TW201920108A - N-(氰基取代之苄基或吡啶基甲基)-3-羥基吡啶醯胺衍生物 - Google Patents
N-(氰基取代之苄基或吡啶基甲基)-3-羥基吡啶醯胺衍生物 Download PDFInfo
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- TW201920108A TW201920108A TW107133504A TW107133504A TW201920108A TW 201920108 A TW201920108 A TW 201920108A TW 107133504 A TW107133504 A TW 107133504A TW 107133504 A TW107133504 A TW 107133504A TW 201920108 A TW201920108 A TW 201920108A
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- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
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- 229960004740 voriconazole Drugs 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
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- 229950000339 xinafoate Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- KGPGQDLTDHGEGT-JCIKCJKQSA-N zeven Chemical compound C=1C([C@@H]2C(=O)N[C@H](C(N[C@H](C3=CC(O)=C4)C(=O)NCCCN(C)C)=O)[C@H](O)C5=CC=C(C(=C5)Cl)OC=5C=C6C=C(C=5O[C@H]5[C@@H]([C@@H](O)[C@H](O)[C@H](O5)C(O)=O)NC(=O)CCCCCCCCC(C)C)OC5=CC=C(C=C5)C[C@@H]5C(=O)N[C@H](C(N[C@H]6C(=O)N2)=O)C=2C(Cl)=C(O)C=C(C=2)OC=2C(O)=CC=C(C=2)[C@H](C(N5)=O)NC)=CC=C(O)C=1C3=C4O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O KGPGQDLTDHGEGT-JCIKCJKQSA-N 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- CPYIZQLXMGRKSW-UHFFFAOYSA-N zinc;iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+3].[Fe+3].[Zn+2] CPYIZQLXMGRKSW-UHFFFAOYSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P9/00—Drugs for disorders of the cardiovascular system
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
Description
本發明係關於N-(氰基取代之苄基或吡啶基甲基)-3-羥基吡啶醯胺衍生物,其為缺氧誘導因子(HIF)脯胺醯基羥化酶之抑制劑;含有該等衍生物之醫藥組成物;及其治療與HIF脯胺醯基羥化酶相關聯之疾病、病症、及病狀之用途。
缺氧誘導因子(HIF)介導回應於細胞氧濃度變化之基因表現。HIF為具有氧調控次單元(HIF-α)及組成性表現之次單元(HIF-β)之異二聚體。HIF脯胺醯基羥化酶亦稱為含脯胺醯基羥化酶結構域之蛋白(PHD),在人體中呈三種同功型(PHD1、PHD2、及PHD3)存在。連同HIF一起,PHD酶回應於細胞氧水準來調控細胞代謝。在具有足夠氧之細胞中,HIF脯胺醯基羥化酶催化HIF-α上之保守脯胺酸殘基之羥化,導致轉錄因子之快速降解。因為氧為PHD酶活性之輔受質,HIF-α避免在缺氧條件下之降解,所以其可移位至與HIF-β二聚化的核中。所得功能性HIF複合物活化各種基因之轉錄,包括編碼紅血球生成素、血管內皮生長因子、及生物學感興趣之其他蛋白之基因。因為HIF脯胺醯基水解酶在細胞氧感測中起重要作用,所以PHD抑制劑可實用於治療心血管病、代謝病、血液病、肺病、腎病、肝病、傷口癒合障礙、及癌症等等。
本發明提供N-(氰基取代之苄基或吡啶基甲基)-3-羥基吡啶醯胺衍生物及含有該等衍生物之醫藥組成物。3-羥基吡啶醯胺衍生物為缺氧誘導因子(HIF)
脯胺醯基羥化酶調節劑(PHD)之抑制劑且可用於治療與PHD相關聯之疾病、病症、及病狀。
本發明之一態樣提供一種式1化合物:
或其醫藥學上可接受之鹽,其中:X1係選自N及CR1,且X2係選自N及CR2,限制條件為:(a)X1及X2中不多於一者為N,且(b)當R4及R5連接以形成乙-1,2-二基、丙-1,3-二基、或甲-1,1-二基氧基時,X1為CR1且X2為CR2,且(c)當X1為CR1且X2為CR2時,R1、R2、R3、R4、R5、R6、R7、R8、及R9中之至少一者不為氫;R1、R2、及R3各獨立地選自氫、鹵基、及視情況經一至三個鹵基取代基取代之C1-4烷基;R4係選自氫、鹵基、及視情況經一至三個鹵基取代基取代之C1-4烷基,且R5係選自氫及C1-4烷基,或R4及R5連接以形成乙-1,2-二基、丙-1,3-二基、或甲-1,1-二基氧基;R6係選自氫及C1-4烷基;R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或
Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之C3-5雜環基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代,且該C3-5雜環基部分具有一或兩個作為環成員之雜原子,其中該等雜原子之一為氮且該等雜原子之另一者當存在時獨立地選自N、O、及S;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基。
本發明之另一態樣提供一種化合物,其係選自實例中所述之化合物及其醫藥學上可接受之鹽之群。
本發明之另一態樣提供一種醫藥組成物,其包括:式1化合物或其醫藥學上可接受之鹽、或前一段落所定義之化合物或醫藥學上或可接受之鹽之任一者;及醫藥學上可接受之賦形劑。
本發明之另一態樣提供一種式1化合物或其醫藥學上可接受之鹽、或前述段落所定義之化合物及醫藥學上可接受之鹽之任一者,其用作藥劑。
本發明之另一態樣提供一種式1化合物或其醫藥學上可接受之鹽、或前述段落所定義之化合物或醫藥學上可接受之鹽之任一者,其用於治療與PHD相關聯之疾病、病症、或病狀。
本發明之另一態樣提供一種式1化合物或其醫藥學上可接受之鹽、或前述段落所定義之化合物或醫藥學上可接受之鹽之任一者,其用於治療選自以下之疾病、病症、或病狀:心血管病、代謝病、血液病、肺病、腎病、肝病、傷口癒合障礙、及癌症。
本發明之另一態樣提供一種式1化合物或其醫藥學上可接受之鹽、或前述段落所定義之化合物或醫藥學上可接受之鹽之任一者,其用於治療選自以下之疾病、病症、或病狀:中風、心肌梗塞、鬱血性心衰竭、動脈粥樣硬化、
慢性靜脈功能不全、心因性肝硬化、急性失代償性心衰竭、心臟病發作後心衰竭、周邊動脈疾病、閉塞性動脈疾病、糖尿病、高血糖、胰島素抗性、X代謝症候群、葡萄糖耐受不良、非酒精性肝脂肪變性、貧血、慢性阻塞性肺臟疾病、肺栓塞、肺性高血壓、高山病、急性呼吸衰竭、間質性肺病、特發性肺纖維化、落屑性間質性肺炎、非特異性間質性肺炎、隱原性器質化肺炎、呼吸性細支氣管炎相關間質性肺病、急性間質性肺炎、淋巴性間質性肺炎、急性腎衰竭、急性腎損傷、慢性腎臟疾病、腎臟缺血再灌注損傷、肝臟缺血再灌注損傷、糖尿病足潰瘍、壓迫性潰瘍、靜脈性潰瘍、動脈性潰瘍、水皰性表皮鬆解症、天皰瘡、及休格倫氏症候群(Sjogren's Syndrome)、以及癌症。
本發明之另一態樣提供一種式1化合物或其醫藥學上可接受之鹽、或前述段落所定義之化合物或醫藥學上可接受之鹽之任一者之用途,其用於製造用於治療與PHD相關聯之疾病、病症、或病狀之藥劑。
本發明之另一態樣提供式1化合物或其醫藥學上可接受之鹽、或前述段落所定義之化合物或醫藥學上可接受之鹽之任一者之用途,其用於製造用於治療選自以下之疾病、病症、或病狀之藥劑:中風、心肌梗塞、鬱血性心衰竭、動脈粥樣硬化、慢性靜脈功能不全、心因性肝硬化、急性失代償性心衰竭、心臟病發作後心衰竭、周邊動脈疾病、閉塞性動脈疾病、糖尿病、高血糖、胰島素抗性、X代謝症候群、葡萄糖耐受不良、非酒精性肝脂肪變性、貧血、慢性阻塞性肺臟疾病、肺栓塞、肺性高血壓、高山病、急性呼吸衰竭、間質性肺病、特發性肺纖維化、落屑性間質性肺炎、非特異性間質性肺炎、隱原性器質化肺炎、呼吸性細支氣管炎相關間質性肺病、急性間質性肺炎、淋巴性間質性肺炎、急性腎衰竭、急性腎損傷、慢性腎臟疾病、腎臟缺血再灌注損傷、肝臟缺血再灌注損傷、糖尿病足潰瘍、壓迫性潰瘍、靜脈性潰瘍、動脈性潰瘍、水皰性表皮鬆解症、天皰瘡、及休格倫氏症候群、以及癌症。
本發明之另一態樣提供一種治療受試者之疾病、病症、或病狀之方法,該方法包含向該受試者投與有效量之式1化合物或其醫藥學上可接受之鹽、或前述段落所定義之化合物或醫藥學上可接受之鹽之任一者,其中該疾病、病症、或病狀與PHD相關聯。
本發明之另一態樣提供一種治療受試者之疾病、病症、或病狀之方法,該方法包含向該受試者投與有效量之式1化合物或其醫藥學上可接受之鹽、或前述段落中所定義之化合物或醫藥學上可接受之鹽之任一者,其中該疾病、病症、或病狀係選自心血管病、代謝病、血液病、肺病、腎病、肝病、傷口癒合障礙、及癌症。
本發明之另一態樣提供一種治療受試者之疾病、病症、或病狀之方法,該方法包含向該受試者投與有效量之式1化合物或其醫藥學上可接受之鹽、或前述段落中所定義之化合物或醫藥學上可接受之鹽之任一者,其中該疾病、病症、或病狀係選自中風、心肌梗塞、鬱血性心衰竭、動脈粥樣硬化、慢性靜脈功能不全、心因性肝硬化、急性失代償性心衰竭、心臟病發作後心衰竭、周邊動脈疾病、閉塞性動脈疾病、糖尿病、高血糖、胰島素抗性、X代謝症候群、葡萄糖耐受不良、非酒精性肝脂肪變性、貧血、慢性阻塞性肺臟疾病、肺栓塞、肺性高血壓、高山病、急性呼吸衰竭、間質性肺病、特發性肺纖維化、落屑性間質性肺炎、非特異性間質性肺炎、隱原性器質化肺炎、呼吸性細支氣管炎相關間質性肺病、急性間質性肺炎、淋巴性間質性肺炎、急性腎衰竭、急性腎損傷、慢性腎臟疾病、腎臟缺血再灌注損傷、肝臟缺血再灌注損傷、糖尿病足潰瘍、壓迫性潰瘍、靜脈性潰瘍、動脈性潰瘍、水皰性表皮鬆解症、天皰瘡、及休格倫氏症候群、以及癌症。
本發明之另一態樣提供一種組合,其包含式1化合物或其醫藥學上可接受之鹽、或前述段落中所定義之化合物或醫藥學上可接受之鹽之任一者;
及至少一種額外藥理學活性劑。
除非另外指示,否則本揭露使用以下提供之定義。
當結合化學取代基或部分(例如,C1-6烷基)使用時,「經取代」意謂取代基或部分之一或多個氫原子經一或多個非氫原子或基團替代,限制條件為滿足化合價要求且由取代產生化學上穩定之化合物。
當結合可測量之數值變量使用時,「約」或「大致」係指變量之指示值以及處於指示值之實驗誤差內或處於指示值之±10%內的所有變量值,無論哪個較大。
「烷基」係指直鏈及分支鏈飽和烴基,其一般具有指定數目之碳原子(例如,C1-4烷基係指具有1至4個(即,1、2、3、或4個)碳原子之烷基,C1-6烷基係指具有1至6個碳原子之烷基,等等)。烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、二級丁基、異丁基、三級丁基、戊-1-基、戊-2-基、戊-3-基、3-甲基丁-1-基、3-甲基丁-2-基、2-甲基丁-2-基、2,2,2-三甲基乙-1-基、正己基、及其類似基團。
「烷二基」係指二價烷基,其中烷基在上文經定義且一般具有指定數目之碳原子(例如,C1-4烷二基係指具有1至4個(即,1、2、3、或4個)碳原子之烷二基,C1-6烷二基係指具有1至6個碳原子之烷二基,等等)。烷二基之實例包括亞甲基、乙-1,1-二基、乙-1,2-二基、丙-1,3-二基、丙-1,2-二基、丙-1,1-二基、丙-2,2-二基、丁-1,4-二基、丁-1,3-二基、丁-1,2-二基、丁-1,1-二基、異丁-1,3-二基、異丁-1,1-二基、異丁-1,2-二基、及其類似基團。
「烯基」係指具有一或多個碳-碳雙鍵之直鏈及分支鏈烴基,且其一
般具有指定數目之碳原子。烯基之實例包括乙烯基、1-丙烯-1-基、1-丙烯-2-基、2-丙烯-1-基、1-丁烯-1-基、1-丁烯-2-基、3-丁烯-1-基、3-丁烯-2-基、2-丁烯-1-基、2-丁烯-2-基、2-甲基-1-丙烯-1-基、2-甲基-2-丙烯-1-基、1,3-丁二烯-1-基、1,3-丁二烯-2-基、及其類似基團。
「炔基」係指具有一或多個碳-碳參鍵之直鏈或分支鏈烴基,且其一般具有指定數目之碳原子。炔基之實例包括乙炔基、1-丙炔-1-基、2-丙炔-1-基、1-丁炔-1-基、3-丁炔-1-基、3-丁炔-2-基、2-丁炔-1-基、及其類似基團。
「鹵基」、「鹵素」、及「鹵代」可互換地使用且係指氟基、氯基、溴基、及碘基。
「鹵烷基」、「鹵烯基」、及「鹵炔基」分別係指經一或多個鹵素原子取代之烷基、烯基、及炔基,其中烷基、烯基、及炔基在上文中經定義且一般具有指定數目之碳原子。鹵烷基之實例包括氟甲基、二氟甲基、三氟甲基、氯甲基、二氯甲基、三氯甲基、1-氟乙基、1,1-二氟乙基、1-氯乙基、1,1-二氯乙基、1-氟-1-甲基乙基、1-氯-1-甲基乙基、及其類似基團。
「環烷基」係指飽和單環及雙環烴基,其一般具有指定數目之構成環或多個環之碳原子(例如,C3-8環烷基係指具有3至8個作為環成員之碳原子的環烷基)。雙環烴基可包括孤立的環(不共享碳原子的兩個環)、螺環(共享一個碳原子的兩個環)、稠環(共享兩個碳原子及在兩個共用碳原子之間的鍵的兩個環)、以及橋聯環(共享兩個碳原子但不共享共用鍵的兩個環)。環烷基可透過任何環原子連接,除非此類連接會違反化合價要求,且在經指示之情況下,可視情況包括一或多個非氫取代基,除非此類取代會違反化合價要求。
單環環烷基之實例包括環丙基、環丁基、環戊基、環己基、及其類似基團。稠合雙環環烷基之實例包括雙環[2.1.0]戊基(即,雙環[2.1.0]戊-1-基、雙環[2.1.0]戊-2-基、及雙環[2.1.0]戊-5-基)、雙環[3.1.0]己基、雙環[3.2.0]庚基、雙
環[4.1.0]庚基、雙環[3.3.0]辛基、雙環[4.2.0]辛基、雙環[4.3.0]壬基、雙環[4.4.0]癸基、及其類似基團。橋聯環烷基之實例包括雙環[2.1.1]己基、雙環[2.2.1]庚基、雙環[3.1.1]庚基、雙環[2.2.2]辛基、雙環[3.2.1]辛基、雙環[4.1.1]辛基、雙環[3.3.1]壬基、雙環[4.2.1]壬基、雙環[3.3.2]癸基、雙環[4.2.2]癸基、雙環[4.3.1]癸基、雙環[3.3.3]十一烷基、雙環[4.3.2]十一烷基、雙環[4.3.3]十二烷基、及其類似基團。螺環烷基之實例包括螺[3.3]庚基、螺[2.4]庚基、螺[3.4]辛基、螺[2.5]辛基、螺[3.5]壬基、及其類似基團。單獨的雙環環烷基之實例包括衍生自以下之基團:雙(環丁烷)、環丁烷環戊烷、雙(環戊烷)、環丁烷環己烷、環戊烷環己烷、雙(環己烷)等。
「伸環烷基」係指二價單環環烷基,其中環烷基在上文中經定義,該環烷基透過基團之單個碳原子來連接且一般具有指定數目的構成環之碳原子(例如,C3-6亞環烷基係指具有3至6個作為環成員之碳原子的伸環烷基)。實例包括伸環丙基、伸環丁基、伸環戊基、及伸環己基。
「環烯基」係指部分不飽和單環及雙環烴基,其一般具有指定數目的構成環或多個環之碳原子。與環烷基一樣,雙環環烯基可包括單獨的環、螺環、稠環、或橋聯環。類似地,環烯基可透過任何環原子來連接,且在經指示之情況下,可視情況包括一或多個非氫取代基,除非此類連接或取代會違反化合價要求。環烯基之實例包括以上所述的環烷基之部分不飽和類似物,諸如環丁烯基(即,環丁烯-1-基及環丁烯-3-基)、環戊烯基、環己烯基、雙環[2.2.1]庚-2-烯基、及其類似基團。
「芳基」係指完全不飽和的單環芳族烴及具有至少一個芳族環的多環烴,單環及多環芳基一般均具有指定數目的構成其環成員之碳原子(例如,C6-14芳基係指具有6至14個作為環成員之碳原子的芳基)。該基團可透過任何環原子來連接,且在經指示之情況下,可視情況包括一或多個非氫取代基,除非此類
連接或取代會違反化合價要求。芳基之實例包括苯基、聯苯基、環丁苯基(cyclobutabenzenyl)、茚基、萘基、苯并環庚基、伸聯苯基、茀基、衍生自環庚三烯陽離子之基團、及其類似基團。
「伸芳基」係指二價芳基,其中芳基在上文中經定義。伸芳基之實例包括伸苯基(即,苯-1,2-二基)。
「雜環」及「雜環基」可互換地使用且係指飽和或部分不飽和單環或雙環基團,其具有由碳原子及1至4個雜原子構成的環原子,該等雜原子獨立地選自氮、氧、及硫。單環及雙環基團一般在其環或多個環中均具有指定數目之碳原子(例如,C2-6雜環基係指具有2至6個碳原子及1至4個作為環成員之雜原子的雜環基)。與雙環環烷基一樣,雙環雜環基可包括單獨的環、螺環、稠環、及橋聯環。雜環基可透過任何環原子來連接,且在經指示之情況下,可視情況包括一或多個非氫取代基,除非此類連接或取代會違反化合價要求或產生化學上不穩定之化合物。雜環基之實例包括環氧乙烷基、硫環丙烷基、氮丙啶基(例如,氮丙啶-1-基及氮丙啶-2-基)、氧雜環丁烷基、硫環丁烷基、氮雜環丁烷基、四氫呋喃基、四氫噻吩基、吡咯啶基、四氫哌喃基、四氫噻喃基、哌啶基、1,4-二噁烷基、1,4-氧硫雜環己烷基、嗎啉基、1,4-二噻烷基、哌嗪基、1,4-氮硫雜環己烷基、氧雜環庚烷基、硫雜環庚烷基、氮雜環庚烷基、1,4-二氧雜環庚烷基、1,4-氧硫雜環庚烷基、1,4-氧氮雜環庚烷基、1,4-二硫雜環庚烷基、1,4-硫氮雜環庚烷基、1,4-二氮雜環庚烷基、3,4-二氫-2H-哌喃基、3,6-二氫-2H-哌喃基、2H-哌喃基、1,2-二氫吡啶基、1,2,3,4-四氫吡啶基、1,2,5,6-四氫吡啶基、1,6-二氫嘧啶基、1,2,3,4-四氫嘧啶基、及1,2-二氫吡唑并[1,5-d][1,2,4]三嗪基。
「雜環-二基」係指透過基團之兩個環原子來連接的雜環基,其中雜環基在上文中經定義。其一般在其環或多個環中具有指定數目之碳原子(例如,C2-6雜環-二基係指具有2至6個碳原子及1至4個作為環成員之雜原子的雜環-
二基)。雜環-二基之實例包括以上所述的雜環基之多價類似物,諸如嗎啉-3,4-二基、吡咯啶-1,2-二基、1-吡咯啶基-2-亞基、1-吡啶基-2-亞基、1-(4H)-吡唑基-5-亞基、1-(3H)-咪唑基-2-亞基、3-噁唑基-2-亞基、1-哌啶基-2-亞基、1-哌嗪基-6-亞基、及其類似基團。
「雜芳族」及「雜芳基」可互換地使用且係指不飽和單環芳族基團及具有至少一個芳族環之多環基團,該等基團均具有由碳原子及1至4個雜原子構成的環原子,該等雜原子獨立地選自氮、氧、及硫。單環及多環基團一般均具有指定數目之碳原子作為環成員(例如,C1-9雜芳基係指具有1至9個碳原子及1至4個作為環成員之雜原子的雜芳基)且可包括以上列出的任何單環雜環稠合至苯環上的任何雙環基團。雜芳基可經由任何環原子(或對於稠環而言為多個環原子)來連接,且在經指示之情況下,可視情況包括一或多個非氫取代基,除非此類連接或取代會違反化合價要求或產生化學上不穩定之化合物。出於本揭露之目的,認為2-吡啶酮及4-吡啶酮、2-喹啉酮及4-喹啉酮、以及其類似基團為對應雜芳族基團(吡啶、喹啉、及其類似基團)之2-側氧基取代及4-側氧基取代之衍生物。
雜芳基之實例包括單環基團,諸如吡咯基(例如,吡咯-1-基、吡咯-2-基、及吡咯-3-基)、呋喃基、噻吩基、吡唑基、咪唑基、異噁唑基、噁唑基、異噻唑基、噻唑基、1,2,3-三唑基、1,3,4-三唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、四唑基、吡啶基、噠嗪基、嘧啶基、及吡嗪基。
雜芳基之實例包括雙環基團,諸如苯并呋喃基、異苯并呋喃基、苯并噻吩基、苯并[c]噻吩基、1H-吲哚基、3H-吲哚基、異吲哚基、1H-異吲哚基、吲哚啉基、異吲哚啉基、苯并咪唑基、1H-吲唑基、2H-吲唑基、苯并三唑基、1H-吡咯并[2,3-b]吡啶基、1H-吡咯并[2,3-c]吡啶基、1H-吡咯并[3,2-c]吡啶基、1H-
吡咯并[3,2-b]吡啶基、3H-咪唑并[4,5-b]吡啶基、3H-咪唑并[4,5-c]吡啶基、1H-吡唑并[4,3-b]吡啶基、1H-吡唑并[4,3-c]吡啶基、1H-吡唑并[3,4-c]吡啶基、1H-吡唑并[3,4-b]吡啶基、7H-嘌呤基、吲哚嗪基、咪唑并[1,2-a]吡啶基、咪唑并[1,5-a]吡啶基、吡唑并[1,5-a]吡啶基、吡咯并[1,2-b]噠嗪基、咪唑并[1,2-c]嘧啶基、喹啉基、異喹啉基、啉基、喹唑啉基、喹喏啉基、酞嗪基、1,6-萘啶基、1,7-萘啶基、1,8-萘啶基、1,5-萘啶基、2,6-萘啶基、2,7-萘啶基、吡啶并[3,2-d]嘧啶基、吡啶并[4,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[2,3-b]吡嗪基、吡啶并[3,4-b]吡嗪基、嘧啶并[5,4-d]嘧啶基、吡嗪并[2,3-b]吡嗪基、嘧啶并[4,5-d]嘧啶基、1,2,3,4-四氫吡啶并[2,3-b]吡嗪基、2,3-二氫苯并[b][1,4]二噁辛基、3,4-二氫-2H-吡啶并[3,2-b][1,4]噁嗪基、2,3-二氫-1H-苯并[d]咪唑基、苯并[d]噻唑基、2,3-二氫-1H-吡咯并[2,3-b]吡啶基、[1,2,4]三唑并[1,5-a]吡啶基、2,3-二氫-1H-咪唑并[4,5-b]吡啶基、四唑并[1,5-a]吡啶基、7H-吡咯并[2,3-d]嘧啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-a]嘧啶基、4,5-二氫-1H-吡唑并[3,4-d]嘧啶基、2,3,6,7-四氫-1H-嘌呤基、5H-吡咯并[2,3-b]吡嗪基、咪唑并[1,2-a]吡嗪基、咪唑并[1,2-b]噠嗪基、及4,5,6,7-四氫吡唑并[1,5-a]吡嗪基。
雜芳基之其他實例亦包括雙環基團2,3-二氫苯并呋喃基、2-側氧基-1,2,5,6,7,8-六氫喹啉基、4-側氧基-4H-吡啶并[1,2-a]嘧啶基、5,6,7,8-四氫吡唑并[5,1-b][1,3]噁氮呯基、5,6-二氫-4H-吡咯并[1,2-b]吡唑基、5-側氧基-5H-噻唑并[3,2-a]嘧啶基、6,7-二氫-5H-環戊[b]吡啶基、6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪基、及吡咯并[1,2-c]嘧啶基。
「伸雜芳基」係指透過基團之兩個環原子來連接的雜芳基,其中雜芳基在上文中經定義。其一般在其環或多個環中具有指定數目之碳原子(例如,C3-5伸雜芳基係指具有3至5個碳原子及1至4個作為環成員之雜原子的伸雜芳基)。伸雜芳基之實例包括以上所述之雜芳基之多價類似物,諸如吡啶-2,3-二基、
吡啶-3,4-二基、吡唑-4,5-二基、吡唑-3,4-二基、及其類似基團。
「側氧基」係指雙鍵鍵結之氧(=O)。
「脫離基」係指在碎斷過程期間離開分子的任何基團,該碎斷過程包括取代反應、消去反應、及加成-消去反應。脫離基可為離核的,其中基團攜帶原先充當脫離基與分子之間的鍵的一對電子脫離;或可為離電子的,其中基團在不攜帶一對電子之情況下脫離。離核脫離基脫離之能力視其鹼性強度而定,其中最強的鹼為最差的脫離基。常見的離核脫離基包括氮(例如,來自重氮鹽);磺酸鹽,包括烷基磺酸鹽(例如,甲磺酸鹽)、氟烷基磺酸鹽(例如,三氟甲磺酸鹽、六氟乙磺酸鹽(hexaflate)、全氟丁烷磺酸鹽、及三氟乙基磺酸鹽)、及芳基磺酸鹽(例如,甲苯磺酸鹽、對溴苯磺酸鹽、氯苯磺酸鹽、及間硝基苯磺酸鹽)。其他離核脫離基包括碳酸鹽、鹵離子、羧酸根陰離子、酚鹽離子、及烷氧化物。一些較強的鹼(諸如NH2 -及OH-)可藉由用酸處理來製得較佳的脫離基。常見的離電子脫離基包括質子、CO2、及金屬。
「相反的鏡像異構物」係指為參考分子之不重疊鏡像的分子,其可藉由反轉參考分子之所有立體中心來獲得。例如,若參考分子具有S絕對立體化學組態,則相反的鏡像異構物具有R絕對立體化學組態。同樣,若參考分子具有S,S絕對立體化學組態,則相反的鏡像異構物具有R,R立體化學組態,等等。
具有給定立體化學組態之化合物的「立體異構物」及「多個立體異構物」係指化合物之相反鏡像異構物及任何非鏡像異構物,包括化合物之幾何異構物(Z/E)。例如,若化合物具有S,R,Z立體化學組態,則其立體異構物將包括其具有R,S,Z組態之相反鏡像異構物及其具有S,S,Z組態、R,R,Z組態、S,R,E組態、R,S,E組態、S,S,E組態、及R,R,E組態之非鏡像異構物。若沒有指定化合物之立體化學組態,則「立體異構物」係指化合物之任一可能的立體化學組態。
「實質上純的立體異構物」及其變體係指含有具有特定立體化學組
態之化合物的樣品且該化合物佔樣品之至少約95%。
「純的立體異構物」及其變體係指含有具有特定立體化學組態之化合物的樣品且該化合物佔樣品之至少約99.5%。
「受試者」係指哺乳動物,包括人類。
「醫藥學上可接受之」物質係指合適於向受試者投與的彼等物質。
「治療(treating)」係指逆轉、緩解、抑制此術語所應用之疾病、病症、或病狀之進展或預防該疾病、病症、或病狀,或逆轉、緩解、抑制此種疾病、病症、或病狀之一或多種症狀的進展或預防該疾病、病症、或病狀之一或多種症狀。
「治療(treatment)」係指如上剛剛定義的「治療(treating)」之行為。
「藥物」、「原料藥」、「活性醫藥成分」、及其類似用語係指可用於治療有治療需要之受試者的化合物(例如,式1化合物,包括亞屬化合物及在說明書中確切命名之化合物)。
藥物之「有效量」、藥物之「治療有效量」、及其類似用語係指可用於治療受試者且可尤其視受試者之體重及年齡以及投與途徑而定的藥物之量。
「賦形劑」係指用於藥物的任何稀釋劑或媒劑。
「醫藥組成物」係指一或多種原料藥及一或多種賦形劑之組合。
「藥物產品」、「醫藥劑型」、「劑型」、「最終劑型」、及其類似用語係指適用於治療有治療需要之受試者且一般可呈錠劑、膠囊、含有粉末或顆粒之囊劑、液體溶液或懸浮液、貼劑、膜劑、及其類似物之形式的醫藥組成物。
「與PHD相關聯之病狀」及類似片語係指在PHD之抑制可為其提供治療或預防益處之受試者中的疾病、病症、或病狀。
本說明書中可使用以下縮寫:Ac(乙醯基);ACN(乙腈);AIBN(偶氮-雙-異丁腈);API(活性醫藥成分);aq(水性);BINAP(2,2'-雙(二苯基膦)-1,1'-聯萘);Boc(三級丁氧羰基);Cbz(苄氧羰基);dba(二亞苄基丙酮);DCC(1,3-二環己基碳二亞胺);DCE(1,1-二氯乙烷);DCM(二氯甲烷);DIPEA(N,N-二異丙基乙胺,胡寧鹼(Hünig's Base));DMA(N,N-二甲基乙醯胺);DMAP(4-二甲基胺基吡啶);DME(1,2-二甲氧基乙烷);DMF(N,N-二甲基甲醯胺);DMSO(二甲亞碸);dppf(1,1'-雙(二苯基膦)二茂鐵);DTT(二硫蘇糖醇);EC50(半最大反應下之有效濃度);EDA(乙氧化十二醇,Brj®35);EDC(N-(3-二甲基胺基丙基)-N'-乙基碳二亞胺);EDTA(乙二胺四乙酸);ee(鏡像異構物超越量);eq(當量);Et(乙基);Et3N(三乙胺);EtOAc(乙酸乙酯);EtOH(乙醇);HATU(2-(3H-[1,2,3]三唑并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基脲六氟磷酸鹽(V));HBTU(2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸鹽);HEPES(4-(2-羥基乙基)哌嗪-1-乙磺酸);AcOH(乙酸);HOBt(1H-苯并[d][1,2,3]三唑-1-醇);IC50(50%抑制時的濃度);IPA(異丙醇);IPAc(乙酸異丙酯);IPE(異丙醚);LDA(二異丙基胺基鋰);LiHMDS(雙(三甲基矽烷基)胺基鋰);mCPBA(間氯過氧苯甲酸);Me(甲基);MeOH(甲醇);MTBE(甲基三級丁基醚);mp(熔點);NaOt-Bu(三級丁醇鈉);NMM(N-甲基嗎啉);NMP(N-甲基吡咯啶酮);OTf(三氟甲磺酸鹽);PE(石油醚);Ph(苯基);pEC50(-log10(EC50),其中EC50係以莫耳(M)單位給出);pIC50(-log10(IC50),其中IC50係以莫耳(M)單位給出);Pr(丙基);c-Pr(環丙基)、i-Pr(異丙基);PTFE(聚四氟乙烯);RT(室溫,大致20℃至25℃);T3P(2,4,6-三丙基-1,3,5,2,4,6-三氧三磷雜環己烷2,4,6-三氧化物);TCEP(參(2-羰乙基)膦);TFA(三氟乙酸);TFAA(2,2,2-三氟乙酸酐);THF(四氫呋喃);TMEDA(N 1,N 1,N 2,N 2-四甲基乙-1,2-二胺);TMS(三甲基矽基);及Tris緩衝液(2-胺基-2-羥甲基-丙-1,3-二醇緩衝液)。
如下所述,本揭露係關於式1化合物及其醫藥學上可接受之鹽。本
揭露亦關於用於製備式1化合物之材料及方法;含有該等式1化合物之醫藥組成物;及式1化合物及其醫藥學上可接受之鹽(視情況與其他藥理學活性劑組合)用於治療與PHD相關聯之疾病、病症、或病狀的用途。
式1化合物包括以下化合物,其中(1):X1係選自N及CR1,且X2係選自N及CR2,限制條件為:(a)X1及X2中不多於一者為N,且(b)當R4及R5連接以形成乙-1,2-二基、丙-1,3-二基、或甲-1,1-二基氧基時,X1為CR1且X2為CR2,且(c)當X1為CR1且X2為CR2時,R1、R2、R3、R4、R5、R6、R7、R8、及R9中之至少一者不為氫;R1、R2、及R3各獨立地選自氫、鹵基、及視情況經一至三個鹵基取代基取代之C1-4烷基;R4係選自氫、鹵基、及視情況經一至三個鹵基取代基取代之C1-4烷基,且R5係選自氫及C1-4烷基,或R4及R5連接以形成乙-1,2-二基、丙-1,3-二基、或甲-1,1-二基氧基;R6係選自氫及C1-4烷基;R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之C3-5雜環基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代,且該C3-5雜環基部分具有一或兩個作為環成員之雜原子,其中該等雜原子之一為氮且該等雜原子之
另一者當存在時獨立地選自N、O、及S;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基。
除實例中之具體化合物之外,式1化合物包括以下化合物,其中:(2)X1為CR1;(3)X2為CR2;或(4)X1為CR1且X2為CR2。
除前述段落中實施例(1)至(4)之一之外或作為其替代,式1化合物包括以下化合物,其中:(5)R1係選自氫、鹵基、及甲基;(6)R1係選自氫、氟基、氯基、及甲基;(7)R1係選自氫、氟基、及甲基;或(8)R1係選自氫及甲基。
除前述段落中實施例(1)至(8)之一之外或作為其替代,式1化合物包括以下化合物,其中:(9)R2係選自氫、鹵基、及甲基;(10)R2係選自氫、氟基、及甲基;或(11)R2係選自氫及甲基。
除前述段落中實施例(1)至(11)之一之外或作為其替代,式1化合物包括以下化合物,其中:(12)R3係選自氫、鹵基、及甲基;(13)R3係選自氫、氟基、及甲基;或(14)R3係選自氫及甲基。
除前述段落中實施例(1)至(14)之一之外或作為其替代,式1化合物包括以下化合物,其中:(15)R4係選自氫、鹵基、及甲基;(16)R4係選自氫、氟基、氯基、及甲基;(17)R4係選自氫、氟基、及甲基;或(18)R4係選自氫及甲基。
除前述段落中實施例(1)至(18)之一之外或作為其替代,式1化合物包括以下化合物,其中:(19)R5係選自氫及甲基;或(20)R5為氫。
除前述段落中實施例(1)至(20)之一之外或作為其替代,式1化合物包括以下化合物,其中:(21)R6係選自氫及甲基;或(22)R6為氫。
除前述段落中實施例(5)至(14)之一之外或作為其替代,式1化合物包括以下化合物,其中:(23)R4及R5連接以形成乙-1,2-二基或丙-1,3-二基;或(24)R4及R5連接以形成乙-1,2-二基。
除前述段落中實施例(1)至(24)之一之外或作為其替代,式1化合物包括以下化合物,其中:(25)R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或
Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之C3-5雜環基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代,且該C3-5雜環基部分具有5或6個環成員及一或兩個作為環成員之雜原子,其中該等雜原子之一為氮且該等雜原子之另一者當存在時獨立地選自N、O、及S;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基;(26)R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之C3-5雜環基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代,且該C3-5雜環基部分具有5或6個環成員及一或兩個作為環成員之雜原子,該一或兩個雜原子各自為氮;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基;(27)R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之C4-5雜環基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代,且該C4-5雜環基部分
具有6個環成員及一或兩個作為環成員之雜原子,其中該等雜原子之一為氮且該等雜原子之另一者當存在時獨立地選自N、O、及S;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基;(28)R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之C4-5雜環基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代,且該C4-5雜環基部分具有6個環成員及一或兩個作為環成員之雜原子,該一或兩個雜原子各自為氮;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基;(29)R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之C3-5雜環基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代,且該C3-5雜環基部分具有一或兩個作為環成員之雜原子,該一或兩個雜原子各自為氮;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且
Rd係選自氫及C1-4烷基;或(30)R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之哌嗪-1-基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基。
除前述段落中實施例(1)至(30)之一之外或作為其替代,式1化合物包括以下化合物,其中:(31)R7係選自氫、鹵基、氰基、及C1-4烷基;(32)R7係選自氫、鹵基、氰基、及甲基;(33)R7係選自氫、鹵基、及甲基;(34)R7係選自氫、氟基、氯基、及甲基;或(35)R7為氫。
除前述段落中實施例(1)至(35)之一之外或作為其替代,式1化合物包括以下化合物,其中:(36)R8係選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、甲基、及-CF3;(37)R8係選自氫、氟基、氯基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-OCH3、甲基、及-CF3;(38)R8係選自氫、氟基、氯基、氰基、-N(H)Rb、-C(O)N(Ra)Rb、-OCH3、甲基、及-CF3;
(39)R8係選自氫、氟基、氯基、氰基、-N(H)Rb、-OCH3、甲基、及-CF3;(40)R8係選自氫、氟基、氯基、氰基、-N(H)CH2OCH3、-N(H)CH2CH2OCH3、-N(H)CH2CH2CH2OCH3、-OCH3、甲基、及-CF3;或(41)R8係選自氫、氟基、氯基、氰基、-N(H)CH2CH2CH2OCH3、-OCH3、甲基、及-CF3。
除前述段落中實施例(1)至(41)之一之外或作為其替代,式1化合物包括以下化合物,其中:(42)R9係選自氫、鹵基、氰基、及C1-4烷基;(43)R9係選自氫、鹵基、氰基、及甲基;(44)R9係選自氫、鹵基、及甲基;(45)R9係選自氫、氟基、氯基、及甲基;或(46)R9為氫。
式1化合物包括前述段落中所述之實施例(1)至(46)及在實例(除了比較例)中具體命名之最終化合物,且可呈鹽、複合物、溶劑合物、水合物、及液晶存在。同樣,作為鹽的式1化合物可呈複合物、溶劑合物、水合物、及液晶存在。
式1化合物可形成醫藥學上可接受之複合物、鹽、溶劑合物、及水合物。此等鹽包括酸加成鹽(包括二酸)及鹼鹽。醫藥學上可接受之酸加成鹽包括衍生自無機酸(諸如鹽酸、硝酸、磷酸、硫酸、氫溴酸、氫碘酸、氫氟酸、及亞磷酸)之鹽,以及衍生自有機酸(諸如脂族單羧酸及二羧酸、苯基取代之烷酸、羥基烷酸、烷雙酸、芳香酸、脂族磺酸、及芳族磺酸等等)之無毒鹽。此類鹽包括乙酸鹽、己酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、碳酸氫鹽、碳酸鹽、硫酸氫鹽、硫酸鹽、硼酸鹽、樟腦磺酸鹽、檸檬酸鹽、環己胺基磺酸鹽、乙二磺酸鹽、乙磺酸鹽、甲酸鹽、反丁烯二酸鹽、葡庚糖酸鹽、葡糖酸鹽、葡糖醛酸
鹽、六氟磷酸鹽、海苯酸鹽(hibenzate)、鹽酸鹽/氯化物、氫溴酸鹽/溴化物、氫碘酸鹽/碘化物、羥乙基磺酸鹽、乳酸鹽、蘋果酸鹽、馬來酸鹽、丙二酸鹽、甲磺酸鹽、甲基硫酸鹽、萘酸鹽、2-萘磺酸鹽、菸酸鹽、硝酸鹽、乳清酸鹽、草酸鹽、棕櫚酸鹽、雙羥萘酸鹽、磷酸鹽、磷酸氫鹽、磷酸二氫鹽、焦麩胺酸鹽、蔗糖酸鹽、硬脂酸鹽、琥珀酸鹽、丹寧酸鹽、酒石酸鹽、甲苯磺酸鹽、三氟乙酸鹽、及昔萘酸鹽。
醫藥學上可接受之鹼鹽包括衍生自鹼之鹽,包括金屬陽離子(諸如鹼金屬陽離子或鹼土金屬陽離子)以及胺。合適的金屬陽離子之實例包括鈉、鉀、鎂、鈣、鋅、及鋁。合適的胺之實例包括精胺酸、N,N'-二苄基乙二胺、氯普魯卡因、膽鹼、二乙胺、二乙醇胺、二環己胺、乙二胺、甘胺酸、離胺酸、N-甲葡糖胺、乙醇胺(olamine)、2-胺基-2-羥甲基-丙-1,3-二醇、及普魯卡因。對於實用之酸加成鹽及鹼鹽之討論,參見S.M.Berge等人,J.Pharm.Sci.(1977)66:1-19;亦參見Stahl及Wermuth,Handbook of Pharmaceutical Salts:Properties,Selection,and Use(2002)。
醫藥學上可接受之鹽可使用各種方法來製備。例如,式1化合物可與適當的酸或鹼反應以得到所要鹽。或者,式1化合物之前驅物可與酸或鹼反應以移除酸不穩定性或鹼不穩定性保護基或打開前驅物之內酯或內醯胺基團。此外,式1化合物之鹽可透過用適當的酸或鹼處理或透過與離子交換樹脂接觸來轉化為另一鹽(或遊離形式)。反應之後,若鹽自溶液中沈澱出,則其可藉由過濾來分離,或藉由蒸發以回收鹽。鹽之游離程度可在完全游離至幾乎非游離之間變化。
式1化合物可以在完全非晶質至完全結晶範圍內的固態連續體形式存在。術語「非晶質」係指一種狀態,在該狀態下材料缺乏分子層面上的長程有序且視溫度而定可展現固體或液體之物理性質。通常此類材料不能給出獨特
的X射線繞射圖案且雖然展現出固體性質,但更正式地係描述為液體。一旦加熱,便發生自固體性質至液體性質之變化,該變化之特徵為狀態之變化,通常為二級的(「玻璃轉移」)。術語「結晶」係指一種固相,在該固相下材料具有分子層面上的規則有序之內部結構且給出帶有限定峰之獨特X射線繞射圖案。當經充分加熱時,此類材料亦將展現液體之性質,但自固體至液體之變化的特徵為相變化,通常為一級的(「熔點」)。
式1化合物亦可以未溶劑合及溶劑合形式存在。術語「溶劑合物」描述包含化合物及一或多種醫藥學上可接受之溶劑分子(例如,乙醇)的分子複合物。術語「水合物」為其中溶劑為水之溶劑合物。醫藥學上可接受之溶劑合物包括其中溶劑可經同位素取代(例如,D2O、丙酮-d 6、DMSO-d 6)的溶劑合物。
用於有機化合物之溶劑合物及水合物的目前公認的分類系統為區別單獨晶格點、通道、以及金屬離子之配位溶劑合物及水合物的分類系統。參見例如,K.R.Morris(H.G.Brittain編)Polymorphism in Pharmaceutical Solids(1995)。單獨晶格點的溶劑合物及水合物為其中溶劑(例如,水)分子藉由介入有機化合物之分子而分離使得彼此不直接接觸的溶劑合物及水合物。在通道溶劑合物中,溶劑分子位於晶格通道中,在該等晶格通道中其緊鄰其他溶劑分子。在金屬離子配位之溶劑合物中,溶劑分子經鍵合至金屬離子。
當溶劑或水緊密結合時,複合物將具有不依賴於濕度的明確定義之立體化學結構。然而,當溶劑或水係弱結合時(如在通道溶劑合物及在吸濕性化合物中),水或溶劑含量將視濕度及乾燥條件而定。在此情況下,通常將觀察非化學計量。
式1化合物亦可呈多組分複合物(而非鹽及溶劑合物)形式而存在,其中化合物(藥物)及至少一種其他組分以化學計量之量或非化學計量之量存在。此類型之複合物包括晶籠化合物(藥物-宿主包容複合物)及共晶體。後者通常係定
義為透過非共價相互作用結合在一起的中性分子成分之結晶複合物,但亦可為中性分子與鹽之複合物。共晶體可藉由熔融結晶、藉由自溶劑中再結晶、或藉由將組分物理研磨在一起來製備。參見例如,O.Almarsson及M.J.Zaworotko,Chem.Commun.(2004)17:1889-1896。關於多組分複合物之一般性綜述,參見J.K.Haleblian,J.Pharm.Sci.(1975)64(8):1269-88。
當經受合適的條件時,式1化合物可以介晶態(中間相或液晶)存在。介晶態位於真正的晶態與真正的液態(溶體或溶液)之間。由溫度變化引起的介晶性係描述為「熱致的」,且由添加第二組分諸如水或另一溶劑導致的介晶性係描述為「溶致的」。具有形成溶致中間相之潛能的化合物係描述為「兩親的」且包括擁有極性離子部分(例如,-COO-Na+、-COO-K+、-SO3 -Na+)或極性非離子部分(諸如-N-N+(CH3)3)之分子。參見,例如N.H.Hartshorne及A.Stuart,Crystals and the Polarizing Microscope(第4版,1970)。
各式1化合物可呈多形體、立體異構物、互變異構物、或其一些組合形式存在,可為經同位素標記的,可由前藥之投與產生,或在投與之後形成代謝物。
「前藥」係指幾乎不具有或不具有藥理學活性之化合物,當在體內代謝時,該化合物可經歷向具有所要藥理學活性之化合物之轉化。前藥可藉由用例如在H.Bundgaar,Design of Prodrugs(1985)中所述之「前部分」來替代存在於藥理學活性化合物中的適當官能基來製備。前藥之實例包括式1化合物之酯、醚、或醯胺衍生物,該等衍生物分別具有羧酸、羥基、或胺基官能基。關於前藥之進一步討論,參見例如T.Higuchi及V.Stella「Pro-drugs as Novel Delivery Systems,」ACS Symposium Series 14(1975)以及E.B.Roche編,Bioreversible Carriers in Drug Design(1987)。
「代謝物」係指當投與藥理學活性化合物時體內形成之化合物。實
例包括式1化合物之羥甲基、羥基、二級胺基、一級胺基、苯酚、及羧酸衍生物,該等衍生物分別具有甲基、烷氧基、三級胺基、二級胺基、苯基、及醯胺基。
式1化合物可呈立體異構物存在,該等立體異構物係由一或多個立體中心、一或多個雙鍵、或兩者之存在而產生。立體異構物可為純的、實質上純的、或混合物。此類立體異構物亦可由酸加成鹽或鹼鹽產生,其中例如當相對離子為D-乳酸鹽或L-離胺酸時,該相對離子為光學活性的。
式1化合物可呈互變異構物形式而存在,該等互變異構物為由互變異構作用而產生的異構物。互變異構之異構現象包括例如亞胺-烯胺、酮基-烯醇、肟-亞硝基、及醯胺-亞胺酸互變異構現象。
式1化合物可展現多於一種類型之異構現象。
幾何(順式/反式)異構物可藉由習知技術諸如層析法及分段結晶來分離。
用於製備或分離具有特定立體化學組態之化合物的習知技術包括:由合適的光學純前驅物中進行對掌性合成或使用例如對掌性高效液相層析法(HPLC)對外消旋體(或鹽或衍生物之外消旋體)進行拆分。或者,外消旋體(或外消旋前驅體)可與合適的光學活性化合物(例如乙醇)反應,或在式1化合物含有酸性或鹼性部分之情況下,與酸或鹼(諸如酒石酸或1-苯基乙胺)反應。所得非鏡像異構混合物可藉由層析法、分段結晶等來分離,且適當的非鏡像異構物轉化為具有必需立體化學組態之化合物。關於用於分離立體異構物的技術之進一步討論,參見E.L.Eliel及S.H.Wilen,Stereochemistry of Organic Compounds(1994)。
式1化合物可擁有同位素變體,其中至少一個原子由具有相同原子序數但原子質量不同於通常在自然中發現的原子質量之原子替換。適用於包容
在式1化合物中的同位素包括例如:氫之同位素,諸如2H及3H;碳之同位素,諸如11C、13C、及14C;氮之同位素,諸如13N及15N;氧之同位素,諸如15O、17O、及18O;硫之同位素,諸如35S;氟之同位素,諸如18F;氯之同位素,諸如36Cl;以及碘之同位素,諸如123I及125I。同位素變體(例如,氘2H)之使用可提供由較大代謝穩定性帶來的某些治療優點,例如體內半衰期增加或劑量要求減少。另外,所揭示之化合物之某些同位素變體可併入放射性同位素(例如,氚3H、或14C),其可適用於藥物及/或受質組織分佈研究中。用正電子發射同位素(諸如11C、18F、15O、及13N)進行取代可適用於檢查受質受體佔有率之正電子發射斷層成像(PET)研究中。同位素標記之化合物可藉由與本揭露中之其他地方所述之方法類似的方法,使用適當經同位素標記之試劑替代非標記試劑來製備。
式1化合物可使用以下所述之技術來製備。一些流程及實例可省略對於有機化學領域之一般技術者而言已知的常見反應(包括氧化、還原等等)、分離技術(萃取、蒸發、沈澱、層析、過濾、濕磨、結晶、及其類似技術)、以及分析程序之細節。此種反應及技術之細節可見於許多專著論文中,包括Richard Larock,Comprehensive Organic Transformations(1999)、以及由Michael B.Smith等編著之多卷系列,Compendium of Organic Synthetic Methods(1974及下列等等)。起始材料及試劑可獲自商業來源或可使用文獻方法製備。一些反應流程可省略由化學轉變而產生的次要產物(例如,來自酯水解之醇、來自二酸去羧之CO2等等)。另外,在一些情況下,反應中間體可無需分離或純化(即,就地)而在隨後的步驟中使用。
在以下的一些反應流程及實例中,某些化合物可使用保護基來製備,該等保護基防止在另外的反應位點處的不希望之化學反應。保護基亦可用來提高溶解度或以另外的方式修改化合物之物理性質。關於保護基策略之討論、用於安置及移除保護基之材料及方法的描述、以及對常見官能基(包括胺、羧酸、
醇、酮、醛等等)有用的保護基之整理,參見T.W.Greene及P.G.Wuts,Protecting Groups in Organic Chemistry(1999)以及P.Kocienski,Protective Groups(2000)。
一般而言,在說明書通篇中所述的化學轉變可使用實質上化學計量之量的反應物來進行,但某些反應可受益於使用過量的一或多種反應物。另外,在說明書通篇中揭露的許多反應可在大約室溫(RT)及周圍壓力下進行,但視反應動力學、產率等等而定,一些反應可在高壓下運作或採用較高溫度(例如,回流條件)或較低溫度(例如,-78℃至0℃)。在本揭露及申請專利範圍中對化學計量範圍、溫度範圍、pH值範圍等之任何提及,無論是否明確使用詞語「範圍」,亦包括指示的端點。
許多化學轉變亦可採用一或多種相容溶劑,該一或多種相容溶劑可影響反應速率及產率。視反應物之性質而定,該一或多種溶劑可為極性質子性溶劑(包括水)、極性非質子性溶劑、非極性溶劑、或一些組合。代表性溶劑包括:飽和脂族烴類(例如,正戊烷、正己烷、正庚烷、正辛烷、環己烷、甲基環己烷);芳族烴類(例如,苯、甲苯、二甲苯);鹵化烴類(例如,二氯甲烷、氯仿、四氯化碳);脂族醇類(例如,甲醇、乙醇、丙-1-醇、丙-2-醇、丁-1-醇、2-甲基-丙-1-醇、丁-2-醇、2-甲基-丙-2-醇、戊-1-醇、3-甲基-丁-1-醇、己-1-醇、2-甲氧基-乙醇、2-乙氧基-乙醇、2-丁氧基-乙醇、2-(2-甲氧基-乙氧基)-乙醇、2-(2-乙氧基-乙氧基)-乙醇、2-(2-丁氧基-乙氧基)-乙醇);醚類(例如,乙醚、二異丙醚、二丁醚、1,2-二甲氧基-乙烷、1,2-二乙氧基-乙烷、1-甲氧基-2-(2-甲氧基-乙氧基)-乙烷、1-乙氧基-2-(2-乙氧基-乙氧基)-乙烷、四氫呋喃、1,4-二噁烷);酮類(例如,丙酮、甲基乙基酮);酯類(乙酸甲酯、乙酸乙酯);含氮溶劑(例如,甲醯胺、N,N-二甲基甲醯胺、乙腈、N-甲基-吡咯啶酮、吡啶、喹啉、硝基苯);含硫溶劑(例如,二硫化碳、二甲亞碸、四氫-噻吩-1,1,-二氧化物);以及含磷溶劑(例如,六甲基磷醯三胺)。
在以下方案中,取代基標識符(例如,X1、X2、R3、R4、R5、R6等)係對於式1如上所定義。然而,如更早所提及,一些起始材料及中間體可包括保護基,該等保護基先於終產物經移除。在此類情況下,取代基標識符係指式1中所定義之部分及具有適當保護基之彼等部分。例如,方案中之起始材料或中間體可包括具有潛在反應性胺之R7取代基。在此類情況下,R7將包括具有或不具有比方說連接至胺之Boc或Cbz基團之部分。
方案A顯示用於製備式1化合物之一般方法。根據該方法,將3-羥基吡啶甲酸衍生物(A1,R10=氫或保護基諸如甲基、苄基等)與胺(A2)反應以得到醯胺(A3)。步驟1可使用標準醯胺偶合劑(諸如HATU、DCC、EDC鹽酸鹽、T3P、及2-氯-1-甲基吡啶-1-碘化鹽)在非親核鹼(例如,Et3N、DIPEA)及一或多種相容極性溶劑(例如,DCM、DMA、DMF、THF)存在下進行。醯胺偶合可在範圍為室溫至約80℃之溫度下進行。可使用HOBt促進反應。當R10為非氫時,羥基經去保護(步驟2)以得到式1化合物。例如,當R10為甲基時,可在高溫(例如,60-80℃)下於DMA中將醯胺(A3)與LiCl反應以得到式1化合物。類似地,當R10=苄基時,可在室溫下在合適催化劑(例如,Pd(OH)2/C)及溶劑(例如,THF、MeOH、EtOH、IPA等)存在下將醯胺(A3)與H2反應以得到式1化合物。當R10為氫時,醯胺(A3)對應於式1化合物且步驟2為非必要的。
方案B顯示用於製備式1化合物之替代方法。根據該方法,將3-鹵基吡啶甲酸衍生物(B1,X3=氟基、氯基、溴基)與胺(A2)反應以得到芳基鹵化物(B2)。步驟1可使用標準醯胺偶合試劑及上文針對方案A所說明之條件進行。然後於MeOH及視情況選用之共溶劑(例如,ACN)將芳基鹵化物(B2)與NaOCH3反應以得到3-甲氧基吡啶甲酸衍生物(A3),其隨後經LiCl/DMA處理以得到式1化合物。
方案中所描繪之方法可按需要有所變化。例如,保護基可經添加或移除,且產物(包括中間體)可經由例如烷基化、醯化、水解、氧化、還原、醯胺化、磺化、炔化、及其類似作用來進一步精心設計以得到所要終產物。此外,包含立體異構物之混合物的任何中間體或終產物可視情況藉由對掌性管柱層析法(例如,超臨界流體層析法)或藉由如上所述用光學上純的試劑進行衍生化來純化,以得到所要立體異構物。
應對式1化合物(包括以上命名之化合物)及其醫藥學上可接受之複合物、鹽、溶劑合物、及水合物的生物醫藥性質進行評估以便選擇適當的劑型及投與途徑,該等性質諸如溶解度及在各pH值下之溶液穩定性、滲透性、及其類似性質。意欲用於醫藥用途之化合物可呈結晶或非晶質產物投與,且可藉由諸如沈澱、結晶、冷凍乾燥、噴霧乾燥、蒸發乾燥、微波乾燥、或射頻乾燥之方法,例如呈固體栓、散劑、或膜劑獲得。
式1化合物可單獨或彼此組合或與一或多種藥理學活性化合物組合投與,該等藥理學活性化合物不同於式1化合物。一般而言,一或多種此等化合物連同一或多種醫藥學上可接受之賦形劑呈醫藥組成物(調配物)投與。賦形劑之選擇尤其視投藥之特定模式、賦形劑對溶解度及穩定性之影響、以及劑型之性質而定。有用的醫藥組成物及其製備方法可見於例如A.R.Gennaro(編),Remington:The Science and Practice of Pharmacy(第20版,2000)中。
式1化合物可經口投與。經口投與可涉及吞咽,在該情況下,化合物經由胃腸道進入血流。或者或另外地,經口投與可涉及黏膜投與(例如,頰內投與、舌下投與、舌上投與)以使得化合物經由口腔黏膜進入血流。
適用於經口投與之調配物包括:固體、半固體及液體系統,諸如錠劑;含有多顆粒或奈米微粒、液體、或粉末之軟膠囊或硬膠囊;口含劑,其可為填充液體的;咀嚼劑;凝膠;快速分散劑型;膜劑;卵形體;噴霧;以及頰內或黏膜黏附貼劑。液體調配物包括懸浮液、溶液、糖漿、及酏劑。此種調配物可作為填充劑在軟膠囊或硬膠囊(例如,由明膠或羥丙基甲基纖維素製得)中採用,且通常包含載劑(例如,水、乙醇、聚乙二醇、丙二醇、甲基纖維素、或適合的油)及一或多種乳化劑、懸浮劑或兩者。液體調配物亦可藉由固體(例如,由囊劑)之復原來製備。
式1化合物亦可用於快速溶解、快速崩解劑型中,諸如在Liang及Chen,Expert Opinion in Therapeutic Patents(2001)11(6):981-986中描述的彼等劑型。
對於錠劑劑型,視劑量而定,活性醫藥成分(API)可佔劑型之約1wt%至約80wt%或更通常佔劑型之約5wt%至約60wt%。除了API之外,錠劑亦可包括一或多種崩解劑、黏合劑、稀釋劑、界面活性劑、助流劑、潤滑劑、抗氧化劑、著色劑、調味劑、防腐劑、以及掩味劑。崩解劑之實例包括羥乙酸澱粉鈉、羧甲基纖維素鈉、羧甲基纖維素鈣、交聯羧甲基纖維素鈉、交聯聚乙烯吡咯酮、聚乙烯吡咯啶酮、甲基纖維素、微晶纖維素、C1-6烷基取代之羥丙基纖維素、澱粉、預膠凝化澱粉、以及海藻酸鈉。通常,崩解劑將佔劑型之約1wt%至約25wt%或約5wt%至約20wt%。
黏合劑一般用於為錠劑調配物賦予內聚品質。適合的黏合劑包括微晶纖維素、明膠、糖、聚乙二醇、天然及合成樹膠、聚乙烯吡咯啶酮、預膠凝
化澱粉、羥丙基纖維素、及羥丙基甲基纖維素。錠劑亦可含有稀釋劑,諸如乳糖(單水合物、經噴霧乾燥之單水合物、無水的)、甘露糖醇、木糖醇、右旋糖、蔗糖、山梨糖醇、微晶纖維素、澱粉、及磷酸氫鈣二水合物。
錠劑亦可包括:界面活性劑,諸如月桂基硫酸鈉及聚山梨醇酯80;以及助流劑,諸如二氧化矽及滑石。當存在時,界面活性劑可佔錠劑之約0.2wt%至約5wt%,且助流劑可佔錠劑之約0.2wt%至約1wt%。
錠劑亦可含有潤滑劑,諸如硬脂酸鎂、硬脂酸鈣、硬脂酸鋅、硬脂醯反丁烯二酸鈉、及硬脂酸鎂與月桂基硫酸鈉之混合物。潤滑劑可佔錠劑之約0.25wt%至約10wt%或約0.5wt%至約3wt%。
錠劑摻合物可直接或藉由碾壓經壓製以形成錠劑。錠劑摻合物或摻合物之部分可在製錠之前替代地經濕式粒化、乾式粒化、或熔融粒化;熔融凝結;或擠出。需要時,組分之一或多者可在摻合之前藉由篩選或碾磨或其兩者來調整大小。最終劑型可包含一或多個層且可為經塗佈、未經塗佈、或膠囊化的。示範性錠劑可含有高達約80wt%之API、約10wt%至約90wt%之黏合劑、約0wt%至約85wt%之稀釋劑、約2wt%至約10wt%之崩解劑、及約0.25wt%至約10wt%之潤滑劑。關於摻合、粒化、碾磨、篩選、製錠、塗佈之論述以及用於製備藥物產品之替代技術的描述,參見A.R.Gennaro(編),Remington:The Science and Practice of Pharmacy(第20版,2000);H.A.Lieberman等人(編),Pharmaceutical Dosage Forms:Tablets,第1-3卷(第2版,1990);及D.K.Parikh及C.K.Parikh,Handbook of Pharmaceutical Granulation Technology,第81卷(1997)。
供人類或獸醫使用之可消耗的口服膜劑為柔韌的水溶性或水可膨脹性薄膜劑型,其可迅速溶解或黏膜黏附。除API之外,典型膜劑亦包括一或多種成膜聚合物、黏合劑、溶劑、濕潤劑、增塑劑、穩定劑或乳化劑、黏度調節
劑、及溶劑。其他膜劑成分可包括抗氧化劑、著色劑、調味劑及增味劑、防腐劑、唾液刺激劑、冷卻劑、共溶劑(包括油)、軟化劑、增積劑、消泡劑、界面活性劑、及掩味劑。調配物之一些組分可執行多於一種功能。
除了給藥要求之外,膜劑中API之量可視其溶解度而定。若為水溶性的,則API通常將佔膜劑中非溶劑組分(溶質)之約1wt%至約80wt%或膜劑中溶質之約20wt%至約50wt%。溶解性較低之API可佔組成物之較大比例,通常高達膜劑中非溶劑組分之約88wt%。
成膜聚合物可選自天然多醣、蛋白質、或合成水膠體且通常佔膜劑之約0.01wt%至約99wt%或約30wt%至約80wt%。
膜劑劑型通常藉由對塗佈在可剝離背襯支撐件或紙上之水性薄膜進行蒸發乾燥來製備,其可在乾燥烘箱或烘道(例如,在組合的塗層乾燥器件中)、在冷凍乾燥設備、或在真空烘箱中進行。
適用於口服之固體調配物可包括立即釋放型調配物及調控釋放型調配物。調控釋放型調配物包括延遲釋放、持續釋放、脈衝釋放、控制釋放、靶向釋放以及按程序釋放。關於適合的調控釋放型調配物之一般描述參見美國專利第6,106,864號。關於其他適用的釋放技術諸如高能量分散以及滲透性及經塗佈之顆粒的細節參見Verma等人,Pharmaceutical Technology On-line(2001)25(2):1-14。
式1化合物亦可直接投與至受試者之血流、肌肉、或內部器官中。用於胃腸外投與之適合技術包括靜脈內投與、動脈內投與、腹膜內投與、鞘內投與、心室內投與、尿道內投與、胸骨內投與、顱內投與、肌肉內投與、滑膜內投與、及皮下投與。用於胃腸外投與之適合裝置包括針型注射器,該等針型注射器包括微針注射器、無針注射器及輸注裝置。
胃腸外調配物通常為水溶液,該等水溶液可含有賦形劑,諸如鹽、
碳水化合物以及緩衝劑(例如約3至約9之pH值)。然而,對於一些應用,式1化合物可更適合地經調配成無菌非水溶液或成待與適合的媒劑諸如無菌無熱原質之水一起使用的乾燥形式。在無菌條件(例如,藉由冷凍乾燥)下的胃腸外調配物之製備可使用標準醫藥技術輕易地完成。
用於胃腸外溶液製備的化合物之溶解度可經由適當的調配技術(諸如併入增溶劑)來增加。用於胃腸外投與之調配物可經調配成立即釋放型或調控釋放型。調控釋放型調配物包括延遲釋放、持續釋放、脈衝釋放、控制釋放、靶向釋放、及按程序釋放。因此,式1化合物可經調配成懸浮液、固體、半固體、或觸變性液體以便以提供活性化合物之調控釋放的植入型儲槽形式來投與。此種調配物之實例包括經藥物塗佈之支架及半固體以及包含載有藥物之聚(DL-乳酸-乙醇酸)共聚物(PGLA)微球體之懸浮液。
式1化合物亦可局部投與、皮內投與或經皮投與至皮膚或黏膜。出於此目的之典型調配物包括凝膠、水凝膠、洗劑、溶液、乳膏、軟膏、撒佈劑、敷料、發泡體、膜劑、皮膚貼劑、糯米紙囊劑、植入物、海綿、纖維、繃帶、及微乳液。亦可使用脂質體。典型載劑可包括乙醇、水、礦物油、液體石蠟、白凡士林、甘油、聚乙二醇、及丙二醇。局部調配物亦可包括滲透增強劑。參見例如,Finnin及Morgan,J.Pharm.Sci.88(10):955-958(1999)。
局部投與之其他手段包括藉由電穿孔、離子電滲療法、聲泳療法、超聲導入、及微針或無針(例如PowderjectTM及BiojectTM)注射來遞送。用於局部投與之調配物可經調配成如上所述之立即釋放型或調控釋放型。
式1化合物亦可通常以乾燥粉末、氣溶膠噴霧、或滴鼻劑之形式鼻內投與或藉由吸入來投與。吸入劑可用來投與乾燥粉末,該乾燥粉末包含單獨的API、API與稀釋劑(諸如乳糖)之粉末摻合物、或包括API及磷脂(諸如磷脂醯膽鹼)之混合組分顆粒。對於鼻內使用,該粉末可包括生物黏附劑,例如聚葡萄
胺糖或環糊精。加壓之容器、泵、噴霧器、霧化器或噴灑器可用來自溶液或懸浮液產生氣溶膠噴霧,該溶液或懸浮液包含:API;一或多種用於分散、溶解、或延長API釋放之試劑(例如具有或不具有水之EtOH);一或多種充當推進劑之溶劑(例如,1,1,1,2-四氟乙烷或1,1,1,2,3,3,3-七氟丙烷);以及視情況可選之界面活性劑(諸如去水山梨醇三油酸酯、油酸、或低聚乳酸)。使用電流體動力學之霧化器可用於產生細霧。
在用於乾燥粉末或懸浮液調配物中之前,藥物產品通常經粉碎成適用於藉由吸入來遞送之顆粒大小(通常以體積計,90%之顆粒具有小於5微米之最大尺寸)。此可藉由任何適當的大小減小方法諸如螺旋噴射碾磨、流化床噴射碾磨、超臨界流體加工、高壓均質化、或噴霧乾燥來實現。
用於吸入器或吹入器之膠囊、泡鼓(blister)及藥筒(例如由明膠或羥丙基甲基纖維素製得)可經調配以含有活性化合物之粉末混合物、適合的粉末基質諸如乳糖或澱粉、以及效能改良劑諸如L-白胺酸、甘露糖醇、或硬脂酸鎂。乳糖可為無水或單水合的。其他適合的賦形劑包括聚葡糖、葡萄糖、麥芽糖、山梨糖醇、木糖醇、果糖、蔗糖及海藻糖。
用於使用電流體動力學來產生細霧之霧化器中的適合的溶液調配物可含有每次致動約1μg至約20mg之API且致動體積可在約1μL至約100μL之間變化。典型調配物可包含一或多種式1化合物、丙二醇、無菌水、EtOH、及NaCl。可代替丙二醇使用的替代溶劑包括甘油及聚乙二醇。
用於吸入投與、鼻內投與或其兩者之調配物可經調配成例如使用PGLA之立即釋放型或調控釋放型。適合的香料(諸如甲醇及左薄荷腦)或甜味劑(諸如糖精或糖精鈉)可添加至意欲吸入/鼻內投與之調配物中。
在乾燥粉末吸入劑及氣溶膠之情況下,藉助於遞送經計量之量的閥來確定劑量單位。單位通常經安排成投與含有約10μg至約1000μg之API的經
計量之劑量或「噴吹型(puff)」。總每日劑量通常將在約100μg至約10mg之範圍內,此可以單一劑量、或更通常地以一整天之分次劑量來投與。
活性化合物可例如以栓劑、子宮托、或灌腸劑之形式直腸或陰道投與。可可脂為傳統栓劑基質,但適當時可使用各種替代物。用於直腸或陰道投與之調配物可經調配成如上所述之立即釋放型或調控釋放型。
式1化合物亦可通常以等滲的pH值經調節之無菌鹽水中的微粒化懸浮液或溶液之滴劑形式直接投與眼或耳。其他適用於眼投與及耳投與之調配物包括軟膏、凝膠、生物可降解之植入物(例如可吸收之凝膠海綿、膠原)、非生物可降解之植入物(例如聚矽氧)、糯米紙囊劑、透鏡、及微粒或多孔系統(諸如囊泡或脂質體)。該調配物可包括一或多種聚合物及防腐劑(諸如氯化苄烷銨)。典型聚合物包括交聯聚丙烯酸、聚乙烯醇、透明質酸、纖維素聚合物(例如,羥丙基甲基纖維素、羥乙基纖維素、甲基纖維素)、及雜多醣聚合物(例如,瓊脂糖樹膠)。此類調配物亦可藉由離子電滲療法來遞送。用於眼或耳投與之調配物可經調配成如上所述之立即釋放型或調控釋放型。
為了改進式1化合物之溶解度、溶解率、掩味性、生物利用率或穩定性,可將式1化合物與可溶性大分子實體組合,該等可溶性大分子實體包括環糊精及其衍生物以及含有聚乙二醇之聚合物。例如,API-環糊精複合物一般適用於大多數劑型及投與途徑。可使用包容及非包容複合物兩者。作為與API直接複合之替代品,環糊精可用作輔助添加劑,亦即作為載劑、稀釋劑、或增溶劑。出於此等目的常使用α-環糊精、β-環糊精、及γ-環糊精。參見,例如WO 91/11172、WO 94/02518、及WO 98/55148。
如上所說明,一或多種式1化合物(包括實例中具體命名之最終化合物)及其醫藥活性複合物、鹽、溶劑合物及水合物可彼此組合或與一或多種其他的活性醫藥活性化合物組合來治療各種疾病、病狀、及病症。在此類情況下,
活性化合物可以如上所述之單一劑型來組合或可以套組形式提供,該套組適用於組成物之共投與。該套組包含(1)兩種或兩種以上不同醫藥組成物,該等醫藥組成物中之至少一者含有式1化合物;及(2)用於分開保留兩種醫藥組成物之裝置,諸如分裝之瓶或分裝之箔片包。此一套組之一實例為用於包裝錠劑或膠囊之熟悉的泡鼓包裝。該套組適用於投與不同類型之劑型(例如,經口及胃腸外)或用於以分開的給藥時間間隔投與不同醫藥組成物,或用於滴定彼此不同之醫藥組成物。為了有助於患者順從性,該套組通常包括用於投與之指導且可配備有記憶輔助工具。
對於向人類患者投與,所主張及揭示之化合物的總每日劑量通常在約0.1mg至約3000mg之範圍內,視投與途徑而定。例如,經口投與可能需要約1mg至約3000mg之總每日劑量,而靜脈內給藥可能僅需要約0.1mg至約300mg之總每日劑量。總每日劑量可以單一或分次劑量形式投與且在醫師之裁量下,可處於以上給出的典型範圍之外。儘管此等劑量係基於質量約60kg至約70kg之平均人類受試者,但醫師將能夠確定質量超出此質量範圍之患者(例如兒科患者)之適當劑量。
式1化合物可用於治療指示PHD之抑制的疾病、病症、及病狀。如上文所指示,PHD之抑制可增加缺氧誘導因子(HIF)之穩定性及/或活性及/或水準。因此,抑制PHD之化合物可實用於治療HIF之活化提供治療或預防益處之各種疾病、病症、及病狀以及涉及缺氧或缺血之病狀。此類疾病、病症、及病狀可包括心血管病、代謝病、血液病、肺病、腎病、肝病、傷口癒合障礙、及癌症等等。
式1化合物可用於治療心血管疾病、病症、及病狀,包括:中風;心肌梗塞,包括急性心肌梗塞;鬱血性心衰竭;動脈粥樣硬化;慢性靜脈功能不全;心因性肝硬化;急性失代償性心衰竭;心臟病發作後心衰竭;周邊動脈
疾病;及閉塞性動脈疾病。
式1化合物可用於治療代謝疾病、病症、及病狀,包括:糖尿病、高血糖、胰島素抗性、X代謝症候群、葡萄糖耐受不良、及非酒精性肝脂肪變性。
式1化合物可用於治療血液疾病、病症、及病狀,包括貧血,其尤其包括但不限於化學療法誘導之貧血,諸如用針對HIV及肝炎之抗病毒藥物方案進行的治療;與慢性疾病相關聯之貧血;與癌症相關聯之貧血,包括由癌症治療造成之貧血;與慢性免疫病症相關聯之貧血,諸如類風濕性關節炎、發炎性腸病、及狼瘡;與月經、鐵加工缺乏、急性或慢性腎臟疾病、感染、發炎、輻射、毒素、糖尿病、及歸因於例如病毒、細菌及/或寄生蟲之感染相關聯之貧血;與歸因於例如創傷、胃潰瘍、十二指腸潰瘍、痔瘡、胃癌或大腸癌、損傷、及外科手術之失血相關聯之貧血;與骨髓衰竭或骨髓功能減退相關聯之貧血;小紅血球性貧血;低色性貧血;含鐵胚血球性貧血;及其類似貧血。
式1化合物可用於治療肺部疾病、病症、及病狀,包括:慢性阻塞性肺臟疾病(COPD);肺栓塞;肺性高血壓;高山病;急性呼吸衰竭;間質性肺病(ILD),包括特發性ILD,諸如特發性肺纖維化、落屑性間質性肺炎、非特異性間質性肺炎、隱原性器質化肺炎、呼吸性細支氣管炎相關間質性肺病、急性間質性肺炎、及淋巴性間質性肺炎。
式1化合物可用於治療腎臟疾病、病症、及病狀,包括:急性腎衰竭;急性腎損傷;慢性腎臟疾病;及腎臟缺血再灌注損傷。
式1化合物可用於治療肝臟疾病、病症、及病狀,包括肝臟缺血再灌注損傷。
式1化合物可用於治療傷口癒合疾病、病症、及病狀,包括尿病足潰瘍、壓迫性潰瘍、靜脈性潰瘍、動脈性潰瘍、水皰性表皮鬆解症(遺傳性及後
天性)、天皰瘡、及休格倫氏症候群。
式1化合物可用於治療癌症,包括白血病(例如,慢性骨髓性白血病及慢性淋巴球性白血病);乳癌;泌尿生殖癌症;皮膚癌;骨癌;前列腺癌;肝癌;腦癌;喉癌、膽囊癌、直腸癌、副甲狀腺癌、甲狀腺癌、腎上腺癌、神經組織癌、膀胱癌、頭部癌、頸部癌、胃癌、支氣管癌、及腎癌;基底細胞癌、鱗狀細胞癌、轉移性皮膚癌、骨肉瘤、尤因氏肉瘤(Ewing's sarcoma)、網狀細胞肉瘤、及卡波濟氏肉瘤(Kaposi's sarcoma);骨髓瘤、巨細胞瘤、胰島細胞瘤、急性及慢性淋巴球性及顆粒球性腫瘤;毛細胞瘤、腺瘤、髓樣癌、嗜鉻細胞瘤、黏膜神經瘤、腸神經節細胞瘤、增生性角膜神經腫瘤、類馬方氏症候群瘤、維爾姆斯瘤(Wilms' tumor)、精原細胞瘤、卵巢腫瘤、平滑肌瘤、子宮頸上皮分化不良、神經胚細胞瘤、視網膜母細胞瘤、骨髓增生異常症候群、橫紋肌肉瘤、星形細胞瘤、非霍奇金淋巴瘤(non-Hodgkin's lymphoma)、惡性高鈣血症、真性紅細胞增多症、腺癌、多形性神經膠質母細胞瘤、神經膠質瘤、淋巴瘤、以及惡性黑色素瘤等等。
所主張及揭示之化合物可與一或多種其他藥理學活性化合物或療法組合以治療一或多種與PHD相關聯之疾病、病症、或病狀。此類組合可提供顯著的治療優點,包括副作用較少、治療缺醫少藥之患者群的能力提高、或協同活性。式1化合物包括實例中具體命名之化合物、以及其醫藥學上可接受之複合物、鹽、溶劑合物、及水合物,可與一或多種針對心血管病、代謝病、血液病、肺病、腎病、肝病、傷口癒合障礙、及癌症等等之化合物或療法組合地同時、順序、或分開投與。
例如,式1化合物可與一或多種心血管藥劑組合,該一或多種心血管藥劑諸如鈣通道阻斷劑,包括胺氯地平(amlodipine)、氯維地平(clevidipine)、地爾硫(diltiazem)、非洛地平(felodipine)、伊拉地平(isradipine)、尼卡地平
(nicardipine)、硝苯地平(nifedipine)、尼索地平(nisoldipine)、及維拉帕米(verapamil);斯他汀類,包括阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、普伐他汀(pravastatin)、瑞舒伐他汀(rosuvastatin)、辛伐他汀(simvastatin)、及匹伐他汀(pitavastatin);貝特類(fibrate),包括吉非羅齊(gemfibrozil)及非諾貝特(fenofibrate);β-阻斷劑,包括醋丁洛爾(acebutolol)、阿替洛爾(atenolol)、倍他洛爾(betaxolol)、畢索洛爾(bisoprolol)、卡維地洛(carvedilol)、艾司洛爾(esmolol)、拉貝洛爾、美托洛爾(metoprolol)、納多洛爾(nadolol)、奈必洛爾(nebivolol)、噴布洛爾(penbutolol)、普萘洛爾(propranolol)、索他洛爾(sotalol)、及噻嗎洛爾(timolol);ACE抑制劑類,包括貝那普利(benazepril)、卡托普利(captopril)、依那普利(enalapril)、福辛普利(fosinopril)、賴諾普利(Lisinopril)、莫昔普利(moexipril)、培哚普利(perindopril)、喹那普利(quinapril)、雷米普利(ramipril)、及群多普利(trandolapril);及血小板凝集抑制劑,包括阿斯匹林、坎格雷洛(cangrelor)、氯吡格雷(clopidogrel)、西洛他唑(cilostazol)、雙嘧達莫(dipyridamole)、普拉格雷(prasugrel)、及替格瑞洛(ticagrelor)。
式1化合物可與一或多種用於治療代謝病之藥劑組合。此等藥劑包括胰脂酶抑制劑(例如,奧利司他(orlistat));胰島素;胰島素敏化劑,包括雙胍類(例如,丁雙胍、二甲雙胍、及苯乙雙胍)及格列酮類(例如,吡格列酮(pioglitazone)及羅格列酮(rosiglitazone));胰島素促分泌劑,包括磺脲類(例如,醋磺己脲、氯磺丙脲、妥拉磺脲(tolazamide)、甲苯磺丁脲、格列齊特(gliclazide)、格列美脲(glimepiride)、格列吡嗪(glipizide)、及格列本脲(glyburide))、及格列奈類(例如,那格列奈(nateglinide)及瑞格列奈(repaglinide));α-葡糖苷酶抑制劑(例如,阿卡波糖(acarbose)及米格列醇(miglitol));類升糖素肽類似物及拮抗劑(例如,艾塞那肽(exenatide)、利拉魯肽(liraglutide)、及他司魯泰(taspoglutide));二肽基肽酶-4抑制劑(例如,阿格列汀(alogliptin)、利拉利汀(linagliptin)、沙格列汀(saxagliptin)、
西他列汀(sitagliptin)、及維達列汀(vildagliptin));及糊精類似物(例如,普蘭林肽(pramlinitide))。
式1化合物可與一或多種用於治療傷口癒合障礙之療法或藥劑組合,包括消炎劑、止痛劑、止癢劑、及抗感染藥。消炎劑之實例包括非類固醇消炎藥(NSAID)及皮質類固醇。代表性NSAID包括:阿紮丙宗(apazone)、阿斯匹林、塞來考昔(celecoxib)、雙氯芬酸(具有及不具有米索前列醇)、二氟尼柳、依託度酸、非諾洛芬(fenoprofen)、氟比洛芬(flurbiprofen)、布洛芬、吲哚美辛(indomethacin)、酮洛芬(ketoprofen)、甲氯芬那酸鈉、甲芬那酸、美洛昔康(meloxicam)、萘丁美酮(nabumetone)、萘普生(naproxen)、奧沙普秦(oxaprozin)、保泰松(phenylbutazone)、吡羅昔康(piroxicam)、膽鹼及水楊酸鎂、雙水楊酯、及舒林酸(sulindac)。代表性皮質類固醇包括倍他米松(betamethasone)、乙酸可的松、地塞米松(dexamethasone)、氫化可的松、甲潑尼龍、潑尼松龍(prednisolone)、及潑尼松(prednisone)。代表性止痛劑包括:對乙醯胺基酚及硫酸嗎啡;以及可待因(codeine)、氫可酮、氧可酮、右丙氧芬(propoxyphene)、及曲馬多(tramadol),所有此等物質具有或不具有對乙醯胺基酚。用於全身使用之代表性止痛劑包括賽庚啶(cyproheptadine)、苯海拉明(diphenhydramine)、加巴噴丁(gabapentin)、羥嗪(hydroxyzine)、及昂丹司瓊(ondansetron)。用於局部使用之代表性止癢劑包括乳酸銨、苯佐卡因(benzocaine)、卡拉明(calamine)、辣椒素、氯碘奎醇(clioquinol)、克羅米通(crotamiton)、苯海拉明、多塞平(doxepin)、氫化可的松、利多卡因(lidocaine)、甲醇、柳酸甲酯、及普莫卡因(pramoxine)。
實例性抗感染劑可包括抗菌劑、抗真菌劑、及抗病毒劑。代表性抗菌劑包括:胺基糖苷類,諸如阿米卡星(amikacin)、慶大黴素(gentamicin)、康黴素、新黴素、巴龍黴素、及妥布黴素(tobramycin);碳氫黴烯類(carbapenem),諸如多尼培南(doripenem)、厄他培南(ertapenem)、亞胺培南(imipenem)、及美羅培
南(meropenem);頭孢菌素類,包括與β-內醯胺酶抑制劑之組合,諸如頭孢他啶(ceftazidime)/阿維巴坦(avibactam)及頭孢洛紮(ceftolozane)/三唑巴坦(tazobactam);第一代頭孢菌素,諸如頭孢卓西(cefadroxil)、頭孢若林(cefazolin)、頭孢力欣(cephalexin)、及頭孢華定(cephradine);第二代頭孢菌素,諸如西弗特坦(cefotetan)、頭孢丙烯(cefprozil)、頭孢呋辛(cefuroxime)、頭孢西丁、及氯碳頭孢(loracarbef);第三代頭孢菌素,諸如頭孢地尼(cefdinir)、頭孢托侖(cefditoren)、希復欣敏(cefixime)、頭孢匹拉(cefoperazone)、頭孢噻肟(cefotaxime)、頭孢泊肟(cefpodoxime)、頭孢他啶、頭孢布烯(ceftibuten)、頭孢唑肟(ceftizoxime)、及頭孢曲松(ceftriaxone);以及第四代及下一代頭孢菌素,諸如頭孢吡肟(cefepime)及頭孢洛林(ceftaroline);醣肽抗生素,諸如達巴萬星(dalbavancin)、奧利萬星(oritavancin)、特拉萬星(telavancin)、及萬古黴素;甘胺四環素類(glycylcycline),諸如替加環素(tigecycline);林可黴素及其衍生物,諸如克林達黴素(clindamycin);巨環內酯類,諸如亞藥索黴素(azithromycin)、克拉黴素(clarithromycin)、紅黴素、及非達黴素(fidaxomicin),及大環內酯衍生物,包括酮內酯類(ketolide),諸如泰利黴素(telithromycin);噁唑烷酮(oxazolidinone)抗生素,諸如利奈唑胺(linezolid)及特地唑胺(tedizolid);青黴素類,包括胺基青黴素,諸如阿莫西林(amoxicillin)及安比西林(ampicillin);抗假單胞菌青黴素,諸如卡苯尼西林(carbenicillin)、哌拉西林(piperacillin)、及替卡西林(ticarcillin);青黴素與β-內醯胺酶抑制劑,諸如阿莫西林/克拉維酸鹽、安比西林/舒巴坦(sulbactam)、哌拉西林/三唑巴坦、及替卡西林/克拉維酸鹽;天然青黴素,諸如青黴素G苄星(penicillin G benzathine)、青黴素V鉀、及普魯卡因青黴素;耐青黴素酶青黴素,諸如二氯噻青黴素、萘夫西林(nafcillin)、及歐西林(oxacillin);喹啉酮類,諸如西諾沙星(cinoxacin)、環丙沙星(ciprofloxacin)、德拉沙星(delafloxacin)、加替沙星(gatifloxacin)、吉米沙星(gemifloxacin)、左氧氟沙星(levofloxacin)、洛美沙星(lomefloxacin)、莫西沙星
(moxifloxacin)、啶酮酸(nalidixic acid)、諾氟沙星(norfloxacin)、氧氟沙星(ofloxacin)、帕氟沙星(sparfloxacin)、及曲氟沙星(trovafloxacin);磺醯胺類,諸如磺胺甲異噁唑/甲氧苄啶(trimethoprim)及磺胺異噁唑;四環素及其衍生物,諸如去甲基氯四環素、去氧羥四環素、去氧羥四環素/ω-3多不飽合脂肪酸、去氧羥四環素/水楊酸、米諾環素(minocycline)、及羥四環素(oxytetracycline)。其他代表性抗菌劑包括阿托喹酮(atovaquone)、胺曲南(aztreonam)、枯草菌素、氯黴素、甲磺酸黏菌素(colistimethate)、達福普丁(dalfopristin)/奎奴普丁(quinupristin)、達托黴素(daptomycin)、紅黴素/磺胺異噁唑、弗斯黴素(fosfomycin)、甲硝唑、噴他脒(pentamidine)、利福昔明(rifaximin)、觀黴素(spectinomycin)、及三甲曲沙(trimetrexate)。
代表性抗真菌劑包括唑類抗真菌劑,諸如克氯黴唑、氟康唑(fluconazole)、艾沙康唑(isavuconazonium)、伊曲康唑(itraconazole)、酮康唑(ketoconazole)、咪康唑(miconazole)、泊沙康唑(posaconazole)、及伏立康唑(voriconazole);棘白菌素類(echinocandin),諸如阿尼芬淨(anidulafungin)、卡泊芬淨(caspofungin)、及米卡芬淨(micafungin);及多烯,諸如雙性黴素B、雙性黴素B硫酸膽固醇酯、雙性黴素B脂質複合物、及寧司泰定(nystatin)。其他代表性抗真菌劑包括氟胞嘧啶(flucytosine)、灰黃黴素(griseofulvin)、及特比奈芬(terbinafine)。
代表性抗病毒劑包括嘌呤核苷,諸如無環鳥苷(acyclovir)、西多福韋(cidofovir)、泛昔洛韋(famciclovir)、更昔洛韋(ganciclovir)、利巴韋林(ribavirin)、伐昔洛韋(valacyclovir)、及纈更昔洛韋(valganciclovir)。
除消炎劑、止痛劑、止癢劑、及抗感染劑之外,式1化合物可與用於治癒傷口之細胞或基因療法組合。
式1化合物亦可與一或多種用於治療癌症之化合物或療法組合。此
等包括化學治療劑(即,細胞毒性劑或抗腫瘤劑),諸如烷化劑、抗生素、抗代謝劑、衍生自植物之藥劑、及拓撲異構酶抑制劑,以及分子靶向藥物,其藉由對涉及腫瘤生長及進展的具體分子進行干擾來阻斷癌症之生長及擴散。分子靶向藥物包括小分子及生物製劑兩者。
代表性烷化劑包括:雙氯乙胺(氮芥),包括苯丁酸氮芥、環磷醯胺、異環磷醯胺、二氯甲二乙胺、美法侖、及尿嘧啶氮芥;氮丙啶,包括噻替派(thiotepa);烷基磺酸酮,包括白消安;亞硝基脲,包括卡莫司汀(carmustine)、洛莫司汀(lomustine)、及鏈脲黴素(streptozocin);非典型烷化劑,包括六甲蜜胺、達卡巴嗪(dacarbazine)、及丙卡巴肼(procarbazine);及鉑化合物,包括卡鉑、順鉑、奈達鉑、奧沙利鉑、沙鉑、及四硝酸三鉑。
代表性抗生素劑包括:蒽環類抗生素,包括阿柔比星(aclarubicin)、胺柔比星(amrubicin)、道諾黴素(daunorubicin)、阿黴素(doxorubicin)、表柔比星(epirubicin)、伊達比星(idarubicin)、吡柔比星(pirarubicin)、戊柔比星(valrubicin)、及佐柔比星(zorubicin));蒽醌類,包括米托蒽醌(mitoxantrone)及匹克生瓊(pixantrone);及鏈黴菌類,包括放線菌素(actinomycin)、博來黴素(bleomycin)、更生黴素(dactinomycin)、絲裂黴素C(mitomycin C)、及普卡黴素(plicamycin)。
代表性抗代謝劑包括:二氫葉酸還原酶抑制劑,包括胺基蝶呤、甲胺蝶呤、及培美曲塞(pemetrexed);胸苷合成酶(hymidylate synthase)抑制劑,包括雷替曲塞(raltitrexed)及培美曲塞;醛葉酸(folinic acid),包括留可佛林(leucovorin);腺苷去胺酶抑制劑,包括噴司他丁(pentostatin);鹵化/核糖核苷酸還原酶抑制劑,包括克拉屈濱(cladribine)、克羅拉濱(clofarabine)、及氟達拉濱(fludarabine);硫嘌呤類,包括硫鳥嘌呤及巰基嘌呤;胸苷酸合成酶抑制劑,包括氟尿嘧啶、卡培他濱(capecitabine)、替加氟(tegafur)、卡莫氟(carmofur)、及氟尿苷(floxuridine);DNA聚合酶抑制劑,包括阿糖胞苷;核糖核苷酸還原酶抑制
劑,包括吉西他濱(gemcitabine);低甲基化劑,包括阿紮胞苷(azacitidine)及地西他濱(decitabine);核糖核苷酸還原酶抑制劑,包括羥基脲;及天冬醯胺耗盡劑,包括天冬醯胺酶。
代表性植物衍生之藥劑包括:長春花生物鹼,包括長春新鹼(vincristine)、長春花鹼(vinblastine)、長春地辛(vindesine)、長春利定(vinzolidine)、及長春瑞濱(vinorelbine);鬼臼毒素,包括依託泊苷(etoposide)及替尼泊苷(teniposide);及紫杉烷,包括多西他賽(docetaxel)、拉羅他賽(larotaxel)、奧他賽(ortataxel)、紫杉醇、及替司他賽(tesetaxel)。
代表性I型拓撲異構酶抑制劑包括喜樹鹼,包括貝洛替康(belotecan)、伊立替康(irinotecan)、魯比替康(rubitecan)、及托泊替康(topotecan)。代表性II型拓撲異構酶抑制劑包括安吖啶、依託泊苷、磷酸依託泊苷、及替尼泊苷(teniposide),該等物質為表鬼臼毒素之衍生物。
分子靶向療法包括生物藥劑諸如細胞因子及其他免疫調節劑。有用的細胞因子包括介白素-2(IL-2,阿地介白素(aldesleukin))、介白素-4(IL-4)、介白素12(IL-12)、及干擾素,干擾素包括多於23種相關亞型。其他細胞因子包括顆粒球集落刺激因子(CSF)(非格司亭(filgrastim))及顆粒球巨噬細胞CSF(沙格司亭(sargramostim))。其他免疫調節劑包括:卡介苗(bacillus Calmette-Guerin)、左旋咪唑(levamisole)、及奧曲肽(octreotide);對抗腫瘤抗原之單株抗體,諸如曲妥珠單抗(trastruzumab)及利妥昔單抗(rituximab);及癌症疫苗,該等癌症疫苗誘導對腫瘤之免疫反應。
此外,對涉及腫瘤生長及進展之具體分子進行干擾的分子靶向藥物包括以下各物之抑制劑:表皮生長因子(EGF)、轉化生長因子-α(TGFα)、TGFβ、調蛋白(heregulin)、胰島素樣生長因子(IGF)、成纖維細胞生長因子(FGF)、角質細胞生長因子(KGF)、集落刺激因子(CSF)、紅血球生成素(EPO)、介白素-2(IL-2)、
神經生長因子(NGF)、血小板衍生生長因子(PDGF)、肝細胞生長因子(HGF)、血管內皮生長因子(VEGF)、血管生成素、表皮生長因子受體(EGFR)、人類表皮生長因子受體2(HER2)、HER4、胰島素樣生長因子1受體(IGF1R)、IGF2R、成纖維細胞生長因子1受體(FGF1R)、FGF2R、FGF3R、FGF4R、血管內皮生長因子受體(VEGFR)、具有免疫球蛋白樣及表皮生長因子樣結構域的酪胺酸激酶2(Tie-2)、血小板衍生生長因子受體(PDGFR)、Abl、Bcr-Abl、Raf、FMS樣酪胺酸激酶3(FLT3)、c-Kit、Src、蛋白激酶c(PKC)、原肌球蛋白受體激酶(Trk)、Ret、哺乳動物雷帕黴素靶蛋白(mTOR)、極光激酶、polo樣激酶(PLK)、促分裂原活化蛋白激酶(MEK)、間質-上皮轉化因子(c-MET)、週期蛋白依賴型激酶(CDK)、Akt、細胞外信號調節激酶(ERK)、聚(ADP)核糖聚合酶(PARP)、及其類似物。
特異性分子靶向藥物包括:選擇性雌激素受體調節劑,諸如他莫西芬(tamoxifen)、托瑞米芬(toremifene)、氟維司群(fulvestrant)、及雷洛昔芬(raloxifene);抗雄激素劑,諸如比卡魯胺(bicalutamide)、尼魯米特(nilutamide)、甲地孕酮(megestrol)、及氟他胺(flutamide);及芳香酶抑制劑,諸如依西美坦(exemestane)、阿那曲唑(anastrozole)、及來曲唑(letrozole)。其他特異性分子靶向藥物包括:抑制信號轉導之藥劑,諸如伊馬替尼(imatinib)、達沙替尼(dasatinib)、尼羅替尼(nilotinib)、曲妥珠單抗(trastuzumab)、吉非替尼(gefitinib)、埃羅替尼(erlotinib)、西妥昔單抗(cetuximab)、拉帕替尼(lapatinib)、帕尼單抗(panitumumab)、及替西羅莫司(temsirolimus);誘導細胞凋亡之藥劑,諸如硼替佐米(bortezomib);阻滯血管生成之試劑,諸如貝伐單抗(bevacizumab)、索拉非尼(sorafenib)及舒尼替尼(sunitinib);幫助免疫系統破壞癌細胞之藥劑,諸如利妥昔單抗及阿侖單抗(alemtuzumab);以及將毒性分子遞送至癌細胞之單株抗體,諸如吉妥珠單抗奧佐米星(gemtuzumab ozogamicin)、托西莫單抗(tositumomab)、131I-托西莫單抗
(131I-tositumoab)、及替伊莫單抗(ibritumomab tiuxetan)。
作為PHD調節劑之化合物之活性可藉由多種方法來測定,包括體外及體內方法。
藉由在50mM HEPES、50mM KCl、0.5mM TCEP、2μM FeCl2、0.1mg/mL BSA中在pH 7.3下混合遞增量之抑制劑與固定量之酶(5nM,最終濃度)及生物素標記肽(生物素-Asp-Leu-Glu-Met-Leu-Ala-Pro-Tyr-Ile-Pro-Met-Asp-Asp-Asp-Phe-Gln-Leu,1μM最終濃度)及2-氧基戊二酸鹽(2μM最終濃度)來確定PHD2酶(殘基181-417)之IC50值。藉由在室溫下在抑制劑存在下預培育酶60分鐘來進行反應。藉由添加肽、2-側氧基戊二酸鹽、及抗壞血酸(1mM最終濃度)來測量遊離酶之活性。60分鐘之後,藉由向檢定混合物中添加過量緊密結合抑制劑來淬滅酶活性。藉由使用LC/MS系統(Agilent HPLC連同Applied Biosystems API3000質譜儀)來測量釋放之產物之量。使用用於確定IC50值之經典等溫方程式來分析資料且將其呈pIC50(即,-log(IC50))報導於以下表1中,其中IC50為50%抑制時測試化合物之莫耳濃度。
將H9c2大鼠心肌細胞(ATCC)接種於96孔組織培養微盤中且培養24小時,之後添加化合物(11點範圍之連續稀釋液)或DMSO媒劑。化合物培育24小時之後,藉由在含有蛋白酶及磷酸酶抑制劑之細胞提取緩衝液(Meso-Scale Discovery)中溶解細胞來製備完整細胞提取物。藉由ELISA(Meso-Scale Discovery)評估HIF1α蛋白含量且表述為相對於獲自陽性對照去鐵敏(desferrioxamine)(Sigma-Aldrich)之最大反應之%。藉由使用XLfit4 MicroSoft Excel曲線擬合軟體計算導致50%去鐵敏最大反應之化合物濃度來獲得各化合物
之EC50。此等資料呈pEC50(即,-log(EC50))報導於以下表1中,其中EC50為50%去鐵敏最大反應時測試化合物之莫耳濃度。
以下實例意欲具說明性及非限制性,且代表本發明之具體實施例。
在以下實例中獲得其中許多化合物之1H核磁共振(NMR)譜。使用用於指示主要峰之習知縮寫,以來自四甲基矽烷之低磁場的百萬分率給出特徵性化學位移(δ),該等縮寫包括s(單峰)、d(雙重峰)、t(三重峰)、q(四重峰)、m(多重峰)、及br(寬峰)。以下縮寫係用於常見溶劑:CDCl3(氘代氯仿)、DMSO-d 6(氘代二甲亞碸)、CD3OD(氘代甲醇)、CD3CN(氘代乙腈)、及THF-d 8 (氘代四氫呋喃)。使用電噴霧電離(ESI-MS)或大氣壓化學電離(APCI-MS)質譜法來記錄質譜[M+H]+之m/z)。
當指示時,某些製備及實例之產物係藉由質量觸發之HPLC(泵:WatersTM 2525;MS:ZQTM;軟體:MassLynxTM)、急驟層析法或製備型薄層層析法(TLC)來純化。逆相層析法通常在酸性條件(「酸模式」)下用分別含有0.035%及0.05%三氟乙酸(TFA)之CH3CN及水流動相溶離;或在鹼性條件(「鹼模式」)下用均含有10mM NH4HCO3之水及20/80(v/v)水/乙腈流動相溶離來在管柱(例如,Phenomenex GeminiTM 5μ,C18,30mm×150mm;AxiaTM,5μ,30mm×75mm)上進行。製備型TLC通常在矽膠60 F254盤上進行。藉由層析法分離之後,移除溶劑且藉由在離心蒸發器(例如,GeneVacTM)、旋轉蒸發器、抽空之燒瓶等中乾燥來獲得產物。惰性氛圍(例如,氮氣)或反應性氛圍(例如,H2)中之反應通常在約1個大氣壓(14.7psi)之壓力下進行。
向配備有攪拌子之100mL圓底燒瓶中裝填5-氯-6-(乙氧基羰基)菸鹼酸(1.13g,4.92mmol)、EDC鹽酸鹽(1.226g,6.40mmol)、HOBt(0.980g,6.40mmol)、Et3N(1.372mL,9.84mmol)、及DMF(16.40mL)。在室溫下將反應混合物攪拌5分鐘。接著添加1-乙基哌嗪(0.758mL,5.91mmol)。在室溫下將反應混合物攪拌隔夜,然後用乙酸乙酯(30mL)稀釋,且用水(2×20mL)接著用鹽水(20mL)洗滌。將有機層收集,經Na2SO4乾燥,且濃縮至殘餘物,將該殘餘物藉由二氧化矽管柱層析法(120g)用5-40%於庚烷中之EtOAc之梯度溶離進行純化,以得到呈黏性黃色油狀物之標題化合物(1.6g,4.91mmol,100%)。1H NMR(400MHz,DMSO-d 6)δ ppm 1.00(t,J=7.20Hz,3 H),1.33(t,J=7.20Hz,3 H),2.27-2.45(m,6 H),3.32(br s,2 H),3.63(br s,2 H),4.40(q,J=7.24Hz,2 H),8.19(d,J=1.52Hz,1 H),8.56-8.67(m,1 H);ESI-MS m/z[M+H]+ 326.1。
在氮氣下向配備有攪拌子之20mL小瓶中裝填3-氯-5-(4-乙基哌嗪-1-羰基)吡啶甲酸乙酯(372mg,1.142mmol)及DMF(2284μL)。在室溫下,向攪拌之溶液中添加苯甲醇(355μL,3.43mmol)及NaH(114mg,2.85mmol)。將反應混合物升溫至40℃且攪拌1小時,冷卻至室溫,且用水淬滅。用EtOAc(5mL)洗滌水層。移除有機層,且使用1N HCl將水層酸化至pH 5並乾燥。將殘餘物
溶解於DMSO(2mL)且藉由製備型HPLC純化,得到呈黃褐色半固體之標題化合物(217mg,51.4%)。ESI-MS m/z[M+H]+ 370.2。
向配備有攪拌子之20mL螺旋蓋小瓶中裝填3-(苄氧基)-5-(4-乙基哌嗪-1-羰基)吡啶甲酸(200mg,0.541mmol)、1H-苯并[d][1,2,3]三唑-1-醇(95mg,0.704mmol)、EDC鹽酸鹽(135mg,0.704mmol)、DMF(2707μL)、及Et3N(302μL,2.166mmol)。在室溫下將混濁的反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3-甲基苯甲腈鹽酸鹽(198mg,1.083mmol)。在室溫下將反應混合物攪拌兩天,然後用水(2mL)稀釋並用EtOAc(2×20mL)萃取。將有機層用鹽水洗滌,經Na2SO4乾燥,且濃縮至殘餘物,得到呈棕色半固體之標題化合物(105.8mg,39.3%)。ESI-MS m/z[M+H]+ 498.3。
以類似於製備2之方式,使用(R)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽代替4-(胺甲基)-3-甲基苯甲腈鹽酸鹽製備標題化合物。ESI-MS m/z[M+H]+
510.3。
向配備有攪拌子之40mL螺旋蓋小瓶中添加3-氯-5-氰基吡啶甲酸(183mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(176mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5000μL)、及Et3N(139μL,1.00mmol)。在室溫下將混濁的反應混合物攪拌5分鐘。接著添加4-(胺甲基)苯甲腈(132mg,1.00mmol),且在室溫下將反應混合物攪拌隔夜。隨後添加Et3N(139μL,1.000mmol),且在室溫下將反應混合物攪拌2小時,然後用水(2mL)及乙醇(2mL)稀釋並用1N HCl酸化至pH 5。收集沈澱物且於濾紙上乾燥,以得到呈灰白色固體之標題化合物(120mg,40.4%)。1H NMR(400MHz,DMSO-d 6)δ ppm 4.57(d,J=5.81Hz,2 H),7.54(d,J=8.59Hz,2 H),7.84(d,J=8.59Hz,2 H),8.75(d,J=1.52Hz,1 H),9.06(d,J=1.52Hz,1 H),9.44-9.49(m,1 H);ESI-MS m/z[M+H]+ 297.0。
將於甲醇(0.5M)中之甲醇鈉(634μL,0.317mmol)添加至3-氯-5-氰基-N-(4-氰基苄基)吡啶醯胺(94mg,0.317mmol)之乙腈(603μL)溶液中。將所得溶液在室溫下攪拌6小時且在60℃下攪拌4小時,然後過濾。將濾液藉由製備型HPLC,用20-45%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(18mg,19%)。1H NMR(400MHz,CD3OD)δ ppm 3.97(s,3 H),4.59(s,1 H),4.65(s,2 H),7.56(d,J=8.59Hz,2 H),7.69-7.73(m,2 H),8.03(s,1
H),8.51(br s,1 H);ESI-MS m/z[M+H]+ 293.1。
向圓底燒瓶中添加二碳酸二-三級丁酯(11.60mL,50.0mmol)、NaHCO3(10.50g,125mmol)、(4-溴-2-甲基苯基)甲胺(5g,24.99mmol)、及二噁烷(54.9mL)。在室溫下將反應混合物攪拌隔夜,然後過濾並濃縮。將殘餘物藉由(二氧化矽)管柱層析法,用5-30%於庚烷中之EtOAc之梯度溶離進行純化,以得到呈白色固體之標題化合物(6.581g,88%)。ESI-MS m/z[M+H]+ 300.2。
在氮氣下向配備有攪拌子之圓底燒瓶中添加(4-溴-2-甲基苄基)胺基甲酸三級丁酯(6.581g,21.92mmol)及二氰基鋅(2.57g,21.92mmol),接著添加DMF(73.1mL)。將所得懸浮液除氣2分鐘,然後添加肆(三苯基膦)鈀(0)(1.267g,1.096mmol)。將反應混合物再除氣2分鐘,然後加熱至100℃並攪拌隔夜。隨後將反應混合物冷卻至室溫並傾倒至含有水(76mL)之分液漏斗中。添加乙酸乙酯(113mL)。振盪之後,將所得乳液透過紙過濾,以幫助分離各層。收集有機層,用鹽水洗滌,經Na2SO4乾燥,且濃縮至油狀物。將油狀物使用MoritexTM管柱(240g二氧化矽),用5-30%於庚烷中之EtOAc之梯度溶離進行純化,以得到呈白色固體之標題化合物(3.972g,73.6%)。ESI-MS m/z[M+H]+ 247.1。
向含有(4-氰基-2-甲基苄基)胺基甲酸三級丁酯(3.972g,16.13mmol)之圓底燒瓶中添加於二噁烷中之HCl(57.6mL,230mmol)。在室溫下將反應混合物攪拌2小時。UPLC指示轉化為所要產物。將粗反應物在真空下乾燥以得到呈灰白色固體之標題化合物之HCL鹽(3.109g)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.38(s,3 H),4.11(br s,2 H),7.55(d,J=7.83Hz,1 H),7.74-7.81(m,2 H),8.28(br s,2 H);ESI-MS m/z[M+H]+ 147.0。
向配備有攪拌子之40mL螺旋蓋小瓶中添加3-氯-5-氰基吡啶甲酸(548mg,3mmol)、1H-苯并[d][1,2,3]三唑-1-醇(527mg,3.90mmol)、EDC鹽酸鹽(748mg,3.90mmol)、DMF(15mL)、及Et3N(836μL,6.00mmol)。在室溫下將混濁的反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3-甲基苯甲腈鹽酸鹽(548mg,3.00mmol)。在室溫下將反應物混合攪拌72小時,然後用水(6mL)及乙醇(6mL)稀釋並用1N HCl酸化至pH 5。收集沈澱物且於濾紙上乾燥,以得到呈白色固體之標題化合物(386mg,41.4%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.38(s,3 H),4.53(d,J=6.06Hz,2 H),7.46-7.50(m,1 H),7.67-7.71(m,2 H),8.75(d,J=1.77Hz,1 H),9.07(d,J=1.77Hz,1 H),9.37(t,J=5.94Hz,1 H);ESI-MS m/z[M+H]+ 311.2。
向於乙腈(2323μL)中之3-氯-5-氰基-N-(4-氰基-2-甲基苄基)吡啶醯胺
(379mg,1.220mmol)中添加0.5M的甲醇鈉(2439μL,1.220mmol)之甲醇溶液。在50℃下將所得溶液攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用20-45%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(144mg,38.5%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.36(s,3 H),3.91(s,3 H),4.48(d,J=5.81 Hz,2 H),7.48(d,J=7.83Hz,1 H),7.65-7.72(m,2 H),8.17(d,J=1.52Hz,1 H),8.63(d,J=1.52Hz,1 H),9.11(t,J=6.06Hz,1 H);ESI-MS m/z(M+H)+ 307.3。
在85℃下將6-甲基菸鹼甲腈(500mg,4.23mmol)、N-溴琥珀醯亞胺(791mg,4.44mmol)、及AIBN(208mg,1.270mmol)於CCl4(5mL)中之漿液加熱20小時。將混合物在真空中濃縮,且將殘餘物藉由矽膠急驟管柱層析法(40g SiO2),用0-40%於己烷中之EtOAc之梯度溶離進行純化,以得到呈淡紅色油狀物之標題化合物(441mg,52.9%)。1H NMR(400MHz,CDCl3)δ ppm 4.58(s,2 H),7.60(dd,J=8.1,0.8Hz,1 H),7.99(dd,J=8.1,2.0Hz,1 H),8.82-8.88(m,1 H);ESI-MS m/z[M+H]+ 197,199。
在0℃下將N,N-(雙-三級丁氧羰基)胺(582mg,2.68mmol)之THF(8mL)溶液添加至NaH(125mg,3.13mmol)中。接著在0℃下添加於THF(8mL)中之6-(溴甲基)菸鹼甲腈(440mg,2.233mmol),且使溶液升溫至25℃。在此溫度下將反應混合物16小時,然後在真空中濃縮。將殘餘物溶解於EtOAc(100mL)
中,用飽和(aq)氯化銨(100mL)及鹽水洗滌,經MgSO2乾燥,且在真空中濃縮。將粗物質藉由矽膠急驟管柱層析法(40g SiO2),用0-40%於己烷中之EtOAc之梯度溶離進行純化,以得到呈淡黃色固體之標題化合物(415mg,55.7%)。1H NMR(400MHz,CDCl3)δ ppm 1.47(s,18 H),4.99(s,2 H),7.32(dd,J=8.2,0.6Hz,1 H),7.93(dd,J=8.2,2.1Hz,1 H),8.82(dd,J=2.0,0.8Hz,1 H);ESI-MS m/z[M+H]+ 334。
向6-(N,N-(雙-三級丁氧羰基)胺甲基)菸鹼甲腈(410mg,1.230mmol)之DCM(8mL)溶液中添加4M於二噁烷中之HCl(1.0mL,4.00mmol)。在20℃下將溶液攪拌19小時,之後再添加一份4M於二噁烷中之HCl(0.5mL)。將反應混合物攪拌3天,然後在真空中濃縮,以得到呈黃色固體之標題化合物之HCl鹽(215mg),其未經進一步純化即使用。1H NMR(400MHz,DMSO-d 6)δ ppm 4.33(q,J=5.8Hz,2 H),7.74(d,J=8.1Hz,1 H),8.42(dd,J=8.2,2.1Hz,1 H),8.57(br s,3 H),9.12(dd,J=2.0,0.8Hz,1 H);ESI-MS m/z[M+H]+ 134。
向配備有攪拌子之螺旋蓋小瓶中添加3-溴-5-氯吡啶甲酸(236mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(176mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(139μL,1.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3,5-二甲基苯甲腈(160mg,1.000mmol)。在室溫下將反應混合物攪拌隔夜,然後在60℃下加熱1小時,且過濾。將濾液
藉由製備型HPLC,用40-65%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(171mg,45.2%)。ESI-MS m/z[M+H]+ 378.0。
向3-溴-5-氯-N-(4-氰基-2,6-二甲基苄基)吡啶醯胺(133mg,0.351mmol)於甲醇(1405μL)中之混合物中添加0.5M的甲醇鈉(702μL,0.351mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜。連續兩天,添加額外的於甲醇(0.5M)中之甲醇鈉(702μL,0.351mmol)。每次添加之後,在50℃下將反應混合物攪拌隔夜。最後一次隔夜反應之後,將反應混合物與單獨的製劑組合且過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(77mg,67%)。ESI-MS m/z[M+H]+ 330.1。
向配備有攪拌子之螺旋蓋小瓶中添加3-氯-5-氰基吡啶甲酸(183mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(204mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3,5-二甲基苯甲腈(160mg,1.00mmol)。在室溫下將反應物攪拌72小時,然後過濾。將濾液藉由製備型HPLC,用40-65%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(75mg,23%)。ESI-MS m/z[M+H]+ 325.0。
向3-氯-5-氰基-N-(4-氰基-2,6-二甲基苄基)吡啶醯胺(75mg,0.231mmol)於甲醇(924μL)中之混合物中添加0.5M的甲醇鈉(462μL,0.231mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜。連續兩天,添加額外的於甲醇(0.5M)中之甲醇鈉(462μL,0.231mmol)。每次添加之後,在50℃下將反應混合物攪拌隔夜。第三次隔夜反應之後,將反應混合物過濾。將濾液藉由製備型HPLC,用20-45%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(12mg,16%)。ESI-MS m/z[M+H]+ 321.2。
向配備有攪拌子之螺旋蓋小瓶中添加3,5-二氟吡啶甲酸(159mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(204mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(139μL,1.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3,5-二甲基苯甲腈(160mg,1.00mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(196mg,65.1%)。ESI-MS m/z[M+H]+ 302.2。
向N-(4-氰基-2,6-二甲基苄基)-3,5-二氟吡啶醯胺(196mg,0.651mmol)於乙腈(1239μL)中之混合物中添加0.5M的甲醇鈉(1301μL,0.651mmol)之甲醇溶液。在室溫下將反應混合物攪拌2小時,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之N-(4-氰基-2,6-二甲基苄基)-5-氟-3-甲氧基吡啶醯胺(94mg,46%),ESI-MS m/z[M+H]+ 314.2;以及呈灰白色固體之N-(4-氰基-2,6-二甲基苄基)-3-氟-5-甲氧基吡啶醯胺(49mg,24%),ESI-MS m/z[M+H]+ 314.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-氯-5-(三氟甲基)吡啶甲酸(226mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(204mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3,5-二甲基苯甲腈鹽酸鹽(256mg,1.300mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用40-65%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(81mg,22%)。ESI-MS m/z[M+H]+ 368.1。
向3-氯-N-(4-氰基-2,6-二甲基苄基)-5-(三氟甲基)吡啶醯胺(81mg,
0.220mmol)於乙腈(420μL)中之混合物中添加0.5M的甲醇鈉(1322μL,0.661mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(54mg,68%)。ESI-MS m/z[M+H]+ 364.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-氟-5-甲氧基吡啶甲酸(171mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(204mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3,5-二甲基苯甲腈鹽酸鹽(256mg,1.30mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(114mg,36.4%)。ESI-MS m/z[M+H]+ 314.2。
向N-(4-氰基-2,6-二甲基苄基)-3-氟-5-甲氧基吡啶醯胺(114mg,0.364mmol)於乙腈(693μL)中之混合物中添加0.5M的甲醇鈉(2183μL,1.092mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(104mg,88%)。ESI-MS m/z[M+H]+ 326.2。
向配備有攪拌子之螺旋蓋小瓶中添加3,5-二氟吡啶甲酸(159mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(176mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加(R)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽(253mg,1.300mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(97mg,32%)。ESI-MS m/z[M+H]+ 300.0。
向(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3,5-二氟吡啶醯胺(97mg,0.324mmol)於乙腈(617μL)中之混合物中添加0.5M的甲醇鈉(648μL,0.324mmol)之甲醇溶液。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(51mg,51%)。ESI-MS m/z[M+H]+ 312.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-溴-5-氯吡啶甲酸(236mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(176mg,1.30mmol)、EDC鹽酸鹽(249mg,1.30mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加(R)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽(253mg,1.300
mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(73mg,19%)。ESI-MS m/z[M+H]+ 376.1。
向(R)-3-溴-5-氯-N-(5-氰基-2,3-二氫-1H-茚-1-基)吡啶醯胺(73mg,0.194mmol)於乙腈(369μL)中之混合物中添加0.5M的甲醇鈉(1163μL,0.581mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(34mg,54%)。ESI-MS m/z[M+H]+ 328.1。
向配備有攪拌子之螺旋蓋小瓶中添加3-氯-5-(三氟甲基)吡啶甲酸(226mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(176mg,1.30mmol)、EDC鹽酸鹽(249mg,1.30mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加(R)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽(253mg,1.30mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(102mg,27.9%)。ESI-MS m/z[M+H]+ 366.0。
向(R)-3-氯-N-(5-氰基-2,3-二氫-1H-茚-1-基)-5-(三氟甲基)吡啶醯胺(102mg,0.279mmol)於乙腈(531μL)中之混合物中添加0.5的甲醇鈉(1673μL,0.837mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(68mg,68%)。ESI-MS m/z[M+H]+ 362.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-氟-5-甲氧基吡啶甲酸(171mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(176mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加(R)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽(253mg,1.300mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(152mg,48.8%)。ESI-MS m/z[M+H]+ 312.2。
向(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-氟-5-甲氧基吡啶醯胺(152mg,0.488mmol)於乙腈(930μL)中之混合物中添加0.5M的甲醇鈉(2930μL,1.465mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用20-45%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(97mg,61%)。ESI-MS m/z[M+H]+ 324.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-氯-5-氰基吡啶甲酸(183mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(176mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加(R)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽(253mg,1.300mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(68mg,21%)。ESI-MS m/z[M+H]+ 323.0。
向(R)-3-氯-5-氰基-N-(5-氰基-2,3-二氫-1H-茚-1-基)吡啶醯胺(68mg,0.211mmol)於乙腈(401μL)中之混合物中添加0.5M的甲醇鈉(1264μL,0.632mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(8mg,12%)。ESI-MS m/z[M+H]+ 319.2。
向配備有攪拌子之螺旋蓋小瓶中添加3,5-二氟吡啶甲酸(159mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(204mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合
物攪拌5分鐘。接著添加4-(胺甲基)-3-甲基苯甲腈鹽酸鹽(237mg,1.300mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(76mg,027%)。ESI-MS m/z[M+H]+ 288.1。
向N-(4-氰基-2-甲基苄基)-3,5-二氟吡啶醯胺(76mg,0.265mmol)於乙腈(504μL)中之混合物中添加0.5M的甲醇鈉(529μL,0.265mmol)之甲醇溶液。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(20mg,25%)。ESI-MS m/z[M+H]+ 300.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-溴-5-氯吡啶甲酸(236mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(204mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3-甲基苯甲腈鹽酸鹽(237mg,1.300mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用40-65%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(86mg,24%)。ESI-MS m/z[M+H]+ 364.0。
向3-溴-5-氯-N-(4-氰基-2-甲基苄基)吡啶醯胺(86mg,0.236mmol)於乙腈(449μL)中之混合物中添加0.5M的甲醇鈉(1415μL,0.708mmol)之甲醇溶液。在室溫下將反應混合物攪拌2小時,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(44mg,59%)。ESI-MS m/z[M+H]+ 316.1。
向配備有攪拌子之螺旋蓋小瓶中添加3-氯-5-(三氟甲基)吡啶甲酸(226mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(204mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3-甲基苯甲腈鹽酸鹽(237mg,1.300mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用40-65%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(72mg,20%)。ESI-MS m/z[M+H]+ 354.1。
向3-氯-N-(4-氰基-2-甲基苄基)-5-(三氟甲基)吡啶醯胺(72mg,0.204mmol)於乙腈(388μL)中之混合物中添加0.5M的甲醇鈉(1221μL,0.611mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型
HPLC,用25-50%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(51mg,72%)。ESI-MS m/z[M+H]+ 350.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-氟-5-甲氧基吡啶甲酸(171mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(204mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3-甲基苯甲腈鹽酸鹽(237mg,1.300mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用25-50%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(136mg,45.4%)。ESI-MS m/z[M+H]+ 300.2。
向N-(4-氰基-2-甲基苄基)-3-氟-5-甲氧基吡啶醯胺(136mg,0.454mmol)於乙腈(866μL)中之混合物中添加0.5M的甲醇鈉(2726μL,1.363mmol)之甲醇溶液。在50℃下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(67mg,47%)。ESI-MS m/z[M+H]+ 312.2。
將60%的氫化鈉於礦物油(3.40g,85mmol)中之分散液於THF(100mL)中成漿液,且冷卻至0℃。以一速率向漿液中添加苯甲醇(8.44mL,81mmol),該速率確保內部溫度不超過5℃。NaH添加完成之後,將溫度升溫至20℃,且攪拌反應混合物直至觀察不到明顯的放氣。將反應混合物緩慢添加至5-溴-3-硝基2-氰吡啶(16.15g,70.8mmol)之THF(125mL)溶液中,同時保持內部溫度低於30℃。腈添加完成之後,使反應混合物在20℃下攪拌30分鐘,且隨後在水(300mL)與乙酸異丙酯(300mL)之間分配。將有機層分離,且用乙酸異丙酯(2×150mL)萃取水相。將有機層合併,用飽和NaCl(aq)(250mL)洗滌,經Na2SO4乾燥,過濾,且在真空中濃縮,以得到紅色固體。在80℃下將紅色固體溶解於乙酸異丙酯(110mL)中,且冷卻至52℃。添加庚烷(51mL),且將溶液在52℃下攪拌1小時,然後加熱至90℃。形成懸浮液,將其冷卻至10℃。將固體過濾,用50%於IPAc中之庚烷洗滌,且在真空下乾燥,以得到標題化合物(13.5g,66%)。1H NMR(400MHz,CDCl3)δ ppm 8.37(d,J=1.77Hz,1 H),7.57(d,J=1.77Hz,1 H),7.37-7.49(m,5 H),5.26(s,2 H);ESI-MS m/z[M+H]+ 289.1(79Br)。
在回流(84℃浴)下將3-(苄氧基)-5-溴2-氰吡啶(13.4g,46.3mmol)、乙醇(75mL)、水(50mL)、及50% w/w NaOH(aq)(23.32mL,440mmol)之懸浮液攪拌4小時,然後使其冷卻。在減壓下移除乙醇。將所得懸浮液用水(150mL)稀釋且用6M HCl(aq)酸化直至所有固體均溶解。將溶液用乙酸異丙酯(1×100
mL)洗滌且用6M HCl(aq)進一步酸化至約pH 4,然後形成固體。劇烈攪拌混合物,得到細粒懸浮液。將固體過濾,用水洗滌,且在60℃下於真空烘箱中乾燥,以得到呈灰白色固體之標題化合物(13.1g,91%)。1H NMR(400MHz,DMSO-d 6)δ ppm 5.30(s,2 H),7.33-7.54(m,5 H),8.03(d,J=1.77Hz,1 H),8.32(d,J=1.77Hz,1 H),13.37(br s,1 H);ESI-MS m/z[M+H]+ 308.1(79Br)。
將3-(苄氧基)-5-溴吡啶甲酸(12.4g,40.2mmol)、NMP(120mL)、4-(胺甲基)-3,5-二甲基苯甲腈鹽酸鹽(9.50g,48.3mmol)、及DIPEA(35.0mL,201mmol)之混合物攪拌30分鐘,且用50wt%的2,4,6-三丙基-1,3,5,2,4,6-三氧三磷雜環己烷-2,4,6-三氧化物之EtOAc(2.00mL,3.36mmol)溶液處理。將反應混合物攪拌1小時且緩慢添加至水(840mL)中。形成固體,且將懸浮液攪拌1小時。將固體過濾,用水洗滌,且在60℃下於真空烘箱中乾燥16小時,以得到標題化合物(16.94g,93%)。1H NMR(400MHz,CDCl3)δ ppm 8.31(d,J=1.77Hz,1 H),7.60(d,J=1.77Hz,1 H),7.52(br s,1 H),7.36-7.46(m,5 H),7.31(s,2H),5.19(s,2 H),4.66(d,J=5.05Hz,2 H),2.36(s,6 H);ESI-MS m/z[M+H]+ 450.1(79Br)。
向配備有攪拌子之40mL螺旋蓋小瓶中裝填3-羥基吡啶甲酸(100mg,0.719mmol)、1H-苯并[d][1,2,3]三唑-1-醇(126mg,0.935mmol)、EDC鹽酸鹽(179mg,0.935mmol)、DMF(3594μL)、及Et3N(301μL,2.157mmol)。在室溫下將混濁的反應混合物攪拌5分鐘。接著添加4-(胺甲基)苯甲腈(105mg,0.791mmol),且在室溫下將反應混合物攪拌14小時。隨後將混濁的溶液用水(1mL)及DMSO(1mL)稀釋,然後藉由製備型HPLC(SunFireTM C18,5μm,ID 30mm×75mm),
用15-40%於H2O(具有0.05% TFA)中之ACN(具有0.035% TFA)之梯度溶離進行純化。將產物流份合併且凍乾,以得到呈白色固體之標題化合物(61.1mg,33.6%)。1H NMR(400MHz,DMSO-d 6)δ ppm 4.57(d,J=6.57Hz,2 H),7.43(dd,J=8.46,1.39Hz,1 H),7.50-7.57(m,3 H),7.80(d,J=7.78Hz,2 H),8.19(dd,J=4.29,1.26Hz,1 H),9.88(t,J=6.32Hz,1 H),12.36(br s,1 H);ESI-MS m/z[M+H]+ 254.1。
以類似於實例1之方式,使用3-(胺甲基)苯甲腈代替4-(胺甲基)苯甲腈製備標題化合物。1H NMR(400MHz,DMSO-d 6)δ ppm 4.55(d,J=6.57Hz,2 H)7.43(d,J=8.57Hz,1 H)7.52-7.58(m,2 H)7.69(d,J=8.08Hz,1 H)7.74(d,J=7.83Hz,1 H)7.79(s,1 H)8.18(dd,J=4.29,1.26Hz,1 H)9.84(t,J=6.32Hz,1 H)12.37(br s,1 H);ESI-MS m/z[M+H]+ 254.1。
將3-羥基吡啶甲酸(127mg,0.913mmol)、5-(胺甲基)2-氰吡啶(122mg,0.913mmol)、及HBTU(346mg,0.913mmol)於DCM(3mL)中之懸浮液用Et3N(0.449mL,3.10mmol)處理。將混合物在50℃下加熱隔夜,然後用DCM稀釋,接連用1N鹽水及水洗滌,經Na2SO4乾燥,且濃縮。將殘餘物使用矽膠急驟管柱層析法(12g SiO2),用0-10%於DCM中之MeOH之梯度溶離進行純化。將含有產物之流份在真空中濃縮,且藉由HPLC,使用45-70%於H2O(具有0.05% TFA)中之ACN(具有0.035% TFA)溶離進行純化,以得到呈橙黃色固體之標題化合物(12.6mg,5.4%)。1H NMR(400MHz,CD3OD)δ ppm 4.85(s,2 H),7.47(dd,J=8.59,
1.52Hz,1 H),7.52-7.57(m,1 H),7.66(dd,J=8.08,4.80Hz,1 H),8.00-8.06(m,1 H),8.19(dd,J=4.55,1.52Hz,1 H),8.62(dd,J=4.80,1.52Hz,1 H);ESI-MS m/z[M+H]+ 255.1。
向配備有攪拌子之40mL螺旋蓋小瓶中添加3-羥基吡啶甲酸(100mg,0.719mmol)、1H-苯并[d][1,2,3]三唑-1-醇(126mg,0.935mmol)、EDC鹽酸鹽(179mg,0.935mmol)、DMF(3594μL)、及Et3N(200μL,1.438mmol)。在室溫下將混濁的反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3-甲基苯甲腈鹽酸鹽(131mg,0.719mmol)。在室溫下將反應物混合攪拌隔夜,然後用水(2mL)及乙醇(2mL)稀釋並用1N HCl酸化至pH 5。收集沈澱物,用水洗滌,且乾燥,以得到呈白色固體之標題化合物(105.8mg,55.1%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.38(s,3 H),4.54(d,J=6.32Hz,2 H),7.39(d,J=7.69Hz,1 H),7.44(dd,J=8.59,1.26Hz,1 H),7.56(dd,J=8.46,4.42Hz,1 H),7.60-7.65(m,1 H),7.65-7.69(m,1 H),8.20(dd,J=4.29,1.26Hz,1 H),9.69-9.90(m,1 H),12.35(s,1 H);ESI-MS m/z[M+H]+ 268.1。
以類似於實例1之方式,使用4-(胺甲基)-3-氟苯甲腈代替4-(胺甲基)苯甲腈製備標題化合物。1H NMR(400MHz,DMSO-d 6)δ ppm 4.62(d,J=6.32Hz,2 H),7.46(dd,J=8.46,1.39Hz,1 H),7.53-7.60(m,2 H),7.69(dd,J=8.08,1.52Hz,1 H),7.87(dd,J=10.11,1.52Hz,1 H),8.21(dd,J=4.42,1.39Hz,1 H),9.79-9.90(m,1
H),12.26(br s,1 H);ESI-MS m/z[M+H]+ 272.1。
以類似於實例4之方式,使用4-(胺甲基)-2-氟苯甲腈鹽酸鹽代替4-(胺甲基)-3-甲基苯甲腈鹽酸鹽製備標題化合物。1H NMR(400MHz,DMSO-d 6)δ ppm 4.59(d,J=6.32Hz,2 H),7.32-7.39(m,1 H),7.40-7.50(m,2 H),7.56(dd,J=8.59,4.29Hz,1 H),7.89(dd,J=7.83,7.07Hz,1 H),8.19(dd,J=4.29,1.26Hz,1 H),9.89(t,J=6.32Hz,1 H),12.29(br s,1 H);ESI-MS m/z[M+H]+ 272.1。
以類似於實例4之方式,使用4-(胺甲基)-3-(三氟甲基)苯甲腈代替4-(胺甲基)-3-甲基苯甲腈鹽酸鹽製備標題化合物。1H NMR(400MHz,DMSO-d 6)δ ppm 4.74(d,J=6.32Hz,2 H),7.46(dd,J=8.46,1.39Hz,1 H),7.59(dd,J=8.46,4.42Hz,1 H),7.68(d,J=8.08Hz,1 H),8.12(d,J=8.25Hz,1 H),8.23(dd,J=4.42,1.39Hz,1 H),8.29(s,1 H),9.93(t,J=6.19Hz,1 H),12.14(br s,1 H);ESI-MS m/z[M+H]+ 322.1。
向裝填有3-(苄氧基)-N-(4-氰基-2-甲基苄基)-5-(4-乙基哌嗪-1-羰基)吡啶醯胺(24mg,0.048mmol)及攪拌子之40mL螺旋蓋小瓶中添加甲酸(1mL,
26.1mmol)。在100℃下將反應混合物攪拌3小時,然後在真空中濃縮。將所得殘餘物用MeOH(2mL)稀釋,且藉由製備型HPLC(SunFireTM C18,5μm,ID 30mm×75mm),用15-40%於H2O(具有0.05% TFA)中之ACN(具有0.035% TFA)之梯度溶離進行純化。將所要流份合併且在真空下乾燥,以得到呈淡棕色玻璃狀物之標題化合物之TFA鹽(9.4mg,47.8%)。1H NMR(400MHz,CD3OD)δ ppm 1.27(t,J=7.33Hz,3 H),2.34(s,3 H),2.92-3.18(m,4 H),3.88(s,6 H),4.56(s,2 H),7.32-7.48(m,4 H),8.08-8.20(m,1 H);ESI-MS m/z[M+H]+ 408.3。
以類似於實例8之方式,使用(R)-3-(苄氧基)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-5-(4-乙基哌嗪-1-羰基)吡啶醯胺代替3-(苄氧基)-N-(4-氰基-2-甲基苄基)-5-(4-乙基哌嗪-1-羰基)吡啶醯胺製備標題化合物之TFA鹽。1H NMR(400MHz,CD3OD)δ ppm 1.42(t,J=7.33Hz,3 H),2.14-2.27(m,1 H),2.63-2.75(m,1 H),2.96-3.28(m,4 H),3.28-3.33(m,2 H),3.38-4.20(m,5 H),4.51-4.92(m,1 H),5.75(br t,J=8.08Hz,1 H),7.47(d,J=7.83Hz,1 H),7.54(s,1 H),7.61(d,J=7.58Hz,1 H),7.69(s,1 H),8.20-8.28(m,1 H);ESI-MS m/z[M+H]+ 420.3。
向配備有攪拌子之40mL螺旋蓋小瓶中添加3-羥基吡啶甲酸(100mg,
0.719mmol)、EDC鹽酸鹽(179mg,0.935mmol)、HOBt(143mg,0.935mmol)、DMF(3594μL)、及Et3N(301μL,2.157mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加4-(胺甲基)-3,5-二甲基苯甲腈鹽酸鹽(170mg,0.863mmol)。將反應混合物在室溫下攪拌隔夜,然後透過針筒過濾器過濾,且藉由製備型HPLC(SunFireTM C18,5μm,ID 30mm×75mm),用15-40%於H2O(具有0.05% TFA)中之ACN(具有0.035% TFA)之梯度溶離進行純化。將所要流份合併且凍乾,以得到呈白色固體之標題化合物(100mg,49.5%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.43(s,6 H),4.57(d,J=5.81Hz,2 H),7.41(dd,J=8.59,1.26Hz,1 H),7.52(br d,J=4.29Hz,1 H),8.06-8.20(m,1 H),9.32(br s,1 H),12.37(s,1 H);[M+H]+ 282.1。
以類似於實例10之方式,使用3-羥基-5-甲基吡啶甲酸代替3-羥基吡啶甲酸製備標題化合物。1H NMR(400MHz,DMSO-d 6)δ ppm 2.43(s,6 H),4.57(d,J=5.81Hz,2 H),7.41(dd,J=8.59,1.26Hz,1 H),7.48-7.51(m,2 H),7.52(br d,J=4.29Hz,1 H),8.06-8.20(m,1 H),9.32(br s,1 H),12.27-12.44(m,1 H);ESI-MS m/z[M+H]+ 296.1。
向配備有攪拌子之20mL螺旋蓋小瓶中添加3-羥基吡啶甲酸(50mg,0.359mmol)、HOBt(71.6mg,0.467mmol)、EDC鹽酸鹽(90mg,0.467mmol)、DMF(3594μL)、及Et3N(200μL,1.438mmol)。在室溫下將混濁的反應混合物
攪拌5分鐘。接著添加4-(胺甲基)-2,5-二甲基苯甲腈鹽酸鹽(92mg,0.467mmol)。將反應混合物在室溫下攪拌48小時,然後用DMSO(1mL)稀釋,且藉由製備型HPLC(SunFireTM C18,5μm,ID 30mm×75mm),用15-40%於H2O(具有0.05% TFA)中之ACN(具有0.035% TFA)之梯度溶離進行純化。將所要流份合併且凍乾,以得到呈白色固體之標題化合物(6.5mg,6.4%)。1H(400MHz,CD3OD)δ ppm 2.38(s,3 H),2.45(s,3 H),4.62(s,2 H),7.31(s,1 H),7.33-7.39(m,1 H),7.47(s,2 H),8.14(dd,J=4.29,1.26Hz,1 H);ESI-MS m/z[M+H]+ 282.1。
以類似於實例12之方式,使用4-(胺甲基)-2-氟-5-甲基苯甲腈鹽酸鹽代替4-(胺甲基)-2,5-二甲基苯甲腈鹽酸鹽製備標題化合物。1H(400MHz,CD3OD)δ ppm 2.35-2.45(m,3 H),4.57-4.67(m,2 H),7.22(d,J=10.36Hz,1 H),7.36(dd,J=8.59,1.26Hz,1 H),7.46(dd,J=8.59,4.29Hz,1 H),7.56(d,J=6.57Hz,1 H),8.15(dd,J=4.29,1.26Hz,1 H);ESI-MS m/z[M+H]+ 286.1。
以類似於實例12之方式,使用4-(胺甲基)-2-氟-3-甲基苯甲腈鹽酸鹽代替4-(胺甲基)-2,5-二甲基苯甲腈鹽酸鹽製備標題化合物。1H(400MHz,CD3OD)δ ppm 2.35(d,J=2.02Hz,3 H),4.63-4.70(m,2 H),7.29(d,J=8.08Hz,1 H),7.32-7.38(m,1 H),7.44(d,J=4.29Hz,1 H),7.54(s,1 H),8.14(dd,J=4.29,1.26Hz,1 H);ESI-MS m/z[M+H]+ 286.1。
以類似於實例12之方式,使用4-(胺甲基)-3-氯苯甲腈鹽酸鹽代替4-(胺甲基)-2,5-二甲基苯甲腈鹽酸鹽製備標題化合物。1H(400MHz,CD3OD)δ ppm 4.74(s,2 H),7.37(d,J=8.34Hz,1 H),7.47(dd,J=8.46,4.42Hz,1 H),7.55(d,J=8.08Hz,1 H),7.66(dd,J=8.08,1.52Hz,1 H),7.84(d,J=1.52Hz,1 H),8.15(d,J=3.79Hz,1 H);ESI-MS m/z[M+H]+ 288.1。
將5-氰基-N-(4-氰基苄基)-3-甲氧基吡啶醯胺(17mg,0.058mmol)及氯化鋰(24.66mg,0.582mmol)於DMA(909μL)中之混合物在室溫下攪拌1小時,然後在60℃下攪拌隔夜。隨後添加額外的氯化鋰(24.66mg,0.582mmol)及DMA(909μL),且將反應混合物在60℃下攪拌72小時,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(5.39mg,33.3%)。1H NMR(400MHz,DMSO-d 6)δ ppm 4.58(d,J=6.06Hz,2 H),7.52(d,J=8.34Hz,2 H),7.80(d,J=8.08Hz,2 H),8.04(s,1 H),8.58(br s,1 H),10.16(br s,1 H),12.64(br s,1 H);ESI-MS m/z[M+H]+ 279.3。
將5-氰基-N-(4-氰基-2-甲基苄基)-3-甲氧基吡啶醯胺(139mg,0.454mmol)及氯化鋰(385mg,9.08mmol)於DMA(7090μL)中之混合物在60℃下攪拌
隔夜。添加額外的氯化鋰(385mg,9.08mmol),且將反應混合物在65℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(42mg,31.7%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.38(s,3 H),4.54(d,J=6.06Hz,2 H),7.40(d,J=8.08Hz,1 H),7.62(dd,J=7.83,1.26Hz,1 H),7.67(d,J=1.01Hz,1 H),8.07(d,J=1.52Hz,1 H),8.61(d,J=1.77Hz,1 H),10.02(t,J=6.19Hz,1 H),12.63(s,1 H);ESI-MS m/z[M+H]+ 293.3。
向配備有攪拌子之螺旋蓋小瓶中添加3-羥基吡啶甲酸(83mg,0.6mmol)、1H-苯并[d][1,2,3]三唑-1-醇(105mg,0.780mmol)、EDC鹽酸鹽(150mg,0.780mmol)、DMF(3000μL)、及Et3N(251μL,1.800mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加5-胺基-5,6,7,8-四氫萘-2-腈鹽酸鹽(125mg,0.600mmol)。在室溫下將反應混合物攪拌48小時,然後過濾。將濾液藉由製備型HPLC,用45-70%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(10.4mg,5.91%)。1H NMR(400MHz,DMSO-d 6)δ ppm 1.74-1.84(m,1 H),1.91-1.99(m,1 H),1.99-2.05(m,2 H),2.77-2.85(m,2 H),5.25(q,J=7.75Hz,1 H),7.34(d,J=8.34Hz,1 H),7.41-7.47(m,1 H),7.51-7.59(m,2 H),7.62(s,1 H),8.15(dd,J=4.29,1.26Hz,1 H),9.50(d,J=9.09Hz,1 H),12.46(br s,1 H);ESI-MS m/z[M+H]+ 294.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-羥基吡啶甲酸(41.7mg,0.3mmol)、1H-苯并[d][1,2,3]三唑-1-醇(52.7mg,0.390mmol)、EDC鹽酸鹽(74.8mg,0.390mmol)、DMF(1500μL)、及Et3N(125μL,0.900mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加(R)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽(58.4mg,0.300mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(4.37mg,5.22%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.22-2.29(m,1 H),2.41-2.46(m,1 H),2.88-2.95(m,1 H),3.03-3.10(m,1 H),5.56-5.64(m,1 H),7.37-7.41(m,1 H),7.42-7.47(m,1 H),7.51-7.57(m,1 H),7.61-7.66(m,1 H),7.73-7.77(m,1 H),8.14-8.18(m,1 H),9.52-9.61(m,1 H),12.42-12.50(m,1 H);ESI-MS m/z[M+H]+ 280.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-羥基吡啶甲酸(278mg,2.00mmol)、1H-苯并[d][1,2,3]三唑-1-醇(351mg,2.60mmol)、EDC鹽酸鹽(498mg,2.60mmol)、DMF(10mL)、及Et3N(836μL,6.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加(R)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽(389mg,2mmol)。在室溫下將反應物混合攪拌96小時,然後用水(5.6mL)及乙醇(5.6mL)稀釋,用1N HCl酸化至pH 5,且過濾。將固體及濾液合併,溶解於DMF中,且藉由製備型HPLC,用15%於水(鹼性條件)中之ACN溶離進行純化,以得到呈灰白色固體之標題化合物(59mg,11%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.24(dq,J=12.38,8.93Hz,1 H),2.39-2.48(m,1 H),2.86-2.95(m,1 H),3.02-3.11(m,1 H),5.60(q,J=8.51Hz,1 H),7.36-7.45(m,2 H),7.52(dd,J=8.59,4.29Hz,1 H),7.63(d,
J=7.83Hz,1 H),7.74(s,1 H),8.13(dd,J=4.29,1.01Hz,1 H),9.65(d,J=8.34Hz,1 H),12.08-12.80(m,1 H);ESI-MS m/z[M+H]+ 280.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-羥基吡啶甲酸(139mg,1mmol)、1H-苯并[d][1,2,3]三唑-1-醇(176mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加(S)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽(195mg,1.000mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用45-70%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(52mg,19%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.20-2.30(m,1 H),2.42-2.48(m,1 H),2.91(dt,J=16.42,8.46Hz,1 H),3.03-3.11(m,1 H),5.60(d,J=8.34Hz,1 H),7.39(d,J=7.83Hz,1 H),7.44(dd,J=8.46,1.39Hz,1 H),7.51-7.57(m,1 H),7.63(d,J=7.83Hz,1 H),7.75(s,1 H),8.15(dd,J=4.29,1.26Hz,1 H),9.58(d,J=8.59Hz,1 H),12.46(br s,1 H);ESI-MS m/z[M+H]+ 280.2。
向配備有攪拌子之螺旋蓋小瓶中添加3-羥基吡啶甲酸(139mg,1.000mmol)、1H-苯并[d][1,2,3]三唑-1-醇(176mg,1.300mmol)、EDC鹽酸鹽(249mg,1.300mmol)、DMF(5mL)、及Et3N(418μL,3.00mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加3-胺基-2,3-二氫苯并呋喃-6-腈(160mg,1mmol)。在室溫下將反應混合物攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用35-60%
於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(23mg,8.2%)。1H NMR(400MHz,DMSO-d 6)δ ppm 4.63(dd,J=9.60,5.81Hz,1 H),4.83(t,J=9.47Hz,1 H),5.85-5.94(m,1 H),7.29-7.38(m,2 H),7.39-7.45(m,1 H),7.46-7.57(m,2 H),8.14(dd,J=4.04,1.01Hz,1 H),9.86(d,J=7.07Hz,1 H),12.12(br s,1 H);ESI-MS m/z[M+H]+ 282.0。
向配備有攪拌子之螺旋蓋小瓶中添加3-羥基-5-甲基吡啶甲酸氫溴酸鹽(74.9mg,0.320mmol)、1H-苯并[d][1,2,3]三唑-1-醇(65.4mg,0.416mmol)、EDC鹽酸鹽(80mg,0.416mmol)、DMF(1.6mL)、及Et3N(178μL,1.280mmol)。在室溫下將反應混合物攪拌5分鐘。接著添加(R)-1-胺基-2,3-二氫-1H-茚-5-腈鹽酸鹽(62.3mg,0.32mmol)。在室溫下將反應混合物攪拌72小時,然後過濾。將濾液藉由製備型HPLC,用45-70%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(8mg,9%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.21-2.28(m,1 H),2.33(s,3 H),2.40-2.45(m,1 H),2.86-2.95(m,1 H),3.02-3.10(m,1 H),5.59(q,J=8.42Hz,1 H),7.27(dd,J=1.64,0.88Hz,1 H),7.37(d,J=7.83Hz,1 H),7.63(d,J=8.84Hz,1 H),7.74(s,1 H),8.01(d,J=1.26Hz,1 H),9.48(d,J=8.59Hz,1 H),12.39(s,1 H);ESI-MS m/z[M+H]+ 294.1。
在150℃下將6-(胺甲基)菸鹼甲腈鹽酸鹽(62.0mg,0.366mmol)、3-羥基吡啶甲酸甲酯(40mg,0.261mmol)、及DIPEA(0.091mL,0.522mmol)於
2-甲氧基乙-1-醇(0.8mL)中之混合物於密封小瓶中加熱19小時。隨後將反應混合物藉由製備型HPLC,用乙腈及水(具有NH4HCO3)溶離進行純化,以得到呈淡黃色固體之標題化合物(19mg,28.6%)。1H NMR(400MHz,DMSO-d 6)δ ppm 4.64(d,J=6.3Hz,2 H),7.38(dd,J=8.5,1.4Hz,1 H),7.46-7.53(m,2 H),8.14(dd,J=4.4,1.4Hz,1 H),8.20(dd,J=8.2,2.1Hz,1 H),8.92(dd,J=2.0,0.8Hz,1 H),9.74(t,J=6.1Hz,1 H),12.22(s,1 H);ESI-MS m/z[M+H]+ 255。
將5-氯-N-(4-氰基-2,6-二甲基苄基)-3-甲氧基吡啶醯胺(77mg,0.233mmol)及氯化鋰(198mg,4.67mmol)於DMA(3648μL)中之混合物在60℃下攪拌隔夜,然後在80℃下攪拌隔夜,且過濾。將濾液藉由製備型HPLC,用55-80%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(28mg,38%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.42(s,6 H),4.56(d,J=5.56Hz,2 H),7.50(s,2 H),7.65(d,J=2.02Hz,1 H),8.16(d,J=2.02Hz,1 H),9.41(t,J=5.31Hz,1 H),12.63(s,1 H):ESI-MS m/z[M+H]+ 316.0。
將5-氰基-N-(4-氰基-2,6-二甲基苄基)-3-甲氧基吡啶醯胺(12mg,0.037mmol)及氯化鋰(31.8mg,0.749mmol)於DMA(585μL)中之混合物在60℃下攪拌隔夜,且在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用40-65%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(1.3mg,11%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.42(s,6 H),4.57
(d,J=5.31Hz,2 H),7.50(s,2 H),8.03(d,J=1.77Hz,1 H),8.54(d,J=1.77Hz,1 H),9.60(t,J=5.18Hz,1 H),12.64(s,1 H);ESI-MS m/z[M+H]+ 307.0。
將N-(4-氰基-2,6-二甲基苄基)-5-氟-3-甲氧基吡啶醯胺(94mg,0.300mmol)及氯化鋰(254mg,6.00mmol)於DMA(4688μL)中之混合物在60℃下攪拌隔夜,且在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用45-70%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(43mg,48%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.42(s,6 H),4.56(d,J=5.56Hz,2 H),7.43(dd,J=10.23,2.40Hz,1 H),7.49(s,2 H),8.15(d,J=2.53Hz,1 H),9.32(t,J=5.43Hz,1 H),12.75(s,1 H);ESI-MS m/z[M+H]+實驗值300.0。
將N-(4-氰基-2,6-二甲基苄基)-3-甲氧基-5-(三氟甲基)吡啶醯胺(54mg,0.149mmol)及氯化鋰(126mg,2.97mmol)於DMA(2322μL)中之混合物在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用55-80%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(12mg,23%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.42(s,6 H),4.58(d,J=5.56Hz,2 H),7.50(s,2 H),7.85(d,J=1.26Hz,1 H),8.46(d,J=1.01Hz,1 H),9.59(t,J=5.18Hz,1 H),12.65(br s,1 H);ESI-MS m/z[M+H]+ 350.2。
將N-(4-氰基-2,6-二甲基苄基)-3,5-二甲氧基吡啶醯胺(104mg,0.320mmol)及氯化鋰(271mg,6.39mmol)於DMA(4994μL)中之混合物在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用55-80%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(25mg,25%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.41-2.44(m,6 H),3.83-3.86(m,3 H),4.52-4.56(m,2 H),6.96-6.99(m,1 H),7.49-7.51(m,2 H),7.81-7.84(m,1 H),9.03-9.10(m,1 H),12.57-12.63(m,1 H);ESI-MS m/z[M+H]+ 312.2。
將(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-5-氟-3-甲氧基吡啶醯胺(51mg,0.164mmol)及氯化鋰(139mg,3.28mmol)於DMA(2560μL)中之混合物在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用50%於水(含有TFA)中之乙腈溶離進行純化,以得到呈灰白色固體之標題化合物(11mg,23%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.20-2.30(m,1 H),2.40-2.46(m,1 H),2.90(dt,J=16.36,8.37Hz,1 H),3.02-3.11(m,1 H),5.60(q,J=8.34Hz,1 H),7.39(d,J=7.83Hz,1 H),7.48(dd,J=10.23,2.40Hz,1 H),7.63(d,J=8.34Hz,1 H),7.75(s,1 H),8.18(d,J=2.53Hz,1 H),9.56(d,J=8.59Hz,1 H),12.87(br s,1 H);ESI-MS m/z[M+H]+ 298.0。
將(R)-5-氯-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-甲氧基吡啶醯胺(34mg,0.104mmol)及氯化鋰(88mg,2.075mmol)於DMA(1621μL)中之混合物在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用55-80%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(6mg,18%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.24(dq,J=12.57,8.86Hz,1 H),2.38-2.47(m,1 H),2.90(dt,J=16.48,8.31Hz,1 H),3.00-3.11(m,1 H),5.59(q,J=8.34Hz,1 H),7.39(d,J=7.83Hz,1 H),7.63(d,J=7.83Hz,1 H),7.66-7.78(m,2 H),8.18(d,J=2.02Hz,1 H),9.65(d,J=8.59Hz,1 H),12.72(br s,1 H);ESI-MS m/z[M+H]+ 314.0。
將(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-甲氧基-5-(三氟甲基)吡啶醯胺(68mg,0.188mmol)及氯化鋰(160mg,3.76mmol)於DMA(2941μL)中之混合物在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用55-80%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(25mg,38%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.20-2.35(m,1 H),2.45(br s,1 H),2.91(dt,J=15.92,7.96Hz,1 H),3.03-3.14(m,1 H),5.62(d,J=8.08Hz,1 H),7.41(d,J=7.58Hz,1 H),7.64(d,J=7.58Hz,1 H),7.75(br s,1 H),7.87(br s,1 H),8.47(br s,1 H),9.88(br s,1 H),12.77(br s,1 H);ESI-MS m/z[M+H]+ 348.0。
將(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3,5-二甲氧基吡啶醯胺(97mg,0.30mmol)及氯化鋰(254mg,6.00mmol)於DMA(4687μL)中之混合物在80℃下
攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用45-70%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(15mg,16%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.23(dq,J=12.51,8.97Hz,1 H),2.40-2.48(m,1 H),2.89(dt,J=16.42,8.46Hz,1 H),3.01-3.09(m,1 H),3.87(s,3 H),5.58(q,J=8.34Hz,1 H),7.01(d,J=2.53Hz,1 H),7.37(d,J=7.83Hz,1 H),7.63(d,J=7.83Hz,1 H),7.74(s,1 H),7.85(d,J=2.53Hz,1 H),9.30(d,J=8.59Hz,1 H),12.71(br s,1 H);ESI-MS m/z[M+H]+ 310.2。
將(R)-5-氰基-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-甲氧基吡啶醯胺(68mg,0.214mmol)及氯化鋰(181mg,4.27mmol)於DMA(3338μL)中之混合物在80℃下攪拌隔夜,且過濾。將濾液藉由製備型HPLC,用45-70%於水(含有甲酸)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(1mg,2%)。1H NMR(400MHz,CD3OD)δ ppm 2.08-2.24(m,1 H),2.57-2.69(m,1 H),2.99(dt,J=16.42,8.46Hz,1 H),3.09-3.20(m,1 H),5.64-5.76(m,1 H),7.43(d,J=7.83Hz,1 H),7.56(d,J=7.58Hz,1 H),7.64(s,1 H),7.78(br s,1 H),8.38(br s,1 H);ESI-MS m/z[M+H]+ 305.0。
將N-(4-氰基-2-甲基苄基)-5-氟-3-甲氧基吡啶醯胺(20mg,0.067mmol)及氯化鋰(56.7mg,1.336mmol)於DMA(1044μL)中之混合物在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用45-70%於水(含有TFA)中之乙腈
之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(5mg,26.2%產率)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.38(s,3 H),4.53(d,J=6.32Hz,2 H),7.38(d,J=8.08Hz,1 H),7.48(dd,J=10.36,2.27Hz,1 H),7.62(d,J=8.08Hz,1 H),7.66(s,1 H),8.23(d,J=2.27Hz,1 H),9.77(t,J=6.06Hz,1 H),12.73(br s,1 H);ESI-MS m/z[M+H]+ 286.1。
將5-氯-N-(4-氰基-2-甲基苄基)-3-甲氧基吡啶醯胺(44mg,0.139mmol)及氯化鋰(118mg,2.79mmol)於DMA(2177μL)中之混合物在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用45-70%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(16mg,38%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.38(s,3 H),4.53(d,J=6.32Hz,2 H),7.38(d,J=7.83Hz,1 H),7.62(dd,J=8.08,1.26Hz,1 H),7.66(s,1 H),7.69(d,J=2.02Hz,1 H),8.24(d,J=2.02Hz,1 H),9.85(t,J=6.19Hz,1 H),12.60(br s,1 H);ESI-MS m/z[M+H]+ 302.1。
將N-(4-氰基-2-甲基苄基)-3-甲氧基-5-(三氟甲基)吡啶醯胺(51mg,0.146mmol)及氯化鋰(124mg,2.92mmol)於DMA(2281μL)中之混合物在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用45-70%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(18mg,37%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.38(s,3 H),4.55(d,J=6.32Hz,2 H),7.41(d,
J=8.08Hz,1 H),7.62(dd,J=7.96,1.39Hz,1 H),7.67(s,1 H),7.90(d,J=1.26Hz,1 H),8.54(d,J=1.01Hz,1 H),10.01(t,J=6.19Hz,1 H),12.66(br s,1 H);ESI-MS m/z[M+H]+ 336.2。
將N-(4-氰基-2-甲基苄基)-3,5-二甲氧基吡啶醯胺(67mg,0.215mmol)及氯化鋰(182mg,4.30mmol)於DMA(3363μL)中之混合物在80℃下攪拌隔夜,然後過濾。將濾液藉由製備型HPLC,用45-70%於水(含有TFA)中之乙腈之梯度溶離進行純化,以得到呈灰白色固體之標題化合物(22mg,34%)。1H NMR(400MHz,DMSO-d 6)δ ppm 2.37(s,3 H),3.87(s,3 H),4.51(d,J=6.32Hz,2 H),7.00(d,J=2.53Hz,1 H),7.36(d,J=7.83Hz,1 H),7.62(dd,J=7.96,1.39Hz,1 H),7.66(s,1 H),7.86-7.93(m,1 H),9.54(t,J=6.19Hz,1 H),12.58(br s,1 H);ESI-MS m/z[M+H]+ 298.2。
向正攪拌的3-羥基吡啶甲酸(0.132g,0.949mmol)、1H-苯并[d][1,2,3]三唑-1-醇(0.192g,1.423mmol)、EDC鹽酸鹽(0.273g,1.423mmol)、及N-乙基-N-異丙基丙-2-胺(0.992mL,5.69mmol)之DMF(2mL)溶液中添加4-(1-胺基乙基)苯甲腈鹽酸鹽(0.260g,1.423mmol)。將反應混合物加熱至50℃達7小時,然後冷卻至室溫,用水(6mL)稀釋,用1M HCl酸化至pH 5.5,且用EtOAc(1×20mL,2×10mL)萃取。將有機層合併,用鹽水(10mL)洗滌,經Na2SO4乾燥且濃縮,以得到油狀物,將其藉由製備型HPLC(SunFireTM C18,5μm,ID 30mm
×75mm),用15-40%於H2O(具有0.05% TFA)中之ACN(具有0.035% TFA)之梯度溶離進行純化。將純流份合併且濃縮,以得到呈黏性橙色油狀物之標題化合物(91mg,36%)。1H NMR(400MHz,DMSO-d 6)δ ppm 1.56(d,J=7.07Hz,3 H),5.17-5.32(m,1 H),7.41(dd,J=8.46,1.39Hz,1 H),7.55(dd,J=8.46,4.42Hz,1 H),7.61-7.66(m,2 H),7.77-7.84(m,2 H),8.20(dd,J=4.42,1.39Hz,1 H),9.68(d,J=8.34Hz,1 H),12.33(br s,1 H);ESI-MS m/z[M+H]+ 268.1。
向3-(苄氧基)-5-溴-N-(4-氰基-2,6-二甲基苄基)吡啶醯胺(16.89g,37.5mmol)之1,4-二噁烷(125mL)溶液中添加三級丁醇鈉(9.01g,94mmol)。將混合物藉由使氮氣鼓泡通過懸浮液達3分鐘來除氣。添加BrettPhos Pd G3(3.40g,3.75mmol)及3-甲氧基丙-1-胺(8.43mL,83mmol)。將反應混合物再次除氣,且在110℃下於封閉系統中攪拌3小時。反應之後,將混合物在水(300mL)與乙酸異丙酯(300mL)之間分配。分離各層,且保留有機層。用乙酸異丙酯(2×150mL)萃取水相。將有機層合併,用飽和NaCl(aq)洗滌,經Na2SO4乾燥,過濾且濃縮。將濃縮物藉由矽膠急驟管柱層析法,用0-5%於二氯甲烷中之甲醇之梯度溶離進行純化,以得到呈固體之標題化合物(6.3g,37%)。ESI-MS m/z[M+H]+ 459.4。
將3-(苄氧基)-N-(4-氰基-2,6-二甲基苄基)-5-((3-甲氧基丙基)胺基)吡
啶醯胺(6.3g,13.74mmol)之THF(70mL)溶液用氮氣除氣。向溶液中添加20%氫氧化鈀/碳(1.929g,2.75mmol)。在室溫下將反應混合物用氫氣(1atm,經由氣球)處理2小時。氫解之後,將反應混合物透過Celite®墊過濾,將其用THF(50mL)洗滌。將濾液濃縮,且將粗產物藉由矽膠急驟管柱層析法,用0-50%於DCM中之EtOAc溶離進行純化。將純流份合併且濃縮,以得到呈固體之標題化合物(4.07g,80%)。1H NMR(500MHz,CD3CN)δ ppm 1.79-1.85(m,2 H),2.45(s,6 H),3.16-3.21(m,2 H),3.30(s,3 H),3.45(t,J=6.10Hz,2 H),4.62(d,J=5.61Hz,2 H),5.22(m,1 H),6.30(d,J=2.44Hz,1 H),7.42(s,2 H),7.45(d,J=2.44Hz,1 H),7.80(m,1 H),12.17(s,1 H);ESI-MS m/z[M+H]+ 369.3。
將3-(苄氧基)-5-溴-N-(4-氰基-2,6-二甲基苄基)吡啶醯胺(102mg,0.227mmol)之甲苯(1mL)溶液用氮氣除氣2分鐘。向溶液中添加碳酸銫(148mg,0.453mmol)、Pd2(dba)3(10.37mg,0.011mmol)、及外消旋-BINAP(14.10mg,0.023mmol),所有均在氮氣氛圍下進行。向正攪拌的懸浮液中添加1-乙基哌嗪(0.035mL,0.272mmol)。將反應混合物於封閉系統中加熱至100℃達1小時,然後冷卻至室溫,用EtOAc(20mL)稀釋,且接連用水(10mL)及飽和NH4Cl(aq)(10mL)洗滌。將有機相經MgSO4乾燥,過濾,且濃縮,以得到油狀物,其未經進一步純化即使用。ESI-MS m/z[M+H]+ 484.3。
將3-(苄氧基)-N-(4-氰基-2,6-二甲基苄基)-5-(4-乙基哌嗪-1-基)吡啶醯胺(111mg,0.230mmol)之THF(3mL)溶液用氮氣除氣。向溶液中添加20%氫氧化鈀/碳(32.2mg,0.046mmol)。在室溫下將反應混合物用氫氣(1atm,經由氣球)處理30分鐘。氫解之後,將反應混合物過濾。將濾液濃縮以得到粗製黃色油狀物,將其藉由製備型HPLC(SunFireTM C18,5μm,ID 30mm×75mm),用15-40%於H2O(具有0.05% TFA)中之ACN(具有0.035% TFA)之梯度溶離進行純化,以得到標題化合物之TFA鹽(22mg,18.5%)。1H NMR(400MHz,DMSO-d 6)δ ppm 1H NMR(500MHz,DMSO-d 6)δ ppm 1.01(t,J=7.32Hz,3 H),2.33(q,J=7.24Hz,2 H),2.44(s,8 H),2.52(m,2 H),2.96-3.06(m,4 H),4.48(d,J=5.37Hz,2 H),5.76(d,J=0.98Hz,1 H),5.97(br s,1 H),7.19-7.24(m,1 H),7.49(s,2 H)12.71(br s,1 H);ESI-MS m/z[M+H]+ 394.3。
將3-(苄氧基)-5-溴-N-(4-氰基-2,6-二甲基苄基)吡啶醯胺(126mg,0.280mmol)之甲苯(1mL)溶液用氮氣除氣。在氮氣下向溶液中添加碳酸銫(283mg,0.867mmol)、Pd2(dba)3(12.81mg,0.014mmol)、及外消旋-BINAP(17.42mg,
0.028mmol)。向正攪拌的懸浮液中添加1-(2,2-二氟乙基)哌嗪鹽酸鹽(57.4mg,0.308mmol)。將反應混合物於封閉系統中加熱至100℃達1小時,然後冷卻,用EtOAc(20mL)稀釋,且接連用水(10mL)及飽和NH4Cl(aq)(10mL)洗滌。將有機相經MgSO4乾燥,過濾,且濃縮。所得粗製油狀物未經進一步純化即使用。ESI-MS m/z[M+H]+ 520.3。
將3-(苄氧基)-N-(4-氰基-2,6-二甲基苄基)-5-(4-(2,2-二氟乙基)哌嗪-1-基)吡啶醯胺(145mg,0.279mmol)及乙二胺(0.5M於THF中之溶液,0.112mL,0.056mmol)之THF(3mL)用氮氣除氣。在氮氣氛圍下向溶液中添加10%鈀/碳(50%濕Degussa®型)(59.4mg,0.028mmol)。將反應混合物用氫氣(1atm,經由氣球)處理16小時。氫解之後,將反應混合物過濾。將濾液濃縮以得到黃色油狀物,將其藉由製備型HPLC(SunFireTM C18,5μm,ID 30mm×75mm),用15-40%於H2O(具有0.05% TFA)中之ACN(具有0.035% TFA)之梯度溶離進行純化,以得到呈固體之標題化合物之TFA鹽(53mg,35%)。1H NMR(400MHz,DMSO-d 6)δ ppm 1H NMR(500MHz,DMSO-d 6)δ ppm 2.42(s,6 H),2.58-2.68(m,4 H),2.72-2.84(m,2 H),3.24-3.33(m,4 H),4.52(d,J=5.61Hz,2 H),5.96-6.35(m,1 H),6.63(s,1 H),7.49(s,2 H),7.81(s,1 H),8.94(br s,1 H),12.32(s,1 H);ESI-MS m/z[M+H]+ 430.3。
表1列舉實例中所示之一些化合物之生物學資料,其中較大pIC50及pEC50值分別代表較高效力或活性。IC50資料(呈pIC50報導於表1中)係使用本說明書中在標題「PHD2酶之抑制」下所述之基於酶之檢定。EC50資料(呈pEC50報導於表1中)係使用本說明書中在標題「基於細胞之HIF-α穩定化檢定」下所述之基於細胞之檢定。
除非文中另外清楚地指出,否則如在本說明書及所附申請專利範圍中所用的單數冠詞諸如「一個/種(a/an)」及「該/該等(the)」可指代單個對象或多
個對象。因此,例如,含有「一種化合物」之組成物可包括單一化合物或二或更多種化合物。以上描述意欲為說明性的且並非為限制性的。在閱讀以上描述之後,許多實施例將為熟習此項技術者所顯而易知。因此,本發明之範疇應根據所附申請專利範圍來確定,且包括該等申請專利範圍賦以權利之等效物之全部範疇。所有本揭露中引用之文章及參考文獻(包括專利、專利申請案、及公開案)之揭露均以全文引用方式併入本文且用於所有目的。
Claims (41)
- 一種式1化合物,
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中X1為CR1。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中X2為CR2。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中X1為CR1且X2為CR2。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R1、R2、及R3各獨立地選自氫、鹵基、及甲基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R1、R2、及R3各獨立地選自氫及甲基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R4係選自氫、鹵基、及甲基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R4係選自氫及甲基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R5係選自氫及甲基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R5為氫。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R6係選自氫及甲基。
- 如申請專利範圍第11項之化合物或醫藥學上可接受之鹽,其中R6為氫。
- 如申請專利範圍第5項之化合物或醫藥學上可接受之鹽,其中R4及R5連接以形成乙-1,2-二基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之C3-5雜環基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代,且該C3-5雜環基部分具有5或6個環成員及一或兩個作為環成員之雜原子,其中該等雜原子之一為氮且該等雜原子之另一者當存在時獨立地選自N、O、及S;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之C3-5雜 環基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代,且該C3-5雜環基部分具有一或兩個作為環成員之雜原子,該一或兩個雜原子各自為氮;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R7、R8、及R9各獨立地選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、及視情況經一至三個鹵基取代基取代之C1-4烷基,其中:Ra及Rb各獨立地選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基,或Ra及Rb連同其所連接之氮原子一起形成視情況經C1-4烷基取代之哌嗪-1-基,其中該C1-4烷基取代基視情況經一至三個鹵基取代基取代;Rc係選自氫及視情況經一至三個獨立地選自鹵基及-ORd之取代基取代之C1-4烷基;且Rd係選自氫及C1-4烷基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R7係選自氫、鹵基、氰基、及C1-4烷基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R7為氫。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R8係選自氫、鹵基、氰基、-N(Ra)Rb、-C(O)N(Ra)Rb、-ORc、甲基、及-CF3。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R8係選自氫、氟基、氯基、氰基、-N(H)CH2CH2CH2OCH3、-OCH3、甲基、 及-CF3。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R9係選自氫、鹵基、氰基、及C1-4烷基。
- 如申請專利範圍第1項之化合物或醫藥學上可接受之鹽,其中R9為氫。
- 如申請專利範圍第1項之化合物,其係選自以下化合物:N-((6-氰基吡啶-3-基)甲基)-3-羥基吡啶醯胺;N-(4-氰基-2-甲基苄基)-3-羥基吡啶醯胺;N-(4-氰基-2-氟苄基)-3-羥基吡啶醯胺;N-(4-氰基-3-氟苄基)-3-羥基吡啶醯胺;N-(4-氰基-2-(三氟甲基)苄基)-3-羥基吡啶醯胺;N-(4-氰基-2-甲基苄基)-5-(4-乙基哌嗪-1-羰基)-3-羥基吡啶醯胺;(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-5-(4-乙基哌嗪-1-羰基)-3-羥基吡啶醯胺;N-(4-氰基-2,6-二甲基苄基)-3-羥基吡啶醯胺;N-(4-氰基-2,6-二甲基苄基)-3-羥基-5-甲基吡啶醯胺;N-(4-氰基-2,5-二甲基苄基)-3-羥基吡啶醯胺;N-(4-氰基-5-氟-2-甲基苄基)-3-羥基吡啶醯胺;N-(4-氰基-3-氟-2-甲基苄基)-3-羥基吡啶醯胺;N-(2-氯-4-氰基苄基)-3-羥基吡啶醯胺;5-氰基-N-(4-氰基苄基)-3-羥基吡啶醯胺;5-氰基-N-(4-氰基-2-甲基苄基)-3-羥基吡啶醯胺;N-(6-氰基-1,2,3,4-四氫萘-1-基)-3-羥基吡啶醯胺;(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-羥基吡啶醯胺; (S)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-羥基吡啶醯胺;N-(6-氰基-2,3-二氫苯并呋喃-3-基)-3-羥基吡啶醯胺;(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-羥基-5-甲基吡啶醯胺;N-((5-氰基吡啶-2-基)甲基)-3-羥基吡啶醯胺;5-氯-N-(4-氰基-2,6-二甲基苄基)-3-羥基吡啶醯胺;5-氰基-N-(4-氰基-2,6-二甲基苄基)-3-羥基吡啶醯胺;N-(4-氰基-2,6-二甲基苄基)-5-氟-3-羥基吡啶醯胺;N-(4-氰基-2,6-二甲基苄基)-3-羥基-5-(三氟甲基)吡啶醯胺;N-(4-氰基-2,6-二甲基苄基)-3-羥基-5-甲氧基吡啶醯胺;(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-5-氟-3-羥基吡啶醯胺;(R)-5-氯-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-羥基吡啶醯胺;(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-羥基-5-(三氟甲基)吡啶醯胺;(R)-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-羥基-5-甲氧基吡啶醯胺;(R)-5-氰基-N-(5-氰基-2,3-二氫-1H-茚-1-基)-3-羥基吡啶醯胺;N-(4-氰基-2-甲基苄基)-5-氟-3-羥基吡啶醯胺;5-氯-N-(4-氰基-2-甲基苄基)-3-羥基吡啶醯胺;N-(4-氰基-2-甲基苄基)-3-羥基-5-(三氟甲基)吡啶醯胺;N-(4-氰基-2-甲基苄基)-3-羥基-5-甲氧基吡啶醯胺;N-(1-(4-氰基苯基)乙基)-3-羥基吡啶醯胺;N-(4-氰基-2,6-二甲基苄基)-3-羥基-5-((3-甲氧基丙基)胺基)吡啶醯胺;N-(4-氰基-2,6-二甲基苄基)-5-(4-乙基哌嗪-1-基)-3-羥基吡啶醯胺;N-(4-氰基-2,6-二甲基苄基)-5-(4-(2,2-二氟乙基)哌嗪-1-基)-3-羥基吡啶醯胺;及該等前述化合物中任一者之醫藥學上可接受之鹽。
- 如申請專利範圍第1項至第23項中任一項所定義之化合物或醫藥學上可接受之鹽,其用作藥劑。
- 如申請專利範圍第1項至第23項中任一項所定義之化合物或醫藥學上可接受之鹽,其用於治療與PHD相關聯之疾病、病症、或病狀。
- 如申請專利範圍第1項至第23項中任一項所定義之化合物或醫藥學上可接受之鹽,其用於治療選自以下之疾病、病症、或病狀:心血管病、代謝病、血液病、肺病、腎病、肝病、傷口癒合障礙、及癌症。
- 如申請專利範圍第1項至第23項中任一項所定義之化合物或醫藥學上可接受之鹽,其用於治療選自以下之疾病、病症、或病狀:中風、心肌梗塞、鬱血性心衰竭、動脈粥樣硬化、慢性靜脈功能不全、心因性肝硬化、急性失代償性心衰竭、心臟病發作後心衰竭、周邊動脈疾病、閉塞性動脈疾病、糖尿病、高血糖、胰島素抗性、X代謝症候群、葡萄糖耐受不良、非酒精性肝脂肪變性、貧血、慢性阻塞性肺臟疾病、肺栓塞、肺性高血壓、高山病、急性呼吸衰竭、間質性肺病、特發性肺纖維化、落屑性間質性肺炎、非特異性間質性肺炎、隱原性器質化肺炎、呼吸性細支氣管炎相關間質性肺病、急性間質性肺炎、淋巴性間質性肺炎、急性腎衰竭、急性腎損傷、慢性腎臟疾病、腎臟缺血再灌注損傷、肝臟缺血再灌注損傷、糖尿病足潰瘍、壓迫性潰瘍、靜脈性潰瘍、動脈性潰瘍、水皰性表皮鬆解症、天皰瘡、及休格倫氏症候群、以及癌症。
- 一種醫藥組成物,其包含:如申請專利範圍第1項至第23項中任一項所定義之化合物或醫藥學上可接受之鹽;及醫藥學上可接受之賦形劑。
- 一種如申請專利範圍第1項至第23項中任一項所定義之化合物 或醫藥學上可接受之鹽用於製造藥劑之用途,其中該藥劑係用於治療與PHD相關聯之疾病、病症、或病狀。
- 一種如申請專利範圍第1項至第23項中任一項所定義之化合物或醫藥學上可接受之鹽用於製造藥劑之用途,其中該藥劑係用於治療選自心血管病、代謝病、血液病、肺病、腎病、肝病、傷口癒合障礙及癌症之疾病、病症、或病狀。
- 一種如申請專利範圍第1項至第23項中任一項所定義之化合物或醫藥學上可接受之鹽用於製造藥劑之用途,其中該藥劑係用於治療選自下列之疾病、病症、或病狀:中風、心肌梗塞、鬱血性心衰竭、動脈粥樣硬化、慢性靜脈功能不全、心因性肝硬化、急性失代償性心衰竭、心臟病發作後心衰竭、周邊動脈疾病、閉塞性動脈疾病、糖尿病、高血糖、胰島素抗性、X代謝症候群、葡萄糖耐受不良、非酒精性肝脂肪變性、貧血、慢性阻塞性肺臟疾病、肺栓塞、肺性高血壓、高山病、急性呼吸衰竭、間質性肺病、特發性肺纖維化、落屑性間質性肺炎、非特異性間質性肺炎、隱原性器質化肺炎、呼吸性細支氣管炎相關間質性肺病、急性間質性肺炎、淋巴性間質性肺炎、急性腎衰竭、急性腎損傷、慢性腎臟疾病、腎臟缺血再灌注損傷、肝臟缺血再灌注損傷、糖尿病足潰瘍、壓迫性潰瘍、靜脈性潰瘍、動脈性潰瘍、水皰性表皮鬆解症、天皰瘡及休格倫氏症候群以及癌症。
- 一種包含如申請專利範圍第1項至第23項中任一項所定義之化合物或醫藥學上可接受之鹽及至少一種額外藥理學活性劑之組合。
- 一種醫藥組成物,其包含:N-(4-氰基苄基)-3-羥基吡啶醯胺或其醫藥學上可接受之鹽;及醫藥學上可接受之賦形劑。
- N-(4-氰基苄基)-3-羥基吡啶醯胺或其醫藥學上可接受之鹽,其用 作藥劑。
- N-(4-氰基苄基)-3-羥基吡啶醯胺或其醫藥學上可接受之鹽,其用於治療與PHD相關聯之疾病、病症、或病狀。
- N-(4-氰基苄基)-3-羥基吡啶醯胺或其醫藥學上可接受之鹽,其用於治療選自心血管病、代謝病、血液病、肺病、腎病、肝病、傷口癒合障礙及癌症之疾病、病症、或病狀。
- N-(4-氰基苄基)-3-羥基吡啶醯胺或其醫藥學上可接受之鹽,其用於治療選自以下之疾病、病症、或病狀:中風、心肌梗塞、鬱血性心衰竭、動脈粥樣硬化、慢性靜脈功能不全、心因性肝硬化、急性失代償性心衰竭、心臟病發作後心衰竭、周邊動脈疾病、閉塞性動脈疾病、糖尿病、高血糖、胰島素抗性、X代謝症候群、葡萄糖耐受不良、非酒精性肝脂肪變性、貧血、慢性阻塞性肺臟疾病、肺栓塞、肺性高血壓、高山病、急性呼吸衰竭、間質性肺病、特發性肺纖維化、落屑性間質性肺炎、非特異性間質性肺炎、隱原性器質化肺炎、呼吸性細支氣管炎相關間質性肺病、急性間質性肺炎、淋巴性間質性肺炎、急性腎衰竭、急性腎損傷、慢性腎臟疾病、腎臟缺血再灌注損傷、肝臟缺血再灌注損傷、糖尿病足潰瘍、壓迫性潰瘍、靜脈性潰瘍、動脈性潰瘍、水皰性表皮鬆解症、天皰瘡及休格倫氏症候群以及癌症。
- 一種N-(4-氰基苄基)-3-羥基吡啶醯胺或其醫藥學上可接受之鹽用於製造藥劑之用途,其中該藥劑係用於治療與PHD相關聯之疾病、病症、或病狀。
- 一種N-(4-氰基苄基)-3-羥基吡啶醯胺或其醫藥學上可接受之鹽用於製造藥劑之用途,其中該藥劑係用於治療選自心血管病、代謝病、血液病、肺病、腎病、肝病、傷口癒合障礙及癌症之疾病、病症、或病狀。
- 一種N-(4-氰基苄基)-3-羥基吡啶醯胺或其醫藥學上可接受之鹽 用於製造藥劑之用途,其中該藥劑係用於治療選自下列之疾病、病症、或病狀:中風、心肌梗塞、鬱血性心衰竭、動脈粥樣硬化、慢性靜脈功能不全、心因性肝硬化、急性失代償性心衰竭、心臟病發作後心衰竭、周邊動脈疾病、閉塞性動脈疾病、糖尿病、高血糖、胰島素抗性、X代謝症候群、葡萄糖耐受不良、非酒精性肝脂肪變性、貧血、慢性阻塞性肺臟疾病、肺栓塞、肺性高血壓、高山病、急性呼吸衰竭、間質性肺病、特發性肺纖維化、落屑性間質性肺炎、非特異性間質性肺炎、隱原性器質化肺炎、呼吸性細支氣管炎相關間質性肺病、急性間質性肺炎、淋巴性間質性肺炎、急性腎衰竭、急性腎損傷、慢性腎臟疾病、腎臟缺血再灌注損傷、肝臟缺血再灌注損傷、糖尿病足潰瘍、壓迫性潰瘍、靜脈性潰瘍、動脈性潰瘍、水皰性表皮鬆解症、天皰瘡及休格倫氏症候群以及癌症。
- 一種包含N-(4-氰基苄基)-3-羥基吡啶醯胺或其醫藥學上可接受之鹽及至少一種額外藥理學活性劑之組合。
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