in the synthesis method of Compound 1, using 1-(3-chlorophenyl)-1H-1,2,3-triazole-4-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid. synthesized.

1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.42 (t, J = 6.3 Hz, 1H), 9.39 (s, 1H), 8.13 (t, J = 2.0 Hz, 1H), 7.99 (dt, J = 8.0, 1.6 Hz, 1H), 7.78 - 7.58 (m, 3H), 7.56 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.66 - 2.57 (m, 1H), 2.42 - 2.29 (m, 1H), 2.05 - 1.93 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 9.42 (t, J = 6.3 Hz, 1H), 9.39 (s, 1H), 8.13 (t, J = 2.0 Hz, 1H) , 7.99 (dt, J = 8.0, 1.6 Hz, 1H), 7.78 - 7.58 (m, 3H), 7.56 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3 , 5.1 Hz, 1H), 4.61 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.66 - 2.57 (m, 1H), 2.42 - 2.29 (m, 1H), 2.05 - 1.93 (m, 1H).

화합물 16. 5,6-디클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-벤조[d]이미다졸-2-카르복사미드Compound 16. 5,6-Dichloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-benzo[d]imi Dazole-2-carboxamide

Figure pat00019
Figure pat00019

6-클로로-1H-인다졸-3-카복실산 대신 5,6-디클로로-1H-벤조[d]이미다졸-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 16을 합성하였다. Compound 16 was synthesized in the same manner as in the synthesis method of Compound 1, using 5,6-dichloro-1H-benzo[d]imidazole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 13.62 (s, 1H), 10.99 (s, 1H), 9.78 (t, J = 6.3 Hz, 1H), 8.03 (s, 1H), 7.75 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.49 (dd, J = 7.9, 1.4 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.4 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.95 - 2.86 (m, 1H), 2.63 - 2.55 (m, 1H), 2.43 - 2.29 (m, 1H), 2.04 - 1.95 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.62 (s, 1H), 10.99 (s, 1H), 9.78 (t, J = 6.3 Hz, 1H), 8.03 (s, 1H), 7.75 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.49 (dd, J = 7.9, 1.4 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.4 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.95 - 2.86 (m, 1H), 2.63 - 2.55 (m , 1H), 2.43 - 2.29 (m, 1H), 2.04 - 1.95 (m, 1H).

화합물 17. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-5-페닐-1H-피라졸-3-카르복사미드Compound 17. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl-5-phenyl-1H-pyrazole- 3-Carboxamide

Figure pat00020
Figure pat00020

6-클로로-1H-인다졸-3-카복실산 대신 5-페닐-4-메틸-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 17을 합성하였다. Compound 17 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-phenyl-4-methyl-1H-pyrazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d 6) δ 13.37 (s, 1H), 10.97 (s, 1H), 8.77 (t, J = 6.4 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.61 - 7.39 (m, 7H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.96 - 2.85 (m, 1H), 2.66 - 2.57 (m, 1H), 2.36 (m, 4H), 2.01 (m, 1H). 1H NMR (400 MHz, DMSO- d 6 ) δ 13.37 (s, 1H), 10.97 (s, 1H), 8.77 (t, J = 6.4 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H) , 7.61 - 7.39 (m, 7H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 ( d, J = 17.3 Hz, 1H), 2.96 - 2.85 (m, 1H), 2.66 - 2.57 (m, 1H), 2.36 (m, 4H), 2.01 (m, 1H).

화합물 18. 4-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)피콜린아미드Compound 18. 4-(4-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)picolinamide

Figure pat00021
Figure pat00021

6-클로로-1H-인다졸-3-카복실산 대신 4-(4-클로로페닐)피콜린산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 18을 합성하였다. Compound 18 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-(4-chlorophenyl)picolinic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d 6) δ 10.99 (s, 1H), 9.58 (t, J = 6.4 Hz, 1H), 8.75 (d, J = 5.1 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 7.97 (dd, J = 5.1, 1.9 Hz, 1H), 7.94 - 7.89 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.56 (s, 1H), 7.54 - 7.46 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 6.2 Hz, 2H), 4.44 (d, J = 17.4 Hz, 1H), 4.30 (d, J = 17.4 Hz, 1H), 3.00 - 2.84 (m, 1H), 2.64 - 2.52 (m, 1H), 2.43 - 2.30 (m, 1H) 2.05 - 1.92 (m, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.99 (s, 1H) , 9.58 (t, J = 6.4 Hz, 1H), 8.75 (d, J = 5.1 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 7.97 (dd, J = 5.1, 1.9 Hz, 1H), 7.94 - 7.89 (m, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.65 - 7.61 (m, 2H), 7.56 (s, 1H), 7.54 - 7.46 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 6.2 Hz, 2H), 4.44 (d, J = 17.4 Hz) , 1H), 4.30 (d, J = 17.4 Hz, 1H), 3.00 - 2.84 (m, 1H), 2.64 - 2.52 (m, 1H), 2.43 - 2.30 (m, 1H) 2.05 - 1.92 (m, 1H) .

화합물 19. 5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)이속사졸-3-카르복사미드Compound 19. 5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)isoxazole-3- carboxamide

Figure pat00022
Figure pat00022

6-클로로-1H-인다졸-3-카복실산 대신 5-(3-클로로페닐)이속사졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 19를 합성하였다. Compound 19 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-(3-chlorophenyl)isoxazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d 6) δ 10.99 (s, 1H), 9.55 (t, J = 6.2 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.92 (dt, J = 6.6, 1.9 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.56 (s, 1H), 7.54 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 6.2 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.2 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.42 - 2.33 (m, 1H), 2.05 - 1.94 (m, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.99 (s, 1H) , 9.55 (t, J = 6.2 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 7.92 (dt, J = 6.6, 1.9 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.56 (s, 1H), 7.54 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 6.2 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.2 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.42 - 2.33 (m, 1H), 2.05 - 1.94 (m, 1H).

화합물 20. 5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)피리미딘-2-카르복사미드Compound 20. 5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)pyrimidine-2- carboxamide

Figure pat00023
Figure pat00023

6-클로로-1H-인다졸-3-카복실산 대신 5-(3-클로로페닐)피리미딘-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 20을 합성하였다.Compound 20 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-(3-chlorophenyl)pyrimidine-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H), 9.58 (t, J = 6.4 Hz, 1H), 8.76 (d, J = 5.1 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 5.1, 2.0 Hz, 1H), 7.84 (m, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.64 - 7.54 (m, 3H), 7.50 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.65 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.90 (m, 1H), 2.64 - 2.55 (m, 1H), 2.44 - 2.30 (m, 1H), 2.00 (m, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.98 (s, 1H) , 9.58 (t, J = 6.4 Hz, 1H), 8.76 (d, J = 5.1 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 5.1, 2.0 Hz, 1H), 7.84 (m, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.64 - 7.54 (m, 3H), 7.50 ( d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.65 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 ( d, J = 17.4 Hz, 1H), 2.90 (m, 1H), 2.64 - 2.55 (m, 1H), 2.44 - 2.30 (m, 1H), 2.00 (m, 1H).

화합물 21. 1-벤질-5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1H-피라졸-3-카르복사미드Compound 21. 1-Benzyl-5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)- 4-methyl-1H-pyrazole-3-carboxamide

Figure pat00024
Figure pat00024

6-클로로-1H-인다졸-3-카복실산 대신 1-벤질-5-(3-클로로페닐)-4-메틸-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 21을 합성하였다. The compound was synthesized in the same manner as in the synthesis method of Compound 1 using 1-benzyl-5-(3-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid. 21 was synthesized.

1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.86 (s, 1H), 7.43 (m, 5H), 7.18 - 6.88 (m, 4H), 5.19 (s, 2H), 4.72 (s, 2H), 4.41 (m, 2H), 2.89 (m, 2H), 2.26 (m, 4H), 1.63 (m, 1H), 1.35 - 1.19 (m, 1H). 1 H NMR (400 MHz, CDCl 3 ) δ 8.10 (s, 1H), 7.86 (s, 1H), 7.43 (m, 5H), 7.18 - 6.88 (m, 4H), 5.19 (s, 2H), 4.72 ( s, 2H), 4.41 (m, 2H), 2.89 (m, 2H), 2.26 (m, 4H), 1.63 (m, 1H), 1.35 - 1.19 (m, 1H).

화합물 22. 4-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)피콜린아미드Compound 22. 4-(3-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)picolinamide

Figure pat00025
Figure pat00025

6-클로로-1H-인다졸-3-카복실산 대신 4-(3-클로로페닐)피콜린산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 22를 합성하였다. Compound 22 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-(3-chlorophenyl)picolinic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H), 9.58 (t, J = 6.4 Hz, 1H), 8.76 (d, J = 5.1 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 5.1, 2.0 Hz, 1H), 7.84 (m, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.64 - 7.54 (m, 3H), 7.50 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.65 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.90 (m, 1H), 2.64 - 2.55 (m, 1H), 2.44 - 2.30 (m, 1H), 2.00 (m, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.98 (s, 1H) , 9.58 (t, J = 6.4 Hz, 1H), 8.76 (d, J = 5.1 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.00 (dd, J = 5.1, 2.0 Hz, 1H), 7.84 (m, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.64 - 7.54 (m, 3H), 7.50 ( d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.65 (d, J = 6.3 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.31 ( d, J = 17.4 Hz, 1H), 2.90 (m, 1H), 2.64 - 2.55 (m, 1H), 2.44 - 2.30 (m, 1H), 2.00 (m, 1H).

화합물 23. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-5-페닐-1H-피라졸-3-카르복사미드Compound 23. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-5-phenyl-1H-pyrazole- 3-Carboxamide

Figure pat00026
Figure pat00026

6-클로로-1H-인다졸-3-카복실산 대신 1-메틸-5-페닐-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 23을 합성하였다. Compound 23 was synthesized in the same manner as in the synthesis method of Compound 1, using 1-methyl-5-phenyl-1H-pyrazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H), 8.88 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 - 7.55 (m, 3H), 7.54 - 7.45 (m, 4H), 6.80 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.92 (s, 3jH), 2.98 - 2.82 (m, 1H), 2.64 - 2.54 (m, 1H), 2.44 - 2.32 (m, 1H), 2.00 (m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 10.98 (s, 1H), 8.88 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.60 - 7.55 (m, 3H), 7.54 - 7.45 (m, 4H), 6.80 (s, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.55 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H) ), 4.31 (d, J = 17.3 Hz, 1H), 3.92 (s, 3jH), 2.98 - 2.82 (m, 1H), 2.64 - 2.54 (m, 1H), 2.44 - 2.32 (m, 1H), 2.00 ( m, 1H).

화합물 24. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-3-페닐-1H-피라졸-5-카르복사미드Compound 24. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-3-phenyl-1H-pyrazole- 5-Carboxamide

Figure pat00027
Figure pat00027

6-클로로-1H-인다졸-3-카복실산 대신 1-메틸-3-페닐-1H-피라졸-5-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 24를 합성하였다. Compound 24 was synthesized in the same manner as in the synthesis method of Compound 1, using 1-methyl-3-phenyl-1H-pyrazole-5-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H), 9.20 (t, J = 6.0 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.72 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.44 (m, 2H), 7.37 - 7.29 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 4.12 (s, 3H), 2.97 - 2.86 (m, 1H), 2.65 - 2.56 (m, 1H), 2.37 (m, 1H), 2.06 - 1.97 (m, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.98 (s, 1H) , 9.20 (t, J = 6.0 Hz, 1H), 7.80 - 7.75 (m, 2H), 7.72 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.44 (m, 2H), 7.37 - 7.29 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H) ), 4.59 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 4.12 (s, 3H), 2.97 - 2.86 (m , 1H), 2.65 - 2.56 (m, 1H), 2.37 (m, 1H), 2.06 - 1.97 (m, 1H).

화합물 25. 5-(2,4-디클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-3-카르복사미드Compound 25. 5-(2,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H- Pyrazole-3-carboxamide

Figure pat00028
Figure pat00028

6-클로로-1H-인다졸-3-카복실산 대신 5-(2,4-디클로로페닐)-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 25를 합성하였다. Compound 25 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-(2,4-dichlorophenyl)-1H-pyrazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 13.85 (s, 1H), 10.98 (s, 1H), 9.12 (s, 1H), 7.87 - 7.66 (m, 3H), 7.64 - 7.35 (m, 4H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.91 (m,1H), 2.63 - 2.56 (m, 1H), 2.42 - 2.31 (m, 1H), 2.04 - 1.96 (m, 1H). 1 H NMR (400 MHz, DMSO) δ 13.85 (s, 1H), 10.98 (s, 1H), 9.12 (s, 1H), 7.87 - 7.66 (m, 3H), 7.64 - 7.35 (m, 4H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.91 (m,1H), 2.63 - 2.56 (m, 1H), 2.42 - 2.31 (m, 1H), 2.04 - 1.96 (m, 1H).

화합물 26. 6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]티아졸-2-카르복사미드Compound 26. 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]thiazole-2-carb copy mid

Figure pat00029
Figure pat00029

6-클로로-1H-인다졸-3-카복실산 대신 6-클로로벤조[d]티아졸-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 26을 합성하였다. Compound 26 was synthesized in the same manner as in the synthesis method of Compound 1, using 6-chlorobenzo[d]thiazole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d 6) δ 10.98 (s, 1H), 9.90 (t, J = 6.3 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.59 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.93 - 2.85 (m, 1H), 2.60 (m, 1H), 2.40 - 2.32 (m, 1H), 2.03 - 1.95 (m, 1H). 1H NMR (400 MHz, DMSO- d6 ) δ 10.98 (s, 1H) , 9.90 (t, J = 6.3 Hz, 1H), 8.42 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 7.75 - 7.66 (m, 2H), 7.59 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 ( d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.93 - 2.85 (m, 1H), 2.60 (m, 1H), 2.40 - 2.32 (m, 1H), 2.03 - 1.95 (m, 1H).

화합물 27. 4-브로모-3-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드Compound 27. 4-Bromo-3-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl) -1H-pyrazole-5-carboxamide

Figure pat00030
Figure pat00030

6-클로로-1H-인다졸-3-카복실산 대신 4-브로모-3-(3-클로로페닐)-1H-피라졸-5-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 27을 합성하였다. Compound 27 was synthesized in the same manner as in the synthesis of Compound 1, using 4-bromo-3-(3-chlorophenyl)-1H-pyrazole-5-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid. did

1H NMR (400 MHz, DMSO-d 6) δ 14.11 (s, 1H), 10.99 (s, 1H), 8.99 (m, 1H), 7.81 (s, 1H), 7.74 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.62 - 7.55 (m, 3H), 7.49 (d, J = 7.8 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 6.1 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.60 (m, 1H), 2.44 - 2.31 (m, 1H), 2.00 (m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 14.11 (s, 1H), 10.99 (s, 1H), 8.99 (m, 1H), 7.81 (s, 1H), 7.74 (d, J = 7.0 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.62 - 7.55 (m, 3H), 7.49 (d, J = 7.8 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 6.1 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.60 (m, 1H), 2.44 - 2.31 (m, 1H), 2.00 (m, 1H).

화합물 28. 5-(2,5-디클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-3-카르복사미드Compound 28. 5-(2,5-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H- Pyrazole-3-carboxamide

Figure pat00031
Figure pat00031

6-클로로-1H-인다졸-3-카복실산 대신 5-(2,5-디클로로페닐)-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 28을 합성하였다. Compound 28 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-(2,5-dichlorophenyl)-1H-pyrazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d 6) δ 14.03 (s, 0.5H), 13.75 (s, 0.4H), 10.99 (s, 1H), 9.27 (s, 0.5H), 8.99 (s, 0.5H), 7.89 - 7.42 (m, 7H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (m, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.64 - 2.56 (m, 1H), 2.43 - 2.29 (m, 1H), 2.05 - 1.95 (m, 1H). 1 H NMR (400 MHz, DMSO- d 6 ) δ 14.03 (s, 0.5H), 13.75 (s, 0.4H), 10.99 (s, 1H), 9.27 (s, 0.5H), 8.99 (s, 0.5H) ), 7.89 - 7.42 (m, 7H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.60 (m, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H). 17.3 Hz, 1H), 2.91 (m, 1H), 2.64 - 2.56 (m, 1H), 2.43 - 2.29 (m, 1H), 2.05 - 1.95 (m, 1H).

화합물 29. 5-(2,4-디메틸페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-3-카르복사미드Compound 29. 5-(2,4-Dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H- Pyrazole-3-carboxamide

Figure pat00032
Figure pat00032

6-클로로-1H-인다졸-3-카복실산 대신 5-(2,4-디메틸페닐)-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 29를 합성하였다.Compound 29 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-(2,4-dimethylphenyl)-1H-pyrazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 13.40 (s, 1H), 11.00 (s, 1H), 8.92 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.20 - 7.05 (m, 2H), 6.78 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.58 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.65 - 2.56 (m, 1H), 2.43 - 2.35 (m, 4H), 2.32 (s, 3H), 2.03 - 1.96 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.40 (s, 1H), 11.00 (s, 1H), 8.92 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.37 (s, 1H), 7.20 - 7.05 (m, 2H), 6.78 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H) ), 4.58 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.65 - 2.56 (m , 1H), 2.43 - 2.35 (m, 4H), 2.32 (s, 3H), 2.03 - 1.96 (m, 1H).

화합물 30. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-[1,1'-비페닐]-3-카르복사미드Compound 30. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-[1,1'-biphenyl]-3-car copy mid

Figure pat00033
Figure pat00033

6-클로로-1H-인다졸-3-카복실산 대신 [1,1'-비페닐]-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 30을 합성하였다.Compound 30 was synthesized in the same manner as in the synthesis method of Compound 1, using [1,1'-biphenyl]-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.30 (t, J = 6.0 Hz, 1H), 8.21 (t, J = 1.8 Hz, 1H), 7.91 (dt, J = 7.8, 1.3 Hz, 1H), 7.86 (m, 1H), 7.78 - 7.74 (m, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.51 (m, 3H), 7.45 - 7.36 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.60 (m, 1H), 2.45 - 2.34 (m, 1H), 2.03 - 1.95 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 9.30 (t, J = 6.0 Hz, 1H), 8.21 (t, J = 1.8 Hz, 1H), 7.91 (dt, J = 7.8, 1.3 Hz, 1H), 7.86 (m, 1H), 7.78 - 7.74 (m, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.62 - 7.57 (m, 2H), 7.51 (m, 3H) ), 7.45 - 7.36 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.64 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.60 (m, 1H), 2.45 - 2.34 (m, 1H), 2.03 - 1.95 (m, 1H).

화합물 31. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸피콜린아미드Compound 31. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methylpicolinamide

Figure pat00034
Figure pat00034

6-클로로-1H-인다졸-3-카복실산 대신 4-메틸피콜린산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 31을 합성하였다.Compound 31 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-methylpicolinic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.46 (t, J = 6.4 Hz, 1H), 8.54 - 8.50 (m, 1H), 7.91 (dd, J = 1.8, 0.9 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.50 - 7.43 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 2.96 - 2.87 (m, 1H), 2.63 - 2.57 (m, 1H), 2.42 (s, 3H), 2.40 - 2.35 (m, 1H), 1.99 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 9.46 (t, J = 6.4 Hz, 1H), 8.54 - 8.50 (m, 1H), 7.91 (dd, J = 1.8, 0.9 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.54 (s, 1H), 7.50 - 7.43 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d , J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.2 Hz, 1H), 2.96 - 2.87 (m, 1H), 2.63 - 2.57 (m, 1H) , 2.42 (s, 3H), 2.40 - 2.35 (m, 1H), 1.99 (m, 1H).

화합물 32. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-페닐피콜린아미드Compound 32. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-phenylpicolinamide

Figure pat00035
Figure pat00035

6-클로로-1H-인다졸-3-카복실산 대신 4-페닐피콜린산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 32를 합성하였다.Compound 32 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-phenylpicolinic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.46 (t, J = 5.9 Hz, 1H), 9.06 (dd, J = 4.7, 2.1 Hz, 2H), 8.54 (t, J = 2.2 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.72 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.57 - 7.51 (m, 3H), 7.49 - 7.45 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.67 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.98 - 2.85 (m, 1H), 2.66 - 2.57 (m, 1H), 2.44 - 2.35 (m, 1H), 2.01 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 9.46 (t, J = 5.9 Hz, 1H), 9.06 (dd, J = 4.7, 2.1 Hz, 2H), 8.54 (t, J = 2.2 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.72 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H), 7.57 - 7.51 (m, 3H), 7.49 - 7.45 (m , 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.67 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz) , 1H), 2.98 - 2.85 (m, 1H), 2.66 - 2.57 (m, 1H), 2.44 - 2.35 (m, 1H), 2.01 (m, 1H).

화합물 33. 6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]옥사졸-2-카르복사미드Compound 33. 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]oxazole-2-carb copy mid

Figure pat00036
Figure pat00036

6-클로로-1H-인다졸-3-카복실산 대신 5-클로로벤조[d]옥사졸-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 33을 합성하였다.Compound 33 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-chlorobenzo[d]oxazole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 10.01 (t, J = 6.3 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.54 - 7.48 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.65 - 2.56 (m, 1H), 2.38 (m, 1H), 2.04 - 1.96 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 10.01 (t, J = 6.3 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.61 - 7.56 (m, 2H), 7.54 - 7.48 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.65 - 2.56 (m, 1H) ), 2.38 (m, 1H), 2.04 - 1.96 (m, 1H).

화합물 34. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드Compound 34. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxamide

Figure pat00037
Figure pat00037

6-클로로-1H-인다졸-3-카복실산 대신 1H-인다졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 34를 합성하였다.Compound 34 was synthesized in the same manner as in the synthesis method of Compound 1, using 1H-indazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 13.64 (s, 1H), 10.99 (s, 1H), 9.13 (t, J = 6.3 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.4, 1.0 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.43 (m, 1H), 7.25 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 1.99 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 13.64 (s, 1H), 10.99 (s, 1H), 9.13 (t, J = 6.3 Hz, 1H), 8.18 (d, J = 8.1 Hz, 1H) , 7.70 (d, J = 7.8 Hz, 1H), 7.63 (dd, J = 8.4, 1.0 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.43 (m, 1H), 7.25 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 ( d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 1.99 (m, 1H).

화합물 35. 3-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-피라졸-5-카르복사미드Compound 35. 3-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-pyrazole -5-carboxamide

Figure pat00038
Figure pat00038

6-클로로-1H-인다졸-3-카복실산 대신 5-브로모-1-메틸-1H-이미다졸-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 35를 합성하였다.Compound 35 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.22 (t, J = 6.0 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.49 - 7.44 (m, 1H), 7.04 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 4.05 (s, 3H), 2.97 - 2.86 (m, 1H), 2.66 - 2.57 (m, 1H), 2.42 - 2.33 (m, 1H), 2.03 - 1.96 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 9.22 (t, J = 6.0 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H) , 7.49 - 7.44 (m, 1H), 7.04 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 4.05 (s, 3H), 2.97 - 2.86 (m, 1H), 2.66 - 2.57 (m, 1H), 2.42 - 2.33 (m, 1H) , 2.03 - 1.96 (m, 1H).

화합물 36. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-인다졸-3-카르복사미드Compound 36. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-indazole-3-carboxa mid

Figure pat00039
Figure pat00039

6-클로로-1H-인다졸-3-카복실산 대신 1-메틸-1H-인다졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 36을 합성하였다.Compound 36 was synthesized in the same manner as in the synthesis method of Compound 1, using 1-methyl-1H-indazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.09 (t, J = 6.3 Hz, 1H), 8.18 (m, 1H), 7.75 (dd, J = 8.5, 0.9 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.53 - 7.43 (m, 2H), 7.28 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.61 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.16 (s, 3H), 2.98 - 2.85 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.05 - 1.96 (m, 1H). 1H NMR (500 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 9.09 (t, J = 6.3 Hz, 1H), 8.18 (m, 1H), 7.75 (dd, J = 8.5, 0.9 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.57 (s, 1H), 7.53 - 7.43 (m, 2H), 7.28 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H) ), 4.61 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 4.16 (s, 3H), 2.98 - 2.85 (m , 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.05 - 1.96 (m, 1H).

화합물 37. 4-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-이미다졸-2-카르복사미드Compound 37. 4-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-imidazole -2-carboxamide

Figure pat00040
Figure pat00040

6-클로로-1H-인다졸-3-카복실산 대신 1-메틸-1H-인다졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 37을 합성하였다.Compound 37 was synthesized in the same manner as in the synthesis method of Compound 1, using 1-methyl-1H-indazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, MeOD) δ 7.79 - 7.75 (m, 1H), 7.56 (m, 1H), 7.53 - 7.48 (m, 1H), 7.28 (s, 1H), 5.14 (dd, J = 13.4, 5.2 Hz, 1H), 4.63 (s, 2H), 4.50 (d, J = 17.0 Hz, 1H), 4.44 (d, J = 17.1 Hz, 1H), 3.99 (s, 3H), 2.95 - 2.85 (m, 1H), 2.77 (m, 1H), 2.48 (m, 1H), 2.21 - 2.12 (m, 1H). 1 H NMR (500 MHz, MeOD) δ 7.79 - 7.75 (m, 1H), 7.56 (m, 1H), 7.53 - 7.48 (m, 1H), 7.28 (s, 1H), 5.14 (dd, J = 13.4, 5.2 Hz, 1H), 4.63 (s, 2H), 4.50 (d, J = 17.0 Hz, 1H), 4.44 (d, J = 17.1 Hz, 1H), 3.99 (s, 3H), 2.95 - 2.85 (m, 1H), 2.77 (m, 1H), 2.48 (m, 1H), 2.21 - 2.12 (m, 1H).

화합물 38. 4-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-피롤-2-카르복사미드Compound 38. 4-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-pyrrole- 2-Carboxamide

Figure pat00041
Figure pat00041

6-클로로-1H-인다졸-3-카복실산 대신 4-브로모-1-메틸-1H-피롤-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 38을 합성하였다.Compound 38 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.75 (t, J = 6.1 Hz, 1H), 7.69 (dd, J = 7.9, 0.7 Hz, 1H), 7.51 (d, J = 1.4 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.13 (d, J = 1.9 Hz, 1H), 6.94 (d, J = 1.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.83 (s, 3H), 2.96 - 2.87 (m, 1H), 2.65 - 2.56 (m, 1H), 2.44 - 2.35 (m, 1H), 2.00 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 8.75 (t, J = 6.1 Hz, 1H), 7.69 (dd, J = 7.9, 0.7 Hz, 1H), 7.51 (d, J = 1.4 Hz, 1H), 7.47 - 7.42 (m, 1H), 7.13 (d, J = 1.9 Hz, 1H), 6.94 (d, J = 1.9 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.83 (s, 3H), 2.96 - 2.87 (m, 1H), 2.65 - 2.56 (m, 1H), 2.44 - 2.35 (m, 1H), 2.00 (m, 1H).

화합물 39. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-4-페닐-1H-피롤-2-카르복사미드Compound 39. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-4-phenyl-1H-pyrrole-2 -Carboxamide

Figure pat00042
Figure pat00042

6-클로로-1H-인다졸-3-카복실산 대신 1-메틸-4-페닐-1H-피롤-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 39를 합성하였다.Compound 39 was synthesized in the same manner as in the synthesis method of Compound 1, using 1-methyl-4-phenyl-1H-pyrrole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.76 (t, J = 6.1 Hz, 1H), 7.72 - 7.69 (m, 1H), 7.55 (s, 1H), 7.53 - 7.50 (m, 2H), 7.48 (d, J = 7.7 Hz, 0H), 7.44 (d, J = 1.9 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.19 - 7.14 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.89 (s, 3H), 2.90 (m, 1H), 2.66 - 2.56 (m, 1H), 2.44 - 2.33 (m, 1H), 2.04 - 1.97 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 8.76 (t, J = 6.1 Hz, 1H), 7.72 - 7.69 (m, 1H), 7.55 (s, 1H), 7.53 - 7.50 (m, 2H), 7.48 (d, J = 7.7 Hz, 0H), 7.44 (d, J = 1.9 Hz, 1H), 7.38 - 7.33 (m, 1H), 7.28 (d, J = 2.0 Hz, 1H) ), 7.19 - 7.14 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.89 (s, 3H), 2.90 (m, 1H), 2.66 - 2.56 (m, 1H), 2.44 - 2.33 (m, 1H), 2.04 - 1.97 (m, 1H) ).

화합물 40. 4-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-피롤-2-카르복사미드Compound 40. 4-(3-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl- 1H-pyrrole-2-carboxamide

Figure pat00043
Figure pat00043

6-클로로-1H-인다졸-3-카복실산 대신 4-(3-클로로페닐)-1-메틸-1H-피롤-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 40을 합성하였다.Compound 40 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-(3-chlorophenyl)-1-methyl-1H-pyrrole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.74 (t, J = 6.1 Hz, 1H), 7.71 (dd, J = 7.8, 0.7 Hz, 1H), 7.56 (m, 3H), 7.51 - 7.45 (m, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.21 (m, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.88 (s, 3H), 2.98 - 2.84 (m, 1H), 2.65 - 2.58 (m, 1H), 2.44 - 2.35 (m, 1H), 2.00 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 8.74 (t, J = 6.1 Hz, 1H), 7.71 (dd, J = 7.8, 0.7 Hz, 1H), 7.56 (m, 3H), 7.51 - 7.45 (m, 2H), 7.38 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.21 (m, 1H), 5.12 (dd, J = 13.3 , 5.1 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.88 (s, 3H), 2.98 - 2.84 (m, 1H), 2.65 - 2.58 (m, 1H), 2.44 - 2.35 (m, 1H), 2.00 (m, 1H).

화합물 41. 5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-이소부틸-4-메틸-1H-피라졸-3 -카르복사미드Compound 41. 5-(3-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-isobutyl -4-methyl-1H-pyrazole-3-carboxamide

Figure pat00044
Figure pat00044

6-클로로-1H-인다졸-3-카복실산 대신 5-(3-클로로페닐)-1-이소부틸-4-메틸-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 41을 합성하였다.6-chloro-1H-indazole-3-carboxylic acid was replaced with 5-(3-chlorophenyl)-1-isobutyl-4-methyl-1H-pyrazole-3-carboxylic acid in the same manner as in the synthesis method of Compound 1. Compound 41 was synthesized.

1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.73 (t, J = 6.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.62 - 7.46 (m, 5H), 7.38 (m, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.54 (d, J = 6.3 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.86 (d, J = 7.3 Hz, 2H), 2.92 (m, 1H), 2.62 (m, 1H), 2.39 (m, 1H), 2.11 (s, 3H), 2.06 - 1.97 (m, 3fH), 0.71 (d, J = 6.7 Hz, 6H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 8.73 (t, J = 6.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.62 - 7.46 (m, 5H), 7.38 (m, 1H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.54 (d, J = 6.3 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 ( d, J = 17.3 Hz, 1H), 3.86 (d, J = 7.3 Hz, 2H), 2.92 (m, 1H), 2.62 (m, 1H), 2.39 (m, 1H), 2.11 (s, 3H), 2.06 - 1.97 (m, 3fH), 0.71 (d, J = 6.7 Hz, 6H).

화합물 42. 5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1-페닐-1H-피라졸-3 -카르복사미드Compound 42. 5-(3-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl- 1-phenyl-1H-pyrazole-3-carboxamide

Figure pat00045
Figure pat00045

6-클로로-1H-인다졸-3-카복실산 대신 5-(3-클로로페닐)-4-메틸-1-페닐-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 42를 합성하였다.The compound was prepared in the same manner as in the synthesis method of Compound 1, using 5-(3-chlorophenyl)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid. 42 was synthesized.

1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.96 (t, J = 6.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.50 - 7.26 (m, 9H), 7.19 (dt, J = 7.3, 1.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.57 (d, J = 6.3 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.99 - 2.84 (m, 1H), 2.64 - 2.58 (m, 1H), 2.37 (m, 1H), 2.24 (s, 3H), 2.00 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 8.96 (t, J = 6.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H) , 7.50 - 7.26 (m, 9H), 7.19 (dt, J = 7.3, 1.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.57 (d, J = 6.3 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.99 - 2.84 (m, 1H), 2.64 - 2.58 (m, 1H), 2.37 (m, 1H), 2.24 (s, 3H), 2.00 (m, 1H).

화합물 43. 5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-(4-플루오로페닐)-4-메틸-1H-피라졸-3-카르복사미드Compound 43. 5-(3-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-(4 -Fluorophenyl)-4-methyl-1H-pyrazole-3-carboxamide

Figure pat00046
Figure pat00046

6-클로로-1H-인다졸-3-카복실산 대신 5-(3-클로로페닐)-1-(4-플루오로벤질)-4-메틸-1H-피라졸-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 43을 합성하였다. of compound 1 using 5-(3-chlorophenyl)-1-(4-fluorobenzyl)-4-methyl-1H-pyrazole-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid Compound 43 was synthesized in the same manner as in the synthesis method.

1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.81 (t, J = 6.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.57 - 7.45 (m, 4H), 7.37 (t, J = 2.0 Hz, 1H), 7.27 (dt, J = 7.1, 1.6 Hz, 1H), 7.14 - 7.07 (m, 2H), 7.03 - 6.96 (m, 2H), 5.29 (s, 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.54 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.66 - 2.55 (m, 1H), 2.44 - 2.33 (m, 1H), 2.13 (s, 3H), 2.01 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 8.81 (t, J = 6.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.57 - 7.45 (m, 4H), 7.37 (t, J = 2.0 Hz, 1H), 7.27 (dt, J = 7.1, 1.6 Hz, 1H), 7.14 - 7.07 (m, 2H), 7.03 - 6.96 (m, 2H), 5.29 (s) , 2H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.54 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz) , 1H), 2.92 (m, 1H), 2.66 - 2.55 (m, 1H), 2.44 - 2.33 (m, 1H), 2.13 (s, 3H), 2.01 (m, 1H).

화합물 44. 5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-(4-플루오로페닐)-4-메틸-1H -피라졸-3-카르복사미드Compound 44. 5-(3-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-(4 -fluorophenyl)-4-methyl-1H -pyrazole-3-carboxamide

Figure pat00047
Figure pat00047

6-클로로-1H-인다졸-3-카복실산 대신 5-클로로벤조[d]티아졸-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 44를 합성하였다. Compound 44 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-chlorobenzo[d]thiazole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (300 MHz, DMSO) δ 10.99 (s, 1H), 9.93 (t, J = 6.3 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.66 (dd, J = 8.7, 2.1 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.62 (d, J = 6.2 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.99 - 2.84 (m, 1H), 2.60 (m, 1H), 2.45 - 2.33 (m, 1H), 2.05 - 1.95 (m, 1H). 1H NMR (300 MHz, DMSO) δ 10.99 (s, 1H), 9.93 (t, J = 6.3 Hz, 1H), 8.30 (d, J = 8.7 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.66 (dd, J = 8.7, 2.1 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 5.11 ( dd, J = 13.2, 5.1 Hz, 1H), 4.62 (d, J = 6.2 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.99 - 2.84 (m, 1H), 2.60 (m, 1H), 2.45 - 2.33 (m, 1H), 2.05 - 1.95 (m, 1H).

화합물 45. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메틸-4-페닐피콜린아미드Compound 45. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methyl-4-phenylpicolinamide

Figure pat00048
Figure pat00048

6-클로로-1H-인다졸-3-카복실산 대신 5-메틸-4-페닐피콜린산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 45를 합성하였다.Compound 45 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-methyl-4-phenylpicolinic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.50 (t, J = 6.4 Hz, 1H), 8.61 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.58 - 7.42 (m, 7H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.65 - 2.56 (m, 1H), 2.45 - 2.37 (m, 1H), 2.35 (s, 3H), 2.05 - 1.92 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.98 (s, 1H), 9.50 (t, J = 6.4 Hz, 1H), 8.61 (s, 1H), 7.85 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.58 - 7.42 (m, 7H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H) ), 4.30 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.65 - 2.56 (m, 1H), 2.45 - 2.37 (m, 1H), 2.35 (s, 3H), 2.05 - 1.92 ( m, 1H).

화합물 46. 5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-페닐피콜린아미드Compound 46. 5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-phenylpicolinamide

Figure pat00049
Figure pat00049

6-클로로-1H-인다졸-3-카복실산 대신 5-클로로-4-페닐피콜린산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 46을 합성하였다.Compound 46 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-chloro-4-phenylpicolinic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.60 (t, J = 6.4 Hz, 1H), 8.84 (s, 1H), 8.01 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.63 - 7.45 (m, 7H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.4 Hz, 1H), 2.91 (m, 1H), 2.66 - 2.55 (m, 1H), 2.44 - 2.31 (m, 1H) 2.04 - 1.95 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 9.60 (t, J = 6.4 Hz, 1H), 8.84 (s, 1H), 8.01 (s, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.63 - 7.45 (m, 7H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.4 Hz, 1H), 2.91 (m, 1H), 2.66 - 2.55 (m, 1H), 2.44 - 2.31 (m, 1H) 2.04 - 1.95 (m, 1H).

화합물 47. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-페닐피라진-2-카르복사미드Compound 47. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-phenylpyrazine-2-carboxamide

Figure pat00050
Figure pat00050

6-클로로-1H-인다졸-3-카복실산 대신 6-페닐피라진-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 47을 합성하였다.Compound 47 was synthesized in the same manner as in the synthesis method of Compound 1, using 6-phenylpyrazine-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO) δ 10.99 (s, 1H), 9.76 (t, J = 6.4 Hz, 1H), 9.51 (s, 1H), 9.15 (s, 1H), 8.46 - 8.39 (m, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.62 - 7.50 (m, 5H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.70 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.03 - 1.95 (m, 1H). 1H NMR (500 MHz, DMSO) δ 10.99 (s, 1H), 9.76 (t, J = 6.4 Hz, 1H), 9.51 (s, 1H), 9.15 (s, 1H), 8.46 - 8.39 (m, 2H) ), 7.71 (d, J = 7.9 Hz, 1H), 7.62 - 7.50 (m, 5H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.70 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.03 - 1.95 (m, 1H).

화합물 48. 3-(2-클로로-6-플루오로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메틸이속사졸-4-카르복사미드Compound 48. 3-(2-chloro-6-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl) -5-methylisoxazole-4-carboxamide

Figure pat00051
Figure pat00051

6-클로로-1H-인다졸-3-카복실산 대신 3-(2-클로로-6-플루오로페닐)-5-메틸이속사졸-4-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 48을 합성하였다.3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylic acid was used instead of 6-chloro-1H-indazole-3-carboxylic acid in the same manner as in the synthesis method of Compound 1. Compound 48 was synthesized.

1H NMR (500 MHz, DMSO-d6) δ 11.00 (s, 1H), 8.69 (t, J = 6.0 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.62-7.54 (m, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.37-7.34 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 6.4 Hz, 2H), 4.40 (s, 1H), 4.29 (d, J = 17.3 Hz, 1H), 2.97-2.86 (m, 1H), 2.67 (s, 3H), 2.64-2.57 (m, 1H), 2.47-2.35 (m, 1H), 2.03-1.97 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 8.69 (t, J = 6.0 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.62-7.54 (m, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.40 (s, 1H), 7.39 (d, J = 8.7 Hz, 1H), 7.37–7.34 (m, 1H), 5.11 (dd, J = 13.3 , 5.1 Hz, 1H), 4.44 (d, J = 6.4 Hz, 2H), 4.40 (s, 1H), 4.29 (d, J = 17.3 Hz, 1H), 2.97–2.86 (m, 1H), 2.67 (s , 3H), 2.64–2.57 (m, 1H), 2.47–2.35 (m, 1H), 2.03–1.97 (m, 1H).

화합물 49. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-페닐-1H-피라졸-5-카르복사미드Compound 49. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-phenyl-1H-pyrazole-5-carboxa mid

Figure pat00052
Figure pat00052

6-클로로-1H-인다졸-3-카복실산 대신 3-페닐-1H-피라졸-5-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 49를 합성하였다.Compound 49 was synthesized in the same manner as in the synthesis method of Compound 1, using 3-phenyl-1H-pyrazole-5-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (300 MHz, DMSO-d6) δ 13.71 (s, 1H), 10.99 (s, 1H), 8.99 (s, 1H), 7.83-7.75 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.47 (t, J = 7.5 Hz, 3H), 7.37 (t, J = 7.3 Hz, 1H), 7.15 (s, 1H), 5.10 (dd, J = 13.2, 5.1 Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.97-2.83 (m, 1H), 2.63 (s, 1H), 2.44-2.26 (m, 1H), 2.05-1.93 (m, 1H). 1 H NMR (300 MHz, DMSO-d 6 ) δ 13.71 (s, 1H), 10.99 (s, 1H), 8.99 (s, 1H), 7.83-7.75 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.47 (t, J = 7.5 Hz, 3H), 7.37 (t, J = 7.3 Hz, 1H), 7.15 (s, 1H), 5.10 (dd, J = 13.2 , 5.1 Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.97–2.83 (m, 1H) ), 2.63 (s, 1H), 2.44–2.26 (m, 1H), 2.05–1.93 (m, 1H).

화합물 50. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-페닐-5-(트리플루오로메틸)-1H-피라졸-4-카르복사미드Compound 50. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-phenyl-5-(trifluoromethyl)- 1H-pyrazole-4-carboxamide

Figure pat00053
Figure pat00053

6-클로로-1H-인다졸-3-카복실산 대신 1-(시클로헥사-1,5-디엔-1-일)-5-(트리플루오로메틸)-1H-피라졸-4-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 50을 합성하였다.1-(cyclohexa-1,5-dien-1-yl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid Compound 50 was synthesized in the same manner as in the synthesis method of Compound 1 using the same method.

1H NMR (300 MHz, DMSO) δ 11.00 (s, 1H), 9.23 (t, J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.63 - 7.46 (m, 7H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 4.47 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.03 - 2.82 (m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 2.01 (m, 1H). 1H NMR (300 MHz, DMSO) δ 11.00 (s, 1H), 9.23 (t, J = 6.0 Hz, 1H), 8.23 (s, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.63 - 7.46 (m, 7H), 5.12 (dd, J = 13.2, 5.1 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 4.47 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 3.03 - 2.82 (m, 1H), 2.60 (m, 1H), 2.40 (m, 1H), 2.01 (m, 1H).

화합물 51. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-[1,1'-비페닐]-4-카르복사미드Compound 51. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-[1,1′-biphenyl]-4-carb copy mid

Figure pat00054
Figure pat00054

6-클로로-1H-인다졸-3-카복실산 대신 [1,1'-비페닐]-4-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 51을 합성하였다.Compound 51 was synthesized in the same manner as in the synthesis method of Compound 1, using [1,1'-biphenyl]-4-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 9.23 (t, J = 6.0 Hz, 1H), 8.04 - 8.00 (m, 2H), 7.83 - 7.79 (m, 2H), 7.77 - 7.73 (m, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.54 - 7.47 (m, 3H), 7.45 - 7.40 (m, 1H), 5.12 (dd, J = 13.4, 5.1 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.67 - 2.57 (m, 1H), 2.39 (m, 1H), 2.07 - 1.94 (m, 1H). 1H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 9.23 (t, J = 6.0 Hz, 1H), 8.04 - 8.00 (m, 2H), 7.83 - 7.79 (m, 2H), 7.77 - 7.73 (m, 2H), 7.71 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.54 - 7.47 (m, 3H), 7.45 - 7.40 (m, 1H), 5.12 (dd, J = 13.4 , 5.1 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.67 - 2.57 (m, 1H), 2.39 (m, 1H), 2.07 - 1.94 (m, 1H).

화합물 52. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-[1,1'-비페닐]-2-카르복사미드Compound 52. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-[1,1'-biphenyl]-2-carb copy mid

Figure pat00055
Figure pat00055

6-클로로-1H-인다졸-3-카복실산 대신 [1,1'-비페닐]-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 52를 합성하였다.Compound 52 was synthesized in the same manner as in the synthesis method of Compound 1, using [1,1'-biphenyl]-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.74 (t, J = 6.0 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.51 (td, J = 7.4, 1.7 Hz, 1H), 7.47 (dd, J = 7.6, 1.7 Hz, 1H), 7.45-7.41 (m, 1H), 7.39 (dd, J = 7.6, 1.3 Hz, 1H), 7.36-7.29 (m, 5H), 7.18 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.41-4.34 (m, 3H), 4.26 (d, J = 17.2 Hz, 1H), 2.98-2.87 (m, 1H), 2.64-2.57 (m, 1H), 2.48-2.38 (m, 1H), 2.04-1.97 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.01 (s, 1H), 8.74 (t, J = 6.0 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.51 (td, J = 7.4, 1.7 Hz, 1H), 7.47 (dd, J = 7.6, 1.7 Hz, 1H), 7.45–7.41 (m, 1H), 7.39 (dd, J = 7.6, 1.3 Hz, 1H), 7.36–7.29 (m , 5H), 7.18 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.41–4.34 (m, 3H), 4.26 (d, J = 17.2 Hz, 1H), 2.98–2.87 (m, 1H), 2.64–2.57 (m, 1H), 2.48–2.38 (m, 1H), 2.04–1.97 (m, 1H).

화합물 53. 1-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)시클로펜탄-1-카르복사미드Compound 53. 1-(4-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)cyclopentane-1- carboxamide

Figure pat00056
Figure pat00056

6-클로로-1H-인다졸-3-카복실산 대신 1-(4-클로로페닐)시클로펜탄-1-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 53을 합성하였다.Compound 53 was synthesized in the same manner as in the synthesis method of Compound 1, using 1-(4-chlorophenyl)cyclopentane-1-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.21 (t, J = 6.1 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.42-7.34 (m, 4H), 7.17 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 5.09 (dd, J = 13.4, 5.1 Hz, 1H), 4.32 (d, J = 17.2 Hz, 1H), 4.28 (d, J = 6.0 Hz, 2H), 4.18 (d, J = 17.2 Hz, 1H), 2.95-2.86 (m, 1H), 2.64-2.54 (m, 3H), 2.43-2.30 (m, 1H), 2.03-1.96 (m, 1H), 1.85-1.77 (m, 2H), 1.67-1.54 (m, 4H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 8.21 (t, J = 6.1 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H), 7.42-7.34 (m, 4H), 7.17 (d, J = 8.0 Hz, 1H), 7.02 (s, 1H), 5.09 (dd, J = 13.4, 5.1 Hz, 1H), 4.32 (d, J = 17.2 Hz, 1H), 4.28 ( d, J = 6.0 Hz, 2H), 4.18 (d, J = 17.2 Hz, 1H), 2.95-2.86 (m, 1H), 2.64-2.54 (m, 3H), 2.43-2.30 (m, 1H), 2.03 -1.96 (m, 1H), 1.85-1.77 (m, 2H), 1.67-1.54 (m, 4H).

화합물 54. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-페닐시클로펜탄-1-카르복사미드Compound 54. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-phenylcyclopentane-1-carboxamide

Figure pat00057
Figure pat00057

6-클로로-1H-인다졸-3-카복실산 대신 1-페닐시클로펜탄-1-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 54를 합성하였다.Compound 54 was synthesized in the same manner as in the synthesis method of Compound 1, using 1-phenylcyclopentane-1-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.40-7.22 (m, 6H), 7.18-7.12 (m, 1H), 7.04 (s, 1H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.32 (d, J = 17.2 Hz, 3H), 4.18 (d, J = 17.3 Hz, 1H), 2.97-2.84 (m, 1H), 2.60 (d, J = 15.9 Hz, 3H), 2.44-2.26 (m, 1H), 2.06-1.92 (m, 1H), 1.91-1.76 (m, 2H), 1.69-1.55 (m, 4H). 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.40-7.22 (m, 6H), 7.18-7.12 (m, 1H), 7.04 (s, 1H), 5.08 (dd, J = 13.2, 5.1 Hz, 1H), 4.32 (d, J = 17.2 Hz, 3H), 4.18 (d, J = 17.3 Hz, 1H), 2.97–2.84 (m , 1H), 2.60 (d, J = 15.9 Hz, 3H), 2.44–2.26 (m, 1H), 2.06–1.92 (m, 1H), 1.91–1.76 (m, 2H), 1.69–1.55 (m, 4H) ).

화합물 55. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-2-옥소-1-페닐피롤리딘-3-카르복사미드Compound 55. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-1-phenylpyrrolidin-3- carboxamide

Figure pat00058
Figure pat00058

6-클로로-1H-인다졸-3-카복실산 대신 2-옥소-1-페닐피롤리딘-3-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 55를 합성하였다.Compound 55 was synthesized in the same manner as in the synthesis method of Compound 1, using 2-oxo-1-phenylpyrrolidine-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.84 (t, J = 5.9 Hz, 1H), 7.68 (dd, J = 9.8, 7.9 Hz, 3H), 7.55 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.43-7.36 (m, 2H), 7.20-7.13 (m, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.57-4.38 (m, 3H), 4.31 (dd, J = 17.4, 2.9 Hz, 1H), 3.95-3.81 (m, 2H), 2.97-2.85 (m, 1H), 2.63 (s, 1H), 2.46-2.28 (m, 3H), 2.05-1.95 (m, 1H). 1 H NMR (300 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 8.84 (t, J = 5.9 Hz, 1H), 7.68 (dd, J = 9.8, 7.9 Hz, 3H), 7.55 (s, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.43-7.36 (m, 2H), 7.20-7.13 (m, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.57-4.38 (m, 3H), 4.31 (dd, J = 17.4, 2.9 Hz, 1H), 3.95–3.81 (m, 2H), 2.97–2.85 (m, 1H), 2.63 (s, 1H), 2.46–2.28 (m) , 3H), 2.05–1.95 (m, 1H).

화합물 56. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조푸란-2-카르복사미드Compound 56. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzofuran-2-carboxamide

Figure pat00059
Figure pat00059

6-클로로-1H-인다졸-3-카복실산 대신 벤조푸란-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 56을 합성하였다.Compound 56 was synthesized in the same manner as in the synthesis method of Compound 1, using benzofuran-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 9.44 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.69 (dd, J = 17.0, 8.2 Hz, 2H), 7.60 (s, 1H), 7.57 (s, 1H), 7.49 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.61 (d, J = 5.9 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.60 (m, 1H), 2.39 (m, 1H), 2.01 (m, 1H). 1H NMR (500 MHz, DMSO) δ 11.00 (s, 1H), 9.44 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.69 (dd, J = 17.0, 8.2 Hz, 2H), 7.60 (s, 1H), 7.57 (s, 1H), 7.49 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H) ), 4.61 (d, J = 5.9 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.97 - 2.85 (m, 1H), 2.60 (m , 1H), 2.39 (m, 1H), 2.01 (m, 1H).

화합물 57. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메톡시-1H-인돌-2-카르복사미드Compound 57. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methoxy-1H-indole-2-carboxa mid

Figure pat00060
Figure pat00060

6-클로로-1H-인다졸-3-카복실산 대신 5-메톡시-1H-인돌-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 57을 합성하였다.Compound 57 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-methoxy-1H-indole-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 11.46 (d, J = 2.2 Hz, 1H), 10.99 (s, 1H), 9.09 (t, J = 6.1 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.10 (dd, J = 6.2, 2.2 Hz, 2H), 6.84 (dd, J = 8.9, 2.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.76 (s, 3H), 2.91 (m, 1H), 2.65 - 2.58 (m, 1H), 2.38 (m, 1H), 2.00 (m, 1H). 1H NMR (400 MHz, DMSO) δ 11.46 (d, J = 2.2 Hz, 1H), 10.99 (s, 1H), 9.09 (t, J = 6.1 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.10 (dd, J = 6.2, 2.2 Hz, 2H), 6.84 ( dd, J = 8.9, 2.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.76 (s, 3H), 2.91 (m, 1H), 2.65 - 2.58 (m, 1H), 2.38 (m, 1H), 2.00 (m, 1H).

화합물 58. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[b]티오펜-2-카르복사미드Compound 58. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[b]thiophene-2-carboxamide

Figure pat00061
Figure pat00061

6-클로로-1H-인다졸-3-카복실산 대신 벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 58을 합성하였다.Compound 58 was synthesized in the same manner as in the synthesis method of Compound 1, using benzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.43 (t, J = 6.0 Hz, 1H), 8.16 (s, 1H), 8.05 - 8.02 (m, 1H), 7.96 (m, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.53 - 7.40 (m, 3H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.00 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.43 (t, J = 6.0 Hz, 1H), 8.16 (s, 1H), 8.05 - 8.02 (m, 1H), 7.96 (m, 1H) ), 7.72 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.53 - 7.40 (m, 3H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H) , 2.00 (m, 1H).

화합물 59. 7-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-히드록시퀴놀린-3-카르복사미드Compound 59. 7-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-hydroxyquinoline-3-carb copy mid

Figure pat00062
Figure pat00062

6-클로로-1H-인다졸-3-카복실산 대신 7-클로로-4-하이드록시퀴놀린-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 59를 합성하였다.Compound 59 was synthesized in the same manner as in the synthesis method of Compound 1, using 7-chloro-4-hydroxyquinoline-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 10.98 (s, 1H), 10.50 - 10.29 (m, 1H), 8.82 (s, 0.5H), 8.73 (s, 0.5H), 8.25 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.56 (s, 1H), 7.54 - 7.43 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.68 (t, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 3.00 - 2.87 (m, 1H), 2.70 - 2.57 (m, 1H), 2.43 - 2.26 (m, 1H), 2.04 - 1.94 (m, 1H). 1H NMR (400 MHz, DMSO) δ 12.75 (s, 1H), 10.98 (s, 1H), 10.50 - 10.29 (m, 1H), 8.82 (s, 0.5H), 8.73 (s, 0.5H), 8.25 (d, J = 8.7 Hz, 1H), 7.77 (d, J = 2.1 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.56 (s, 1H) , 7.54 - 7.43 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.68 (t, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 ( d, J = 17.2 Hz, 1H), 3.00 - 2.87 (m, 1H), 2.70 - 2.57 (m, 1H), 2.43 - 2.26 (m, 1H), 2.04 - 1.94 (m, 1H).

화합물 60. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-2-옥소-2H-크로멘-3-카르복사미드Compound 60. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2H-chromene-3-carboxa mid

Figure pat00063
Figure pat00063

6-클로로-1H-인다졸-3-카복실산 대신 2-옥소-2H-크로멘-3-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 60을 합성하였다.Compound 60 was synthesized in the same manner as in the synthesis method of Compound 1, using 2-oxo-2H-chromene-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.26 (t, J = 6.1 Hz, 1H), 8.89 (s, 1H), 8.00 (dd, J = 7.8, 1.6 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.52 (t, J = 7.9 Hz, 2H),7.45 (t, J = 7.5 Hz, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.67 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.64 - 2.57 (m, 1H), 2.38 (m, 1H), 2.06 - 1.95 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.26 (t, J = 6.1 Hz, 1H), 8.89 (s, 1H), 8.00 (dd, J = 7.8, 1.6 Hz, 1H), 7.80 - 7.74 (m, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.52 (t, J = 7.9 Hz, 2H),7.45 (t, J = 7.5 Hz, 1H) ), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.67 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H) ), 2.92 (m, 1H), 2.64 - 2.57 (m, 1H), 2.38 (m, 1H), 2.06 - 1.95 (m, 1H).

화합물 61. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)신놀린-4-카르복사미드Compound 61. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)cinnoline-4-carboxamide

Figure pat00064
Figure pat00064

6-클로로-1H-인다졸-3-카복실산 대신 신놀린-4-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 61을 합성하였다.Compound 61 was synthesized in the same manner as in the synthesis method of Compound 1, using cinnoline-4-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.66 (t, J = 5.9 Hz, 1H), 9.53 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.08 - 8.02 (m, 1H), 8.00 - 7.94 (m, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.72 (d, J = 5.9 Hz, 2H), 4.49 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.93 (m, 1H), 2.67 - 2.56 (m, 1H), 2.43 - 2.29 (m, 1H), 2.18 - 1.86 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.00 (s, 1H), 9.66 (t, J = 5.9 Hz, 1H), 9.53 (s, 1H), 8.58 (d, J = 8.4 Hz, 1H) , 8.28 (d, J = 8.3 Hz, 1H), 8.08 - 8.02 (m, 1H), 8.00 - 7.94 (m, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 5.13 (dd, J = 13.3, 5.1 Hz, 1H), 4.72 (d, J = 5.9 Hz, 2H), 4.49 (d, J = 17.3 Hz, 1H), 4.36 (d, J = 17.3 Hz, 1H), 2.93 (m, 1H), 2.67 - 2.56 (m, 1H), 2.43 - 2.29 (m, 1H), 2.18 - 1.86 (m, 1H).

화합물 62. 5-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-이소부틸-4-메틸-1H-피라졸-3 -카르복사미드Compound 62. 5-(4-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-isobutyl -4-methyl-1H-pyrazole-3-carboxamide

Figure pat00065
Figure pat00065

6-클로로-1H-인다졸-3-카복실산 대신 5-(4-클로로페닐)-1-이소부틸-4-메틸-1H-피라졸-3-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 62를 합성하였다.6-Chloro-1H-indazole-3-carboxylic acid was replaced with 5-(4-chlorophenyl)-1-isobutyl-4-methyl-1H-pyrazole-3-carboxylic acid. Compound 62 was synthesized by the method.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.71 (t, J = 6.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.54 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.46 - 7.40 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 (d, J = 6.2 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.85 (d, J = 7.3 Hz, 2H), 2.92 (m, 1H), 2.60 (m, 1H), 2.39 (m, 1H), 2.10 (s, 3H), 2.02 (m, 2H), 0.70 (d, J = 6.7 Hz, 6H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.71 (t, J = 6.3 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.54 (s, 1H), 7.47 (d, J = 7.8 Hz, 1H), 7.46 - 7.40 (m, 2H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.54 (d, J = 6.2 Hz) , 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.85 (d, J = 7.3 Hz, 2H), 2.92 (m, 1H), 2.60 (m , 1H), 2.39 (m, 1H), 2.10 (s, 3H), 2.02 (m, 2H), 0.70 (d, J = 6.7 Hz, 6H).

화합물 63. 5-(3-클로로페닐)-1-시클로프로필-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1H-피라졸-3 -카르복사미드Compound 63. 5-(3-Chlorophenyl)-1-cyclopropyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl) -4-methyl-1H-pyrazole-3-carboxamide

Figure pat00066
Figure pat00066

6-클로로-1H-인다졸-3-카복실산 대신 5-(3-클로로페닐)-1-시클로프로필-4-메틸-1H-피라졸-3-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 63을 합성하였다.6-Chloro-1H-indazole-3-carboxylic acid was replaced with 5-(3-chlorophenyl)-1-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylic acid. Compound 63 was synthesized by the method.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.72 (t, J = 6.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 - 7.56 (m, 3H), 7.53 (s, 1H), 7.49 - 7.42 (m, 2H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.66 (m, 1H), 2.92 (m, 1H), 2.60 (m, 1H), 2.44 - 2.29 (m, 1H), 2.13 (s, 3H), 2.00 (m, 1H), 1.01 (m, 2H), 0.87 (m, 2H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.72 (t, J = 6.4 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 - 7.56 (m, 3H), 7.53 (s, 1H), 7.49 - 7.42 (m, 2H), 5.11 (dd, J = 13.3, 5.0 Hz, 1H), 4.53 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.3 Hz) , 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.66 (m, 1H), 2.92 (m, 1H), 2.60 (m, 1H), 2.44 - 2.29 (m, 1H), 2.13 (s, 3H), 2.00 (m, 1H), 1.01 (m, 2H), 0.87 (m, 2H).

화합물 64. 5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1-(2,2,2- 트리플루오로에틸)-1H-피라졸-3-카르복사미드Compound 64. 5-(3-Chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl- 1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide

Figure pat00067
Figure pat00067

6-클로로-1H-인다졸-3-카복실산 대신 5-(3-클로로페닐)-4-메틸-1-(2,2,2-트리플루오로에틸)-1H-피라졸-3-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 64를 합성하였다.5-(3-chlorophenyl)-4-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxyl instead of 6-chloro-1H-indazole-3-carboxylic acid Compound 64 was synthesized in the same manner as in the synthesis method of compound 1 using an acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.80 (t, J = 6.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.54 (m, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.39 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.97 (q, J = 8.9 Hz, 2H), 4.56 (d, J = 6.3 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.64 - 2.56 (m, 1H), 2.38 (m, 1H), 2.11 (s, 3H), 2.04 - 1.99 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.80 (t, J = 6.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.64 - 7.58 (m, 2H), 7.54 (m, 2H), 7.47 (d, J = 7.9 Hz, 1H), 7.39 (m, 1H), 5.11 (dd, J = 13.3, 5.1 Hz, 1H), 4.97 (q, J = 8.9 Hz, 2H) ), 4.56 (d, J = 6.3 Hz, 2H), 4.46 (d, J = 17.4 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.92 (m, 1H), 2.64 - 2.56 (m , 1H), 2.38 (m, 1H), 2.11 (s, 3H), 2.04 - 1.99 (m, 1H).

화합물 65. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메톡시벤조[b]티오펜-2-카르복사미드Compound 65. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methoxybenzo[b]thiophene-2- carboxamide

Figure pat00068
Figure pat00068

6-클로로-1H-인다졸-3-카복실산 대신 5-메톡시벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 65를 합성하였다.Compound 65 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-methoxybenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.39 (t, J = 6.3 Hz, 1H), 8.05 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.44 (s, 1H), 7.11 (d, J = 2.3 Hz, 1H), 5.10 (dd, J = 13.3, 5.0 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 4.50 - 4.41 (m, 1H), 4.36 - 4.27 (m, 1H), 3.83 (s, 3H), 2.97 - 2.84 (m, 1H), 2.64 - 2.55 (m, 1H), 2.45 - 2.33 (m, 1H), 2.04 - 1.95 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.97 (s, 1H), 9.39 (t, J = 6.3 Hz, 1H), 8.05 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H) , 7.71 (d, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.44 (s, 1H), 7.11 (d, J = 2.3 Hz, 1H) , 5.10 (dd, J = 13.3, 5.0 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 4.50 - 4.41 (m, 1H), 4.36 - 4.27 (m, 1H), 3.83 (s, 3H) ), 2.97 - 2.84 (m, 1H), 2.64 - 2.55 (m, 1H), 2.45 - 2.33 (m, 1H), 2.04 - 1.95 (m, 1H).

화합물 66. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메틸벤조[b]티오펜-2-카르복사미드Compound 66. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methylbenzo[b]thiophene-2-carb copy mid

Figure pat00069
Figure pat00069

6-클로로-1H-인다졸-3-카복실산 대신 6-메틸벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 66을 합성하였다.Compound 66 was synthesized in the same manner as in the synthesis method of Compound 1, using 6-methylbenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.36 (t, J = 6.0 Hz, 1H), 8.09 (s, 1H), 7.83 (d, J = 9.2 Hz, 2H), 7.71 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 5.10 (dd, J = 13.4, 4.9 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 4.50 - 4.41 (m, 1H), 4.36 - 4.27 (m, 1H), 2.97 - 2.84 (m, 1H), 2.64 - 2.55 (m, 1H), 2.44 (s, 3H), 2.42 - 2.31 (m, 1H), 2.03 - 1.95 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 9.36 (t, J = 6.0 Hz, 1H), 8.09 (s, 1H), 7.83 (d, J = 9.2 Hz, 2H) , 7.71 (d, J = 7.9 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 5.10 (dd, J = 13.4, 4.9 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 4.50 - 4.41 (m, 1H), 4.36 - 4.27 (m, 1H), 2.97 - 2.84 (m, 1H), 2.64 - 2.55 (m, 1H), 2.44 (s, 3H), 2.42 - 2.31 (m, 1H), 2.03 - 1.95 (m, 1H).

화합물 67. 3-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메틸벤조[b]티오펜-2-카르복사미드Compound 67. 3-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methylbenzo[b]thiophene -2-carboxamide

Figure pat00070
Figure pat00070

6-클로로-1H-인다졸-3-카복실산 대신 3-클로로-6-메틸벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 67을 합성하였다.Compound 67 was synthesized in the same manner as in the synthesis method of Compound 1, using 3-chloro-6-methylbenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.05 (t, J = 6.5 Hz, 1H), 7.91 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 13.0, 4.8 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H), 4.52 - 4.43 (m, 1H), 4.38 - 4.29 (m, 1H), 2.98 - 2.86 (m, 1H), 2.65 - 2.56 (m, 1H), 2.48 (s, 3H), 2.44 - 2.36 (m, 1H), 2.05 - 1.97 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.99 (s, 1H), 9.05 (t, J = 6.5 Hz, 1H), 7.91 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H) , 7.73 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 5.12 (dd, J = 13.0, 4.8 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H), 4.52 - 4.43 (m, 1H), 4.38 - 4.29 (m, 1H), 2.98 - 2.86 (m, 1H), 2.65 - 2.56 (m, 1H), 2.48 (s, 3H), 2.44 - 2.36 (m, 1H), 2.05 - 1.97 (m, 1H).

화합물 68. 3-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메톡시벤조[b]티오펜-2-카르복사미드Compound 68. 3-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methoxybenzo[b]thiol Ophen-2-carboxamide

Figure pat00071
Figure pat00071

6-클로로-1H-인다졸-3-카복실산 대신 3-클로로-6-메톡시벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 68을 합성하였다.Compound 68 was synthesized in the same manner as in the synthesis method of Compound 1, using 3-chloro-6-methoxybenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.94 (t, J = 6.1 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.70-7.66 (m, 1H), 7.59 (s, 1H), 7.55-7.48 (m, 1H), 7.19 (dd, J = 8.9, 2.4 Hz, 1H), 5.15-5.06 (m, 1H), 4.63 (d, J = 5.9 Hz, 2H), 4.51-4.42 (m, 1H), 4.37-4.28 (m, 1H), 3.86 (s, 3H), 2.97-2.85 (m, 1H), 2.64-2.55 (m, 1H), 2.46-2.31 (m, 1H), 2.04-1.96 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 8.94 (t, J = 6.1 Hz, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.70-7.66 (m, 1H), 7.59 (s, 1H), 7.55-7.48 (m, 1H), 7.19 (dd, J = 8.9, 2.4 Hz, 1H), 5.15-5.06 (m , 1H), 4.63 (d, J = 5.9 Hz, 2H), 4.51–4.42 (m, 1H), 4.37–4.28 (m, 1H), 3.86 (s, 3H), 2.97–2.85 (m, 1H), 2.64-2.55 (m, 1H), 2.46-2.31 (m, 1H), 2.04-1.96 (m, 1H).

화합물 69. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5,6-디메톡시벤조[b]티오펜-2-카르복사미드Compound 69. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5,6-dimethoxybenzo[b]thiophene- 2-Carboxamide

Figure pat00072
Figure pat00072

6-클로로-1H-인다졸-3-카복실산 대신 5,6-디메톡시벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 69를 합성하였다.Compound 69 was synthesized in the same manner as in the synthesis method of Compound 1, using 5,6-dimethoxybenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.27 (t, J = 6.5 Hz, 1H), 7.98 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.57 (s, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 5.11 (dd, J = 13.4, 5.0 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.50-4.41 (m, 1H), 4.36-4.28 (m, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 2.97-2.85 (m, 1H), 2.64-2.55 (m, 1H), 2.45-2.35 (m, 1H), 2.04-1.96 (m, 1H). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 9.27 (t, J = 6.5 Hz, 1H), 7.98 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H) , 7.57 (s, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.40 (s, 1H), 5.11 (dd, J = 13.4, 5.0 Hz, 1H), 4.59 (d, J = 5.9 Hz, 2H), 4.50-4.41 (m, 1H), 4.36-4.28 (m, 1H), 3.84 (s, 3H), 3.83 (s, 3H), 2.97-2.85 (m, 1H), 2.64-2.55 (m, 1H), 2.45–2.35 (m, 1H), 2.04–1.96 (m, 1H).

화합물 70. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드Compound 70. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-(trifluoromethyl)benzo[b]thiol Ophen-2-carboxamide

Figure pat00073
Figure pat00073

6-클로로-1H-인다졸-3-카복실산 대신 4-(트리플루오로메틸)벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 70을 합성하였다.Compound 70 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.70 (m, 1H), 8.41 (m, 2H), 7.86 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.64 (d, J = 5.8 Hz, 2H), 4.47 (d, J = 17.3 Hz, 1H), 4.33 (d, J = 17.4 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.43 - 2.27 (m, 1H), 2.01 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.70 (m, 1H), 8.41 (m, 2H), 7.86 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.59 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.64 (d, J = 5.8 Hz, 2H), 4.47 (d, J = 17.3 Hz, 1H), 4.33 (d, J = 17.4 Hz, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.43 - 2.27 (m, 1H), 2.01 (m, 1H).

화합물 71. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-7-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드Compound 71. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-7-(trifluoromethyl)benzo[b]thiol Ophen-2-carboxamide

Figure pat00074
Figure pat00074

6-클로로-1H-인다졸-3-카복실산 대신 7-(트리플루오로메틸)벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 71을 합성하였다.Compound 71 was synthesized in the same manner as in the synthesis method of Compound 1, using 7-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.60 (m, 1H), 8.31 (m, 1H), 7.92 (d, J = 7.5 kjHz, 1H), 7.77 - 7.63 (m, 2H), 7.59 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.2, 4.9 Hz, 1H), 4.64 (d, J = 5.8 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.34 (d, J = 16.0, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.42 - 2.32 (m, 1H), 2.00 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.60 (m, 1H), 8.31 (m, 1H), 7.92 (d, J = 7.5 kjHz, 1H), 7.77 - 7.63 (m, 2H) ), 7.59 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.2, 4.9 Hz, 1H), 4.64 (d, J = 5.8 Hz, 2H), 4.46 (d , J = 17.3 Hz, 1H), 4.34 (d, J = 16.0, 1H), 2.91 (m, 1H), 2.60 (m, 1H), 2.42 - 2.32 (m, 1H), 2.00 (m, 1H).

화합물 72. 3-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드Compound 72. 3-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-(trifluoromethyl)benzo [b]thiophene-2-carboxamide

Figure pat00075
Figure pat00075

6-클로로-1H-인다졸-3-카복실산 대신 3-클로로-6-(트리플루오로메틸)벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 72를 합성하였다.Compound 72 was prepared in the same manner as in the synthesis method of Compound 1, using 3-chloro-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid. was synthesized.

1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.26 (m, 1H), 8.71 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 5.12 (dd, J = 13.3, 4.9 Hz, 1H), 4.66 (d, J = 5.4 Hz, 2H), 4.48 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.4 Hz, 1H), 3.00 - 2.83 (m, 1H), 2.65 - 2.58 (m, 1H), 2.40 (m, 1H), 2.08 - 1.94 (m, 1H). 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.26 (m, 1H), 8.71 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 7.9 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 5.12 (dd, J = 13.3, 4.9 Hz, 1H), 4.66 (d, J = 5.4 Hz, 2H), 4.48 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.4 Hz, 1H), 3.00 - 2.83 (m, 1H), 2.65 - 2.58 (m , 1H), 2.40 (m, 1H), 2.08 - 1.94 (m, 1H).

화합물 73. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드Compound 73. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-(trifluoromethyl)benzo[b]thiol Ophen-2-carboxamide

Figure pat00076
Figure pat00076

6-클로로-1H-인다졸-3-카복실산 대신 5-(트리플루오로메틸)벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 73을 합성하였다.Compound 73 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.60 (m, 1H), 8.41 (s, 1H), 8.34 - 8.25 (m, 2H), 7.75 (dd, J = 17.5, 8.2 Hz, 2H), 7.59 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 4.8 Hz, 1H), 4.63 (d, J = 5.8 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.60 (m, 1H), 2.39 (m, 1H), 2.00 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.60 (m, 1H), 8.41 (s, 1H), 8.34 - 8.25 (m, 2H), 7.75 (dd, J = 17.5, 8.2 Hz , 2H), 7.59 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 4.8 Hz, 1H), 4.63 (d, J = 5.8 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.60 (m, 1H), 2.39 (m, 1H), 2.00 (m, 1H) .

화합물 74. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메톡시벤조[b]티오펜-2-카르복사미드Compound 74. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methoxybenzo[b]thiophene-2- carboxamide

Figure pat00077
Figure pat00077

6-클로로-1H-인다졸-3-카복실산 대신 4-메톡시벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 74를 합성하였다.Compound 74 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-methoxybenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.58 - 9.36 (m, 1H), 8.28 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J = z6.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.95 (s, 3H), 3.01 - 2.83 (m, 1H), 2.60 (m, 1H), 2.44 - 2.32 (m, 1H), 2.07 - 1.92 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.58 - 9.36 (m, 1H), 8.28 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.56 (d, J = z6.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.4 Hz, 1H), 3.95 (s, 3H) ), 3.01 - 2.83 (m, 1H), 2.60 (m, 1H), 2.44 - 2.32 (m, 1H), 2.07 - 1.92 (m, 1H).

화합물 75. 5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드Compound 75. 5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene -2-carboxamide

Figure pat00078
Figure pat00078

6-클로로-1H-인다졸-3-카복실산 대신 5-클로로-3-메틸벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 75를 합성하였다.Compound 75 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-chloro-3-methylbenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.10 - 8.90 (m, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.98 (m, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.54 - 7.45 (m, 2H), 5.12 (dd, J = 13.5, 4.9 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 4.47 (d, J = 17.4 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 2.98 - 2.86 (m, 1H), 2.60 (m, 4H), 2.47 - 2.32 (m, 1H), 1.99 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.10 - 8.90 (m, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.98 (m, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.54 - 7.45 (m, 2H), 5.12 (dd, J = 13.5, 4.9 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 4.47 (d, J = 17.4 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 2.98 - 2.86 (m, 1H), 2.60 (m, 4H), 2.47 - 2.32 (m, 1H), 1.99 ( m, 1H).

화합물 76. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드Compound 76. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene-2-carb copy mid

Figure pat00079
Figure pat00079

6-클로로-1H-인다졸-3-카복실산 대신 3-메틸벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 76을 합성하였다.Compound 76 was synthesized in the same manner as in the synthesis method of Compound 1, using 3-methylbenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.93 (t, J = 6.0 Hz, 1H), 8.07 - 7.95 (m, 1H), 7.94 - 7.84 (m, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.54 - 7.46 (m, 3H), 5.12 (dd, J = 13.5, 4.9 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 4.47 (d, J = 17.3 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 3.00 - 2.83 (m, 1H), 2.62 (m, 4H), 2.44 - 2.30 (m, 1H), 2.06 - 1.96 (m, 1H). 1 H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 8.93 (t, J = 6.0 Hz, 1H), 8.07 - 7.95 (m, 1H), 7.94 - 7.84 (m, 1H), 7.73 (d , J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.54 - 7.46 (m, 3H), 5.12 (dd, J = 13.5, 4.9 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H) , 4.47 (d, J = 17.3 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 3.00 - 2.83 (m, 1H), 2.62 (m, 4H), 2.44 - 2.30 (m, 1H), 2.06 - 1.96 (m, 1H).

화합물 77. 4-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드Compound 77. 4-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene -2-carboxamide

Figure pat00080
Figure pat00080

6-클로로-1H-인다졸-3-카복실산 대신 4-클로로-3-메틸벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 77을 합성하였다.Compound 77 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-chloro-3-methylbenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.14 (m, 1H), 8.08 - 7.96 (m, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H), 7.52 - 7.47 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 5.12 (dd, J = 13.4, 4.9 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 4.48 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.4 Hz, 1H), 2.98 - 2.87 (m, 1H), 2.82 (s, 3H), 2.61 (m, 1H), 2.40 (m, 1H), 2.06 - 1.96 (m, 1H). 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.14 (m, 1H), 8.08 - 7.96 (m, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.58 (s, 1H) ), 7.52 - 7.47 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 5.12 (dd, J = 13.4, 4.9 Hz, 1H), 4.60 (d, J = 5.8 Hz, 2H), 4.48 (d, J = 17.2 Hz, 1H), 4.34 (d, J = 17.4 Hz, 1H), 2.98 - 2.87 (m, 1H), 2.82 (s, 3H), 2.61 (m, 1H), 2.40 (m, 1H), 2.06 - 1.96 (m, 1H).

화합물 78. 7-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드Compound 78. 7-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene -2-carboxamide

Figure pat00081
Figure pat00081

6-클로로-1H-인다졸-3-카복실산 대신 7-클로로-3-메틸벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 78을 합성하였다.Compound 78 was synthesized in the same manner as in the synthesis method of Compound 1, using 7-chloro-3-methylbenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.06 (m, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.56 - 7.48 (m, 2H), 5.12 (dd, J = 13.4, 5.0 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H), 4.48 (d, J = 17.4 Hz, 1H), 4.33 (d, J = 17.4 Hz, 1H), 3.02 - 2.86 (m, 1H), 2.64 (m, 4H), 2.43 - 2.31 (m, 1H), 2.01 (m, 1H). 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.06 (m, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.64 ( d, J = 7.6 Hz, 1H), 7.58 (s, 1H), 7.56 - 7.48 (m, 2H), 5.12 (dd, J = 13.4, 5.0 Hz, 1H), 4.60 (d, J = 5.9 Hz, 2H) ), 4.48 (d, J = 17.4 Hz, 1H), 4.33 (d, J = 17.4 Hz, 1H), 3.02 - 2.86 (m, 1H), 2.64 (m, 4H), 2.43 - 2.31 (m, 1H) , 2.01 (m, 1H).

화합물 79. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-플루오로-3-메틸벤조[b]티오펜-2-카르복사미드Compound 79. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-fluoro-3-methylbenzo[b]thiol Ophen-2-carboxamide

Figure pat00082
Figure pat00082

6-클로로-1H-인다졸-3-카복실산 대신 4-플루오로-3-메틸벤조[b]티오펜-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 79를 합성하였다.Compound 79 was synthesized in the same manner as in the synthesis method of Compound 1, using 4-fluoro-3-methylbenzo[b]thiophene-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.06 (m, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.49 (m, 2H), 7.23 (dd, J = 12.2, 8.1 Hz, 1H), 5.12 (dd, J = 13.4, 4.9 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H), 4.47 (d, J = 17.3 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 2.99 - 2.85 (m, 2H), 2.72 (s, 3H), 2.61 (m, 1H), 2.46 - 2.35 (m, 1H), 2.01 (m, 1H). 1H NMR (400 MHz, DMSO) δ 11.00 (s, 1H), 9.06 (m, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.58 ( s, 1H), 7.49 (m, 2H), 7.23 (dd, J = 12.2, 8.1 Hz, 1H), 5.12 (dd, J = 13.4, 4.9 Hz, 1H), 4.59 (d, J = 5.8 Hz, 2H) ), 4.47 (d, J = 17.3 Hz, 1H), 4.33 (d, J = 17.3 Hz, 1H), 2.99 - 2.85 (m, 2H), 2.72 (s, 3H), 2.61 (m, 1H), 2.46 - 2.35 (m, 1H), 2.01 (m, 1H).

화합물 80. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조푸란-2-카르복사미드Compound 80. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzofuran-2-carboxamide

Figure pat00083
Figure pat00083

6-클로로-1H-인다졸-3-카복실산 대신 3-메틸벤조푸란-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 80을 합성하였다.Compound 80 was synthesized in the same manner as in the synthesis method of Compound 1, using 3-methylbenzofuran-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.28 - 9.20 (m, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.49 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 2.98 - 2.82 (m, 1H), 2.55 (s, 4H), 2.38 (m, 1H), 2.00 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.28 - 9.20 (m, 1H), 7.76 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.49 (m, 2H), 7.36 (t, J = 7.6 Hz, 1H), 5.11 (dd, J = 13.2, 5.0 Hz, 1H), 4.58 (d, J = 6.1 Hz) , 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.2 Hz, 1H), 2.98 - 2.82 (m, 1H), 2.55 (s, 4H), 2.38 (m, 1H) , 2.00 (m, 1H).

화합물 81. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메톡시벤조푸란-2-카르복사미드Compound 81. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methoxybenzofuran-2-carboxamide

Figure pat00084
Figure pat00084

6-클로로-1H-인다졸-3-카복실산 대신 5-메톡시벤조푸란-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 81을 합성하였다.Compound 81 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-methoxybenzofuran-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.36 (m, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.60 - 7.44 (m, 4H), 7.28 (m, 1H), 7.06 (m, 1H), 5.11 (dd, J = 13.5, 4.9 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 3.81 (s, 3H), 2.98 - 2.84 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.06 - 1.95 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.36 (m, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.60 - 7.44 (m, 4H), 7.28 (m, 1H) ), 7.06 (m, 1H), 5.11 (dd, J = 13.5, 4.9 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d , J = 17.4 Hz, 1H), 3.81 (s, 3H), 2.98 - 2.84 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.06 - 1.95 (m, 1H).

화합물 82. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-7-메톡시벤조푸란-2-카르복사미드Compound 82. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-7-methoxybenzofuran-2-carboxamide

Figure pat00085
Figure pat00085

6-클로로-1H-인다졸-3-카복실산 대신 7-메톡시벤조푸란-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 82를 합성하였다.Compound 82 was synthesized in the same manner as in the synthesis method of Compound 1, using 7-methoxybenzofuran-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.25 (m, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.56 (s, 1H), 7.52 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.21 (s, 1H), 6.98 (dd, J = 8.6, 2.1 Hz, 1H), 5.11 (dd, J = 13.2, 4.9 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.84 (s, 3H), 2.91 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.04 - 1.93 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.25 (m, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.56 ( s, 1H), 7.52 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.21 (s, 1H), 6.98 (dd, J = 8.6, 2.1 Hz, 1H), 5.11 (dd, J = 13.2, 4.9 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 3.84 (s, 3H) ), 2.91 (m, 1H), 2.60 (m, 1H), 2.38 (m, 1H), 2.04 - 1.93 (m, 1H).

화합물 83. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메톡시벤조푸란-2-카르복사미드Compound 83. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methoxybenzofuran-2-carboxamide

Figure pat00086
Figure pat00086

6-클로로-1H-인다졸-3-카복실산 대신 6-메톡시벤조푸란-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 83을 합성하였다.Compound 83 was synthesized in the same manner as in the synthesis method of Compound 1, using 6-methoxybenzofuran-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.46 - 9.25 (m, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.57 (m, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 5.11 (dd, J = 13.4, 4.9 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 3.97 (s, 3H), 3.02 - 2.82 (m, 1H), 2.60 (m, 1H), 2.36 (m, 1H), 2.00 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.46 - 9.25 (m, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.57 (m, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 5.11 (dd, J = 13.4 , 4.9 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 3.97 (s, 3H), 3.02 - 2.82 (m, 1H), 2.60 (m, 1H), 2.36 (m, 1H), 2.00 (m, 1H).

화합물 84. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3,6-디메틸벤조푸란-2-카르복사미드Compound 84. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3,6-dimethylbenzofuran-2-carboxamide

Figure pat00087
Figure pat00087

6-클로로-1H-인다졸-3-카복실산 대신 3,6-디메틸벤조푸란-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 84를 합성하였다.Compound 84 was synthesized in the same manner as in the synthesis method of Compound 1, using 3,6-dimethylbenzofuran-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.17 (t, J = 6.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.99 - 2.85 (m, 1H), 2.60 (m, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 2.41 - 2.32 (m, 1H), 2.07 - 1.94 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.17 (t, J = 6.2 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 5.11 (dd, J = 13.3, 4.9 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.3 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.99 - 2.85 (m, 1H), 2.60 (m, 1H), 2.51 (s, 3H), 2.47 (s, 3H), 2.41 - 2.32 (m, 1H), 2.07 - 1.94 (m, 1H).

화합물 85. 5-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조푸란-2-카르복사미드Compound 85. 5-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzofuran-2- carboxamide

Figure pat00088
Figure pat00088

6-클로로-1H-인다졸-3-카복실산 대신 5-브로모-3-메틸벤조푸란-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 85를 합성하였다.Compound 85 was synthesized in the same manner as in the synthesis method of Compound 1, using 5-bromo-3-methylbenzofuran-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.38 - 9.27 (m, 1H), 8.01 (m, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.66 - 7.54 (m, 3H), 7.49 (d, J = 7.8 Hz, 1H), 5.11 (dd, J = 13.4, 4.9 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.2 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.60 (m, 1H), 2.51 (s, 3H), 2.37 (m, 1H), 2.10 - 1.94 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.38 - 9.27 (m, 1H), 8.01 (m, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.66 - 7.54 (m , 3H), 7.49 (d, J = 7.8 Hz, 1H), 5.11 (dd, J = 13.4, 4.9 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.45 (d, J = 17.2 Hz) , 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.90 (m, 1H), 2.60 (m, 1H), 2.51 (s, 3H), 2.37 (m, 1H), 2.10 - 1.94 (m, 1H).

화합물 86. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)나프토[2,1-b]푸란-2-카르복사미드Compound 86. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)naphtho[2,1-b]furan-2-carb copy mid

Figure pat00089
Figure pat00089

6-클로로-1H-인다졸-3-카복실산 대신 나프토[2,1-b]푸란-2-카르복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 화합물 86을 합성하였다.Compound 86 was synthesized in the same manner as in the synthesis method of Compound 1, using naphtho[2,1-b]furan-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.45 (t, J = 6.2 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.70 (m, 2H), 7.60 (m, 2H), 7.52 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.4, 4.9 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.98 - 2.83 (m, 1H), 2.60 (m, 1H), 2.42 - 2.29 (m, 1H), 2.06 - 1.92 (m, 1H). 1H NMR (400 MHz, DMSO) δ 10.99 (s, 1H), 9.45 (t, J = 6.2 Hz, 1H), 8.38 (d, J = 8.0 Hz, 1H), 8.27 (s, 1H), 8.09 ( d, J = 8.1 Hz, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.84 (d, J = 9.1 Hz, 1H), 7.70 (m, 2H), 7.60 (m, 2H), 7.52 ( d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.4, 4.9 Hz, 1H), 4.64 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 ( d, J = 17.3 Hz, 1H), 2.98 - 2.83 (m, 1H), 2.60 (m, 1H), 2.42 - 2.29 (m, 1H), 2.06 - 1.92 (m, 1H).

<비교예 1. 글루타이미드 모핵을 갖는 이소인돌리논 유도체 비교화합물의 합성 및 물리화학적 특성 확인><Comparative Example 1. Synthesis of Comparative Compounds with Isoindolinone Derivatives Having a Glutimide Core and Confirmation of Physical and Chemical Characteristics>

이하 비교화합물 1 내지 3의 물리화학적 특성은 하기와 같다.The physicochemical properties of Comparative Compounds 1 to 3 are as follows.

비교화합물 1. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)이소퀴놀린-3-카르복사미드Comparative compound 1. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)isoquinoline-3-carboxamide

Figure pat00090
Figure pat00090

6-클로로-1H-인다졸-3-카복실산 대신 이소퀴놀린-3-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 비교화합물 1을 합성하였다. Comparative Compound 1 was synthesized in the same manner as in the synthesis method of Compound 1, using isoquinoline-3-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.62 (t, J = 6.4 Hz, 1H), 9.41 (s, 1H), 8.59 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.89 (t, J = 7.5 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.98 - 2.84 (m, 1H), 2.59 (m, 1H), 2.37 (m, 1H), 2.03 - 1.92 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 9.62 (t, J = 6.4 Hz, 1H), 9.41 (s, 1H), 8.59 (s, 1H), 8.27 (d, J = 8.1 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.89 (t, J = 7.5 Hz, 1H), 7.85 - 7.79 (m, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.51 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.44 ( d, J = 17.3 Hz, 1H), 4.30 (d, J = 17.3 Hz, 1H), 2.98 - 2.84 (m, 1H), 2.59 (m, 1H), 2.37 (m, 1H), 2.03 - 1.92 (m , 1H).

비교화합물 2. N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)퀴녹살린-2-카르복사미드Comparative compound 2. N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoxaline-2-carboxamide

Figure pat00091
Figure pat00091

6-클로로-1H-인다졸-3-카복실산 대신 퀴녹살린-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 비교화합물 2를 합성하였다. Comparative compound 2 was synthesized in the same manner as in the synthesis method of compound 1, using quinoxaline-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.77 (t, J = 6.4 Hz, 1H), 9.50 (s, 1H), 8.22 (m, 2H), 8.04 - 7.98 (m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.59 (m, 1H), 2.43 - 2.32 (m, 1H), 2.06 - 1.95 (m, 1H). 1 H NMR (500 MHz, DMSO-d 6 ) δ 10.98 (s, 1H), 9.77 (t, J = 6.4 Hz, 1H), 9.50 (s, 1H), 8.22 (m, 2H), 8.04 - 7.98 ( m, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.54 (d, J = 7.9 Hz, 1H), 5.10 (dd, J = 13.3, 5.1 Hz, 1H), 4.69 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.3 Hz, 1H), 2.91 (m, 1H), 2.59 (m, 1H), 2.43 - 2.32 (m, 1H), 2.06 - 1.95 (m, 1H).

비교화합물 3. 6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)퀴놀린-2-카르복사미드Comparative Compound 3. 6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)quinoline-2-carboxamide

Figure pat00092
Figure pat00092

6-클로로-1H-인다졸-3-카복실산 대신 6-클로로퀴놀린-2-카복실산을 사용하여 화합물 1의 합성법과 동일한 방법으로 비교화합물 3을 합성하였다. Comparative compound 3 was synthesized in the same manner as in the synthesis method of compound 1, using 6-chloroquinoline-2-carboxylic acid instead of 6-chloro-1H-indazole-3-carboxylic acid.

1H NMR (300 MHz, DMSO) δ 10.98 (s, 1H), 9.65 (t, J = 6.4 Hz, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.90 (dd, J = 9.0, 2.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.53 (dd, J = 7.8, 1.4 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.69 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.99 - 2.84 (m, 1H), 2.59 (m, 1H), 2.35 (m, 1H), 2.06 - 1.94 (m, 1H). 1H NMR (300 MHz, DMSO) δ 10.98 (s, 1H), 9.65 (t, J = 6.4 Hz, 1H), 8.57 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.16 (d, J = 9.1 Hz, 1H), 7.90 (dd, J = 9.0, 2.4 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.53 (dd, J = 7.8, 1.4 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.69 (d, J = 6.3 Hz, 2H), 4.45 (d, J = 17.4 Hz, 1H), 4.31 (d, J = 17.4 Hz, 1H), 2.99 - 2.84 (m, 1H), 2.59 (m, 1H), 2.35 (m, 1H), 2.06 - 1.94 (m, 1H).

<실험예 1. CRBN에 대한 기질 단백질 분해활성 평가><Experimental Example 1. Evaluation of substrate proteolysis activity for CRBN>

본 발명의 화합물이 CRBN(celebron)에 특이적으로 결합하여 CRBN의 기능을 저해할 수 있는지 확인하기 위하여 탈리도마이드 및 이의 유사체와 결합시 CRBN 단백질에 의해서 분해되는 Ikaros (IKZF1) 단백질(Chamberlain, P. P. et al., 2014) 또는 GSPT1 단백질(Matyskiela, M. E. et al., 2016)의 분해 활성에 본 화합물이 미치는 영향을 조사하였다.In order to determine whether the compound of the present invention can specifically bind to CRBN (celebron) and inhibit the function of CRBN, Ikaros (IKZF1) protein (Chamberlain, PP et al. , 2014) or GSPT1 protein (Matyskiela, ME et al., 2016), the effect of this compound on the degradation activity was investigated.

본 발명에 따른 화합물의 Ikaros (IKZF1) 단백질 또는 GSPT1 단백질의 분해활성을 평가하기 위해, 다음과 같이 실험하였다.In order to evaluate the degradation activity of the Ikaros (IKZF1) protein or GSPT1 protein of the compound according to the present invention, the following experiment was conducted.

KG-1 세포를 12웰 플레이트에 5×105 세포를 분주(seeding)한 다음, 각 화합물을 정해진 농도만큼 각 웰에 처리하였다. 6시간 후에 TBSN 버퍼를 이용해서 cell lysate을 모았다. Ikaros 단백질 분해활성은 Ikaros 단백질에 대한 항체를 이용하고, GSPT1 단백질 분해활성은 GSPT1 단백질에 대한 항체를 이용하여 웨스턴 블롯(Western blot)으로 평가하였고, 이를 위하여 4-15% gradient gel의 각 웰에 동일한 양의 단백질을 로딩한 다음 전기영동 후 PVDF 멤브레인으로 단백질을 트랜스퍼 하고, 각 단백질에 대한 1차 항체로 결합시켰다. 이후 HRP가 부착된 2차 항체를 결합시키고, HRP substrate를 이용해서 현상하였다.KG-1 cells were seeded in 5×10 5 cells in a 12-well plate, and then each compound was treated at a predetermined concentration in each well. After 6 hours, cell lysate was collected using TBSN buffer. Ikaros proteolytic activity was evaluated by Western blot using an antibody against Ikaros protein, and GSPT1 proteolytic activity was evaluated by Western blot using an antibody against GSPT1 protein. After loading the amount of protein, the protein was transferred to a PVDF membrane after electrophoresis and bound with a primary antibody against each protein. Thereafter, the secondary antibody to which HRP was attached was coupled, and developed using an HRP substrate.

그 결과, 도 1에서 보듯이 KG-1 세포주에서도 각각 6시간 동안 처리한 결과, 본 발명의 화합물 10이 GSPT1 단백질을 선택적으로 분해를 촉진하는 것을 확인할 수 있었다.As a result, as shown in FIG. 1, as a result of treatment in the KG-1 cell line for 6 hours, it was confirmed that the compound 10 of the present invention selectively promotes the degradation of the GSPT1 protein.

<실험예 2. 세포독성 실험><Experimental Example 2. Cytotoxicity test>

본 발명 화합물의 암세포에 미치는 영향을 확인하기 위하여 다음과 같이 세포독성 실험을 수행하였다.In order to confirm the effect of the compound of the present invention on cancer cells, a cytotoxicity test was performed as follows.

암세포 (KG-1)를 96웰 플레이트에 각 웰당 10,000개의 세포가 되도록 분주한 다음에 본 발명 실시예 화합물과 비교물질(비교물질, 비교화합물 1, 2, 3)을 미리 정해진 농도별로 처리하였다. 72시간 후에 WST-1 시약을 넣고, 1시간 뒤에 450 ㎚에서 spectramax 스펙트로메터(spectrophotometer)를 이용하여 흡광도를 측정함으로써 암세포 사멸정도를 측정하였다. 측정된 값을 이용하여 graphpad prism 프로그램으로 IC50(μM) 값을 산출하여 표 1에 나타내었다.Cancer cells (KG-1) were dispensed in a 96-well plate to make 10,000 cells per well, and then the compounds of the present invention and comparative substances (comparative substances, comparative compounds 1, 2, and 3) were treated at predetermined concentrations. After 72 hours, the WST-1 reagent was added, and after 1 hour, the degree of cancer cell death was measured by measuring the absorbance at 450 nm using a spectramax spectrophotometer. IC 50 (μM) values were calculated using the graphpad prism program using the measured values and are shown in Table 1.

NCI-H1155 (폐암세포) 생존율은 CytoX cell viability assay kit (LPS solution, #CYT3000)를 이용하여 측정했다. NCI-H1155 세포를 12웰 플레이트에 접종하였고, 그 후 각각의 본 발명 실시예 화합물과 비교물질(CC-90009)을 10 nM 농도와 500 nM 농도로 72시간 동안 처리했다. 그런 다음, 세포에 CytoX 용액을 첨가하고 1시간 동안 배양한 후 microplate reader를 이용하여 450 nm에서 각 well의 흡광도를 측정하여 % 생존율(% viability)을 산출하여 표 2에 나타내었다.NCI-H1155 (lung cancer cell) viability was measured using the CytoX cell viability assay kit (LPS solution, #CYT3000). NCI-H1155 cells were seeded in a 12-well plate, and then treated with each of the compound of the present invention and a comparative substance (CC-90009) at 10 nM and 500 nM concentrations for 72 hours. Then, CytoX solution was added to the cells, and after incubation for 1 hour, the absorbance of each well was measured at 450 nm using a microplate reader to calculate % viability, which is shown in Table 2.

화합물 번호compound number ICIC 5050 (μM)(μM) 화합물 번호compound number ICIC 5050 (μM)(μM) KG-1KG-1 KG-1KG-1 화합물 1compound 1 ++++++++ 화합물 28compound 28 ++++++++ 화합물 2compound 2 ++++++++ 화합물 29compound 29 ++++++++ 화합물 4compound 4 ++++++++ 화합물 30compound 30 ++ 화합물 5compound 5 ++++++++ 화합물 31compound 31 ++ 화합물 6compound 6 ++++++ 화합물 34compound 34 ++++++ 화합물 7compound 7 ++++++ 화합물 35compound 35 ++ 화합물 8compound 8 ++++++ 화합물 38compound 38 ++++ 화합물 9compound 9 ++++++ 화합물 39compound 39 ++++++++ 화합물 10compound 10 ++++++++ 화합물 40compound 40 ++++++++ 화합물 11compound 11 ++++++++ 화합물 41compound 41 ++++++++ 화합물 13compound 13 ++++++ 화합물 42compound 42 ++++++++ 화합물 14compound 14 ++++++++ 화합물 43compound 43 ++++++++ 화합물 15compound 15 ++++++++ 화합물 44compound 44 ++++++ 화합물 16compound 16 ++++++ 화합물 45compound 45 ++++++++ 화합물 17compound 17 ++++++++ 화합물 46compound 46 ++++++++ 화합물 18compound 18 ++++++++ 화합물 52compound 52 ++ 화합물 19compound 19 ++++++++ 화합물 53compound 53 ++ 화합물 20compound 20 ++++++++ 화합물 54compound 54 ++ 화합물 21compound 21 ++++++++ 화합물 55compound 55 ++++ 화합물 23compound 23 ++++++++ 비교화합물 1comparative compound 1 ++ 화합물 25compound 25 ++++++++ 비교화합물 2comparative compound 2 ++ 화합물 26compound 26 ++++++ 비교화합물 3comparative compound 3 ++ 화합물 27compound 27 ++++++++ 비교물질

Figure pat00093
comparator
Figure pat00093
++ ※ IC50 값
++++: 0.0001~0.01μM, +++: 0.01~1μM, ++: 1~10μM, +: 10~50μM※ IC 50 value
++++: 0.0001 to 0.01 μM, +++: 0.01 to 1 μM, ++: 1 to 10 μM, +: 10 to 50 μM

화합물 번호compound number NCI-H1155 (% viability)NCI-H1155 (% viability) at 10 nMat 10 nM at 500 nMat 500 nM 화합물 56compound 56 29.8229.82 5.945.94 화합물 57compound 57 83.7883.78 21.2521.25 화합물 58compound 58 4.314.31 2.962.96 화합물 59compound 59 102.33102.33 40.0840.08 화합물 60compound 60 8282 22.2722.27 화합물 61compound 61 96.7996.79 87.1787.17 화합물 62compound 62 18.9518.95 9.569.56 화합물 65compound 65 31.731.7 23.4223.42 화합물 66compound 66 32.1332.13 26.1126.11 화합물 67compound 67 26.1526.15 24.3824.38 화합물 68compound 68 29.8729.87 26.4126.41 화합물 71compound 71 24.224.2 24.4424.44 화합물 72compound 72 33.0333.03 24.5524.55 화합물 73compound 73 40.3640.36 26.0126.01 화합물 74compound 74 26.5626.56 25.3625.36 화합물 75compound 75 32.1332.13 24.5324.53 화합물 76compound 76 28.0228.02 26.3326.33 화합물 77compound 77 23.9823.98 24.0124.01 화합물 78compound 78 15.6715.67 15.6415.64 화합물 79compound 79 16.2516.25 15.2015.20 화합물 82compound 82 38.9838.98 17.6117.61 화합물 83compound 83 26.1026.10 15.9315.93 화합물 84compound 84 28.8528.85 18.2318.23 화합물 85compound 85 36.6236.62 18.5918.59 화합물 86compound 86 14.6814.68 14.6514.65 CC-90009
(Eragidomide)CC-90009
(Eragidomide) 85.085.0 23.523.5

표 1, 표 2에서 보듯이 헤테로아릴 아미드 구조를 가지는 본 발명 실시예 화합물들은 암세포에서 우수한 세포독성을 가지는 것을 알 수 있다. 특히 본 발명 화합물의 구조-활성 비교를 통해, R1이 단고리 형태의 아릴(비교물질) 또는 헤테로아릴(화합물 37, 38)일 때보다 이중고리 형태의 헤테로아릴(화합물 3, 7, 10)일 때, KG-1 및 NCI-H1155 암세포에 대한 세포독성 활성이 더욱 우수함을 확인할 수 있었다.As shown in Tables 1 and 2, it can be seen that the compounds of the present invention having a heteroaryl amide structure have excellent cytotoxicity in cancer cells. In particular, through structure-activity comparison of the compounds of the present invention, when R 1 is a monocyclic aryl (comparative material) or heteroaryl (Compounds 37 and 38), the heteroaryl (Compounds 3, 7, and 10) in the form of a double ring is more , it was confirmed that the cytotoxic activity against KG-1 and NCI-H1155 cancer cells was more excellent.

R1이 (6+5)각의 이중고리 형태의 헤테로아릴인 화합물 중에서, R1이 인돌, 인다졸, 벤즈이미다졸, 벤조이속사졸, 벤조옥사졸, 벤조티아졸, 벤조푸란, 및 벤조티오펜(화합물 3, 4, 6-10, 26, 33, 34, 36, 44, 56, 57, 65-84)일때, R1이 (6+6)각의 이중고리 형태의 헤테로아릴인 퀴놀린, 이소퀴놀린 및 퀴녹살린으로 치환된 화합물(비교화합물 1-3)일 때보다 KG-1 및 암세포에 대한 세포독성 활성이 더욱 우수함을 확인할 수 있었다.Among the compounds in which R 1 is a (6+5) bicyclic heteroaryl, R 1 is indole, indazole, benzimidazole, benzoisoxazole, benzooxazole, benzothiazole, benzofuran, and benzothione; When opene (Compounds 3, 4, 6-10, 26, 33, 34, 36, 44, 56, 57, 65-84), R 1 is a (6+6) bicyclic heteroaryl quinoline; It was confirmed that the cytotoxic activity against KG-1 and cancer cells was more excellent than that of the compounds substituted with isoquinoline and quinoxaline (Comparative Compounds 1-3).

R1이 단고리 형태의 헤테로아릴이면서 동시에 R2가 아릴 치환체가 존재할 때 세포독성 활성이 현저하게 우수해짐을 확인하였다. 전체적 구조가 비슷한 화합물 중에서 R1이 단고리 형태의 헤테로아릴이면서 R2가 동시에 아릴 치환체가 존재하는 화합물(화합물 2, 5, 11, 13-15, 17-21, 23, 25, 29, 32, 39, 40, 45, 46)이 그렇지 않은 화합물(화합물 30, 38)일 때보다 암세포에 대한 세포독성 활성이 보다 더 우수함을 확인하였다.It was confirmed that the cytotoxic activity was remarkably improved when R 1 was a monocyclic heteroaryl and at the same time R 2 had an aryl substituent. Among compounds having a similar overall structure, compounds in which R 1 is a monocyclic heteroaryl and R 2 has an aryl substituent at the same time (Compounds 2, 5, 11, 13-15, 17-21, 23, 25, 29, 32, 39 , 40, 45, 46) was found to have more excellent cytotoxic activity against cancer cells than other compounds (Compounds 30 and 38).

또한, 전체적 구조가 비슷한 화합물 중에서 R1이 단고리 형태의 헤테로아릴이면서 R2에 동시에 아릴 치환체가 존재하는 화합물(화합물 17, 23, 39, 40)인 경우, 이중고리 형태의 헤테로아릴(화합물 8, 9, 26)일 때보다 활성이 현저하게 우수해짐을 확인하였다.In addition, among compounds having a similar overall structure, R 1 is a monocyclic heteroaryl and R 2 is a compound having an aryl substituent at the same time (Compounds 17, 23, 39, 40), a double-cyclic heteroaryl (Compound 8, 9, 26), it was confirmed that the activity was significantly improved.

표 2의 H1155 세포(% viability)에서는, 표 1과 같이 R1이 (6+6)각의 이중고리 형태의 헤테로아릴인 화합물(화합물 59, 60, 61)보다 (6+5)각의 이중고리 형태의 헤테로아릴 화합물(화합물 56-58, 62-70)에서 암세포에 대한 세포독성 활성이 더욱 우수함을 확인할 수 있었다. In the H1155 cells (% viability) of Table 2, as shown in Table 1, R 1 is heteroaryl in the form of a (6+6) each double ring rather than the compound (Compound 59, 60, 61). It was confirmed that the cyclic heteroaryl compounds (Compounds 56-58 and 62-70) had more excellent cytotoxic activity against cancer cells.

<제제예 1. 산제의 제조><Formulation Example 1. Preparation of Powder>

본 발명 화합물 1 2g, 유당 1g을 혼합하고 기밀포에 충진하여 산제를 제조하였다.A powder was prepared by mixing 2 g of Compound 1 of the present invention and 1 g of lactose and filling in an airtight bag.

<제제예 2. 정제의 제조><Formulation Example 2. Preparation of tablets>

본 발명 화합물 1 100㎎, 미결정셀룰로오스 100㎎, 유당수화물 60㎎, 저치환도히드록시프로필셀룰로오스 20㎎ 및 스테아르산마그네슘 2㎎을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조하였다.Tablets were prepared by mixing 100 mg of Compound 1 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, and then tableting according to a conventional tablet manufacturing method. .

<제제예 3. 캡슐제의 제조><Formulation Example 3. Preparation of capsules>

본 발명 화합물 1 100㎎, 미결정셀룰로오스 100㎎, 유당수화물 60㎎, 저치환도히드록시프로필셀룰로오스 20㎎ 및 스테아르산마그네슘 2㎎을 혼합한 후 통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조하였다.After mixing 100 mg of Compound 1 of the present invention, 100 mg of microcrystalline cellulose, 60 mg of lactose hydrate, 20 mg of low-substituted hydroxypropyl cellulose, and 2 mg of magnesium stearate, the above ingredients were mixed according to a conventional capsule preparation method, Capsules were prepared by filling gelatin capsules.

<제제예 4. 환제의 제조><Formulation Example 4. Preparation of pills>

본 발명 화합물 1 90㎎, 찹쌀전분 5㎎ 및 정제수 5㎎ 및 흡습성을 저해하는 첨가제로서 덱스트린, 말토덱스트린, 옥수수전분, 미결정셀룰로오스(MCC)를 소량 혼합한 후, 통상의 방법에 따라 100㎎의 환제를 만들었다.After mixing 90 mg of Compound 1 of the present invention, 5 mg of glutinous rice starch, 5 mg of purified water, and dextrin, maltodextrin, corn starch, and microcrystalline cellulose (MCC) as additives that inhibit hygroscopicity, 100 mg of pills according to a conventional method made

<제제예 5. 주사제의 제조><Formulation Example 5. Preparation of Injections>

본 발명 화합물 1 10㎎, 주사용 멸균 증류수 적량 및 pH 조절제 적량을 혼합한 후 통상의 주사제의 제조방법에 따라 1 앰플당(2㎖) 상기의 성분 함량으로 제조하였다.After mixing 10 mg of Compound 1 of the present invention, an appropriate amount of sterilized distilled water for injection, and an appropriate amount of a pH adjusting agent, the above ingredients were prepared per ampoule (2 ml) according to a conventional method for preparing an injection.

Claims (7)

하기 화학식 1로 표시되는 화합물, 이의 광학이성질체, 또는 이의 약학적으로 허용 가능한 염:
[화학식 1]
Figure pat00094

상기 식에서,
l은 0 내지 3의 정수이며;
n은 0 또는 1의 정수이며;
p는 1 또는 2의 정수이며;
R1은 C5-13 헤테로아릴, C6-10 아릴, C4-10 시클로알킬, C4-10 헤테로시클로알킬이며;
R2는 독립적으로 수소, 할로겐, 케톤, C1-5알킬, C1-3알콕시, 할로C1-3알킬, 할로C1-3알콕시, C3-6사이클로알킬, 치환 또는 비치환된 페닐 및 치환 또는 비치환된 벤질로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되고,
여기서 상기 치환된 페닐 또는 벤질은 할로겐 또는 C1-5알킬로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되며;
R3는 수소 또는 중수소(D; deuterium)로 치환; 된다.A compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
Figure pat00094

In the above formula,
l is an integer from 0 to 3;
n is an integer of 0 or 1;
p is an integer of 1 or 2;
R 1 is C 5-13 heteroaryl, C 6-10 aryl, C 4-10 cycloalkyl, C 4-10 heterocycloalkyl;
R 2 is independently hydrogen, halogen, ketone, C 1-5 alkyl, C 1-3 alkoxy, haloC 1-3 alkyl, haloC 1-3 alkoxy, C 3-6 cycloalkyl, substituted or unsubstituted phenyl And substituted with one or more substituents selected from the group consisting of substituted or unsubstituted benzyl,
wherein the substituted phenyl or benzyl is substituted with one or more substituents selected from the group consisting of halogen or C 1-5 alkyl;
R 3 is substituted with hydrogen or deuterium; do. 제1항에 있어서,
상기 화학식 1에서,
R1은 피롤일, 피라졸일, 이미다졸일, 이속사졸일, 트리아졸일, 피리딘일, 피라진일, 피리미딘일, 인돌일, 인다졸일, 벤조이미다졸일, 벤조푸란일, 벤조피리딘일, 벤조피란일, 벤조피리다진일, 벤조이속사졸일, 벤조옥사졸일, 벤조티아졸일, 벤조티오펜일 및 나프토푸란일로 이루어진 군에서 선택되는 1종의 치환기로 치환되는 것을 특징으로 하는 화합물, 이의 광학이성질체 또는 이의 약학적으로 허용 가능한 염.According to claim 1,
In Formula 1,
R 1 is pyrroleyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl; pyrimidinyl, indolyl, indazolyl, benzoimidazolyl, benzofuranyl, benzopyridinyl, benzopyranyl, benzopyridazinyl, benzoisoxazolyl, benzooxazolyl, benzothiazolyl, benzothiophenyl and A compound characterized in that it is substituted with one substituent selected from the group consisting of naphthofuranyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. 제1항에 있어서,
상기 화학식 1에서,
R1은 C5-13 헤테로아릴이며;
R2는 치환 또는 비치환된 페닐 및 치환 또는 비치환된 벤질로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환되고,
여기서 상기 치환된 페닐 또는 벤질은 할로겐 또는 C1-5알킬로 이루어진 군에서 선택되는 1종 이상의 치환기로 치환:
되는 것을 특징으로 하는 화합물, 이의 광학이성질체 또는 이의 약학적으로 허용 가능한 염.According to claim 1,
In Formula 1,
R 1 is C 5-13 heteroaryl;
R 2 is substituted with one or more substituents selected from the group consisting of substituted or unsubstituted phenyl and substituted or unsubstituted benzyl;
wherein the substituted phenyl or benzyl is substituted with one or more substituents selected from the group consisting of halogen or C 1-5 alkyl:
A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, characterized in that it is. 제3항에 있어서,
상기 화학식 1에서,
R1은 피롤일, 피라졸일, 이미다졸일, 이속사졸일, 트리아졸일, 피리딘일, 피라진일, 피리미딘일, 인돌일, 인다졸일, 벤조이미다졸일, 벤조푸란일, 벤조피리딘일, 벤조피란일, 벤조피리다진일, 벤조이속사졸일, 벤조옥사졸일, 벤조티아졸일, 벤조티오펜일 및 나프토푸란일로 이루어진 군에서 선택되는 1종의 치환기로 치환되는 것을 특징으로 하는 화합물, 이의 광학이성질체 또는 이의 약학적으로 허용 가능한 염.According to claim 3,
In Formula 1,
R 1 is pyrroleyl, pyrazolyl, imidazolyl, isoxazolyl, triazolyl, pyridinyl, pyrazinyl; pyrimidinyl, indolyl, indazolyl, benzoimidazolyl, benzofuranyl, benzopyridinyl, benzopyranyl, benzopyridazinyl, benzoisoxazolyl, benzooxazolyl, benzothiazolyl, benzothiophenyl and A compound characterized in that it is substituted with one substituent selected from the group consisting of naphthofuranyl, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. 제1항 또는 제2항에 있어서,
상기 화학식 1의 화합물은
6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드(화합물 1);
3-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드(화합물 2);
5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-벤조[d]이미다졸-2-카르복사미드(화합물 3);
5,6-디클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드(화합물 4);
3-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드(화합물 5);
6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인돌-3-카르복사미드(화합물 6);
5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인돌-3-카르복사미드(화합물 7);
5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드(화합물 8);
6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인돌-2-카르복사미드(화합물 9);
6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]이속사졸-3-카르복사미드(화합물 10);
5-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)이속사졸-3-카르복사미드(화합물 11);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-페닐피콜린아미드(화합물 12);
3-(3,4-디클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드(화합물 13);
4-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피롤-2-카르복사미드(화합물 14);
1-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-1,2,3-트리아졸-4-카르복사미드(화합물 15);
5,6-디클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-벤조[d]이미다졸-2-카르복사미드(화합물 16);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-5-페닐-1H-피라졸-3-카르복사미드(화합물 17);
4-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)피콜린아미드(화합물 18);
5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)이속사졸-3-카르복사미드(화합물 19);
5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)피리미딘-2-카르복사미드(화합물 20);
1-벤질-5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1H-피라졸-3-카르복사미드(화합물 21);
4-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)피콜린아미드(화합물 22);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-5-페닐-1H-피라졸-3-카르복사미드(화합물 23);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-3-페닐-1H-피라졸-5-카르복사미드(화합물 24);
5-(2,4-디클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-3-카르복사미드(화합물 25);
6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]티아졸-2-카르복사미드(화합물 26);
4-브로모-3-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-5-카르복사미드(화합물 27);
5-(2,5-디클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-3-카르복사미드(화합물 28);
5-(2,4-디메틸페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-피라졸-3-카르복사미드 (화합물 29);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-[1,1'-비페닐]-3-카르복사미드 (화합물 30);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸피콜린아미드 (화합물 31);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-페닐피콜린아미드 (화합물 32);
6-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]옥사졸-2-카르복사미드 (화합물 33);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1H-인다졸-3-카르복사미드 (화합물 34);
3-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-피라졸-5-카르복사미드 (화합물 35);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-인다졸-3-카르복사미드 (화합물 36);
4-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-이미다졸-2-카르복사미드 (화합물 37);
4-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-피롤-2-카르복사미드 (화합물 38);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-4-페닐-1H-피롤-2-카르복사미드 (화합물 39);
4-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-메틸-1H-피롤-2-카르복사미드 (화합물 40);
5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-이소부틸-4-메틸-1H-피라졸-3 -카르복사미드 (화합물 41);
5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1-페닐-1H-피라졸-3-카르복사미드 (화합물 42);
5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-(4-플루오로페닐)-4-메틸-1H-피라졸-3-카르복사미드 (화합물 43);
5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[d]티아졸-2-카르복사미드 (화합물 44);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메틸-4-페닐피콜린아미드 (화합물 45);
5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-페닐피콜린아미드 (화합물 46);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-페닐피라진-2-카르복사미드 (화합물 47);
3-(2-클로로-6-플루오로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메틸이속사졸-4-카르복사미드 (화합물 48);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-페닐-1H-피라졸-5-카르복사미드 (화합물 49);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-페닐-5-(트리플루오로메틸)-1H-피라졸-4-카르복사미드 (화합물 50);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-[1,1'-비페닐]-4-카르복사미드 (화합물 51);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-[1,1'-비페닐]-2-카르복사미드 (화합물 52);
1-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)시클로펜탄-1-카르복사미드 (화합물 53);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-페닐시클로펜탄-1-카르복사미드 (화합물 54);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-2-옥소-1-페닐피롤리딘-3-카르복사미드 (화합물 55);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조푸란-2-카르복사미드 (화합물 56);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메톡시-1H-인돌-2-카르복사미드 (화합물 57);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)벤조[b]티오펜-2-카르복사미드 (화합물 58);
7-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-히드록시퀴놀린-3-카르복사미드 (화합물 59);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-2-옥소-2H-크로멘-3-카르복사미드 (화합물 60);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)신놀린-4-카르복사미드 (화합물 61);
5-(4-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-1-이소부틸-4-메틸-1H-피라졸-3 -카르복사미드 (화합물 62);
5-(3-클로로페닐)-1-시클로프로필-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1H-피라졸-3 -카르복사미드 (화합물 63);
5-(3-클로로페닐)-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메틸-1-(2,2,2-트리플루오로에틸)-1H-피라졸-3-카르복사미드 (화합물 64);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메톡시벤조[b]티오펜-2-카르복사미드 (화합물 65);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메틸벤조[b]티오펜-2-카르복사미드 (화합물 66);
3-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메틸벤조[b]티오펜-2-카르복사미드 (화합물 67);
3-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메톡시벤조[b]티오펜-2-카르복사미드 (화합물 68);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5,6-디메톡시벤조[b]티오펜-2-카르복사미드 (화합물 69);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드 (화합물 70);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-7-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드 (화합물 71);
3-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드 (화합물 72);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-(트리플루오로메틸)벤조[b]티오펜-2-카르복사미드 (화합물 73);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-메톡시벤조[b]티오펜-2-카르복사미드 (화합물 74);
5-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 75);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 76);
4-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 77);
7-클로로-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 78);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-4-플루오로-3-메틸벤조[b]티오펜-2-카르복사미드 (화합물 79);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조푸란-2-카르복사미드 (화합물 80);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-5-메톡시벤조푸란-2-카르복사미드 (화합물 81);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-7-메톡시벤조푸란-2-카르복사미드 (화합물 82);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-6-메톡시벤조푸란-2-카르복사미드 (화합물 83);
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3,6-디메틸벤조푸란-2-카르복사미드 (화합물 84);
5-브로모-N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)-3-메틸벤조푸란-2-카르복사미드 (화합물 85); 및
N-((2-(2,6-디옥소피페리딘-3-일)-1-옥소이소인돌린-5-일)메틸)나프토[2,1-b]푸란-2-카르복사미드 (화합물 86);
로 이루어진 군에서 선택되는 것을 특징으로 하는 화합물, 이의 광학이성질체, 또는 이의 약학적으로 허용 가능한 염.According to claim 1 or 2,
The compound of Formula 1 is
6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxamide (compound One);
3-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol-5- carboxamide (Compound 2);
5-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-benzo[d]imidazole-2-carb copy mid (compound 3);
5,6-Dichloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxamide (Compound 4);
3-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol-5- carboxamide (compound 5);
6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indole-3-carboxamide (Compound 6 );
5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indole-3-carboxamide (Compound 7 );
5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxamide (compound 8);
6-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indole-2-carboxamide (Compound 9 );
6-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]isoxazole-3-carboxamide ( compound 10);
5-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)isoxazole-3-carboxamide (Compound 11);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-phenylpicolinamide (Compound 12);
3-(3,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol- 5-carboxamide (Compound 13);
4-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrrole-2-carb copymid (compound 14);
1-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-1,2,3 -Triazole-4-carboxamide (Compound 15);
5,6-Dichloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-benzo[d]imidazole-2 -carboxamide (compound 16);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl-5-phenyl-1H-pyrazole-3-carb copymid (compound 17);
4-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)picolinamide (Compound 18);
5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)isoxazole-3-carboxamide (Compound 19);
5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)pyrimidine-2-carboxamide (Compound 20);
1-benzyl-5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl -1H-pyrazole-3-carboxamide (Compound 21);
4-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)picolinamide (Compound 22);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-5-phenyl-1H-pyrazole-3-carb copymid (compound 23);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-3-phenyl-1H-pyrazole-5-carb copymid (Compound 24);
5-(2,4-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol- 3-carboxamide (Compound 25);
6-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]thiazole-2-carboxamide ( compound 26);
4-Bromo-3-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H- pyrazole-5-carboxamide (Compound 27);
5-(2,5-dichlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol- 3-carboxamide (Compound 28);
5-(2,4-dimethylphenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-pyrazol- 3-carboxamide (Compound 29);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-[1,1'-biphenyl]-3-carboxamide ( compound 30);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methylpicolinamide (Compound 31);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-phenylpicolinamide (Compound 32);
6-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]oxazole-2-carboxamide ( compound 33);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1H-indazole-3-carboxamide (Compound 34);
3-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-pyrazole-5- carboxamide (compound 35);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-indazole-3-carboxamide (compound 36);
4-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-imidazole-2- carboxamide (compound 37);
4-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-pyrrole-2-carb copymid (Compound 38);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-4-phenyl-1H-pyrrole-2-carboxyl Mead (Compound 39);
4-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-pyrrole -2-carboxamide (Compound 40);
5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-isobutyl-4- methyl-1H-pyrazole-3-carboxamide (Compound 41);
5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl-1-phenyl -1H-pyrazole-3-carboxamide (Compound 42);
5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-(4-fluoro phenyl)-4-methyl-1H-pyrazole-3-carboxamide (Compound 43);
5-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[d]thiazole-2-carboxamide ( compound 44);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methyl-4-phenylpicolinamide (Compound 45);
5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-phenylpicolinamide (Compound No. 46);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-phenylpyrazine-2-carboxamide (Compound 47);
3-(2-chloro-6-fluorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5- methylisoxazole-4-carboxamide (Compound 48);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-phenyl-1H-pyrazole-5-carboxamide (compound 49);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-phenyl-5-(trifluoromethyl)-1H-pyra sol-4-carboxamide (Compound 50);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-[1,1'-biphenyl]-4-carboxamide ( compound 51);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-[1,1'-biphenyl]-2-carboxamide ( compound 52);
1-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)cyclopentane-1-carboxamide (Compound 53);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-phenylcyclopentane-1-carboxamide (Compound 54);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-1-phenylpyrrolidine-3-carboxamide (Compound 55);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzofuran-2-carboxamide (Compound 56);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methoxy-1H-indole-2-carboxamide (compound 57);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)benzo[b]thiophene-2-carboxamide (Compound 58);
7-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-hydroxyquinoline-3-carboxamide ( compound 59);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-oxo-2H-chromene-3-carboxamide (compound 60);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)cinnoline-4-carboxamide (Compound 61);
5-(4-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-1-isobutyl-4- methyl-1H-pyrazole-3-carboxamide (Compound 62);
5-(3-chlorophenyl)-1-cyclopropyl-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4- methyl-1H-pyrazole-3-carboxamide (Compound 63);
5-(3-chlorophenyl)-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methyl-1-( 2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide (Compound 64);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methoxybenzo[b]thiophene-2-carboxamide (Compound 65);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methylbenzo[b]thiophene-2-carboxamide ( compound 66);
3-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methylbenzo[b]thiophene-2- carboxamide (compound 67);
3-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methoxybenzo[b]thiophene-2 -carboxamide (compound 68);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5,6-dimethoxybenzo[b]thiophene-2-carb duxamide (Compound 69);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-(trifluoromethyl)benzo[b]thiophene-2 -carboxamide (compound 70);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-7-(trifluoromethyl)benzo[b]thiophene-2 -carboxamide (compound 71);
3-chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-(trifluoromethyl)benzo[b] thiophene-2-carboxamide (Compound 72);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-(trifluoromethyl)benzo[b]thiophene-2 -carboxamide (compound 73);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-methoxybenzo[b]thiophene-2-carboxamide (Compound 74);
5-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene-2- carboxamide (compound 75);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene-2-carboxamide ( compound 76);
4-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene-2- carboxamide (compound 77);
7-Chloro-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzo[b]thiophene-2- carboxamide (compound 78);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-4-fluoro-3-methylbenzo[b]thiophene-2 -carboxamide (compound 79);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzofuran-2-carboxamide (Compound 80);
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-5-methoxybenzofuran-2-carboxamide (Compound 81) ;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-7-methoxybenzofuran-2-carboxamide (Compound 82) ;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-6-methoxybenzofuran-2-carboxamide (Compound 83) ;
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3,6-dimethylbenzofuran-2-carboxamide (Compound 84 );
5-Bromo-N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-3-methylbenzofuran-2-carboxamide (Compound 85); and
N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)naphtho[2,1-b]furan-2-carboxamide ( compound 86);
A compound characterized in that it is selected from the group consisting of, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. 제1항 또는 제2항의 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 나병, 만성 이식편대숙주병, 염증성 질환 또는 암 예방 또는 치료용 약학적 조성물.A pharmaceutical composition for preventing or treating leprosy, chronic graft-versus-host disease, inflammatory disease or cancer, comprising the compound represented by Formula 1 of claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. 제6항에 있어서,
상기 암은 유방암, 대장암, 폐암, 소세포폐암, 위암, 간암, 혈액암, 골암, 췌장암, 피부암, 두부 또는 경부암, 피부 또는 안구내 흑색종, 자궁암, 난소암, 직장암, 항문부근암, 결장암, 유방암, 나팔관암종, 자궁내막암종, 자궁경부암, 질암, 음문암종, 호지킨병, 식도암, 소장암, 내분비선암, 갑상선암, 부갑상선암, 부신암, 연조직육종, 요도암, 음경암, 전립선암, 만성 또는 급성 백혈병, 림프구 림프종, 방광암, 신장 또는 수뇨관 암, 신장세포 암종, 신장골반 암종, CNS 종양, 1차 CNS 림프종, 척수 종양, 뇌간신경교종 및 뇌하수체 선종으로 이루어진 군에서 선택되는 나병, 만성 이식편대숙주병, 염증성 질환 또는 암 예방 또는 치료용 약학적 조성물.According to claim 6,
The cancer is breast cancer, colon cancer, lung cancer, small cell lung cancer, stomach cancer, liver cancer, blood cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, skin or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, proximal anal cancer, colon cancer, Breast cancer, fallopian tube carcinoma, endometrial carcinoma, cervical cancer, vaginal cancer, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or leprosy selected from the group consisting of acute leukemia, lymphocytic lymphoma, bladder cancer, renal or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, CNS tumor, primary CNS lymphoma, spinal cord tumor, brainstem glioma, and pituitary adenoma, chronic graft A pharmaceutical composition for preventing or treating host disease, inflammatory disease or cancer.
KR1020220148244A 2021-11-09 2022-11-08 Glutarimide moiety based isoindolinone derivatives and use thereof KR20230068335A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP22893205.9A EP4431505A1 (en) 2021-11-09 2022-11-09 Isoindolinone derivative having glutarimide mother nucleus, and use thereof
CN202280074437.2A CN118234721A (en) 2021-11-09 2022-11-09 Isoindolinone derivative with glutarimide mother nucleus and application thereof
PCT/KR2022/017592 WO2023085785A1 (en) 2021-11-09 2022-11-09 Isoindolinone derivative having glutarimide mother nucleus, and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20210153439 2021-11-09
KR1020210153439 2021-11-09

Publications (1)

Publication Number Publication Date
KR20230068335A true KR20230068335A (en) 2023-05-17

Family

ID=86547418

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020220148244A KR20230068335A (en) 2021-11-09 2022-11-08 Glutarimide moiety based isoindolinone derivatives and use thereof

Country Status (1)

Country Link
KR (1) KR20230068335A (en)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100671366B1 (en) 2002-11-14 2007-01-19 셀진 코포레이션 Pharmaceutical compositions and dosage forms of thalidomide
KR20110019761A (en) 2008-05-30 2011-02-28 셀진 코포레이션 5-substituted isoindoline compounds
KR101696938B1 (en) 2008-10-29 2017-01-16 셀진 코포레이션 Isoindoline compounds for use in the treatment of cancer
KR20180095094A (en) 2016-01-08 2018-08-24 셀진 코포레이션 The use of biomarkers as predictors of clinical susceptibility to treatment methods and therapies for cancer
KR20200054046A (en) 2018-11-09 2020-05-19 한국화학연구원 Novel piperidine-2,6-dione derivatives and use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100671366B1 (en) 2002-11-14 2007-01-19 셀진 코포레이션 Pharmaceutical compositions and dosage forms of thalidomide
KR20110019761A (en) 2008-05-30 2011-02-28 셀진 코포레이션 5-substituted isoindoline compounds
KR101696938B1 (en) 2008-10-29 2017-01-16 셀진 코포레이션 Isoindoline compounds for use in the treatment of cancer
KR20180095094A (en) 2016-01-08 2018-08-24 셀진 코포레이션 The use of biomarkers as predictors of clinical susceptibility to treatment methods and therapies for cancer
KR20200054046A (en) 2018-11-09 2020-05-19 한국화학연구원 Novel piperidine-2,6-dione derivatives and use thereof

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
Chamberlain, P. P. et al., Nat Struct Mol Biol., 21(9), 803-809, 2014
Chamberlain, P. P. et al., Structure of the human Cereblon-DDB1-lenalidomide complex reveals basis for responsiveness to thalidomide analogs, Nat Struct Mol Biol., 21(9), 803-809, 2014.
Chauvin, Celine, et al. Human eukaryotic release factor 3a depletion causes cell cycle arrest at G1 phase through inhibition of the mTOR pathway, Molecular and cellular biology, 27(16), 5619-5629, 2007.
Costa, P. T. et al., Thalidomide and pentoxifylline prevent the development of chronic cardiomyopathy provoked by doxorubicin in rats without inhibiting its antitumoral effect, Blood, 92(Suppl 1, Pt 2), 235b, 1998.
Marx, G. M. et al., A phase I/II trial of thalidomide as an antiangiogenic agent in the treatment of advanced cancer, Proc Am Soc Clin Oncol., 454a, 1999.
Matyskiela, M. E. et al., A novel cereblon modulator recruits GSPT1 to the CRL4(CRBN) ubiquitin ligase, Nature, 535(7611), 252-257, 2016.
Preis, Anne, et al. Cryoelectron microscopic structures of eukaryotic translation termination complexes containing eRF1-eRF3 or eRF1-ABCE1, Cell reports, 8(1), 59-65, 2014.
Singhal, S. et al., Antitumor activity of thalidomide in refractory multiple myeloma, N Engl J Med., 341(21), 1565-1571, 1999.
Surka, Christine, et al. CC-90009, a novel cereblon E3 ligase modulator, targets acute myeloid leukemia blasts and leukemia stem cells, Blood, The Journal of the American Society of Hematology 137.5, 661-677, 2021.
Xiao, Ruilin, et al. miRNA-144 suppresses proliferation and migration of colorectal cancer cells through GSPT1, Biomedicine & Pharmacotherapy 74, 138-144, 2015.
Zwart, D., Clinical observations in the influence of thalidomide in the treatment of a leiomyoma in a dog, Arzneimittelforschung, 16(12), 1688-1689, 1966.
미국등록특허 제05643915호, Treatment of ischemia/reperfusion injury with thalidomide alone or in combination with other therapies, 1997년 07월 01일, 등록.
호주공개특허 제 2019284608호, Aminoamide compounds, 2019년 12월 19일, 공개.

Similar Documents

Publication Publication Date Title
JP4754821B2 (en) Novel compounds useful for the treatment of obesity, type II diabetes and CNS disorders
KR100979577B1 (en) 1-sulfonyl-piperidine-3-carboxylic acid amide derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase for the treatment of type ii diabetes mellitus
KR101804588B1 (en) Hematopoietic growth factor mimetic small molecule compounds and their uses
CA2458533C (en) Imidazole derivates as anti-inflammatory agents
EP2455370A1 (en) Pharmaceutical product containing lactam or benzene sulfonamide compound
JP5800814B2 (en) Heterocyclic compounds and uses thereof
KR101738866B1 (en) Cyclic N,N&#39;-diarylthioureas and N,N&#39;-diarylureas as androgen receptor antagonists, anti-cancer agent, method for producing and using same
WO2006036024A1 (en) Proton pump inhibitors
JP6042060B2 (en) Pyrazoloquinolinone derivatives, their preparation and therapeutic use
WO2001056607A1 (en) Integrin expression inhibitors
KR20050098286A (en) Cyclic urea derivatives, preparation method thereof and pharmaceutical use of same as kinase inhibitors
KR20010085984A (en) 2-Ureido-thiazole derivatives, process for their preparation, and their use as antitumor agents
CA2993312A1 (en) 1-substituted 1,2,3,4-tetrahydro-1,7-naphthyridin-8-amine derivatives and their use as ep4 receptor antagonists
TW200916446A (en) Chiral cis-imidazolines
WO2014067417A1 (en) Novel quinoline compound and use thereof
JP2003313126A (en) Medicine comprising imidazopyridine derivative as active ingredient
US20130196960A1 (en) Cannabinoid Receptor Agonists
WO2008072634A1 (en) Fused heterocyclic compound
JP2000143635A (en) Arterialization inhibitor
EA029415B1 (en) 2-OXO-3,4-DIHYDRO-2H-BENZO[e][1,3]OXAZIN DERIVATIVES
WO2017040451A1 (en) Triazolopyridine inhibitors of myeloperoxidase
EP3227291B1 (en) N-substituted beta-carbolinium compounds as potent p-glycoprotein inducers
CN102781914B (en) Indole derivative
AU2021347360A1 (en) Modulators of mas-related g-protein receptor x2 and related products and methods
US7071182B2 (en) Antagonists of melanin concentrating hormone effects on the melanin concentrating hormone receptor