TW201607925A - Morpholine compound - Google Patents
Morpholine compound Download PDFInfo
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- TW201607925A TW201607925A TW103137333A TW103137333A TW201607925A TW 201607925 A TW201607925 A TW 201607925A TW 103137333 A TW103137333 A TW 103137333A TW 103137333 A TW103137333 A TW 103137333A TW 201607925 A TW201607925 A TW 201607925A
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Abstract
Description
本發明係關於可用於用以預防或治療高血磷症、或與高血磷症相關連的疾病之化合物或其藥理容許鹽。 The present invention relates to a compound or a pharmacologically acceptable salt thereof which can be used for the prevention or treatment of hyperphosphatemia or a disease associated with hyperphosphatemia.
磷在DNA、RNA或骨等中作為重要的構成成分，於生物體內以各種型態存在，在生命維持活動中扮演重要的角色。 Phosphorus is an important constituent in DNA, RNA, bone, etc., and exists in various forms in living organisms, and plays an important role in life-sustaining activities.
磷酸主要來自食物在消化道裡以無機磷的形式吸收，自腎臟以尿液形式排泄(非專利文獻1)。 Phosphoric acid is mainly derived from food in the form of inorganic phosphorus in the digestive tract and excreted in the form of urine from the kidney (Non-Patent Document 1).
血中磷濃度係藉由維他命D或副甲狀腺賀爾蒙(PTH)等之作用，控制於消化道之吸收、腎排泄及從骨之吸收．代謝，而維持一定。 The concentration of phosphorus in the blood is controlled by the absorption of the digestive tract, renal excretion and absorption from the bone by the action of vitamin D or parathyroid hormone (PTH). Metabolism, while maintaining a certain.
就腎衰竭而言，由於磷酸自腎之排泄降低，而在大多數情況下呈現血中磷濃度顯示異常高值之高血磷症。過剩的磷酸與血中鈣結合，於心血管系統中引起異位性鈣化(ectopic calcification)，而成為心肌梗塞等之心血管系統疾病之危險因子(非專利文獻2)。 In the case of renal failure, since the excretion of phosphate from the kidney is lowered, in most cases, the phosphorus concentration in the blood shows an abnormally high value of hyperphosphatemia. Excessive phosphoric acid binds to calcium in the blood, causing ectopic calcification in the cardiovascular system, and is a risk factor for cardiovascular diseases such as myocardial infarction (Non-Patent Document 2).
又，高血磷症會二次性的引起低鈣血症，而作為其補償而使特徵為血中PTH濃度上昇的副甲狀腺機能亢進 症發作，此亦為腎骨失養症(renal osteodystrophy)之主要原因。如上所述，慢性腎衰竭患者中之高血磷症，係使骨折．骨痛等之慢性腎衰竭患者之生命品質(QOL)降低，且亦成為慢性腎衰竭患者之死亡的主要因素。 In addition, hyperphosphatemia causes secondary hypocalcemia, and as a compensation, it causes hyperparathyroidism characterized by an increase in blood PTH concentration. The onset of the disease is also the main cause of renal osteodystrophy. As mentioned above, hyperphosphatemia in patients with chronic renal failure is a fracture. The quality of life (QOL) of patients with chronic renal failure such as bone pain is reduced, and it is also a major cause of death in patients with chronic renal failure.
現在，作為高血磷症治療藥，除了飲食限制，亦將藉由於消化道中吸附磷酸而抑制其之吸收的磷酸吸附藥作為處方。作為口服吸附藥，有使用鈣製劑(沈澱碳酸鈣等)、聚合物製劑(鹽酸司維拉姆(sevelamer hydrochloride))、金屬鹽製劑(氫氧化鋁、碳酸鑭)等各種藥劑，然而各個藥劑亦有被指出問題點。 Now, as a therapeutic drug for hyperphosphatemia, in addition to dietary restrictions, a phosphate adsorbent that inhibits its absorption by adsorbing phosphoric acid in the digestive tract is also prescribed. Examples of the oral adsorbent include various preparations such as a calcium preparation (precipitated calcium carbonate), a polymer preparation (sevelamer hydrochloride), and a metal salt preparation (aluminum hydroxide, cesium carbonate). There are points that are pointed out.
就鈣製劑而言，顯示因高鈣血症而助長血管鈣化(非專利文獻3)；關於聚合物製劑，有因1天服用數g之服藥遵囑性(medication compliance)之問題、便秘．下痢等之消化器官症狀之問題(非專利文獻4)。 In the case of a calcium preparation, it shows that vascular calcification is promoted by hypercalcemia (Non-Patent Document 3); for a polymer preparation, there is a problem of medication compliance due to taking a few g per day, constipation. The problem of digestive organ symptoms such as squatting (Non-Patent Document 4).
另外，金屬鹽製劑已被指出有蓄積於體內的危險性(非專利文獻5)，作為高血磷症治療藥，目前適當的治療藥並不存在。 In addition, the metal salt preparation has been pointed out to have a risk of accumulation in the body (Non-Patent Document 5), and as a therapeutic drug for hyperphosphatemia, an appropriate therapeutic drug does not exist at present.
對於消化道中之無機磷酸吸收，於小腸上皮細胞發現的鈉依存性磷酸運輸蛋白(transporter)係扮演重要的角色(非專利文獻6)，特異性地抑制該磷酸的主動傳輸之化合物，與口服吸附藥相比，可有效率地抑制自消化道之磷吸收，而期待可解決口服吸附藥中成為問題的服藥遵囑性之改善、消化器官症狀、蓄積之問題。 The sodium-dependent phosphate transporter found in intestinal epithelial cells plays an important role in the absorption of inorganic phosphate in the digestive tract (Non-Patent Document 6), specifically inhibiting the active transport of the phosphate, and oral adsorption Compared with the drug, the phosphorus absorption from the digestive tract can be efficiently suppressed, and it is expected to solve the problem of improvement in compliance with the drug, symptoms of the digestive organs, and accumulation in the oral drug.
鑑於如上所述之情事，而殷切期盼新的用以預防或治療高血磷症、或與高血磷症相關連的疾病之藥劑的開發。 In view of the above-mentioned circumstances, the development of new agents for preventing or treating hyperphosphatemia or diseases associated with hyperphosphatemia is eagerly awaited.
作為關於本發明之化合物，有WO02011/136269中所記載之化合物，但所謂的本發明之化合物之必要部分結構不同。 As the compound of the present invention, there is a compound described in WO02011/136269, but the essential part of the compound of the present invention has a different structure.
專利文獻1 WO02011/136269 Patent Document 1 WO02011/136269
非專利文獻1 H. Murer et al. Pflugers Arch - Eur J Physiol (2004) 447:763-767 Non-Patent Document 1 H. Murer et al. Pflugers Arch - Eur J Physiol (2004) 447:763-767
非專利文獻2 F. Verbeke et al. Clinical Journal of the American Society of Nephrology 6, 153 (2011) Non-Patent Document 2 F. Verbeke et al. Clinical Journal of the American Society of Nephrology 6, 153 (2011)
非專利文獻3 T. Kakuta et al. Am J Kidney Dis. 57(3):422 (2011) Non-Patent Document 3 T. Kakuta et al. Am J Kidney Dis. 57(3): 422 (2011)
非專利文獻4 T. Maruyama et al. CLINICAL CALCIUM 19, 2, 100(248), (2009) Non-Patent Document 4 T. Maruyama et al. CLINICAL CALCIUM 19, 2, 100(248), (2009)
非專利文獻5 M. R. Wills, J. Savory J. Lancet 2, 29 (1983) Non-Patent Document 5 M. R. Wills, J. Savory J. Lancet 2, 29 (1983)
非專利文獻6 S. C. Schiavi et al. J Am Soc Nephrol 23: 1691, 2012 Non-Patent Document 6 S. C. Schiavi et al. J Am Soc Nephrol 23: 1691, 2012
提供一種可用於作為用以預防及治療高血磷症之有效成分的化合物或其藥理容許鹽。 A compound or a pharmacologically acceptable salt thereof which can be used as an active ingredient for preventing and treating hyperphosphatemia is provided.
本發明者們有目的性地進行專心研究開發可用於作為用以預防及治療高血磷症之有效成分的化合物之結果，進而完成本發明。即，本發明係如以下說明。 The present inventors have objectively studied and developed a compound which can be used as an active ingredient for preventing and treating hyperphosphatemia, and completed the present invention. That is, the present invention is as follows.
[1] [1]
一種具有通式(I)之化合物或其藥理容許鹽。 A compound of the formula (I) or a pharmacologically acceptable salt thereof.
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
R1：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 1 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
R2：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 2 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
A：單鍵、或-C(=O)-NH- A: single bond, or -C(=O)-NH-
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
F：單鍵、或-C(=O)-NH- F: single bond, or -C(=O)-NH-
G：氫原子、可經取代之芳基、可經取代之芳烷基、或可經取代之雜環基 G: a hydrogen atom, a substituted aryl group, a substituted aralkyl group, or a substituted heterocyclic group
X：CH、或N X: CH, or N
Y：-C(=O)-、或-S(=O)2-] Y:-C(=O)-, or -S(=O) 2 -]
[2] [2]
如[1]所記載的化合物或其藥理容許鹽，其中具有通式(I)之化合物係具有通式(I’)之化合物。 The compound according to the above [1], wherein the compound of the formula (I) has a compound of the formula (I'), or a pharmacologically acceptable salt thereof.
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
R1：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 1 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
R2：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 2 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
X：CH、或N X: CH, or N
Y：-C(=O)-、或-S(=O)2-] Y:-C(=O)-, or -S(=O) 2 -]
[3] [3]
如[2]所記載的化合物或其藥理容許鹽，其中R1為氫原子的情形下，R2為二乙胺基、哌啶基、或吡咯啶基，R2為氫原子的情形下，R1為二乙胺基、哌啶基、或吡咯啶基。 The compound according to the above [2], wherein R 1 is a hydrogen atom, and when R 1 is a hydrogen atom, R 2 is a diethylamino group, a piperidinyl group or a pyrrolidinyl group, and when R 2 is a hydrogen atom, R 1 is a diethylamino group, a piperidinyl group, or a pyrrolidinyl group.
[4] [4]
如[2]或[3]所記載的化合物或其藥理容許鹽，其中E中可經取代之芳環的芳環為苯環、可經取代之雜環的雜環為選自以下之群組中的任一環。 The compound according to the above [2] or the pharmacologically acceptable salt thereof, wherein the aromatic ring of the aromatic ring which may be substituted in E is a benzene ring, and the heterocyclic ring of the hetero ring which may be substituted is selected from the group below. Any of the rings.
雜環群組：吖呾(azetidine)、氧環丁烷、硫環丁烷、吡咯啶、四氫呋喃、四氫噻吩、哌啶、四氫吡喃、四氫噻喃、吡咯、呋喃、噻吩、吡啶、咪唑、吡唑、唑、噻唑、咪唑啉、吡、嗒、嘧啶、啉、噻、吲哚、異吲哚、苯并咪唑、嘌呤、喹啉、異喹啉、喹啉、啉、喋啶、唍烯、異唍烯、二氫吲哚、二氫異吲哚、二氫苯并咪唑、二氫嘌呤、四氫喹啉、四氫異喹啉、四氫異喹啉、四氫喹啉、四氫啉、四氫喋啶、二氫唍烯、二氫異唍烯、1,6-啶、5,6,7,8-四氫-1,6-啶、1,7-啶、5,6,7,8-四氫-1,7-啶、1,7-四氫啶 Heterocyclic group: azetidine, oxycyclobutane, thiocyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran, pyrrole, furan, thiophene, pyridine , imidazole, pyrazole, Oxazole, thiazole, imidazoline, pyridyl ,despair Pyrimidine, Porphyrin , hydrazine, isoindole, benzimidazole, indole, quinoline, isoquinoline, quin Porphyrin, Porphyrin, acridine, Terpene, different Terpene, indoline, dihydroisoindole, dihydrobenzimidazole, indoline, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroisoquinoline, tetrahydroquine Porphyrin, tetrahydrogen Porphyrin, tetrahydroacridine, dihydrogen Terpene, dihydrogen Terpene, 1,6- Pyridine, 5,6,7,8-tetrahydro-1,6- Pyridine, 1,7- Pyridine, 5,6,7,8-tetrahydro-1,7- Pyridine, 1,7-tetrahydrogen Pyridine
[5] [5]
如[4]所記載的化合物或其藥理容許鹽，其中E中可經取代之芳環、或可經取代之雜環中，「可經取代之基」係選自以下之取代基群組中的任一基團。 The compound according to the above [4], wherein the "substitutable group" is selected from the following group of substituents, or a pharmacologically acceptable salt thereof, wherein the substituted aromatic ring or the substituted heterocyclic ring in E Any of the groups.
取代基群組：鹵素原子、C1-C6烷基、C3-C6環烷基、鹵化C1-C6烷基、C1-C6烷氧基羰基、C1-C6烷基羰基 Group of substituents: halogen atom, C1-C6 alkyl group, C3-C6 cycloalkyl group, halogenated C1-C6 alkyl group, C1-C6 alkoxycarbonyl group, C1-C6 alkylcarbonyl group
[6] [6]
如[4]所記載的化合物或其藥理容許鹽，其中E中可經取代之芳環、或可經取代之雜環中，「可經取代之基」係選自以下之取代基群組中的任一基團。 The compound according to the above [4], wherein the "substitutable group" is selected from the following group of substituents, or a pharmacologically acceptable salt thereof, wherein the substituted aromatic ring or the substituted heterocyclic ring in E Any of the groups.
取代基群組：氟原子、氯原子、甲基、乙基、C3-C6環烷基、三氟甲基、三級丁氧基羰基、2,2-二甲基丙基羰基 Group of substituents: fluorine atom, chlorine atom, methyl group, ethyl group, C3-C6 cycloalkyl group, trifluoromethyl group, tert-butoxycarbonyl group, 2,2-dimethylpropylcarbonyl group
[7] [7]
如選自[4]-[6]中之任一項所記載的化合物或其藥理容許鹽，其中E為可經取代之雜環。 The compound of any one of [4] to [6] or a pharmacologically acceptable salt thereof, wherein E is a heterocyclic ring which may be substituted.
[8] [8]
如[1]所記載的化合物或其藥理容許鹽，其中具有通式(I)之化合物為具有通式(I”)之化合物。 The compound of the formula (I) or a pharmacologically acceptable salt thereof, wherein the compound of the formula (I) is a compound of the formula (I").
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
R1：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 1 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
R2：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 2 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
G：可經取代之芳基、或可經取代之雜環基 G: a aryl group which may be substituted or a heterocyclic group which may be substituted
X：CH、或N X: CH, or N
Y：-C(=O)-、或-S(=O)2-] Y:-C(=O)-, or -S(=O) 2 -]
[9] [9]
如[8]所記載的化合物或其藥理容許鹽，其中R1為氫原子的情形下，R2為二乙胺基、哌啶基、或吡咯啶基，R2為氫原子的情形下，R1為二乙胺基、哌啶基、或吡咯啶基。 The compound according to the above [8], wherein R 1 is a hydrogen atom, and when R 1 is a hydrogen atom, R 2 is a diethylamino group, a piperidinyl group or a pyrrolidinyl group, and when R 2 is a hydrogen atom, R 1 is a diethylamino group, a piperidinyl group, or a pyrrolidinyl group.
[10] [10]
如[8]或[9]所記載的化合物或其藥理容許鹽，其中E、或G中可經取代之芳環的芳環為苯環，可經取代之雜環的雜環為選自以下之群組中的任一環。 The compound according to the above [8] or the pharmacologically acceptable salt thereof, wherein the aromatic ring of the optionally substituted aromatic ring in E or G is a benzene ring, and the heterocyclic ring of the substituted heterocyclic ring is selected from the group consisting of Any of the rings in the group.
雜環群組：吖呾、氧環丁烷、硫環丁烷、吡咯啶、四氫呋喃、四氫噻吩、哌啶、四氫吡喃、四氫噻喃、吡咯、呋喃、噻吩、吡啶、咪唑、吡唑、唑、噻唑、咪唑啉、吡、嗒、嘧啶、啉、噻、吲哚、異吲哚、苯并咪唑、嘌呤、喹啉、異喹啉、喹啉、啉、喋啶、唍烯、異唍烯、二氫吲哚、二氫異吲哚、二氫苯并咪唑、二氫嘌呤、四氫喹啉、四氫異喹啉、四氫異喹啉、四氫喹啉、四氫啉、四氫喋啶、二氫唍烯、二氫異唍烯、1,6-啶、5,6,7,8-四氫-1,6-啶、1,7-啶、5,6,7,8-四氫-1,7-啶、1,7-四氫啶 Heterocyclic group: anthracene, oxycyclobutane, thiocyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran, pyrrole, furan, thiophene, pyridine, imidazole, Pyrazole, Oxazole, thiazole, imidazoline, pyridyl ,despair Pyrimidine, Porphyrin , hydrazine, isoindole, benzimidazole, indole, quinoline, isoquinoline, quin Porphyrin, Porphyrin, acridine, Terpene, different Terpene, indoline, dihydroisoindole, dihydrobenzimidazole, indoline, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroisoquinoline, tetrahydroquine Porphyrin, tetrahydrogen Porphyrin, tetrahydroacridine, dihydrogen Terpene, dihydrogen Terpene, 1,6- Pyridine, 5,6,7,8-tetrahydro-1,6- Pyridine, 1,7- Pyridine, 5,6,7,8-tetrahydro-1,7- Pyridine, 1,7-tetrahydrogen Pyridine
[11] [11]
如[10]所記載的化合物或其藥理容許鹽，其中E、或G中可經取代之芳環、或可經取代之雜環中，「可經取代之基」係選自以下之取代基群組中的任一基團。 The compound according to the above [10], wherein the "substitutable group" is selected from the following substituents, or a substituted heterocyclic ring in E or G, wherein the substituted aromatic ring or the substituted heterocyclic ring Any group in the group.
取代基群組：鹵素原子、C1-C6烷基、C3-C6環烷基、C3-C6環烷基氧基、C3-C6環烷基胺基、鹵化C1-C6烷基、C1-C6烷氧基羰基、C1-C6烷基羰基 Group of substituents: halogen atom, C1-C6 alkyl group, C3-C6 cycloalkyl group, C3-C6 cycloalkyloxy group, C3-C6 cycloalkylamino group, halogenated C1-C6 alkyl group, C1-C6 alkane Oxycarbonyl, C1-C6 alkylcarbonyl
[12] [12]
如[10]所記載的化合物或其藥理容許鹽，其中E、或G中可經取代之芳環、或可經取代之雜環中，「可經取代之基」係選自以下之取代基群組中的任一基團。 The compound according to the above [10], wherein the "substitutable group" is selected from the following substituents, or a substituted heterocyclic ring in E or G, wherein the substituted aromatic ring or the substituted heterocyclic ring Any group in the group.
取代基群組：氟原子、氯原子、甲基、乙基、環己基、環己基氧基、環己基胺基、三氟甲基、三級丁氧基羰基、2,2-二甲基丙基羰基 Group of substituents: fluorine atom, chlorine atom, methyl group, ethyl group, cyclohexyl group, cyclohexyloxy group, cyclohexylamino group, trifluoromethyl group, tert-butoxycarbonyl group, 2,2-dimethyl group Alkylcarbonyl
[13] [13]
如[1]所記載的化合物或其藥理容許鹽，其中具有通式(I)之化合物為具有通式(I''')之化合物。 The compound according to the above [1], wherein the compound having the formula (I) is a compound having the formula (I'''), or a pharmacologically acceptable salt thereof.
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
R1：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 1 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
R2：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 2 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
G：可經取代之芳基、可經取代之芳烷基、或可經取代之雜環基 G: a substituted aryl group, a substituted aralkyl group, or a substituted heterocyclic group
X：CH、或N X: CH, or N
Y：-C(=O)-、或-S(=O)2-] Y:-C(=O)-, or -S(=O) 2 -]
[14] [14]
如[13]所記載的化合物或其藥理容許鹽，其中R1為氫原子的情形下，R2為二乙胺基、哌啶基、或吡咯啶基，R2為氫原子的情形下，R1為二乙胺基、哌啶基、或吡咯啶基。 The compound according to the above [13], wherein R 1 is a hydrogen atom, and when R 1 is a hydrogen atom, R 2 is a diethylamino group, a piperidinyl group or a pyrrolidinyl group, and when R 2 is a hydrogen atom, R 1 is a diethylamino group, a piperidinyl group, or a pyrrolidinyl group.
[15] [15]
如[13]或[14]所記載的化合物或其藥理容許鹽，其中E、或G中可經取代之芳環的芳環為苯環，可經取代之雜環的雜環為選自以下之群組中的任一環。 The compound according to the above [13] or the pharmacologically acceptable salt thereof, wherein the aromatic ring of the aromatic ring which may be substituted in E or G is a benzene ring, and the heterocyclic ring of the substituted hetero ring is selected from the group consisting of Any of the rings in the group.
雜環群組：吖呾、氧環丁烷、硫環丁烷、吡咯啶、四氫呋喃、四氫噻吩、哌啶、四氫吡喃、四氫噻喃、吡咯、呋喃、噻吩、吡啶、咪唑、吡唑、唑、噻唑、咪唑啉、吡、嗒、嘧啶、啉、噻、吲哚、異吲哚、苯并咪唑、嘌呤、喹啉、異喹啉、喹啉、啉、喋啶、唍烯、異唍烯、二氫吲哚、二氫異吲哚、二氫苯并咪唑、二氫嘌呤、四氫喹啉、四氫異喹啉、四氫異喹啉、四氫喹啉、四氫啉、四氫喋啶、二氫唍烯、二氫異唍烯、1,6-啶、5,6,7,8-四氫-1,6-啶、1,7-啶、5,6,7,8-四氫-1,7-啶、1,7-四氫啶 Heterocyclic group: anthracene, oxycyclobutane, thiocyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran, pyrrole, furan, thiophene, pyridine, imidazole, Pyrazole, Oxazole, thiazole, imidazoline, pyridyl ,despair Pyrimidine, Porphyrin , hydrazine, isoindole, benzimidazole, indole, quinoline, isoquinoline, quin Porphyrin, Porphyrin, acridine, Terpene, different Terpene, indoline, dihydroisoindole, dihydrobenzimidazole, indoline, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroisoquinoline, tetrahydroquine Porphyrin, tetrahydrogen Porphyrin, tetrahydroacridine, dihydrogen Terpene, dihydrogen Terpene, 1,6- Pyridine, 5,6,7,8-tetrahydro-1,6- Pyridine, 1,7- Pyridine, 5,6,7,8-tetrahydro-1,7- Pyridine, 1,7-tetrahydrogen Pyridine
[16] [16]
如[13]或[14]所記載的化合物或其藥理容許鹽，其中G中可經取代之芳烷基的芳烷基係選自以下之群組中的任一基團。 The compound according to the above [13] or the pharmacologically acceptable salt thereof, wherein the aralkyl group of the aralkyl group which may be substituted in G is selected from any one of the group below.
芳烷基：苄基、苯乙基、四氫萘基(tetralinyl) Aralkyl: benzyl, phenethyl, tetralinyl
[17] [17]
如[15]或[16]所記載的化合物或其藥理容許鹽，其中E、或G中可經取代之芳基(芳環)、可經取代之芳烷基、或可經取代之雜環基(雜環)中，「可經取代之基」係選自以下之取代基群組中的任一基團。 The compound according to [15] or [16] or a pharmacologically acceptable salt thereof, wherein an aryl group (aromatic ring), a substituted aralkyl group, or a substituted heterocyclic ring which may be substituted in E or G In the group (heterocyclic ring), the "substitutable group" is selected from any of the following groups of substituents.
取代基群組：鹵素原子、C1-C6烷基、C3-C6環烷基、C3-C6環烷基氧基、C3-C6環烷基胺基、鹵化C1-C6烷基、C1-C6烷氧基羰基、C1-C6烷基羰基 Group of substituents: halogen atom, C1-C6 alkyl group, C3-C6 cycloalkyl group, C3-C6 cycloalkyloxy group, C3-C6 cycloalkylamino group, halogenated C1-C6 alkyl group, C1-C6 alkane Oxycarbonyl, C1-C6 alkylcarbonyl
[18] [18]
如[15]或[16]所記載的化合物或其藥理容許鹽，其中E、或G中可經取代之芳基(芳環)、可經取代之芳烷基、或可經取代之雜環基(雜環)中，「可經取代之基」係選自以下之取代基群組中的任一基團。 The compound according to [15] or [16] or a pharmacologically acceptable salt thereof, wherein an aryl group (aromatic ring), a substituted aralkyl group, or a substituted heterocyclic ring which may be substituted in E or G In the group (heterocyclic ring), the "substitutable group" is selected from any of the following groups of substituents.
取代基群組：氟原子、氯原子、甲基、乙基、環己基、環己基氧基、環己基胺基、三氟甲基、三級丁氧基羰基、2,2-二甲基丙基羰基 Group of substituents: fluorine atom, chlorine atom, methyl group, ethyl group, cyclohexyl group, cyclohexyloxy group, cyclohexylamino group, trifluoromethyl group, tert-butoxycarbonyl group, 2,2-dimethyl group Alkylcarbonyl
[19] [19]
一種化合物或其藥理容許鹽，其係選自以下所記載之化合物群組中的任一者。 A compound or a pharmacologically acceptable salt thereof, which is selected from any one of the group of compounds described below.
6-{[2-({3-[甲基(2-啉基乙基)胺甲醯基]苯甲醯基}胺基)-5-(1-哌啶基)苯甲醯基]胺基}-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯 6-{[2-({3-[methyl(2-) Polinylethyl)amine-methylmethyl]benzhydryl}amino)-5-(1-piperidinyl)benzylidene]amino}-3,4-dihydro-1H-isoquinoline- 2-carboxylic acid tertiary butyl ester
N3-甲基-N3-(2-啉基乙基)-N1-[4-(1-哌啶基)-6-{[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]胺甲醯基}環己-2,4-二烯-1-基]苯-1,3-二甲醯胺 N3-methyl-N3-(2- Lolinylethyl)-N1-[4-(1-piperidinyl)-6-{[1-(2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]aminecarboxamide Cyclohexyl-2,4-dien-1-yl]benzene-1,3-dimethylguanamine
2-({3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基}胺基)-5-(1-哌啶基)-N-{3-(三氟甲基)-1-[3-(三氟甲基)苯基]吡唑-4-基}苯甲醯胺 2-({3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl}amino)-5-(1-piperidinyl)-N-{3-(trifluoromethyl)-1-[3-(trifluoromethyl) Phenyl]pyrazol-4-yl}benzamide
N-{4-異丙基-1-[3-(三氟甲基)苯基]吡唑-3-基}-2-({3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基}胺基)-5-(1-哌啶基)苯甲醯胺 N-{4-isopropyl-1-[3-(trifluoromethyl)phenyl]pyrazol-3-yl}-2-({3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl}amino)-5-(1-piperidinyl)benzamide
N5-甲基-N5-(2-啉基乙基)-N3-(4-(1-哌啶基)-2-{[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]胺甲醯基}苯基)吡啶-3,5-二甲醯胺 N5-methyl-N5-(2- Phytylethyl)-N3-(4-(1-piperidinyl)-2-{[1-(2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]aminecarboxamide Phenyl)pyridine-3,5-dimethylguanamine
5-[甲基(2-啉基乙基)胺磺醯基]-N-(4-(1-哌啶基)-2-{[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]胺甲醯基}苯基)吡啶-3-甲醯胺 5-[methyl (2- Lolinylethyl)amine sulfonyl]-N-(4-(1-piperidinyl)-2-{[1-(2-pyridyl)-3-(trifluoromethyl)pyrazole-4- Aminomethyl}phenyl)pyridine-3-carboxamide
N’-[4-(二乙胺基)-2-(4-{[3-(三氟甲基)苄基]胺甲醯基}嘧啶-2-基)苯基]-N-甲基-N-[2-(啉-4-基)乙基]異酞醯胺 N'-[4-(Diethylamino)-2-(4-{[3-(trifluoromethyl)benzyl]aminemethanoyl}pyrimidin-2-yl)phenyl]-N-methyl -N-[2-( Phenyl-4-yl)ethyl]isodecylamine
N’-[4-(二乙胺基)-2-{4-[(1S)-1,2,3,4-四氫萘-1-基胺甲醯基]嘧啶-2-基}苯基]-N-甲基-N-[2-(啉-4-基)乙基]異酞醯胺 N'-[4-(Diethylamino)-2-{4-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylaminemethylindenyl]pyrimidin-2-yl}benzene Base]-N-methyl-N-[2-( Phenyl-4-yl)ethyl]isodecylamine
N3-[4-(二乙胺基)-2-(5-{[3-(三氟甲基)苯基]甲基胺甲醯基}唑-2-基)苯基]-N1-甲基-N1-(2-啉基乙基)苯-1,3-二甲醯胺 N3-[4-(diethylamino)-2-(5-{[3-(trifluoromethyl)phenyl]methylaminemethanyl} Zin-2-yl)phenyl]-N1-methyl-N1-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N’-[4-(二乙胺基)-2-(4-{[3-(三氟甲基)苄基]胺甲醯基}-1,3-噻唑并-2-基)苯基]-N-甲基-N-[2-(四氫-2H-吡喃-4-基)乙基]苯-1,3-二甲醯胺 N'-[4-(Diethylamino)-2-(4-{[3-(trifluoromethyl)benzyl]amine-carbamoyl}-1,3-thiazolo-2-yl)phenyl ]-N-methyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]benzene-1,3-dimethylguanamine
1-[2-[[4-[2-(環己基氧基)嘧啶-5-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 1-[2-[[4-[2-(cyclohexyloxy)pyrimidin-5-yl]phenyl]aminecarboxylidene]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N1-[2-[[4-[6-(環己基氧基)-3-吡啶基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[6-(cyclohexyloxy)-3-pyridyl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N1-[2-[[4-[5-(環己基氧基)-2-吡啶基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[5-(cyclohexyloxy)-2-pyridyl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N1-[2-[[5-[2-(環己基氧基)嘧啶-5-基]-2-吡啶]胺甲醯基]-4-(1-哌啶)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[5-[2-(cyclohexyloxy)pyrimidin-5-yl]-2-pyridyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-A base-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N1-[2-[[4-[5-(環己基氧基)吡-2-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[5-(cyclohexyloxy)pyridyl) -2-yl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N1-[2-[[4-[6-(環己基氧基)嗒-3-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[6-(cyclohexyloxy)fluorene) -3-yl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N1-[2-[[4-[2-(環己基胺基)嘧啶-5-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[2-(cyclohexylamino)pyrimidin-5-yl]phenyl]aminecarboxylidene]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N1-[2-[[6-[2-(環己基氧基)嘧啶-5-基]-3-吡啶基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[6-[2-(cyclohexyloxy)pyrimidin-5-yl]-3-pyridinyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3 -methyl-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N1-[2-[[3-[2-(環己基氧基)嘧啶-5-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[3-[2-(cyclohexyloxy)pyrimidin-5-yl]phenyl]aminecarboxylidene]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N-[4-[6-(環己基氧基)-3-吡啶基]苯基]-2-[[3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基]胺基]-5-(1-哌啶基)苯甲醯胺 N-[4-[6-(cyclohexyloxy)-3-pyridyl]phenyl]-2-[[3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl]amino]-5-(1-piperidinyl)benzamide
N-[4-[6-(環己基氧基)-3-吡啶基]苯基]-2-[[3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基]胺基]-5-(1-哌啶基)苯甲醯胺 N-[4-[6-(cyclohexyloxy)-3-pyridyl]phenyl]-2-[[3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl]amino]-5-(1-piperidinyl)benzamide
N’-[2-{[2-(3,3-二甲基丁醯基)-1,2,3,4-四氫異喹啉-6-基]胺甲醯基}-4-(哌啶-1-基)苯基]-N-甲基-N-[2-(啉-4-基)乙基]苯-1,3-二甲醯胺 N'-[2-{[2-(3,3-Dimethylbutylidene)-1,2,3,4-tetrahydroisoquinolin-6-yl]aminecarbenyl}-4-(piperidine) -1-yl)phenyl]-N-methyl-N-[2-( Physo-4-yl)ethyl]benzene-1,3-dimethylguanamine
2-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]aminemethylmercapto}benzylidene)amino]-5-(piperidin-1-yl)benzhydryl}amino)-7,8-dihydro-1 ,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
三級丁基-7-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-3,4-二氫異喹啉-2(1H)-甲酸酯 Tert-butyl -7-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]amine-methylmethyl}benzhydryl)amino]-5-(piperidin-1-yl)benzhydryl}amino)-3,4-dihydroisoquine Porphyrin-2(1H)-formate
三級丁基-6-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-3,4-二氫喹啉-1(2H)-甲酸酯 Tertiary butyl-6-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]amine-methylmethyl}benzhydryl)amino]-5-(piperidin-1-yl)benzhydryl}amino)-3,4-dihydroquinoline -1(2H)-formate
2-{2-[(3-{甲基[2-(啉-4-基)乙基]胺磺醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯基}-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-{2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]amine sulfonyl}benzhydryl)amino]-5-(piperidin-1-yl)phenyl}-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
2-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-5,8-二氫-1,7-啶-7(5H)-甲酸三級丁酯 2-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]aminemethylmercapto}benzylidene)amino]-5-(piperidin-1-yl)benzhydryl}amino)-5,8-dihydro-1 , 7- Pyridin-7(5H)-carboxylic acid tert-butyl butyl ester
三級丁基-3-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-7,8-二氫-1,6-啶-6(5H)-甲酸酯 Tert-butyl-3-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]aminemethylmercapto}benzylidene)amino]-5-(piperidin-1-yl)benzhydryl}amino)-7,8-dihydro-1 ,6- Pyridine-6(5H)-formate
[20] [20]
一種醫藥組成物，其含有選自如[1]-[19]中之任一項所記載的化合物或其藥理容許鹽。 A pharmaceutical composition containing a compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof.
[21] [twenty one]
如[20]所記載的醫藥組成物，其係用以抑制磷之攝取。 The pharmaceutical composition according to [20] for inhibiting the uptake of phosphorus.
[22] [twenty two]
如[20]所記載的醫藥組成物，其係用以預防或治療高血磷症。 The pharmaceutical composition according to [20] for preventing or treating hyperphosphatemia.
[23] [twenty three]
一種如[1]-[19]中之任一項所記載的化合物或其藥理容許鹽之用途，其係用以製造用以預防或治療高血磷症之醫藥組成物。 The use of a compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof for the manufacture of a pharmaceutical composition for preventing or treating hyperphosphatemia.
[24] [twenty four]
一種如[1]-[19]中之任一項所記載的化合物或其藥理容許鹽之用途，其係用以預防或治療高血磷症。 The use of a compound according to any one of [1] to [19] or a pharmacologically acceptable salt thereof for preventing or treating hyperphosphatemia.
[25] [25]
一種高血磷症之預防或治療方法，其係藉由投與如[1]-[19]中之任一項所記載的化合物或其藥理容許鹽之有效量。 A method for the prophylaxis or treatment of hyperphosphatemia, which is an effective amount of a compound as described in any one of [1] to [19] or a pharmacologically acceptable salt thereof.
本發明之具有通式(I)之化合物或其藥事上容許鹽，係可使用作為高血磷症等之預防及/或治療劑。 The compound of the formula (I) or a pharmaceutically acceptable salt thereof of the present invention can be used as a prophylactic and/or therapeutic agent for hyperphosphatemia or the like.
以下詳細說明本發明。 The invention is described in detail below.
本說明書中所使用的取代基等之用語意指如下。 The terms of the substituents and the like used in the present specification mean the following.
以下說明本發明化合物之具有通式(I)之化合物。 The compounds of the formula (I) of the compounds of the invention are illustrated below.
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
R1：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 1 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
R2：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 2 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
A：單鍵、或-C(=O)-NH- A: single bond, or -C(=O)-NH-
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
F：單鍵、或-C(=O)-NH- F: single bond, or -C(=O)-NH-
G：氫原子、可經取代之芳基、可經取代之芳烷基、或可經取代之雜環基 G: a hydrogen atom, a substituted aryl group, a substituted aralkyl group, or a substituted heterocyclic group
X：CH、或N X: CH, or N
Y：-C(=O)-、或-S(=O)2-] Y:-C(=O)-, or -S(=O) 2 -]
R1及R2：二C1-C6烷基胺基：於胺基上經2個C1-C6烷基鍵結之基，例如二甲胺基、乙基甲基胺基、二乙胺基、二丙胺基等。 R 1 and R 2 : a di-C1-C6 alkylamino group: a group bonded to two C1-C6 alkyl groups on an amine group, for example, a dimethylamino group, an ethylmethylamino group, a diethylamino group, Dipropylamine and the like.
C1-C6烷基：碳數為1-6個的直鏈或支鏈之基，例如甲基、乙基、丙基、異丙基、n-丁基、異丁基、三級丁基、n-戊基、n-己基等。 C1-C6 alkyl: a straight or branched chain having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, N-pentyl, n-hexyl and the like.
C2-5環烷基胺基：碳數為2-5之環狀基，其環中含有1個氮原子之基，例如氮丙啶、吖呾、吡咯啶、哌啶等。 C2-5 cycloalkylamino group: a cyclic group having 2 to 5 carbon atoms, and a ring containing one nitrogen atom in the ring, for example, aziridine, anthracene, pyrrolidine, piperidine or the like.
E：可經取代之芳環：所謂的芳環為苯環或萘環。芳環上可取代之基為鹵素原子、C1-C6烷基、C3-C6環烷基、鹵化C1-C6烷基、C1-C6烷氧基羰基、C1-C6烷基羰基等。 E: an aromatic ring which may be substituted: the so-called aromatic ring is a benzene ring or a naphthalene ring. The group which may be substituted on the aromatic ring is a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyl group and the like.
此外，由表示具有通式(I)之化合物的結構式係顯而易見的，該芳環具有與A及F鍵結之結合鍵。 Further, as apparent from the structural formula indicating the compound of the formula (I), the aromatic ring has a bond to bond with A and F.
所謂的鹵素原子為氟原子、氯原子、溴原子、或碘原子。 The halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
C1-C6烷基、C3-C6環烷基係與上述相同意義。 The C1-C6 alkyl group and the C3-C6 cycloalkyl group have the same meanings as described above.
所謂的鹵化C1-C6烷基，係於C1-C6烷基上經適當數量之鹵素原子取代之基，例如三氟甲基、二氟甲基、氟甲基、2,2,2-三氟乙基等。 The so-called halogenated C1-C6 alkyl group is a group substituted on the C1-C6 alkyl group with an appropriate number of halogen atoms, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoro. Ethyl and the like.
所謂的C1-C6烷氧基羰基，係於C1-C6烷基上鍵結氧原子，再於前者上經羰基鍵結之基，例如甲氧基羰基、乙氧基羰基、丙氧基羰基、異丙基氧基羰基、n-丁氧基羰基、異丁基氧基羰基、三級丁氧基羰基、n-戊氧基羰基、n-己基氧基羰基等。 The so-called C1-C6 alkoxycarbonyl group is bonded to an oxygen atom on a C1-C6 alkyl group, and a carbonyl-bonded group on the former, such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, Isopropyloxycarbonyl, n-butoxycarbonyl, isobutyloxycarbonyl, tert-butoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, and the like.
所謂的C1-C6烷基羰基，係於C1-C6烷基上經羰基鍵結之基，例如甲基羰基、乙基羰基、丙基羰基、異丙基羰基、n-丁基羰基、異丁基羰基、三級丁基羰基、n-戊基羰基、n-己基羰基等。 The so-called C1-C6 alkylcarbonyl group is a carbonyl-bonded group on a C1-C6 alkyl group, such as methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutyl A carbonyl group, a tertiary butylcarbonyl group, an n-pentylcarbonyl group, an n-hexylcarbonyl group or the like.
可經取代之雜環：所謂的雜環，係藉由2種類以上的元素所構成之環狀化合物，本發明的情形下，係藉由選自碳原子、氧原子、氮原子、及硫原子中之原子所構成之環狀化合物。亦有包含3-6員之環、苯環等與其他環稠合、包含複數環之情形。較佳為吖呾、氧環丁烷、硫環丁烷、吡咯啶、四氫呋喃、四氫噻吩、哌啶、四氫吡喃、四氫噻喃、吡 咯、呋喃、噻吩、吡啶、咪唑、吡唑、唑、噻唑、咪唑啉、吡、嗒、嘧啶、啉、噻、吲哚、異吲哚、苯并咪唑、嘌呤、喹啉、異喹啉、喹啉、啉、喋啶、唍烯、異唍烯、二氫吲哚、二氫異吲哚、二氫苯并咪唑、二氫嘌呤、四氫喹啉、四氫異喹啉、四氫異喹啉、四氫喹啉、四氫啉、四氫喋啶、二氫唍烯、二氫異唍烯、1,6-啶、5,6,7,8-四氫-1,6-啶、1,7-啶、5,6,7,8-四氫-1,7-啶、1,7-四氫啶等。亦可取代至雜環上之基為鹵素原子、C1-C6烷基、C3-C6環烷基、鹵化C1-C6烷基、C1-C6烷氧基羰基、C1-C6烷基羰基等。 Heterocyclic ring which may be substituted: a heterocyclic ring which is a cyclic compound composed of two or more kinds of elements, and in the case of the present invention, is selected from a carbon atom, an oxygen atom, a nitrogen atom, and a sulfur atom. a cyclic compound composed of atoms in the middle. There are also cases in which a ring of 3-6 members, a benzene ring, and the like are fused to other rings and include a plurality of rings. Preferred are hydrazine, oxocyclobutane, thiocyclobutane, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, piperidine, tetrahydropyran, tetrahydrothiopyran, pyrrole, furan, thiophene, pyridine, imidazole, pyrazole , Oxazole, thiazole, imidazoline, pyridyl ,despair Pyrimidine, Porphyrin , hydrazine, isoindole, benzimidazole, indole, quinoline, isoquinoline, quin Porphyrin, Porphyrin, acridine, Terpene, different Terpene, indoline, dihydroisoindole, dihydrobenzimidazole, indoline, tetrahydroquinoline, tetrahydroisoquinoline, tetrahydroisoquinoline, tetrahydroquine Porphyrin, tetrahydrogen Porphyrin, tetrahydroacridine, dihydrogen Terpene, dihydrogen Terpene, 1,6- Pyridine, 5,6,7,8-tetrahydro-1,6- Pyridine, 1,7- Pyridine, 5,6,7,8-tetrahydro-1,7- Pyridine, 1,7-tetrahydrogen Acridine and so on. The group which may be substituted on the hetero ring is a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyl group or the like.
此外，由表示具有通式(I)之化合物的結構式係顯而易見的，該雜環具有與A及F鍵結之結合鍵。 Further, it is apparent from the structural formula indicating the compound of the formula (I) which has a bond to the bond between A and F.
G：可經取代之芳基及可經取代之雜環基，係與上述可經取代之芳環及可經取代之雜環相同意義。但可經取代之芳基、及可經取代之雜環基具有鍵結至F的結合鍵。 G: a aryl group which may be substituted and a heterocyclic group which may be substituted, have the same meanings as the above-mentioned substituted aromatic ring and the substituted heterocyclic ring. However, the aryl group which may be substituted, and the heterocyclic group which may be substituted have a bond bond bonded to F.
可經取代之芳烷基：所謂的芳烷基係於芳基上經甲基鍵結之基，例如苄基、苯乙基、四氫萘基(tetralinyl)等。亦可取代至芳烷基上之基為鹵素原子、C1-C6烷基、C3-C6環烷基、鹵化C1-C6烷基、C1-C6烷氧基羰基、C1-C6烷基羰基等，各取代基係與上述相同意義。 The aralkyl group which may be substituted: the so-called aralkyl group is a methyl group bonded to an aryl group, such as a benzyl group, a phenethyl group, a tetralinyl group or the like. The group which may be substituted on the aralkyl group is a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a halogenated C1-C6 alkyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylcarbonyl group, or the like. Each substituent has the same meaning as described above.
所謂的「可經取代之」，係未經取代或經1至3個之取代。 The so-called "substitutable" is unsubstituted or substituted by one to three.
所謂的「其藥理容許鹽」係表示可使用作為醫藥之鹽。就化合物而言，其於具有酸性基或鹼性基的情形下，由於可藉由使其與鹼或酸反應，而為「與鹼之鹽」或「酸加成鹽」，而表示其鹽。 The term "the pharmacologically acceptable salt" means a salt which can be used as a medicine. In the case of a compound having an acidic group or a basic group, it can be represented by a salt of a base or an acid addition salt by reacting it with a base or an acid. .
作為化合物之藥理容許「與鹼之鹽」，較佳為如鈉鹽、鉀鹽、鋰鹽之鹼金屬鹽；如鎂鹽、鈣鹽之鹼土族金屬鹽；如N-甲基啉鹽、三乙胺鹽、三丁胺鹽、二異丙基乙基胺鹽、二環己基胺鹽、N-甲基哌啶鹽、吡啶鹽、4-吡咯啶基(pyrrolidino)吡啶鹽、甲吡啶鹽之有機鹼鹽類或如甘胺酸鹽、離胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽之胺基酸鹽，較佳為鹼金屬鹽。 The pharmacologically acceptable compound is a salt of a base, preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a magnesium salt or a calcium salt; for example, an N-methyl group a porphyrin salt, a triethylamine salt, a tributylamine salt, a diisopropylethylamine salt, a dicyclohexylamine salt, an N-methylpiperidine salt, a pyridinium salt, a pyrrolidino pyridinium salt, An organic base salt of a pyridyl salt or an amine salt such as a glycinate, an aminate, a arginine, an alanate, a glutamate or an aspartate, preferably a base. Metal salt.
作為化合物之藥理容許「酸加成鹽」，較佳為如氫氟酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽之氫鹵酸鹽；如硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等之無機酸鹽；如甲磺酸鹽、三氟甲磺酸鹽、乙磺酸鹽之低級烷烴磺酸鹽；如苯磺酸鹽、p-甲苯磺酸鹽之芳磺酸鹽；如乙酸鹽、蘋果酸鹽、反丁烯二酸鹽、丁二酸鹽、檸檬酸鹽、抗壞血酸鹽、酒石酸鹽、乙二酸鹽、馬來酸鹽等之有機酸鹽；及如甘胺酸鹽、離胺酸鹽、精胺酸鹽、鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽之胺基酸鹽，最佳為氫鹵酸鹽(特別是鹽酸鹽)。 As the pharmacology of the compound, an "acid addition salt" is allowed, preferably a hydrohalide salt such as a hydrofluoric acid salt, a hydrochloride salt, a hydrobromide salt or a hydroiodide salt; for example, a nitrate salt, a perchlorate salt, a sulfuric acid salt a mineral acid salt of a salt, a phosphate or the like; a lower alkane sulfonate such as a methanesulfonate, a triflate or an ethanesulfonate; an aromatic sulfonic acid such as a besylate or a p-toluenesulfonate a salt; an acid salt such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, etc.; Amino acid salt of aminate, a persalt, arginine, aguanate, glutamate, aspartate, preferably a hydrohalide (especially a hydrochloride).
本發明之化合物或其藥理容許鹽，其有藉由放置於大氣中或進行再結晶，而吸收水分、附著吸附水，而形 成水合物的情況，本發明亦包含這樣的各種水合物、溶劑合物及多晶型(crystalline polymorphism)化合物。 a compound of the present invention or a pharmacologically acceptable salt thereof, which is obtained by being placed in the atmosphere or undergoing recrystallization to absorb moisture and adhere to adsorbed water. In the case of a hydrate formation, the present invention also encompasses such various hydrates, solvates, and crystalline polymorphism compounds.
本發明之化合物，依據取代基之種類，可存在互變異構物、幾何異構物。本說明書中，本發明之化合物雖有僅以異構物之一形態來記載，但本發明亦包含其以外的異構物，亦包含異構物之經分離者，或其等之混合物。 The compound of the present invention may contain tautomers or geometric isomers depending on the kind of the substituent. In the present specification, the compound of the present invention is described in the form of only one of the isomers, but the present invention also includes other isomers, and also includes a separator of the isomer, or a mixture thereof.
本發明之化合物有具有不對稱碳原子、不對稱軸的情況，基於此而可存在光學異構物。本發明亦包含光學異構物之經分離者，或其等之混合物。 The compound of the present invention has a case of having an asymmetric carbon atom and an asymmetric axis, and based on this, an optical isomer may exist. The invention also encompasses isolates of optical isomers, or mixtures thereof.
本發明之化合物亦包含標幟體，亦即以同位元素(例如2H、3H、13C、14C、35S等)取代化合物之1或2以上之原子而成之化合物。 The compound of the present invention also includes a label body, that is, a compound obtained by substituting one or more atoms of the compound with an isomer (for example, 2 H, 3 H, 13 C, 14 C, 35 S, etc.).
本發明亦包含本發明之化合物之藥理學容許前藥。所謂的藥理學容許前藥，係具有藉由加溶劑分解或在生理學的條件下，可被轉換成胺基、羥基、羧基等之基的化合物。作為形成前藥之基，可列舉例如：Prog.Med.,5,2157-2161(1985)中所記載之基。 The invention also encompasses pharmacologically acceptable prodrugs of the compounds of the invention. The so-called pharmacologically acceptable prodrug is a compound which can be converted into an amino group, a hydroxyl group, a carboxyl group or the like by decomposition with a solvent or under physiological conditions. Examples of the group forming the prodrug include a group described in Prog. Med., 5, 2157-2161 (1985).
作為該前藥，更具體而言，於化合物上存在胺基的情況，可列舉其胺基經醯化、烷化、磷酸化的化合物(例如其胺基經二十醯基化、丙胺醯基化、戊基胺基羰基化、(5-甲基-2-側氧-1,3-二氧戊環(dioxolen)-4-基)甲氧基羰基化、四 氫呋喃基化、吡咯啶基甲基化、三甲基乙醯氧基甲基化、三級丁基化之化合物等)等；於化合物上存在羥基的情況，可列舉其羥基經醯化、烷化、磷酸化、硼酸化之化合物(例如其羥基經乙醯基化、棕櫚醯基化、丙醯基化、三甲基乙醯基化、琥珀醯基化、延胡索醯基化、丙胺醯基化、二甲基胺基甲基羰基化之化合物等。)等；於化合物上存在羧基的情況，可列舉其羧基經酯化、醯胺化之化合物(例如其羧基經乙酯化、苯酯化、羧基甲酯化、二甲基胺基甲酯化、三甲基乙醯氧基甲酯化、乙氧基羰氧基乙酯化、醯胺化或甲基醯胺化之化合物等)等。 As the prodrug, more specifically, in the case where an amine group is present on the compound, a compound in which an amine group is deuterated, alkylated, or phosphorylated (for example, an amine group thereof is thiolated, an amidino group) , pentylaminocarbonylation, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation, four Hydrofuranylation, pyrrolidinylmethylation, trimethylacetoxymethylation, tertiary butylated compound, etc.); in the case where a hydroxyl group is present on the compound, the hydroxyl group is deuterated, Alkylated, phosphorylated, or borated compounds (eg, its hydroxyl group is acetylated, palmitoylated, propylated, trimethylacetylated, amber thiolated, fumarate, prilocamine) a compound, a dimethylaminomethylcarbonylated compound, etc., etc.; in the case where a carboxyl group is present on the compound, a compound whose carboxyl group is esterified or amided (for example, a carboxyl group thereof is ethylated, benzene) Esterification, carboxymethylation, dimethylaminomethylation, trimethylacetoxymethylation, ethoxycarbonyloxyethylation, amide or methylammonium compounds )Wait.
本發明之化合物及其藥理容許鹽，可利用基於其基本構造或取代基之種類之特徴，而應用各種周知之合成法而製造。 The compound of the present invention and its pharmacologically acceptable salt can be produced by applying various well-known synthetic methods based on the characteristics of the basic structure or the type of the substituent.
此時，根據官能基之種類，在從原料至中間體之階段中，將該官能基取代成適當之保護基(可容易轉化成該官能基之基)，其在製造技術上係屬有效用的。作為此種保護基，可列舉例如Wuts(P.G.M.Wuts)及Greene(T.W.Greene)著之Greene's Protective Groups in Organic Synthesis(第4版、2006年)中所記載之保護基等，因應此等之反應條件而適當地選擇使用即可。 At this time, depending on the kind of the functional group, in the stage from the raw material to the intermediate, the functional group is substituted into a suitable protecting group (which can be easily converted into a group of the functional group), which is effective in manufacturing technology. of. Examples of such a protective group include a protecting group described in Greens's Protective Groups in Organic Synthesis (4th edition, 2006) by Wuts (PGMWuts) and Greene (TW Greene), and the reaction conditions are determined in accordance with these conditions. And you can choose to use it appropriately.
就此種方法而言，導入該保護基而進行反應後，因應需要，藉由去除保護基，而可以得到期望之化合物。 此外，本發明之化合物之前藥，與上述保護基相同，可藉由在從原料至中間體的階段，導入特定之基，或使用所得到之化合物進一步進行反應而製造。反應可藉由應用一般之酯化、醯胺化、脫水等之方法而進行。 In such a method, after the reaction group is introduced and the reaction is carried out, a desired compound can be obtained by removing the protective group if necessary. Further, the prodrug of the compound of the present invention can be produced by introducing a specific group from the raw material to the intermediate, or by further reacting the obtained compound, in the same manner as the above-mentioned protecting group. The reaction can be carried out by a method such as general esterification, amide amination, dehydration or the like.
以下敘明關於化合物之製造方法。然而，製造方法不受下述方法任何限制。 The method for producing the compound is described below. However, the manufacturing method is not limited by the following methods.
A法係製造具有通式(I’)之化合物的化合物(A6)之方法。 The method of A is a process for producing a compound (A6) having a compound of the formula (I').
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
R1：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 1 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
R2：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 2 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
X：CH、或N X: CH, or N
Y：-C(=O)-、或-S(=O)2-] Y:-C(=O)-, or -S(=O) 2 -]
步驟A-1係使(i)化合物(A1)與草醯氯反應活性化後，與化合物(A2)反應，而製造化合(A3)、或(ii)使化合物(A1)與化合物(A2)在縮合劑的存在下反應，而製造化合物(A3)步驟。 Step A-1 is a method in which (i) a compound (A1) is reacted with grass chloroform, and then reacted with a compound (A2) to produce a compound (A3), or (ii) a compound (A1) and a compound (A2). The compound (A3) step is produced by reacting in the presence of a condensing agent.
在(i)的情形下，係藉由下述方式進行，例如於化合物(A1)的二氯甲烷溶液中，於0℃-室溫添加草醯氯與少量的二甲基甲醯胺，暫時放置後，於0℃-室溫添加化合物(A2)與吡啶等之鹼。通常，將反應溫度設為室溫-80℃左右，而反應時間則設為1-24小時左右。 In the case of (i), for example, in the dichloromethane solution of the compound (A1), grassy chlorine and a small amount of dimethylformamide are added at 0 ° C to room temperature, temporarily After standing, the compound (A2) and a base such as pyridine are added at 0 ° C to room temperature. Usually, the reaction temperature is set to about room temperature to about 80 ° C, and the reaction time is set to about 1 to 24 hours.
在(ii)的情形下，在縮合劑、鹼的存在下，於溶劑中進行反應。 In the case of (ii), the reaction is carried out in a solvent in the presence of a condensing agent or a base.
所使用的縮合劑，可列舉1-[雙(二甲胺基)亞甲基]-1H-苯并三唑鎓-3-氧化物六氟磷酸鹽(以下有稱為HBTU)的情形。)、2-(1H-7-吖苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸鹽(以下有稱為HATU的情形。)、4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鹽酸鹽n水合物(以下有稱為DMT-MM的情形。)1-乙基-3-(3-二甲胺基丙基)碳二亞胺(carbodiimide)鹽酸塩(以下有稱為WSC、或EDCI的情形。)等。 The condensing agent to be used may, for example, be 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate (hereinafter referred to as HBTU). ), 2-(1H-7-indole benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (hereinafter referred to as HATU), 4- (4,6-dimethoxy-1,3,5-three -2-yl)-4-methyl Phytate hydrochloride n hydrate (hereinafter referred to as DMT-MM.) 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide guanidine hydrochloride (hereinafter referred to as The case of WSC, or EDCI.).
所使用的鹼，可列舉二異丙基乙基胺、三乙胺、N-甲基啉等之3級胺。 The base to be used may, for example, be diisopropylethylamine, triethylamine or N-methyl. a tertiary amine such as a porphyrin.
所使用的溶劑，可列舉二氯甲烷、二氯化伸乙基、二甲基甲醯胺、二甲基乙醯胺、甲醇等。 Examples of the solvent to be used include dichloromethane, diethylamethylene dichloride, dimethylformamide, dimethylacetamide, methanol, and the like.
反應溫度為室溫-80℃左右。 The reaction temperature is about room temperature - about 80 °C.
反應時間為1-24小時左右。 The reaction time is about 1 to 24 hours.
步驟A-2係還原化合物(A3)之硝基，而製造化合物(A4)之步驟。 Step A-2 is a step of producing a compound (A4) by reducing a nitro group of the compound (A3).
本步驟係於觸媒存在下、氫氣環境下、溶劑中進行反應。 This step is carried out in the presence of a catalyst, in a hydrogen atmosphere, or in a solvent.
所使用的觸媒係可列舉10%鈀碳、10%氫氧化鈀等 Examples of the catalyst used include 10% palladium carbon, 10% palladium hydroxide, and the like.
所使用的溶劑係可列舉四氫呋喃(以下有稱為THF的情形。)等之醚類、乙酸乙酯等之酯類、乙醇等之醇類、或彼等之混合溶劑。 The solvent to be used may, for example, be an ether such as tetrahydrofuran (hereinafter referred to as THF), an ester such as ethyl acetate, an alcohol such as ethanol, or a mixed solvent thereof.
反應壓力為常壓。 The reaction pressure is normal pressure.
反應溫度為室溫-60℃。 The reaction temperature is room temperature - 60 °C.
反應時間為1-24小時。 The reaction time is from 1 to 24 hours.
又，本步驟亦可藉由於乙醇/水溶劑中加熱回流，而進行由鐵粉與氯化銨所引起之還原反應。 Further, this step can also carry out a reduction reaction caused by iron powder and ammonium chloride by heating under reflux in an ethanol/water solvent.
步驟A-3係使化合物(A4)與化合物(A5)縮合，而製造化合物(A6)之步驟。 Step A-3 is a step of producing a compound (A6) by condensing the compound (A4) with the compound (A5).
本步驟係於縮合劑、鹼的存在下，於溶劑中進行反應。 This step is carried out in a solvent in the presence of a condensing agent or a base.
所使用的縮合劑，可列舉HBTU、HATU、DMT-MM、WSC等。 Examples of the condensing agent to be used include HBTU, HATU, DMT-MM, WSC, and the like.
所使用的鹼，可列舉二異丙基乙基胺、三乙胺、N-甲基啉等之3級胺。 The base to be used may, for example, be diisopropylethylamine, triethylamine or N-methyl. a tertiary amine such as a porphyrin.
所使用的溶劑，可列舉二氯甲烷、二氯化乙烯、二甲基甲醯胺、二甲基乙醯胺、甲醇等。 Examples of the solvent to be used include dichloromethane, ethylene dichloride, dimethylformamide, dimethylacetamide, methanol, and the like.
反應溫度為室溫-80℃左右。 The reaction temperature is about room temperature - about 80 °C.
反應時間為1-24小時左右。 The reaction time is about 1 to 24 hours.
B法係製造具有通式(I”)之化合物的化合物(B6)之方法。 The B method is a method for producing a compound (B6) having a compound of the formula (I").
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
R1：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 1 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
R2：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 2 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
G：可經取代之芳基、或可經取代之雜環基 G: a aryl group which may be substituted or a heterocyclic group which may be substituted
X：CH、或N X: CH, or N
Y：-C(=O)-、或-S(=O)2- Y:-C(=O)-, or -S(=O) 2 -
Z：鹵素原子、或三氟甲磺醯氧基] Z: halogen atom, or trifluoromethanesulfonyloxy group]
步驟B-1係使化合物(B1)與化合物(B2)鍵結，而製造化合物(B3)之步驟。 Step B-1 is a step of producing a compound (B3) by bonding a compound (B1) to a compound (B2).
本步驟係於觸媒、鹼的存在下，於溶劑中進行反應。 This step is carried out in a solvent in the presence of a catalyst or a base.
所使用的觸媒，可列舉包含肆三苯基膦鈀(0)、雙(三苯基膦)二氯化鈀(II)、氯(2-二環己基膦基-2’,4’6’-三異丙基-1,1’-聯苯)[2-(2’-胺基-1,1’-聯苯)鈀(II)等、各種過渡金屬及各種配位子之觸媒。 The catalyst to be used may, for example, be a triphenylphosphine palladium (0), bis(triphenylphosphine)palladium(II) chloride, or chloro(2-dicyclohexylphosphino-2', 4'6. '-Triisopropyl-1,1'-biphenyl)[2-(2'-Amino-1,1'-biphenyl)palladium (II), etc., various transition metals and various ligands .
所使用的鹼，可列舉磷酸鉀、乙酸鉀、碳酸鈉、三級丁氧基鈉等。 Examples of the base to be used include potassium phosphate, potassium acetate, sodium carbonate, and tertiary sodium butoxide.
所使用的溶劑，可列舉二甲氧乙烷(以下有稱為DME的情形。)、THF、1,4-二烷等之醚類與水之混合溶劑。 The solvent to be used may, for example, be dimethoxyethane (hereinafter referred to as DME), THF, 1,4-two. A mixed solvent of an ether such as an alkane and water.
反應溫度為室溫-100℃。 The reaction temperature is from room temperature to 100 °C.
反應時間為1-24小時左右。 The reaction time is about 1 to 24 hours.
步驟B-2係還原化合物(B3)之硝基，而製造化合物(B4)之步驟，以與步驟A-2同樣的條件進行之步驟。 Step B-2 is a step of reducing the nitro group of the compound (B3) to produce the compound (B4), and performing the same conditions as in the step A-2.
步驟B-3係使化合物(B4)與化合物(B5)縮合，而製造化合物(B6)之步驟，以與步驟A-3同樣的條件進行之步驟。 Step B-3 is a step in which the compound (B4) is condensed with the compound (B5) to produce the compound (B6), and the steps are carried out under the same conditions as those in the step A-3.
C法係製造具有通式(I''')之化合物的化合物(C6)之方法。 The C method is a method for producing a compound (C6) having a compound of the formula (I''').
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
R1：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 1 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
R2：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 2 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
G：可經取代之芳基、可經取代之芳烷基、或可經取代之雜環基 G: a substituted aryl group, a substituted aralkyl group, or a substituted heterocyclic group
X：CH、或N X: CH, or N
Y：-C(=O)-、或-S(=O)2- Y:-C(=O)-, or -S(=O) 2 -
Z：鹵素原子、或三氟甲磺醯基氧基] Z: halogen atom, or trifluoromethanesulfonyloxy]
步驟C-1係使化合物(C1)與化合物(C2)鍵結，而製造化合物(C3)之步驟，以與步驟B-1同樣的條件進行之步驟。 Step C-1 is a step in which the compound (C1) is bonded to the compound (C2) to produce a compound (C3), and the steps are carried out under the same conditions as in the step B-1.
步驟C-2係還原化合物(C3)之硝基，而製造化合物(C4)之步驟，以與步驟A-2同樣之條件進行之步驟。 Step C-2 is a step of reducing the nitro group of the compound (C3) to produce a compound (C4), which is carried out under the same conditions as those in the step A-2.
步驟C-3係使化合物(C4)與化合物(C5)縮合，而製造化合物(C6)之步驟，以與步驟A-3同樣之條件進行之步驟。 Step C-3 is a step in which the compound (C4) is condensed with the compound (C5) to produce a compound (C6) in the same manner as in the step A-3.
C’法係製造於C法中所使用之化合物(C3)的其他方法。 The C' method is another method for producing the compound (C3) used in the C method.
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
R1：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 1 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
R2：氫原子、二C1-C6烷基胺基、或C2-5環烷基胺基 R 2 : a hydrogen atom, a di-C1-C6 alkylamino group, or a C2-5 cycloalkylamino group
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
G：可經取代之芳基、可經取代之芳烷基、或可經取代之雜環基 G: a substituted aryl group, a substituted aralkyl group, or a substituted heterocyclic group
X：CH、或N X: CH, or N
Y：-C(=O)-、或-S(=O)2- Y:-C(=O)-, or -S(=O) 2 -
Z：鹵素原子、或三氟甲磺醯基氧基 Z: halogen atom, or trifluoromethanesulfonyloxy
R’：C1-C6烷基] R': C1-C6 alkyl]
步驟C’-1係使化合物(C1)與化合物(C’2)鍵結，而製造化合物(C’3)之步驟，以與步驟B-1同樣的條件進行之步驟。 Step C'-1 is a step in which the compound (C1) is bonded to the compound (C'2) to produce a compound (C'3), and the steps are carried out under the same conditions as in the step B-1.
步驟C’-2係將化合物(C’3)之酯基水解生成之羧酸與化合物(C’4)縮合，而製造化合物(C3)之步驟，以與步驟A-2同樣之條件進行之驟。 Step C'-2 is a step of producing a compound (C3) by condensing a carboxylic acid obtained by hydrolysis of an ester group of the compound (C'3) with a compound (C'4), and performing the same conditions as in the step A-2. Step.
D法係於R1或R2為二C1-C6烷基胺基、或C2-5環烷基胺基的情形，於製造步驟之途中，導入R1或R2之取代基之方法。以下說明R1為哌啶基，R2為氫原子之情形，製造A法之化合物(A3)的例子。 The D method is a method in which a substituent of R 1 or R 2 is introduced in the middle of the production step in the case where R 1 or R 2 is a di-C1-C6 alkylamino group or a C2-5 cycloalkylamino group. Hereinafter, an example in which R 1 is a piperidinyl group and R 2 is a hydrogen atom, and a compound (A3) of the method A is produced will be described.
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
E：可經取代之芳環、或可經取代之雜環] E: a substituted aromatic ring, or a substituted heterocyclic ring]
步驟D-1係使化合物(D1)與哌啶鍵結，而製造化合物(A3)之步驟。 Step D-1 is a step of producing a compound (A3) by bonding the compound (D1) to piperidine.
本步驟係於溶劑中進行反應。 This step is carried out by reacting in a solvent.
所使用的溶劑，較佳為THF等之醚類。 The solvent to be used is preferably an ether such as THF.
反應溫度為室溫-80℃。 The reaction temperature is room temperature - 80 °C.
反應時間為1-24小時左右。 The reaction time is about 1 to 24 hours.
D’法係於R1或R2為二C1-C6烷基胺基、或C2-5環烷基胺基的情形，於製造步驟之途中，導入R1或R2之取代基之方法。以下說明R1為哌啶基，R2為氫原子之情形，製造B法之化合物(B3)的例子。 The D' method is a method in which a substituent of R 1 or R 2 is introduced in the middle of the production step in the case where R 1 or R 2 is a di-C1-C6 alkylamino group or a C2-5 cycloalkylamino group. Hereinafter, an example in which R 1 is a piperidinyl group and R 2 is a hydrogen atom, and a compound (B3) of the B method is produced will be described.
[式中，各取代基係如以下所定義。 [wherein each substituent is as defined below.
E：可經取代之芳環、或可經取代之雜環 E: a substituted aromatic ring or a substituted heterocyclic ring
G：可經取代之芳基、可經取代之芳烷基、或可經取代之雜環基] G: a substituted aryl group, a substituted aralkyl group, or a substituted heterocyclic group]
步驟D’-1係使化合物(D’1)與哌啶鍵結，而製造化合物(B3)之步驟，以與步驟D-1同樣之條件進行之步驟。 Step D'-1 is a step in which the compound (D'1) is bonded to piperidine to produce a compound (B3) in the same manner as in the step D-1.
本步驟係於溶劑中進行反應。 This step is carried out by reacting in a solvent.
所使用的溶劑，所使用的溶劑，較佳為THF等之醚類。 The solvent to be used, and the solvent to be used, are preferably ethers such as THF.
反應溫度為室溫-80℃。 The reaction temperature is room temperature - 80 °C.
反應時間為1-24小時左右。 The reaction time is about 1 to 24 hours.
以上述之方法製造之化合物，可藉由周知之方法，例如萃取、沈澱、蒸餾、層析、分段結晶、再結晶等進行單離、純化。 The compound produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional crystallization, recrystallization, or the like.
此外，化合物或製造之中間體具有不對稱碳的情況下，存在有光學異構物。此等光學異構物，可藉由與適當的鹽再結晶之分段結晶(鹽分離，salt resolution)、或管柱層析等之常法，而單離、純化各個異構物。作為從消旋物分離光學異構物之方法的參考文獻可列舉J.Jacques等、「Enantiomers,Racemates and Resolution,John Wiley And Sons,Inc.」。 Further, in the case where the compound or the intermediate produced has an asymmetric carbon, an optical isomer exists. These optical isomers can be isolated and purified by a conventional method such as fractional crystallization (salt resolution) or column chromatography with a suitable salt for recrystallization. As a reference for the method of separating optical isomers from racemates, J. Jacques et al., "Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc." can be cited.
發明之化合物之藥理活性係藉由以下之試驗確認。 The pharmacological activity of the compounds of the invention is confirmed by the following tests.
使用前一天經斷食之雄性SD大鼠(5-7週齡)，將實施例中所記載之化合物於0.5%甲基纖維素等之溶劑中懸浮或溶解(3-6mg/mL)，以投與量為30mg/kg方式，進行強制經口投與。又，關於控制組，以5mL/kg溶劑方式投與。投與30分鐘後，以7.2mL/kg方式強制經口投與33P磷酸液(8.3mM NaH2PO4,0.35MBq/mL)，於其15、30、60、120分鐘後，在異氟醚(isoflurane)麻醉下，從頸靜脈進行採血。使用液體閃爍計數器測定血清50μL中之放射活性，從放射活性值算出AUC0-60min作為磷酸吸收 量。關於化合物之磷酸吸收抑制活性，係由以下數學式算出。 The compound described in the examples was suspended or dissolved in a solvent of 0.5% methylcellulose or the like (3-6 mg/mL) by using a male SD rat (5-7 weeks old) that was fasted one day before use. The amount of administration was 30 mg/kg, and forced oral administration was carried out. Further, the control group was administered as a solvent of 5 mL/kg. After 30 minutes of administration, 33 P phosphoric acid solution (8.3 mM NaH 2 PO 4 , 0.35 MBq/mL) was orally administered at 7.2 mL/kg, and after 15, 30, 60, and 120 minutes, in isoflurane. Under anesthesia with ether (isoflurane), blood was collected from the jugular vein. The radioactivity in 50 μL of serum was measured using a liquid scintillation counter, and AUC 0-60 min was calculated from the radioactivity value as the amount of phosphate uptake. The phosphoric acid absorption inhibitory activity of the compound is calculated by the following mathematical formula.
磷酸吸收抑制活性(%)=[(100-化合物投與組之磷酸吸收量)/控制組之磷酸吸收量]×100 Phosphoric acid absorption inhibitory activity (%) = [(100 - phosphate absorption amount of the compound administration group) / phosphoric acid absorption amount of the control group] × 100
投與係經由錠劑、丸劑、膠囊劑、顆粒劑、散劑、液劑等之經口投與；或經由關節肉、靜脈肉、肌肉內等之注射劑；栓劑、點眼劑、眼軟膏、經皮用液劑、軟膏劑、經皮用貼劑、經黏膜液劑、經黏膜貼劑、吸入劑等之非經口投與之任一形態均可。 Administration by oral administration of tablets, pills, capsules, granules, powders, liquids, etc.; or injections through joint meat, vein meat, intramuscular, etc.; suppositories, eye drops, eye ointments, menses Any form of non-oral administration such as a liquid preparation, an ointment, a transdermal patch, a mucosal solution, a transmucosal patch, an inhalant, or the like may be used.
作為用以經口投與之固體組成物，可使用錠劑、散劑、顆粒劑等。此種固體組成物中混合1種或2種以上之有效成分與至少1種非活性之賦形劑，例如乳糖、甘露醇、葡萄糖、羥丙基纖維素、微結晶纖維素、澱粉、聚乙烯吡咯啶酮、及/或偏矽酸鋁鎂(magnesium aluminometasilicate)等。根據常法，組成物亦可含有非活性之添加劑，例如：如硬脂酸鎂之潤滑劑、或如羧甲 基澱粉鈉等之崩散劑、安定劑、溶解輔助劑。錠劑或丸劑按需要亦可以糖衣或胃溶性或腸溶性物質之薄膜被膜。 As the solid composition for oral administration, a tablet, a powder, a granule, or the like can be used. The solid composition is mixed with one or more active ingredients and at least one inactive excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyethylene. Pyrrolidone, and/or magnesium aluminometasilicate. According to conventional methods, the composition may also contain inactive additives such as, for example, a lubricant such as magnesium stearate or a carboxymethyl group. A disintegrating agent such as sodium starch or the like, a stabilizer, and a dissolution aid. Tablets or pills may also be coated with a film of a sugar-coated or enteric-soluble or enteric material as needed.
用以經口投與之液體組成物，包含藥劑可容許乳濁劑、溶液劑、懸浮劑、糖漿劑或酏劑等，且可包含一般所使用的非活性稀釋劑、例如純水或乙醇。該液體組成物除了非活性稀釋劑以外，亦可含有如增溶劑、濕潤劑、懸浮劑之輔助劑、甜劑、風劑、芳香劑、防腐劑。 A liquid composition for oral administration, which comprises a emulsifiable agent, a solution, a suspension, a syrup or an elixir, and the like, and may contain a non-reactive diluent such as pure water or ethanol which is generally used. The liquid composition may contain, in addition to the inactive diluent, an adjuvant such as a solubilizing agent, a wetting agent, a suspending agent, and a sweetener. Agent, wind Agents, fragrances, preservatives.
用以非經口投與之注射劑，含有無菌之水性或非水性之溶液劑、懸浮劑或乳濁劑。作為水性之溶劑，可包含例如注射用蒸餾水或生理食鹽水。作為非水性之溶劑，係例如丙二醇、聚乙二醇或如橄欖油之植物油、如乙醇之醇類、或聚山梨醇酯80(polysorbate80)等。此種組成物，亦可進一步包含等張化劑(tonicity agent)、防腐劑、濕潤劑、乳化劑、分散劑、安定劑、或溶解輔助劑。此等可藉由通過例如细菌截留過濾器之濾過、殺菌劑之摻混或放射線照射而被無菌化。此外，此等亦可製造無菌之固體組成物，於使用前溶解或懸浮於無菌水或無菌之注射用溶劑中後，再加以使用。 An injection for parenteral administration containing a sterile aqueous or nonaqueous solution, suspension or opacifier. As the aqueous solvent, for example, distilled water for injection or physiological saline can be contained. As the nonaqueous solvent, for example, propylene glycol, polyethylene glycol or vegetable oil such as olive oil, alcohol such as ethanol, or polysorbate 80 or the like can be mentioned. Such a composition may further comprise a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersing agent, a stabilizer, or a dissolution aid. These can be sterilized by filtration through, for example, a bacteria-retaining filter, blending of a bactericide, or radiation. In addition, these can also be used to produce a sterile solid composition which is dissolved or suspended in sterile water or a sterile injectable solvent before use.
作為外用劑，可包含軟膏劑、硬膏劑、霜劑(creams)、凝膠劑、泥罨劑(cataplasm)、噴霧劑、乳液(lotion)、點眼劑、眼軟膏等。含有一般所使用的軟膏基劑、乳液基劑、水性或非水性之液劑、懸浮劑、乳劑等。作為例如軟膏或乳液基劑，係可列舉聚乙二醇、丙二醇、 白色凡士林、白蜜蠟、聚氧乙烯氫化蓖麻油、單硬酯酸甘油酯、硬脂醇、十六醇、聚桂醇(lauromacrogol)、山梨醇酐倍半油酸酯(sorbitan sesquioleate)等。 As the external preparation, an ointment, a plaster, a cream, a gel, a cataplasm, a spray, a lotion, an eye drop, an eye ointment and the like may be contained. It contains an ointment base, an emulsion base, an aqueous or non-aqueous liquid preparation, a suspension, an emulsion, and the like which are generally used. Examples of the ointment or emulsion base include polyethylene glycol and propylene glycol. White petrolatum, white beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, sorbitan sesquioleate, and the like.
吸入劑、經鼻劑等之經黏膜劑，可使用固體、液體或半固體狀者，可依據以往周知之方法製造。例如周知的賦形劑，或進一步亦可適當地添加pH調整劑、防腐劑、界面活性劑、潤滑劑、安定劑、或增黏劑等。投與可使用適當的用以吸入或吹送的裝置。例如使用計量投與吸入裝置等周知的裝置及噴霧器，可將化合物以單獨或經處方之混合物的粉末，或與醫藥上許可之載體組合後，以溶液或懸浮液的方式進行投與。乾燥粉末吸入器等，亦可為單次或數次投與用者，可使用乾燥粉末或含有粉末的膠囊。或者，亦可為適當的噴出劑，例如使用氯氟烷、氫氟烷(hydrofluoroalkane)或二氧化碳等適合的氣體的加壓氣溶膠噴霧等形態。 A transmucosal agent such as an inhalant or a nasal spray can be used in the form of a solid, a liquid or a semi-solid, and can be produced by a conventionally known method. For example, a well-known excipient, or a pH adjuster, a preservative, a surfactant, a lubricant, a stabilizer, or a tackifier may be further added as appropriate. Suitable devices for inhalation or insufflation can be used for administration. For example, a compound or a nebulizer such as a metered administration inhalation device can be used, and the compound can be administered as a solution or suspension by combining a powder of a single or a prescribed mixture or a pharmaceutically acceptable carrier. A dry powder inhaler or the like may be used for single or several administrations, and a dry powder or a capsule containing a powder may be used. Alternatively, it may be a suitable ejecting agent, for example, a pressurized aerosol spray using a suitable gas such as chlorofluorocarbon, hydrofluoroalkane or carbon dioxide.
通常經口投與的情況下，合適的1天投與量為每單位體重約0.001~100mg/kg、較佳為0.1~30mg/kg、更佳為0.1~10mg/kg，將其以1次或分成2次以上進行投與。靜脈內投與的情形，合適的1天投與量為每單位體重約0.0001~10mg/kg，1天1次或分成多次進行投與。另外，作為經黏膜劑，將每單位體重約0.001~100mg/kg，以1天1次或分成多次進行投與。投與量可考慮症狀、年齡、性別等，因應各種情形而適當地加以決定。 In the case of oral administration, a suitable one-day administration amount is about 0.001 to 100 mg/kg, preferably 0.1 to 30 mg/kg, more preferably 0.1 to 10 mg/kg per unit body weight, which is 1 time. Or divided into 2 or more to be administered. In the case of intravenous administration, a suitable dose for one day is about 0.0001 to 10 mg/kg per unit body weight, once a day or divided into multiple doses. Further, as a transmucosal agent, about 0.001 to 100 mg/kg per unit body weight is administered, and administration is performed once a day or in divided portions. The amount of administration can be determined in consideration of symptoms, age, gender, etc., depending on various situations.
本發明之化合物可與被認為該化合物顯示有效性之疾病的各種治療劑或預防劑併用。該併用可以同時投與、或個別地連續投與，或於所期望的時間間隔進行投與。同時投與製劑可為摻合劑亦可個別製劑化。 The compound of the present invention can be used in combination with various therapeutic or prophylactic agents for diseases which are considered to be effective for the compound. The combination can be administered simultaneously, or continuously, individually, or at the desired time interval. At the same time, the formulation can be formulated as a blending agent or can be formulated separately.
藉由將5g本發明之化合物、895g乳糖及100g玉米澱粉以攪拌器混合，而可得到散劑。 A powder can be obtained by mixing 5 g of the compound of the present invention, 895 g of lactose and 100 g of corn starch with a stirrer.
將5g本發明之化合物、865g乳糖及100g低取代度羥丙基纖維素混合後，添加300g之10%羥丙基纖維素水溶液混練。使用擠壓造粒機將其造粒、乾燥，可得到顆粒劑。 After mixing 5 g of the compound of the present invention, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose, 300 g of a 10% aqueous hydroxypropylcellulose solution was added and kneaded. The granules are obtained by granulating and drying them using an extrusion granulator.
由將5g本發明之化合物、90g乳糖、34g玉米澱粉、20g結晶纖維素及1g硬脂酸鎂以攪拌器混合，以打錠機打錠，而可得到錠劑。 A lozenge was obtained by mixing 5 g of the compound of the present invention, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate in a stirrer and tableting with a tableting machine.
以下，列舉實施例及參考例，進一步詳細說明本發明，但本發明之範圍並非受限於此等者。 Hereinafter, the present invention will be described in more detail by way of examples and reference examples, but the scope of the invention is not limited thereto.
又，以下所使用之簡稱具有如以下之意義。 Further, the abbreviations used below have the following meanings.
mg：毫克，g：公克，mL：毫升，MHz：兆赫。 Mg: mg, g: g, mL: ml, MHz: megahertz.
DCM：二氯甲烷 DCM: dichloromethane
DEE：乙醚 DEE: ether
DME：二甲氧乙烷 DME: Dimethoxyethane
DMF：N,N-二甲基甲醯胺 DMF: N,N-dimethylformamide
THF：四氫呋喃 THF: tetrahydrofuran
EtOH：乙醇 EtOH: ethanol
MeOH：甲醇 MeOH: methanol
己烷：n-己烷 Hexane: n-hexane
DPPA：疊氮磷酸二苯酯 DPPA: diphenyl azide
DIPEA：二異丙基乙基胺 DIPEA: Diisopropylethylamine
WSC：1-乙基-3-(3-二甲胺基丙基)碳二亞胺 鹽酸鹽(Water Soluble Carbodiimide) WSC: 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (Water Soluble Carbodiimide)
HOBt：1-羥基苯并三唑 HOBt: 1-hydroxybenzotriazole
DMT-MM：4(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓鹽酸鹽水合物 DMT-MM: 4 (4,6-dimethoxy-1,3,5-three -2-yl)-4-methyl Phosphonium hydrochloride hydrate
HATU：2-(1H-7-吖苯并三唑-1-基)-1,1,3,3-四甲基脲鎓 六氟磷酸鹽 HATU: 2-(1H-7-indole benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
HBTU：1-[雙(二甲胺基)亞甲基]-1H-苯并三唑鎓-3-氧化物 六氟磷酸鹽 HBTU: 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate
Pd(PPh3)4：肆(三苯基膦)鈀(0) Pd(PPh 3 ) 4 : 肆(triphenylphosphine)palladium (0)
Boc：三級丁氧基羰基 Boc: tertiary butoxycarbonyl
DMAP：4-二甲胺基吡啶 DMAP: 4-dimethylaminopyridine
在以下之實施例中，核磁共振(以下，稱為1H-NMR)光譜，係以四甲基矽烷作為標準物質，將化學位移值以δ值(ppm)記載。分裂圖形係將單峰以s表示，將雙峰以d表示，將三重峰以t表示，將四重峰以q表示，將多重峰以m表示，將寬峰以br表示。 In the following examples, the nuclear magnetic resonance (hereinafter referred to as 1 H-NMR) spectrum uses tetramethylnonane as a standard material, and the chemical shift value is described as a δ value (ppm). The split pattern is represented by a single peak in s, a doublet represented by d, a triplet represented by t, a quadruple peak represented by q, a multiplet represented by m, and a broad peak represented by br.
質量分析(以下，稱為MS)係以EI(電子電離，Electron Ionization)法、ESI(電噴灑電離，Electron Spray Ionization)法、或FAB(快速原子撞擊，Fast Atom Bombardment)法進行。 The mass analysis (hereinafter referred to as MS) is carried out by an EI (Electron Ionization) method, an ESI (Electron Spray Ionization) method, or a FAB (Fast Atom Bombardment) method.
6-{[2-({3-[甲基(2-啉基乙基)胺甲醯基]苯甲醯基}胺基)-5-(1-哌啶基)苯甲醯基]胺基}-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯 6-{[2-({3-[methyl(2-) Polinylethyl)amine-methylmethyl]benzhydryl}amino)-5-(1-piperidinyl)benzylidene]amino}-3,4-dihydro-1H-isoquinoline- 2-carboxylic acid tertiary butyl ester
6-{[2-胺基-5-(1-哌啶基)苯甲醯基]胺基}-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯 6-{[2-Amino-5-(1-piperidinyl)benzylidene]amino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl butyl ester
在2-硝基-5-(哌啶-1-基)苯甲酸(CAS登錄號：118159-39-0)(1.2g)之DCM(20mL)溶液中，於室溫添加6-胺基-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯(CAS登錄號：164148-92-9)(1.0g)、DIPEA(2.1mL)及HBTU(2.3g)。加熱反應混合物，於回流下攪拌8小時攪拌後，於室溫靜置一晚。濃縮反應混合物，以管柱層析純化殘留物，得到呈黃色固體之6-{[2-硝基-5-(1-哌啶基)苯甲醯基]胺基}-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯1.26g(54%)。於所得到之6-{[2-胺基-5-(1-哌啶基)苯甲醯基]胺基}-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯(1.26g)的MeOH(26mL)溶液中，添加氫氧化鈀-碳(120mg)，於氫氣環境下激烈攪拌3.5小時。將反應混合物過濾後，濃縮，以管柱層析純化殘留物，得到呈黃色固體之標題化合物1.16g(98%)。 In a solution of 2-nitro-5-(piperidin-1-yl)benzoic acid (CAS accession number: 118159-39-0) (1.2 g) in DCM (20 mL) 3,4-Dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (CAS accession number: 164148-92-9) (1.0 g), DIPEA (2.1 mL), and HBTU (2.3 g). The reaction mixture was heated, stirred under reflux for 8 hours, and then stood at room temperature overnight. The reaction mixture was concentrated, and the residue was purifiedjjjjjjjjjjjjjjjjjjjjjjjjjjjj Hydrogen-1H-isoquinoline-2-carboxylic acid tert-butyl butyl ester 1.26 g (54%). 6-{[2-Amino-5-(1-piperidinyl)benzylidene]amino}-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl A solution of the ester (1.26 g) in MeOH (26 mL) was evaporated. After the reaction mixture was filtered, m~~~~~~
6-{[2-({3-[甲基(2-啉基乙基)胺甲醯基]苯甲醯基}胺基)-5-(1-哌啶基)苯甲醯基]胺基}-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯 6-{[2-({3-[methyl(2-) Polinylethyl)amine-methylmethyl]benzhydryl}amino)-5-(1-piperidinyl)benzylidene]amino}-3,4-dihydro-1H-isoquinoline- 2-carboxylic acid tertiary butyl ester
於實施例1(1a)中所得到之化合物(1.16g)的DMF(10mL)溶液中，添加3-[甲基(2-啉基乙基)胺甲醯基]苯甲酸(CAS登錄號：1354652-99-5,WO20126473)(1.02g)、DIPEA(1.35mL)與HBTU(1.47g)。於室溫攪拌反應混合物5小時，靜置一晚後，以乙酸乙酯及水稀釋。將有機層以水及飽和食鹽水洗淨，以硫酸鎂乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色固體之標題化合物1.37g(73%)。 To a solution of the compound (1.16 g) obtained in Example 1 (1a) in DMF (10 mL) Phytylethyl)amine-mercapto]benzoic acid (CAS Accession No.: 1354652-99-5, WO20126473) (1.02 g), DIPEA (1.35 mL) and HBTU (1.47 g). The reaction mixture was stirred at room temperature for 5 hr and then stood overnight and diluted with ethyl acetate and water. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
N3-甲基-N3-(2-啉基乙基)-N1-[4-(1-哌啶基)-6-{[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]胺甲醯基}環己-2,4-二烯-1-基]苯-1,3-二甲醯胺 N3-methyl-N3-(2- Lolinylethyl)-N1-[4-(1-piperidinyl)-6-{[1-(2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]aminecarboxamide Cyclohexyl-2,4-dien-1-yl]benzene-1,3-dimethylguanamine
N-[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]胺基甲酸三級丁酯 N-[1-(2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]carbamic acid tert-butyl butyl ester
於1-(2-吡啶基)-3-(三氟甲基)吡唑-4-甲酸(CAS登錄號：1003579-18-7,WO200811131A2)(20.9g)的三級丁醇(280mL)溶液中，於室溫添加DIPEA(28.4mL)及DPPA(19.3mL)。將反應混合物加熱至90℃，攪拌4小時後，冷卻至室溫，進行濃縮。以DEE稀釋殘留物，以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨，以硫酸鎂乾燥， 過濾，接著進行濃縮。於殘留物中添加己烷，靜置，濾取經析出之固體，減壓乾燥，得到呈白色固體之標題化合物。另一方面，為了單離濾液中所含之標題化合物，濃縮濾液，以管柱層析純化殘留物，得到呈白色固體之標題化合物，合計28.8g(定量的產量)。 A solution of 1-butanol (280 mL) in 1-(2-pyridyl)-3-(trifluoromethyl)pyrazole-4-carboxylic acid (CAS accession number: 1003579-18-7, WO200811131A2) (20.9 g) Among them, DIPEA (28.4 mL) and DPPA (19.3 mL) were added at room temperature. The reaction mixture was heated to 90 ° C, stirred for 4 hours, cooled to room temperature and concentrated. The residue was diluted with aq. EtOAc (EtOAc) Filter and then concentrate. Hexane was added to the residue, and the residue was evaporated. On the other hand, in order to isolate the title compound, the filtrate was concentrated, and the residue was purified by column chromatography to afford the title compound as a white solid (28.8 g).
1-(2-吡啶基)-3-(三氟甲基)吡唑-4-胺鹽酸鹽 1-(2-pyridyl)-3-(trifluoromethyl)pyrazole-4-amine hydrochloride
於實施例2(2a)中所得到之化合物(28.7g)的THF(100mL)溶液中，於室溫添加5~10%鹽酸MeOH溶液(200mL)。將反應混合物加熱至60℃，攪拌2小時。將反應混合物冷卻至室溫，濃縮。於殘留物中添加MeOH(100mL)，於50℃溶解後，冷卻至0℃，以DEE(500mL)稀釋。濾取經析出之固體，減壓乾燥，得到呈白色固體之標題化合物19.8g(92%)。 A solution of the compound obtained in Example 2 (2a) (28.7 g) in THF (100 mL). The reaction mixture was heated to 60 ° C and stirred for 2 hours. The reaction mixture was cooled to room temperature and concentrated. MeOH (100 mL) was added to the residue, which was dissolved at 50 <0>C, cooled to 0 <0>C and diluted with <RTIgt; The precipitated solid was filtered and dried <jjjjjjjjj
5-氟-2-硝基-N-[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]苯甲醯胺 5-fluoro-2-nitro-N-[1-(2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]benzamide
於5-氟-2-硝基苯甲酸(CAS登錄號：320-98-9)(18.3g)的DCM(500mL)溶液中，於室溫添加草醯氯(9.0mL)及DMF(0.38mL)。於室溫將反應混合物攪拌2.5小時，濃縮反應混合物，以DCM(300mL)稀釋。於此DCM溶液中，於0℃緩緩添加吡啶(15.9mL)及實施例2(2b)中所得到之化合物(19.8g)的DCM(100mL)溶液。於室溫將反應混合物攪拌1小時後，以飽和碳酸氫鈉水溶液稀釋，以DCM萃取。將有機層以硫酸鎂乾燥，過濾，濃縮。以DEE過 濾經析出之固體，以減壓乾燥，得到呈白色固體標題化合物27.4g(92%)。 To a solution of 5-fluoro-2-nitrobenzoic acid (CAS accession number: 320-98-9) (18.3 g) in DCM (500 mL), EtOAc (EtOAc) ). The reaction mixture was stirred at room temperature for 2.5 hr. A solution of the pyridine (15.9 mL) and the compound (19.8 g) obtained in Example 2 (2b) in DCM (100 mL) was slowly added to the DCM solution. After the reaction mixture was stirred at room temperature for 1 hour, it was diluted with aq. The organic layer was dried with MgSO4, filtered and evaporated. With DEE The precipitated solid was filtered, dried mjjjjjjjj
2-硝基-5-(1-哌啶基)-N-[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]苯甲醯胺 2-nitro-5-(1-piperidinyl)-N-[1-(2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]benzamide
於實施例2(2c)中所得到之化合物(27.4g)的THF(350mL)溶液中，於室溫添加哌啶(20.5mL)。將反應混合物加熱，於60℃攪拌5小時後，冷卻至室溫，以DEE稀釋。濾取經析出之固體，以DEE洗淨，以減壓乾燥，得到呈黃色固體之標題化合物30.5g(96%)。 To a solution of the compound (27.4 g) obtained from m. The reaction mixture was heated, stirred at 60 ° C for 5 hours, cooled to room temperature and diluted with EtOAc. The precipitated solid was filtered, washed with EtOAc EtOAcjjjjjj
(2e)2-胺基-5-(1-哌啶基)-N-[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]苯甲醯胺 (2e) 2-Amino-5-(1-piperidinyl)-N-[1-(2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]benzamide
於實施例2(2d)中所得到之化合物(27.5g)的MeOH(100mL)、THF(200mL)溶液中，於室溫添加氫氧化鈀-碳(2g)，加熱至60℃。其後，以空氣冷卻下徐徐冷卻至室溫，並於氫氣環境下激烈攪拌4.5小時。將反應混合物過濾後，濃縮，得到呈淡黃色固體之標題化合物25.4g(99%)。 To a solution of the compound (27.5 g) obtained in Example 2 (2d), MeOH (100 mL), THF (200 mL). Thereafter, the mixture was cooled to room temperature under air cooling, and vigorously stirred under a hydrogen atmosphere for 4.5 hours. The reaction mixture was filtered and evaporated tolululululu
(2f)N3-甲基-N3-(2-啉基乙基)-N1-[4-(1-哌啶基)-6-{[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]胺甲醯基}環己-2,4-二烯-1-基]苯-1,3-二甲醯胺 (2f)N3-methyl-N3-(2- Lolinylethyl)-N1-[4-(1-piperidinyl)-6-{[1-(2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]aminecarboxamide Cyclohexyl-2,4-dien-1-yl]benzene-1,3-dimethylguanamine
以與實施例1(1b)同樣的方法，從於實施例2(2e)中所得到之化合物(14.0g)與3-[甲基(2-啉基乙基)胺甲醯基]苯甲酸(CAS登錄號：1354652-99-5,WO20126473)(11.4g)，得到呈黃色固體之標題化合物19.8g(86%)。 The compound (14.0 g) obtained from Example 2 (2e) and 3-[methyl (2-) were obtained in the same manner as in Example 1 (1b). The title compound 19.8 g (86%) was obtained as a yellow solid. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
2-({3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基}胺基)-5-(1-哌啶基)-N-{3-(三氟甲基)-1-[3-(三氟甲基)苯基]吡唑-4-基}苯甲醯胺 2-({3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl}amino)-5-(1-piperidinyl)-N-{3-(trifluoromethyl)-1-[3-(trifluoromethyl) Phenyl]pyrazol-4-yl}benzamide
3-(三氟甲基)-1-[3-(三氟甲基)苯基]吡唑-4-甲酸乙酯 Ethyl 3-(trifluoromethyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-carboxylate
於3-(三氟甲基)-1H-吡唑-4-甲酸乙酯(1.0g)的甲苯(5mL)溶液中，於室溫添加1-碘-3-(三氟甲基)苯(0.83mL)、碘化銅(274mg)、(1R,2R)-N,N'-二甲基環己烷-1,2-二胺(0.45mL)與碳酸鉀(1.39g)。加熱反應混合物，於110℃攪拌2小時後，冷卻至室溫，以乙酸乙酯稀釋，以飽和氯化銨水溶液洗淨。將有機層以硫酸鎂乾燥，過濾，濃縮。將殘留物溶解於DCM中，並添加己烷，濾取經析出之固體，得到呈白色固體之標題化合物728mg(43%)。 Add 1-iodo-3-(trifluoromethyl)benzene at room temperature in a solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (1.0 g) in toluene (5 mL) 0.83 mL), copper iodide (274 mg), (1 R , 2 R )-N, N'-dimethylcyclohexane-1,2-diamine (0.45 mL) and potassium carbonate (1.39 g). The reaction mixture was heated and stirred at 110 ° C for 2 hr then cooled to EtOAc. The organic layer was dried with MgSO4, filtered and evaporated. The residue was dissolved in EtOAc EtOAc (EtOAc)
N-{3-(三氟甲基)-1-[3-(三氟甲基)苯基]吡唑-4-基}胺基甲酸三級丁酯 N-{3-(trifluoromethyl)-1-[3-(trifluoromethyl)phenyl]pyrazol-4-yl}carbamic acid tert-butyl butyl ester
於實施例3(3a)中所得到之化合物(728mg)的MeOH(10mL)溶液中，於室溫添加5N NaOH水溶液(1.24mL)。將反應混合物攪拌14小時後，於反應混合物中添加5NHCl水溶液(反應混合物為白濁之量)，以水稀釋，接著以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨，以硫酸鎂乾燥，過濾，接著進行濃縮。以與實施例2(2a) 同樣之方法，由殘留物(461mg)得到呈白色固體之標題化合物560mg(定量的產量)。 A solution of the compound (728 mg) in MeOH (10 mL) After the reaction mixture was stirred for 14 hours, aq. 5N HCl solution (the mixture was obtained as white turbid) was diluted with water and then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. And with Example 2 (2a) In the same manner, 560 mg (quant. yield) of the title compound was obtained as a white solid.
3-(三氟甲基)-1-[3-(三氟甲基)苯基]吡唑-4-胺鹽酸鹽 3-(Trifluoromethyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-amine hydrochloride
以與實施例2(2b)同樣的方法，由實施例3(3b)中所得到之化合物(560mg)，得到呈白色固體之標題化合物396mg(95%)。 The compound (560 mg) obtained from m.
5-氟-2-硝基-N-{3-(三氟甲基)-1-[3-(三氟甲基)苯基]吡唑-4-基}苯甲醯胺 5-fluoro-2-nitro-N-{3-(trifluoromethyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-yl}benzamide
以與實施例2(2c)同樣的方法，由實施例3(3c)中所得到之化合物(396mg)與5-氟-2-硝基苯甲酸(372mg)，得到呈白色固體之標題化合物642mg(定量的產量)。 The title compound 642 mg (yield: 356 mg), m. (quantitative yield).
2-胺基-5-(1-哌啶基)-N-{3-(三氟甲基)-1-[3-(三氟甲基)苯基]吡唑-4-基}苯甲醯胺 2-Amino-5-(1-piperidinyl)-N-{3-(trifluoromethyl)-1-[3-(trifluoromethyl)phenyl]pyrazole-4-yl}benzene Guanamine
於實施例3(3d)中所得到之化合物(396mg)的THF(10mL)溶液中，於室溫添加哌啶(0.25mL)。加熱反應混合物，於50℃攪拌2小時後，冷卻至室溫，濃縮。於殘留物之MeOH(5mL)、THF(5mL)溶液中，於室溫添加氫氧化鈀-碳(50mg)。將反應混合物於氫氣環境下，於室溫激烈攪拌2小時。過濾反應混合物後，濃縮，得到呈黃色固體之標題化合物380mg(89%)。 A solution of the compound (396 mg) obtained from m. The reaction mixture was heated and stirred at 50 ° C for 2 hr then cooled to room temperature and concentrated. Palladium hydroxide-carbon (50 mg) was added at room temperature to a solution of EtOAc (5 mL)EtOAc. The reaction mixture was vigorously stirred at room temperature for 2 hours under a hydrogen atmosphere. After the reaction mixture was filtered, EtOAcjjjjjjjjj
2-({3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基}胺基)-5-(1-哌啶基)-N-{3-(三氟甲基)-1-[3-(三氟甲基)苯基]吡唑-4-基}苯甲醯胺 2-({3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl}amino)-5-(1-piperidinyl)-N-{3-(trifluoromethyl)-1-[3-(trifluoromethyl) Phenyl]pyrazol-4-yl}benzamide
以與實施例1(1b)同樣的方法，由實施例3(3e)中所得到之化合物(100mg)與參考例1中所得到之3-[甲基(2-啉基乙基)胺磺醯基]苯甲酸(79mg)，得到呈黃色固體之標題化合物124mg。 The compound (100 mg) obtained in Example 3 (3e) and the 3-[methyl (2-) obtained in Reference Example 1 were obtained in the same manner as in Example 1 (1b). Phenylethyl)amine sulfonyl]benzoic acid (79 mg) gave the title compound 124m.
N-{4-異丙基-1-[3-(三氟甲基)苯基]吡唑-3-基}-2-({3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基}胺基)-5-(1-哌啶基)苯甲醯胺 N-{4-isopropyl-1-[3-(trifluoromethyl)phenyl]pyrazol-3-yl}-2-({3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl}amino)-5-(1-piperidinyl)benzamide
4-溴-1-[3-(三氟甲基)苯基]吡唑-3-胺 4-bromo-1-[3-(trifluoromethyl)phenyl]pyrazole-3-amine
於1-[3-(三氟甲基)苯基]吡唑-3-胺(1.0g)的THF(20mL)溶液中，於室溫添加NBS(0.86g)。將反應混合物於室溫攪拌1小時後，以DCM、飽和碳酸氫鈉水溶液、10%硫代硫酸鈉水溶液稀釋，以DCM萃取。將有機層以硫酸鎂乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈白色固體之標題化合物1.28g(95%)。 To a solution of 1-[3-(trifluoromethyl)phenyl]pyrazol-3-amine (1.0 g) in THF (20 mL) After the reaction mixture was stirred at room temperature for 1 hour, diluted with DCM, sat. The organic layer was dried over magnesium sulfate, filtered and then concentrated. The residue was purified by EtOAcjjjjjjjjj
N-[4-溴-1-[3-(三氟甲基)苯基]吡唑-3-基]-5-氟-2-硝基-苯甲醯胺 N-[4-bromo-1-[3-(trifluoromethyl)phenyl]pyrazol-3-yl]-5-fluoro-2-nitro-benzamide
以與實施例2(2c)同樣的方法，由實施例4(4a)中所得到之化合物(1.16g)，得到呈白色固體之標題化合物760mg(38%)。 The title compound (760 mg) (yield: 38%)
N-{4-溴-1-[3-(三氟甲基)苯基]吡唑-3-基}-2-硝基-5-(1-哌啶基)苯甲醯胺 N-{4-bromo-1-[3-(trifluoromethyl)phenyl]pyrazol-3-yl}-2-nitro-5-(1-piperidyl)benzamide
以與實施例2(2d)同樣的方法，由實施例4(4b)中所得到之化合物(760mg)，得到呈黃色固體之標題化合物904mg(定量的產量)。 The title compound (904 mg) was obtained as a yellow solid (yield).
N-{4-異丙基-1-[3-(三氟甲基)苯基]吡唑-3-基}-2-({3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基}胺基)-5-(1-哌啶基)苯甲醯胺 N-{4-isopropyl-1-[3-(trifluoromethyl)phenyl]pyrazol-3-yl}-2-({3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl}amino)-5-(1-piperidinyl)benzamide
於實施例4(4c)中所得到之化合物(504mg)的THF/EtOH(2.5：1,7mL)溶液中，於室溫添加鐵粉(261mg)及飽和氯化銨水溶液(2mL)。將反應混合物加熱至70℃，攪拌2小時後，將反應混合物以THF及水洗淨，並過濾，將濾液以乙酸乙酯萃取。將有機層以硫酸鎂乾燥，過濾，濃縮。以管柱層析純化殘留物，得到呈黃色油狀物之2-胺基-N-{4-溴-1-[3-(三氟甲基)苯基]吡唑-3-基}-5-(1-哌啶基)苯甲醯胺426mg(83%)。 An iron powder (261 mg) and a saturated aqueous ammonium chloride solution (2 mL) were added at room temperature to a solution of THF/EtOH (2.5:1, 7 mL). After the reaction mixture was heated to 70 ° C and stirred for 2 hr, the mixture was washed with THF and water and filtered, The organic layer was dried with MgSO4, filtered and evaporated. The residue was purified by column chromatography eluting elut elut elut eluting 5-(1-piperidinyl)benzamide 426 mg (83%).
以與實施例3(3f)同樣的方法，由2-胺基-N-{4-溴-1-[3-(三氟甲基)苯基]吡唑-3-基}-5-(1-哌啶基)苯甲醯胺(426mg)，得到呈黃色固體之N-{4-溴-1-[3-(三氟甲基)苯基]吡唑-3-基}-2-({3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基}胺基)-5-(1-哌啶基)苯甲醯胺370mg(54%)。於所得到之N-{4-溴-1-[3-(三氟甲基)苯基]吡唑-3-基}-2-({3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基}胺 基)-5-(1-哌啶基)苯甲醯胺(100mg)的1,4-二烷/水(3：1,4mL)溶液中，於室溫添加2-異丙烯基-4,4,5,5-四甲基-1,3,2-二氧環戊硼烷(0.11mL)、Pd(PPh3)4(14mg)、磷酸三鉀(78mg)。將反應混合物於微波照射下、於130℃攪拌1小時。將反應混合物冷卻至室溫，以水稀釋，以乙酸乙酯萃取，將有機層以硫酸鎂乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色固體之標題化合物80mg(80%)。 In the same manner as in Example 3 (3f), 2-amino-N-{4-bromo-1-[3-(trifluoromethyl)phenyl]pyrazol-3-yl}-5-( 1-piperidinyl)benzamide (426 mg) afforded N-{4-bromo-1-[3-(trifluoromethyl)phenyl]pyrazol-3-yl}-2- ({3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl}amino)-5-(1-piperidinyl)benzamide 370 mg (54%). N-{4-bromo-1-[3-(trifluoromethyl)phenyl]pyrazol-3-yl}-2-({3-[methyl(2-) obtained 1,4-diethyl sulfonyl)benzhydryl}amino)-5-(1-piperidinyl)benzamide (100 mg) In a solution of alkane/water (3:1, 4 mL), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane (0.11 mL) was added at room temperature. ), Pd(PPh 3 ) 4 (14 mg), tripotassium phosphate (78 mg). The reaction mixture was stirred at 130 ° C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc. The residue was purified with EtOAc EtOAcjjjjjj
N5-甲基-N5-(2-啉基乙基)-N3-(4-(1-哌啶基)-2-{[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]胺甲醯基}苯基)吡啶-3,5-二甲醯胺 N5-methyl-N5-(2- Phytylethyl)-N3-(4-(1-piperidinyl)-2-{[1-(2-pyridyl)-3-(trifluoromethyl)pyrazol-4-yl]aminecarboxamide Phenyl)pyridine-3,5-dimethylguanamine
以與實施例1(1b)同樣的方法，由實施例2(2e)中所得到之化合物(500mg)及參考例2中所得到之化合物(620mg)，得到呈黃色固體之標題化合物855mg(84%)。 The compound (500 mg) obtained in Example 2 (2e) and the title compound ( 620 mg) %).
5-[甲基(2-啉基乙基)胺磺醯基]-N-(4-(1-哌啶基)-2-{[1-(2-吡啶基)-3-(三氟甲基)吡唑-4-基]胺甲醯基}苯基)吡啶-3-甲醯胺 5-[methyl (2- Lolinylethyl)amine sulfonyl]-N-(4-(1-piperidinyl)-2-{[1-(2-pyridyl)-3-(trifluoromethyl)pyrazole-4- Aminomethyl}phenyl)pyridine-3-carboxamide
以與實施例1(1b)同樣的方法，由實施例2(2e)中所得到之化合物(150mg)及參考例3中所得到之化合物(135mg)，得到呈黃色固體之標題化合物83mg(32%)。 The title compound (32 mg) was obtained from the title compound (m. %).
N’-[4-(二乙胺基)-2-(4-{[3-(三氟甲基)苄基]胺甲醯基}嘧啶-2-基)苯基]-N-甲基-N-[2-(啉-4-基)乙基]異酞醯胺 N'-[4-(Diethylamino)-2-(4-{[3-(trifluoromethyl)benzyl]aminemethanoyl}pyrimidin-2-yl)phenyl]-N-methyl -N-[2-( Phenyl-4-yl)ethyl]isodecylamine
2-氯-N-[3-(三氟甲基)苄基]嘧啶-4-甲醯胺 2-chloro-N-[3-(trifluoromethyl)benzyl]pyrimidine-4-carboxamide
於2-氯嘧啶-4-甲酸(500mg)的DMF(30mL)溶液中，於室溫添加3-(三氟乙基)苄基胺(CAS登錄號：2740-83-2)(276mg)、WSC(1.2g)及HOBt(638.7mg)。將反應混合物攪拌2小時，以水稀釋，以乙酸乙酯萃取。將有機層以飽和碳酸氫鈉及飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈無色液體之標題化合物710mg(70%)。 3-(Trifluoroethyl)benzylamine (CAS Accession No.: 2740-83-2) (276 mg) was added to a solution of 2-chloropyrimidine-4-carboxylic acid (500 mg) in DMF (30 mL). WSC (1.2 g) and HOBt (638.7 mg). The reaction mixture was stirred for 2 hrs, diluted with water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting elut elut elut elut elut
2-(5-氟-2-硝基苯基)-N-[3-(三氟甲基)苄基]嘧啶-4-甲醯胺 2-(5-fluoro-2-nitrophenyl)-N-[3-(trifluoromethyl)benzyl]pyrimidine-4-carboxamide
於實施例7(7a)中所得到之化合物(200mg)及2-(5-氟-2-硝基-苯基)-4,4,5,5-四甲基-1,3,2-二氧環戊硼烷(CAS登錄號：925207-14-3,Organic and Biomolecular Chemistry,2007,vol.5,# 1,p.114-120)(169mg)的DME(10mL)及水(1mL)溶液中，於室溫添加氯(2-二環己基膦基-2’,4’,6’-三異丙基-1,1’-聯苯)[2-(2’-胺基-1,1’-聯苯)鈀(II)(50mg)及磷酸三鉀(404mg)。將反應混合物於80℃攪拌6小時，以水稀釋，以乙酸乙酯萃取。將有機層以飽和碳酸氫鈉及飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈無色液體之標題化合物292mg(100%)。 The compound (200 mg) obtained in Example 7 (7a) and 2-(5-fluoro-2-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2- Dioxetaneborane (CAS Accession No.: 925207-14-3, Organic and Biomolecular Chemistry, 2007, vol. 5, #1, p. 114-120) (169 mg) of DME (10 mL) and water (1 mL) In the solution, add chlorine (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1) at room temperature , 1 '-biphenyl) palladium (II) (50 mg) and tripotassium phosphate (404 mg). The reaction mixture was stirred at 80 <0>C for 6 h, diluted with water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcqqqqqq
2-[5-(二乙胺基)-2-硝基苯基]-N-[3-(三氟甲基)苄基]嘧啶-4-甲醯胺 2-[5-(Diethylamino)-2-nitrophenyl]-N-[3-(trifluoromethyl)benzyl]pyrimidine-4-carboxamide
於實施例7(7b)中所得到之化合物(600mg)的DMF(20mL)溶液中，於室溫添加碳酸鉀(790mg)及二乙胺(3.0mL)。將反應混合物於70℃攪拌4小時，以水稀釋，以乙酸乙酯萃取。將有機層以飽和碳酸氫鈉及飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮，得到粗生成物2-[2-胺基-5-(二乙胺基)苯基]-N-[3-(三氟甲基)苄基]嘧啶-4-甲醯胺(620mg)。 Potassium carbonate (790 mg) and diethylamine (3.0 mL) were added at room temperature to a solution of the compound (600 mg). The reaction mixture was stirred at 70 <0>C for 4 h, diluted with water andEtOAc. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and then concentrated to give the crude product 2-[2-amino-5-(diethylamino)phenyl]- N-[3-(Trifluoromethyl)benzyl]pyrimidine-4-carboxamide (620 mg).
N’-[4-(二乙胺基)-2-(4-{[3-(三氟甲基)苄基]胺甲醯基}嘧啶-2-基)苯基]-N-甲基-N-[2-(啉-4-基)乙基]異酞醯胺 N'-[4-(Diethylamino)-2-(4-{[3-(trifluoromethyl)benzyl]aminemethanoyl}pyrimidin-2-yl)phenyl]-N-methyl -N-[2-( Phenyl-4-yl)ethyl]isodecylamine
於2-[2-胺基-5-(二乙胺基)苯基]-N-[3-(三氟甲基)苄基]嘧啶-4-甲醯胺(620mg)的MeOH(20mL)溶液中，於室溫添加10%鈀-碳。將反應混合物於氫氣環境下，於室溫攪拌6小時。以矽藻土進行過濾，接著進行濃縮，得到粗生成物N’-[4-(二乙胺基)-2-(4-{[3-(三氟甲基)苄基]胺甲醯基}嘧啶-2-基)苯基]-N-甲基-N-[2-(啉-4-基)乙基]異酞醯胺(420mg)。 2-[2-Amino-5-(diethylamino)phenyl]-N-[3-(trifluoromethyl)benzyl]pyrimidine-4-carboxamide (620 mg) in MeOH (20 mL) In the solution, 10% palladium-carbon was added at room temperature. The reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. Filtration with diatomaceous earth followed by concentration gave the crude product N'-[4-(diethylamino)-2-(4-{[3-(trifluoromethyl)benzyl]aminecarbamyl }pyrimidin-2-yl)phenyl]-N-methyl-N-[2-( Polin-4-yl)ethyl]isodecylamine (420 mg).
N’-[4-(二乙胺基)-2-(4-{[3-(三氟甲基)苄基]胺甲醯基}嘧啶-2-基)苯基]-N-甲基-N-[2-(啉-4-基)乙基]異酞醯胺 N'-[4-(Diethylamino)-2-(4-{[3-(trifluoromethyl)benzyl]aminemethanoyl}pyrimidin-2-yl)phenyl]-N-methyl -N-[2-( Phenyl-4-yl)ethyl]isodecylamine
於N’-[4-(二乙胺基)-2-(4-{[3-(三氟甲基)苄基]胺甲醯基}嘧啶-2-基)苯基]-N-甲基-N-[2-(啉-4-基)乙基]異酞醯胺(90mg)及3-[甲基(2-啉基乙基)胺甲醯基]苯甲 酸(59.4mg)的DMF(2mL)溶液中，於室溫添加4-(4,6-二甲氧基-1,3,5-三-2-基)-4-甲基啉鎓鹽酸鹽水合物(119.6mg)。將反應混合物於室溫攪拌20小時，以水稀釋，以乙酸乙酯萃取。將有機層以飽和碳酸氫鈉及飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色固體之標題化合物122mg(85%)。 In N'-[4-(diethylamino)-2-(4-{[3-(trifluoromethyl)benzyl]amine-carbamoyl}pyrimidin-2-yl)phenyl]-N- base-N-[2-( Phenyl-4-yl)ethyl]isodecylamine (90 mg) and 3-[methyl (2- Addition of 4-(4,6-dimethoxy-1,3,5-triol) at room temperature to a solution of phenyl phenylethyl) carbamoyl]benzoic acid (59.4 mg) in DMF (2 mL) -2-yl)-4-methyl Bordrine hydrochloride hydrate (119.6 mg). The reaction mixture was stirred at room temperature for 20 hr, diluted with water andEtOAc. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
N’-[4-(二乙胺基)-2-{4-[(1S)-1,2,3,4-四氫萘-1-基胺甲醯基]嘧啶-2-基}苯基]-N-甲基-N-[2-(啉-4-基)乙基]異酞醯胺 N'-[4-(Diethylamino)-2-{4-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylaminemethylindenyl]pyrimidin-2-yl}benzene Base]-N-methyl-N-[2-( Phenyl-4-yl)ethyl]isodecylamine
2-氯-N-[(1S)-1,2,3,4-四氫萘-1-基]嘧啶-4-甲醯胺 2-Chloro-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrimidine-4-carboxamide
於2-氯嘧啶-4-甲酸(CAS登錄號：149849-92-3)(248mg)的DMF(10mL)溶液中，於室溫添加(S)-(+)-1,2,3,4-四氫-1-萘基胺(CAS登錄號：23357-52-0)(276mg)、WSC(600mg)及HOBt(210mg)。將反應混合物攪拌3小時，以水稀釋，以乙酸乙酯萃取。將有機層以飽和碳酸氫鈉及飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈無色液體之標題化合物366mg(79%)。 Add (S)-(+)-1,2,3,4 at room temperature to a solution of 2-chloropyrimidine-4-carboxylic acid (CAS accession number: 149849-92-3) (248 mg) in DMF (10 mL) Tetrahydro-1-naphthylamine (CAS Accession No.: 23357-52-0) (276 mg), WSC (600 mg), and HOBt (210 mg). The reaction mixture was stirred for 3 hrs, diluted with water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjjj
2-(5-氟-2-硝基苯基)-N-[(1S)-1,2,3,4-四氫萘-1-基]嘧啶-4-甲醯胺 2-(5-Fluoro-2-nitrophenyl)-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrimidine-4-carboxamide
於實施例8(8a)中所得到之化合物(366mg)及2-(5-氟-2-硝基-苯基)-4,4,5,5-四甲基-1,3,2-二氧環戊硼烷(341mg)的DME(10mL)及水(1mL)溶液中，於室溫添加氯(2-二環己基膦基-2’,4’,6’-三異丙基-1,1’-聯苯)[2-(2’-胺基-1,1’-聯苯)鈀(II)(100mg)及磷酸三鉀(812mg)。將反應混合物於90℃攪拌6小時，以水稀釋，以乙酸乙酯萃取。將有機層以飽和碳酸氫鈉及飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈無色固體之標題化合物592mg(100%)。 The compound (366 mg) obtained in Example 8 (8a) and 2-(5-fluoro-2-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2- Add dichlorocyclopentane borane (341 mg) in DME (10 mL) and water (1 mL) at room temperature and add chloro (2-dicyclohexylphosphino-2',4',6'-triisopropyl- 1,1'-biphenyl) [2-(2'-Amino-1,1'-biphenyl)palladium (II) (100 mg) and tripotassium phosphate (812 mg). The reaction mixture was stirred at 90 <0>C for 6 h, diluted with water andEtOAc. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAcjjjjjj
2-[5-(二乙胺基)-2-硝基苯基]-N-[(1S)-1,2,3,4-四氫萘-1-基]嘧啶-4-甲醯胺 2-[5-(Diethylamino)-2-nitrophenyl]-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrimidine-4-carboxamide
於實施例8(8b)中所得到之化合物(1.5g)的DMF(40mL)溶液中，於室溫添加碳酸鉀(3.0mg)及二乙胺(3.0mL)。將反應混合物於70℃攪拌4小時，以水稀釋，以乙酸乙酯萃取。將有機層以飽和碳酸氫鈉及飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色固體之標題化合物1.3g(73%)。 Potassium carbonate (3.0 mg) and diethylamine (3.0 mL) were added at room temperature to a solution of the compound (1.5 g). The reaction mixture was stirred at 70 <0>C for 4 h, diluted with water andEtOAc. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjjj
2-[2-胺基-5-(二乙胺基)苯基]-N-[(1S)-1,2,3,4-四氫萘-1-基]嘧啶-4-甲醯胺 2-[2-Amino-5-(diethylamino)phenyl]-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrimidine-4-carboxamide
於實施例8(8c)中所得到之化合物(1.3g)的MeOH(50mL)溶液中，於室溫添加10%鈀-碳(1.0g)。將反應混合物於氫氣環境下，於室溫攪拌6小時。以矽藻土 進行過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色固體之標題化合物1.34g(100%)。 A solution of the compound (1.3 g) obtained in EtOAc (EtOAc m. The reaction mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere. Diatomaceous earth Filtration was carried out followed by concentration. The residue was purified by EtOAcjjjjjjjjj
N’-[4-(二乙胺基)-2-{4-[(1S)-1,2,3,4-四氫萘-1-基胺甲醯基]嘧啶-2-基}苯基]-N-甲基-N-[2-(啉-4-基)乙基]異酞醯胺 N'-[4-(Diethylamino)-2-{4-[(1S)-1,2,3,4-tetrahydronaphthalen-1-ylaminemethylindenyl]pyrimidin-2-yl}benzene Base]-N-methyl-N-[2-( Phenyl-4-yl)ethyl]isodecylamine
於實施例8(8d)中所得到之化合物(110mg)及3-[甲基(2-啉基乙基)胺甲醯基]苯甲酸(136.4mg)的DMF(3mL)溶液中，於室溫添加DMT-MM(167.4mg)。將反應混合物於室溫攪拌20小時，以水稀釋，以乙酸乙酯萃取。將有機層以飽和碳酸氫鈉及飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色固體之定量的產率的標題化合物182mg。 The compound (110 mg) obtained in Example 8 (8d) and 3-[methyl (2- To a solution of phenyl phenylethyl) carbamoyl]benzoic acid (136.4 mg) in DMF (3 mL) The reaction mixture was stirred at room temperature for 20 hr, diluted with water andEtOAc. The organic layer was washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcqqqqqq
N3-[4-(二乙胺基)-2-(5-{[3-(三氟甲基)苯基]甲基胺甲醯基}唑-2-基)苯基]-N1-甲基-N1-(2-啉基乙基)苯-1,3-二甲醯胺 N3-[4-(diethylamino)-2-(5-{[3-(trifluoromethyl)phenyl]methylaminemethanyl} Zin-2-yl)phenyl]-N1-methyl-N1-(2- Polinylethyl)benzene-1,3-dimethylguanamine
2-(5-氟-2-硝基-苯基)唑-5-甲酸乙酯 2-(5-fluoro-2-nitro-phenyl) Ethyl azole-5-carboxylate
於2-(5-氟-2-硝基-苯基)-4,4,5,5-四甲基-1,3,2-二氧環戊硼烷(273mg)的1,4-二烷/水(4：1,5mL)溶液中，於室溫添加2-溴唑-5-甲酸乙酯(150mg)、氯(2-二環己基膦基-2’,4’,6’-三異丙基-1,1’-聯苯)[2-(2’-胺基-1,1’-聯苯)鈀(II)(54mg)、磷酸三鉀(434mg)。將反應混合物於微 波照射下，於130℃攪拌1小時。將反應混合物冷卻至室溫，以水稀釋，以乙酸乙酯萃取，將有機層以硫酸鎂乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈白色固體之標題化合物48mg(25%)。 1,4-two of 2-(5-fluoro-2-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane borane (273 mg) Add 2-bromo at room temperature in alkane/water (4:1, 5 mL) solution Ethyl azole-5-carboxylate (150 mg), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'- Amino-1,1'-biphenyl)palladium (II) (54 mg), tripotassium phosphate (434 mg). The reaction mixture was stirred at 130 ° C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, diluted with EtOAc EtOAc. The residue was purified by EtOAcqqqqqq
2-[5-(二乙胺基)-2-硝基-苯基)唑-5-甲酸乙酯 2-[5-(diethylamino)-2-nitro-phenyl) Ethyl azole-5-carboxylate
以與實施例2(2d)同樣的方法，由實施例9(9a)中所得到之化合物(118mg)及二乙胺(1mL)，得到呈黃色固體之標題化合物132mg(94%) The title compound (132 mg) (yield: 94%) Compound Compound Compound Compound Compound Compound Compound
2-[5-(二乙胺基)-2-硝基-苯基]-N-{[3-(三氟甲基)苯基]甲基}唑-5-甲醯胺 2-[5-(Diethylamino)-2-nitro-phenyl]-N-{[3-(trifluoromethyl)phenyl]methyl} Oxazol-5-carboxamide
於實施例9(9b)中所得到之化合物(132mg)的MeOH(8mL)溶液中，於室溫添加5N NaOH水溶液。將反應混合物加熱，於60℃攪拌3小時後，冷卻至室溫。於反應混合物中添加HCl水溶液至變成pH4為止，濃縮。將殘留物溶解於MeOH(4mL)中，於室溫添加3-(三氟甲基)苄基胺(0.21mL)及DMT-MM(387mg)。將反應混合物於室溫攪拌4小時後，以飽和碳酸氫鈉水溶液稀釋，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，濃縮。以管柱層析純化殘留物，得到呈黃色油狀物之標題化合物184mg(定量的產量)。 A solution of the compound (132 mg) obtained from m. The reaction mixture was heated, stirred at 60 ° C for 3 hours and then cooled to room temperature. An aqueous HCl solution was added to the reaction mixture until it became pH 4, and concentrated. The residue was dissolved in MeOH (4 mL) EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 4 hr. The organic layer was washed with brine, dried over sodium sulfate The residue was purified by column chromatography eluting elut elut elut eluting
N3-[4-(二乙胺基)-2-(5-{[3-(三氟甲基)苯基]甲基胺甲醯基}唑-2-基)苯基]-N1-甲基-N1-(2-啉基乙基)苯-1,3-二甲醯胺 N3-[4-(diethylamino)-2-(5-{[3-(trifluoromethyl)phenyl]methylaminemethanyl} Zin-2-yl)phenyl]-N1-methyl-N1-(2- Polinylethyl)benzene-1,3-dimethylguanamine
於實施例9(9c)中所得到之化合物(184mg)的MeOH(2mL)、THF(2mL)溶液中，於室溫添加氫氧化鈀-碳(20mg)。將反應混合物於氫氣環境下，於室溫激烈攪拌2小時。將反應混合物過濾後，濃縮，得到殘留物169mg。以與實施例1(1b)同樣的方法，由殘留物(76mg)及3-[甲基(2-啉基乙基)胺甲醯基]苯甲酸(77mg)，得到呈黃色固體之標題化合物96mg(77%)。 A solution of the compound (184 mg) obtained in EtOAc (MeOH) (EtOAc) The reaction mixture was vigorously stirred at room temperature for 2 hours under a hydrogen atmosphere. After filtering the reaction mixture, it was concentrated to give 179 mg. In the same manner as in Example 1 (1b), the residue (76 mg) and 3-[methyl (2-) The title compound 96 mg (77%) was obtained as a yellow solid.
N’-[4-(二乙胺基)-2-(4-{[3-(三氟甲基)苄基]胺甲醯基}-1,3-噻唑并-2-基)苯基]-N-甲基-N-[2-(四氫-2H-吡喃-4-基)乙基]苯-1,3-二甲醯胺 N'-[4-(Diethylamino)-2-(4-{[3-(trifluoromethyl)benzyl]amine-carbamoyl}-1,3-thiazolo-2-yl)phenyl ]-N-methyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]benzene-1,3-dimethylguanamine
2-(5-氟-2-硝基苯基)-1,3-噻唑-4-甲酸乙酯 Ethyl 2-(5-fluoro-2-nitrophenyl)-1,3-thiazole-4-carboxylate
於2-(5-氟-2-硝基苯基)-4,4,5,5-四甲基-1,3,2-二氧環戊硼烷(2.3g)的二甲氧乙烷溶液(20mL)中，於室溫添加2-溴-1,3-噻唑-4-甲酸乙酯(1.2g)、磷酸鉀(4.2g)、氯(2-二環己基膦基-2’,4’,6’-三異丙基-1,1’-聯苯)[2-(2’-胺基-1,1’-聯苯)鈀(II)(0.39g)、水(4mL)。將反應混合物於70℃攪拌1小時。將反應溶液注入水中，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈無色固體之標題化合物1.2g(77%)。 Dimethoxyethane of 2-(5-fluoro-2-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentane borane (2.3 g) Ethyl 2-bromo-1,3-thiazole-4-carboxylate (1.2 g), potassium phosphate (4.2 g), and chloro(2-dicyclohexylphosphino-2' were added to the solution (20 mL) at room temperature. 4',6'-Triisopropyl-1,1'-biphenyl)[2-(2'-Amino-1,1'-biphenyl)palladium(II) (0.39 g), water (4 mL) . The reaction mixture was stirred at 70 ° C for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
2-[5-(二乙胺基)-2-硝基苯基]-1,3-噻唑-4-甲酸乙酯 Ethyl 2-[5-(diethylamino)-2-nitrophenyl]-1,3-thiazole-4-carboxylate
於實施例10(10a)中所得到之化合物(0.36g)的DMF(2mL)溶液中，於室溫添加二乙胺(1.2mL)。將反應混合物於室溫攪拌6小時。將反應溶液注入水中，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈無色固體之標題化合物0.40g(100%)。 To a solution of the compound (0.36 g), m. The reaction mixture was stirred at room temperature for 6 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
2-[5-(二乙胺基)-2-硝基苯基]-1,3-噻唑-4-甲酸 2-[5-(diethylamino)-2-nitrophenyl]-1,3-thiazole-4-carboxylic acid
於實施例10(10b)中所得到之化合物(0.48g)的THF溶液(2mL)中，添加MeOH(1mL)、2MNaOH水溶液(2mL)，於室溫攪拌1小時。於減壓下蒸餾去除溶劑後，以DEE稀釋，以2MHCl水溶液使溶液變成酸性後，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，濃縮，得到標題化合物之粗純化物(0.44g)。此物不再進行任何純化，而使用於下述步驟。 THF (1 mL) and a 2M aqueous NaOH solution (2 mL) were added to the THF solution (2 mL). After distilling off the solvent under reduced pressure, the mixture was diluted with EtOAc, and the solution was acidified with 2M aqueous HCl. The organic layer was washed with EtOAc EtOAc m. This material was not subjected to any purification and was used in the following procedure.
2-[5-(二乙胺基)-2-硝基苯基]-N-[3-(三氟甲基)苄基]-1,3-噻唑-4-甲醯胺 2-[5-(Diethylamino)-2-nitrophenyl]-N-[3-(trifluoromethyl)benzyl]-1,3-thiazole-4-carboxamide
於實施例10(10c)中所得到之化合物之粗純化物(0.44g)的DMF溶液(3mL)中，於室溫添加1-[3-(三氟甲基)苯基]甲烷胺(0.46mL)、DMT-MM(0.55g)。將反應混合物於室溫攪拌2小時。將反應溶液注入水中，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。利用再結晶將殘留物純化，得到呈無色固體之標題化合物0.45g(69%)。 To a crude purified product (0.44 g) of EtOAc (EtOAc m. mL), DMT-MM (0.55 g). The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAc (EtOAc):
2-[2-胺基-5-(二乙胺基)苯基]-N-[3-(三氟甲基)苄基]-1,3-噻唑-4-甲醯胺 2-[2-Amino-5-(diethylamino)phenyl]-N-[3-(trifluoromethyl)benzyl]-1,3-thiazole-4-carboxamide
於實施例10(10d)中所得到之化合物(0.64g)的EtOH溶液(5mL)中，添加10%鈀-碳(0.20g)，將系統內以氫取代。將反應混合物於室溫攪拌8小時後，將反應溶液以矽藻土過濾，接著進行濃縮。利用再結晶將殘留物純化，得到呈淡黃色固體之標題化合物0.43g(71%)。 To a solution of the compound (0.64 g) obtained in Example 10 (10d) in EtOH (5 mL), 10% palladium-carbon (0.20 g) was added, and the system was replaced with hydrogen. After the reaction mixture was stirred at room temperature for 8 hours, the reaction solution was filtered over Celite, and then concentrated. The residue was purified by EtOAcqqqqqqq
N’-[4-(二乙胺基)-2-(4-{[3-(三氟甲基)苄基]胺甲醯基}-1,3-噻唑并-2-基)苯基]-N-甲基-N-[2-(四氫-2H-吡喃-4-基)乙基]苯-1,3-二甲醯胺 N'-[4-(Diethylamino)-2-(4-{[3-(trifluoromethyl)benzyl]amine-carbamoyl}-1,3-thiazolo-2-yl)phenyl ]-N-methyl-N-[2-(tetrahydro-2H-pyran-4-yl)ethyl]benzene-1,3-dimethylguanamine
於實施例10(10e)中所得到之化合物(0.14g)的DMF溶液(1mL)中，添加3-[甲基[2-(啉-4-基)乙基]胺甲醯基]苯甲酸(0.11g)、DMT-MM(0.11g)。將反應混合物於室溫攪拌4小時後，將反應溶液注入水中，以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈淡黃色固體之標題化合物0.11g(52%)。 In the DMF solution (1 mL) of the compound (0.14 g) obtained in Example 10 (10e), 3-[methyl[2-( Phenyl-4-yl)ethyl]amine-mercapto]benzoic acid (0.11 g), DMT-MM (0.11 g). After the reaction mixture was stirred at room temperature for 4 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
1-[2-[[4-[2-(環己基氧基)嘧啶-5-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 1-[2-[[4-[2-(cyclohexyloxy)pyrimidin-5-yl]phenyl]aminecarboxylidene]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
5-溴-2-(環己基氧基)嘧啶 5-bromo-2-(cyclohexyloxy)pyrimidine
將5-溴-2-氯嘧啶(2.90g)及環己醇(2.58g)溶解於DMF(10mL)及THF(40mL)，於0℃添加氫化鈉(0.60g)，於室溫攪拌3小時。以飽和氯化銨水溶液停止反應，以己烷/乙酸乙酯(3/1)萃取。將有機層以水、飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色固體之標題化合物867.5mg(23%)。 5-Bromo-2-chloropyrimidine (2.90 g) and cyclohexanol (2.58 g) were dissolved in DMF (10 mL) and THF (40 mL), sodium hydride (0.60 g). . The reaction was quenched with saturated aq. EtOAc (EtOAc)EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
4-[2-(環己基氧基)嘧啶-5-基]苯胺 4-[2-(cyclohexyloxy)pyrimidin-5-yl]aniline
將實施例11(11a)中所得到之化合物(1385.6mg)、4-(4,4,5,5-四甲基-1,3,2-二氧環戊硼烷-2-基)苯胺(942.2mg)、碳酸鉀(1644.9mg)、Pd(PPh3)4(436.0mg)懸浮於1,4-二烷(40mL)及水(10mL)中，於90℃攪拌4.5小時。冷卻至室溫後，添加飽和氯化銨水溶液，以乙酸乙酯萃取。將有機層以水、飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色固體之標題化合物1278.9mg(88%)。 The compound obtained in Example 11 (11a) (1385.6 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxocyclopentan-2-yl)aniline (942.2 mg), potassium carbonate (1644.9 mg), Pd(PPh 3 ) 4 (436.0 mg) suspended in 1,4-two The mixture was stirred at 90 ° C for 4.5 hours in hexane (40 mL) and water (10 mL). After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added and ethyl acetate was evaporated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
2-胺基-N-[4-[2-(環己基氧基)嘧啶-5-基]苯基]-5-(1-哌啶基)苯甲醯胺 2-amino-N-[4-[2-(cyclohexyloxy)pyrimidin-5-yl]phenyl]-5-(1-piperidyl)benzamide
由實施例11(11b)中所得到之化合物(442.5mg)及5-氟-2-硝基苯甲酸，以與實施例1(1b)同樣的方法，得到N-{4-[2-(環己基氧基)嘧啶-5-基]苯基}-5-氟-2-硝基苯甲醯胺後，溶解於THF(40mL)，添加哌啶(945μL)，於60℃攪拌2小時。返回室溫後，濃縮，將所得到之殘渣溶 解於乙酸乙酯(30mL)及THF(20mL)中，添加100mg之10%鈀-碳觸媒(dry)，於氫氣環境下，於室溫攪拌5小時。以矽藻土過濾後，濃縮，將殘渣以管柱層析純化，得到呈黃色固體之標題化合物78.5mg(9.1%、3步驟)。 From the compound (442.5 mg) obtained in Example 11 (11b) and 5-fluoro-2-nitrobenzoic acid, N-{4-[2-() was obtained in the same manner as in Example 1 (1b). After cyclohexyloxy)pyrimidin-5-yl]phenyl}-5-fluoro-2-nitrobenzamide, it was dissolved in THF (40 mL), and piperidine (945 μL) was added thereto, and the mixture was stirred at 60 ° C for 2 hours. After returning to room temperature, concentrate and dissolve the residue obtained. After dissolving in ethyl acetate (30 mL) and THF (20 mL), 100 mg of 10% palladium-carbon catalyst (dry) was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere. After filtration over celite, EtOAc (EtOAc)EtOAc.
N1-[2-[[4-[2-(環己基氧基)嘧啶-5-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[2-(cyclohexyloxy)pyrimidin-5-yl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
將實施例11(11c)中所得到之化合物(72.0mg)及HATU(115.1mg)溶解於DMF(2mL)，於室溫攪拌30分鐘後，添加3-[甲基(2-啉基乙基)胺甲醯基]苯甲酸(78.5mg)的DMF(2mL)及DIPEA(75μL)，於室溫攪拌24小時。以飽和氯化銨水溶液使反應停止，以己烷/乙酸乙酯(3/1)萃取。將有機層以水、飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈茶色固體之標題化合物78.5mg(63%)。 The compound (72.0 mg) obtained in Example 11 (11c) and HATU (115.1 mg) were dissolved in DMF (2 mL), and stirred at room temperature for 30 minutes, then 3-[methyl(2-) Dolin (78.5 mg) in DMF (2 mL) and DIPEA (75 μL) was stirred at room temperature for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc/EtOAc (EtOAc). The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
N1-[2-[[4-[6-(環己基氧基)-3-吡啶基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[6-(cyclohexyloxy)-3-pyridyl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
5-溴-2-(環己基氧基)吡啶 5-bromo-2-(cyclohexyloxy)pyridine
與實施例11(11a)同樣地進行，由2-氟-5-溴吡啶(768μL)及環己醇(872μL)，得到呈黃色油狀物質之標題化合物814.4mg(42%)。 In the same manner as in Example 11 (11a), the title compound (yield:yield:yield:::::::::::::::::::::::::
4-[6-(環己基氧基)-3-吡啶基]苯胺 4-[6-(cyclohexyloxy)-3-pyridyl]aniline
與實施例11(11b)同樣地進行，由實施例12(12a)中所得到之化合物(255.9mg)及4-(4,4,5,-四甲基-1,3,-二氧環戊硼烷-2-基)苯胺(219.1mg)，得到呈淡茶色油狀物質之標題化合物123.5mg(46%)。 The compound (255.9 mg) obtained in Example 12 (12a) and 4-(4,4,5,-tetramethyl-1,3,-dioxane were obtained in the same manner as in Example 11 (11b). Pentaboran-2-yl)aniline (219.1 mg) gave the title compound 123.5 mg (46%).
N1-[2-[[4-[6-(環己基氧基)-3-吡啶基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[6-(cyclohexyloxy)-3-pyridyl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
由實施例12(12b)中所得到之化合物(123.5mg)及5-氟-2-硝基苯甲酸(128.5mg)，以與實施例11(11c)及(11d)同樣的方法，得到呈黃色固體之標題化合物96.5mg(35%、4步驟)。 The compound (123.5 mg) obtained in Example 12 (12b) and 5-fluoro-2-nitrobenzoic acid (128.5 mg) were obtained in the same manner as in Example 11 (11c) and (11d). The title compound was 96.5 mg (35%, 4 steps).
N1-[2-[[4-[5-(環己基氧基)-2-吡啶基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[5-(cyclohexyloxy)-2-pyridyl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
2-溴-5-(環己基氧基)吡啶 2-bromo-5-(cyclohexyloxy)pyridine
將2-溴-5-羥基吡啶(1376.6mg)、環己醇(920μL)、三苯基膦(2490.0mg)溶解於THF(50mL)中，於0℃滴下偶氮二甲酸二異丙酯的1.9mol/L甲苯溶液。於室溫攪拌16小時後，添加飽和氯化銨水溶液停止反應。以乙酸乙酯萃取，所得到之將有機層以水、飽和食鹽水洗淨，以硫 酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色油狀物質之標題化合物1015.9mg(50%)。 2-Bromo-5-hydroxypyridine (1376.6 mg), cyclohexanol (920 μL), triphenylphosphine (2490.0 mg) was dissolved in THF (50 mL), and diisopropyl azodicarboxylate was dropped at 0 °C. 1.9 mol/L toluene solution. After stirring at room temperature for 16 hours, the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride. Extracted with ethyl acetate, and the organic layer was washed with water and saturated brine to give sulfur The sodium salt was dried, filtered and then concentrated. The residue was purified by EtOAcjjjjjjjjj
4-[5-(環己基氧基)-2-吡啶基]苯胺 4-[5-(cyclohexyloxy)-2-pyridyl]aniline
與實施例11(11b)同樣地進行，由實施例13(13a)中所得到之化合物(260.5mg)及4-(4,4,5,5-四甲基-1,3,2-二氧環戊硼烷-2-基)苯胺(222.9mg)，得到呈淡黃色固體之標題化合物217.4mg(80%)。 The compound (260.5 mg) and 4-(4,4,5,5-tetramethyl-1,3,2-di) obtained in Example 13 (13a) were obtained in the same manner as in Example 11 (11b). Oxy-cyclopentane-2-yl)aniline (222.9 mg) gave the title compound 21.
N1-[2-[[4-[5-(環己基氧基)-2-吡啶基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[5-(cyclohexyloxy)-2-pyridyl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
與實施例11(11c)及(11d)同樣地進行，由實施例13(13b)中所得到之化合物(217.4mg)及5-氟-2-硝基苯甲酸(225.5mg)，得到呈黃色固體之標題化合物66.9mg(12%、4步驟)。 The compound (217.4 mg) obtained in Example 13 (13b) and 5-fluoro-2-nitrobenzoic acid (225.5 mg) were obtained in the same manner as in Example 11 (11c) and (11d). The title compound was 66.9 mg (12%, 4 steps).
N1-[2-[[5-[2-(環己基氧基)嘧啶-5-基]-2-吡啶]胺甲醯基]-4-(1-哌啶)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[5-[2-(cyclohexyloxy)pyrimidin-5-yl]-2-pyridyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-A base-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
5-[2-(環己基氧基)嘧啶-5-基]吡啶-2-胺 5-[2-(cyclohexyloxy)pyrimidin-5-yl]pyridin-2-amine
將實施例11(11a)中所得到之化合物(184.7mg)、2-胺基-5-(4,4,5,5-四甲基-1,3,2-二氧環戊硼烷-2-基)吡啶(158.1mg)、Pd(PPh3)4(57.9mg)，懸浮於二甲基乙醯胺 (10mL)及水(2mL)中，於100℃攪拌8小時。冷卻至室溫後，添加飽和氯化銨水溶液，以乙酸乙酯萃取。將有機層以水、飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈無色固體之標題化合物158.1mg(81%)。 The compound (184.7 mg) obtained in Example 11 (11a), 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxycyclopentaneborane- 2-Base)pyridine (158.1 mg) and Pd(PPh 3 ) 4 (57.9 mg) were suspended in dimethylacetamide (10 mL) and water (2 mL) and stirred at 100 ° C for 8 hours. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added and ethyl acetate was evaporated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
N1-[2-[[5-[2-(環己基氧基)嘧啶-5-基]-2-吡啶]胺甲醯基]-4-(1-哌啶)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[5-[2-(cyclohexyloxy)pyrimidin-5-yl]-2-pyridyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-A base-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
由實施例14(14a)中所得到之化合物(157.0mg)及5-氟-2-硝基苯甲酸(150.4mg)，以與實施例11(11c)及(11d)同樣的方法，得到呈黃色固體之標題化合物56.5mg(13%、4步驟)。 The compound (157.0 mg) and 5-fluoro-2-nitrobenzoic acid (150.4 mg) obtained in Example 14 (14a) were obtained in the same manner as in Example 11 (11c) and (11d). The title compound was 56.5 mg (13%, 4 steps).
N1-[2-[[4-[5-(環己基氧基)吡-2-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[5-(cyclohexyloxy)pyridyl) -2-yl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
2-溴-5-(環己基氧基)吡 2-bromo-5-(cyclohexyloxy)pyrene
與實施例11(11a)同樣地，由2、5-二溴吡(2.38g)及環己醇(1.00g)，得到呈黃色油狀物質之標題化合物2.82g(>99%)。 In the same manner as in Example 11 (11a), 2,5-dibromopyridinium (2.38 g) and cyclohexanol (1.00 g) gave the title compound (2.
4-[5-(環己基氧基)吡-2-基]苯胺 4-[5-(cyclohexyloxy)pyridinium -2-yl]aniline
與實施例11(11b)同樣地，由實施例15(15a)中所得到之化合物(400.0mg)及4-(4,4,5,5-四甲基-1,3,2-二氧環戊硼烷-2-基)苯胺(340.9mg)，得到呈淡黃色固體之標題化合物198.7mg(47%)。 The compound (400.0 mg) obtained in Example 15 (15a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxane were obtained in the same manner as in Example 11 (11b). Cyclopentane-2-yl)aniline (340.9 mg) gave the title compound 19.
N1-[2-[[4-[5-(環己基氧基)吡-2-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[5-(cyclohexyloxy)pyridyl) -2-yl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
與實施例11(11c)及(11d)同樣地進行，由實施例15(15b)中所得到之化合物(232.0mg)及5-氟-2-硝基苯甲酸(239.4mg)，得到呈黃色固體之標題化合物340.8mg(53%、4步驟)。 The compound (232.0 mg) obtained in Example 15 (15b) and 5-fluoro-2-nitrobenzoic acid (239.4 mg) were obtained in the same manner as in Example 11 (11c) and (11d). The title compound of the solid was 340.8 mg (53%, 4 steps).
N1-[2-[[4-[6-(環己基氧基)嗒-3-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[6-(cyclohexyloxy)fluorene) -3-yl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
3-氯-6-(環己基氧基)嗒 3-chloro-6-(cyclohexyloxy)indole
於實施例11(11a)同樣地，由3,6-二氯嗒(1133.5mg)及環己醇(762mg)，得到呈無色固體之標題化合物342.6mg(21%)。 Similarly, in Example 11 (11a), from 3,6-dichloropurine (1133.5 mg) and cyclohexanol (762 mg), m.
4-[6-(環己基氧基)嗒-3-基]苯胺 4-[6-(cyclohexyloxy)anthracene -3-yl]aniline
將實施例16(16a)中所得到之化合物(128.9mg)、4-(4,4,5,5-四甲基-1,3,2-二氧環戊硼烷-2-基)苯胺 (125.5mg)、碳酸鉀(124.5mg)、雙(三苯基膦)二氯化鈀(II)(18.1mg)，懸浮於1,4-二烷(8mL)及水(2mL)中，於100℃攪拌5.5小時。冷卻至室溫後，添加飽和氯化銨水溶液，以乙酸乙酯萃取。將有機層以水、飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮。以管柱層析純化殘留物，得到呈黃色固體之標題化合物150.6mg(92%)。 The compound obtained in Example 16 (16a) (128.9 mg), 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)aniline (125.5 mg), potassium carbonate (124.5 mg), bis(triphenylphosphine)palladium(II) chloride (18.1 mg), suspended in 1,4-two The mixture was stirred at 100 ° C for 5.5 hours in hexane (8 mL) and water (2 mL). After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added and ethyl acetate was evaporated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
N1-[2-[[4-[6-(環己基氧基)嗒-3-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[6-(cyclohexyloxy)fluorene) -3-yl]phenyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3-methyl-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
與實施例11(11c)及(11d)同樣地進行，由實施例16(16b)中所得到之化合物(147.0mg)及5-氟-2-硝基苯甲酸(152.5mg)，得到呈黃色固體之標題化合物212.3mg(83%、4步驟)。 The compound (147.0 mg) obtained in Example 16 (16b) and 5-fluoro-2-nitrobenzoic acid (152.5 mg) were obtained in the same manner as in Example 11 (11c) and (11d). The title compound was 212.3 mg (83%, 4 steps).
N1-[2-[[4-[2-(環己基胺基)嘧啶-5-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[2-(cyclohexylamino)pyrimidin-5-yl]phenyl]aminecarboxylidene]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
5-溴-N-環己基-嘧啶-2-胺 5-bromo-N-cyclohexyl-pyrimidin-2-amine
將5-溴-2-氯嘧啶(1.70g)溶解於EtOH(30mL)，於0℃添加環己基胺(1mL)、DIPEA(4.6mL)，攪拌1小時後，於80℃攪拌4小時。冷卻至室溫後，添加飽和氯化銨水溶液，以乙酸乙酯萃取。將有機層以水、飽和食鹽水洗 淨，以硫酸鈉乾燥，過濾，接著進行濃縮，得到呈無色固體之標題化合物2.31g(>99%)。 5-Bromo-2-chloropyrimidine (1.70 g) was dissolved in EtOH (30 mL), and cyclohexylamine (1 mL) and DIPEA (4.6 mL) were added at 0 ° C, and stirred for 1 hour, and then stirred at 80 ° C for 4 hours. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added and ethyl acetate was evaporated. Wash the organic layer with water and saturated brine The title compound was dried over EtOAc EtOAc (EtOAc)
5-(4-胺基苯基)-N-環己基-嘧啶-2-胺 5-(4-Aminophenyl)-N-cyclohexyl-pyrimidin-2-amine
與實施例11(11b)同樣地，由實施例17(17a)中所得到之化合物(266.8mg)及4-(4,4,5,5-四甲基-1,3,2-二氧環戊硼烷-2-基)苯胺(228.5mg)，得到呈淡茶色固體之標題化合物106.6mg(38%)。 The compound (266.8 mg) obtained in Example 17 (17a) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxane were obtained in the same manner as in Example 11 (11b). Cyclopentyl-2-yl)aniline (228.5 mg) gave the title compound 106.6 mg (38%).
N1-[2-[[4-[2-(環己基胺基)嘧啶-5-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[2-(cyclohexylamino)pyrimidin-5-yl]phenyl]aminecarboxylidene]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
與實施例11(11c)及(11d)同樣地，由實施例17(17b)中所得到之化合物(104.2mg)及5-氟-2-硝基苯甲酸(109.1mg)，得到呈黃色油狀物質之標題化合物99.5mg(34%、4步驟)。 The compound (104.2 mg) obtained in Example 17 (17b) and 5-fluoro-2-nitrobenzoic acid (109.1 mg) were obtained as yellow oil in the same manner as in Example 11 (11c) and (11d). The title compound was 99.5 mg (34%, 4 steps).
N1-[2-[[6-[2-(環己基氧基)嘧啶-5-基]-3-吡啶基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[6-[2-(cyclohexyloxy)pyrimidin-5-yl]-3-pyridinyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3 -methyl-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
N-[6-[2-(環己基氧基)嘧啶-5-基]-3-吡啶基-5-氟-2-硝基-苯甲醯胺 N-[6-[2-(cyclohexyloxy)pyrimidin-5-yl]-3-pyridyl-5-fluoro-2-nitro-benzamide
將實施例11(11a)中所得到之化合物(2.47g)、雙聯頻哪醇硼酸酯(bis(pinacolate)diboron)(2.93g)、乙酸鉀 (2.83g)、1,1’-雙(二苯基膦基)二茂鐵-二氯化鈀(II)．二氯甲烷錯合物(0.39g)，懸浮於DMF(50mL)中，於80℃攪拌21小時。冷卻至室溫後，添加飽和氯化銨水溶液，以乙酸乙酯萃取。將有機層以水、飽和食鹽水洗淨，以硫酸鈉乾燥，過濾，接著進行濃縮，將所得到之殘渣以管柱層析純化，得到含有2-(環己基氧基)-5-(4,4,5,5-四甲基-1,3,2-二氧環戊硼烷-2-基)嘧啶之無色固體1.57g。由此化合物(91.8mg)及5-胺基-2-溴吡啶(52.4mg)，與實施例11(11b)同樣地進行，得到含有6-[2-(環己基氧基)嘧啶-5-基]吡啶-3-胺之無色油狀物質65.4mg。由此所得到之化合物(65.4mg)及5-氟-2-硝基苯甲酸(90.5mg)，以與實施例11(11c)同樣的方法，得到呈無色固體之標題化合物47.0mg。 The compound obtained in Example 11 (11a) (2.47 g), bis(pinacolate) diboron (2.93 g), potassium acetate (2.83g), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride. The dichloromethane complex (0.39 g) was suspended in DMF (50 mL) and stirred at 80 ° C for 21 hr. After cooling to room temperature, a saturated aqueous solution of ammonium chloride was added and ethyl acetate was evaporated. The organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and then concentrated, and the obtained residue was purified by column chromatography to give 2-(cyclohexyloxy)-5-(4) , a colorless solid of 4,5,5-tetramethyl-1,3,2-dioxacyclopentan-2-yl)pyrimidine, 1.57 g. The compound (91.8 mg) and 5-amino-2-bromopyridine (52.4 mg) were obtained in the same manner as in Example 11 (11b) to give 6-[2-(cyclohexyloxy)pyrimidine-5-. 65.4 mg of a colorless oily substance of pyridin-3-amine. The thus obtained compound (65.4 mg) and 5-fluoro-2-nitrobenzoic acid (90.5 mg) were obtained.
N1-[2-[[6-[2-(環己基氧基)嘧啶-5-基]-3-吡啶基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[6-[2-(cyclohexyloxy)pyrimidin-5-yl]-3-pyridinyl]amine-carbamoyl]-4-(1-piperidinyl)phenyl]-N3 -methyl-N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
將實施例18(18a)中所得到之化合物(47.0mg)溶解於THF(10mL)，添加哌啶(80μL)，於60℃攪拌4.5小時。冷卻至室溫後，濃縮，將所得到之殘渣溶解於THF(5mL)及乙酸乙酯(5mL)，添加10%鈀-碳觸媒(dry)，於氫氣環境下，於室溫攪拌2小時。以矽藻土過濾後，濃縮，將所得到之殘渣使用於下述反應，與實施例11(11d)同樣地進行，得到標題化合物39.2mg(49%、3步驟)。 The compound (47.0 mg) obtained in Example 18 (18a) was dissolved in THF (10 mL), and piperidine (80 μL) was added, and the mixture was stirred at 60 ° C for 4.5 hours. After cooling to room temperature, it was concentrated, and the obtained residue was dissolved in THF (5 mL) and ethyl acetate (5 mL), and 10% palladium-carbon catalyst (dry) was added, and the mixture was stirred at room temperature for 2 hours under hydrogen atmosphere. . The mixture was filtered through celite, and the residue was evaporated. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
N1-[2-[[3-[2-(環己基氧基)嘧啶-5-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[3-[2-(cyclohexyloxy)pyrimidin-5-yl]phenyl]aminecarboxylidene]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
3-[2-(環己基氧基)嘧啶-5-基]苯胺 3-[2-(cyclohexyloxy)pyrimidin-5-yl]aniline
與實施例11(11b)同樣地進行，由實施例11(11a)中所得到之化合物(1052.6mg)及3-(4,4,5,5-四甲基-1,3,2-二氧環戊硼烷-2-基)苯胺(897.5mg)，得到呈淡黃色固體之標題化合物1059.7mg(96%)。 The compound (1052.6 mg) and 3-(4,4,5,5-tetramethyl-1,3,2-di) obtained in Example 11 (11a) were obtained in the same manner as in Example 11 (11b). Oxycyclocycloboran-2-yl)aniline (897.5 mg) gave the title compound: m.
N1-[2-[[3-[2-(環己基氧基)嘧啶-5-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[3-[2-(cyclohexyloxy)pyrimidin-5-yl]phenyl]aminecarboxylidene]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
由實施例19(19a)中所得到之化合物(1055.0mg)及5-氟-2-硝基苯甲酸(1159.6mg)，以與實施例11(11c)及(11d)同樣的方法，得到呈淡黃色固體之標題化合物45.2mg(20%、4步驟)。 The compound (1055.0 mg) obtained in Example 19 (19a) and 5-fluoro-2-nitrobenzoic acid (1159.6 mg) were obtained in the same manner as in Example 11 (11c) and (11d). The title compound was 45.2 mg (20%, 4 steps).
N-[4-[6-(環己基氧基)-3-吡啶基]苯基]-2-[[3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基]胺基]-5-(1-哌啶基)苯甲醯胺 N-[4-[6-(cyclohexyloxy)-3-pyridyl]phenyl]-2-[[3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl]amino]-5-(1-piperidinyl)benzamide
2-氯-5-(環己基氧基)嘧啶 2-chloro-5-(cyclohexyloxy)pyrimidine
與實施例13(13a)同樣地進行，由2-氯-5-羥基嘧啶(1005.1mg)及環己醇(1060μL)，得到呈淡黃色固體之標題化合物1083.8mg(66%)。 The title compound 1083.8 mg (66%) was obtained as a pale yellow solid from 2-chloro-5-hydroxypyrimidine (1005.1 mg) and cyclohexanol (1060 μL).
4-[5-(環己基氧基)嘧啶-2-基] 4-[5-(cyclohexyloxy)pyrimidin-2-yl]
與實施例11(11b)同樣地進行，由實施例20(20a)中所得到之化合物(400.0mg)及4-(4,4,5,5-四甲基-1,3,2-二氧環戊硼烷-2-基)苯胺(412.1mg)，得到呈淡茶色固體之標題化合物400.8mg(79%)。 The compound (400.0 mg) obtained in Example 20 (20a) and 4-(4,4,5,5-tetramethyl-1,3,2-di) were obtained in the same manner as in Example 11 (11b). Oxycyclopentane-2-yl)aniline (412.1 mg) gave the title compound 40.
N1-[2-[[4-[5-(環己基氧基)嘧啶-2-基]苯基]胺甲醯基]-4-(1-哌啶基)苯基]-N3-甲基-N3-(2-啉基乙基)苯-1,3-二甲醯胺 N1-[2-[[4-[5-(cyclohexyloxy)pyrimidin-2-yl]phenyl]aminecarboxylidene]-4-(1-piperidinyl)phenyl]-N3-methyl -N3-(2- Polinylethyl)benzene-1,3-dimethylguanamine
由實施例20(20b)中所得到之化合物(396.7mg)及5-氟-2-硝基苯甲酸(409.5mg)，以與實施例11(11c)及(11d)同樣的方法，得到呈淡黃色固體之標題化合物81.5mg(21%、4步驟)。 The compound (396.7 mg) and 5-fluoro-2-nitrobenzoic acid (409.5 mg) obtained in Example 20 (20b) were obtained in the same manner as in Example 11 (11c) and (11d). The title compound was 81.5 mg (21%, 4 steps).
N-[4-[6-(環己基氧基)-3-吡啶基]苯基]-2-[[3-[甲基(2-啉基乙基)胺磺醯基]苯甲醯基]胺基]-5-(1-哌啶基)苯甲醯胺 N-[4-[6-(cyclohexyloxy)-3-pyridyl]phenyl]-2-[[3-[methyl(2-) Phenylethyl)amine sulfonyl]benzhydryl]amino]-5-(1-piperidinyl)benzamide
與實施例11(11c)及(11d)同樣地進行，由實施例12(12b)中所得到之化合物(139.9mg)及參考例1中所得到之化合物(164.7mg)，得到呈淡黃色固體之標題化合物208.1mg(90%)。 The compound (139.9 mg) obtained in Example 12 (12b) and the compound (164.7 mg) obtained in Reference Example 1 were obtained in the same manner as in Example 11 (11c) and (11d) to give a pale yellow solid. The title compound was 208.1 mg (90%).
N’-[2-{[2-(3,3-二甲基丁醯基)-1,2,3,4-四氫異喹啉-6-基]胺甲醯基}-4-(哌啶-1-基)苯基]-N-甲基-N-[2-(啉-4-基)乙基]苯-1,3-二甲醯胺 N'-[2-{[2-(3,3-Dimethylbutylidene)-1,2,3,4-tetrahydroisoquinolin-6-yl]aminecarbenyl}-4-(piperidine) -1-yl)phenyl]-N-methyl-N-[2-( Physo-4-yl)ethyl]benzene-1,3-dimethylguanamine
將實施例1中所得到之6-{[2-({3-[甲基(2-啉基乙基)胺甲醯基]苯甲醯基}胺基)-5-(1-哌啶基)苯甲醯基]胺基}-3,4-二氫-1H-異喹啉-2-甲酸三級丁酯以鹽酸處理而得到N-甲基-N-[2-(啉-4-基)乙基]-N’-[4-(哌啶-1-基)-2-(1,2,3,4-四氫異喹啉-6-基胺甲醯基)苯基]苯-1,3-二甲醯胺 鹽酸鹽，於N-甲基-N-[2-(啉-4-基)乙基]-N’-[4-(哌啶-1-基)-2-(1,2,3,4-四氫異喹啉-6-基胺甲醯基)苯基]苯-1,3-二甲醯胺 鹽酸鹽(126.0mg)的DCM(10mL)溶液中，添加DIPEA(0.15mL)及氯化3,3-二甲基丁醯基(45.1mg)，於室溫攪拌一晚。將反應液之溶劑減壓蒸餾去除後，以矽膠管柱層析純化，得到呈淡黃色固體之標題化合物137.8mg(95%)。 6-{[2-({3-[methyl(2-) obtained in Example 1) Polinylethyl)amine-methylmethyl]benzhydryl}amino)-5-(1-piperidinyl)benzylidene]amino}-3,4-dihydro-1H-isoquinoline- 2-K-butyl carboxylic acid is treated with hydrochloric acid to give N-methyl-N-[2-( Physo-4-yl)ethyl]-N'-[4-(piperidin-1-yl)-2-(1,2,3,4-tetrahydroisoquinolin-6-ylaminocarbamoyl) Phenyl]benzene-1,3-dimethylamine hydrochloride, in N-methyl-N-[2-( Physo-4-yl)ethyl]-N'-[4-(piperidin-1-yl)-2-(1,2,3,4-tetrahydroisoquinolin-6-ylaminocarbamoyl) To a solution of phenyl]benzene-1,3-dimethylguanamine hydrochloride (126.0 mg) in DCM (10 mL), DIPEA (0.15mL) and 3,3-dimethylbutylidene (45.1 mg), Stir at room temperature for one night. The solvent of the reaction mixture was evaporated under reduced pressure.
2-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]aminemethylmercapto}benzylidene)amino]-5-(piperidin-1-yl)benzhydryl}amino)-7,8-dihydro-1 ,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
2-[(5-氟-2-硝基苯甲醯基)胺基]-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-[(5-fluoro-2-nitrobenzhydryl)amino]-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
於5-氟-2-硝基苯甲酸(320.1mg)的DCM(30mL)溶液中，依序添加草醯氯(0.20mL)及DMF數滴，於室溫攪拌 1小時。將反應液之溶劑減壓蒸餾去除，與甲苯共沸。於DIPEA(0.4mL)、2-胺基-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯(CAS登錄號：1149333-40-3,WO2009/56556A1)(0.30g)的DCM溶液中，滴下殘渣之DCM溶液，於室溫攪拌5小時。將溶劑減壓蒸餾去除，將所得到之殘渣以矽膠管柱層析純化，得到呈淡黃色油狀物之標題化合物327.4mg(65%)。 To a solution of 5-fluoro-2-nitrobenzoic acid (320.1 mg) in DCM (30 mL), EtOAc (EtOAc) The solvent of the reaction liquid was distilled off under reduced pressure, and azeotroped with toluene. In DIPEA (0.4 mL), 2-amino-7,8-dihydro-1,6- To a solution of pyridine-6(5H)-carboxylic acid tert-butyl ester (CAS No.: 1149333-40-3, WO2009/56556A1) (0.30 g) in DCM. The solvent was evaporated under reduced pressure. EtOAc m.
2-[{2-硝基-5-(哌啶-1-基)苯甲醯基}胺基]-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-[{2-nitro-5-(piperidin-1-yl)benzimidyl}amino]-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
於實施例22(22a)中所得到之化合物(327.0mg)的THF(10mL)溶液中，添加哌啶(0.8mL)，於加熱回流下攪拌5小時。將溶劑於減壓下蒸餾去除，將所得到之殘渣以矽膠管柱層析純化，得到呈黃色油狀物之標題化合物417.6mg(<100%)。 To a solution of the compound (327.0 mg) obtained from m. The solvent was evaporated under reduced pressure. EtOAc m.
2-[{2-胺基-5-(哌啶-1-基)苯甲醯基}胺基]-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-[{2-Amino-5-(piperidin-1-yl)benzylidenyl}amino]-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
於實施例22(22c)中所得到之化合物(0.30g)的THF(15mL)及MeOH(15mL)溶液中，添加10%鈀-碳(0.050g)，於氫氣環境下攪拌2小時。將反應液過濾，將殘渣依序以THF、乙酸乙酯洗淨。將濾液之溶劑減壓蒸餾去除，得到呈淡黃色油狀物之標題化合物159.4mg(71%)。 To a solution of the compound (0.30 g) obtained from m. The reaction solution was filtered, and the residue was washed with THF and ethyl acetate. The solvent of the filtrate was evaporated to dryness crystals crystals crystals crystals
2-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]aminemethylmercapto}benzylidene)amino]-5-(piperidin-1-yl)benzhydryl}amino)-7,8-dihydro-1 ,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
於實施例23(23c)中所得到之化合物(159.4mg)的DMF(4mL)溶液中，添加HATU(201.2mg)、DIPEA(0.20mL)、3-[甲基(2-啉基乙基)羧基]苯甲酸(120.1mg)，於室溫攪拌一晚。將反應液注入食鹽水，以乙酸乙酯萃取。將萃取液依序以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥。於減壓下將溶劑蒸餾去除，將殘渣以矽膠管柱層析純化。將溶劑減壓蒸餾去除，於殘渣中添加水，濾取所生成之固體，以水洗淨，以真空泵乾燥，得到呈淡黃色固體之標題化合物136.9mg(53%)。 To a solution of the compound (159.4 mg) obtained in EtOAc (m.m. Polinylethyl)carboxy]benzoic acid (120.1 mg) was stirred at room temperature overnight. The reaction solution was poured into brine and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. The solvent was evaporated under reduced pressure. Water was evaporated, evaporated, evaporated, evaporated, evaporated
三級丁基-7-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-3,4-二氫異喹啉-2(1H)-甲酸酯 Tert-butyl -7-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]amine-methylmethyl}benzhydryl)amino]-5-(piperidin-1-yl)benzhydryl}amino)-3,4-dihydroisoquine Porphyrin-2(1H)-formate
7-{(5-氟-2-硝基苯甲醯基)胺基}-3,4-二氫異喹啉-2(1H)-甲酸三級丁酯 7-{(5-fluoro-2-nitrobenzhydryl)amino}-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl butyl ester
由5-氟-2-硝基苯甲酸(300.1mg)、草醯氯(0.20mL)、DIPEA(0.4mL)、7-胺基-3,4-二氫異喹啉-2(1H)-甲酸三級丁酯(300.1mg)，與實施例23(23a)同樣地進行，得到呈淡黃色泡沫狀物之標題化合物481.2mg(96%)。 From 5-fluoro-2-nitrobenzoic acid (300.1 mg), grass chloroform (0.20 mL), DIPEA (0.4 mL), 7-amino-3,4-dihydroisoquinoline-2 (1H)- The title compound (481.2 mg (96%)) was obtained from the title compound (30%).
7-[{2-硝基-5-(哌啶-1-基)苯甲醯基}胺基]-3,4-二氫異喹啉-2(1H)-甲酸三級丁酯 7-[{2-Nitro-5-(piperidin-1-yl)benzimidyl}amino]-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl acrylate
由實施例24(24a)中所得到之化合物(480.2mg)、哌啶(0.4mL)，與實施例23(23b)同樣地進行，得到呈黃色固體之標題化合物0.52g(94%)。 The compound (480.2 mg) obtained from Example 24 (24a), m.p.
7-[{2-胺基-5-(哌啶-1-基)苯甲醯基}胺基]-3,4-二氫異喹啉-2(1H)-甲酸三級丁酯 7-[{2-Amino-5-(piperidin-1-yl)benzylidenyl}amino]-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl butyl ester
於實施例24(24b)中所得到之化合物(0.52g)的EtOH(20mL)及水(5mL)的混合溶液中，依序添加鐵粉(0.30g)及氯化銨(58.1mg)，於加熱回流下攪拌4小時。放冷後以矽藻土過濾。將殘渣以乙酸乙酯洗淨後，合併濾液，將溶劑減壓蒸餾去除。將所得到之殘渣以矽膠管柱層析純化，得到呈淡黃色固體0.41g(84%)之標題化合物。 Iron powder (0.30 g) and ammonium chloride (58.1 mg) were sequentially added to a mixed solution of the compound (0.52 g) obtained in Example 24 (24b) in EtOH (20 mL) and water (5 mL). The mixture was stirred under heating and reflux for 4 hours. After cooling, filter with diatomaceous earth. After the residue was washed with ethyl acetate, the filtrate was combined, and the solvent was evaporated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc elutcd
7-{2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-3,4-二氫異喹啉-2(1H)-甲酸三級丁酯 7-{2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]amine-methylmethyl}benzhydryl)amino]-5-(piperidin-1-yl)benzhydryl}amino)-3,4-dihydroisoquine Porphyrin-2(1H)-tricarboxylic acid tert-butyl ester
由實施例24(24c)中所得到之化合物(0.41g)、HATU(0.52g)、DIPEA(0.45mL)、3-[甲基(2-啉基乙基)羧基]苯甲酸(0.35g)，與實施例23(23d)同樣地進行，得到呈淡黃色固體之標題化合物513.1mg(78%)。 Compound (0.41 g) obtained from Example 24 (24c), HATU (0.52 g), DIPEA (0.45 mL), 3-[methyl (2- The morphylethyl)carboxy]benzoic acid (0.35 g) was obtained.
三級丁基-6-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-3,4-二氫喹啉-1(2H)-甲酸酯 Tertiary butyl-6-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]amine-methylmethyl}benzhydryl)amino]-5-(piperidin-1-yl)benzhydryl}amino)-3,4-dihydroquinoline -1(2H)-formate
6-{(5-氟-2-硝基苯甲醯基)胺基}-3,4-二氫喹啉-1(2H)-甲酸三級丁酯 6-{(5-fluoro-2-nitrobenzhydryl)amino}-3,4-dihydroquinolin-1(2H)-carboxylic acid tert-butyl butyl ester
由6-胺基-3,4-二氫-喹啉-1(2H)-甲酸三級丁酯(US2002/103203 A1)(0.47g)、5-氟-2-硝基苯甲酸(0.42g)，與實施例23(23a)同樣地，得到呈黃色泡沫狀物之標題化合物0.63g(82%)。 From 3-amino-3,4-dihydro-quinoline-1(2H)-carboxylic acid tert-butyl acrylate (US2002/103203 A1) (0.47 g), 5-fluoro-2-nitrobenzoic acid (0.42 g) In the same manner as in Example 23 (23a), m.
6-[{2-硝基-5-(哌啶-1-基)苯甲醯基}胺基]-3,4-二氫喹啉-1(2H)-甲酸三級丁酯 6-[{2-Nitro-5-(piperidin-1-yl)benzimidyl}amino]-3,4-dihydroquinolin-1(2H)-carboxylic acid tert-butyl butyl ester
由實施例25(25a)中所得到之化合物(0.41g)及哌啶(0.5mL)，與實施例23(23b)同樣地，得到呈黃色泡沫狀物標題化合物0.47g(<100%)。 The compound (0.41 g) obtained in Example 25 (25a), m.p.
6-[{2-胺基-5-(哌啶-1-基)苯甲醯基}胺基]-3,4-二氫喹啉-1(2H)-甲酸三級丁酯 6-[{2-Amino-5-(piperidin-1-yl)benzylidenyl}amino]-3,4-dihydroquinolin-1(2H)-carboxylic acid tert-butyl butyl ester
使用實施例25(25b)中所得到之化合物(0.52g)、10%鈀-碳(0.050g)，與實施例23(23c)同樣地進行，得到呈淡黃色油狀物之標題化合物0.42g(86%)。 Using the compound (0.52 g) obtained in Example 25 (25b), m.p. (86%).
6-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-3,4-二氫喹啉-1(2H)-甲酸三級丁酯 6-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]amine-methylmethyl}benzhydryl)amino]-5-(piperidin-1-yl)benzhydryl}amino)-3,4-dihydroquinoline -1(2H)-tricarboxylic acid tert-butyl ester
由實施例25(25c)中所得到之化合物(120.0mg)、HBTU(180.1mg)、DIPEA(0.40mL)、參考例1中所得到之3-{甲基(2-啉基乙基)羧基}苯甲酸(101.2mg)，與實施例23(23d)同樣地進行，得到呈淡黃色固體之標題化合物125.1mg(65%)。 The compound (120.0 mg), HBTU (180.1 mg), DIPEA (0.40 mL) obtained in Example 25 (25c), 3-{methyl (2-) obtained in Reference Example 1. The morphylethyl) carboxy} benzoic acid (101.2 mg) was obtained.
2-{2-[(3-{甲基[2-(啉-4-基)乙基]胺磺醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯基}-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-{2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]amine sulfonyl}benzhydryl)amino]-5-(piperidin-1-yl)phenyl}-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
2-(5-氟-2-硝基苯基)-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-(5-fluoro-2-nitrophenyl)-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
於2-(三氟甲基磺醯氧基)-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯(CAS登錄號：1149333-39-0,WO2009/56556A1)(300.1mg)及2-(5-氟-2-硝基苯基)-4,4,5,5-四甲基-1,3,2-二側氧碳硼烷(2-(5-fluoro-2-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxocarborane)(314.2mg)的1,2-二甲氧乙烷(2mL)溶液中，添加0.5M磷酸鉀水溶液(6.2mL)，以超音波除氣數分鐘。添加氯(2-二環己基膦基-2’,4’,6’-三異丙基-1,1’-聯苯)[2-(2’-胺基-1,1’-聯苯)]鈀(II)，於加熱回流下攪拌 2小時半。放冷後，將經乙酸乙酯稀釋之反應混合物注入食鹽水中，分液後，將水層以乙酸乙酯萃取。將萃取液依序以水及飽和食鹽水洗淨，以無水硫酸鈉乾燥。於減壓下將溶劑蒸餾去除，將所得到之殘渣以矽膠管柱層析純化，得到呈淡茶色泡沫狀物之標題化合物328.3mg(95%)。 In 2-(trifluoromethylsulfonyloxy)-7,8-dihydro-1,6- Pyridin-6(5H)-tricarboxylic acid tert-butyl ester (CAS accession number: 1149333-39-0, WO2009/56556A1) (300.1 mg) and 2-(5-fluoro-2-nitrophenyl)-4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-4,4,5,5-tetramethyl-1,3,2- To a solution of dioxocarborane) (314.2 mg) in 1,2-dimethoxyethane (2 mL), a 0.5 M aqueous potassium phosphate solution (6.2 mL) was added and degassed by ultrasonic for several minutes. Adding chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl) )] Palladium (II) was stirred under heating and reflux for 2 hours and a half. After allowing to cool, the reaction mixture diluted with ethyl acetate was poured into brine, and after separation, the aqueous layer was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and then evaporated, m.
2-{2-硝基-(5-哌啶-1-基)苯基}-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-{2-nitro-(5-piperidin-1-yl)phenyl}-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
由實施例26(26a)中所得到之化合物(0.29g)及哌啶(0.7mL)，與實施例23(23b)同樣地，得到呈黃色泡沫狀物之標題化合物0.34g(<100%)。 The title compound (0.34 g (<100%) was obtained as a yellow foamy compound from the compound (0.29 g) of the compound (26). .
2-{2-胺基-(5-哌啶-1-基)苯基}-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-{2-Amino-(5-piperidin-1-yl)phenyl}-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
使用實施例26(26d)中所得到之化合物(0.30g)、10%鈀-碳(0.050g)，與實施例23(23c)同樣地進行，得到呈淡黃色油狀物之標題化合物0.25g(89%)。 Using the compound obtained in Example 26 (26d) (0.30 g), 10% palladium-carbon (0.050 g), the title compound 0.25 g (89%).
2-{2-[(3-{甲基[2-(啉-4-基)乙基]胺磺醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯基}-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 2-{2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]amine sulfonyl}benzhydryl)amino]-5-(piperidin-1-yl)phenyl}-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
由實施例26(26c)中所得到之化合物(100.1mg)、HBTU(90.2mg)、DIPEA(0.076mL)、參考例1中所得到之3-{甲基[2-(啉-4-基)乙基]胺磺醯基}苯甲酸 (70.0mg)，與實施例23(23d)同樣地進行，得到呈淡黃色固體之標題化合物60.1mg(57%)。 The compound (100.1 mg), HBTU (90.2 mg), DIPEA (0.076 mL) obtained in Example 26 (26c), and 3-{methyl[2-( And the title compound (60.1 mg (57%))
2-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-5,8-二氫-1,7-啶-7(5H)-甲酸三級丁酯 2-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]aminemethylmercapto}benzylidene)amino]-5-(piperidin-1-yl)benzhydryl}amino)-5,8-dihydro-1 , 7- Pyridin-7(5H)-carboxylic acid tert-butyl butyl ester
2-胺基-6,8-二氫-1,7-啶-7(5H)-甲酸三級丁酯 2-amino-6,8-dihydro-1,7- Pyridin-7(5H)-carboxylic acid tert-butyl butyl ester
將2-氯-6,8-二氫-1,7-啶-7(5H)-甲酸三級丁酯(400.1mg)、[1-(2-二苯基二氧磷基苯基-1-萘基)-2-萘基]-二苯基膦([1-(2-diphenylphosphophenyl-1-naphthyl)-2-naphthyl]-diphenylphosphane)(92.6mg)、二苯基甲基亞胺(0.37mL)、碳酸銫(728.3mg)，懸浮於甲苯(10mL)，以超音波除氣。添加乙酸鈀(33.5mg)，於室溫攪拌數分鐘後，於加熱回流下攪拌一晚。放冷後，將反應液之溶劑減壓蒸餾去除，於殘渣中添加MeOH(10mL)後，添加乙酸鈉(258.1mg)及羥胺鹽酸鹽(217.1mg)，於室溫攪拌6小時。將反應液之溶劑減壓蒸餾去除，將殘渣以矽膠管柱層析純化，得到呈無色油狀物之標題化合物81.2mg(22%)。 2-chloro-6,8-dihydro-1,7- Pyridin-7(5H)-carboxylic acid tert-butyl butyl ester (400.1 mg), [1-(2-diphenylphosphorylphenyl-1-naphthalenyl)-2-naphthyl]-diphenylphosphine ( [1-(2-diphenylphosphophenyl-1-naphthyl)-2-naphthyl]-diphenylphosphane) (92.6 mg), diphenylmethylimine (0.37 mL), cesium carbonate (728.3 mg), suspended in toluene (10 mL) , degassed by ultrasonic waves. Palladium acetate (33.5 mg) was added, and the mixture was stirred at room temperature for several minutes, and then stirred under reflux with heating overnight. After cooling, the solvent of the reaction mixture was evaporated under reduced pressure. MeOH (10 mL) was added to the residue, and then sodium acetate (258.1 mg) and hydroxylamine hydrochloride (217.1 mg) were added, and the mixture was stirred at room temperature for 6 hours. The solvent of the reaction mixture was evaporated under reduced pressure.
2-{(5-氟-2-硝基-苯甲醯基)胺基}-6,8-二氫-1,7-啶-7(5H)-甲酸三級丁酯 2-{(5-fluoro-2-nitro-benzylidenyl)amino}-6,8-dihydro-1,7- Pyridin-7(5H)-carboxylic acid tert-butyl butyl ester
由實施例27(27a)中所得到之化合物(81.0mg)、5-氟-2-硝基苯甲酸(100.1mg)，與實施例23(23a)同樣地，得到呈無色泡沫狀物之標題化合物162.1mg(98%)。 The title compound (81.0 mg) and 5-fluoro-2-nitrobenzoic acid (100.1 mg) obtained from Example 27 (27a) gave the title of colorless foam. Compound 162.1 mg (98%).
2-[{2-硝基-(5-哌啶-1-基)-苯甲醯基}胺基]-6,8-二氫-1,7-啶-7(5H)-甲酸三級丁酯 2-[{2-nitro-(5-piperidin-1-yl)-benzylidenyl}amino]-6,8-dihydro-1,7- Pyridin-7(5H)-carboxylic acid tert-butyl butyl ester
由實施例27(27b)中所得到之化合物(0.15g)及哌啶(0.5mL)，與實施例23(23b)同樣地，得到呈黃色泡沫狀物之標題化合物200.1mg(92%)。 The title compound (200.1 mg (92%)) Compound Compound Compound Compound Compound Compound Compound Compound
6-[{2-胺基-5-(哌啶-1-基)苯甲醯基}胺基]-6,8-二氫-1,7-啶-7(5H)-甲酸三級丁酯 6-[{2-Amino-5-(piperidin-1-yl)benzylidenyl}amino]-6,8-dihydro-1,7- Pyridin-7(5H)-carboxylic acid tert-butyl butyl ester
使用實施例27(27c)中所得到之化合物(0.18g)、10%鈀-碳(0.050g)，與實施例23(23c)同樣地進行，得到呈淡黃色油狀物之標題化合物0.11g(63%)。 Using the compound obtained in Example 27 (27c) (0.18 g), 10% palladium-carbon (0.050 g), m. (63%).
三級丁基-2-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-5,8-二氫-1,7-啶-7(5H)-甲酸酯 Tert-butyl-2-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]aminemethylmercapto}benzylidene)amino]-5-(piperidin-1-yl)benzhydryl}amino)-5,8-dihydro-1 , 7- Pyridin-7(5H)-formate
由實施例27(27d)中所得到之6-[{2-胺基-5-(哌啶-1-基)苯甲醯基}胺基]-6,8-二氫-1,7-啶-7(5H)-甲酸三級丁酯(107.2mg),HBTU(135.2mg)、DIPEA(0.10mL)、3-{甲基(2-啉基乙基)羧基}苯甲酸(85.1mg)，與實施例23(23d)同樣地進行，得到呈淡黃色固體之標題化合物97.2mg(57%)。 6-[{2-Amino-5-(piperidin-1-yl)benzylidenyl}amino]-6,8-dihydro-1,7- obtained from Example 27 (27d). Pyridin-7(5H)-tricarboxylic acid tert-butyl ester (107.2 mg), HBTU (135.2 mg), DIPEA (0.10 mL), 3-{methyl (2- The morphylethyl) carboxy} benzoic acid (85.1 mg) was obtained.
三級丁基-3-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-7,8-二氫-1,6-啶-6(5H)-甲酸酯 Tert-butyl-3-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]aminemethylmercapto}benzylidene)amino]-5-(piperidin-1-yl)benzhydryl}amino)-7,8-dihydro-1 ,6- Pyridine-6(5H)-formate
3-胺基-{(5-氟-2-硝基苯甲醯基)胺基}-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 3-amino-{(5-fluoro-2-nitrobenzhydryl)amino}-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
由3-胺基-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯(CAS登錄號：355819-02-2,Synthetic Communications,2001,vol.31,# 5,pp.787-798)(350.1mg)、5-氟-2-硝基苯甲酸(311.2mg)，與實施例23(23a)同樣地，得到呈褐色固體之標題化合物550.1mg(94%)。 From 3-amino-7,8-dihydro-1,6- Pyridin-6(5H)-tricarboxylic acid tert-butyl ester (CAS accession number: 355819-02-2, Synthetic Communications, 2001, vol. 31, #5, pp. 787-798) (350.1 mg), 5-fluoro- 2-Nitrobenzoic acid (311.2 mg), m.p.
3-[{2-硝基-(5-哌啶-1-基)-苯甲醯基}胺基]-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 3-[{2-nitro-(5-piperidin-1-yl)-benzylidenyl}amino]-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
由實施例28(28a)中所得到之化合物(0.55g)及哌啶(0.7mL)，與實施例23(23b)同樣地，得到呈黃色泡沫狀物之標題化合物0.45g(71%)。 The title compound (0.45 g (71%)) was obtained from the title compound (yield:
3-[{2-胺基-(5-哌啶-1-基)-苯甲醯基}胺基]-7,8-二氫-1,6-啶-6(5H)-甲酸三級丁酯 3-[{2-Amino-(5-piperidin-1-yl)-benzylidenyl}amino]-7,8-dihydro-1,6- Pyridin-6(5H)-carboxylic acid tert-butyl butyl ester
使用實施例28(28b)中所得到之化合物(0.45g)、10%鈀-碳(0.10g)，與實施例23(23c)同樣地進行，得到呈淡黃色泡沫狀物之標題化合物0.38g(90%)。 Using the compound (0.45 g) obtained in Example 28 (28b), m.p. (90%).
三級丁基-3-({2-[(3-{甲基[2-(啉-4-基)乙基]胺甲醯基}苯甲醯基)胺基]-5-(哌啶-1-基)苯甲醯基}胺基)-7,8-二氫-1,6-啶-6(5H)-甲酸酯 Tert-butyl-3-({2-[(3-{methyl[2-( Phenyl-4-yl)ethyl]aminemethylmercapto}benzylidene)amino]-5-(piperidin-1-yl)benzhydryl}amino)-7,8-dihydro-1 ,6- Pyridine-6(5H)-formate
由實施例28(28c)中所得到之化合物(80.1mg),HBTU(150.1mg)、DIPEA(0.10mL)、3-{甲基(2-啉基乙基)羧基}苯甲酸(90.1mg)，與實施例23(23d)同樣地進行，得到呈淡黃色固體之標題化合物85.1mg(66%)。 Compound (80.1 mg) obtained from Example 28 (28c), HBTU (150.1 mg), DIPEA (0.10 mL), 3-{methyl (2- The morphylethyl) carboxy} benzoic acid (90.1 mg) was obtained.
3-[甲基(2-啉基乙基)胺磺醯基]苯甲酸 3-[methyl (2- Polinylethyl)amine sulfonyl]benzoic acid
3-[甲基(2-啉基乙基)胺磺醯基]苯甲酸苄酯 3-[methyl (2- Benzylethyl)amine sulfonyl]benzyl benzoate
於3-氯磺醯基苯甲醯氯(2.01g)、吡啶(2.04mL)的DCM(30mL)中，於0℃緩緩加入苄醇(0.87mL)。將反應混合物於0℃攪拌30分鐘後，於0℃添加N-甲基-2-啉基-乙烷胺(10.7g)。將反應混合物於室溫下，進一步攪拌1小時後，以飽和碳酸氫鈉水溶液稀釋，以DCM萃取。將有機層以硫酸鎂乾燥，過濾，濃縮。以管柱層析純化殘留物，得到呈無色油狀物之標題化合物1.91g(54%)。 To a solution of 3-chlorosulfonyl benzhydrin chloride (2.01 g), pyridine (2.04 mL) in EtOAc (30 mL). After the reaction mixture was stirred at 0 ° C for 30 minutes, N-methyl-2- was added at 0 ° C. Lolinyl-ethaneamine (10.7 g). The reaction mixture was further stirred at room temperature for 1 hr. The organic layer was dried with MgSO4, filtered and evaporated. The residue was purified by EtOAcjjjjjjjjj
3-[甲基(2-啉基乙基)胺磺醯基]苯甲酸 3-[methyl (2- Polinylethyl)amine sulfonyl]benzoic acid
於參考例(1a)中所得到之化合物(1.91g)的MeOH(20mL)溶液中，添加氫氧化鈀-碳(100mg)，於氫氣環境下激烈攪拌1小時。將反應混合物過濾後，濃縮，以管柱層析純化殘留物，得到呈白色固體之標題化合物1.5g(定量的產量)。 To a solution of the compound (1.91 g) in MeOH (20 mL), m.p. After the reaction mixture was filtered, EtOAcjjjjjjjjj
5-[甲基(2-啉基乙基)胺甲醯基]吡啶-3-甲酸 鈉鹽 5-[methyl (2- Sodium phenylethyl)amine methyl sulfonyl]pyridine-3-carboxylate
5-[甲基(2-啉基乙基)胺甲醯基]吡啶-3-甲酸乙酯 5-[methyl (2- Ethyl phenylethyl)amine methyl sulfonyl]pyridine-3-carboxylate
以與實施例(1a)同樣的方法，由5-乙氧基羰基吡啶-3-甲酸(1.45g)及N-甲基-2-啉基-乙烷胺(1.29g)，得到呈淡黃色油狀物之標題化合物2.4g(定量的產量)。 In the same manner as in Example (1a), 5-ethoxycarbonylpyridine-3-carboxylic acid (1.45 g) and N-methyl-2- The title compound 2.4 g (quantitative yield) was obtained as a pale yellow oil.
5-[甲基(2-啉基乙基)胺甲醯基]吡啶-3-甲酸鈉鹽 5-[methyl (2- Sodium phenylethyl)amine methyl sulfonyl]pyridine-3-carboxylate
於參考例(1a)中所得到之化合物(2.4g)的MeOH(20mL)溶液中，於室溫添加5N NaOH水溶液(2.97mL)。將反應混合物加熱，於70℃攪拌15分鐘後，冷卻至室溫，濃縮。將殘留物以異丙醇稀釋，沈澱物生成為止，以DEE稀釋。將沈澱物過濾，減壓乾燥，得到呈白色固體之標題化合物2.0g(86%)。 A solution of the compound (2.4 g) obtained in EtOAc (EtOAc m. The reaction mixture was heated and stirred at 70 ° C for 15 min then cooled to room temperature and concentrated. The residue was diluted with isopropanol and the precipitate was formed and diluted with DEE. The precipitate was filtered and dried <jjjjjjjjjj
5-{甲基[2-(啉-4-基)乙基]胺磺醯基}菸鹼酸 鈉鹽 5-{methyl[2-( Phenyl-4-yl)ethyl]amine sulfonyl} Nicotinate sodium salt
5-[甲基(2-啉基乙基)胺磺醯基]吡啶-3-甲酸甲酯 5-[methyl (2- Methyl phenylethyl)amine sulfonyl]pyridine-3-carboxylate
於2-氯-5-氯磺醯基-吡啶-3-甲酸甲酯(300mg)的DCM(10mL)溶液中，於0℃添加N-甲基-2-啉基-乙烷胺(192mg)、吡啶(0.27mL)及DMAP(4mg)。將反應混合物於0℃攪拌2小時後，添加水，以DCM萃取，將有機層以硫酸鎂乾燥，過濾，濃縮。於殘留物(483mg)之乙酸(10mL)溶液中，於室溫添加經以1N鹽酸洗淨後並經乾燥之鋅粉末(362mg)。將反應混合物加熱，於80℃攪拌6小時後，冷卻至室溫，靜置一晚，再度於80℃攪拌5小 時，冷卻至室溫後，濃縮。將殘留物以MeOH及DCM稀釋，經過濾後濃縮。以管柱層析純化殘留物，得到呈淡黃色油狀物之標題化合物84mg(24%)。 Add N-methyl-2- at 0 ° C in a solution of methyl 2-chloro-5-chlorosulfonyl-pyridine-3-carboxylate (300 mg) in DCM (10 mL) Polinyl-ethaneamine (192 mg), pyridine (0.27 mL) and DMAP (4 mg). After the reaction mixture was stirred at EtOAc (EtOAc)EtOAc. A solution of the residue (483 mg) in acetic acid (10 mL) was then evaporated. The reaction mixture was heated, stirred at 80 ° C for 6 hours, cooled to room temperature, stood still overnight, then stirred at 80 ° C for 5 hours, cooled to room temperature and then concentrated. The residue was diluted with MeOH and EtOAc then filtered. The residue was purified by EtOAcjjjjjjd
5-{甲基[2-(啉-4-基)乙基]胺磺醯基}菸鹼酸 鈉鹽 5-{methyl[2-( Phenyl-4-yl)ethyl]amine sulfonyl} Nicotinate sodium salt
於參考例(3a)中所得到之化合物(121mg)的MeOH(2mL)溶液中，於室溫添加5N NaOH水溶液(0.08mL)。將反應混合物於室溫攪拌15小時，濃縮，得到標題化合物(定量的產率) A solution of the compound (121 mg) in MeOH (2 mL) The reaction mixture was stirred at room temperature for 15 h and concentrated to give
以下，顯示於實施例及參考例製造之化合物的結構式及物理化學的數據。 The structural formula and physical and chemical data of the compounds produced in the examples and the reference examples are shown below.
ExNo表示實施例編號，RefExNo表示參考例編號。 ExNo represents the embodiment number, and RefExNo represents the reference example number.
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| TW201700458A (en) * | 2015-04-24 | 2017-01-01 | 第一三共股份有限公司 | Method for producing dicarboxylic acid compound |
| CN106316987B (en) * | 2015-07-03 | 2020-11-17 | 江苏恒瑞医药股份有限公司 | Benzamide derivative, preparation method and medical application thereof |
| BR112021016795A8 (en) * | 2019-02-27 | 2022-08-16 | Millennium Pharm Inc | ADMINISTRATION OF JUICE ACTIVATING ENZYME INHIBITOR AND CHECKPOINT INHIBITORS |
| CN114621135B (en) * | 2020-12-11 | 2024-01-30 | 上海拓界生物医药科技有限公司 | LPA1 small molecule antagonist |
| CN115819354A (en) * | 2022-12-13 | 2023-03-21 | 杭州澳赛诺生物科技有限公司 | Synthesis method of alkyl-substituted 6-alkyl-4-aminopyridazine or salt thereof |
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| JP5617919B2 (en) * | 2010-04-28 | 2014-11-05 | アステラス製薬株式会社 | Tetrahydrobenzothiophene compound |
| JP5827326B2 (en) * | 2010-07-07 | 2015-12-02 | アーデリクス，インコーポレーテッド | Compounds and methods for inhibiting phosphate transport |
| EP2591354B1 (en) * | 2010-07-07 | 2016-09-07 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| WO2012006474A2 (en) * | 2010-07-07 | 2012-01-12 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| EP2590656B1 (en) * | 2010-07-07 | 2017-11-15 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| EA023955B1 (en) * | 2011-10-27 | 2016-07-29 | Астеллас Фарма Инк. | Aminoalkyl-substituted n-thienyl benzamide derivative |
| WO2013129435A1 (en) * | 2012-02-28 | 2013-09-06 | 協和発酵キリン株式会社 | Fused thiophene derivative |
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- 2014-10-29 TW TW103137333A patent/TW201607925A/en unknown
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