KR20240028959A - Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same - Google Patents
Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same Download PDFInfo
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- KR20240028959A KR20240028959A KR1020230112027A KR20230112027A KR20240028959A KR 20240028959 A KR20240028959 A KR 20240028959A KR 1020230112027 A KR1020230112027 A KR 1020230112027A KR 20230112027 A KR20230112027 A KR 20230112027A KR 20240028959 A KR20240028959 A KR 20240028959A
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- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- 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
- C07D417/02—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 two hetero rings
- C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/10—Spiro-condensed systems
Abstract
본 발명은 오토탁신의 억제를 위한 신규한 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용가능한 염 및 이를 함유하는 약제학적 조성물에 관한 것이다.The present invention relates to novel compounds for inhibiting autotaxin, stereoisomers thereof, hydrates thereof, solvates or pharmaceutically acceptable salts thereof, and pharmaceutical compositions containing the same.
Description
본 발명은 오토탁신의 활성화 또는 리소포스파티드산의 농도 증가에 의한 병태 또는 질환의 치료 및 예방을 위한 신규 오토탁신 저해 화합물 및 이를 함유하는 약제학적 조성물에 관한 것이다.The present invention relates to a novel autotaxin inhibitory compound and a pharmaceutical composition containing the same for the treatment and prevention of conditions or diseases caused by activation of autotaxin or increased concentration of lysophosphatidic acid.
오토탁신(Autotaxin, ATX)은 복수 및 혈장에서의 리소포스파티드산(Lysophosphatidic acid, LPA)의 증가의 원인이 되는 효소로서, 리소파티딜콜린(LPC)을 생활성 신호화 분자인 리소포스파티드산으로 전환하는 과정에서 중요한 분비 효소이다. 오토탁신은 엑토뉴클레오티드 피로포스파타제/포스포다이에스터라제-2(ecto-nucleotide pyrophosphatase/phosphodiesterase-2, ENPP-2) 또는 리소포스포리파제 D(lysophospholipase D, lysoPLD)로도 지칭되며, 섬유증, 관절염 염증, 신경 퇴화, 신경병성 통증, 및 암을 포함한 병태를 유발하는 역할을 한다.Autotaxin (ATX) is an enzyme that causes an increase in lysophosphatidic acid (LPA) in ascites and plasma. It converts lysophosphatidic acid (LPC) into lysophosphatidic acid, a bioactive signaling molecule. It is an important secreted enzyme in the conversion process. Autotaxin, also referred to as ecto-nucleotide pyrophosphatase/phosphodiesterase-2 (ENPP-2) or lysophospholipase D (lysoPLD), is used to treat fibrosis, arthritis inflammation, It plays a role in causing conditions including neurodegeneration, neuropathic pain, and cancer.
리소포스파티드산는 다양한 세포 유형의 이동, 증식, 및 생존에 영향을 미치는 생리활성 지질이다. 혈장 내 리소포스파티드산은 오토탁신의 활성과 매우 연관되어 있으므로, 오토탁신은 세포 외 리소포스파티드산의 중요한 공급원인 것으로 여겨진다.Lysophosphatidic acid is a bioactive lipid that affects migration, proliferation, and survival of various cell types. Since lysophosphatidic acid in plasma is highly correlated with the activity of autotaxin, autotaxin is believed to be an important source of extracellular lysophosphatidic acid.
병리학적으로 상기 오토탁신을 억제하는 경우 리소포스파티드산을 감소시키며, 리소포스파티드산 또는 오토탁신의 활성화에 의해 유발되거나 매개되는 암, 림프구 귀소, 만성 염증, 신경병성 통증, 섬유성 질환, 예컨대 특발성 폐 섬유화증 (IPF), 혈전증, 및 담즙정체 가려움증 등의 질환에 치료 효과가 있는 것으로 알려져 있다.Inhibiting autotaxin pathologically reduces lysophosphatidic acid and causes cancer, lymphocyte homing, chronic inflammation, neuropathic pain, fibrotic diseases caused or mediated by activation of lysophosphatidic acid or autotaxin, such as It is known to be effective in treating diseases such as idiopathic pulmonary fibrosis (IPF), thrombosis, and cholestasis.
종양 환자를 치료하기 위해 리소포스파티드산 수준을 낮추는 것이 바람직하며, 예를 들어, 오토탁신과 같은 리소포스파티드산 생합성과 관련된 효소를 저해시키는 것을 통해 달성될 수 있다. 오토탁신은 뉴클레오티드 피로포스파타아제 및 포스포디에스테라아제의 효소 패밀리에 속하며, 항종양 요법을 위한 중요한 출발점을 제시한다. 이는 오토탁신이 종양에서 증가된 정도로 발현되어 종양 세포 증식 및 이웃 조직으로의 침투에 영향을 주며, 이것이 전이의 형성을 야기할 수 있기 때문이다.To treat patients with tumors, lowering lysophosphatidic acid levels is desirable and can be achieved, for example, by inhibiting enzymes involved in lysophosphatidic acid biosynthesis, such as autotaxin. Autotaxin belongs to the enzyme family of nucleotide pyrophosphatases and phosphodiesterases and represents an important starting point for antitumor therapy. This is because autotaxin is expressed to an increased extent in tumors, affecting tumor cell proliferation and invasion into neighboring tissues, which may lead to the formation of metastases.
즉, 오토탁신은 종양에서 발현되고 주변 조직으로 종양 세포 증식 및 침습에 영향을 미치며 이들 모두 전이의 형성을 야기할 수 있기 때문에, 오토탁신은 항-종양 치료의 표적이다. 또한, 혈관 신생 과정에서, 오토탁신은 다른 항-혈관 신생인자와 함께 혈관 형성을 일으킨다. 혈관 신생은 종양 성장 동안에 종양에 영양분을 공급한다. 따라서, 혈관 신생의 억제는 암 및 종양 요법의 중요한 출발점이라 할 수 있다. That is, autotaxins are targets for anti-tumor therapy because they are expressed in tumors and affect tumor cell proliferation and invasion into surrounding tissues, both of which can lead to the formation of metastases. Additionally, during angiogenesis, autotaxin causes blood vessel formation together with other anti-angiogenic factors. Angiogenesis supplies nutrients to tumors during tumor growth. Therefore, inhibition of angiogenesis can be considered an important starting point for cancer and tumor therapy.
위의 원리에 기초하여, 오토탁신을 억제하고 다양한 유형의 암을 치료할 수 있는 항종양 화합물의 종류에 대한 필요성이 시급하고 증가하고 있다.Based on the above principles, there is an urgent and growing need for a class of antitumor compounds that can inhibit autotaxin and treat various types of cancer.
이에, 본 발명의 발명자들은 신규한 구조의 화합물이 오토탁신에 대해 뛰어난 억제 활성을 나타냄을 확인하고 본 발명을 완성하였다.Accordingly, the inventors of the present invention confirmed that a compound with a novel structure exhibits excellent inhibitory activity against autotaxin and completed the present invention.
본 발명의 목적은 오토탁신의 활성화에 의한 병태 또는 질환의 치료 및 예방을 위한 신규한 오토탁신 저해 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염을 제공하는 것이다.The purpose of the present invention is to provide novel autotaxin inhibitory compounds, stereoisomers thereof, hydrates thereof, solvates thereof, or pharmaceutically acceptable salts thereof for the treatment and prevention of conditions or diseases caused by activation of autotaxin.
본 발명의 다른 목적은, 상기 오토탁신 저해 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 함유하는 것을 특징으로 하는 오토탁신 저해제 조성물을 제공하는 것이다.Another object of the present invention is to provide an autotaxin inhibitor composition comprising the autotaxin inhibitory compound, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 다른 목적은, 상기 오토탁신 저해 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염을 유효성분으로 함유하는 것을 특징으로 하는 오토탁신 활성과 관련된 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to prevent diseases related to autotaxin activity, or To provide a pharmaceutical composition for treatment.
상기 목적을 달성하기 위하여, 본 발명은 오토탁신의 활성을 효과적으로 억제할 수 있는 신규한 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염을 제공한다.In order to achieve the above object, the present invention provides a novel compound represented by the following formula (1), a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof, which can effectively inhibit the activity of autotaxin. do.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
A는 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 11원의 모노- 또는 바이- 헤테로사이클릭 환이고,A is a substituted or unsubstituted 5- to 11-membered mono- or bi-heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur,
L은 단일결합, -C(=O)-, -C(=O)-NR1-, -C(=O)-NR2-(CR3R4)a-, 또는 -S(=O)2-NR5-이고, L is a single bond, -C(=O)-, -C(=O)-NR 1 -, -C(=O)-NR 2 -(CR 3 R 4 ) a -, or -S(=O) 2 -NR 5 -,
B는 치환 또는 비치환된 카보사이클릭 환; 또는 치환 또는 비치환된 헤테로사이클릭 환이고,B is a substituted or unsubstituted carbocyclic ring; Or a substituted or unsubstituted heterocyclic ring,
R1 내지 R5는 각각 독립적으로 수소, 또는 치환 또는 비치환된 C1-C10의 알킬기이고,R 1 to R 5 are each independently hydrogen or a substituted or unsubstituted C1-C10 alkyl group,
a는 1 내지 5의 정수이다.a is an integer from 1 to 5.
상기 A는 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 6원의 헤테로아릴 환; 트리아졸기를 포함하는 치환 또는 비치환된 9원 내지 10원의 바이사이클릭 헤테로사이클릭 환; 또는 옥사졸리디논기를 포함하는 치환 또는 비치환된 9원 내지 10원의 바이사이클릭 헤테로사이클릭 환일 수 있다.Wherein A is a substituted or unsubstituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; A substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing a triazole group; Alternatively, it may be a substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing an oxazolidinone group.
상기 A는 치환 또는 비치환된 피리딘기, 치환 또는 비치환된 티아졸기, 치환 또는 비치환된 벤족사졸론기, 치환 또는 비치환된 벤조트리아졸기, 치환 또는 비치환된 테트라하이드로벤조트리아졸기, 치환 또는 비치환된 트리아졸로피리딘기 또는 치환 또는 비치환된 테트라하이드로트리아졸로피리딘기일 수 있다.Wherein A is a substituted or unsubstituted pyridine group, a substituted or unsubstituted thiazole group, a substituted or unsubstituted benzoxazolone group, a substituted or unsubstituted benzotriazole group, a substituted or unsubstituted tetrahydrobenzotriazole group, a substituted Alternatively, it may be an unsubstituted triazolopyridine group or a substituted or unsubstituted tetrahydrotriazolopyridine group.
상기 A는 하기 구조에서 선택되는 것일 수 있다.The A may be selected from the structures below.
상기 Ra는 수소, R6-S(=O)2-NH-, R6-S(=O)2-CH2- 또는 테트라졸일기이고,The Ra is hydrogen, R 6 -S(=O) 2 -NH-, R 6 -S(=O) 2 -CH 2 - or a tetrazolyl group,
Rb는 할로겐, 또는 치환 또는 비치환된 C1-C10의 알콕시기이고,Rb is halogen or a substituted or unsubstituted C1-C10 alkoxy group,
R6는 히드록시기, 또는 치환 또는 비치환된 C1-C10의 알킬기이고,R 6 is a hydroxy group or a substituted or unsubstituted C1-C10 alkyl group,
d는 0 내지 6의 정수이고,d is an integer from 0 to 6,
e는 0 내지 3의 정수이다.e is an integer from 0 to 3.
상기 A는 하기 구조에서 선택되는 것일 수 있다.The A may be selected from the structures below.
상기 Rb는 할로겐, 또는 치환 또는 비치환된 C1-C10의 알콕시기이고,Rb is a halogen or a substituted or unsubstituted C1-C10 alkoxy group,
e는 0 내지 1의 정수이다.e is an integer from 0 to 1.
상기 L은 하기 구조에서 선택되는 것일 수 있다.The L may be selected from the structures below.
상기 R3 및 R4는 각각 독립적으로 수소, 또는 치환 또는 비치환된 C1-C5의 알킬기이다.R 3 and R 4 are each independently hydrogen or a substituted or unsubstituted C1-C5 alkyl group.
상기 B는 치환 또는 비치환된 C6-C10 카보사이클릭 환; 또는 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 11원의 모노- 또는 바이- 헤테로사이클릭 환일 수 있다.Wherein B is a substituted or unsubstituted C6-C10 carbocyclic ring; Alternatively, it may be a substituted or unsubstituted 5- to 11-membered mono- or bi-heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
상기 B는 치환 또는 비치환된 C6-C10의 아릴렌; 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 6원의 헤테로아릴렌; 또는 이소옥사졸기를 포함하는 치환 또는 비치환된 8원 내지 11원의 스피로 사이클릭 환일 수 있다.B is substituted or unsubstituted C6-C10 arylene; a substituted or unsubstituted 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Alternatively, it may be a substituted or unsubstituted 8- to 11-membered spiro cyclic ring containing an isoxazole group.
상기 B는 치환 또는 비치환된 페닐렌, 치환 또는 비치환된 피리도닐렌, 치환 또는 비치환된 이소옥사졸릴렌, 치환 또는 비치환된 피라졸릴렌, 치환 또는 비치환된 티아졸릴렌 또는 치환 또는 비치환된 티아디아졸릴렌일 수 있다.Wherein B is substituted or unsubstituted phenylene, substituted or unsubstituted pyridonylene, substituted or unsubstituted isoxazolylene, substituted or unsubstituted pyrazolilene, substituted or unsubstituted thiazolilene or substituted or It may be unsubstituted thiadiazolylene.
상기 B는 하기 구조에서 선택되는 것일 수 있다.The B may be selected from the structures below.
상기 Rc 및 Rc1 내지 Rc6은 각각 독립적으로 수소, 할로겐기, 히드록시기, 카복실기, 치환 또는 비치환된 C1-C10의 일킬기, 치환 또는 비치환된 C1-C10의 알콕시기, -NR7R8 또는 -C(=O)OR9이되, 상기 R7 및 R8는 서로 연결되어 포화 단환고리를 형성할 수 있고, 상기 형성된 고리는 질소 또는 산소로부터 선택되는 헤테로원자를 하나 이상 포함할 수 있으며, 히드록시기 및 치환 또는 비치환된 C1-C10의 알킬기로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있고,Rc and Rc1 to Rc6 are each independently hydrogen, a halogen group, a hydroxy group, a carboxyl group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C10 alkoxy group, -NR 7 R 8 or -C(=O)OR 9 , wherein R 7 and R 8 may be connected to each other to form a saturated monocyclic ring, and the formed ring may contain one or more heteroatoms selected from nitrogen or oxygen, and a hydroxy group and may be further substituted with one or more substituents selected from substituted or unsubstituted C1-C10 alkyl groups,
R9는 수소, 치환 또는 비치환된 C1-C10의 알킬기 또는 치환 또는 비치환된 C3-C10의 사이클로알킬기이고,R 9 is hydrogen, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C3-C10 cycloalkyl group,
f는 0 내지 4의 정수이고, g는 0 내지 2의 정수이고, h는 0 내지 3의 정수이고, s 및 t는 서로 같거나 상이하고, 각각 독립적으로 0 내지 4의 정수이고, 이때 s 및 t의 합은 2 내지 5이다.f is an integer from 0 to 4, g is an integer from 0 to 2, h is an integer from 0 to 3, s and t are the same or different from each other and are each independently an integer from 0 to 4, where s and The sum of t is 2 to 5.
상기 B는 하기 구조에서 선택되는 것일 수 있다.The B may be selected from the structures below.
상기 Rc는 수소, 할로겐기, 히드록시기, 카복실기, 치환 또는 비치환된 C1-C10의 일킬기, 치환 또는 비치환된 C1-C10의 알콕시기, -NR7R8 또는 -C(=O)OR9이되, 상기 R7 및 R8는 서로 연결되어 포화 단환고리를 형성할 수 있고, 상기 형성된 고리는 질소 또는 산소로부터 선택되는 헤테로원자를 하나 이상 포함할 수 있으며, Rc is hydrogen, halogen group, hydroxy group, carboxyl group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C1-C10 alkoxy group, -NR 7 R 8 or -C(=O)OR 9 , wherein R 7 and R 8 may be connected to each other to form a saturated monocyclic ring, and the formed ring may contain one or more heteroatoms selected from nitrogen or oxygen,
R9는 수소 또는 치환 또는 비치환된 C1-C10의 알킬기이고,R 9 is hydrogen or a substituted or unsubstituted C1-C10 alkyl group,
f는 0 내지 4의 정수이다.f is an integer from 0 to 4.
또한 본 발명은 상기 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 것을 특징으로 하는 오토탁신 저해제 조성물을 제공한다.In addition, the present invention provides an autotaxin inhibitor composition containing the above compound, its stereoisomer, its hydrate, its solvate, or its pharmaceutically acceptable salt as an active ingredient.
또한 본 발명은 상기 화학식 1로 표시되는 화합물에 대한 우수한 오토탁신 억제 활성을 확인함으로써, 상기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 것을 특징으로 하는 오토탁신 활성과 관련된 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.In addition, the present invention confirms the excellent autotaxin inhibitory activity of the compound represented by Formula 1, thereby demonstrating the effectiveness of the compound represented by Formula 1, its stereoisomer, its hydrate, its solvate, or its pharmaceutically acceptable salt. Provided is a pharmaceutical composition for preventing or treating diseases related to autotaxin activity, characterized in that it contains as an ingredient.
본 발명에 따른 화합물은 신규한 화합물로서, 오토탁신에 대한 매우 높은 저해 활성을 나타냄으로써, 오토탁신에 의해 매개되어 유발되는 질환의 치료, 예방 및 경감에 부작용없이 유용하게 사용될 수 있다.The compound according to the present invention is a novel compound and exhibits very high inhibitory activity against autotaxin, so it can be usefully used in the treatment, prevention and alleviation of diseases caused by autotaxin without side effects.
이하, 본 발명을 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
하기의 설명은 본 개시내용의 구체예를 기술하는 것으로 이해되어야 하며, 본 개시내용이 반드시 이에 한정되는 것은 아니다. 본 개시내용의 실시예는 다양한 변경을 가할 수 있고, 다양한 형태로 실시할 수 있다. 따라서, 본 개시내용의 사상 및 기술적 특징의 동일성이 인정되는 범위의 모든 변경, 균등물 내지 대체물을 포함하는 것으로 이해하여야 한다.The following description should be understood as describing embodiments of the present disclosure, and is not necessarily limited thereto. Embodiments of the present disclosure may be subject to various changes and may be implemented in various forms. Accordingly, it should be understood to include all changes, equivalents, and substitutes within the scope where the same spirit and technical features of the present disclosure are acknowledged.
달리 명시하지 않았더라도, 본 개시내용에 사용된 모든 숫자는 모든 경우마다 "약"이란 용어가 수식하고 있는 것으로 이해되어야 한다. 수식어 “약”은 통상적으로 인식되는 대략적으로의 의미를 갖도록 하기 위한 것인데, 이는 수식된 값의 특정 퍼센트 이내의 의미로서 더욱 정확하게 해석될 수 있고, 보다 구체적으로는 ±20%, ±10%, ±5%, ±2% 또는 ±1% 또는 그 미만을 의미할 수 있다.Unless otherwise specified, all numbers used in this disclosure are to be understood in all instances as being modified by the term “about.” The modifier “about” is intended to have a commonly recognized approximate meaning, which can be more accurately interpreted as meaning within a certain percentage of the modified value, and more specifically, ±20%, ±10%, ± It may mean 5%, ±2% or ±1% or less.
본 명세서에서 사용되는 각 치환기의 정의에 대해 상세히 설명한다. 명시하지 않는 한, 각 치환기는 하기의 정의를 갖는다.The definition of each substituent used in this specification will be described in detail. Unless otherwise specified, each substituent has the following definition.
본 발명의 용어 “알킬”은 탄소 및 수소 원자만으로 구성된 1가의 직쇄 또는 분쇄 포화 탄화수소기를 의미하는 것으로, 1 내지 10개의 탄소원자, 바람직하게는 1 내지 7개의 탄소원자를 가질 수 있다. 이러한 알킬기의 예는 메틸, 에틸, 프로필, 이소프로필, 부틸, 이소부틸, sec-부틸, tert-부틸, 펜틸, 이소펜틸, 네오펜틸, 1-에틸프로필, 헥실, 이소헥실, 1,1-디메틸부틸, 2,2-디메틸부틸, 3,3-디메틸부틸, 2-에틸부틸 등을 포함하지만 이에 한정되지는 않는다.The term “alkyl” in the present invention refers to a monovalent straight-chain or branched saturated hydrocarbon group consisting only of carbon and hydrogen atoms, and may have 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms. Examples of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethyl. Includes but is not limited to butyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, etc.
본 발명의 용어 “아릴”은 하나의 수소 제거에 의해서 방향족 탄화수소로부터 유도된 카보사이클릭 유기기로, 각 고리에 적절하게는 4 내지 7개, 바람직하게는 5 또는 6개의 고리원자를 포함하는 단일 또는 융합 고리계를 포함하며, 다수개의 아릴이 단일결합으로 연결되어 있는 형태까지 포함한다. 구체적인 예로 페닐, 나프틸, 비페닐, 안트릴, 인데닐(indenyl), 플루오레닐 등을 포함하지만, 이에 한정되지는 않는다. 아릴은 방향족 고리 상의 적정 위치에서 다른 기와 연결될 수 있다.The term “aryl” in the present invention refers to a carbocyclic organic group derived from an aromatic hydrocarbon by removal of one hydrogen, and each ring contains a single or 7 ring atom, preferably 4 to 7, preferably 5 or 6. It includes a fused ring system and even includes forms in which multiple aryls are connected by a single bond. Specific examples include, but are not limited to, phenyl, naphthyl, biphenyl, anthryl, indenyl, fluorenyl, etc. Aryl can be connected to other groups at appropriate positions on the aromatic ring.
본 발명의 용어 “헤테로아릴”은 방향족 고리 골격 원자로서 N, O 및 S로부터 선택되는 1 내지 4개의 헤테로원자를 포함하고, 나머지 방향족 고리 골격 원자가 탄소인 아릴 그룹을 의미하는 것으로, 5 내지 6원 단환 헤테로아릴, 및 하나 이상의 벤젠환과 축합된 다환식 헤테로아릴이며, 부분적으로 포화될 수도 있다. 또한, 본 발명에서의 헤테로아릴은 하나 이상의 헤테로아릴이 단일결합으로 연결된 형태도 포함한다. 상기 헤테로아릴기의 예는 피롤, 퀴놀린, 이소퀴놀린, 피리딘, 피리미딘, 옥사졸, 티아졸, 티아디아졸, 트리아졸, 이미다졸, 벤조이미다졸, 이소옥사졸, 벤조이소옥사졸, 티오펜, 벤조티오펜, 퓨란, 벤조퓨란 등을 포함하지만, 이에 한정되지는 않는다.The term “heteroaryl” of the present invention refers to an aryl group containing 1 to 4 heteroatoms selected from N, O and S as aromatic ring skeleton atoms, and the remaining aromatic ring skeleton atoms are carbon, and is 5 to 6 members. Monocyclic heteroaryl, and polycyclic heteroaryl condensed with one or more benzene rings, and may be partially saturated. In addition, heteroaryl in the present invention also includes forms in which one or more heteroaryls are linked by a single bond. Examples of the heteroaryl group include pyrrole, quinoline, isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, benzoimidazole, isoxazole, benzoisoxazole, thiophene, Including, but not limited to, benzothiophene, furan, benzofuran, etc.
본 발명의 용어 “할로” 또는 “할로겐”은 할로겐족 원소를 나타내며, 예컨대, 플루오로, 클로로, 브로모 및 요오도를 포함한다.The term “halo” or “halogen” in the present invention refers to elements of the halogen group and includes, for example, fluoro, chloro, bromo and iodo.
본 발명의 용어 “시클로알킬”은 하나 이상의 고리로 구성된 1가의 포화 카보사이클릭 유기기로, 3 내지 10개의 탄소원자 바람직하게는 3 내지 7개의 탄소원자를 가질 수 있다. 구체적인 예로는 시클로프로필, 시클로부틸, 시클로펜틸, 시클로헥실 등을 들 수 있으나, 이에 한정되지는 않는다.The term “cycloalkyl” of the present invention refers to a monovalent saturated carbocyclic organic group consisting of one or more rings, and may have 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
본 발명의 용어 “알콕시”는 -O-알킬 유기기로, 1 내지 10개의 탄소원자, 바람직하게는 1 내지 7개의 탄소원자를 가질 수 있다. 여기서 ‘알킬’은 상기 정의한 바와 같다. 구체적인 예로는 메톡시, 에톡시, 이소프로폭시, 부톡시, 이소부톡시, tert-부톡시 등을 포함되지만 이에 한정되지는 않는다.The term “alkoxy” in the present invention refers to an -O-alkyl organic group, which may have 1 to 10 carbon atoms, preferably 1 to 7 carbon atoms. Here, ‘alkyl’ is as defined above. Specific examples include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, etc.
본 발명의 용어 "헤테로사이클"은 고리 구성 원자로서 탄소 원자 이외의 질소 원자, 황 원자 및 산소 원자에서 선택되는 헤테로원자를 함유하는 방향족 또는 비방향족 고리를 의미하며, 바람직하게는 1 내지 4의 상기 헤테로원자를 포함하는 4원 내지 10원, 더욱 바람직하게는 5원 내지 9원의 방향족 또는 비방향족환을 포함한다. 이러한 방향족환의 예는 티에닐, 푸릴, 피롤릴, 이미다졸릴, 피라졸릴, 티아졸릴, 이소티아졸릴, 옥사졸릴, 이속사졸릴, 피리딜, 피라지닐, 피리미디닐, 피리다지닐, 1,2,4-옥사디아졸릴, 1,3,4-옥사디아졸릴, 1,2,4-티아디아졸릴, 1,3,4-티아디아졸릴, 트리아졸릴, 테트라졸릴, 트리아지닐 및 벤조티아졸일을 포함한다. 또한 이러한 비방향족환의 예는 테트라히드로티에닐, 테트라히드로푸라닐, 피롤리닐, 피롤리디닐, 이미다졸리닐, 이미다졸리디닐, 옥사졸리닐, 옥사졸리디닐, 피라졸리닐, 피라졸리디닐, 티아졸리닐, 티아졸리디닐, 테트라히드로이소티아졸릴, 테트라히 드로옥사졸릴, 테트라히드로이속사졸릴, 피페리디닐, 피페라지닐, 테트라히드로피리디닐, 디히드로피리디닐, 디히드로티오피라닐, 테트라히드로피리미디닐, 테트라히드로피리다지닐, 디히드로피라닐, 테트라히드로피라닐, 테트라히드로티오피라닐, 모르폴리닐, 티오모르폴리닐, 아제파닐, 디아제파닐 및 아제피닐을 포함한다.The term "heterocycle" in the present invention refers to an aromatic or non-aromatic ring containing heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms other than carbon atoms as ring constituent atoms, preferably 1 to 4 of the above. It contains a 4-membered to 10-membered, more preferably 5- to 9-membered aromatic or non-aromatic ring containing a heteroatom. Examples of such aromatic rings include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1, 2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and benzothiazolyl Includes. Additionally, examples of such non-aromatic rings include tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, and pyrazolidinyl. , thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydroxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, Includes tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanil, diazepanil and azepinyl. .
본 발명의 용어 “아릴렌” 및 “헤테로아릴렌”은 방향족고리 및 헤테로방향족고리의 2가 유기기를 의미한다.The terms “arylene” and “heteroarylene” in the present invention refer to divalent organic groups of aromatic rings and heteroaromatic rings.
본 발명의 용어 “헤테로시클로알킬렌” 및 “헤테로시클로알케닐렌”은 포화 헤테로고리 및 불포화 헤테로고리의 2가 유기기를 의미한다.The terms “heterocycloalkylene” and “heterocycloalkenylene” in the present invention refer to divalent organic groups of saturated heterocycles and unsaturated heterocycles.
본 발명은 하기 화학식 1로 표시되는 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염을 제공한다.The present invention provides a compound represented by the following formula (1), a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
상기 화학식 1에서,In Formula 1,
A는 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 11원의 모노- 또는 바이- 헤테로사이클릭 환이고,A is a substituted or unsubstituted 5- to 11-membered mono- or bi-heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur,
L은 단일결합, -C(=O)-, -C(=O)-NR1-, -C(=O)-NR2-(CR3R4)a-, 또는 -S(=O)2-NR5-이고, L is a single bond, -C(=O)-, -C(=O)-NR 1 -, -C(=O)-NR 2 -(CR 3 R 4 ) a -, or -S(=O) 2 -NR 5 -,
B는 치환 또는 비치환된 카보사이클릭 환; 또는 치환 또는 비치환된 헤테로사이클릭 환이고,B is a substituted or unsubstituted carbocyclic ring; Or a substituted or unsubstituted heterocyclic ring,
R1 내지 R5는 각각 독립적으로 수소, 또는 치환 또는 비치환된 C1-C10의 알킬기이고,R 1 to R 5 are each independently hydrogen or a substituted or unsubstituted C1-C10 alkyl group,
a는 1 내지 5의 정수이다.a is an integer from 1 to 5.
본 발명에 따른 화학식 1의 화합물은 신규한 화합물로서, 오토탁신에 대한 매우 높은 억제 활성으로 인해 리소포스파티드산의 생성을 저해하므로, 오토탁신에 의해 매개되는 질환, 특히 신장 질환, 간 질환, 염증성 질환, 신경계 질환, 섬유성 질병 및 급성 또는 만성 장기 이식 거부반응의 치료제 및 예방제로 유용하다.The compound of formula 1 according to the present invention is a novel compound, which inhibits the production of lysophosphatidic acid due to its very high inhibitory activity against autotaxin, and is therefore effective in treating diseases mediated by autotaxin, especially kidney disease, liver disease, and inflammatory diseases. It is useful as a treatment and preventive agent for diseases, neurological diseases, fibrotic diseases, and acute or chronic organ transplant rejection.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 A는 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 6원의 헤테로아릴 환; 트리아졸기를 포함하는 치환 또는 비치환된 9원 내지 10원의 바이사이클릭 헤테로사이클릭 환; 또는 옥사졸리디논기를 포함하는 치환 또는 비치환된 9원 내지 10원의 바이사이클릭 헤테로사이클릭 환인 것일 수 있다.In the compound according to one embodiment of the present invention, A is a substituted or unsubstituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; A substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing a triazole group; Alternatively, it may be a substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing an oxazolidinone group.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 A는 치환 또는 비치환된 피리딘기, 치환 또는 비치환된 티아졸기, 치환 또는 비치환된 벤족사졸론기, 치환 또는 비치환된 벤조트리아졸기, 치환 또는 비치환된 테트라하이드로벤조트리아졸기, 치환 또는 비치환된 트리아졸로피리딘기 또는 치환 또는 비치환된 테트라하이드로트리아졸로피리딘기일 수 있다.In the compound according to one embodiment of the present invention, A is a substituted or unsubstituted pyridine group, a substituted or unsubstituted thiazole group, a substituted or unsubstituted benzoxazolone group, a substituted or unsubstituted benzotriazole group, It may be a substituted or unsubstituted tetrahydrobenzotriazole group, a substituted or unsubstituted triazolopyridine group, or a substituted or unsubstituted tetrahydrotriazolopyridine group.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 A는 하기 구조에서 선택되는 것일 수 있다.In the compound according to an embodiment of the present invention, A may be selected from the following structures.
상기 구조들에서, 상기 Ra는 수소, R6-S(=O)2-NH-, R6-S(=O)2-CH2- 또는 테트라졸일기()이고, Rb는 할로겐, 또는 치환 또는 비치환된 C1-C10의 알콕시기이고, R6는 히드록시기, 또는 치환 또는 비치환된 C1-C10의 알킬기이고, d는 0 내지 6의 정수이고, e는 0 내지 3의 정수이다.In the above structures, Ra is hydrogen, R 6 -S(=O) 2 -NH-, R 6 -S(=O) 2 -CH 2 - or a tetrazolyl group ( ), Rb is a halogen or a substituted or unsubstituted C1-C10 alkoxy group, R 6 is a hydroxy group or a substituted or unsubstituted C1-C10 alkyl group, d is an integer of 0 to 6, and e is It is an integer from 0 to 3.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 A는 하기 구조에서 선택되는 것일 수 있다.In the compound according to an embodiment of the present invention, A may be selected from the following structures.
상기 구조들에서, 상기 Rb는 할로겐, 또는 치환 또는 비치환된 C1-C10의 알콕시기이고, e는 0 내지 1의 정수이다.In the above structures, Rb is halogen or a substituted or unsubstituted C1-C10 alkoxy group, and e is an integer of 0 to 1.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 L은 하기 구조에서 선택되는 것일 수 있다.In the compound according to an embodiment of the present invention, L may be selected from the following structures.
상기 구조들에서, 상기 R3 및 R4는 각각 독립적으로 수소, 또는 치환 또는 비치환된 C1-C5의 알킬기이다.In the above structures, R 3 and R 4 are each independently hydrogen or a substituted or unsubstituted C1-C5 alkyl group.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 B는 치환 또는 비치환된 C6-C10 카보사이클릭 환; 또는 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 11원의 모노- 또는 바이- 헤테로사이클릭 환인 것일 수 있다.In the compound according to an embodiment of the present invention, B is a substituted or unsubstituted C6-C10 carbocyclic ring; Alternatively, it may be a substituted or unsubstituted 5- to 11-membered mono- or bi-heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 B는 치환 또는 비치환된 C6-C10의 아릴렌; 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 6원의 헤테로아릴렌; 또는 이소옥사졸기를 포함하는 치환 또는 비치환된 8원 내지 11원의 스피로 사이클릭 환인 것일 수 있다.In the compound according to an embodiment of the present invention, B is substituted or unsubstituted C6-C10 arylene; a substituted or unsubstituted 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Alternatively, it may be a substituted or unsubstituted 8- to 11-membered spiro cyclic ring containing an isoxazole group.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 B는 치환 또는 비치환된 페닐렌, 치환 또는 비치환된 피리도닐렌, 치환 또는 비치환된 이소옥사졸릴렌, 치환 또는 비치환된 피라졸릴렌, 치환 또는 비치환된 티아졸릴렌 또는 치환 또는 비치환된 티아디아졸릴렌인 것일 수 있다.In the compound according to an embodiment of the present invention, B is substituted or unsubstituted phenylene, substituted or unsubstituted pyridonylene, substituted or unsubstituted isoxazolylene, or substituted or unsubstituted pyrazolilene. , may be substituted or unsubstituted thiazolilene or substituted or unsubstituted thiadiazolylene.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 B는 하기 구조에서 선택되는 것일 수 있다.In the compound according to an embodiment of the present invention, B may be selected from the structures below.
상기 구조들에서, 상기 Rc 및 Rc1 내지 Rc6은 각각 독립적으로 수소, 할로겐기, 히드록시기, 카복실기, 치환 또는 비치환된 C1-C10의 일킬기, 치환 또는 비치환된 C1-C10의 알콕시기, -NR7R8 또는 -C(=O)OR9이되, 상기 R7 및 R8는 서로 연결되어 포화 단환고리를 형성할 수 있고, 상기 형성된 고리는 질소 또는 산소로부터 선택되는 헤테로원자를 하나 이상 포함할 수 있으며, 히드록시기 및 치환 또는 비치환된 C1-C10의 알킬기로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있고, R9는 수소, 치환 또는 비치환된 C1-C10의 알킬기 또는 치환 또는 비치환된 C3-C10의 사이클로알킬기이고, f는 0 내지 4의 정수이고, g는 0 내지 2의 정수이고, h는 0 내지 3의 정수이고, s 및 t는 서로 같거나 상이하고, 각각 독립적으로 0 내지 4의 정수이고, 이때 s 및 t의 합은 2 내지 5이다.In the above structures, Rc and Rc1 to Rc6 are each independently hydrogen, a halogen group, a hydroxy group, a carboxyl group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C10 alkoxy group, - NR 7 R 8 or -C(=O)OR 9 , where R 7 and R 8 may be connected to each other to form a saturated monocyclic ring, and the formed ring contains one or more heteroatoms selected from nitrogen or oxygen. may be further substituted with one or more substituents selected from hydroxy groups and substituted or unsubstituted C1-C10 alkyl groups, and R 9 is hydrogen, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C1-C10 alkyl group. is a C3-C10 cycloalkyl group, f is an integer from 0 to 4, g is an integer from 0 to 2, h is an integer from 0 to 3, s and t are the same as or different from each other, and each independently from 0 to 3. It is an integer of 4, and the sum of s and t is 2 to 5.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 B는 하기 구조에서 선택되는 것일 수 있다.In the compound according to an embodiment of the present invention, B may be selected from the structures below.
상기 구조들에서, 상기 Rc는 수소, 할로겐기, 히드록시기, 카복실기, 치환 또는 비치환된 C1-C10의 일킬기, 치환 또는 비치환된 C1-C10의 알콕시기, -NR7R8 또는 -C(=O)OR9이되, 상기 R7 및 R8는 서로 연결되어 포화 단환고리를 형성할 수 있고, 상기 형성된 고리는 질소 또는 산소로부터 선택되는 헤테로원자를 하나 이상 포함할 수 있으며, R9는 수소 또는 치환 또는 비치환된 C1-C10의 알킬기이고, f는 0 내지 4의 정수이다.In the above structures, Rc is hydrogen, a halogen group, a hydroxy group, a carboxyl group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C10 alkoxy group, -NR 7 R 8 or -C (=O)OR 9 , where R 7 and R 8 may be connected to each other to form a saturated monocyclic ring, and the formed ring may contain one or more heteroatoms selected from nitrogen or oxygen, and R 9 may be It is hydrogen or a substituted or unsubstituted C1-C10 alkyl group, and f is an integer of 0 to 4.
본 발명의 일실시예에 따른 화합물에 있어서, 상기 화합물은 구체적으로 하기 표 1의 구조로부터 선택될 수 있으며, 이에 한정되는 것은 아니다. In the compound according to an embodiment of the present invention, the compound may be specifically selected from the structures shown in Table 1 below, but is not limited thereto.
본 발명에 따른 화학식 1의 화합물은 생화학적 및 약리학적 시험 결과 오토탁신에 대한 우수한 저해활성을 나타냄과 동시에 리소포스파티드산의 농도를 낮추어 오토탁신의 활성화 또는 리소포스파티드산의 농도 증가에 의한 병태 또는 질환의 치료 및 예방 효과를 나타낼 수 있다.The compound of Formula 1 according to the present invention shows excellent inhibitory activity against autotaxin as a result of biochemical and pharmacological tests, and at the same time lowers the concentration of lysophosphatidic acid to prevent conditions caused by activation of autotaxin or increased concentration of lysophosphatidic acid. Alternatively, it may exhibit effects in treating and preventing diseases.
본 발명에 따른 상기 화학식 1로 표시되는 화합물은 생체내 흡수를 증진시키거나 용해도를 증가시키기 위하여 수화물, 용매화물 및 약제학적으로 허용되는 염의 형태로 만들어 사용할 수 있으므로, 상기의 수화물, 용매화물 및 약제학적으로 허용되는 염 역시 본 발명의 범위에 속한다. 또한, 상기 화학식 1로 표시되는 화합물은 키랄 탄소를 갖고 있어서, 그의 입체이성질체가 존재하며, 이러한 입체이성질체 역시 본 발명의 범주 내에 포함된다.The compound represented by Formula 1 according to the present invention can be prepared and used in the form of hydrates, solvates, and pharmaceutically acceptable salts in order to improve absorption in the body or increase solubility, so the above hydrates, solvates, and pharmaceuticals Scientifically acceptable salts also fall within the scope of the present invention. In addition, the compound represented by Formula 1 has a chiral carbon, so its stereoisomers exist, and these stereoisomers are also included within the scope of the present invention.
용어 "약제학적으로 허용되는 염"은, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 화합물의 제형을 의미한다. 용어 "수화물", "용매화물", "이성질체" 역시 상기와 같은 의미를 가진다. 상기 약제학적 염은, 약제학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들어, 염산, 황산, 질산, 인산, 브롬화수고산, 요드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플로로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리신산 등과 같은 유기 카본산, 메탄설폰산, 에탄술폰산, 벤젠설폰산, p-톨루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 예를 들어, 약제학적으로 허용되는 카르복실산 염에는, 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 금속염 또는 알칼리 토금속 염, 라이신, 아르지닌, 구아니딘 등의 아미노산 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸)메틸아민, 디에탄올아민, 콜린 및 트리에틸아민 등과 같은 유기염 등이 포함된다. 본 발명에 따른 화학식 1의 화합물은 통상적인 방법에 의해 그것의 염으로 전환시킬 수도 있다.The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to the organism to which the compound is administered and does not impair the biological activity and physical properties of the compound. The terms “hydrate”, “solvate”, and “isomer” also have the same meaning as above. The pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, and formic acid. , organic carbonic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed with the same sulfonic acid, etc. are included. For example, pharmaceutically acceptable carboxylic acid salts include metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N Organic salts such as -methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, and triethylamine are included. The compound of formula 1 according to the present invention can also be converted into its salt by conventional methods.
용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intermolecular force)에 의해 결합된 화학양론적(stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다.The term “hydrate” refers to a compound of the present invention containing a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. or its salt.
용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 양의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있다.The term “solvate” refers to a compound of the invention or a salt thereof containing a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Preferred solvents therefor are solvents that are volatile, non-toxic, and/or suitable for administration to humans.
용어 "이성질체(isomer)"는 동일한 화학식 또는 분자식을 가지지만 구조적 또는 입체적으로 다른 본 발명의 화합물 또는 그것의 염을 의미한다. 이러한 이성질체에는 호변 이성질체(tautomer) 등의 구조 이성질체와, 비대칭 탄소 중심을 가지는 R 또는 S 이성질체, 기하이성질체(트랜스, 시스) 등의 입체 이성질체가 모두 포함된다. 이들 모든 이성질체 및 그것의 혼합물들 역시 본 발명의 범위에 포함된다.The term “isomer” refers to a compound of the present invention or a salt thereof that has the same chemical or molecular formula but is structurally or sterically different. These isomers include both structural isomers such as tautomers, and stereoisomers such as R or S isomers with asymmetric carbon centers and geometric isomers (trans, cis). All these isomers and mixtures thereof are also included within the scope of the present invention.
기타 용어들은 본 발명이 속하는 분야에서 통상적으로 이해되는 의미로서 해석될 수 있다.Other terms may be interpreted as commonly understood in the field to which the present invention pertains.
또한, 본 발명은 상기 화학식 1의 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 오토탁신 저해제 조성물을 제공한다.In addition, the present invention provides an autotaxin inhibitor composition comprising the compound of Formula 1 above, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
또한, 본 발명은 상기 화학식 1의 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 함유하는 것을 특징으로 하는 오토탁신 활성과 관련된 질환의 예방 또는 치료용 약제학적 조성물을 제공한다.In addition, the present invention provides a method for the prevention or treatment of diseases related to autotaxin activity, characterized in that it contains the compound of formula 1, a stereoisomer thereof, a hydrate, a solvate or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutical compositions are provided.
상기한 바와 같이, 화학식 1의 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용가능한 염은 오토탁신에 대한 높은 억제 활성을 나타냄과 동시에 리소포스파티드산의 생성을 저해하므로, 이들을 유효성분으로 포함하는 약제학적 조성물은 오토탁신에 의해 매개되는 질환, 예를 들어 심혈관 질환, 암, 비만, 당뇨병, 급성 신부전, 만성 신장병, 당뇨병성 신증, 급성 신장 이식 거부반응, 만성 동종이식 신증, 간 경화증, 간 출혈, 소양증, 비알코올성 지방간염, 급성 및 만성 간 이식 거부반응, 관절염, 아토피 피부염, 천식, 신경성 동통, 정신 분열증, 신경세포염증, 말초신경 신경장애, 자율신경 신경장애, 전신병, 혈관염, 유육종증, 과민성 폐렴, 폐포 단백질증, 랑게르한스 세포 육아종증, 림프관평활근종증, 방사선 유발 섬유증, 규폐증, 석면 유도된 폐 섬유증, 급성 호흡곤란 증후군(ARDS), 심근 및 혈관 섬유증, 신장 섬유증, 간 섬유증, 폐 섬유증, 피부 섬유증, 경피증, 포낭성 복막염, 신장 간질성 섬유증, 사구체 경화증, 비알코올성 간 지방증, 간 섬유증, 간 경화증, 특발성 폐 섬유증, 증식성 및 비증식성 망막증, 건조 및 습한 연령 관련 황반 변성(AMD), 황반 부종, 중추 동맥/정맥 폐쇄, 외상성 손상, 녹내장, 담즙울체성 형태의 만성소양증 및 급성 또는 만성 장기 이식 거부반응에 대한 효율적인 예방 및 치료제로 부작용없이 유용하게 사용할 수 있다.As described above, the compound of Formula 1, its stereoisomer, its hydrate, its solvate, or its pharmaceutically acceptable salt exhibits high inhibitory activity against autotaxin and at the same time inhibits the production of lysophosphatidic acid, Pharmaceutical compositions containing these as active ingredients can be used to treat diseases mediated by autotaxin, such as cardiovascular disease, cancer, obesity, diabetes, acute renal failure, chronic kidney disease, diabetic nephropathy, acute kidney transplant rejection, and chronic allograft nephropathy. , liver cirrhosis, liver bleeding, pruritus, non-alcoholic steatohepatitis, acute and chronic liver transplant rejection, arthritis, atopic dermatitis, asthma, neuropathic pain, schizophrenia, neuronal inflammation, peripheral nerve neuropathy, autonomic neuropathy, systemic disease. , vasculitis, sarcoidosis, hypersensitivity pneumonitis, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), myocardial and vascular fibrosis, renal fibrosis, liver. Fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, cystic peritonitis, renal interstitial fibrosis, glomerular sclerosis, non-alcoholic hepatic steatosis, liver fibrosis, liver cirrhosis, idiopathic pulmonary fibrosis, proliferative and non-proliferative retinopathy, dry and wet age-related macula. It can be usefully used as an effective preventive and treatment for AMD, macular edema, central artery/venous occlusion, traumatic injury, glaucoma, cholestatic form of chronic pruritus, and acute or chronic organ transplant rejection without side effects.
심혈관 질환은 비제한적으로 급성 관동맥 증후군, 관동맥성 심장병, 심근 경색, 동맥 및 폐 고혈압, 심장 부정맥, 예컨대 심박 세동, 뇌졸중 및 다른 혈관 손상을 포함한다.Cardiovascular diseases include, but are not limited to, acute coronary syndrome, coronary heart disease, myocardial infarction, arterial and pulmonary hypertension, cardiac arrhythmias such as atrial fibrillation, stroke, and other vascular injuries.
암은 비제한적으로 유방암, 난소암, 폐암, 전립선암, 중피종, 신경교종, 간암종, 위암 등을 포함한다.Cancer includes, but is not limited to, breast cancer, ovarian cancer, lung cancer, prostate cancer, mesothelioma, glioma, liver carcinoma, stomach cancer, etc.
대사성 질환은 비제한적으로 비만 및 당뇨병을 포함한다.Metabolic diseases include, but are not limited to, obesity and diabetes.
신장 질환은 비제한적으로 급성 신부전, 및 단백뇨를 동반하거나 동반하지 않는 만성 신장병(말기 신장병 포함(ESRD))을 포함한다. 보다 상세히, 신장 질환은 감소된 크레아니틴 청소율 및 감소된 사구체 여과율, 미세알부민뇨, 알부민뇨 및 단백뇨, 유의한 세포과다를 갖거나 갖지 않는 망상 혈관간 기질의 팽창을 갖는 사구체 경화증(특히 당뇨병성 신장증 및 아밀로이드증), 사구체 모세관의 초점 혈전증(특히 혈전성 미세혈관증), 전반적인 섬유성 괴사, 허혈성 병변, 악성 신장 경화증(예컨대, 허혈성 수축, 감소된 신장 혈류량 및 신장 동맥질환), 모세혈관 내(내피 및 혈관사이) 및/또는 모세혈관 외 세포(반월체)의 부종 및 증식, 예컨대 사구체 신염 개체, 초점성 분절 사구체 경화증, IgA 신증, 혈관염/전신병 뿐만 아니라 급성 및 만성 신장 이식 거부반응을 포함한다.Kidney disease includes, but is not limited to, acute renal failure, and chronic kidney disease (including end-stage renal disease (ESRD)) with or without proteinuria. More specifically, kidney disease includes glomerulosclerosis (especially diabetic nephropathy and amyloidosis), focal thrombosis of the glomerular capillaries (especially thrombotic microangiopathy), generalized fibrotic necrosis, ischemic lesions, malignant nephrosclerosis (e.g. ischemic contraction, reduced renal blood flow and renal artery disease), intracapillary (endothelial and edema and proliferation of intervascular) and/or extracapillary cells (meniscus), such as glomerulonephritis entities, focal segmental glomerulosclerosis, IgA nephropathy, vasculitis/systemic disease, as well as acute and chronic renal transplant rejection.
본 발명의 일 실시예에 있어서, 신장 질환은 급성 신부전, 만성 신장병, 당뇨병성 신증, 급성 신장 이식 거부반응 및 만성 동종이식 신증으로 이루어진 군으로부터 선택된다.In one embodiment of the invention, the kidney disease is selected from the group consisting of acute renal failure, chronic kidney disease, diabetic nephropathy, acute kidney transplant rejection, and chronic allograft nephropathy.
간 질환은 비제한적으로 간 경화증, 간 출혈, 담즙울체성 간 질환, 예컨대 소양증, 비알코올성 지방간염 및 급성 및 만성 간 이식 거부반응을 포함한다.Liver diseases include, but are not limited to, liver cirrhosis, liver hemorrhage, cholestatic liver disease such as pruritus, non-alcoholic steatohepatitis, and acute and chronic liver transplant rejection.
본 발명의 일 실시예에 있어서, 간 질환은 급성 및 만성 신장 이식 거부반응이다.In one embodiment of the invention, the liver disease is acute and chronic kidney transplant rejection.
염증성 질환은 비제한적으로 아토피 피부염, 관절염, 골관절염, 다발성 경화증, 전신 홍반성 낭창 뿐만 아니라 염증성 기도 질병, 예컨대 특발성 폐 섬유증(IPF), 만성 폐쇄성 폐 질환(COPD) 또는 만성 기관지 천식을 포함한다.Inflammatory diseases include, but are not limited to, atopic dermatitis, arthritis, osteoarthritis, multiple sclerosis, systemic lupus erythematosus, as well as inflammatory airway diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), or chronic bronchial asthma.
본 발명의 일 실시예에 있어서, 염증성 질환은 관절염, 아토피 피부염 및 천식으로부터 선택된다.In one embodiment of the invention, the inflammatory disease is selected from arthritis, atopic dermatitis and asthma.
신경계 질환은 비제한적으로 신경성 동통, 정신 분열증, 신경세포염증(예컨대, 성상교세포증), 말초 및/또는 자율신경 (당뇨병성) 신경장애 등을 포함한다.Neurological diseases include, but are not limited to, neuropathic pain, schizophrenia, neuronal inflammation (e.g., astrogliosis), peripheral and/or autonomic (diabetic) neuropathy, and the like.
본 발명의 일 실시예에 있어서, 신경계 질환은 신경성 통증이다.In one embodiment of the invention, the neurological disease is neuropathic pain.
호흡계 질환은 비제한적으로 상이한 병인의 다른 미만성 조직질실성 폐 질병, 예컨대 의원성 약물-유도 섬유증, 직업적 및/또는 환경적 유도된 섬유증, 전신병 및 혈관염, 육아종성 질병(유육종증, 과민성 폐렴), 콜라겐 혈관 질병, 폐포 단백질증, 랑게르한스 세포 육아종증, 림프관평활근종증, 유전병(헤르만스키-푸드락(Hermansky-Pudlak) 증후군, 결정성 결화증, 신경섬유종증, 대사 축적병, 가족성 간질성 폐 질병), 방사선 유발 섬유증, 규폐증, 석면 유도된 폐 섬유증 또는 급성 호흡곤란 증후군(ARDS)을 포함한다.Respiratory diseases include, but are not limited to, other diffuse parenchymal lung diseases of different etiology, such as iatrogenic drug-induced fibrosis, occupational and/or environmentally induced fibrosis, systemic diseases and vasculitis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen Vascular diseases, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, hereditary diseases (Hermansky-Pudlak syndrome, crystalloidosis, neurofibromatosis, metabolic storage disease, familial interstitial lung disease), Includes radiation-induced fibrosis, silicosis, asbestos-induced pulmonary fibrosis or acute respiratory distress syndrome (ARDS).
섬유성 질병은 비제한적으로 심근 및 혈관 섬유증, 신장 섬유증, 간 섬유증, 폐 섬유증, 피부 섬유증, 경피증 및 포낭성 복막염을 포함한다. 또한, 상기 섬유성 질병은 신장 간질성 섬유증 또는 사구체 경화증이거나, 비알코올성 간 지방증, 간 섬유증 또는 간 경화증이거나, 특발성 폐 섬유증이다.Fibrotic diseases include, but are not limited to, myocardial and vascular fibrosis, renal fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, and cystic peritonitis. Additionally, the fibrotic disease is renal interstitial fibrosis or glomerulosclerosis, non-alcoholic hepatic steatosis, liver fibrosis or cirrhosis, or idiopathic pulmonary fibrosis.
본 발명의 일 실시예에 있어서, 섬유성 질병은 포낭성 복막염, 특발성 폐 섬유증, 비알코올성 간 지방증, 간 섬유증 및 간 경화증으로부터 선택된다.In one embodiment of the invention, the fibrotic disease is selected from cystic peritonitis, idiopathic pulmonary fibrosis, non-alcoholic hepatic steatosis, liver fibrosis and liver cirrhosis.
안구 질환은 비제한적으로 증식성 및 비증식성(당뇨병성) 망막증, 건조 및 습한 연령 관련 황반 변성(AMD), 황반 부종, 중추 동맥/정맥 폐쇄, 외상성 손상, 녹내장 등을 포함한다.Eye diseases include, but are not limited to, proliferative and non-proliferative (diabetic) retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central artery/venous occlusion, traumatic injury, glaucoma, etc.
용어 "약제 조성물(pharmaceutical composition)"은 본 발명의 화합물과 희석제 또는 담체와 같은 다른 화학 성분들의 혼합물을 의미한다. 약제 조성물은 생물체내로 화합물의 투여를 용이하게 한다. 화합물을 투여하는 다양한 기술들이 존재하며, 여기에는 경구, 주사, 에어로졸, 비경구, 및 국소 투여 등이 포함되지만, 이들만으로 한정되는 것은 아니다. 약제 조성물은 염산, 브롬산, 황산, 질산, 인산, 메탄술폰산, p-톨루엔술폰산, 살리실산 등과 같은 산 화합물들을 반응시켜서 얻어질 수도 있다.The term “pharmaceutical composition” refers to a mixture of a compound of the invention with other chemical ingredients such as diluents or carriers. Pharmaceutical compositions facilitate administration of compounds into an organism. There are a variety of techniques for administering compounds, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions may be obtained by reacting acid compounds such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.
용어 "약리학적 유효량(therapeutically effective amount)"은 투여되는 화합물의 양이 치료하는 장애의 하나 또는 그 이상의 증상을 어느 정도 경감 또는 줄이거나, 예방을 요하는 질병의 임상학적 마커 또는 증상의 개시를 지연시키는데 유효한 활성성분의 량을 의미한다. 따라서, 약리학적 유효량은, (1) 질환의 진행 속도를 역전시키는 효과, (2) 질환의 그 이상의 진행을 어느 정도 금지시키는 효과, 및/또는 (3) 질환과 관련된 하나 또는 그 이상의 증상을 어느 정도 경감(바람직하게는, 제거)하는 효과를 가지는 량을 의미한다. 약리학적 유효량은 치료를 요하는 질병에 대한 공지된 생채내(in vivo) 및 생체외(in vitro) 모델 시스템에서 화합물을 실험함으로써 경험적으로 결정될 수 있다.The term “therapeutically effective amount” refers to the amount of a compound administered that alleviates or reduces to some extent one or more symptoms of the disorder being treated or delays the onset of clinical markers or symptoms of the disease being treated. It refers to the amount of active ingredient effective for the treatment. Therefore, a pharmacologically effective amount has the effect of (1) reversing the rate of progression of the disease, (2) inhibiting further progression of the disease to some extent, and/or (3) reducing one or more symptoms associated with the disease to some extent. It refers to the amount that has the effect of reducing (preferably, eliminating) the degree. Pharmacologically effective amounts can be determined empirically by testing the compound in known in vivo and in vitro model systems for the disease requiring treatment.
용어 "담체(carrier)"는 세포 또는 조직내로의 화합물의 부가를 용이하게 하는 화합물로 정의된다. 예를 들어, 디메틸 술폭사이드(DMSO)는 생물체의 세포 또는 조직내로의 많은 유기 화합물들의 투입을 용이하게 하는 통상 사용되는 담체이다.The term “carrier” is defined as a compound that facilitates the addition of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the introduction of many organic compounds into the cells or tissues of an organism.
용어 "희석제(diluent)"는 대상 화합물의 생물학적 활성 형태를 안정화시킬 뿐만 아니라, 화합물을 용해시키게되는 물에서 희석되는 화합물로 정의된다. 버퍼 용액에 용해되어 있는 염은 당해 분야에서 희석제로 사용된다. 통상 사용되는 버퍼 용액은 포스페이트 버퍼 식염수이며, 이는 인간 용액의 염 상태를 모방하고 있기 때문이다. 버퍼 염은 낮은 농도에서 용액의 pH를 제어할 수 있기 때문에, 버퍼 희석제가 화합물의 생물학적 활성을 변형하는 일은 드물다.The term “diluent” is defined as a compound that is diluted in water, which not only stabilizes the biologically active form of the compound of interest, but also dissolves the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline because it mimics the salt conditions of human solutions. Because buffer salts can control the pH of a solution at low concentrations, it is rare for buffer diluents to modify the biological activity of the compound.
여기에 사용된 화합물들은 인간 환자에게 그 자체로서, 또는 결합 요법에서와 같이 다른 활성 성분들과 함께 또는 적당한 담체나 부형제와 함께 혼합된 약제 조성물로서, 투여될 수 있다. 본 응용에서의 화합물의 제형 및 투여에 관한 기술은 "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990에서 확인할 수 있다.The compounds used herein can be administered to human patients as such, or as pharmaceutical compositions mixed with other active ingredients, such as in combination therapy, or with suitable carriers or excipients. Descriptions of the formulation and administration of compounds in this application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.
본 발명의 약제 조성물은, 예를 들어, 통상적인 혼합, 용해, 과립화, 당제-제조, 분말화, 에멀션화, 캡슐화, 트래핑과 또는 동결건조 과정들의 수단에 의해, 공지 방식으로 제조될 수 있다.The pharmaceutical compositions of the invention may be prepared in a known manner, for example by means of conventional mixing, dissolving, granulating, confection-making, powdering, emulsifying, encapsulating, trapping and or lyophilization processes. .
따라서, 본 발명에 따른 사용을 위한 약제 조성물은, 약제학적으로 사용될 수 있는 제형으로의 활성 화합물의 처리를 용이하게 하는 부형제들 또는 보조제들을 포함하는 것으로 구성되어 있는 하나 또는 그 이상의 약리학적으로 허용되는 담체를 사용하여 통상적인 방법으로 제조될 수도 있다. 적합한 제형은 선택된 투여 루트에 따라 좌우된다. 공지 기술들, 담체 및 부형제들 중의 어느 것이라도 적합하게, 그리고 당해 분야, 예를 들어, 앞서 설명한 Remingston's Pharmaceutical Sciences에서 이해되는 바와 같이 사용될 수 있다. 본 발명에서는 화학식 1의 화합물을 목적하는 바에 따라 주사용 제제 및 경구용 제제 등으로 제형화될 수 있다.Accordingly, the pharmaceutical composition for use according to the invention consists of one or more pharmaceutically acceptable compounds consisting of excipients or auxiliaries that facilitate the processing of the active compound into formulations that can be used pharmaceutically. It can also be manufactured by conventional methods using a carrier. The suitable formulation will depend on the route of administration chosen. Any of the known techniques, carriers and excipients may be used as appropriate and understood in the art, such as Remingston's Pharmaceutical Sciences, described above. In the present invention, the compound of Formula 1 can be formulated into an injectable preparation or an oral preparation depending on the purpose.
주사를 위해서, 본 발명의 성분들은 액상 용액으로, 바람직하게는 Hank 용액, Ringer 용액, 또는 생리 식염수버포와 같은 약리학적으로 맞는 버퍼로 제형될 수 있다. 점막 투과 투여를 위해서, 통과할 배리어에 적합한 비침투성제가 제형에 사용된다. 그러한 비침투성제들은 당업계에 일반적으로 공지되어 있다.For injection, the ingredients of the present invention may be formulated in a liquid solution, preferably in a pharmacologically compatible buffer such as Hank's solution, Ringer's solution, or saline buffer. For transmucosal administration, an impermeable agent suitable for the barrier through which it will pass is used in the formulation. Such impermeable agents are generally known in the art.
경구 투여를 위해서, 화합물들은 당업계에 공지된 약리학적으로 허용되는 담체들을 활성 화합물들과 조합함으로써 용이하게 제형될 수 있다. 이러한 담체들은 본 발명의 화합물들이 정제, 알약, 산제, 입제, 당제, 캡슐, 액체, 겔, 시럽, 슬러리, 현탁액 등으로 제형화될 수 있도록 하여 준다. 바람직하게는 캅셀제, 정제, 환제, 산제 및 입제가 가능하고, 특히 캅셀제와 정제가 유용하다. 정제 및 환제는 장피제로 제조하는 것이 바람직하다. 경구 사용을 위한 약제 준비는 본 발명의 하나 또는 둘 이상의 화합물들과 하나 또는 둘 이상의 부형제를 혼합하고, 경우에 따라서는 이러한 혼합물을 분쇄하고, 필요하다면 적절한 보조제를 투과한 이후 과립의 혼합물을 처리하여 정제 또는 당체 코어를 얻을 수 있다. 적절한 부형제들은 락토스, 수크로즈, 만니톨, 또는 소르비톨과 같은 필러; 옥수수 녹말, 밀 녹말, 쌀 녹말, 감자 녹말, 겔라틴, 검 트래거켄스, 메틸 셀룰로우즈, 히드록시프로필메틸-셀룰로우즈, 소듐 카르복시메틸 셀룰로우즈, 및/또는 폴리비닐피롤리돈(PVP)와 같은 셀룰루오즈계 물질 등이다. 필요하다면, 가교 폴리비닐 피롤리돈, 우뭇가사리, 또는 알긴산 또는 알긴산 나트륨과 같은 그것의 염 등의 디스인터그레이팅 에이전트와 마그네슘 스테아레이트와 같은 윤활제, 결합제 등과 같은 담체가 첨가될 수도 있다.For oral administration, compounds can be readily formulated by combining the active compounds with pharmacologically acceptable carriers known in the art. These carriers allow the compounds of the present invention to be formulated into tablets, pills, powders, granules, confections, capsules, liquids, gels, syrups, slurries, suspensions, etc. Preferably, capsules, tablets, pills, powders and granules are available, and capsules and tablets are particularly useful. Tablets and pills are preferably manufactured as intestinal coating agents. Preparation of pharmaceuticals for oral use is accomplished by mixing one or more compounds of the invention with one or more excipients, grinding this mixture, if necessary, and processing the mixture of granules, if necessary, after permeation with appropriate auxiliaries. You can get tablets or sugar cores. Suitable excipients include fillers such as lactose, sucrose, mannitol, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone ( Cellulose-based materials such as PVP). If necessary, disintegrating agents such as cross-linked polyvinyl pyrrolidone, agar, or alginic acid or its salts such as sodium alginate, and carriers such as lubricants such as magnesium stearate, binders, etc. may be added.
경구에 사용될 수 있는 제약 준비물은, 겔라틴 및 글리콜 또는 소르비톨과 같은 가소제로 만들어진 부드러운 밀봉 캡슐뿐만 아니라, 겔라틴으로 만들어진 밀어 고정하는 캡슐을 포함할 수도 있다. 밀어 고정하는 캡슐은 락토오스와 같은 필러, 녹말과 같은 바인더, 및/또는 활석 또는 마그네슘 스테아레이트와 같은 활제와의 혼합물로서, 활성 성분들을 포함할 수도 있다. 연질 캡슐에서, 활성 화합물들은 지방산, 액체 파라핀, 또는 액체 폴리에틸렌 글리콜과 같은 적합한 용체에 용해 또는 분산될 수도 있다. 또한, 안정화제가 포함될 수도 있다. 경구투여를 위한 모든 조제들은 그러한 투여에 적합한 함량으로 되어 있어야 한다.Pharmaceutical preparations that can be used orally may include push-lock capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycol or sorbitol. Push-on capsules may contain the active ingredients in a mixture with a filler such as lactose, a binder such as starch, and/or a lubricant such as talc or magnesium stearate. In soft capsules, the active compounds may be dissolved or dispersed in a suitable solvent such as fatty acids, liquid paraffin, or liquid polyethylene glycol. Additionally, a stabilizer may be included. All preparations for oral administration must be in a dosage suitable for such administration.
화합물들은, 주사에 의해, 예를 들어, 큰 환약 주사나 연속적인 주입에 의해, 비경구 투입용으로 제형화될 수도 있다. 주사용 제형은, 예를 들어, 방부제를 부가한 앰플 또는 멀티-도스 용기로서 단위 용량 형태로 제공될 수도 있다. 조성물은 유성 또는 액상 비히클상의 현탁액, 용액, 에멀션과 같은 형태를 취할 수도 있으며, 현탁제, 안정화제 및/또는 분산제와 같은 제형용 성분들을 포함할 수도 있다.The compounds may also be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion. Formulations for injection may be presented in unit dose form, for example, as ampoules or multi-dose containers with added preservatives. The composition may take the form of a suspension, solution, or emulsion in an oily or liquid vehicle, and may also contain formulation ingredients such as suspending agents, stabilizing agents, and/or dispersing agents.
또한, 예를 들어, 발열물질이 제거되고 무균인 물로, 사용 전에 녹여 사용하는 건조 분말의 형태일 수도 있다.Additionally, for example, it may be in the form of a dry powder that is dissolved before use in sterile water from which pyrogens have been removed.
화합물들은, 예를 들어, 코코아 버터나 다른 글리세라이드와 같은 통상적인 좌약 기재를 포함하고 있는 좌약 또는 정체관장과 같은 직장 투여 조성물로 제형될 수도 있다.The compounds may also be formulated in compositions for rectal administration, such as suppositories or retention enemas containing conventional suppository bases such as, for example, cocoa butter or other glycerides.
본 발명에서 사용에 적합한 약제학적 조성물에는, 활성 성분들이 그것의 의도된 목적을 달성하기에 유효한 량으로 함유되어 있는 조성물이 포함된다. 더욱 구체적으로, 치료적 유효량은 치료될 객체의 생존을 연장하거나, 질환의 증상을 방지, 경감 또는 완화시키는데 유효한 화합물의 량을 의미한다. 치료적 유효량의 결정은, 특히, 여기에 제공된 상세한 개시 내용 측면에서, 당업자의 능력 범위 내에 있다.Pharmaceutical compositions suitable for use in the present invention include compositions containing the active ingredients in amounts effective to achieve their intended purpose. More specifically, a therapeutically effective amount refers to an amount of a compound effective to prolong the survival of the subject being treated or to prevent, lessen, or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the ability of one skilled in the art, especially in light of the detailed disclosure provided herein.
단위 용량 형태로 제형화하는 경우, 활성성분으로서 화학식 1의 화합물은 약 0.1 내지 1,000 mg의 단위 용량으로 함유되는 것이 바람직하다. 화학식 1의 화합물의 투여량은 환자의 체중, 나이 및 질병의 특수한 성질과 심각성과 같은 요인에 따라 의사의 처방에 따른다. 그러나, 성인 치료에 필요한 투여량은 투여의 빈도와 강도에 따라 하루에 1회 내지 3회 투여할 수 있으며 일회 투여량은 약 1 내지 1,000 mg 범위가 보통이다. 성인에게 근육내 또는 정맥내 투여시 일회 투여량으로 분리하여 하루에 1회 내지 3회 투여할 수 있으며 일회 투여량은 보통 약 1 내지 1,000 mg의 투여량이면 충분할 것이나, 일부 환자의 경우 더 높은 일일 투여량이 바람직할 수 있다.When formulated in unit dosage form, the compound of Formula 1 as the active ingredient is preferably contained in a unit dose of about 0.1 to 1,000 mg. The dosage of the compound of Formula 1 is as prescribed by the physician, depending on factors such as the patient's weight, age, and the specific nature and severity of the disease. However, the dose required for adult treatment can be administered once to three times a day depending on the frequency and intensity of administration, and the single dose is usually in the range of about 1 to 1,000 mg. When administered intramuscularly or intravenously to adults, it can be divided into single doses and administered once to three times a day. A single dose of about 1 to 1,000 mg is usually sufficient, but for some patients, higher daily doses are required. Dosages may be desirable.
본 발명의 약제학적 조성물은 오토탁신의 활성을 저해한다. 본 발명에 따르면, 상기 화학식 1의 화합물은 리소포스파티딜콜린의 리소포스파티드산으로의 전환의 근본적인 조절제인 오토탁신의 활성을 효율적으로 억제한다. 본 발명에서 용어 “저해”는 대상 물질의 생체 내 발현량 또는 생물학적 활성을 유의한 수준으로 감소시키는 것을 의미한다.The pharmaceutical composition of the present invention inhibits the activity of autotaxin. According to the present invention, the compound of Formula 1 efficiently inhibits the activity of autotaxin, a fundamental regulator of the conversion of lysophosphatidylcholine to lysophosphatidic acid. In the present invention, the term “inhibition” means reducing the in vivo expression level or biological activity of a target substance to a significant level.
이하, 바람직한 실시예를 통하여 본 발명을 보다 상세히 설명하기로 한다. 다만, 이는 본 발명의 예시로 제시되는 것으로 어떠한 의미로도 이에 의해 본 발명의 권리범위가 한정되는 것은 아니며, 본 발명의 권리범위는 후술하는 청구범위에 따라 정의될 뿐이다.Hereinafter, the present invention will be described in more detail through preferred embodiments. However, this is presented as an example of the present invention and does not limit the scope of the present invention in any way, and the scope of the present invention is only defined according to the claims described later.
제조예Manufacturing example
[제조예 1] 중간체 A의 제조[Preparation Example 1] Preparation of Intermediate A
(제조예 A-1) 5-Bromo-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 A-1)의 제조 (Preparation Example A-1) Preparation of 5-Bromo- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate A-1)
5-브로모-2-클로로피리미딘 (5.0 g, 25.8 mmol), 2-아미노인단 (4.0 mL, 31.0 mmol), N,N-디이소프로필에틸아민 (11.3 mL, 64.6 mmol)을 에탄올(15 mL)에 용해시키고 80 ℃에서 4 시간 교반하였다. 반응 종결 후, 실온까지 냉각시켜 생성된 고체를 여과하고 에탄올(40 mL)로 세정한 후 건조하여 베이지색의 고체로 표제화합물을 얻었다. (6.76 g, 90%)5-Bromo-2-chloropyrimidine (5.0 g, 25.8 mmol), 2-aminoindan (4.0 mL, 31.0 mmol), and N,N-diisopropylethylamine (11.3 mL, 64.6 mmol) were dissolved in ethanol (15). mL) and stirred at 80°C for 4 hours. After completion of the reaction, the resulting solid was cooled to room temperature, filtered, washed with ethanol (40 mL), and dried to obtain the title compound as a beige solid. (6.76 g, 90%)
MS m/z: 290 [M+1]+ MS m/z: 290 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 8.27 (s, 2H), 7.24-7.18 (m, 4H), 5.45 (d, 1H), 4.77-4.70 (m, 1H), 3.38 (dd, 2H), 2.87 (dd, 2H).1H NMR (CDCl 3 , 400MHz), δ ppm: 8.27 (s, 2H), 7.24-7.18 (m, 4H), 5.45 (d, 1H), 4.77-4.70 (m, 1H), 3.38 (dd, 2H) , 2.87 (dd, 2H).
(제조예 A-2) N-(2,3-dihydro-1H-inden-2-yl)-5-iodopyrimidin-2-amine (중간체 A-2)의 제조 (Preparation Example A-2) Preparation of N -(2,3-dihydro-1 H -inden-2-yl)-5-iodopyrimidin-2-amine (Intermediate A-2)
제조예 A-1과 같은 방법으로 5-브로모-2-클로로피리미딘 대신 2-클로로-5-아이오도피리미딘 (5.0 g, 20.8 mmol)을 사용하여 베이지색의 고체로 표제화합물을 얻었다. (6.6 g, 95%)The title compound was obtained as a beige solid in the same manner as Preparation Example A-1, using 2-chloro-5-iodopyrimidine (5.0 g, 20.8 mmol) instead of 5-bromo-2-chloropyrimidine. (6.6 g, 95%)
MS m/z: 338 [M+1]+ MS m/z: 338 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.45 (s, 2H), 7.73 (m, 1H), 7.21-7.15 (m, 4H), 4.54 (m, 1H), 3.25-3.22 (m, 2H), 2.90-2.86 (m, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.45 (s, 2H), 7.73 (m, 1H), 7.21-7.15 (m, 4H), 4.54 (m, 1H), 3.25-3.22 (m, 2H), 2.90-2.86 (m, 2H).
(제조예 A-3) N-(2,3-dihydro-1H-inden-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (중간체 A-3)의 제조 (Preparation Example A-3) N -(2,3-dihydro-1 H -inden-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )Preparation of pyrimidin-2-amine (Intermediate A-3)
중간체 A-1 (6.72 g, 23.16 mmol), 비스(피나콜레토)디보론 (7.65 g, 30.11 mmol), [1,1’-비스(디페닐포스피노)페로센]디클로로팔라듐(II) (1.89 g, 2.32 mmol), 아세트산칼륨 (6.82 g, 69.48 mmol)의 혼합물에 1,4-디옥산 (55 mL)을 가하고, 반응혼합물을 질소 분위기 하, 100 ℃에서 18 시간 교반하였다. 반응 종결 후, 실온까지 냉각시킨 후 불용물을 셀라이트를 통해 제거하고 아세트산에틸로 세정한 여과액에 증류수 (150 mL)를 가하고 아세트산에틸(50 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 15 : 85)로 정제하여 흰색의 고체로 표제화합물을 얻었다. (5.38 g, 69%)Intermediate A-1 (6.72 g, 23.16 mmol), bis(pinacoletto)diborone (7.65 g, 30.11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.89 g, 2.32 mmol) and potassium acetate (6.82 g, 69.48 mmol) were added to 1,4-dioxane (55 mL), and the reaction mixture was stirred at 100°C for 18 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, insoluble matter was removed through Celite, and distilled water (150 mL) was added to the filtrate washed with ethyl acetate, followed by extraction three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 15:85) to obtain the title compound as a white solid. (5.38 g, 69%)
MS m/z: 338 [M+1]+ MS m/z: 338 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.44 (s, 2H), 7.90 (d, 1H), 7.21-7.12 (m, 4H), 4.68-4.63 (m, 1H), 3.24 (dd, 2H), 2.88 (dd, 2H), 1.27 (s, 12H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.44 (s, 2H), 7.90 (d, 1H), 7.21-7.12 (m, 4H), 4.68-4.63 (m, 1H), 3.24 (dd , 2H), 2.88 (dd, 2H), 1.27 (s, 12H).
(제조예 A-4) Ethyl 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carboxylate (중간체 A-4)의 제조 (Preparation Example A-4) Preparation of Ethyl 2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidine-5-carboxylate (Intermediate A-4)
에틸 2-클로로피리미딘-5-카복실레이트(2.0 g, 10.7 mmol)와 2-아미노인단(1.7 mL, 12.9 mmol), N,N-디이소프로필에틸아민(4.7 mL, 26.8 mmol)을 에탄올(6 mL)에 용해시키고, 80 ℃에서 18 시간 교반하였다. 반응 종결 후, 실온으로 식혀 생성된 고체를 여과하고 에탄올로 씻어 흰색의 고체로 표제화합물을 얻었다. (2.54 g, 84%)Ethyl 2-chloropyrimidine-5-carboxylate (2.0 g, 10.7 mmol), 2-aminoindan (1.7 mL, 12.9 mmol), and N,N-diisopropylethylamine (4.7 mL, 26.8 mmol) were dissolved in ethanol ( 6 mL) and stirred at 80°C for 18 hours. After completion of the reaction, the resulting solid was cooled to room temperature, filtered, and washed with ethanol to obtain the title compound as a white solid. (2.54 g, 84%)
MS m/z: 284 [M+1]+ MS m/z: 284 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.76 (d, 2H), 8.46 (s, 1H), 7.22-7.15 (m, 4H), 4.70 (m, 1H), 4.27 (q, 2H), 3.29-3.25 (m, 2H), 2.95-2.91 (m, 2H), 1.29 (t, 3H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.76 (d, 2H), 8.46 (s, 1H), 7.22-7.15 (m, 4H), 4.70 (m, 1H), 4.27 (q, 2H) ), 3.29-3.25 (m, 2H), 2.95-2.91 (m, 2H), 1.29 (t, 3H).
(제조예 A-5) 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-3-oxopropanenitrile (중간체 A-5)의 제조 (Preparation Example A-5) Preparation of 3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-3-oxopropanenitrile (Intermediate A-5)
무수 톨루엔(15 mL)에 무수 아세토니트릴(0.74 mL, 13.12 mmol)을 가한 후 영하 78 ℃로 냉각하여 n-부틸리튬 2M 헥산 용액(5.6 mL, 14.1 mmol)을 천천히 적가하고 20 분간 교반하였다. 반응 혼합물에 무수 톨루엔(15 mL)에 용해시킨 중간체 A-4(1.00 g, 3.53 mmol)을 적가하고 천천히 온도를 높여 실온에서 2 시간 교반하였다. 1N 염화수소 수용액을 가하여 반응을 종결시키고, 아세트산에틸(10 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피 (아세트산에틸 : n-헥산 = 0 : 10 → 2 : 3)로 정제하여 황색 고체로 표제화합물을 얻었다.(0.67 g, 68 %)Anhydrous acetonitrile (0.74 mL, 13.12 mmol) was added to anhydrous toluene (15 mL), cooled to -78°C, and n -butyllithium 2M hexane solution (5.6 mL, 14.1 mmol) was slowly added dropwise and stirred for 20 minutes. Intermediate A-4 (1.00 g, 3.53 mmol) dissolved in anhydrous toluene (15 mL) was added dropwise to the reaction mixture, the temperature was slowly raised, and the mixture was stirred at room temperature for 2 hours. The reaction was terminated by adding 1N aqueous hydrogen chloride solution, and extracted three times with ethyl acetate (10 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 → 2: 3) to obtain the title compound as a yellow solid (0.67 g, 68 %).
MS m/z: 279 [M+1]+ MS m/z: 279 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 8.87 (s, 1H), 8.76 (s, 1H), 7.27-7.21 (m, 4H), 6.03 (s, 1H), 4.93 (s, 1H), 3.90 (s, 2H), 3.43 (d, 2H), 2.93 (d, 2H).1H NMR (CDCl 3 , 400MHz), δ ppm: 8.87 (s, 1H), 8.76 (s, 1H), 7.27-7.21 (m, 4H), 6.03 (s, 1H), 4.93 (s, 1H), 3.90 (s, 2H), 3.43 (d, 2H), 2.93 (d, 2H).
(제조예 A-6) 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbonitrile (중간체 A-6)의 제조 (Preparation Example A-6) Preparation of 2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidine-5-carbonitrile (Intermediate A-6)
중간체 A-1(2.5 g, 8.6 mmol)을 N,N-디메틸포름아미드(41 mL)에 용해시키고, 시안화구리 (1.0 g, 11.20 mmol)을 첨가하여 180 ℃에서 18 시간 교반하였다. 반응 종결 후, 아세트산에틸 (40mL)를 가해 희석하고 10% 시안화나트륨 수용액(50 mL)으로 두 번 세정하였다. 유기층을 모아 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 2 : 8)로 정제하여 흰색의 고체로 표제화합물을 얻었다.(1.5 g, 74%)Intermediate A-1 (2.5 g, 8.6 mmol) was dissolved in N,N-dimethylformamide (41 mL), copper cyanide (1.0 g, 11.20 mmol) was added, and the mixture was stirred at 180°C for 18 hours. After completion of the reaction, it was diluted with ethyl acetate (40 mL) and washed twice with 10% aqueous sodium cyanide solution (50 mL). The organic layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate : n-hexane = 2 : 8) to obtain the title compound as a white solid (1.5 g, 74%).
MS m/z: 237 [M+1]+ MS m/z: 237 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 8.56 (s, 1H), 8.25 (s, 1H), 7.26-7.18 (m, 4H), 6.19 (d, 1H), 4.90-4.82 (m, 1H), 3.43-3.38 (m, 2H), 2.92-2.85 (m, 2H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 8.56 (s, 1H), 8.25 (s, 1H), 7.26-7.18 (m, 4H), 6.19 (d, 1H), 4.90-4.82 (m, 1H) ), 3.43-3.38 (m, 2H), 2.92-2.85 (m, 2H).
[제조예 2] 중간체 B의 제조[Preparation Example 2] Preparation of intermediate B
(제조예 B-1) 4,5,6,7-Tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine hydrochloride (중간체 B-1)의 제조 (Preparation Example B-1) Preparation of 4,5,6,7-Tetrahydro-1 H -[1,2,3]triazolo[4,5- c ]pyridine hydrochloride (Intermediate B-1)
(단계 1) 1H-[1,2,3]triazolo[4,5-c]pyridine의 제조(Step 1) Preparation of 1 H -[1,2,3]triazolo[4,5- c ]pyridine
3,4-디아미노피리딘(2.0g, 48 mmol)을 2N 염화수소 수용액(25mL)에 녹인 후, 0 ℃로 냉각시키고, 아질산나트륨(1.9g, 27 mmol)을 증류수(3mL)에 녹여 천천히 첨가하고, 1 시간 동안 교반하였다. 생성된 고체를 여과하고 증류수로 세정하여 황색 고체로 표제 화합물을 얻었다. (1.96g, 89%)3,4-Diaminopyridine (2.0 g, 48 mmol) was dissolved in 2N aqueous hydrogen chloride solution (25 mL), cooled to 0 °C, and sodium nitrite (1.9 g, 27 mmol) was dissolved in distilled water (3 mL) and slowly added. , and stirred for 1 hour. The resulting solid was filtered and washed with distilled water to obtain the title compound as a yellow solid. (1.96g, 89%)
MS m/z: 121 [M+1]+.MS m/z: 121 [M+1] + .
1H NMR (DMSO-d6, 400MHz), δ ppm: 9.47 (s, 1H), 8.49 (d, 1H), 7.89 (d, 1H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 9.47 (s, 1H), 8.49 (d, 1H), 7.89 (d, 1H).
(단계 2) 4,5,6,7-Tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine hydrochloride의 제조(Step 2) Preparation of 4,5,6,7-Tetrahydro-1 H -[1,2,3]triazolo[4,5- c ]pyridine hydrochloride
상기 (단계 1)에서 제조한 화합물(1.0 g, 8.3 mmol)을 메탄올(60 mL)에 녹인 후 Pd/C(10 wt%, 2.0 g) 과 진한 염산(1 mL)을 가하고 수소 가압 하에 (75 psi) 7 시간 동안 반응시켰다. 불용물을 셀라이트를 통해 제거하고 메탄올로 세정한 여과액을 감압 하에서 농축하여 황색 고체로 표제화합물을 정량적으로 얻었다. (1.38 g)The compound (1.0 g, 8.3 mmol) prepared in step 1 above was dissolved in methanol (60 mL), then Pd/C (10 wt%, 2.0 g) and concentrated hydrochloric acid (1 mL) were added, and the mixture was reacted at (75%) under hydrogen pressure. psi) and reacted for 7 hours. Insoluble matter was removed through Celite, and the filtrate was washed with methanol and concentrated under reduced pressure to quantitatively obtain the title compound as a yellow solid. (1.38 g)
MS m/z: 125 [M+1]+.MS m/z: 125 [M+1] + .
1H NMR (DMSO-d6, 400MHz), δ ppm: 9.54(s, 2H), 4.34(s, 2H), 2.98(t, 2H). 1 H NMR (DMSO-d 6 , 400MHz), δ ppm: 9.54(s, 2H), 4.34(s, 2H), 2.98(t, 2H).
(제조예 B-2) (S)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (중간체 B-2)의 제조 (Preparation Example B-2) Preparation of ( S )-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-2)
(단계 1) 1-azido-4-nitrobenzene의 제조(Step 1) Preparation of 1-azido-4-nitrobenzene
p-톨루엔설폰산(124 g, 651 mmol)과 4-니트로아닐린 (10.0 g, 72.4 mmol)을 증류수(800 mL)에 녹여 실온에서 30 분간 교반한 후, 아질산나트륨(45.0 g, 651 mmol)을 1 시간 동안 천천히 첨가하였다. 출발물질이 다 사라진 것을 TLC로 확인한 후 아자이드화나트륨(7.53 g, 115 mmol)을 반응 혼합물에 1 시간 동안 천천히 첨가하고 실온에서 교반하였다. 반응 종결 후, 생성된 고체를 여과하고 증류수(500 mL)로 세정하여 황색 고체로 표제화합물을 얻었다. (13.0 g, 90%)Dissolve p-toluenesulfonic acid (124 g, 651 mmol) and 4-nitroaniline (10.0 g, 72.4 mmol) in distilled water (800 mL) and stir at room temperature for 30 minutes, then add sodium nitrite (45.0 g, 651 mmol). It was added slowly over 1 hour. After confirming by TLC that all starting materials had disappeared, sodium azide (7.53 g, 115 mmol) was slowly added to the reaction mixture for 1 hour and stirred at room temperature. After completion of the reaction, the resulting solid was filtered and washed with distilled water (500 mL) to obtain the title compound as a yellow solid. (13.0 g, 90%)
MS m/z: 165 [M+1]+ MS m/z: 165 [M+1] +
(단계 2) Ethyl (S)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylate, Ethyl (R)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylate의 제조(Step 2) Ethyl ( S )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylate, Ethyl ( R )-4,5,6, Preparation of 7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylate
상기 (단계 1)에서 제조한 화합물(11.9 g, 72.4 mmol)을 N,N-디메틸포름아미드(100 mL)에 녹인 후, 에틸 4-옥소사이클로-1-카복실레이트(9.5 g, 55.7 mmol)와 아세트산암모늄(21.5 g, 278 mmol)을 순차적으로 첨가한 후, 80 ℃에서 16 시간 동안 교반하였다. 실온까지 냉각시킨 후 증류수를 200 mL 가하여 반응을 종료시키고 아세트산에틸 (150 mL)로 2회 추출하였다. 유기층을 포화 식염수(100 mL)로 세정하고 무수 황산나트륨으로 건조시킨 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피 (아세트산에틸 : 석유에테르 = 5 : 95 → 10 : 90)로 정제하여 붉은 색의 오일로 표제화합물의 라세미 혼합물을 얻었다. (7.50 g, 71%)The compound prepared in (step 1) (11.9 g, 72.4 mmol) was dissolved in N,N-dimethylformamide (100 mL), and then mixed with ethyl 4-oxocyclo-1-carboxylate (9.5 g, 55.7 mmol). Ammonium acetate (21.5 g, 278 mmol) was sequentially added, and then stirred at 80°C for 16 hours. After cooling to room temperature, 200 mL of distilled water was added to terminate the reaction, and extraction was performed twice with ethyl acetate (150 mL). The organic layer was washed with saturated saline solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 5:95 → 10:90) to obtain a racemic mixture of the title compound as a red oil. (7.50 g, 71%)
라세미 혼합물 (17.0 g)을 SFC로 정제하여 (S)-이성질체 (peak1, Rt=4.122, 8.0 g, ee >99%)와 (R)-이성질체 (peak 2, Rt=4.347, 8.1 g, ee >99%)을 얻었다 (ChiralPak IC, 250 × 50 mm I.D. 10 ㎛); mobile phase A:CO2, B: 0.1% NH4OH/EtOH; gradient: 5%-40% B; Flow rate: 2.5 mL/min)The racemic mixture (17.0 g) was purified by SFC to produce ( S )-isomer (peak1, R t =4.122, 8.0 g, ee >99%) and ( R )-isomer (peak 2, R t =4.347, 8.1 g). , ee >99%) was obtained (ChiralPak IC, 250 × 50 mm ID 10 μm); mobile phase A:CO 2 , B: 0.1% NH 4 OH/EtOH; gradient: 5%-40% B; Flow rate: 2.5 mL/min)
MS m/z: 196 [M+1]+ MS m/z: 196 [M+1] +
(S)-이성질체 1H NMR (CDCl3, 500MHz), δ ppm: 4.27 - 4.11 (m, 2H), 3.13 - 3.06 (m, 1H), 3.02 - 2.89 (m, 2H), 2.85 - 2.72 (m, 2H), 2.33 - 2.24 (m, 1H), 1.97 (dtd, 1H), 1.28 (t, 3H).( S )-isomer 1H NMR (CDCl 3 , 500MHz), δ ppm: 4.27 - 4.11 (m, 2H), 3.13 - 3.06 (m, 1H), 3.02 - 2.89 (m, 2H), 2.85 - 2.72 (m) , 2H), 2.33 - 2.24 (m, 1H), 1.97 (dtd, 1H), 1.28 (t, 3H).
(R)-이성질체 1H NMR (CDCl3, 500MHz), δ ppm: 4.20 (q, 2H), 3.13 - 3.06 (m, 1H), 3.02 - 2.89 (m, 2H), 2.86 - 2.71 (m, 2H), 2.36 - 2.24 (m, 1H), 1.98 (dtd, 1H), 1.28 (t, 3H).( R )-isomer 1 H NMR (CDCl 3 , 500 MHz), δ ppm: 4.20 (q, 2H), 3.13 - 3.06 (m, 1H), 3.02 - 2.89 (m, 2H), 2.86 - 2.71 (m, 2H) ), 2.36 - 2.24 (m, 1H), 1.98 (dtd, 1H), 1.28 (t, 3H).
(단계 3) (S)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid의 제조(Step 3) Preparation of ( S )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid
상기 (단계 3)에서 제조한 (S)-이성질체 (8.0 g, 40.9 mmol)을 메탄올(50 mL)과 증류수(50 mL)의 혼합용매에 녹인 후, 수산화나트륨(3.28 g, 81.9 mmol)을 첨가하여 45 ℃에서 6 시간 동안 교반하였다. 황색의 현탁액을 감압 하에 농축한 후 1N 염화수소 수용액을 가하여 액성이 pH 5가 되도록 하고 다시 농축하였다. 잔류물에 염화메틸렌/메탄올 (1/1, 40 mL)을 가하여 흰색의 고체로 표제화합물을 얻었다. (6.0 g, 87%, ee =98.96%)Dissolve the ( S )-isomer (8.0 g, 40.9 mmol) prepared in (step 3) in a mixed solvent of methanol (50 mL) and distilled water (50 mL), and then add sodium hydroxide (3.28 g, 81.9 mmol). and stirred at 45°C for 6 hours. The yellow suspension was concentrated under reduced pressure, then 1N aqueous hydrogen chloride solution was added to adjust the pH to 5 and concentrated again. Methylene chloride/methanol (1/1, 40 mL) was added to the residue to obtain the title compound as a white solid. (6.0 g, 87%, ee =98.96%)
MS m/z: 169 [M+1]+ MS m/z: 169 [M+1] +
1H NMR (DMSO- d6, 400MHz), δ ppm: 2.86 - 2.64 (m, 3H), 2.62 - 2.52 (m, 2H), 2.14 - 2.04 (m, 1H), 1.81 - 1.67 (m, 1H). 1H NMR (DMSO- d 6 , 400MHz), δ ppm: 2.86 - 2.64 (m, 3H), 2.62 - 2.52 (m, 2H), 2.14 - 2.04 (m, 1H), 1.81 - 1.67 (m, 1H) .
(제조예 B-3) (R)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (중간체 B-3)의 제조 (Preparation Example B-3) Preparation of ( R )-4,5,6,7-tetrahydro- 1H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-3)
제조예 B-2 (단계 2)에서 제조한 (R)-이성질체(8.1 g, 41.2 mmol)를 사용하여 제조예 B-2 (단계 3)과 같은 방법으로 흰색 고체의 표제화합물을 얻었다. (6.8 g, 98%, ee =97.98%)The title compound as a white solid was obtained in the same manner as Preparation Example B-2 (Step 3) using the ( R )-isomer (8.1 g, 41.2 mmol) prepared in Preparation Example B-2 (Step 2). (6.8 g, 98%, ee =97.98%)
MS m/z: 169 [M+1]+ MS m/z: 169 [M+1] +
1H NMR (DMSO- d6, 400MHz), δ ppm: 2.82 - 2.65 (m, 3H), 2.59 - 2.52 (m, 1H), 2.47 - 2.39 (m, 1H), 2.13 - 2.02 (m, 1H), 1.77 - 1.65 (m, 1H). 1H NMR (DMSO- d 6 , 400MHz), δ ppm: 2.82 - 2.65 (m, 3H), 2.59 - 2.52 (m, 1H), 2.47 - 2.39 (m, 1H), 2.13 - 2.02 (m, 1H) , 1.77 - 1.65 (m, 1H).
(제조예 B-4) 6-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (중간체 B-4)의 제조 (Preparation Example B-4) Preparation of 6-fluoro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-4)
(단계 1) methyl 4-amino-2-fluoro-5-nitrobenzoate의 제조(Step 1) Preparation of methyl 4-amino-2-fluoro-5-nitrobenzoate
메틸 2,4-디플루오로-5-나이트로벤조에이트(1.0 g, 4.6 mmol)를 테트라히드로퓨란(9 mL)에 용해시키고, 0 ℃에서 28% 암모니아수(0.9 mL, 12.9 mmol)를 첨가하고 실온에서 40 시간 교반하였다. 반응 종결 후, 용매를 감압 농축하였다. 잔류물에 증류수(30 mL)를 가하여 생성된 황색 고체를 여과하여 감압 하에 건조하여 표제화합물을 얻었다. (0.96 g, 97%)Methyl 2,4-difluoro-5-nitrobenzoate (1.0 g, 4.6 mmol) was dissolved in tetrahydrofuran (9 mL), and 28% aqueous ammonia (0.9 mL, 12.9 mmol) was added at 0 °C. It was stirred at room temperature for 40 hours. After completion of the reaction, the solvent was concentrated under reduced pressure. Distilled water (30 mL) was added to the residue, and the resulting yellow solid was filtered and dried under reduced pressure to obtain the title compound. (0.96 g, 97%)
MS m/z: 215 [M+1]+ MS m/z: 215 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.59 (d, 1H), 8.08 (s, 1H), 6.78 (d, 1H), 3.81 (s, 3H).1H NMR (DMSO-d 6 , 400 MHz), δ ppm: 8.59 (d, 1H), 8.08 (s, 1H), 6.78 (d, 1H), 3.81 (s, 3H).
(단계 2) methyl 4,5-diamino-2-fluorobenzoate의 제조(Step 2) Preparation of methyl 4,5-diamino-2-fluorobenzoate
상기 (단계 1)에서 제조한 화합물(0.96 g, 4.46 mmol)을 메탄올(30 mL)과 아세트산에틸(30 mL) 혼합용매에 녹인 후, Pd/C (10 wt%, 186 mg)을 첨가한 후 1 기압의 수소 하, 실온에서 16 시간 동안 교반하였다. 불용물을 셀라이트를 통해 제거하고 메탄올로 세정한 여과액을 감압 농축하여 갈색의 고체로 표제화합물을 얻었다. (943 mg)Dissolve the compound (0.96 g, 4.46 mmol) prepared in step 1 above in a mixed solvent of methanol (30 mL) and ethyl acetate (30 mL), and then add Pd/C (10 wt%, 186 mg). It was stirred at room temperature under 1 atm of hydrogen for 16 hours. Insoluble matter was removed through Celite, and the filtrate was washed with methanol and concentrated under reduced pressure to obtain the title compound as a brown solid. (943 mg)
MS m/z: 185 [M+1]+ MS m/z: 185 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 7.30 (m, 1H), 6.40 (dd, 1H), 4.00 (brs, 2H), 3.85 (s, 3H), 3.15 (brs, 2H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 7.30 (m, 1H), 6.40 (dd, 1H), 4.00 (brs, 2H), 3.85 (s, 3H), 3.15 (brs, 2H).
(단계 3) methyl 6-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylate의 제조(Step 3) Preparation of methyl 6-fluoro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylate
상기 (단계 2)에서 제조한 화합물(0.90 g, 4.89 mmol)을 아세트산(7 mL)에 용해시키고, 0 ℃에서 아질산나트륨(0.37 g, 5.38 mmol)을 증류수(1.4 mL)에 녹인 용액을 첨가하여 실온에서 10 분 동안 교반하였다. 용매를 감압 농축하고 남은 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : 염화메틸렌 = 20 : 80)로 정제하여 진한 갈색의 고체로 표제화합물을 얻었다.(0.72 g, 75%)The compound (0.90 g, 4.89 mmol) prepared in step 2 above was dissolved in acetic acid (7 mL), and a solution of sodium nitrite (0.37 g, 5.38 mmol) dissolved in distilled water (1.4 mL) was added at 0°C. Stirred at room temperature for 10 minutes. The solvent was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (ethyl acetate: methylene chloride = 20:80) to obtain the title compound as a dark brown solid (0.72 g, 75%).
MS m/z: 196 [M+1]+ MS m/z: 196 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.54 (d, 1H), 7.85 (d, 1H), 3.90 (s, 3H). 1 H NMR (DMSO-d 6 , 400 MHz), δ ppm: 8.54 (d, 1H), 7.85 (d, 1H), 3.90 (s, 3H).
(단계 4) 6-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxylic acid의 제조(Step 4) Preparation of 6-fluoro-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid
상기 (단계 3)에서 제조한 화합물(0.72 g, 3.69 mmol)을 테트라히드로퓨란/증류수 혼합용매 (1/1, 7 mL)에 용해시키고, 수산화리튬 일수화물(0.77 g, 18.45 mmol)을 첨가하여 실온에서 3 시간 교반하였다. 반응혼합물을 감압 농축하고 1N 염화수소 수용액을 가하여 액상을 pH 2로 맞추고, 아세트산에틸 (50 mL)로 2 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 여과하였다. 여과액을 감압하에 농축하여 얻은 잔류물에 디에틸 에테르를 가하여 생성된 고체를 여과하고 디에틸 에테르로 세정한 후 건조하여 갈색의 고체로 표제화합물을 얻었다. (0.54 g, 81%)The compound prepared in step 3 (0.72 g, 3.69 mmol) was dissolved in a tetrahydrofuran/distilled water mixed solvent (1/1, 7 mL), and lithium hydroxide monohydrate (0.77 g, 18.45 mmol) was added. It was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous hydrogen chloride solution was added to adjust the liquid phase to pH 2, and extracted twice with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and filtered. Diethyl ether was added to the residue obtained by concentrating the filtrate under reduced pressure, and the resulting solid was filtered, washed with diethyl ether, and dried to obtain the title compound as a brown solid. (0.54 g, 81%)
MS m/z: 182 [M+1]+ MS m/z: 182 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.50 (d, 1H), 7.81 (d, 1H). 1 H NMR (DMSO-d 6 , 400 MHz), δ ppm: 8.50 (d, 1H), 7.81 (d, 1H).
(제조예 B-5) 6-methoxy-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (중간체 B-5)의 제조 (Preparation Example B-5) Preparation of 6-methoxy-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-5)
(단계 1) methyl 4,5-diamino-2-methoxybenzoate의 제조(Step 1) Preparation of methyl 4,5-diamino-2-methoxybenzoate
메틸 4-아미노-2-메톡시-5-나이트로벤조에이트(0.5 g, 2.2 mmol)을 아세트산에틸(22 mL)에 용해시키고, Pd/C (10 wt%, 100 mg)을 첨가하여 1 기압의 수소 하, 50 ℃에서 18 시간 동안 교반하였다. 불용물을 셀라이트를 통해 제거하고 메탄올로 세정한 여과액을 감압 하에 농축하여 갈색의 고체로 표제화합물을 얻었다. (0.43 g, 99%)Methyl 4-amino-2-methoxy-5-nitrobenzoate (0.5 g, 2.2 mmol) was dissolved in ethyl acetate (22 mL), Pd/C (10 wt%, 100 mg) was added, and the mixture was incubated at 1 atm. Under hydrogen, it was stirred at 50°C for 18 hours. Insoluble matters were removed through Celite, and the filtrate was washed with methanol and concentrated under reduced pressure to obtain the title compound as a brown solid. (0.43 g, 99%)
MS m/z: 197 [M+1]+ MS m/z: 197 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 7.02 (s, 1H), 6.24 (s, 1H), 5.35 (s, 2H), 4.24 (brs, 2H), 3.64 (s, 6H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 7.02 (s, 1H), 6.24 (s, 1H), 5.35 (s, 2H), 4.24 (brs, 2H), 3.64 (s, 6H).
(단계 2) methyl 6-methoxy-1H-benzo[d][1,2,3]triazole-5-carboxylate의 제조(Step 2) Preparation of methyl 6-methoxy-1 H -benzo[ d ][1,2,3]triazole-5-carboxylate
상기 (단계 1)에서 제조한 화합물(0.43 g, 2.18 mmol)을 아세트산(3 mL)에 용해시키고, 0 ℃에서 아질산나트륨(0.16 g, 2.40 mmol)을 증류수(0.6 mL)에 녹인 용액을 첨가하여 실온에서 1 시간 동안 교반하였다. 용매를 감압 농축하여 남은 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올 : 염화메틸렌 = 5 : 95)로 정제하여 연한 갈색의 고체로 표제화합물을 얻었다. (0.39 g, 86%)The compound (0.43 g, 2.18 mmol) prepared in step 1 above was dissolved in acetic acid (3 mL), and a solution of sodium nitrite (0.16 g, 2.40 mmol) dissolved in distilled water (0.6 mL) was added at 0°C. Stirred at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the remaining residue was purified by silica gel column chromatography (methanol: methylene chloride = 5:95) to obtain the title compound as a light brown solid. (0.39 g, 86%)
MS m/z: 208 [M+1]+ MS m/z: 208 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.24 (s, 1H), 7.33 (s, 1H), 3.90 (s, 3H), 3.83 (s, 3H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.24 (s, 1H), 7.33 (s, 1H), 3.90 (s, 3H), 3.83 (s, 3H).
(단계 3) 6-methoxy-1H-benzo[d][1,2,3]triazole-5-carboxylic acid의 제조(Step 3) Preparation of 6-methoxy-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid
상기 (단계 2)에서 제조한 화합물(0.39 g, 1.89 mmol)을 테트라히드로퓨란/메탄올/증류수 혼합용매 (3/2/1, 6 mL)에 용해시키고, 수산화리튬 일수화물(0.55 g, 13.2 mmol)을 첨가하여 실온에서 18 시간 동안 교반하였다. 반응혼합물을 감압 농축하고 1N 염화수소 수용액을 가하여 액상을 pH 2로 맞추고, 아세트산에틸 (50 mL)로 2 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 여과하였다. 여과액을 감압하에 농축하여 얻은 고체를 디에틸 에테르로 세정한 후 건조하여 갈색의 고체로 표제화합물을 얻었다. (0.32 g, 88%)The compound prepared in (step 2) (0.39 g, 1.89 mmol) was dissolved in tetrahydrofuran/methanol/distilled water mixed solvent (3/2/1, 6 mL), and lithium hydroxide monohydrate (0.55 g, 13.2 mmol) ) was added and stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous hydrogen chloride solution was added to adjust the liquid phase to pH 2, and extracted twice with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the obtained solid was washed with diethyl ether and dried to obtain the title compound as a brown solid. (0.32 g, 88%)
MS m/z: 194 [M+1]+ MS m/z: 194 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 12.88 (brs, 1H), 8.19 (s, 1H), 7.30 (s, 1H), 3.90 (s, 3H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 12.88 (brs, 1H), 8.19 (s, 1H), 7.30 (s, 1H), 3.90 (s, 3H).
(제조예 B-6) 6-(2,2-difluoroethoxy)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid (중간체 B-6)의 제조 (Preparation Example B-6) Preparation of 6-(2,2-difluoroethoxy)-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid (Intermediate B-6)
(단계 1) methyl 4-amino-2-fluoro-5-nitrobenzoate의 제조(Step 1) Preparation of methyl 4-amino-2-fluoro-5-nitrobenzoate
메틸 2,4-디플루오로-5-니트로벤조에이트(1.0 g, 4.6 mmol)를 테트라히드로퓨란(9 mL)에 용해시키고, 0 ℃에서 28% 암모니아수(0.9 mL)를 적하하고 실온에서 40 시간 동안 교반하였다. 용매를 감압 하에 농축하여 제거한 후 증류수 (50 mL)를 가하여 생성된 고체를 여과하고 증류수로 세정하여 황색의 고체로 표제화합물을 얻었다. (0.96 g, 97%)Methyl 2,4-difluoro-5-nitrobenzoate (1.0 g, 4.6 mmol) was dissolved in tetrahydrofuran (9 mL), 28% aqueous ammonia (0.9 mL) was added dropwise at 0°C, and incubated at room temperature for 40 hours. It was stirred for a while. The solvent was removed by concentration under reduced pressure, distilled water (50 mL) was added, and the resulting solid was filtered and washed with distilled water to obtain the title compound as a yellow solid. (0.96 g, 97%)
MS m/z: 215 [M+1]+ MS m/z: 215 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.59 (d, 1H), 8.08 (s, 1H), 6.78 (d, 1H), 3.81 (s, 3H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.59 (d, 1H), 8.08 (s, 1H), 6.78 (d, 1H), 3.81 (s, 3H).
(단계 2) methyl 4-amino-2-(2,2-difluoroethoxy)-5-nitrobenzoate의 제조(Step 2) Preparation of methyl 4-amino-2-(2,2-difluoroethoxy)-5-nitrobenzoate
2,2-디플루오로에탄올(0.14 mL, 2.24 mmol)을 테트라히드로퓨란(9 mL)에 용해시키고, 칼륨 터트-부톡사이드(0.25 g, 2.24 mmol)을 첨가하여 실온에서 30 분 교반하였다. 반응혼합물에 상기 (단계 1)에서 제조한 화합물(0.40 g, 1.87 mmol)를 천천히 가하고 실온에서 18 시간 동안 교반하였다. 증류수 (30 mL)를 가하여 반응을 종결시킨 후 아세트산에틸(50 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 40 : 60)로 정제하여 황색의 고체로 표제화합물을 얻었다. (0.44 g, 86%)2,2-difluoroethanol (0.14 mL, 2.24 mmol) was dissolved in tetrahydrofuran (9 mL), potassium tert-butoxide (0.25 g, 2.24 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The compound prepared in step 1 (0.40 g, 1.87 mmol) was slowly added to the reaction mixture and stirred at room temperature for 18 hours. The reaction was terminated by adding distilled water (30 mL), and then extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 40:60) to obtain the title compound as a yellow solid. (0.44 g, 86%)
MS m/z: 277 [M+1]+ MS m/z: 277 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.52 (s, 1H), 7.89 (s, 2H), 6.56 (s, 1H), 6.54-6.27 (t, 1H), 4.38-4.32 (m, 2H), 3.75 (s, 3H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.52 (s, 1H), 7.89 (s, 2H), 6.56 (s, 1H), 6.54-6.27 (t, 1H), 4.38-4.32 (m , 2H), 3.75 (s, 3H).
(단계 3) methyl 4,5-diamino-2-(2,2-difluoroethoxy)benzoate의 제조(Step 3) Preparation of methyl 4,5-diamino-2-(2,2-difluoroethoxy)benzoate
상기 (단계 2)에서 제조한 화합물(0.44 g, 1.61 mmol)을 아세트산에틸(16 mL)에 용해시키고, Pd/C (10 wt%, 89 mg)을 첨가하여 1 기압의 수소 하, 실온에서 18 시간 동안 교반하였다. 반응 종결 후, 불용물을 셀라이트를 통해 제거하고 아세트산에틸로 세정한 여과액을 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 30 : 70 → 60 : 40)로 정제하여 갈색의 고체로 표제화합물을 얻었다. (0.27 g, 67%)The compound prepared in (step 2) (0.44 g, 1.61 mmol) was dissolved in ethyl acetate (16 mL), Pd/C (10 wt%, 89 mg) was added, and the mixture was incubated at room temperature for 18 hours under 1 atm of hydrogen. Stirred for an hour. After completion of the reaction, insoluble matter was removed through Celite, and the filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 30:70 → 60:40) to obtain the title compound as a brown solid. (0.27 g, 67%)
MS m/z: 247 [M+1]+ MS m/z: 247 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 7.02 (s, 1H), 6.41-6.14 (m, 2H), 5.39 (s, 2H), 4.40 (s, 2H), 4.12-4.04 (m, 2H), 3.67 (s, 3H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 7.02 (s, 1H), 6.41-6.14 (m, 2H), 5.39 (s, 2H), 4.40 (s, 2H), 4.12-4.04 (m) , 2H), 3.67 (s, 3H).
(단계 4) methyl 6-(2,2-difluoroethoxy)-1H-benzo[d][1,2,3]triazole-5-carboxylate의 제조(Step 4) Preparation of methyl 6-(2,2-difluoroethoxy)-1 H -benzo[ d ][1,2,3]triazole-5-carboxylate
상기 (단계 3)에서 제조한 화합물(0.27 g, 1.08 mmol)을 아세트산(2 mL)에 용해시키고, 0 ℃에서 아질산나트륨(0.082 g, 1.19 mmol)을 증류수(1 mL)에 녹인 용액을 첨가하여 실온에서 2 시간 동안 교반하였다. 반응 종결 후, 용매를 감압 하에 농축하여 제거하고 남은 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올 : 염화메틸렌 = 5 : 95)로 정제하여 연한 갈색의 고체로 표제화합물을 얻었다. (0.27 g, 97%)The compound (0.27 g, 1.08 mmol) prepared in step 3 above was dissolved in acetic acid (2 mL), and a solution of sodium nitrite (0.082 g, 1.19 mmol) dissolved in distilled water (1 mL) was added at 0°C. It was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and the remaining residue was purified by silica gel column chromatography (methanol: methylene chloride = 5:95) to obtain the title compound as a light brown solid. (0.27 g, 97%)
MS m/z: 258 [M+1]+ MS m/z: 258 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.29 (s, 1H), 7.50 (s, 1H), 6.56-6.28 (t, 1H), 4.52-4.44 (m, 2H), 3.84 (s, 3H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.29 (s, 1H), 7.50 (s, 1H), 6.56-6.28 (t, 1H), 4.52-4.44 (m, 2H), 3.84 (s) , 3H).
(단계 5) 6-(2,2-difluoroethoxy)-1H-benzo[d][1,2,3]triazole-5-carboxylic acid의 제조(Step 5) Preparation of 6-(2,2-difluoroethoxy)-1 H -benzo[ d ][1,2,3]triazole-5-carboxylic acid
상기 (단계 4)에서 제조한 화합물(0.27 g, 1.05 mmol)을 테트라히드로퓨란/메탄올/증류수 혼합용매 (3/2/1, 2 mL)에 용해시키고, 수산화리튬 일수화물(0.22 g, 5.27 mmol)을 첨가하여 실온에서 7 시간 동안 교반하였다. 반응혼합물을 감압 농축하고, 1N 염화수소 수용액을 가하여 액상을 pH 2로 조정하고, 아세트산에틸 (50 mL)로 2 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 염화메틸렌으로 세정하여 갈색의 고체로 표제화합물을 얻었다. (0.21 g, 83%)The compound prepared in (step 4) (0.27 g, 1.05 mmol) was dissolved in tetrahydrofuran/methanol/distilled water mixed solvent (3/2/1, 2 mL), and lithium hydroxide monohydrate (0.22 g, 5.27 mmol) ) was added and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, 1N aqueous hydrogen chloride solution was added to adjust the liquid phase to pH 2, and extracted twice with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with methylene chloride to obtain the title compound as a brown solid. (0.21 g, 83%)
MS m/z: 243 [M+1]+ MS m/z: 243 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 12.99 (brs, 1H), 8.23 (s, 1H), 7.46 (s, 1H), 6.56-6.28 (t, 1H), 4.51-4.43 (m, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 12.99 (brs, 1H), 8.23 (s, 1H), 7.46 (s, 1H), 6.56-6.28 (t, 1H), 4.51-4.43 (m) , 2H).
(제조예 B-7) 6-(methylsulfonamido)nicotinic acid (중간체 B-7)의 제조 (Preparation Example B-7) Preparation of 6-(methylsulfonamido)nicotinic acid (Intermediate B-7)
메틸 6-아미노피리딘-3-카복실레이트(1.0 g, 6.57 mmol)와 트리에틸아민(1.1 mL, 7.89 mmol)을 염화메틸렌(22 mL)에 용해시키고, 0 ℃에서 염화메탄설포닐(0.6 mL, 7.3 mmol)을 첨가하여 실온에서 18 시간 동안 교반하였다. TLC로 반응 확인 후, 메탄올(24 mL)와 4N 수산화나트륨 수용액(8 mL)를 첨가하여 실온에서 1 시간 동안 교반하였다. 반응 종결 후, 유기 용매를 감압 농축하였다. 1N 염화수소 수용액을 가하여 pH 2가 되도록한 다음, 아세트산에틸로 추출하였다. 유기층을 모아 무수 황산나트륨으로 건조하고 필터한 다음, 용매를 감압 농축하였다. 잔류물을 여과하고 디에틸 에테르로 세정하여 베이지색의 고체로 표제화합물을 얻었다. (0.52 g, 37%)Methyl 6-aminopyridine-3-carboxylate (1.0 g, 6.57 mmol) and triethylamine (1.1 mL, 7.89 mmol) were dissolved in methylene chloride (22 mL), and methanesulfonyl chloride (0.6 mL, 7.3 mmol) was added and stirred at room temperature for 18 hours. After confirming the reaction by TLC, methanol (24 mL) and 4N aqueous sodium hydroxide solution (8 mL) were added and stirred at room temperature for 1 hour. After completion of the reaction, the organic solvent was concentrated under reduced pressure. A 1N aqueous hydrogen chloride solution was added to adjust the pH to 2, and then extracted with ethyl acetate. The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the solvent was concentrated under reduced pressure. The residue was filtered and washed with diethyl ether to obtain the title compound as a beige solid. (0.52 g, 37%)
MS m/z: 217 [M+1]+ MS m/z: 217 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.72 (s, 1H), 8.18-8.15 (m, 1H), 7.04 (d, 1H), 3.31 (s, 3H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.72 (s, 1H), 8.18-8.15 (m, 1H), 7.04 (d, 1H), 3.31 (s, 3H).
(제조예 B-8) 2-(methylsulfonamido)isonicotinic acid (중간체 B-8)의 제조 (Preparation Example B-8) Preparation of 2-(methylsulfonamido)isonicotinic acid (Intermediate B-8)
제조예 B-7과 같은 방법으로 메틸 6-아미노피리딘-3-카복실레이트 대신 메틸 2-아미노피리딘-4-카복실레이트(2.0 g, 13.15 mmol)를 사용하여 베이지색의 고체로 표제화합물을 얻었다 (1.33 g, 47%).In the same manner as Preparation Example B-7, using methyl 2-aminopyridine-4-carboxylate (2.0 g, 13.15 mmol) instead of methyl 6-aminopyridine-3-carboxylate, the title compound was obtained as a beige solid ( 1.33 g, 47%).
MS m/z: 217 [M+1]+ MS m/z: 217 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.43 (d, 1H), 7.44-7.41 (m, 2H), 3.32 (m, 3H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.43 (d, 1H), 7.44-7.41 (m, 2H), 3.32 (m, 3H).
(제조예 B-9) 2-(methylsulfonamido)thiazole-4-carboxylic acid (중간체 B-9)의 제조 (Preparation Example B-9) Preparation of 2-(methylsulfonamido)thiazole-4-carboxylic acid (Intermediate B-9)
제조예 B-7과 같은 방법으로 메틸 6-아미노피리딘-3-카복실레이트 대신 에틸 2-아미노사이아졸-4-카복실레이트(0.93 g, 5.37 mmol)를 사용하여 흰색 고체로 표제화합물을 얻었다. (0.14 g, 48%)The title compound was obtained as a white solid in the same manner as Preparation Example B-7, using ethyl 2-aminothiazole-4-carboxylate (0.93 g, 5.37 mmol) instead of methyl 6-aminopyridine-3-carboxylate. (0.14 g, 48%)
MS m/z: 223 [M+1]+ MS m/z: 223 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 7.62 (s, 1H), 2.94 (s, 3H). 1 H NMR (DMSO-d 6, 400 MHz), δ ppm: 7.62 (s, 1H), 2.94 (s, 3H).
(제조예 B-10) 6-((methylsulfonyl)methyl)nicotinic acid (중간체 B-10)의 제조 (Preparation Example B-10) Preparation of 6-((methylsulfonyl)methyl)nicotinic acid (Intermediate B-10)
(단계 1) methyl 6-(bromomethyl)nicotinate의 제조(Step 1) Preparation of methyl 6-(bromomethyl)nicotinate
메틸 6-(히드록시메틸)니코티네이트(1.5 g, 9.0 mmol)을 클로로포름(38 mL)에 녹인 후, 0 ℃에서 브롬화인(1.0 mL, 10.8 mmol)을 천천히 적하하고 실온에서 3 시간 동안 교반하였다. 탄산나트륨 포화수용액 (20 mL)을 가하여 반응을 종결시키고, 클로로포름(50 mL)으로 3회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 30 : 70)로 정제하여 흰색 고체로 표제화합물을 얻었다. (1.5 g, 73%)After dissolving methyl 6-(hydroxymethyl)nicotinate (1.5 g, 9.0 mmol) in chloroform (38 mL), phosphorus bromide (1.0 mL, 10.8 mmol) was slowly added dropwise at 0°C and stirred at room temperature for 3 hours. did. The reaction was terminated by adding saturated aqueous sodium carbonate solution (20 mL), and extracted three times with chloroform (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 30:70) to obtain the title compound as a white solid. (1.5g, 73%)
MS m/z: 231 [M+1]+ MS m/z: 231 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 9.16 (s, 1H), 8.30 (dd, 1H), 7.53 (d, 1H), 4.58 (s, 2H), 3.96 (s, 3H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 9.16 (s, 1H), 8.30 (dd, 1H), 7.53 (d, 1H), 4.58 (s, 2H), 3.96 (s, 3H).
(단계 2) 6-((methylsulfonyl)methyl)nicotinic acid의 제조(Step 2) Preparation of 6-((methylsulfonyl)methyl)nicotinic acid
상기 (단계 1)에서 제조한 화합물(0.3 g, 1.3 mmol)을 N,N-디메틸포름아미드(15 mL)에 녹인 후 메탄설핀산나트륨 (0.27 g, 2.6 mmol)을 첨가하여 120 ℃에서 2 시간 동안 교반하였다. 반응 종결 후, 감압 하에 농축하여 용매를 제거한 후 잔류물을 테트라히드로퓨란(2 mL)에 녹이고 1N 수산화나트륨 수용액(4 mL)를 가하여 70 ℃에서 3 시간 동안 교반하였다. 반응 혼합물을 실온까지 식힌 후, 2N 염화수소 수용액을 가하여 액성을 pH 2로 조정하고, 아세트산에틸(30 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하여 베이지색 고체로 표제화합물을 얻었다. (0.20 g, 72%)Dissolve the compound prepared in (step 1) (0.3 g, 1.3 mmol) in N,N-dimethylformamide (15 mL), add sodium methanesulfinate (0.27 g, 2.6 mmol), and incubate at 120°C for 2 hours. It was stirred for a while. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), 1N aqueous sodium hydroxide solution (4 mL) was added, and the mixture was stirred at 70°C for 3 hours. After the reaction mixture was cooled to room temperature, 2N aqueous hydrogen chloride solution was added to adjust the pH to 2, and the mixture was extracted three times with ethyl acetate (30 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound as a beige solid. (0.20 g, 72%)
MS m/z: 216 [M+1]+ MS m/z: 216 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 13.49 (s, 1H), 9.22 - 8.95 (m, 1H), 8.33 (dt, 1H), 7.65 (d, 1H), 4.77 (s, 2H), 3.05 (s, 3H). 1H NMR (DMSO-d 6, 400MHz), δ ppm: 13.49 (s, 1H), 9.22 - 8.95 (m, 1H), 8.33 (dt, 1H), 7.65 (d, 1H), 4.77 (s, 2H) ), 3.05 (s, 3H).
(제조예 B-11) 2-((methylsulfonyl)methyl)isonicotinic acid (중간체 B-11)의 제조 (Preparation Example B-11) Preparation of 2-((methylsulfonyl)methyl)isonicotinic acid (Intermediate B-11)
(단계 1) methyl 2-(hydroxymethyl)isonicotinate의 제조(Step 1) Preparation of methyl 2-(hydroxymethyl)isonicotinate
메틸이소니코티네이트(5.0 g, 36.5 mmol)을 메탄올(50 mL)에 녹인 후, 황산(0.2 mL)을 첨가하고 50 ℃에서 교반 중에 과황산암모늄(15 g, 65.6 mmol) 수용액 (25 mL)을 천천히 가하고, 100 ℃에서 30 분 더 교반하였다. 반응 종결 후, 실온까지 냉각하여 탄산나트륨 포화수용액(30 mL)으로 중화한 후 아세트산에틸 (50 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 50 : 50)로 정제하여 황색 고체로 표제화합물을 얻었다. (2.26 g, 37%)After dissolving methylisonicotinate (5.0 g, 36.5 mmol) in methanol (50 mL), sulfuric acid (0.2 mL) was added, and while stirring at 50° C., an aqueous solution of ammonium persulfate (15 g, 65.6 mmol) (25 mL) was added. was slowly added and stirred at 100°C for another 30 minutes. After completion of the reaction, it was cooled to room temperature, neutralized with saturated aqueous sodium carbonate solution (30 mL), and extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate : n-hexane = 50 : 50) to obtain the title compound as a yellow solid. (2.26 g, 37%)
MS m/z: 168 [M+1]+ MS m/z: 168 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 8.51 (d, 1H), 7.80 (s, 1H), 7.58 (d, 1H), 4.70 (s, 3H), 3.81 (d, 3H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 8.51 (d, 1H), 7.80 (s, 1H), 7.58 (d, 1H), 4.70 (s, 3H), 3.81 (d, 3H).
(단계 2) methyl 2-(bromomethyl)isonicotinate의 제조(Step 2) Preparation of methyl 2-(bromomethyl)isonicotinate
상기 (단계 1)에서 제조한 화합물(1.2 g, 7.18 mmol)을 클로로포름(30 mL)에 녹인 후, 0 ℃에서 브롬화인 (0.8 mL, 8.61 mmol)을 천천히 적하한 후 실온에서 3 시간 교반하였다. 탄산나트륨 포화수용액 (20 mL)을 가하고 반응을 종결시키고, 클로로포름(50 mL)으로 3회 추출하였다 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하여 얻은 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 30 : 70)로 정제하여 흰색 고체로 표제화합물을 얻었다. (1.38 g, 84%)After dissolving the compound (1.2 g, 7.18 mmol) prepared in step 1 above in chloroform (30 mL), phosphorus bromide (0.8 mL, 8.61 mmol) was slowly added dropwise at 0°C and stirred at room temperature for 3 hours. Saturated sodium carbonate aqueous solution (20 mL) was added to terminate the reaction, and extraction was performed three times with chloroform (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The title compound was obtained as a white solid by purification by ethyl acetate:n-hexane = 30:70. (1.38 g, 84%)
MS m/z: 231 [M+1]+ MS m/z: 231 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 8.73 (d, 1H), 7.99 (s, 1H), 7.77 (d, 1H), 4.61 (s, 2H), 3.97 (s, 3H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 8.73 (d, 1H), 7.99 (s, 1H), 7.77 (d, 1H), 4.61 (s, 2H), 3.97 (s, 3H).
(단계 3) 2-((methylsulfonyl)methyl)isonicotinic acid의 제조(Step 3) Preparation of 2-((methylsulfonyl)methyl)isonicotinic acid
상기 (단계 2)에서 제조한 화합물(0.3 g, 1.3 mmol)을 N,N-디메틸포름아미드(15 mL)에 녹인 후 메탄설핀산 나트륨(0.27 g, 2.6 mmol)을 첨가하여 120 ℃에서 2 시간 동안 교반하였다. 반응 종결 후, 용매를 감압증류 후 1N 수산화나트륨 수용액(3.9 mL)과 테트라히드로퓨란(1.3 mL) 녹인 후, 70 ℃에서 3 시간 교반하였다. 반응 종료 후, 2N 염화수소 수용액을 가하여 액성이 pH 2 이하가 되도록 하고 고체가 생성되도록 하였다. 생성된 고체를 여과하고 증류수로 세정한 후, 건조하여 갈색 고체로 표제화합물을 얻었다. (0.22 g, 79%)The compound prepared in (step 2) (0.3 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (15 mL), then sodium methanesulfinate (0.27 g, 2.6 mmol) was added and incubated at 120°C for 2 hours. It was stirred for a while. After completion of the reaction, the solvent was distilled under reduced pressure, 1N aqueous sodium hydroxide solution (3.9 mL) and tetrahydrofuran (1.3 mL) were dissolved, and the mixture was stirred at 70°C for 3 hours. After completion of the reaction, 2N aqueous hydrogen chloride solution was added to bring the liquid to pH 2 or less and to produce a solid. The resulting solid was filtered, washed with distilled water, and dried to obtain the title compound as a brown solid. (0.22 g, 79%)
MS m/z: 216 [M+1]+ MS m/z: 216 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.78 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 4.78 (s, 2H), 3.03 (s, 3H). 1H NMR (DMSO-d 6, 400MHz), δ ppm: 8.78 (d, 1H), 7.97 (s, 1H), 7.82 (d, 1H), 4.78 (s, 2H), 3.03 (s, 3H).
(제조예 B-12) 6-(sulfomethyl)nicotinic acid (중간체 B-12)의 제조 (Preparation Example B-12) Preparation of 6-(sulfomethyl)nicotinic acid (Intermediate B-12)
중간체 B-10의 (단계 1)에서 제조한 화합물(0.40 g, 1.74 mmol)을 증류수(20 mL)에 녹인 후 아황산나트륨(0.22 g, 1.74 mmol)을 첨가한 뒤, 100 ℃에서 16 시간 교반하였다. 반응 종결 후, 용매를 감압증류 후 4M 염화수소 수용액(20 mL)에 녹인 후, 100 ℃에서 16 시간 교반하였다. 반응 종료 후, 실온으로 냉각한 후 감압 하에 농축하여 얻은 잔류물을 메탄올과 증류수로 세정하여 흰색의 고체로 표제화합물을 얻었다. (0.21 g, 56%)The compound (0.40 g, 1.74 mmol) prepared in (Step 1) of Intermediate B-10 was dissolved in distilled water (20 mL), sodium sulfite (0.22 g, 1.74 mmol) was added, and the mixture was stirred at 100°C for 16 hours. . After completion of the reaction, the solvent was distilled under reduced pressure, dissolved in 4M aqueous hydrogen chloride solution (20 mL), and stirred at 100°C for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was washed with methanol and distilled water to obtain the title compound as a white solid. (0.21 g, 56%)
MS m/z: 218 [M+1]+ MS m/z: 218 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 9.07 (s, 1H), 8.52 (s, 1H), 7.86 (d, 1H), 4.12 (s, 2H). 1H NMR (DMSO-d 6, 400MHz), δ ppm: 9.07 (s, 1H), 8.52 (s, 1H), 7.86 (d, 1H), 4.12 (s, 2H).
(제조예 B-13) 6-(1H-tetrazol-5-yl)nicotinic acid (중간체 B-13)의 제조 (Preparation Example B-13) Preparation of 6-(1 H -tetrazol-5-yl)nicotinic acid (Intermediate B-13)
(단계 1) methyl 6-cyanonicotinate의 제조(Step 1) Preparation of methyl 6-cyanonicotinate
메틸 6-브로모니코티네이트(1.0 g, 4.6 mmol)을 N,N-디메틸포름아미드(6.5 mL)에 녹인 후, 테트라키스(트리페닐포스핀)팔라듐(0)(267 mg, 0.23 mmol), 시안화아연 (326 mg, 2.78 mmol) 첨가한 뒤 질소 분위기 하, 100 ℃에서 18 시간 동안 교반하였다. 증류수 (30 mL)를 가하여 반응을 종결시킨 후 아세트산에틸 (50 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 20 : 80)로 정제하여 흰색 고체로 표제화합물을 얻었다. (0.57 g, 72%)After dissolving methyl 6-bromonicotinate (1.0 g, 4.6 mmol) in N,N-dimethylformamide (6.5 mL), tetrakis(triphenylphosphine)palladium(0) (267 mg, 0.23 mmol), Zinc cyanide (326 mg, 2.78 mmol) was added and stirred at 100°C for 18 hours under a nitrogen atmosphere. The reaction was terminated by adding distilled water (30 mL), and then extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 20:80) to obtain the title compound as a white solid. (0.57 g, 72%)
MS m/z: 163 [M+1]+ MS m/z: 163 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 9.29 (d, 1H), 8.44 (dd, 1H), 7.80 (d, 1H), 4.00 (s, 3H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 9.29 (d, 1H), 8.44 (dd, 1H), 7.80 (d, 1H), 4.00 (s, 3H).
(단계 2) methyl 6-(1H-tetrazol-5-yl)nicotinate의 제조(Step 2) Preparation of methyl 6-( 1H -tetrazol-5-yl)nicotinate
상기 (단계 1)에서 제조한 화합물(0.57 g, 3.53 mmol)을 N,N-디메틸포름아미드(36 mL)에 녹인 후 아자이드화 나트륨(0.25 g, 3.88 mmol), 염화암모늄(0.20 g, 3.88 mmol), 염화리튬(0.075 g, 1.76 mmol)을 첨가한 뒤 질소 분위기 하, 110 ℃에서 18 시간 동안 교반하였다. 반응 종결 후, 실온까지 냉각하고 불용물을 셀라이트를 통해 제거하고 아세트산에틸 세정한 여과액을 감압 하에 농축하였다. 잔류물을 증류수와 1N 염화수소 수용액을 가하여 재결정하여 베이지색의 고체로 표제화합물을 얻었다. (0.65 g, 90%)The compound prepared in (step 1) (0.57 g, 3.53 mmol) was dissolved in N,N-dimethylformamide (36 mL), and then sodium azide (0.25 g, 3.88 mmol) and ammonium chloride (0.20 g, 3.88 mmol) were dissolved in N,N-dimethylformamide (36 mL). mmol) and lithium chloride (0.075 g, 1.76 mmol) were added and stirred at 110°C for 18 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, the insoluble matter was removed through Celite, and the filtrate washed with ethyl acetate was concentrated under reduced pressure. The residue was recrystallized by adding distilled water and 1N aqueous hydrogen chloride solution to obtain the title compound as a beige solid. (0.65 g, 90%)
MS m/z: 206 [M+1]+ MS m/z: 206 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 9.34 (s, 1H), 8.57-8.47 (m, 2H), 4.02 (s, 3H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 9.34 (s, 1H), 8.57-8.47 (m, 2H), 4.02 (s, 3H).
(단계 3) 6-(1H-tetrazol-5-yl)nicotinic acid의 제조(Step 3) Preparation of 6-(1 H -tetrazol-5-yl)nicotinic acid
상기 (단계 2)에서 제조한 화합물(0.65 g, 3.18 mmol)을 테트라히드로퓨란(32 mL)에 녹인 후 1N 수산화리튬 수용액 (32 mL)를 첨가하여 실온에서 3 시간 동안 교반하였다. 반응 종료 후, 2N 염화수소 수용액을 가하여 액성을 pH 2로 조정하여 고체가 생성되도록 하였다. 생성된 고체를 여과하고 증류수로 세정한 후, 건조하여 베이지색 고체로 표제화합물을 얻었다. (0.43 g, 70%)The compound (0.65 g, 3.18 mmol) prepared in step 2 above was dissolved in tetrahydrofuran (32 mL), and then 1N lithium hydroxide aqueous solution (32 mL) was added and stirred at room temperature for 3 hours. After completion of the reaction, 2N aqueous hydrogen chloride solution was added to adjust the liquid to pH 2 to produce a solid. The resulting solid was filtered, washed with distilled water, and dried to obtain the title compound as a beige solid. (0.43 g, 70%)
MS m/z: 192 [M+1]+ MS m/z: 192 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 9.23 (d, 1H), 8.53 (m, 1H), 8.36 (m, 1H). 1H NMR (DMSO-d 6, 400MHz), δ ppm: 9.23 (d, 1H), 8.53 (m, 1H), 8.36 (m, 1H).
(제조예 B-14) 1H-benzo[d][1,2,3]triazole-5-sulfonyl chloride (중간체 B-14)의 제조 (Preparation Example B-14) Preparation of 1 H -benzo[ d ][1,2,3]triazole-5-sulfonyl chloride (Intermediate B-14)
(단계 1) 4-chloro-3-nitrobenzenesulfonyl chloride의 제조(Step 1) Preparation of 4-chloro-3-nitrobenzenesulfonyl chloride
1-클로로-2-니트로벤젠(1.0 g, 6.3 mmol)을 클로로설폰산(5 mL)에 용해시키고, 120 ℃에서 18 시간 동안 교반하였다. 반응혼합물을 얼음물에 천천히 가하여 반응을 종결시킨 후 아세트산에틸(50 mL)로 3회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하여 갈색의 액체로 표제화합물을 정량적으로 얻었다. (1.73 g)1-Chloro-2-nitrobenzene (1.0 g, 6.3 mmol) was dissolved in chlorosulfonic acid (5 mL) and stirred at 120°C for 18 hours. The reaction mixture was slowly added to ice water to terminate the reaction, and then extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively obtain the title compound as a brown liquid. (1.73 g)
MS m/z: 257 [M+1]+ MS m/z: 257 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 8.54 (d, 1H), 8.19-8.17 (m, 1H), 7.88-7.86 (m, 1H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 8.54 (d, 1H), 8.19-8.17 (m, 1H), 7.88-7.86 (m, 1H).
(단계 2) 4-amino-3-nitrobenzenesulfonamide의 제조(Step 2) Preparation of 4-amino-3-nitrobenzenesulfonamide
상기 (단계 1)에서 제조한 화합물(1.73 g, 6.76 mmol)을 1,4-디옥산(6 mL)에 용해시키고, 28% 암모니아수(25 mL)를 첨가하여 120 ℃에서 30 시간 동안 교반하였다. 증류수 (30 mL)를 가하여 반응을 종결시키고 아세트산에틸 (50 mL)로 3회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 30 : 70 ~ 80 : 20)로 정제하여 황색의 고체로 표제화합물을 얻었다. (0.87g, 59%)The compound (1.73 g, 6.76 mmol) prepared in step 1 above was dissolved in 1,4-dioxane (6 mL), 28% aqueous ammonia (25 mL) was added, and the mixture was stirred at 120°C for 30 hours. The reaction was terminated by adding distilled water (30 mL) and extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 30:70 ~ 80:20) to obtain the title compound as a yellow solid. (0.87g, 59%)
MS m/z: 218 [M+1]+ MS m/z: 218 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.40 (d, 1H), 7.94 (s, 2H), 7.73-7.70 (m, 1H), 7.29 (s, 2H), 7.13-7.11 (m, 1H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.40 (d, 1H), 7.94 (s, 2H), 7.73-7.70 (m, 1H), 7.29 (s, 2H), 7.13-7.11 (m) , 1H).
(단계 3) 3,4-diaminobenzenesulfonamide의 제조(Step 3) Preparation of 3,4-diaminobenzenesulfonamide
상기 (단계 3)에서 제조한 화합물(0.87 g, 4.01 mmol)을 에탄올(20 mL)에 용해시키고, 염화제일주석 이수화물(4.52 g, 20.05 mmol)을 첨가하여 70 ℃에서 18 시간 동안 교반하였다. 반응 종결 후, 탄산나트륨 포화수용액을 가하여 액상을 pH 7이 되도록 하고 아세트산에틸 (50 mL)로 3회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올 : 염화메틸렌 = 10 : 90)로 정제하여 적갈색의 고체로 표제화합물을 얻었다. (0.70g, 93%)The compound prepared in step 3 (0.87 g, 4.01 mmol) was dissolved in ethanol (20 mL), stannous chloride dihydrate (4.52 g, 20.05 mmol) was added, and the mixture was stirred at 70°C for 18 hours. After completion of the reaction, saturated aqueous sodium carbonate solution was added to adjust the liquid phase to pH 7 and extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol : methylene chloride = 10 : 90) to obtain the title compound as a reddish-brown solid. (0.70g, 93%)
MS m/z: 188 [M+1]+ MS m/z: 188 [M+1] +
(단계 4) 1H-benzo[d][1,2,3]triazole-5-sulfonamide의 제조(Step 4) Preparation of 1 H -benzo[ d ][1,2,3]triazole-5-sulfonamide
상기 (단계 3)에서 제조한 화합물(0.70 g, 3.72 mmol)을 아세트산(5.5 mL)에 용해시키고, 0 ℃에서 아질산나트륨(0.28 g, 4.1 mmol)를 증류수(1 mL)에 녹인 용액을 첨가하여 실온에서 4 시간 동안 교반하였다. 반응 종결 후, 감압 하에 농축하고 잔류물을 컬럼 크로마토그래피(메탄올 : 염화메틸렌 = 10 : 90 ~ 20 : 80)로 정제하여 적갈색의 고체로 표제화합물을 얻었다. (0.52 g, 71%)The compound (0.70 g, 3.72 mmol) prepared in step 3 above was dissolved in acetic acid (5.5 mL), and a solution of sodium nitrite (0.28 g, 4.1 mmol) dissolved in distilled water (1 mL) was added at 0°C. It was stirred at room temperature for 4 hours. After completion of the reaction, the residue was concentrated under reduced pressure and the residue was purified by column chromatography (methanol: methylene chloride = 10:90 to 20:80) to obtain the title compound as a reddish-brown solid. (0.52 g, 71%)
MS m/z: 199 [M+1]+ MS m/z: 199 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.38 (s, 1H), 8.09 (d, 1H), 7.89 (d, 1H), 7.51 (s, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.38 (s, 1H), 8.09 (d, 1H), 7.89 (d, 1H), 7.51 (s, 2H).
(단계 5) 1H-benzo[d][1,2,3]triazole-5-sulfonyl chloride의 제조(Step 5) Preparation of 1 H -benzo[ d ][1,2,3]triazole-5-sulfonyl chloride
상기 (단계 4)에서 제조한 화합물(0.050 g, 0.25 mmol)을 클로로설폰산(1 mL)에 용해시키고, 100 ℃에서 2 시간 동안 교반하였다. 반응혼합물을 얼음물에 천천히 가하여 반응을 종결시킨 후 아세트산에틸(50 mL)로 3회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하여 갈색의 액체로 표제화합물을 정량적으로 얻어 별도의 정제 과정 없이 바로 었다. (0.055 g) 별도의 정제 과정 없이 곧바로 다음 반응에 사용하였다.The compound (0.050 g, 0.25 mmol) prepared in step 4 above was dissolved in chlorosulfonic acid (1 mL) and stirred at 100°C for 2 hours. The reaction mixture was slowly added to ice water to terminate the reaction, and then extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound quantitatively as a brown liquid, which was immediately purified without further purification. (0.055 g) was used directly in the next reaction without any additional purification process.
MS m/z: 218 [M+1]+ MS m/z: 218 [M+1] +
(제조예 B-15) 2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxylic acid (중간체 B-15)의 제조 (Preparation Example B-15) Preparation of 2-oxo-2,3-dihydrobenzo[ d ]oxazole-6-carboxylic acid (Intermediate B-15)
4-아미노-3-하이드록시벤조산(2.0 g, 13 mmol)과 탄산칼륨(2.9 g, 20.9 mmol)을 증류수(16 mL)에 용해시키고, 40 ℃에서 메틸클로로포르메이트(1.5 mL, 19.6 mmol)을 첨가한 후 80 ℃에서 18시간 동안 교반하였다. 반응 종결 후, 2N 염화수소 수용액을 가하여 액상을 pH 2가 되도록 하여 생성된 고체를 여과하고 증류수로 세정, 건조하여 갈색의 고체로 표제화합물을 얻었다 (1.55 g, 66%).4-Amino-3-hydroxybenzoic acid (2.0 g, 13 mmol) and potassium carbonate (2.9 g, 20.9 mmol) were dissolved in distilled water (16 mL) and methylchloroformate (1.5 mL, 19.6 mmol) at 40°C. After addition, it was stirred at 80°C for 18 hours. After completion of the reaction, 2N aqueous hydrogen chloride solution was added to adjust the liquid phase to pH 2, and the resulting solid was filtered, washed with distilled water, and dried to obtain the title compound as a brown solid (1.55 g, 66%).
MS m/z: 180 [M+1]+ MS m/z: 180 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 7.80 (d, 1H), 7.74 (s, 1H), 7.17 (d, 1H). 1 H NMR (DMSO-d 6 , 400 MHz), δ ppm: 7.80 (d, 1H), 7.74 (s, 1H), 7.17 (d, 1H).
[제조예 3] 중간체 C의 제조[Preparation Example 3] Preparation of Intermediate C
(제조예 C-1) Methyl 3-(aminomethyl)-5-bromobenzoate의 제조 (Preparation Example C-1) Preparation of Methyl 3-(aminomethyl)-5-bromobenzoate
메틸 3-브로모-5-(브로모메틸)벤조에이트(1.80 g, 5.84 mmol)를 다이메틸설폭사이드(15 mL)에 녹인 후 (디포밀아미노)소듐(0.93 g, 8.77 mmol)을 첨가하고 80 ℃에서 16 시간 동안 교반하였다. 출발 물질이 소진된 것을 TLC로 확인한 후, 6 N 염화수소 수용액(3 mL)과 에탄올(20 mL)을 첨가하고 75 ℃에서 16 시간 동안 교반하였다. 반응 종료 후, 탄산수소나트륨 포화 수용액으로 액성을 pH = 8로 조정한 후, 염화메틸렌/메탄올 (9/1) 혼합 용매 (50 mL)로 3 회 추출했다. 유기층을 증류수와 포화 식염수로 세정하고 무수 황산마그네슘으로 건조시킨 후, 감압 하에 농축했다. 잔류물을 역상 분취용 고성능 액체 크로마토그래피(Preparative HPLC, 컬럼 : Boston Uni C18 40×150×5㎛; 이동상: 0.1% TFA 아세토니트릴 : 증류수 = 5 : 95 ~ 35 : 45)로 정제하고 동결 건조하여 흰색의 고체로 표제화합물을 얻었다. (0.70 g, 38%)Methyl 3-bromo-5-(bromomethyl)benzoate (1.80 g, 5.84 mmol) was dissolved in dimethyl sulfoxide (15 mL), and then (diformylamino)sodium (0.93 g, 8.77 mmol) was added. It was stirred at 80°C for 16 hours. After confirming by TLC that the starting material was consumed, 6 N aqueous hydrogen chloride solution (3 mL) and ethanol (20 mL) were added and stirred at 75°C for 16 hours. After completion of the reaction, the liquid was adjusted to pH = 8 with a saturated aqueous solution of sodium bicarbonate, and then extracted three times with a methylene chloride/methanol (9/1) mixed solvent (50 mL). The organic layer was washed with distilled water and saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by reverse-phase high-performance liquid chromatography (Preparative HPLC, column: Boston Uni C18 40×150×5㎛; mobile phase: 0.1% TFA acetonitrile: distilled water = 5:95 ~ 35:45) and freeze-dried. The title compound was obtained as a white solid. (0.70 g, 38%)
MS m/z: 245 [M+1]+ MS m/z: 245 [M+1] +
1H NMR (DMSO-d6, 400 MHz), δ ppm: 8.29 (br s, 3H), 8.12 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 4.15 (s, 2H), 3.93 - 3.87 (m, 3H). 1 H NMR (DMSO-d 6, 400 MHz), δ ppm: 8.29 (br s, 3H), 8.12 (s, 1H), 8.08 (s, 1H), 8.01 (s, 1H), 4.15 (s, 2H) ), 3.93 - 3.87 (m, 3H).
(제조예 C-2) 1-bromo-3-isopropoxy-5-nitrobenzene (중간체 C-2)의 제조 (Preparation Example C-2) Preparation of 1-bromo-3-isopropoxy-5-nitrobenzene (Intermediate C-2)
(단계 1) 2-amino-3-bromo-5-nitrophenol의 제조(Step 1) Preparation of 2-amino-3-bromo-5-nitrophenol
2-아미노-5-니트로페놀(1.00 g, 6.49 mmol)을 아세토나이트릴(40.6 mL)에 용해시키고, 0 ℃에서 N-브로모숙신이미드(1.19 g, 6.68 mmol)을 첨가하여 실온에서 1 시간 동안 교반하였다. 반응 종결 후, 용매를 감압 하에 농축하여 제거하고 남은 잔류물에 아세트산에틸/n-헥산 (1:1) 혼합용매를 가하여 생성된 고체를 여과하여 갈색의 고체로 표제화합물을 얻었다. (1.31 g, 87%)2-Amino-5-nitrophenol (1.00 g, 6.49 mmol) was dissolved in acetonitrile (40.6 mL), and N-bromosuccinimide (1.19 g, 6.68 mmol) was added at 0 °C to obtain 1 mL at room temperature. Stirred for an hour. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and ethyl acetate/n-hexane (1:1) mixed solvent was added to the remaining residue. The resulting solid was filtered to obtain the title compound as a brown solid. (1.31 g, 87%)
MS m/z: 233 [M+1]+ MS m/z: 233 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 10.69 (s, 1H), 7.86 (s, 1H), 7.49 (s, 1H), 6.17 (brs, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 10.69 (s, 1H), 7.86 (s, 1H), 7.49 (s, 1H), 6.17 (brs, 2H).
(단계 2) 3-bromo-5-nitrophenol의 제조(Step 2) Preparation of 3-bromo-5-nitrophenol
상기 (단계 1)에서 제조한 화합물 (1.31 g, 5.62 mmol)을 에탄올(22 mL)에 용해시키고 진한 황산(0.6 mL)을 첨가한 후, 75 ℃에서 30분 동안 교반하였다. 반응혼합물을 실온으로 식힌 후 아질산나트륨(0.97 g, 14.06 mmol)을 첨가한 후 75 ℃에서 1 시간 더 교반하였다. 반응 종결 후, 용매를 감압 하에 농축한 후 증류수 (50 mL)를 가하고 아세트산에틸(50 mL)로 3 회 추출하였다. 유기층을 모아 무수 황산나트륨으로 건조하고 여과한 여과액을 감압 농축하였다. 잔류물을 실리카겔 컬럼크로마토그래피(아세트산에틸 : n-헥산 = 10 : 90)로 정제하여 갈색의 고체로 표제화합물을 얻었다.(0.62 g, 51%)The compound prepared in step 1 (1.31 g, 5.62 mmol) was dissolved in ethanol (22 mL), concentrated sulfuric acid (0.6 mL) was added, and the mixture was stirred at 75°C for 30 minutes. After the reaction mixture was cooled to room temperature, sodium nitrite (0.97 g, 14.06 mmol) was added and stirred at 75°C for an additional hour. After completion of the reaction, the solvent was concentrated under reduced pressure, distilled water (50 mL) was added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic layer was collected, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 10:90) to obtain the title compound as a brown solid (0.62 g, 51%).
MS m/z: 218 [M+1]+ MS m/z: 218 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 10.94 (brs, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.41 (s, 1H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 10.94 (brs, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.41 (s, 1H).
(단계 3) 1-bromo-3-isopropoxy-5-nitrobenzene의 제조(Step 3) Preparation of 1-bromo-3-isopropoxy-5-nitrobenzene
상기 (단계 2)에서 제조한 화합물(0.30 g, 1.38 mmol)과 탄산칼륨(0.76 g, 5.50 mmol)을 N,N-디메틸포름아미드(3 mL)에 용해시키고, 0 ℃에서 2-브로모프로판(0.52 mL, 5.50 mmol)을 첨가하여 80 ℃에서 20 시간 동안 교반하였다. 반응 종결 후, 증류수 (50 mL)를 가하고 아세트산에틸 (70 mL)로 3 회 추출하였다. 유기층을 포화 식염수로 씻어준 후, 유기층을 모아 무수 황산나트륨으로 건조하고 여과한 여과액을 감압 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 0 : 100 → 10 : 90)로 정제하여 주황색의 액체로 표제화합물을 얻었다.(0.32 g, 90%)The compound prepared in step 2 (0.30 g, 1.38 mmol) and potassium carbonate (0.76 g, 5.50 mmol) were dissolved in N,N-dimethylformamide (3 mL) and dissolved in 2-bromopropane at 0°C. (0.52 mL, 5.50 mmol) was added and stirred at 80°C for 20 hours. After completion of the reaction, distilled water (50 mL) was added and extracted three times with ethyl acetate (70 mL). After washing the organic layer with saturated saline solution, the organic layers were collected, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 100 → 10: 90) to obtain the title compound as an orange liquid (0.32 g, 90%).
MS m/z: 260 [M+1]+ MS m/z: 260 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 7.93 (s, 1H), 7.65 (s, 1H), 7.34 (s, 1H), 4.64-4.59 (m, 1H), 1.39 (s, 6H).1H NMR (CDCl 3 , 400MHz), δ ppm: 7.93 (s, 1H), 7.65 (s, 1H), 7.34 (s, 1H), 4.64-4.59 (m, 1H), 1.39 (s, 6H).
(제조예 C-3) 3-bromo-N,N-dimethyl-5-nitroaniline (중간체 C-3)의 제조 (Preparation Example C-3) Preparation of 3-bromo- N , N -dimethyl-5-nitroaniline (Intermediate C-3)
3-브로모-5-나이트로아닐린(0.50g, 2.30 mmol)과 37% 폼알데하이드 용액(0.56 mL)을 아세토나이트릴(23 mL)에 용해시키고, 0 ℃에서 아세트산(3.5 mL)과 시안화수소화붕소나트륨(0.66 g, 10.55 mmol)을 첨가하여 실온에서 36시간 동안 교반하였다. 증류수 (50mL)를 가하여 반응을 종결시키고 아세트산에틸(50 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 20 : 80)로 정제하여 주황색의 고체로 표제화합물을 얻었다 (548 mg, 97%).3-Bromo-5-nitroaniline (0.50 g, 2.30 mmol) and 37% formaldehyde solution (0.56 mL) were dissolved in acetonitrile (23 mL), and acetic acid (3.5 mL) and boron cyanide were added at 0 °C. Sodium (0.66 g, 10.55 mmol) was added and stirred at room temperature for 36 hours. The reaction was terminated by adding distilled water (50 mL) and extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate : n-hexane = 20 : 80) to obtain the title compound as an orange solid (548 mg, 97%).
MS m/z: 245 [M+1]+ MS m/z: 245 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 7.64 (s, 1H), 7.41 (s, 1H), 7.04 (s, 1H), 3.05 (s, 6H).1H NMR (CDCl 3 , 400MHz), δ ppm: 7.64 (s, 1H), 7.41 (s, 1H), 7.04 (s, 1H), 3.05 (s, 6H).
(제조예 C-4) 4-(3-bromo-5-nitrophenyl)morpholine (중간체 C-4)의 제조 (Preparation Example C-4) Preparation of 4-(3-bromo-5-nitrophenyl)morpholine (Intermediate C-4)
1-브로모-3-플루오로-5-니트로벤젠(0.50 g, 2.27 mmol), 모르폴린(0.20 mL, 2.5 mmol), 탄산세슘(0.74 g, 2.27 mmol)을 N,N-디메틸포름아미드 (6 mL)에 용해시키고 100 ℃에서 3 시간 동안 교반하였다. 반응 종료 후, 증류수(30 mL)를 가하고 아세트산에틸(50 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 20 : 80)로 정제하여 흰색 고체로 표제화합물을 얻었다. (0.25 g, 38%)1-Bromo-3-fluoro-5-nitrobenzene (0.50 g, 2.27 mmol), morpholine (0.20 mL, 2.5 mmol), and cesium carbonate (0.74 g, 2.27 mmol) were mixed with N,N-dimethylformamide ( 6 mL) and stirred at 100°C for 3 hours. After completion of the reaction, distilled water (30 mL) was added and extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 20:80) to obtain the title compound as a white solid. (0.25 g, 38%)
MS m/z: 288 [M+1]+ MS m/z: 288 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 7.77 (s, 1H), 7.61 (s, 1H), 7.26 (s, 1H), 3.87 (m, 4H), 3.25 (m, 4H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 7.77 (s, 1H), 7.61 (s, 1H), 7.26 (s, 1H), 3.87 (m, 4H), 3.25 (m, 4H).
(제조예 C-5) N-(1-(4-bromophenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide (중간체 C-5)의 제조 (Preparation Example C-5) Preparation of N -(1-(4-bromophenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide (Intermediate C-5)
(단계 1) 1-(4-bromophenyl)-2,2-difluoroethan-1-one의 제조(Step 1) Preparation of 1-(4-bromophenyl)-2,2-difluoroethan-1-one
1-브로모-4-아이오도벤젠 (1.5 g, 5.30 mmol)을 무수 테트라하이드로퓨란(10 mL)에 용해시키고, -78 ℃에서 n-부틸리튬 2.5 M 헥산 용액 (2.55 mL, 6.36 mmol)을 가하고 30 분 교반하였다. 에틸 2,2-다이플루오로아세테이트 (0.67 mL, 6.36 mmol)를 가하여 -78 ℃를 유지하며 1 시간 교반한 후, 0 ℃로 온도를 올린 후 1 시간 더 교반하였다. 1N 염산 수용액으로 반응물을 중화시켜 종결시킨 후, 증류수 (20 mL)로 희석한 후, 아세트산에틸 (20 mL)로3 회 추출하였다. 유기층을 모아 무수황산마그네슘으로 건조시킨 후 감압 하에 농축했다. 잔류물을 실리카겔 컬럼 크로마토그래피 (아세트산에틸 : n-헥산 = 0 : 10 ~ 2 : 8)로 정제하여 무색 액상의 표제화합물을 얻었다.(758 mg, 61%)1-Bromo-4-iodobenzene (1.5 g, 5.30 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), and n-butyllithium 2.5 M hexane solution (2.55 mL, 6.36 mmol) was added at -78 °C. Added and stirred for 30 minutes. Ethyl 2,2-difluoroacetate (0.67 mL, 6.36 mmol) was added and stirred for 1 hour while maintaining -78°C, then the temperature was raised to 0°C and stirred for an additional hour. The reaction was terminated by neutralizing it with a 1N aqueous hydrochloric acid solution, diluted with distilled water (20 mL), and extracted three times with ethyl acetate (20 mL). The organic layer was collected, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 0: 10 ~ 2: 8) to obtain the title compound as a colorless liquid (758 mg, 61%).
1H NMR (CDCl3, 400MHz), δ ppm: 7.95 (d, 2H), 7.69 (d, 2H), 6.24 (td, 1H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 7.95 (d, 2H), 7.69 (d, 2H), 6.24 (td, 1H).
(단계 2) (Z)-N-(1-(4-bromophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide의 제조(Step 2) Preparation of ( Z )-N-(1-(4-bromophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide
상기 (단계 1)에서 제조한 화합물(758 mg, 3.23 mmol)을 무수 테트라하이드로퓨란(6.5 mL)에 용해시킨 후, 교반 중에 터트-부틸설핀아미드(586 mg, 4.84 mmol)와 티타늄 테트라에톡사이드(2.0 mL, 9.68 mmol)를 적가하고 60 ℃에서 18 시간 교반하였다. 반응 혼합물을 실온으로 냉각하고 소량의 물을 가해 반응을 종결시킨 후, 불용물을 셀라이트를 통해 제거하고 아세트산에틸과 증류수로 세정한 여과액을 모아 추출하여 유기층을 모아 다시 포화식염수로 세정하고 무수황산마그네슘으로 건조시킨 후, 감압 하에 농축하여 노란색 고체의 표제화합물을 얻었다. (293 mg, 27%)The compound (758 mg, 3.23 mmol) prepared in step 1 above was dissolved in anhydrous tetrahydrofuran (6.5 mL), and then, while stirring, tert-butylsulfinamide (586 mg, 4.84 mmol) and titanium tetraethoxide were added. (2.0 mL, 9.68 mmol) was added dropwise and stirred at 60°C for 18 hours. The reaction mixture was cooled to room temperature and a small amount of water was added to terminate the reaction. Insoluble matter was removed through celite, and the filtrate washed with ethyl acetate and distilled water was collected and extracted, and the organic layer was collected and washed again with saturated saline solution and anhydrous. After drying with magnesium sulfate, the product was concentrated under reduced pressure to obtain the title compound as a yellow solid. (293 mg, 27%)
MS m/z: 339 [M+1]+ MS m/z: 339 [M+1] +
1H NMR (CDCl3, 400 MHz), δ ppm: 7.95 (d, 1H), 7.69 (d, 1H), 7.58 (d, 2H), 6.24 (t, 1H), 1.34 (s, 9H). 1 H NMR (CDCl 3, 400 MHz), δ ppm: 7.95 (d, 1H), 7.69 (d, 1H), 7.58 (d, 2H), 6.24 (t, 1H), 1.34 (s, 9H).
(단계 3) N-(1-(4-bromophenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide의 제조(Step 3) Preparation of N -(1-(4-bromophenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide
상기 (단계 2)에서 제조한 화합물(293 mg, 0.87 mmol)을 테트라하이드로퓨란무수(5.0 mL)에 용해시킨 후, -10 ℃에서 교반 중에 소듐 보로하이드라이드(65.5 mg, 1.73 mmol)를 천천히 가하고 3 시간 교반하였다. 증류수 (10 mL)로 반응물을 희석하고, 아세트산에틸 (20 mL)로 3회 추출하였다. 유기층을 모아 무수황산마그네슘으로 건조시킨 후 감압 하에 농축하여 노란색 액체의 표제화합물을 얻었다. (292 mg, 99%)After dissolving the compound (293 mg, 0.87 mmol) prepared in step 2 above in anhydrous tetrahydrofuran (5.0 mL), sodium borohydride (65.5 mg, 1.73 mmol) was slowly added while stirring at -10°C. It was stirred for 3 hours. The reaction was diluted with distilled water (10 mL) and extracted three times with ethyl acetate (20 mL). The organic layer was collected, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain the title compound as a yellow liquid. (292 mg, 99%)
MS m/z: 341 [M+1]+ MS m/z: 341 [M+1] +
[제조예 4] 중간체 D의 제조[Preparation Example 4] Preparation of Intermediate D
(제조예 D-1) 5-(3-aminophenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-1)의 제조 (Preparation Example D-1) Preparation of 5-(3-aminophenyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate D-1)
3-브로모아닐린(100 mg, 0.58 mmol)을 1,4-디옥산(6 mL)에 녹인 후, 중간체 A-3(0.24 g, 0.70 mmol), 테트라키스(트리페닐포스핀)팔라듐(0)(67 mg, 0.06 mmol), 2N 탄산나트륨 수용액(0.9 mL, 1.74 mmol)을 첨가한 뒤 질소 분위기 하, 80 ℃에서 19 시간 동안 교반하였다. 반응 종결 후, 실온까지 냉각하여, 불용물을 셀라이트를 통해 제거하고 아세트산에틸로 세정한 여과액에 증류수 (30 mL)를 가하고 아세트산에틸(30 mL)로 3회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 40 : 60)로 정제하여 갈색 고체로 표제화합물을 얻었다. (0.16 g, 88%)After dissolving 3-bromoaniline (100 mg, 0.58 mmol) in 1,4-dioxane (6 mL), intermediate A-3 (0.24 g, 0.70 mmol), tetrakis(triphenylphosphine)palladium (0 ) (67 mg, 0.06 mmol) and 2N aqueous sodium carbonate solution (0.9 mL, 1.74 mmol) were added and stirred at 80°C for 19 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature, the insoluble matter was removed through Celite, and distilled water (30 mL) was added to the filtrate washed with ethyl acetate, followed by extraction three times with ethyl acetate (30 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 40:60) to obtain the title compound as a brown solid. (0.16 g, 88%)
MS m/z: 303 [M+1]+ MS m/z: 303 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.52 (s, 2H), 7.57 (d, 1H), 7.23-7.13 (m, 4H), 7.08 (t, 1H), 6.76 (s, 1H), 6.73 (d, 1H), 6.53 (d, 1H), 5.13 (s, 2H), 4.68-4.63 (m, 1H), 3.30-3.24 (m, 2H), 2.95-2.89 (m, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.52 (s, 2H), 7.57 (d, 1H), 7.23-7.13 (m, 4H), 7.08 (t, 1H), 6.76 (s, 1H) , 6.73 (d, 1H), 6.53 (d, 1H), 5.13 (s, 2H), 4.68-4.63 (m, 1H), 3.30-3.24 (m, 2H), 2.95-2.89 (m, 2H).
상기 제조예 D-1과 같은 방법으로 3-브로모아닐린 대신, 하기 표 2에 따른 브롬화 화합물(반응물)을 사용하여 제조예 D-2 내지 제조예 D-11에 따른 화합물을 합성하였다. (중간체 D-2~중간체 D-11)Compounds according to Preparation Examples D-2 to D-11 were synthesized in the same manner as Preparation Example D-1, using brominated compounds (reactants) according to Table 2 instead of 3-bromoaniline. (Intermediate D-2 to Intermediate D-11)
(제조예 D-2) 5-(5-amino-2-methylphenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-2)의 제조 (Preparation Example D-2) Preparation of 5-(5-amino-2-methylphenyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate D-2)
(제조예 D-3) 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-4-methylthiazol-2-amine (중간체 D-3)의 제조 (Preparation Example D-3) 5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-4-methylthiazol-2-amine (Intermediate D-3 )Manufacture of
(제조예 D-4) 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)thiazol-2-amine (중간체 D-4)의 제조 (Preparation Example D-4) Preparation of 5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)thiazol-2-amine (Intermediate D-4)
(제조예 D-5) 5-(3-amino-1-methyl-1H-pyrazol-5-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-5)의 제조 (Preparation Example D-5) 5-(3-amino-1-methyl-1 H -pyrazol-5-yl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2- Preparation of amine (Intermediate D-5)
(제조예 D-6) (S)-5-(4-(1-aminoethyl)phenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-6)의 제조 (Preparation Example D-6) ( S )-5-(4-(1-aminoethyl)phenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D -6) Manufacturing
(제조예 D-7) (R)-5-(4-(1-amino-2,2,2-trifluoroethyl)phenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-7)의 제조 (Preparation Example D-7) ( R )-5-(4-(1-amino-2,2,2-trifluoroethyl)phenyl) -N- (2,3-dihydro- 1H -inden-2-yl) Preparation of pyrimidin-2-amine (Intermediate D-7)
(제조예 D-8) 5-(3-(aminomethyl)phenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-8)의 제조 (Preparation Example D-8) Preparation of 5-(3-(aminomethyl)phenyl)- N -(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (Intermediate D-8)
(제조예 D-9) (R)-5-(3-(1-aminoethyl)phenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-9)의 제조 (Preparation Example D-9) ( R )-5-(3-(1-aminoethyl)phenyl) -N- (2,3-dihydro- 1H -inden-2-yl)pyrimidin-2-amine (Intermediate D -9) Manufacturing of
(제조예 D-10) 5-(3-(aminomethyl)-4-fluorophenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-10)의 제조 (Preparation Example D-10) 5-(3-(aminomethyl)-4-fluorophenyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate D-10) manufacture of
(제조예 D-11) Methyl 3-(aminomethyl)-5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)benzoate (중간체 D-11)의 제조 (Preparation Example D-11) Methyl 3-(aminomethyl)-5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)benzoate (Intermediate D-11 )Manufacture of
(제조예 D-12) 5-(4-(1-amino-2,2-difluoroethyl)phenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride (중간체 D-12)의 제조 (Preparation Example D-12) 5-(4-(1-amino-2,2-difluoroethyl)phenyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine hydrochloride Preparation of (Intermediate D-12)
(단계 1) N-(1-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2-difluoroethyl)-2-methylpropane-2-sulfinamide의 제조(Step 1) N -(1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2-difluoroethyl)- Preparation of 2-methylpropane-2-sulfinamide
제조에 D-1에서 사용한 3-브로모아닐린 대신 중간체 C-7 (0.29 g, 0.86 mmol)을 사용하여 동일한 방법으로 표제화합물을 노란색 고체로 표제화합물을 얻었다 (0.17 g, 42%).The title compound was obtained as a yellow solid in the same manner using intermediate C-7 (0.29 g, 0.86 mmol) instead of 3-bromoaniline used in D-1 (0.17 g, 42%).
MS m/z: 471 [M+1]+ MS m/z: 471 [M+1] +
1H NMR (CDCl3, 400 MHz), δ ppm: 8.51 (d, 2H), 7.51 (t, 2H), 7.48-7.42 (m, 2H), 7.26-7.22 (m, 2H), 7.21-7.15 (m, 2H), 6.17-5.80 (m, 1H), 5.59-5.52 (m, 1H), 4.93-4.79 (m, 1H), 4.74-4.65 (m, 1H), 3.90-3.81(m, 1H), 3.43 (dd, 2H), 2.92 (dd, 2H), 1.26 (s, 9H). 1 H NMR (CDCl 3, 400 MHz), δ ppm: 8.51 (d, 2H), 7.51 (t, 2H), 7.48-7.42 (m, 2H), 7.26-7.22 (m, 2H), 7.21-7.15 ( m, 2H), 6.17-5.80 (m, 1H), 5.59-5.52 (m, 1H), 4.93-4.79 (m, 1H), 4.74-4.65 (m, 1H), 3.90-3.81(m, 1H), 3.43 (dd, 2H), 2.92 (dd, 2H), 1.26 (s, 9H).
(단계 2) 5-(4-(1-amino-2,2-difluoroethyl)phenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride의 제조(Step 2) Preparation of 5-(4-(1-amino-2,2-difluoroethyl)phenyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine hydrochloride
상기 (단계 1)에서 제조한 화합물(0.17 g, 0.37 mmol)을 염화메틸렌(1.5 mL)에 용해시킨 후, 4M 염화수소 디옥산용액(0.5 mL)를 첨가하고 실온에서 1 시간 교반하였다. 반응 종결 후, 용매를 감압 하에 제거하고 잔류물을 디에틸 에테르로 세정한 후, 건조하여 고체상태의 표제화합물을 정량적으로 얻었다 (147 mg).The compound prepared in step 1 (0.17 g, 0.37 mmol) was dissolved in methylene chloride (1.5 mL), then 4M hydrogen chloride dioxane solution (0.5 mL) was added and stirred at room temperature for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was washed with diethyl ether and dried to quantitatively obtain the title compound in solid state (147 mg).
MS m/z: 367 [M+1]+ MS m/z: 367 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 9.14 (s, 3H), 8.74 (s, 2H), 7.79 (d, 2H), 7.64-7.60 (m, 3H), 7.25-7.21 (m, 2H), 7.18-7.15 (m, 2H), 6.52 (td, 1H), 4.97 (s, 1H), 4.73-4.66 (m, 1H), 3.28 (dd, 2H), 2.94 (dd, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 9.14 (s, 3H), 8.74 (s, 2H), 7.79 (d, 2H), 7.64-7.60 (m, 3H), 7.25-7.21 (m) , 2H), 7.18-7.15 (m, 2H), 6.52 (td, 1H), 4.97 (s, 1H), 4.73-4.66 (m, 1H), 3.28 (dd, 2H), 2.94 (dd, 2H).
(제조예 D-13) 5-(3-amino-5-methoxyphenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-13)의 제조 (Preparation Example D-13) Preparation of 5-(3-amino-5-methoxyphenyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate D-13)
(단계 1) N-(2,3-dihydro-1H-inden-2-yl)-5-(3-methoxy-5-nitrophenyl)pyrimidin-2-amine의 제조(Step 1) Preparation of N -(2,3-dihydro- 1H -inden-2-yl)-5-(3-methoxy-5-nitrophenyl)pyrimidin-2-amine
제조에 D-1에서 사용한 3-브로모아닐린 대신 1-브로모-3-메톡시-5-니트로벤젠을 사용하여 동일한 방법으로 표제화합물을 합성하였다.The title compound was synthesized in the same manner using 1-bromo-3-methoxy-5-nitrobenzene instead of 3-bromoaniline used in D-1.
MS m/z: 363 [M+1]+ MS m/z: 363 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 8.53 (s, 2H), 7.94 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 7.24-7.18 (m, 4H), 5.53 (m, 1H), 4.85 (m, 1H), 3.92 (s, 3H), 3.42 (m, 2H), 2.90 (m, 2H). 1H NMR (CDCl 3 , 400MHz), δ ppm: 8.53 (s, 2H), 7.94 (s, 1H), 7.68 (s, 1H), 7.29 (s, 1H), 7.24-7.18 (m, 4H), 5.53 (m, 1H), 4.85 (m, 1H), 3.92 (s, 3H), 3.42 (m, 2H), 2.90 (m, 2H).
(단계 2) 5-(3-amino-5-methoxyphenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine의 제조(Step 2) Preparation of 5-(3-amino-5-methoxyphenyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine
상기 (단계 1)에서 제조한 화합물(0.27 g, 0.75 mmol)을 아세트산에틸/테트라히드로퓨란 혼합용매(1/1, 14 mL)에 녹이고 Pd/C (10 wt%, 30 mg)을 첨가한 후 1 기압의 수소 하, 실온에서 24 시간 동안 교반하였다. 불용물을 셀라이트를 통해 제거하고 메탄올로 세정한 여과액을 감압 하에 농축하여 황색 고체로 표제화합물을 얻었다. (0.22 g, 88%)Dissolve the compound prepared in (step 1) (0.27 g, 0.75 mmol) in ethyl acetate/tetrahydrofuran mixed solvent (1/1, 14 mL) and add Pd/C (10 wt%, 30 mg). It was stirred at room temperature under 1 atm of hydrogen for 24 hours. Insoluble matter was removed through Celite, and the filtrate was washed with methanol and concentrated under reduced pressure to obtain the title compound as a yellow solid. (0.22 g, 88%)
MS m/z: 333 [M+1]+ MS m/z: 333 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.52 (s, 2H), 7.60 (d, 1H), 7.22-7.15 (m, 4H), 6.36 (s, 1H), 6.32 (s, 1H), 6.11 (s, 1H), 5.17 (s, 2H), 4.66-4.64 (m, 1H), 3.71 (s, 3H), 3.29-3.25 (m, 2H), 2.94-2.88 (m, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.52 (s, 2H), 7.60 (d, 1H), 7.22-7.15 (m, 4H), 6.36 (s, 1H), 6.32 (s, 1H) ), 6.11 (s, 1H), 5.17 (s, 2H), 4.66-4.64 (m, 1H), 3.71 (s, 3H), 3.29-3.25 (m, 2H), 2.94-2.88 (m, 2H).
상기 제조예 D-13과 같은 2 단계 합성법으로 1-브로모-3-메톡시-5-니트로벤젠 대신, 하기 표 3에 따른 중간체 C-2 내지 중간체 C-4를 사용하여 제조예 D-14 내지 제조예 D-16에 따른 화합물을 합성하였다. (중간체 D-14~중간체 D-16)Preparation Example D-14 using intermediates C-2 to C-4 according to Table 3 below instead of 1-bromo-3-methoxy-5-nitrobenzene using the same two-step synthesis method as Preparation Example D-13. Compounds according to Preparation Example D-16 were synthesized. (Intermediate D-14~Intermediate D-16)
(제조예 D-14) 5-(3-amino-5-isopropoxyphenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-14)의 제조 (Preparation Example D-14) Preparation of 5-(3-amino-5-isopropoxyphenyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate D-14)
(제조예 D-15) 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-N 1 ,N 1-dimethylbenzene-1,3-diamine (중간체 D-15)의 제조 (Preparation Example D-15) 5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)- N 1 , N 1 -dimethylbenzene-1,3- Preparation of diamine (Intermediate D-15)
(제조예 D-16) 5-(3-amino-5-morpholinophenyl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-16)의 제조 (Preparation Example D-16) Preparation of 5-(3-amino-5-morpholinophenyl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate D-16)
(제조예 D-17) 5-amino-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)pyridin-2(1H)-one (중간체 D-17)의 제조 (Production Example D-17) 5-amino-1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)pyridin-2(1 H )-one Preparation of (Intermediate D-17)
(단계 1) tert-butyl (6-oxo-1,6-dihydropyridin-3-yl)carbamate의 제조(Step 1) Preparation of tert -butyl (6-oxo-1,6-dihydropyridin-3-yl)carbamate
5-아미노-2-하이드록시피리딘(2.0 g, 18.2 mmol)을 터트-부탄올(30 mL)에 용해시키고, 0 ℃에서 디-터트-부틸 디카보네이트(4.2 mL, 18.2 mmol)을 첨가하여 85 ℃에서 16 시간 동안 교반하였다. 반응 종결 후, 증류수(20 mL)를 가하고 아세트산에틸(30 mL)로 2 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물에 디에틸 에테르를 가하여 얻은 고체를 여과하여 녹색의 고체로 표제화합물을 얻었다 (1.75 g, 46%).5-Amino-2-hydroxypyridine (2.0 g, 18.2 mmol) was dissolved in tert-butanol (30 mL) and di-tert-butyl dicarbonate (4.2 mL, 18.2 mmol) was added at 0 °C and incubated at 85 °C. It was stirred for 16 hours. After completion of the reaction, distilled water (20 mL) was added and extracted twice with ethyl acetate (30 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the residue, and the solid obtained was filtered to obtain the title compound as a green solid (1.75 g, 46%).
MS m/z: 211 [M+1]+ MS m/z: 211 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 11.28 (br s, 1H), 9.01 (br s, 1H), 7.52 (br s, 1H), 7.41 (dd, 1H), 6.31 (d, 1H), 1.44 (s, 9H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 11.28 (br s, 1H), 9.01 (br s, 1H), 7.52 (br s, 1H), 7.41 (dd, 1H), 6.31 (d, 1H) ), 1.44 (s, 9H).
(단계 2) 5-amino-1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)pyridin-2(1H)-one의 제조(Step 2) Preparation of 5-amino-1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)pyridin-2(1 H )-one
상기 (단계 1)에서 제조한 화합물(1.16 g, 5.51 mmol)을 디메틸설폭사이드(15 mL)에 용해시키고, 탄산칼륨(0.76 g, 5.51 mmol)과 요오드화제일구리(53 mg, 0.28 mmol), L-프롤린(32 mg, 0.28 mmol), 중간체 A-1(0.80 g, 2.76 mmol)을 첨가하여 100 ℃에서 5일간 교반하였다. 반응 종결 후, 증류수(40 mL)를 가하고 염화메틸렌(50 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올 : 염화메틸렌 = 1 : 99 → 10 : 90)로 정제하여 갈색의 고체로 표제화합물을 얻었다.(0.081 g, 5%) The compound prepared in (step 1) (1.16 g, 5.51 mmol) was dissolved in dimethyl sulfoxide (15 mL), potassium carbonate (0.76 g, 5.51 mmol), cuprous iodide (53 mg, 0.28 mmol), L -Proline (32 mg, 0.28 mmol) and Intermediate A-1 (0.80 g, 2.76 mmol) were added and stirred at 100°C for 5 days. After completion of the reaction, distilled water (40 mL) was added and extracted three times with methylene chloride (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: methylene chloride = 1:99 → 10:90) to obtain the title compound as a brown solid (0.081 g, 5%).
MS m/z: 320 [M+1]+ MS m/z: 320 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.35 (br s, 2H), 7.84 (d, 1H), 7.25 - 7.14 (m, 5H), 6.81 (d, 1H), 6.37 (d, 1H), 4.63 (sxt, 1H), 4.40 (br s, 2H), 3.27 (dd, 2H), 2.93 (dd, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.35 (br s, 2H), 7.84 (d, 1H), 7.25 - 7.14 (m, 5H), 6.81 (d, 1H), 6.37 (d, 1H) ), 4.63 (sxt, 1H), 4.40 (br s, 2H), 3.27 (dd, 2H), 2.93 (dd, 2H).
(제조예 D-18) 5-(3-amino-1H-pyrazol-1-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-18)의 제조 (Preparation Example D-18) 5-(3-amino-1 H -pyrazol-1-yl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine (Intermediate D -18) Manufacturing of
중간체 A-2(2.23 g, 6.62 mmol)과 3-아미노-1H-피라졸(0.50 g, 6.02 mmol), 탄산세슘(2.94 g, 9.03 mmol), 브롬화구리 (0.086 g, 0.60 mmol)을 N-메틸-2-피롤리돈(12 mL)에 용해시킨 후, 반응혼합물을 질소 분위기 하, 120 ℃에서 6 시간 동안 교반하였다. 반응 종결 후, 실온까지 냉각시킨 후 셀라이트를 이용해 불용물을 여과하여 제거하였다. 여과액에 증류수(10 mL)를 가하고 아세트산에틸(20 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산마그네슘으로 건조시킨 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피 (아세트산에틸 : n-헥산 = 2 : 3 → 9 : 1)로 정제하여 베이지색 고체로 표제화합물을 얻었다.(1.27 g, 72 %).Intermediate A-2 (2.23 g, 6.62 mmol), 3-amino-1H-pyrazole (0.50 g, 6.02 mmol), cesium carbonate (2.94 g, 9.03 mmol), and copper bromide (0.086 g, 0.60 mmol) were reacted with N- After dissolving in methyl-2-pyrrolidone (12 mL), the reaction mixture was stirred at 120°C for 6 hours under a nitrogen atmosphere. After completion of the reaction, the mixture was cooled to room temperature and the insoluble matter was removed by filtration using Celite. Distilled water (10 mL) was added to the filtrate and extracted three times with ethyl acetate (20 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate : n-hexane = 2 : 3 → 9 : 1) to obtain the title compound as a beige solid (1.27 g, 72 %).
MS m/z: 293 [M+1]+ MS m/z: 293 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.56 (s, 2H), 7.92 (s, 1H), 7.48-7.47 (d, 1H), 7.17-7.08 (m, 4H), 5.65 (s, 1H), 4.97 (s, 2H), 4.58-4.53 (m, 1H), 3.24-3.18 (dd, 2H), 2.88-2.82 (dd, 2H), 2.39-2.37 (t, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.56 (s, 2H), 7.92 (s, 1H), 7.48-7.47 (d, 1H), 7.17-7.08 (m, 4H), 5.65 (s, 1H), 4.97 (s, 2H), 4.58-4.53 (m, 1H), 3.24-3.18 (dd, 2H), 2.88-2.82 (dd, 2H), 2.39-2.37 (t, 2H).
(제조예 D-19) 5-(3-amino-5-methyl-1H-pyrazol-1-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine (중간체 D-19)의 제조 (Preparation Example D-19) 5-(3-amino-5-methyl-1 H -pyrazol-1-yl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2- Preparation of amine (Intermediate D-19)
제조예 D-18과 같은 방법으로 3-아미노-1H-피라졸 대신 5-메틸-1H-피라졸-3-아민을 사용하여 표제화합물을 얻었다.The title compound was obtained in the same manner as Preparation Example D-18, using 5-methyl-1H-pyrazol-3-amine instead of 3-amino-1H-pyrazole.
MS m/z: 307 [M+1]+ MS m/z: 307 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm:. 8.69 (s, 2H), 7.25-7.20 (m, 4H), 5.65 (br, 2H), 4.72 (m, 1H), 3.42 (dd, 2H), 2.92 (dd, 2H), 2.21(s, 3H)1H NMR (CDCl 3 , 400MHz), δ ppm:. 8.69 (s, 2H), 7.25-7.20 (m, 4H), 5.65 (br, 2H), 4.72 (m, 1H), 3.42 (dd, 2H), 2.92 (dd, 2H), 2.21(s, 3H)
(제조예 D-20) 5-(4-amino-1H-pyrazol-1-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride (중간체 D-20)의 제조 (Preparation Example D-20) 5-(4-amino-1 H -pyrazol-1-yl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine hydrochloride (Intermediate) Manufacturing of D-20)
(단계 1) ethyl 1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazole-4-carboxylate의 제조(Step 1) Preparation of ethyl 1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1 H -pyrazole-4-carboxylate
에틸 1H-피라졸-4-카복실레이트(1.1 g, 7.85 mmol)와 중간체 A-2(2.91 g, 8.63 mmol), 요오드화제일구리(149.5 mg, 0.79 mmol)을, L-프롤린(180.8 mg, 1.57 mmol), 제삼인산칼륨(4.17 g, 19.62 mmol)을 N-메틸-2-피롤리돈 (26 mL)에 용해시키고, 질소를 통과시킨 후, 160 ℃에서 18 시간 동안 교반하였다. 반응 종결 후, 반응혼합물을 실온까지 식힌 후 포화 염화암모늄 수용액 (50 mL)을 가하고 셀라이트를 이용해 불용물을 여과하여 제거하였다. 여과액을 아세트산에틸(50 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 30 : 70 → 메탄올 : 염화메틸렌 = 10 : 90)로 정제하여 흰색의 고체로 표제화합물을 얻었다.(0.15 g, 5%)Ethyl 1H-pyrazole-4-carboxylate (1.1 g, 7.85 mmol), intermediate A-2 (2.91 g, 8.63 mmol), cuprous iodide (149.5 mg, 0.79 mmol), L-proline (180.8 mg, 1.57 mmol) mmol), tripotassium phosphate (4.17 g, 19.62 mmol) was dissolved in N-methyl-2-pyrrolidone (26 mL), nitrogen was passed through it, and the mixture was stirred at 160°C for 18 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution (50 mL) was added, and insoluble matter was removed by filtration using Celite. The filtrate was extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 30:70 → methanol: methylene chloride = 10:90) to obtain the title compound as a white solid (0.15 g, 5%).
MS m/z: 350 [M+1]+ MS m/z: 350 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.92 (s, 1H), 8.78 (s, 2H), 8.12 (s, 1H), 7.92 (s, 1H), 7.22-7.15 (m, 4H), 4.65 (m, 1H), 4.27 (m, 2H), 3.26 (m, 2H), 2.95-2.91 (m, 2H), 1.30 (m, 3H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.92 (s, 1H), 8.78 (s, 2H), 8.12 (s, 1H), 7.92 (s, 1H), 7.22-7.15 (m, 4H) , 4.65 (m, 1H), 4.27 (m, 2H), 3.26 (m, 2H), 2.95-2.91 (m, 2H), 1.30 (m, 3H).
(단계 2) 1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazole-4-carboxylic acid의 제조(Step 2) Preparation of 1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1 H -pyrazole-4-carboxylic acid
상기 (단계 1)에서 제조한 화합물(0.15 g, 0.42 mmol)을 테트라히드로퓨란/메탄올/증류수 혼합용매(3/2/1, 24 mL)에 용해시키고, 수산화리튬 일수화물(0.18 mg, 4.23 mmol)을 첨가하여 실온에서 6 시간 교반하였다. 반응 종결 후, 유기 용매를 감압 농축하였다. 잔류물에 1N 염화수소 수용액을 가하여 pH 2로 조정하여 생성된 고체를 여과하고 증류수로 세정하여 베이지색의 고체로 표제화합물을 얻었다 (0.13 g, 96%).The compound prepared in (step 1) (0.15 g, 0.42 mmol) was dissolved in tetrahydrofuran/methanol/distilled water mixed solvent (3/2/1, 24 mL), and lithium hydroxide monohydrate (0.18 mg, 4.23 mmol) ) was added and stirred at room temperature for 6 hours. After completion of the reaction, the organic solvent was concentrated under reduced pressure. 1N aqueous hydrogen chloride solution was added to the residue to adjust the pH to 2, and the resulting solid was filtered and washed with distilled water to obtain the title compound as a beige solid (0.13 g, 96%).
MS m/z: 322 [M+1]+ MS m/z: 322 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.84 (s, 1H), 8.78 (s, 2H), 8.07 (s, 1H), 7.91 (brs, 1H), 7.25-7.13 (m, 4H), 4.67-4.61 (m, 1H), 3.31-3.25 (m, 2H), 2.95-2.90 (m, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.84 (s, 1H), 8.78 (s, 2H), 8.07 (s, 1H), 7.91 (brs, 1H), 7.25-7.13 (m, 4H) , 4.67-4.61 (m, 1H), 3.31-3.25 (m, 2H), 2.95-2.90 (m, 2H).
(단계 3) tert-butyl (1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-4-yl)carbamate의 제조(Step 3) of tert -butyl (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl) -1H -pyrazol-4-yl)carbamate manufacturing
상기 (단계 2)에서 제조한 화합물(0.17 g, 0.54 mmol)을 터트-부탄올(1.8 mL)/N,N-디메틸포름아미드(1 mL) 혼합용매에 용해시키고, 디페닐포스포릴 아자이드(0.23 mL, 1.09 mmol)와 N,N-디이소프로필에틸아민(0.19 mL, 1.09 mmol)을 첨가하여 90 ℃에서 18 시간 교반하였다. 반응 종결 후, 증류수(30 mL)를 가하고 아세트산에틸(50 mL)로 3 회 추출하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 30 : 70)로 정제하여 베이지색의 고체로 표제화합물을 얻었다.(0.091 g, 43%)The compound (0.17 g, 0.54 mmol) prepared in step 2 above was dissolved in a mixed solvent of tert-butanol (1.8 mL)/N,N-dimethylformamide (1 mL), and diphenylphosphoryl azide (0.23 mL, 1.09 mmol) and N,N-diisopropylethylamine (0.19 mL, 1.09 mmol) were added and stirred at 90°C for 18 hours. After completion of the reaction, distilled water (30 mL) was added and extracted three times with ethyl acetate (50 mL). The residue was purified by silica gel column chromatography (ethyl acetate : n-hexane = 30 : 70) to obtain the title compound as a beige solid (0.091 g, 43%).
MS m/z: 393 [M+1]+ MS m/z: 393 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 8.55 (s, 2H), 8.03 (s, 1H), 7.56 (s, 1H), 7.25-7.16 (m, 4H), 4.80-4.79 (m, 1H), 3.99 (m, 1H), 3.26-3.15 (m, 2H), 2.94-2.89 (m, 2H), 1.52 (s, 9H).1H NMR (CDCl 3 , 400MHz), δ ppm: 8.55 (s, 2H), 8.03 (s, 1H), 7.56 (s, 1H), 7.25-7.16 (m, 4H), 4.80-4.79 (m, 1H) , 3.99 (m, 1H), 3.26-3.15 (m, 2H), 2.94-2.89 (m, 2H), 1.52 (s, 9H).
(단계 4) 5-(4-amino-1H-pyrazol-1-yl)-N-(2,3-dihydro-1H-inden-2-yl)pyrimidin-2-amine hydrochloride의 제조(Step 4) Preparation of 5-(4-amino-1 H -pyrazol-1-yl)- N -(2,3-dihydro-1 H -inden-2-yl)pyrimidin-2-amine hydrochloride
상기 (단계 3)에서 제조한 화합물(0.091 g, 0.23 mmol)을 염화메틸렌(0.8 mL)에 용해시키고, 4M 염화수소 1,4-디옥산 용액(0.8 mL)를 첨가하여 40 에서 18 시간 동안 교반하였다. 반응 종결 후, 감압 하에 농축하여 베이지색의 고체로 표제화합물(0.094 g)을 얻어 별도의 정제과정 없이 곧바로 다음 반응에 사용하였다.The compound (0.091 g, 0.23 mmol) prepared in (step 3) was dissolved in methylene chloride (0.8 mL), and 4M hydrogen chloride 1,4-dioxane solution (0.8 mL) was added to dissolve the compound (0.091 g, 0.23 mmol) in 40 mL. It was stirred for 18 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the title compound (0.094 g) as a beige solid, which was immediately used in the next reaction without further purification.
MS m/z: 293 [M+1]+ MS m/z: 293 [M+1] +
(제조예 D-21) 5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-amine (중간체 D-21)의 제조 (Preparation Example D-21) 5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-amine ( Preparation of intermediate D-21)
중간체 A-6(0.50 g, 2.12 mmol)과 티오세미카바자이드(0.25 g, 2.75 mmol)을 트리플루오로화아세트산(10 mL)에 용해시키고, 80 ℃에서 18 시간 동안 교반하였다. 반응 종결 후, 25% 암모니아수 (20 mL)를 가하고 30 분 동안 교반하였다. 생성된 고체를 여과하고 증류수로 세정하고 실리카겔 컬럼 크로마토그래피(메탄올 : 염화메틸렌 = 5 : 95 → 10 : 90)로 정제하여 베이지색의 고체로 표제화합물을 얻었다.(0.42 g, 64%)Intermediate A-6 (0.50 g, 2.12 mmol) and thiosemicarbazide (0.25 g, 2.75 mmol) were dissolved in trifluoroacetic acid (10 mL) and stirred at 80°C for 18 hours. After completion of the reaction, 25% ammonia water (20 mL) was added and stirred for 30 minutes. The resulting solid was filtered, washed with distilled water, and purified by silica gel column chromatography (methanol: methylene chloride = 5:95 → 10:90) to obtain the title compound as a beige solid (0.42 g, 64%).
MS m/z: 311 [M+1]+ MS m/z: 311 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.66 (s, 2H), 8.03 (s, 1H), 7.32 (s, 2H), 7.22-7.15 (m, 4H), 4.67 (m, 1H), 3.26 (m, 2H), 2.95-2.91 (m, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.66 (s, 2H), 8.03 (s, 1H), 7.32 (s, 2H), 7.22-7.15 (m, 4H), 4.67 (m, 1H) , 3.26 (m, 2H), 2.95-2.91 (m, 2H).
(제조예 D-22) 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)isoxazol-5-amine (중간체 D-22)의 제조 (Preparation Example D-22) Preparation of 3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)isoxazol-5-amine (Intermediate D-22)
중간체 A-5(0.10 g, 0.36 mmol)을 1N 수산화나트륨 수용액 (0.7 mL)에 용해시키고, 염화하이드록실암모늄(27.5 mg, 0.40 mmol)을 첨가하여 100 ℃에서 5 시간 교반하였다. 반응 종결 후, 포화 염화암모늄 수용액(30 mL)을 가하고 아세트산에틸(30 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 여과 하고 디에틸 에테르로 세정하여 베이지색의 고체로 표제화합물을 얻었다 (0.032 g, 30%).Intermediate A-5 (0.10 g, 0.36 mmol) was dissolved in 1N aqueous sodium hydroxide solution (0.7 mL), hydroxylammonium chloride (27.5 mg, 0.40 mmol) was added, and the mixture was stirred at 100°C for 5 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was performed three times with ethyl acetate (30 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was filtered and washed with diethyl ether to obtain the title compound as a beige solid (0.032 g, 30%).
MS m/z: 294 [M+1]+ MS m/z: 294 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 12.71 (brs, 1H), 8.77-8.70 (m, 2H), 8.36 (s, 1H), 7.32-6.78 (m, 5H), 4.70 (m, 1H), 3.29-3.25 (m, 2H), 2.94-2.90 (m, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 12.71 (brs, 1H), 8.77-8.70 (m, 2H), 8.36 (s, 1H), 7.32-6.78 (m, 5H), 4.70 (m) , 1H), 3.29-3.25 (m, 2H), 2.94-2.90 (m, 2H).
(제조예 D-23) 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,2,4-oxadiazol-5-amine (중간체 D-23)의 제조 (Preparation Example D-23) 3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,2,4-oxadiazol-5-amine ( Preparation of intermediate D-23)
(단계 1) 2-((2,3-dihydro-1H-inden-2-yl)amino)-N'-hydroxypyrimidine-5-carboximidamide의 제조(Step 1) Preparation of 2-((2,3-dihydro- 1H -inden-2-yl)amino) -N' -hydroxypyrimidine-5-carboximidamide
중간체 A-6(0.30 g, 1.27 mmol)을 에탄올(10 mL)에 용해시키고, 하이드록실아민 염산염 (0.7 g, 10.2 mmol)과 트리에틸아민 (1.03 g, 10.16 mmol)을 첨가하여 85 ℃에서 16 시간 교반하였다. 반응혼합물을 감압 하에 농축하여 용매를 제거하고 잔류물에 증류수 (10 mL)를 가하고 실온에서 30 분간 교반하여 흰색의 고체로 표제화합물을 얻었다 (0.21 g, 61%).Intermediate A-6 (0.30 g, 1.27 mmol) was dissolved in ethanol (10 mL), hydroxylamine hydrochloride (0.7 g, 10.2 mmol) and triethylamine (1.03 g, 10.16 mmol) were added and incubated at 85°C for 16 minutes. It was stirred for some time. The reaction mixture was concentrated under reduced pressure to remove the solvent. Distilled water (10 mL) was added to the residue and stirred at room temperature for 30 minutes to obtain the title compound as a white solid (0.21 g, 61%).
MS m/z: 270 [M+1]+ MS m/z: 270 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 9.51 (s, 1H), 8.53 (s, 2H), 7.72 (d, 1H), 7.26 - 7.18 (m, 2H), 7.17 - 7.09 (m, 2H), 5.82 (s, 2H), 4.73 - 4.55 (m, 1H), 3.25 (dd, 2H), 2.95 - 2.84 (m, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 9.51 (s, 1H), 8.53 (s, 2H), 7.72 (d, 1H), 7.26 - 7.18 (m, 2H), 7.17 - 7.09 (m) , 2H), 5.82 (s, 2H), 4.73 - 4.55 (m, 1H), 3.25 (dd, 2H), 2.95 - 2.84 (m, 2H).
(단계 2) 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,2,4-oxadiazol-5-amine의 제조(Step 2) Preparation of 3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,2,4-oxadiazol-5-amine
상기 (단계 2)에서 얻은 화합물(0.21 g, 0.78 mmol)을 톨루엔(8 mL)에 용해시켜 트리플루오로아세트산무수물(0.26 g, 0.86 mmol)을 적가한 후, 반응 혼합물을 110 ℃에서 16 시간 교반하였다. 반응혼합물을 감압 하에 농축하여 용매를 제거한 후 잔류물을 메탄올(10 mL)에 용해시키고, 7M 암모니아 메탄올 용액 (2 mL)를 가하고 실온에서 16 시간 교반하였다. 생성된 고체를 여과하고 메탄올로 세정하여 갈색의 고체로 표제화합물을 얻었다 (0.12 g, 50%).The compound (0.21 g, 0.78 mmol) obtained in step 2 above was dissolved in toluene (8 mL), trifluoroacetic anhydride (0.26 g, 0.86 mmol) was added dropwise, and the reaction mixture was stirred at 110°C for 16 hours. did. The reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in methanol (10 mL), 7M ammonia methanol solution (2 mL) was added, and the mixture was stirred at room temperature for 16 hours. The resulting solid was filtered and washed with methanol to obtain the title compound as a brown solid (0.12 g, 50%).
MS m/z: 295 [M+1]+ MS m/z: 295 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.69 (d, 2H), 8.11 (d, 1H), 7.94 (s, 2H), 7.21 (dd, 2H), 7.17 - 7.10 (m, 2H), 4.77 - 4.59 (m, 1H), 3.26 (dd, 2H), 2.91 (dd, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.69 (d, 2H), 8.11 (d, 1H), 7.94 (s, 2H), 7.21 (dd, 2H), 7.17 - 7.10 (m, 2H) ), 4.77 - 4.59 (m, 1H), 3.26 (dd, 2H), 2.91 (dd, 2H).
(제조예 D-24) N-(2,3-dihydro-1H-inden-2-yl)-5-(5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)pyrimidin-2-amine (중간체 D-24)의 제조 (Preparation Example D-24) N -(2,3-dihydro-1 H -inden-2-yl)-5-(5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl )Preparation of pyrimidin-2-amine (Intermediate D-24)
(단계 1) (2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)methanol(Step 1) (2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)methanol
중간체 A-4(2.34 g, 8.26 mmol)을 테트라히드로퓨란(28 mL)에 용해시키고, 영하 78 ℃에서 1M DIBAL-H 톨루엔 용액(27 mL)를 천천히 적하한 후 실온에서 5 시간 동안 교반하였다. 반응 혼합물을 다시 0 ℃로 냉각시킨 후 1N 수산화나트륨 수용액 (40 mL)를 천천히 가하여 반응을 종결시키고, 불용물을 셀라이트를 통해 제거하였다. 여과액을 감압 하에 농축한 후 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올 : 염화메틸렌 = 10 : 90)로 정제하여 흰색의 고체로 표제화합물을 얻었다.(1.85 g, 93%)Intermediate A-4 (2.34 g, 8.26 mmol) was dissolved in tetrahydrofuran (28 mL), and 1M DIBAL-H toluene solution (27 mL) was slowly added dropwise at -78°C and stirred at room temperature for 5 hours. The reaction mixture was cooled again to 0°C, 1N aqueous sodium hydroxide solution (40 mL) was slowly added to terminate the reaction, and insoluble matter was removed through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol: methylene chloride = 10:90) to obtain the title compound as a white solid (1.85 g, 93%).
MS m/z: 242 [M+1]+ MS m/z: 242 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.24 (s, 2H), 7.38 (d, 1H), 7.22-7.12 (m, 4H), 5.02 (t, 1H), 4.62-4.57 (m, 1H), 4.30 (d, 2H), 3.26-3.21 (m, 2H), 2.90-2.84 (m, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.24 (s, 2H), 7.38 (d, 1H), 7.22-7.12 (m, 4H), 5.02 (t, 1H), 4.62-4.57 (m) , 1H), 4.30 (d, 2H), 3.26-3.21 (m, 2H), 2.90-2.84 (m, 2H).
(단계 2) 2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbaldehyde의 제조(Step 2) Preparation of 2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidine-5-carbaldehyde
상기 (단계 1)에서 제조한 화합물(1.85 g, 7.67 mmol)을 염화메틸렌(17 mL)/디메틸설폭사이드(9 mL) 혼합용매에 용해시키고, 데스-마틴 퍼아이오디난(DMP, 5.2 g, 12.3 mmol)을 첨가하여 실온에서 1 시간 동안 교반하였다. 반응 종결 후, 감압 하에 농축하고 난 잔류물에 증류수(20 mL)를 가하고 아세트산에틸(30 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 10 : 90 → 30 : 70)로 정제하여 베이지색의 고체로 표제화합물을 얻었다.(0.76 g, 41%)The compound prepared in step 1 (1.85 g, 7.67 mmol) was dissolved in a mixed solvent of methylene chloride (17 mL) and dimethyl sulfoxide (9 mL), and Dess-Martin periodinane (DMP, 5.2 g, 12.3 mmol) was added and stirred at room temperature for 1 hour. After completion of the reaction, distilled water (20 mL) was added to the residue, which was concentrated under reduced pressure, and extracted three times with ethyl acetate (30 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 10:90 → 30:70) to obtain the title compound as a beige solid (0.76 g, 41%).
MS m/z: 240 [M+1]+ MS m/z: 240 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 9.74 (s, 1H), 8.81-8.80 (s, 1H), 8.73-8.68 (m, 2H), 7.24-7.13 (m, 4H), 4.90-4.72 (m, 1H), 3.29-3.25 (m, 2H), 2.97-2.91 (m, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 9.74 (s, 1H), 8.81-8.80 (s, 1H), 8.73-8.68 (m, 2H), 7.24-7.13 (m, 4H), 4.90- 4.72 (m, 1H), 3.29-3.25 (m, 2H), 2.97-2.91 (m, 2H).
(단계 3) (E)-2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidine-5-carbaldehyde oxime의 제조(Step 3) Preparation of ( E )-2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidine-5-carbaldehyde oxime
상기 (단계 2)에서 제조한 화합물(0.66 g, 2.75 mmol)을 에탄올(16 mL)에 용해시키고, 염화하이드록실암모늄(0.57 g, 8.26 mmol)과 피리딘(0.67 mL, 8.26 mmol)을 첨가하여 실온에서 18 시간 동안 교반하였다. 반응 종결 후 생성된 고체를 여과하고 에탄올로 세정하여 베이지색의 고체로 표제화합물을 얻었다 (0.57 g, 81%).The compound (0.66 g, 2.75 mmol) prepared in step 2 above was dissolved in ethanol (16 mL), hydroxylammonium chloride (0.57 g, 8.26 mmol) and pyridine (0.67 mL, 8.26 mmol) were added, and the mixture was incubated at room temperature. It was stirred for 18 hours. After completion of the reaction, the resulting solid was filtered and washed with ethanol to obtain the title compound as a beige solid (0.57 g, 81%).
MS m/z: 255 [M+1]+ MS m/z: 255 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 11.03 (s, 1H), 8.50 (s, 2H), 7.98 (s, 1H), 7.87 (d, 1H), 7.22-7.13 (m, 4H), 4.66-4.61 (m, 1H), 3.28-3.22 (m, 2H), 2.93-2.87 (m, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 11.03 (s, 1H), 8.50 (s, 2H), 7.98 (s, 1H), 7.87 (d, 1H), 7.22-7.13 (m, 4H) , 4.66-4.61 (m, 1H), 3.28-3.22 (m, 2H), 2.93-2.87 (m, 2H).
(단계 4) tert-butyl 7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carboxylate의 제조(Step 4) tert -butyl 7-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4] Preparation of oct-6-ene-2-carboxylate
상기(단계 3)에서 제조한 화합물(0.57 g, 2.23 mmol)을 N,N-디메틸포름아미드(5 mL)에 용해시키고, 0 ℃에서 N-클로로숙신이미드(0.33 g, 2.46 mmol)을 첨가하여 실온에서 1 시간 동안 교반하였다. 반응 종결 후, 증류수(20 mL)를 가하고 아세트산에틸(30 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하여 얻은 잔류물을 테트라히드로퓨란(8 mL)에 용해시키고, 0 ℃로 냉각하여 터트-부틸 3-메틸렌아지티딘-1-카복실레이트(0.84 mL, 4.86 mmol)와 트리에틸아민(1.4 mL, 9.71 mmol)을 첨가한 후 70 ℃에서 3 시간 동안 교반하였다. 반응 종결 후, 증류수(30 mL)를 가하고 아세트산에틸 (50 mL)로 3 회 추출하였다. 유기층을 모아 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(아세트산에틸 : n-헥산 = 20 : 80 → 60 : 40)로 정제하여 황색의 고체로 표제화합물을 얻었다.(0.36 g, 38%)The compound prepared in step 3 (0.57 g, 2.23 mmol) was dissolved in N,N-dimethylformamide (5 mL), and N-chlorosuccinimide (0.33 g, 2.46 mmol) was added at 0 °C. This was stirred at room temperature for 1 hour. After completion of the reaction, distilled water (20 mL) was added and extracted three times with ethyl acetate (30 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (8 mL), cooled to 0°C, and tert-butyl 3-methyleneazitidine-1-. Carboxylate (0.84 mL, 4.86 mmol) and triethylamine (1.4 mL, 9.71 mmol) were added and stirred at 70°C for 3 hours. After completion of the reaction, distilled water (30 mL) was added and extracted three times with ethyl acetate (50 mL). The organic layer was collected, washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 20:80 → 60:40) to obtain the title compound as a yellow solid (0.36 g, 38%).
MS m/z: 422 [M+1]+ MS m/z: 422 [M+1] +
1H NMR (CDCl3, 400MHz), δ ppm: 8.54 (s, 2H), 7.25-7.17 (m, 4H), 5.66 (d, 1H), 4.87-4.82 (m, 1H), 4.32 (d, 1H), 4.08 (d, 1H), 3.50 (s, 2H), 3.44-3.38 (m, 2H), 2.92-2.87 (m, 2H), 1.46 (s, 9H).1H NMR (CDCl 3 , 400MHz), δ ppm: 8.54 (s, 2H), 7.25-7.17 (m, 4H), 5.66 (d, 1H), 4.87-4.82 (m, 1H), 4.32 (d, 1H) , 4.08 (d, 1H), 3.50 (s, 2H), 3.44-3.38 (m, 2H), 2.92-2.87 (m, 2H), 1.46 (s, 9H).
(단계 5) N-(2,3-dihydro-1H-inden-2-yl)-5-(5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)pyrimidin-2-amine의 제조(Step 5) N -(2,3-dihydro-1 H -inden-2-yl)-5-(5-oxa-2,6-diazaspiro[3.4]oct-6-en-7-yl)pyrimidin- Preparation of 2-amine
상기 (단계 5)에서 제조한 화합물(0.36 g, 0.85 mmol)을 염화메틸렌(3 mL)에 용해시키고, 트리플루오로아세트산(2.8 mL)를 첨가하여 실온에서 2 시간 동안 교반하였다. 반응 종결 후, 감압 하에 농축하여 연한 황색의 고체로 표제화합물을 트리플루오로아세트산 염으로서 얻었다. (0.37 g)The compound (0.36 g, 0.85 mmol) prepared in step 5 above was dissolved in methylene chloride (3 mL), trifluoroacetic acid (2.8 mL) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the title compound as a trifluoroacetic acid salt as a light yellow solid. (0.37 g)
MS m/z: 322 [M+1]+ MS m/z: 322 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.91 (brs, 1H), 8.66 (brs, 1H), 8.56 (s, 2H), 8.13 (d, 1H), 7.23-7.14 (m, 4H), 4.69-4.63 (m, 1H), 4.34-.20 (m, 2H), 3.76 (s, 2H), 3.29-3.23 (m, 2H), 2.94-2.89 (m, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.91 (brs, 1H), 8.66 (brs, 1H), 8.56 (s, 2H), 8.13 (d, 1H), 7.23-7.14 (m, 4H) , 4.69-4.63 (m, 1H), 4.34-.20 (m, 2H), 3.76 (s, 2H), 3.29-3.23 (m, 2H), 2.94-2.89 (m, 2H).
(제조예 D-25) N-(2,3-dihydro-1H-inden-2-yl)-5-(1-oxa-2,7-diazaspiro[4.4]non-2-en-3-yl)pyrimidin-2-amine (중간체 D-25)의 제조 (Preparation Example D-25) N -(2,3-dihydro-1 H -inden-2-yl)-5-(1-oxa-2,7-diazaspiro[4.4]non-2-en-3-yl )Preparation of pyrimidin-2-amine (Intermediate D-25)
제조예 D-24의 (단계 3)에서 얻은 화합물을 사용하여 터트-부틸 3-메틸렌아지티딘-1-카복실레이트 대신 터트-부틸 3-메틸렌피롤리딘-1-카복실레이트를 사용하여 제조예 D-24의 단계 4, 단계 5과 같은 방법을 통해 표제화합물을 트리플루오로아세트산 염으로서 얻었다.Preparation Example D using the compound obtained in (step 3) of Preparation Example D-24, using tert-butyl 3-methylenepyrrolidine-1-carboxylate instead of tert-butyl 3-methyleneazitidine-1-carboxylate The title compound was obtained as a trifluoroacetic acid salt through the same method as steps 4 and 5 of -24.
MS m/z: 336 [M+1]+ MS m/z: 336 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.56 (s, 2H), 8.05 (d, 1H), 7.24 - 7.21 (m, 2H), 7.16- 7.14 (m, 2H), 4.70 - 4.63 (m, 1H), 3.43 (br, 2H), 3.27-3.23 (br, 2H), 3.13 - 2.89 (m, 6H), 2.11 - 1.96 (m, 2H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.56 (s, 2H), 8.05 (d, 1H), 7.24 - 7.21 (m, 2H), 7.16- 7.14 (m, 2H), 4.70 - 4.63 ( m, 1H), 3.43 (br, 2H), 3.27-3.23 (br, 2H), 3.13 - 2.89 (m, 6H), 2.11 - 1.96 (m, 2H).
(제조예 D-26) N-(2,3-dihydro-1H-inden-2-yl)-5-(1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl)pyrimidin-2-amine (중간체 D-26)의 제조 (Preparation Example D-26) N -(2,3-dihydro-1 H -inden-2-yl)-5-(1-oxa-2,8-diazaspiro[4.5]dec-2-en-3-yl )Preparation of pyrimidin-2-amine (Intermediate D-26)
제조예 D-24의 (단계 3)에서 얻은 화합물을 사용하여 터트-부틸 3-메틸렌아지티딘-1-카복실레이트 대신 터트-부틸 4-메틸렌피페리딘-1-카복실레이트를 사용하여 제조예 D-24의 단계 4 및 단계 5과 같은 방법을 통해 표제 화합물을 트리플루오로아세트산 염으로서 얻었다.Preparation Example D using the compound obtained in (Step 3) of Preparation Example D-24, using tert-butyl 4-methylenepiperidine-1-carboxylate instead of tert-butyl 3-methyleneazitidine-1-carboxylate The title compound was obtained as a trifluoroacetic acid salt through the same method as step 4 and step 5 of -24.
MS m/z: 350 [M+1]+ MS m/z: 350 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.53 (s, 2H), 8.26 (s, 1H), 8.03 (d, 1H), 7.22 - 7.18 (m, 2H), 7.14 - 7.09 (m, 2H), 4.70 - 4.57 (m, 1H), 3.58 (br s, 1H), 3.26 (d, 4H), 3.04 - 2.99 (m, 2H), 2.91 - 2.85 (m, 2H), 1.81 - 1.62 (m, 5H).1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.53 (s, 2H), 8.26 (s, 1H), 8.03 (d, 1H), 7.22 - 7.18 (m, 2H), 7.14 - 7.09 (m, 2H), 4.70 - 4.57 (m, 1H), 3.58 (br s, 1H), 3.26 (d, 4H), 3.04 - 2.99 (m, 2H), 2.91 - 2.85 (m, 2H), 1.81 - 1.62 (m , 5H).
실시예Example
실시예 1: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamide(화합물 1)의 제조 Example 1: N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-1,4,6,7-tetrahydro- 5 Preparation of H -[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 1)
중간체 D-1(38.7 mg, 0.13 mmol)을 N,N-디메틸포름아미드(1.3 mL)에 용해시키고, N,N-디이소프로필에틸아민(0.07 mL, 0.52 mmol), 1,1'-카보닐디이미다졸(25.3 mg, 0.16 mmol)을 순차적으로 첨가하고 반응혼합물을 질소 분위기 하, 실온에서 18 시간 동안 교반하였다. 출발물질이 모두 반응한 것을 TLC로 확인하고, 중간체 B-1(41 mg, 0.26 mmol)을 천천히 첨가하고, 반응혼합물을 질소 분위기 하, 실온에서 18 시간 동안 교반하였다. 반응 종결 후, 증류수(10 mL)를 가하고 아세트산에틸(20 mL)로 3 회 추출하였다. 유기층을 모아 염화암모늄 수용액과 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올 : 염화메틸렌 = 5 : 95)로 정제하여 흰색 고체로 표제화합물을 얻었다. (16.7 mg, 28%)Intermediate D-1 (38.7 mg, 0.13 mmol) was dissolved in N,N-dimethylformamide (1.3 mL), N,N-diisopropylethylamine (0.07 mL, 0.52 mmol), 1,1'-carbohydrate Nildiimidazole (25.3 mg, 0.16 mmol) was sequentially added, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. It was confirmed by TLC that all starting materials had reacted, Intermediate B-1 (41 mg, 0.26 mmol) was slowly added, and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. After completion of the reaction, distilled water (10 mL) was added and extracted three times with ethyl acetate (20 mL). The organic layer was collected, washed with aqueous ammonium chloride solution and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol : methylene chloride = 5 : 95) to obtain the title compound as a white solid. (16.7 mg, 28%)
MS m/z: 453 [M+1]+ MS m/z: 453 [M+1] +
1H NMR (DMSO- d6, 400MHz), δ ppm: 8.78 (s, 1H), 8.58 (s, 2H), 7.70-7.64 (m, 2H), 7.48 (d, 1H), 7.32 (m, 1H), 7.23-7.13 (m, 5H), 4.68 (m, 3H), 3.81 (m, 2H), 3.28 (dd, 2H), 2.92 (dd, 2H), 2.81 (m, 2H). 1H NMR (DMSO- d 6 , 400MHz), δ ppm: 8.78 (s, 1H), 8.58 (s, 2H), 7.70-7.64 (m, 2H), 7.48 (d, 1H), 7.32 (m, 1H) ), 7.23-7.13 (m, 5H), 4.68 (m, 3H), 3.81 (m, 2H), 3.28 (dd, 2H), 2.92 (dd, 2H), 2.81 (m, 2H).
상기 실시예 1과 동일한 방법으로 중간체 D-1 대신, 하기 표 4에 따른 중간체를 사용하여 다음의 실시예 2 내지 실시예 9의 화합물을 합성하였다.The compounds of Examples 2 to 9 were synthesized in the same manner as Example 1, using the intermediates according to Table 4 instead of Intermediate D-1.
실시예 2: (S)-N-(1-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamide(화합물 2)의 제조 Example 2 : ( S ) -N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-1 Preparation of 4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 2)
실시예 3: (R)-N-(1-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2,2-trifluoroethyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamide(화합물 3)의 제조 Example 3: ( R ) -N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2 Preparation of ,2-trifluoroethyl)-1,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 3)
실시예 4: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)benzyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamide(화합물 4)의 제조 Example 4: N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)benzyl)-1,4,6,7-tetrahydro- 5 Preparation of H -[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 4)
실시예 5: (R)-N-(1-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamide(화합물 5)의 제조 Example 5: ( R ) -N- (1-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-1 Preparation of 4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 5)
실시예 6: N-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-2-fluorobenzyl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamide(화합물 6)의 제조 Example 6: N -(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-2-fluorobenzyl)-1,4,6,7 Preparation of -tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 6)
실시예 7: Methyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-((4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamido)methyl)benzoate(화합물 7)의 제조 Example 7: Methyl 3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-((4,5,6,7-tetrahydro- 1 Preparation of H -[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamido)methyl)benzoate (Compound 7)
실시예 8: N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-3-yl)-1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamide(화합물 8)의 제조 Example 8: N -(1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1 H -pyrazol-3-yl)-1, Preparation of 4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamide (Compound 8)
실시예 9: (7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-2-yl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone(화합물 9)의 제조 Example 9: (7-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct- Preparation of 6-en-2-yl)(1,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridin-5-yl)methanone (Compound 9)
실시예 10: (3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-7-yl)(1,4,6,7-tetrahydro-5H-[1,2,3]triazolo[4,5-c]pyridin-5-yl)methanone(화합물 10)의 제조 Example 10 : (3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,7-diazaspiro[4.4]non- Preparation of 2-en-7-yl)(1,4,6,7-tetrahydro-5 H -[1,2,3]triazolo[4,5- c ]pyridin-5-yl)methanone (Compound 10)
실시예 11: 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-((4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine-5-carboxamido)methyl)benzoic acid(화합물 11)의 제조 Example 11 : 3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-((4,5,6,7-tetrahydro-1 Preparation of H -[1,2,3]triazolo[4,5- c ]pyridine-5-carboxamido)methyl)benzoic acid (Compound 11)
실시예 7에서 제조한 화합물 화합물(68.8 mg, 0.13 mmol)을 테트라히드로퓨란(1.5 mL)에 녹인 후 1N 수산화리튬 수용액(1.5 mL)를 첨가하여 실온에서 2 시간 교반하였다. 반응 종료 후, 2N 염화수소 수용액을 가하여 액성을 pH 2로 하여 생성된 고체를 여과하고 증류수로 세정한 후, 건조하여 흰색 고체로 표제화합물을 얻었다. (47.2 mg, 70.5%)The compound prepared in Example 7 (68.8 mg, 0.13 mmol) was dissolved in tetrahydrofuran (1.5 mL), then 1N lithium hydroxide aqueous solution (1.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, 2N aqueous hydrogen chloride solution was added to adjust the pH to 2. The resulting solid was filtered, washed with distilled water, and dried to obtain the title compound as a white solid. (47.2 mg, 70.5%)
MS m/z: 511 [M+1]+ MS m/z: 511 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.64 (s, 2H), 7.97 (s, 1H), 7.81 (s, 1H), 7.74 (m, 2H), 7.42 (m, 1H), 7.23-7.14 (m, 4H), 4.67 (m, 1H), 4.57 (s, 2H), 4.35 (d, 2H), 3.69 (m, 2H), 3.27 (dd, 2H), 2.92 (dd, 2H), 2. 72 (m, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.64 (s, 2H), 7.97 (s, 1H), 7.81 (s, 1H), 7.74 (m, 2H), 7.42 (m, 1H), 7.23-7.14 (m, 4H), 4.67 (m, 1H), 4.57 (s, 2H), 4.35 (d, 2H), 3.69 (m, 2H), 3.27 (dd, 2H), 2.92 (dd, 2H) , 2. 72 (m, 2H).
실시예 12: (S)-N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 12)의 제조 Example 12: ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-4,5,6, Preparation of 7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 12)
중간체 D-1(30 mg, 0.1 mmol)을 N,N-디메틸포름아미드(1.0 mL)에 녹인 후 중간체 B-2(25 mg, 0.15 mmol), N,N-디이소프로필에틸아민(0.13 mL, 0.74 mmol)를 순차적으로 첨가하고, 0 ℃로 냉각시켜 벤조트리아졸-1-일 옥시-트리피롤리디노포스포늄 헥사플루오로포스페이트(129 mg, 0.25 mmol)을 천천히 첨가한 후 질소 하, 40 ℃에서 36 시간 동안 교반하였다. 반응 종료 후, 증류수 (10 mL)를 가하고 아세트산에틸(20 mL)로 3 회 추출하였다. 유기층을 증류수와 포화 식염수로 세정하고 무수 황산나트륨으로 건조한 후 감압 하에 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올 : 아세트산에틸 = 5 : 95)로 정제하여 흰색 고체로 표제화합물을 얻었다. (12.3 mg, 27%)Intermediate D-1 (30 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (1.0 mL), then intermediate B-2 (25 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.13 mL). , 0.74 mmol) were sequentially added, cooled to 0°C, benzotriazol-1-yl oxy-tripyrrolidinophosphonium hexafluorophosphate (129 mg, 0.25 mmol) was added slowly, and then incubated under nitrogen for 40 minutes. Stirred at ℃ for 36 hours. After completion of the reaction, distilled water (10 mL) was added and extracted three times with ethyl acetate (20 mL). The organic layer was washed with distilled water and saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol : ethyl acetate = 5 : 95) to obtain the title compound as a white solid. (12.3 mg, 27%)
MS m/z: 452 [M+1]+ MS m/z: 452 [M+1] +
1H NMR (DMSO- d6, 400MHz), δ ppm: 10.13 (m, 1H), 8.60 (d, 1H), 7.88-7.57 (m, 3H), 7.40-7.32 (m, 2H), 7.23-7.15 (m, 4H), 4.68 (m, 1H), 3.27 (m, 2H), 2.93-2.81(m, 7H), 2.18 (m, 1H), 1.87 (m, 1H). 1H NMR (DMSO- d 6 , 400MHz), δ ppm: 10.13 (m, 1H), 8.60 (d, 1H), 7.88-7.57 (m, 3H), 7.40-7.32 (m, 2H), 7.23-7.15 (m, 4H), 4.68 (m, 1H), 3.27 (m, 2H), 2.93-2.81(m, 7H), 2.18 (m, 1H), 1.87 (m, 1H).
상기 실시예 12과 동일한 방법으로 중간체 B-2 및 중간체 D-1 대신, 하기 표 5에 따른 중간체를 사용하여 다음의 실시예 13 내지 실시예 55의 화합물을 합성하였다.The following compounds of Examples 13 to 55 were synthesized in the same manner as Example 12, using intermediates according to Table 5 instead of Intermediate B-2 and Intermediate D-1.
실시예 13: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 13)의 제조 Example 13 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-fluoro-1 H -benzo[ d ][1,2,3]Preparation of triazole-5-carboxamide (Compound 13)
실시예 14: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-methoxy-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 14)의 제조 Example 14 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-methoxy-1 H -benzo[ d ][1,2,3]Preparation of triazole-5-carboxamide (Compound 14)
실시예 15: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-(methylsulfonamido)isonicotinamide(화합물 15)의 제조 Example 15 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-(methylsulfonamido)isonicotinamide (Compound 15) manufacture of
실시예 16: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-(methylsulfonamido)nicotinamide(화합물 16)의 제조 Example 16 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-(methylsulfonamido)nicotinamide (Compound 16) manufacture of
실시예 17: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-(methylsulfonamido)thiazole-4-carboxamide(화합물 17)의 제조 Example 17 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-(methylsulfonamido)thiazole-4-carboxamide Preparation of (Compound 17)
실시예 18: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-((methylsulfonyl)methyl)nicotinamide(화합물 18)의 제조 Example 18 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-((methylsulfonyl)methyl)nicotinamide ( Preparation of compound 18)
실시예 19: (5-((3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)carbamoyl)pyridin-2-yl)methanesulfonic acid(화합물 19)의 제조 Example 19 : (5-((3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)carbamoyl)pyridin-2-yl)methanesulfonic Preparation of acid (compound 19)
실시예 20: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-((methylsulfonyl)methyl)isonicotinamide(화합물 20)의 제조 Example 20 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2-((methylsulfonyl)methyl)isonicotinamide ( Preparation of compound 20)
실시예 21: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-(1H-tetrazol-5-yl)nicotinamide(화합물 21)의 제조 Example 21 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-6-(1 H -tetrazol-5- Preparation of yl)nicotinamide (Compound 21)
실시예 22: (S)-N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 22)의 제조 Example 22 : ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-4,5 Preparation of ,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 22)
실시예 23: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-6-fluoro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 23)의 제조 Example 23 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-6-fluoro-1 H - Preparation of benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 23)
실시예 24: 6-(2,2-difluoroethoxy)-N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 24)의 제조 Example 24 : 6-(2,2-difluoroethoxy)- N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5- Preparation of methoxyphenyl)-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 24)
실시예 25: (S)-N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-isopropoxyphenyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 25)의 제조 Example 25 : ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-isopropoxyphenyl)-4,5 Preparation of 6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 25)
실시예 26: (S)-N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-(dimethylamino)phenyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 26)의 제조 Example 26 : ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-(dimethylamino)phenyl)-4,5, Preparation of 6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 26)
실시예 27: (S)-N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-morpholinophenyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 27)의 제조 Example 27 : ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-morpholinophenyl)-4,5,6,7 Preparation of -tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 27)
실시예 28: (S)-N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-4-methylphenyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 28)의 제조 Example 28 : ( S ) -N- (3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-4-methylphenyl)-4,5 Preparation of ,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 28)
실시예 29: (S)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-6-oxo-1,6-dihydropyridin-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 29)의 제조 Example 29 : ( S ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-6-oxo-1,6- Preparation of dihydropyridin-3-yl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 29)
실시예 30: 6-(2,2-difluoroethoxy)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-6-oxo-1,6-dihydropyridin-3-yl)-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 30)의 제조 Example 30 : 6-(2,2-difluoroethoxy)- N -(1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-6- Preparation of oxo-1,6-dihydropyridin-3-yl)-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 30)
실시예 31: (S)-N-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 31)의 제조 Example 31 : ( S ) -N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol- Preparation of 2-yl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 31)
실시예 32: N-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl)-6-methoxy-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 32)의 제조 Example 32 : N -(5-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1,3,4-thiadiazol-2-yl) Preparation of -6-methoxy-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 32)
실시예 33: (S)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 33)의 제조 Example 33 : ( S ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1H - pyrazol-3-yl )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 33) Preparation
실시예 34: (R)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 34)의 제조 Example 34 : ( R ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1H - pyrazol-3-yl )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 34) Preparation
실시예 35: N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-3-yl)-6-methoxy-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 35)의 제조 Example 35 : N -(1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1 H -pyrazol-3-yl)-6- Preparation of methoxy-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 35)
실시예 36: 6-(2,2-difluoroethoxy)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-3-yl)-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 36)의 제조 Example 36 : 6-(2,2-difluoroethoxy)- N -(1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1 H Preparation of -pyrazol-3-yl)-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 36)
실시예 37: (S)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 37)의 제조 Example 37 : ( S ) -N- (1-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1H - pyrazol-4-yl )-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 37) Preparation
실시예 38: (S)-N-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)thiazol-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 38)의 제조 Example 38 : ( S ) -N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)thiazol-2-yl)-4, Preparation of 5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 38)
실시예 39: (S)-N-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-4-methylthiazol-2-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 39)의 제조 Example 39 : ( S ) -N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-4-methylthiazol-2-yl) Preparation of -4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 39)
실시예 40: (S)-N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-methyl-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 40)의 제조 Example 40: ( S ) -N- (1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-methyl-1H-pyrazol-3 Preparation of -yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide (Compound 40)
실시예 41: (S)-N-(5-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-methyl-1H-pyrazol-3-yl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 41)의 제조 Example 41: ( S ) -N- (5-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1-methyl- 1H- pyrazol Preparation of -3-yl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 41)
실시예 42: (S)-N-((S)-1-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 42)의 제조 Example 42 : ( S ) -N -(( S )-1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl) Preparation of ethyl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 42)
실시예 43: (S)-N-((R)-1-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 43)의 제조 Example 43: ( S ) -N -(( R )-1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl) Preparation of -2,2,2-trifluoroethyl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 43)
실시예 44: (R)-N-(1-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2,2-trifluoroethyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide(화합물 44)의 제조 Example 44: ( R ) -N- (1-(4-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2 Preparation of ,2-trifluoroethyl)-2-oxo-2,3-dihydrobenzo[ d ]oxazole-6-carboxamide (Compound 44)
실시예 45: (5S)-N-(1-(4-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2,2-difluoroethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 45)의 제조 Example 45 : (5 S )- N -(1-(4-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)-2, Preparation of 2-difluoroethyl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 45)
실시예 46: (R)-N-((R)-1-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazole-5-carboxamide(화합물 46)의 제조 Example 46: ( R ) -N -(( R )-1-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl) Preparation of ethyl)-4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazole-5-carboxamide (Compound 46)
실시예 47: (R)-N-(1-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carboxamide(화합물 47)의 제조 Example 47: ( R ) -N- (1-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)phenyl)ethyl)-2 Preparation of -oxo-2,3-dihydrobenzo[ d ]oxazole-6-carboxamide (Compound 47)
실시예 48: (S)-(7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-2-yl)(4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-5-yl)methanone(화합물 48)의 제조 Example 48: ( S )-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[ 3.4] Preparation of oct-6-en-2-yl)(4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazol-5-yl)methanone (Compound 48)
실시예 49: (R)-(7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-en-2-yl)(4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-5-yl)methanone(화합물 49)의 제조 Example 49 : ( R )-(7-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[ 3.4] Preparation of oct-6-en-2-yl)(4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazol-5-yl)methanone (Compound 49)
실시예 50: 6-(7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carbonyl)benzo[d]oxazol-2(3H)-one(화합물 50)의 제조 Example 50 : 6-(7-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4] Preparation of oct-6-ene-2-carbonyl)benzo[ d ]oxazol-2( 3H )-one (Compound 50)
실시예 51: N-(4-(7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carbonyl)pyridin-2-yl)methanesulfonamide(화합물 51)의 제조 Example 51 : N -(4-(7-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro [3.4] Preparation of oct-6-ene-2-carbonyl)pyridin-2-yl)methanesulfonamide (Compound 51)
실시예 52: N-(5-(7-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro[3.4]oct-6-ene-2-carbonyl)pyridin-2-yl)methanesulfonamide(화합물 52)의 제조 Example 52 : N -(5-(7-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-oxa-2,6-diazaspiro [3.4] Preparation of oct-6-ene-2-carbonyl)pyridin-2-yl)methanesulfonamide (Compound 52)
실시예 53: (3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,7-diazaspiro[4.4]non-2-en-7-yl)((S)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-5-yl)methanone(화합물 53)의 제조 Example 53 : (3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,7-diazaspiro[4.4]non-2 Preparation of -en-7-yl)((S)-4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-5-yl)methanone (Compound 53)
실시예 54: (S)-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl)(4,5,6,7-tetrahydro-1H-benzo[d][1,2,3]triazol-5-yl)methanone(화합물 54)의 제조 Example 54 : ( S )-(3-(2-((2,3-dihydro- 1H -inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,8-diazaspiro[ Preparation of 4.5]dec-2-en-8-yl)(4,5,6,7-tetrahydro-1 H -benzo[ d ][1,2,3]triazol-5-yl)methanone (Compound 54)
실시예 55: N-(4-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,8-diazaspiro[4.5]dec-2-ene-8-carbonyl)pyridin-2-yl)methanesulfonamide(화합물 55)의 제조 Example 55 : N -(4-(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1-oxa-2,8-diazaspiro [4.5] Preparation of dec-2-ene-8-carbonyl)pyridin-2-yl)methanesulfonamide (Compound 55)
실시예 56: N-(3-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-1H-benzo[d][1,2,3]triazole-5-sulfonamide(화합물 56)의 제조 Example 56 : N -(3-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-5-methoxyphenyl)-1 H -benzo[ d ] Preparation of [1,2,3]triazole-5-sulfonamide (Compound 56)
중간체 D-13(84 mg, 0.25 mmol)을 N,N-디메틸포름아미드(1 mL)에 용해시키고, 트리에틸아민(0.07 mL, 0.5 mmol)을 첨가하여 실온에서 30 분 교반한 후 0 ℃로 온도를 낮춰 중간체 B-14(55 mg, 0.25 mmol)를 염화메틸렌(1 mL)에 녹인 용액을 적가하고, 실온으로 온도를 올려 18 시간 교반하였다. 반응 종결 후, 염화암모늄 포화수용액(10 mL)을 가하고 아세트산에틸(20 mL)로 3 회 추출하였다. 유기층을 모아 무수 황산나트륨으로 건조하고 여과하여 모은 여액을 감압 농축하였다. 잔류물을 실리카겔 컬럼 크로마토그래피(메탄올 : 아세트산에틸 = 0 : 100 → 10 : 90)로 정제하여 베이지색의 고체로 표제화합물을 얻었다.(5.0 mg, 4%)Intermediate D-13 (84 mg, 0.25 mmol) was dissolved in N,N-dimethylformamide (1 mL), triethylamine (0.07 mL, 0.5 mmol) was added, stirred at room temperature for 30 minutes, and then cooled to 0°C. The temperature was lowered and a solution of Intermediate B-14 (55 mg, 0.25 mmol) dissolved in methylene chloride (1 mL) was added dropwise. The temperature was raised to room temperature and stirred for 18 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (10 mL) was added, and extraction was performed three times with ethyl acetate (20 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and the collected filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol : ethyl acetate = 0 : 100 → 10 : 90) to obtain the title compound as a beige solid (5.0 mg, 4%).
MS m/z: 514 [M+1]+ MS m/z: 514 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.46 (s, 2H), 8.33 (s, 1H), 7.92 (m, 2H), 7.71-7.66 (m, 2H), 7.22-7.15 (m, 4H), 6.88 (s, 1H), 6.79 (s, 1H), 6.65 (s, 1H), 4.66 (m, 1H), 3.70 (s, 3H), 3.32 (m, 2H), 2.94-2.90 (m, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.46 (s, 2H), 8.33 (s, 1H), 7.92 (m, 2H), 7.71-7.66 (m, 2H), 7.22-7.15 (m) , 4H), 6.88 (s, 1H), 6.79 (s, 1H), 6.65 (s, 1H), 4.66 (m, 1H), 3.70 (s, 3H), 3.32 (m, 2H), 2.94-2.90 ( m, 2H).
실시예 57: N-(1-(2-((2,3-dihydro-1H-inden-2-yl)amino)pyrimidin-5-yl)-1H-pyrazol-3-yl)-1H-benzo[d][1,2,3]triazole-5-sulfonamide(화합물 57)의 제조 Example 57 : N -(1-(2-((2,3-dihydro-1 H -inden-2-yl)amino)pyrimidin-5-yl)-1 H -pyrazol-3-yl)-1 H Preparation of -benzo[ d ][1,2,3]triazole-5-sulfonamide (Compound 57)
실시예 56에서 사용한 중간체 D-13 대신 중간체 D-18을 사용하여 동일한 방법을 통해 다음의 표제화합물을 합성하였다.The following title compounds were synthesized through the same method using Intermediate D-18 instead of Intermediate D-13 used in Example 56.
MS m/z: 474 [M+1]+ MS m/z: 474 [M+1] +
1H NMR (DMSO-d6, 400MHz), δ ppm: 8.51 (s, 2H), 8.46 (s, 1H), 8.10 (d, 2H), 7.88 (s, 1H), 7.71 (s, 1H), 7.20 (s, 2H), 7.14 (s, 2H), 6.29 (s, 1H), 4.60 (s, 1H), 3.29-3.24 (m, 2H), 2.89 (d, 2H). 1H NMR (DMSO-d 6 , 400MHz), δ ppm: 8.51 (s, 2H), 8.46 (s, 1H), 8.10 (d, 2H), 7.88 (s, 1H), 7.71 (s, 1H), 7.20 (s, 2H), 7.14 (s, 2H), 6.29 (s, 1H), 4.60 (s, 1H), 3.29-3.24 (m, 2H), 2.89 (d, 2H).
실험예Experiment example
본 발명에 따른 화합물의 오토탁신 저해 활성을 측정하기 위하여 다음과 같은 시험을 수행하였다.The following test was performed to measure the autotaxin inhibitory activity of the compound according to the present invention.
실험예 1: 인간 오토탁신의 저해 활성 측정(In vitro ATX activity assay (FS-3))Experimental Example 1: Measurement of inhibitory activity of human autotaxin (In vitro ATX activity assay (FS-3))
각 피험 화합물 용액(10 μM, 100% 디메틸술폭시드)을 96-well V bottom plate(Costar 3363)에서 4배씩 희석한다. 피험 화합물 용액(100% 디메틸설폭시드) 각각을 3차 증류수로 10배 희석한 후 10 ㎕(10% 디메틸설폭시드)를 black flat bottom 96-well plate(Costar 3915)에 분주한다. 1.6X Assay 용액(224 mM NaCl, 80mM Tris-HCl(pH 8.0), 8mM KCl, 1.6 mM CaCl2, 1.6 mM MgCl2, 1.6 mg/mL fatty acid free BSA) 50 ㎕를 첨가하고 계속해서, 20 nM 인간 ENPP2 용액(완충액 : 140 mM NaCl, 50 mM Tris-HCl(pH 8.0), 5 mM KCl, 1 mM CaCl2, 1 mM MgCl2, 1 mg/mL fatty acid free BSA, 0.01% Brij35) 20 ㎕와 5 μM FS-3 용액(완충액 : 3차 증류수) 20 ㎕를 각각 첨가하여 혼합한다. Envision Xcite Multilabel Reader로 37 ℃에서 60 분간 반응시키면서, 5 분마다 형광 광도 측정(Ex: 485nm, Em: 535nm)을 행했다. 각 검액의 △CFU30min값(30 분에서 측정된 CFU값 - 0 분에서 측정된 CFU 값)을 구하고, 100 - (검액의 △CFU30min / 대조군의 △CFU30min 평균값 ) × 100 의 식으로 저해활성 백분율값(% inhibition)을 구한다. 또한 표 6에 나타내는 IC50값은 저해활성 백분율값을 토대로 GraphPad Prism® 소프트웨어[Windows 용 GraphPad 버전 9.3.1 GraphPad Software, La Jolla California USA, www.graphpad.com]의 4-파라미터 변수방법을 사용하여 억제 곡선을 피팅하여 결정하였다.Each test compound solution (10 μM, 100% dimethyl sulfoxide) is diluted four-fold in a 96-well V bottom plate (Costar 3363). Each test compound solution (100% dimethyl sulfoxide) was diluted 10 times with distilled water, and then 10 ㎕ (10% dimethyl sulfoxide) was dispensed into a black flat bottom 96-well plate (Costar 3915). Add 50 ㎕ of 1.6 20 μl of human ENPP2 solution (buffer: 140mM NaCl, 50mM Tris-HCl (pH 8.0), 5mM KCl, 1mM CaCl2 , 1mMMgCl2 , 1mg/mL fatty acid free BSA, 0.01% Brij35) Add 20 μl of 5 μM FS-3 solution (buffer: triple distilled water) to each and mix. The reaction was carried out at 37°C for 60 minutes using Envision Calculate the △CFU30min value of each test solution (CFU value measured at 30 minutes - CFU value measured at 0 minutes), and calculate the inhibitory activity percentage value ( Calculate % inhibition. Additionally, the IC 50 values shown in Table 6 were calculated using the 4-parameter variable method of GraphPad Prism® software [GraphPad version 9.3.1 GraphPad Software for Windows, La Jolla California USA, www.graphpad.com] based on the percentage inhibitory activity values. Determined by fitting the inhibition curve.
(저해활성의 표시 A: IC50 < 5 nM; B: IC50 = 5 nM~10 nM; C: IC50 > 10 nM)(Indication of inhibitory activity A: IC 50 < 5 nM; B: IC 50 = 5 nM to 10 nM; C: IC 50 > 10 nM)
상기 표 6의 결과로부터, 본 발명의 화합물은 유의한 오토탁신 저해 활성을 갖는 것을 확인하였다.From the results in Table 6, it was confirmed that the compounds of the present invention had significant autotaxin inhibitory activity.
실험예 2: 인간 또는 마우스 혈청에서 오토탁신 저해 활성 에세이 측정 (LC-MS/MS 분석에 의한 LysoPLD 저해 활성 측정)Experimental Example 2: Measurement of autotaxin inhibitory activity assay in human or mouse serum (Measurement of LysoPLD inhibitory activity by LC-MS/MS analysis)
각 피험 화합물 용액(2mM, 100% 디메틸설폭시드) 5 ㎕을 메탄올 495 ㎕로 100배 희석한 다음, 희석된 메탄올 용액(1% 디메틸설폭시드) 3 ㎕를 1.5 mL 튜브에서 인간 또는 마우스 혈청 용액 57 ㎕과 혼합한다. 혼합한 피험 화합물 용액을 12 ㎕씩 100% 혈청 48 ㎕에 차례로 희석하여 5개의 농도로 만들고, 각각의 튜브를 37 ℃ 항온수조에 15 분간 둔다. 계속해서, 10mg/mL 18:1 LPC 용액(50% 에탄올)을 혈청으로 375 ㎍/mL의 농도로 희석한 용액을 각 튜브에 2 ㎕씩 분주하여 50 ㎕가 되게 한다. 각 튜브를 37℃ 항온수조에서 3시간 동안 반응시킨다. 반응을 마친 튜브에 0.5 μM 17:0 LPA 용액 (Chloroform/Methanol/Water=65/35/8) 200 ㎕를 분주하여 혼합한다. 원심분리기에서 14,000 rpm, 4 ℃의 조건으로 10분간 원심분리한다. 50% 메탄올 용액 100 ㎕를 96-well polypropylene plate(Agilent Technology 5042-1385)에 먼저 분주하고, 원심분리를 끝낸 튜브의 상층액 50 ㎕를 조심스럽게 plate에 옮겨 혼합한다. Well cap(Thermo 276011)으로 덮은 후 LC-MS/MS(Agilent 1260)으로 분석을 행했다. 5 ㎕ of each test compound solution (2mM, 100% dimethyl sulfoxide) was diluted 100-fold with 495 ㎕ of methanol, and then 3 ㎕ of the diluted methanol solution (1% dimethyl sulfoxide) was added to the human or mouse serum solution 57 in a 1.5 mL tube. Mix with ㎕. 12 ㎕ of the mixed test compound solution was sequentially diluted in 48 ㎕ of 100% serum to make 5 concentrations, and each tube was placed in a constant temperature water bath at 37°C for 15 minutes. Subsequently, 2 ㎕ of 10 mg/mL 18:1 LPC solution (50% ethanol) diluted with serum to a concentration of 375 ㎍/mL is dispensed into each tube to make 50 ㎕. Each tube is reacted in a constant temperature water bath at 37°C for 3 hours. Dispense 200 μl of 0.5 μM 17:0 LPA solution (Chloroform/Methanol/Water=65/35/8) into the tube where the reaction has been completed and mix. Centrifuge for 10 minutes at 14,000 rpm and 4°C in a centrifuge. First, dispense 100 ㎕ of 50% methanol solution into a 96-well polypropylene plate (Agilent Technology 5042-1385), and then carefully transfer 50 ㎕ of the supernatant from the centrifuged tube to the plate and mix. After covering with a well cap (Thermo 276011), analysis was performed by LC-MS/MS (Agilent 1260).
100 - (3시간 혈청 + 검액 / 3시간 혈청 + 대조군) × 100 의 식으로 백분율값(% inhibition)을 구한 뒤, GraphPad Prism® 소프트웨어[Windows 용 GraphPad 버전 9.3.1 GraphPad Software, La Jolla California USA, www.graphpad.com] 의 4-파라미터 변수방법을 사용하여 억제 곡선을 피팅하여 결정하였다. After calculating the percentage value (% inhibition) using the equation 100 - (3-hour serum + test solution / 3-hour serum + control) × 100, GraphPad Prism® software [GraphPad for Windows version 9.3.1 GraphPad Software, La Jolla California USA, It was determined by fitting the inhibition curve using the 4-parameter variable method of [www.graphpad.com].
하기 표 7에서 마우스 혈청은 (m), 인간 혈청은 (h)로 표기하였다.In Table 7 below, mouse serum is indicated as (m) and human serum is indicated as (h).
(저해활성의 표시 A: IC50 < 10 nM; B: IC50 = 10 nM~100 nM; C: IC50 > 100 nM)(Indication of inhibitory activity A: IC 50 < 10 nM; B: IC 50 = 10 nM to 100 nM; C: IC 50 > 100 nM)
상기 표 7의 결과로부터, 본 발명의 화합물은 마우스 또는 인간 혈청 존재하에서 리소포스파티드산을 감소시키며, 오토탁신에 의한 리소포스파티드산의 생성을 억제할 수 있음을 확인하였다.From the results in Table 7, it was confirmed that the compound of the present invention can reduce lysophosphatidic acid in the presence of mouse or human serum and inhibit the production of lysophosphatidic acid by autotaxin.
실험예 3: 인간 혈청에서 오토탁신 저해 활성 에세이 (LysoPLD (TOOS)) 측정Experimental Example 3: Measurement of autotaxin inhibitory activity assay (LysoPLD (TOOS)) in human serum
각 피험 화합물 용액(0.5mM, 100% 디메틸설폭시드)을 96-well V bottom plate(Costar 3363)에서 4배씩 희석한다. 피험 화합물 용액(100% 디메틸설폭시드) 각각을 1X lysoPLD buffer(100mM Tris-HCl(pH 9.0), 500mM NaCl, 5mM MgCl2, 0.05% TritonX-100)로 10배 희석한 후 10 ㎕ (10% 디메틸설폭시드)를 96-well plate(Thermo ScientificTM, 카탈로그번호 269620)에 분주한다. 1X lysoPLD buffer 5 ㎕를 첨가하고 계속해서 Pooled Human plasma (Innovative research, Inc. 카탈로그번호 IPLANAH50ML-32895)를 10 ㎕ 첨가하여 혼합한 후 37℃ incubator에서 30분간 반응한다. 이어서 2mg/mL 18:1 Lyso PC (Avanti Polar Llipid, Inc., 카탈로그번호 845875P)를 1X lysoPLD buffer에 희석하여 25 ㎕씩 첨가한 후 37℃ incubator에서 24 시간 동안 추가 반응한다. 검출 용액 (4.5mM 4-animoantioyrine, 2.7mM TOOS (N-ethyl-N-[2-hydroxy-3-sulfopropyl]-3-methylaniline), 20U/mL horseradish peroxidase, 3U/mL choline oxidase, 50mM Tris-HCl (pH 8.0), 4.5mM MgCl2)을 50 ㎕씩 첨가하고 상온에서 10분간 반응한다. EPOCH2 microplate spectrophotometer (BioTek)를 이용하여 555nm 파장에서 흡광도를 측정한다. 다음과 같은 수식[100 - [(검액 OD - blank OD) / (대조군 OD - blank OD)] × 100]으로 백분율값(% inhibition)을 구한 뒤, GraphPad Prism ® 소프트웨어[Windows 용 GraphPad 버전 9.3.1 GraphPad Software, La Jolla California USA, www.graphpad.com] 의 4-파라미터 변수방법을 사용하여 IC50값을 산출하였다.Each test compound solution (0.5mM, 100% dimethyl sulfoxide) is diluted four-fold in a 96-well V bottom plate (Costar 3363). Each test compound solution (100% dimethyl sulfoxide) was diluted 10 times with 1X lysoPLD buffer (100mM Tris-HCl (pH 9.0), 500mM NaCl, 5mM MgCl 2 , 0.05% Triton sulfoxide) is dispensed into a 96-well plate (Thermo Scientific TM , catalog number 269620). Add 5 ㎕ of 1X lysoPLD buffer, then add 10 ㎕ of Pooled Human plasma (Innovative research, Inc. catalog number IPLANAH50ML-32895), mix, and react in an incubator at 37°C for 30 minutes. Next, 2mg/mL 18:1 Lyso PC (Avanti Polar Llipid, Inc., catalog number 845875P) was diluted in 1 Detection solution (4.5mM 4-animoantioyrine, 2.7mM TOOS (N-ethyl-N-[2-hydroxy-3-sulfopropyl]-3-methylaniline), 20U/mL horseradish peroxidase, 3U/mL choline oxidase, 50mM Tris-HCl (pH 8.0), add 50 ㎕ of 4.5mM MgCl 2 ) and react at room temperature for 10 minutes. Absorbance is measured at a wavelength of 555 nm using an EPOCH2 microplate spectrophotometer (BioTek). After calculating the percentage inhibition using the following formula [100 - [(sample OD - blank OD) / (control OD - blank OD)] IC 50 values were calculated using the 4-parameter variable method of [GraphPad Software, La Jolla California USA, www.graphpad.com].
(저해활성의 표시 A: IC50 < 10 nM; B: IC50 = 10 nM ~ 50 nM; C: IC50 > 50 nM)(Indications of inhibitory activity A: IC 50 < 10 nM; B: IC 50 = 10 nM ~ 50 nM; C: IC 50 > 50 nM)
상기 표 8의 결과로부터, 본 발명의 화합물은 인간 혈청 존재하에서 리소포스파티드산을 감소시키며, 오토탁신에 의한 리소포스파티드산의 생성을 억제할 수 있음을 확인하였다.From the results in Table 8, it was confirmed that the compound of the present invention can reduce lysophosphatidic acid in the presence of human serum and inhibit the production of lysophosphatidic acid by autotaxin.
실험예 4: CTGF 발현 저해 활성 에세이 측정Experimental Example 4: CTGF expression inhibition activity assay measurement
일차 폐 섬유 아세포주 LL29(CCL-134)를 12 웰 플레이트에 웰 당 200,000 세포의 농도로 밤새 평판 배양하였다. 세포는 15% FBS(fetal bovine serum)와 항생제(100U/㎖ 페니실린, 100 ㎍/㎖ 스트렙토마이신)가 첨가된 Ham's F-12K 배지(Gibco, 카탈로그번호 21127022)을 사용하여 37℃, 5% CO2 조건에서 배양하였다. 이후 무혈청 배지로 교환 후 4시간 동안 혈청 결핍(Serum starvation) 상태를 유지한다. 혈청 결핍된 LL29 세포에 18:1 LPC 용액 25 μM (Avanti, 카탈로그번호 845875)와 인간 ENPP2 효소 1nM로 처리함과 동시에 화합물을 1 μM 처리 후 하루 간 배양한다. 이후 AccuPrep® Universal RNA Extraction Kit (Bioneer, 카탈로그번호 K-3140)으로 RNA를 추출 후 RNA로부터 AccuPower® RT PreMix & Master Mix (Bioneer, 카탈로그번호 K-2044)를 사용하여 cDNA를 합성하였다. qPCR 반응액은 2ng(총 RNA량 기준) Luna® Universal qPCR Master Mix (New england biolabs, 카탈로그번호 M3003S) 및 10 μM 프라이머 각각을 1 ㎕를 첨가하여 총 10 ㎕로 구성하였다. qPCR은 QuantStudio 1 Real-Time PCR (Applied Biosystems)을 사용하여 95℃, 10분간 변성한 후 95℃, 15초, 60℃, 1분간 40회 반응조건으로 시행하였다. CTGF 유전자 카피수의 정량을 위해 18srRNA 내부 표준 유전자(Housekeeping gene)를 사용하여 샘플간의 표적 유전자 카피수를 보정하였다. 화합물이 처리된 각 샘플의 CTGF 유전자 Ct로부터 내부 표준 유전자의 Ct를 차감함으로써 샘플 간의 카피수를 보정하였다. 이후 표적 유전자의 Ct값과 LPC가 처리된 샘플의 Ct값의 차이(델타 Ct)와 각 화합물이 처리된 샘플을 비교함으로서 %저해활성 수치를 산출하고, 그 결과를 하기 표 9에 나타내었다.Primary lung fibroblast cell line LL29 (CCL-134) was plated overnight in 12 well plates at a concentration of 200,000 cells per well. Cells were grown using Ham's F-12K medium (Gibco, catalog number 21127022) supplemented with 15% FBS (fetal bovine serum) and antibiotics (100 U/ml penicillin, 100 μg/ml streptomycin) at 37°C and 5% CO 2. Cultured under conditions. Afterwards, the medium is exchanged for serum-free medium and a state of serum starvation is maintained for 4 hours. Serum-starved LL29 cells were treated with 25 μM of 18:1 LPC solution (Avanti, catalog number 845875) and 1 nM of human ENPP2 enzyme, and incubated for one day after treatment with 1 μM of the compound. Afterwards, RNA was extracted with AccuPrep® Universal RNA Extraction Kit (Bioneer, catalog number K-3140), and cDNA was synthesized from RNA using AccuPower® RT PreMix & Master Mix (Bioneer, catalog number K-2044). The qPCR reaction solution consisted of 2 ng (based on total RNA amount) Luna® Universal qPCR Master Mix (New England Biolabs, catalog number M3003S) and 1 μl each of 10 μM primers, making a total of 10 μl. qPCR was performed using QuantStudio 1 Real-Time PCR (Applied Biosystems) under denaturation at 95°C for 10 minutes, followed by 40 reaction conditions of 95°C, 15 seconds, and 60°C for 1 minute. To quantify the CTGF gene copy number, the target gene copy number between samples was corrected using an 18srRNA internal standard gene (housekeeping gene). The copy number between samples was corrected by subtracting the Ct of the internal standard gene from the Ct of the CTGF gene of each sample treated with the compound. Thereafter, the % inhibitory activity value was calculated by comparing the difference (delta Ct) between the Ct value of the target gene and the Ct value of the LPC-treated sample with the sample treated with each compound, and the results are shown in Table 9 below.
(%저해활성의 표시 A: >70%; B: 30%~70%; C: <30%)(Indication of % inhibitory activity A: >70%; B: 30%~70%; C: <30%)
상기 표 9의 결과로부터, 본 발명의 화합물은 오토탁신에 의한 CTGF 발현을 억제할 수 있음을 확인하였다.From the results in Table 9 above, it was confirmed that the compound of the present invention can inhibit CTGF expression by autotaxin.
이상, 본 발명의 실시예를 설명하였지만, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자는 본 발명이 그 기술적 사상이나 필수적인 특징으로 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 그러므로 이상에서 기술한 실시예는 모든 면에서 예시적인 것이며 한정적이 아닌 것으로 이해해야만 한다.Although the embodiments of the present invention have been described above, those skilled in the art will understand that the present invention can be implemented in other specific forms without changing its technical idea or essential features. . Therefore, the embodiments described above should be understood in all respects as illustrative and not restrictive.
Claims (15)
[화학식 1]
상기 화학식 1에서,
A는 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 11원의 모노- 또는 바이- 헤테로사이클릭 환이고,
L은 단일결합, -C(=O)-, -C(=O)-NR1-, -C(=O)-NR2-(CR3R4)a-, 또는 -S(=O)2-NR5-이고,
B는 치환 또는 비치환된 카보사이클릭 환; 또는 치환 또는 비치환된 헤테로사이클릭 환이고,
R1 내지 R5는 각각 독립적으로 수소, 또는 치환 또는 비치환된 C1-C10의 알킬기이고,
a는 1 내지 5의 정수이다.A compound represented by the following formula (1), a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
[Formula 1]
In Formula 1,
A is a substituted or unsubstituted 5- to 11-membered mono- or bi-heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur,
L is a single bond, -C(=O)-, -C(=O)-NR 1 -, -C(=O)-NR 2 -(CR 3 R 4 ) a -, or -S(=O) 2 -NR 5 -,
B is a substituted or unsubstituted carbocyclic ring; Or a substituted or unsubstituted heterocyclic ring,
R 1 to R 5 are each independently hydrogen or a substituted or unsubstituted C1-C10 alkyl group,
a is an integer from 1 to 5.
상기 A는 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 6원의 헤테로아릴 환; 트리아졸기를 포함하는 치환 또는 비치환된 9원 내지 10원의 바이사이클릭 헤테로사이클릭 환; 또는 옥사졸리디논기를 포함하는 치환 또는 비치환된 9원 내지 10원의 바이사이클릭 헤테로사이클릭 환인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염.In paragraph 1:
Wherein A is a substituted or unsubstituted 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; A substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing a triazole group; or a substituted or unsubstituted 9- to 10-membered bicyclic heterocyclic ring containing an oxazolidinone group, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
상기 A는 치환 또는 비치환된 피리딘기, 치환 또는 비치환된 티아졸기, 치환 또는 비치환된 벤족사졸론기, 치환 또는 비치환된 벤조트리아졸기, 치환 또는 비치환된 테트라하이드로벤조트리아졸기, 치환 또는 비치환된 트리아졸로피리딘기 또는 치환 또는 비치환된 테트라하이드로트리아졸로피리딘기인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염.In paragraph 1:
Wherein A is a substituted or unsubstituted pyridine group, a substituted or unsubstituted thiazole group, a substituted or unsubstituted benzoxazolone group, a substituted or unsubstituted benzotriazole group, a substituted or unsubstituted tetrahydrobenzotriazole group, a substituted or a compound having an unsubstituted triazolopyridine group or a substituted or unsubstituted tetrahydrotriazolopyridine group, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
상기 A는 하기 구조에서 선택되는 것인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염:
상기 Ra는 수소, R6-S(=O)2-NH-, R6-S(=O)2-CH2- 또는 테트라졸일기이고,
Rb는 할로겐, 또는 치환 또는 비치환된 C1-C10의 알콕시기이고,
R6는 히드록시기, 또는 치환 또는 비치환된 C1-C10의 알킬기이고,
d는 0 내지 6의 정수이고,
e는 0 내지 3의 정수이다.In paragraph 1:
Wherein A is a compound selected from the following structures, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
The Ra is hydrogen, R 6 -S(=O) 2 -NH-, R 6 -S(=O) 2 -CH 2 - or a tetrazolyl group,
Rb is halogen or a substituted or unsubstituted C1-C10 alkoxy group,
R 6 is a hydroxy group or a substituted or unsubstituted C1-C10 alkyl group,
d is an integer from 0 to 6,
e is an integer from 0 to 3.
상기 A는 하기 구조에서 선택되는 것인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염:
상기 Rb는 할로겐, 또는 치환 또는 비치환된 C1-C10의 알콕시기이고,
e는 0 내지 1의 정수이다.In paragraph 1:
Wherein A is a compound selected from the following structures, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
Rb is a halogen or a substituted or unsubstituted C1-C10 alkoxy group,
e is an integer from 0 to 1.
상기 L은 하기 구조에서 선택되는 것인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염:
상기 R3 및 R4는 각각 독립적으로 수소 또는 치환 또는 비치환된 C1-C5의 알킬기이다.In paragraph 1:
Wherein L is a compound selected from the following structures, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
R 3 and R 4 are each independently hydrogen or a substituted or unsubstituted C1-C5 alkyl group.
상기 B는 치환 또는 비치환된 C6-C10 카보사이클릭 환; 또는 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 11원의 모노- 또는 바이- 헤테로사이클릭 환인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염.In paragraph 1:
Wherein B is a substituted or unsubstituted C6-C10 carbocyclic ring; or a compound that is a substituted or unsubstituted 5- to 11-membered mono- or bi-heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, stereoisomers thereof, hydrates thereof, and solvates thereof. Or a pharmaceutically acceptable salt thereof.
상기 B는 치환 또는 비치환된 C6-C10의 아릴렌; 질소, 산소 및 황으로부터 독립적으로 선택된 1 내지 4개의 헤테로원자를 갖는 치환 또는 비치환된 5원 내지 6원의 헤테로아릴렌; 또는 이소옥사졸기를 포함하는 치환 또는 비치환된 8원 내지 11원의 스피로 사이클릭 환인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염.In paragraph 1:
B is substituted or unsubstituted C6-C10 arylene; a substituted or unsubstituted 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a substituted or unsubstituted 8- to 11-membered spirocyclic ring containing an isoxazole group, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
상기 B는 치환 또는 비치환된 페닐렌, 치환 또는 비치환된 피리도닐렌, 치환 또는 비치환된 이소옥사졸릴렌, 치환 또는 비치환된 피라졸릴렌, 치환 또는 비치환된 티아졸릴렌 또는 치환 또는 비치환된 티아디아졸릴렌인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염.In paragraph 1:
Wherein B is substituted or unsubstituted phenylene, substituted or unsubstituted pyridonylene, substituted or unsubstituted isoxazolylene, substituted or unsubstituted pyrazolilene, substituted or unsubstituted thiazolilene or substituted or A compound that is an unsubstituted thiadiazolylene, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof.
상기 B는 하기 구조에서 선택되는 것인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염:
상기 Rc 및 Rc1 내지 Rc6은 각각 독립적으로 수소, 할로겐기, 히드록시기, 카복실기, 치환 또는 비치환된 C1-C10의 일킬기, 치환 또는 비치환된 C1-C10의 알콕시기, -NR7R8 또는 -C(=O)OR9이되, 상기 R7 및 R8는 서로 연결되어 포화 단환고리를 형성할 수 있고, 상기 형성된 고리는 질소 또는 산소로부터 선택되는 헤테로원자를 하나 이상 포함할 수 있으며, 히드록시기 및 치환 또는 비치환된 C1-C10의 알킬기로부터 선택되는 하나 이상의 치환체로 더 치환될 수 있고,
R9는 수소, 치환 또는 비치환된 C1-C10의 알킬기 또는 치환 또는 비치환된 C3-C10의 사이클로알킬기이고,
f는 0 내지 4의 정수이고,
g는 0 내지 2의 정수이고,
h는 0 내지 3의 정수이고,
s 및 t는 서로 같거나 상이하고, 각각 독립적으로 0 내지 4의 정수이고, 이때 s 및 t의 합은 2 내지 5이다.In paragraph 1:
wherein B is a compound selected from the following structures, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
Rc and Rc1 to Rc6 are each independently hydrogen, a halogen group, a hydroxy group, a carboxyl group, a substituted or unsubstituted C1-C10 alkyl group, a substituted or unsubstituted C1-C10 alkoxy group, -NR 7 R 8 or -C(=O)OR 9 , wherein R 7 and R 8 may be connected to each other to form a saturated monocyclic ring, and the formed ring may contain one or more heteroatoms selected from nitrogen or oxygen, and a hydroxy group and may be further substituted with one or more substituents selected from substituted or unsubstituted C1-C10 alkyl groups,
R 9 is hydrogen, a substituted or unsubstituted C1-C10 alkyl group, or a substituted or unsubstituted C3-C10 cycloalkyl group,
f is an integer from 0 to 4,
g is an integer from 0 to 2,
h is an integer from 0 to 3,
s and t are the same as or different from each other and are each independently an integer from 0 to 4, where the sum of s and t is 2 to 5.
상기 B는 하기 구조에서 선택되는 것인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염:
상기 Rc는 수소, 할로겐기, 히드록시기, 카복실기, 치환 또는 비치환된 C1-C10의 일킬기, 치환 또는 비치환된 C1-C10의 알콕시기, -NR7R8 또는 -C(=O)OR9이되,
상기 R7 및 R8는 서로 연결되어 포화 단환고리를 형성할 수 있고, 상기 형성된 고리는 질소 또는 산소로부터 선택되는 헤테로원자를 하나 이상 포함할 수 있으며,
R9는 수소 또는 치환 또는 비치환된 C1-C10의 알킬기이고,
f는 0 내지 4의 정수이다.In paragraph 1:
wherein B is a compound selected from the following structures, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
Rc is hydrogen, halogen group, hydroxy group, carboxyl group, substituted or unsubstituted C1-C10 alkyl group, substituted or unsubstituted C1-C10 alkoxy group, -NR 7 R 8 or -C(=O)OR 9
R 7 and R 8 may be linked to each other to form a saturated monocyclic ring, and the formed ring may contain one or more heteroatoms selected from nitrogen or oxygen,
R 9 is hydrogen or a substituted or unsubstituted C1-C10 alkyl group,
f is an integer from 0 to 4.
상기 화합물은 하기 구조의 화합물들로부터 선택되는 것인 화합물, 이의 입체 이성질체, 이의 수화물, 이의 용매화물 또는 이의 약제학적으로 허용 가능한 염:
.In paragraph 1:
The compound is selected from compounds having the following structure, a stereoisomer thereof, a hydrate thereof, a solvate thereof, or a pharmaceutically acceptable salt thereof:
.
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