TWI811236B - B型肝炎抗病毒試劑 - Google Patents
B型肝炎抗病毒試劑 Download PDFInfo
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- TWI811236B TWI811236B TW107129940A TW107129940A TWI811236B TW I811236 B TWI811236 B TW I811236B TW 107129940 A TW107129940 A TW 107129940A TW 107129940 A TW107129940 A TW 107129940A TW I811236 B TWI811236 B TW I811236B
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- 239000003443 antiviral agent Substances 0.000 title abstract description 6
- 208000006454 hepatitis Diseases 0.000 title description 2
- 231100000283 hepatitis Toxicity 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 547
- 150000003839 salts Chemical class 0.000 claims abstract description 90
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 60
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 51
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 229940079593 drug Drugs 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 208000002672 hepatitis B Diseases 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 40
- 241000700721 Hepatitis B virus Species 0.000 abstract description 39
- 229940002612 prodrug Drugs 0.000 abstract description 15
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- 108090000623 proteins and genes Proteins 0.000 abstract description 12
- 208000015181 infectious disease Diseases 0.000 abstract description 11
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 325
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- 239000000243 solution Substances 0.000 description 231
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 216
- -1 substituted Chemical class 0.000 description 211
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 158
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 131
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 118
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- 238000006243 chemical reaction Methods 0.000 description 83
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 79
- 239000000377 silicon dioxide Substances 0.000 description 77
- 239000012043 crude product Substances 0.000 description 75
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- 125000001072 heteroaryl group Chemical group 0.000 description 35
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- 125000000623 heterocyclic group Chemical group 0.000 description 31
- 239000011734 sodium Substances 0.000 description 31
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 30
- 125000000753 cycloalkyl group Chemical group 0.000 description 28
- 238000002953 preparative HPLC Methods 0.000 description 28
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 28
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- 210000000234 capsid Anatomy 0.000 description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 25
- 125000001424 substituent group Chemical group 0.000 description 25
- 239000000725 suspension Substances 0.000 description 23
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- 238000003756 stirring Methods 0.000 description 22
- 125000003342 alkenyl group Chemical group 0.000 description 21
- 125000005843 halogen group Chemical group 0.000 description 21
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- 150000001413 amino acids Chemical class 0.000 description 19
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- 125000003107 substituted aryl group Chemical group 0.000 description 18
- 238000011282 treatment Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 16
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
- 229910020008 S(O) Inorganic materials 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 16
- 238000010791 quenching Methods 0.000 description 16
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- 150000001412 amines Chemical class 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 239000002904 solvent Substances 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
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- 125000000392 cycloalkenyl group Chemical group 0.000 description 12
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
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- 125000003277 amino group Chemical group 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 10
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Classifications
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- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
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- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Abstract
本發明揭露了式(I)的化合物或其醫藥上可接受的鹽、酯或前藥:X-A-Y-L-R (I)其抑制由B型肝炎病毒(hepatitis B virus,HBV)所編碼的蛋白質或干擾B型肝炎病毒的HBV生命週期的功能,且作為抗病毒試劑也是有用的。本發明更有關於包含上述化合物之用於投予受HBV感染之苦的對象的醫藥組合物。本發明亦有關於藉由投予包含本發明之化合物的醫藥組合物,來治療對象中的HBV感染的方法。
Description
本發明基本上係關於新穎抗病毒試劑。具體而言,本發明係關於可抑制由B型肝炎病毒(hepatitis B virus,HBV)所編碼的蛋白質或干擾HBV生命週期功能的化合物、包含這種化合物的組合物、HBV病毒複製的抑制方法、或HBV感染的治療或預防方法及這些化合物的製造製程。
[優先權]
本申請案基於2017年08月28日提申的美國臨時申請案號No.62/550,992主張優惠。上述申請案的完整教示引入於本文作為參考。
HBV感染仍然是主要的公共衛生問題,影響全世界約20億人。在那些人之中,全世界3.5億人和美國140萬人罹患慢性感染,其可導致慢性持續性肝炎(chronic persistent hepatitis)、肝硬化(liver cirrhosis)和肝細胞癌(hepatocellular carcinoma,HCC)。每年有500,000至100萬人死於由HBV感染所引起的肝臟疾病的末期(end stage)。
儘管可取得預防性(prophylactic)HBV疫苗,由於在大部分的開發中世界中之次佳的治療選項和新感染率持續不斷,慢性HBV感染的負擔仍然是一個重要、未滿足的全世界性醫療問題。目前的治療未提供治癒,且僅限於兩類的試劑(干擾素和病毒聚合酶的核苷(nucleoside)類似物/抑制劑);抗藥性、低功效(efficacy)和耐受性(tolerability)問題限制了它們的影響。HBV的低治癒率至少部分歸因於感染的肝細胞的核中之共價閉合環狀DNA(covalently closed circular DNA,cccDNA)的存在和持續性。然而,HBV DNA之持續性的抑制減緩肝臟疾病的進展且幫助預防HCC。目前對HBV感染患者的治療目標是導向將血清HBV DNA降低(reduce)至低程度或無法偵測的程度,且最終降低或預防硬化和HCC的發展。
HBV是肝去氧核糖核酸病毒科(Hepadnaviridae)的包膜、部分雙股DNA(double-stranded,dsDNA)病毒。HBV衣殼(capsid)或核心蛋白質(core protein,CP)在HBV複製中扮演重要角色。衣殼蛋白質的主要生物學功能是作為結構蛋白質以用殼體包裹(encapsidate)前基因體(pre-genomic)RNA且形成未成熟的衣殼顆粒,其從細胞質中的核心二聚體的許多副本(copy)中自發地自我組裝。衣殼蛋白質也透過其C端磷酸化位的不同磷酸化狀態,來調控病毒DNA的合成。此外,衣殼蛋白質可藉由位於衣殼蛋白質的C端區的精胺酸富含域(arginine-rich domain)中的核定位訊號,來促進病毒的鬆弛環狀基因體的核轉位(nuclear
translocation)。在細胞核中,作為病毒cccDNA微染色體的組成,衣殼蛋白質可在cccDNA微染色體的功能性中扮演結構和調控的角色。衣殼蛋白質也在內質網(endoplasmic reticulum,ER)中與病毒大包膜蛋白質交互作用,且觸發完整病毒顆粒自肝細胞釋放。
已報導了衣殼相關抗HBV抑制劑。舉例而言,苯基丙烯醯胺(phenylpropen-amide)衍生物,包含名為AT-61和AT-130的化合物(Feld J.et al.Antiviral Res.2007,76,168)以及來自Valeant的一類的噻唑烷-4-酮(thiazolidin-4-one)(W02006/033995)已顯示出抑制前基因體RNA(pregenomic RNA,pgRNA)包裝。在基於組織培養的篩選中發現雜芳基二氫吡喃-二胺(Heteroaryldihydropyrimi-dine或HAP)(Weber et al.Antiviral Res.2002,54,69)。這些HAP類似物作為合成的異位活化劑(allosteric activator)且能夠誘導異常的衣殼形成,其導致核心蛋白質的降解。磺胺基醯胺(sulphamoylarylamide)的次類(subclass)顯示出對HBV的活性(WO2013/006394、WO2013/096744、WO2014/184365和WO2017/136403)。亦顯示了,小分子bis-ANS作為分子「楔形(wedge)」且干擾正常衣殼-蛋白質的幾何形狀和衣殼的形成(Zlotnick A.et al.J.Virol.2002,4848)。
本領域需要治療、改善或預防HBV感染的新穎治療試劑。以單一療法或與其他HBV治療或輔助(ancillary)治療組合,
來將這些治療劑投予至HBV感染的患者會使預後(prognosis)顯著改善、疾病的進展減少和血清轉換率(seroconversion rate)增強。
本發明係關於新穎的抗病毒化合物、包含這種化合物的醫藥組合物,以及治療或預防需要用所述化合物的這種治療的對象中的病毒(特別是HBV)感染的方法。本發明的化合物抑制由B型肝炎病毒(hepatitis B virus,HBV)所編碼的蛋白質或干擾HBV的生命週期,且也作為抗病毒試劑也是有用的。此外,本發明包含所述化合物的製備製程。
在其主要面向,本發明提供式(I)的化合物:X-A-Y-L-R (I)或其醫藥上可接受的鹽,其中:X和Y各自獨立地選自於視需要而定經取代的芳基(aryl)或視需要而定經取代的雜芳基(heteroaryl);在一實施例中,X和Y中的一個是視需要而定經取代的苯基(phenyl);在另一實施例中,X和Y均為視需要而定經取代的苯基;A選自由-NHC(O)-、和所組成的群組;較佳地,A為is-NHC(O)-;L為S(O)2、S(O)、S或O;以及R透過碳原子連接至L,且獨立地選自由視需要而定經取代的
-C1至C10烷基(alkyl)、視需要而定經取代的-C2至C10烯基(alkenyl)、視需要而定經取代的-C2至Cl0炔基(alkynyl)、視需要而定經取代的芳基、視需要而定經取代的雜芳基、視需要而定經取代的-C3至C12環烷基(cycloallkyl)、視需要而定經取代的-C3至C12環烯基(cycloalkenyl)、視需要而定經取代的3至12員雜環(heterocyclic)所組成的群組;在一實施例中,R是視需要而定經取代的-C5至C12環烷基或視需要而定經取代的5至12員雜環,其各自視需要而定被以下一或多個取代:稠合環(fused ring)、一或多個螺環(spiro ring)或一或多個橋環部分(bridging ring moiety)。在另一實施例中,R是視需要而定經取代的C3至C12環烷基-C1至C6-烷基-、視需要而定經取代的C3至C12環烯基-C1至C6-烷基-或視需要而定經取代的3至12員雜環-C1至C6-烷基-。
上述各個較佳基團可與一個、任何或所有其他較佳的基團組合使用。
在本發明的一實施例中,是上述式(I)的化合物或其醫藥上可接受的鹽。
在某些實施例中,本發明係關於式(I)的化合物及其醫藥上可接受的鹽,其中X是視需要而定經取代的苯基。在某些實施例中,X是被一或多個取代基取代的苯基,例如1、2、3、4或5個取代基。較佳地,取代基獨立地選自鹵原子(halogen)、CN、視
需要而定經取代的-C1至C3烷氧基(alkoxy)、視需要而定經取代的-C1至C3烷基和視需要而定經取代的-C3-C6環烷基。在某些實施例中,X是被一或多個取代基取代的苯基,前述取代基獨立地選自氟、氯、溴、甲基、二氟甲基(difluoromethyl)、三氟甲基(trifluoromethyl)、CN和環丙基(cyclopropyl)。在某些實施例中,X選自以下基團(group):
在某些實施例中,本發明係關於式(I)的化合物及其醫藥上可接受的鹽,其中X是視需要而定經取代的單環雜芳基。在某些實施例中,本發明係關於式(I)的化合物或、和其醫藥上可接受的鹽,其中X是視需要而定經取代的噻吩基(thiophenyl)、視需要而定經取代的噻唑基(thiazolyl)、視需要而定經取代的吡啶基(pyridyl)或視需要而定經取代的嘧啶基(pyrimidinyl)。在某些實
施例中,本發明係關於式(I)的化合物或、和其醫藥上可接受的鹽,其中X是視需要而定經取代的嘧啶基、視需要而定經取代的噠嗪基(pyridazyl)或視需要而定經取代的吡嗪基(pyrazyl),如下所示:
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X是視需要而定經取代的雙環雜芳基(bicyclic heteroaryl)。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X是視需要而定經取代的5/6雙環雜芳基且透過所述5/6雙環雜芳基的6員環的碳或氮原子,較佳地碳原子來連接至A。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X是視需要而定經取代的苯並咪唑基(benzimidazolyl)、苯並噻唑基(benzothiazolyl)、苯並噁唑基(benzoxazolyl)、吲唑基(indazolyl)、喹啉基(quinolyl)、異喹啉基(isoquinolyl)或喹唑基(quinazolyl)。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定經取代的苯基。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是被鹵原子、CN、視需要而定經取代的-C1至C6烷氧基、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C1至C6烯基、視需要而定經取代的-C3至C6環烷基、視需要而定經取代的芳基和視需要而定經取代的雜芳基所取代的苯基。在某些實施例中,本發明
係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定經取代的1,3-亞苯基(phenylene),例如和。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定經取代的1,3-亞苯基,例如
和。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定經取代的2,4-亞吡咯(pyrrolylene),例如或
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定經取代的單環雜芳基。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定經取代的噻吩基、視需要而定經取代的噻唑基、視需要而定經取代的吡咯基(pyrrolyl)、視需要而定經取代的吡唑基(pyrazolyl)、視需要而定經取代的咪唑基(imidazolyl)、視需要而定經取代的吡啶基或視需要而定經取代的嘧啶基。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定被鹵原子、CN和視需要而定經取代的-C1-C3烷基所取代的吡咯基。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定經取代的雙環雜芳基。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定經取代的5/6雙環雜芳基,且透過所述5/6雙環雜芳基的5員環的碳或氮原子,來連接至A。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中Y是視需要而定經取代的苯並咪唑基、苯並噻唑基、苯並噁唑基、吲唑基、喹啉基、異喹啉基或喹唑基。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X和Y各自獨立地為視需要而定經取代的單環雜芳基。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X是視需要而定經取代的苯基,且Y是視需要而定經取代的單環雜芳基。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X是視需要而定經取代的單環雜芳基,且Y是視需要而定經取代的苯基。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X和Y各自獨立地為苯基或單環雜芳基,其各自視需要而定被1至3個選自由鹵原子、CN、視需要而定經取代的甲基、視需要而定經取代的甲氧基(methoxy)和視需要而定經取代的環丙基所組成的群組的取代基所取代。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X和Y各自獨立地選自由視需要而定經取代的苯基、視需要而定經取代的噻吩基、視需要而定經取代的吡啶基和視需要而定經取代的嘧啶基(pyrimidyl)組成的群組。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X和Y各自獨立地為視需要而定經取代的苯基。在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中X是視需要而定經取代的苯基,且Y是視需要而定經取代的吡咯基。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中A為-NHC(O)-。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中L為S(O)2。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中L為S(O)。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中L為S。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中L為O。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中R是視需要而定經取代的-C1至C10烷基、視需要而定經取代的-C2至C10烯基或視需要而定經取代的-C2至C10炔基。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中R是視需要而定經取代的芳基或視需要而定經取代的雜芳基。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中R是視需要而定經取代的-C3至C12環烷基或視需要而定經取代的3至12員雜環。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中R是視需要而定經取代的C3至C12環烷基-C1至C6-烷基-、視需要而定經取代的C3至C12環烯基-C1至C6-烷基-或視需要而定經取代的3至12員雜環-C1至C6烷基-。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中R是視需要而定經取代的-C5至C12環烷基
或視需要而定經取代的5至12員雜環,各自視需要而定被一或多個稠合環取代。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中R是視需要而定經取代的-C5至C12環烷基或視需要而定經取代的5至12員雜環,各自視需要而定被一或多個螺環取代。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中R是視需要而定經取代的-C5至C12環烷基或視需要而定經取代的5至12員雜環,各自視需要而定被一或多個橋接部分(bridging moiety)取代。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中R為-C(R10)3、 或,其中n每次出現時獨立地選自0、1、2或3;T每次出現時獨立地選自C(R10)和N;E每次出現時獨立地選自-C(R10)2-、-N(R10)-、O、S、S(O)和S(O)2;其中R10每次出現時獨立地選自由氫、鹵素(halo)、-CN、-NO2、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C2至C8烯基、視需要而定經取代的-C2至C8炔基、視需要而定經取代的-C3至C8環烷基、視需要而定經取代的3至8員雜環、視需要而定經取代的芳基、視需要而定經取代的雜芳基和-L1-R1所組成的群組;其中L1為-O-、-S、、
-NR1-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)N(R1)-、-N(R1)C(O)-、-OC(O)N(R1)-、-N(R1)C(O)O-、-N(R1)C(O)N(R1)-、-S(O)-、-S(O)2-、-S(O)2N(R1)-、-N(R1)S(O)2-;R1每次出現時獨立地選自由氫、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C2至C8烯基、視需要而定經取代的-C2至C8炔基、視需要而定經取代的-C3至C8環烷基、視需要而定經取代的3至8員雜環、視需要而定經取代的芳基和視需要而定經取代的雜芳基所組成的群組。
在某些實施例中,每個R10獨立地選自氫、鹵素、羥基(hydroxy)、被保護的羥基、-CN、-NO2、胺基(amino)、被保護的胺基、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C1至C6烷氧基、視需要而定經取代的芳基、視需要而定經取代的雜芳基和-O-(羥基前藥(prodrug)基團)。在某些實施例中,羥基前藥基團是磷酸酯(phosphate)或胺基磺酸酯(sulfamate)。在某些實施例中,所述羥基前藥基團是衍生自胺基酸、較佳地α-胺基酸的醯基(acyl group)。
在某些實施例中,每個R10獨立地為-C1至C6烷基,其視需要而定被一或多個選自由鹵素、羥基、被保護的羥基、胺基、被保護的胺基和視需要而定經取代的雜芳基所組成的群組的取代基所取代。
在某些實施例中,取兩個相鄰的R10基團還有它們所連接的碳或氮原子,來形成烯烴(olefinic)或亞胺基雙鍵(iminic
double-bond)或稠合環。在某些實施例中,兩個成對的(geminal)R10基團一起形成側氧基(oxo)、視需要而定經取代的烯烴(olefin)、視需要而定經取代的肟(oxime)或螺環。在某些實施例中,取兩個遙遠的R10基團還有它們所連接的原子和任何介於中間的(intervening)原子,來形成橋接部分。
在某些實施例中,本發明係關於式(I)的化合物和其醫藥上可接受的鹽,其中R是視需要而定經取代的-(CH2)0-4-C(R10)3、或,其中n、E、T和Rl0是先前所定義的;v選自1、2、3或4。在某些實施例中,每個R10獨立地選自氫、鹵素、羥基、被保護的羥基、-CN、-NO2、胺基、被保護的胺基、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C1至C6烷氧基、視需要而定經取代的芳基、視需要而定經取代的雜芳基和-O-(羥基前藥基團)。在某些實施例中,羥基前藥基團是磷酸酯或胺基磺酸酯。在某些實施例中,所述羥基前藥基團是衍生自胺基酸、較佳地α-胺基酸的醯基。在某些實施例中,每個R10獨立地為視需要而定被一或多個選自由鹵素、羥基、被保護的羥基、胺基、被保護的胺基和視需要而定經取代的雜芳基所組成的群組的取代基所取代的-C1至C6烷基。在某些實施例中,取兩個相鄰的R10基團還有它們所連接的碳或氮原子,來形成烯烴雙鍵、亞胺基雙鍵或稠合的(fused)碳環或雜環。在某些實施例中,兩個成對的R10基團一起形成側氧基、視需要而定經取代的烯烴、
視需要而定經取代的肟或螺環。在某些實施例中,取兩個遙遠的R10基團還有它們所連接的原子和任何介於中間的原子,來形成橋接部分。
在某些實施例中,本發明係關於由式(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)或(IIh)所表示之式(I)的化合物或其醫藥上可接受的鹽,其中X和Y各自獨立地為視需要而定經取代的苯基或視需要而定經取代的單環雜芳基。
在某些實施例中,本發明係關於由式(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)或(IIh)所表示之式(I)的化合物或其醫藥上可接受的鹽,X和Y各自獨立地為視需要而定經取代的苯基。
在某些實施例中,本發明係關於由式(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)或(IIh)所表示之式(I)的化合物或其醫藥上可接受的鹽,其中X為視需要而定經取代的苯基,且Y為視需要而定經取代的5員雜芳基。
在某些實施例中,本發明係關於由式(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)或(IIh)所表示之式(I)的化合物或其醫藥上可接受的鹽,其中X為視需要而定經取代的5員雜芳基,且Y為視需要而定經取代的苯基。
在某些實施例中,本發明係關於由式(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)或(IIh)所表示之式(I)的化合物或其醫藥上可接受的鹽,其中X為視需要而定經取代的苯基,且Y為視需要而定經取代的吡咯基。
在某些實施例中,本發明係關於由式(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)或(IIh)所表示之式(I)的化合物或其醫藥上可接受的鹽,其中X和Y各自獨立地為視需要而定經取代的苯基、視需要而定經取代的萘基(naphthyl)、視需要而定經取代的吡啶基、視需要而定經取代的嘧啶基、視需要而定經取代的噻吩基、視需要而定經取代的吡咯基、視需要而定經取代的噻唑基、視需要而定經取代的噻二唑基(thiadiazolyl)、視需要而定經取代的噁唑基(oxazolyl)、視需要而定經取代的異噁唑基(isoxazolyl)、視需要而定經取代的惡二唑基(oxadiazolyl)、視需要而定經取代的咪唑基(inidiazolyl)、視需要而定經取代的吡唑基、視需要而定經取代的三唑基(triazolyl)或視需要而定經取代的喹啉基(quinolinyl)。
在另一實施例中,式(I)的化合物由式(IIIa)、(IIIb)、(IIIc)或(IIId)或前述之式的醫藥上可接受的鹽所表示:
其中m每次出現時獨立地為0、1、2、3或4;R14每次出現時獨立地選自由羥基、被保護的羥基、鹵原子、-CN、-NO2、視需要而定經取代的胺基、N3、視需要而定經取代的芳基、視需要而定經取代的雜芳基、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C2至C8烯基、視需要而定經取代的-C2至C8炔基、視需要而定經取代的-C3至C8環烷基、視需要而定經取代的3至8員雜環、視需要而定經取代的-C1至C6烷氧基、-C(O)2-C1至C6烷基、-C(O)NH-C1至C6烷基和-C(O)-C1至C6烷基所組成的群組;且R如先前所定義。
在另一實施例中,式(I)的化合物由式(Va)、(Vb)、(Vc)、(Vd)或(Ve)或前述之式的醫藥上可接受的鹽所表示:
其中m1每次出現時獨立地為1、2或3;m2每次出現時獨立地為0、1或2;m3每次出現時獨立地為0、1、2或3;R21每次出現時獨立地選自由鹵原子、CN、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C1至C6烷氧基和視需要而定經取代的C3至C8環烷基所組成的群組;R22每次出現時獨立地選自由鹵原子、CN、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C1至C6烷氧基、視需要而定經取代的芳基和視需要而定經取代的雜芳基所組成的群組;E、n和R10如先前所定義。
在另一實施例中,式(I)的化合物由式(Vf)、(Vg)、(Vh)或(Vj)或前述之式的醫藥上可接受的鹽所表示:
其中m4每次出現時獨立地為0、1或2;R30為氫、視需要而定經取代的-C1至C6烷基、羥基保護基團或羥基前藥基團;m1、m2、n、E、R10、R21和R22如先前所定義。在某些實施例中,R30是磷酸酯或胺基磺酸酯。在某些實施例中,R30是衍生自胺基酸、較佳地α-胺基酸的醯基。
在另一實施例中,式(I)的化合物由式(VIa)、(VIb)、(VIc)、(VId)、(VIe)或(VIf)或前述之式的醫藥上可接受的鹽所表示:
其中m1每次出現時獨立地為1、2或3;m2每次出現時獨立地為1或2;n、R21、R22和R30如先前所定義。在某些實施例中,R30是磷酸酯或胺基磺酸酯。在某些實施例中,R30是衍生自胺基酸、較佳地α-胺基酸的醯基。
在另一實施例中,式(I)的化合物由式(VIa)、(VIb)、(VIc)、(VId)、(VIe)或(VIf)或前述之式的醫藥上可接受
的鹽所表示,其中m1每次出現時獨立地為2或3;m2每次出現時為1;n每次出現時獨立地為0、1或2;R21為鹵原子、CN、視需要而定經取代的甲基、視需要而定經取代的甲氧基和視需要而定經取代的環丙基;R22為鹵原子、CN、視需要而定經取代的甲基和視需要而定經取代的甲氧基;R30為衍生自胺基酸的醯基。在某些實施例中,R30為衍生自具有脂族(aliphatic)側鏈的α-胺基酸的醯基。在某些實施例中,R30為衍生自丙胺酸(alanine)或纈胺酸(valine)的醯基。
在另一實施例中,式(I)的化合物由式(VIIa)、(VIIb)、(VIIc)、(VIId)或(VIIe)或前述之式的醫藥上可接受的鹽所表示:
其中m1、m3、n、E、R10、R21和R22如先前所定義。
在另一實施例中,式(1)的化合物由式(VIIa-1)、(VIIb-1)、(VIIc-1)、(VIId-1)或(VIIe-1)或前述之式的醫藥上
可接受的鹽所表示:
其中R23每次出現時獨立地選自由氫、鹵原子、CN、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C1至C6烷氧基和視需要而定經取代的C3至C8環烷基所組成的群組;m3、n、E、R10、R21和R22如先前所定義。
在另一實施例中,式(I)的化合物由式(VIIa-2)、(VIIb-2)、(VIIc-2)或(VIId-2)或前述之式的醫藥上可接受的鹽所表示:
其中m4、n、E、R10、R21、R22、R23和R30如先前所定義。在某
些實施例中,R30為氫。在某些實施例中,R30為衍生自胺基酸、較佳地α-胺基酸的醯基。
在另一實施例中,式(I)的化合物由式(VIIa-2)、(VIIb-2)、(VIIc-2)或(VIId-2)或前述之式的醫藥上可接受的鹽所表示,其中n每次出現時獨立地為0、1或2;R21每次出現時獨立地為鹵原子、CN、視需要而定經取代的甲基、視需要而定經取代的甲氧基或視需要而定經取代的環丙基;R22為鹵原子、CN、視需要而定經取代的甲基或視需要而定經取代的甲氧基;R23為氫或鹵原子;R10為氫、鹵原子、羥基或視需要而定經取代的C1至C6烷基;R30為氫或衍生自胺基酸的醯基。在某些實施例中,R21每次出現時為氟。在某些實施例中,R22為氟或氯。在某些實施例中,R10為氫、鹵原子、羥基、視需要而定被一或多個選自鹵原子、羥基和視需要而定經取代的C1至C6烷氧基的基團所取代的C1至C6烷基。在某些實施例中,R23為氫或氟。在某些實施例中,R30為衍生自丙胺酸或纈胺酸的醯基。
在另一實施例中,式(I)的化合物由式(VIIIa)、(VIIIb)、(VIIIc)或(VIIId)或前述之式的醫藥上可接受的鹽所表示:
其中R11每次出現時獨立地選自由氫、鹵原子、羥基、被保護的羥基、-CN、胺基、被保護的胺基、視需要而定經取代的芳基、視需要而定經取代的雜芳基、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C2至C8烯基、視需要而定經取代的-C2至C8炔基、視需要而定經取代的-C3至C8環烷基、視需要而定經取代的3至8員雜環、視需要而定經取代的-C1至C6烷氧基、視需要而定經取代的-NH-C1至C6烷基、視需要而定經取代的-N(C1至C6烷基)2、-CO2H、視需要而定經取代的-C(O)2-C1至C6烷基、視需要而定經取代的-C(O)NH-C1至C6烷基和視需要而定經取代的-C(O)-C1至C6烷基所組成的群組;m、n、E、T、R10和R14如先前所定義。在某些實施例中,較佳的R11基團包含氫、鹵原子、羥基、被保護的羥基、被保護的胺基、視需要而定經取代的芳基、視需要而定經取代的雜芳基、-CO2H、視需要而定經取代的-C1至C6烷基、視需要而定經取代的NHC(O)2-C1至C6烷基和視需要而定經取代的-C1至C6烷氧基。在某些實施例中,R11為視需要而定經取代的-C1至C6烷基、視需要而定經取代的芳基、視需要而定經取代的雜芳基和視需要而定經取代的-C1至C6烷氧基。
在另一實施例中,式(I)的化合物由式(VIIIa-1)、(VIIIb-1)、(VIIIc-1)或(VIIId-1)或前述之式的醫藥上可接受的鹽所表示:
其中m、n、E、R10、R11和R14如先前所定義。
在另一實施例中,式(I)的化合物由式(XIIa)、(XIIb)、(XIIc)或(XIId)或前述之式的醫藥上可接受的鹽所表示:
其中R31每次出現時獨立地選自由氫、視需要而定經取代的芳基、視需要而定經取代的雜芳基、視需要而定經取代的-C1至C6烷基、視需要而定經取代的-C2至C8烯基、視需要而定經取代的-C2至C8炔基、視需要而定經取代的-C3至C8環烷基和視需要而定經取代的3至8員雜環所組成的群組;m1、m2、m4、n、R10、R11、R21、R22和R30如先前所定義。在某些實施例中,R31是視需要定定被一或多個選自鹵原子、羥基、視需要而定經取代的C1至C6烷氧基、胺基、視需要而定經取代的-NH-C1至C6烷基、視需要而定經取代的-N(C1至C6烷基)2、視需要而定經取代的-CO2-C1至C6烷基、視需要而定經取代的-C(O)NH-C1至C6烷基、視需要而定經取代的-NHC(O)-C1至C6烷基、視需要而定經取代的-C(O)-C1至C6烷基和視需要而定經取代的-NHS(O)2-C1至C6烷基的基團所取代的-C1至C6烷基。
其中R32每次出現時獨立地選自由氫、視需要而定經取代的C1至C6烷基、視需要而定經取代的-C(O)-C1至C6烷基、視需要而定經取代的-C(O)-C2至C8烯基、視需要而定經取代的-C(O)-C2至C8炔基、視需要而定經取代的-C(O)-C3至C8環烷基、視需要而定經取代的-C(O)-芳基、視需要而定經取代的-C(O)-(3至8員雜環)、視需要而定經取代的-C(O)-C1至C6烷基、視需要而定經取代的-CO2-C1至C6烷基、視需要而定經取代的S(O)2-C1至C6烷基、視需要而定經取代的S(O)2-C2至C6烯基所組成的群組;較佳地,當一個R32是視需要而定經取代的-C(O)-C1至C6烷基、視需要而定經取代的-C(O)-C2至C8烯基、視需要而定經取代的-C(O)-C2至C8炔基、視需要而定經取代的-C(O)-C3至C8環烷基、視需要而定經取代的-C(O)-芳基、視需要而定經取代的-C(O)-(3至8員雜環)、視需要而定經取代的-C(O)-C1至C6烷基、視需要而定經取代的-CO2-C1至C6烷基、視需要而定經取代的S(O)2-C1至C6烷基、視需要而定經取代的S(O)2-C2至C6烯基時,另一個R32是氫或視需要而定經取代的C1至C6烷基;m1、m2、m4、n、R10、R11、R21、R22和R30
如先前所定義。在某實施例中,取兩個R32基團還有它們所連接的氮原子,來形成3至8員雜環。
在另一實施例中,式(I)的化合物由式(XIVa)、(XIVb)、(XIVc)或(XIVd)或前述之式的醫藥上可接受的鹽所表示:
其中R33每次出現時獨立地選自由氫、視需要而定經取代的C1至C6烷基、視需要而定經取代的-C2至C8烯基、視需要而定經取代的-C2至C8炔基、視需要而定經取代的C3至C8環烷基、視需要而定經取代的3至8員雜環、視需要而定經取代的-C1至C6烷氧基、視需要而定經取代的-NH-C1至C6烷基、視需要而定經取代的-N(C1至C6烷基)2、視需要而定經取代的-NH-C1至C6烯基、視需要而定經取代的-NH-(3至8員雜環)所組成的群組;m1、m2、m4、n、R10、R11、R21、R22和R30如先前所定義。
在另一實施例中,式(I)的化合物由式(XVa)、(XVb)、(XVc)或(XVd)或前述之式的醫藥上可接受的鹽所表示:
其中R34每次出現時獨立地選自由氫、視需要而定經取代的C1至C6烷基、視需要而定經取代的-C2至C8烯基、視需要而定經取代的-C2至C8炔基、視需要而定經取代的-C3至C8環烷基和視需要而定經取代的3至8員雜環所組成的群組;m1、m2、m4、n、R10、R11、R21、R22和R31如先前所定義。
在另一實施例中,式(I)的化合物由式(XVI)或前述之式的醫藥上可接受的鹽所表示:
其中R21、R21’和R21”獨立地選自氫、氟、甲基、二氟甲基和三氟甲基;且R35為-[CH(R36)]p-C(R37)(R38)OH或-CH2-O-CH2-[CH(R36)]pC(R37)(R38)OH,其中p為0或1;R36是氫、甲基或羥基且R37和R38獨立地為氫或甲基。較佳地,R21、R21’和R21”中的至少兩個不是氫。更佳地,(i)R21、R21’和R21”都不是氫;或(ii)R21為氫且R21’和R21”不是氫。在較佳實施例中,R21、R21’和R21”中
的至少兩個是氟。在另一些實施例中,R21、R21’和R21”中的每一個都是氟。
在另一實施例中,式(I)的化合物由式(XVII)或前述之式的醫藥上可接受的鹽所表示:
其中R21、R21’和R21”獨立地選自氫、氟、甲基、二氟甲基和三氟甲基;R39為氫或羥基;且R40為-[C(R41)(R42)]q-R43,其中q為0、1或2;R41和R42各自獨立地為氫、甲基或羥基;或者替換地,可取R41和R42來一起形成側氧基;且R43為氫、羥基、視需要而定經取代的C1至C6烷基、視需要而定經取代的C3至C6環烷基、視需要而定經取代的3至12員雜環、視需要而定經取代的芳基或視需要而定經取代的雜芳基。較佳地,R21、R21’和R21”中的至少兩個不是氫。更佳地,(i)R21、R21’和R21”均不是氫;或(ii)R21為氫,且R21’和R21”不是氫。在較佳實施例中,R21、R21’和R21”中的至少兩個是氟。在另一些實施例中,R21、R21’和R21”中的每一個都是氟。較佳地,R39是羥基;q是1或2;R41和R42各自獨立地為氫或羥基;且R43是視需要而定經取代的C1至C6烷基、視需要而定經取代的C3至C6環烷基、視需要而定經取代的3至12員雜環、視需要而定經取代的芳基或視需要而定經取代的雜芳基。更佳地,R39是羥基;q是1或2;R41是氫;R42是羥基;且R43是視需要而定經取代的C1至C6
烷基、視需要而定經取代的C3至C6環烷基、視需要而定經取代的3至12員雜環或視需要而定經取代的雜芳基。在較佳實施例中,R39是氫或羥基;q是1或2;R41是氫或甲基;R42是羥基;且R43是視需要而定經取代的C1至C6烷基或視需要而定經取代的C3至C6環烷基。在另一些實施例中,R39是氫或羥基;q是1或2;R41是氫或甲基;R42是羥基;且R43是視需要而定經取代的3至12員雜環或視需要而定經取代的雜芳基。在較佳實施例中,R43是甲基、乙基、丙基、異丙基、環丙基、環丁基(cyclobutyl)、吡啶基、嘧啶基、噁唑基、噻唑基、噁唑基或異噁唑基。
應理解的是,本文中的本發明的描述應被視為與化學鍵結的定律和原理一致。在一些範例中,可能需要除去氫原子以在任何給定的位置容納取代基。
還應理解的是,本發明的化合物可含有一或多個不對稱碳原子,且可以外消旋(racemic)、非鏡像異構物(diastereoisomeric)和光學活性形式存在。仍應理解的是,本發明的某些化合物可以不同的互變異構物(tautomeric)形式存在。所有的互變異構物都被視為(contemplate)在本發明的範圍內。
在一面向中,本發明的化合物藉由破壞(disrupt)、加速、減低、延遲和/或抑制正常病毒核心蛋白質功能,其包含但不限於與病毒鬆弛環狀(relaxed circular,rc)DNA、cccDNA或反轉錄酶的直接或間接交互作用、與宿主蛋白質例如組蛋白(histone)或宿主伴侶(host partner)例如激酶(kinase)、和/或未成熟或成熟
顆粒的衣殼組裝拆解(disassembly)的直接或間接交互作用,藉此誘導異常的衣殼形態(morphology)且導致抗病毒功效,例如破壞病毒體(virion)的組裝和/或拆解、病毒體成熟和/或病毒流出(egress),而在HBV治療中是有用的。在一實施例中,衣殼組裝的破壞劑(disruptor)與成熟或未成熟的病毒衣殼交互作用,以擾亂衣殼的穩定性,因此影響組裝和/或拆解。在另一實施例中,衣殼組裝的破壞劑擾亂病毒衣殼的穩定性、功能和/或正常形態所需的蛋白質折疊和/或鹽橋,藉此破壞和/或加速衣殼組裝和/或拆解。在又另一實施例中,本發明的化合物結合衣殼且改變細胞聚合蛋白質(polyprotein)和前驅物(precursor)的代謝,導致蛋白質單體和/或寡聚物和/或異常顆粒的異常累積,這導致細胞毒性和受感染的細胞的死亡。在另一實施例中,本發明的化合物導致最佳穩定性衣殼的形成失敗,影響病毒的有效率脫殼(uncoating)和/或拆解(例如,在感染(infectivity)期間)。
在一實施例中,當衣殼蛋白質未成熟時,本發明的化合物破壞和/或加速衣殼組裝和/或拆解。在另一實施例中,當衣殼蛋白質成熟時,本發明的化合物破壞和/或加速衣殼組裝和/或拆解。在又另一實施例中,在病毒感染期間,本發明的化合物破壞和/或加速衣殼組裝和/或拆解。在又另一實施例中,衣殼組裝和/或拆解的破壞和/或加速減弱(attenuate)了HBV的病毒感染和/或降低了病毒載量。在又另一實施例中,衣殼組裝和/或拆解的破壞、加速、抑制、延遲和/或減低從宿主有機體中根除(eradicate)病毒。在又
另一實施例中,在病毒感染期間,本發明的化合物破壞和/或調節(modulate)核心蛋白質和病毒rcDNA、cccDNA或反轉錄酶之間的交互作用。在又另一實施例中,在病毒感染期間,本發明的化合物破壞和/或調節核心蛋白質與宿主伴侶或蛋白質之間的交互作用。在又另一實施例中,從宿主中根除HBV有利地排除(obviate)對慢性長期治療的需要和/或減低長期治療的持續時間。
在一實施例中,本文所述的化合物適合單一療法(monotherapy),且對天然(natural)或原生(native)HBV株和對目前已知的藥物有抗性的HBV株有效。在另一實施例中,本文所述的化合物適合組合治療中的用途。
在另一實施例中,本發明的化合物可用於調節(例如抑制、破壞或加速)HBV cccDNA的活性的方法中。在又另一實施例中,本發明的化合物可用於減少(diminish)或預防HBV cccDNA的形成的方法中。在另一實施例中,額外治療試劑選自免疫調節劑或免疫刺激劑療法,其包含T細胞反應活化劑AIC649和屬於干擾素類的生物試劑,例如干擾素alpha 2a或2b或經修飾的干擾素,例如聚乙二醇化(pegylated)干擾素、alpha 2a、alpha 2b、lamda;或STING(干擾素基因的刺激物(stimulator of interferon genes))調節劑;或TLR調節劑例如TLR-7促效劑(agonist)、TLR-8促效劑或TLR-9促效劑;或刺激HBV特異性免疫反應的治療性疫苗,例如由HBcAg和HBsAg所構成的類病毒(virus-like)顆粒、HBsAg和HBsAb的免疫複合物或在酵母菌載體的背景下包含
HBx、HBsAg和HBcAg的重組蛋白質;或某些細胞病毒RNA感測器,例如RIG-I、NOD2和MDA5蛋白質的免疫活化劑,例如SB-9200;或RNA干擾(RNA interference,RNAi)或小干擾RNA(small interfering RNA,siRNA),例如ARC-520、ARC-521、ARB-1467和ALN-HBV RNAi;或另一核心蛋白質抑制劑或調節劑;或阻擋病毒進入或成熟或以HBV聚合酶為標靶的抗病毒試劑,例如核苷(nucleoside)或核苷酸或非核苷(酸)聚合酶抑制劑,以及有特殊或未知機制的試劑,包含破壞HBV複製或持續性所需的其他必需病毒蛋白質或宿主蛋白質的功能的試劑,例如REP 2139和RG7834。在組合療法的一實施例中,反轉錄酶抑制劑是齊多夫定(Zidovudine)、去羥肌苷(Didanosine)、扎西他濱(Zalcitabine)、ddA、司他夫定(Stavudine)、拉米夫定(Lamivudine)、阿巴卡韋(Aba-cavir)、恩曲他濱(Emtricitabine)、恩替卡韋(Entecavir)、阿普力比(Apricitabine)、阿他韋拉平(Atevirapine)、利巴韋林(ribavirin)、阿昔洛韋(acyclovir)、泛昔洛韋(famciclovir)、伐昔洛韋(valacyclovir)、更昔洛韋(ganciclovir)、纈更昔洛韋(valganciclovir)、替諾福韋(Tenofovir)、阿德福韋(Adefovir)、PMPA、西多福韋(cidofovir)、依法韋侖(Efavirenz)、奈韋拉平(Nevirapine)、拉韋啶(Delavirdine)或依曲韋林(Etravirine)中的至少一種。
在組合療法的另一實施例中,TLR-7促效劑選自由SM360320(9-芐基-8-羥基-2-(2-甲氧基-乙氧基)-烯丙
基)(9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)ad-enine)、AZD 8848(甲基[3-({[3-(6-胺基-2-丁氧基-8-側氧基-7,8-二氫-9H-嘌呤-9-基)丙基][3-(4-嗎啉基)丙基]胺基)甲基)苯基]乙酸酯)(methyl[3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]amino)methyl)phenyl]acetate)、GS-9620(4-胺基-2-丁氧基-8-[3-(1-吡咯烷基甲基)芐基]-7,8-二氫-6(5H)-二哌啶酮)(4-Amino-2-butoxy-8-[3-(1-pyrrolidinylmethyl)benzyl]-7,8-dihydro-6(5H)-pteridinone)和RO6864018所組成的群組。
在組合療法的另一實施例中,TLR-8促效劑是GS-9688。
在這些組合療法的一實施例中,化合物和額外治療試劑是共同調配(co-formulate)的。在另一實施例中,共同投予化合物和額外的治療試劑。
在組合療法的另一實施例中,與有此需要的個體中需要達到類似於預防性地治療HBV感染的結果,而單獨投予的至少一種額外治療試劑相比,投予本發明的化合物允許以較低劑量或頻率,來投予額外治療試劑。
在組合療法的另一實施例中,在投予治療上有效量的本發明化合物之前,已知個體對選自由HBV聚合酶抑制劑、干擾素、病毒進入抑制劑、病毒成熟抑制劑、特殊的衣殼組裝調節劑、
特殊或未知機制的抗病毒化合物及前述之組合所組成的群組的化合物有耐性(refractory)。
在此方法的又另一實施例中,與投予選自由HBV聚合酶抑制劑、干擾素、病毒進入抑制劑、病毒成熟抑制劑、特殊的衣殼組裝調節劑、特殊或未知機制的抗病毒化合物及前述之組合所組成的群組的化合物相比,本發明化合物的投予減低個體中的病毒載量至更大的程度。
在另一實施例中,本發明化合物的投予導致病毒突變和/或病毒抗性的發生率比投予選自由HBV聚合酶抑制劑、干擾素、病毒進入抑制劑、病毒成熟抑制劑、特殊的衣殼組裝調節劑、特殊或未知機制的抗病毒化合物及前述之組合所組成的群組的化合物還低。
應理解的是,本發明所涵蓋的化合物是適合穩定作為醫藥試劑用途的那些化合物。
定義
以下所列的是用於描述本發明的各種術語的定義。除非在特定情況下,單獨地或作為較大群組的一部分來另外限制,這些定義適用於整個說明書和申請專利範圍中使用的術語。
本文所使用的術語「芳基」是指包含至少一個芳香環的單或多環碳環系統,包含但不限於苯基、萘基、四氫萘基(tetrahydronaphthyl)、茚滿基(indanyl)和茚基(indenyl)。多環
芳基是包含至少一個芳香環的多環系統。多環芳基可包含稠合環、共價連接的環或其組合。
本文所使用的術語「雜芳基」是指具有一或多個選自S、O和N的環原子的單或多環芳香族自由基;且剩餘的環原子是碳,其中環中所含有的任何N或S可視需要而定被氧化。雜芳基包含但不限於吡啶基(pyridinyl)、吡嗪基(pyrazinyl)、嘧啶基、吡咯基、吡唑基、咪唑基、噻唑基、噁唑基、異噁唑基、噻二唑基、惡二唑基、噻吩基、呋喃基(furanyl)、喹啉基、異喹啉基、苯並咪唑基、苯並噁唑基、喹喔啉基(quinoxalinyl)。多環雜芳基可包含稠合環、共價連接的環或其組合。
根據本發明,芳香族基團(aromatic group)可被取代或未被取代。
術語「雙環芳基」或「雙環雜芳基」是指由兩個環組成的環系統,其中至少一個環是芳香族;且這兩個環可稠合或共價連接。
本文所使用的術語「烷基」是指飽和直鏈或支鏈烴(hydrocarbon)自由基。「C1至C3烷基」、「C1至C6烷基」、「C1至C10烷基」、「C2至C4烷基」或「C3至C6烷基」分別是指含有一至三個、一至六個、一至十個碳原子、二至四個和三至六個碳原子的烷基基團。C1至C8烷基自由基的範例包含但不限於甲基、乙基、丙基、異丙基、正丁基、叔丁基(tert-butyl)、新戊基(neopentyl)、正己基(n-hexyl)、庚基(heptyl)和辛基(octyl)自由基。
本文所使用的術語「烯基」是指藉由除去單一氫原子而具有至少一個碳-碳雙鍵的直鏈或支鏈烴自由基。「C2至C10烯
基」、「C2至C8烯基」、「C2至C4烯基」或「C3至C6烯基」分別是指含有從二至十個、二至八個、二至四個或三至六個碳原子的烯基。烯基基團包含但不限於,例如乙烯基(ethenyl)、丙烯基(propenyl)、丁烯基(butenyl)、1-甲基-2-丁烯-1-基(1-methyl-2-buten-1-yl)、庚烯基(heptenyl)、辛烯基(octenyl)或前述類似基團。
本文所使用的術語「炔基」是指藉由除去單一氫原子而具有至少一個碳-碳三鍵的直鏈或支鏈烴自由基。「C2至C10炔基」、「C2至C8炔基」、「C2至C4炔基」或「C3至C6炔基」分別是指含有從二至十個、二至八個、二至四個或三至六個碳原子的炔基。代表性的炔基基團包含但不限於,例如乙炔基(ethynyl)、1-丙炔基(1-propynyl)、1-丁炔基(1-butynyl)、庚炔基(heptynyl)、辛炔基(octynyl)或前述類似基團。
如本文所使用地,術語「環烷基」是指單環或多環飽和碳環或雙或三環基團稠合、橋接或螺旋(spiro)系統,且碳原子可視需要而定被側氧基取代或視需要而定被環外烯烴(exocyclic olefinic)、亞胺基或肟基(oximic)雙鍵取代。較佳的環烷基基團包含C3至C12環烷基、C3至C6環烷基、C3至C8環烷基和C4至C7環烷基。C3至C12環烷基的範例包含但不限於環丙基(cyclopropyl)、環丁基(cyclobutyl)、環戊基(cyclopentyl)、環己基(cyclohexyl)、環戊基(cyclopentyl)、環辛基(cyclooctyl)、4-亞甲基-環己基(4-methylene-cyclohexyl)、雙環[2.2.1]庚基(bicyclo[2.2.1]heptyl)、雙環[3.1.0]己基(bicyclo[3.1.0]hexyl)、螺[2.5]]辛基(spiro[2.5]octyl)、3-亞
甲基雙環[3.2.1]辛基(3-methylenebicyclo[3.2.1]octyl)、螺[4.4]壬基(spiro[4.4]nonanyl)或前述類似基團。
如本文所使用地,術語「環烯基」是指具有至少一個碳-碳雙鍵的單環或多環碳環或雙或三環基團稠合、橋接或螺旋系統,且碳原子可視需要而定被側氧基取代或視需要而定被環外烯烴、亞胺基或肟基雙鍵取代。較佳的環烯基基團包含C3至C12環烯基、C3至C8環烯基或C5至C7環烯基基團。C3至C12環烯基的範例包含但不限於環丙烯基(cyclopropenyl)、環丁烯基(cyclobutenyl)、環戊烯基(cyclopentenyl)、環己烯基(cyclohexenyl)、環庚烯基(cycloheptenyl)、環辛烯基(cyclooctenyl)、雙環[2.2.1]庚-2-烯基(bicyclo[2.2.1]hept-2-enyl)、雙環[3.1.0]己-2-烯基(bicyclo[3.1.0]hex-2-enyl)、螺[2.5]辛-4-烯基(spiro[2.5]oct-4-enyl)、螺[4.4]壬-1-烯基(spiro[4.4]non-1-enyl)、雙環[4.2.1]壬-3-烯-9-基(bicyclo[4.2.1]non-3-en-9-yl)或前述類似基團。
如本文所使用地,術語「芳烷基(arylalkyl)」意思是其中亞烷基(alkylene)鏈連接至芳基基團的官能基,例如-CH2CH2-苯基。術語「經取代的芳烷基」意思是其中芳基基團被取代的芳烷基官能基。類似地,術語「雜芳烷基」意思是其中亞烷基鏈連接至雜芳基基團的官能基。術語「經取代的雜芳烷基」是指其中雜芳基基團被取代的雜芳烷基官能基。
如本文所使用地,單獨或與其它術語組合使用的術語「烷氧基」意思是具有指定碳原子數的烷基基團,其透過氧原子
以連接至分子的剩餘部分,例如甲氧基(methoxy)、乙氧基(ethoxy)、1-丙氧基(1-propoxy)、2-丙氧基(異丙氧基)(2-propoxy或isopropoxy)和高級同系物(homolog)和異構物,除非另有說明。較佳的烷氧基是(C1至C3)烷氧基。
應理解的是,本文所述的任何烷基、烯基、炔基、環烷基、雜環和環烯基部分也可為脂肪族基團(aliphatic group)或脂環族基團(alicyclic group)。
「脂肪族(aliphatic)」基團是由碳原子、氫原子、鹵原子、氧、氮或其他原子的任何組合所包含的非芳香族部分,且視需要而定含有一或多個不飽和單元,例如雙和/或三鍵。脂肪族基團的範例是官能基,例如烷基、烯基、炔基、O、OH、NH、NH2、C(O)、S(O)2、C(O)O、C(O)NH、OC(O)O、OC(O)NH、OC(O)NH2、S(O)2NH、S(O)2NH2、NHC(O)NH2、NHC(O)C(O)NH、NHS(O)2NH、NHS(O)2NH2、C(O)NHS(O)2、C(O)NHS(O)2NH或C(O)NHS(O)2NH2、或前述類似基團、包含一或多個官能基的基團、非芳香族烴(視需要而定經取代的)、和其中非芳香族烴(視需要而定經取代的)的一或多個碳被官能基取代的基團。脂肪族基團的碳原子可視需要而定被側氧基取代。脂肪族基團可為直鏈、支鏈、環狀或其組合,且較佳地含有介於約1和約24個之間的碳原子、更通常介於約1和約12個之間的碳原子。除了脂肪族烴基團之外,如本文所使用地,脂肪族基團明確地包含,例如烷氧基烷基(alkoxyalkyl)、聚烷氧基烷基(polyalkoxyalkyl),例如聚亞烷基二醇(polyalkylene glycol)、多胺(polyamine)和多亞胺(polyimine),例如。脂肪族基團可視需要而定被取代。
術語「雜環」或「雜環烷基」可互換使用,且是指非芳香環或雙或三環基團稠合、橋接或螺旋系統,其中(i)每個環系統含有至少一個雜原子獨立地選自氧、硫和氮,(ii)每個環系統可為飽和或不飽和,(iii)氮和硫雜原子可視需要而定被氧化,(iv)氮雜原子可視需要而定被季銨化(quaternized),(v)任何上述環可與芳香環稠合,且(vi)剩餘的環原子是可視需要而定被側氧基取代或視需要而定被環外烯烴、亞胺或肟雙鍵取代的碳原子。代表性的雜環烷基基團包含但不限於1,3-二氧戊環(1,3-dioxolane)、吡咯烷基(pyrrolidinyl)、吡唑啉基(pyrazolinyl)、吡唑烷基(pyrazolidinyl)、咪唑啉基(imidazolinyl)、咪唑烷基(imidazolidinyl)、哌啶基(piperidinyl)、哌嗪基(piperazinyl)、噁唑烷基(oxazolidinyl)、異噁唑烷基(isoxazolidinyl)、嗎啉基(morpholinyl)、噻唑烷基(thiazolidinyl)、異噻唑烷基(isothiazolidinyl)、喹喔啉基(quinoxalinyl)、噠嗪酮基(pyridazinonyl)、2-氮雜雙環[2.2.1]-庚基(2-azabicyclo[2.2.1]-heptyl)、8-氮雜雙環[3.2.1]辛基(8-azabicyclo[3.2.1]octyl)、5-氮雜螺[2.5]辛基(5-azaspiro[2.5]octyl)、1-氧雜-7-氮雜螺[4.4]壬基(1-oxa-7-azaspiro[4.4]nonanyl)、7-側氧基氧雜環庚烷-4-基(7-oxooxepan-4-yl)和四氫呋喃基(tetrahydrofuryl)。這樣的雜環基團可進一步被取代。雜芳基或雜環基團可為C-連接的或N-連接的(在可能的地方)。
應理解的是,當作為連接二或更多個基團或取代基的連結(linkage)時,本文所述的任何烷基、烯基、炔基、脂環族
(alicyclic)、環烷基、環烯基、芳基、雜芳基、雜環、脂肪族(aliphatic)部分或前述類似基團也可為二價或多價基團,其可在相同或不同的原子上。本發明所屬技術領域中具有通常知識者可輕易地從其發生的背景中確定任何這種基團的化合價(valence)。
術語「經取代的(substituted)」是指藉由用取代基獨立取代一、二或三或更多個氫原子的取代,前述取代基包含但不限於-F、-Cl、-Br、-I、-OH、C1至C12-烷基;C2至C12-烯基、C2至C12-炔基、被保護的羥基、-NO2、-N3、-CN、-NH2、被保護的胺基、側氧基、硫代(thioxo)、-NH-C1至C12-烷基、-NH-C2至C8-烯基、-NH-C2至C8-炔基、-NH-C3至C12-環烷基、-NH-芳基、-NH-雜芳基、-NH-雜環烷基、-二烷基胺基(dialkylamino)、-二芳基胺基(diarylamino)、-二雜芳基胺基(diheteroarylamino)、-O-C1至C12-烷基、-O-C2-C8-烯基、-O-C2-C8-炔基、-O-C3至C12-環烷基、-O-芳基、-O-雜芳基、-O-雜環烷基、-C(O)-C1至C12-烷基、-C(O)-C2至C8-烯基、-C(O)-C2至C8-炔基、-C(O)-C3至C12-環烷基、-C(O)-芳基、-C(O)-雜芳基、-C(O)-雜環烷基、-CONH2、-CONH-C1至C12-烷基、-CONH-C2至C8-烯基、-CONH-C2至C8-炔基、-CONH-C3至C12-環烷基、-CONH-芳基、-CONH-雜芳基、-CONH-雜環烷基、-OCO2-C1至C12-烷基、-OCO2-C2至C8-烯基、-OCO2-C2至C8-炔基、-OCO2-C3至C12-環烷基、-OCO2-芳基、-OCO2-雜芳基、-OCO2-雜環烷基、-CO2-C1至C12烷基、-CO2-C2至C8烯基、-CO2-C2至C8炔基、CO2-C3至C12-環烷基、-CO2-芳基、CO2-雜
芳基、CO2-雜環烷基、-OCONH2、-OCONH-C1至C12-烷基、-OCONH-C2至C8-烯基、-OCONH-C2至C8-炔基、-OCONH-C3至C12-環烷基、-OCONH-芳基、-OCONH-雜芳基、-OCONH-雜環-烷基、-NHC(O)H、-NHC(O)-C1至C12-烷基、-NHC(O)-C2至C8-烯基、-NHC(O)-C2至C8-炔基,-NHC(O)-C3至C12-環烷基、-NHC(O)-芳基、-NHC(O)-雜芳基、-NHC(O)-雜環-烷基、-NHCO2-C1至C12-烷基、-NHCO2-C2至C8-烯基、-NHCO2-C2至C8-炔基、-NHCO2-C3至C12-環烷基、-NHCO2-芳基、-NHCO2-雜芳基、-NHCO2-雜環烷基、-NHC(O)NH2、-NHC(O)NH-C1至C12-烷基、-NHC(O)NH-C2至C8-烯基、-NHC(O)NH-C2至C8-炔基、-NHC(O)NH-C3至C12-環烷基、-NHC(O)NH-芳基、-NHC(O)NH-雜芳基、-NHC(O)NH-雜環烷基、NHC(S)NH2、-NHC(S)NH-C1至C12-烷基、-NHC(S)NH-C2至C8-烯基、-NHC(S)NH-C2至C8-炔基、-NHC(S)NH-C3至C12-環烷基、-NHC(S)NH-芳基、-NHC(S)NH-雜芳基、-NHC(S)NH-雜環烷基、-NHC(NH)NH2、-NHC(NH)NH-C1至C12-烷基、-NHC(NH)NH-C2至C8-烯基、-NHC(NH)NH-C2至C8-炔基、-NHC(NH)NH-C3至C12-環烷基、-NHC(NH)NH-芳基、-NHC(NH)NH-雜芳基、-NHC(NH)NH-雜環烷基、-NHC(NH)-C1至C12-烷基、-NHC(NH)-C2至C8-烯基、-NHC(NH)-C2至C8-炔基、-NHC(NH)-C3至C12-環烷基、-NHC(NH)-芳基、-NHC(NH)-雜芳基、-NHC(NH)-雜環烷基、-C(NH)NH-C1至C12-烷基、-C(NH)NH-C2至C8-烯基、-C(NH)NH-C2至C8-炔基、-C(NH)NH-C3至C12-環烷基、-C(NH)NH-芳基、-C(NH)NH-雜
芳基、-C(NH)NH-雜環烷基、-S(O)-C1至C12-烷基、-S(O)-C2至C8-烯基、-S(O)-C2至C8-炔基、-S(O)-C3至C12-環烷基、-S(O)-芳基、-S(O)-雜芳基、-S(O)-雜環烷基、-SO2NH2、-SO2NH-C1至C12-烷基、-SO2NH-C2至C8-烯基、-SO2NH-C2至C8-炔基、-SO2NH-C3至C12-環烷基、-SO2NH-芳基、-SO2NH-雜芳基、-SO2NH-雜環烷基、-NHSO2-C1至C12-烷基、-NHSO2-C2至C8-烯基、-NHSO2-C2至C8-炔基、-NHSO2-C3至C12-環烷基、-NHSO2-芳基、-NHSO2-雜芳基、-NHSO2-雜環烷基、-CH2NH2、-CH2SO2CH3、-芳基、芳烷基、-雜芳基、-雜芳烷基、-雜環烷基、-C3至C12-環烷基、聚烷氧基烷基、聚烷氧基(polyalkoxy)、-甲氧基甲氧基(methoxymethoxy)、-甲氧基乙氧基(methoxyethoxy)、-SH、-S-C1至C12-烷基、-S-C2至C8-烯基、-S-C2至C8-炔基、-S-C3至C12-環烷基、-S-芳基、-S-雜芳基、-S-雜環烷基或甲硫基-甲基(methylthio-methyl)。在某些實施例中,取代基獨立地選自鹵素,較佳為Cl和F;C1至C4烷基,較佳為甲基和乙基;C2至C4烯基;鹵素-C1至C4-烷基,例如氟甲基、二氟甲基和三氟甲基;鹵素-C2至C4-烯基;C3至C6-環烷基,例如環丙基;-CN;-OH;NH2;C1至C4-烷基胺基;二(C1至C4-烷基)胺基;和NO2。應理解的是,取代基,例如芳基、雜芳基、烷基及前述類似取代基為視需要而定被進一步取代。在一些情況下,取代部分中的每個取代基另外地視需要而定被一或多個基團取代,每個基團獨立地選自C1至C4-烷基;CF3、C1至C4-烷氧基;-OCF3、-F、-Cl、-Br、-I、-OH、-NO2、-CN和-NH2。
應理解的是,芳基、雜芳基、烷基、環烷基及前述類似基團可進一步被取代。
單獨或作為另一取代基的一部分之本文所使用的術語「鹵素」或「鹵原子」是指氟、氯、溴或碘原子。
如本文所使用地,術語「視需要而定經取代的」是指所引用的基團可被取代或未被取代。在一實施例中,所引用的基團視需要而定被零個取代基取代,即所引用的基團未被取代。在另一實施例中,所引用的參考基團視需要而定被一或多個個別且獨立地選自本文所述的基團的額外基團所取代。
術語「氫」包含氫和氘(deuterium)。此外,只要產生的化合物是醫藥上可接受的,原子的記載包含那個原子的其他同位素。
在某些實施例中,本文每個式的化合物定義為包含同位素標記的化合物。「同位素標記的化合物」是其中至少一個原子位置富含指定元素的特定同位素至顯著大於那個同位素的天然豐富度的程度的化合物。舉例而言,可以用氘使化合物中的一或多個氫原子位置富含至顯著大於氘的天然豐富度的程度,例如,富含至至少1%、較佳至少20%或至少50%的程度。例如,這種氘化(deuterated)化合物可例如,比其非氘化類似物更慢地代謝,因此當投予至對象時,表現出較長的半衰期。可使用本領域已知的方法,例如藉由使用氘化的起始材料,來合成這些化合物。除非相反地說明,否則同位素標記的化合物是醫藥上可接受的。
如本文所使用地,術語「羥基活化基團」是指本領域已知可活化羥基基團以使其在合成流程中,例如在取代或消除反
應中脫離的不穩定(labile)化學部分。羥基活化基團的範例包含但不限於甲磺酸酯(mesylate)、甲苯磺酸酯(tosylate)、三氟甲磺酸酯(triflate)、對硝基苯甲酸酯(p-nitrobenzoate)、膦酸酯(phosphonate)及前述類似基團。
如本文所使用地,術語「活化的羥基」是指用如上述所定義的羥基活化基團包含例如甲磺酸酯、甲苯磺酸酯、三氟甲磺酸酯、對硝基苯甲酸酯、膦酸酯基團,來活化的羥基基團。
如本文所使用地,術語「羥基保護基團」是指本領域已知在合成流程中保護羥基基團免於不希望的反應的不穩定化學部分。在所述合成流程之後,可視需要而定除去如本文所述的羥基保護基團。本領域已知的羥基保護基團一般描述於T.H.Greene和P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd edition,John Wiley&Sons,New York(1999)中。羥基保護基團的範例包含芐氧基羰基(benzyloxycarbonyl)、4-甲氧基芐氧基羰基(4-methoxybenzyloxycarbonyl)、叔丁氧基羰基(tert-butoxy-carbonyl)、異丙氧基羰基(isopropoxycarbonyl)、二苯基甲氧基羰基(diphenylmethoxycarbonyl)、2,2,2-三氯乙氧基羰基(2,2,2-trichloroethoxycarbonyl)、烯丙氧基羰基(allyloxycarbonyl)、乙醯基(acetyl)、甲醯基(formyl)、氯乙醯基(chloroacetyl)、三氟乙醯基(trifluoroacetyl)、甲氧基乙醯基(methoxyacetyl)、苯氧基乙醯基(phenoxyacetyl)、苯甲醯基(benzoyl)、甲基、t-丁基、2,2,2-三氯乙基(2,2,2-trichloroethyl),2-三甲基甲矽烷基乙基(2-trimethylsilyl ethyl)、烯丙基(allyl)、芐基(benzyl)、三苯
基-甲基(三苯甲基)(triphenyl-methyl(trityl))、甲氧基甲基(methoxymethyl)、甲硫基甲基(methylthiomethyl)、芐氧基甲基(benzyloxymethyl)、2-(三甲基甲矽烷基)-乙氧基甲基(2-(trimethylsilyl)-ethoxymethyl)、甲磺醯基(methanesulfonyl)、三甲基甲矽烷基(trimethylsilyl)、三異丙基甲矽烷基(triisopropylsilyl)及前述類似基團。
如本文所使用地,術語「被保護的羥基」是指用如上述所定義的羥基保護基團包含例如苯甲醯基、乙醯基、三甲基甲矽烷基、三乙基甲矽烷基(triethylsilyl)、甲氧基甲基,來保護的羥基基團。
本文所使用的術語「羥基前藥基團」是指本領域已知藉由覆蓋或遮蔽羥基基團,以瞬時方式改變原型藥物(parent drug)的物理化學性質,因此改變其生物學性質的前體基團(promoiety group)。在所述合成流程之後,如本文所述的羥基前藥基團必能夠在體內(in vivo)回復至羥基。本領域已知的羥基前藥基團一般描述於Kenneth B.Sloan,Prodrugs,Topical and Ocular Drug Delivery,(Drugs and the Pharmaceutical Sciences;Volume 53),Marcel Dekker,Inc.,New York(1992)中以及描述於S.S.Dhareshwar和V.J.Stella的「Prodrugs of Alcohols and Phenols」中,其於由V.J.Stella,et al編輯的Prodrugs Challenges and Rewards Part-2,(Biotechnology:Pharmaceutical Aspects),Springer和AAPSPress,2007,pp 31-99中。
如本文所使用地,術語「胺基保護基團」是指本領域已知在合成過程中保護胺基免於不希望的反應的不穩定化學部分。在所述合成流程之後,可視需要而定除去如本文所述的胺基保護基團。本領域已知的胺基保護基團通常描述於T.H.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd edition,John Wiley & Sons,New York(1999)中。胺基保護基的範例包含但不限於甲氧基羰基(methoxycarbonyl)、叔丁氧基羰基(t-butoxycarbonyl)、9-芴基-甲氧基羰基(9-fluorenyl-methoxycarbonyl)、芐氧基羰基及前述類似基團。
如本文所使用地,術語「被保護的胺基」是指用如上述所定義的胺基保護基團來保護的胺基。
術語「胺基酸」是指天然存在的和合成的α、β、γ或δ胺基酸,且包含但不限於在蛋白質中發現的胺基酸或胺基酸或蛋白質代謝中的中間物(intermediate),即甘胺酸(glycine)、丙胺酸(alanine)、纈胺酸(valine)、白胺酸(leucine)、異白胺酸(isoleucine)、甲硫胺酸(methionine)、苯丙胺酸(phenylalanine)、色胺酸(tryptophan)、脯胺酸(proline)、絲胺酸(serine)、蘇胺酸(threonine)、半胱胺酸(cysteine)、酪胺酸(tyrosine)、天冬醯胺(asparagine)、穀氨醯胺(glutamine)、天門冬胺酸鹽(aspartate)、穀胺酸鹽(glutamate)、離胺酸(lysine)、瓜胺酸(citrulline)、精胺酸(arginine)和組胺酸(histidine)。在某些實施例中,胺基酸是以L-組態(configuraticn)。在某些實施例中,胺基酸是以D-組態。在某些實施例中,胺基酸作為本文所述之化合物的取代基來提供,其中胺基酸是選自由丙胺醯(alanyl)、
纈胺醯(valinyl)、白胺醯(leucinyl)、異白胺醯(isoleuccinyl)、脯胺醯(prolinyl)、苯丙胺醯(phenylalaninyl)、色胺醯(tryptophanyl)、甲硫胺醯(methioninyl)、甘胺醯(glycinyl)、絲胺醯(serinyl)、蘇胺醯(threoninyl)、半胱胺醯(cysteinyl)、酪胺醯(tyrosinyl)、天冬醯胺醯(asparaginyl)、穀氨醯胺醯(glutaminyl)、天門冬胺醯(aspartoyl)、穀胺醯(glutaroyl)、離胺醯(lysinyl)、精胺醯(argininyl)、組胺醯(histidinyl)、β-丙胺醯、β-纈胺醯、β-白胺醯、β-異白胺醯、β-脯胺醯、β-苯丙胺醯、β-色胺醯、β-甲硫胺醯、β-甘胺醯、β-絲胺醯、β-蘇胺醯、β-半胱胺醯、β-酪胺醯、β-天冬醯胺醯、β-穀氨醯胺醯、β-天門冬胺醯、β-穀胺醯、β-離胺醯、β-精胺醯和β-組胺醯所組成的群組的殘基。
術語「胺基酸衍生物」是指可衍生自天然或非天然存在的胺基酸的基團,如本文所述和舉例說明的。胺基酸衍生物對於本發明所屬技術領域中具有通常知識者是顯而易見的,且包含但不限於天然和非天然存在的胺基酸的酯(ester)、胺基醇(amino alcohol)、胺基醛(amino aldehyde)、胺基內酯(amino lactone)和N-甲基(N-methyl)衍生物。在一實施例中,提供胺基酸衍生物作為本文所述之化合物的取代基,其中取代基是-NRu-G(Sc)-C(O)-Q1,其中Q1是-SRv、-NRvRv或烷氧基,Rv是氫或烷基,Sc是天然存在的或非天然存在的胺基酸的側鏈,G是C1至C2烷基,且Ru是氫;或取Ru和Sc還有它們所連接的原子,來形成五員雜環。在一實施例中,提供胺基酸衍生物作為本文所述之化合物的取代基,其中取代基是-O-C(O)-G(Sc)-NH-Q2,其中Q2是氫或烷氧基,Sc是天然存在或非天然存在的胺基酸的側鏈,且G是C1
至C2烷基。在某些實施例中,取Q2和Sc還有它們所連接的原子,來形成五員雜環。在某些實施例中,G是視需要而定經取代的亞甲基(methylene)且Sc選自由氫、烷基、芳烷基、雜環烷基(heterocycloalkyl)、羧基烷基(carboxylalkyl)、雜芳烷基(heteroarylalkyl)、胺基烷基(aminoalkyl)、羥基烷基(hydroxylalkyl)、胺基亞胺基胺基烷基(aminoiminoaminoalkyl)、胺基羰基烷基(aminocarbonylalkyl)、硫烷基烷基(sulfanylalkyl)、胺甲醯基烷基(carbamoylalkyl)、烷基硫烷基烷基(alkylsulfanylalkyl)和羥基芳烷基(hydroxylarylalkyl)所組成的群組。在一實施例中,提供胺基酸衍生物作為本文所述之化合物的取代基,其中胺基酸衍生物是以D-組態。在一實施例中,提供胺基酸衍生物作為本文所述之化合物的取代基,其中胺基酸衍生物是以L-組態。
術語「離去基團(leaving group)」是指在取代反應中,例如親核取代(nucleophilic substitution)反應中,可被另一官能基或原子所替代的的官能基或原子。藉由範例的方式來說,代表性離去基團包含氯、溴和碘基團;磺酸酯基團(sulfonic ester group),例如甲磺酸酯、甲苯磺酸酯、溴苯磺酸酯(brosylate)、硝基苯磺酸酯(nosylate)和前述類似基團;和醯氧基團,如乙醯氧基(acetoxy)、三氟乙醯氧基(trifluoroacetoxy)和前述類似基團。
如本文所使用地,術語「非質子溶劑(aprotic solvent)」是指對質子活性相對惰性的溶劑,即不作為質子供體。範例包含但不限於烴,例如己烷和甲苯(toluene),例如鹵化烴,例
如舉例而言氯甲烷(methylene chloride)、氯乙烷(ethylene chloride)、氯仿和前述類似物、雜環化合物,例如舉例而言四氫呋喃(tetrahydrofuran)和N-甲基吡咯烷酮(N-methylpyrrolidinone),和醚類例如乙醚(diethyl ether)、雙甲氧基甲基醚(bis-methoxymethyl ether)。這樣的化合物為本發明所屬技術領域中具有通常知識者所熟知的,且對於本發明所屬技術領域中具有通常知識者顯而易見的是,對於特定的化合物和反應條件,個別溶劑或其混合物可能是較佳的,這取決於例如舉例而言,藥劑(reagent)的溶解度、藥劑的反應性和較佳的溫度範圍的因素。可在有機化學教科書中或在專門的專論(specialized monograph)中找到非質子溶劑的進一步討論,例如:Organic Solvents Physical Properties and Methods of Purification,4th ed,由John A.Riddick et al編輯,Vol.II,於Techniques of Chemistry Series,John Wiley & Sons,NY,1986中。
如本文所使用的術語「質子溶劑」是指傾向提供質子的溶劑,例如醇,舉例而言甲醇、乙醇、丙醇、異丙醇、丁醇、叔丁醇和前述類似醇類。這樣的溶劑為本發明所屬技術領域中具有通常知識者所熟知的,且對於本發明所屬技術領域中具有通常知識者顯而易見的是,對於特定的化合物和反應條件,個別溶劑或其混合物可能是較佳的,這取決於例如舉例而言藥劑的溶解度、藥劑的反應性和較佳的溫度範圍的因素。可在有機化學教科書中或在專門的專論(specialized monograph)中找到質子溶劑的進一步討論,
例如:Organic Solvents Physical Properties and Methods of Purification,4th ed,由John A.Riddick et al編輯,Vol.II,於Techniques of Chemistry Series,John Wiley and Sons,NY,1986中。
本發明所設想的(envision)取代基和變數的組合僅為導致形成穩定化合物的那些。如本文所使用地,術語「穩定的」是指擁有足夠允許製造的穩定性且使化合物的完整性維持一段足夠的時間,以對本文詳述的目的(例如,治療性或預防性投予至對象)有用的化合物。
合成的化合物可以從反應混合物中分離出來,且藉由例如管柱層析(column chromatography)、高壓液相層析(high pressure liquid chromatography)或再結晶(recrystallization)的方法來進一步純化。如本發明所屬技術領域中具有通常知識者所可理解的,合成本文之化學式的化合物的其他方法對於本發明所屬技術領域中具有通常知識者來說是明顯的。另外,可用交替的順序或次序執行各種合成步驟,以給出期望化合物。於合成本文所述之化合物中有用的合成化學轉換(transformation)和保護基團方法(保護和去保護)是本領域已知的,且包含舉例而言,例如在R.Larock,Comprehensive Organic Transformations,2nd Ed.Wiley-VCH(1999);T.W.Greene and P.G.M.Wuts,Protective Groups in Organic Synthesis,3rd Ed.,John Wiley 和Sons(1999);L.Fieser and M.Fieser,Fieser and Fieser's Reagents for Organic Synthesis,John Wiley and Sons(1994);and L.Paquette,ed.,Encyclopedia of Reagents for Organic
Synthesis,John Wiley and Sons(1995)及前述的後續版本中所述的那些。
如本文所使用地,術語「對象」是指動物。較佳地,動物是哺乳動物。更佳地,哺乳動物是人。對象亦指例如狗、貓、馬、牛、豬、天竺鼠(guinea pig)、魚、鳥和前述類似動物。
可藉由追加(append)適當的官能性(functionality)來修飾本發明的化合物,以增強選擇性的生物性質。這些修飾是本領域已知的,且可包含增加至給定生物系統(例如,血液、淋巴系統、中樞神經系統)中的生物滲透、增加口服可用性、增加溶解度以允許藉由注射來投予、改變代謝和改變排泄率的那些修飾。
本文所述的化合物含有一或多個不對稱中心,因此產生對掌異構物(enantiomer)、非鏡像異構物(diastereomer)和就絕對立體化學而言,可定義為(R)-或(S)-、或為用於胺基酸的(D)-或(L)-的其他立體異構物(stereoisomeric)形式。本發明意在包含所有這些可能的異構物,以及它們的外消旋和光學純形式。光學異構物可藉由上述的流程或藉由解析(resolve)外消旋混合物,由它們各自的光學活性前驅物製備。可在解析試劑的存在下,藉由層析或藉由重複的結晶或藉由本發明所屬技術領域中具有通常知識者已知的這些技術的某種組合,來進行解析。可在Jacques,et al,Enantiomers,Racemates,and Resolutions(John Wiley & Sons,1981)中找到關於分辨率的進一步細節。當本文所述的化合物含有烯烴雙鍵、其他不飽和或其他幾何不對稱的中心時,除非另有說明,否則意味著化合物包含E和Z幾何異構物或順式和反式異構
物。同樣地,所有互變異構物(tautomeric)形式也打算被包含。互變異構物可為環狀或非環狀的(acyclic)。本文中出現的任何碳-碳雙鍵的組態(configuration)僅為了方便而選擇的,並不打算指定特定的組態,除非上下文如此陳述;因此,本文任意描述為反式的碳-碳雙鍵或碳-雜原子雙鍵可以是順式、反式或兩者以任何比例的混合物。
本發明的某些化合物也可以不同的穩定構形(conformational)形式存在,其可以是可分離的。由於圍繞不對稱單鍵,例如因為空間阻礙(steric hindrance)或環張力(ring strain)之受限制的旋轉而引起的扭轉不對稱(Torsicnal asymmetry),可允許不同構形異構物(conformer)的分離。本發明包含這些化合物的每種構形的異構物及其混合物。
如本文所使用地,術語「醫藥上可接受的鹽」是指在正當的醫學判斷範圍內,適合用於與人和低等動物的組織接觸而沒有過度毒性、刺激(irritation)、過敏反應和前述類似反應,且與合理的效益/風險比(benefit/risk ratio)相稱的那些鹽類。醫藥上可接受的鹽在本領域中是眾所皆知的。舉例而言,在J.Pharmaceutical Sciences,66:1-19(1977)中,S.M.Berge等人詳細描述了醫藥上可接受的鹽。在本發明化合物的最終分離和純化的期間,可原位(in situ)製備鹽或者藉由使游離鹼官能基與合適的有機酸反應,來分開地製備鹽。醫藥上可接受的鹽的範例包含但不限於,無毒酸添加鹽(nontoxic acid addition salt)是與無機酸或與有機酸或藉由使用本領域中所使用的其他方法,例如離子交換,所形成的胺基基團的鹽。前述無機酸為例如鹽酸(hydrochloric
acid)、氫溴酸(hydrobromic acid)、磷酸(phosphoric acid)、硫酸(sulfuric acid)和過氯酸(perchloric acid);前述有機酸為例如乙酸(acetic acid)、馬來酸(maleic acid)、酒石酸(tartaric acid)、檸檬酸(citric acid)、琥珀酸(succinic acid)或丙二酸(malonic acid)。其他醫藥上可接受的鹽包含但不限於己二酸鹽(adipate)、海藻酸鹽(alginate)、抗壞血酸鹽(ascorbate)、天門冬胺酸鹽(aspartate)、苯磺酸鹽(benzenesulfonate)、苯甲酸鹽(benzoate)、硫酸氫鹽(bisulfatc)、硼酸鹽(borate)、丁酸鹽(butyrate)、樟腦磺酸鹽(camphorate)、樟腦磺酸鹽(camphorsulfonate)、檸檬酸鹽(citrate)、環戊烷丙酸鹽(cyclopentane-propionate)、二葡萄糖酸鹽(digluconate)、十二烷基硫酸鹽(dodecylsulfate)、乙磺酸鹽(ethanesulfonate)、甲酸鹽(formate)、富馬酸鹽(fumarate)、葡庚糖酸鹽(glucoheptonate)、甘油磷酸鹽(glycerophosphate)、葡萄糖酸鹽(gluconate)、半硫酸鹽(hemisulfate)、庚酸鹽(heptanoate)、己酸鹽(hexanoate)、氫碘酸鹽(hydroiodide)、2-羥基乙磺酸鹽(2-hydroxy-ethanesulfonate)、乳糖酸鹽(lactobionate)、乳酸鹽(lactate)、月桂酸鹽(laurate)、十二烷基硫酸鹽(lauryl sulfate)、蘋果酸鹽(malate)、馬來酸鹽(maleate)、丙二酸鹽(malonate)、甲磺酸鹽(methanesulfonate)、2-萘磺酸鹽(2-naphthalenesulfonate)、菸酸鹽(nicotinate)、硝酸鹽(nitrate)、油酸鹽(oleate)、草酸鹽(oxalate)、棕櫚酸鹽(palmitate)、雙羥萘酸鹽(pamoate)、果膠酸鹽(pectinate)、過硫酸鹽(persulfate)、3-苯基丙酸鹽(3-phenylpropionate)、磷酸
鹽(phosphate)、苦味酸鹽(picrate)、新戊酸鹽(pivalate)、丙酸鹽(propionate)、硬脂酸鹽(stearate)、琥珀酸鹽succinate()、硫酸鹽(sulfate)、酒石酸鹽(tartrate)、硫氰酸鹽(thiocyanate)、對甲苯磺酸鹽(p-toluenesulfonate)、十一酸鹽(undecanoate)、戊酸鹽(valerate)和前述類似鹽。代表性的鹼金屬或鹼土金屬鹽包含鈉(sodium)、鋰(lithium)、鉀(potassium)、鈣(calcium)、鎂(magnesium)和前述類似鹽。適當時,其它醫藥上可接受的鹽包含使用相對離子(counterion),例如鹵化物(halide)、氫氧化物(hydroxide)、羧酸鹽(carboxylate)、硫酸鹽(sulfate)、磷酸鹽(phosphate)、硝酸鹽(nitrate)、具有1至6個碳原子的烷基、磺酸鹽(sulfonate)和芳基磺酸鹽(aryl sulfonate)所形成的無毒銨(nontoxic ammonium)、季銨(quaternary ammonium)和胺(amine)陽離子。
如本文所使用,術語「醫藥上可接受的酯」是指在體內(in vivo)水解且包含在人體內容易分解而留下母化合物(parent compound)或其鹽的酯。合適的酯基團包含,例如衍生自醫藥上可接受的脂肪族羧酸(aliphatic carboxylic acid),特別是烷酸(alkanoic acid)、烯酸(alkenoic acid)、環烷酸(cycloalkanoic acid)和烷二酸(alkanedioic acid)的那些,其中每個烷基或烯基部分有利地具有不超過6個碳原子。特定酯的範例包含但不限於C1至C6烷酸的酯,例如乙酸酯(acetate ester)、丙酸酯(propionate ester)、丁酸酯(butyrate ester)和新戊酸酯(pivalate ester)。
醫藥組合物
本發明的醫藥組合物包含與一或多個醫藥上可接受的載體或賦形劑(excipient)一起調配(formulate)之治療上有效量的本發明之化合物。
如本文所使用地,術語「醫藥上可接受的載體或賦形劑」是指無毒的惰性固體、半固體或液體填充劑、稀釋劑、密封材料(encapsulating material)或任何類型的調配助劑(formulation auxiliary)。可作為醫藥上可接受的載體的材料的一些範例是糖類,例如乳糖(lactose)、葡萄糖和蔗糖;澱粉,例如玉米澱粉和馬鈴薯澱粉;纖維素(cellulose)及其衍生物,例如羧甲基纖維素鈉(sodium carboxymethyl cellulose)、乙基纖維素(ethyl cellulose)和醋酸纖維素(cellulose acetate);粉末黃蓍草(tragacanth);麥芽(malt);明膠(gelatin);滑石(talc);賦形劑,例如可可脂(cocoa butter)和栓劑蠟(suppository wax);油,例如花生油、棉籽油(cottonseed oil)、紅花油(safflower oil)、芝麻油(sesame oil)、橄欖油(olive oil)、玉米油(corn oil)和大豆油(soybean oil);二元醇(glycol),例如丙二醇(propylene glycol);酯,例如油酸乙酯(ethyl oleate)和月桂酸乙酯(ethyl laurate);瓊脂(agar);緩衝劑,例如氫氧化鎂和氫氧化鋁;海藻酸;無熱原水(pyrogen-free water);等滲透壓食鹽水(isotonic saline);Ringer氏液(Ringer's solution);乙醇和磷酸鹽緩衝溶液,以及其他無毒相容的潤滑劑,例如十二烷基硫酸鈉(sodium lauryl sulfate)和硬脂酸鎂(magnesium stearate),以及著色劑、
脫模劑、塗層劑、甜味劑、調味劑和芳香劑,根據調配者(formulator)的判斷,防腐劑和抗氧化劑也可存在於組合物中。
可經口服(orally)、胃腸外(parenterally)、藉由吸入噴霧(inhalation spray)、局部(topically)、直腸(rectally)、鼻腔(nasally)、口腔(buccally)、陰道(vaginally)或透過植入的儲庫(reservoir),來投予本發明的醫藥組合物,較佳地藉由口服投予或藉由注射投予。本發明的醫藥組合物可含有任何常規的無毒之醫藥上可接受的載體、佐劑(adjuvant)或媒介物(vehicle)。在一些情況下,可用醫藥上可接受的酸、鹼或緩衝劑,來調整調配物(formulation)的pH,以增強所調配的化合物或其遞送形式的穩定性。本文所使用的術語胃腸外包含皮下(subcutaneous)、皮內(intracutaneous)、靜脈內(intravenous)、肌肉內(intramuscular)、關節內(intraarticular)、動脈內(intra-arterial)、滑膜內(intrasynovial)、胸骨內(intrasternal)、鞘內(intrathecal)、病灶內(intralesional)和顱內注射(intracranial injection)或輸注技術。
用於口服投予的液體劑型包含醫藥上可接受的乳液(emulsion)、微乳液(microemulsion)、溶液、懸浮液、糖漿和酏劑(elixir)。除了活性化合物之外,液體劑型可含有本領域常用的惰性稀釋劑,例如舉例來說,水或其它溶劑、助溶劑和乳化劑,例如乙醇、異丙醇、碳酸乙酯(ethyl carbonate)、乙酸乙酯(ethyl acetate)、芐基醇(benzyl alcohol)、苯甲酸芐酯(benzyl benzoate)、丙二醇、1,3-丁二醇(1,3-butylene glycol)、二甲基甲醯胺(dimethylformamide)、油(特別是棉籽、花生
(groundnut)、玉米、胚芽(germ)、橄欖油、蓖麻(castor)油和芝麻油)、甘油(glycerol)、四氫糠醇(tetrahydrofurfuryl alcohol)、聚乙二醇(polyethylene glycol)和山梨糖醇的脂肪酸酯及前述混合物。除了惰性稀釋劑之外,口服組合物亦可包含佐劑,例如潤濕劑(wetting agent)、乳化劑和懸浮劑、甜味劑、調味劑和芳香劑(perfuming agent)。
可根據已知技術使用合適的分散劑或潤濕劑和懸浮劑,來調配可注射製劑,例如無菌可注射水性或油性(oleaginous)懸浮液。無菌可注射製劑也可為在無毒的胃腸外可接受的稀釋劑或溶劑中的無菌可注射溶液、懸浮液或乳液,例如作為在1,3-丁二醇中的溶液。在可使用之可接受的媒介物和溶劑中的是水、Ringer氏液、U.S.P和等滲透壓氯化鈉溶液。此外,無菌的固定油常規地用作為溶劑或懸浮介質來使用。為此目的,可使用任何溫和的(bland)固定油,包含合成的單或雙酸甘油酯。此外,脂肪酸例如油酸用於可注射式的製備中。
例如,可藉由通過細菌截留過濾器過濾,或可藉由將可在使用前溶解或分散於無菌水或其它無菌可注射介質中的無菌固體組合物形式的滅菌劑併入,來將可注射製劑滅菌。
為了延長藥物的效果,減緩自皮下或肌內注射的藥物的吸收通常是可期望的。這可藉由使用水溶性差的結晶或非晶形材料的液體懸浮液來實現。然後,藥物的吸收速率取決於其溶解速率,而溶解速率又取決於晶體大小和晶形。或者,藉由將藥物溶解或懸浮於油性媒介物中,來實現胃腸外投予的藥物形式的延遲吸收。藉由在可生物降解的聚合物,例如聚乳酸-聚甘醇
(polylactide-polyglycolide)中形成藥物的微粒包覆基質(microencapsule matrix),來製造可注射的貯存形式。取決於藥物與聚合物的比例和所用的特定聚合物的性質,可控制藥物釋放的速率。其他可生物降解的聚合物的範例包含聚(原酸酯(orthoester))和聚(酸酐(anhydride))。亦藉由將藥物捕獲於與身體組織相容的脂質體或微乳液中,來製備貯存可注射製劑。
用於直腸或陰道投予的組合物較佳為栓劑(suppository),其可藉由將本發明的化合物與合適的無刺激性賦形劑或載體,例如可可脂、聚乙二醇或栓劑蠟混合來製備,前述賦形劑或載體在環境溫度下是固體但在體溫下是液體,因此在直腸或陰道腔內融化並釋放出活性化合物。
用於口服投予的固體劑型包含膠囊、片劑(tablet)、丸劑(pill)、粉劑(powder)和顆粒劑(granule)。在這種固體劑型中,活性化合物與至少一種惰性的醫藥上可接受的賦形劑或載體,例如檸檬酸鈉或磷酸二鈣(dicalcium phosphate)和/或:a)填充劑或增量劑(extender),例如澱粉、乳糖、蔗糖、葡萄糖、甘露醇(mannitol)和矽酸(silicic acid),b)黏合劑,例如羧甲基纖維素(carboxymethylcellulose)、海藻酸鹽、明膠、聚乙烯基吡咯烷酮(polyvinylpyrrolidinone)、蔗糖和阿拉伯膠(acacia),c)保濕劑(humectant),例如甘油,d)崩解劑(disintegrating agent),例如瓊脂(agar-agar)、碳酸鈣、馬鈴薯或木薯澱粉(tapioca starch)、海藻酸、某些矽酸鹽和碳酸鈉,e)溶液阻滯劑(solution retarding agent)例如石蠟(paraffin),f)吸收加速劑例如季銨化合物,g)潤濕劑例如鯨蠟醇(cetyl alcohol)和單硬脂酸甘油酯
(glycerol monostearate),h)吸收劑如高嶺土(kaolin)和膨潤土(bentonite clay),和i)潤滑劑,例如滑石(talc)、硬脂酸鈣(calcium stearate)、硬脂酸鎂(magnesium stearate)、固體聚乙二醇(solid polyethylene glycol)、十二烷基硫酸鈉(sodium lauryl sulfat)及前述之混合物混合。在膠囊、片劑和丸劑的情況下,劑型亦可包含緩衝劑。
類似類型的固體組合物也可用作為軟性和硬性填充的明膠膠囊中的填充劑,使用例如乳糖或奶糖以及高分子重量的聚乙二醇和前述類似物的賦形劑。
可用包衣(coating)和外殼,例如腸溶包衣(enteric coating)和醫藥調製領域熟知的其它包衣,來製備片劑、糖衣錠(dragee)、膠囊、丸劑和顆粒劑的固體劑型。它們可視需要而定含有失透劑(opacifying agent),且亦可以是視需要而定以延遲的方式僅在或優先在腸道的某一部分,釋放活性成分的組合物。可使用的包埋組合物(embedding composition)的範例包含聚合物物質(polymeric substance)和蠟。
本發明之化合物用於局部或經皮(transdermal)投予的劑型包含軟膏(ointment)、糊劑(paste)、乳膏(cream)、乳液(lotion)、凝膠(gel)、粉末、溶液、噴霧劑(spray)、吸入劑(inhalant)或貼劑(patch)。在無菌條件下,將活性成分與醫藥上可接受的載體和任何所需的防腐劑或可能需要的緩衝劑混合(admix)。眼科製劑、耳液、眼用軟膏、粉末和溶液也被認為在本發明的範圍內。
除本發明的活性化合物之外,軟膏、糊劑、乳膏和凝膠還可含有賦形劑,例如動物和植物脂肪、油、蠟、石蠟、澱粉、
黃蓍草、纖維素衍生物、聚乙二醇、矽氧烷(silicone)、膨潤土、矽酸、滑石和氧化鋅或前述之混合物。
除了本發明的化合物之外,粉末和噴霧劑還可含有賦形劑,例如乳糖、滑石、矽酸、氫氧化鋁、矽酸鈣和聚醯胺(polyamide)粉末或這些物質的混合物。噴霧劑可額外含有慣用的(customary)推進劑(propellant),例如氯氟烴(chlorofluorohydrocarbon)。
經皮貼劑具有提供控制化合物遞送至身體的附加優點。可藉由將化合物溶解或配藥(dispense)於適當的介質中,來製備這種劑型。吸收增強劑也可用於增加化合物通過皮膚的通量(flux)。可藉由提供速率控制膜或藉由將化合物分散在聚合物基質或凝膠中,來控制速率。
對於肺部(pulmonary)遞送,以固體或液體顆粒形式來調配本發明的治療組合物且藉由直接投予例如吸入至呼吸系統中,來投予至患者。用於實施(practice)本發明所製備的活性化合物的固體或液體顆粒形式包含可呼吸尺寸的顆粒:即,尺寸夠小以在吸入時通過口腔和喉部(larynx)且進入肺部的支氣管(bronchi)和肺泡(alveolus)的顆粒。霧化(aerosolized)治療劑的遞送,特別是霧化抗生素是本領域已知的(參見例如Van Devanter et al的美國專利號5,767,068、Smith et al的美國專利號5,508,269和Montgomery的WO 98/43650,所有這些都藉由引用併入本文。)
抗病毒活性
本發明的化合物的抑制量或劑量可為從約0.01mg/Kg至約500mg/Kg、或者從約1至約50mg/Kg。抑制量或劑量也會取決於投予途徑(route)以及與其他試劑(agent)共同使用的可能性而變化。
根據本發明的治療方法,於患者中例如人類或其它動物,藉由對患者投予治療上有效量的本發明之化合物,以達到預期結果所必需的量和時間,來治療或預防病毒感染的病情(condition)。
藉由「治療上有效量」的本發明之化合物是指以適用於任何醫學治療的合理的效益/風險比,來賦予治療對象治療效果的化合物的量。治療效果可以是客觀的(即,藉由某些測試或標記而可測量的)或主觀的(即,對象給出有效果的指示或感覺到效果)。上述化合物的有效量可為從約0.1mg/Kg至約500mg/Kg、較佳從約1至約50mg/Kg。有效劑量也會取決於投予途徑以及與其他試劑共同使用的可能性而變化。然而,應該理解的是,本發明的化合物和組合物的每日總使用量將由主治醫師於正當的醫學判斷範圍內決定。任何特定患者的特定治療上有效劑量的程度將取決於多種因素,包含所治療的病症(disorder)和此病症的嚴重程度;所用的特定化合物的活性;所用的特定組成;患者的年齡、體重、一般健康狀況、性別和飲食;投予時間、投予途徑和所用的特定化合物的排出率;治療的持續時間;與所用的特定化合物組合或同時使用的藥物;和醫學領域眾所皆知的類似因素。
本發明化合物之以單一劑量(single dose)或分劑量(divided dose)投予至人類或其它動物的每日總劑量可在量的方
面,例如為從0.01至50mg/kg體重或更通常從0.1至25mg/kg體重。單一劑量組合物可含有此量或其因數(submultiple)以構成每日劑量。通常,根據本發明的治療方案(therapy regimen)包含每天以單一劑量或多劑量,對需要這種治療的患者投予從約10mg至約1000mg的本發明的化合物。
每4到120小時,以從約0.1至約500mg/kg體重的劑量或者1mg和1000mg/劑之間的劑量或根據特定藥物的要求,可藉由例如注射、靜脈內、動脈內、表皮下(subdermally)、腹腔內(intraperitoneally)、肌肉內或皮下;或口服、口腔、鼻腔、跨黏膜(transmucosally)、局部、以眼科製品(preparation)或藉由吸入,來投予本文所述之本發明化合物。本文的方法考慮有效量的化合物或化合物組合物的投予,以達到所期望或所述的效果。通常,會以每天從約1至約6次或者作為連續灌注(infusion),來投予本發明的醫藥組合物。這種投予可作為慢性或急性療法(therapy)。可與醫藥上的賦形劑或載體組合以產生單一劑型的活性成分的量將取決於所治療的宿主和特定的投予模式而變化。典型的製品(preparation)會含有從約5%至約95%的活性化合物(w/w)。或者,此類製品可含有從約20%至約80%的活性化合物。
可能需要比以上記載的那些劑量更低或更高的劑量。任何特定患者的具體劑量和治療方案取決於多種因素,包含所用的特定化合物的活性、年齡、體重、一般健康狀況、性別、飲食、投予時間、排出率、藥物組合、疾病的嚴重程度和病程、病情或症狀、患者對疾病、病情或症狀的處置(disposition)以及治療醫師的判斷。
在改善患者的病情後,如果需要的話,可投予本發明化合物、組合物或組合的維持劑量。隨後,當症狀已經緩解至所期望的程度時,可將投予劑量或頻率或兩者,作為症狀的函數降低至保持病情改善的程度。然而,在任何疾病症狀的復發時,患者可能需要長期的間歇性治療。
當本發明的組合物包含本文所述的化學式(formula)的化合物與一或多個額外治療試劑或預防試劑的組合時,化合物和額外試劑應當以在單一治療方案(monotherapy regimen)中通常投予的劑量的約1至100%之間、更佳地約5至95%之間的劑量程度存在。作為多劑量療法(multiple dose regimen)的一部分,額外試劑可與本發明的化合物分開投予。或者,那些試劑可為以單一組合物的形式與本發明化合物混合在一起的單一劑型的一部分。
所述「額外治療或預防試劑」包含但不限於,免疫療法(例如干擾素)、治療性疫苗、抗纖維化試劑(antifibrotic agent)、抗發炎試劑例如皮質類固醇(corticosteroid)或NSAID、支氣管擴張劑(bronchodilator)例如beta-2腎上腺素促效劑(beta-2 adrenergic agonist)和黃嘌呤(xanthine)(例如茶鹼(theophylline))、黏液溶解劑(mucolytic agent)、抗毒蕈鹼(anti-muscarinic)、抗白三烯(anti-leukotriene)、細胞附著的抑制劑(例如ICAM拮抗劑)、抗氧化劑(例如N-乙醯半胱胺酸)、細胞激素促效劑、細胞激素拮抗劑、肺表面活性劑和/或抗微生物和抗病毒試劑(例如利巴韋林(ribavirin)和金剛烷胺(amantidine))。根據
本發明的組合物亦可與基因替代療法(gene replacement therapy)組合使用。
HBV的組合和交替療法
已經認知到,在用抗病毒試劑長時間治療後,可出現HIV、HBV和HCV的抗藥性變異體。抗藥性最典型地藉由編碼蛋白質的基因的突變而發生,例如用於病毒複製的酵素,且最典型地在HIV的情況下為反轉錄酶、蛋白質酶或DNA聚合酶,且在HBV的情況下為DNA聚合酶或在HCV的情況下為RNA聚合酶、蛋白質酶或解旋酶(helicase)。最近已展現出,藉由與誘導不同於主藥(principle drug)所導致的突變的突變之第二、及也許第三抗病毒化合物組合或交替投予化合物,可延長、加強(augment)或恢復藥物的抗HIV感染功效(efficacy)。化合物可用於組合,且選自由HBV聚合酶抑制劑、干擾素、TLR調節劑(TLR modulator)例如TLR-7促效劑或TLR-9促效劑、治療性疫苗、某些細胞病毒RNA感測器的免疫活化劑、病毒進入抑制劑、病毒成熟抑制劑、特殊的(distinct)衣殼組裝調節劑、特殊或未知機制的抗病毒化合物及前述之組合所組成的群組。或者,可藉由這種組合或交替療法,來改變藥物的藥物動力學(pharmacokinetics)、生物分布(biodistribution)或其他參數。基本上,組合療法通常優於交替療法,因為它在病毒上誘導多個同時的壓力。
用於HBV的治療的組合或交替療法的較佳化合物包含3TC、FTC、L-FMAU、干擾素、阿德福韋酯(adefovir dipivoxil)、恩替卡韋(entecavir)、替比夫定
(telbivudine)(L-dT)、伐托他濱(valtorcitabine)(3’-纈胺醯L-dC)、β-D-二氧戊環基鳥嘌呤(β-D-dioxolanyl-guanine DXG)、β-D-二氧戊環基-2,6-二氨基嘌呤(β-D-dioxolanyl-2,6-diaminopurine,DAPD)和β-D-二氧戊環基-6-氯嘌呤(β-D-dioxolanyl-6-chloropurine,ACP)、泛昔洛韋(famciclovir)、噴昔洛韋(penciclovir)、洛布卡韋(lobucavir)、更昔洛韋(ganciclovir)和利巴韋林(ribavirin)。
儘管已經描述了本發明之關於各種較佳實施例,但並不意圖限制於此,相反地,本發明所屬技術領域中具有通常知識者將認知的是,可在其中進行在本發明的精神和所附申請專利範圍的範圍內的變化和修飾。
縮寫
可在之後的方案(scheme)和實施例的描述中所使用的縮寫是:Ac用於乙醯(acetyl);AcOH用於乙酸(acetic acid);AIBN用於偶氮二異丁腈(azobisisobutyronitrile);BINAP用於2,2’-雙(二苯基膦基)-1,1’-聯萘(2,2’-bis(diphenylphosphino)-1,1’-binaphthyl);Boc2O用於二叔丁基二碳酸酯(di-tert-butyl-dicarbonate);Boc為叔丁氧基羰基(t-butoxycarbonyl);Bpoc用於1-甲基-1-(4-聯苯基)乙基羰基(1-methyl-1-(4-biphenylyl)ethyl carbonyl);Bz為苯甲醯(benzoyl);Bn用於芐基(benzyl);BocNHOH用於N-羥基胺基甲酸叔丁酯(tert-butyl N-hydroxycarbamate);t-BuOK用於叔丁
醇鉀(potassium tert-butoxide);Bu3SnH用於三丁基氫化錫(tributyltin hydride);BOP用於(苯並三唑-1-基氧基)三(二甲基胺基)磷酸六氟磷酸鹽((benzotriazol-1-yloxy)tris(dimethylamino)phospho-nium Hexafluorophosphate);Brine用於水中的氯化鈉溶液(sodium chloride solution in water);BSA用於N,O-雙-(三甲基矽烷基)乙醯胺(N,O-bis-(trimethylsilyl)acetamide);CDI用於羰基二咪唑(carbonyldiimidazole);CH2Cl2用於二氯甲烷(dichloromethane);CH3用於甲基(methyl);CH3CN用於乙腈(acetonitrile);Cs2CO3用於碳酸銫(cesium carbonate);CuCl用於氯化銅(copper(I)chloride);CuI用於碘化銅(copper(I)iodide);dba用於二亞芐基丙酮(dibenzylidene acetone);dppb用於二苯基膦基丁烷(diphenylphos-phinobutane);DBU用於1,8-二氮雜雙環[5.4.0]-十一碳-7-烯(1,8-diazabicyclo[5.4.0]-undec-7-ene);DCC用於N,N’-二環己基碳二亞胺(N,N’-dicyclohexyl-carbodiimide);DEAD用於偶氮二羧酸二乙酯(diethylazodicarboxylate);DIAD用於偶氮二羧酸二異丙酯(diisopropyl azodicarboxylate);DIPEA或(i-Pr)2EtN用於N,N,-二異丙基乙基胺(N,N,-diisopropylethyl amine);Dess-Martin periodinane用於1,1,1-三(乙醯氧基)-1,1-二氫-1,2-苯碘醯-3-(1H)-酮(1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)
-one);DMAP用於4-二甲基胺基吡啶(4-dimethylamino-pyridine);DME用於1,2-二甲氧基乙烷(1,2-dimethoxyethane);DMF用於N,N-二甲基甲醯胺(N,N-dimethylformamide);DMSO用於二甲基亞碸(dimethyl sulfoxide);DMT用於二(對甲氧基苯基)-苯基甲基(di(p-methoxyphenyl)-phenylmethyl)或二甲氧基三苯甲基(dimethoxytrityl);DPPA用於二苯基磷醯基疊氮化物(diphenylphosphoryl azide);EDC用於N-(3-二甲基胺基丙基)-N’-乙基碳二亞胺(N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide);EDC HCl用於N-(3-二甲基胺基丙基)-N’-乙基碳二亞胺鹽酸鹽(N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride);EtOAc用於乙酸乙酯(ethyl acetate);EtOH用於乙醇(ethanol);Et2O用於乙醚(diethyl ether);HATU用於O-(7-氮雜苯並三唑-1-基)-N,N,N’,N’,-四甲基脲六氟磷酸鹽(O-(7-azabenzotriazol-1-yl)-N,N,N’,N’,-tetramethyluronium Hexafluoro-phosphate);HCl用於氯化氫(hydrogen chloride);HOBT用於1-羥基苯並三唑(1-hydroxybenzotriazole);K2CO3用於碳酸鉀(potassium carbonate);n-BuLi用於正丁基鋰(n-butyl lithium);i-BuLi用於異丁基鋰(i-butyl lithium);t-BuLi用於叔丁基鋰(t-butyl lithium);PhLi用於苯基鋰(phenyl lithium);LDA用於二異丙基
胺基鋰(lithium diisopropylamide);LiTMP用於2,2,6,6-四甲基哌啶酸鋰(lithium 2,2,6,6-tetramethyl-piperidinate);MeOH用於甲醇(methanol);Mg用於鎂(magnesium);MOM用於甲氧基甲基(methoxymethyl);Ms用於甲磺醯基(mesyl)或(-SO2-CH3);Ms2O用於甲磺酸酐(methanesulfonic anhydride)或甲磺醯基酐(mesyl-anhydride);MTBE用於叔丁基甲基醚(t-butyl methyl ether);NaN(TMS)2用於雙(三甲基甲矽烷基)胺基鈉(sodium bis(trimethylsilyl)amide);NaCl用於氯化鈉(sodium chloride);NaH用於氫化鈉(sodium hydride);NaHCO3用於重碳酸氫鈉(sodium bicarbonate)或碳酸氫鈉(sodium hydrogen carbonate);Na2CO3用於碳酸鈉(sodium carbonate);NaOH用於氫氧化鈉(sodium hydroxide);Na2SO4用於硫酸鈉(sodium sulfate);NaHSO3用於重亞硫酸鈉(sodium bisulfite)或亞硫酸氫鈉(sodium hydrogen sulfite);Na2S2O3用於硫代硫酸鈉(sodium thiosulfate);NH2NH2用於聯胺(hydrazine);NH4HCO3用於碳酸氫銨(ammonium bicarbonate);NH4Cl用於氯化銨(ammonium chloride);NMO用於N-甲基-嗎啉N-氧化物(N-methyl-morpholine N-oxide);NaIO4用於高碘酸鈉(sodium periodate);Ni用於鎳(nickel);NSFI用於N-氟苯磺醯亞胺(N-fluorobenzene-sulfonimide);OH用於羥(hydroxyl);o/n用於隔夜(overnight);OsO4用於四氧化鋨(osmium tetroxide);PTSA用於對甲苯磺酸
(p-toluenesulfonic acid);PPTS用於對甲苯磺酸吡啶鎓(pyridinium p-toluenesulfonate);TBAF用於四丁基氟化銨(tetrabutyl-ammonium fluoride);TEA或Et3N用於三甲基胺(trimethylamine);TES用於三乙基矽烷(triethylsilyl);TESCl用於三乙基甲矽烷基氯(triethylsilyl chloride);TESOTf用於三乙基甲矽烷基三氟甲磺酸鹽(triethylsilyl trifluoro-methanesulfonate);TFA用於三氟乙酸(trifluoroacetic acid);THF用於四氫呋喃(tetrahydro-furan);TMEDA用於N,N,N’,N’-四甲基乙二胺(N,N,N’,N’-tetramethylethylene-diamine);TPP或PPh3用於三苯基膦(triphenyl-phosphine);Troc用於2,2,2-三氯乙基羰基(2,2,2-trichloroethyl carbonyl);Ts用於甲苯磺醯(tosyl)或(-SO2-C6H4CH3);Ts2O用於甲苯磺酸酐(tolylsulfonic anhydride)或甲苯磺醯基酐(tosyl-anhydride);TsOH用於對甲苯磺酸(p-tolylsulfonic acid);Pd用於鈀(palladium);Ph用於苯基(phenyl);POPd用於二氫二氯二(二叔丁基膦基-κP)鈀(II)(dihydrogen dichlorobis(di-tert-butylphosphinito-κP)palladate(II));Pd2(dba)3用於三(二亞芐基丙酮)二鈀(0)(tris(dibenzylideneacetone)dipalladium(0));Pd(PPh3)4用於四(三苯基膦)鈀(0)(tetrakis(triphenyl-phosphine)palladium(0));PdCl2(PPh3)2用於反式二氯雙(三苯基膦)鈀(II)
(trans-dichlorobis-(triphenylphosphine)palladium(II));Pt用於鉑(platinum);Rh用於銠(rhodium);rt用於室溫(room temperature);Ru用於釕(ruthenium);SFC用於超臨界流體層析(supercritical fluid chromatography);TBS用於叔丁基二甲基甲矽烷基(tert-butyl dimethylsilyl);TMS用於三甲基甲矽烷基(trimethylsilyl);或TMSCl用於三甲基甲矽烷基氯(trimethylsilyl chloride)。
合成方法
結合以下所說明之可用來製備本發明的化合物的方法之合成方案,將更好地理解本發明的化合物及製程。這些方案是說明性的目的,並不意圖限制本發明的範圍。在不脫離合成方法的一般範圍的情況下,均等、相似或合適的溶劑、藥劑或反應條件可用來取代本文所述的那些特定溶劑、藥劑或反應條件。可如WO 2017/136403中所一般描述地,進行某些反應。
可使用本發明所屬技術領域中具有通常知識者已知的化學轉化(transformation),透過幾種不同的合成途徑,從各種視需要而定經取代的苯基、雜芳基或稠合雙環芳基或雜芳基前驅物,來製備式I的化合物。策略上,可建構式I的化合物以在右端形成磺醯基基團,接著在左端形成基團A。或者,可建構式I的化合物以在左端形成基團A,接著在右端形成磺醯基基團。可藉由硫化物的氧化(由k.S Schank,The Chemistry of Sulfones and Sulfoxides,Wiley,New York,1988,Chap.7綜述)或低價硫物
種(sulfur species)例如亞磺酸鹽(sulfinate salt)的烷基化/芳基化(由G.Liu,C.Fan,J.Wu,Org.Biomol.Chem.2015,13,1592綜述),來實現碸基(sulfone)的製備。可透過對有機鹵化物或磺酸酯親核取代、或對環氧化物(epoxide)、氮丙啶(aziridine)或不飽和物質親核加成(由G.Solladie,Comprehensive Organic Synthesis,1991,Vol 6,133綜述)、或對不飽和物質的硫醇自由基加成,從硫醇(thiol)前驅物合成硫化物。可藉由磺醯鹵化物的還原(由Schubart,R.Sulfinic Acids and Derivatives,Ullmann's Encyclopedia of Industrial Chemistry,2000,677綜述)或芳基或雜芳基鹵化物的過渡金屬催化反應(A.Shavnya,S.S.Coffey,A.C.Smith,V.Mascitti,Org.Lett.,2013,15,6226)或硼酸(A.Shavnya,K.D.Hesp,V.Mascitti,A.C.Smith,Angew.Chem.Int.Ed.,2015,54,13571),用偏亞硫酸氫鉀(potassium metabisulfite)來評估亞磺酸鹽(sulfonate salt)。可藉由用強鹼去質子化(deprotonation),接著使所得陰離子與親電子試劑例如有機鹵化物、醛、酮、親電鹵化藥劑或不飽和物例如Michael加成接受者反應,來進一步將碸基化合物官能化(functionalize);可透過兩輪順序的去質子化和陰離子親核反應,從初級碸基(primary sulfone)製備叔碸基。可藉由酸鹵化物或酸酐與胺(amine)的反應或在偶合劑(coupling reagent)例如DCC、EDC或HATU存在下,藉由羧酸與胺的直接偶合(coupling),來形成醯胺(amide)鍵。
如方案1中所示,其中X、Y和R如先前所定義;LG1、LG2每次出現時為離去基團且各自獨立地選自鹵原子、甲苯磺酸酯、甲磺酸酯和三氟甲磺酸酯。在一手段(approach)中,視需要而定在鹼例如但不限於三乙胺(triethylamine)、DIPEA或吡啶的存在下,視需要而定經取代的芳基或雜芳基胺1-1可在溶劑例如但不限於甲苯、四氫呋喃、二氯甲烷或前述之混合物中,視需要而定與各種酸氯化物1-2反應,以提供各種醯胺中間物1-3。然後用還原劑例如但不限於三苯基膦、SnCl2、Sn/HCl、Zn/HCl或Pd/HCOOH,來處理醯胺中間物1-3,以提供硫醇中間物1-4。硫醇中間物1-4視需要而定在鹼例如但不限於碳酸鉀、碳酸鈉、三乙胺或DIPEA的存在下,藉由親核置換(nucleophilic displacement)的方式,與中間物1-5反應,給予硫化物中間物。在氧化劑例如但不限於過氧化氫(hydrogen peroxide)、間氯過苯甲酸(meta-chloroperbenzoic acid)、過苯甲酸(perbenzoic acid)或叔丁基過氧化物(tert-butyl peroxide)的存在下,硫化物中間物在合適的溶劑中轉化為式IIa之化合物。或者,使用與上述類似的化學或藉由用有機金屬試劑(R-M,其中M是Mg-或Zn-物種)的親核取代,將羧酸酯1-6轉換為碸中間物1-7。可用鹼例如但不限於氫氧化鋰、氫氧化鈉或氫氧化鉀,將碸中間物1-7皂化(saponify)以產出羧酸1-8。視需要而定在鹼例如但不限於三乙胺、DIPEA或吡啶的存在下,於合適的溶劑中,在偶合劑例如但不限於DCC、EDC或HATU的存在下,羧酸1-8
可與胺1-1反應以產出式IIa的化合物。
於下方的方案2中描述式IIb之化合物的製備。醛2-1與TMSCF3反應,給出三氟乙醇(trifluoroethyl alcohol)2-2。藉由在鹼例如DIPEA的存在下與Tf2O反應,將三氟乙醇2-2轉化為三氟甲磺酸酯,接著用胺X-NH2置換,給予式IIb的化合物。
於方案3中舉例說明含有胺基氧雜環丁烷基(aminooxetanyl)部分的式IIc之化合物的合成。在酸例如乙酸或p-TsA的存在下,將芳基胺或雜芳基胺3-1與氧雜環丁烷-3-酮(oxetan-3-one)縮合(condense),給出亞胺3-2。用親核3-3處理亞胺3-2,其中M1是有機金屬物種包含但不限於與硼酸/酯、有機錫(organotin)、有機鋅(organozinc)、有機鋰(organolithium)或有機鎂(organomagesium)部分有關的有機金屬物種,給予式IIc之化
合物。
如方案4中所示,可從式IIa之化合物製備式IId之化合物。在鹼例如但不限於NaH或LDA的存在下,式IIa之化合物可與芐基溴反應,給出化合物4-1。藉由與草醯氯(oxalyl chloride)反應,接著用氟化劑例如但不限於DAST、SF4或Et3N-HF處理,將化合物4-1轉換為化合物4-2。可在合適的催化劑例如但不限於Pd/C、PtO2或Pd(OH)2/C的存在下,用氫氣處理化合物4-2,給予式IId之化合物。
應當理解的是,有適當操作和任何化學功能的保護,可藉由類似於上述那些方法和實驗部分中所述的那些方法,來實現式I之化合物的合成。可在T W Greene and P G M Wuts「Protective Groups in Organic Synthesis」,3rd Ed(1999),J Wiley and Sons中找到合適的保護基團,但不限制於在其中找到的那些。
本文引用的所有參考文獻,無論是印刷版、電子版、電腦可讀式儲存媒介或其他形式,均藉由引用而明確地全部併入本
文,包含但不限於摘要、文章、期刊、出版物、文本、論文(treatise)、網路網站、數據庫、專利和專利公開物。
對所揭露的實施例的各種變化和修飾對於本發明所屬技術領域中具有通常知識者而言是顯而易見的,且可在沒有背離本發明的精神和所附申請專利範圍的範圍的情況下,進行包含但不限於那些關於本發明的化學結構、取代基、衍生物、製劑和/或方法的這種變化和修飾。
儘管已經描述了本發明之關於各種較佳實施例,但並不打算限制於此,相反地,本發明所屬技術領域中具有通常知識者將認知的是,可在其中進行在本發明的精神和所附申請專利範圍的範圍內的變化和修飾。
實施例
結合以下實施例將更好地理解本發明的化合物和製程,這些實施例僅意圖作為說明而不是限制本發明的範圍。對所揭露的實施例的各種變化和修飾對於本發明所屬技術領域中具有通常知識者而言是顯而易見的,且可在沒有背離本發明的精神和所附申請專利範圍的範圍的情況下,進行包含但不限於那些關於本發明的化學結構、取代基、衍生物、製劑和/或方法的這種變化和修飾。
步驟Int 1a,將在SOCl2(5.0mL)中的4-氯-3-(氯磺醯基)-苯甲酸
(4-chloro-3-(chlorosulfonyl)-benzoic acid)(0.86g,3.4mmol)的混合物加熱至回流(reflux)隔夜。將其濃縮,以給出期望粗產物,將其直接用於下一步驟。
步驟Int 1b,於90℃將在甲苯(10mL)中之來自步驟Int 1a的化合物(0.91g,3.3mmol)和3,4,5-三氟苯胺(3,4,5-trifluoroaniline)(0.49g,3.3mmol)攪拌隔夜。將其濃縮,給出粗期望化合物,將其直接用於下一步驟。
步驟Int 1c,於80℃將在甲苯(12mL)中之來自步驟Int 1b的化合物(0.89g,2.3mmol)和三苯基膦(3.4g,13mmol)攪拌4小時。將其用EtOAc稀釋,且用飽和NaHCO3水溶液和食鹽水(brine)洗滌。將有機物乾燥(Na2SO4)、過濾並濃縮。將殘餘物進行層析(矽(silica),己烷/EtOAc),給出為白色固體的期望化合物(0.49g,71%)。ESI-MS m/z=316.0、318.0[M-H]-。
步驟Int 2a,將在乙腈(89ml)中之2-亞甲基丙烷-1,3一二基二乙酸酯(2-methylenepropane-1,3-diyl diacetat)(2.69g,15.62mmol)、Pd(OAc)2(0.210g,0.937mmol)、Ph3P(0.983g,3.75mmol)和1-(環戊-1-烯-1-基)吡咯(1-(cyclopent-1-en-1-yl)pyrrolidine)(3.19ml,21.86mmol)
的混合物加熱至且在65℃保持18小時。將水(45ml)加入並將反應混合物攪拌1小時。將飽和食鹽水加入,且用乙酸乙酯將其萃取。將有機相乾燥(Na2SO4)、過濾並濃縮。將殘餘物進行層析(矽(silica),己烷/EtOAc)以給出為無色油狀物的期望化合物(1.53g,71.9%產率)。
步驟Int 2b,將在THF(300mL)中之來自步驟Int 2a的化合物(41.725g,306mmol)的溶液冷卻至-78℃,接著將LiAlH4(於THF中1M,92mL,92mmol)加入。攪拌15分鐘後,藉由水(3.4mL)、NaOH(1M,3.4mL)和水(10.2mL)將其淬滅(quench)。將有機物乾燥(Na2SO4)、經矽藻土(Celite)過濾並濃縮以給出粗期望化合物(48.4g,97%,含有15% THF w/w),將其用於後面的步驟。
步驟Int 2c,於0℃對在DMF(400mL)中之來自步驟Int 2b之經攪拌的化合物(50.7g,367mmol)和咪唑(62.4g,58.8mmol)添加TBSCl(66.3g,440mmol)。在室溫將產生的(resulting)反應混合物攪拌16小時。用己烷稀釋反應,且用水、食鹽水來洗滌混合物。將有機層乾燥(Na2SO4)、過濾並濃縮以給出為白色固體的期望化合物(101.0g,100%)。
步驟Int 2d,於室溫對在二噁烷-水(dioxane-water)(1.1L/0.36L)中之來自步驟Int 2c的懸浮化合物(101g,368mmol)添加2,6-二甲基吡啶(2,6-dimethylpyridine)(86ml,735mmol)、氧化鋨(VIII)(osmium(VIII)oxide)(1.87g,7.35mmol)和高碘酸鈉
(sodium periodate)(280g,1.31mol),且在室溫將混合物攪拌20小時。用Na2S2O3水溶液將其淬滅,用MBTE萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮以給出為白色固體的期望產物(100g,99%)。
步驟Int 2e,於0℃對在MTBE(1.2L)中之步驟Int 2d的化合物(118.5g,466mmol)添加LiBH4(314mL,629mmol,在THF中2M)。於0℃將產生的反應混合物攪拌2小時。用NH4Cl水溶液將反應淬滅且用MBTE萃取混合物,用水、食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。無進一步純化即使用粗產物(117g,98%,有利於期望異構物之10:1的非鏡像異構物比例(diastereomeric ratio,dr))。
步驟Int 2f,對在甲苯(5ml)中之來自步驟Int 2e(315mg,1.23mmol)的經攪拌的溶液和來自步驟Int 1c的化合物(390mg,1.23mmol)添加2-(三丁基-λ5-亞磷醯基)乙腈(2-(tributyl-λ5-phosphanylidene)acetonitrile)(0.81ml,3.07mmol),且在100℃將混合物攪拌60小時。將其冷卻至室溫,用MBTE稀釋,用NaOH(0.5N)、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮、矽柱以得到期望化合物(362mg,53%)。ESI-MS m/z=554.15、556.15[M-H]-。
步驟Int 2g,在室溫對在MeOH(11mL)中之來自步驟Int 2f的化合物(0.53g,0.95mmol)的懸浮液添加濃HCl(1.0mL),且在室溫攪拌24小時。在真空下將其濃縮,以除去大部分的MeOH,且用
EtOAc萃取殘餘物。用水、10% K2CO3、食鹽水洗滌有機相,用Na2SO4乾燥、過濾、濃縮並從EtOAc/己烷再結晶(recrystallize)以給出為白色固體的期望產物(0.33g,78%)。ESI-MS m/z=440.07、442.07[M-H]-。
步驟Int 2h,在室溫對在DMSO(10mL)中之來自步驟Int 2g的化合物(1.8g,3.8mmol)的溶液添加IBX(4.3g,15.3mmol),且在室溫將混合物攪拌20小時。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入,且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾並濃縮以給出標題化合物(1.65g,92%)。ESI-MS m/z=470.04、472.04[M-H]-。
步驟Int 3a,於0℃對在DMSO(20mL)中之中間物2(1.76g,4.0mmol)和三甲基-氧化硫碘(trimethyl-sulfoxonium iodide)(1.76g,8.0mmol)的溶液添加t-BuOK(1.12g,10mmol)。在室溫將產生的反應混合物攪拌1小時。用NH4Cl水溶液將反應淬滅,且用EtOAc萃取混合物,用水、食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc)以給出為白色固體的期望化合物(1.36g,75%)。ESI-MS m/z=452.07、454.07[M-H]-。
步驟Int 3b,對在DMF(2.5mL)中之來自步驟Int 3a的化合物(78mg,0.17mmol)之經攪拌的溶液添加NH4Cl(17mg,0.32mmol)和NaN3(44mg,0.67mmol),然後在60℃攪拌24小時。用EtOAc將其稀釋,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮、進行層析(矽,己烷/EtOAc)以給出為白色固體的期望化合物(73mg,88%)。ESI-MS m/z=495.08、497.08[M-H]-。
步驟Int 3c,對在NMP(2.0mL)中之來自步驟Int 3b的化合物(0.20g,0.40mmol)的溶液中添加m-CPBA(0.27g,77%,1.2mmol),且在室溫攪拌O/N。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮並進行層析(矽,己烷/EtOAc)以給出為白色固體的期望化合物(0.21g,98%)。ESI-MS m/z=527.07、529.07[M-H]-。
步驟Int 3d,對在MeOH(2mL)和THF(1mL)中之實施例257(540mg,1.02mmol)的溶液中添加雷氏鎳(Raney nickel)(用MeOH洗滌,50mg)。引入填充氫氣的氣球。在室溫將其攪拌2小時。通過矽藻土墊將混合物過濾,用MeOH洗滌。將濾液濃縮以給出標題化合物(440mg,86%)。ESI-MS m/z=501.08、503.08[M-H]-。
步驟Int 4a,於0℃對在無水二氯甲烷(20mL)中之來自步驟Int 2b的化合物(7.7g,於THF中77.18%,43mmol)的溶液中添加DBU(7.9g,5.2mmol)和1,1,2,2,3,3,4,4,4-九氟丁烷-1-磺醯氟(1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonyl fluoride)(14.4g,48mmol)。在將反應濃縮至乾之前,將反應維持於0℃持續0.5小時。將殘餘物溶於己烷(70mL)中。用HCl(0.5M)、水、NaHCO3、食鹽水洗滌溶液並乾燥(Na2SO4)。通過矽膠層將其過濾,用己烷(300mL)洗滌並濃縮以給出無色油狀物(16.8g,92%)。1HNMR(400MHz,CDCl3)δ 5.13(t,1H),4.85(s,2H),2.67(d,2H),2.46(brs,2H),2.04(dd,2H),1.72(m,2H),1.58(m,2H)。
步驟Int 4b,於室溫對在丙酮-水(4.5mL/0.5mL)中之來自步驟Int 4a的化合物(2.101g,5mmol)和4-甲基嗎啉4-氧化物(4-methylmorpho-line 4-oxide)(0.703g,6.00mmol)的混合物添加氧化鋨(VIII)(0.628ml,於t-BuOH中2.5%),且在室溫攪拌隔夜。將Na2S2O3(1.58g,10mmol)和水(2mL)加入,在室溫攪拌30分鐘。將其區分(partition)(EtOAc/水)。用1N HCl、NaHCO3水溶液、食鹽水洗滌有機物且乾燥(Na2SO4)。過濾後,將
粗產物濃縮以給出期望產物(2.24g,99%)。1HNMR(400MHz,CDCl3)δ 5.03(t,1H),3.60(s,2H),2.44(brs,2H),199(ddd,4H),1.82(m,4H),1.61(m,2H)。
步驟Int 4c,於室溫將在THF(4mL)中之來自步驟Int 4b的化合物(1.84g,5.81mmol)、三苯基膦(0.063g,0.024mmol)的懸浮液脫氣(degas),接著將叔丁醇鉀(Potassium t-butoxide)(於THF中1M,5.32mL,5.32mmol)加入。在5分鐘內,將在THF(9mL)中之來自步驟1c的化合物(2.2g,4.84mmol)加入,且在60℃攪拌24小時。冷卻後,用MBTE(60mL)將其稀釋,過濾且用MTBE洗滌。用0.5N NaOH、鹽水洗滌合併的溶液並乾燥(Na2SO4)。通過短矽塞(10g矽膠)將其過濾且用EtOAc(50mL)洗滌。在真空下將合併的有機物濃縮以給出粗產物2.5g(110%)。
步驟Int 4d,對在NMP(5mL)中之來自步驟Int 4c的化合物(1.80g,3.81mmol)的溶液添加m-CPBA(77wt%,2.14g,9.54mmol)。在將NaS2O3(3mL)水溶液加入以及接著將NaHCO3水溶液(3mL)和MeOH水溶液(5mL)加入之前,在室溫將其攪拌20小時。真空下收集白色固體且用NaHCO3水溶液、水洗滌。從MeOH將此混合物進一步再結晶以給出標題化合物(1.7g,87%)。ESI-MS m/z=502.07、504.07[M-H]-。
對在DCM(12ml)中之來自中間物4的化合物(2.00g,3.97mmol)、DIPEA(3.47mL,19.84mmol)和DMSO(6.2ml,87mmol)的混合物添加SO3吡啶複合物(SO3 pyridine complex)(1.895g,11.9mmol)。在室溫將反應攪拌3小時。用EtOAc將其稀釋且用1M HCl和食鹽水洗滌。將有機物乾燥(Na2SO4)、過濾並濃縮。將殘餘物進行層析(矽,己烷/丙酮)以給出標題化合物(1.59g,3.18mmol,80%產率)。ESI-MS m/z=500.05、502.05[M-H]-。
使用類似於中間物1中所述的流程(procedure),來製備標題化合物。ESI-MS m/z=297.99,299.99[M-H]-。
步驟1a,對在DMF(1.0mL)中之中間物3(50mg,0.10mmol)
和(叔丁氧基羰基)-L-脯胺酸((tert-butoxycarbonyl)-L-proline)(26mg,0.12mmol)的溶液中添加DIPEA(0.051mL,0.30mmol)和HATU(45mg,0.12mmoL)。在室溫將其攪拌2小時,且在製備型HPLC(C-18,乙腈/水)上純化以給予為白色固體的期望化合物(20mg,29%)。ESI-MS m/z=698.19、700.19[M-H]-。
步驟1b,對在THF(0.4mL)中之來自步驟1a的化合物(16mg,0.023mmol)的溶液中添加HCl(於二噁烷中4M,0.4mL,1.6mmol)。在室溫將其攪拌3小時,且濃縮以給予為白色固體的期望化合物(14mg,99%)。ESI-MS m/z=598.14、600.14[M-H]-。
步驟1c,對在THF(0.5mL)中之來自步驟1b的化合物(12mg,0.019mmol)、甲醛(0.1mL 37%水溶液)和DIPEA(0.033mL,0.019mmol)和幾滴乙酸的溶液中添加NaBH(OAc)3(12mg,0.057mmol)。在室溫將其攪拌2小時,且將NaHCO3飽和水溶液加入。用EtOAc將其萃取,用水、食鹽水洗滌,用無水Na2SO4乾燥、過濾、濃縮且在製備型HPLC(C-18,乙腈/水)上將粗產物純化,以給予為白色固體的標題化合物(8.2mg,71%)。ESI-MS m/z=612.12、614.12[M-H]-。
於室溫對在THF(0.5mL)中之來自中間物4(30mg,0.06mmol)的化合物、胺磺醯氯(sulfamoyl chloride)(8.5mg,0.072mmol)的溶液添加TEA(4滴),且在室溫將混合物攪拌3小時。將其濃縮,且藉由製備型HPLC(C18柱,乙腈/水)洗脫液(eluent)純化,以給出標題化合物(13.5mg,38%)。ESI-MS m/z=581.04、583.04[M-H]-。
步驟4a,於0℃對在THF(10mL)中之中間物2(880mg,2.0mmol)的溶液中添加丙-1-烯-1-基氯化鎂(prop-1-en-1-ylmagnesium chloride)(0.5M,12mL),且在用NH4Cl(20mL)將溶液淬滅之前,在這樣的溫度將其攪拌30分鐘。用EtOAc將其萃取。用食鹽水將有機物洗滌、乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,乙酸乙酯/己烷),以給出期望化合物之為白色固體的Z-異構物(252mg,26%產率)和E-異構物(596mg,61%)。ESI-MS m/z=502.09、504.07[M-H]-。
步驟4b,對在丙酮(5mL)/水(1mL)中之步驟4a的Z-異構物(252mg,0.523mmol)和NMO(123mg,1.05mmol)的溶液添加OsO4(於t-BuOH中4%,0.066mL,0.01mmol),且在室溫將溶液攪拌隔夜。用EtOAc將其稀釋,用Na2S2O3、NaHCO3、水和食鹽水
洗滌並濃縮。將此粗產物溶於THF(3mL)中。將m-CPBA(77w%,234mg,1.1mmol)加入且在室溫攪拌隔夜。用Na2SO3水溶液和NaHCO3水溶液淬滅之後,在將其乾燥並濃縮之前,用EtOAc將其萃取。從熱MeOH將粗產物結晶,以給出為白色固體的標題化合物(223mg,78%,外消旋)。ESI-MS m/z=546.06、548.06[M-H]-。
按照步驟4b中所述的類似流程,從步驟4a的E-異構物來製備標題化合物(外消旋,白色固體)。ESI-MS m/z=546.06、548.06[M-H]-。
步驟6a,於室溫對在甲苯(30ml)中之來自步驟Int 2b的化合物(1.400g,4.67mmol)和中間物6(0.922g,5.14mmol)的混合物添加三苯基膦(triphenylphosphine)(1.715g,6.54mmol),接著逐滴地(dropwise)將DIAD(1.181ml,6.07mmol)加入。在允許冷卻至室溫且藉由管柱層析(矽,己烷/EtOAc)直接純化,給予為白色結晶的期望產物(1.760g,90%)之前,於95℃將混合物
攪拌隔夜。ESI-MS m/z=418.07、420.06[M-H]-。
步驟6b,於室溫對在THF(40ml)和水(0.5ml)中之來自步驟6a的化合物(1.760g,4.19mmol)的澄清溶液添加NMO(2.455g,20.96mmol),接著逐滴地將四氧化鋨(osmium tetroxide)(於水中4wt%,1.644ml,0.210mmol)加入。在室溫將混合物攪拌隔夜。將更多的四氧化鋨(於水中4wt%,1.644ml,0.210mmol)加入。在室溫將黃色溶液攪拌隔夜。將飽和Na2S2O3溶液加入,以將反應淬滅。在室溫下20分鐘後,用THF稀釋混合物。用THF回萃(back-extract)水層(*1)。用食鹽水洗滌合併的有機層(*2),Na2SO4(s)乾燥、過濾並濃縮。從沸騰的MeOH(40ml)將殘留的固體再結晶,以給予為白色結晶的期望產物(1.620g,80%)。ESI-MS m/z=484.04、486.04[M-H]-。
步驟6c,對在0℃冷卻之在DCM(8ml)和DMSO(4.24ml)中之來自步驟6b的化合物(1.320g,2.72mmol)和DIPEA(2.467ml,14.13mmol)的溶液添加三氧化硫吡啶複合物(sulfur trioxide pyridine complex)(1.340g,8.42mmol)。在0℃將產生的溶液攪拌4小時。用EtOAc/THF稀釋混合物,然後用0.1N HCl水溶液(*2)、水(*1)和食鹽水(*1)洗滌。用Na2SO4(s)將有機層乾燥、過濾並濃縮。將固體溶於DCM/THF(1/1)中,且藉由通過短管柱(矽,己烷/THF)過濾來純化,以給予為灰白色(off-white)泡沫的期望產物,(1.420g,定量產率)。ESI-MS m/z=482.04、484.04[M-H]-。
步驟6d,於室溫對在DMSO(3ml)中之來自步驟6c的化合物
(0.150g,0.310mmol)和在甲醇(1.328ml,9.30mmol)中之7N氨(ammonia)的溶液添加乙二醛(glyoxal)(於水中40%,0.071ml,0.620mmol)。在室溫將所產生的溶液攪拌隔夜。混合物不含揮發物。藉由HPLC(H2O中40%-90% CH3CN)來直接純化剩餘溶液,給予為白色固體的標題化合物(42.0mg,26%)。ESI-MS m/z =520.07、522.07[M-H]-。
步驟7a,對在-78℃冷卻之在THF(4ml)中的來自步驟6c的化合物(0.120g,0.248mmol)的溶液逐滴添加溴化甲基鎂(methylmagnesium bromide)(於Et2O中3M,0.413ml,1.240mmol)。在-78℃將反應混合物攪拌30分鐘。將更多的溴化甲基鎂(於Et2O中3M,0.413ml,1.240mmol)加入。在允許溫熱至室溫且用飽和NH4Cl溶液淬滅之前,於-78℃將反應混合物攪拌2小時。用THF和水稀釋混合物。用食鹽水(*2)洗滌有機層,用Na2SO4(s)乾燥、過濾並濃縮。將殘餘物溶於DMSO(4ml)中,且藉由HPLC(於水中40%-90% ACN)純化,以給予為白色固體的標題化合物(39.0mg,31%,外消旋)。ESI-MS m/z=498.07、500.07[M-H]-。
步驟9a,在將中間物5(502mg,1.0mmol)加入之前,於室溫用NaH(60% w/w,120mg,3.0mmol)處理在THF(10mL)中之2-(二乙氧基磷醯基)乙酸乙酯(ethyl 2-(diethoxyphosphoryl)acetate)(673mg,3.0mmol)的溶液30分鐘。在室溫將其攪拌隔夜。用EtOAc將其稀釋且用NH4Cl水溶液和食鹽水洗滌。將有機物乾燥(Na2SO4)、過濾並濃縮。將殘餘物進行層析(矽,己烷/丙酮),以給出期望化合物(280mg,49%)。ESI-MS m/z=570.09、572.09[M-H]-。
步驟9b,在將第二份NaBH4(20mg)加入之前,對在THF(1mL)/EtOH(1mL)中之步驟9a(80mg,0.14mmol)的溶液中添加NaBH4(16mg,0.42mmol),且在室溫下攪拌2小時。在用水將其淬滅和用EtOAc萃取之前,將其再攪拌3小時。將有機物乾燥(Na2SO4)、過濾並濃縮。藉由製備型HPLC(C18柱,乙腈/水)來純化粗產物以給出標題化合物(13.5mg,38%)。ESI-MS m/z=530.08、532.08[M-H]-。
步驟10a,於0℃對在THF(5.0mL)中之膦醯基乙酸三乙酯(triethyl phosphonoacetate)(0.520ml,2.60mmol)的溶液添加NaH(0.104g,60%,2.6mmol)。於0℃將產生的反應混合物攪拌30分鐘。將在THF(2.0mL)中的中間物2(0.15g,0.34mmol)的溶液加入,並在室溫下攪拌2小時。用NH4Cl水溶液將反應淬滅,且將混合物用EtOAc萃取,用水、食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(0.50g,98%)。ESI-MS m/z=508.10、510.10[M-H]-。
步驟10b,於-78℃對在THF(5.0mL)中之來自步驟10a的化合物(0.32g,0.627mmol)的溶液添加DibAL-H(2.5mL於己烷中之l.0M溶液,2.5mmol)。在-78℃將產生的反應混合物攪拌1小時。用酒石酸鉀鈉(potassium sodium tartrate)水溶液來處理反應3小時,且將混合物用EtOAc萃取,用水、食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(132mg,45%)。ESI-MS m/z=466.06、468.07[M-H]-。
步驟10c,於室溫對在丙酮(3.0mL)中之來自步驟10b的化合物(43mg,0.092mmol)和NMO(64mg,0.55mmol)的混合物添加四氧化鋨(0.58ml,4%水溶液,0.092mmol),且在室溫將混合物攪拌16小時。用Na2SO3水溶液將其淬滅,用EtOAc萃取,用水、3N HCl、NaHCO3、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且
藉由製備型HPLC(C18柱,乙腈/水)來純化,以給出標題化合物(18mg,37%外消旋)。ESI-MS m/z=578.07、580.07[M+HCO2]-。
步驟11a,對在THF(10mL)中之中間物2(880mg,2.0mmol)的溶液中添加乙烯基氯化鎂(vinylmagnesium chloride)(於THF 3.75ml中1.6M,6.0mmol)。在將NH4Cl水溶液加入之前,將其攪拌30分鐘。將其用EtOAc萃取兩次。將有機物用食鹽水洗滌並乾燥(Na2SO4)。濃縮至10mL後,在真空下將混合物過濾以提供期望產物(616mg,66%)。ESI-MS m/z=466.08、468.08[M-H]-。
步驟11b,對在THF(2mL)中之步驟11a的溶液(94mg,0.2mmol)的溶液中添加m-CPBA(77w%,224mg,1.0mmol)且在室溫攪拌隔夜。用Na2SO3水溶液和NaHCO3水溶液淬滅後,將其用EtOAc萃取、乾燥並濃縮。將粗產物進行層析(矽,乙酸乙酯/己烷),以給出為白色固體的期望化合物(75mg,73%產率)。ESI-MS m/z=514.08、516.08[M-H]-。
步驟11c,對在DMF(1mL)中之步驟11b(75mg,0.14mmol)的溶液中添加NaN3(29mg,0.44mmol)和NH4Cl(8mg,1.5mmol)且在55℃攪拌隔夜。冷卻之後,用EtOAc將其稀釋且過濾。濃縮之後,藉由製備型HPLC(C18柱,乙腈/水)洗脫液純化,
以給出為白色固體的標題化合物(13.5mg,38%,外消旋)。ESI-MS m/z=557.04、559.04[M-H]-。
對在DMF(1ml)中之中間物3(50mg,0.10mmol)和(S)-四氫呋喃-2-羧酸((S)-tetrahydrofuran-2-carboxylic acid)(14.43μl,0.149mmol)的溶液添加EDC(38mg,0.20mmol)和DMAP(36mg,0.30mmol)。在室溫將反應攪拌2小時。用EtOAc將反應萃取,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(14mg,23%,單一對掌異構物)。ESI-MS m/z=599.125、601.122[M-H]-。
於室溫對在DMF(1mL)中之中間物3(75mg,0.15mmol)和DIPEA(52.1μl,0.298mmol)和環己-3-烯-1-羧酸(cyclohex-3-ene-1-carboxylic acid)(18.8mg,0.15mmol)的溶液中添加HATU(68.0mg,0.18mmol)且在室溫攪拌4天。藉由製備型HPLC(C-18,乙腈/水)來將其純化,給予為白色固體的
標題化合物(65mg,71%)。ESI-MS m/z=609.14、611.14[M-H]-。
於室溫用四氧化鋨(0.042ml,在水中4%,0.0065mmol)來處理在丙酮/水(2.0/0.2mL)中之來自實施例18的化合物(40mg、0.065mmol)和NMO(23mg、0.196mmol)的混合物16小時。用Na2SO3水溶液將其淬滅,用EtOAc萃取,用水、3N HCl、NaHCO3、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且藉由製備型HPLC(C18柱,乙腈/水)純化,以給出標題化合物(26mg,61%,單一異構物,未確定立體化學)。ESI-MS m/z=643.15、645.15[M-H]-。
步驟20a,於0℃對在THF(16mL)中之(甲氧基甲基)三苯基氯化鏻((methoxymethyl)triphenylphosphonium chloride)(3.43g,10mmol)的懸浮液中添加t-BuOK(1.68g、15mmol)。在室溫將產生的混合物攪拌30分鐘。將在THF(4.0mL)中之中間物2(2.2g,5.0mmol)的溶液加入且在室溫攪拌20小時。用NH4Cl水溶液將其淬滅,且用EtOAc萃取混合物,用水、食鹽水洗滌。將有
機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(2.08g,89%)。ESI-MS m/z=466.13、468.13[M-H]-。
步驟20b,於室溫對在THF(10mL)中之來自步驟20a的化合物(1.1g,2.35mmol)的溶液中添加濃HCl(1.5mL),且在室溫攪拌2小時。在真空下將其濃縮以除去大部分的THF,且用EtOAc萃取殘餘物。用水、10% K2CO3、食鹽水洗滌有機相,用Na2SO4乾燥、過濾、濃縮,以給出期望化合物(0.95g,89%)。ESI-MS m/z=452.07、454.07[M-H]-。
步驟20c,於0℃對在THF(6.0mL)中之來自步驟20b的化合物(0.27g,0.59mmol)的溶液添加乙烯基溴化鎂(vinyl magnesium bromide)(2.37mL,於THF中1M,2.37mmol)。在0℃將產生的反應混合物攪拌1小時。用NH4Cl水溶液將反應淬滅,且用EtOAc萃取混合物,用水、食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為非鏡像異構物的混合物的期望化合物(50mg,17%)。ESI-MS m/z=480.08,482.08[M-H]-。
步驟20d,於室溫對在丙酮(3.0mL)中之來自步驟20c的化合物(50mg,0.104mmol)和NMO(73mg、0.62mmol)的混合物添加四氧化鋨(0.66ml,於水中4%,0.104mmol),且在室溫將混合物攪拌16小時。用Na2SO3水溶液將其淬滅,用EtOAc萃取,用水、3N HCl、NaHCO3、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮並
藉由製備型HPLC,使用C18柱和乙腈/水作為洗脫液來純化,以給出為非鏡像異構物的混合物的標題化合物(21mg,37%)。ESI-MS m/z=546.06、548.06[M-H]-。
步驟21a,於-78℃對在THF(5ml)中之2-甲基丁-3-炔-2-醇(2-methylbut-3-yn-2-ol)(0.115g,1.364mmol)的澄清溶液逐滴添加BuLi(於己烷中2.6M,1.091ml,2.73mmol)。在-78℃將產生的澄清溶液攪拌1小時。在-78℃將在THF(1ml)中之中間物2(0.150g,0.341mmol)的溶液加入。在允許溫熱至室溫且在室溫攪拌30分鐘之前,在-78℃將混合物攪拌1小時。將飽和NH4Cl溶液加入以將反應淬滅。用EtOAc和水將混合物稀釋。用食鹽水洗滌有機層(*2),用Na2SO4(s)乾燥、過濾並濃縮。藉由管柱層析(矽,己烷/EtOAc)來純化殘餘物,以給予為黃色固體的期望產物(0.152g,85%)。ESI-MS m/z=522.11、524.11[M-H]-。
步驟21b,於室溫對在乙酸乙酯(12ml)中之來自步驟21a的化合物(140mg,0.267mmol)的溶液添加Lindlar催化劑(114mg,0.053mmol)。在室溫用H2氣球將懸浮液攪拌隔夜。LC-MS顯示約20%的轉換率。通過矽藻土短墊將混合物過濾。濃縮濾液。藉由管柱層析(矽,己烷/丙酮)來純化殘餘物,以給予為白色固體的期望產物
(23.5mg,17%)。ESI-MS m/z=524.11、526.11[M-H]-。
步驟21c,於室溫對在THF(2.80ml)和水(0.200ml)中之來自步驟21b的化合物(23.5mg,0.045mmol)的澄清溶液添加NMO(26.2mg,0.223mmol),接著將四氧化鋨(於水中4%,0.057ml,8.94μmol)加入。在55℃攪拌2個隔夜之前,在室溫將溶液攪拌過週末。更多的四氧化鋨(於水中4%,0.057ml,8.94μmol)加入。在用飽和Na2S2O3溶液淬滅且用THF稀釋之前,在55℃將混合物攪拌隔夜。用食鹽水洗滌有機層(*2),用Na2SO4(s)乾燥、過濾並濃縮。將殘餘物溶於DMSO(2ml)中,且藉由HPLC(於水中40-90% ACN)來純化,以給予為白色固體的標題化合物(3.5mg,14%)。ESI-MS m/z=556.12、558.11[M-H]-。
藉由按照實施例14中所述的流程,從中間物3和環戊-3-烯-1-羧酸(cyclopent-3-ene-1-carboxylic acid)製備標題化合物(44mg,84%)。ESI-MS m/z=641.13、643.13(M+HCO2)-。
步驟26a,按照類似於步驟Int 3d中所述的流程,由實施例11的化
合物製備期望化合物,ESI-MS m/z=531.09、533.09[M-H]-。
步驟26b,於室溫用MsCl(38mg,0.33mmol)處理室溫的在THF-水(1.0/0.1ml)中之來自步驟26a的化合物(50mg,0.091mmol)和DMAP(60mg,0.49mmol)的溶液1小時。在真空下將其濃縮且藉由製備型HPLC(C18,乙腈/水)來純化,以給出標題化合物(13mg,23%)。ESI-MS m/z=609.07、611.07[M-H]-。
步驟27a,使用類似於實施例14中所述的方法,由中間物3和(叔丁氧基羰基)-L-天冬醯胺來製備期望化合物。ESI-MS m/z=715.18、717.18[M-H]-。
步驟27b,在室溫用HCl(在二噁烷中4M)處理來自步驟27a的化合物兩小時。將其濃縮,以HCl鹽給出為白色固體的標題化合物。ESI-MS m/z=615.12、617.12[M-H-56]-。
步驟28a,將金剛烷醇(Adonitol)(1.0g,6.57mmol)和鹽酸吡啶(pyridine hydrochloride)(1.215g,10.52mmol)混合整齊(neat)且加熱至150℃維持4小時。將粗產物進行層析(矽,
EtOAc/MeOH),以給出為無色膠質(gum)的期望化合物(882mg,100%)。
步驟28b,對在丙酮(26.303ml)中之來自步驟28a的化合物和2,2-二甲氧基丙烷(3.23ml,26.3mmol)的溶液添加PTSA(250mg,1.315mmol),然後在室溫攪拌30分鐘。用NaHCO3水溶液將反應淬滅,且將混合物用EtOAc萃取,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,二氯甲烷/MeOH),以給出為無色油狀物的期望化合物(852mg,74%)。
步驟28c,對在乙腈(2ml)和水(2ml)中之來自步驟28b的化合物(327mg,1.88mmol)的溶液添加TEMPO(59mg,0.375mmol)和二乙酸碘苯(iodobenzene diacetate)(1.21g,3.75mmol)。在室溫將反應攪拌1小時。用EtOAc萃取反應物,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。無需進一步純化,即可使用粗酸(crude acid)(454mg,50%純度,64%)。
步驟28d,對在DMF(3ml)中之中間物3(150mg,0.30mmol)和來自步驟28c的化合物(168mg,0.447mmol,50%純度)的溶液添加EDC(114mg,0.60mmol)和DMAP(109mg,0.90mmol)。在室溫將反應攪拌2小時。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(117mg,58%)。ESI-MS m/z=717.153、719.151[M+CO2H]-。
對在THF(5ml)和甲醇(10ml)中之來自實施例28的化合物(115mg,0.171mmol)的溶液添加HCl(4ml,2M水溶液,8mmol)。將反應加熱至60℃、1小時。用EtOAc萃取反應,用NaHCO3、水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(76mg,70%)。ESI-MS m/z=677.119、679.117[M+CO2H]-。
步驟32a,於-78℃對在THF(36ml)中之中間物2(3.20g,7.27mmol)和(1-甲氧基乙烯基)-氧基)二甲基矽烷(tert-butyl((1-methoxyvinyl)-oxy)dimethylsilane)(1.905ml,8.73mmol)的溶液添加BF3二乙醚合物(diethyl etherate)(1.11ml,8.73mmol)。在-78℃攪拌1小時,然後溫熱至室溫1小時。用NaHCO3(aq)將反應淬滅。將粗產物用EtOAc萃取,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(2.976g,80%)。ESI-MS m/z=511.8、513.8[M-H]-。
步驟32b,對在NMP(29ml)中之來自步驟32a的材料(2.976g,5.79mmol)的溶液添加m-CPBA(3.89g,17.37mmol,77%)。在室溫將反應攪拌18小時。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。用甲醇將殘餘物磨碎(triturate)並過濾,以給出為白色固體的標題化合物(2.50g,4.58mmol)。ESI-MS m/z=544.076、546.074[M-H]-。
對在THF(27ml)和甲醇(18ml)中之實施例32的化合物(2.50g,4.58mmol)的溶液添加LiOH(9.16ml,18.32mmol,2M aq)。在室溫將其攪拌6小時。用HCl(2M,aq)將反應酸化至pH 3。將粗產物用EtOAc萃取,用食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮,以給出標題化合物(2.40g,99%)。ESI-MS m/z=498.068、500.066[M-H]-。
步驟34a,於0℃對在DMSO(20mL)中之中間物2的化合物(1.76g,4.0mmol)和三甲基-氧化硫碘(trimethyl-sulfoxonium iodide)(1.76g,8.0mmol)的溶液添加t-BuOK(1.12g,10
mmol)。在室溫將產生的反應混合物攪拌1小時。用NH4Cl水溶液將反應淬滅,且將混合物用EtOAc萃取,用水、食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(1.36g,75%)。ESI-MS m/z=452.07、454.07[M-H]-。
步驟34b,在室溫對來自步驟34a的化合物(0.12g,0.264mmol)和環戊-3-烯-1-醇(cyclopent-3-en-1-ol)(0.523mL,6.61mmol)的混合物添加叔丁醇鉀(297mg,2.64mmol),且在80℃加熱1小時,然後50℃持續16小時。用NH4Cl水溶液將反應淬滅,且將混合物用EtOAc萃取,用水、食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出期望化合物(82mg,57%)。ESI-MS m/z=536.11、538.11[M-H]-。
步驟34c,於室溫對在丙酮(2.0mL)中之來自步驟34b的化合物(50mg,0.093mmol)和NMO(65.3mg,0.558mmol)的混合物添加四氧化鋨(0.29ml,於水中4%,0.046mmol)的混合物,且在室溫將混合物攪拌2天。用Na2SO3水溶液將其淬滅,用EtOAc萃取,用水、3N HCl、NaHCO3、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且藉由製備型HPLC,使用C18柱和乙腈/水作為洗脫液來純化,給出結構暫時指定的標題化合物(11mg,19%)。ESI-MS m/z=602.12、604.12[M-H]-。
從實施例34中分離出標題化合物(12mg,21%)。ESI-MS m/z=602.12、604.12[M-H]-。
步驟36a,於0℃對在DMF(5.0mL)中之NaH(160mg,60%,4.00mmol)的懸浮液添加巴豆醇(crotyl alcohol)(341μl,4.00mmol),且在室溫攪拌30分鐘。將來自步驟34a的化合物(182mg,0.40mmol)加入且在室溫攪拌16小時。用NH4Cl水溶液將其淬滅,用EtOAc萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且進行層析(矽,己烷/EtOAc)以給出期望產物(195mg,93%)。ESI-MS m/z 524.11、526.11[M-H]-。
步驟36b,在室溫對在丙酮(2.5mL)中之來自步驟36a的化合物(190mg,0.36mmol)和NMO(254mg,2.17mmol)的混合物添加四氧化鋨(1.15ml,於水中4%,0.181mmol),且在室溫將混合物攪拌2天。用Na2SO3水溶液將其淬滅,用EtOAc萃取,用水、3N HCl、NaHCO3、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且
藉由製備型HPLC,使用C18柱和乙腈/水作為洗脫液來純化,以給出結構暫時指定的標題化合物(36mg,17%)。ESI-MS m/z=590.11,592.11[M-H]-。
步驟37a,於室溫對在NMP(12mL)中之來自步驟Int 2g的化合物(1.9g,4.30mmol)的溶液添加m-CPBA(2.89g,12.90mmol)。在室溫將混合物攪拌隔夜。用Na2S2O3水溶液和NaHCO3水溶液與幾滴三乙胺將其淬滅。用EtOAc萃取混合物。用水、食鹽水洗滌有機層,用Na2SO4乾燥、過濾並濃縮。從MeOH將殘留的固體再結晶,給予為白色固體的期望產物(1.8g,88%)。ESI-MS m/z=472.06、474.06[M-H]-。
步驟37b,於室溫對在DMSO(10mL)中之來自步驟37a的化合物(1.8g,3.8mmol)的溶液添加IBX(4.3g,15.3mmol)。在45℃將混合物攪拌20小時。將Na2S2O3水溶液和NaHCO3水溶液以及幾滴Et3N加入。在室溫將混合物攪拌1小時。用EtOAc將其萃取。用水、食鹽水洗滌有機層,用Na2SO4乾燥、過濾並濃縮,給出期望化合物(1.65g,92%)。ESI-MS m/z=470.04、472.04[M-H]-。
步驟37c,於5-10℃對在THF(2mL)中之來自步驟37b的化合物(104mg,0.220mmol)的溶液逐滴地添加溴化甲基鎂(於乙醚中
3M,367μl,1.102mmol)。將更多的THF(2.5mL)加入且在室溫將混合物攪拌1小時。用EtOAc將其稀釋,用水、Na2SO3水溶液和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。藉由製備型TLC(矽,己烷/EtOAc)來純化粗產物,以給出期望化合物(85mg,79%)。ESI-MS m/z=486.08、488.08[M-H]-。
步驟37d,於室溫對在THF/MeOH(1/1,2.0ml)中之來自步驟37c的化合物(30.0mg,0.061mmol)的澄清溶液一次性地(one portion)添加10% Pd/C(6.5mg,6.15μmol)。用H2將懸浮液氣沖(purge)3次,然後在室溫用H2氣球攪拌隔夜。然後,於室溫在H2(60psi)下,將懸浮液攪拌4小時。將更多的10% Pd/C(13.0mg,12.3μmol)加入。用H2將懸浮液氣沖3次,然後於室溫在H2(約15psi)下,將懸浮液攪拌過週末。通過矽藻土短墊將混合物過濾。濾液不含揮發物。用DCM將固體殘餘物磨碎,以給予為白色固體的標題化合物(20.0mg,72%)。ESI-MS m/z=452.11、453.11[M-H]-。
步驟38a,於室溫將在THF/水(3.0/1.0mL)中之來自步驟Int 3a的化合物(214mg,0.47mmol)的溶液用TFA(0.40mL)在室溫處理6小時。在真空下將其濃縮以除去大部分THF。用EtOAc萃取殘
餘物。用水、10% K2CO3、食鹽水洗滌有機相,用Na2SO4乾燥、過濾並濃縮,以給出期望化合物(0.20g,90%)。ESI-MS m/z=470.08、472.08[M-H]-。
步驟38b,於室溫對在DMSO(6ml)中之來自步驟38a的化合物(0.340g,0.720mmol)的溶液添加IBX(0.303g,1.081mmol)。在室溫將產生的乳狀混合物攪拌2小時。用EtOAc和水稀釋混合物。用食鹽水洗滌有機層(*2),用Na2SO4(s)乾燥、過濾並濃縮。在真空下將殘餘物乾燥,以給予為白色固體的期望產物(0.324g,96%)。ESI-MS m/z=468.05、470.05[M-H]-。
步驟38c,在室溫對在t-BuOH(6.0ml)和水(2.0ml)中之來自步驟38b的化合物(0.324g,0.690mmol)的懸浮液添加磷酸鉀(potassium phosphate),一元鹼(0.657g,4.83mmol),接著將2-甲基-2-丁烯(2-methyl-2-butene)(1.826ml,17.24mmol)加入。一次性地將亞氯酸鈉(Sodium chlorite)(80%,0.702g,6.21mmol)加至懸浮液。在室溫將產生的澄清溶液攪拌1小時。用MTBE和1.0M NaOH(8mL)將其稀釋。用EtOAc稀釋有機層,用0.5M HCl aq(*1)洗滌,然後用食鹽水(*1)洗滌。用Na2SO4(s)將有機物乾燥、過濾並濃縮。在真空下將殘餘物乾燥,以給予為白色固體的期望產物(0.306g,91%)。ESI-MS m/z=484.05、486.05[M-H]-。
步驟38d,於室溫對在乙腈(3ml)中之來自步驟38c的化合物(50.0mg,0.103mmol)、丁-2-烯-1-胺鹽酸鹽(but-2-en-1-amine
hydrochloride)(12.18mg,0.113mmol)和DIPEA(0.054ml,0.309mmol)的懸浮液一次性地添加HATU(47.0mg,0.123mmol)。在室溫將產生的微乳狀溶液攪拌隔夜。將更多的DIPEA(0.054ml,0.309mmol)和HATU(47.0mg,0.123mmol)加入。在室溫將產生的溶液攪拌4小時,然後在55℃攪拌2小時。混合物不含揮發物。藉由管柱層析(矽,己烷/EtOAc)來純化殘餘物,以給予為白色固體的期望產物(7.0mg,12%)。ESI-MS m/z=583.11、585.11[M-H]-。
步驟38e,於室溫對在THF(2.0ml)和水(0.14ml)中之來自步驟38d的化合物(7.0mg,0.013mmol)的澄清溶液添加NMO(7.61mg,0.065mmol),接著將四氧化鋨(0.083ml,0.013mmol)加入。在50℃將溶液攪拌隔夜。用飽和Na2S2O3溶液將混合物淬滅且用THF稀釋。用食鹽水(*2)洗滌有機層,用Na2SO4(s)乾燥、過濾並濃縮。將殘餘物溶於DMSO(1ml)中且藉由HPLC(於水中40-90% ACN)來純化以給予為白色固體的標題化合物(3.0mg,38%,非鏡像異構物的外消旋混合物)。ESI-MS m/z=649.13、651.13[M+HCO2]-。
步驟42a,於室溫對在CH2Cl2(3.7mL)中之來自步驟82a的化合物
(173mg,0.37mmol)的溶液添加(Z)-丁-2-烯-1,4-二基二乙酸酯((Z)-but-2-ene-1,4-diyl diacetate)(234μl,1.479mmol)和Grubbs-Hoveyda第二代催化劑(23.1mg,0.037mmol),然後將混合物脫氣並維持回流24小時。將混合物濃縮,且將殘餘物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(160mg,80%)。ESI-MS m/z=584.10、586.10(M+HCO2)-。
步驟42b,於室溫對在MeOH(1.3mL)中之來自步驟42a的化合物(20.5mg,0.038mmol)的溶液添加碳酸鉀(10.5mg,0.076mmol),然後將混合物維持在室溫1小時。用水稀釋反應混合物且用CH2Cl2萃取,用Na2SO4有機相乾燥、濃縮以給出期望產物(19mg),無需進一步純化。ESI-MS m/z=542.10、544.10(M+HCO2)-。
步驟42c,對在丙酮/H2O(0.8mL,4:1)中之來自步驟42b的化合物(18.9mg,0.038mmol)的溶液添加NMO(26.7mg,0.228mmol)和四氧化鋨(298μl,0.038mmol)。將混合物維持在50℃、2天。用Na2S2O3水溶液將其淬滅,用EtOAc萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且藉由製備型HPLC使用C18柱和乙腈/水作為洗脫液來純化,以給出標題化合物(3.9mg,18%)。ESI-MS m/z=608.10、610.10(M+HCO2)-。
步驟51a,於-78℃對在THF(15ml)中之1-甲氧基-4-((丙-2-炔-1-基氧基)甲基)苯(1-methoxy-4-((prop-2-yn-1-yloxy)methyl)benzene)(801mg,4.55mmol)的澄清溶液逐滴添加BuLi(於己烷中2.6M,1.819ml,4.55mmol)。在-78℃將產生的澄清溶液攪拌0.5小時。在-78℃下將在THF(3ml)中的中間物2(500mg,1.137mmol)的溶液逐滴地加入。在用飽和NH4Cl溶液淬滅之前,在-78℃將混合物攪拌1小時。允許將其溫熱至室溫且用EtOAc和水稀釋。用食鹽水(*1)洗滌有機層,用Na2SO4(s)乾燥過濾並濃縮。藉由管柱層析(矽,己烷/EtOAc)來純化殘餘物,以給予為白色固體的期望產物(0.440g,63%)。ESI-MS m/z=614.14、616.14[M-H]-。
步驟51b,於室溫對在乙酸乙酯(10ml)中之來自步驟51a的化合物(0.140g,0.227mmol)的溶液添加Lindlar催化劑(0.097g,0.045mmol)。在室溫用H2氣球將懸浮液攪拌2小時。通過矽藻土短墊將混合物過濾。將濾液濃縮。藉由管柱層析(矽,己烷/EtOAc)純化殘餘物,以給予為白色固體的期望產物(96.0mg,68%)。ESI-MS m/z=616.15、618.15[M-H]-。
步驟51c,於室溫對在DCM(2ml)中之來自步驟51c的化合物(46.0
mg,0.074mmol)的澄清溶液添加pH 7的緩衝液(0.4ml),接著將DDQ加入(33.8mg,0.149mmol)。在室溫將兩相(biphasic)混合物攪拌3小時。用飽和NaHCO3溶液將其淬滅且用DCM稀釋。用Na2SO4將有機層乾燥、過濾並濃縮。藉由層析(矽,己烷/EtOAc)來純化殘餘物,以給予為白色固體的期望產物(20.2mg,54%)。ESI-MS m/z=496.09、498.09[M-H]-。
步驟51d,於室溫對在THF(5.60ml)和水(0.56ml)中之來自步驟51c的化合物(45.6mg,0.092mmol)的澄清溶液添加NMO(53.6mg,0.458mmol),接著將在叔丁醇中的四氧化鋨(2.5%,0.186ml,0.018mmol)加入。在室溫將溶液攪拌4小時,然後在50℃攪拌2個隔夜。用飽和Na2S2O3溶液將混合物淬滅且用THF稀釋。用食鹽水(*2)洗滌有機層,用Na2SO4(s)乾燥、過濾並濃縮。將殘餘物溶於DMSO(2ml)中且藉由HPLC(於水中30-90% ACN)來純化,以給予為白色固體的標題化合物(15.0mg,29%)。ESI-MS m/z=608.09、610.08[M+HCO2]-。
對在DMF(0.9ml)中之來自實施例33(50mg,0.094mmol),3-甲基丁-2-烯-1-醯胺鹽酸鹽(3-methylbut-2-en-1-amide hydrochloride)(12.6mg,0.103mmol)和DIPEA(0.5ml,0.282
mmol)的溶液添加在DMF(0.5ml)中的HATU(54mg,0.141mmol)的溶液。在室溫攪拌2小時。將粗反應混合物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(40mg,71%)。ESI-MS m/z=596.8、598.8[M-H]-。
對在丙酮(5ml)中之實施例52(40mg,0.067mmol)的溶液添加OsO4(0.085ml,4% w/w水,0.013mmol)和NMO(19.6mg,0.167mmol)。在室溫將其攪拌48小時,然後蒸發至矽上。將殘餘物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(18mg,43%)。ESI-MS m/z=630.8、632.8[M-H]-。
步驟61a,對在THF-水(1.5/0.5mL)中之來自實施例34的化合物(0.030g,0.050mmol)和碳酸氫鈉(8.4mg,0.10mmol)的混合物添加高碘酸鈉(0.032g,0.150mmol)且在室溫攪拌16小時。用EtOAC將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮,且不經進一步純化用於下一步驟中。ESI-MS m/z=600.10、602.10[M-H]-。
步驟61b,於0℃對在THF-MeOH(1.5/0.5mL)中之來自步驟61a的化合物(30mg,0.050mmol)的溶液添加NaBH4(7.57mg,0.20mmol),然後在0℃攪拌30分鐘。用NH4Cl水溶液將其淬滅,用EtOAc萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且藉由製備型HPLC使用C18柱和乙腈/水作為洗脫液來純化,以給出標題化合物(7.6mg,25%)。ESI-MS m/z=604.13、606.13[M-H]-。
步驟64a,於冰水浴中,對在THF(5ml)中的中間物5(250mg,0.50mmol)的溶液添加在THF中之乙烯基氯化鎂(1.6M,1.25mL,2.0mmol),且在用NH4Cl水溶液將其淬滅之前,在室溫攪拌1小時。用EtOAc將其萃取且用食鹽水洗滌。乾燥(Na2SO4)之後,將其濃縮以給出粗期望化合物,其不經進一步純化用於下一步驟。ESI-MS m/z=528.07、530.07[M-H]-。
步驟64b,對在丙酮(5ml)和水(1mL)中之步驟64a的粗化合物(最多0.3mmol)的溶液添加NMO(67mg,0.57mmol)和OsO4(在水中4%,0.12mL,0.02mmol),且在室溫攪拌2天。在用Na2S2O3水溶液淬滅之後,在乾燥並濃縮之前用EtOAc將其萃取。將粗產物進行層析(矽,丙酮/己烷),以給出為兩對外消旋產物的混合物的標
題化合物(122mg,57%,白色固體)。ESI-MS m/z=562.08、564.08[M-H]-。
步驟70a,對在DMF(2.4ml)中之中間物3(119mg,0.237mmol)、Boc-(L)-丙胺酸(Boc-(L)-alanine)(49mg,0.260mmol)和DIPEA(0.124ml,0.71mmol)的溶液添加HATU(135mg,0.355mmol)。在室溫將反應攪拌3小時。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的期望產物,(54mg,34%)。
步驟70b,對在THF(2ml)中之來自步驟70a的化合物(54mg,0.08mmol)的溶液添加HCl(2ml,8mmol,在二噁烷中4M)。將反應攪拌2小時,然後蒸發給出無需進一步純化即使用的粗產物。
步驟70c,對在DMF中之來自步驟70b的化合物(23mg,0.04mmol)和DIPEA(0.017ml,0.1mmol)的溶液添加氯甲酸異丙酯(isopropyl chloroformate)(0.048ml,0.048mmol,在甲苯中1M)。在室溫攪拌15分鐘。將粗反應混合物進行層析(製備型HPLC,乙腈/水),給出為白色固體的標題化合物(3.8mg,14%)。ESI-MS m/z=660.0、662.0[M+H]+。
於室溫對在DMSO(0.6mL)中之來自實施例8的化合物(62mg,0.092mmol)的溶液添加IBX(38.6mg,0.138mmol),且在45℃攪拌16小時。用MeOH將其淬滅,且藉由製備型HPLC使用C18柱和乙腈/水作為洗脫液來純化,以給出標題化合物(11mg,18%)。ESI-MS m/z=670.13、672.13[M-H]-。
步驟76a,於室溫對在DMF(3ml)中之中間物3(95.0mg,0.189mmol)和(2S,3R)-1-(叔丁氧基羰基)-3-羥基吡咯烷-2-羧酸((2S,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid)(43.7mg,0.189mmol)的溶液添加DIPEA(0.099ml,0.567mmol),接著將HATU(108mg,0.283mmol)加入。在室溫將產生的澄清溶液攪拌1小時。混合物不含揮發物。用一些THF將殘餘物溶解於DCM和中,且藉由管柱層析(矽,DCM/MeOH)來純化,以給予為無色黏稠(sticky)油狀物的標題化合物(128mg,95%)。ESI-MS m/z=760.20、762.20[M+HCO2]-。
步驟78a,於室溫對在THF(2ml)中之來自實施例76的化合物(0.064g,0.090mmol)的溶液添加HCl(在1,4-二噁烷中4M,0.900ml,3.60mmol)。在室溫將產生的澄清溶液攪拌3小時。其變成懸浮液。將混合物濃縮。殘餘固體直接用於下一步驟。ESI-MS m/z=660.15、662.15[M+HCO2]-。
步驟78b,於室溫對在DMF(2.0ml)中之來自步驟78a的化合物(0.090mmol)的溶液中添加DIPEA(0.157ml,0.900mmol),接著將在DMF(0.1ml)中之氯甲酸甲酯(methyl chloroformate)(6.97μl,0.090mmol)的溶液加入。在除去揮發物之前,在室溫將產生的黃色溶液攪拌1小時。將殘餘物溶解於DMSO(2ml)中,且藉由HPLC(於水中40-90% ACN)來純化,以給予為白色固體的標題化合物(20.0mg,經過2步驟33%)。ESI-MS m/z=718.16、720.16[M+HCO2]-。
步驟82a,於冰水浴中,對在THF(5ml)中之來自步驟150d的化合物(210mg,0.50mmol)的溶液添加在THF中之乙烯基氯化鎂(1.6
M,0.94mL,1.5mmol)。在用NH4Cl水溶液將其淬滅之前,在室溫將其攪拌1小時。用EtOAc將其萃取且用食鹽水洗滌。乾燥(Na2SO4)之後,將其濃縮且將殘餘物進行層析(矽,EtOAc/己烷),給出為白色固體的期望化合物(201mg,94%)。ESI-MS m/z=448.08、450.08[M-H]-。
步驟82b,對在丙酮(1ml)和水(0.2mL)中之步驟82a的化合物(152mg,0.34mmol)的溶液添加NMO(79mg,0.68mmol)和OsO4(於t-BuOH中2.5%,0.12mL,0.007mmol)。在用Na2S2O3水溶液淬滅之前,在室溫將其攪拌隔夜。用EtOAc將其萃取,乾燥並濃縮。從MeOH將粗產物結晶,以給出為白色固體的標題化合物(141mg,84%,外消旋)。ESI-MS m/z=514.08、516.08[M-H]-。
從實施例13的化合物的製備中分離出標題化合物(單一對掌異構物)。ESI-MS m/z=645.11、647.11[M-H]-。
藉由SFC層析,從實施例4的化合物中分離出標題化合物(單一對掌異構物,暫時指定)。
藉由SFC層析,從實施例5的化合物中分離出標題化合物(單一對掌異構物,暫時指定)。
於室溫對在THF(1ml)和水(0.67ml)中之來自實施例119的化合物(50mg,0.083mmol)的溶液添加LiOH(0.33ml,0.67mmol,2M水溶液)。將反應攪拌1小時,然後用2M HCl酸化至pH 3。用EtOAc萃取反應物,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮,以給出為白色固體的標題化合物(40mg,82%)。ESI-MS m/z=586.8、588.8[M-H]-。
步驟121a,於室溫對在THF(2mL)中之來自步驟34a的化合物(170mg,0.375mmol)和1,3-二甲氧基丙-2-醇(dimethoxypropan-2-ol)(900mg,7.49mmol)的溶液添加2-甲
基丙-2-醇鉀(potassium 2-methylpropan-2-olate)(630mg,5.62mmol),然後在60℃將混合物攪拌20小時。將其冷卻至室溫,用NH4Cl水溶液淬滅,用EtOAc萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮並進行層析(矽,己烷/EtOAc)以給出期望產物(98mg,45%)。ESI-MS m/z 572.15、574.15[M-H]-。
步驟121b,對在NMP(1.5mL)中之來自步驟121a的化合物(95mg,0.165mmol)的溶液添加mCPBA(0.167g,77%,0.745mmol),且在室溫攪拌20小時。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且藉由製備型HPLC使用C18柱和乙腈/水作為洗脫液來純化,以給出標題化合物(44mg,44%)。ESI-MS m/z=604.14、606.14[M-H]-。
步驟124a,於0℃對在THF(1.0mL)中之溴化甲基三苯基鏻(0.24g,0.67mmol)的懸浮液添加t-BuOK(0.11g,1.0mmol)。在室溫將產生的反應混合物攪拌30分鐘。將在THF(1.0mL)中之來自中間物2的化合物(0.15g,0.34mmol)的溶液加入,且在室溫攪拌24小時。用NH4Cl水溶液將反應淬滅,且用EtOAc萃取混合物,用水、食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物
進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(1.36g,75%)。ESI-MS m/z=436.08、438.07[M-H]-。
步驟124b,於室溫對在丙酮-水(6mL/1mL)中之來自步驟124a的化合物(0.35g,0.80mmol)和NMO(0.375g,3.2mmol)的懸浮液添加四氧化鋨(1.0ml,0.080mmol),且在室溫將混合物攪拌18小時。用Na2SO3水溶液將其淬滅,用EtOAc萃取,用水、3NHCl、NaHCO3、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮以給出碸和亞碸的混合物。
步驟124c,於0℃對在DMF(1.5mL)中之來自步驟124b的化合物(156mg,0.32mmol)的溶液添加NaH(45mg,60%,1.12mmol)和MeI(45mg,0.32mmol)。在0℃、1.5小時後,用NH4Cl水溶液將反應淬滅,用EtOAc萃取,且用水和食鹽水洗滌有機層。將有機層乾燥(Na2SO4)、過濾並濃縮,在製備型HPLC(C-18,乙腈/水)上純化以給予為白色固體的標題化合物(61mg,38%)。ESI-MS m/z=500.09、502.09[M-H]-。
步驟124d,對在NMP(1.5mL)中之來自步驟124c的化合物(61mg,0.122mmol)的溶液添加mCPBA(0.11g,77%,0.49mmol)並在室溫攪拌20小時。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾並濃縮以給出標題化合物(63mg,100%)。ESI-MS m/z=516.08、518.08[M-H]-。
步驟125a,對在DMF(1ml)中之步驟Int 3a的化合物(91mg,0.2mmol)的溶液添加(S)-1-胺基丙-2-醇((S)-1-aminopropan-2-ol)(45mg,0.6mmol),且在冷卻之前,於90℃攪拌20小時。將其濃縮以給出不經進一步純化而用於下一步驟的粗期望化合物。ESI-MS m/z=527.12、529.12[M-H]-。
步驟125b,對在CH2Cl2(1ml)中之一半的步驟125a的化合物(約0.1mmol)的溶液添加TEA(3滴)和乙酸酐(acetic anhydride)(20mg)。在濃縮之前,將其攪拌2小時。將NMP(1mL)加入,接著將m-CPBA(13.5mg,6mmol)加入且在室溫攪拌20小時。藉由製備型HPLC(C18,乙腈/水)來純化粗產物,以給出標題化合物(18mg,30%,三步驟)。ESI-MS m/z=601.13、603.13[M-H]-。
步驟130a,於0℃對在DMF(3mL)中之(R)-丙烷-1,2-二醇((R)-propane-1,2-diol)(168mg,2.20mmol)的溶液添加NaH(88mg,60%,220mmol),且在室溫攪拌30分鐘。將來自步驟34a的化合物(100mg,0.220mmol)加入,且在55℃加熱20小
時。將其冷卻至室溫,用NH4Cl水溶液淬滅,用EtOAc萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且進行層析(矽,己烷/EtOAc)以給出期望產物(65mg,56%)。ESI-MS m/z 528.12、530.12[M-H]-。
步驟130b,對在NMP(1.5mL)中之來自步驟130a的化合物(80mg,0.15mmol)的溶液添加mCPBA(0.169g,77%,0.75mmol)且在室溫攪拌20小時。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮並藉由製備型HPLC使用C18柱和乙腈/水作為洗脫液來純化,以給出標題化合物(65mg,77%,單一對掌異構物)。ESI-MS m/z=560.11、562.11[M-H]-。
藉由SFC層析,從實施例4的化合物中分離出標題化合物(單一對掌異構物,暫時指定)。ESI-MS m/z=546.10[M+H]+。
藉由SFC層析,從實施例5的化合物中分離出標題化合物(單一對掌異構物,暫時指定)。ESI-MS m/z=546.05[M+H]+。
步驟141a,對在50ml的甲苯中之中間物1(1.23g,3.88mmol)、3-外-羥基-8-氮雜雙環[3.2.1]辛烷-8-羧酸叔丁酯(3-exo-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester)(801mg,3.52mmol)的溶液添加2-(三丁基-1,5-亞磷醯基)乙腈(2-(tributyl-15-phosphanylidene)acetonitrile)(2.13g,8.81mmol),然後在85℃攪拌隔夜。用甲基叔丁基醚將其稀釋,用0.5N NaOH水溶液、水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮。將殘餘物進行層析(矽,己烷/EtOAc)以給出為白色固體的期望化合物(1.63g,86%)。ESI-MS m/z=525.12、527.12(M-H)-。
步驟141b,於室溫對在N-甲基-2-吡咯烷酮(N-Methyl-2-pyrrolidinone)(8.29ml)中之來自步驟141a的化合物(1.31g,2.48mmol)的溶液添加mCPBA(1.95g,8.70mmol),然後將混合物維持在室溫隔夜。用Na2S2O3水溶液將反應淬滅。用EtOAc將混合物萃取,且用Na2SO4將合併的有機相乾燥、過濾並濃縮。將殘餘物進行層析(矽,己烷/EtOAc)以給出為白色固體的期望化合物(1.28g,92%)。ESI-MS m/z=557.11、559.11(M-H)-。
步驟141c,於室溫對來自步驟141b的化合物(131mg,0.234mmol)的溶液添加在二噁烷中之2N HCl,然後將混合物維持在室溫4小時。將溶液濃縮以給出白色固體(106mg,99%)。ESI-MS m/z=457.06、459.06(M-H)-。
步驟141d,於室溫對在DMF(1.8mL)中之來自步驟141c的化合物(45mg,0.091mmol)的溶液添加iPr2EtN(63.5μl,0.363mmol)、(甲氧基羰基)-L-丙胺酸((methoxycarbonyl)-L-alanine)(13.4mg,0.091mmol)和HATU(51.8mg,0.136mmol)。將混合物維持在室溫隔夜。將混合物在EtOAc和水之間區分。用NaHCO3水溶液、水和食鹽水洗滌有機相,用Na2SO4乾燥、過濾並濃縮。將殘餘物進行層析(矽,CH2Cl2/MeOH)以給出為白色固體的標題化合物(37mg,69%,單一對掌異構物)。ESI-MS m/z=586.10、588.10(M-H)-。
於室溫對在MeOH(0.99mL)中之來自步驟141c的化合物(49mg,0.099mmol)的溶液添加(R)-2,2-二甲基-1,3-二氧戊環-4-甲醛((R)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde)(19.31mg,0.148mmol)和NaCNBH4(12.4mg,0.198mmol),然後將混合物維持在室溫隔夜。於室溫用NH4Cl水溶液將反應淬滅。將
反應混合物在EtOAc和水之間區分,然後用水和食鹽水洗滌有機相,用Na2SO4乾燥、過濾並濃縮。將殘餘物進行層析(矽,CH2Cl2/MeOH)以給出為白色固體的標題化合物(45mg,79%,單一對掌異構物)。ESI-MS m/z=571.12、573.12(M-H)-。
步驟150a,於0℃對在DCM(1L)中之來自步驟Int 2e的化合物(246g,959mmol)和吡啶(pyridine)(155ml,1.92mol)的溶液添加3-硝基苯磺醯氯(3-nitrobenzenesulfonyl chloride)(217g,978mmol)。在0℃將反應混合物攪拌30分鐘且在室溫攪拌2天。用水(100mL)將其淬滅且在室溫攪拌1小時,接著用MBTE(4L)萃取。用水(2X1L)、1N HCl(1L)、水(500mL)、飽和NaHCO3(500mL)和食鹽水(500mL)洗滌有機層,用Na2SO4乾燥,通過矽藻土過濾且濃縮至約(500mL),然後將己烷(500mL)加入。在真空下將混合物濃縮以誘導沉澱,冷卻至室溫並過濾,用冷己烷洗滌以給出期望產物(321g,76%)。
步驟150b,對在DMF(250mL)中之來自步驟150a的化合物(108.6g,246mmol)、中間物4(70g,234mmol)的溶液添加碳酸銫(cesium carbonate)(96g,295mmol)。將反應混合物脫氣且緩慢加熱至70℃並在70℃攪拌14小時。將其冷卻至室溫,用MBTE
稀釋,用水和食鹽水洗滌,用Na2SO4乾燥、過濾並濃縮以給出無需進一步純化即使用的期望產物(123g,98%)。
步驟150c,在冷水浴中,對在MeOH(1.6L)中之來自步驟150b的化合物(50g,93mmol)的懸浮液緩慢添加濃HCl(200mL),以使溫度維持在30℃以下,然後在室溫攪拌隔夜。在真空下將反應混合物濃縮至約700mL的體積,冷卻至0℃,然後過濾以收集固體,用冷MeOH將其洗滌。然後將母液(mother liquor)濃縮至300mL,冷卻至0℃,過濾以收集固體。將固體風乾14小時以給出期望產物(36g,91%)。
步驟150d,在室溫對在DMSO(150mL)中之來自步驟150c的化合物(36g,85mmol)的溶液添加IBX(30.9g,110mmol),然後在50℃攪拌2小時。將混合物倒至1.2L冷水中,用EtOAc(2 x 500mL)將其萃取。藉由過濾除去一些白色固體。用飽和NaHCO3水溶液、食鹽水洗滌EtOAc萃取物,用Na2SO4乾燥。過濾並濃縮至約150mL,然後冷卻至0℃,給出藉由過濾收集的期望固體。將母液濃縮至50mL以給出第二批(second crop)的期望產物(34.1g,95%)。
步驟150e,於0℃對在DMF(180ml)中之三甲基氧化硫碘(trimethylsulfoxonium iodide)(36.3g,165mmol)的懸浮液添加叔丁醇鉀(18.51g,165mmol,1.6當量(eq)),然後在室溫攪拌30分鐘。透過套管(cannula),將在DMF(120ml)中之來自步驟150d的化合物(43.5g,103mmol)的溶液加到反應混合物中(溫度
低於10℃),且在室溫攪拌16小時。將反應混合物倒至冷飽和NH4Cl(500mL)和MBTE(1.2L)中。用水(3x500mL)和飽和NaCl(2x300mL)洗滌有機層。用Na2SO4將有機層乾燥,通過矽塞過濾,用MBTE洗滌並濃縮以給予不經進一步純化即使用的粗期望產物。
步驟150f,於冰/水浴中,對在THF/水(220/70mL)中之來自步驟150e的粗材料的溶液添加TFA(30.8ml,400mmol),然後在室溫攪拌6.5小時,然後冷卻至0℃,且將20mL飽和NaHCO3緩慢加入,接著將固體NaOH(16.00g,400mmol)加入。將EtOAc(800mL)和水(600mL)加入。用NaHCO3和食鹽水的混合溶液洗滌有機層,然後用食鹽水洗滌,乾燥(Na2SO4)、過濾並濃縮至約150mL,然後將450mL環己烷加入,冷卻至0℃,過濾,用環己烷/EtOAc洗滌(3/1)以給出期望產物(39g,83mmol,2步驟的產率81%)。
步驟150g,在0℃對在NMP(40ml)中之來自步驟150f的化合物(5.75g,12.67mmol)的溶液一次性地添加m-CPBA(8.52g,38.0mmol,77%)。在室溫攪拌隔夜。用EtOAc稀釋,用Na2S2O3、NaHCO3、水和食鹽水洗滌。用Na2SO4乾燥、過濾並濃縮。從MeOH將粗產物再結晶。於室溫在真空乾燥隔夜,以給出標題化合物(4.10g,8.44mmol,66.6%產率)。ESI-MS m/z=484.08、486.08[M-H]-。
於室溫將在AcOH(500μl,8.73mmol)中之來自實施例144的化合物的溶液攪拌隔夜。將反應混合物濃縮,且將殘餘物進行層析(矽,CH2Cl2/MeOH)以給出為白色固體的標題化合物(17mg,88%,單一對掌異構物)。ESI-MS m/z=577.10、579.10(M+HCO2)-。
於105℃將在二噁烷(0.5mL)中之中間物3(78mg,0.155mmol)和硫酸二醯胺(sulfuric diamide)(44.7mg,0.465mmol)攪拌3小時。將其冷卻至室溫且藉由製備型HPLC使用C18柱和乙腈/水作為洗脫液來純化,以給出標題化合物(42mg,46%)。ESI-MS m/z=580.06、582.06[M-H]-。
藉由對掌性(chiral)SFC,來分離實施例36的兩種對掌異構物。較
早洗脫出標題化合物(暫時指定)。ESI-MS m/z=590.11、592.11[M-H]-。
藉由對掌性SFC,來分離實施例36的兩種對掌異構物。較晚洗脫出標題化合物(暫時指定)。ESI-MS m/z=590.11、592.11[M-H]-。
藉由SFC層析,從實施例82的化合物中分離出標題化合物(單一對掌異構物,暫時指定,較早洗脫出)。ESI-MS m/z=514.09、516.09[M-H]-。
藉由SFC層析,從實施例82的化合物中分離出標題化合物(單一對掌異構物,暫時指定,較晚洗脫出)。ESI-MS m/z=514.09、516.09[M-H]-。
藉由SFC層析,從實施例172的化合物中分離出標題化合物(單一對掌異構物,暫時指定,較早洗脫出)。ESI-MS m/z=528.10、530.10[M-H]-。
藉由SFC層析,從實施例172的化合物中分離出標題化合物(單一對掌異構物,暫時指定,較晚洗脫出)。ESI-MS m/z=528.10、530.10[M-H]-。
藉由SFC層析,從實施例173的化合物中分離出標題化合物(單一對掌異構物,較早洗脫出)。ESI-MS m/z=528.10、530.10[M-H]-。
藉由SFC層析,從實施例173的化合物中分離出標題化合物(單一對掌異構物,較晚洗脫出)。ESI-MS m/z=528.10、530.10[M-H]-。
步驟202a,於-78℃對在THF(1ml)中之(R)-2,2-二甲基-1,3-二氧戊環-4-羧酸甲酯(methyl(R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate)(55mg,0.35mmol)的溶液添加新鮮配製於THF中的LDA(0.34mmol),且在將在THF(1mL)中之中間物2(100mg,0.23mmol)的溶液加入之前,在相同溫度攪拌15分鐘。在1小時內將其升至0℃且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,EtOAc/己烷)以給出期望化合物(79mg,用中間物2汙染)。ESI-MS m/z=598.12、600.12[M-H]-。
步驟202b,對在THF(2ml)中之步驟202a的化合物(79mg,0.13mmol)的溶液添加m-CPBA(112mg,0.5mmol)且在室溫攪拌隔夜。藉由製備型HPLC(C18,乙腈/水)來純化粗產物,以給出標題化合物(13mg,10%,兩步驟)。ESI-MS m/z=630.11、632.11[M-H]-。
對在DMSO(2.1ml)中之實施例150的化合物(207mg,0.426mmol)的溶液添加IBX(179mg,0.639mmol)。在室溫將反應攪拌2小時。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮)以給出為白色固體的標題化合物(175mg,85%)。ESI-MS m/z=481.6、483.6[M-H]-。
對在THF(2ml)和NaHCO3(飽和水溶液,1ml)中之實施例150的化合物(103mg,0.212mmol)的溶液添加NaIO4(140mg,0.655mmol)。在室溫將反應攪拌2小時。用EtOAc萃取反應物,用水和食鹽水洗滌。將有機層乾燥(Na2SO4),過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮)以給出為白色固體的標題化合物,(60mg,62%)。ESI-MS m/z=452.05、454.05[M-H]-。
對在THF(3ml)和水(1ml)中之實施例203的化合物(140mg,0.289mmol)、2-甲基-2-丁烯(2-methyl-2-butene)(0.77ml,7.23mmol)、KH2PO4(276mg,2.025mmol)的溶液添加NaClO2(294mg,2.60mmol)。在室溫將反應攪拌1小時。用1M HCl將反應酸化至pH 4,然後用EtOAc萃取,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮)以給出為白色固體的標題化合物(109mg,75%)。ESI-MS m/z=497.7、499.6[M-H]-。
對在THF(0.5ml)和MeOH(0.5ml)中之實施例204的化合物(22mg,0.048mmol)的溶液添加NaBH4(9mg、0.244mmol)。在室溫將反應攪拌15分鐘。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮以給出為白色固體的標題化合物(21mg,95%,未確定立體化學)。ESI-MS m/z=453.6、455.6[M-H]-。
於室溫對在THF(911μl)中之來自步驟11b的化合物(47mg,0.091mmol)的溶液添加2N LiBH4溶液(22.77μl,0.046mmol),然後將混合物維持在室溫隔夜。用NH4Cl水溶液將反應淬滅,且用EtOAc萃取混合物。用水和食鹽水洗滌合併的有機相,用Na2SO4乾燥、過濾並濃縮。將殘餘物進行層析(矽,CH2Cl2/MeOH)以給出為白色固體的標題化合物(14mg,30%)。ESI-MS m/z=562.09、564.09、(M+HCO2)-。
步驟272a,於0℃對在DMF(5.0mL)中之Me3SOI(1.98g,9.0mmol)的懸浮液添加t-BuOK(1.01g、9.0mmol),且在室溫攪拌1小時。將反應冷卻至0℃。將在DMF(2.0mL)中之使用類似於步驟Int 2a中所述的那些流程來製備的(1R,5S)-3-亞甲基雙環[3.2.1]辛烷-8-酮-6,6,7,7-d4((1R,5S)-3-methylenebicyclo[3.2.1]octan-8-one-6,6,7,7-d4)逐滴給料(charge)至反應混合物。將反應攪拌2小時。對反應混合物逐滴添加15% NH4Cl,且用MTBE萃取。藉由MTBE來再萃取水相。然後將所有有機相合併且用水和食鹽水洗滌。用Na2SO4將有機相乾燥、過濾並濃縮至乾,以給出期望產物(0.59g,64%)。
步驟272b,於0℃對在THF/水(3.9/1.3mL)中之來自步驟272a的化合物(0.59g,3.83mmol)的溶液添加TFA(0.589mL,7.65mmol)。在室溫將反應攪拌20小時。將反應冷卻至0℃且將Na2CO3緩慢加入並將pH調整至7-8。將EtOAc和水加入。分離這兩層(將食鹽水加入以輔助分離),用水和食鹽水洗滌有機層。用Na2SO4將有機相乾燥、過濾並濃縮至乾,以給出期望產物(0.50g,76%)。
步驟272c,對在DMF(4.0mL)中之來自步驟272b的化合物(0.48g,2.8mmol)、咪唑(0.57g,8.4mmol)的溶液添加TBSCl(0.63g,4.2mmol),且在室溫攪拌18小時。藉由倒至冷水中來將其淬滅。用己烷萃取產物。用食鹽水洗滌有機相,用Na2SO4乾燥、過濾並濃縮,以給出粗產物(0.97g,100%)。
步驟272d,對在二噁烷-水(18/6.0mL)中之來自步驟272c的化合物(1.43g,5.0mmol)的溶液添加2,6-二甲基吡啶(2,6-lutidine)(1.16mL,10mmol)和OsO4(0.78mL,在叔丁醇中2.5%溶液,0.05mmol)。將混合物冷卻至0℃,且將NaIO4(3.21g,15mmol)加入。在室溫將懸浮液攪拌16小時。將Na2S2O3水溶液加入。將混合物攪拌1小時且通過矽藻土過濾。用MBTE/己烷萃取混合物。用水、1N HCl、飽和NaHCO3和食鹽水洗滌有機相。分離有機相,用Na2SO4乾燥、過濾並濃縮,以得到粗產物(1.0g,69%)。
步驟272e,於0℃對LiBD4(0.108g,4.2mmol)的溶液逐滴添加在MBTE(12mL)中之來自步驟272d的化合物(0.577g,2.0
mmol)。在0℃將產生的溶液攪拌2小時。藉由NH4Cl水溶液的緩慢加入將反應淬滅,使溫度維持低於15℃。用MBTE和水稀釋反應混合物。分離混合物,且用食鹽水洗滌有機層。用Na2SO4將混合物乾燥、過濾並在真空下濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(0.39g,67%)。
步驟272f,於室溫對在DCM(2mL)中之來自步驟272e的化合物(0.39g,1.34mmol)和吡啶(0.216mL,2.68mmol)的溶液添加TsCl(0.306g,1.60mmol),且在室溫攪拌40小時。用H2O將其淬滅且用EtOAc萃取。用H2O、1M HCl、飽和NaHCO3和食鹽水洗滌混合物。收集有機相,用Na2SO4乾燥、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc)以給出為白色固體的期望化合物(0.59g,99%)。
步驟272g,對在MeOH(22mL)中之來自步驟272f的化合物(1.7g,3.81mmol)的溶液添加濃HCl(1.0mL),且在室溫攪拌16小時。用EtOAc將其稀釋,且用水、飽和NaHCO3、食鹽水洗滌混合物,用Na2SO4乾燥、過濾並濃縮。從己烷/MBTE將粗產物再結晶,以給出期望產物(1.1g,87%)。
步驟272h,於75℃將在DMF(1.0mL)中之來自步驟272g的化合物(0.16g,0.48mmol)、中間物6(0.12g,0.40mmol)和Cs2CO3(0.128g,0.392mmol)的溶液攪拌16小時。用EtOAc將其稀釋,且用水、食鹽水洗滌混合物,用Na2SO4乾燥、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物
(0.162g,88%)。ESI-MS m/z=457.12、459.12[M-H]-。
步驟272i,於室溫將在NMP(2.0mL)中之來自步驟272h的化合物(0.16g,0.35mmol)和m-CPBA(253mg,1.13mmol,77%)的溶液攪拌24小時。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾,從MeOH再結晶以給出標題化合物(118mg,68%)。ESI-MS m/z=489.11、491.11[M-H]-。
步驟279a,於0℃對在DMF(120mL)中之Me3SOI(48.5g,220mmol)的懸浮液添加t-BuOK(24.72g,220mmol),且在室溫攪拌1小時。將反應冷卻至0℃。將在DMF(80mL)中之中間物2a(20g,147mmol)的溶液逐滴給料至反應混合物。將反應攪拌2小時。對反應混合物逐滴添加15% NH4Cl,且用MTBE萃取。藉由MTBE來再萃取水相。用水和食鹽水洗滌合併的有機層,用Na2SO4乾燥、過濾並濃縮,以給出期望產物(19.9g,90%)。
步驟279b,於0℃對在THF/水(150/50mL)中之來自步驟279a的化合物(20g,133mmol)的溶液添加TFA(30.8mL,399mmol)。在室溫將反應攪拌3小時,然後冷卻至0℃且將Na2CO3緩慢加入並將pH調整至7-8。將EtOAc和水加入。將這兩層分離(將食鹽水加入
以輔助分離),用水和鹽水洗滌有機層,用Na2SO4乾燥、過濾並濃縮,以提供期望產物(17.7g,79%)。
步驟279c,對在DMF(80mL)中之來自步驟279b的化合物(10g,59.4mmol)、咪唑(10.2g,148mmol)的溶液添加TBSCl(10.7g,71.3mmol),且在室溫攪拌18小時。藉由倒至冷水中來將其淬滅。用己烷萃取產物。用食鹽水洗滌有機相,用Na2SO4乾燥、過濾並濃縮,以給出粗產物(18.1g,100%)。
步驟279d,對在二噁烷-水(170/60mL)中之來自步驟279c的化合物(16.8g,59.4mmol)的溶液添加2,6-二甲基吡啶(13.8mL,119mmol)和OsO4(9.3mL,於叔丁醇中2.5%,0.59mmol)。將混合物冷卻且將NaIO4(37.1g,178.2mmol)加入。在室溫將懸浮液攪拌16小時。將Na2S2O3水溶液加入。將混合物攪拌1小時且通過矽藻土過濾。用MBTE/己烷萃取混合物。用水、1N HCl、飽和NaHCO3和食鹽水洗滌有機相。將有機相分離,用Na2SO4乾燥、過濾並濃縮,以給出粗產物(16.6g,94%)。
步驟279f,對在CD3OD(3.0mL)中之來自步驟279d的化合物(143mg,0.503mmol)的溶液添加MeONa(5.4mg,0.10mmol),且在室溫將混合物攪拌3小時。將其濃縮且將殘餘物再溶解於CD3OD(3.0mL)中並攪拌3小時。將相同的反應循環再重複兩次,且將溶液冷卻至0℃,並將NaBD4(0.10g,2.4mmol)分批(portionwise)加入。1小時後,藉由NH4Cl水溶液的緩慢加入來將其淬滅。將MBTE和水加入。將混合物分離,且用食鹽水洗滌有機
層。用Na2SO4將混合物乾燥、過濾並在真空下濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(0.070g,50%)。
步驟279g,於室溫對在甲苯(1.5mL)中之中間物6(73mg,0.24mmol)和來自步驟279f的化合物(71mg,0.24mmol)的混合物添加氰基亞甲基三丁基-正膦(cyanomethylenetributyl-phosphorane)(176mg,0.73mmol),且在75℃攪拌16小時。將混合物冷卻至室溫且進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(0.11g,79%)。ESI-MS m/z=571.21、573.21[M-H]-。
步驟279h,對在MeOH(3.0mL)中之來自步驟279g的化合物(0.11g,0.19mmol)的溶液添加濃HCl(0.3mL),且在室溫攪拌2小時。用EtOAc將其稀釋,且用水、飽和NaHCO3、食鹽水洗滌混合物,用Na2SO4乾燥、過濾並濃縮。從己烷/MBTE將粗產物再結晶,以給出期望產物(0.083g,94%)。ESI-MS m/z=457.12、459.12[M-H]-。
步驟279i,於室溫將在NMP(2.0mL)中之來自步驟279h的化合物(0.083g,0.18mmol)和m-CPBA(0.14g,0.63mmol,77%)的溶液攪拌24小時。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮,藉由製備型HPLC(C18,乙腈/水)來
純化以給出標題化合物(48mg,54%)。ESI-MS m/z=489.11、491.11[M-H]-。
步驟281a,對在DMSO(22mL)中之來自步驟150f的化合物(4.0g,8.11mmol)的溶液添加IBX(3.70g,13.22mmol)。將反應混合物加熱至50℃、3小時。然後將反應混合物冷卻至室溫,且用EtOAc稀釋。過濾反應混合物,丟棄固體,且用水和飽和NaCl洗滌濾液。將有機層用Na2SO4乾燥、過濾並濃縮,以給予不經進一步純化即使用的粗期望產物(3.90g,98%)。
步驟281b,於-78℃對在THF(0.53mL)中之來自步驟281a的化合物(50mg,0.111mmol)的溶液添加異丙基氯化鎂(isopropylmagnesium chloride)、氯化鋰複合物(lithium chloride complex)(237μL,0.243mmol,在THF中1.3M)。將反應混合物攪拌30分鐘,且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,EtOAc/己烷)以給出期望化合物(18mg,33%)。ESI-MS m/z=540.14、542.14[M+HCO2]-。
步驟281c,對在NMP(0.5ml)中之來自步驟281b的化合物(18mg,0.01mmol)的溶液添加m-CPBA(24mg,0.096mmol,77%)且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有
機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(14mg,73%)。ESI-MS m/z=572.13、574.13[M+HCO2]-。
步驟283a,於-78℃對在THF(0.53mL)中之來自步驟281a的化合物(50mg,0.111mmol)的溶液添加苯基溴化鎂(phenylmagnesium bromide)(237μL,0.243mmol,於THF中1M)。將反應混合物攪拌30分鐘且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,EtOAc/己烷)以給出期望化合物(17mg,29%)。ESI-MS m/z=574.13、576.13[M+HCO2]-。
步驟283b,對在NMP(0.5ml)中之來自步驟283a的化合物(17mg,0.03mmol)的溶液添加m-CPBA(22mg,0.096mmol,77%),且在室溫攪拌隔夜。藉由製備型HPLC(C18,乙腈/水)來純化粗產物,以給出標題化合物(3mg,17%)。ESI-MS m/z=606.12、608.12[M+HCO2]-。
步驟284a,於0℃對在THF(1mL)中之2-溴吡啶(2-bromopyridine)(46μL,0.49mmol)的溶液添加異丙基氯化鎂、氯化鋰複合物(0.49mL,0.49mmol,於THF中1.3M)。將反應混合物溫熱至室溫且攪拌30分鐘,然後冷卻至-78℃,接著將在THF(1mL)中之來自步驟281a的化合物(100mg,0.221mmol)的溶液加入。將反應混合物攪拌18小時,緩慢溫熱至室溫且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取,且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,丙酮/己烷)以給出期望化合物(11mg,9%)。ESI-MS m/z=575.12、577.12[M+HCO2]-。
步驟284b,對在NMP(1ml)中之步驟284a的化合物(11mg,0.02mmol)的溶液添加p-TSA(20mg,0.105mmol)和m-CPBA(20mg,0.089mmol,77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(6mg,51%)。ESI-MS m/z=607.13、609.13[M+HCO2]-。
藉由SFC層析,從實施例284的化合物中分離出標題化合物(單一對掌異構物,暫時指定),較早洗脫出的化合物。
藉由SFC層析,從實施例284的化合物中分離出標題化合物(單一對掌異構物,暫時指定),較晚洗脫出的化合物。
步驟285a,於0℃對在THF(1mL)中之3-溴吡啶(46μL,0.49mmol)的溶液添加異丙基氯化鎂、氯化鋰複合物(0.49mL,0.49mmol,於THF中1.3M)。將反應混合物溫熱至室溫且攪拌30分鐘,然後冷卻至-78℃,接著將在THF(1mL)中之步驟281a的化合物(100mg,0.221mmol)的溶液加入。將反應混合物攪拌18小時,緩慢溫熱至室溫且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,丙酮/己烷),以給出期望化合物(15mg,13%)。ESI-MS m/z=575.12、577.12[M+HCO2]-。
步驟285b,對在NMP(1ml)中之步驟285a的化合物(15mg,0.028mmol)的溶液添加p-TSA(20mg,0.105mmol)和m-CPBA(20mg,0.089mmol,77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將
粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(8mg,50%)。ESI-MS m/z=607.13、609.13[M+HCO2]-。
藉由SFC層析,從實施例285的化合物中分離出標題化合物(單一對掌異構物,暫時指定),較早洗脫出的化合物。
藉由SFC層析,從實施例285的化合物中分離出標題化合物(單一對掌異構物,暫時指定),較晚洗脫出的化合物。
步驟286a,於0℃對在THF(1.5mL)中之4-碘吡啶(159mg,0.774mmol)的溶液添加正丁基鋰(0.31mL,0.774mmol,於己烷中2.5M)。將此反應混合物溫熱至室溫且攪拌30分鐘,然後冷卻至-78℃,接著將在THF(1mL)中之來自步驟281a的化合物(100mg,0.221mmol)的溶液加入。將反應混合物攪拌18小時,緩慢溫熱至室溫且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食
鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,丙酮/己烷),以給出期望化合物(45mg,38%)。ESI-MS m/z=575.30、577.30[M+HCO2]-。
步驟286b,對在NMP(2ml)中之步驟286a的化合物(45mg,0.085mmol)的溶液添加p-TSA(48mg,0.254mmol)和m-CPBA(57mg,0.254mmol,77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(8mg,17%)。ESI-MS m/z=607.29、609.29[M+HCO2]-。
步驟287a,於-78℃對在THF(1mL)中之1-(二乙氧基)-1H-咪唑(1-(diethoxy)-1H-imidazole)(159mg,0.487mmol)的溶液添加正丁基鋰(0.195mL,0.487mmol,於己烷中2.5M)。將反應混合物攪拌30分鐘,接著將在THF(1mL)中之來自步驟281a的化合物(100mg,0.221mmol)的溶液加入。將反應混合物攪拌18小時,緩慢溫熱至室溫且藉由NH4Cl水溶液淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,丙酮/己烷),以給出期望化合物(22mg,38%)。ESI-MS m/z=564.29、566.29[M+HCO2]-。
步驟287b,對在NMP(2ml)中之步驟287a的化合物(22mg,0.042mmol)的溶液添加p-TSA(50mg,0.263mmol)和m-CPBA(50mg,0.223mmol,77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。藉由製備型HPLC(C18,乙腈/水)對粗產物進行層析,以給出為白色固體的標題化合物(6mg,26%)。ESI-MS m/z=596.28、598.28[M+HCO2]-。
步驟288a,於0℃對在THF(1.5mL)中之1-甲基-1H-吡唑(64μL,0.774mmol)的溶液添加正丁基鋰(0.31mL,0.774mmol,於己烷中2.5M)。將反應混合物攪拌30分鐘,接著將在THF(1mL)中之來自步驟281a的化合物(100mg,0.221mmol)的溶液加入。將反應混合物攪拌18小時,緩慢溫熱至室溫且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,丙酮/己烷),以給出期望化合物(79mg,67%)。ESI-MS m/z=578.32、580.31[M+HCO2]-。
步驟288b,對在NMP(2ml)中之步驟288a的化合物(79mg,0.148mmol)的溶液添加m-CPBA(99mg、0.444mmol、77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層
乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,丙酮/己烷),以給出為白色固體的標題化合物(65mg,78%)。ESI-MS m/z=610.30、612.30[M+HCO2]-。
步驟289a,於-78℃對在THF(2mL)中之4-溴-1-甲基-1H-吡唑(4-bromo-1-methyl-1H-pyrazole)(69μL,0.664mmol)的溶液添加正丁基鋰(0.31mL,0.774mmol,於己烷中2.5M)。將反應混合物攪拌30分鐘,接著將在THF(1mL)中之來自步驟281a的化合物(100mg,0.221mmol)的溶液加入。將反應混合物攪拌18小時,緩慢溫熱至室溫且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,丙酮/己烷),以給出期望化合物(23mg,19%)。ESI-MS m/z=578.31、580.31[M+HCO2]-。
步驟289b,對在NMP(2ml)中之步驟289a的化合物(23mg)的溶液添加m-CPBA(29mg,77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,丙酮/己烷),以給出為白色固體的標題化合物(22mg,90%)。ESI-MS m/z=610.30、612.31[M+HCO2]-。
步驟290a,於0℃對在THF(1.5mL)中之噁唑(76μL,1.162mmol)的溶液添加i-PrMgCl-LiCl(0.894mL,1.162mmol,於THF中1.3M)。將反應混合物攪拌30分鐘,接著將在THF(1.5mL)中之來自步驟281a的化合物(150mg,0.332mmol)的溶液加入。將反應混合物攪拌3小時,緩慢溫熱至室溫且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,丙酮/己烷),以給出期望化合物(22mg,38%)。ESI-MS m/z=565.28、567.28[M+HCO2]-。
步驟290b,對在NMP(2.5ml)中之步驟290a的化合物(133mg,0.042mmol)的溶液添加p-TSA(243mg,1.276mmol)和m-CPBA(172mg,0.766mmol,77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。藉由藉由製備型HPLC(C18,乙腈/水)對粗產物進行層析,以給出為白色固體的標題化合物(20mg,14%)。ESI-MS m/z=597.26、599.26[M+HCO2]-。
步驟291a,於-78℃對在THF(3mL)中之2-溴-5-氟吡啶(2-bromo-5-fluoropyridine)(302mg,1.715mmol)的溶液逐滴添加正丁基鋰(0.730ml,1.826mmol,於THF中2.5M)。在相同溫度攪拌1小時後,於-78℃將在THF(1.5mL)中之來自步驟281a的化合物(250mg,0.553mmol)的溶液加到混合物中。將反應緩慢溫熱至室溫且攪拌16小時。將飽和NH4Cl溶液加入。用EtOAc萃取混合物,用Na2SO4乾燥,且藉由管柱層析(矽,MeOH/DCM)來純化,以給出為淺棕色(pale brown)固體的期望化合物(70mg,0.128mmol,23%產率)。
步驟291b,於0℃對在NMP(1mL)中之來自步驟291a的化合物(70mg,0.128mmol)、p-TSA(72.8mg,0.383mmol)的溶液添加m-CPBA(86mg,0.383mmol,77%)。將反應緩慢溫熱至室溫且攪拌16小時。將飽和Na2S2O3溶液和NaHCO3溶液加入,且在室溫將產生的混合物攪拌1小時。用EtOAc萃取混合物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,且用Na2SO4乾燥。藉由管柱層析(矽,MeOH/DCM)來純化粗材料,以給出為淡棕色(light brown)固體的標題化合物(17.0mg,0.128mmol,23%產率)。ESI-MS m/z=580.00、582.01[M-H]-。
藉由SFC層析,從實施例291的化合物中分離出標題化合物(單一對掌異構物,暫時指定),較早洗脫出的化合物。
藉由SFC層析,從實施例291的化合物中分離出標題化合物(單一對掌異構物,暫時指定),較晚洗脫出的化合物。
藉由管柱層析(於DCM中0-20% MeOH)純化來自步驟291b的粗材料,以給出為淡棕色固體的標題化合物(9.3mg,0.016mmol,12%產率)。ESI-MS m/z=596.00、598.01[M-H]-。
步驟293a,於-78℃對在THF(1.5mL)中之2-溴-5-甲基吡啶(2-bromo-5-methylpyridine)(200mg,1.16mmol)的溶液添加正丁基鋰(0.465mL,1.16mmol,於己烷中2.5M)。將反應混合物攪拌30分鐘,接著將在THF(1.5mL)中之來自步驟281a的化合
物(150mg,0.332mmol)的溶液加入。將反應混合物攪拌1小時,緩慢溫熱至室溫且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,丙酮/己烷),以給出期望化合物(129mg,71%)。ESI-MS m/z=589.14、591.14[M+HCO2]-。
步驟293b,對在NMP(2.4ml)中之步驟293a的化合物(129mg,0.24mmol)的溶液添加p-TSA(225mg,1.18mmol)和m-CPBA(159mg,0.71mmol,77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(109mg,80%)。ESI-MS m/z=621.13、623.13[M+HCO2]-。
步驟297a,於-78℃對在THF(1.5mL)中之2-溴-3-氟吡啶(2-bromo-3-fluoropyridine)(204mg,1.16mmol)的溶液添加正丁基鋰(0.465mL,1.16mmol,於己烷中2.5M)。將反應混合物攪拌30分鐘,接著將在THF(1.5mL)中之來自步驟281a的化合物(150mg,0.332mmol)的溶液加入。將反應混合物攪拌1小時,緩慢溫熱至室溫且藉由NH4Cl水溶液來淬滅。用EtOAc將其萃取且用食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,將粗產物進行層析(矽,
丙酮/己烷),以給出期望化合物(129mg,71%)。ESI-MS m/z=563.12、565.10[M+HCO2]-。亦分離出3-(((1R,3r,5S,8r)-8-((2-溴-3-氟吡啶-4-基)(羥基)甲基)-8-羥基雙環[3.2.1]辛-3-基)硫代)-4-氯-N-(3,4-二氟苯基)苯甲醯胺(3-(((1R,3r,5S,8r)-8-((2-bromo-3-fluoropyridin-4-yl)(hydroxy)methyl)-8-hydroxybicyclo[3.2.1]octan-3-yl)thio)-4-chloro-N-(3,4-difluorophenyl)benzamide)(77mg,37%)。ESI-MS m/z=671.03、673.04[M+HCO2]-。
步驟297b,對在NMP(0.2ml)中之步驟297a的化合物(10mg,0.018mmol)的溶液添加p-TSA(17mg,0.09mmol)和m-CPBA(12mg,0.055mmol,77%)且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(4.7mg,44%)。ESI-MS m/z=625.11、627.11[M+HCO2]-。
步驟298,對在NMP(1.3ml)中之來自步驟297a的副產物3-(((1R,3r,5S,8r)-8-((2-溴-3-氟吡啶-4-基)(羥基)甲基)-8-羥基雙環[3.2.1]辛-3-基)硫代)-4-氯-N-(3,4-二氟苯基)苯甲醯胺(77mg,0.123mmol)的溶液添加p-TSA(117mg,0.613mmol)
和m-CPBA(82mg,0.368mmol,77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物(64mg,79%)。ESI-MS m/z=703.01、705.12[M+HCO2]-。
步驟307a,於0℃在1分鐘內,透過吸量管(pipette)對在ACN(70ml)和DBU(3.25ml,21.59mmol)中之來自實施例150d的化合物(7.04g,16.61mmol)的混合物添加九氟丁烷-1-磺醯氟(Nonafluorobutane-1-sulfonyl fluoride)(5.52g,18.27mmol),且在此溫度攪拌1小時。當其仍然冷卻時,將200mL MTBE加入。用水、1N HCl兩次、然後水、NaHCO3水溶液兩次、食鹽水兩次來洗滌溶液。乾燥(Na2SO4)且濃縮之後,得到13.5g淡黃色固體。在真空下過濾之前,對其添加MTBE/己烷約1:10(200mL)且在室溫攪拌30分鐘。用MTBE/己烷(1:10,100mL)洗滌收集的固體,以給出灰白色(off white)固體(10.1g,86%)。ESI-MS m/z=704.02、706.02[M-H]-。
步驟307b,對在DMF(2mL)中之來自步驟307a的化合物(200mg,0.283mmol)的溶液添加甲基異丙胺(methyl
isopropylamine)(0.15mL),且在75℃攪拌2天。用EtOAc稀釋粗產物,用水洗滌兩次,用食鹽水滌兩次且乾燥(Na2SO4)並濃縮。將粗產物進行層析(矽,MeOH/DCM),以給出為與其它雜質的混合物的期望化合物。ESI-MS m/z=477.15、479.15[M-H]-。
步驟307c,按照實施例284b中所述的流程,從步驟307b的化合物獲得標題化合物,且藉由製備型HPLC來純化。ESI-MS m/z=509.14、511.14[M-H]-。
對在THF(10mL)中之來自步驟82a的化合物(570mg,1.27mmol)的溶液添加m-CPBA(77% w/w,1.42g,6.33mmol),且在室溫攪拌隔夜。對其添加Na2S2O3(10mL)和NaHCO3(10mL)水溶液,接著將4滴TEA和EtOAc(50mL)加入。在分離之前,於室溫將其攪拌1.5小時。用EtOAc萃取水相。將合併的有機物用NaHCO3、食鹽水洗滌並乾燥(Na2SO4)。濃縮之後,在加熱(熱風槍)下,將粗淡黃色固體溶於MeOH(50mL)中,且在維持於0℃、30分鐘之前,緩慢冷卻至室溫。在真空下收集形成的結晶,以給予為白色固體的標題化合物(510mg,81%)。ESI-MS m/z=496.20、498.20[M-H]-。
對在DMF(0.5mL)中之來自實施例308的化合物(50mg,0.10mmol)的溶液添加1,1-二側氧基異噻唑烷(Dioxoisothiazolidine)(18.3mg,0.15mmol),接著將K2CO3加入(14mg,0.1mmol)且在50℃攪拌隔夜。在製備型HPLC(C-18,乙腈/水)上將粗產物純化,以給出為白色固體的標題化合物(16mg,26%)。ESI-MS m/z=617.25、619.25[M-H]-。
步驟314a,於0℃對在DMF(1mL)中之Me3SOI(365mg,1.66mmol)的漿液(slurry)添加叔丁醇鉀(186mg,1.66mmol)。將混合物溫熱至室溫且攪拌45分鐘。將在DMF(2mL)中之來自步驟281a的化合物(150mg,0.33mmol)逐滴加到反應混合物中。在室溫攪拌4小時後,將反應混合物冷卻至0℃,將飽和NH4Cl溶液加入,用MTBE萃取,且用Na2SO4乾燥。藉由管柱層析(於己烷中0-50% EtOAc)來純化粗產物,以給出為白色固體的期望化合物(42.0mg,0.090mmol,27%產率)。
步驟314b,對在DMF(2mL)中之來自步驟314a的化合物(42mg,
0.090mmol)的溶液添加1H-吡唑(12.27mg,0.180mmol)、碳酸鉀(18.69mg,0.135mmol)。在65℃將反應攪拌15小時。用EtOAc萃取混合物,用Na2SO4乾燥,且藉由管柱層析(於己烷中0-70% EtOAc)來純化,以給出為灰白色固體的期望化合物(30.0mg,0.056mmol,62%產率)。
步驟314c,於0℃對在NMP(0.2mL)中之來自步驟314b的化合物(30mg,0.056mmol)和10-樟腦磺酸(10-camphorsulfonic acid,CSA)(19.57mg,0.084mmol)的溶液添加m-CPBA(37.8mg,0.169mmol,77%)。將反應緩慢溫熱至室溫且攪拌15小時。將飽和Na2S2O3溶液和NaHCO3溶液加到混合物中,且攪拌1小時。用EtOAc萃取反應物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,且用Na2SO4乾燥。藉由管柱層析(矽,己烷/丙酮)來純化粗材料,以給出為灰白色固體的標題化合物(20mg,0.035mmol,63%產率)。ESI-MS m/z=565.30、567.29[M-H]-。
步驟315a,於0℃對在DMF(1mL)中之噁唑烷-2-酮(oxazolidin-2-one)(42.0mg,0.483mmol)的溶液添加氫化鈉(17.38mg,0.435mmol)。在室溫將混合物攪拌1小時,且冷卻至0℃。將在DMF(1mL)中之來自步驟314a的化合物(45mg,
0.097mmol)的溶液加到反應中。將混合物加熱至55℃、15小時。將反應冷卻至室溫且將飽和NH4Cl溶液加入。用EtOAc萃取混合物,用Na2SO4乾燥,且藉由管柱層析(矽,己烷/EtOAc)來純化,以給出為白色固體的期望化合物(40mg,0.072mmol,75%產率)。
步驟315b,於0℃對在NMP(1mL)中之來自步驟315a的化合物(38mg,0.069mmol)的溶液添加m-CPBA(46.2mg,0.206mmol,77%)。將反應緩慢溫熱至室溫且攪拌16小時。用EtOAc萃取反應物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,且用Na2SO4乾燥。藉由管柱層析(矽,MeOH/DCM)來純化粗材料,以給出為灰白色固體的標題化合物(14.0mg,0.024mmol,35%產率)。ESI-MS m/z=584.02、586.02[M-H]-。
步驟316a,於-78℃對在THF(2mL)中之1-(二乙氧基甲基)-1H-咪唑(1-(diethoxymethyl)-1H-imidazole)(0.053ml,0.322mmol)的溶液添加正丁基鋰(0.116ml,0.290mmol,於THF中2.5M)。將混合物溫熱至0℃且攪拌45分鐘,然後冷卻至-78℃。將在THF(1mL)中之來自步驟314a的化合物(30mg,0.064mmol)的溶液加到反應混合物中。將混合物加熱至50℃且攪拌16小時。將反應冷卻至室溫且將飽和NH4Cl溶液加入。用EtOAc萃取
混合物,用Na2SO4乾燥,且藉由管柱層析(矽,己烷/EtOAc)來純化,以給出為灰白色固體的期望化合物(13mg,0.024mmol,38%產率)。
步驟316b,於0℃對在NMP(1mL)中之來自步驟316a的化合物(13mg,0.024mmol)、CSA(8.48mg,0.037mmol)的溶液添加m-CPBA(16.37mg,0.073mmol,77%)。將反應緩慢溫熱至室溫且攪拌15小時。用EtOAc萃取反應物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,且用Na2SO4乾燥。藉由管柱層析(矽,己烷/丙酮)來純化粗材料,以給出為灰白色固體的標題化合物(5.8mg,0.010mmol,42%產率)。ESI-MS m/z=565.02、566.02[M-H]-。
步驟317a,於-78℃對在THF(3mL)中之4-甲基吡啶(4-methylpyridine)(0.134ml,1.372mmol)的溶液逐滴添加二異丙基胺基鋰(1.372ml,1.372mmol,於THF中1M)。在相同溫度將混合物攪拌1小時。於-78℃將在THF(1.5mL)中之步驟281a的化合物(200mg,0.443mmol)的溶液加到混合物中。將混合物緩慢溫熱至室溫且攪拌16小時。將飽和NH4Cl溶液加入。用EtOAc萃取混合物,用Na2SO4乾燥,且藉由管柱層析(矽,MeOH/DCM)
來純化,以給出為黏稠油狀物的的期望化合物(91mg,0.167mmol,38%產率)。
步驟317b,於0℃對在NMP(1mL)中之來自步驟317a的化合物(91mg,0.167mmol)、p-TSA(95mg,0.501mmol)的溶液添加m-CPBA(112mg,0.501mmol,77%)。將反應緩慢溫熱至室溫並攪拌16小時。用EtOAc萃取反應物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,且用Na2SO4乾燥。藉由管柱層析(矽,己烷/丙酮)來純化粗材料,以給出為灰白色固體的標題化合物(61.0mg,0.106mmol,63%產率)。ESI-MS m/z=576.04、578.04[M-H]-。
步驟318a,於-78℃對在THF(3mL)中之3-甲基吡啶(3-methylpyridine)(0.134ml,1.372mmol)的溶液逐滴添加二異丙基胺基鋰(1.372ml,1.372mmol,於THF中1M)。在相同溫度攪拌30分鐘後,將混合物溫熱至0℃且攪拌30分鐘,並冷卻至-78℃。於-78℃將THF(1.5mL)中之來自步驟281a的化合物(200mg,0.443mmol)的溶液加到混合物中。將反應緩慢溫熱至室溫且攪拌15小時。將飽和NH4Cl溶液加入。用EtOAc萃取混合物,用Na2SO4乾燥,且藉由管柱層析(矽,MeOH/DCM)來純化,以給出
為淺黃色固體的期望化合物(70mg,0.128mmol,29%產率)。
步驟318b,於0℃對在NMP(1mL)中之來自步驟318a的化合物(70mg,0.128mmol)、p-TSA(73.3mg,0.385mmol)的溶液添加m-CPBA(86mg,0.385mmol,77%)。將反應緩慢溫熱至室溫且攪拌16小時。將飽和Na2S2O3溶液和NaHCO3溶液加入,且在室溫將產生的混合物攪拌1小時。用EtOAc萃取反應物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,且用Na2SO4乾燥。藉由管柱層析(矽,己烷/丙酮)來純化粗材料,以給出為白色固體的標題化合物(27.0mg,0.047mmol,36%產率)。ESI-MS m/z=576.04、578.04[M-H]-。
步驟319a,於-78℃對在THF(3mL)中之2-甲基吡啶(0.135ml,1.372mmol)的溶液逐滴添加二異丙基胺基鋰(0.549ml,1.372mmol,於THF中1M)。在相同溫度攪拌1小時後,於-78℃將在THF(1.5mL)中之來自步驟281a的化合物(200mg,0.443mmol)的溶液加到混合物中。將反應緩慢溫熱至室溫且攪拌16小時。將飽和NH4Cl溶液加入。用EtOAc萃取混合物,用Na2SO4乾燥,且藉由管柱層析(矽,MeOH/DCM)來純化,以給出為淺黃色固體的期望化合物(130mg,0.239mmol,54%產率)。
步驟319b,於0℃對在NMP(1mL)中之來自步驟319a的化合物(130mg,0.239mmol)、p-TSA(136mg,0.716mmol)的溶液添加m-CPBA(160mg,0.716mmol,77%)。將反應緩慢溫熱至室溫並攪拌16小時。將飽和Na2S2O3溶液和NaHCO3溶液加入,且在室溫將產生的混合物攪拌1小時。用EtOAc萃取混合物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,且用Na2SO4乾燥。藉由管柱層析(矽,己烷/丙酮)來純化粗材料,以給出為白色固體的標題化合物(80.0mg,0.139mmol,58%產率)。ESI-MS m/z=576.04、578.04[M-H]-。
步驟320a,對在DCM(5mL)中之來自實施例82a的化合物(450mg,1.00mmol)的溶液添加烯丙基溴(allylbromide)(363mg,3.0mmol),接著將Hoveyda-Grubbs第二代催化劑(12.5mg,0.2mmol)加入且在室溫攪拌隔夜。將反應濃縮。將粗產物進行層析(矽,EtOAc/己烷),以給出為灰白色固體的期望化合物(410mg,期望和起始材料的比例為1.1:1的混合物)。ESI-MS m/z=542.16、544.16[M-H]-。
步驟320b,對在DMF(2mL)中之來自步驟320a的化合物(170mg,0.31mmol)的溶液添加二異噻唑烷
(Dioxoisothiazolidine)(38mg,0.31mmol),接著將K2CO3(44mg,0.31mmol)加入且在65℃攪拌隔夜。用EtOAc稀釋粗產物,用水洗滌兩次,用食鹽水洗滌兩次且乾燥(Na2SO4)並濃縮。將粗產物進行層析(矽,MTBE/己烷),以給出灰白色固體的期望化合物(59mg,32%)。ESI-MS m/z=627.12、629.12[M-H+HCOOH]-。
步驟320c,按照實施例4b中所述的流程,從步驟320b的化合物獲得標題化合物。ESI-MS m/z=693.30、695.30[M-H+HCOOH]-。
步驟321a,對在DMF(2mL)中之來自步驟82a的化合物(100mg,0.222mmol)和3-溴吡啶(3-bromopyridine)(26μL,0.267mmol)的溶液添加Et3N(62μL,0.445mmol)、三鄰甲苯基膦(tri-o-tolylphosphine)(6.8mg,0.022mmol)和乙酸鈀(palladium acetate)(2.5mg,0.011mmol)。於120℃將反應混合物攪拌18小時。將反應混合物冷卻,然後用EtOAc萃取,用水和食鹽水洗滌,用Na2SO4乾燥、過濾並濃縮。藉由管柱層析(矽,己烷/丙酮)來純化粗材料,以給出期望化合物(100mg,0.190mmol,85%產率)。ESI-MS m/z=571.30、573.30[M-H]-。
步驟321b,對在丙酮(1mL)和水(0.2mL)中之來自步驟321a的化合物(52mg,0.099mmol)的溶液添加OsO4(25μL,4.93
μmol,於水中5%)和NMO(58mg,0.493mmol)。在室溫將反應混合物攪拌72小時。用乙酸乙酯稀釋反應混合物,然後用飽和Na2S2O3和飽和NaCl洗滌。用Na2SO4將有機層乾燥、過濾並濃縮。無需進一步純化即使用粗材料。
步驟321c,對在NMP(2mL)中之來自步驟321b的粗材料的溶液添加p-TSA(56mg,0.294mmol)和m-CPBA(110mg,0.49mmol,77%),且在室溫攪拌隔夜。用EtOAc萃取反應物,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物。ESI-MS m/z=637.32、639.32[M+HCO2]-。
步驟322a,對在DMF中之來自步驟82a的化合物(100mg,0.222mmol)和4-溴-1-甲基-1H-吡唑(4-bromo-1-methyl-1H-pyrazole)(28μL,0.267mmol)的(2mL)溶液添加Et3N(62μL,0.445mmol)、三-鄰甲苯基膦(6.8mg,0.022mmol)和乙酸鈀(2.5mg,0.011mmol)。在120℃將反應混合物攪拌18小時。將反應混合物冷卻,然後用EtOAc萃取,用水和食鹽水洗滌,用Na2SO4乾燥、過濾並濃縮。藉由管柱層析(矽,己烷/丙酮)純化粗材料,以給出期望化合物(12mg,0.023
mmol,10%產率)。ESI-MS m/z=574.32、576.32[M-H]-。
步驟322b,對在丙酮(0.5mL)和水(0.1mL)中之來自步驟322a的化合物(12mg,0.099mmol)的溶液添加OsO4(6μL,1.13μmol,於水中5%)和NMO(13mg,0.113mmol)。在室溫將反應混合物攪拌72小時。用乙酸乙酯稀釋反應混合物,然後用飽和Na2S2O3和飽和NaCl洗滌。用Na2SO4將有機層乾燥、過濾並濃縮。無需進一步純化即使用粗混合物。
步驟322c,對在NMP(1mL)中之來自步驟322b的粗材料的溶液添加m-CPBA(16mg,0.069mmol,77%),且在室溫攪拌隔夜。用EtOAc萃取反應,用水和食鹽水洗滌。將有機層乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/丙酮),以給出為白色固體的標題化合物。ESI-MS m/z=640.33、642.33[M+HCO2]-。
步驟323a,於-78℃對在THF(1.66ml)中之三甲基甲矽烷基乙炔(trimethylsilylacetylene)(0.50ml,3.56mmol)的溶液添加n-BuLi(1.426ml,3.56mmol,於THF中2.5M)。在相同溫度將產生的混合物攪拌1小時。於-78℃將在THF(1.66mL)中之來自步驟281a的化合物(0.3g,0.664mmol)的溶液加到反應中。將產生的淡黃色溶液緩慢溫熱至室溫且攪拌3小時。將NH4Cl溶液加
入。用EtOAc萃取混合物,用Na2SO4乾燥,且無需進一步純化即使用。
步驟323b,於室溫對在MeOH(3ml)和水(0.3ml)中之來自步驟323a的化合物(365mg,0.664mmol)的溶液添加碳酸鉀(459mg,3.32mmol)。在室溫將混合物攪拌15小時。真空除去溶劑,且用EtOAc萃取產生的混合物,用Na2SO4乾燥,然後藉由管柱層析(矽,己烷/EtOAc)來純化,以給出為白色固體的期望化合物(204.9mg,0.429mmol,65%產率)。
步驟323c,於室溫將甲醛(109μl,1.465mmol)、乙酸(12.58μl,0.220mmol)和THF(1mL)的混合物攪拌15分鐘。將疊氮化鈉(Sodium azide)(14.28mg,0.220mmol)加入,接著將來自步驟323b的化合物(70mg,0.146mmol)加入。將混合物攪拌10分鐘,且將抗壞血酸鈉(sodium ascorbate)(5.80mg,0.029mmol)加入,接著將在150uL的水中之硫酸銅(II)(copper(II)sulfate)(1.169mg,7.32μmol)加入。將反應加熱至50℃且攪拌16小時,然後用EtOAc萃取,用Na2SO4乾燥,然後藉由管柱層析(矽,MeOH/DCM)來純化,以給出為類綠色(greenish)固體的期望化合物(53.4mg,0.103mmol,70%產率)。
步驟323d,於0℃對在NMP(1mL)中之來自步驟323c的化合物(53.4mg,0.102mmol)和p-TsOH(97mg,0.512mmol)的溶液添加m-CPBA(68.9mg,0.307mmol,77%)。將反應緩慢溫熱至室溫並攪拌15小時。將飽和Na2S2O3溶液和NaHCO3溶液加
入,且在室溫將產生的混合物攪拌1小時。用EtOAc萃取混合物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,且用Na2SO4乾燥。藉由管柱層析(矽,含有0.1% NH3之MeOH/DCM)來純化粗材料,以給出為灰白色固體的標題化合物(15.0mg,0.027mmol,27%產率)。ESI-MS m/z=549.95、551.97[M-H]-。
步驟327a,用步驟Int 2e中所述的條件來處理來自步驟279d的化合物,給出期望產物。1H NMR(400MHz,氯仿-d)δ 3.90(m,1H),3.43(s,2H),2.69(s,1H),1.84(m,4H),1.70(m 2H),1.57(m,2H),1.45(t,J=6.7Hz,3H),0.83(s,9H),0.00(s,6H)。
步驟327b,於0℃對在CH2Cl2(74.0ml)中之步驟327a的化合物(10.6g,37.0mmol)的溶液添加吡啶(8.98ml,111mmol)、DMAP(0.226g,1.850mmol)和苯磺醯氯(benzenesulfonyl chloride)(5.19ml,40.7mmol)。在室溫攪拌隔夜後,將水(15mL)加入且攪拌30分鐘。將其濃縮,然後用EtOAc(400mL)稀釋,且用飽和NaHCO3水溶液、水、1M HCl、水、食鹽水洗滌。將有機層乾燥(Na2SO4)且濃縮,以給出不經進一步純化用於下一步驟的粗產物。
步驟327c,於室溫對在2-甲基-THF(58.5ml)中之步驟
327b(15.60g,36.6mmol)的溶液添加濃HCl(11.70ml,140mmol)。於室溫將產生的澄清溶液攪拌3小時。將混合物分批倒至飽和NaHCO3水溶液和DCM的混合物中。用DCM萃取水層兩次。用食鹽水洗滌合併的有機相,乾燥(Na2SO4)、過濾並濃縮。在真空下將殘餘物乾燥,以給予直接用於下一步驟的白色固體。
步驟327d,於0℃對在CH2Cl2(122ml)中之步驟327c的化合物(11.42g,36.6mmol)的溶液添加DMAP(0.447g,3.66mmol)、吡啶(8.87ml,110mmol)和乙酸酐(3.79ml,40.2mmol)。在室溫將反應攪拌隔夜。將飽和NaHCO3水溶液(30mL)加入並攪拌15分鐘。分離之後,用CH2Cl2(100mL x 2)萃取水相,將合併的有機相乾燥(Na2SO4)並濃縮。將粗產物進行層析,以給出為灰白色固體的期望化合物(11.4g,93%三步驟)。
步驟327e,於室溫對在乙酸(45ml)中之來自步驟327d的化合物(4.000g,11.29mmol)的溶液添加雙(三氟甲磺酸)錳(manganese bis(trifluoromethanesulfonate))(0.91ml,0.011mmol)(在9/1的乙酸/水中之0.0125M)和2,2’-聯吡啶(2,2'-bipyridine)(0.018g,0.113mmol)。在室溫下攪拌10分鐘後,在約10分鐘內逐滴將過乙酸/KOH(peracetic acid/KOH)混合物(其藉由將10% KOH(3.0ml)加到35%過乙酸(10.0ml),11.79ml,39.5mmol來製備)加入。在室溫下進一步攪拌15分鐘,接著將丙酮(130ml)加入。在室溫下1分鐘後,通過矽藻土短墊過濾微渾濁(cloudy)溶液,用丙酮洗滌。將濾液濃縮。將粗殘餘物進行層析(矽,EtOAc/
己烷),以給予為無色油狀物的期望化合物(2.130g,51%)。
步驟327f,於室溫對在DMF(5.78ml)中之步驟327e(2.130g,5.78mmol)和中間物6(1.820g,6.07mmol)的澄清溶液添加碳酸鉀(0.799g,5.78mmol)。在冷卻之前,於70℃將混合物攪拌12小時。用EtOAc和飽和NH4Cl溶液稀釋混合物。用水/食鹽水(1/1,*2)、食鹽水(*1)洗滌有機層,乾燥並濃縮。將粗殘餘物進行層析(矽,EtOAc/DCM),以給予期望化合物(2.10g,70%)。ESI-MS m/z=508.07、510.07[M-H]-。
步驟327g,於0℃對在EtOH中之來自步驟327f的化合物(40mg,0.078mmol)的溶液添加NaBH4(6mg,0.16mmol)。30分鐘後,將第2份之2當量(eq.)的NaBH4加入且在室溫攪拌3小時。將總共約10當量的NaBH4加入。將其濃縮除去揮發物。將粗產物溶於EtOAc中,且用NH4Cl和食鹽水洗滌、乾燥、濃縮以給出為白色固體的粗期望化合物(60mg)。此材料無需進一步純化即用於下一步驟。ESI-MS m/z=468.08、470.08[M-H]-。
步驟327h,藉由按照實施例130b中所述的流程,從步驟327g獲得標題化合物。ESI-MS m/z=500.07、502.07[M-H]-。
步驟328a,於0℃對在EtOH(50mL)/MeOH(15mL)中之來自
步驟327f的化合物(610mg,1.2mmol)添加NaBH4(360mg,9.6mmol)。15分鐘後,將第二份的NaBH4(200mg)加入。10分鐘後,將第三份的NaBH4(100mg)加入,再攪拌10分鐘。當仍然冷卻時,將稀HCl(0.5M)逐滴加入直到不再起泡(bubbling)。將EtOAc(200mL)加入,接著將50mL的水加入。用水、食鹽水洗滌有機物,乾燥(Na2SO4)並濃縮。將粗殘餘物進行層析(矽,EtOAc/己烷),以給予為白色固體的期望化合物(410mg,67%)。ESI-MS m/z=510.09、512.09[M-H]-。
步驟328b,對在甲苯(1mL)中之步驟328a的化合物(382mg,0.77mmol)的溶液添加在甲苯(3mL)中之2-(三丁基-1,5-亞磷醯基)乙腈(2-(tributyl-l5-phosphaneylidene)acetonitrile)(647mg,2.68mmol)的溶液。在95至100℃將其加熱1小時,將第二份2-(三丁基-1,5-亞磷醯基)乙腈(400mg)加入且再加熱1.5小時。在冷卻並濃縮之前,將第三份2-(三丁基-1,5-亞磷醯基)乙腈(500mg)加入,且再加熱1.5小時。將粗產物進行層析(矽,MTBE/己烷),以給出為白色固體的期望化合物(302mg,80%)。ESI-MS m/z=492.08、494.08[M-H]-。
步驟328c,對在乙酸酐(5mL)中之來自步驟328b(295mg,0.60mmol)的溶液添加BF3乙酸鹽(etherate)(0.6mL,4.8mmol)並在室溫下攪拌30分鐘。於冰水浴中,緩慢將反應加到NaHCO3水溶液(40mL)中。將其用EtOAc萃取兩次。用水、食鹽水洗滌合併的有機物並乾燥(Na2SO4)。濃縮之後,將粗殘餘物進行層析(矽,EtOAc/
己烷),以給予為白色固體的期望化合物(245mg,69%),為雙乙酸酯和三乙酸酯的混合物。ESI-MS m/z=552.10、554.10[M-H]-二乙酸(bis-acetates)、m/z=594.11、596.11[M-H]-(tri-acetates)。
步驟328d,將K2CO3(183mg,1.33mmol)加到在MeOH(3mL)中之來自步驟328c的化合物(245mg,0.44mmol)的溶液中。2小時後,在用EtOAc稀釋且用水洗滌之前,將額外的K2CO3(25mg)加入並再攪拌1小時。用EtOAc萃取水相。用食鹽水洗滌合併的有機相,乾燥(Na2SO4)並濃縮。將粗產物進行層析(矽,MTBE/己烷),以給出灰白色固體的期望化合物(148mg,71%)。ESI-MS m/z=468.08、470.08[M-H]-。
步驟328e,按照實施例130b中所述的流程,從步驟328d的化合物獲得標題化合物。ESI-MS m/z=500.07、502.07[M-H]-。
對在乙腈(5mL)中之來自實施例150的化合物(250mg,0.514mmol)的溶液添加(2R,3R,4S,5S,6S)-2-溴-6-(甲氧基羰基)四氫-2H-吡喃-3,4,5-三乙基三乙酸酯((2R,3R,4S,5S,6S)-2-bromo-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate)(613mg,1.543mmol)和Ag2CO3(1.42g,2.57mmol,於矽藻土上50% w/w)。在80℃
將反應混合物加熱18小時。通過矽藻土來過濾粗反應混合物、濃縮且藉由層析(矽,丙酮/己烷)來純化,以給出標題化合物(195mg,47%)。ESI-MS m/z=846.17、848.16(M+HCO2)-。
對在THF(3mL)、甲醇(1mL)和水(2mL)中之來自實施例329的化合物(195mg,0.243mmol)的溶液添加LiOH(50mg,2.09mmol)。在40℃將反應混合物加熱1小時。用EtOAc稀釋粗反應混合物且用1M HCl酸化至pH 4。用食鹽水洗滌有機層,用Na2SO4乾燥、過濾並濃縮。藉由製備型HPLC(C18,乙腈/水)來純化粗產物,以給出標題化合物(10mg,6%)。ESI-MS m/z=660.11、662.11(M-H)-。
於室溫將在DMSO(1.5mL)中之實施例182(159mg,0.30mmol)和IBX(101mg,0.36mmol)的混合物攪拌4小時。將Na2S2O3水溶液加入,且用EtOAc萃取混合物。用水、食鹽水洗滌有機層,用Na2SO4乾燥、過濾、濃縮並藉由製備型HPLC(C18柱,乙腈/
水)來純化,以給出標題化合物(58mg,36%)。ESI-MS m/z=572.27、574.27(M+HCO2)-。
於-78℃對在THF(5ml)中之來自步驟331的化合物(230mg,0.436mmol)的溶液添加溴化甲基鎂(0.508ml,1.525mmol)。在相同溫度下攪拌3小時。將水加入,且用EtOAc萃取混合物,用Na2SO4乾燥。藉由管柱層析(矽,己烷/丙酮)來純化粗材料,以給出為白色固體的標題化合物(34.3mg,0.063mmol,15%產率)。ESI-MS m/z=541.01、543.01[M-H]-。
步驟333a,於室溫將在DCM(2.0mL)中之來自步驟82a的化合物(112mg,0.25mmol)、E-己-3-烯(E-hex-3-ene)(630mg,7.5mmol)和Hoveyda-Grubbs第二代催化劑(15.7mg,0.025mmol)的混合物攪拌20小時。藉由管柱層析(矽,己烷/EtOAc)純化混合物,以給出為白色固體的期望化合物(78mg,65%)。ESI-MS m/z=476.13、478.13[M-H]-。
步驟333b,於室溫對在丙酮-水(2.1mL/0.3mL)中之來自步驟
333a的化合物(78mg,0.163mmol)和NMO(0.115g,0.98mmol)的懸浮液添加四氧化鋨(0.205ml,於叔丁醇中2.5%,0.016mmol),且在室溫將混合物攪拌20小時。用Na2SO3水溶液將其淬滅,用EtOAc萃取,用水、3N HCl、NaHCO3、食鹽水洗滌,用Na2SO4乾燥、過濾並濃縮以給出碸和亞碸的混合物,無進一步純化即使用。
步驟333c,對在NMP(2mL)中之來自步驟333b的化合物的溶液添加m-CPBA(0.183g,0.85mmol,77%),且在室溫攪拌20小時。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入,且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾、濃縮且藉由製備型HPLC(C18,乙腈/水)來純化,以給出外消旋產物。使用MeOH作為洗脫液,藉由對掌性SFC來分離外消旋產物,以給出標題化合物(18mg,20%)。ESI-MS m/z=542.29、544.29[M-H]-。
步驟334,從實施例333中分離出標題化合物(18mg,20%)。ESI-MS m/z=542.29、544.29[M-H]-。
於室溫將在DMSO(5mL)中之實施例182的化合物(1.05g,1.98mmol)和IBX(0.777g,2.77mmol)的溶液攪拌隔夜。用Na2S2O3水溶液和NaHCO3水溶液將其淬滅。用EtOAc萃取反應混合物,用水和食鹽水洗滌,用Na2SO4乾燥、過濾並濃縮。藉由製備型HPLC(C18,乙腈/水)來純化產生的粗產物,以給出為白色固體的標題化合物(32mg,3.1%)。ESI-MS m/z=570.26、572.26[M+HCO2]-。
步驟337a,透過套管於30分鐘、在0℃對在THF(135ml)中之來自步驟Int 2a的化合物(92.0g,676mmol)的溶液添加丙-1-炔-1-基溴化鎂(prop-1-yn-1-ylmagnesium bromide)(1554ml,777mmol)的溶液。在除去冰浴之前將其攪拌5分鐘。將混合物溫熱至室溫並維持於室溫30分鐘。將反應混合物冷卻至0℃,將飽和NH4Cl水溶液(500mL)加入,接著將MTBE(500mL)加入。分離水相並用MTBE(500mL)萃取。用食鹽水洗滌合併的有機相且乾燥(Na2SO4)。將溶液通過短矽膠柱且濃縮,以給出黃色油狀物(125
g,105%產率)。
步驟337b,於0℃對在二噁烷(400mL)和水(133mL)中之來自步驟337a的化合物(50.0g,284mmol)的溶液添加2,6-二甲基吡啶(2,6-lutidine)(66.1ml,567mmol)和高碘酸鈉(sodium periodate)(212g,993mmol),接著將OsO4的溶液(1.803ml,0.284mmol,於水中4%)加入。將此混合物溫熱至室溫且在室溫攪拌2天,然後冷卻至0℃且用飽和Na2S2O3水溶液淬滅。在0℃將混合物攪拌1小時,然後用1L水稀釋,用MTBE(1L X 3)萃取。將合併的有機相用1N HCl洗滌兩次、用水、NaHCO3水溶液、水和食鹽水洗滌、乾燥(Na2SO4)並濃縮。將粗殘餘物進行層析,以給予灰白色固體的期望產物(40.2g,80%)。
步驟337c,將LAH(於THF中1M,265mL,265mmol)和DME(430mL)的溶液冷卻至0℃。於約0.5小時內,將在DME(80mL)中之來自步驟337b的化合物(18.9g,106mmol)的溶液逐滴加入,且再攪拌1小時。在冷卻至0℃之前,將其加熱至且保持在80℃、2小時。用10mL的水和10mL的15% NaOH溶液、30mL的水小心地將其淬滅,接著將72g的Na2SO4固體加入,且在過濾之前攪拌1小時。濃縮之後,將粗殘餘物進行層析,以給出灰白色固體的期望產物(12.6g,65%)。
步驟337d,於室溫對在二氯甲烷(dichloromethane)(50mL)中之步驟337c(4.58g,25.1mmol)的溶液中添加吡啶(4.1mL,50mmol)和苯磺醯氯(5.33g,30.2mmol)。在將水(30mL)加入之
前,在室溫下將反應攪拌隔夜。將混合物攪拌1小時。分離後,用DCM(100mL)萃取水相。用HCl(1M,20mL*2)、水、NaHCO3、食鹽水洗滌合併的有機相且乾燥(Na2SO4)。濃縮之後,將粗殘餘物進行層析,以給予灰白色固體的期望產物(6.67g,82%)。
步驟337e,於0℃對在t-BuOH(40mL)/水(40mL)中之K2OsO6˙2H2O(381mg,1.03mmol)、(DHQ)2PHAL(1.61mg,2.07mmol)、K2CO3(8.58g,62.1mmol)和K3FeCN6(20.4g,62.1mmol)的溶液添加來自步驟337d的化合物(6.67g,20.69mmol)和MeSO2NH2(5.90g,62.1mmol)。將反應溫熱至室溫且攪拌一天。將其冷卻至0℃且將Na2SO3(30g)加入。在用EtOAc(50mL)區分之前,於0℃將混合物攪拌15分鐘,然後在室溫下攪拌1小時。用EtOAc回萃(back extract)水相。用Na2S2O3水溶液、水、1N HCl(20mL * 2)、水、2M KOH(10mL * 2)、水、食鹽水*2洗滌合併的有機物。將其乾燥(Na2SO4)並濃縮,以給出為灰白色固體的期望產物(7.20g,97%)。此材料無進一步純化即用於下一步驟。
步驟337f,於0℃對在CH2Cl2(50ml)中之步驟337e的化合物(7.20g,20.20mmol)的溶液添加DIPEA(14.11ml,81mmol)和乙酸酐(5.72ml,60.6mmol)。在室溫將反應攪拌隔夜。將飽和NaHCO3水溶液(30mL)加入且攪拌15分鐘。分離之後,用CH2Cl2(100mL x 2)萃取水相,將合併的有機相乾燥(Na2SO4)且濃縮。將粗產物進行層析,以給出為灰白色固體的期望化合物(8.2
g,100%)。
步驟337g,於室溫對在六氟異丙醇(hexfluoroisopropanol)(40ml)中之來自步驟337f的化合物(5.09g,11.55mmol)的澄清溶液添加雙(三氟甲磺酸)錳(manganese bis(trifluoromethanesulfonate))(20mg ml,0.058mmol)和2,2’-聯吡啶(0.09g,0.58mmol)。在室溫攪拌10分鐘後,透過注射泵在1小時內將過乙酸/KOH混合物(藉由將10%KOH(3.0ml)加到35%過乙酸(10.0ml)、11.79ml、39.5mmol)來製備)加入。將丙酮(100ml)加入。攪拌10分鐘後,將其濃縮。將粗殘餘物進行層析(矽,EtOAc/己烷),以給予回收的起始材料3.1g和較高極性的混合物1.79g。此高極性混合物直接用於下一步驟。
步驟337h,藉由按照步驟327f,對來自步驟337g的高極性混合物的溶液添加中間物6,以給予兩組混合物。一組混合物含有酮產物;ESI-MS m/z=640.31、642.31[M+HCOO-]-。另一組含有醇產物。ESI-MS m/z=642.32、644.32[M+HCOO-]-。
步驟337i,依序用步驟328d和328e中所述的條件處理來自步驟337h的醇產物,且藉由製備型HPLC(C-18,乙腈/水)來純化,以提供為白色固體的標題化合物。ESI-MS m/z=590.27、592.27[M+HCOO-]-。
步驟339a,於0℃對在THF(18mL)中之中間物2a(2.29g,16.8mmol)的溶液添加乙炔基溴化鎂(ethynylmagnesium bromide)(40.4mL,20.2mmol,於THF中0.5M),且於0℃攪拌30分鐘。藉由NH4Cl水溶液的緩慢加入,來將反應淬滅。將MBTE和水加入。分離混合物,且用水和食鹽水洗滌有機層。用Na2SO4將混合物乾燥、過濾並在真空下濃縮,以給出期望產物(2.73g,100%)。
步驟339b,於0℃對在THF(12mL)中之來自步驟339a的化合物(1.7g,8.38mmol)的溶液逐滴添加n-BuLi(7.38mL,18.4mmol,於己烷中2.5M)。在0℃下20分鐘後,將CD3I(0.69mL,10.9mmol)加入且在室溫下將混合物攪拌20小時。藉由NH4Cl水溶液的緩慢加入,來將反應淬滅。將MBTE和水加入。將MBTE和水加入。分離混合物,且用水和食鹽水洗滌有機層。用Na2SO4將混合物乾燥、過濾並在真空下濃縮。將粗產物進行層析(矽,己烷/MBTE),以給出期望產物(1.09g,65%)。
步驟339c,對在二噁烷-水(12/4mL)中之來自步驟339b的化合物(0.986g,5.5mmol)的溶液添加2,6-二甲基吡啶(2,6-lutidine)(1.45mL,11mmol)和OsO4(0.18mL,於叔丁醇中
2.5%,0.017mmol)。將混合物冷卻並將NaIO4(4.12g,19.25mmol)加入。在室溫將懸浮液攪拌16小時。將Na2S2O3水溶液加入。將混合物攪拌1小時且通過矽藻土過濾。用MBTE/己烷萃取混合物。用水、1N HCl、飽和NaHCO3和食鹽水洗滌有機相,用Na2SO4乾燥、過濾並濃縮以給出粗產物(0.64g,64.2%)。
步驟339d,對在CD3OD(10mL)中之來自步驟339c的化合物(0.64g,3.53mmol)的溶液添加MeONa(23mg,0.42mmol),且在室溫將混合物攪拌3小時。將其濃縮,且將殘餘物再溶解於CD3OD(5mL)中並攪拌3小時。將相同的反應循環再重複兩次,且用D2O來淬滅溶液。用MBTE萃取混合物。用D2O和在D2O中之飽和NaCl溶液洗滌有機層,用Na2SO4乾燥、過濾並在真空下濃縮,以給出所需化合物(0.62g,95%)。
步驟339e,於-40℃對LiBH4(3.35mL,6.70mmol,於THF中2M)的溶液添加在MBTE(20mL)中之來自步驟339d的化合物(0.62g,3.35mmol)。1小時內將產生的溶液溫熱至0℃。藉由NH4Cl水溶液的緩慢加入,來淬滅反應。將MBTE和水加入。分離混合物,且用食鹽水洗滌有機層。用Na2SO4將混合物乾燥、過濾並在真空下濃縮。將粗產物進行層析(矽,己烷/MBTE),以給出為白色固體的期望化合物(0.45g,72%)。
步驟339f,將在DME(12mL)中之來自步驟339e的化合物(0.45g,2.40mmol)、LAH(6.01mL,6.01mmol,在THF中1M)和MeONa(26mg,0.48mmol)的溶液加熱至並維持於80℃、2小
時。將反應混合物冷卻至0℃,用0.23mL的水和0.23mL的15% NaOH溶液小心地淬滅,維持10分鐘,然後將0.69mL的水加入,接著將5g的Na2SO4固體加入,且在過濾之前攪拌1小時。將濾液濃縮。將粗產物進行層析(矽,己烷/MBTE),以給出期望化合物(0.32g,70%)。
步驟339g,於室溫對在二氯甲烷(3.5mL)中之來自步驟339f的化合物(0.32g,1.69mmol)的溶液添加吡啶(0.33mL,4.3mmol)和4-甲苯磺醯氯(4-toluenesulfonyl chloride)(0.387g,2.02mmol)。在室溫將反應攪拌隔夜,將水加入。將混合物攪拌1小時。分離之後,用DCM萃取水相。用1N HCl、水、NaHCO3、食鹽水洗滌合併的有機相,用Na2SO4乾燥並濃縮。將粗產物進行層析(矽,己烷/MBTE),以給出期望化合物(0.52g,90%)。
步驟339h,於0℃對在叔丁醇(7.0mL)/水(7.0mL)中之K2OsO6˙2H2O(27mg,0.073mmol)、(DHQ)2PHAL(85mg,0.109mmol)、K2CO3(0.604g,4.37mmol)和K3FeCN6(1.44g,4.37mmol)的溶液添加來自步驟339g的化合物(0.50g,1.46mmol)和MeSO2NH2(0.277g,2.91mmol)。允許反應緩慢溫熱至室溫且攪拌3天。將混合物冷卻至0℃,接著將Na2SO3加入。在用EtOAc區分之前,於0℃將混合物攪拌15分鐘,然後在室溫1小時。用EtOAc回萃水相。用Na2S2O3水溶液、水、1N HCl、水、2M KOH、水、食鹽水洗滌合併的有機物,乾燥(Na2SO4)、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),然後懸浮於MeOH
(5.6mL)中16小時,且過濾以收集為白色固體的期望產物(0.39g,70%)。
步驟339i,於70℃將在DMF(1.1mL)中之來自步驟339h的化合物(0.39g,1.03mmol)、中間物6(0.316g,1.06mmol)和K2CO3(0.143g,1.03mmol)的溶液攪拌16小時。用EtOAc將其稀釋,且用水、食鹽水洗滌混合物,用Na2SO4乾燥、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(0.37g,71%)。ESI-MS m/z=503.16、505.16[M-H]-。
步驟339j,於室溫將在NMP(3.0mL)中之來自步驟339i的化合物(0.37g,0.73mmol)和m-CPBA(0.575g,2.56mmol,77%)的溶液攪拌24小時。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾,從MeOH再結晶以給出標題化合物(0.33g,84%)。ESI-MS m/z=535.15、537.15[M-H]-。
步驟340a,於45℃將在DMSO(20mL)中之來自步驟337c的化合物(3.2g,17.6mmol)和IBX(6.8g,24.3mmol)的混合物攪拌14小時。在室溫將Na2S2O3水溶液加入,且用EtOAc萃取混合物。用水、食鹽水洗滌有機層,用Na2SO4乾燥、過濾並濃縮。將粗產
物進行層析(矽,己烷/MBTE),以給出期望產物(2.3g,72%)。
步驟340b,對在CD3OD(20mL)中之來自步驟340a的化合物(2.3g,12.8mmol)的溶液添加MeONa(138mg,2.55mmol),且在室溫將混合物攪拌3小時。將其濃縮,且將殘餘物再溶解於CD3OD(20mL)中並攪拌3小時。將相同的反應循環再重複兩次,且用D2O來淬滅溶液。用MBTE萃取混合物。用D2O和在D2O中之飽和NaCl溶液洗滌有機層,用Na2SO4乾燥、過濾並在真空下濃縮,以給出期望化合物(2.0g,85%)。
步驟340c,於-40℃對LiBH4(10.8mL,21.6mmol,在THF中2M)的溶液添加在MBTE(60mL)中之來自步驟340b的化合物(2.0g,10.8mmol)。在1小時內將產生的溶液溫熱至0℃。藉由NH4Cl水溶液的緩慢加入來淬滅反應,然後用MBTE和水稀釋。分離混合物,且用食鹽水洗滌有機層。用Na2SO4將混合物乾燥、過濾並濃縮。將粗產物進行層析(矽,己烷/MBTE),以給出為白色固體的期望化合物(1.4g,69%)。
步驟340d,於室溫對在二氯甲烷(1.5mL)中之來自步驟340c的化合物(0.216g,1.16mmol)的溶液添加吡啶(0.28mL,3.48mmol)和3-硝基苯磺醯氯(0.385g,1.74mmol)。在室溫將反應攪拌。將水加入,然後攪拌1小時。分離後,用DCM萃取水相。用1N HCl、水、NaHCO3和食鹽水洗滌合併的有機相,用Na2SO4乾燥、過濾並濃縮。將粗產物進行層析(矽,己烷/MBTE),以給出期望化合物(0.37g,86%)。
步驟340e,於80℃將在DMF(1.1mL)中之來自步驟340d的化合物(0.36g,0.97mmol)、4-氯-3-巰基苯甲酸甲酯(methyl 4-chloro-3-mercaptobenzoate)(0.206g,1.02mmol)和Cs2CO3(0.316g,0.97mmol)的溶液攪拌16小時。用EtOAc將其稀釋,且用水、食鹽水洗滌混合物,用Na2SO4乾燥、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(0.25g,69%)。
步驟340f,對在THF(3.0mL)中之來自步驟340e的化合物(0.25g,0.674mmol)的溶液添加LiOH(2.7mL,1.35mmol,於水中0.5M溶液),且在室溫將混合物攪拌3小時。藉由1N HCl的加入,來淬滅反應。將EtOAc和水加入。分離混合物,且用食鹽水洗滌有機層。用Na2SO4將混合物乾燥、過濾並在真空下濃縮,以給出為白色固體的期望化合物(0.23g,96%)。ESI-MS m/z=355.24、357.24[M-H]-。
步驟340g,對在DMF(2.5mL)中之來自步驟340f的化合物(0.23g,0.644mmol)、3,4-二氟苯-2,6-D2-胺(3,4-difluorobenzene-2,6-D2-amine)(0.127g,0.967mmol)、DMAP(0.039g,0.322mmol)的溶液添加EDC(0.185g,0.967mmol),且在室溫攪拌16小時。用EtOAc將其稀釋,且用水、食鹽水洗滌混合物,用Na2SO4乾燥、過濾並濃縮。將粗產物進行層析(矽,己烷/EtOAc),以給出期望化合物(0.26g,86%)。ESI-MS m/z=468.31、470.31[M-H]-。
步驟340h,於室溫對在丙酮-水(2.1mL/0.3mL)中之來自步驟340g的化合物(260mg,0.553mmol)和NMO(0.324g,2.77mmol)的懸浮液添加入四氧化鋨(0.28ml,0.055mmol,於水中5%),且在室溫將混合物攪拌20小時。用Na2SO3水溶液將其淬滅,用EtOAc萃取,用水、1N HCl、NaHCO3、食鹽水洗滌,用Na2SO4乾燥、過濾並濃縮,以給出無進一步純化即使用的碸和亞碸的混合物。
步驟340i,對在NMP(2.5mL)中之來自步驟340h的化合物的溶液添加m-CPBA(0.41g,1.83mmol,77%),且在室溫攪拌20小時。將Na2S2O3水溶液、NaHCO3和幾滴Et3N加入,且在室溫攪拌1小時。用EtOAc將其萃取,用水、食鹽水洗滌,用Na2SO4乾燥、過濾並濃縮,以給出期望產物(0.27g,96%)。ESI-MS m/z=580.33、582.33(M+HCO2)-。
步驟340j,於室溫將在DMSO(5.0mL)中之來自步驟340i的化合物(362mg,0.675mmol)和IBX(227mg,0.81mmol)的混合物攪拌4小時。將Na2S2O3水溶液加入,且用EtOAc萃取混合物。用水、食鹽水洗滌有機層,用Na2SO4乾燥、過濾、濃縮並藉由製備型HPLC(C18柱,乙腈/水)純化,以給出標題化合物(150mg,41%)。ESI-MS m/z=578.32、580.32(M+HCO2)-。
步驟341a,在冰浴中,將1-甲基-1H-吡咯-2-羧酸(1-methyl-1H-pyrrole-2-carboxylic acid)(3g,23.98mmol)分批溶解於氯磺酸(12ml,179mmol)中。在相同溫度下將反應攪拌70分鐘。緩慢地藉由將冰/水(100mL)加入(很有反應性!!),來將混合物淬滅,且攪拌15分鐘。過濾沉澱物,用水潤洗(rinse),將產生的固體溶解於EtOAc中,用NaSO4乾燥。真空除去溶劑,且真空乾燥隔夜,以給出為灰白色固體的期望化合物(3.60g,16.10mmol,67%產率)。
步驟341b,對在DCM(20mL)和DMF(0.02mL)中之來自步驟341a的化合物(1g,4.47mmol)的混合物添加草醯氯(oxalyl chloride)(11.18ml,22.36mmol)。在室溫將反應攪拌5小時。真空除去溶劑,然後用苯(x3)追踪(chase),以給出為淺黃色固體的期望化合物(1.08g,100%產率)。
步驟341c,於室溫對在甲苯(15mL)中之來自步驟341b的化合物(400mg,1.652mmol)的溶液添加在甲苯(1mL)中之3,4-二氟苯胺(3,4-difluoroaniline)(0.164ml,1.652mmol)。在110℃將混合物加熱並攪拌1小時,然後冷卻至室溫並攪拌16小時。濾出固體且真空除去所產生的濾液,無進一步純化即使用(553mg,100%
產率)。
步驟341d,對在甲苯(10mL)中之來自步驟341c的化合物(550mg,1.643mmol)的懸浮液添加三苯基膦(2.16g,8.22mmol)。將反應加熱至85℃並攪拌6小時。將反應冷卻至室溫並將10mL的H2O加入。用水(5mL)洗滌有機層兩次,接著用1N NaOH洗滌。收集水層。藉由1N HCl將水層酸化至pH 4。當將HCl加入時,其變成白色乳液。用EtOAc將其萃取,且產生的混合物變為澄清無色溶液。收集有機層,用Na2SO4乾燥以給出為白色固體的期望化合物(220mg,0.820mmol,50%產率)。
步驟341e,對在DMF(0.5mL)中之來自步驟341d的化合物(130mg,0.485mmol)和來自步驟337d的化合物(187mg,0.505mmol)的溶液添加碳酸銫(197mg,0.606mmol)。將反應加熱至70℃並攪拌17小時。用EtOAc萃取混合物,用Na2SO4乾燥,然後藉由管柱層析(矽,己烷/EtOAc)來純化,以給出為白色固體的期望化合物(170mg,0.364mmol,72%產率)。
步驟341f,於0℃對在NMP(0.3mL)中之來自步驟341e的化合物(35mg,0.075mmol)的溶液添加m-CPBA(50.4mg,0.225mmol,77%)。將反應緩慢溫熱至室溫並攪拌15小時。將飽和Na2S2O3溶液和NaHCO3溶液加入,且在室溫將產生的混合物攪拌1小時。用EtOAc萃取混合物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,且用Na2SO4乾燥。藉由管柱層析(矽,己烷
/EtOAc)純化粗材料,以給出為白色固體的標題化合物(24.0mg,0.048mmol,64%產率)。ESI-MS m/z=497.52、499.53[M-H]-。
步驟344a,對在2-甲基-四氫呋喃(3mL)中之來自步驟307a的化合物(500mg,0.71mmol)的溶液添加(R)-1-胺基丙-2-醇((R)-1-aminopropan-2-ol)(160mg,2.12mmol),然後在75℃攪拌一天。用EtOAc稀釋粗產物,用水洗滌兩次,用食鹽水洗滌兩次且乾燥(Na2SO4)並濃縮。將粗產物進行層析(矽,MeOH/DC),來給出為期望化合物與其它雜質的混合物的期望化合物(255mg)。ESI-MS m/z=479.27、481.27[M-H]-。
步驟344b,對在2-甲基-四氫呋喃(2mL)中之來自步驟344a的混合物(255mg,0.53mmol)的溶液添加CDI(112mg,0.69mmol)和TEA(0.15mL,1.06mmol)。在冷卻並濃縮之前,將反應混合物加熱至50℃、1小時。將粗產物進行層析(矽,EtOAc/己烷),來給出為與其它雜質的混合物之期望化合物。ESI-MS m/z=505.26、507.26[M-H]-。
步驟344c,用步驟130b中所述的條件處理來自步驟344b的化合物,且藉由製備型HPLC(C-18,乙腈/水)來純化,以提供為白色固體的標題化合物。ESI-MS m/z=537.26、539.26[M-H]-。
步驟345a,於室溫對在CH2Cl2(21mL)中之來自步驟182的化合物(1.046g,2.100mmol)的溶液添加三乙胺(0.586ml,4.20mmol)和Ac2O(0.238ml,2.52mmol),然後將混合物維持於室溫隔夜。然後在NaHCO3水溶液和CH2Cl2之間區分反應混合物。用Na2SO4將合併的有機相乾燥、濃縮,且藉由快速管柱層析(flash column chromatography)來純化粗產物,以給出兩種不可分離的單醯化產物的混合物(415mg)。ESI-MS m/z=584.13、586.13[M+HCO2]-。
步驟345b,對在CH2Cl2中之來自步驟345a的化合物(415mg,0.768mmol)的溶液添加2-碘甲基苯甲酸(2-iodoxylbenzoic acid)(430mg,1.54mmol)。將混合物維持在室溫隔夜,然後將飽和Na2S2O3水溶液加入。在EtOAc和水之間區分混合物。用食鹽水洗滌合併的有機相,用Na2SO4乾燥並濃縮。將產生的粗產物進行層析(矽,己烷/EtOAc),以給出為白色固體的期望產物(39mg,,2步驟8.2%)。ESI-MS m/z=582.12、584.12[M+HCO2]-。
步驟345c,於室溫對在THF(0.3mL)和MeOH(1.1mL)中之來自步驟345b的化合物(39.1mg,0.073mmol)的溶液添加K2CO3(10mg,0.073mmol)。然後將混合物維持在室溫1小時。
用MTBE稀釋反應混合物,用水洗滌,用Na2SO4乾燥並濃縮,以給出為白色固體的期望粗產物(19mg,53%),不經進一步純化將其用於下一步驟。ESI-MS m/z=540.11、542.11[M+HCO2]-。
步驟345d,於室溫對在CH2Cl2(1.9mL)中之來自步驟345c的化合物(19mg,0.038mmol)的溶液添加m-CPBA(34.3mg,0.153mmol,77%),且在室溫攪拌隔夜。用飽和Na2S2O3水溶液和NaHCO3水溶液將反應淬滅。在EtOAc和水相之間區分反應混合物。用食鹽水洗滌合併的有機相,用Na2SO4乾燥並濃縮。將產生的粗產物進行層析,以給出為白色固體的期望產物(11mg,2步驟29%)。ESI-MS m/z=572.09、574.09[M+HCO2]-。
步驟346a,於-78℃對在THF(4.50ml)中之乙炔基環丙烷(ethynylcyclopropane)(1.864ml,22.03mmol)的溶液添加n-BuLi(8.81ml,22.03mmol,於THF中2.5M)。在相同溫度下將產生的混合物攪拌1小時。於-78℃將在THF(9ml)中之來自步驟Int 2a的化合物(2.0g,14.68mmol)的溶液加到反應中。在相同溫度下將產生的混合物攪拌1小時。將得到的淡黃色溶液緩慢溫熱至室溫並攪拌2小時。將飽和NH4Cl溶液加入。用MTBE萃取混合物,用Na2SO4乾燥以給出2.95g(99%產率)之為黃色油狀物的
期望化合物,其不經進一步純化而使用。
步驟346b,於5℃對在二噁烷(122mL)和水(25mL)中之來自步驟346a的化合物(2.97g,14.68mmol)的溶液添加2,6-二甲基吡啶(3.42ml,29.4mmol)、高碘酸鈉(10.99g,51.4mmol)。將OsO4(0.921ml,0.073mmol,於t-BuOH中2.5%)加入,且在室溫下將產生的混合物攪拌15小時。將Na2S2O3(50mL)和EtOAc(100mL)加入。將混合物攪拌30分鐘,然後過濾。用EtOAc(x3)洗滌固體。收集濾液且用0.5N HCl(x4)洗滌。用EtOAc回萃水層,且將合併的有機層用Na2SO4乾燥。將粗材料進行層析(矽,己烷/丙酮),以給出為淡黃色油狀物的期望化合物(2.25g,11.01mmol,75%產率)。
步驟346c,於-50℃對在MTBE(22.03ml)中之LiBH4(13.77ml,27.5mmol,在THF中2M)的溶液添加在MTBE(5mL)中之來自步驟346b的化合物(2.25g,11.01mmol)的溶液。在-50℃將反應攪拌3小時。將NH4Cl(50mL)加入。在-50℃將反應攪拌3小時。將NH4Cl(50mL)加入。用EtOAc(100mL)萃取混合物,用食鹽水洗滌,用Na2SO4乾燥並進行層析(矽,己烷/EtOAc),以給出為白色固體的期望化合物(1.62g,7.85mmol,71%產率)。
步驟346d,於室溫對在DME(15mL)中之LAH(13.77ml,13.77mmol,於THF中1M)和NaOMe(0.074g,1.377mmol)的混合物添加在DME(2mL)中之來自步驟346c的化合物(1.42g,6.88mmol)的溶液。將反應加熱至80℃且攪拌3小時。將反應冷卻
至0℃,小心地用水和1N NaOH溶液來淬滅。將混合物過濾。用MTBE萃取濾液,用Na2SO4乾燥。用MTBE和Hex將產生的材料再結晶,以給出為白色固體的期望化合物(1.30g,6.24mmol,91%產率)。
步驟346e,於0℃對在DCM(10ml)中之來自步驟346d的化合物(1.6g,7.68mmol)的溶液添加吡啶(1.243ml,15.36mmol)。將4-甲基苯磺醯氯(4-methylbenzenesulfonyl chloride)(1.904g,9.99mmol)加入。將混合物緩慢溫熱至室溫並攪拌16小時。將水加入,用DCM萃取混合物,用Na2SO4乾燥。藉由管柱層析(矽,己烷,EtOAc)來純化粗材料,以給出為無色油狀物的期望化合物(2.10g,5.79mmol,75%產率)。
步驟346f,於0℃對t-BuOH(29.0ml)和水(29.0ml)的混合物添加二水合鋨酸鉀(potassium osmate dihydrate)(0.064g,0.174mmol)、(DHQ)2PHAL(0.203g,0.261mmol)、六氰合鐵(III)酸鉀(potassium hexacyanoferrate(III))(5.72g,17.38mmol)和碳酸鉀(2.402g,17.38mmol),接著將甲磺醯胺(3.31g,34.8mmol)和來自步驟346e的化合物(2.1g,5.79mmol)加入。將反應物緩慢溫熱至室溫並攪拌50小時。於0℃將Na2SO3(3.7g)加入且在室溫將產生的混合物攪拌1小時。將EtOAc加入,通過矽藻土過濾固體,且用EtOAc(x2)洗滌。用EtOAc萃取有機層,用1N HCl(x3)洗滌,接著用2N K2CO3溶液和食鹽水洗滌,且用Na2SO4乾燥以給出1.85g(4.67mmol,81%產率)之為灰白色固體期望產物,
其無進一步純化即使用。
步驟346g,於室溫對在DMF(15.55ml)中之來自步驟346f的化合物(1.85g,4.67mmol)的溶液添加K2CO3(0.632g,4.57mmol)。將4-氯-N-(3,4-二氟苯基)-3-巰基苯甲醯胺(4-chloro-N-(3,4-difluorophenyl)-3-mercaptobenzamide)(1.468g,4.90mmol)加入。將產生的混合物加熱至75℃並攪拌15小時。將反應冷卻至室溫,將水加入,且用EtOAc(x3)萃取,用食鹽水洗滌,用Na2SO4乾燥。將粗材料進行層析(矽,己烷/EtOAc)以給出為灰白色固體的期望化合物(1.91g,3.64mmol,75%產率)。
步驟346h,於0℃對在NMP(10mL)中之來自步驟346g的化合物(1.91g,3.64mmol)的溶液添加m-CPBA(2.451g,10.93mmol,77%)。將混合物溫熱至室溫並攪拌15小時。用飽和Na2S2O3溶液和NaHCO3溶液將反應淬滅且攪拌1小時。用EtOAc萃取混合物,用飽和Na2S2O3溶液和NaHCO3溶液(x2)、食鹽水洗滌,用Na2SO4乾燥。將粗材料進行層析(矽,己烷/丙酮),以給出為白色固體的期望化合物(1.26g,2.27mmol,42%產率)。ESI-MS m/z=555.02、557.02[M-H]-。
步驟347a,於-78℃對在THF(4.50ml)中之3-甲基丁-1-炔(3-methylbut-1-yne)(2.253ml,22.03mmol)的溶液添加n-BuLi(8.81ml,22.03mmol,於THF中2.5M)。在相同溫度下將產生的混合物攪拌1小時。於-78℃將在THF(10ml)中之來自步驟Int 2a的化合物(2.0g,14.68mmol)的溶液加到反應中。將產生的淡黃色溶液緩慢溫熱至室溫且攪拌2小時。將飽和NH4Cl溶液加入。用MTBE萃取混合物,用Na2SO4乾燥以給出3.0g(99%產率)之為黃色油狀物的期望化合物,其不經進一步純化而使用。
步驟347b,於5℃對在二噁烷(122mL)和水(25mL)中之來自步驟347a的化合物(3.0g,14.68mmol)的溶液添加2,6-二甲基吡啶(3.42ml,29.4mmol)、高碘酸鈉(10.99g,51.4mmol)。將四氧化鋨(0.921ml,0.073mmol,在tBuOH中2.5%)加入,且在室溫將產生的混合物攪拌16小時。將Na2S2O3(50mL)和EtOAc(100mL)加入。將混合物攪拌30分鐘,然後過濾。用EtOAc(x3)洗滌固體。收集濾液,用0.5N HCl(x4)洗滌。用EtOAc回萃水層,且用Na2SO4將合併的有機層乾燥。將粗材料進行層析(矽,己烷/丙酮),以給出為淺黃色油狀物的期望化合物(1.60g,7.76mmol,53%產率)。
步驟347c,於-50℃對在MTBE(15.51ml)中之LiBH4(9.70ml,19.39mmol,在THF中2M)的溶液添加在MTBE(5mL)中之來自步驟347b的化合物(1.60g,7.76mmol)的溶液。在-50℃將反應攪拌3小時。將NH4Cl(50mL)加入。用EtOAc(100mL)
萃取混合物,用食鹽水洗滌,用Na2SO4乾燥。將粗材料進行層析(矽,己烷/EtOAc),以給出為白色發泡(foaming)固體的期望化合物(1.16g,5.58mmol,72%產率)。
步驟347d,於室溫對在DME(15mL)中之LAH(11.16ml,11.16mmol,在THF中1M)和甲醇鈉(sodium methoxide)(0.060g,1.116mmol)的混合物添加在DME(2mL)中之來自步驟347c的化合物的溶液(1.162g,5.58mmol)。將反應加熱至80℃並攪拌3小時。將反應冷卻至0℃,小心地用水和1N NaOH溶液淬滅。過濾混合物。用MTBE萃取濾液,用Na2SO4乾燥。用MTBE和Hex將產生的材料再結晶,以給出為白色固體的期望化合物(1.06g,5.02mmol,90%產率)。
步驟347e,按照實施例346e中所述的流程,從步驟347d的化合物獲得為混濁油狀物的期望化合物(1.51g,4.14mmol,87%產率)。
步驟347f,按照實施例346f中所述的流程,從步驟347e的化合物獲得為灰白色固體的期望化合物(1.01g,2.53mmol,61%產率)。
步驟347g,按照實施例346g中描述的流程,從步驟347f的化合物獲得為灰白色固體的期望化合物(0.87g,1.65mmol,65%產率)。
步驟347h,按照實施例346h中描述的流程,從步驟347g的化合物獲得為白色固體的期望化合物(0.74g,1.32mmol,80%產率)。ESI-MS m/z=557.03、559.02[M-H]-。
步驟348a,於室溫對在DCE(2ml)中之來自實施例82a的化合物(50mg,0.111mmol)的溶液添加2-側氧基-5-乙烯基噁唑烷-3-羧酸叔丁酯(2-oxo-5-vinyloxazolidine-3-carboxylate)(71.1mg,0.333mmol)和Grubbs-Hoveyda第二代催化劑(6.96mg,0.011mmol)。用起泡的N2將混合物脫氣5分鐘,且加熱至60℃並攪拌15小時。將反應冷卻至室溫。將水加入。用DCM萃取混合物,用Na2SO4乾燥。將粗材料進行層析(矽,己烷/EtOAc),以給出為灰白色固體的期望化合物(45mg,0.071mmol,64%產率)。
步驟348b,於室溫對在丙酮(3ml)和水(0.8ml)中之來自步驟348a的化合物(45mg,0.071mmol)的溶液添加NMO(33.2mg,0.283mmol)、OsO4(178μl,0.014mmol,於t-BuOH中2.5%)。將反應攪拌16小時。用飽和Na2S2O3溶液淬滅,且用EtOAc萃取,用食鹽水洗滌並用Na2SO4乾燥。粗材料無需進一步純化即使用。
步驟348c,於室溫對在DCM(1ml)中之來自步驟348b的化合物(50mg,0.071mmol)的溶液添加TFA(0.027ml,0.355mmol)。將反應攪拌2小時。除去溶劑。用DCM萃取混合物,用飽和NaHCO3溶液洗滌,用Na2SO4乾燥。藉由管柱層析(矽,MeOH/DCM)來純化粗材料,以給出為灰白色固體的期望化合物(2:1之異構物混合
物,14.5mg,0.024mmol,34%產率)。ESI-MS m/z=600.02、602.02[M-H]-。
生物活性
方法:如先前所報導地,來維持HepAD38細胞(Ladner et al,Antimicrob.Agents Chemother.1997,4,1715)。簡而言之,在10% FBS、Penn/Strep、250ug/mL G418和1ug/ml四環黴素(tetracycline)的存在下,於DMEM/F12培養基中達到鋪滿(confluency)之後,將細胞繼代(passage)。藉由先用PBS洗滌細胞三次以除去四環黴素,且以35,000細胞/孔來平盤接種(plate)於96孔盤中,來篩選新穎的化合物。然後將溶解於
DMSO中的化合物,以1:200稀釋至含有細胞的孔中。化合物加入五天後,收穫材料用於分析。對於延長的8天分析,如上所述地平盤接種和處理細胞,但在初始處理後的d2和d5,更新培養基和化合物。
在收穫日,藉由用Sidestep Lysis和Stabilization Buffer裂解,來獲得病毒體DNA,然後透過定量即時PCR來定量。在稀釋樣品以匹配其各個測定(assay)的線性範圍後,藉由按照製造商推薦的規章(protocol),使用市售的ELISA套組(kit)來定量病毒蛋白質HBsAg(Alpco)或HbeAg(US Biological)。不論讀值(readout)如何,報導了相對於無藥物的對照,減少50%的細胞裂解物或上清液中的病毒產物累積的化合物濃度(EC50);EC50範圍如下:A<0.1M;B0.1-0.2M;C>0.2M.
藉由以15,000個細胞/孔接種細胞,且如上所述地用化合物處理,來評估化合物毒性。化合物加入三天後,用ATPLite藥劑處理細胞,且報導了相對於無藥物的對照,減少50%的孔中總ATP程度的化合物濃度(CC50);CC50範圍如下:A>25M;B10-25M;C<10M。
雖然已經參考其較佳實施例,來特別顯示和描述本發明,但本發明所屬技術領域中具有通常知識者將理解的是,可在其中做出形式和細節上的各種改變,而不背離由所附申請專利範圍所涵蓋之本發明的範圍。
Claims (15)
- 如申請專利範圍第1項所述之化合物,其中R37為氫。
- 如申請專利範圍第2項所述之化合物,其中R21’和R21”為氟,R21為氫。
- 如申請專利範圍第2項所述之化合物,其中R21、R21’和R21”為氟。
- 一種醫藥組合物,包括一如申請專利範圍第1至13項中任一項所述之化合物以及一醫藥上可接受的載體或賦形劑。
- 一種如申請專利範圍第1至13項中任一項所述之化合物用於製備治療或預防B型肝炎病毒感染的藥物之用途。
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