TW201930295A - 環烷基乙酸型二醯胺衍生物 - Google Patents
環烷基乙酸型二醯胺衍生物 Download PDFInfo
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- TW201930295A TW201930295A TW107143706A TW107143706A TW201930295A TW 201930295 A TW201930295 A TW 201930295A TW 107143706 A TW107143706 A TW 107143706A TW 107143706 A TW107143706 A TW 107143706A TW 201930295 A TW201930295 A TW 201930295A
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- -1 Cycloalkyl acetic acid Chemical compound 0.000 title claims description 252
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title description 8
- 150000001470 diamides Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 446
- 150000003839 salts Chemical class 0.000 claims abstract description 62
- 102100038885 Histone acetyltransferase p300 Human genes 0.000 claims abstract description 33
- 101000882390 Homo sapiens Histone acetyltransferase p300 Proteins 0.000 claims abstract description 33
- 101000896987 Homo sapiens CREB-binding protein Proteins 0.000 claims abstract description 30
- 238000000034 method Methods 0.000 claims description 88
- 125000000217 alkyl group Chemical group 0.000 claims description 72
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 67
- 229910052757 nitrogen Inorganic materials 0.000 claims description 57
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 56
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 52
- 125000003545 alkoxy group Chemical group 0.000 claims description 51
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 47
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 47
- 206010028980 Neoplasm Diseases 0.000 claims description 43
- 125000001424 substituent group Chemical group 0.000 claims description 43
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 39
- 125000005843 halogen group Chemical group 0.000 claims description 36
- 102100021975 CREB-binding protein Human genes 0.000 claims description 29
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 25
- 229910052799 carbon Inorganic materials 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- IDZNHFASMBVREM-SECBINFHSA-N (2R)-1-pyridin-3-ylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCN1C1=CC=CN=C1 IDZNHFASMBVREM-SECBINFHSA-N 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 13
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- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 12
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- 206010060862 Prostate cancer Diseases 0.000 claims description 11
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 11
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- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 11
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- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000004434 sulfur atom Chemical group 0.000 claims description 11
- FEESCIAHPNUGDA-SECBINFHSA-N (2R)-1-pyridin-3-ylpyrrolidine-2-carboxamide Chemical compound NC(=O)[C@H]1CCCN1C1=CC=CN=C1 FEESCIAHPNUGDA-SECBINFHSA-N 0.000 claims description 10
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 10
- 206010005003 Bladder cancer Diseases 0.000 claims description 10
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- 239000002246 antineoplastic agent Substances 0.000 claims description 10
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 10
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 claims description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 5
- 125000002619 bicyclic group Chemical group 0.000 claims description 5
- 125000006580 bicyclic heterocycloalkyl group Chemical group 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- XTTPQTQYGCYITB-OAQYLSRUSA-N (2R)-1-[1-[4-(hydroxymethyl)piperidin-1-yl]cyclopentanecarbonyl]-N-(1H-indazol-4-yl)pyrrolidine-2-carboxamide Chemical compound OCC1CCN(CC1)C1(CCCC1)C(=O)N1[C@H](CCC1)C(=O)NC1=C2C=NNC2=CC=C1 XTTPQTQYGCYITB-OAQYLSRUSA-N 0.000 claims description 4
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- UAPNIBACNQZDFT-LLGFUMIMSA-N (2R)-1-[1-[(3aR,6aS)-1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl]cyclopentanecarbonyl]-N-(1H-indazol-4-yl)pyrrolidine-2-carboxamide Chemical compound N1N=CC2=C(C=CC=C12)NC([C@@H]1N(CCC1)C(=O)C1(CCCC1)N1C[C@@H]2[C@H](C1)COC2)=O UAPNIBACNQZDFT-LLGFUMIMSA-N 0.000 claims description 3
- RBXHXFNQJWNEEM-VGOFRKELSA-N (2R,4R)-4-hydroxy-N-(1H-indol-4-yl)-1-[1-(4-methoxypiperidin-1-yl)cyclopentanecarbonyl]pyrrolidine-2-carboxamide Chemical compound O[C@@H]1C[C@@H](N(C1)C(=O)C1(CCCC1)N1CCC(CC1)OC)C(=O)NC1=C2C=CNC2=CC=C1 RBXHXFNQJWNEEM-VGOFRKELSA-N 0.000 claims description 3
- XBUDXKFKCQHINV-LQJMHCDQSA-N (2R,4R)-N-(2-cyanophenyl)-4-fluoro-1-[1-(1-hydroxy-4-methoxycyclohexyl)cyclopentanecarbonyl]pyrrolidine-2-carboxamide Chemical compound C(#N)C1=C(C=CC=C1)NC([C@@H]1N(C[C@@H](C1)F)C(=O)C1(CCCC1)C1(CCC(CC1)OC)O)=O XBUDXKFKCQHINV-LQJMHCDQSA-N 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 3
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 claims description 3
- 201000004253 NUT midline carcinoma Diseases 0.000 claims description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical group C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 claims description 3
- FGZHHPJMQRLCJH-DNVCBOLYSA-N (2R,4R)-4-fluoro-1-[1-(4-methoxypiperidin-1-yl)cyclopentanecarbonyl]-N-(1H-pyrazolo[4,3-b]pyridin-5-yl)pyrrolidine-2-carboxamide Chemical compound F[C@@H]1C[C@@H](N(C1)C(=O)C1(CCCC1)N1CCC(CC1)OC)C(=O)NC1=CC=C2C(=N1)C=NN2 FGZHHPJMQRLCJH-DNVCBOLYSA-N 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical group OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 claims description 2
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004647 alkyl sulfenyl group Chemical group 0.000 claims description 2
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000001984 thiazolidinyl group Chemical group 0.000 claims description 2
- KOXTZOURZRMSJW-YLJYHZDGSA-N (2R,4R)-4-fluoro-1-[1-[4-(hydroxymethyl)-4-methoxypiperidin-1-yl]cyclohexanecarbonyl]-N-(1H-pyrazolo[4,3-b]pyridin-5-yl)pyrrolidine-2-carboxamide Chemical compound F[C@@H]1C[C@@H](N(C1)C(=O)C1(CCCCC1)N1CCC(CC1)(OC)CO)C(=O)NC1=CC=C2C(=N1)C=NN2 KOXTZOURZRMSJW-YLJYHZDGSA-N 0.000 claims 1
- 125000004122 cyclic group Chemical group 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 264
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 153
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 43
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 21
- 239000000126 substance Substances 0.000 description 19
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- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
本發明係提供具有優異的EP300及/或CREBBP之組蛋白乙醯基轉移酶(histone acetyltransferase)抑制活性的化合物或其藥理上可容許的鹽。
一種式(1)所表示的化合物或其藥理上可容許的鹽。
(其中,式(1)中之環Q1、環Q2、R1、R2、R3、及R4係各自與說明書中的定義為同義。)
Description
本發明係關於具有優異的EP300及/或CREBBP之組蛋白乙醯基轉移酶抑制活性的低分子化合物或其藥理上可容許的鹽。
染色體係藉由其構成成分的DNA的甲基化修飾或組蛋白(組蛋白H2A、H2B、H3、H4)的各式各樣的修飾(乙醯基化、甲基化、磷酸化、泛素化等)而使其高階結構變化,且動態地控制基因的複製或轉錄(非專利文獻1)。
組蛋白或組蛋白以外的蛋白質之可逆的乙醯基化係真核生物中常發生的轉譯後修飾。組蛋白乙醯基轉移酶係使乙醯基轉移至組蛋白的離胺酸側鏈的酵素,組蛋白去乙醯酶(histone deacetylase)係自離胺酸殘基去除乙醯基的酵素。由胺基酸序列的同源性、高階結構、及其機能,組蛋白乙醯基轉移酶被大致分類成4種類,彼等為EP300/CREBBP(E1A結合蛋白p300/CREB結合蛋白)、GCN5/PCAF(general control nonrepressed-protein 5/P300/CBP-關連因子)、MYST(MOZ、Ybf2/Sas3、Sas2、 及Tip60)、及Rtt109(Regulator of Tyl Transposition gene production 109)。EP300與其同種同源物(paralog)CREBBP有90%以上之胺基酸序列同源性,除了HAT域以外,有CH1/CH2/CH3域(富含半胱胺酸-組胺酸域(cysteine-histidine rich domains))、KIX域、及布羅莫結構域(bromodomain)等(非專利文獻2)。
EP300及CREBBP係各自被發現為E1A腺病毒蛋白及cAMP調節的強化子結合蛋白(cAMP-regulated enhancer binding protein)的結合配對體(binding partner)(非專利文獻3-5)。之後,辨明於EP300/CREBBP存在有組蛋白乙醯基轉移酶活性(非專利文獻6、7),亦詳查其基質特異性,已報告除了組蛋白(H2A、H2B、H3及H4)之離胺酸殘基以外,亦將p53(非專利文獻8)、MyoD(非專利文獻9)、STAT3(非專利文獻10)、雄性素受體(Androgen receptor)(非專利文獻11)等乙醯基化。EP300不僅作為組蛋白乙醯基轉移酶而作用,亦作為轉錄因子的構成因子、或者藉由將轉錄因子與其他轉錄相關的蛋白質連結,而參與轉錄的活化(非專利文獻12、13)。又,EP300/CREBBP亦參與分裂、增殖、分化等之許多活體反應(非專利文獻12)。
已報告EP300/CREBBP之高表現、變異或其機能亢進與各式各樣的癌症有關連。就其例而言,可列舉前列腺癌(非專利文獻14、15)、肝癌(非專利文獻16、17)、肺癌(非專利文獻18、19、20)、乳癌(非專利文獻21)、大腸癌及胃癌(非專利文獻22)、血液癌(非專利文 獻23、24)、胰臟癌(pancreatic cancer)(非專利文獻25)、膀胱癌(非專利文獻26)、胃腸道基質瘤(gastrointestinal stromal tumor)(非專利文獻27)、NUT中線癌(NUT midline carcinoma)(非專利文獻28)或卵巢癌(非專利文獻29)。
由以上來看,抑制EP300/CREBBP之組蛋白乙醯基轉移酶活性的藥劑係被期待作為抗腫瘤劑的有用性。然而,難以探查抑制活性強且具有更特異性的組蛋白乙醯基轉移酶抑制活性的化合物(非專利文獻30)。最近,雖發現作為特異性的EP300抑制劑之C646(非專利文獻31),但冀求開發具有更強的抑制活性及選擇性的新穎構造之化合物。
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本發明係提供一種新穎的低分子化合物,其具有同時抑制EP300及CREBBP的組蛋白乙醯基轉移酶活性的作用,且對依賴於EP300及/或CREBBP的癌症顯示抗癌作用。
本發明係關於下列[1]至[20]。
[1]一種下述通式(1)所表示的化合物或其藥理上可容許的鹽;
[式中,環Q1表示可具有1至3個獨立選自下述A群的取代基的3員至7員之環烷基;可具有1至3個獨立選自下述A群的取代基的3員至7員之雜環烷基,其中該3員至7員之雜環烷基於環內具有1至2個獨立選自包含氮原子、氧原子及硫原子的群組的雜原子;或可具有1至3個獨立選自下述A群的取代基的8員至10員之二環性之雜環烷基,其中該8員至10員之二環性之雜環烷基於環內具有1至3個獨立選自包含氮原子、氧原子及硫原子的群組的雜原子;環Q2表示可具有1至3個獨立選自下述B群的取代基的苯基;可具有1至3個獨立選自下述B群的取代基的萘基;可具有1至3個獨立選自下述B群的取代基的5員或6員之芳香族雜環基,其中該5員或6員之芳香族雜環基於環內具有1至3個氮原子;或可具有1至3個獨立選自下述B群的取代基的8員至10員之二環性之芳香族雜環基,其中該8員至10員之二環性之芳香族雜環基於環內具有1至4個獨立選自包含氮原子、氧原子及硫原子的群組的雜原子;R1及R2係各自獨立表示C1-6烷基、或C1-6烷氧基; 或R1及R2係與R1及R2所鍵結的碳原子一起,形成可具有1至3個獨立選自下述C群的取代基的3員至7員之環烷基環;可具有1至3個獨立選自下述C群的取代基的四氫哌喃環;或可具有1至3個獨立選自下述C群的取代基的二烷環;R3表示氫原子、C1-6烷基、或羥基C2-6烷基;R4表示氫原子、C1-6烷基、羥基C1-6烷基、或C1-6烷基磺醯基C1-6烷基;或R3及R4係與R3所鍵結的氮原子及R4所鍵結的碳原子一起,形成可具有1至3個獨立選自下述D群的取代基的吖呾環;可具有1至3個獨立選自下述D群的取代基的吡咯啶環;可具有1至3個獨立選自下述D群的取代基的六亞甲基亞胺環;可具有1至3個獨立選自下述D群的取代基的噻唑啶(thiazolidine)環;可具有1至3個獨立選自下述D群的取代基的1-側氧噻唑啶環;可具有1至3個獨立選自下述D群的取代基的1,1-二側氧噻唑啶環;或可具有1至3個獨立選自下述D群的取代基的4-側氧吡咯啶環];A群:鹵素原子、羥基、羧基、胺基、C1-6烷基、鹵C1-6烷基、羥基C1-6烷基、C1-6烷氧基C1-6烷基、C1-6烷氧基、鹵C1-6烷氧基、C1-6烷氧基C1-6烷氧基、C2-7烷醯基、羥基C2-7烷醯基、C2-7烷醯基胺基、C1-6烷基磺醯基、C1-6烷基磺醯基胺基、苄基、苄氧基、側氧基;B群:鹵素原子、氰基、胺基、C1-6烷基、C1-6烷氧 基、羥基C1-6烷基、C1-6烷基胺基·C1-6烷基胺基C1-6烷基、啉基C1-6烷氧基、苯基、苄氧基、C1-6烷氧基C1-6烷基、羥基、鹵C1-6烷基、C1-6烷氧基羰基、C2-7烷醯基胺基、鹵C1-6烷氧基、C1-6烷氧基C1-6烷氧基、C1-6烷基磺醯基胺基、啉基C1-6烷基、C1-6烷基磺醯基;C群:鹵素原子、C1-6烷基、C1-6烷氧基;D群:鹵素原子、羥基、C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6烷氧基、C2-6炔基、C2-7烷醯基胺基、胺基、二C1-6烷基胺基。
[2]如[1]記載之化合物或其藥理上可容許的鹽,其中環Q1表示下述式(2A)至(2F)之任一者;
[式中,V表示氮原子、或-CR5,W表示氧原子、-NR6、-CR7R8、或-SO2,R5表示氫原子、或羥基,R6表示氫原子、C1-6烷基、C2-7烷醯基、羥基C2-7烷醯基、C1-6烷基磺醯基、或苄基,R7及R8各自獨立表示氫原子、鹵素原子、羥基·羧基、胺基、C1-6烷基、鹵C1-6烷基、羥基C1-6烷基、烷氧基C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6烷氧基、 鹵C1-6烷氧基、C2-7烷醯基胺基、C1-6烷基磺醯基胺基、或苄基,R9及R10各自獨立表示氫原子、鹵素原子、或C1-6烷氧基,R11及R12各自獨立表示氫原子、羥基、C1-6烷氧基、或苄氧基,或R11及R12係一起形成側氧基,R13表示C1-6烷氧基,環Q3表示苯環、吡唑環、或四氫呋喃環,n表示1或2]。
[3]如[1]記載之化合物或其藥理上可容許的鹽,其中環Q1表示下述式(3A)至(3E)之任一者;
[式中,R14表示甲氧基、二氟甲氧基、或三氟甲氧基,R15表示甲基、或三氟甲基]。
[4]如[1]至[3]之任一者記載之化合物或其藥理上可容許的鹽,其中環Q2係可具有1個或2個獨立選自包含羥基、氟原子、氯原子、氰基、甲基、甲氧基、及苄氧基的群組的取代基的苯基。
[5]如[1]至[3]之任一者記載之化合物或其藥理上可容許的鹽,其中環Q2表示下述式(4A)或(4B);
[式中,X表示氮原子、或-CR16,Y表示氮原子、或-CR17,Z表示氮原子、或-CH,R16表示氫原子、氟原子、或氰基,R17表示氫原子、C1-6烷基、或羥基C1-6烷基]。
[6]如[1]至[3]之任一者記載之化合物或其藥理上可容許的鹽,其中環Q2表示下述式(5A)至(5D)之任一者;
[式中,Y1表示氮原子、或-CH]。
[7]如[1]至[6]之任一者記載之化合物或其藥理上可容許的鹽,其中R1及R2係各自獨立為甲基。
[8]如[1]至[6]之任一者記載之化合物或其藥理上可容許的鹽,其中R1及R2係與R1及R2所鍵結的碳原子一起,形成環丁烷環、3,3-二鹵環丁烷環、3,3-二C1-6烷基環丁烷環、環戊烷環、環己烷環、4,4-二鹵環己烷環、四氫哌喃環、環庚烷環、或螺[3.3]庚烷環。
[9]如[1]至[6]之任一者記載之化合物或其藥理上 可容許的鹽,其中R1及R2係與R1及R2所鍵結的碳原子一起,形成環戊烷環、環己烷環、或4,4-二氟環己烷環。
[10]如[1]至[9]之任一者記載之化合物或其藥理上可容許的鹽,其中R3為甲基,R4為甲基、或羥甲基。
[11]如[1]至[9]之任一者記載之化合物或其藥理上可容許的鹽,其中R3及R4係與R3所鍵結的氮原子及R4所鍵結的碳原子一起,表示下述式(6);
[式中,R18表示氫原子、鹵素原子、羥基、C1-6烷氧基、或C1-6烷氧基C1-6烷氧基,R19表示氫原子、或羥基]。
[12]如[1]至[9]之任一者記載之化合物或其藥理上可容許的鹽,其中R3及R4係與R3所鍵結的氮原子及R4所鍵結的碳原子一起,表示下述式(7);
[式中,R20表示氫原子、氟原子、羥基、或甲氧基甲氧基]。
[13]如[1]記載之化合物或其藥理上可容許的鹽,其 中環Q1表示下述式(3A)至(3E)之任一者;
[式中,R14表示甲氧基、二氟甲氧基、或三氟甲氧基,R15表示甲基、或三氟甲基];環Q2表示下述式(5A)至(5D)之任一者;
[式中,Y1表示氮原子、或-CH];R1及R2係與R1及R2所鍵結的碳原子一起,形成環戊烷環、環己烷環、或4,4-二氟環己烷環;R3及R4係與R3所鍵結的氮原子及R4所鍵結的碳原子一起,表示下述式(7);
[式中,R20表示氫原子、氟原子、羥基、或甲氧基甲氧基]。
[14]一種選自下述群組之任一者的化合物或其藥理 上可容許的鹽,N-1H-吲唑-4-基-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-D-脯胺醯胺、N-1H-吲唑-4-基-1-({1-[(3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基]環戊基}羰基)-D-脯胺醯胺、1-({1-[4-(羥甲基)哌啶-1-基]環戊基}羰基)-N-1H-吲唑-4-基-D-脯胺醯胺、(4R)-4-羥基-N-1H-吲哚-4-基-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-D-脯胺醯胺、(4R)-N-(2-氰基苯基)-4-氟-1-{[1-(1-羥基-4-甲氧基環己基)環戊基]羰基}-D-脯胺醯胺、(4R)-4-氟-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-({1-[4-(羥甲基)-4-甲氧基哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、1-{[1-(1-羥基-4-甲氧基環己基)環戊基]羰基}-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-[2-(1-羥基-4-甲氧基環己基)-2-甲基丙醯基]-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[4,4-二氟-1-(4-羥基-4-甲基哌啶-1-基)環己基]羰基}-4-氟-N-1H-吡咯并[3,2-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-({1-[4-羥基-4-(三氟甲基)哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-({1-[4-(2-羥基丙烷-2-基)-4-甲氧基哌 啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、N2-[2-(4-甲氧基哌啶-1-基)-2-甲基丙醯基]-N2-甲基-N-1H-吡咯并[2,3-b]吡啶-6-基-D-丙胺醯胺、(4R)-1-{[(1’r,4’R)-4,4-二氟-4’-甲氧基-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[(1’s,4’S)-4,4-二氟-4’-甲氧基-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[(1’r,4’R)-4’-(二氟甲氧基)-4,4-二氟-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[4,4-二氟-4’-羥基-4’-(三氟甲基)-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[(1’r,4’R)-4,4-二氟-4’-(三氟甲氧基)-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺。
[15]一種醫藥組成物,其係以如[1]至[14]之任一者記載之化合物或其藥理上可容許的鹽作為有效成分。
[16]一種EP300及/或CREBBP抑制劑,其係以如[1]至[14]之任一者記載之化合物或其藥理上可容許的鹽作為有效成分。
[17]一種抗腫瘤劑,其係以如[1]至[14]之任一者記 載之化合物或其藥理上可容許的鹽作為有效成分。
[18]如[17]記載之抗腫瘤劑,其中腫瘤為前列腺癌、肝癌、肺癌、乳癌、大腸癌、胃癌、血液癌、胰臟癌、食道癌、膀胱癌、胃腸道基質瘤、NUT中線癌、或卵巢癌。
[19]一種腫瘤之治療方法,其包含投予如[1]至[14]之任一者記載之化合物或其藥理上可容許的鹽。
[20]如[19]記載之治療方法,其中腫瘤為前列腺癌、肝癌、肺癌、乳癌、大腸癌、胃癌、血液癌、胰臟癌、食道癌、膀胱癌、胃腸道基質瘤、NUT中線癌、或卵巢癌。
[21]一種用於腫瘤之治療之如[1]至[14]之任一者記載之化合物或其藥理上可容許的鹽。
[22]如[21]記載之化合物或其藥理上可容許的鹽,其中腫瘤為前列腺癌、肝癌、肺癌、乳癌、大腸癌、胃癌、血液癌、胰臟癌、食道癌、膀胱癌、胃腸道基質瘤、NUT中線癌、或卵巢癌。
本發明之化合物或其藥理上可容許的鹽係顯示優異的EP300及/或CREBBP之抑制活性。即,藉由將含有本發明之化合物或其藥理上可容許的鹽的醫藥組成物投予哺乳動物(人類、牛、馬、或豬等)或鳥類(雞等),可用於依賴於EP300及/或CREBBP的癌症的治療。據此,本發明之化合物或其藥理上可容許的鹽可使用作為抗腫瘤劑的有效成分。就腫瘤而言,可列舉例如:前列 腺癌、肝癌、肺癌、乳癌、大腸癌、胃癌、血液癌、胰臟癌、食道癌、膀胱癌、胃腸道基質瘤、NUT中線癌、或卵巢癌。
於本發明,「鹵素原子」係指氟原子、氯原子、溴原子或碘原子,較佳為氟原子。
於本發明,「C1-6烷基」表示碳數1至6個之直鏈或分枝鏈之烷基。可列舉例如:甲基、乙基、正丙基、異丙基、正丁基、二級丁基、三級丁基、正戊基、異戊基、2-甲基丁基、新戊基、1-乙基丙基、正己基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基等。
於本發明,「C1-6烷氧基」表示上述「C1-6烷基」與氧原子結合的基。可列舉例如:甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、二級丁氧基、三級丁氧基、正戊氧基、異戊氧基、2-甲基丁氧基、正己氧基等。
於本發明,「3員至7員之環烷基(環)」表示3員至7員之單環或螺環之飽和烴基(環)。可列舉例如:環丙基、環丁基、環戊基、環己基、環庚基、螺[3.3]庚 基等。
於本發明,「羥基C1-6烷基」表示上述「C1-6烷基」之1個或2個之氫原子經羥基取代的基。可列舉例如:羥甲基、1-羥乙基、2-羥乙基、1-羥丙基、2-羥丙基、1-羥異丙基、1-羥丁基、2-羥丁基、1-羥戊基、2-羥戊基、1-羥己基、1,2-二羥乙基等。
於本發明,「羥基C2-6烷基」表示碳數2至6個之直鏈或分枝鏈之烷基的1個或2個之氫原子經羥基取代的基。可列舉例如:1-羥乙基、2-羥乙基、1-羥丙基、2-羥丙基、1-羥異丙基、1-羥丁基、2-羥丁基、1-羥戊基、2-羥戊基、1-羥己基、2,3-二羥丙基等。
於本發明,「鹵C1-6烷基」表示上述「C1-6烷基」之1至3個之氫原子經上述「鹵素原子」取代的基。可列舉例如:氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、1-氟乙基、1-氯乙基、2-氟乙基、1,2-二氟丙基、2,2,2-三氟乙基等。
於本發明,「鹵C1-6烷氧基」表示上述「C1-6烷氧基」之1至3個之氫原子經上述「鹵素原子」取代的基。可列舉例如:氟甲氧基、二氟甲氧基、三氟甲氧基、氯甲氧基、二氯甲氧基、三氯甲氧基、1-氟乙氧基、1-氯乙氧基、2-氟乙氧基、1,2-二氟丙氧基、2,2,2-三氟乙氧基等。
於本發明,「C1-6烷氧基羰基」表示上述「C1-6烷氧基」與羰基的碳原子結合的基。可列舉例如:甲氧基羰基、乙氧基羰基、正丙氧基羰基、異丙氧基羰基、 正丁氧基羰基、二級丁氧基羰基、三級丁氧基羰基等。
於本發明,「C2-7烷醯基」表示上述「C1-6烷基」與羰基的碳原子結合的基。可列舉例如:乙醯基、丙醯基、丁醯基、異丁醯基、三甲基乙醯基、戊醯基、異戊醯基、己醯基、庚醯基等。
於本發明,「羥基C2-7烷醯基」表示上述「C2-7烷醯基」之1個或2個之氫原子經羥基取代的基。可列舉例如羥基乙醯基、羥基丙醯基、羥基丁醯基等。
於本發明,「C2-7烷醯基胺基」表示上述「C2-7烷醯基」與胺基結合的基。可列舉例如:乙醯基胺基、丙醯基胺基、丁醯基胺基、異丁醯基胺基、戊醯基胺基等。
於本發明,「C1-6烷基磺醯基」表示上述「C1-6烷基」與磺醯基的硫原子結合的基。可列舉例如:甲基磺醯基、乙基磺醯基、正丙基磺醯基、異丙基磺醯基、正丁基磺醯基、二級丁基磺醯基、三級丁基磺醯基、正戊基磺醯基等。
於本發明,「C1-6烷基磺醯基胺基」表示上述「C1-6烷基磺醯基」與胺基結合的基。可列舉例如:甲基磺醯基胺基、乙基磺醯基胺基、正丙基磺醯基胺基、異丙基磺醯基胺基、正丁基磺醯基胺基、二級丁基磺醯基胺基、三級丁基磺醯基胺基、正戊基磺醯基胺基等。
於本發明,「C1-6烷基胺基」表示胺基的1個氫原子經上述「C1-6烷基」取代的基。可列舉例如:甲基胺基、乙基胺基、正丙基胺基、異丙基胺基、正丁 基胺基、二級丁基胺基、三級丁基胺基、正戊基胺基等。
於本發明,「C1-6烷基胺基C1-6烷基」表示上述「C1-6烷基」之1個氫原子經上述「C1-6烷基胺基」取代的基。可列舉例如:甲基胺基甲基、甲基胺基乙基、乙基胺基甲基、正丙基胺基甲基、異丙基胺基甲基、正丁基胺基甲基、二級丁基胺基甲基、三級丁基胺基甲基、三級丁基胺基乙基、正戊基胺基甲基等。
於本發明,「啉基C1-6烷基」表示上述「C1-6烷基」之1個氫原子經啉基取代的基。可列舉例如:啉基甲基、2-啉基乙基、3-啉基丙基、4-啉基丁基、5-啉基戊基、6-啉基己基等。
於本發明,「啉基C1-6烷氧基」表示上述「啉基C1-6烷基」與氧原子結合的基。可列舉例如:啉基甲氧基、2-啉基乙氧基、3-啉基丙氧基、4-啉基丁氧基、5-啉基戊氧基、6-啉基己氧基等。
於本發明,「C1-6烷氧基C1-6烷基」表示上述「C1-6烷基」之1個氫原子經上述「C1-6烷氧基」取代的基。可列舉例如:甲氧基甲基、乙氧基甲基、正丙氧基甲基、異丙氧基甲基、甲氧基乙基、乙氧基乙基、丙氧基乙基、異丙氧基乙基等。
於本發明,「C1-6烷氧基C1-6烷氧基」表示上述「C1-6烷氧基」之1個氫原子經上述「C1-6烷氧基」取代的基。可列舉例如:甲氧基甲氧基、乙氧基甲氧基、正丙氧基甲氧基、異丙氧基甲氧基、甲氧基乙氧基、乙氧基乙氧基、正丙氧基乙氧基、或異丙氧基乙氧基等。
於本發明,「C2-6炔基」表示碳數2至6個之直鏈或分枝鏈炔基。可列舉例如:乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-乙炔基-2-丙炔基、1-甲基-2-丙炔基、1-戊炔基、1-己炔基、1,3-己二炔基、1,5-己二炔基等。
於本發明,「二C1-6烷基胺基」表示胺基之2個氫原子各自經上述「C1-6烷基」取代的基。可列舉例如:二甲基胺基、二乙基胺基、二丙基胺基、二異丙基胺基、二丁基胺基、二異丁基胺基、二戊基胺基、二新戊基胺基、二己基胺基、N-乙基-N-甲基胺基、N-甲基-N-丙基胺基、N-異丙基-N-甲基胺基、N-丁基-N-甲基胺基、N-異丁基-N-甲基胺基、N-乙基-N-丙基胺基、N-乙基-N-異丙基胺基、N-丁基-N-乙基胺基、N-乙基-N-異戊基胺基等。
於本發明,「C1-6烷基磺醯基C1-6烷基」表示上述「C1-6烷基」之1個氫原子經上述「C1-6烷基磺醯基」取代的基。可列舉例如:甲基磺醯基甲基、甲基磺醯基乙基、乙基磺醯基甲基、正丙基磺醯基甲基、異丙基磺醯基甲基、正丁基磺醯基甲基、二級丁基磺醯基甲基、三級丁基磺醯基甲基、三級丁基磺醯基乙基、正戊基磺醯基甲基等。
於本發明,「環內具有1至2個獨立選自包含氮原子、氧原子、及硫原子的群組的雜原子的3員至7員之雜環烷基」表示由環之構成原子除了碳原子以外亦包含1至2個雜原子(氮原子、氧原子、或硫原子)的3 員至7員之單環之非芳香族化合物所衍生的基,於環的一部分可具有不飽和鍵。於環的構成原子包含氮原子的情形,該氮原子與R1及R2所鍵結的碳原子可結合。可列舉例如:吖基、氧基、吖呾基、氧呾基、吡咯啶基、2-側氧吡咯啶基、1,2-二氫-5-側氧吡咯基、四氫呋喃基、四氫噻吩基、哌啶基、哌基、啉基、四氫哌喃基、二烷基、四氫噻喃基、吖基、氧基等。
於本發明,「於環內具有1至3個獨立選自包含氮原子、氧原子、及硫原子的群組的雜原子的8員至10員之二環性之雜環烷基」表示由環之構成原子除了碳原子以外亦包含1至3個雜原子(氮原子、氧原子、或硫原子)的8員至10員之稠合非芳香族化合物所衍生的基。於環的一部分可具有不飽和鍵,與R1及R2所鍵結的碳原子未結合的環可為芳香族環。於環之構成原子包含氮原子的情形,該氮原子與R1及R2所鍵結的碳原子可結合。可列舉例如:3,3a,4,5,6,6a-六氫-1H-呋喃并[3,4-c]吡咯基、3a,4,5,6,6a-六氫-1H-噻吩并[3,4-c]吡咯基、4,5,6,7-四氫-2H-吡唑并[4,3-c]吡啶基、4,5,6,7-四氫-2H-吡唑并[4,3-b]吡啶基、4,5,6,7-四氫-2H-吡咯并[4,3-c]吡啶基、4,5,6,7-四氫-2H-吡咯并[4,3-b]吡啶基、1,2,3,4-四氫異喹啉基、1,2,3,4-四氫喹啉基等。
於本發明,「於環內具有1至3個氮原子的5員或6員之芳香族雜環基」表示自環之構成原子除了碳原子以外亦包含1至3個之氮原子的5員或6員之單環之芳香族化合物所衍生的基。可列舉例如:吡啶基、 嘧啶基、嗒基、吡基、三基、吡咯基、吡唑基、咪唑基、側氧吡啶基等。環Q2中的「於環內具有1至3個有氮原子的5員或6員之芳香族雜環基」較佳為吡啶基、嘧啶基、吡唑基。
於本發明,「於環內具有1至4個獨立選自包含氮原子、氧原子、及硫原子的群組的雜原子的8員至10員之二環性之芳香族雜環基」表示由環之構成原子除了碳原子以外亦包含1至4個之雜原子(氮原子、氧原子、或硫原子)的8員至10員之稠合芳香族化合物所衍生的基,於二環性之環的一部分可具有飽和鍵。可列舉例如:吡咯并吡唑基、吲唑基、喹啉基、苯并咪唑基、吡咯并吡啶基、2-側氧-2,3-二氫-1H-吡咯并吡啶基、2-側氧-2,3-二氫-1H-苯并咪唑基、吡唑并吡啶基、3-側氧-3,4-二氫-2H-吡啶并[1,4]基、2-側氧-1,2,3,4-四氫喹啉基、異吲哚啉基、吲哚啉基、吲基、嘌呤基、喹基、異喹啉基、啶基、呔基、喹啉基、喹唑啉基、喋啶基等。環Q2中的「於環內具有1至4個獨立選自包含氮原子、氧原子、及硫原子的群組的雜原子的8員至10員之二環性芳香族雜環基」較佳為吡唑并吡啶基、吡咯并吡啶基、吲唑基。
於本發明,將腫瘤、惡性腫瘤、癌症、惡性新生物(malignant neoplasm)、癌腫、肉瘤等統稱而表現為「腫瘤」或「癌症」。
於本發明,「EP300之抑制」意指EP300之組蛋白乙醯基轉移酶活性的抑制。
於本發明,「CREBBP之抑制」意指CREBBP之組蛋白乙醯基轉移酶活性的抑制。
於本發明,「EP300及/或CREBBP之組蛋白乙醯基轉移酶活性」意指EP300及/或CREBBP所具有之將組蛋白H3的第27號的離胺酸進行乙醯基化的酵素活性。
以下說明關於本發明之化合物中的較佳取代基。
環Q1較佳為下述(2A)至(2F)之任一者。
[式中,V表示氮原子、或-CR5,W表示氧原子、-NR6、-CR7R8、或-SO2,R5表示氫原子、或羥基,R6表示氫原子、C1-6烷基、C2-7烷醯基、羥基C2-7烷醯基、C1-6烷基磺醯基、或苄基,R7及R8各自獨立表示氫原子、鹵素原子、羥基、羧基、胺基、C1-6烷基、鹵C1-6烷基、羥基C1-6烷基、烷氧基C1-6烷基、C1-6烷氧基、C1-6烷氧基C1-6烷氧基、鹵C1-6烷氧基、C2-7烷醯基胺基、C1-6烷基磺醯基胺基、或苄基,R9及R10各自獨立表示氫原子、鹵素原子、或C1-6 烷氧基,R11及R12各自獨立表示氫原子、羥基、C1-6烷氧基、或苄氧基,或R11及R12係一起形成側氧基,R13表示C1-6烷氧基,環Q3表示苯環、吡唑環、或四氫呋喃環,n表示1或2]。
環Q1更佳為下述(3A)至(3E)之任一者。
[式中,R14表示甲氧基、二氟甲氧基、或三氟甲氧基,R15表示甲基、或三氟甲基]。
環Q2較佳為可具有1個或2個獨立選自包含羥基、氟原子、氯原子、氰基、甲基、甲氧基、及苄氧基的群組的取代基的苯基,更佳為氰基苯基。
環Q2更佳為下述(4A)或(4B)。
[式中,X表示氮原子、或-CR16, Y表示氮原子、或-CR17,Z表示氮原子、或-CH,R16表示氫原子、氟原子、或氰基,R17表示氫原子、C1-6烷基、或羥基C1-6烷基]。
環Q2進一步更佳為下述(5A)至(5D)之任一者。
[式中,Y1表示氮原子、或-CH]。
R1及R2較佳為甲基。
R1及R2更佳為與R1及R2所鍵結的碳原子一起,形成環丁烷環、3,3-二鹵環丁烷環、3,3-二C1-6烷基環丁烷環、環戊烷環、環己烷環、4,4-二鹵環己烷環、四氫哌喃環、環庚烷環、或螺[3.3]庚烷環。
R1及R2進一步更佳為與R1及R2所鍵結的碳原子一起,形成環戊烷環、環己烷環、或4,4-二氟環己烷環。
R3較佳為甲基,R4較佳為甲基、或羥甲基。
R3及R4更佳為與R3所鍵結的氮原子及R4所鍵結的碳原子一起,表示下述式(6)。
[式中,R18表示氫原子、鹵素原子、羥基、C1-6烷氧基、或C1-6烷氧基C1-6烷氧基,R19表示氫原子、或羥基]。
R3及R4進一步更佳為與R3所鍵結的氮原子及與R4所鍵結的碳原子一起,表示下述式(7)。
[式中,R20表示氫原子、氟原子、羥基、或甲氧基甲氧基]。
就本發明之化合物而言,較佳為選自下述之化合物或其藥理上可容許的鹽之1者:N-1H-吲唑-4-基-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-D-脯胺醯胺、N-1H-吲唑-4-基-1-({1-[(3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基]環戊基}羰基)-D-脯胺醯胺、1-({1-[4-(羥甲基)哌啶-1-基]環戊基}羰基)-N-1H-吲唑-4-基-D-脯胺醯胺、(4R)-4-羥基-N-1H-吲哚-4-基-1-{[1-(4-甲氧基哌啶 -1-基)環戊基]羰基}-D-脯胺醯胺、(4R)-N-(2-氰基苯基)-4-氟-1-{[1-(1-羥基-4-甲氧基環己基)環戊基]羰基}-D-脯胺醯胺、(4R)-4-氟-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-({1-[4-(羥甲基)-4-甲氧基哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、1-{[1-(1-羥基-4-甲氧基環己基)環戊基]羰基}-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-[2-(1-羥基-4-甲氧基環己基)-2-甲基丙醯基]-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[4,4-二氟-1-(4-羥基-4-甲基哌啶-1-基)環己基]羰基}-4-氟-N-1H-吡咯并[3,2-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-({1-[4-羥基-4-(三氟甲基)哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-({1-[4-(2-羥基丙烷-2-基)-4-甲氧基哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、N2-[2-(4-甲氧基哌啶-1-基)-2-甲基丙醯基]-N2-甲基-N-1H-吡咯并[2,3-b]吡啶-6-基-D-丙胺醯胺、(4R)-1-{[(1’r,4’R)-4,4-二氟-4’-甲氧基-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[(1’s,4’S)-4,4-二氟-4’-甲氧基-1,1’-二(環 己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[(1’r,4’R)-4’-(二氟甲氧基)-4,4-二氟-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[4,4-二氟-4’-羥基-4’-(三氟甲基)-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[(1’r,4’R)-4,4-二氟-4’-(三氟甲氧基)-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺。
於本發明之化合物,依取代基的種類,可存在有幾何異構物或互變異構物。又,於本發明之化合物具有不對稱碳原子的情形,可存在有光學異構物。於本發明,包含此等異構物之經分離者(例如,鏡像異構物或非鏡像異構物)、或混合物(例如,外消旋體或非鏡像異構物混合物)。又,標識體化合物,即,本發明化合物之1個以上的原子以任意比率經對應的放射性同位素或非放射性同位素取代的化合物亦包含於本發明。
本發明之化合物於具有胺基等鹼性基的情形,依期望可形成藥理上可容許的酸加成鹽。就此種酸加成鹽而言,可列舉例如氫氟酸鹽、鹽酸鹽、氫溴酸鹽、氫碘酸鹽等之氫鹵酸鹽;硝酸鹽、過氯酸鹽、硫酸鹽、磷酸鹽等之無機酸鹽;甲磺酸鹽、三氟甲磺酸鹽、乙磺酸鹽等之低級烷烴磺酸鹽;苯磺酸鹽、對甲苯磺酸鹽等 之芳基磺酸鹽;乙酸鹽、蘋果酸鹽、反丁烯二酸鹽、琥珀酸鹽、檸檬酸鹽、酒石酸鹽、草酸鹽、順丁烯二酸鹽等之有機酸鹽;或鳥胺酸鹽、麩胺酸鹽、天冬胺酸鹽等之胺基酸鹽,較佳為氫鹵酸鹽及有機酸鹽。
本發明之化合物具有羧基等之酸性基的情形,一般而言可形成藥理上可容許的鹼加成鹽。就此種鹼加成鹽而言,可列舉例如鈉鹽、鉀鹽、鋰鹽等之鹼金屬鹽;鈣鹽、鎂鹽等之鹼土金屬鹽;銨鹽等之無機鹽;或二苄基胺鹽、啉鹽、苯基甘胺酸烷基酯鹽、乙二胺鹽、N-甲基還原葡糖胺鹽(N-methylglucamine salt)、二乙基胺鹽、三乙基胺鹽、環己基胺鹽、二環己基胺鹽、N,N’-二苄基乙二胺鹽、二乙醇胺鹽、N-苄基-N-(2-苯基乙氧基)胺鹽、哌鹽、四甲基銨鹽、參(羥甲基)胺基甲烷鹽等之有機胺鹽等。
本發明之化合物亦作為無溶媒合物或溶媒合物而存在。就溶媒合物而言,只要為藥理上可容許者,則並未特別限定,具體而言,較佳為水合物、乙醇合物等。又,於通式(1)所表示的化合物中存在有氮原子的情形,可成為N-氧化物體,此等溶媒合物及N-氧化物體亦包含於本發明之範圍。
於本發明之化合物,依取代基之種類及組合,可存在有順式體、反式體等之幾何異構物、互變異構物或d體、l體等之光學異構物等之各種異構物,但本發明之化合物於未特別限定的情形,亦包含彼等全部之異構物及任一比率之此等異構物之混合物。
又,本發明之化合物於構成此種化合物的原子之1個以上可含有非天然比率之同位素。就同位素而言,可列舉例如:氘(2H;D)、氚(3H;T)、碘-125(125I)或碳-14(14C)等。又,本發明之化合物可藉由例如氚(3H)、碘-125(125I)、或碳-14(14C)等之放射性同位素而進行放射性標識。經放射性標識的化合物有用於作為治療或預防劑、研究試藥(例如,分析試藥)、及診斷劑(例如,活體內影像診斷劑)。含有全部之比例之放射性或非放射性同位素的本發明之化合物係包含於本發明之範圍。
其次,說明關於通式(1)所表示的化合物之代表性的製造法。本發明之化合物可藉由各種製造法製造,以下所示的製造法為一例,本發明不應被解釋為限定於此等例。
通式(1)所表示的化合物、其藥理上可容許的鹽及彼等之製造中間體,可利用基於彼等之基本骨架或取代基之種類之特徵,應用各種周知之製造方法來製造。就周知之方法而言,有例如於「ORGANIC FUNCTIONAL GROUP PREPARATIONS」,第2版,ACADEMIC PRESS,INC.,1989年;「Comprehensive Organic Transformations」,VCH Publishers Inc.,1989年等記載的方法。
此時,依化合物中存在的官能基的種類,有於原料或中間體之階段中預先以適當的保護基保護該官能基、或將該官能基預先取代為可容易轉化為該官能基 的基而對製造技術上有效的情形。
就此種官能基而言,有例如胺基、羥基及羧基等,就彼等之保護基而言,有例如P.G.Wuts著,「Protective Groups in Organic Synthesis(第5版,2014年)」記載之保護基。
保護基或可容易轉化為該官能基的基只要因應化合物製造用之製造方法之各自的反應條件加以適當選擇使用即可。
若依據此種方法,於導入該基而進行反應後,可因應必要去除保護基、或轉化為所期望的基,藉此獲得所期望的化合物。
通式(1)所表示的化合物可藉由例如下述A法或B法加以製造。為製造中間體的化合物2a、2b、3a及6a可藉由例如下述C至K法加以製造。
於下述A至K法之各步驟的反應中,成為反應基質的化合物具有胺基、羥基、羧基或環狀化合物上之雜原子等之抑制目的反應的官能基或部分構造的情形,因應必要可適當進行對彼等之保護基的導入及經導入的保護基之去除。此種保護基只要為通常使用的保護基,則並未特別限定,可為例如前述之「Protective Groups in Organic Synthesis(第5版,2014年)」記載的保護基。彼等保護基之導入及去除用之反應,可按照上述文獻記載的通常方法進行。
下述A至K法之各化合物係依化合物中存在的官能基的種類,於原料或中間體之階段,可取代為可 容易轉化為所期望的官能基的基。轉化為該所期望的官能基可於適當階段,按照周知方法來進行。有例如前述之「ORGANIC FUNCTIONAL GROUP PREPARATIONS」、「Comprehensive Organic Transformations」等記載的方法。
下述A至K法之各化合物可為與該化合物一起形成的鹽。可列舉例如,鹽酸鹽或硫酸鹽等、或者鈉鹽或鉀鹽等。
於下述A至K法之各步驟的反應所使用的溶媒只要為不抑制反應並部分溶解起始原料者,則並未特別限定,例如選自下述溶媒群組。溶媒群組包含:如己烷、戊烷、石油醚、環己烷的脂肪族烴類;如苯、甲苯、二甲苯的芳香族烴類;如二氯甲烷(methylene chloride)、氯仿、四氯化碳、二氯乙烷、氯苯、二氯苯的鹵化烴類;如二乙基醚、二異丙基醚、四氫呋喃、二烷、二甲氧基乙烷、二乙二醇二甲基醚的醚類;如丙酮、甲基乙基酮、甲基異丁基酮、環己酮的酮類;如乙酸乙酯、乙酸丙酯、乙酸丁酯的酯類;如乙腈、丙腈、丁腈、異丁腈的腈類;如乙酸、丙酸的羧酸類;如甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-丁醇、2-甲基-1-丙醇、2-甲基-2-丙醇的醇類;如甲醯胺、N,N-二甲基甲醯胺、N,N-二甲基乙醯胺、N-甲基-2-吡咯啶酮、六甲基磷醯三胺(hexamethylphosphorotriamide)的醯胺類;如二甲基亞碸、四氫噻吩1,1-二氧化物的亞碸類;水;及彼等之混合物。
於下述A至K法之各步驟的反應所使用的酸,只要為不抑制反應者,則並未特別限定,選自下述酸群組。酸群組包含:如鹽酸、氫溴酸、氫碘酸、磷酸、硫酸、硝酸的無機酸;如乙酸、丙酸、三氟乙酸、五氟丙酸的有機酸;如甲磺酸、三氟甲磺酸、對甲苯磺酸、樟腦磺酸的有機磺酸;及如三溴化硼、溴化銦(III)、三氟化硼、氯化鋁(III)、三氟甲磺酸三甲基矽基酯的路易士酸。
於下述A至K法之各步驟的反應所使用的鹼,只要為不抑制反應者,則並未特別限定,選自下述鹼群組。鹼群組包含:如碳酸鋰、碳酸鈉、碳酸鉀、碳酸銫的鹼金屬碳酸鹽;如碳酸氫鋰、碳酸氫鈉、碳酸氫鉀的鹼金屬碳酸氫鹽;如氫氧化鋰、氫氧化鈉、氫氧化鉀的鹼金屬氫氧化物;如氫氧化鈣、氫氧化鋇的鹼土金屬氫氧化物;如氫化鋰、氫化鈉、氫化鉀的鹼金屬氫化物;如胺化鋰(lithium amide)、胺化鈉(sodium amide)、胺化鉀(potassium amide)的鹼金屬胺化物;如甲醇鋰、甲醇鈉、乙醇鈉、三級丁醇鈉、三級丁醇鉀的鹼金屬烷氧化物;如二異丙基胺化鋰的烷基胺化鋰;如雙三甲基矽基胺化鋰、雙三甲基矽基胺化鈉的矽基胺化物;如正丁基鋰、二級丁基鋰、三級丁基鋰的烷基鋰;如氯化甲鎂(methylmagnesium chloride)、溴化甲鎂(methylmagnesium bromide)、碘化甲鎂(methylmagnesium iodide)、氯化乙鎂(ethylmagnesium chloride)、溴化乙鎂(ethylmagnesium bromide)、氯化異丙鎂 (isopropylmagnesium chloride)、溴化異丙鎂(isopropylmagnesium bromide)、氯化異丁鎂(isobutylmagnesium chloride)的鹵化烷基鎂;及如三乙基胺、三丁基胺、N,N-二異丙基乙基胺、1-甲基哌啶、4-甲基啉、4-乙基啉、吡啶、甲吡啶(picoline)、4-二甲基胺基吡啶、4-吡咯啶并吡啶、2,6-二-三級丁基-4-甲基吡啶、喹啉、N,N-二甲基苯胺、N,N-二乙基苯胺、1,5-二吖雙環[4,3,0]-5-壬烯(DBN)、1,4-二吖雙環[2,2,2]辛烷(DABCO)、1,8-二吖雙環[5,4,0]-7-十一烯(DBU)、咪唑的有機胺。
於下述A至K法之各步驟的反應中,反應溫度依溶媒、起始原料、試藥等而異,反應時間依溶媒、起始原料、試藥、反應溫度等而異。
於下述A至K法之各步驟的反應中,反應結束後,各步驟之目的化合物係按照通常方法自反應混合物單離。目的化合物係藉由例如下述而獲得:(i)因應需要濾除觸媒等之不溶物;(ii)於反應混合物中添加水及不與水混合的溶媒(例如,二氯甲烷、二乙基醚、乙酸乙酯等),萃取目的化合物;(iii)將有機層水洗,使用無水硫酸鎂等之乾燥劑而使其乾燥;(iv)將溶媒餾除。獲得的目的化合物,因應需要,可藉由通常方法,例如再結晶、再沉澱、蒸餾、或者使用矽膠或氧化鋁等的管柱層析(包含順相及逆相)等,而進一步純化。獲得的目的化合物係藉由元素分析、NMR、質量分析(mass spectroscopy)、IR分析等之標準的分析技術而被鑑定,可分析其組成或純 度。又,各步驟之目的化合物亦可不純化而直接使用於下一反應。
於下述A至K法之各步驟中,可藉由使用如(R)-(+)-或(S)-(-)-1-苯乙基胺的光學活性胺、或者如(+)-或(-)-10-樟腦磺酸的光學活性羧酸等之分別再結晶、或是使用光學活性管柱的分離,而將光學異構物分離、純化。
本發明之化合物之製造所使用的原料及試藥可購自商業上的供給者,或者可藉由文獻記載的方法或與其類似的方法來合成。
[式中,R1、R2、R3、R4、Q1及Q2係與前述同義。R21表示氮原子上之保護基,可列舉例如:三級丁氧基羰基(Boc基)、9-茀基甲氧基羰基(Fmoc基)或苄氧基羰基(Cbz基)等。R22表示氫原子、或羧基之保護基,可列舉例如:甲基、乙基、苄基或三級丁基等]。
以下說明A法及B法之各步驟的反應。
可藉由於對反應為惰性的溶媒中(例如二氯甲烷、四氫呋喃、N,N-二甲基甲醯胺、吡啶等),於鹼(例如三乙基胺、N,N-二異丙基乙基胺、吡啶、4-二甲基胺基吡啶、碳酸氫鈉等)存在下,使化合物3a與衍生自化合物2a的 羧酸鹵化物或羧酸活性酯反應而實施。較佳地,反應溫度為-15℃至100℃,反應時間為5分鐘至6日。
自化合物4a至化合物5a的變換係依R21的種類而方法不同。
R21為Boc基的情形,可藉由將包含該官能基的化合物4a,於對反應為惰性的溶媒中(例如甲醇、乙醇、四氫呋喃、1,4-二烷、二氯甲烷等),以酸(例如氯化氫、三氟乙酸等)處理而實施。或者,可藉由於鹼(2,6-二甲吡啶(2,6-lutidine)等)存在下,以酸(三氟甲磺酸三甲基矽基酯等)處理。任一反應皆較佳為反應溫度為-15℃至室溫,反應時間為30分鐘至12小時。
R21為Fmoc基的情形,可藉由將包含該官能基的化合物4a,於對反應為惰性的溶媒中(例如二氯甲烷、四氫呋喃、或N,N-二甲基甲醯胺等),以鹼(例如,哌啶、DBU等)處理而實施。較佳地,反應溫度為-30℃至100℃,反應時間為5分鐘至24小時。
R21為Cbz基的情形,可藉由將包含該官能基的化合 物4a,於對反應為惰性的溶媒中(例如甲醇、乙醇、乙酸乙酯等),於還原觸媒(例如鈀-碳、氫氧化鈀、雷氏鎳(Raney nickel)、鉑-碳、或氧化鉑等)存在下,於氫氣環境下攪拌而實施。較佳地,反應溫度為室溫至溶媒之沸點為止,反應時間為30分鐘至24小時。
自化合物5a至化合物1的變換可藉由與A-1步驟相同的方法來實施。
自化合物2b至化合物3b的變換可藉由與A-1步驟相同的方法來實施。
自化合物3b至化合物4b的變換係依R22的種類而不同。此外,R22為氫原子的情形,不需要本步驟。
R22為甲基、乙基或苄基等的情形,可藉由將包含該官能基的化合物3b,於對反應為惰性的溶媒中(包含水及其他溶媒,其他溶媒可列舉例如甲醇、乙醇、四氫呋喃、二烷等、或此等之混合溶媒,但較佳為可與水以任意比率混合的有機溶媒),以鹼(例如氫氧化鈉、氫氧化鉀、 氫氧化鋰、氫氧化四丁基銨等)處理而實施。較佳地,反應溫度為-30℃至溶媒的沸點為止,反應時間為30分鐘至3日。
R22為苄基等的情形,亦可藉由與A-2-3步驟相同的方法來實施。
R22為三級丁基等的情形,可藉由與A-2-1步驟相同的方法來實施。
自化合物4b至化合物1的變換可藉由與A-1步驟相同的方法來實施。
接著說明關於化合物2a之製造方法。
化合物2a為周知,或者將周知化合物作為起始原料而按照周知方法或與其類似的方法來製造。周知化合物可購自商業上的供給者,或者可藉由文獻記載的方法或與其類似的方法而容易地合成。就周知文獻而言,已提出例如WO2012/162635 A1、WO2015/118342 A1、J.Med.Chem.,35,2582-2591(1992)、J.Org.Chem.,61,566-572(1996)、J.Med.Chem.,46,2057-2073(2003)、Adv.Synth.Catal.,354,2635-2640(2012)、Synlett,11,1279-1281(1998)、Tetrahedron,49, 4201-4210(1993)、US6124354 A、J.Org.Chem.,63,2442-2450(1998)等許多報告。
接著說明關於化合物3a之製造方法。
化合物3a為周知,或者將周知化合物作為起始原料而按照周知方法或與其類似的方法來製造。以下雖記載C至D法作為化合物3a之製法例,但3a之合成方法並未被限定於此等例。
[式中,Q2係與前述同義。L表示脫離基,可列舉例如氯原子、溴原子、碘原子、甲烷磺醯氧基(MsO基)或對甲苯磺醯氧基(TsO基)等]。
化合物3a於化合物1c或化合物2c為周知的情形,可按照周知方法或與其類似的方法而容易地製造。就周知之方法而言,可列舉例如除了前述之「ORGANIC FUNCTIONAL GROUP PREPARATIONS」、「Comprehensive Organic Transformations」,Org.Lett.,3,3417-3419(2001)、Org.Lett.,3,2729-2732(2001)等記載的方法。
通式(3a)所表示的化合物係以下述之化合物 3a-1表示的情形,可藉由D法製造。
[式中,R21係與前述同義。R23及R24表示氫原子、或氮原子上之保護基,可列舉例如三甲基矽基(TMS基)或三苯基矽基等]。
可藉由於對反應為惰性的溶媒中(例如,四氫呋喃等),於金屬觸媒(例如,參(二亞苄基丙酮)二鈀(0)等)及配位子(2-二環己基膦基-2’,4’,6’-三異丙基聯苯、2-(二-三級丁基膦基)聯苯等)存在下,使化合物1d與矽基胺(silylamine)化合物(雙(三甲基矽基)胺化鋰、三苯基矽基胺等)反應而實施。較佳地,反應溫度為室溫至溶媒的沸點為止,反應時間為30分鐘至24小時。化合物2d較佳為未單離而使用於下一反應。
可藉由於對反應為惰性的溶媒中(例如,四氫呋喃等),使化合物2d與保護基導入試藥(例如,二碳酸二-三級丁酯、氯甲酸苄酯等)反應而實施。較佳地,反應溫度為-30℃至溶媒的沸點為止,反應時間為5分鐘至24小時。化合物3d較佳為未單離而使用於下一反應。
可藉由將化合物3d於對反應為惰性的溶媒中(例如,四氫呋喃等),以去矽化(desilylation)試藥(例如,氟化四丁基銨、氟化氫等)處理而實施。較佳地,反應溫度為-30℃至溶媒的沸點為止,反應時間為5分鐘至24小時。
通式(3a)所表示的化合物係以下述之化合物3a-3表示的情形,可藉由E法製造。
[式中,R21係與前述同義。]
可藉由將化合物1e於對反應為惰性的溶媒中(例如,二氯甲烷等),使氧化劑(例如,3-氯過苯甲酸等)作用而實施。較佳地,反應溫度為-30℃至溶媒的沸點為止,反應時間為5分鐘至5小時。
可藉由於對反應為惰性的溶媒中(例如,二氯甲烷等),於鹼(例如,三乙基胺、N,N-二異丙基乙基胺等)存在下,使化合物2e與縮合劑(例如,三吡咯啶基溴化鏻六氟磷酸鹽(bromotripyrrolidinophosphonium hexafluorophosphate)(PyBroP)、1H-苯并三唑-1-氧三吡咯啶基鏻六氟磷酸鹽(1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate)(PyBop)等)及氨反應而實施。較佳地,反應溫度為-30℃至溶媒的沸點為止,反應時間為5分鐘至48小時。
關於E法,就周知文獻而言,可列舉例如Org.Lett.,12,5254-5257(2010)等。
其次說明關於化合物6a之製造方法。
化合物6a為周知,或者將周知化合物作為起始原料而按照周知方法或與其類似的方法來製造。以下雖記載F至K法作為化合物6a之製法例,但6a之合成方法並未限定於此等例。
[式中,Q1、R1及R2係與前述同義。R25表示氰基、苄氧基羰基、或C1-6烷氧基羰基,可列舉例如甲氧基羰基、乙氧基羰基或三級丁氧基羰基等]。
可藉由將化合物1f於對反應為惰性的溶媒中(例如,N,N-二甲基甲醯胺、二甲基亞碸、四氫呋喃等),於鹼(例如,氫化鈉、氫化鉀等)存在下,使鹵化物等(例如,碘甲烷、1,3-二溴丙烷、1,4-二溴丁烷、1,5-二溴戊烷、表氯醇等)作用而實施。較佳地,反應溫度為-30℃至70℃為止,反應時間為30分鐘至3日。依取代基的組合,可添加冠醚類(例如,18-冠6-醚等)作為反應促進劑。
自化合物2f至化合物6a的變換係依R25的種類而方法不同。
R25為氰基、甲氧基羰基或乙氧基羰基等的情形,可藉由將包含該官能基的化合物2f於對反應為惰性的溶媒中(可列舉例如甲醇、乙醇、乙二醇、水、四氫呋喃、二烷等、或此等之混合溶媒,但較佳為可與水以任意比率混合的有機溶媒),以鹼(例如氫氧化鈉、氫氧化鉀、氫氧化鋰等)或酸(硫酸、鹽酸等)處理而實施。較佳地,反應溫度為室溫至溶媒的沸點為止,反應時間為5分鐘至3日。
R25為苄氧基羰基的情形,可藉由與A-2-3步驟相同的方法而實施。
R25為三級丁氧基羰基的情形,可藉由與A-2-1步驟相同的方法來實施。
R25為氰基的情形,亦可經由化合物3f而製造化合物6a。
自化合物2f至化合物3f的變換,可藉由於對反應為惰性的溶媒中(例如,甲苯、己烷、四氫呋喃等),使化合物2f與還原劑(例如,氫化二異丁基鋁等) 反應而實施。較佳地,反應溫度為-100℃至室溫為止,反應時間為5分鐘至40小時。
自化合物3f至化合物6a的變換,可藉由於對反應為惰性的溶媒中(例如,三級丁醇、水、乙腈等、或此等之混合溶媒),於2-甲基-2-丁烯及磷酸二氫鈉存在下,使化合物3f與氧化劑(例如,亞氯酸鈉等)反應而實施。較佳地,反應溫度為0℃至50℃為止,反應時間為5分鐘至2日。
關於F法,就周知文獻而言,可列舉例如:J.Med.Chem.,58,7341-7348(2015)、J.Org.Chem.,59,6464-6469(1994)、Bioorg.Med.Chem.Lett.,21,1438-1441(2011)、Bioorg.Med.Chem.Lett.,12,2141-2144(2002)、Chem.Pharm.Bull.,53,965-973(2005)、Chem.Pharm.Bull.,59,1376-1385(2011)等。
通式(6a)所表示的化合物係以下述之化合物6a-1表示的情形,可藉由G法至I法製造。
[式中,R1及R2係與前述同義。R26及R27係與R26及R27所鍵結的氮原子一起,形成可具有取代基的雜環烷基環,例如形成吡咯啶環、哌啶環等]。
可藉由於對反應為惰性的溶媒中(例如,四氫呋喃等),於有機銀試藥(例如,三氟甲磺酸銀等)存在下,使化合物1g與化合物2g反應而實施。較佳地,反應溫度為-100℃至70℃為止,反應時間為30分鐘至24小時。
關於G法,就周知之文獻而言,可列舉例如Bioorg.Med.Chem.Lett.,13,2573-2576(2003)等。
[式中,R1、R2、R22、R26及R27係與前述同義。]
可藉由於對反應為惰性的溶媒中(例如,乙腈等),於鹼(例如碳酸鉀等)存在下,使化合物1h與鹵化物(例如,1,6-二溴己烷等)反應而實施。較佳地,反應溫度為0℃至100℃為止,反應時間為30分鐘至48小時。
自化合物2h至化合物6a-1的變換,可藉由與F-2-1至F-2-3步驟相同的方法而實施。
關於H法,就周知之文獻而言,可列舉例如J.Org.Chem.,54m 1810-1815(1989)等。
[式中,R1、R2、R26及R27係與前述同義。]
可藉由於對反應為惰性的溶媒中(例如甲醇等),於氰化金屬(例如氰化鈉等)存在下,使化合物1i與化合物2i反應而實施。較佳地,反應溫度為-30℃至50℃為止,反應時間為30分鐘至48小時。
可藉由將化合物3i於對反應為惰性的溶媒中(例如 己烷等),以酸(例如硫酸等)處理而實施。較佳地,反應溫度為-30℃至60℃,反應時間為1小時至72小時。
可藉由將化合物4i以酸(例如鹽酸等)處理而實施。較佳地,反應溫度為0℃至100℃為止,反應時間為1小時至72小時。
關於I法,就周知之文獻而言,可列舉例如ACS Med.Chem.Lett.,5,857-862(2014)、Tetrahedron:Asymmetry,21,2868-2871(2010)等。
通式(6a)所表示的化合物係以下述之化合物6a-2表示的情形,可藉由J法製造。
[式中,R1、R2及R22係與前述同義。R28表示C1-6烷基,可列舉例如甲基等]。
可藉由於對反應為惰性的溶媒中(例如甲醇等),於鹼(例如碳酸鉀等)存在下,使化合物1j與化合物2j反應而實施。較佳地,反應溫度為0℃至溶媒的沸點為止,反應時間為30分鐘至48小時。
可藉由於對反應為惰性的溶媒中(例如甲醇等),使化合物3j與金屬氫化物(例如硼氫化鈉等)反應而實施。較佳地,反應溫度為-30℃至50℃為止,反應時間為30分鐘至48小時。
可藉由於對反應為惰性的溶媒中(例如N,N-二甲基甲醯胺等),於鹼(例如氫化鈉等)存在下,使化合物4j與鹵化物(例如碘甲烷等)反應而實施。較佳地,反應溫度為-30℃至50℃為止,反應時間為30分鐘至48小時。
關於J法,就周知之文獻而言,可列舉例如Bioorg.Med.Chem.,18,7675-7699(2010)等。
通式(6a)所表示的化合物係以下述之化合物6a-3表示的情形,可藉由K法製造。
[式中,R1、R2及L係與前述同義。Q3表示可具有取代基的芳香環,可列舉例如苯環等。Q4表示可具有取代基的環烷基環,可列舉例如環己烷環等]。
可藉由於對反應為惰性的溶媒中(例如,四氫呋喃等),使化合物1k與化合物2k反應而實施。較佳地,反應溫度為-100℃至70℃為止,反應時間為30分鐘至24小時。
可藉由於對反應為惰性的溶媒中(例如,二氯甲烷等),於酸(例如,溴化銦(III)、三氟化硼二乙基醚錯合物等)存在下,使化合物3k與氰基化試藥(例如,氰基三甲基矽烷等)反應而實施。較佳地,反應溫度為-100℃至50℃為止,反應時間為5分鐘至24小時。
自化合物4k至化合物5k的變換,可藉由與F-2-1步驟相同的方法來實施。
可藉由於對反應為惰性的溶媒中(例如,乙醇等),於金屬觸媒(例如,銠-氧化鋁等)存在下,使化合物5k與氫反應而實施。較佳地,反應溫度為0℃至100℃為止,反應時間為3小時至5日。
關於K法,就周知之文獻而言,可列舉例如Tetrahedron,70,4563-4570(2014)等。
EP300或CREBBP之組蛋白乙醯基轉移酶活性可使用下述之試驗例1或2記載的組蛋白乙醯基轉移酶分析而測定。或者,於組蛋白乙醯基轉移酶活性之檢測,可利用例如:以放射性同位素檢測的方法(Lau OD,et al.J.Biol.Chem.2000;275:21953-21959)、將組蛋白乙醯基轉移酶反應時作為副產物生成的CoA-SH以螢光檢測的方法(Gao T,et al.Methods Mol Biol.2013;981:229-38)、及藉由NADH檢測的方法(Berndsen CE,Denu JM.Methods.2005;36:321-331)等。
本發明之化合物或其藥理上可容許的鹽之細胞的增殖抑制活性可使用該技術領域中具有通常知識者通常使用的增殖抑制試驗法進行調查。細胞之增殖抑制活性可藉由例如,如下述之試驗例3所記載,將於試驗化合物之存在下或不存在下的細胞增殖程度進行比較而 實施。增殖的程度,例如,可使用測定活細胞的試驗系統來調查。就活細胞的測定方法而言,可列舉例如:[3H]-胸苷的攝入試驗、BrdU法或MTT分析等。
又,活體內的抗腫瘤活性可使用該技術領域中具有通常知識者通常使用的抗腫瘤試驗法進行調查。例如,如下述之試驗例4所記載,將各種腫瘤細胞移植至小鼠、大鼠等,在確認移植細胞的存活後,將本發明之化合物進行經口投予、靜脈內投予等,於數日~數週後,將藥劑無投予組中的腫瘤增殖與化合物投予組中的腫瘤增殖進行比較,藉此可確認本發明之活體內的抗腫瘤活性。
本發明之化合物或其藥理上可容許的鹽因具有同時抑制EP300及CREBBP之組蛋白乙醯基轉移酶活性的作用,較佳為對依賴於EP300及/或CREBBP的癌症使用。就EP300及/或CREBBP之表現亢進的腫瘤而言,已知有前列腺癌、肝癌、肺癌、乳癌、大腸癌、胃癌、血液癌、胰臟癌、食道癌、膀胱癌、胃腸道基質瘤、NUT中線癌、或卵巢癌。
EP300及/或CREBBP之表現亢進與否,可藉由將患者之被檢組織(例如,藉由採血、生檢等而採取)中之EP300及/或CREBBP,使用利用南方氏印漬、北方氏印漬、西方氏印漬、ELISA、DNA晶片、FISH分析、組織免疫染色、其他周知之基因解析法{例如,PCR、LCR(連接酶連鎖反應(Ligase chain reaction))、SDA(鏈置換擴增(Strand displacement an plification))、NASBA(基 於核酸序列的擴增(Nucleic acid sequence-based amplification))、ICAN(等溫且嵌合引子起始之擴增(Isothermal and chineric primer-initiated amplification))、LAMP法(環圈媒介的等溫擴增(Loop-mediated isothernal amplification))等}等的解析、病理學的手法等周知之方法加以確認。
於EP300及/或CREBBP是否存有變異,可藉由調查基因體DNA之鹼基序列而確認。
本發明之化合物或其藥理上可容許的鹽可與其他抗腫瘤劑併用。可列舉例如:烷化劑、代謝拮抗劑、抗腫瘤抗生素、抗腫瘤性植物成分、BRM(生物反應調節劑(biological response modifier))、激素、維生素、抗腫瘤性抗體、分子標靶藥物、其他之抗腫瘤劑等。
更具體而言,作為烷化劑,可列舉例如:氮芥(nitrogen mustard)、氮芥N-氧化物或氮芥苯丁酸(chlorambucil)等之烷化劑;卡巴醌(carboquone)或噻替哌(thiotepa)等之吖系烷化劑;二溴甘露糖醇或二溴半乳糖醇(dibromodulcitol)等之環氧化物系烷化劑;卡莫司汀(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、鹽酸尼莫司汀(nimustine hydrochloride)、鏈脲黴素(streptozocin)、氯脲黴素(chlorozotocin)或雷莫司汀(ranimustine)等之亞硝基脲系烷化劑;白消安(busulfan)、對甲苯磺酸英丙舒凡(improsulfan tosilate)或達卡巴仁(dacarbazine)等。
作為代謝拮抗劑,可列舉例如:6-巰基嘌呤、 6-硫鳥嘌呤或硫肌苷(thioinosine)等之嘌呤代謝拮抗劑;氟尿嘧啶(fluorouracil)、替加氟(tegafur)、替加氟尿嘧啶(tegafur-uracil)、卡莫氟(carmofur)、去氧氟尿苷(doxifluridine)、溴尿苷(broxuridine)、阿糖胞苷(cytarabine)或依諾他濱(enocitabine)等之嘧啶代謝拮抗劑;甲胺喋呤(methotrexate)或三甲曲沙(trimetrexate)等之葉酸代謝拮抗劑等。
作為抗腫瘤性抗生素,可列舉例如:道諾黴素(daunorubicin)、阿柔比星(aclarubicin)、多柔比星(doxorubicin)、吡柔比星(pirarubicin)或泛艾黴素(epirubicin)等之蒽環(anthracycline)系抗生素抗腫瘤劑;絲裂黴素C(mitomycin C)、博萊黴素(bleomycin)、培洛黴素(peplomycin)、色黴素A3(chromomycin A3)或放線菌素D等。
作為抗腫瘤性植物成分,可列舉例如:長春地辛(vindesine)、長春新鹼(vincristine)或長春花鹼(vinblastine)等之長春花屬生物鹼(vinca alkaloid)類;紫杉醇(paclitaxel)、多西他賽(docetaxel)等之紫杉烷類;或者依托泊苷(etoposide)或替尼泊苷(teniposide)等之表鬼臼毒素類(epipodophyllotoxin)。
作為BRM,可列舉例如腫瘤壞死因子或吲哚美辛(indomethacin)等。
作為激素,可列舉例如:氫化可體松(hydrocortisone)、地塞米松(dexamethasone)、甲基去氫皮質醇(methylprednisolone)、去氫皮質醇 (prednisolone)、去氫異雄甾酮(prasterone)、貝皮質醇(betamethasone)、特安皮質醇(triamcinolone)、羥甲烯龍(oxymetholone)、諾龍(nandrolone)、美替諾龍(methenolone)、磷雌酚(fosfestrol)、乙烯雌二醇(ethinylestradiol)、氯地孕酮(chlormadinone)或甲羥助孕酮(medroxyprogesterone)等。
作為維生素,可列舉例如維生素C或維生素A等。
作為抗腫瘤性抗體、分子標靶藥物,可列舉曲妥珠單抗(trastuzumab)、利妥昔單抗(rituximab)、西妥昔單抗(cetuximab)、尼妥珠單抗(nimotuzumab)、地諾單抗(denosumab)、貝伐單抗(bevacizumab)、英利昔單抗(infliximab)、甲磺酸伊馬替尼(imatinib mesilate)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)、舒尼替尼(sunitinib)、拉帕替尼(lapatinib)、索拉非尼(sorafenib)等。
作為其他之抗腫瘤劑,可列舉例如:順鉑(cisplatin)、卡鉑(carboplatin)、奧沙利鉑(oxaliplatin)、他莫昔芬(tamoxifen)、喜樹鹼(camptothecin)、依弗醯胺(ifosfamide)、環磷醯胺(cyclophosphamide)、黴法蘭(melphalan)、L-天冬醯胺酶(L-asparaginase)、醋葡醛內酯(aceglatone)、裂褶菌多醣(schizophyllan)、必醫你舒(picibanil)、丙卡巴肼(procarbazine)、哌泊溴烷(pipobroman)、新制癌菌素(neocarzinostatin)、羥基脲、烏苯美司(ubenimex)或克速鎮(krestin)等。
含有本發明之化合物或其藥理上可容許的鹽作為有效成分的製劑,可使用通常製劑中使用的載體(carrier)、賦形劑等之添加劑而調製。本發明之化合物之投予可為以錠劑、丸劑、膠囊劑、顆粒劑、散劑、液劑等之形態的經口投予、或以注射劑(例如,靜脈注射、肌肉注射等)、栓劑、經皮劑、經鼻劑、吸入劑等之形態的非經口投予。本發明之化合物之投予量及投予次數,可考慮症狀、投予對象的年齡或性別等,因應個別情形而適當決定。投予量於經口投予的情形,通常成人每1次為0.001mg/kg至100mg/kg,於靜脈投予的情形,通常成人每1次為0.0001mg/kg至10mg/kg。投予次數通常為1日1次至6次或1日1次至7日1次。
依據本發明之用以經口投予的固體製劑可為錠劑、散劑、顆粒劑等。此種製劑係藉由將一種或其以上之活性物質與惰性的賦形劑、助滑劑、崩散劑、或溶解輔助劑等混合而按照通常方法製造。賦形劑可為例如乳糖、甘露糖醇、葡萄糖。助滑劑可為例如硬脂酸鎂。崩散劑可為例如羧甲基澱粉鈉。錠劑或丸劑依必要可藉由糖衣或者胃溶性或腸溶性包衣劑被覆。
經口投予用之液體製劑可為藥劑上可容許的乳劑、液劑、懸浮劑、糖漿劑、或酏劑等。此種製劑含有一般使用的惰性溶劑(例如純水、乙醇),又可含有增溶劑、濕潤劑、懸浮化劑、甘味劑、矯味劑、芳香劑、或防腐劑。
非經口投予用之注射劑可為無菌之水性或非 水性之液劑、懸浮劑、或乳劑。注射劑用之水性溶劑可為例如蒸餾水或生理食鹽水。注射劑用之非水性溶劑可為例如:丙二醇、聚乙二醇、如橄欖油的植物油、如乙醇的醇類、或聚山梨醇酯80(藥典名)。此種製劑可進一步含有等張化劑、防腐劑、濕潤劑、乳化劑、分散劑、安定化劑、或溶解輔助劑。此等之製劑可藉由例如利用細菌截留過濾器(bacteria-retaining filter)的過濾、殺菌劑的摻合、或放射線照射而無菌化。又,作為此等之製劑亦可使用:將無菌之固體組成物於使用前溶解或懸浮於無菌的水或注射用溶媒而獲得的組成物。
以下,記載實施例、試驗例,對於本發明進一步詳細說明,但本發明之範圍並未限定於此等例。
參考例及實施例之管柱層析法中的洗提係在利用薄層層析(TLC)之觀察下進行。於TLC觀察,採用Merck公司製之矽膠60F254或60NH2F254S作為TLC板,採用管柱層析法中用作洗提溶媒的溶媒作為展開溶媒,採用UV檢測器或呈色試藥作為檢測方法。管柱用矽膠係使用同樣Merck公司製之矽膠SK-85、或FUJI SILYSIA CHEMICAL之Chromatorex NH。除了此等之外,使用山善公司或Biotage公司之自動精製裝置。
此外,參考例及實施例所使用的縮寫,具有如下列的意義。
Me=甲基、tBu=三級丁基、Bn=苄基、TBDMS=三級丁基二甲基矽基、TBDPS=三級丁基二苯基矽基、Cbz= 苄氧基羰基、Boc=三級丁氧基羰基、Fmoc=9-茀基甲氧基羰基、Ms=甲烷磺醯基、Ts=對甲苯磺醯基、PyBrop=三吡咯啶基溴化鏻六氟磷酸鹽、COMU=(1-氰基-2-乙氧基-2-側氧亞乙基胺氧基)二甲基胺基啉基三價碳鎓六氟磷酸鹽、HATU=O-(7-吖苯并三唑-1-基)-N,N,N’,N’-四甲基脲鎓六氟磷酸鹽、DBU=1,8-二吖雙環[5.4.0]-7-十一烯。
於以下之實施例,核磁共振(以下,1H-NMR:400MHz)光譜係以四甲基矽烷作為標準物質,將化學位移值記載為δ值(ppm)。分裂形式(splitting pattern)係將單峰以s表示,二重峰以d表示,三重峰以t表示,四重峰以q表示,多重峰以m表示,寬峰以br表示。質量分析法係使用ESI法、APCI法、或ESI/APCI法之任一者作為離子源。
於4-硝基-1H-吲唑(10.0g)之二氯甲烷(200mL)溶液中添加三乙基胺(10.2mL)、二碳酸二-三級丁酯(14.7g),並於室溫攪拌6小時。分配於水及二氯甲烷,將有機層以無水硫酸鈉乾燥。將濃縮而獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,接著再結晶(己烷/二乙基醚),而獲得呈固體之標題化合物(15.1g)。
1H-NMR(CDCl3)δ:1.75(9H,s),7.66-7.71(1H,m),8.27(1H,d,J=7.9Hz),8.64(1H,d,J=8.5Hz),8.83(1H,s).
於上述步驟1獲得的化合物(15.0g)之甲醇(250mL)懸浮液中,冰冷下,添加鋅末(26.1g)、飽和氯化銨水溶液(250mL),並於室溫攪拌4小時。將反應液以矽藻土(Celite)過濾後,將濾液以乙酸乙酯萃取3次,將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。過濾、減壓濃縮後,將獲得的殘渣以矽膠管柱層析(乙酸乙酯/己烷)純化,藉此獲得呈固體之標題化合物(12.4g)。
1H-NMR(CDCl3)δ:1.72(9H,s),4.18(2H,br s),6.52(1H,d,J=7.3Hz),7.27-7.33(1H,m),7.54(1H,d,J=8.5Hz),8.12(1H,s).
於1-[(苄氧基)羰基]-D-脯胺酸(3.00g)之N,N-二甲基 甲醯胺(60.0mL)溶液中,添加{{[(1-氰基-2-乙氧基-2-側氧亞乙基)胺基]氧基}-4-啉基亞甲基}二甲基銨六氟磷酸鹽(5.67g)、N,N-二異丙基乙基胺(2.73mL)並於室溫攪拌15分鐘後,添加上述步驟2獲得的化合物(2.81g),並於室溫攪拌整夜。於反應液中添加飽和氯化銨水溶液,以乙酸乙酯萃取3次,將有機層以飽和碳酸氫鈉水溶液、飽和食鹽水洗淨後,以無水硫酸鈉乾燥。過濾、減壓濃縮後,將獲得的殘渣以矽膠管柱層析(氯仿/乙酸乙酯,接著己烷/乙酸乙酯)純化,藉此獲得呈固體之標題化合物(4.06g)。
1H-NMR(DMSO-D6,100℃)δ:1.66(9H,s),1.88-2.05(3H,m),2.30(1H,s),3.47-3.59(2H,m),4.53-4.58(1H,m),5.08(2H,s),7.13-7.44(5H,m),7.51(1H,t,J=7.9Hz),7.68(1H,d,J=7.3Hz),7.82(1H,d,J=8.5Hz),8.42(1H,s),10.11(1H,s).MS(m/z):465[M+H]+.
於上述步驟3獲得的化合物(3.60g)之乙醇(70.0mL)溶液中添加鈀-碳觸媒(1.50g),氫氣環境下,於室溫攪拌3小時。將反應液過濾、減壓濃縮後,對獲得的固體添加二乙基醚及己烷並懸浮,濾取固體並乾燥,藉此獲得呈固體之標題化合物(2.05g)。
1H-NMR(CDCl3)δ:1.73(9H,s),1.77-1.89(2H,m),2.07-2.15(1H,m),2.23-2.36(2H,m),3.03-3.09(1H,m), 3.13-3.19(1H,m),3.97(1H,s),7.50(1H,t,J=8.2Hz),7.90(1H,d,J=8.5Hz),7.96(1H,d,J=7.9Hz),8.21(1H,s),10.35(1H,s).MS(m/z):331[M+H]+.
氮氣環境下,將(4R)-1-(三級丁氧基羰基)-4-氟-D-脯胺酸(1.00g)及2-胺基苯甲腈(0.608g)溶解於吡啶(20.0mL),於冰鹽浴中冷卻至-15℃後,滴加氯化磷醯(0.432mL),自相同溫度至0℃攪拌10小時。將反應液以乙酸乙酯稀釋,以10%檸檬酸水溶液洗淨3次,以飽和碳酸氫鈉水溶液、飽和食鹽水洗淨後,以無水硫酸鈉乾燥。過濾、減壓濃縮後,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,藉此獲得呈固體之標題化合物(0.976g)。
1H-NMR(DMSO-D6,100℃)δ:1.41(9H,s),2.29-2.38(1H,m),2.51-2.68(1H,m),3.59-3.75(2H,m),4.48(1H,d,J=8.5Hz),5.29(1H,d,J=53.2Hz),7.30-7.34(1H,m),7.65-7.77(3H,m),9.67(1H,s).MS(m/z):234 [M-CO2tBu+H]+.
於上述步驟1獲得的化合物(0.960g)之二氯甲烷(15.0mL)溶液中,冰冷下,添加三氟乙酸(5.00mL),並於室溫攪拌1小時。將反應液注入冰冷的10%碳酸鈉水溶液中,以二氯甲烷萃取3次,將有機層以無水硫酸鈉乾燥。以食鹽使水層飽和,以氯仿-甲醇(10-1)萃取6次,將有機層以無水硫酸鎂乾燥。合併乾燥的有機層而過濾後,減壓濃縮,將獲得的殘渣以胺基矽膠管柱層析(己烷/乙酸乙酯)純化,藉此獲得呈固體之標題化合物(0.357g)。
1H-NMR(DMSO-D6)δ:2.15-2.36(2H,m),3.12-3.30(2H,m),3.68(1H,s),3.92-3.95(1H,m),5.27(1H,d,J=53.8Hz),7.26(1H,t,J=7.6Hz),7.67-7.71(1H,m),7.80(1H,dd,J=7.9,1.8Hz),8.25(1H,d,J=8.5Hz),10.75(1H,s).MS(m/z):234[M+H]+.
將5-氯-1H-吡唑并[4,3-b]吡啶(14.7g)、參(二亞苄基丙酮)二鈀(0)(2.27g)、2-二環己基膦基-2’,4’,6’-三異丙基聯苯(1.83g)、雙(三甲基矽基)胺化鋰(1.09mol/L,四氫呋喃溶液,200mL)、四氫呋喃(100mL)之混合物回流攪拌6.3小時。將反應液冷卻至室溫,靜置15.8小時,冷卻至0℃,一點一點地添加二碳酸二-三級丁酯(22.4g),於0℃攪拌40分鐘。於0℃添加氟化四丁基銨(1mol/L,四氫呋喃溶液,279mL),於相同溫度攪拌1.1小時。於0℃添加水,以乙酸乙酯萃取後,將獲得的有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。將減壓下餾除溶媒而獲得的殘渣供予矽膠管柱層析(己烷/乙酸乙酯),以二乙基醚/己烷混合溶媒作成漿液後,進行濾取,獲得呈固體之標題化合物(16.6g)。
1H-NMR(CDCl3)δ:1.70(9H,s),4.60(2H,br s),6.70(1H,d,J=8.5Hz),8.04(1H,s),8.21(1H,d,J=9.1Hz).
於上述步驟1獲得的化合物(0.162g)、N,N-二異丙基乙基胺(0.157mL)、二氯甲烷(3.00mL)混合物中,冰冷下,滴加9H-茀-9-基甲基(2R,4R)-2-(氯羰基)-4-氟吡啶-1-甲酸酯(0.260g)之二氯甲烷(3.00mL)溶液,於室溫攪 拌1小時半。於反應液中添加1mol/L鹽酸,以二氯甲烷萃取3次,將有機層以無水硫酸鈉乾燥。過濾、減壓濃縮後,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,藉此獲得呈固體之標題化合物(0.320g)。
1H-NMR(DMSO-D6,100℃)δ:1.66(9H,s),2.32-2.41(1H,m),2.52-2.70(1H,m),3.66-3.83(2H,m),4.23-4.32(3H,m),4.67(1H,d,J=9.7Hz),5.32(1H,d,J=53.8Hz),7.15-7.38(4H,m),7.63(2H,s),7.81(2H,s),8.26-8.29(1H,m),8.39-8.42(2H,m),10.44(1H,s).MS(m/z):572[M+H]+.
於上述步驟2獲得的化合物(0.310g)之N,N-二甲基甲醯胺(10.0mL)溶液中,冰冷下,添加哌啶(0.500mL),冰冷下攪拌15分鐘,於室溫攪拌15分鐘。於反應液中添加水,並以乙酸乙酯萃取3次,將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。合併水層,以二氯甲烷萃取2次,將有機層以無水硫酸鈉乾燥。合併獲得的有機層而過濾、減壓濃縮後,將殘渣以矽膠管柱層析(乙酸乙酯/甲醇)純化,藉此獲得呈固體之標題化合物(0.174g)。
1H-NMR(DMSO-D6)δ:1.66(9H,s),2.21-2.41(2H,m),3.07-3.26(2H,m),3.54(1H,s),3.92(1H,d,J=7.3Hz),5.26(1H,d,J=54.4Hz),8.41-8.48(3H,m),10.57 (1H,s).MS(m/z):350[M+H]+.
使用9H-茀-9-基甲基(2R)-2-氯羰基吡咯啶-1-甲酸酯(0.501g)與參考例3之步驟1獲得的化合物(0.300g),藉由進行與參考例3之步驟2相同的操作,獲得呈無色固體之標題化合物(0.662g)。
1H-NMR(DMSO-D6)δ:1.66(9H,s),1.82-2.10(3H,m),2.19-2.39(1H,m),3.36-3.59(2H,m),4.00-4.73(4H,m),6.98-8.55(11H,m),10.89-11.13(1H,m).
使用上述步驟1獲得的化合物(0.662g),藉由進行與參考例3之步驟3相同的操作,獲得呈無色固體之標題化合物(0.365g)。
1H-NMR(CDCl3)δ:1.55(9H,s),1.74-1.83(2H,m),2.02-2.12(1H,m),2.20-2.30(2H,m),3.04-3.15(1H,m), 3.88-3.94(1H,m),8.20-8.23(1H,m),8.42-8.46(1H,m),8.53-8.57(1H,m),10.45(1H,s).
將1H-吡咯并[3,2-b]吡啶(24.9g)之四氫呋喃(400mL)溶液冷卻至0℃,添加二碳酸二-三級丁酯(48.3g),於室溫攪拌19小時。以甲苯在減壓下共沸餾除,將殘渣溶解於二氯甲烷(400mL)後,冷卻至0℃,添加3-氯過苯甲酸(純度≦77%,54.6g),於室溫攪拌1.5小時。添加飽和碳酸氫鈉水溶液、硫代硫酸鈉(30g)而攪拌後,以二氯甲烷與氯仿萃取。將獲得的有機層以飽和碳酸氫鈉水溶液洗淨,以無水硫酸鈉乾燥。將減壓下餾除溶媒而獲得的殘渣以二異丙基醚作成漿液後,進行濾取,獲得呈固體之標題化合物(33.5g)。
1H-NMR(CDCl3)δ:1.69(9H,s),7.07(1H,d,J=3.6Hz),7.17(1H,dd,J=8.5,6.0Hz),7.75(1H,d,J=4.2 Hz),8.02-8.09(1H,m),8.21(1H,d,J=6.7Hz).
將上述步驟1獲得的化合物(10.0g)之二氯甲烷(200mL)溶液冷卻至0℃,添加PyBrop(47.8g)、N,N-二異丙基乙基胺(29.7mL)、氨(0.5mol/L,1,4-二烷溶液,200mL),並於室溫攪拌20.5小時。減壓下餾除溶媒,添加乙酸乙酯及飽和碳酸氫鈉水溶液,以乙酸乙酯萃取,以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣供予胺基矽膠管柱層析(己烷/乙酸乙酯),進一步供予矽膠管柱層析(己烷/乙酸乙酯),獲得呈油狀物之標題化合物(1.42g)。
1H-NMR(CDCl3)δ:1.66(9H,s),4.36(2H,br s),6.46-6.50(2H,m),7.66(1H,br s),8.13(1H,br s).
使用9H-茀-9-基甲基(2R,4R)-2-(氯羰基)-4-氟吡啶-1-甲酸酯(0.445g)及上述步驟2獲得的化合物(0.292g),藉由進行與參考例3之步驟2相同的操作,獲得呈固體之標題化合物(0.415g)。
1H-NMR(DMSO-D6)δ:1.64(9H,s),2.36(1H,dd,J=20.8,14.6Hz),2.51-2.68(1H,m),3.65-3.84(2H,m),4.24(1H,br s),4.32(2H,d,J=6.1Hz),4.65(1H,d,J=9.8Hz),5.31(1H,d,J=53.7Hz),6.67(1H,d,J=3.7 Hz),7.09-7.41(4H,m),7.63(2H,d,J=6.7Hz),7.82(2H,br s),7.89(1H,d,J=3.7Hz),8.03(1H,d,J=8.5Hz),8.30(1H,d,J=9.2Hz),10.10(1H,br s).MS(m/z):571[M+H]+.
使用上述步驟3獲得的化合物(0.365g),藉由進行與參考例3之步驟3相同的操作,獲得呈固體之標題化合物(0.246g)。
1H-NMR(CDCl3)δ:1.68(9H,s),2.25-2.46(2H,m),2.63(1H,dd,J=21.4,14.0Hz),3.28(1H,ddd,J=36.0,12.2,3.7Hz),3.47(1H,dd,J=21.4,12.2Hz),4.03(1H,d,J=10.4Hz),5.23(1H,d,J=53.1Hz),6.63(1H,d,J=3.7Hz),7.80(1H,br s),8.28(1H,d,J=9.2Hz),8.34(1H,br s),10.16(1H,br s).MS(m/z):349[M+H]+.
N-1H-吲唑-4-基-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-D-脯胺醯胺
冰冷下,於甲醇(100mL)中添加亞硫醯氯(3.93mL)、1-胺基環戊烷甲酸(3.50g),於70℃攪拌8小時後,於室溫放置整夜。將反應液減壓濃縮,於獲得的殘渣中添加飽和碳酸氫鈉水溶液,以二氯甲烷萃取3次,將有機層以無水硫酸鈉乾燥。藉由過濾、減壓濃縮,獲得呈油狀物之標題化合物(2.67g)。
1H-NMR(CDCl3)δ:1.56-1.62(4H,m),1.72-1.89(4H,m),2.05-2.12(2H,m),3.72(3H,s).
氮氣環境下,於上述步驟1獲得的化合物(2.67g)之甲醇(35.0mL)溶液中添加碳酸鉀(0.258g),加熱回流下,耗費45分鐘滴加碘化1-乙基-1-甲基-4-側氧哌啶鎓(7.53g)之水(15.0mL)溶液後,攪拌1小時。再耗費20分鐘滴加碘化1-乙基-1-甲基-4-側氧哌啶鎓(2.51g)之水 (5.00mL)溶液,添加碳酸鉀(0.0644g),加熱回流下攪拌1小時後,於室溫放置整夜。減壓餾除有機溶媒,於獲得的殘渣中添加水,以二氯甲烷萃取3次後,以無水硫酸鈉乾燥。過濾、減壓濃縮後,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,藉此獲得呈固體之標題化合物(1.83g)。
1H-NMR(CDCl3)δ:1.62-1.83(6H,m),2.32-2.38(2H,m),2.43(4H,t,J=6.0Hz),2.88(4H,t,J=6.0Hz),3.70(3H,s).MS(m/z):226[M+H]+.
於硼氫化鈉(0.151g)之甲醇(40.0mL)溶液中,冰冷下,添加上述步驟2獲得的化合物(0.900g),並於室溫攪拌6小時。將反應液減壓濃縮後,於獲得的殘渣中添加飽和碳酸氫鈉水溶液,以乙酸乙酯萃取3次,將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。藉由過濾、減壓濃縮,獲得呈固體之標題化合物(0.904g)。
1H-NMR(CDCl3)δ:1.40(1H,d,J=4.8Hz),1.48-1.65(6H,m),1.70-1.77(2H,m),1.86-1.91(2H,m),2.25-2.35(4H,m),2.84-2.89(2H,m),3.59-3.68(1H,m),3.70(3H,s).MS(m/z):228[M+H]+.
氮氣環境下,將上述步驟3獲得的化合物(0.900g)之N,N-二甲基甲醯胺(20.0mL)溶液冰冷,添加氫化鈉(純 度55%,0.259g),並於室溫攪拌30分鐘。再次冰冷,添加碘甲烷(0.296mL),並於室溫攪拌整夜。於反應液中添加飽和碳酸氫鈉水溶液及水,以乙酸乙酯萃取3次,將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。過濾、減壓濃縮後,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,藉此獲得呈油狀物之標題化合物(0.577g)。
1H-NMR(CDCl3)δ:1.40(1H,d,J=4.8Hz),1.48-1.65(6H,m),1.70-1.77(2H,m),1.86-1.91(2H,m),2.25-2.35(4H,m),2.84-2.89(2H,m),3.59-3.68(1H,m),3.70(3H,s).
MS(m/z):242[M+H]+.
冰冷下,於水(5.00mL)中添加35%鹽酸(5.00mL)後,添加上述步驟4獲得的化合物(0.570g),於100℃攪拌12小時後,於室溫放置整夜。將反應液減壓濃縮後,於殘渣中添加四氫呋喃(14.0mL)、甲醇(7.00mL)、1mol/L氫氧化鈉水溶液(9.45mL),並於室溫攪拌整夜。將反應液於加熱回流下攪拌12小時,於室溫放置整夜。減壓餾除有機溶媒後,於殘渣中添加水,以二乙基醚洗淨2次,於水層中添加1mol/L鹽酸並作成酸性,減壓濃縮。於殘渣中添加乙醇,濾除不溶物,將濾液減壓濃縮,藉此獲得呈固體之標題化合物之粗純化物(0.440g)。
MS(m/z):228[M+H]+(游離型).
於上述步驟5獲得的化合物(0.430g)之N,N-二甲基甲醯胺(8.00mL)溶液中,冰冷下,添加N,N-二異丙基乙基胺(0.852mL)及({[(1-氰基-2-乙氧基-2-側氧亞乙基)胺基]氧基}-4-啉基亞甲基)二甲基銨六氟磷酸鹽(0.768g),於室溫攪拌10分鐘後,添加參考例1獲得的化合物(0.539g),並於室溫攪拌整夜。於反應液中添加飽和碳酸氫鈉水溶液,以乙酸乙酯萃取3次,將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。過濾、減壓濃縮後,將獲得的殘渣以胺基矽膠管柱層析(己烷/乙酸乙酯)純化後,以矽膠管柱層析(己烷/乙酸乙酯)再純化,藉此獲得呈固體之標題化合物(0.664g)。
1H-NMR(CDCl3)δ:1.41-1.66(6H,m),1.73(9H,s),1.82-1.92(6H,m),2.01-2.23(5H,m),2.57-2.69(3H,m),3.10-3.16(1H,m),3.31(3H,s),3.65(1H,s),4.44(1H,s),4.91(1H,dd,J=8.5,3.6Hz),7.45(1H,t,J=8.2Hz),7.84(1H,d,J=8.5Hz),8.04(1H,d,J=7.3Hz),8.38(1H,s),10.66(1H,s).MS(m/z):540[M+H]+.
於上述步驟6獲得的化合物(0.655g)之二氯甲烷(7.50mL)溶液中,冰冷下,添加三氟乙酸(7.50mL),於 室溫攪拌1小時半。將反應液減壓濃縮後,於獲得的殘渣中添加飽和碳酸氫鈉水溶液,以二氯甲烷萃取3次,將有機層以無水硫酸鈉乾燥。過濾、減壓濃縮後,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化。減壓濃縮後,將獲得的殘渣溶解於乙醇,添加水,濾取析出的固體並乾燥,藉此獲得呈固體之標題化合物(0.455g)。
1H-NMR(CDCl3)δ:1.43-1.66(6H,m),1.81-1.95(6H,m),2.05-2.25(5H,m),2.54-2.73(3H,m),3.11-3.18(1H,m),3.31(3H,s),3.69(1H,s),4.43(1H,s),4.92(1H,dd,J=7.9,3.6Hz),7.17(1H,d,J=8.5Hz),7.32(1H,t,J=8.2Hz),7.89(1H,d,J=7.3Hz),8.26(1H,s),10.46-10.54(2H,m).MS(m/z):440[M+H]+.
1-{[1-(吖-1-基)環戊基]羰基}-N-1H-吲唑-4-基-D-脯胺醯胺
於1-胺基環戊烷甲酸甲酯鹽酸鹽(1.00g)之乙腈(20mL)溶液中,添加碳酸鉀(3.80g)及溴化四丁基銨(0.180g)後,添加1,6-二溴己烷(1.0mL)及碘化鉀 (1.80g),於90℃攪拌15小時。將反應混合物以乙腈稀釋,過濾不溶物。將濾液濃縮,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(0.986g)。
1H-NMR(CDCl3)δ:1.51-1.78(14H,m),2.11-2.23(2H,m),2.64-2.74(4H,m),3.68(3H,s).MS(m/z):226[M+H]+
於上述步驟1獲得的化合物(0.500g)之四氫呋喃(15mL)溶液中,添加甲醇(7.5mL)及1mol/L氫氧化鈉水溶液(22mL),加熱回流下,攪拌60小時。冷卻至室溫後,餾除溶媒。於獲得的殘渣中添加水,將水溶液以二乙基醚洗淨後,於水層中添加1mol/L鹽酸並作成酸性,進行濃縮。於獲得的殘渣中添加乙醇,過濾不溶物,將濾液濃縮,藉此獲得呈固體之標題化合物(0.771g)。
1H-NMR(DMSO-D6)δ:1.45-2.05(12H,m),2.16-2.32(4H,m),3.20-3.52(4H,m),10.21(1H,br s),14.17(1H,br s).MS(m/z):212[M+H]+(游離型).
使用上述步驟2獲得的化合物(0.262g)及參考例1獲得的化合物(0.250g),藉由進行與實施例1之步驟6相同的操作,獲得呈固體之標題化合物(0.258g)。
1H-NMR(CDCl3)δ:1.42-1.79(23H,m),1.82-1.99(2H,m),2.03-2.33(3H,m),2.43-2.51(4H,m),2.61-2.70(1H,m),3.72-3.81(1H,m),4.41(1H,dt,J=12.9,5.6Hz),4.94(1H,dd,J=8.2,3.3Hz),7.45(1H,t,J=8.2Hz),7.84(1H,d,J=8.5Hz),8.04(1H,d,J=7.9Hz),8.40(1H,s),10.68(1H,s).MS(m/z):524[M+H]+.
使用上述步驟3獲得的化合物(0.255g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.158g)。
1H-NMR(CDCl3)δ:1.43-1.70(12H,m),1.70-1.81(2H,m),1.83-1.98(2H,m),2.05-2.25(2H,m),2.28-2.38(1H,m),2.43-2.55(4H,m),2.59-2.70(1H,m),3.70-3.79(1H,m),4.40-4.49(1H,m),4.96(1H,dd,J=8.2,3.3Hz),7.18(1H,d,J=8.5Hz),7.32(1H,t,J=7.9Hz),7.88(1H,d,J=7.3Hz),8.27(1H,s),10.25(1H,br s),10.48(1H,br s).MS(m/z):424[M+H]+.
1-{[1-(3,3-二氟吡咯啶-1-基)環戊基]羰基}-N-1H-吲唑-4-基-D-脯胺醯胺
將環戊酮(1.00g)及3,3-二氟吡咯啶鹽酸鹽(3.80g)之甲醇(20mL)溶液冷卻至0℃,添加水(20mL)及碳酸氫鈉(1.60g)後,添加氰化鈉(1.20g),升溫至室溫,攪拌20小時。將反應混合物濃縮,於獲得的殘渣中添加水,並以二乙基醚萃取。將有機層以無水硫酸鈉乾燥,過濾、濃縮,獲得呈油狀物之標題化合物(2.39g)。
1H-NMR(CDCl3)δ:1.80-1.91(6H,m),2.05-2.19(2H,m),2.26-2.39(2H,m),2.91(2H,t,J=7.3Hz),3.07(2H,t,J=13.1Hz).
將上述步驟1獲得的化合物(1.00g)之己烷(10.0mL)溶液冷卻至0℃,滴加硫酸(8.2mL),一邊緩緩升溫至室溫,一邊攪拌16小時。將反應混合物滴加至冷卻至0℃的10%碳酸鉀水溶液,以氯仿/甲醇(95/5)之混合溶媒萃取。將有機層濃縮,獲得呈固體之標題化合物(1.12g)。
1H-NMR(CDCl3)δ:1.59-1.80(6H,m),1.99-2.09(2H,m),2.18-2.31(2H,m),2.80(2H,t,J=7.0Hz),2.95 (2H,t,J=13.3Hz),5.38(1H,br s),6.89(1H,br s).MS(m/z):219[M+H]+
於上述步驟2獲得的化合物(0.700g)中添加35%鹽酸(10mL),加熱回流下,攪拌7小時。冷卻至室溫後,將反應混合物濃縮,於獲得的殘渣中添加乙醇,再次濃縮,減壓下乾燥。於獲得的殘渣中添加乙醇,過濾不溶物而去除後,將濾液濃縮、乾燥,獲得呈固體之標題化合物(0.900g)。
1H-NMR(DMSO-D6)δ:1.62-1.74(2H,m),1.76-1.88(2H,m),1.91-2.07(2H,m),2.09-2.20(2H,m),2.42-2.57(2H,m),3.41-4.17(4H,m).MS(m/z):220[M+H]+(游離型).
使用上述步驟3獲得的化合物(0.232g)及參考例1獲得的化合物(0.250g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之標題化合物(0.290g)。
1H-NMR(CDCl3)δ:1.50-1.70(4H,m),1.73(9H,s),1.76-1.99(4H,m),2.07-2.32(5H,m),2.57-2.82(3H,m),2.85-2.99(2H,m),3.63-3.72(1H,m),4.09-4.21(1H,m),4.92(1H,dd,J=7.6,3.3Hz),7.46(1H,t,J=8.2Hz),7.85(1H,d,J=7.9Hz),8.02(1H,d,J=7.9Hz),8.36 (1H,s),10.43(1H,s).MS(m/z):532[M+H]+
使用上述步驟4獲得的化合物(0.285g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.191g)。
1H-NMR(CDCl3)δ:1.55-1.74(4H,m),1.77-2.01(4H,m),2.08-2.33(5H,m),2.49-2.60(1H,m),2.64-2.72(1H,m),2.77-2.85(1H,m),2.87-2.99(2H,m),3.69-3.78(1H,m),4.10-4.19(1H,m),4.92(1H,dd,J=7.6,3.9Hz),7.18(1H,d,J=8.5Hz),7.31(1H,t,J=8.2Hz),7.87(1H,d,J=7.3Hz),8.25(1H,s),10.25(1H,s),10.61(1H,br s).MS(m/z):432[M+H]+.
1-{[1-(4,4-二氟哌啶-1-基)環戊基]羰基}-N-1H-吲唑-4-基-D-脯胺醯胺
使用環戊酮(1.00g)及4,4-二氟哌啶 鹽酸鹽(4.10g),藉由進行與實施例3之步驟1相同的操作,獲得呈油狀物之標題化合物(2.32g)。
1H-NMR(CDCl3)δ:1.71-1.81(2H,m),1.83-1.96(4H,m),1.98-2.11(4H,m),2.22-2.31(2H,m),2.68-2.78(4H,m).
使用上述步驟1獲得的化合物(1.00g),藉由進行與實施例3之步驟2相同的操作,獲得呈油狀物之標題化合物(1.04g)。
1H-NMR(CDCl3)δ:1.57-1.79(6H,m),1.93-2.06(6H,m),2.56(4H,t,J=5.4Hz),5.33(1H,br s),6.89(1H,br s).MS(m/z):233[M+H]+.
使用上述步驟2獲得的化合物(0.700g),藉由進行與實施例3之步驟3相同的操作,獲得呈固體之標題化合物(0.897g)。
1H-NMR(DMSO-D6)δ:1.60-1.75(2H,m),1.78-1.91(2H,m),2.09-2.61(8H,m),3.17-3.67(4H,m).MS(m/z):234[M+H]+(游離型).
使用上述步驟3獲得的化合物(0.245g)及參考例1獲得的化合物(0.250g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之標題化合物(0.335g)。
1H-NMR(CDCl3)δ:1.48-1.66(4H,m),1.73(9H,s),1.80-2.00(8H,m),2.07-2.17(2H,m),2.19-2.29(1H,m),2.44-2.58(4H,m),2.59-2.70(1H,m),3.63-3.72(1H,m),4.27-4.37(1H,m),4.91(1H,dd,J=7.9,3.6Hz),7.46(1H,t,J=8.2Hz),7.86(1H,d,J=8.5Hz),8.00(1H,d,J=7.9Hz),8.36(1H,s),10.44(1H,br s).MS(m/z):546[M+H]+.
使用上述步驟4獲得的化合物(0.330g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.202g)。
1H-NMR(CDCl3)δ:1.52-1.70(4H,m),1.80-2.02(8H,m),2.09-2.29(3H,m),2.46-2.63(5H,m),3.69-3.83(1H,m),4.22-4.33(1H,m),4.91(1H,dd,J=7.9,3.6Hz),7.18(1H,d,J=8.5Hz),7.32(1H,t,J=7.9Hz),7.87(1H,d,J=7.9Hz),8.27(1H,s),10.28(1H,s),10.65(1H,br s).MS(m/z):446[M+H]+.
1-{[1-(4-苄基哌-1-基)環戊基]羰基}-N-1H-吲唑 -4-基-D-脯胺醯胺
將1-胺基環戊烷甲酸甲酯鹽酸鹽(1.00g)、溴化四丁基銨(0.180g)、碘化鉀(1.85g)、碳酸鉀(3.85g)、N-苄基-N,N-雙(2-氯乙基)胺鹽酸鹽(1.64g)、乙腈(20mL)之混合物於加熱回流下,攪拌4小時。過濾不溶物,將濾液濃縮而將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈固體之標題化合物(1.28g)。
1H-NMR(CDCl3)δ:1.55-1.64(4H,m),1.69-1.76(2H,m),2.27-2.34(2H,m),2.42-2.49(4H,m),2.57-2.63(4H,m),3.50(2H,s),3.70(3H,s),7.23-7.33(5H,m).MS(m/z):303[M+H]+.
使用上述步驟1獲得的化合物(1.28g),藉由進行與實施例2之步驟2相同的操作,獲得呈固體之標題化合物(0.998g)。
1H-NMR(DMSO-D6)δ:1.46-1.55(4H,m),1.59-1.68(2H,m),2.07-2.16(2H,m),2.28-2.42(4H,m),2.52-2.60(4H,m),3.43(2H,s),7.20-7.35(5H,m).
使用上述步驟2獲得的化合物(0.218g)及參考例1獲得的化合物(0.250g),藉由進行與實施例1之步驟6相同的操作,獲得呈固體之標題化合物(0.422g)。
1H-NMR(CDCl3)δ:1.47-1.65(4H,m),1.72(9H,s),1.82-2.50(15H,m),2.61-2.69(1H,m),3.44(2H,dd,J=15.7,12.7Hz),3.63-3.72(1H,m),4.34-4.45(1H,m),4.88-4.93(1H,m),7.20-7.32(5H,m),7.41-7.49(1H,m),7.85(1H,d,J=8.2Hz),8.02(1H,d,J=8.2Hz),8.36(1H,s),10.64(1H,s).MS(m/z):601[M+H]+.
使用上述步驟3獲得的化合物(0.0892g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.0465g)。
1H-NMR(CDCl3)δ:1.47-2.57(19H,m),2.60-2.71(1H,m),3.40-3.48(2H,m),3.59-3.74(1H,m),4.36-4.47(1H,m),4.93(1H,dd,J=7.9,3.6Hz),7.17-7.36(7H,m),7.88(1H,d,7.3),8.23(1H,s),10.03(1H,br s),10.45(1H,s).MS(m/z):501[M+H]+.
N-1H-吲唑-4-基-1-{[1-(4-甲氧基-2-側氧-2,5-二氫-1H-吡咯-1-基)環戊基]羰基}-D-脯胺醯胺
於1-胺基環戊烷甲酸苄酯鹽酸鹽(12.4g)之乙腈(40.0mL)懸浮液中,於室溫添加三乙基胺(6.79mL)及乙酸鉀(2.34g)而攪拌1.5小時後,再滴加(E)-4-氯-3-甲氧基-2-丁烯酸甲酯(3.31mL)之乙腈(20.0mL)溶液,加熱回流14小時。將反應液於減壓下濃縮而將獲得的殘渣以乙酸乙酯稀釋,依序以水、飽和碳酸氫鈉水溶液、1mol/L鹽酸、及飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣供予矽膠管柱層析(己烷/乙酸乙酯),獲得呈油狀物之標題化合物(4.65g)。
1H-NMR(CDCl3)δ:1.67-1.86(4H,m),2.18-2.37(4H,m),3.77(3H,s),3.94(2H,s),5.07(1H,s),5.15(2H,s),7.25-7.38(5H,m).
於上述步驟1獲得的化合物(1.00g)之甲醇(30.0mL)溶液中,於室溫添加1mol/L氫氧化鈉水溶液(15.0mL)而攪拌18小時。將反應液於減壓下濃縮,將獲得的殘渣以水稀釋後,冰冷下添加1mol/L鹽酸(15.0mL)。將上述混合物以氯仿/甲醇(9/1)混合溶媒萃取,將獲得的有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。於減壓下餾除溶媒而獲得的殘渣中添加己烷/二乙基醚混合溶媒,攪拌後,濾取不溶物,獲得呈固體之標題化合物(0.473g)。
1H-NMR(DMSO-D6)δ:1.56-1.73(4H,m),2.08-2.13(4H,m),3.76(3H,s),3.99(2H,s),5.11(1H,s),12.38(1H,br s).
於包含上述步驟2獲得的化合物(0.200g)、1-羥基苯并三唑(0.144g)、及N,N-二甲基甲醯胺(10.0mL)的混合物中,於室溫添加1-(3-二甲基胺基丙基)-3-乙基碳二亞胺鹽酸鹽(0.221g)而攪拌1小時。將上述混合物於室溫添加至包含N-1H-吲唑-4-基-D-脯胺醯胺鹽酸鹽(0.308g)、N,N-二異丙基胺(0.233mL)、及N,N-二甲基甲醯胺(20.0mL)的混合物中,攪拌1.5小時。將反應液以乙酸乙酯稀釋,以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣供予矽膠管柱層析(氯仿/甲醇),獲得呈固體之標題化合物(0.341g)。
1H-NMR(DMSO-D6)δ:1.51-1.97(8H,m),2.01-2.24(3H,m),2.46-2.58(1H,m),3.27-3.33(1H,m),3.42-3.50(1H,m),3.79(3H,s),4.16(1H,d,J=17.8Hz),4.22(1H,d,J=17.8Hz),4.52(1H,dd,J=8.2,5.1Hz),5.17(1H,s),7.21-7.30(2H,m),7.38-7.46(1H,m),8.20(1H,s),9.76(1H,s),13.00(1H,s).MS(m/z):438[M+H]+.
N-1H-吲唑-4-基-1-({1-[(3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基]環戊基}羰基)-D-脯胺醯胺
使用環戊酮(0.500g)及(3aR,6aS)-六氫-1H-呋喃并[3,4-c]吡咯鹽酸鹽(2.00g),藉由進行與實施例3之步驟1相同的操作,獲得呈油狀物之標題化合物(1.10g)。
1H-NMR(CDCl3)δ:1.77-1.91(6H,m),2.07-2.19(2H,m),2.59(2H,dd,J=8.8,2.1Hz),2.71-2.77(2H,m),2.77-2.88(2H,m),3.50(2H,dd,J=9.1,4.2Hz),3.93(2H,dd,J=8.8,7.0Hz).
使用上述步驟1獲得的化合物(1.10g),藉由進行與實施例3之步驟2相同的操作,獲得呈固體之標題化合物(1.20g)。
1H-NMR(DMSO-D6)δ:1.45-1.71(6H,m),1.81-1.89(2H,m),2.34(2H,dd,J=9.1,1.8Hz),2.51-2.56(2H,m),2.57-2.68(2H,m),3.33-3.38(2H,m),3.77(2H,dd,J=8.5,7.3Hz),6.95(1H,s),7.00(1H,s).
使用上述步驟2獲得的化合物(0.500g),藉由進行與實施例3之步驟3相同的操作,獲得呈固體之標題化合物(0.575g)。
1H-NMR(DMSO-D6)δ:1.58-1.82(4H,m),1.90-2.01(2H,m),2.07-2.18(2H,m),2.81-2.97(4H,m),3.31-3.47(2H,m),3.55-3.66(4H,m).MS(m/z):226[M+H]+(游離型).
使用上述步驟3獲得的化合物(0.238g)及參考例1獲得的化合物(0.250g),藉由進行與實施例1之步驟6 相同的操作,獲得呈油狀物之標題化合物(0.328g)。
1H-NMR(CDCl3)δ:1.47-1.67(4H,m),1.73(9H,s),1.79-1.97(4H,m),2.03-2.28(3H,m),2.36-2.43(2H,m),2.51-2.75(5H,m),3.38-3.46(2H,m),3.69-3.78(1H,m),3.80-3.92(2H,m),4.22-4.31(1H,m),4.89-4.96(1H,m),7.44-7.48(1H,m),7.84-7.87(1H,m),8.01-8.04(1H,m),8.37(1H,s),10.57(1H,s).MS(m/z):538[M+H]+.
使用上述步驟4獲得的化合物(0.320g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.207g)。
1H-NMR(CDCl3)δ:1.50-1.69(4H,m),1.81-1.97(4H,m),2.05-2.31(3H,m),2.37-2.48(2H,m),2.53-2.75(5H,m),3.40-3.48(2H,m),3.70-3.81(1H,m),3.82-3.91(2H,m),4.22-4.32(1H,m),4.94(1H,dd,J=7.9,3.6Hz),7.17-7.20(1H,m),7.30-7.35(1H,m),7.87-7.90(1H,m),8.25(1H,s),10.28-10.44(2H,m).MS(m/z):438[M+H]+.
N-1H-吲唑-4-基-1-{[1-(2,4,6,7-四氫-5H-吡唑并[4,3-c]吡啶-5-基)環戊基]羰基}-D-脯胺醯胺
於1-(4-側氧哌啶-1-基)環戊烷甲酸苄酯(1.50g)之溶液中,添加N,N-二甲基甲醯胺二甲基縮醛(3.3mL),於80℃攪拌20小時。將反應混合物濃縮而將獲得的殘渣供予矽膠管柱層析(氯仿/甲醇),獲得呈油狀物之標題化合物(1.01g)。
1H-NMR(CDCl3)δ:1.55-1.82(6H,m),2.34-2.45(4H,m),2.83(2H,t,J=6.0Hz),2.99(6H,s),3.67(2H,s),5.17(2H,s),7.30-7.39(5H,m),7.41(1H,s).
於上述步驟1獲得的化合物(0.500g)之乙醇(10mL)溶液中,添加肼一水和物(0.136mL),室溫下攪拌20小 時。將反應混合物濃縮而將獲得的殘渣以乙酸乙酯稀釋,依序以水及飽和食鹽水洗淨。將有機層以無水硫酸鈉乾燥,過濾、濃縮,而獲得呈油狀物之標題化合物(0.379g)。
1H-NMR(CDCl3)δ:1.55-1.84(6H,m),2.40-2.49(2H,m),2.72-2.79(2H,m),2.91(2H,t,J=5.7Hz),3.72(2H,s),5.16(2H,s),7.28-7.41(6H,m).
將上述步驟2獲得的化合物(0.340g)之二氯甲烷(6.8mL)溶液冷卻至0℃,添加三乙基胺(0.217mL)後,滴加二碳酸二-三級丁酯(0.296g)之二氯甲烷(1.7mL)溶液,於室溫攪拌20小時。將反應混合物濃縮而將獲得的殘渣以矽膠管柱層析(氯仿)純化,獲得呈油狀物之作為與位置異構物的混合物之標題化合物(0.217g)。
1H-NMR(CDCl3)δ:1.52-1.83(15H,m),2.35-2.48(2H,m),2.75-3.01(4H,m),3.70(2H,s),5.14-5.20(2H,m),7.31-7.39(5H,m),7.73(1H,s).MS(m/z):426[M+H]+.
於上述步驟3獲得的化合物(0.210g)之乙酸乙酯(20mL)溶液中添加鈀-碳觸媒(0.105g),氫氣環境下,於 室溫攪拌6小時。將反應混合物過濾,將濾液濃縮,獲得呈固體之作為與位置異構物的混合物之標題化合物(0.170g)。
1H-NMR(CDCl3)δ:1.64(9H,s),1.70-1.93(6H,m),2.14-2.25(2H,m),2.52-3.11(4H,m),3.72(2H,s),7.82(1H,s).MS(m/z):334[M-H]-.
使用上述步驟4獲得的化合物(0.155g)及參考例1獲得的化合物(0.183g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之包含位置異構物的標題化合物(0.300g)。
1H-NMR(CDCl3)δ:1.53-1.76(23H,m),1.77-2.08(6H,m),2.11-2.21(1H,m),2.28-2.39(1H,m),2.54-2.98(4H,m),3.34-3.66(3H,m),4.15-4.26(1H,m),4.88-4.98(1H,m),7.44-7.50(1H,m),7.66(1H,s),7.84-7.89(1H,m),8.01-8.06(1H,m),8.40(1H,s).MS(m/z):648[M+H]+.
使用上述步驟5獲得的化合物(0.300g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合 物(0.130g)。
1H-NMR(CDCl3)δ:1.52-2.10(9H,m),2.16-2.27(1H,m),2.29-2.40(1H,m),2.51-2.61(1H,m),2.64-2.79(4H,m),3.44-3.58(2H,m),3.61-3.72(1H,m),4.18-4.28(1H,m),4.93-5.00(1H,m),7.16-7.23(2H,m),7.34(1H,t,J=7.9Hz),7.87(1H,d,J=7.9Hz),8.26(1H,s),10.36(1H,s).MS(m/z):448[M+H]+.
1-{[1-(3,4-二氫異喹啉-2(1H)-基)環戊基]羰基}-N-1H-吲唑-4-基-D-脯胺醯胺
於1,2,3,4-四氫異喹啉(0.100g)及N,N-二異丙基胺(0.52mL)之四氫呋喃(5mL)溶液中,室溫下,耗費20分鐘滴加1-溴環己烷甲酸(0.171g)之四氫呋喃(3mL)溶液及三氟甲磺酸銀(0.212g)之四氫呋喃(3mL)溶液。攪拌3小時後,將反應混合物以矽膠管柱層析(氯仿/甲醇/水)純化。將獲得的殘渣以乙酸乙酯稀釋,濾取固體,乾燥,獲得呈固體之標題化合物(0.116g)。
1H-NMR(DMSO-D6)δ:1.25-1.44(4H,m),1.53-1.76(4H,m),1.86-1.97(2H,m),2.76(4H,s),3.77(2H,s),7.03-7.12(4H,m),12.34(1H,br s).MS(m/z):260[M+H]+.
使用上述步驟1獲得的化合物(0.100g)及參考例1獲得的化合物(0.153g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之標題化合物(0.160g)。
1H-NMR(CDCl3)δ:1.06-1.20(1H,m),1.22-1.38(1H,m),1.49-1.92(17H,m),1.95-2.06(1H,m),2.13-2.21(1H,m),2.23-2.32(1H,m),2.51-2.63(1H,m),2.67-2.87(4H,m),3.50-3.60(1H,m),3.70-3.78(1H,m),3.85-3.93(1H,m),4.60-4.70(1H,m),5.00-5.07(1H,m),6.93-6.99(1H,m),7.04-7.16(3H,m),7.47(1H,t,J=8.2Hz),7.87(1H,d,J=8.5Hz),8.03(1H,d,J=7.9Hz),8.43(1H,s),10.41(1H,s).MS(m/z):572[M+H]+.
使用上述步驟2獲得的化合物(0.160g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.090g)。
1H-NMR(CDCl3)δ:1.08-1.21(1H,m),1.31-1.46 (1H,m),1.50-1.82(6H,m),1.84-1.96(2H,m),1.97-2.08(1H,m),2.15-2.24(1H,m),2.25-2.33(1H,m),2.46-2.57(1H,m),2.71-2.93(4H,m),3.55-3.66(1H,m),3.75(1H,d,J=14.5Hz),3.92(1H,d,J=14.5Hz),4.58-4.70(1H,m),5.00-5.07(1H,m),6.95-7.01(1H,m),7.06-7.15(3H,m),7.20(1H,d,J=8.5Hz),7.34(1H,t,J=7.9Hz),7.91(1H,d,J=7.9Hz),8.34(1H,s),10.27(1H,s),10.47(1H,br s).MS(m/z):472[M+H]+.
1-({1-[4-(羥甲基)哌啶-1-基]環戊基}羰基)-N-1H-吲唑-4-基-D-脯胺醯胺
於6mol/L鹽酸(3.96mL)、甲醇(15.0mL)、水(10.0mL)之混合溶液中,冰冷下,依序添加哌啶-4-基甲醇(11.0g)、環戊酮(2.00g)之甲醇(10.0mL)溶液,於相同溫度攪拌15分鐘後,添加氰化鈉(2.33g)之水(10.0mL)溶液。於室溫攪拌整夜後,於反應液中添加水,而以乙酸 乙酯萃取5次。將有機層以無水硫酸鈉乾燥後,將濃縮而獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,而獲得呈油狀物之標題化合物(4.37g)。
1H-NMR(CDCl3)δ:1.24-1.37(3H,m),1.53-1.62(1H,m),1.71-1.93(8H,m),2.24-2.32(4H,m),2.97(2H,d,J=11.5Hz),3.51(2H,t,J=5.7Hz).
使用上述步驟1獲得的化合物(2.37g),藉由進行與實施例3之步驟2相同的操作,獲得呈固體之標題化合物(2.85g)。
1H-NMR(DMSO-D6)δ:1.10-1.20(2H,m),1.42-1.63(9H,m),1.86-2.01(4H,m),2.72(2H,d,J=11.5Hz),3.52(2H,d,J=6.7Hz),6.90(1H,s),7.02(1H,s).MS(m/z):227[M+H]+.
使用上述步驟2獲得的化合物(2.57g),藉由進行與實施例3之步驟3相同的操作,獲得標題化合物(2.56g)之粗製物。
MS(m/z):228[M+H]+.
於上述步驟3獲得的化合物(0.500g)之N,N-二甲基甲醯胺(10.0mL)溶液中,添加碳酸銫(2.47g)及溴甲苯 (0.248mL),於室溫攪拌整夜。於反應液中添加水,以乙酸乙酯萃取3次,將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。過濾、減壓濃縮後,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,藉此獲得呈油狀物之標題化合物(0.249g)。
1H-NMR(CDCl3)δ:1.15-1.47(4H,m),1.54-1.74(8H,m),2.14-2.21(2H,m),2.35-2.41(2H,m),2.95-3.01(2H,m),3.46(2H,d,J=6.0Hz),5.16(2H,s),7.30-7.37(5H,m).
MS(m/z):318[M+H]+.
於上述步驟4獲得的化合物(0.250g)之乙醇(10.0mL)溶液中添加鈀-碳觸媒(0.100g),氫氣環境下,於室溫攪拌1小時。氮取代後,於反應液中添加4mol/L氯化氫-1,4-二烷(0.500mL),於室溫攪拌10分鐘後,過濾,將濾液減壓濃縮,藉此獲得呈固體之標題化合物(0.211g)。
1H-NMR(CD3OD)δ:1.55-1.66(2H,m),1.75-1.91(5H,m),2.00-2.06(2H,m),2.13-2.21(2H,m),2.31-2.38(2H,m),3.20-3.26(2H,m),3.46(2H,d,J=6.0Hz),3.56(2H,d,J=12.1Hz).
使用上述步驟5獲得的化合物及參考例1獲得的化 合物(0.276g),藉由進行與實施例1之步驟6相同的操作,獲得呈固體之標題化合物(0.253g)。
1H-NMR(CDCl3)δ:1.07-1.20(2H,m),1.34-1.61(7H,m),1.73(10H,s),1.83-1.93(4H,m),2.02-2.22(5H,m),2.59-2.72(3H,m),3.46(2H,s),3.66(1H,br s),4.40(1H,s),4.92(1H,dd,J=7.9,3.6Hz),7.41-7.46(1H,m),7.81-7.85(1H,m),8.01-8.04(1H,m),8.37(1H,s),10.63(1H,s).MS(m/z):540[M+H]+.
使用上述步驟6獲得的化合物(0.248g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.0970g)。
1H-NMR(CDCl3)δ:1.09-1.21(2H,m),1.42-1.75(8H,m),1.84-1.94(4H,m),2.04-2.25(5H,m),2.59-2.74(3H,m),3.46(2H,d,J=6.0Hz),3.68(1H,br s),4.39(1H,br s),4.94(1H,dd,J=7.9,3.6Hz),7.16-7.19(1H,m),7.29-7.34(1H,m),7.86-7.89(1H,m),8.24(1H,s),10.26-10.43(2H,m).MS(m/z):440[M+H]+.
(4R)-N-1H-吲哚-4-基-4-(甲氧基甲氧基)-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-D-脯胺醯胺
於1-胺基環戊烷甲酸苄酯(10.0g)之乙醇(500mL)溶液中,添加碘化1-乙基-1-甲基-4-側氧哌啶鎓(24.5g)及碳酸鉀(0.630g),於90℃攪拌4小時。減壓下餾除溶媒,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(7.17g)。
1H-NMR(CDCl3)δ:1.55-1.83(6H,m),2.32-2.44(6H,m),2.83-2.91(4H,m),5.14(2H,s),7.28-7.41(5H,m).
使用上述步驟1獲得的化合物(7.16g),藉由進行與實施例1之步驟3相同的操作,獲得標題化合物(6.75g)。
1H-NMR(CDCl3)δ:1.39-1.91(11H,m),2.25-2.40(4H,m),2.80-2.92(2H,m),3.51-3.63(1H,m),5.16(2H,s),7.28-7.40(5H,m).
使用上述步驟2獲得的化合物(6.75g),藉由進行與實施例1之步驟4相同的操作,獲得呈油狀物之標題化合物(2.50g)。
1H-NMR(CDCl3)δ:1.41-1.92(10H,m),2.24-2.40(4H,m),2.82-2.92(2H,m),3.04-3.16(1H,m),3.30(3H,s),5.15(2H,s),7.28-7.40(5H,m).
於上述步驟3獲得的化合物(2.50g)之乙醇(70mL)溶液中,添加鈀-碳觸媒(0.500g),氫氣環境下,攪拌5小時。將反應液以矽藻土過濾,減壓下餾除溶媒,獲得呈固體之標題化合物(1.76g)。
1H-NMR(CD3OD)δ:1.67-2.41(14H,m),3.13-3.24(2H,m),3.35(3H,s),3.44-3.58(1H,m).
使用上述步驟4獲得的化合物(1.76g)及(4R)-4-羥基-D-脯胺酸苄酯(1.80g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之標題化合物(0.950g)。
1H-NMR(CDCl3)δ:1.39-1.63(6H,m),1.71-2.01(6H,m),2.05-2.30(4H,m),2.56-2.77(2H,m),3.10-3.22(1H,m),3.32(3H,s),3.45-3.55(1H,m),3.59-3.70(1H,m),4.27-4.38(1H,m),4.45-4.53(1H,m),4.62-4.77(1H, m),5.13(1H,d,J=12.1Hz),5.30(1H,d,J=12.1Hz),7.27-7.40(5H,m).
於上述步驟5獲得的化合物(0.100g)之二氯甲烷(1.2mL)溶液中,於0℃添加N,N-二異丙基胺(0.291mL)、氯甲基甲基醚(0.105mL),於室溫攪拌整夜。再度冷卻至0℃,添加N,N-二異丙基胺(0.291mL)、氯甲基甲基醚(0.105mL),於室溫攪拌3小時。於反應液中添加水,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(0.102g)。
1H-NMR(CDCl3)δ:1.37-2.23(15H,m),2.35-2.45(1H,m),2.57-2.70(1H,m),2.72-2.83(1H,m),3.08-3.17(1H,m),3.31(3H,s),3.32(3H,s),3.73-3.85(1H,m),4.12-4.21(1H,m),4.34-4.50(1H,m),4.55-4.63(3H,m),5.09(1H,d,J=12.1Hz),5.20(1H,d,J=12.1Hz),7.27-7.39(5H,m).
使用上述步驟6獲得的化合物(0.102g),藉由進行與上述步驟4相同的操作,獲得呈油狀物之標題化合物 (0.0826g)。
使用上述步驟7獲得的化合物(0.0820g)及4-胺基吲哚(0.0338g),藉由進行與實施例1之步驟6相同的操作,獲得呈固體之標題化合物(0.0908g)。
1H-NMR(CDCl3)δ:1.40-1.63(6H,m),1.73-1.99(4H,m),1.99-2.32(5H,m),2.57-2.67(1H,m),2.67-2.79(2H,m),3.10-3.21(1H,m),3.31(3H,s),3.38(3H,s),3.71-3.86(1H,m),4.21-4.30(1H,m),4.61-4.80(3H,m),4.81-4.89(1H,m),6.59-6.64(1H,m),7.12-7.20(3H,m),7.86-7.91(1H,m),8.27(1H,s),9.45(1H,s).MS(m/z):499[M+H]+.
(4R)-4-羥基-N-1H-吲哚-4-基-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-D-脯胺醯胺
於實施例11之步驟8獲得的化合物(0.0518g)之甲醇(1.7mL)溶液中,於0℃添加3mol/L鹽酸(0.86mL),並攪拌10分鐘。再追加6mol/L鹽酸(0.86mL),於室溫攪拌2 小時。於0℃,於反應液中添加飽和碳酸氫鈉水溶液後,以乙酸乙酯萃取,將有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈固體之標題化合物(0.0123g)。
1H-NMR(CDCl3)δ:1.43-1.65(6H,m),1.78-1.93(4H,m),2.04-2.26(5H,m),2.47-2.71(3H,m),3.10-3.21(1H,m),3.30(3H,s),4.08-4.17(1H,m),4.20-4.29(1H,m),4.44-4.52(1H,m),4.99-5.04(1H,m),5.07-5.11(1H,m),6.66-6.71(1H,m),7.14-7.24(3H,m),7.66-7.72(1H,m),8.25(1H,br s),9.60(1H,br s).MS(m/z):455[M+H]+.
1-(1-{[(2R)-2-(1H-吲唑-4-基胺甲醯基)吡咯啶-1-基]羰基}環戊基)哌啶-4-甲酸
使用哌啶-4-甲酸三級丁酯鹽酸鹽(1.20g)及1-溴環戊烷甲酸(1.00g),藉由進行與實施例9之步驟1相同的操作,獲得呈固體之標題化合物(0.190g)。
1H-NMR(DMSO-D6)δ:1.38(9H,s),1.46-1.67(8H,m),1.71-1.80(2H,m),2.09-2.22(3H,m),2.25-2.36(2H,m),2.83-2.92(2H,m).MS(m/z):298[M+H]+.
使用上述步驟1獲得的化合物(0.220g)及參考例1獲得的化合物(0.293g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之標題化合物(0.325g)。
1H-NMR(CDCl3)δ:1.42(9H,s),1.48-1.66(6H,m),1.73(9H,s),1.81-1.95(5H,m),1.98-2.26(6H,m),2.60-2.72(3H,m),3.59-3.73(1H,m),4.32-4.45(1H,m),4.88-4.94(1H,m),7.43-7.48(1H,m),7.82-7.86(1H,m),8.03-8.06(1H,m),8.38(1H,s),10.66(1H,s).MS(m/z):610[M+H]+.
使用上述步驟2獲得的化合物(0.300g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.040g)。
1H-NMR(DMSO-D6)δ:1.33-1.64(6H,m),1.69-2.24(13H,m),2.61-2.73(1H,m),2.79-2.90(1H,m),3.81-3.93(1H,m),3.99-4.13(1H,m),4.59-4.66(1H,m),7.19-7.28(2H,m),7.59-7.64(1H,m),8.21-8.28(1H,m), 12.11(1H,br s),13.04(1H,br s).MS(m/z):454[M+H]+
(4R)-N-(2-氰基苯基)-4-氟-1-{[1-(1-羥基-4-甲氧基環己基)環戊基]羰基}-D-脯胺醯胺
氮氣環境下,將二異丙基胺化鋰(1.13mol/L,n-己烷-四氫呋喃溶液,31.0mL)冷卻至-78℃,並添加環戊烷甲酸(1.90mL)。於室溫攪拌2小時後,冷卻至-78℃,添加4-甲氧基環己酮(2.25g)。於0℃攪拌30分鐘後,添加1mol/L鹽酸,並以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥。減壓下餾除溶媒,將獲得的殘渣以矽膠管柱層析(二氯甲烷/甲醇)純化,獲得呈固體之標題化合物(0.665g)。
1H-NMR(CDCl3)δ:1.50-1.83(13H,m),1.90-1.99(2H,m),2.07-2.14(2H,m),3.08-3.17(1H,m),3.36(3H,s).
使用上述步驟1獲得的化合物(0.162g)及參考例2獲得的化合物(0.120g),藉由進行與實施例1之步驟6 相同的操作,獲得呈固體之標題化合物(0.0304g)。
1H-NMR(CDCl3)δ:1.15-2.61(18H,m),2.95-3.06(2H,m),3.30(3H,s),3.77-3.92(1H,m),4.84-4.97(2H,m),5.23-5.39(1H,m),7.11-7.17(1H,m),7.53-7.60(2H,m),8.37(1H,d,J=8.5Hz),8.73(1H,s).MS(m/z):458[M+H]+.
1-{[1-(4-苄基-4-羥基哌啶-1-基)環己基]羰基}-N-1H-吲唑-4-基-D-脯胺醯胺
使用4-苄基哌啶-4-醇(0.924g)及1-溴環己烷甲酸(0.500g),藉由進行與實施例9之步驟1相同的操作,獲得呈固體之標題化合物(0.495g)。
1H-NMR(DMSO-D6)δ:1.16-1.61(14H,m),1.79-1.89(2H,m),2.51-2.56(2H,m),2.67-2.77(2H,m),4.19(1H,br s),7.13-7.29(5H,m).MS(m/z):318[M+H]+.
使用上述步驟1獲得的化合物(0.115g)及參考例1獲得的化合物(0.100g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之標題化合物(0.100g)。
1H-NMR(CDCl3)δ:0.98-1.97(25H,m),1.99-2.14(1H,m),2.16-2.27(1H,m),2.38-2.57(2H,m),2.58-2.79(4H,m),3.36-3.61(1H,m),4.73-5.04(2H,m),7.15-7.21(2H,m),7.23-7.36(3H,m),7.44-7.49(1H,m),7.84-7.88(1H,m),8.00-8.03(1H,m),8.39(1H,s),10.44(1H,s).MS(m/z):630[M+H]+.
使用上述步驟2獲得的化合物(0.100g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.0699g)。
1H-NMR(CDCl3)δ:1.00-1.66(10H,m),1.68-2.00(4H,m),2.02-2.15(2H,m),2.16-2.26(1H,m),2.42-2.63(3H,m),2.66-2.79(4H,m),3.40-3.67(1H,m),4.68-5.05(2H,m),7.15-7.21(3H,m),7.22-7.36(4H,m),7.87(1H,d,J=7.9Hz),8.27(1H,s),10.16-10.48(2H,m).MS(m/z):530[M+H]+.
1-({1-[順式-3-(苄氧基)環丁基]環戊基}羰基)-N-1H-吲唑-4-基-D-脯胺醯胺
氮氣環境下,將二異丙基胺化鋰(1.13mol/L,n-己烷-四氫呋喃溶液,19.8mL)冷卻至-78℃,添加[順式-3-(苄氧基)環丁基]乙腈(1.50g)之四氫呋喃(15mL)溶液,於相同溫度攪拌30分鐘。添加1,4-二碘丁烷(1.20mL),於相同溫度攪拌1小時,於室溫攪拌1小時。於0℃添加飽和氯化銨水溶液,以乙酸乙酯萃取反應混合物。將有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(0.649g)。
1H-NMR(CDCl3)δ:1.46-1.97(9H,m),1.97-2.11(2H,m),2.26-2.42(2H,m),3.81-3.92(1H,m),4.43(2H,s),7.23-7.38(5H,m).MS(m/z):256[M+H]+.
氮氣環境下,於上述步驟1獲得的化合物(0.649g) 之甲苯(16mL)溶液中,於-78℃添加氫化二異丁基鋁(1mol/L,甲苯溶液,3.82mL),於相同溫度攪拌1小時。於反應液中添加飽和酒石酸鉀鈉水溶液,升溫至室溫。以乙酸乙酯萃取,將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(0.601g)。
1H-NMR(CDCl3)δ:1.44-1.66(6H,m),1.67-1.79(2H,m),1.83-1.95(2H,m),2.09-2.21(1H,m),2.22-2.32(2H,m),3.86-3.94(1H,m),4.40(2H,s),7.25-7.38(5H,m),9.48(1H,s).MS(m/z):259[M+H]+.
將上述步驟2獲得的化合物(0.600g)、三級丁醇(15mL)、水(3mL)之混合物冰冷後,添加2-甲基-2-丁烯(1.23mL)、磷酸二氫鈉(0.558g)、亞氯酸鈉(0.421g),並於室溫攪拌2小時。於0℃,於反應液中添加10%檸檬酸水溶液,以乙酸乙酯萃取,將有機層以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(0.611g)。
1H-NMR(CDCl3)δ:1.48-1.81(8H,m),2.00-2.11(2H,m),2.19-2.32(3H,m),3.79-3.90(1H,m),4.40(2H,s),7.22-7.37(5H,m).MS(m/z):273[M-H]-.
於上述步驟3獲得的化合物(0.300g)之二氯甲烷(10mL)溶液中,於0℃添加草醯氯(0.282mL)、N,N-二甲基甲醯胺(0.050mL),於35℃攪拌2小時半。減壓下餾除溶媒,獲得粗製之酸氯化物。於粗製之酸氯化物之二氯甲烷(10mL)溶液中,於0℃添加參考例1獲得的化合物(0.369g)、N,N-二異丙基胺(0.572mL)、4-二甲基胺基吡啶(0.0671g),並於室溫攪拌5小時。於反應液中添加冰後,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(0.430g)。
1H-NMR(CDCl3)δ:1.50-2.28(16H,m),1.72(9H,s),2.56-2.69(1H,m),3.47-3.57(1H,m),3.67-3.81(2H,m),4.21-4.30(2H,m),4.95-5.02(1H,m),7.19-7.34(5H,m),7.40-7.48(1H,m),7.81-7.88(1H,m),7.99-8.05(1H,m),8.41(1H,s),10.60(1H,br s).MS(m/z):587[M+H]+.
使用上述步驟4獲得的化合物(0.0501g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.0411g)。
1H-NMR(CDCl3)δ:1.52-2.31(16H,m),2.57-2.68 (1H,m),3.48-3.58(1H,m),3.66-3.81(2H,m),4.18-4.27(2H,m),4.98-5.05(1H,m),7.15-7.36(7H,m),7.86-7.91(1H,m),8.28(1H,s),10.20(1H,br s),10.42(1H,br s).MS(m/z):487[M+H]+.
1-{[1-(順式-3-羥基環丁基)環戊基]羰基}-N-1H-吲唑-4-基-D-脯胺醯胺
於實施例16之步驟4獲得的化合物(0.0500g)之乙醇(3mL)溶液中,添加20%氫氧化鈀碳(0.100g),氫氣環境下,攪拌4小時。將反應液以矽藻土過濾,將獲得的濾液於減壓下濃縮,藉此獲得呈油狀物之標題化合物(0.0267g)。
1H-NMR(CDCl3)δ:1.48-2.36(17H,m),1.73(9H,s),2.51-2.60(1H,m),3.52-3.81(2H,m),3.89-4.03(1H,m),4.90-5.06(1H,m),7.37-7.44(1H,m),7.79-7.85(1H,m),7.92-7.99(1H,m),8.40(1H,s),10.39(1H,br s).MS(m/z):495[M-H]-.
於上述步驟1獲得的化合物(0.0267g)之二氯甲烷(2mL)溶液中,於0℃添加4mol/L氯化氫-1,4-二烷(2mL),並於室溫攪拌2小時,於45℃攪拌1小時半。於室溫追加4mol/L氯化氫-1,4-二烷(1mL),並於45℃攪拌1小時。添加飽和碳酸氫鈉水溶液後,以氯仿:異丙醇=3:1之混合溶媒萃取,將有機層以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣以矽膠管柱層析(乙酸乙酯/甲醇)純化,獲得呈固體之標題化合物(0.0222g)。
1H-NMR(CDCl3)δ:1.49-2.40(16H,m),2.42-2.58(1H,m),2.59-2.82(1H,m),3.61-3.77(2H,m),3.90-4.01(1H,m),4.95-5.02(1H,m),7.15(1H,d,J=8.5Hz),7.24-7.31(1H,m),7.87(1H,d,J=7.9Hz),8.27(1H,s),10.30(1H,s),11.03(1H,br s).MS(m/z):395[M-H]-.
N-1H-吲唑-4-基-1-{[1-(順式-3-甲氧基環丁基)環戊基]羰基}-D-脯胺醯胺
於實施例17之步驟1獲得的化合物(0.0500g)之丙酮 (5mL)溶液中,添加碘甲烷(0.25mL)及氧化銀(0.935g),於室溫攪拌16小時。過濾不溶物,減壓下餾除濾液,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈固體之標題化合物(0.0309g)。
1H-NMR(CDCl3)δ:1.48-2.28(16H,m),1.73(9H,s),2.59-2.69(1H,m),3.09(3H,s),3.47-3.63(2H,m),3.70-3.83(1H,m),4.94-5.02(1H,m),7.44(1H,dd,J=8.5,7.9Hz),7.85(1H,d,J=8.5Hz),8.01(1H,d,J=7.9Hz),8.39(1H,s),10.59(1H,br s).MS(m/z):509[M-H]-.
使用上述步驟1獲得的化合物(0.0309g),藉由進行與實施例17之步驟2相同的操作,獲得呈固體之標題化合物(0.0215g)。
1H-NMR(CDCl3)δ:1.48-2.30(16H,m),2.59-2.68(1H,m),3.08(3H,s),3.50-3.61(2H,m),3.73-3.82(1H,m),4.99-5.04(1H,m),7.19(1H,d,J=8.5Hz),7.33(1H,dd,J=8.5,7.9Hz),7.87(1H,d,J=7.9Hz),8.26(1H,s),10.17(1H,br s),10.40(1H,br s).MS(m/z):409[M-H]-.
(4R)-4-氟-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
使用實施例1之步驟5獲得的化合物(0.174g)及參考例3獲得的化合物(0.230g),藉由進行與實施例1之步驟6相同的操作,獲得呈固體之標題化合物(0.377g)。
1H-NMR(CDCl3)δ:1.49-1.68(6H,m),1.72(9H,s),1.79-2.06(5H,m),2.17-2.41(4H,m),2.62-2.86(7H,m),4.04-4.27(1H,m),4.58-4.87(2H,m),5.21-5.42(1H,m),8.18(1H,s),8.35-8.43(1H,m),8.44-8.52(1H,m),8.80(1H,s).MS(m/z):559[M+H]+.
使用上述步驟1獲得的化合物(0.370g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.187g)。
1H-NMR(DMSO-D6)δ:1.37-1.59(6H,m),1.65-1.97(5H,m),2.01-2.26(4H,m),2.53-2.66(1H,m),2.73-2.86 (1H,m),2.96-3.30(5H,m),4.07-4.27(1H,m),4.31-4.49(1H,m),4.63-4.80(1H,m),5.18-5.43(1H,m),7.91-8.12(3H,m),9.98(1H,br s),13.03(1H,br s).MS(m/z):459[M+H]+.
(4R)-4-氟-1-({1-[4-(羥甲基)-4-甲氧基哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
於(4-甲氧基哌啶-4-基)甲醇鹽酸鹽(9.83g)及飽和碳酸氫鈉水溶液(30.0mL)之混合物中,於室溫添加N-(苄氧基羰氧基)琥珀醯亞胺(12.4g)之1,4-二烷(50.0mL)溶液,並攪拌3日。將反應液以乙酸乙酯稀釋,依序以10%檸檬酸水溶液、飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣供予矽膠管柱層析(己烷/乙酸乙酯),獲得呈油狀物之標題化合物(9.46g)。
1H-NMR(CDCl3)δ:1.37-1.49(2H,m),1.82(2H,d,J=12.1Hz),3.08-3.32(2H,m),3.24(3H,s),3.44-3.57(2H,m),3.76-3.94(2H,m),5.13(2H,s),7.24-7.39(5H,m).
於上述步驟1獲得的化合物(7.55g)及咪唑(3.68g)之N,N-二甲基甲醯胺(30.0mL)溶液中,冰冷下添加三級丁基二甲基氯矽烷(3.99g),並於室溫攪拌21小時。將反應液以乙酸乙酯稀釋,依序以水及飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣供予矽膠管柱層析(己烷/乙酸乙酯),獲得呈油狀物之標題化合物(9.64g)。
1H-NMR(DMSO-D6)δ:0.04(6H,s),0.86(9H,s),1.32-1.44(2H,m),1.66(2H,d,J=13.3Hz),3.17(3H,s),3.31-3.34(2H,m),3.50(2H,s),3.76(2H,d,J=12.7Hz),5.06(2H,s),7.27-7.42(5H,m).
使用上述步驟2獲得的化合物(9.64g),藉由進行與實施例11之步驟4相同的操作,獲得呈油狀物之標題化合物(6.25g)。
1H-NMR(CDCl3)δ:0.05(6H,s),0.90(9H,s), 1.37-1.80(5H,m),2.76-2.94(4H,m),3.27(3H,s),3.51(2H,s).
使用1-溴環己烷-1-甲酸(2.00g)及上述步驟3獲得的化合物(3.26g),藉由進行與實施例9之步驟1相同的操作,獲得呈固體之標題化合物(0.777g)。
1H-NMR(DMSO-D6)δ:0.04(6H,s),0.87(9H,s),1.19-1.69(12H,m),1.76-1.88(2H,m),2.39(2H,t,J=10.2Hz),2.68(2H,d,J=10.2Hz),3.12(3H,s),3.47(2H,s).MS(m/z):384[M-H]-.
使用上述步驟4獲得的化合物(0.276g)及參考例3獲得的化合物(0.250g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之標題化合物(0.360g)。
1H-NMR(CDCl3)δ:0.06(6H,s),0.90(9H,s),1.30-1.79(24H,m),2.06-2.86(7H,m),3.24(3H,s),3.51(2H,s),4.78-4.94(1H,m),5.17-5.38(1H,m),8.17(1H,s),8.34-8.52(2H,m),8.75(1H,br s).MS(m/z):717[M+H]+.
將上述步驟5獲得的化合物(0.360g)之二氯甲烷(7.2mL)溶液冷卻至0℃,添加三氟乙酸(3.6mL),於室溫攪拌1小時。將反應混合物濃縮而將獲得的殘渣以乙腈(7.2mL)及水(1.8mL)稀釋,於0℃添加三氟乙酸(1.8mL),並於室溫攪拌1小時。將反應混合物濃縮至3分之1左右,以乙酸乙酯稀釋後,添加飽和碳酸氫鈉水溶液。以乙酸乙酯萃取,以無水硫酸鈉乾燥。將濃縮而獲得的殘渣以矽膠管柱層析(乙酸乙酯/甲醇)純化。於獲得的殘渣中添加二乙基醚,濾取生成的固體,乾燥,獲得呈固體之標題化合物(0.167g)。
1H-NMR(DMSO-D6)δ:1.03-1.17(1H,m),1.37-1.72(11H,m),1.84-2.06(2H,m),2.10-2.31(1H,m),2.37-2.70(4H,m),2.99-3.20(6H,m),3.32(2H,s),4.00-4.42(2H,m),5.15-5.38(1H,m),7.92-8.11(3H,m),10.01(1H,br s),13.03(1H,br s).MS(m/z):503[M+H]+.
1-{[1-(1-羥基-4-甲氧基環己基)環戊基]羰基}-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
使用實施例14之步驟1獲得的化合物(0.192g)及參考例4獲得的化合物(0.263g),藉由進行與實施例1之步驟6相同的操作,獲得呈固體之標題化合物(0.286g)。
1H-NMR(CDCl3)δ:1.37-2.18(29H,m),2.51-2.59(1H,m),3.02-3.08(1H,m),3.31-3.35(3H,m),3.59-3.64(1H,m),4.43-4.49(1H,m),4.73-4.79(1H,m),8.21(1H,s),8.41(1H,d,J=9.7Hz),8.49(1H,d,J=9.7Hz),9.11(1H,s).MS(m/z):556[M+H]+.
使用上述步驟1獲得的化合物(0.363g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.190g)。
1H-NMR(DMSO-D6)δ:1.22-1.89(17H,m),2.08-2.26(3H,m),2.94-3.01(1H,m),3.20(3H,s), 3.76-3.83(1H,m),3.87-3.94(1H,m),4.33-4.38(1H,m),4.59-4.64(1H,m),8.01(1H,d,J=9.1Hz),8.08-8.13(2H,m),10.48(1H,s),13.26(1H,s).MS(m/z):456[M+H]+.
(4R)-4-氟-1-[2-(1-羥基-4-甲氧基環己基)-2-甲基丙醯基]-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
氮氣環境下,將鋅粉末(3.17g)、氯三甲基矽烷(0.37mL)、N,N-二甲基甲醯胺(20mL)之混合物,於室溫攪拌10分鐘後,耗費1小時20分鐘添加2-溴-2-甲基丙酸苄酯(7.49g)及4-甲氧基環己酮(3.73g)之混合物。於室溫攪拌1小時後,添加冰、1mol/L鹽酸,以乙酸乙酯萃取。將有機層以飽和食鹽水洗淨,以無水硫酸鎂乾燥。減壓下餾除溶媒,將獲得的殘渣供予矽膠管柱層析(己烷/乙酸乙酯),獲得呈油狀物之標題化合物(3.73g)。
1H-NMR(CDCl3)δ:1.25(6H,s),1.40-1.50(2H,m),1.58-1.69(4H,m),1.81-1.87(2H,m),3.01-3.08(1H,m),3.23(1H,s),3.34(3H,s),5.15(2H,s),7.32-7.40(5H, m).
使用上述步驟1獲得的化合物(3.41g),藉由進行與實施例11之步驟4相同的操作,獲得呈油狀物之標題化合物(2.34g)。
1H-NMR(CDCl3)δ:1.26(6H,s),1.51-1.73(6H,m),1.90-1.96(2H,m),3.08-3.16(1H,m),3.37(3H,s).
使用上述步驟2獲得的化合物(0.303g)及參考例3獲得的化合物(0.400g),藉由進行與實施例1之步驟6相同的操作,獲得呈無色固體之標題化合物(0.305g)。
1H-NMR(CDCl3)δ:1.23-1.94(23H,m),2.21-2.39(1H,m),2.64(1H,t,J=16.0Hz),3.06-3.14(1H,m),3.33(3H,s),3.91-4.05(2H,m),4.72(1H,dd,J=24.8,12.7Hz),5.03(1H,d,J=9.1Hz),5.32(1H,d,J=52.0Hz),8.22(1H,s),8.41(1H,d,J=9.1Hz),8.57(1H,d,J=9.1Hz),9.63(1H,s).
使用上述步驟3獲得的化合物(0.305g),藉由進行與 實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.189g)。
1H-NMR(DMSO-D6)δ:1.14(3H,s),1.27(3H,s),1.33-1.78(9H,m),2.14-2.25(1H,m),2.95-3.04(1H,m),3.20(3H,s),4.02-4.17(1H,m),4.28-4.42(1H,m),4.73-4.80(2H,m),5.33(1H,d,J=53.8Hz),8.00-8.10(3H,m),10.09(1H,s),13.26(1H,s).MS(m/z):448[M+H]+.
(4R)-1-{[4,4-二氟-1-(4-羥基-4-甲基哌啶-1-基)環己基]羰基}-4-氟-N-1H-吡咯并[3,2-b]吡啶-5-基-D-脯胺醯胺
使用4-甲基-4-[(三乙基矽基)氧基]哌啶(0.236g)及1-溴-4,4-二氟環己烷甲酸(0.100g),藉由進行與實施例9之步驟1相同的操作,獲得呈固體之標題化合物 (0.0615g)。
1H-NMR(DMSO-D6)δ:0.54(6H,q,J=7.9Hz),0.92(9H,t,J=7.9Hz),1.20(3H,s),1.43-1.57(4H,m),1.68-1.89(4H,m),1.90-2.09(4H,m),2.54-2.64(4H,m).MS(m/z):392[M+H]+.
使用上述步驟1獲得的化合物(0.058g)及參考例5獲得的化合物(0.057g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之標題化合物(0.066g)。
1H-NMR(CDCl3)δ:0.57(6H,q,J=7.9Hz),0.95(9H,t,J=7.9Hz),1.25(3H,s),1.43-2.83(29H,m),4.70-4.92(1H,m),5.17-5.40(1H,m),6.56(1H,d,J=3.1Hz),7.77(1H,s),8.13-8.63(3H,m).MS(m/z):722[M+H]+.
使用上述步驟2獲得的化合物(0.066g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.038g)。
1H-NMR(DMSO-D6,100℃)δ:1.08(3H,s), 1.22-1.32(2H,m),1.45-1.57(4H,m),1.68-1.85(2H,m),1.87-2.71(11H,m),4.00-4.25(1H,m),4.29-4.50(1H,m),5.17-5.37(1H,m),6.36-6.40(1H,m),7.48-7.52(1H,m),7.72(1H,d,J=8.5Hz),7.77(1H,d,J=8.5Hz),9.70(1H,br s),10.94(1H,br s).MS(m/z):508[M+H]+.
(4R)-4-氟-1-({1-[4-羥基-4-(三氟甲基)哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
將1-苄氧基羰基-4-哌啶酮(3.08g)之四氫呋喃(10mL)溶液冷卻至0℃後,添加三乙基(三氟甲基)矽烷(3.23mL)及氟化四丁基銨(1mol/L,四氫呋喃溶液,0.066mL),並攪拌1小時。將反應混合物濃縮,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(2.00g)。
1H-NMR(CDCl3)δ:0.66(6H,q,J=7.9Hz),0.96(9H,t,J=7.9Hz),1.65-1.81(4H,m),3.01-3.19(2H,m), 3.99-4.21(2H,m),5.08-5.18(2H,m),7.30-7.41(5H,m).MS(m/z):418[M+H]+.
使用上述步驟1獲得的化合物(1.90g),藉由進行與實施例8之步驟4相同的操作,獲得呈油狀物之標題化合物(1.20g)。
1H-NMR(CDCl3)δ:0.66(6H,q,J=7.9Hz),0.97(9H,t,J=7.6Hz),1.65-1.73(4H,m),2.90-2.97(4H,m).
使用上述步驟2獲得的化合物(1.20g)及1-溴環己烷甲酸(0.450g),藉由進行與實施例9之步驟1相同的操作,獲得呈固體之標題化合物(0.674g)。
1H-NMR(DMSO-D6)δ:0.61(6H,q,J=7.9Hz),0.93(9H,t,J=7.9Hz),1.21-1.42(4H,m),1.46-1.76(8H,m),1.76-1.87(2H,m),2.36-2.47(2H,m),2.82-2.92(2H,m),12.24(1H,br s).MS(m/z):410[M+H]+.
使用上述步驟3獲得的化合物(0.300g)及參考例3獲得的化合物(0.256g),藉由進行與實施例1之步驟6 相同的操作,獲得呈固體之標題化合物(0.299g)。
1H-NMR(CDCl3)δ:0.64(6H,q,J=7.9Hz),0.94(9H,t,J=7.9Hz),1.04-1.21(1H,m),1.31-1.97(23H,m),2.01-2.47(2H,m),2.51-2.97(4H,m),4.01-4.28(1H,m),4.63-4.96(1H,m),5.20-5.43(1H,m),8.15(1H,s),8.35-8.52(2H,m),8.60(1H,br s).MS(m/z):741[M+H]+.
使用上述步驟4獲得的化合物(0.290g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.168g)。
1H-NMR(DMSO-D6,100℃)δ:1.03-1.19(1H,m),1.34-1.83(11H,m),1.89-2.08(2H,m),2.11-2.27(1H,m),2.35-2.59(3H,m),2.65-2.75(1H,m),2.77-2.89(1H,m),4.13-4.36(2H,m),4.95(1H,br s),5.14-5.45(2H,m),7.95(1H,d,J=8.5Hz),7.99-8.07(2H,m),9.86(1H,br s),12.93(1H,br s).MS(m/z):527[M+H]+.
(4R)-4-氟-1-({1-[4-(2-羥基丙烷-2-基)-4-甲氧基哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
氮氣環境下,將氫化鈉(純度55%,8.10g)之N,N-二甲基甲醯胺(100mL)懸浮液冰冷,於其中滴加1-苄基-4-羥基哌啶-4-甲酸乙酯(Bioorg.Med.Chem.,24,1384-1391(2016);20.8g)之四氫呋喃(100mL)溶液,於相同溫度攪拌1小時。接著,滴加碘甲烷(5.44mL),於室溫攪拌24小時。將反應液注入冰水中,攪拌後,以乙酸乙酯萃取。將獲得的有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣供予胺基矽膠管柱層析(己烷/乙酸乙酯),獲得含標題化合物(8.86g)的混合物。
氮氣環境下,於上述步驟1獲得的化合物(4.00g)之四氫呋喃(50.0mL)溶液中,於0℃滴加溴化甲鎂(0.910mol/L,四氫呋喃溶液,47.5mL)而於相同溫度攪拌1.5小時。於反應液中添加飽和氯化銨水溶液而使反應停 止後,以乙酸乙酯萃取。將獲得的有機層以水及飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣供予胺基矽膠管柱層析(己烷/乙酸乙酯),獲得呈油狀物之標題化合物(2.16g)。
1H-NMR(CDCl3)δ:1.23(6H,s),1.59-1.63(1H,m),1.71(2H,td,J=13.1,4.0Hz),1.79-1.86(2H,m),2.11-2.21(2H,m),2.69-2.77(2H,m),3.46(3H,s),3.50(2H,s),7.21-7.37(5H,m).
於上述步驟2獲得的化合物(2.16g)、2,6-二甲吡啶(1.91mL)、及二氯甲烷(20.0mL)之混合物中,冰冷下滴加三氟甲磺酸三乙基矽基酯(2.22mL),於相同溫度攪拌1小時。將反應液以二氯甲烷稀釋,以水及飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣懸浮於己烷,攪拌後,濾取不溶物而獲得呈固體之標題化合物(3.27g)。
1H-NMR(DMSO-D6)δ:0.58(6H,q,J=8.0Hz),0.92(8H,t,J=8.0Hz),1.17(6H,s),1.71-1.84(2H,m),1.96(2H,d,J=14.0Hz),2.99(2H,q,J=11.1Hz),3.23(2H,d,J=11.5Hz),3.34(3H,s),4.33(2H,d,J=5.5Hz),7.45-7.55(5H,m),8.99(1H,br s).
使用上述步驟3獲得的化合物(3.00g),藉由進行與實施例11之步驟4相同的操作,獲得呈固體之標題化合物(1.60g)。
1H-NMR(CDCl3)δ:0.61(6H,q,J=7.9Hz),0.96(9H,t,J=7.9Hz),1.22(6H,s),1.60-1.70(2H,m),1.84-1.92(2H,m),2.72-3.04(5H,m),3.41(3H,s).
使用上述步驟4獲得的化合物(1.60g)及1-溴環己烷甲酸(0.570g),藉由進行與實施例9之步驟1相同的操作,獲得呈固體之標題化合物(0.520g)。
1H-NMR(CD3OD)δ:0.67(6H,q,J=7.9Hz),0.99(9H,t,J=7.9Hz),1.13-1.24(1H,m),1.27(6H,s),1.46-1.57(2H,m),1.62-1.82(5H,m),1.90-2.01(2H,m),2.07-2.16(2H,m),2.25-2.33(2H,m),3.10-3.21(2H,m),3.34-3.41(2H,m),3.42(3H,s).MS(m/z):414[M+H]+.
使用上述步驟5獲得的化合物(0.250g)及參考例3獲得的化合物(0.211g),藉由進行與實施例1之步驟6相同的操作,獲得呈固體之標題化合物(0.210g)。
1H-NMR(CDCl3)δ:0.61(6H,q,J=7.9Hz),0.96(9H,t,J=7.9Hz),1.06-1.28(7H,m),1.40-1.94(24H,m),1.98-2.25(2H,m),2.44-2.80(4H,m),3.38(3H,s),4.75-4.97(1H,m),5.18-5.39(1H,m),8.16(1H,s),8.36-8.55(2H,m),8.74(1H,br s).
使用上述步驟6獲得的化合物(0.200g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.110g)。
1H-NMR(DMSO-D6,100℃)δ:1.01-1.17(7H,m),1.37-1.80(11H,m),1.88-2.07(2H,m),2.13-2.28(1H,m),2.34-2.53(3H,m),2.54-2.66(1H,m),2.69-2.81(1H,m),3.32(3H,s),3.73(1H,br s),4.13-4.47(2H,m),4.82-5.12(1H,m),5.16-5.37(1H,m),7.91-8.09(3H,m),9.80(1H,br s),12.93(1H,br s).MS(m/z):531[M+H]+.
N2-[2-(4-甲氧基哌啶-1-基)-2-甲基丙醯基]-N2-甲基-N-1H-吡咯并[2,3-b]吡啶-6-基-D-丙胺醯胺
將2-溴-2-甲基丙酸苄酯(2.00g)、4-甲氧基哌啶(1.34g)、碳酸鉀(3.23g)、丙酮(30mL)之混合物於60℃攪拌18小時。過濾不溶物,將濾液濃縮而將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(1.29g)。
1H-NMR(CDCl3)δ:1.32(6H,s),1.48-1.60(2H,m),1.83-1.91(2H,m),2.22-2.30(2H,m),2.77-2.85(2H,m),3.10-3.18(1H,m),3.31(3H,s),5.16(2H,s),7.29-7.40(5H,m).
使用上述步驟1獲得的化合物(1.29g),藉由進行與實施例11之步驟4相同的操作,獲得呈固體之標題化合物(0.861g)。
1H-NMR(DMSO-D6)δ:1.24(6H,s),1.66-1.76(2H,m),1.93-2.01(2H,m),2.72-2.80(2H,m),2.93-3.01(2H,m),3.23(3H,s),3.31-3.38(1H,m).
使用上述步驟2獲得的化合物(0.300g)及(2R)-2-(甲基胺基)丙酸苄酯(0.360g),藉由進行與實施例1之步驟6相同的操作,獲得呈油狀物之標題化合物(0.417g)。
1H-NMR(CDCl3)δ:1.21(3H,d,J=7.5Hz),1.23(3H,d,J=7.5Hz),1.39-1.49(2H,m),1.42(3H,d,J=7.1Hz),1.76-1.86(2H,m),2.15-2.27(2H,m),2.65-2.75(2H,m),3.06-3.15(1H,m),3.31(3H,s),3.46(3H,s),4.82(1H,q,J=7.1Hz),5.08-5.17(2H,m),7.29-7.38(5H,m).
使用上述步驟3獲得的化合物(0.417g),藉由進行與實施例11之步驟4相同的操作,獲得呈固體之標題化合物(0.311g)。
1H-NMR(DMSO-D6)δ:1.09-1.17(6H,m),1.23-1.44(5H,m),1.78-1.89(2H,m),2.13-2.23(2H,m),2.56-2.75(5H,m),3.06-3.18(1H,m),3.17-3.22(3H,m),4.50-4.60(1/2H,m),6.35-6.43(1/2H,m).
於上述步驟4獲得的化合物(0.310g)、1H-吡咯并 [2,3-b]吡啶-6-胺(0.360g)、吡啶(5mL)之混合物中添加氧氯化磷(0.198mL),於相同溫度攪拌1小時。將反應液以乙酸乙酯稀釋,以水、飽和食鹽水洗淨後,將有機層以無水硫酸鎂乾燥。減壓下餾除溶媒,將獲得的殘渣供予矽膠管柱層析(己烷/乙酸乙酯),獲得呈固體之標題化合物(0.171g)。
1H-NMR(DMSO-D6,100℃)δ:1.20(6H,s),1.39-1.49(5H,m),1.78-1.85(2H,m),2.19-2.29(2H,m),2.61-2.70(2H,m),2.99(3H,s),3.06-3.32(5H,m),6.37(1H,s),7.24-7.27(1H,m),7.71(1H,d,J=8.5Hz),7.87(1H,d,J=8.5Hz),9.29(1H,s),11.06(1H,s).MS(m/z):402[M+H]+.
(4R)-1-{[(1’r,4’R)-4,4-二氟-4’-甲氧基-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
於4-苄氧基苯基溴化鎂(1.0mol/L,四氫呋喃溶液,99.8mL)中,冰冷下滴加4,4-二氟環己酮(12.0g)之四氫呋喃(30mL)溶液,一邊緩緩回到室溫一邊攪拌1小時。冰冷下,於反應液中添加1mol/L鹽酸(100mL),於室溫攪拌後,以乙酸乙酯萃取。將獲得的有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣供予矽膠管柱層析(己烷/乙酸乙酯),獲得呈固體之標題化合物(21.3g)。
1H-NMR(DMSO-D6)δ:1.68-1.78(2H,m),1.83-1.97(4H,m),2.06-2.31(2H,m),5.09(3H,s),6.95(2H,dt,J=9.2,3.1Hz),7.30-7.45(7H,m).
於包含溴化銦(III)(2.37g)、三甲基矽氰(trimethylsilylcyanide)(17.3mL)、及二氯甲烷(100mL)的混合物中,冰冷下,滴加上述步驟1獲得的化合物(21.3g)之二氯甲烷(100mL)溶液,一邊緩緩回到室溫一邊攪拌1.5小時。將反應液以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨後,以無水硫酸鈉乾燥。減壓下餾除溶媒,將獲得的殘渣懸浮於包含二乙基醚/己烷的混合溶媒,攪拌後,濾取不溶物,獲得呈固體之標題化合物(15.1g)。
1H-NMR(DMSO-D6)δ:1.91-2.38(8H,m),5.13(2H,s),7.08(2H,d,J=9.2Hz),7.38-7.44(7H,m).
於氫氧化鉀(21.4g)之乙二醇(125mL)溶液中,添加上述步驟2獲得的化合物(12.5g),並於200℃攪拌1小時。於反應混合物中添加35%鹽酸(35mL),作成酸性後,以水稀釋,濾取生成的固體,乾燥,獲得呈固體之標題化合物(13.0g)。
1H-NMR(DMSO-D6)δ:1.78-2.09(6H,m),2.32-2.48(2H,m),5.09(2H,s),7.00(2H,d,J=8.5Hz),7.28-7.48(7H,m),12.72(1H,br s).
使用上述步驟3獲得的化合物(10.0g),藉由進行與實施例11之步驟4相同的操作,獲得呈固體之標題化合物(6.51g)。
1H-NMR(DMSO-D6)δ:1.75-2.07(6H,m),2.27-2.58(2H,m),6.73(2H,d,J=8.5Hz),7.21(2H,d,J=8.5Hz),9.42(1H,br s),12.66(1H,br s).
於上述步驟4獲得的化合物(3.00g)之乙醇(60mL)溶液中添加銠-氧化鋁(3.00g),氫氣環境下,於60℃攪拌6小時。冷卻至室溫後,使用乙醇而進行矽藻土過濾。將濾液濃縮,獲得呈固體之作為順式體及反式體之混合物的粗生成物之標題化合物(3.30g)。
於上述步驟5獲得的化合物(2.70g)之N,N-二甲基甲醯胺(27mL)溶液中,添加碳酸鉀(2.80g)及溴甲苯(1.8mL),室溫下,攪拌5小時。於反應混合物中添加二乙基醚,依序以水、1mol/L鹽酸、飽和食鹽水洗淨後,以無水硫酸鈉乾燥。將濃縮而獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,各自獲得呈固體之順式體之標題化合物(2.10g)、呈固體之反式體之標題化合物(0.973g)。
1H-NMR(CDCl3)δ:1.08-1.12(1H,m),1.35-1.50(7H,m),1.53-1.85(6H,m),1.94-2.06(2H,m),2.16-2.25(2H,m),3.98-4.04(1H,m),5.16(2H,s),7.30-7.41(5H,m).MS(m/z):335[M+H-H2O]+.
1H-NMR(CDCl3)δ:0.97-1.28(4H,m),1.34-1.46(2H,m),1.49-1.60(2H,m),1.61-1.82(4H,m),1.91-2.06(4H,m),2.14-2.24(2H,m),3.37-3.49(1H,m),5.15(2H,s),7.30-7.42(5H,m).MS(m/z):335[M+H-H2O]+.
於上述步驟6獲得的反式體化合物(0.400g)及氧化 銀(2.10g)之乙腈(12mL)懸浮液中,添加碘甲烷(1.4mL),於室溫攪拌60小時。進一步添加碘甲烷(1.4mL)及氧化銀(2.10g),並於50℃攪拌8小時。將反應混合物冷卻至室溫後,以矽藻土過濾,並將濾液濃縮。將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈固體之標題化合物(0.366g)。
1H-NMR(CDCl3)δ:0.94-1.16(4H,m),1.37-1.82(7H,m),1.93-2.10(4H,m),2.14-2.24(2H,m),2.88-3.01(1H,m),3.31(3H,s),5.16(2H,s),7.31-7.42(5H,m).
使用上述步驟7獲得的化合物(0.360g),藉由進行與實施例8之步驟4相同的操作,獲得呈固體之標題化合物(0.265g)。
1H-NMR(CDCl3)δ:1.05-1.24(4H,m),1.41-1.64(3H,m),1.72-1.94(4H,m),1.98-2.24(6H,m),3.01-3.11(1H,m),3.34(3H,s).MS(m/z):275[M-H]-.
將上述步驟8獲得的化合物(0.208g)之四氫呋喃(4mL)溶液冷卻至0℃後,添加1-氯-N,N,2-三甲基-1-丙烯基胺(0.149mL),並於室溫攪拌30分鐘。再度冷卻至 0℃後,添加參考例3獲得的化合物(0.342g)之四氫呋喃(4mL)溶液及三乙基胺(0.160mL),於室溫攪拌16小時。將反應混合物以乙酸乙酯稀釋,依序以水及飽和食鹽水洗淨。將有機層以無水硫酸鈉乾燥,過濾、濃縮,將獲得的殘渣以矽膠管柱層析(乙酸乙酯/甲醇)純化,獲得呈固體之標題化合物(0.277g)。
1H-NMR(CDCl3)δ:1.09-1.30(4H,m),1.51-2.47(23H,m),2.62-2.76(1H,m),3.00-3.12(1H,m),3.32(3H,s),3.81-3.98(1H,m),4.14-4.28(1H,m),4.89-4.98(1H,m),5.30-5.51(1H,m),8.18(1H,s),8.38-8.49(2H,m),8.72(1H,br s).MS(m/z):608[M+H]+.
於上述步驟9獲得的化合物(0.275g)之甲醇(15mL)溶液中,添加碳酸鉀(0.125g),室溫下,攪拌2小時。將反應混合物濃縮,分配於飽和氯化銨水溶液及乙酸乙酯。將有機層以飽和食鹽水洗淨後,以無水硫酸鈉乾燥。將濃縮而獲得的殘渣供予矽膠管柱層析(乙酸乙酯/甲醇),獲得呈固體之標題化合物(0.216g)。
1H-NMR(CDCl3)δ:1.11-1.34(4H,m),1.55-2.50(14H,m),2.55-2.69(1H,m),3.03-3.14(1H,m),3.34(3H,s),3.84-4.03(1H,m),4.13-4.29(1H,m),4.86-4.98(1H,m),5.27-5.49(1H,m),7.76(1H,d,J=9.2Hz),8.07(1H, s),8.25(1H,d,J=9.2Hz),8.54(1H,s),10.74(1H,br s).MS(m/z):508[M+H]+.
(4R)-1-{[(1’s,4’S)-4,4-二氟-4’-甲氧基-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
使用實施例27之步驟6獲得的順式體化合物(0.400g),藉由進行與實施例1之步驟4相同的操作,獲得呈油狀物之標題化合物(0.340g)。
1H-NMR(CDCl3)δ:1.21-1.82(11H,m),1.92-2.05(4H,m),2.12-2.20(2H,m),3.25(3H,s),3.38-3.42(1H,m),5.15(2H,s),7.30-7.40(5H,m).
使用上述步驟1獲得的化合物(0.330g),藉由進行與 實施例8之步驟4相同的操作,獲得呈固體之標題化合物(0.253g)。
1H-NMR(CDCl3)δ:1.25-1.65(9H,m),1.73-2.10(6H,m),2.13-2.23(2H,m),3.29(3H,s),3.43-3.48(1H,m).
使用上述步驟2獲得的化合物(0.150g)及參考例3獲得的化合物(0.247g),藉由進行與實施例27之步驟9相同的操作,獲得呈固體之標題化合物(0.207g)。
1H-NMR(CDCl3)δ:1.18-2.39(27H,m),2.56-2.69(1H,m),3.17(3H,s),3.33-3.39(1H,m),3.76-3.93(1H,m),4.05-4.20(1H,m),4.84-4.92(1H,m),5.22-5.42(1H,m),8.10(1H,s),8.29-8.41(2H,m),8.62(1H,br s).MS(m/z):608[M+H]+.
使用上述步驟3獲得的化合物(0.200g),藉由進行與實施例27之步驟10相同的操作,獲得呈固體之標題化合物(0.116g)。
1H-NMR(CDCl3)δ:1.23-2.49(18H,m),2.55-2.69 (1H,m),3.25(3H,s),3.41-3.48(1H,m),3.86-4.04(1H,m),4.11-4.27(1H,m),4.88-4.98(1H,m),5.27-5.49(1H,m),7.76(1H,d,J=9.2Hz),8.06(1H,s),8.26(1H,d,J=9.2Hz),8.52(1H,br s),10.62(1H,br s).MS(m/z):508[M+H]+.
(4R)-1-{[(1’r,4’R)-4’-(二氟甲氧基)-4,4-二氟-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
於實施例27之步驟6獲得的反式體化合物(0.300g)與碘化銅(I)(0.081g)之乙腈(6mL)溶液中,氮氣環境下,於50℃,耗費1小時滴加2,2-二氟-2-(氟磺醯基)乙酸(0.186mL)之乙腈(3mL)溶液。於相同溫度攪拌1小時後,冷卻至室溫。將反應混合物濃縮,將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈固體之標題化合 物(0.271g)。
1H-NMR(CDCl3)δ:0.97-1.11(2H,m),1.24-1.59(5H,m),1.61-1.81(4H,m),1.93-2.05(4H,m),2.15-2.24(2H,m),3.81-3.91(1H,m),5.16(2H,s),6.19(1H,t,J=75.4Hz),7.31-7.42(5H,m).
使用上述步驟1獲得的化合物(0.250g),藉由進行與實施例8之步驟4相同的操作,獲得呈固體之標題化合物(0.199g)。
1H-NMR(CDCl3)δ:1.12-1.29(2H,m),1.35-1.53(3H,m),1.54-1.66(2H,m),1.74-1.95(4H,m),1.99-2.24(6H,m),3.95-4.05(1H,m),6.22(1H,t,J=75.1Hz).MS(m/z):311[M-H]-.
使用上述步驟2獲得的化合物(0.160g)及參考例3獲得的化合物(0.233g),藉由進行與實施例27之步驟9相同的操作,獲得呈固體之標題化合物(0.248g)。
1H-NMR(CDCl3)δ:1.18-1.32(2H,m),1.37-1.89(17H,m),1.91-2.48(8H,m),2.62-2.74(1H,m),3.80-4.06(2H,m),4.16-4.29(1H,m),4.88-4.96(1H,m), 5.32-5.50(1H,m),6.21(1H,t,J=75.4Hz),8.18(1H,s),8.37-8.49(2H,m),8.56(1H,br s).MS(m/z):644[M+H]+.
使用上述步驟3獲得的化合物(0.240g),藉由進行與實施例27之步驟10相同的操作,獲得呈固體之標題化合物(0.167g)。
1H-NMR(CDCl3)δ:1.20-1.33(2H,m),1.37-1.93(8H,m),1.98-2.50(8H,m),2.56-2.69(1H,m),3.83-4.06(2H,m),4.16-4.28(1H,m),4.88-4.95(1H,m),5.31-5.49(1H,m),6.22(1H,t,J=75.3Hz),7.80(1H,d,J=9.1Hz),8.08(1H,s),8.30(1H,d,J=9.1Hz),8.48(1H,br s),10.52(1H,br s).MS(m/z):544[M+H]+.
(4R)-1-{[4,4-二氟-4’-羥基-4’-(三氟甲基)-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
於實施例27之步驟6獲得的順式體化合物(0.500g)之二氯甲烷(20mL)溶液中,添加戴斯-馬丁氧化劑(Dess-Martin Periodinane)(0.722g),並於室溫下攪拌30分鐘。於反應混合物中添加飽和硫代硫酸鈉水溶液,攪拌20分鐘後,添加飽和碳酸氫鈉水溶液,以乙酸乙酯萃取。將有機層依序以飽和碳酸氫鈉水溶液及飽和食鹽水洗淨,以無水硫酸鈉乾燥,過濾、濃縮。將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈固體之標題化合物(0.495g)。
1H-NMR(CDCl3)δ:1.36-1.50(2H,m),1.54-2.09(9H,m),2.15-2.41(6H,m),5.17(2H,s),7.29-7.42(5H,m).
使用上述步驟1獲得的化合物(0.450g),藉由進行與實施例24之步驟1相同的操作,獲得呈油狀物之標題化合物(0.505g)。
1H-NMR(CDCl3)δ:0.54-0.68(6H,m),0.87-1.00(9H,m),1.21-2.08(13H,m),2.14-2.28(4H,m),5.15(2H,s),7.31-7.42(5H,m).
使用上述步驟2獲得的化合物(0.500g),藉由進行與實施例8之步驟4相同的操作,獲得呈固體之標題化合物(0.414g)。
1H-NMR(CDCl3)δ:0.00-0.15(6H,m),0.36-0.46(9H,m),0.84-1.80(17H,m).MS(m/z):443[M-H]-
使用上述步驟3獲得的化合物(0.200g)及參考例3獲得的化合物(0.204g),藉由進行與實施例27之步驟9相同的操作,獲得呈固體之標題化合物(0.119g)。
1H-NMR(CDCl3)δ:0.47-0.59(6H,m),0.79-0.93(9H,m),1.33-1.79(20H,m),1.87-2.42(7H,m),2.55-2.69(1H,m),3.75-3.92(1H,m),4.06-4.20(1H,m),4.81-4.90(1H,m),5.25-5.44(1H,m),8.10(1H,s),8.31-8.42(2H,m),8.55(1H,br s).MS(m/z):776[M+H]+.
使用上述步驟4獲得的化合物(0.110g),藉由進行與實施例1之步驟7相同的操作,獲得呈固體之標題化合物(0.061g)。
1H-NMR(CDCl3)δ:1.39-2.50(18H,m),2.57-2.70(1H,m),3.81-4.00(1H,m),4.16-4.33(1H,m),4.87-4.97(1H,m),5.30-5.52(1H,m),7.83(1H,d,J=9.2Hz),8.10(1H,s),8.34(1H,d,J=9.2Hz),8.44(1H,s),10.34(1H,br s).MS(m/z):562[M+H]+.
(4R)-1-{[(1’r,4’R)-4,4-二氟-4’-(三氟甲氧基)-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺
於實施例27之步驟6獲得的反式體化合物(0.352g)、三氟甲磺酸銀(0.385g)、N-氟-N’-(氯甲基)三乙二胺雙(四氟硼酸鹽)(0.265g)、氟化鉀(0.116g)、2-氟吡啶(0.13mL)之乙酸乙酯(2.5mL)懸浮液中,添加(三氟甲基)三甲基矽烷(0.23mL),並於室溫攪拌16小時。將反應混合物以乙酸乙酯稀釋後,進行矽藻土過濾,並將濾液濃縮。將獲得的殘渣以矽膠管柱層析(己烷/乙酸乙酯)純化,獲得呈油狀物之標題化合物(0.0770g)。
1H-NMR(CDCl3)δ:0.96-1.11(2H,m),1.24-1.45(3H,m),1.47-1.59(2H,m),1.61-1.82(4H,m),1.93-2.11(4H,m),2.15-2.25(2H,m),3.86-3.97(1H,m),5.16(2H,s),7.32-7.42(5H,m).
使用上述步驟1獲得的化合物(0.075g),藉由進行與實施例8之步驟4相同的操作,獲得呈固體之標題化合物(0.059g)。
1H-NMR(CDCl3)δ:1.13-1.30(2H,m),1.38-1.65(5H,m),1.72-1.95(4H,m),1.97-2.24(6H,m),4.02-4.12(1H,m).
使用上述步驟2獲得的化合物(0.055g)及參考例3獲得的化合物(0.087g),藉由進行與實施例27之步驟9相同的操作,獲得呈固體之標題化合物(0.080g)。
1H-NMR(CDCl3)δ:1.17-1.34(2H,m),1.42-1.91(17H,m),1.92-2.50(8H,m),2.60-2.75(1H,m),3.78-3.96(1H,m),4.03-4.15(1H,m),4.16-4.30(1H,m),4.86-4.97(1H,m),5.31-5.52(1H,m),8.17(1H,s),8.37-8.59(3H,m).MS(m/z):662[M+H]+.
使用上述步驟3獲得的化合物(0.075g),藉由進行與實施例27之步驟10相同的操作,獲得呈固體之標題化合物(0.057g)。
1H-NMR(CDCl3)δ:1.19-1.35(2H,m),1.41-1.95(8H,m),1.97-2.51(8H,m),2.56-2.70(1H,m),3.80-4.00(1H,m),4.03-4.30(2H,m),4.85-4.96(1H,m),5.31-5.50(1H,m),7.81(1H,d,J=9.2Hz),8.08(1H,s),8.32(1H,d,J=9.2Hz),8.45(1H,s),10.44(1H,br s).MS(m/z):562[M+H]+.
將1.5重量%之實施例化合物,於10容量%之丙二 醇中攪拌,接著,以注射用水調整為一定容量後,滅菌而作成注射劑。
將100mg之粉末狀實施例化合物、128.7mg之乳糖、70mg之纖維素及1.3mg之硬脂酸鎂混合,通過60篩目之篩後,將獲得的粉末置入250mg之3號明膠膠囊,作成膠囊劑。
將100mg之粉末狀實施例化合物、124mg之乳糖、25mg之纖維素及1mg之硬脂酸鎂混合,藉由打錠機打錠,作成1錠250mg之錠劑。此錠劑因應需要可施予糖衣。
本發明之化合物之藥理活性係藉由以下之試驗確認。
將包含不同濃度之實施例1~31之化合物的10μL反應液(50mM Tris-HCl(pH8.0),0.1mM EDTA,1mM二硫蘇糖醇,0.01%Tween-20,0.01%牛血清白蛋白,330nM曲古黴素A(trichostatin A),2μM乙醯輔酶A(Acetyl-CoA)(Sigma-Aldrich,#A2056),100nM組蛋白H4(1-25)-GSGSK(生物素)(Anaspec,#65242-1),1% 二甲基亞碸,10-0.0006μM化合物,50ng/mL EP300或125ng/mL CREBBP),添加於384-孔盤之各孔,並於28℃培養1小時。之後,於各孔中各添加5μL之溶解於LANCE偵測緩衝液(PerkinElmer,#CR97-100)的10μM Lys-CoA(第一三共股份有限公司),進一步於各孔中各添加5μL之包含0.5nM Eu-anti pan-Ac(PerkinElmer,#TRF0412)及12.5nM之Sta-Ulight(PerkinElmer,#TRF0102)的LANCE偵測緩衝液後,於室溫培養一晚。以EnVision(PerkinElmer,2104-0020型),測定ULight訊號(665nm)。基於測定的ULight訊號,測定各濃度下的實施例1~31之化合物的酵素抑制率,將獲得的資料以醫療統計解析軟體GraphPad Prism(GraphPad Software,Inc.)解析而算出IC50值。EP300及CREBBP係由DAIICHI SANKYO RD NOVARE股份有限公司生產及純化。
將源自人類肺扁平上皮癌的LK2細胞,以40000個細胞/100μL/孔而接種於96孔盤,於37℃、5%CO2下培養一晚。LK2細胞係購自Human Science Research Resources Bank。之後,添加實施例1~31之化合物溶液11μL(二甲基亞碸之最終濃度為0.1%),於37℃、5%CO2下培養6小時。丟棄上清液,添加4%聚甲醛(paraformaldehyde)以使其成為100μL/孔,於室溫靜置15分鐘。丟棄4%聚甲醛,以TBS-T洗淨。添加淬滅緩衝液(Quenching buffer)(含有1%H2O2的PBS-T)以使其 成為100μL/孔,於室溫靜置10分鐘。以PBS-T洗淨後,添加封阻緩衝液(Blocking Buffer)(StartingBlocK T20(TBS)Blocking Buffer(Thermo SCIENTIFIC,#37543))200μL/孔,於室溫靜置1小時。丟棄上清液,添加50μL/孔之以封阻緩衝液稀釋的乙醯化組蛋白H3(Acetyl-Histone H3)(Lys27)(D5E4)XP(註冊商標)兔mAb(Cell Signaling,#8173),於4℃培養一晚。以PBS-T洗淨後,添加50μL/孔之以封阻緩衝液稀釋的抗兔IgG-HRP(Cell Signaling,#7074S),於室溫培養1小時。以PBS-T洗淨後,添加50μL/孔之SuperSignalTMELISA Pico Chemiluminescent Substrate(Thermo SCIENTIFIC,#37069),以EnVision測定訊號(425nm)。基於測定的訊號,測定各濃度下的實施例1~31之化合物的酵素抑制率,將獲得的資料以醫療統計解析軟體GraphPad Prism(GraphPad Software,Inc.)解析而算出IC50值。
作為各細胞之培養用培養基,使用添加10%FBS的RPMI1640培養基(LK-2細胞,源自人類食道癌之TE-8細胞)。LK2細胞係購自Human Science Research Resources Bank,TE-8細胞係購自理化學研究所細胞開發銀行。藉由Freedom EVO 150(Tecan Trading AG)而稀釋調製實施例1~31之化合物(4倍稀釋,10階段,10mM -38nM)。使用Echo555(Labcyte Inc.),於384孔盤(Corning,#3712)中以成為40nL/孔的方式添加於各孔。 於該盤中接種LK2或TE-8細胞以使其成為400個細胞/40μL/孔(第0日),培養3日。於化合物添加當日(第0日)及化合物添加3日後(第3日),於各孔中各添加10μL/孔之為ATP測定用試藥的CellTiter-GloTM2.0 Assay(Promega,#G9242),以EnVision測定各孔之發光量。由化合物添加當日之發光量(C0)、培養3日後之化合物非添加組(C3)及化合物添加組(T3)之發光量,基於下式算出細胞生存率。
細胞生存率(%)=(T3-C0)/(C3-C0)×100
各化合物之將TE-8及LK-2細胞之增殖抑制50%的濃度(GI50值)係將各濃度下的細胞生存率及化合物濃度進行半對數作圖而算出。
將試驗例1至3之結果示於表1。
將源自人類nut中線癌(NUT midline carcinoma)之NMC10-15細胞以5×106個細胞/頭之比率,移植至雌性BALB/c-nu/nu小鼠之右側腹部皮下,8日後基於推定腫瘤體積(長徑×短徑×短徑/2)及體重,進行分組使各組各為5隻。NMC10-15細胞係讓渡自布萊根婦女醫院(The Brigham and Women’s Hospital,Inc.)。雌性BALB/c-nu/nu小鼠係購自Charles River Japan股份有限公司。自分組當日起,將實施例29之化合物以2mg/kg/日的用量設定,或者將實施例31之化合物以0.5mg/kg/日的用量設定,而以1日1次,連續投予7日(QD×7)之預定計畫進行經口投予。自分組日起至移植15日後(試驗結束日)為止,測定每個個體的推定腫瘤體積。
試驗例4之對NMC10-15細胞皮下移植模式的抗腫瘤活性係於各自之試驗結束日藉由下式算出。
腫瘤增殖抑制率%=(1-TVCt/TVCc)×100
TVC=(試驗結束日之每個個體的腫瘤體積)-(分組日之每個個體的腫瘤體積)
TVCt:投藥組之TVC平均值
TVCc:非投藥組之TVC平均值
將試驗例4之結果示於表2。
本發明之通式(1)所表示的化合物或其藥理上可容許的鹽因具有優異的EP300/CREBBP之組蛋白乙醯基轉移酶抑制活性,而有用於作為對腫瘤的治療藥。具體而言,本發明之通式(1)所表示的化合物或其藥理上可容許的鹽係有用於作為腫瘤之治療藥,較佳係作為前列腺癌、肝癌、肺癌、乳癌、大腸癌、胃癌、血液癌、胰臟癌、食道癌、膀胱癌、胃腸道基質瘤、NUT中線癌、或卵巢癌之治療藥,更佳係作為前列腺癌、肺癌、血液癌、食道癌、NUT中線癌之治療藥。
Claims (22)
- 一種下述通式(1)所表示的化合物或其藥理上可容許的鹽,
- 如請求項1之化合物或其藥理上可容許的鹽,其中環Q 1表示下述式(2A)至(2F)之任一者:
- 如請求項1之化合物或其藥理上可容許的鹽,其中環Q 1表示下述式(3A)至(3E)之任一者:
- 如請求項1至3中任一項之化合物或其藥理上可容許的鹽,其中環Q 2係可具有1個或2個獨立選自包含羥基、氟原子、氯原子、氰基、甲基、甲氧基、及苄氧基的群組的取代基的苯基。
- 如請求項1至3中任一項之化合物或其藥理上可容許的鹽,其中環Q 2表示下述式(4A)或(4B):
- 如請求項1至3中任一項之化合物或其藥理上可容許的鹽,其中環Q 2表示下述式(5A)至(5D)之任一者:
- 如請求項1至6中任一項之化合物或其藥理上可容許的鹽,其中R 1及R 2係各自獨立為甲基。
- 如請求項1至6中任一項之化合物或其藥理上可容許的鹽,其中R 1及R 2係與R 1及R 2所鍵結的碳原子一起,形成環丁烷環、3,3-二鹵環丁烷環、3,3-二C 1-6烷基環丁烷環、環戊烷環、環己烷環、4,4-二鹵環己 烷環、四氫哌喃環、環庚烷環、或螺[3.3]庚烷環。
- 如請求項1至6中任一項之化合物或其藥理上可容許的鹽,其中R 1及R 2係與R 1及R 2所鍵結的碳原子一起,形成環戊烷環、環己烷環、或4,4-二氟環己烷環。
- 如請求項1至9中任一項之化合物或其藥理上可容許的鹽,其中R 3為甲基,R 4為甲基、或羥甲基。
- 如請求項1至9中任一項之化合物或其藥理上可容許的鹽,其中R 3及R 4係與R 3所鍵結的氮原子及R 4所鍵結的碳原子一起,表示下述式(6):
- 如請求項1至9中任一項之化合物或其藥理上可容許的鹽,其中R 3及R 4係與R 3所鍵結的氮原子及R 4所鍵結的碳原子一起,表示下述式(7):
- 如請求項1之化合物或其藥理上可容許的鹽,其中環Q 1表示下述式(3A)至(3E)之任一者:
- 一種選自下述群組之任一者的化合物或其藥理上可容許的鹽,N-1H-吲唑-4-基-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-D-脯胺醯胺、N-1H-吲唑-4-基-1-({1-[(3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基]環戊基}羰基)-D-脯胺醯胺、1-({1-[4-(羥甲基)哌啶-1-基]環戊基}羰基)-N-1H-吲唑-4-基-D-脯胺醯胺、(4R)-4-羥基-N-1H-吲哚-4-基-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-D-脯胺醯胺、(4R)-N-(2-氰基苯基)-4-氟-1-{[1-(1-羥基-4-甲氧基環己基)環戊基]羰基}-D-脯胺醯胺、(4R)-4-氟-1-{[1-(4-甲氧基哌啶-1-基)環戊基]羰基}-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-({1-[4-(羥甲基)-4-甲氧基哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、1-{[1-(1-羥基-4-甲氧基環己基)環戊基]羰基}-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-[2-(1-羥基-4-甲氧基環己基)-2-甲基丙醯基]-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[4,4-二氟-1-(4-羥基-4-甲基哌啶-1-基)環己基]羰基}-4-氟-N-1H-吡咯并[3,2-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-({1-[4-羥基-4-(三氟甲基)哌啶-1-基]環己 基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-4-氟-1-({1-[4-(2-羥基丙烷-2-基)-4-甲氧基哌啶-1-基]環己基}羰基)-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、N 2-[2-(4-甲氧基哌啶-1-基)-2-甲基丙醯基]-N 2-甲基-N-1H-吡咯并[2,3-b]吡啶-6-基-D-丙胺醯胺、(4R)-1-{[(1’r,4’R)-4,4-二氟-4’-甲氧基-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[(1’s,4’S)-4,4-二氟-4’-甲氧基-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[(1’r,4’R)-4’-(二氟甲氧基)-4,4-二氟-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[4,4-二氟-4’-羥基-4’-(三氟甲基)-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺、(4R)-1-{[(1’r,4’R)-4,4-二氟-4’-(三氟甲氧基)-1,1’-二(環己基)-1-基]羰基}-4-氟-N-1H-吡唑并[4,3-b]吡啶-5-基-D-脯胺醯胺。
- 一種醫藥組成物,其係以如請求項1至14中任一項之化合物或其藥理上可容許的鹽作為有效成分。
- 一種EP300及/或CREBBP抑制劑,其係以如請求項1至14中任一項之化合物或其藥理上可容許的鹽作為 有效成分。
- 一種抗腫瘤劑,其係以如請求項1至14中任一項之化合物或其藥理上可容許的鹽作為有效成分。
- 如請求項17之抗腫瘤劑,其中腫瘤為前列腺癌、肝癌、肺癌、乳癌、大腸癌、胃癌、血液癌、胰臟癌(pancreatic cancer)、食道癌、膀胱癌、胃腸道基質瘤(gastrointestinal stromal tumor)、NUT中線癌(NUT midline carcinoma)、或卵巢癌。
- 一種腫瘤之治療方法,其包含投予如請求項1至14中任一項之化合物或其藥理上可容許的鹽。
- 如請求項19之治療方法,其中腫瘤為前列腺癌、肝癌、肺癌、乳癌、大腸癌、胃癌、血液癌、胰臟癌、食道癌、膀胱癌、胃腸道基質瘤、NUT中線癌、或卵巢癌。
- 一種用於腫瘤之治療之如請求項1至14中任一項之化合物或其藥理上可容許的鹽。
- 如請求項21之化合物或其藥理上可容許的鹽,其中腫瘤為前列腺癌、肝癌、肺癌、乳癌、大腸癌、胃癌、血液癌、胰臟癌、食道癌、膀胱癌、胃腸道基質瘤、NUT中線癌、或卵巢癌。
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