TWI813957B - Mcl-1抑制劑 - Google Patents
Mcl-1抑制劑 Download PDFInfo
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- TWI813957B TWI813957B TW110107128A TW110107128A TWI813957B TW I813957 B TWI813957 B TW I813957B TW 110107128 A TW110107128 A TW 110107128A TW 110107128 A TW110107128 A TW 110107128A TW I813957 B TWI813957 B TW I813957B
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- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 229950005787 uprosertib Drugs 0.000 description 1
- 229950000815 veltuzumab Drugs 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- CILBMBUYJCWATM-HGBQGYOLSA-N vinorelbine D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.OC(=O)[C@@H](O)[C@H](O)C(O)=O.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 CILBMBUYJCWATM-HGBQGYOLSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229960004854 viral vaccine Drugs 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- OGUJBRYAAJYXQP-IJFZAWIJSA-N vuw370o5qe Chemical compound CC(O)=O.CC(O)=O.C1([C@H](O)[C@@H](O)[C@H]2C(=O)N[C@H](C(=O)N3CC[C@H](O)[C@H]3C(=O)N[C@H](NCCN)[C@H](O)C[C@@H](C(N[C@H](C(=O)N3C[C@H](O)C[C@H]3C(=O)N2)[C@@H](C)O)=O)NC(=O)CCCCCCCC[C@@H](C)C[C@@H](C)CC)[C@H](O)CCN)=CC=C(O)C=C1 OGUJBRYAAJYXQP-IJFZAWIJSA-N 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- 229940095188 zydelig Drugs 0.000 description 1
Classifications
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
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- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/08—Bridged systems
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- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
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- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本發明大體上係關於可用於治療癌症之方法中之化合物及醫藥組合物。
Description
本申請案大體上係關於抑制MCL-1之特定化合物、包含該等化合物之醫藥組合物、該等化合物治療癌症之用途及製造該等化合物之方法。
細胞凋亡(程式化細胞死亡)為用於自生物體中消除不合需要之或具潛在危險之細胞之方法。細胞凋亡避免對於腫瘤之發展及持續生長為關鍵的。骨髓細胞白血病1蛋白(MCL-1,亦縮寫為Mcl-1或MCL1)為Bcl-2家族蛋白之抗細胞凋亡成員。MCL-1在許多癌症中過度表現。MCL-1之過度表現防止癌細胞經歷細胞凋亡。研究顯示,MCL-1抑制劑可用於治療癌症。因此,需要抑制MCL-1之新型化合物。
本發明解決前述需要。詳言之,本文提供MCL-1抑制劑。
在一個實施例中,本發明提供式(I)化合物:;
其中:為單鍵或雙鍵;
X為O或NR7
;
R12
為氫或-C(O)R1
;
R1
為C1 - 6
烷基、C1 - 6
鹵烷基、C2 - 6
烯基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、3-12員雜環基、5-10員雜芳基、-OR7
或-NR8
R9
,其中
該C1 - 6
烷基、C1 - 6
雜烷基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、3-12員雜環基及5-10員雜芳基視情況經1-5個R10
基團取代;
R2
為氫、C1 - 6
烷基、C1 - 6
雜烷基、C3 - 10
環烷基或3-12員雜環基,其中
該C1 - 6
烷基、C1 - 6
雜烷基、C3 - 10
環烷基及3-12員雜環基視情況經1-5個R10
基團取代;
R3
及R4
獨立地為氫、C1 - 6
烷基、-OR7
、C1 - 6
雜烷基、-NR8
R9
、NR8
C(O)R9
、-NR8
C(O)OR9
、C6 - 10
芳基、C3 - 10
環烷基、5-10員雜芳基、3-12員雜環基、-C(O)R7
、-C(O)OR7
、-C(O)NR8
R9
、-OC(O)NR8
R9
、-CN或-SO2
R7
,其中
該C1 - 6
烷基、C1 - 6
雜烷基、C6 - 10
芳基、C3 - 10
環烷基、5-10員雜芳基及3-12員雜環基視情況經1-5個R10
基團取代;
R5
為氫、C1 - 6
烷基、-(CH2
CH2
O)p
R7
、C1 - 6
雜烷基、C6 - 10
芳基、C3 - 10
環烷基、5-10員雜芳基或3-12員雜環基,其中
該C1 - 6
烷基、C1 - 6
雜烷基、C6 - 10
芳基、C3 - 10
環烷基、5-10員雜芳基及3-12員雜環基視情況經1-5個R10
基團取代;
R6
為氫或鹵基;
各R7
獨立地為氫、C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基或5-10員雜芳基,其中
該C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基及5-10員雜芳基視情況經1-5個R10
取代;
各R8
及R9
獨立地為氫、C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基或5-10員雜芳基,或R8
及R9
連同其所連接之原子一起形成3-12員雜環,其中
該C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基及5-10員雜芳基視情況經1-5個R10
取代;
各R10
獨立地為C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基、5-10員雜芳基、鹵基、側氧基、-ORa
、-C(O)Ra
、-C(O)ORa
、-C(O)NRa
Rb
、-OC(O)NRa
Rb
、-NRa
Rb
、-NRa
C(O)Rb
、-NRa
C(O)ORb
、-S(O)q
Ra
、-S(O)2
NRa
Rb
、-NRa
S(O)2
Rb
、-N3
、-CN或-NO2
,或兩個R10
基團形成稠合、螺或橋聯C3 - 10
環烷基或3-12員雜環基,其中
各C1 - 6
烷基、C1 - 6
雜烷基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、3-12員雜環及5-10員雜芳基視情況經1-5個R20
基團取代;
各Ra
及Rb
獨立地為氫、C1 - 6
烷基、C2 - 6
烯基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基、5-10員雜芳基,或Ra
及Rb
連同其所連接之原子一起形成3-12員雜環基,其中
該C1 - 6
烷基、C2 - 6
烯基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基、5-10員雜芳基視情況經1-5個R20
基團取代;
各R20
獨立地為C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6
-C10
芳基、5-10員雜芳基、羥基、C1 - 6
烷氧基、胺基、-CN、-C(O)H、-C(O)NH2
、-C(O)NH(C1 - 6
烷基)、-C(O)N(C1 - 6
烷基)2
、-COOH、-C(O)C1 - 6
烷基、-C(O)OC1 - 6
烷基或鹵素;
n為0、1或2;
p為0、1或2;且
q為0、1或2;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本文提供包含式(I)化合物或其互變異構體或醫藥學上可接受之鹽及醫藥學上可接受之賦形劑之醫藥組合物。
在一些實施例中,本文提供抑制患者中之MCL-1之方法,其包含向患者投與式(I)化合物或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本文提供治療患者之癌症之方法,其包含向患者投與式(I)化合物或其互變異構體或醫藥學上可接受之鹽。
相關申請之交叉參考
本申請案主張2018年5月14日申請之美國臨時申請案第62/671,306號及2018年10月24日申請之美國臨時申請案第62/749,918號之優先權,該等案兩者之全文均併入本文中。
除非上下文另有要求,否則在整個本說明書及申請專利範圍中,字語「包含(comprise)」及諸如「包含(comprises/comprising)」之其變化形式應自開放性包括性意義上解釋,亦即解釋為「包括但不限於」。
諸如「Cu - v
」或(Cu
-Cv
)之前綴指示以下基團具有u至v個碳原子,其中u及v為整數。舉例而言,「C1 - 6
烷基」指示烷基具有1至6個碳原子。
不在兩個字母或符號之間之破折號(「-」)用於指示取代基之連接點。舉例而言,-C(O)NH2
經由碳原子連接。在化學基團之前端或末端處之破折號係出於方便之目的;可在具有或不具有一或多個破折號之情況下描繪化學基團而不丟失其普通含義。除非在化學上或在結構上需要,否則化學基團所書寫或命名之次序不指示或暗示方向性。
例如之如下文所示之化學基團上之彎曲線指示連接點,亦即其顯示使該基團連接至另一所描述基團之斷裂鍵。
術語「經取代」意謂烴上之一或多個氫原子經一或多個除氫以外之原子或基團置換,其限制條件為不超過一或多個特指碳原子之正常價。「取代基」為當烴上之氫原子「經取代」時置換其之原子或基團。除非另外規定,否則在將基團描述為視情況經取代之情況下,該基團之任何取代基本身未經取代。
術語「約」係指±10%指定量之值或參數。
如本文所使用之「烷基」為直鏈或分支鏈飽和單價烴。烷基之實例包括但不限於甲基(Me、-CH3
)、乙基(Et、-CH2
CH3
)、1-丙基(n-Pr、正丙基、-CH2
CH2
CH3
)、2-丙基(i-Pr、異丙基、-CH(CH3
)2
)、1-丁基(n-Bu、正丁基、-CH2
CH2
CH2
CH3
)、2-甲基-1-丙基(i-Bu、異丁基、-CH2
CH(CH3
)2
)、2-丁基(s-Bu、第二丁基、-CH(CH3
)CH2
CH3
)、2-甲基-2-丙基(t-Bu、第三丁基、-C(CH3
)3
)、1-戊基(正戊基、-CH2
CH2
CH2
CH2
CH3
)、2-戊基(-CH(CH3
)CH2
CH2
CH3
)、3-戊基(-CH(CH2
CH3
)2
)、2-甲基-2-丁基(-C(CH3
)2
CH2
CH3
)、3-甲基-2-丁基(-CH(CH3
)CH(CH3
)2
)、3-甲基-1-丁基(-CH2
CH2
CH(CH3
)2
)、2-甲基-1-丁基(-CH2
CH(CH3
)CH2
CH3
)、1-己基(-CH2
CH2
CH2
CH2
CH2
CH3
)、2-己基(-CH(CH3
)CH2
CH2
CH2
CH3
)、3-己基(-CH(CH2
CH3
)(CH2
CH2
CH3
))、2-甲基-2-戊基(-C(CH3
)2
CH2
CH2
CH3
)、3-甲基-2-戊基(-CH(CH3
)CH(CH3
)CH2
CH3
)、4-甲基-2-戊基(-CH(CH3
)CH2
CH(CH3
)2
)、3-甲基-3-戊基(-C(CH3
)(CH2
CH3
)2
)、2-甲基-3-戊基(-CH(CH2
CH3
)CH(CH3
)2
)及2,3-二甲基-2-丁基(-C(CH3
)2
CH(CH3
)2
)、3,3-二甲基-2-丁基(-CH(CH3
)C(CH3
)3
。
「烯基」係指含有至少一個碳-碳雙鍵之脂族基。烯基之實例包括乙烯基、丙烯基、丁二烯基(包括1,2-丁二烯基及1,3-丁二烯基)。
如本文所使用之「烷氧基」係指式-ORA
基團,其中RA
為如上文所定義之烷基。烷氧基之非限制性實例包括甲氧基、乙氧基、丙氧基及丁氧基。
「炔基」係指含有至少一個碳-碳三鍵之脂族基。
「芳基」係指具有單個環(例如單環)或多個環(例如雙環或三環) (包括其中一或多個稠環為完全或部分不飽和之稠環系統)之單價或二價芳族碳環基。如本文所使用之芳基之非限制性實例包括苯基、萘基、芴基、二氫茚基、四氫茚基及蒽基。然而,芳基不以任何方式涵蓋下文所定義之雜芳基或與其重疊。若一或多個芳基與雜芳基環稠合,則所得環系統為雜芳基。單價基團或二價基團之分類指示芳基終止鏈(單價基團)或處於鏈內(二價基團)。以上定義不排除芳基上之額外取代基。舉例而言,如本文所使用之「A-芳基-B」中之芳基為二價基團,而「A-B-芳基」中之芳基為單價基團,但在各芳基上可存在額外取代基。
術語「芳氧基」係指基團-O-芳基。
「環烷基」係指具有單個環或多個環(包括稠合、橋聯及螺環系統)之飽和或部分飽和環烷基。環烷基之實例包括環丙基、環丁基、環戊基及環己基。
「鹵基」及「鹵素」在本文中用於指氟(-F)、氯(-Cl)、溴(-Br)及碘(-I)。
如本文所使用之術語「鹵烷基」係指如本文所定義之烷基,其中烷基之一或多個氫原子獨立地經可相同或不同之鹵素取代基置換。舉例而言,C1 - 6
鹵烷基為C1 - 6
烷基,其中C1 - 6
烷基之氫原子中之一或多個已經鹵基取代基置換。鹵烷基之實例包括但不限於氟甲基、氟氯甲基、二氟甲基、二氟氯甲基、三氟甲基、1,1,1-三氟乙基及五氟乙基。
「雜烷基」係指其中碳原子(及任何相關氫原子)中之一或多個各自獨立地經相同或不同雜原子基團置換之烷基。術語「雜烷基」包括具有碳及選自氮、硫、磷及氧之雜原子之非分支或分支飽和鏈。「雜烷基」內之雜原子可經氧化,例如-N(O)-、-S(O)-、-S(O)2
-。雜烷基之實例包括-OCH3
、-CH2
OCH3
、-SCH3
、-CH2
SCH3
、-NRCH3
及-CH2
NRCH3
,其中R為氫或烷基。
「雜芳基」係指具有單個環、多個環或多個稠環之單價或二價芳族基,其中一或多個環雜原子獨立地選自氮、氧及硫。「雜芳基」內之雜原子可經氧化,例如-N(O)-、-S(O)-、-S(O)2
-。該術語包括稠環系統,其中一或多個稠環為完全或部分不飽和的。單價基團或二價基團之分類指示雜芳基終止鏈(單價基團)或處於鏈內(二價基團)。以上定義不排除雜芳基上之額外取代基。舉例而言,「A-雜芳基-B」中之雜芳基為二價基團,而「A-B-雜芳基」中之雜芳基為單價基團,但在各雜芳基上可存在額外取代基。雜芳基不涵蓋如上文所定義之芳基或與其重疊。雜芳基之非限制性實例包括但不限於氮呯基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并間二氧雜環戊烯基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、苯并[b][1,4]二氧呯基、1,4-苯并二噁烷基、苯并萘并呋喃基、苯并噁唑基、苯并間二氧雜環戊烯基、苯并間二氧雜環己烯基、苯并哌喃基、苯并哌喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(benzothienyl/benzothiophenyl)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、咔唑基、㖕啉基、二苯并呋喃基、二苯并噻吩基、呋喃基、呋喃酮基、異噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、異吲哚基、吲哚啉基、異吲哚啉基、異喹啉基、吲哚嗪基、異噁唑基、㖠啶基、噁二唑基、2-側氧基氮呯基、噁唑基、環氧乙烷基、1-氧離子基吡啶基、1-氧離子基嘧啶基、1-氧離子基吡嗪基、1-氧離子基噠嗪基、1-苯基-1H-吡咯基、啡嗪基、啡噻嗪基、啡噁嗪基、酞嗪基、喋啶基、嘌呤基、吡咯基、吡唑基、吡啶基、吡嗪基、嘧啶基、噠嗪基、喹唑啉基、喹喏啉基、喹啉基、啶基、異喹啉基、四氫喹啉基、噻唑基、噻二唑基、三唑基、四唑基、三嗪基及苯硫基。
術語「雜芳氧基」係指基團-O-雜芳基。
術語「雜環基」、「雜環(heterocycle/heterocyclic)」係指具有單個環或多個縮合環之單價或二價飽和或不飽和基團,該(等)環具有於環內之一或多個選自氮、硫、磷及/或氧之雜原子。「雜環基」內之雜原子可經氧化,例如-N(O)-、-S(O)-、-S(O)2
-。雜環基可為單個環或多個環,其中多個環可經稠合、橋聯或螺。含有至少一個雜原子之任何非芳環均視為雜環基,而不考慮連接(亦即可經由碳原子或雜原子結合)如何。例示性雜環基包括但不限於氮雜環丁烷基、二氧戊環基、噻吩基[1,3]二噻烷基、十氫異喹啉基、咪唑啉基、咪唑啶基、異噻唑啶基、異噁唑啶基、嗎啉基、八氫吲哚基、八氫異吲哚基、2-側氧基哌嗪基、2-側氧基哌啶基、2-側氧基吡咯啶基、噁唑啶基、哌啶基、哌嗪基、4-哌啶酮基、吡咯啶基、吡唑啶基、啶基、噻唑啶基、四氫呋喃基、硫雜環丁烷基、三噻烷基、四氫哌喃基、硫代嗎啉基、噻嗎啉基、1-側氧基-硫代嗎啉基及1,1-二側氧基-硫代嗎啉基。
術語「氰基」係指基團-CN。
術語「側氧基」係指基團=O。
術語「羧基」係指基團-C(O)-OH。
「異構體」為具有相同分子式之不同化合物。異構體包括立體異構體、對映異構體及非對映異構體。
「立體異構體」為僅在原子於空間中之排列方式方面不同之異構體。
「對映異構體」為作為彼此不可重疊之鏡像之一對立體異構體。一對對映異構體之1:1混合物為「外消旋」混合物。符號「(±)」用於在適當時表示外消旋混合物。
「非對映異構體」為具有至少兩個不對稱原子但不為彼此鏡像之立體異構體。
如本文所使用之「治療(treatment/treating)」為用於獲得有益或所需結果之方法。出於本發明之目的,有益或所需結果包括但不限於疾病或病況相關之症狀減輕及/或症狀程度減弱。在一個實施例中,「治療」包括以下中之一或多者:a)抑制疾病或病況(例如減少一或多種由疾病或病況導致之症狀,及/或減弱疾病或病況之程度);b)減緩或遏制一或多種疾病或病況相關症狀之發展(例如使疾病或病況穩定,延緩疾病或病況之惡化或進展);及c)緩解疾病或病況,例如使臨床症狀消退,改善疾病狀態,延緩疾病進展,提高生活品質及/或延長生存期。
如本文所使用之「預防(prevention/preventing)」係指防止疾病或病症發作以使得疾病或病症之臨床症狀不發展之方案。因此,「預防」係關於在可於個體中偵測疾病徵象之前向個體投與療法。個體可為處於罹患疾病或病症之風險下之個體,諸如具有已知與疾病或病症之罹患或發作相關之一或多個風險因素之個體。
如本文所使用之術語「治療有效量」或「有效量」係指可有效引發所需生物或醫學反應之量,包括在向個體投與以用於治療疾病時足以使該疾病治療生效之化合物之量。有效量應視特定化合物及諸如年齡、體重等之待治療之個體之特徵而變化。有效量可包括一定範圍之量。如此項技術中所理解,有效量可在一或多次劑量內,亦即單次劑量或多次劑量可為達成所需治療終點所需。在投與一或多種治療劑之情形下可考慮有效量,且若單一藥劑與一或多種其他藥劑結合,則可考慮以有效量給與單一藥劑,可達成或達成所期望或有益之結果。任何共投與化合物之合適劑量均可視情況因化合物之組合作用(例如累加或協同效應)而減少。
如本文所使用之「共投與」包括在投與單位劑量之一或多種額外治療劑之前或之後投與單位劑量之本文所揭示之化合物,例如在投與一或多種額外治療劑之數秒、數分鐘或數小時內投與本文所揭示之化合物。舉例而言,在一些實施例中,首先投與單位劑量之本發明之化合物,隨後在數秒或數分鐘內投與單位劑量之一或多種額外治療劑。可替代地,在其他實施例中,首先投與單位劑量之一或多種額外治療劑,隨後在數秒或數分鐘內投與單位劑量之本發明之化合物。在一些實施例中,首先投與單位劑量之本發明之化合物,隨後在數小時(例如1-12小時)時段之後投與單位劑量之一或多種額外治療劑。在其他實施例中,首先投與單位劑量之一或多種額外治療劑,隨後在數小時(例如1-12小時)時段之後投與單位劑量之本發明之化合物。
本文亦提供本文所描述之化合物之醫藥學上可接受之鹽、水合物、溶劑合物、互變異構形式、多晶型物及前驅藥。「醫藥學上可接受」或「生理學上可接受」係指適用於獸醫或人類醫藥用途之化合物、鹽、組合物、劑型及其他物質。
本文所描述之化合物可以醫藥學上可接受之鹽之形式來製備及/或調配。醫藥學上可接受之鹽為擁有所需游離鹼之藥理學活性之游離鹼形式之化合物的無毒鹽。此等鹽可衍生自無機或有機酸或鹼。舉例而言,含有鹼氮之化合物可藉由使該化合物與無機酸或有機酸接觸而製備為醫藥學上可接受之鹽。醫藥學上可接受之鹽之非限制性實例包括硫酸鹽、焦硫酸鹽、硫酸氫鹽、亞硫酸鹽、亞硫酸氫鹽、磷酸鹽、磷酸單氫鹽、磷酸二氫鹽、偏磷酸鹽、焦磷酸鹽、氯化物、溴化物、碘化物、乙酸鹽、丙酸鹽、癸酸鹽、辛酸鹽、丙烯酸鹽、甲酸鹽、異丁酸鹽、己酸鹽、庚酸鹽、丙炔酸鹽、草酸鹽、丙二酸鹽、丁二酸鹽、辛二酸鹽、癸二酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、丁炔-1,4-二酸鹽、己炔-1,6-二酸鹽、苯甲酸鹽、氯苯甲酸鹽、甲基苯甲酸鹽、二硝基苯甲酸鹽、羥基苯甲酸鹽、甲氧基苯甲酸鹽、鄰苯二甲酸鹽、磺酸鹽、甲基磺酸鹽、丙基磺酸鹽、苯磺酸鹽、二甲苯磺酸鹽、萘-1-磺酸鹽、萘-2-磺酸鹽、苯乙酸鹽、苯丙酸鹽、苯丁酸鹽、檸檬酸鹽、乳酸鹽、γ-羥丁酸鹽、乙醇酸鹽、酒石酸鹽及杏仁酸鹽。其他合適之醫藥學上可接受之鹽之清單見於Remington: The Science and Practice of Pharmacy, 第21版, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006中。
本文所揭示之化合物之「醫藥學上可接受之鹽」之非限制性實例亦包括衍生自諸如鹼金屬(例如鈉、鉀)、鹼土金屬(例如鎂)、銨及NX4 +
(其中X為C1
-C4
烷基)的適當鹼的鹽。亦包括諸如鈉鹽或鉀鹽之鹼加成鹽。
「立體異構體」係指由藉由相同鍵鍵結之相同原子構成但具有不可互換之不同三維結構之化合物。本發明涵蓋各種立體異構體及其混合物,且包括「對映異構體」,該等「對映異構體」係指分子為彼此不可重疊之鏡像之兩種立體異構體。
「互變異構體」係指質子自分子之一個原子移位至同一分子之另一原子。本發明包括任何該等化合物之互變異構體。
「溶劑合物」係藉由溶劑與化合物之相互相用形成。亦提供本文所描述之化合物之鹽之溶劑合物。亦提供本文所描述之化合物之水合物。
如本文所使用之術語「前驅藥」為在向人體投與時根據某一化學或酶路徑轉化成生物活性親本藥物之藥物之生物非活性衍生物。縮寫及 頭字語 清單
化合物
縮寫 | 含義 |
ACN MeTHF | 乙腈 2-甲基四氫呋喃 |
Boc | 第三丁氧基羰基 |
BSA | 牛血清白蛋白 |
calcd或calc'd | 計算值 |
DCM DIPEA | 二氯甲烷 N,N-二異丙基乙胺 |
DMAP | 4-二甲胺基吡啶 |
DMF | 二甲基甲醯胺 |
DMSO | 二甲亞碸 |
Et EDCI | 乙基 1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺 |
EDTA | 乙二胺四乙酸 |
ESI | 電灑游離 |
EtOAc | 乙酸乙酯 |
EtOH | 乙醇 |
h或hr(s) | 小時 |
i-Pr KHMDS | 異丙基 雙(三甲基矽烷基)醯胺鉀 |
LCMS或LC/MS | 液相層析質譜法 |
MeOH | 甲醇 |
min | 分鐘 |
MS | 質譜法 |
m/z | 質荷比 |
NMR | 核磁共振光譜 |
n-BuLi | 正丁基鋰 |
RT或rt STAB | 室溫 三乙醯氧基硼氫化鈉 |
SFC TBAF | 超臨界流體層析法 氟化四正丁基銨 |
TBDMS | 第三丁基二甲基矽烷基 |
TBDMSCl | 第三丁基二甲基矽烷基氯 |
TBSOTf | 第三丁基二甲基矽烷基三氟甲磺酸酯 |
TEA | 三甲胺 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
TLC | 薄層層析法 |
在一些實施例中,本發明提供式(I)化合物:;
其中:為單鍵或雙鍵;
X為O或NR7
;
R12
為氫或-C(O)R1
;
R1
為C1 - 6
烷基、C1 - 6
鹵烷基、C2 - 6
烯基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、3-12員雜環基、5-10員雜芳基、-OR7
或-NR8
R9
,其中
該C1 - 6
烷基、C1 - 6
雜烷基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、3-12員雜環基及5-10員雜芳基視情況經1-5個R10
基團取代;
R2
為氫、C1 - 6
烷基、C1 - 6
雜烷基、C3 - 10
環烷基或3-12員雜環基,其中
該C1 - 6
烷基、C1 - 6
雜烷基、C3 - 10
環烷基及3-12員雜環基視情況經1-5個R10
基團取代;
R3
及R4
獨立地為氫、C1 - 6
烷基、-OR7
、C1 - 6
雜烷基、-NR8
R9
、NR8
C(O)R9
、-NR8
C(O)OR9
、C6 - 10
芳基、C3 - 10
環烷基、5-10員雜芳基、3-12員雜環基、-C(O)R7
、-C(O)OR7
、-C(O)NR8
R9
、-OC(O)NR8
R9
、-CN或-SO2
R7
,其中
該C1 - 6
烷基、C1 - 6
雜烷基、C6 - 10
芳基、C3 - 10
環烷基、5-10員雜芳基及3-12員雜環基視情況經1-5個R10
基團取代;
R5
為氫、C1 - 6
烷基、-(CH2
CH2
O)p
R7
、C1 - 6
雜烷基、C6 - 10
芳基、C3 - 10
環烷基、5-10員雜芳基或3-12員雜環基,其中
該C1 - 6
烷基、C1 - 6
雜烷基、C6 - 10
芳基、C3 - 10
環烷基、5-10員雜芳基及3-12員雜環基視情況經1-5個R10
基團取代;
R6
為氫或鹵基;
各R7
獨立地為氫、C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基或5-10員雜芳基,其中
該C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基及5-10員雜芳基視情況經1-5個R10
取代;
各R8
及R9
獨立地為氫、C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基或5-10員雜芳基,或R8
及R9
連同其所連接之原子一起形成3-12員雜環,其中
該C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基及5-10員雜芳基視情況經1-5個R10
取代;
各R10
獨立地為C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基、5-10員雜芳基、鹵基、側氧基、-ORa
、-C(O)Ra
、-C(O)ORa
、-C(O)NRa
Rb
、-OC(O)NRa
Rb
、-NRa
Rb
、-NRa
C(O)Rb
、-NRa
C(O)ORb
、-S(O)q
Ra
、-S(O)2
NRa
Rb
、-NRa
S(O)2
Rb
、-N3
、-CN或-NO2
,或兩個R10
基團形成稠合、螺或橋聯C3 - 10
環烷基或3-12員雜環基,其中
各C1 - 6
烷基、C1 - 6
雜烷基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、3-12員雜環及5-10員雜芳基視情況經1-5個R20
基團取代;
各Ra
及Rb
獨立地為氫、C1 - 6
烷基、C2 - 6
烯基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基、5-10員雜芳基,或Ra
及Rb
連同其所連接之原子一起形成3-12員雜環基,其中
該C1 - 6
烷基、C2 - 6
烯基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基、5-10員雜芳基視情況經1-5個R20
基團取代;
各R20
獨立地為C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6
-C10
芳基、5-10員雜芳基、羥基、C1 - 6
烷氧基、胺基、-CN、-C(O)H、-C(O)NH2
、-C(O)NH(C1 - 6
烷基)、-C(O)N(C1 - 6
烷基)2
、-COOH、-C(O)C1 - 6
烷基、-C(O)OC1 - 6
烷基或鹵素;
n為0、1或2;
p為0、1或2;且
q為0、1或2;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供根據式(Ia)之式(I)化合物:;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(II)化合物:;
其中:為單鍵或雙鍵;
R1
為C1 - 6
烷基、C1 - 6
鹵烷基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、5-10員雜芳基、C1 - 6
羥烷基、-OC1 - 6
烷基、-NHC1 - 6
烷基、-NHC1 - 6
鹵烷基、4-6員雜環基、C3 - 6
環烷基、-NHC3 - 10
環烷基或-N(C1 - 6
烷基)2
,其中
該C1 - 6
烷基視情況經C1 - 6
烷氧基、-N(C1 - 6
烷基)2
、5-10員雜芳基、C3 - 6
環烷基、-SO2
C1 - 6
烷基、苯基、5員雜芳氧基、苯氧基或-O-(4-10員雜環基)取代,
該5-10員雜芳基視情況經1或2個選自鹵基、C1 - 6
烷基及C1 - 6
鹵烷基之取代基取代,
該5員雜芳氧基視情況經1-3個C1 - 6
烷基取代,且
該苯基視情況經1-3個鹵基或C1 - 6
鹵烷基取代;
該-NHC3 - 6
環烷基視情況經C1 - 3
鹵烷基取代;
該-NHC1 - 6
烷基視情況經苯基、5-6員雜芳基或C3 - 6
環烷基取代,其中
該苯基視情況經1-5個鹵基取代,
該5至6員雜芳基視情況經1-3個鹵基或C1 - 6
烷基取代,且
該C1 - 6
羥烷基視情況經苯基取代;
該C3 - 6
環烷基視情況經5員雜芳基取代,其中
該5員雜芳基視情況經C1 - 6
烷基取代;
該-OC1 - 6
烷基視情況經5員雜芳基取代,其中
該5員雜芳基視情況經C1 - 6
烷基取代;
該5-10員雜芳基視情況經C1 - 6
烷基取代;
R2
為氫或C1 - 6
烷基;
R3
為氫或C1 - 6
烷基;
R4
為氫;且
R5
為氫或C1 - 6
烷基,其中
該C1 - 6
烷基視情況經5-6員雜環基取代;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供根據式(IIa)之式(II)化合物:;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)或式(IIa)化合物,其中:
R2
為氫或C1 - 3
烷基;
R3
為氫或C1 - 3
烷基;
R4
為氫;且
R5
為C1 - 3
烷基,其中
該C1 - 3
烷基視情況經5-6員雜環基取代;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)或式(IIa)化合物,其中:
R2
為氫、甲基或乙基;
R3
為氫或甲基;
R4
為氫;且
R5
為氫、甲基、;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)或式(IIa)化合物,其中:
R2
為氫;且
R3
為C1 - 3
烷基;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)或式(IIa)化合物,其中:
R2
為C1 - 3
烷基;且
R3
為氫;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)或式(IIa)化合物,其中:
R2
為氫;且
R3
為氫;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)或式(IIa)化合物,其中:
R2
為C1 - 3
烷基;且
R3
為C1 - 3
烷基;
或其醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(III)化合物或其醫藥學上可接受之鹽:;
其中:為單鍵或雙鍵;
R1
為C1 - 6
烷基、C1 - 6
鹵烷基、C2 - 6
烯基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、3-12員雜環基、5-10員雜芳基、-OR7
或-NR8
R9
;
其中R1
之該C1 - 6
烷基、C1 - 6
鹵烷基、C2 - 6
烯基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、3-12員雜環基及5-10員雜芳基獨立地視情況經1-5個R10
基團取代;
各R2
、R3
、R4
及R5
獨立地為氫或C1 - 6
烷基;
R6
為氫或鹵基;
各R7
獨立地為氫或C1 - 6
烷基,其中
該C1 - 6
烷基視情況經1-5個R10
取代;
各R8
及R9
獨立地為氫、C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基或5-10員雜芳基,或R8
及R9
連同其所連接之原子一起形成3-12員雜環,其中
R8
及R9
之該C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基及5-10員雜芳基獨立地視情況經1-5個R10
取代;
各R10
獨立地為C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基、5-10員雜芳基、鹵基、側氧基、-ORa
、-C(O)Ra
、-C(O)ORa
、-C(O)NRa
Rb
、-OC(O)NRa
Rb
、-NRa
Rb
、-NRa
C(O)Rb
、-NRa
C(O)ORb
、-S(O)q
Ra
、-S(O)2
NRa
Rb
、-NRa
S(O)2
Rb
、-N3
、-CN或-NO2
,或兩個R10
基團形成稠合、螺或橋聯C3 - 10
環烷基或3-12員雜環基,其中
R10
之各C1 - 6
烷基、C1 - 6
雜烷基、C2 - 6
炔基、C3 - 10
環烷基、C6 - 10
芳基、3-12員雜環及5-10員雜芳基獨立地視情況經1-5個R20
基團取代;
各Ra
及Rb
獨立地為氫、C1 - 6
烷基、C2 - 6
烯基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基或5-10員雜芳基,或Ra
及Rb
連同其所連接之原子一起形成3-12員雜環基,其中
Ra
及Rb
之該各C1 - 6
烷基、C2 - 6
烯基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基、5-10員雜芳基獨立地視情況經1-5個R20
基團取代;
各R20
獨立地為C1 - 6
烷基、C3 - 10
環烷基、C1 - 6
雜烷基、3-12員雜環基、C6 - 10
芳基、5-10員雜芳基、羥基、C1 - 6
烷氧基、胺基、-CN、-C(O)H、-C(O)NH2
、-C(O)NH(C1 - 6
烷基)、-C(O)N(C1 - 6
烷基)2
、-COOH、-C(O)C1 - 6
烷基、-C(O)OC1 - 6
烷基或鹵素;
n為0、1或2;且
q為0、1或2。
在一些實施例中,本發明提供根據式(IIIa)之式(III)化合物:;
或其醫藥學上可接受之鹽。
在一些實施例中,本發明提供根據式(IIIb)之式(III)化合物或其醫藥學上可接受之鹽:;
其中:R1
為C1 - 6
烷基、C3 - 10
環烷基、C6 - 10
芳基、5-10員雜芳基、-NHC1 - 6
烷基、-NHC1 - 6
鹵烷基、4-6員雜環基、C3 - 6
環烷基、-NHC3 - 10
環烷基或-NH(4-6員雜環基);
R1
之各C1 - 6
烷基及-NHC1 - 6
烷基獨立地視情況經1-3個獨立地選自羥基、C1 - 6
烷氧基、5-10員雜芳基、C3 - 6
環烷基、苯基或-O-(4-10員雜環基)之取代基取代;
其中各5-10員雜芳基、C3 - 6
環烷基、苯基及-O-(4-10員雜環基)獨立地視情況經1-4個獨立地選自鹵基、C1 - 6
烷基及C1 - 6
鹵烷基之取代基取代;
R1
之各C6 - 10
芳基及5-10員雜芳基視情況經1-3個獨立地選自鹵基、羥基、-CN、C1 - 6
烷基、C1 - 6
鹵烷基、C1 - 6
雜烷基、4-6員雜環基及C3 - 6
環烷基之取代基取代;且
R1
之各4-6員雜環基、C3 - 6
環烷基、-NHC3 - 10
環烷基及-NH(4-6員雜環基)視情況經1至3個獨立地選自鹵基、側氧基、羥基、-CN、C1 - 6
烷基、C1 - 6
鹵烷基、C1 - 6
雜烷基、-C(O)ORa
、C6 - 10
芳基、5-10員雜芳基、4-6員雜環基及C3 - 6
環烷基之取代基取代;
其中各C6 - 10
芳基、5-10員雜芳基、4-6員雜環基及C3 - 6
環烷基獨立地視情況經1-3個獨立地選自鹵基、C1 - 4
烷基及C1 - 4
鹵烷基之取代基取代;
各R2
、R3
、R4
及R5
獨立地為氫或C1 - 6
烷基;且
R6
為氫或鹵基。
在一些實施例中,本發明提供式(IIIc)化合物或其醫藥學上可接受之鹽:;
各R1
、R2
、R3
、R4
、R5
及R6
如上文或本發明中之其他地方所定義。
在一些實施例中,本發明提供式(IIId)化合物或其醫藥學上可接受之鹽:;
各R1
、R2
、R3
、R4
、R5
及R6
如上文或本發明中之其他地方所定義。
在一些實施例中,本發明提供式(IV)化合物或其醫藥學上可接受之鹽:;
其中:R1
為C3 - 10
環烷基、3-12員雜環基、C6 - 10
芳基或5-10員雜芳基;
其中R1
獨立地視情況經1-4個R10
取代;
其中各R10
獨立地選自鹵基、羥基、-CN、C1 - 6
烷基、C1 - 6
雜烷基、C3 - 10
環烷基及3-12員雜環基;
其中R10
之C1 - 6
烷基、C1 - 6
雜烷基、C3 - 10
環烷基及3-12員雜環基獨立地視情況經1-4個獨立地選自鹵基、C1 - 4
烷基、C1 - 4
鹵烷基及C1 - 4
雜烷基之取代基取代;
R2
為氫、C1 - 6
烷基或C1 - 6
雜烷基;
其中R2
之C1 - 6
烷基及C1 - 6
雜烷基視情況經1-3個獨立地選自鹵基、側氧基及羥基之取代基取代;
R3
及R4
獨立地為氫、C1 - 6
烷基、C1 - 6
雜烷基、-OR7
或-SO2
R7
;
其中R3
及R4
之C1 - 6
烷基及C1 - 6
雜烷基獨立地視情況經1-3個獨立地選自鹵基、側氧基、C3 - 6
環烷基、4-6員雜環基、C6 - 10
芳基及5-10員雜芳基之取代基取代;
其中C3 - 6
環烷基、4-6員雜環基、C6 - 10
芳基及5-10員雜芳基獨立地視情況經1-3個獨立地選自鹵基、C1 - 4
烷基及C1 - 4
雜烷基之取代基取代;
R5
為氫、C1 - 6
烷基或C1 - 6
雜烷基;
其中R5
之C1 - 6
烷基及C1 - 6
雜烷基視情況經1-3個獨立地選自鹵基、側氧基、C3 - 6
環烷基及4-6員雜環基之取代基取代;且
R7
獨立地為氫、C1 - 6
烷基、C1 - 6
雜烷基、C3 - 10
環烷基、3-10員雜環基、C6 - 10
芳基或5-10員雜芳基;
其中R7
之C1 - 6
烷基、C1 - 6
雜烷基、C3 - 10
環烷基、3-10員雜環基、C6 - 10
芳基及5-10員雜芳基視情況經1-4個獨立地選自鹵基、側氧基、C1 - 4
烷基、C1 - 4
鹵烷基及C1 - 4
雜烷基之取代基取代。
在一些實施例中,本發明提供根據式(IVa)之式(IV)化合物或其醫藥學上可接受之鹽:;
其中:R1
為3-12員雜環基或5-10員雜芳基;
其中R1
獨立地視情況經1-4個R10
取代;
其中各R10
獨立地選自鹵基、羥基、-CN、C1 - 4
烷基、C1 - 4
烷氧基、C3 - 6
環烷基及3-6員雜環基;
各R2
、R3
及R4
獨立地為氫、C1 - 4
烷基或C1 - 4
烷氧基。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中雜環基為含有一或多個雙鍵之部分不飽和環系統。在一些實施例中,雜環基為與一個芳環及一個非芳環之稠環系統,但非完全芳環系統。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R2
為氫。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R2
為C1 - 3
烷基。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R2
為甲基。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R3
為C1 - 3
烷基。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R3
為甲基。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R4
為氫。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R5
為C1 - 3
烷基。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R5
為甲基。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R6
為Cl。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)或式(IIa)化合物,其中-C(O)R1
選自由以下組成之群: ;
或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R1
選自: ;或其醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R1
選自: ;或其醫藥學上可接受之鹽。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)或式(IIIb)化合物或其互變異構體或醫藥學上可接受之鹽,其中R1
選自: 。
在一些實施例中,本發明提供式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其醫藥學上可接受之鹽,其中R1
為視情況經1-2個R10
取代之3-12員雜環基或5-10員雜芳基。
在一些實施例中,本發明提供式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其醫藥學上可接受之鹽,其中R1
選自:;其中之各者視情況經1-2個R10
取代。在一些實施例中,各R10
獨立地選自-CH3
、-CHF2
及-OCH3
。
在一些實施例中,R1
為,其視情況經1-2個R10
取代。在一些實施例中,R1
為,其視情況經1-2個R10
取代。在一些實施例中,R10
獨立地選自C1 - 4
烷基及C1 - 4
烷氧基。在一些實施例中,R10
獨立地選自-CH3
及-OCH3
。在一些實施例中,R1
為,其經-CH3
及-OCH3
取代。
在一些實施例中,R1
為。在一些實施例中,R1
為。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其醫藥學上可接受之鹽,其中R2
為氫或C1 - 3
烷基。在一些實施例中,R2
選自氫及甲基。在一些實施例中,R2
為氫。在一些實施例中,R2
為甲基。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其醫藥學上可接受之鹽,其中R3
為氫或C1 - 3
烷基。在一些實施例中,R3
選自氫及甲基。在一些實施例中,R3
為甲基。在一些實施例中,R3
為氫。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其醫藥學上可接受之鹽,其中R4
為氫、C1 - 3
烷基或C1 - 3
烷氧基。在一些實施例中,R4
選自氫、甲基及-OCH3
。在一些實施例中,R4
為氫。在一些實施例中,R4
為-OCH3
。在一些實施例中,R4
為甲基。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其醫藥學上可接受之鹽,其中R2
及R4
為氫,且R3
為甲基。在一些實施例中,R2
及R3
為甲基,且R4
為氫。在一些實施例中,R2
為氫,R3
為甲基,且R4
為-OCH3
。
在一些實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)或式(IV)化合物或其醫藥學上可接受之鹽,其中R5
為氫或C1 - 3
烷基。在一些實施例中,R5
為甲基。在一些實施例中,R5
為氫。
在一些實施例中,本發明提供選自實例1-464之化合物。
在一些實施例中,本發明提供選自實例1-154之化合物。
在一些實施例中,本發明提供選自實例155-464之化合物。
在一些實施例中,本發明提供選自由以下組成之群之化合物: ;
或其醫藥學上可接受之鹽。
在一些實施例中,本發明提供選自以下之化合物: 。
在一些實施例中,本發明提供選自以下之化合物: 。
在一些實施例中,本文提供經同位素標記形式之式(I)、式(Ia)、式(II)或式(IIa)化合物。在一些實施例中,本文提供經同位素標記形式之式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物。除一或多個原子經具有選定原子質量或質量數之同位素置換之外,經同位素標記之化合物具有由本文所給出之式所描繪之結構。除一或多個原子經具有選定原子質量或質量數之同位素置換之外,經同位素標記之化合物具有由本文所給出之式所描繪之結構。可摻入本發明之化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素,諸如但不限於2
H (氘, D)、3
H (氚)、11
C、13
C、14
C、15
N、18
F、31
P、32
P、35
S、36
Cl及125
I。各種本發明之經同位素標記之化合物(例如其中摻入有諸如3
H、13
C及14
C之放射性同位素之經同位素標記之化合物)係在本發明的範圍內。該等經同位素標記之化合物可適用於代謝研究、反應動力學研究、偵測或成像技術(諸如正電子發射斷層攝影術(PET)或單光子發射電腦斷層攝影術(SPECT),包括藥物或受質組織分佈分析)或適用於治療患者。該等本發明之化合物之經同位素標記之類似物亦可適用於治療本文所揭示之疾病,此係因為其可相對於未經標記形式之相同化合物提供經改良之藥物動力學及/或藥效學特性。該等同位素級形式之本文化合物或本文化合物之類似物係在本發明之範圍內。熟習此項技術者能夠遵循用於對化合物或化合物態樣進行同位素標記之程序製備及使用該等經同位素標記之形式以得到本文所揭示之化合物之同位素或放射性標記類似物。
本文所揭示之化合物可含有一或多個不對稱中心且因此可產生對映異構體、非對映異構體及可就絕對立體化學而言針對胺基酸定義為(R
)-或(S
)-或定義為(D)-或(L)-之其他立體異構形式。本發明意在包括所有該等可能性異構體以及其外消旋及光學純形式。具光學活性之(+)及(-)、(R
)-及(S
)-或(D)-及(L)-異構體可使用對掌性合成子或對掌性試劑來製備,或使用例如層析法及分步結晶法之習知技術來分解。用於製備/分離個別對映異構體之習知技術包括由合適光學純前驅體進行對掌性合成,或使用例如對掌性高壓液相層析法(HPLC)對外消旋體(或鹽或衍生物之外消旋體)進行分解。同樣,亦意欲包括所有互變異構形式。
在某些實施例中,本發明提供包含本發明之化合物或其醫藥學上可接受之鹽及醫藥學上可接受之賦形劑的醫藥組合物。在某些實施例中,醫藥組合物包含如下文更詳細地描述之一或多種額外治療劑。
包含本文所揭示之化合物或其醫藥學上可接受之鹽之醫藥組合物可用可根據一般實踐選擇之一或多種醫藥學上可接受之賦形劑來製備。「醫藥學上可接受之賦形劑」包括但不限於任何佐劑、載劑、賦形劑、滑動劑、甜味劑、稀釋劑、防腐劑、染料/著色劑、風味增強劑、界面活性劑、潤濕劑、分散劑、懸浮劑、穩定劑、等張劑、溶劑或乳化劑,該等試劑已經美國食品藥物管理局(United States Food and Drug Administration)批准為可接受用於人類或家畜。
在某些實施例中,提供呈包括固體口服劑型(諸如錠劑)之固體劑型之醫藥組合物。錠劑可含有包括滑動劑、填充劑、黏合劑及其類似物之賦形劑。水性組合物可以無菌形式製備,且在意欲用於藉由除經口投與以外之途徑進行遞送時一般可為等張的。所有組合物均可視情況含有賦形劑,諸如Rowe等人, Handbook of Pharmaceutical Excipients, 第6版, American Pharmacists Association, 2009中所闡述之賦形劑。賦形劑可包括抗壞血酸及其他抗氧化劑、螯合劑(諸如EDTA)、碳水化合物(諸如糊精)、羥烷基纖維素、羥烷基甲基纖維素、硬脂酸及其類似物。
本文所揭示之醫藥組合物包括適用於包括經口投與之各種投與途徑之醫藥組合物。組合物可以單位劑型呈現,且可藉由製藥技術中眾所周知之方法中之任一種來製備。該等方法包括使活性成分(例如本發明之化合物或其醫藥鹽)與一或多種醫藥學上可接受之賦形劑結合之步驟。組合物可藉由使活性成分與液體賦形劑或細粉狀固體賦形劑或兩者均勻且緊密地結合,且隨後視需要使產物成形來製備。技術及配方一般見於Remington: The Science and Practice of Pharmacy, 第21版, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006中。
適用於經口投與之本文所描述之組合物可以包括但不限於各自含有預定量之活性成分之膠囊、扁囊劑或錠劑之離散單元(單位劑型)形式呈現。在一個實施例中,醫藥組合物為錠劑。
本文所揭示之醫藥組合物包含一或多種本文所揭示之化合物或其醫藥學上可接受之鹽以及醫藥學上可接受之賦形劑及視情況選用之其他治療劑。含有活性成分之醫藥組合物可呈適用於預期投與方法之任何形式。當用於例如經口使用時,可製備錠劑、糖衣錠、口含錠、水性或油性懸浮液、可分散散劑或顆粒劑、乳液、硬膠囊或軟膠囊、糖漿或酏劑。可根據製造醫藥組合物之技術中已知之任何方法製備意欲用於口服使用之組合物,且該等組合物可含有一或多種包括甜味劑、調味劑、著色劑及防腐劑之賦形劑以便提供可口製劑。含有與適用於製造錠劑之無毒醫藥學上可接受之賦形劑混合之活性成分的錠劑為可接受的。此等賦形劑可為例如惰性稀釋劑,諸如碳酸鈣或碳酸鈉、乳糖、單水合乳糖、交聯羧甲纖維素鈉、聚維酮、磷酸鈣或磷酸鈉;粒化劑及崩解劑,諸如玉米澱粉或海藻酸;黏合劑,諸如纖維素、微晶纖維素、澱粉、明膠或阿拉伯膠;及潤滑劑,諸如硬脂酸鎂、硬脂酸或滑石。錠劑可未經包覆或可藉由包括微膠囊化之已知技術包覆以延緩在胃腸道中之崩解及吸附,且藉此在較長時段內提供持續作用。舉例而言,可單獨或與蠟一起採用諸如單硬脂酸甘油酯或二硬脂酸甘油酯之時間延遲物質。
可與非活性成分組合以產生劑型之活性成分之量可視預期治療個體及特定投與模式而變化。舉例而言,在一些實施例中,用於向人類經口投與之劑型可含有約1至1000 mg活性物質,該活性物質與適當且適宜量之醫藥學上可接受之賦形劑一起調配。在某些實施例中,醫藥學上可接受之賦形劑在總組合物之約5至約95% (重量:重量)範圍內變化。
方法
在一些實施例中,本發明提供抑制MCL-1之方法。在一些實施例中,本發明提供抑制個體(例如人類)中之MCL-1之方法,其包含向個體投與式(I)化合物或其互變異構體或醫藥學上可接受之鹽。
在一些實施例中,本發明提供治療或預防癌症之方法。在某些實施例中,本發明提供治療或預防癌症之方法,其包含向患者投與治療有效量之式(I)化合物或其互變異構體或醫藥學上可接受之鹽。在一些實施例中,癌症為惡性血液病。在一些實施例中,癌症為多發性骨髓瘤。在一些實施例中,癌症係選自由以下組成之群:乳癌、結腸直腸癌、皮膚癌、黑色素瘤、卵巢癌、腎癌、小細胞肺癌、非小細胞肺癌、淋巴瘤及白血病。
本文所揭示之化合物可藉由適用於本文所描述之方法中之任何途徑來投與。合適途徑包括經口、經直腸、經鼻、局部(包括頰內及舌下)、經皮、經陰道及非經腸(包括皮下、肌內、靜脈內、皮內、鞘內及硬膜外)及其類似途徑。
本文所揭示之化合物可根據有效給藥方案投與至個體達所需時間段或持續時間,諸如至少一週、至少約一個月、至少約2個月、至少約3個月、至少約6個月或至少約12個月或更長。在一個變化形式中,按每日或間歇性時程投與化合物達個體生命之持續時間。
本發明之化合物之劑量或給藥頻率可在治療過程基於投與醫師之判斷來調整。
本文所揭示之化合物之治療有效量為約0.00001 mg/kg體重/天至約10 mg/kg體重/天,諸如約0.0001 mg/kg體重/天至約10 mg/kg體重/天,或諸如約0.001 mg/kg體重/天至約1 mg/kg體重/天,或諸如約0.01 mg/kg體重/天至約1 mg/kg體重/天,或諸如約0.05 mg/kg體重/天至約0.5 mg/kg體重/天,或諸如約0.3 μg至約30 mg/天,或諸如約0.3 μg至約30 mg/天。
式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與本發明之化合物的任何劑量(例如1 mg至1000 mg化合物)的一或多種額外治療劑組合。式(I)、式(Ia)、式(II)或式(IIa)化合物或其互變異構體或醫藥學上可接受之鹽之治療有效量可在約0.01 mg/劑量至約1000 mg/劑量,諸如約0.01 mg/劑量至約100 mg/劑量,或諸如約0.1 mg/劑量至約100 mg/劑量,或諸如約1 mg/劑量至約100 mg/劑量,或諸如約1 mg/劑量至約10 mg/劑量範圍內。式(I)、式(Ia)、式(II)或式(IIa)化合物之其他治療有效量為約1 mg/劑量,或約2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或約100 mg/劑量。式(I)、式(Ia)、式(II)或式(IIa)化合物之其他治療有效量為約100 mg/劑量,或約125、150、175、200、225、250、275、300、350、400、450或約500 mg/劑量。
式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽之治療有效量可在約0.01 mg/劑量至約1000 mg/劑量,諸如約0.01 mg/劑量至約100 mg/劑量,或諸如約0.1 mg/劑量至約100 mg/劑量,或諸如約1 mg/劑量至約100 mg/劑量,或諸如約1 mg/劑量至約10 mg/劑量範圍內。式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物之其他治療有效量為約1 mg/劑量,或約2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95或約100 mg/劑量。式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物之其他治療有效量為約100 mg/劑量,或約125、150、175、200、225、250、275、300、350、400、450或約500 mg/劑量。
可每小時、每日或每週投與單次劑量。舉例而言,單次劑量可每1小時、2小時、3小時、4小時、6小時、8小時、12小時、16小時投與一次或每24小時投與一次。單次劑量亦可每1天、2天、3天、4天、5天、6天投與一次或每7天投與一次。單次劑量亦可每1週、2週、3週投與一次或每4週投與一次。在某些實施例中,單次劑量可每週投與一次。單次劑量亦可每月投與一次。在一些實施例中,在本文所揭示之方法中本文所揭示之化合物每日投與一次。在一些實施例中,在本文所揭示之方法中本文所揭示之化合物每日投與兩次。
本文所揭示之化合物之給藥頻率應由個別患者之需要確定,且可為例如每天一次或兩次或每天更多次。化合物之投與持續治療癌症所必需之時長。舉例而言,可將本文所揭示之化合物投與至患有癌症之人類達20天至180天之時段,或例如達20天至90天之時段,或例如達30天至60天之時段。
投與可為間歇性的,其中在數天或更多天之時段期間患者接受日劑量之本文所揭示之化合物,隨後在數天或更多天之時段期間患者不接受日劑量之化合物。舉例而言,患者可每隔一天或每週三次接受一劑量之化合物。再次作為非限制性實例,患者可每日接受一劑量之化合物達1天至14天之時段,隨後在7天至21天之時段期間患者不接受一劑量之化合物,隨後在後續時段(例如1天至14天)期間患者再次接受日劑量之化合物。可視治療患者之臨床需要來重複交替時段之化合物投與,繼而化合物不投與。
組合療法
亦提供治療方法,其中向患者給與與一或多種額外活性劑或療法組合之式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽。
因此,在一個實施例中,一種治療癌症及/或疾病或共呈現或由癌症加劇或觸發之症狀(例如過敏性病症及/或自體免疫疾病及/或發炎性疾病及/或急性發炎性反應)之方法,其包含向有需要之患者投與視情況與可適用於治療癌症、過敏性病症及/或自體免疫疾病及/或發炎性疾病及/或作為癌症意外事件或與癌症共呈現之急性發炎性反應之額外藥劑(例如第二、第三、第四或第五活性劑)組合的有效量之式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽。利用第二、第三、第四或第五活性劑進行之治療可在利用式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽進行之治療之前、與其同時或在其之後。在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽與呈單一劑型之另一活性劑組合。可與式(I)、式(Ia)、式(II)或式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽組合使用之合適抗腫瘤或抗癌治療劑包括但不限於化學治療劑,例如絲裂黴素C、卡鉑(carboplatin)、紫杉醇、順鉑、太平洋紫杉醇、依託泊苷(etoposide)、小紅莓或包含前述化學治療劑中之至少一種的組合。亦可單獨或與化學治療劑組合使用放射性治療抗腫瘤劑。
式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可適用作化學敏化劑,且因此可適用於與其他化學治療藥物(詳言之,誘導細胞凋亡之藥物)組合。因此,在一個實施例中,本發明提供用於增加癌細胞對化學療法之敏感度之方法,其包含以足以增加癌細胞對化學治療劑之敏感度之量向需要化學療法或經受化學療法之患者投與化學治療劑以及式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽。
可與式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽組合使用之其他化學治療藥物之實例包括拓樸異構酶I抑制劑(喜樹鹼或拓朴替康(topotecan))、拓樸異構酶II抑制劑(例如道諾黴素(daunomycin)及依託泊苷)、烷基化劑(例如環磷醯胺、美法侖(melphalan)及BCNU)、微管蛋白定向劑(例如紫杉醇及長春花鹼)及生物藥劑(例如諸如抗CD20抗體之抗體、IDEC 8、免疫毒素及細胞介素)。
在一些實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽與Rituxan® (利妥昔單抗(Rituximab))及/或藉由選擇性耗乏CD20+ B細胞而起作用之其他藥劑組合使用。
本文包括治療方法,其中式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽與消炎劑組合投與。消炎劑包括但不限於NSAID、非特異性及COX-2特異性環氧酶酶抑制劑、金化合物、皮質類固醇、甲胺喋呤、腫瘤壞死因子受體(TNF)受體拮抗劑、免疫抑制劑及甲胺喋呤。
NSAID之實例包括但不限於布洛芬(ibuprofen)、氟比洛芬(flurbiprofen)、萘普生(naproxen)及萘普生鈉、雙氯芬酸(diclofenac)、雙氯芬酸鈉與米索前列醇(misoprostol)之組合、舒林酸(sulindac)、奧沙普嗪(oxaprozin)、二氟尼柳(diflunisal)、吡羅昔康(piroxicam)、吲哚美辛(indomethacin)、依託度酸(etodolac)、非諾洛芬鈣(fenoprofen calcium)、酮洛芬(ketoprofen)、萘丁美酮鈉(sodium nabumetone)、柳氮磺胺吡啶(sulfasalazine)、托美丁鈉(tolmetin sodium)及羥氯喹(hydroxychloroquine)。NSAID之實例亦包括COX-2特異性抑制劑(亦即抑制IC50
比COX-1之IC50
低至少50倍之COX-2之化合物),諸如塞內昔布(celecoxib)、伐地昔布(valdecoxib)、盧米羅可(lumiracoxib)、依他昔布(etoricoxib)及/或羅非昔布(rofecoxib)。
在另一實施例中,消炎劑為水楊酸鹽。水楊酸鹽包括但不限於乙醯水楊酸或阿司匹靈(aspirin)、水楊酸鈉及水楊酸膽鹼以及水楊酸鎂。
消炎劑亦可為皮質類固醇。舉例而言,皮質類固醇可選自皮質酮、地塞米松(dexamethasone)、甲潑尼龍(methylprednisolone)、潑尼龍、潑尼龍磷酸鈉及潑尼松(prednisone)。在一些實施例中,消炎治療劑為金化合物,諸如硫代蘋果酸金鈉或金諾芬(auranofin)。在一些實施例中,消炎劑為代謝抑制劑,諸如二氫葉酸還原酶抑制劑,諸如甲胺喋呤;或二氫乳清酸去氫酶抑制劑,諸如來氟米特(leflunomide)。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽與至少一種消炎化合物組合使用,該至少一種消炎化合物為抗C5單株抗體(諸如依庫珠單抗(eculizumab)或培克珠單抗(pexelizumab))、TNF拮抗劑(諸如依那西普(entanercept))、或作為抗TNF α單株抗體之英夫利昔單抗(infliximab)。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽與至少一種活性劑組合使用,該至少一種活性劑為諸如甲胺喋呤、來氟米特、環孢靈(cyclosporine)、他克莫司(tacrolimus)、硫唑嘌呤(azathioprine)或黴酚酸嗎啉乙酯之免疫抑制劑化合物。
在其他實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽與一或多種磷脂醯肌醇3-激酶(PI3K)抑制劑組合使用,該等抑制劑包括例如化合物A、B及C (其結構提供於下文中)或其醫藥學上可接受之鹽。
化合物A | 化合物B | 化合物C |
化合物A、B及C揭示於WO2015/017460及WO2015/100217中。PI3K抑制劑之額外實例包括但不限於ACP-319、AEZA-129、AMG-319、AS252424、AZD8186、BAY 10824391、BEZ235、布帕利布(buparlisib) (BKM120)、BYL719 (阿博利布(alpelisib))、CH5132799、庫潘尼西(copanlisib) (BAY 80-6946)、杜維力絲(duvelisib)、GDC-0941、GDC-0980、GSK2636771、GSK2269557、艾代拉里斯(idelalisib) (Zydelig®)、IPI-145、IPI-443、IPI-549、KAR4141、LY294002、LY3023414、MLN1117、OXY111A、PA799、PX-866、RG7604、瑞戈替布(rigosertib)、RP5090、泰尼西布(taselisib)、TG100115、TGR-1202、TGX221、WX-037、X-339、X-414、XL147 (SAR245408)、XL499、XL756、渥曼青黴素(wortmannin)、ZSTK474,及WO 2005/113556 (ICOS)、WO 2013/052699 (Gilead Calistoga)、WO 2013/116562 (Gilead Calistoga)、WO 2014/100765 (Gilead Calistoga)、WO 2014/100767 (Gilead Calistoga)及WO 2014/201409 (Gilead Sciences)中所描述之化合物。
在又另一實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與脾酪胺酸激酶(SYK)抑制劑組合使用。SYK抑制劑之實例包括但不限於6-(1H-吲唑-6-基)-N-(4-嗎啉基苯基)咪唑并[1,2-a]吡嗪-8-胺、BAY-61-3606、賽度替尼(cerdulatinib) (PRT-062607)、恩妥替尼(entospletinib)、福他替尼(fostamatinib) (R788)、HMPL-523、NVP-QAB 205 AA、R112、R343、塔馬替尼(tamatinib) (R406)以及U.S. 8450321 (Gilead Connecticut)中所描述之SYK抑制劑及U.S. 2015/0175616中所描述之SYK抑制劑。
在又另一實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與酪胺酸-激酶抑制劑(TKI)組合使用。TKI可靶向表皮生長因子受體(EGFR)及用於纖維母細胞生長因子(FGF)、血小板源性生長因子(PDGF)及血管內皮生長因子(VEGF)之受體。TKI之實例包括但不限於阿法替尼(afatinib)、ARQ-087、asp5878、AZD3759、AZD4547、伯舒替尼(bosutinib)、布加替尼(brigatinib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、克諾拉尼(crenolanib)、達可替尼(dacomitinib)、達沙替尼(dasatinib)、多韋替尼(dovitinib)、E-6201、厄達替尼(erdafitinib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、吉列替尼(gilteritinib) (ASP-2215)、FP-1039、HM61713、埃克替尼(icotinib)、伊馬替尼(imatinib)、KX2-391 (Src)、拉帕替尼(lapatinib)、來他替尼(lestaurtinib)、米哚妥林(midostaurin)、尼達尼布(nintedanib)、ODM-203、奧希替尼(osimertinib) (AZD-9291)、普納替尼(ponatinib)、波齊替尼(poziotinib)、喹雜替尼(quizartinib)、拉多替尼(radotinib)、羅西替尼(rociletinib)、索凡替尼(sulfatinib) (HMPL-012)、舒尼替尼(sunitinib)及TH-4000。
在又其他實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與一或多種類離胺醯氧化酶2 (LOXL)或結合至LOXL之物質之抑制劑組合使用,該等抑制劑包括例如具有針對人類LOXL2之免疫球蛋白IgG4同型之人類化單株抗體(mAb)。LOXL抑制劑之實例包括但不限於WO 2009/017833 (Arresto Biosciences)中所描述之抗體。LOXL2抑制劑之實例包括但不限於WO 2009/017833 (Arresto Biosciences)、WO 2009/035791 (Arresto Biosciences)及WO 2011/097513 (Gilead Biologics)中所描述之抗體。
在又另一實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與類鐸受體8 (TLR8)抑制劑組合使用。TLR8抑制劑之實例包括但不限於E-6887、IMO-4200、IMO-8400、IMO-9200、MCT-465、MEDI-9197、莫托莫特(motolimod)、雷西莫特(resiquimod)、VTX-1463及VTX-763。
在又另一實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與類鐸受體9(TLR9)抑制劑組合使用。TLR9抑制劑之實例包括但不限於IMO-2055、IMO-2125、勒菲妥莫特(lefitolimod)、利騰莫特(litenimod)、MGN-1601及PUL-042。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽適用於與BTK (布魯東氏酪胺酸激酶(Bruton's Tyrosine kinase))抑制劑組合來治療癌症。該BTK抑制劑之實例為美國專利7,405,295中所揭示之化合物。BTK抑制劑之額外實例包括但不限於(S)-6-胺基-9-(1-(丁-2-炔醯基)吡咯啶-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮、阿卡拉布魯替尼(acalabrutinib) (ACP-196)、BGB-3111、HM71224、依魯替尼(ibrutinib)、M-2951、泰盧替尼(tirabrutinib) (ONO-4059)、PRN-1008、司培替尼(spebrutinib) (CC-292)及TAK-020。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽適用於與BTK抑制劑組合來治療癌症。該BET抑制劑之實例為WO2014/182929中所揭示之化合物,該文獻之全部內容以引用之方式併入本文中。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽適用於與TBK (Tank結合激酶)抑制劑組合來治療癌症。該TBK抑制劑之實例為WO2016/049211中所揭示之化合物。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽適用於與OX40抑制劑組合來治療癌症。該OX40抑制劑之實例為U.S. 8,450,460中所揭示之化合物,該文獻之全部內容以引用之方式併入本文中。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽適用於與JAK-1抑制劑組合來治療癌症。該JAK-1抑制劑之實例為WO2008/109943中所揭示之化合物。其他JAK抑制劑之實例包括但不限於AT9283、AZD1480、巴瑞替尼(baricitinib)、BMS-911543、非達替尼(fedratinib)、費戈替尼(filgotinib) (GLPG0634)、甘多替尼(gandotinib) (LY2784544)、INCB039110、來他替尼(lestaurtinib)、莫羅替尼(momelotinib) (CYT0387)、NS-018、帕瑞替尼(pacritinib) (SB1518)、皮非替尼(peficitinib) (ASP015K)、魯索利替尼(ruxolitinib)、托法替尼(tofacitinib) (以前為塔索替尼(tasocitinib))及XL019。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽適用於與吲哚胺-吡咯-2,3-二氧酶(IDO)抑制劑組合來治療癌症。該IDO抑制劑之實例為WO2016/186967中所揭示之化合物。在一個實施例中,式(I)、式(Ia)、式(II)或式(IIa)化合物適用於與IDO1抑制劑組合來治療癌症,該等IDO1抑制劑包括但不限於BLV-0801、艾帕斯塔(epacadostat)、F-001287、GBV-1012、GBV-1028、GDC-0919、因多莫特(indoximod)、NKTR-218、基於NLG-919之疫苗、PF-06840003、哌喃并萘醌衍生物(SN-35837)、雷米諾他(resminostat)、SBLK-200802及shIDO-ST。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽適用於與促分裂原活化蛋白激酶(MEK)抑制劑組合來治療癌症。適用於與(多種)式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物之組合治療之MEK抑制劑包括安卓奎諾爾(antroquinonol)、畢尼替尼(binimetinib)、考比替尼(cobimetinib) (GDC-0973、XL-518)、MT-144、司美替尼(selumetinib) (AZD6244)、索拉非尼(sorafenib)、曲美替尼(trametinib) (GSK1120212)、阿瑟替布(uprosertib)及曲美替尼(trametinib)。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽適用於與細胞凋亡信號調節激酶(ASK)抑制劑組合來治療癌症,ASK抑制劑包括但不限於WO 2011/008709 (Gilead Sciences)及WO 2013/112741 (Gilead Sciences)中所描述之ASK抑制劑,包括例如司隆色替(selonsertib)。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與分化簇47 (CD47)抑制劑組合。CD47抑制劑之實例包括但不限於抗CD47 mAb (Vx-1004)、抗人類CD47 mAb (CNTO-7108)、CC-90002、CC-90002-ST-001、人類化抗CD47抗體(Hu5F9-G4)、NI-1701、NI-1801、RCT-1938及TTI-621。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與週期蛋白依賴型激酶(CDK)抑制劑組合。CDK抑制劑包括CDK 1、CDK 2、CDK 3、CDK 4、CDK 6及CDK 9抑制劑,諸如玻瑪西尼(abemaciclib)、奧爾沃昔布(alvocidib) (HMR-1275、夫拉平度(flavopiridol))、AT-7519、FLX-925、LEE001、帕博西尼(palbociclib)、瑞博西尼(ribociclib)、瑞戈替布、西林俄(selinexor)、UCN-01及TG-02。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與盤狀域受體(Discoidin Domain Receptor,DDR)抑制劑組合以用於治療癌症。DDR抑制劑包括DDR1及/或DDR2抑制劑。DDR抑制劑之實例包括但不限於WO 2014/047624 (Gilead Sciences)、US 2009-0142345 (Takeda Pharmaceutical)、US 2011-0287011 (Oncomed Pharmaceuticals)、WO 2013/027802 (Chugai Pharmaceutical)及WO 2013/034933 (Imperial Innovations)中所揭示之DDR抑制劑。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與組蛋白去乙醯酶(HDAC)抑制劑組合,該等HDAC抑制劑諸如美國專利8,575,353中所揭示之HDAC抑制劑及其等效物。HDAC抑制劑之額外實例包括但不限於阿貝諾他(abexinostat)、ACY-241、AR-42、BEBT-908、貝利諾他(belinostat)、CKD-581、CS-055 (HBI-8000)、CUDC-907、恩替諾他(entinostat)、吉維諾他(givinostat)、莫塞諾他(mocetinostat)、帕比諾他(panobinostat)、普拉諾他(pracinostat)、奎西諾他(quisinostat) (JNJ-26481585)、雷米諾他(resminostat)、瑞科諾他(ricolinostat)、SHP-141、丙戊酸(valproic acid) (VAL-001)及伏立諾他(vorinostat)。
在一個實施例中,式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽適用於與各別癌症治療中之標準照護組合來治療癌症。熟習此項技術者知道截至既定日期時在特定癌症療法領域中或針對既定癌症之標準照護。
本申請案之某些實施例包括或使用一或多種額外治療劑。一或多種額外治療劑可為適用於治療癌症、炎症、自體免疫疾病及/或相關病況之藥劑。一或多種額外治療劑可為化學治療劑、抗血管生成劑、抗纖維化劑、消炎劑、免疫調節劑、免疫治療劑、治療性抗體、放射性治療劑、抗腫瘤劑、抗癌劑、抗增生劑或其任何組合。在一些實施例中,(多種)本文所描述之化合物可與以下一起使用或組合:化學治療劑、抗血管生成劑、抗纖維化劑、消炎劑、免疫調節劑、免疫治療劑、治療性抗體、放射性治療劑、抗贅生劑或抗癌劑、抗增生劑或其任何組合。
在一個實施例中,視情況與本文所描述之額外抗癌劑組合之式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可與以下一起使用或組合:抗贅生劑或抗癌劑、抗纖維化劑、消炎劑或免疫調節劑。
在一個實施例中,提供包含有包含式(I)、式(Ia)、式(II)或式(IIa)化合物或其互變異構體或醫藥學上可接受之鹽之醫藥組合物及至少一種額外抗癌劑或其醫藥學上可接受之鹽以及至少一種醫藥學上可接受之載劑的套組。在一個實施例中,提供包含有包含式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽之醫藥組合物及至少一種額外抗癌劑或其醫藥學上可接受之鹽以及至少一種醫藥學上可接受之載劑的套組。在一個實施例中,套組包含用於癌症治療之說明書。在一個實施例中,套組中之說明書係關於醫藥組合物用於治療惡性血液病、多發性骨髓瘤、乳癌、結腸直腸癌、皮膚癌、黑色素瘤、卵巢癌、腎癌、小細胞肺癌、非小細胞肺癌、淋巴瘤及/或白血病之用途。
本申請案亦提供用於治療經受一或多種諸如化學療法、放射線療法、免疫療法、手術或其組合之標準療法之個體之方法,其包含向該個體投與或共投與式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽。因此,一或多種式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽可在投與化學療法、放射線療法、免疫療法、手術或其組合之前、期間或之後投與。
在一個實施例中,個體可為(i)實質上難以用至少一種化學療法治療來治療或(ii)在用化學療法治療之後復發或(i)及(ii)兩者之人類。在實施例中之一些中,個體難以用至少兩種、至少三種或至少四種化學療法治療(包括標準或實驗化學療法)來治療。
在一個實施例中,個體難以用選自以下之至少一種、至少兩種、至少三種或至少四種化學療法治療(包括標準或實驗化學療法)來治療:氟達拉濱(fludarabine);利妥昔單抗;奧比珠單抗(obinutuzumab);烷基化劑;阿侖單抗(alemtuzumab);及其他化學療法治療,諸如CHOP (環磷醯胺、小紅莓、長春新鹼、潑尼松);R-CHOP (利妥昔單抗-CHOP);高CVAD (高分次環磷醯胺、長春新鹼、小紅莓、地塞米松、甲胺喋呤、阿糖胞苷(cytarabine));R-高CVAD (利妥昔單抗-高CVAD);FCM (氟達拉濱、環磷醯胺、米托蒽醌(mitoxantrone));R-FCM (利妥昔單抗、氟達拉濱、環磷醯胺、米托蒽醌);硼替佐米(bortezomib)及利妥昔單抗;替西羅莫司(temsirolimus)及利妥昔單抗;替西羅莫司及Velcade®
;碘-131托西莫單抗(tositumomab) (Bexxar®
)及CHOP;CVP (環磷醯胺、長春新鹼、潑尼松);R-CVP (利妥昔單抗-CVP);ICE (異環磷醯胺、卡鉑、依託泊苷);R-ICE (利妥昔單抗-ICE);FCR (氟達拉濱、環磷醯胺、利妥昔單抗);FR (氟達拉濱、利妥昔單抗);以及D.T. PACE (地塞米松、沙立度胺(thalidomide)、順鉑、Adriamycin®
、環磷醯胺、依託泊苷)。
化學療法治療之其他實例(包括標準或實驗化學療法)描述於下文中。另外,某些淋巴瘤之治療綜述於Cheson, B.D., Leonard, J.P., 「Monoclonal Antibody Therapy for B-Cell Non-Hodgkin's Lymphoma」The New England Journal of Medicine
2008, 359(6), 第613-626頁;及Wierda, W.G., 「Current and Investigational Therapies for Patients with CLL」Hematology
2006, 第285-294頁中。美國淋巴瘤發病率模式剖析於Morton, L.M.,等人 「Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001」Blood
2006, 107(1), 第265-276頁中。
治療淋巴瘤或白血病之免疫治療劑之實例包括但不限於利妥昔單抗(諸如美羅華(Rituxan))、阿侖單抗(諸如坎帕斯(Campath)、麻布坎帕斯(MabCampath))、抗CD19抗體、抗CD20抗體、抗MN-14抗體、抗TRAIL、抗TRAIL DR4及DR5抗體、抗CD74抗體、阿泊珠單抗(apolizumab)、貝伐單抗(bevacizumab)、CHIR-12.12、依帕珠單抗 (hLL2-抗CD22人類化抗體)、加利昔單抗(galiximab)、ha20、替伊莫單抗(ibritumomab tiuxetan)、盧米西單抗(lumiliximab)、米拉珠單抗(milatuzumab)、奧伐木單抗(ofatumumab)、PRO131921、SGN-40、WT-1模擬肽疫苗、WT1 126-134肽疫苗、托西莫單抗(tositumomab)、自體人類腫瘤源性HSPPC-96及維托珠單抗(veltuzumab)。額外免疫療法劑包括基於個別患者腫瘤之基因組成使用癌症疫苗,諸如淋巴瘤疫苗,實例為GTOP-99 (MyVax®
)。
用於治療淋巴瘤或白血病之化學療法劑之實例包括阿地白介素(aldesleukin)、奧爾沃昔布、抗新普拉通AS2-1、抗新普拉通A10、抗胸腺細胞球蛋白、三水合阿米福汀(amifostine trihydrate)、胺基喜樹鹼、三氧化二砷、β阿立辛(beta alethine)、Bcl-2家族蛋白抑制劑ABT-263、BMS-345541、硼替佐米(Velcade®
)、苔蘚蟲素1、硫酸布他卡因、卡鉑、坎帕斯-1H、CC-5103、卡莫司汀(carmustine)、乙酸卡泊芬淨(caspofungin acetate)、氯法拉濱(clofarabine)、順鉑、克拉屈濱(Cladribine) (祿斯得停(Leustarin))、苯丁酸氮芥(瘤可寧(Leukeran))、薑黃素、環孢靈、環磷醯胺(科洛仙(Cyloxan)、癌得星(Endoxan)、癌得仙(Endoxana)、科洛斯汀(Cyclostin))、阿糖胞苷、地尼白介素、地塞米松、DT PACE、多西他賽(docetaxel)、尾海兔素10、小紅莓(Adriamycin®
,阿黴素(Adriblastine))、鹽酸阿黴素(doxorubicin hydrochloride)、恩紮妥林(enzastaurin)、阿法依泊汀(epoetin alfa)、依託泊苷、依維莫司(Everolimus) (RAD001)、非瑞替尼(fenretinide)、非格司亭(filgrastim)、美法侖、美司鈉(mesna)、夫拉平度、氟達拉濱(氟達拉)、格爾德黴素(Geldanamycin) (17-AAG)、依弗醯胺、鹽酸伊立替康(irinotecan hydrochloride)、伊沙匹隆(ixabepilone)、來那度胺(Lenalidomide) (Revlimid®
,CC-5013)、淋巴激素活化殺手細胞、美法侖、甲胺喋呤、鹽酸米托蒽醌、莫特沙芬釓(motexafin gadolinium)、黴酚酸嗎啉乙酯、奈拉濱(nelarabine)、奧利默森(oblimersen) (根納三思(Genasense)) 奧巴克拉(Obatoclax) (GX15-070)、奧利默森、乙酸奧曲肽(octreotide acetate)、ω−3脂肪酸、奧沙利鉑(oxaliplatin)、太平洋紫杉醇、PD0332991、聚乙二醇化脂質體鹽酸阿黴素、派非格司亭(pegfilgrastim)、噴司他汀(Pentstatin) (尼噴提(Nipent))、哌立福新(perifosine)、潑尼龍、潑尼松、R-羅斯維汀(R-roscovitine) (塞利西利(Selicilib),CYC202)、重組干擾素α、重組介白素-12、重組介白素-11、重組flt3配位體、重組人類血小板生成素、利妥昔單抗、沙格司亭(sargramostim)、檸檬酸西地那非(sildenafil citrate)、辛伐他汀(simvastatin)、西羅莫司(sirolimus)、苯乙烯基碸、他克莫司、坦螺旋黴素、替西羅莫司(Temsirolimus) (CCl-779)、沙立度胺(Thalidomide)、治療性同種異體淋巴球(therapeutic allogeneic lymphocytes)、噻替派(thiotepa)、替吡法尼(tipifarnib)、Velcade®
(硼替佐米或PS-341)、長春新鹼(安可平(Oncovin))、硫酸長春新鹼、二酒石酸長春瑞濱(vinorelbine ditartrate)、伏立諾他(Vorinostat) (SAHA)、伏立諾他及FR (氟達拉濱、利妥昔單抗)、CHOP (環磷醯胺、小紅莓、長春新鹼、潑尼松)、CVP (環磷醯胺、長春新鹼及潑尼松)、FCM (氟達拉濱、環磷醯胺、米托蒽醌)、FCR (氟達拉濱、環磷醯胺、利妥昔單抗)、高CVAD (高分次環磷醯胺、長春新鹼、小紅莓、地塞米松、甲胺喋呤、阿糖胞苷)、ICE (異環磷醯胺、卡鉑及依託泊苷)、MCP (米托蒽醌、苯丁酸氮芥及潑尼龍)、R-CHOP (利妥昔單抗加上CHOP)、R-CVP (利妥昔單抗加上CVP)、R-FCM (利妥昔單抗加上FCM)、R-ICE (利妥昔單抗-ICE)及R-MCP (利妥昔單抗-MCP)。
在一些實施例中,癌症為黑色素瘤。適用於與本文所描述之化合物組合使用之藥劑包括但不限於達卡巴嗪(dacarbazine) (DTIC),其視情況連同以下一起組合使用:其他化學療法藥物,諸如卡莫司汀(BCNU)及順鉑;「達特茅斯方案(Dartmouth regimen)」,其由DTIC、BCNU、順鉑及他莫昔芬(tamoxifen)組成;順鉑、長春花鹼及DTIC、替莫唑胺(temozolomide)或YERVOY™之組合。本文所揭示之化合物亦可在黑色素瘤治療中與包括諸如干擾素α、介白素2及腫瘤壞死因子(TNF)之細胞介素之免疫療法藥物組合。
此處所描述之化合物亦可在黑色素瘤治療中與疫苗療法組合使用。抗黑色素瘤疫苗在一些方面類似於用於預防諸如脊髓灰質炎、麻疹及流行性腮腺炎之由病毒造成之疾病之抗病毒疫苗。可將弱化黑色素瘤細胞或稱為抗原之黑色素瘤細胞部分注射至患者中以刺激身體免疫系統來破壞黑色素瘤細胞。
限制於臂部或腿部之黑色素瘤亦可使用例如高溫隔離肢體灌注技術,用包括一或多種本文所描述之化合物之藥劑組合進行治療。此治療方案使所涉及肢體之循環與身體其餘部分暫時分離,且向供給肢體之動脈中注射高劑量之化學療法,因此在無可能以其他方式造成嚴重副作用之內臟向此等劑量之暴露之情況下向腫瘤區域提供高劑量。通常,使流體升溫至102℉至104℉。美法侖為最常用於此化學療法程序中之藥物。此可給與有稱為腫瘤壞死因子(TNF)且視情況與式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物組合之另一藥劑。
治療性治療可補充有具有幹細胞移植或治療之前述療法中之任一種或與其組合。經修改方法之一個實例為放射免疫療法,其中單株抗體與諸如銦In 111、釔Y 90、碘I-131之放射性同位素粒子組合。組合療法之實例包括但不限於碘-131托西莫單抗(Bexxar®
)、釔-90替伊莫單抗(Zevalin®
)、Bexxar®
及CHOP。
適用於與用式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽進行之治療組合之其他治療性程序包括末梢血液幹細胞移植、自體造血幹細胞移植、自體骨髓移植、抗體療法、生物療法、酶抑制劑療法、全身照射、幹細胞輸注、骨髓幹細胞載體剝蝕、活體外治療之末梢血液幹細胞移植、臍帶血移植、免疫酶技術、藥理學研究、低LET鈷-60 γ射線療法、博萊黴素(bleomycin)、習知手術、輻射療法及非骨髓破壞式同種異體造血幹細胞移植。
在一些實施例中,本發明提供包含與MMP9結合蛋白及/或一或多種額外治療劑以及醫藥學上可接受之稀釋劑、載劑或賦形劑組合之式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽的醫藥組合物。在一個實施例中,醫藥組合物包含MMP9結合蛋白、一或多種額外治療劑及醫藥學上可接受之賦形劑、載劑或稀釋劑。在一些實施例中,醫藥組合物包含式(I)化合物及抗MMP9抗體AB0045。
在一個實施例中,醫藥組合物包含式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽、抗MMP9抗體AB0045、作為免疫調節劑之至少一種額外治療劑及醫藥學上可接受之稀釋劑、載劑或賦形劑。在某些其他實施例中,醫藥組合物包含抗MMP9抗體AB0045、作為消炎劑之至少一種額外治療劑及醫藥學上可接受之稀釋劑、載劑或賦形劑。在某些其他實施例中,醫藥組合物包含式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽、抗MMP9抗體AB0045、作為抗贅生性劑或抗癌劑之至少一種額外治療劑及醫藥學上可接受之稀釋劑、載劑或賦形劑。在一個實施例中,適用於與式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽之組合治療之MMP9化合物包括但不限於馬立馬司他(marimastat) (BB-2516)、西馬司他(cipemastat) (Ro 32-3555)及WO 2012/027721中所描述之化合物(Gilead Biologics)。
在一個實施例中,一或多種額外治療劑為免疫調節劑,例如免疫刺激劑或免疫抑制劑。在某些其他實施例中,免疫調節劑為能夠更改免疫檢查點之功能之藥劑,該等免疫檢查點包括CTLA-4、LAG-3、B7-H3、B7-H4、Tim3、BTLA、KIR、A2aR、CD200及/或PD-1路徑。在其他實施例中,免疫調節劑為免疫檢查點調節劑。例示性免疫檢查點調節劑包括抗CTLA-4抗體(例如伊匹單抗)、抗LAG-3抗體、抗B7-H3抗體、抗B7-H4抗體、抗Tim3抗體、抗BTLA抗體、抗KIR抗體、抗A2aR抗體、抗CD200抗體、抗PD-1抗體、抗PD-L1抗體、抗CD28抗體、抗CD80抗體或抗CD86抗體、抗B7RP1抗體、抗B7-H3抗體、抗HVEM抗體、抗CD137抗體或抗CD137L抗體、抗OX40抗體或抗OX40L抗體、抗CD40抗體或抗CD40L抗體、抗GAL9抗體、抗IL-10抗體及A2aR藥物。對於某些該等免疫路徑基因產物,考慮使用該等基因產物之拮抗劑或促效劑,亦考慮使用該等基因產物之小分子調節劑。在一個實施例中,免疫調節劑為抗PD-1抗體或抗PD-L1抗體。在一些實施例中,免疫調節劑包括能夠更改介質在細胞介素介導之信號傳導路徑中之功能之彼等藥劑。
在一些實施例中,一或多種額外療法或抗癌劑為癌症基因療法或細胞療法。癌症基因療法及細胞療法包括用於置換經突變或經更改之基因之向癌細胞中之正常基因插入;用於使經突變之基因靜默之基因修飾;用於直接殺滅癌細胞之基因方法;包括輸注設計成置換大部分患者自身免疫系統以增強針對癌細胞之免疫反應,或活化患者自身免疫系統(T細胞或自然殺手細胞)以殺滅癌細胞,或發現且殺滅癌細胞的免疫細胞;用於修改細胞活性以進一步更改針對癌症的內源性免疫反應性的基因方法。非限制性實例為艾普塞爾-L (Algenpantucel-L) (2種胰臟細胞株)、西普亮塞-T (Sipuleucel-T)、基因p53之SGT-53脂質體奈米級遞送(scL);T細胞療法,諸如CD19 CAR-T替沙津魯-T (CD19 CAR-T tisagenlecleucel-T) (CTL019) WO2012079000、WO2017049166、西卡思羅(axicabtagene ciloleucel) (KTE-C19) US7741465、US6319494、JCAR-015 US7446190、JCAR-014、JCAR-020、JCAR-024、JCAR-023、JTCR-016、JCAR-018 WO2016090190、JCAR-017 (WO2016196388、WO2016033570、WO2015157386)、BPX-501 US9089520、WO2016100236、AU-105、UCART-22、ACTR-087、P-BCMA-101;活化同種異體自然殺手細胞CNDO-109-AANK、FATE-NK100及LFU-835造血幹細胞。
在一個實施例中,一或多種額外治療劑為免疫檢查點抑制劑。腫瘤係藉由利用稱為T細胞耗竭之機制來破壞免疫系統,該T細胞耗竭係由長期暴露於抗原導致且特徵在於抑制受體之上調。此等抑制受體充當免疫檢查點以便防止不可控之免疫反應。
PD-1以及諸如細胞毒性T淋巴球抗原4 (CTLA-4)、B及T淋巴球衰減因子(BTLA;CD272)、T細胞免疫球蛋白及黏蛋白域-3 (Tim-3)、淋巴球活化基因-3 (Lag-3;CD223)及其他共抑制受體之共抑制受體常常稱為檢查點調節劑。其充當分子決定子以基於胞外資訊影響細胞週期進程及其他胞內信號傳導過程係否應進行。
除經由T細胞受體(TCR)進行之特異性抗原辨識之外,T細胞活化亦經由由共刺激受體提供之正信號與負信號之平衡來加以調節。此等表面蛋白通常為TNF受體或B7超家族之成員。針對活化共刺激分子之促效抗體及針對負共刺激分子之阻斷抗體可增強T細胞刺激以促進腫瘤破壞。
作為55-kD 1型跨膜蛋白之程式化細胞死亡蛋白1 (PD-1或CD279)為CD28家族T細胞共刺激受體之成員,該家族包括免疫球蛋白超家族成員CD28、CTLA-4、可誘導共刺激子(ICOS)及BTLA。PD-1在活化T細胞及B細胞上高度表現。亦可在記憶T細胞亞群上偵測到具有可變表現量之PD-1表現。已鑑別出對PD-1具有特異性之兩種配位體:程式化死亡配位體1 (PD-L1,亦稱為B7-H1或CD274)及PD-L2 (亦稱為B7-DC或CD273)。已顯示PD-L1及PD-L2在與小鼠系統及人類系統兩者中之PD-1結合後下調T細胞活化(Okazaki等人,Int . Immunol .
, 2007; 19: 813-824)。表現於抗原呈現細胞(APC)及樹突狀細胞(DC)上之PD-1與其配位體PD-L1及PD-L2之相互作用傳輸負調節性刺激以下調活化T細胞免疫反應。PD-1阻斷遏制此負信號且放大T細胞反應。諸多研究指示,癌症微環境操縱PD-L1/PD-1信號傳導路徑,且PD-L1表現之誘導與針對癌症之免疫反應之抑制相關聯,由此准許癌症進展及癌轉移。由於若干原因,PD-L1/PD-1信號傳導路徑為癌症免疫逃避之主要機制。此路徑涉及於周邊中所見之活化T效應細胞之免疫反應負調節中。PD-L1在癌症微環境中上調,同時PD-1亦在活化腫瘤浸潤性T細胞中上調,由此可能增強惡性抑制循環。此路徑亦複雜地涉及於經由雙向信號傳導進行之先天性免疫調節及適應性免疫調節兩者中。此等因素使PD-1/PD-L1複合物成為中心點,癌症可經由該中心點操縱免疫反應且促進其自身進展。
待於臨床試驗中測試之第一免疫檢查點抑制劑為作為CTLA-4 mAb之伊匹單抗(易沃伊(Yervoy),Bristol-Myers Squibb)。CTLA-4屬於免疫球蛋白超家族受體,該超家族亦包括PD-1、BTLA、TIM-3及T細胞活化之V域免疫球蛋白抑制因子(VISTA)。抗CTLA-4 mAb為強力檢查點抑制劑,其自原初細胞及經歷過抗原之細胞兩者移除「破裂」。
療法增強CD8+ T細胞之抗腫瘤功能,增加CD8+ T細胞與Foxp3+ T調節細胞之比率,且抑制T調節細胞之遏制功能。TIM-3已鑑別為由經耗竭之CD8+ T細胞表現之另一重要抑制受體。在小鼠癌症模型中,已顯示大部分功能異常之腫瘤浸潤性CD8+ T細胞實際上共表現PD-1及LAG-3。LAG-3為用以限制效應T細胞功能且加強T調節細胞之遏制活性之另一新近鑑別之抑制受體。近期已揭露,在小鼠中PD-1及LAG-3由腫瘤浸潤性T細胞深入共表現,且在小鼠癌症模型中PD-1及LAG-3之組合阻斷引起強效協同性抗腫瘤免疫反應。
因此,在一個實施例中,本發明提供與一或多種額外免疫檢查點抑制劑組合之式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽之用途。在一個實施例中,本發明提供式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽及一或多種免疫檢查點抑制劑以及抗MMP9抗體或其抗原結合片段用於治療或預防癌症之用途。在一些實施例中,免疫檢查點抑制劑可為抗PD-1抗體及/或抗PD-L1抗體或抗PD-1/PD-L1相互作用抑制劑。在一些實施例中,抗PD-L1抗體可為B7-H1抗體、BMS 936559抗體、MPDL3280A (阿特珠單抗(atezolizumab))抗體、MEDI-4736抗體、MSB0010718C抗體或其組合。根據另一實施例,抗PD-1抗體可為納武單抗(nivolumab)抗體、派姆單抗(pembrolizumab)抗體、皮立珠單抗(pidilizumab)抗體或其組合。
另外,PD-1亦可經作為PD-L2-IgG重組融合蛋白之AMP-224靶向。免疫反應中之抑制性路徑之額外拮抗劑包括IMP321,該IMP321為可溶性LAG-3 Ig融合蛋白及MHC II類促效劑,其用於增加針對腫瘤之免疫反應。利瑞路單抗(Lirilumab)為針對KIR受體之拮抗劑,且BMS 986016為LAG3之拮抗劑。TIM-3-半乳糖凝集素-9路徑為亦作為檢查點抑制之前景性靶標之另一抑制性檢查點路徑。RX518靶向且活化糖皮質激素誘導之腫瘤壞死因子受體(GITR),該受體為在多種類型之免疫細胞之表面上表現之TNF受體超家族的成員,該等多種類型之免疫細胞包括調節T細胞、效應T細胞、B細胞、自然殺手(NK)及活化樹突狀細胞。因此,在一個實施例中,式(I)化合物或其互變異構體或醫藥學上可接受之鹽與IMP321、利瑞路單抗及/或BMS 986016組合使用。
可用於本文所描述之組合物及方法中之抗PD-1抗體包括但不限於:作為完全人類lgG4抗PD-1單株抗體之納武單抗/MDX-1106/BMS-936558/ONO1152;作為人類化lgG1單株抗體之皮立珠單抗(MDV9300/CT-011);作為人類化單株IgG4抗體之派姆單抗(MK-3475/派姆單抗/拉立珠單抗(lambrolizumab));德瓦魯單抗(durvalumab) (MEDI-4736)及阿特珠單抗。可用於本文所描述之組合物及方法中之抗PD-L1抗體包括但不限於:阿維魯單抗(avelumab);作為完全人類IgG4抗體之BMS-936559;作為人類單株抗體之阿特珠單抗(MPDL3280A/RG-7446);MEDI4736;MSB0010718C及MDX1105-01。
在一個實施例中,將式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽與抗PD-1抗體納武單抗、派姆單抗及/或皮立珠單抗組合投與至有需要之患者。在一個實施例中,適用於與式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽之組合治療之抗PD-L1抗體為BMS-936559、阿特珠單抗或阿維魯單抗。在一個實施例中,免疫調節劑抑制免疫檢查點路徑。在另一實施例中,免疫檢查點路徑係選自CTLA-4、LAG-3、B7-H3、B7-H4、Tim3、BTLA、KIR、A2aR、CD200及PD-1。可與式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽組合用於本文所描述之組合物及方法中之額外抗體包括分別在美國專利第8,008,449號及第7,943,743號中揭示的抗PD-1抗體及抗PD-L1抗體。
在一個實施例中,一或多種額外治療劑為消炎劑。在某些其他實施例中,消炎劑為腫瘤壞死因子α (TNF-α)抑制劑。如本文所使用之術語「TNF α」、「TNF-α」及「TNFα」可互換。TNF-α為主要由巨噬細胞且亦由各種其他細胞類型分泌之促炎性細胞介素,該等各種其他細胞類型包括淋巴細胞、肥胖細胞、內皮細胞、心肌細胞、脂肪組織、纖維母細胞及神經元組織。TNF-α亦稱為血清中之內毒素誘導因子、惡病質素及分化誘導因子。腫瘤壞死因子(TNF)家族包括TNF α、TNF β、CD40配位體(CD40L)、Fas配位體(FasL)、TNF相關細胞凋亡誘導配位體(TRAIL)及LIGHT (與淋巴毒素同源,展現可誘導表現,且與HSV糖蛋白D競爭HVEM,該HVEM為由T淋巴球表現之受體)、除其他生理學過程之外亦涉及於全身性炎症、腫瘤溶解、細胞凋亡及急性期反應起始中之最重要細胞介素中的一些。
上文治療劑在與本文所揭示之(多種)化合物組合使用時可例如以在例如Physicians Desk Reference之所參考手冊中所指示之彼等量或以一般為合格護理人員(亦即一般熟習此項技術者)已知之量使用。在本發明之方法中,該(等) (多種)其他治療劑可在投與(多種)式(I)、式(Ia)、式(II)、式(IIa)、式(III)、式(IIIa)、式(IIIb)、式(IIIc)、式(IIId)、式(IV)或式(IVa)化合物或其互變異構體或醫藥學上可接受之鹽之前、同時或之後投與。某些其他治療劑可在能夠如此組合時組合為單一調配物或套組。舉例而言,錠劑、膠囊或液體調配物可與其他錠劑、膠囊或液體調配物組合為一種固定或組合劑量調配物或方案。其他組合可獨立地、同期地或以其他方式給與。化合物製備
本發明之一些實施例係關於適用於製備本發明化合物或其醫藥學上可接受之鹽之方法及中間物。
本文所描述之化合物可藉由此項技術中已知之手段中之任一種來純化,該等手段包括層析手段,諸如高效液相層析法(HPLC)、製備型薄層層析法、急驟管柱層析法及離子交換層析法。可使用任何合適之固定相,包括正相及反相以及離子樹脂。所揭示之化合物最通常經由矽膠及/或氧化鋁層析法來純化。
在用於製備本發明化合物之過程中之任一個期間,保護所關注分子中之任一種上之敏感性或反應性基團可能為必需的及/或期望的。此可藉助於如諸如T. W. Greene及P. G. M. Wuts, 「Protective Groups in Organic Synthesis」, 第4版, Wiley, New York 2006之標準著作中所描述之習知保護基團來達成。保護基團可在適宜後續階段使用此項技術中已知之方法來移除。通用合成流程 流程 1 :製備光學純式 ( I ) 化合物
中間物 A
及E
可使用國際公開案第WO 2016/033486號中所描述之程序來製備。
步驟 1 : 中間物 B
可藉由以下來製備:將於例如THF之適當溶劑中之溶液A
用諸如氫化鈉之適當鹼處理,且隨後用諸如碘甲烷之適當烷化劑處理。
步驟 2 : 中間物 C
可藉由以下來製備:用諸如氫化鈉之適當鹼處理於例如DMF之適當溶劑中之溶液B
,且隨後用諸如碘甲烷之適當烷化劑處理混合物。
步驟 3 : 中間物 D
可藉由以下來製備:在高溫、較佳60℃下用於例如MeOH、EtOH或THF之適當溶劑中之諸如NaOH、KOH或LiOH水溶液之適當鹼處理中間物 C
過夜。在冷卻混合物之後,用諸如HCl之適當酸性劑酸化,濃縮,且過濾,將所得固體羧酸溶解於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中。可添加例如亞硫醯氯或草醯氯之適當酸氯化物形成劑以提供中間物 D
,其可緊接著用於下一步驟中。
步驟 4 : 中間物 F
可藉由以下來製備:在適當溫度下、較佳在0℃下將中間物 E
溶解於諸如THF、DMF或CH2
Cl2
之適當溶劑中,用諸如三甲胺、二異丙基乙胺或咪唑之適當有機鹼及諸如TBDMSCl或TBDMSOTf之適當矽烷化劑處理。
步驟 5 : 中間物 G
可藉由以下來製備:在N2
氛圍下將Ph3
PCl2
懸浮於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中,添加諸如三甲胺或二異丙基乙胺之適當有機鹼,且隨後添加於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之中間物 F
溶液,繼而鼓入氨氣。
步驟 6 : 中間物 H
可藉由以下來製備:將中間物 D
溶解於諸如乙腈之適當極性溶劑中,且添加噠嗪,繼而添加於諸如乙腈之適當極性溶劑中之中間物 G
。
步驟 7 : 中間物 I - 1
及I - 2
可藉由以下來製備:在冰浴冷卻下將三乙胺及酸氯化物添加至於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之中間物 H
溶液中。可在純化期間分離兩種立體異構體。
步驟 8 及 9
:J - 1
及J - 2
可藉由以下來製備:在高溫、較佳60℃下將中間物 I
-1
或I - 2
分別與於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之哈維達格拉布第2代催化劑一起攪拌。在濃縮之後,可藉由製備型HPLC或藉由矽膠管柱層析法來純化殘餘物。流程 2 :製備光學純式 ( I ) 化合物
J - 1
及J - 2
亦可如流程2中所示由H
製備。可在冰浴冷卻下在存在諸如DIPEA或TEA之適當鹼之情況下用二碳酸二第三丁酯處理於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之中間物 H
溶液,且在rt下攪拌過夜。在濃縮且藉由矽膠層析法純化之後,可在高溫下、較佳在60℃下用於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之哈維達格拉布第2代催化劑處理Boc保護之非對映異構體的混合物。在濃縮之後,可用適當醯化劑、該酸氯化物及有機鹼或羧酸與EDCI及有機鹼醯化非對映異構體L
之混合物。流程 3 :製備光學純式 ( I ) 化合物
醯化中間物 H
且用哈維達格拉布第2代催化劑巨環化中間物 I
,之後亦可藉由矽膠管柱層析法或藉由手性HPLC來分離J - 1
及J - 2
。 流程 4 : 製備光學純式 ( I ) 化合物
步驟 1 :中間物 K - 1
及K - 2
可藉由以下來製備:在冰浴冷卻下將三乙胺及二碳酸二第三丁酯添加至於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之中間物 H
溶液中,且將混合物在rt下攪拌過夜。在濃縮反應混合物之後,可藉由製備型HPLC或矽膠管柱層析法來純化殘餘物以分離非對映異構體。
步驟 2 及 3 : J - 1
及J - 2
可藉由以下來製備:在高溫下、較佳在60℃下攪拌中間物 K - 1
或K - 2
及於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之哈維達格拉布第2代催化劑。在濃縮反應混合物且藉由製備型HPLC純化殘餘物之後,將適當醯化劑、該酸氯化物及有機鹼或羧酸與EDCI及有機鹼添加至醯化物中間物 L - 1
或L - 2
中,可藉由製備型HPLC或藉由矽膠管柱層析法來純化該醯化物中間物,獲得J - 1
或J - 2
。流程 5 :製備光學純式 ( I ) 化合物
進行Boc保護且用哈維達格拉布第2代催化劑進行巨環化,之後可藉由矽膠管柱層析法或藉由手性HPLC來分離中間物 L - 1
及L - 2
,且隨後進行醯化以分別提供J - 1
及J - 2
。 流程 6 : 製備光學純式 ( I ) 化合物
N - 1
及N - 2
可如流程6中所示由L
製備,醯化,繼而用哈維達格拉布第2代催化劑巨環化,之後藉由矽膠管柱層析法或藉由手性HPLC分離。流程 7 及 8 : 製備式 ( I ) 化合物 , 其中 - C ( O ) R1 為 - C ( O ) NHR8
M - 2
可藉由在冰浴冷卻下添加於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之三乙胺及經取代之異氰酸酯由L - 2
製備。
可替代地,在存在諸如三乙胺之適當鹼之情況下用於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之經取代異氰酸酯處理L - 2
之後,可藉由矽膠管柱層析法或藉由手性HPLC來分離兩種立體異構體M - 1
及M - 2
。 流程 9 : 製備式 ( I ) 化合物 , 其中 - C ( O ) R1 為 - C ( O ) NR8
R9
M - 3
可藉由用碳酸二苯酯、繼而用適當胺處理L - 2
來製備(流程9)。流程 10 、 11 及 12 : 製備式 ( I ) 化合物 , 其中 - C ( O ) R1 為 - C ( O ) OR7
O - 2
可藉由用於諸如CH2
Cl2
或1,2-二氯乙烷之適當溶劑中之適當氯甲酸酯及適當鹼(諸如三甲胺)處理L - 2
來製備。
可替代地,O - 2
可藉由用碳酸二苯酯、繼而用適當醇處理L - 2
來製備。
可替代地,在冰浴冷卻下,在利用碳酸二苯酯、繼而利用適當醇作為親核劑或利用經取代之氯甲酸酯處理非對映異構混合物L
之後,可藉由矽膠管柱層析法或藉由手性HPLC來分離兩種立體異構體,獲得O - 2
(流程12)。
實例
本發明之例示性化學實體提供於以下特定實例中。熟習此項技術者應認識到,為獲得各種本文中之化合物,可適當地選擇起始材料以使得適當時在有或無保護之情況下經由反應流程攜載最終所需取代基以產生所需產物。可替代地,採用代替最終所需取代基之可經由反應流程攜載且適當時經該所需取代基置換之合適基團可能為必需的或期望的。此外,熟習此項技術者應認識到,以下流程中所示之轉換可以與特定側基之官能度相容之任何次序執行。
本文所提供之實例描述本文所揭示之化合物之合成以及用於製備該等化合物之中間物。應理解,可組合本文所描述之個別步驟。亦應理解,獨立批次之化合物可經組合且隨後繼續用於下一合成步驟中。
在以下實例描述中,描述特定實施例。足夠詳細地描述此等實施例以使熟習此項技術者能夠實踐本發明之某些實施例。可利用其他實施例,且可在不脫離本發明之範疇之情況下作出邏輯及其他改變。因此,以下描述並不意欲限制本發明之範疇。實例 1
.
步驟 1 : 製備 ( S )- 6 '- 氯 - 5 -((( 1R , 2R )- 2 -(( S )- 1 - 羥基烯丙基 ) 環丁基 ) 甲基 )- 3 ', 4 , 4 ', 5 - 四氫 - 2H , 2 ' H - 螺 [ 苯并 [ b ][ 1 , 4 ] 噁氮呯 - 3 , 1 '- 萘 ]- 7 - 甲酸 甲 酯 ( 1 - 1 ) :
向於THF (10 mL)中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(根據國際專利申請案第WO 2016/033486號中所描述之程序製備) (1.02 g,2.18 mmol)之經攪拌溶液中添加於冰浴中之氫化鈉(於礦物油中60%,183.1 mg,4.57 mmol),繼而添加碘甲烷(618.7 mg,4.359 mmol)。將所得混合物在rt下攪拌5 h。隨後,將反應混合物傾入冰冷H2
O中且用CH2
Cl2
萃取。將有機層濃縮且藉由矽膠管柱(EtOAc/己烷= 2 / 3)來純化,獲得(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸甲酯。LCMS-ESI+: (m/z):C28
H32
ClNO4
[M+H]+計算值:482.0;實驗值:482.2。
步驟 2 : 製備 ( S )- 6 '- 氯 - 5 -((( 1R , 2R )- 2 -(( S )- 1 - 甲氧基烯丙基 ) 環丁基 ) 甲基 )- 3 ', 4 , 4 ', 5 - 四氫 - 2H , 2 ' H - 螺 [ 苯并 [ b ][ 1 , 4 ] 噁氮呯 - 3 , 1 '- 萘 ]- 7 - 甲酸 甲 酯 ( 1 - 2 ) :
向於DMF (8 mL)中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸甲酯(707.0 mg,1.4 mmol)之經攪拌溶液中添加於冰浴中之氫化鈉(於礦物油中60%,88.0 mg,2.2 mmol),繼而添加碘甲烷(312.3 mg,2.2 mmol)。將所得混合物在rt下攪拌過夜。隨後,將反應混合物傾入冰冷H2
O中且用CH2
Cl2
萃取。將有機層濃縮且藉由矽膠管柱(EtOAc/己烷= 1 / 4)來純化,獲得(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b] [1,4]噁氮呯-3,1'-萘]-7-甲酸甲酯。LCMS-ESI+: (m/z):C29
H34
ClNO4
[M+H]+計算值:496.0;實驗值:496.2。
步驟 3 :製備 (S)-6'- 氯 -5-(((1R,2R)-2-((S)-1- 甲氧基烯丙基 ) 環丁基 ) 甲基 )-3',4,4',5- 四氫 -2H,2'H- 螺 [ 苯并 [b][1,4] 噁氮呯 -3,1'- 萘 ]-7- 碳醯氯 (1-3) :
將(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸甲酯(659.0 mg,1.33 mmol)在60℃下在2N NaOH (3 mL)及MeOH (8 mL)水溶液中攪拌過夜。在冷卻之後,將混合物用HCl酸化且濃縮。將所得固體用CH2
Cl2
處理且過濾。濃縮濾液,且將174.5 mg (0.36 mmol)溶解於CH2
Cl2
(6 mL)中。將亞硫醯氯(1.5 mL)添加至於冰浴中之該溶液中。將所得混合物在rt下攪拌2 h且濃縮。將粗製物(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-碳醯氯直接用於下一步驟中。
步驟 4 :製備 (2R,3S)-N-( 第三丁基二甲基矽烷基 )-3- 甲基己 -5- 烯 -2- 磺醯胺 (1-4) :
向於THF (16 mL)中之(2R,3S)-3-甲基己-5-烯-2-磺醯胺(2.00 g,11.28 mmol)之經攪拌溶液中緩慢地添加於冰浴中之三乙胺(3.15 mL,22.57 mmol),繼而緩慢地添加於THF (8 mL)中之TBDMSCl (2.13 g,14.10 mmol)。將所得混合物在rt下攪拌2天。將沈澱物過濾且用醚洗滌。將濾液濃縮且藉由矽膠管柱(EtOAc/己烷= 1 / 4)來純化,獲得(2R,3S)-N-(第三丁基二甲基矽烷基)-3-甲基己-5-烯-2-磺醯胺。1
H NMR (400 MHz,氘代氯仿) δ 5.76 - 5.67 (m, 1H), 5.08 - 5.02 (m, 2H), 3.95 (s, 1H), 3.95 - 2.97 (m, 1H), 2.44 - 2.41 (m, 1H), 2.14 - 2.08 (m, 1H), 2.02 - 1.96 (m, 1H), 1.27 (d, J = 8.0 Hz, 3H), 1.02 (d, J = 8.0 Hz, 3H), 0.94 (m, 9H), 0.27 - 0.26 (m, 6H)。
步驟 5 :製備 (2R,3S)-N'-( 第三丁基二甲基矽烷基 )-3- 甲基己 -5- 烯 -2- 磺醯咪醯胺 (1-5) :
在N2
氛圍下向於CH2
Cl2
(4.0 mL)中之Ph3
PCl2
(754.33 mg,2.264 mmol)之經攪拌懸浮液中添加三甲胺(0.43 mL,3.087 mmol)。將混合物在rt下攪拌10 min,隨後冷卻至0℃,且添加於CH2
Cl2
(4 mL)中之(2R,3S)-N-(第三丁基二甲基矽烷基)-3-甲基己-5-烯-2-磺醯胺(600.00 mg,2.058 mmol)之溶液。將反應混合物在0℃下攪拌1 h。將氨氣鼓入反應混合物中。將反應容器密封,在0℃下攪拌2 h。將所得沈澱物過濾且用CH2
Cl2
洗滌。將濾液濃縮且藉由矽膠管柱(EtOAc/己烷= 1 / 4)來純化,獲得(2R,3S)-N'-(第三丁基二甲基矽烷基)-3-甲基己-5-烯-2-磺醯咪醯胺(1-5)
。1
H NMR (400 MHz,氘代氯仿) δ 5.80 - 5.69 (m, 1H), 5.08 - 5.02 (m, 2H), 4.17 (w, 2H), 3.06 - 2.98 (m, 1H), 2.54 - 2.46 (m, 1H), 2.11 - 1.95 (m, 2H), 1.29 - 1.26 (m, 3H), 1.01 - 0.98 (m, 3H), 0.92 - 0.88 (m, 9H), 0.13 - 0.11 (m, 6H)。
步驟 6 :製備 (3S)-N-( 胺基 ((2R,3S)-3- 甲基己 -5- 烯 -2- 基 )( 側氧基 )-l6- 硫酮 )-6'- 氯 -5-(((1R,2R)-2-((S)-1- 甲氧基烯丙基 ) 環丁基 ) 甲基 )-3',4,4',5- 四氫 -2H,2'H- 螺 [ 苯并 [b][1,4] 噁氮呯 -3,1'- 萘 ] -7- 甲醯胺 (1-6) :
向於乙腈(2.0 mL)中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-碳醯氯(181.00 mg,0.362 mmol)之經攪拌溶液中添加於2 mL乙腈中之噠嗪(0.03 mL,0.362 mmol),繼而添加於乙腈溶液(2.0 mL)中之(2R,3S)-N'-(第三丁基二甲基矽烷基)-3-甲基己-5-烯-2-磺醯咪醯胺(126.00 mg,0.434 mmol)。將所得混合物在rt下攪拌3h。在濃縮之後,藉由矽膠管柱(EtOAc/己烷= 2 / 3)純化殘餘物,獲得(3S)-N-(胺基((2R,3S)-3-甲基己-5-烯-2-基)(側氧基)-l6-硫酮)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺。1
H NMR (400 MHz,氘代氯仿) δ 7.70 (d, J = 11.6 Hz, 1H), 7.62 - 7.58 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.10 - 7.07 (m, 1H), 6.95 (d, J = 8.4 Hz, 1H), 5.80 - 5.49 (m, 2H), 5.18 - 5.02 (m, 4H), 4.15 (dd, J = 12.0, 5.2 Hz, 1H), 4.05 (dd, J = 12.0, 4.4 Hz, 1H), 3.71 - 3.61 (m, 2H), 3.49 - 3.28 (m, 3H), 3.25 - 3.24 (m, 3H), 2.81 - 2.45 (m, 5H), 2.15 - 1.52 (m, 10H), 1.40 (dd, J = 12.8, 6.8 Hz, 3H), 1.09 (dd, J = 28.4, 6.8 Hz, 3H)。LCMS-ESI+: (m/z):C35
H46
ClN3
O4
S [M+H]+計算值:640.3;實驗值:640.3。
步驟 7 :製備 1-7 及 1-8 :
向於CH2
Cl2
(4.0 mL)中之(3S)-N-(胺基((2R,3S)-3-甲基己-5-烯-2-基)(側氧基)-l6-硫酮)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(30.00 mg,0.047 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.01 mL,0.07 mmol),繼而添加丙醯氯(5.20 mg,0.056 mmol)。將所得混合物在rt下攪拌2h。在濃縮之後,藉由製備型HPLC (Phenomenex Luna 5 μm C18 (2),150×21.2 mm,具有0.1%三氟乙酸之50%至90-95%乙腈/水,15 mL/min,除非另外提及,否則用於整個此實驗部分中)純化殘餘物,獲得1-7
(較高極性溶離份)及1-8
(較低極性溶離份)。LCMS-ESI+: (m/z):C38
H50
ClN3
O5
S [M+H]+計算值:696.3;實驗值:696.3。
步驟 8 :製備實例 1 :
將來自步驟7之單一非對映異構體1-7
(11.0 mg,0.016 mmol)及哈維達格拉布第2代催化劑(2.0 mg,0.003 mmol)在60℃下在1,2-二氯乙烷(6.0 mL)中攪拌4h。在濃縮之後,藉由製備型HPLC純化殘餘物,獲得實例 1
。1
H NMR (400 MHz,氘代氯仿) δ 7.72 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.2, 1.8 Hz, 1H), 7.19 - 7.16 (m, 2H), 7.08 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.86 - 5.80 (m, 1H), 5.69 (dd, J = 15.8, 7.4 Hz, 1H), 4.30 - 4.26 (m, 1H), 4.05 (dd, J = 22.8, 12.0 Hz, 2H), 3.80 - 3.72 (m, 3H), 3.37 (d, J = 14.4 Hz, 1H), 3.27 (s, 3H), 3.06 (dd, J = 14.8, 10.8 Hz, 1H), 2.85 - 2.75 (m, 3H), 2.58 - 1.68 (m, 14H), 1.42 (d, J = 6.8 Hz, 3H), 1.15 (t, J = 7.6 Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H)。LCMS-ESI+: (m/z):C36
H46
ClN3
O5
S [M+H]+計算值:668.3;實驗值:668.3。實例 2.
以與實例 1
(步驟8)相同之方式使用非對映異構體1-8
而不使用1-7
來合成實例 2
。1
H NMR (400 MHz,氘代氯仿) δ 7.70 (d,J
= 8.8 Hz, 1H), 7.18 (dd,J
= 8.4, 2.4 Hz, 1H), 7.13 (d,J
= 8.4 Hz, 1H), 7.08 (d,J
= 2.4 Hz, 1H), 7.02 (s, 1H), 6.94 (d,J
= 8.0 Hz, 1H), 5.99 - 5.92 (m, 1H), 5.50 (dd,J
= 15.2, 8.8 Hz, 1H), 4.47 (w, 1H), 4.13 - 4.04 (m, 2H), 3.82 (d,J
= 15.2 Hz, 1H), 3.71 - 3.65 (m, 2H), 3.31 - 3.24 (m, 1H), 3.22 (s, 3H), 2.99 (dd,J
= 15.2, 10.0 Hz, 1H), 2.80 - 2.70 (m, 3H), 2.49 - 1.64 (m, 13H), 1.54 (d,J
= 6.8 Hz, 3H), 1.42 - 1.36 (m, 1H), 1.17 (t,J
= 7.6 Hz, 3H), 1.02 (d,J
= 6.4 Hz, 3H)。LCMS-ESI+ (m/z):C36
H46
ClN3
O5
S [M+H]+計算值:668.3;實驗值:668.3。實例 3 及 4.
實例3 | 實例4 |
步驟 1 :製備 N'-( 第三丁基二甲基矽烷基 ) 戊 -4- 烯 -1- 磺醯咪醯胺
:以與實例 1
(步驟4及步驟5)相同之方式使用戊-4-烯-1-磺醯胺而不使用(2R,3S)-3-甲基己-5-烯-2-磺醯胺)製備N'-(第三丁基二甲基矽烷基)戊-4-烯-1-磺醯咪醯胺。1
H NMR (400 MHz,氘代氯仿) δ 5.78 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.09 - 5.01 (m, 2H), 3.13 - 3.05 (m, 2H), 2.22 - 2.16 (m, 2H), 1.98 - 1.90 (m, 2H), 0.90 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H)。
步驟 2 :製備 (3S)-N-( 胺基 ( 側氧基 )( 戊 -4- 烯 -1- 基 )-l6- 硫酮 )-6'- 氯 -5-(((1R,2R)-2-((S)-1- 甲氧基烯丙基 ) 環丁基 ) 甲基 )-3',4,4',5- 四氫 -2H,2'H- 螺 [ 苯并 [b][1,4] 噁氮呯 -3,1'- 萘 ]-7- 甲醯胺
:在存在噠嗪之情況下以與實例 1
(步驟6)中之方式類似之方式用(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-碳醯氯處理N'-(第三丁基二甲基矽烷基)戊-4-烯-1-磺醯咪醯胺,得到標題化合物。
步驟 3 :製備 (S)-6'- 氯 -5-(((1R,2R)-2-((S)-1- 甲氧基烯丙基 ) 環丁基 ) 甲基 )-N-((R)- 側氧基 ( 戊 -4- 烯 -1- 基 )( 丙醯胺基 )-l6- 硫酮 )-3',4,4',5- 四氫 -2H,2'H- 螺 [ 苯并 [b][1,4] 噁氮呯 -3,1'- 萘 ]-7- 甲醯胺:
向於CH2
Cl2
(5.0 mL)中之(3S)-N-(胺基(側氧基)(戊-4-烯-1-基)-l6-硫酮)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(66 mg,0.11 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.02 mL,0.162 mmol),繼而添加丙醯氯(11.97 mg,0.129 mmol)。將所得混合物在rt下攪拌2h。在濃縮之後,藉由製備型HPLC純化殘餘物,獲得(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-N-((R)-側氧基(戊-4-烯-1-基)(丙醯胺基)-l6-硫酮)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺。
步驟 4 :製備實例 3 及實例 4 :
將(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-N-((R)-側氧基(戊-4-烯-1-基)(丙醯胺基)-l6-硫酮)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(55.0 mg,0.082 mmol)及哈維達格拉布第2代催化劑(5.14 mg,0.008 mmol)在60℃下在1,2-二氯乙烷(16.0 mL)中攪拌4 h。在濃縮之後,藉由製備型HPLC純化殘餘物,獲得實例 3
(較高極性溶離份) (LCMS-ESI+ (m/z):C34
H42
ClN3
O5
S [M+H]+計算值:640.2;實驗值:640.2)及實例 4
(較低極性溶離份) (1
H NMR (400 MHz,氘代氯仿) δ 7.68 (d,J
= 9.2 Hz, 1H), 7.37 - 7.35 (m, 1H), 7.23 (s, 1H), 7.08 - 7.06 (m, 2H), 6.92 (d,J
= 8.4 Hz, 1H), 5.86 - 5.82 (m, 1H), 5.74 - 5.70 (m, 1H), 4.06 (d,J
= 12.0 Hz, 1H), 3.99 - 3.95 (m, 2H), 3.81 - 3.71 (m, 4H), 3.59 - 3.57 (m, 1H), 3.34 (d,J
= 14.8 Hz, 1H), 3.29 (s, 3H), 3.04 - 2.98 (m, 1H), 2.78 - 2.73 (m, 4H), 2.50 (q, J = 7.4 Hz, 2H), 2.38 - 1.66 (m, 10H), 1.39 - 1.34 (m, 1H), 1.22 (t,J
= 7.4 Hz, 3H)。LCMS-ESI+ (m/z):C34
H42
ClN3
O5
S [M+H]+計算值:640.2;實驗值:640.2)。實例 5 及 6. 方法 1 :
步驟 1 :製備 ((R)-N-((S)-6'- 氯 -5-(((1R,2R)-2-((S)-1- 甲氧基烯丙基 ) 環丁基 ) 甲基 )-3',4,4',5- 四氫 -2H,2'H- 螺 [ 苯并 [b][1,4] 噁氮呯 -3,1'- 萘 ]-7- 羰基 ) 戊 -4- 烯 -1- 基磺醯亞胺醯基 ) 胺基甲酸第三丁酯及 (N-((S)-6 ' - 氯 -5-(((1R,2R)-2-((S)-1- 甲氧基烯丙基 ) 環丁基 ) 甲基 )-3',4,4',5- 四氫 -2H,2'H- 螺 [ 苯并 [b][1,4] 噁氮呯 -3,1'- 萘 ] -7- 羰基 ) 戊 -4- 烯 -1- 基磺醯亞胺醯基 ) 胺基甲酸第三丁酯:
向於CH2
Cl2
(5.0 mL)中之(3S)-N-(胺基(側氧基)(戊-4-烯-1-基)-l6-硫酮)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(實例 3/4
步驟2,32.00 mg,0.052 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.02 mL,0.105 mmol),繼而添加二碳酸二第三丁酯(17.11 mg,0.078 mmol)。將所得混合物在rt下攪拌過夜。在濃縮之後,藉由製備型HPLC純化來自較高極性溶離份之殘餘物,獲得((R)-N-((S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-羰基)戊-4-烯-1-基磺醯亞胺醯基)胺基甲酸第三丁酯,且藉由製備型HPLC純化來自較低極性溶離份之殘餘物,獲得(N-((S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-羰基)戊-4-烯-1-基磺醯亞胺醯基)胺基甲酸第三丁酯。
步驟 2 :製備實例 5 :
將(N-((S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b] [1,4]噁氮呯-3,1'-萘]-7-羰基)戊-4-烯-1-基磺醯亞胺醯基)胺基甲酸第三丁酯(14 mg,0.02 mmol)及哈維達格拉布第2代催化劑(1.25 mg,0.002 mmol)在60℃下在1,2-二氯乙烷(6.0 mL)中攪拌4 h。在濃縮之後,藉由製備型HPLC純化殘餘物,獲得實例 5
。LCMS-ESI+ (m/z):C31
H38
ClN3
O4
S [M+H]+計算值:584.2;實驗值:584.2。
步驟 3 :製備實例 6 :
以與實例 5
相同之方式使用((R)-N-((S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-羰基)戊-4-烯-1-基磺醯亞胺醯基)胺基甲酸第三丁酯合成實例 6
。LCMS-ESI+ (m/z):C31
H38
ClN3
O4
S [M+H]+計算值:584.2;實驗值:584.2。方法 2 :
步驟 1 :製備 ((R)-N-((S)-6 ' - 氯 -5-(((1R,2R)-2-((S)-1- 甲氧基烯丙基 ) 環丁基 ) 甲基 )-3',4,4',5- 四氫 -2H,2'H- 螺 [ 苯并 [b][1,4] 噁氮呯 -3,1'- 萘 ]-7- 羰基 ) 戊 -4- 烯 -1- 基磺醯亞胺醯基 ) 胺基甲酸第三丁酯:
向於CH2
Cl2
(5.0 mL)中之(3S)-N-(胺基(側氧基)(戊-4-烯-1-基)-l6-硫酮)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺(140.00 mg,0.229 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.06 mL,0.458 mmol),繼而添加二碳酸二第三丁酯(74.97 mg,0.343 mmol)。將所得混合物在rt下攪拌過夜。在濃縮之後,藉由製備型HPLC純化殘餘物,獲得呈非對映異構體混合物形式之((R)-N-((S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-羰基)戊-4-烯-1-基磺醯亞胺醯基)胺基甲酸第三丁酯。
步驟 2 及步驟 3 :
將來自方法2步驟1之Boc保護之非對映異構體混合物(112.0 mg,0.157 mmol)及哈維達格拉布第2代催化劑(9.83 mg,0.016 mmol)在60℃下在1,2-二氯乙烷(6.0 mL)中攪拌4 h。在濃縮之後,藉由製備型HPLC純化殘餘物,獲得呈非對映異構體混合物形式之中間物5-1
,藉由矽膠管柱層析法(EtOAc/己烷= 3/2)將其純化,得到實例 5
(較低極性溶離份)及實例 6
(較高極性溶離份)。方法 3 :
步驟 1 :製備
(1-苯基乙基)碳酸(S)-4-硝基苯酯(5-3-1
):將(1S)-1-(4-苯基苯基)乙醇混合物(8.7 g,71.2 mmol)溶解於MeTHF (90 mL)中且冷卻至0℃。向此冷經攪拌溶液中添加吡啶(7.1 mL)。隨後,經由滴液漏斗逐滴添加於MeTHF (60.0 mL)中之4-硝基-苯基-氯甲酸酯(14.4 g,71.2 mmol)之溶液。在添加之後,將所得混合物自冷卻浴中移除且在周圍下攪拌2 hr。TLC顯示(1S)-1-(4-苯基苯基)乙醇已消耗掉,但4-硝基-苯基-氯甲酸酯仍保留。添加額外之(1S)-1-(4-苯基苯基)乙醇(2.6 g,21.3 mmol)及吡啶(1.0 mL)且繼續攪拌過夜。隨後,將反應物用1N HCl (2×)、鹽水(2×)洗滌,經硫酸鈉乾燥,過濾且濃縮。隨後,將殘餘物溶解於DCM中且與矽膠混合,濃縮至乾,分為兩輪,藉由正相層析法(矽膠,0-20% EtOAc/己烷)純化。將所需溶離份組合且濃縮,得到5-3-1
。1H NMR (400 MHz,氘代氯仿) δ 8.34 - 8.16 (m, 2H), 7.48 - 7.31 (m, 7H), 5.84 (q, J = 6.6 Hz, 1H), 1.70 (d, J = 6.6 Hz, 3H)。
步驟 2 :
將於THF (100 mL)中之N'-(第三丁基二甲基矽烷基)戊-4-烯-1-磺醯咪醯胺(2.0 g,7.18 mmol)之溶液冷卻至-50℃。將於己烷(9.65 mL,15.4 mmol)中之1.6 M n-BuLi逐滴添加至此冷溶液中。在緩慢地逐滴添加於THF (60 mL)中之(4-硝基苯基) [(1S)-1-苯基乙基]碳酸酯之溶液之前,將新形成之混合物在-50℃下攪拌20 min。將所得混合物在-50℃下攪拌15 min且隨後轉至冰水浴,且在0℃下攪拌3 hr。將反應物用冰驟冷且用EtOAc (1×)萃取。將有機層用1N NaOH (3×)、鹽水(1×)洗滌,經硫酸鈉乾燥,過濾,濃縮,且藉由正相層析法(矽膠,0-20% EtOAc/己烷)純化。重複純化,且將所需溶離份組合且濃縮,得到非對映異構體(5-3-2
)及(5-3-3
)之混合物。隨後,藉由手性SFC將非對映異構體混合物分離成單獨非對映異構體。指定第一溶析峰以如(5 - 3 - 2
)中所描繪之手性;指定第二溶析峰以如(5 - 3 - 3
)中所描繪之手性。對於非對映異構體混合物之1
H NMR (400 MHz,氘代氯仿):δ 7.41 - 7.29 (m, 5H), 5.84 - 5.59 (m, 2H), 5.08 - 4.93 (m, 2H), 3.37 - 3.16 (m, 2H), 2.19 - 2.07 (m, 2H), 1.83 (h, J = 7.3, 6.7 Hz, 2H), 1.57 (dq, J = 6.6, 1.8 Hz, 3H), 0.91 - 0.85 (m, 9H), 0.18 (兩組s, 3H), 0.12 (兩組s, 3H)。對於(5-3-2
)之1H NMR (400 MHz,氘代氯仿):δ 7.39 - 7.30 (m, 5H), 5.86 - 5.58 (m, 2H), 5.07 - 4.93 (m, 2H), 3.28 (tq, J = 13.9, 7.9, 7.1 Hz, 2H), 2.13 (p, J = 7.7, 7.2 Hz, 2H), 1.85 (p, J = 7.2 Hz, 2H), 1.57 (dd, J = 6.6, 2.2 Hz, 3H), 0.93 - 0.91 (m, 9H), 0.19 (兩組s, 6H)。
步驟 3 :
在rt下將於THF (24 mL)中之中間物(5-3-2
) (858 mg,2.1 mmol)之溶液用於THF (6.3 mL,6.3 mmol)中之1.0 M四丁基氟化銨處理達60 min。隨後,將反應物濃縮且藉由正相層析法(矽膠,0-80% EtOAc/己烷)純化,得到5-3-3A
。1H NMR (400 MHz,氘代氯仿) δ 7.45 - 7.31 (m, 4H), 5.83 - 5.59 (m, 2H), 5.12 - 4.96 (m, 2H), 3.35 - 3.21 (m, 2H), 2.28 - 2.11 (m, 2H), 2.01 - 1.87 (m, 2H), 1.59 (d, J = 6.7 Hz, 3H)。
步驟 4 :
在0℃下向於DCM (20 mL)中之(3S)-6'-氯-5-[[(1R,2R)-2-[(1S)-1-甲氧基烯丙基]環丁基]甲基]螺[2,4-二氫-1,5-苯并噁氮呯-3,1'-四氫萘]-7-碳醯氯(215 mg,0.45 mmol)之混合物中添加1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺(152 mg,0.98 mmol),繼而添加4-(二甲基胺基)吡啶(120 mg,0.98 mmol)。在攪拌5 min之後,添加於DCM (3 mL)中之中間物(5-3-3A)
(159 mg,0.54 mmol)之溶液,且將所得混合物自冷卻浴中移除且在rt下攪拌過夜。將反應物進一步用DCM (30 mL)稀釋且用1N HCl (15 mL)、飽和碳酸氫鈉(15 mL)及鹽水(15 mL)洗滌,經硫酸鈉乾燥,過濾,濃縮且藉由正相層析法(矽膠管柱,0-80% EtOAc/己烷)純化,得到中間物5-3-4
。LCMS-ESI+ (m/z):[M+H]+計算值:761.0,實驗值:759.9。1
H NMR (400 MHz,氘代氯仿) δ 7.67 (d, J = 8.5 Hz, 1H), 7.50 (s, 1H), 7.39 - 7.28 (m, 6H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.86 (p, J = 6.3 Hz, 1H), 5.77 - 5.48 (m, 2H), 5.21 - 5.08 (m, 2H), 5.08 - 4.96 (m, 2H), 4.14 - 4.04 (m, 2H), 3.81 - 3.71 (m, 2H), 3.70 - 3.48 (m, 3H), 3.39 - 3.13 (m, 5H), 2.84 - 2.69 (m, 2H), 2.52 (dd, J = 10.7, 7.4 Hz, 1H), 2.16 (dt, J = 13.3, 7.6 Hz, 3H), 2.01 - 1.74 (m, 7H), 1.70 - 1.39 (m, 7H)。
步驟 5 :
在添加哈維達-格拉布第2代催化劑(7 mg,0.011 mmol)之前,使於DCE (10 mL)中之中間物5-3-4
溶液充有氮氣達5 min。使新形成之混合物再脫氣2分鐘,且隨後將其封蓋且在60℃下加熱16 hr。隨後,將反應物冷卻至rt,濃縮,藉由正相層析法(矽膠,0-5% DCM/MeOH (具有2.0 N NH3
))純化,得到實例 5
(第一溶析峰:LCMS-ESI+ (m/z):[M+H]+計算值:584.2;實驗值:583.4);及胺基甲酸酯保護之巨環中間物5-3-5
(第二溶析峰:LCMS-ESI+ (m/z):[M+H]+計算值:732.3;實驗值:730.8)。
步驟 6 :
在0℃下將中間物5-3-5
(15.8 mg,0.022 mmol)溶解於DCM (1.0 mL)中。將TFA (1.0 mL)添加至此冷溶液中。將所得混合物在0℃下攪拌2 min且隨後在rt下攪拌1 hr。將反應物冷卻回至0℃且用1N NaOH鹼化至pH~8。用DCM (2×)萃取混合物。將合併有機層用鹽水(1×)洗滌,經硫酸鈉乾燥,過濾,濃縮且藉由Combiflash (矽膠,0-100% EtOAc/己烷)純化,得到實例 5
。LCMS-ESI+ (m/z):[M+H]+計算值:584.2;實驗值:583.3。對於(8)之1
H NMR (400 MHz,氘代氯仿):δ 7.73 (d, J = 8.6 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.33 (d, J = 1.8 Hz, 1H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.04 - 5.93 (m, 1H), 5.73 - 5.61 (m, 1H), 4.12 - 3.94 (m, 2H), 3.88 - 3.68 (m, 2H), 3.62 - 3.51 (m, 2H), 3.40 - 3.17 (m, 6H), 3.00 (dd, J = 15.0, 11.0 Hz, 1H), 2.82 - 2.63 (m, 4H), 2.47 - 2.20 (m, 4H), 1.99 - 1.59 (m, 6H), 1.37 (t, J = 13.1 Hz, 1H)。
以與實例 5 ( 方法 3-
步驟3-6)
相同之方式使用中間物5-3-3
而不使用中間物5-3-2
來合成實例 6
。實例 7 及 8.
以與實例 3
及實例 4
類似之方式使用2-甲氧基乙醯氯而不使用丙醯氯來製備實例 7
及實例 8
。
實例 7 :
LCMS-ESI+ (m/z):C34
H42
ClN3
O6
S [M+H]+計算值:656.2;實驗值:656.2。
實例 8 :
LCMS-ESI+ (m/z):C34
H42
ClN3
O6
S [M+H]+計算值:656.2;實驗值:656.2。實例 9 及 10.
實例9 | 實例10 |
製備實例 9 及實例 10 :
向於CH2
Cl2
(5.0 mL)中之中間物5-1
(實例5/6方法2,10.40 mg,0.018 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.004 mL,0.027 mmol),繼而添加氯甲酸乙酯(2.32 mg,0.021 mmol)。將所得混合物在rt下攪拌2h。在濃縮之後,藉由製備型HPLC純化殘餘物,獲得實例 9
(較高極性溶離份) (LCMS-ESI+ (m/z):C34
H42
ClN3
O6
S [M+H]+計算值:656.2;實驗值:656.2)及實例 10
(較低極性溶離份)。實例 11 及 12.
步驟 1 :製備中間物 11-1 :
向於EtOAc (5 mL)中之中間物5-1
(實例5/6方法2,17.90 mg,0.031 mmol)之經攪拌溶液中添加氧化鉑(IV) (3.48 mg,0.015 mmol)。將所得混合物在rt下在H2
下攪拌0.5 h。將反應混合物經由矽藻土過濾,且用EtOAc洗滌。濃縮濾液。將粗產物(18.0 mg)直接用於下一步驟。
步驟 2 :製備實例 11 及實例 12 :
向於CH2
Cl2
(4.0 mL)中之中間物11-1
(18.0 mg,0.031 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.006 mL,0.046 mmol),繼而添加丙醯氯(3.41 mg,0.037 mmol)。將所得混合物在rt下攪拌2 h。在濃縮之後,藉由製備型HPLC純化殘餘物,獲得實例 11
(較高極性溶離份) (LCMS-ESI+ (m/z):C34
H44
ClN3
O5
S [M+H]+計算值:642.3;實驗值:642.2)及實例 12
(較低極性溶離份) (LCMS-ESI+ (m/z):C34
H44
ClN3
O5
S [M+H]+計算值:642.3;實驗值:642.3)。實例 13 及 14.
製備實例 13 及實例 14 :
向於CH2
Cl2
(4.0 mL)中之中間物5-1
(實例 5 及 6
方法2,10.9 mg,0.019 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.004 mL,0.028 mmol),繼而添加異氰酸乙酯(1.59 mg,0.022 mmol)。將所得混合物在rt下攪拌2 h。在濃縮之後,藉由製備型HPLC、繼而藉由製備型TLC (5% MeOH / CH2
Cl2
)純化殘餘物,獲得實例 13
(較高極性溶離份) (LCMS-ESI+ (m/z):C34
H43
ClN4
O5
S [M+H]+計算值:655.3;實驗值:655.2),及實例 14
(較低極性溶離份) (1
H NMR (400 MHz,氘代氯仿) δ 7.71 (w, 1H), 7.31 (w, 1H), 7.16 (w, 2H), 7.02 (w, 1H), 6.78 (w, 1H), 5.76 (w, 2H), 4.02 - 3.94 (m, 2H), 3.72 - 2.65 (m, 11H), 2.34 - 0.84 (m, 17H)。LCMS-ESI+ (m/z):C34
H43
ClN4
O5
S [M+H]+計算值:655.3;實驗值:655.2。實例 15.
向於CH2
Cl2
(3 mL)中之3-(二甲基胺基)丙酸鹽酸鹽(3.94 mg,0.026 mmol)之經攪拌溶液中添加Et3
N (0.01 mL,0.068 mmol)、EDCI (5.32 mg,0.034 mmol)及DMAP (4.18 mg,0.034 mmol),繼而添加中間物5-1
(實例 5/6
方法2,10.00 mg,0.017 mmol)。將所得混合物在rt下攪拌3 h且濃縮。藉由製備型HPLC純化殘餘物,獲得實例 15
。LCMS-ESI+ (m/z):C36
H47
ClN4
O5
S [M+H]+計算值:683.3;實驗值:683.3。實例 16 及 17.
步驟 1 :製備中間物 16-1 :
向於MeOH (5 mL)中之中間物5-1
(實例5/6方法2,20.00 mg,0.034 mmol)之經攪拌溶液中添加Pd/C (10重量%,0.36 mg,0.03 mmol)。將所得混合物在rt下在H2
下攪拌1.5 h。將反應混合物經由矽藻土過濾,且用MeOH洗滌。濃縮濾液。將粗產物直接用於下一步驟。
步驟 2 :製備實例 16 及實例 17
:隨後,使來自步驟1之粗中間物16-1
與丙醯氯偶合且以與實例 11
及實例 12
類似之方式純化,得到實例 16
(較低極性溶離份) (LCMS-ESI+ (m/z):C34
H45
N3
O5
S [M+H]+計算值:607.8;實驗值:608.3)及實例 17
(較高極性溶離份) (LCMS-ESI+ (m/z):C34
H45
N3
O5
S [M+H]+計算值:607.8;實驗值:608.4)。實例 18.
向於CH2
Cl2
(2 mL)中之3-甲氧基丙酸(2.3 mg,0.022 mmol)之經攪拌溶液中添加EDCI (4.52 mg,0.029 mmol)及DMAP (3.56 mg,0.029 mmol),繼而添加實例 5
(8.50 mg,0.015 mmol)。將所得混合物在rt下攪拌3 h且濃縮。藉由製備型HPLC純化殘餘物,獲得實例 18
。1
H NMR (400 MHz,氘代氯仿) δ 7.73 (d,J
= 8.8 Hz, 1H), 7.41 (dd,J
= 8.4, 2.0 Hz, 1H), 7.29 - 7.28 (m, 1H), 7.13 (dd,J
= 8.4, 2.4 Hz, 1H), 7.09 (d,J
= 2.4 Hz, 1H), 6.94 (d,J
= 8.4 Hz, 1H), 5.88 (dt,J
= 15.8, 5.0 Hz, 1H), 5.75 (dd,J
= 15.8, 7.8 Hz, 1H), 4.05 (dd,J
= 32.4, 12.0 Hz, 2H), 3.95 - 3.73 (m, 6H), 3.60 (dd,J
= 8.0, 3.2 Hz, 1H), 3.46 (s, 3H), 3.37 (d,J
= 14.4 Hz, 1H), 3.32 (s, 3H), 3.04 (dd,J
= 15.0, 11.0 Hz, 1H), 2.80 - 2.71 (m, 5H), 2.43 - 2.28 (m, 4H), 2.11 - 1.69 (m, 8H), 1.42 - 1.36 (m, 1H)。LCMS-ESI+ (m/z):C35
H44
ClN3
O6
S [M+H]+計算值:670.3;實驗值:670.4。實例 19.
向於CH2
Cl2
(2.0 mL)中之實例 5
(8.5 mg,0.015 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.003 mL,0.022 mmol),繼而添加異氰酸異丙酯(1.86 mg,0.022 mmol)。將所得混合物在rt下攪拌2 h。在濃縮之後,藉由製備型HPLC、繼而藉由製備型TLC (5% MeOH / CH2
Cl2
)純化殘餘物,獲得實例 19
。LCMS-ESI+ (m/z):C35
H45
ClN4
O5
S [M+H]+計算值:669.3;實驗值:691.3。實例 20.
以與實例 18
相同之方式使用2-(吡嗪-2-基)乙酸而不使用3-甲氧基丙酸來合成實例 20
。LCMS-ESI+ (m/z):C37
H42
ClN5
O5
S [M+H]+計算值:704.3;實驗值:704.4。實例 21.
向於CH2
Cl2
(2.0 mL)中之實例 5
(10.0 mg,0.017 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.004 mL,0.026 mmol),繼而添加環丙基乙醯氯 (3.04 mg,0.026 mmol)。將所得混合物在rt下攪拌2 h。在濃縮之後,藉由製備型HPLC純化殘餘物,獲得實例 21
。LCMS-ESI+ (m/z):C36
H44
ClN3
O5
S [M+H]+計算值:666.3;實驗值:666.3。實例 22.
以與實例 18
相同之方式使用3-(1-甲基-1H-吡唑-5-基)丙酸而不使用3-甲氧基丙酸來合成實例 22
。1
H NMR (400 MHz,氘代氯仿) δ 7.64 (d,J
= 2.0 Hz, 1H), 7.47 (d,J
= 8.8 Hz, 1H), 7.29 - 7.27 (m, 1H), 7.04 (d,J
= 2.0 Hz, 2H), 6.99 (d,J
= 8.0 Hz, 1H), 6.64 - 6.61 (m, 1H), 6.33 (d,J
= 2.4 Hz, 1H), 5.82 (d,J
= 4.8 Hz, 2H), 3.99 - 3.94 (m, 6H), 3.70 - 3.56 (m, 4H), 3.45 - 3.28 (m, 4H), 3.11 - 2.98 (m, 4H), 2.87 - 2.72 (m, 4H), 2.58 - 1.75 (m, 12H), 1.32 - 1.26 (m, 1H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O5
S [M+H]+計算值:720.3;實驗值:720.4。實例 23
以與實例 21
相同之方式使用3,3,3-三氟丙醯氯而不使用環丙基乙醯氯來合成實例 23
。LCMS-ESI+ (m/z):C34
H39
ClF3
N3
O5
S [M+H]+計算值:694.2;實驗值:694.4。實例 24.
以與實例 18
相同之方式使用氧雜環丁烷-3-甲酸而不使用3-甲氧基丙酸來合成實例 24
。1
H NMR (400 MHz,甲醇-d4
) δ 7.75 (d,J
= 8.4 Hz, 1H), 7.23 (dd,J
= 8.0, 2.0 Hz, 1H), 7.17 - 7.14 (m, 2H), 7.07 (d,J
= 2.4 Hz, 1H), 6.79 (d,J
= 8.0 Hz, 1H), 6.06 (dt,J
= 15.4, 6.2 Hz, 1H), 5.60 (dd,J
= 15.6, 8.8 Hz, 1H), 4.90 - 4.76 (m, 4H), 4.17 - 3.93 (m, 4H), 3.91 - 3.79 (m, 3H), 3.72 - 3.47 (m, 5H), 3.24 (s, 3H), 3.02 (dd,J
= 15.0, 10.6 Hz, 1H), 2.83 - 2.69 (m, 2H), 2.65 - 1.37 (m, 11H)。LCMS-ESI+ (m/z):C35
H42
ClN3
O6
S [M+H]+計算值:668.3;實驗值:668.6。實例 25.
以與實例 21
相同之方式使用乙醯氯而不使用環丙基乙醯氯來合成實例 25
。LCMS-ESI+ (m/z):C33
H40
ClN3
O5
S [M+H]+計算值:626.2;實驗值:626.4。實例 26.
以與實例 21
相同之方式使用異戊醯氯而不使用環丙基乙醯氯來合成實例 26
。LCMS-ESI+ (m/z):C36
H46
ClN3
O5
S [M+H]+計算值:668.3;實驗值:668.4。實例 27.
以與實例 21
相同之方式使用環丙烷碳醯氯而不使用環丙基乙醯氯來合成實例 27
。LCMS-ESI+ (m/z):C35
H42
ClN3
O5
S [M+H]+計算值:652.3;實驗值:652.4。實例 28.
以與實例 18
相同之方式使用3-(甲基磺醯基)丙酸而不使用3-甲氧基丙酸來合成實例 28
。LCMS-ESI+ (m/z):C35
H44
ClN3
O7
S2
[M+H]+計算值:718.3;實驗值:718.3。實例 29.
以與實例 18
相同之方式使用2-(1-甲基-1H-吡唑-5-基)乙酸而不使用3-甲氧基丙酸來合成實例 29
。LCMS-ESI+ (m/z):C37
H44
ClN5
O5
S [M+H]+計算值:706.3;實驗值:706.4。實例 30.
以與實例 18
相同之方式使用2-(嘧啶-2-基)乙酸而不使用3-甲氧基丙酸來合成實例 30
。LCMS-ESI+ (m/z):C37
H42
ClN5
O5
S [M+H]+計算值:704.3;實驗值:704.3。實例 31.
以與實例 21
相同之方式使用環丁甲醯氯而不使用環丙基乙醯氯來合成實例 31
。1
H NMR (400 MHz,甲醇-d4
) δ 7.78 (d,J
= 8.4 Hz, 1H), 7.26 (d,J
= 8.4 Hz, 1H), 7.18 (d,J
= 8.4 Hz, 1H), 7.12 (d,J
= 8.4 Hz, 1H), 6.82 (d,J
= 8.4 Hz, 1H), 6.10 (dt,J
= 15.6, 6.4 Hz, 1H), 5.60 (dd,J
= 15.6, 8.8 Hz, 1H), 4.25 - 4.13 (m, 1H), 4.03 (dd,J
= 21.6, 12.0 Hz, 3H), 3.94 - 3.85 (m, 2H), 3.74 - 3.66 (m, 2H), 3.35 - 3.30 (m, 2H), 3.27 (s, 3H), 3.22 0 3.14 (m, 1H), 3.04 (dd,J
= 15.2, 10.4 Hz, 1H), 2.86 - 2.72 (m, 2H), 2.39 - 1.72 (m, 17H), 1.46 - 1.40 (m, 1H)。LCMS-ESI+ (m/z):C36
H44
ClN3
O5
S [M+H]+計算值:666.3;實驗值:666.4。實例 32.
以與實例 19
相同之方式使用1-異氰酸基-1-(三氟甲基)環丙烷而不使用異氰酸異丙酯來合成實例 32
。1
H NMR (400 MHz,甲醇-d4
) δ 7.75 (d,J
= 8.4 Hz, 1H), 7.21 (d,J
= 8.4 Hz, 1H), 7.15 (dd,J
= 8.8, 2.4 Hz, 1H), 7.12 (s, 1H), 7.07 (d,J
= 2.4 Hz, 1H), 6.78 (d,J
= 8.4 Hz, 1H), 6.08 - 6.02 (m, 1H), 5.62 - 5.56 (m, 1H), 3.99 (dd,J
= 21.8, 12.2 Hz, 3H), 3.83 - 3.76 (m, 2H), 3.67 - 3.64 (m, 3H), 3.34 - 3.30 (m, 2H), 3.24 (s, 3H), 3.07 - 3.00 (m, 1H), 2.83 - 2.69 (m, 2H), 2.53 - 1.68 (m, 11H), 1.44 - 1.37 (m, 1H), 1.22 - 1.04 (m, 4H)。LCMS-ESI+ (m/z):C36
H42
ClF3
N4
O5
S [M+H]+計算值:735.3;實驗值:735.3。實例 33.
以與實例 18
相同之方式使用2-丁炔酸而不使用3-甲氧基丙酸來合成實例 33
。LCMS-ESI+ (m/z):C35
H40
ClN3
O5
S [M+H]+計算值:650.2;實驗值:650.3。實例 34.
以與實例 19
相同之方式使用1,1,1-三氟-2-異氰酸基-2-甲基丙烷而不使用異氰酸異丙酯來合成實例 34
。LCMS-ESI+ (m/z):C36
H44
ClF3
N4
O5
S [M+H]+計算值:737.3;實驗值:737.3。實例 35.
以與實例 18
相同之方式使用3-(吡嗪-2-基)丙酸而不使用3-甲氧基丙酸來合成實例 35
。1
H NMR (400 MHz,甲醇-d4
) δ 8.58 (s, 1H), 8.53 (s, 1H), 8.43 (d,J
= 2.8 Hz, 1H), 7.78 (d,J
= 8.4 Hz, 1H), 7.42 - 7.35 (m, 2H), 7.24 - 7.18 (m, 1H), 7.12 (s, 1H), 6.91 (d,J
= 8.4 Hz, 1H), 5.92 - 5.80 (m, 2H), 4.11 - 3.94 (m, 3H), 3.83 - 3.68 (m, 3H), 3.60 - 3.41 (m, 3H), 3.27 (s, 3H), 3.21 - 3.10 (m, 3H), 2.94 (t,J
= 7.0 Hz, 2H), 2.85 - 2.78 (m, 4H), 2.48 - 1.80 (m, 10H), 1.45 (t,J
= 12.8 Hz, 1H)。LCMS-ESI+ (m/z):C38
H44
ClN5
O5
S [M+H]+計算值:718.3;實驗值:718.3。實例 36.
以與實例 18
相同之方式使用4,4-二甲基戊-2-炔酸而不使用3-甲氧基丙酸來合成實例 36
。LCMS-ESI+ (m/z):C38
H46
ClN3
O5
S [M+H]+計算值:692.3;實驗值:692.3。實例 37.
以與實例 19
相同之方式使用異氰酸4-氟苄酯而不使用異氰酸異丙酯來合成實例 37
。1
H NMR (400 MHz,甲醇-d4
) δ 7.76 (d,J
= 8.8 Hz, 1H), 7.36 - 7.27 (m, 4H), 7.17 (d,J
= 8.4 Hz, 1H), 7.12 (d,J
= 2.4 Hz, 1H), 7.04 (t,J
= 8.6 Hz, 2H), 6.90 (d,J
= 8.0 Hz, 1H), 5.99 - 5.93 (m, 1H), 5.77 - 5.71 (m, 1H), 4.36 (s, 2H), 4.05 (dd,J
= 26.4, 12.0 Hz, 2H), 3.92 (w, 2H), 3.83 (d,J
= 15.2 Hz, 1H), 3.72 (d,J
= 14.0 Hz, 1H), 3.63 (d,J
= 8.8 Hz, 1H), 3.51 - 3.38 (m, 3H), 3.30 (s, 3H), 3.15 - 3.08 (m, 1H), 2.85 - 2.77 (m, 3H), 2.66 - 1.79 (m, 10H), 1.44 (t,J
= 12.8 Hz, 1H)。LCMS-ESI+ (m/z):C39
H44
ClFN4
O5
S [M+H]+計算值:735.3;實驗值:735.3。實例 38.
以與實例 18
相同之方式使用3-嘧啶-4-基-丙酸而不使用3-甲氧基丙酸來合成實例 38
。1
H NMR (400 MHz,甲醇-d4
) δ 9.04 (s, 1H), 8.62 (d,J
= 5.2 Hz, 1H), 7.78 (d,J
= 8.4 Hz, 1H), 7.47 (d,J
= 5.2 Hz, 1H), 7.42 (s, 1H), 7.36 (d,J
= 8.4 Hz, 1H), 7.19 (dd,J
= 9.0, 2.2 Hz, 1H), 7.12 (d,J
= 2.4 Hz, 1H), 6.91 (d,J
= 8.4 Hz, 1H), 5.92 - 5.80 (m, 2H), 4.11 - 3.94 (m, 3H), 3.81 (d,J
= 14.8 Hz, 1H), 3.75 (d,J
= 14.4 Hz, 1H), 3.62 - 3.42 (m, 5H), 3.27 (s, 3H), 3.19 - 3.10 (m, 3H), 2.94 (t,J
= 7.0 Hz, 2H), 2.85 - 2.77 (m, 3H), 2.54 - 1.78 (m, 10H), 1.45 (t,J
= 12.4 Hz, 1H)。LCMS-ESI+ (m/z):C38
H44
ClN5
O5
S [M+H]+計算值:718.3;實驗值:718.3。實例 39.
以與實例 18
相同之方式使用3-吡唑-1-基-丙酸而不使用3-甲氧基丙酸來合成實例 39
。1
H NMR (400 MHz,甲醇-d4
) δ 7.77 (d,J
= 8.4 Hz, 1H), 7.65 (d,J
= 2.4 Hz, 1H), 7.49 (d,J
= 1.6 Hz, 1H), 7.40 (d,J
= 2.0 Hz, 1H), 7.34 (dd,J
= 8.2, 1.8 Hz, 1H), 7.19 (d,J
= 8.0 Hz, 1H), 7.12 (d,J
= 2.4 Hz, 1H), 6.90 (d,J
= 8.4 Hz, 1H), 6.26 - 6.25 (m, 1H), 5.94 - 5.79 (m, 2H), 4.49 (t,J
= 6.6 Hz, 2H), 4.05 (dd,J
= 33.4, 12.2 Hz, 2H), 3.96 - 3.91 (m, 1H), 3.81 (d,J
= 15.2 Hz, 1H), 3.75 (d,J
= 14.4 Hz, 1H), 3.68 - 3.55 (m, 3H), 3.51 - 3.41 (m, 2H), 3.31 (s, 3H), 3.16 - 3.10 (m, 1H), 2.96 (t,J
= 6.6 Hz, 2H), 2.85 - 2.77 (m, 3H), 2.46 - 1.79 (m, 10H), 1.45 (t,J
= 12.6 Hz, 1H)。LCMS-ESI+ (m/z):C37
H44
ClN5
O5
S [M+H]+計算值:706.3;實驗值:706.3。實例 40.
以與實例 18
相同之方式使用3-吡啶丙酸而不使用3-甲氧基丙酸來合成實例 40
。1
H NMR (400 MHz,甲醇-d4
) δ 8.78 (s, 1H), 8.65 (d,J
= 5.6 Hz, 1H), 8.50 (d,J
= 8.4 Hz, 1H), 7.90 (dd,J
= 8.0, 6.0 Hz, 1H), 7.77 (d,J
= 8.4 Hz, 1H), 7.40 (d,J
= 2.0 Hz, 1H), 7.29 (d,J
= 8.0 Hz, 1H), 7.18 (dd,J
= 8.6, 2.2 Hz, 1H), 7.12 (d,J
= 2.4 Hz, 1H), 6.92 (d,J
= 8.4 Hz, 1H), 5.92 - 5.81 (m, 2H), 4.11 - 3.95 (m, 4H), 3.81 - 3.73 (m, 2H), 3.56 - 3.43 (m, 4H), 3.32 (s, 3H), 3.25 - 3.11 (m, 3H), 2.90 (t,J
= 6.8 Hz, 2H), 2.85 - 2.78 (m, 2H), 2.26 - 1.80 (m, 11H), 1.44 (t,J
= 12.8 Hz, 1H)。LCMS-ESI+ (m/z):C39
H45
ClN4
O5
S [M+H]+計算值:717.3;實驗值:717.4。實例 41.
以與實例 18
相同之方式使用3-(吡啶-4-基)丙酸而不使用3-甲氧基丙酸來合成實例 41
。1
H NMR (400 MHz,甲醇-d4
) δ 8.64 (d,J
= 6.0 Hz, 2H), 7.93 (d,J
= 5.6 Hz, 2H), 7.76 (d,J
= 8.4 Hz, 1H), 7.40 (d,J
= 2.0 Hz, 1H), 7.31 (dd,J
= 8.2, 1.8 Hz, 1H), 7.17 (dd,J
= 8.4, 2.4 Hz, 1H), 7.12 (d,J
= 2.4 Hz, 1H), 6.92 (d,J
= 8.0 Hz, 1H), 5.92 - 5.81 (m, 2H), 4.11 - 3.97 (m, 3H), 3.81 - 3.73 (m, 2H), 3.55 - 3.43 (m, 3H), 3.32 (s, 3H), 3.31 - 3.20 (m, 3H), 3.17 - 3.11 (m, 1H), 2.94 (t,J
= 7.0 Hz, 2H), 2.87 - 2.77 (m, 3H), 2.54 - 1.80 (m, 10H), 1.47 - 1.41 (m, 1H)。LCMS-ESI+ (m/z):C39
H45
ClN4
O5
S [M+H]+計算值:717.3;實驗值:717.3。實例 42.
以與實例 18
相同之方式使用3-(1H-1,2,4-三唑-1-基)丙酸而不使用3-甲氧基丙酸來合成實例 42
。LCMS-ESI+ (m/z):C36
H43
ClN6
O5
S [M+H]+計算值:707.3;實驗值:707.3。實例 43.
以與實例 18
相同之方式使用3-(1-甲基-1H-咪唑-2-基)丙酸而不使用3-甲氧基丙酸來合成實例 43
。LCMS-ESI+ (m/z):C38
H46
ClN5
O5
S [M+H]+計算值:720.3;實驗值:721.3。實例 44.
以與實例 18
相同之方式使用3-(嘧啶-2-基)丙酸而不使用3-甲氧基丙酸來合成實例 44
。1
H NMR (400 MHz,甲醇-d4
) δ 8.73 (d,J
= 4.8 Hz, 2H), 7.76 (d,J
= 8.8 Hz, 1H), 7.40 (d,J
= 2.0 Hz, 1H), 7.38 - 7.34 (m, 2H), 7.17 (dd,J
= 8.8, 2.4 Hz, 1H), 7.11 (d,J
= 2.0 Hz, 1H), 6.91 (d,J
= 8.4 Hz, 1H), 5.93 - 5.79 (m, 2H), 4.10 - 3.93 (m, 3H), 3.80 (d,J
= 15.2 Hz, 1H), 3.74 (d,J
= 14.4 Hz, 1H), 3.67 - 3.59 (m, 1H), 3.55 (dd,J
= 8.2, 3.0 Hz, 1H), 3.43 (d,J
= 14.4 Hz, 1H), 3.35 - 3.30 (m, 4H), 3.25 (s, 3H), 3.16 - 3.09 (m, 1H), 3.00 (t,J
= 6.8 Hz, 2H), 2.86 - 2.73 (m, 3H), 2.52 - 1.78 (m, 10H), 1.47 - 1.41 (m, 1H)。LCMS-ESI+ (m/z):C38
H44
ClN5
O5
S [M+H]+計算值:718.3;實驗值:719.4。實例 45.
以與實例 18
相同之方式使用3-(1-乙基-1H-吡唑-5-基)丙酸而不使用3-甲氧基丙酸來合成實例 45
。1
H NMR (400 MHz,甲醇-d4
) δ 7.77 (d,J
= 8.4 Hz, 1H), 7.42 - 7.35 (m, 3H), 7.17 (d,J
= 8.4 Hz, 1H), 7.12 (s, 1H), 6.91 (d,J
= 8.4 Hz, 1H), 6.14 (s, 1H), 5.93 - 5.81 (m, 2H), 4.17 (q,J
= 7.2 Hz, 2H), 4.11 - 3.94 (m, 3H), 3.81 (d,J
= 14.8 Hz, 1H), 3.74 (d,J
= 14.8 Hz, 1H), 3.63 - 3.50 (m, 2H), 3.44 (d,J
= 14.4 Hz, 1H), 3.34 - 3.31 (m, 2H), 3.31 (s, 3H), 3.17 - 3.10 (m, 1H), 3.02 -3.00 (m, 2H), 2.87 - 2.79 (m, 5H), 2.55 - 1.79 (m, 10H), 1.48 - 1.35 (m, 4H)。LCMS-ESI+ (m/z):C39
H48
ClN5
O5
S [M+H]+計算值:734.4;實驗值:734.4。實例 46.
以與實例 18
相同之方式使用3-(2-甲基-2H-1,2,3-三唑-4-基)丙酸而不使用3-甲氧基丙酸來合成實例 46
。1
H NMR (400 MHz,甲醇-d4
) δ 7.77 (d,J
= 8.4 Hz, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 7.35 (d,J
= 8.4 Hz, 1H), 7.19 (d,J
= 8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d,J
= 8.0 Hz, 1H), 5.96 - 5.90 (m, 1H), 5.82 (dd,J
= 16.2, 8.6 Hz, 1H), 4.10 - 3.94 (m, 6H), 3.82 (d,J
= 15.2 Hz, 1H), 3.74 (d,J
= 14.4 Hz, 1H), 3.68 - 3.50 (m, 2H), 3.42 (d,J
= 14.4 Hz, 1H), 3.34 - 3.32 (m, 2H), 3.31 (s, 3H), 3.16 - 3.09 (m, 1H), 3.01 (t,J
= 7.2 Hz, 2H), 2.85 - 2.75 (m, 5H), 2.50 - 1.78 (m, 10H), 1.48 - 1.42 (m, 1H)。LCMS-ESI+ (m/z):C37
H45
ClN6
O5
S [M+H]+計算值:721.3;實驗值:721.3。實例 47.
以與實例 18
相同之方式使用2-吡啶丙酸而不使用3-甲氧基丙酸來合成實例 47
。1
H NMR (400 MHz,甲醇-d4
) δ 8.60 (d,J
= 5.6 Hz, 1H), 8.26 (t,J
= 7.8 Hz, 1H), 7.82 (d,J
= 8.0 Hz, 1H), 7.78 (d,J
= 8.4 Hz, 1H), 7.69 (t,J
= 6.6 Hz, 1H), 7.40 (s, 1H), 7.31 (dd,J
= 8.2, 1.8 Hz, 1H), 7.19 (d,J
= 8.8 Hz, 1H), 7.12 (s, 1H), 6.91 (d,J
= 8.0 Hz, 1H), 5.92 - 5.79 (m, 2H), 4.12 - 3.92 (m, 3H), 3.82 - 3.74 (m, 2H), 3.57 - 3.51 (m, 2H), 3.44 (d,J
= 14.8 Hz, 1H), 3.29 (s, 3H), 3.33 - 3.24 (m, 4H), 3.17 - 3.11 (m,1H), 2.96 (t,J
= 6.8 Hz, 2H), 2.92 - 2.78 (m, 3H), 2.49 - 1.81 (m, 10H), 1.48 - 1.41 (m, 1H)。LCMS-ESI+ (m/z):C39
H45
ClN4
O5
S [M+H]+計算值:717.3;實驗值:717.5。實例 48.
以與實例 18
相同之方式使用3-(1-甲基-1H-吡唑-5-基)丙酸及實例 6
而不使用3-甲氧基丙酸及實例 5
來合成實例 48
。LCMS-ESI+ (m/z):C38
H46
ClN5
O5
S [M+H]+計算值:720.3;實驗值:720.0。實例 49.
步驟 1 :
向於CH2
Cl2
(15.0 mL)中之(3S)-N-(胺基((2R,3S)-3-甲基己-5-烯-2-基)(側氧基)-l6-硫酮)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲醯胺1-6
(309.00 mg,0.483 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.14 mL,0.965 mmol),繼而添加DMAP (23.58 mg,0.193 mmol)及二碳酸二第三丁酯(157.99 mg,0.724 mmol)。將所得混合物在rt下攪拌過夜。在濃縮之後,藉由製備型HPLC分離非對映異構體混合物,獲得49-1
(較低極性溶離份)及49-2
(較高極性溶離份)。
步驟 2 :
使用實例 5
方法1步驟2中所示之類似程序由中間物49-1
合成中間物49-3
。
步驟 3 :
以與實例 18
相同之方式使用3-(1-甲基-1H-吡唑-5-基)丙酸及中間物49-3
來合成實例 49
。1
H NMR (400 MHz,甲醇-d4
) δ 7.75 (d,J
= 8.8 Hz, 1H), 7.38 (s, 1H), 7.19 (d,J
= 8.4 Hz, 2H), 7.13 (d,J
= 2.0 Hz, 1H), 7.05 (s, 1H), 6.93 (d,J
= 8.4 Hz, 1H), 6.15 (s, 1H), 6.00 - 5.93 (m, 1H), 5.60 (dd,J
= 15.4, 9.0 Hz, 1H), 4.32 - 4.28 (m, 1H), 4.09 (s, 2H), 3.85 - 3.81 (m, 4H), 3.75 - 3.67 (m, 3H), 3.51 - 3.79 (m, 1H), 3.25 (s, 3H), 3.16 - 3.09 (m, 1H), 3.01 (t,J
= 7.2 Hz, 2H), 2.85 - 2.79 (m, 5H), 2.48 - 1.77 (m, 10H), 1.51 - 1.44 (m, 4H), 1.06 (d,J
= 5.6 Hz, 3H)。LCMS-ESI+ (m/z):C40
H50
ClN5
O5
S [M+H]+計算值:748.4;實驗值:748.0。實例 50.
用實例 49
(步驟2及步驟3)中所描述之程序使用中間物49-2
而不使用中間物49-1
來合成實例 50
。LCMS-ESI+ (m/z):C40
H50
ClN5
O5
S [M+H]+計算值:748.4;實驗值:748.0。實例 51.
以與實例 18
相同之方式使用3- (1-甲基-1H-吡唑-3-基)丙酸而不使用3-甲氧基丙酸來合成實例 51
。1
H NMR (400 MHz,甲醇-d4
) δ 7.77 (d,J
= 8.4 Hz, 1H), 7.44 (d,J
= 8.4 Hz, 2H), 7.36 (d,J
= 8.0 Hz, 1H), 7.19 (d,J
= 8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d,J
= 8.4 Hz, 1H), 6.12 (d,J
= 2.4 Hz, 1H), 5.94 - 5.81 (m, 2H), 4.11 - 3.94 (m, 3H), 3.83 - 3.80 (m, 4H), 3.75 (d,J
= 14.4 Hz, 1H), 3.68 - 3.47 (m, 2H), 3.43 (d,J
= 14.8 Hz, 1H), 3.34 - 3.31 (m, 5H), 3.16 - 3.10 (m, 1H), 2.94 (t,J
= 7.8 Hz, 2H), 2.85 - 2.78 (m, 3H), 2.74 (t,J
= 7.6 Hz, 2H), 2.53 - 1.78 (m, 10H), 1.45 (t,J
= 12.6 Hz, 1H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O5
S [M+H]+計算值:720.3;實驗值:720.0。實例 52.
以與實例 18
相同之方式使用3-吲唑-1-基-丙酸而不使用3-甲氧基丙酸來合成實例 52
。LCMS-ESI+ (m/z):C41
H46
ClN5
O5
S [M+H]+計算值:756.4;實驗值:756.2。實例 53.
以與實例 18
相同之方式使用3-(嘧啶-5-基)丙酸而不使用3-甲氧基丙酸來合成實例 53
。1
H NMR (400 MHz,甲醇-d4
) δ 9.00 (s, 1H), 8.74 (s, 2H), 7.77 (d,J
= 8.4 Hz, 1H), 7.41 (s, 1H), 7.34 (dd,J
= 8.0, 1.6 Hz, 1H), 7.17 (d,J
= 8.4 Hz, 1H), 7.11 (s, 1H), 6.90 (d,J
= 8.4 Hz, 1H), 5.92 - 5.81 (m, 2H), 4.11 - 3.91 (m, 3H), 3.82 - 3.68 (m, 2H), 3.60 - 3.50 (m, 2H), 3.43 (d,J
= 14.4 Hz, 1H), 3.35 - 3.33 (m, 5H), 3.16 - 3.10 (m, 1H), 3.02 (t,J
= 7.3 Hz, 2H), 2.87 - 2.78 (m, 4H), 2.55 - 1.78 (m, 10H), 1.44 (t,J
= 12.8 Hz, 1H)。LCMS-ESI+ (m/z):C38
H44
ClN5
O5
S [M+H]+計算值:718.3;實驗值:718.1。實例 54.
以與實例 18
相同之方式使用3-(1H-1,2,3-三唑-1-基)丙酸鈉而不使用3-甲氧基丙酸來合成實例 54
。LCMS-ESI+ (m/z):C36
H43
ClN6
O5
S [M+H]+計算值:707.3;實驗值:707.1。實例 55.
以與實例 18
相同之方式使用3-(4-氯-1H-吡唑-1-基)丙酸而不使用3-甲氧基丙酸來合成實例 55
。1
H NMR (400 MHz,甲醇-d4
) δ 7.77 (d,J
= 8.8 Hz, 1H), 7.73 (s, 1H), 7.44 (s, 1H), 7.41 (s, 1H), 7.35 (d,J
= 8.4 Hz, 1H), 7.19 (d,J
= 8.4 Hz, 1H), 7.12 (d,J
= 2.4 Hz, 1H), 6.90 (d,J
= 8.4 Hz, 1H), 5.94 - 5.79 (m, 2H), 4.44 (t,J
= 6.2 Hz, 2H), 4.05 (dd,J
= 33.8, 12.2 Hz, 2H), 3.97 - 3.89 (m, 1H), 3.81 (d,J
= 14.8 Hz, 1H), 3.75 (d,J
= 14.4 Hz, 1H), 3.64 - 3.50 (m, 2H), 3.43 (d,J
= 14.4 Hz, 1H), 3.34 - 3.31 (m, 5H), 3.16 - 3.10 (m, 1H), 2.96 (t,J
= 6.4 Hz, 2H), 2.85 - 2.77 (m, 3H), 2.53 - 1.79 (m, 10H), 1.45 (t,J
= 12.6 Hz, 1H)。LCMS-ESI+ (m/z):C37
H43
Cl2
N5
O5
S [M+H]+計算值:740.7;實驗值:740.0。實例 56.
以與實例 18
相同之方式使用3-(5-甲基-1H-吡唑-1-基)丙酸來合成實例 56
。LCMS-ESI+ (m/z):C38
H46
ClN5
O5
S [M+H]+計算值:720.3;實驗值:720.1。實例 57.
以與實例 18
相同之方式使用3-異噁唑-4-基-丙酸而不使用3-甲氧基丙酸來合成實例 57
。1
H NMR (400 MHz,甲醇-d4
) δ 8.51 (s, 1H), 8.35 (s, 1H), 7.77 (d,J
= 8.8 Hz, 1H), 7.42 (s, 1H), 7.36 (d,J
= 8.0 Hz, 1H), 7.17 (d,J
= 8.4 Hz, 1H), 7.12 (s, 1H), 6.91 (d,J
= 8.4 Hz, 1H), 5.93 - 5.81 (m, 2H), 4.11 - 3.92 (m, 3H), 3.81 (d,J
= 15.2 Hz, 1H), 3.75 (d,J
= 14.4 Hz, 1H), 3.64 - 3.49 (m, 2H), 3.44 (d,J
= 14.4 Hz, 1H), 3.36 - 3.31 (m, 7H), 3.17 - 3.10 (m, 1H), 2.87 - 2.77 (m, 3H), 2.70 (t,J
= 7.2 Hz, 2H), 2.55 - 1.79 (m, 10H), 1.45 (t,J
= 12.6 Hz, 1H)。LCMS-ESI+ (m/z):C37
H43
ClN4
O6
S [M+H]+計算值:707.3;實驗值:707.1。實例 58.
以與實例 18
相同之方式使用3-(1,2-噁唑-3-基)丙酸而不使用3-甲氧基丙酸來合成實例 58
。1
H NMR (400 MHz,甲醇-d4
) δ 8.54 (d,J
= 1.6 Hz, 1H), 7.77 (d,J
= 8.8 Hz, 1H), 7.40 (s, 1H), 7.35 (d,J
= 8.4 Hz, 1H), 7.18 (d,J
= 8.4 Hz, 1H), 7.12 (d,J
= 2.4 Hz, 1H), 6.90 (d,J
= 8.4 Hz, 1H), 6.43 (d,J
= 1.6 Hz, 1H), 5.95 - 5.89 (m, 1H), 5.82 (dd,J
= 16.0, 8.4 Hz, 1H), 4.11 - 3.92 (m, 3H), 3.82 (d,J
= 15.2 Hz, 1H), 3.74 (d,J
= 14.4 Hz, 1H), 3.68 - 3.47 (m, 2H), 3.42 (d,J
= 14.4 Hz, 1H), 3.35 - 3.32 (m, 2H), 3.31 (s, 3H), 3.16 - 3.04 (m, 3H), 2.85 - 2.72 (m, 5H), 2.51 - 1.78 (m, 10H), 1.45 (t,J
= 12.6 Hz, 1H)。LCMS-ESI+ (m/z):C37
H43
ClN4
O6
S [M+H]+計算值:707.3;實驗值:707.0。實例 59.
以與實例 18
相同之方式使用3-(3-甲基-1H-吡唑-1-基)丙酸而不使用3-甲氧基丙酸來合成實例 59
。H NMR (400 MHz,甲醇-d4
) δ 7.78 (d,J
= 8.8 Hz, 1H), 7.51 (d,J
= 2.4 Hz, 1H), 7.41 (s, 1H), 7.34 (dd,J
= 8.2, 1.8 Hz, 1H), 7.19 (d,J
= 8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d,J
= 8.4 Hz, 1H), 6.02 (d,J
= 2.4 Hz, 1H), 5.95 - 5.80 (m, 2H), 4.39 (t,J
= 6.6 Hz, 2H), 4.06 (dd,J
= 34.2, 12.2 Hz, 2H), 3.98 - 3.91 (m, 1H), 3.81 (d,J
= 15.2 Hz, 1H), 3.75 (d,J
= 14.4 Hz, 1H), 3.68 - 3.47 (m, 2H), 3.43 (d,J
= 14.4 Hz, 1H), 3.35 - 3.31 (m, 5H), 3.16 - 3.10 (m, 1H), 2.93 (t,J
= 6.4 Hz, 2H), 2.85 - 2.75 (m, 3H), 2.53 - 1.79 (m, 13H), 1.45 (t,J
= 12.6 Hz, 1H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O5
S [M+H]+計算值:720.3;實驗值:720.1。實例 60.
以與實例 18
相同之方式使用3-(5-甲基-1,3,4-噁二唑-2-基)丙酸鋰而不使用3-甲氧基丙酸來合成實例 60
。LCMS-ESI+ (m/z):C37
H44
ClN5
O6
S [M+H]+計算值:722.3;實驗值:722.1。實例 61.
以與實例 18
相同之方式使用3-(4-甲基-1H-吡唑-1-基)丙酸而不使用3-甲氧基丙酸來合成實例 61
。1
H NMR (400 MHz,甲醇-d4
) δ 7.77 (d,J
= 8.4 Hz, 1H), 7.41 (s, 2H), 7.34 (d,J
= 8.0 Hz, 1H), 7.28 (s, 1H), 7.19 (d,J
= 8.4 Hz, 1H), 7.12 (s, 1H), 6.90 (d,J
= 8.4 Hz, 1H), 5.93 - 5.80 (m, 2H), 4.40 (td,J
= 6.4, 2.4 Hz, 2H), 3.81 (dd,J
= 34.0, 12.4 Hz, 2H), 3.97 - 3.90 (m, 1H), 3.81 (d,J
= 14.8 Hz, 1H), 3.75 (d,J
= 14.4 Hz, 1H), 3.63 - 3.47 (m, 2H), 3.43 (d,J
= 14.8 Hz, 1H), 3.35 - 3.33 (m, 5H), 3.17 - 3.10 (m, 1H), 2.92 (t,J
= 6.6 Hz, 2H), 2.85 - 2.75 (m, 3H), 2.52 - 1.78 (m, 13H), 1.45 (t,J
= 12.8 Hz, 1H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O5
S [M+H]+計算值:720.3;實驗值:720.1。實例 62 及 63.
步驟 1 :
向於四氫呋喃中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b] [1,4]噁氮呯-3,1'-萘]-7-甲酸(2.0 g,4.27 mmol)之經攪拌溶液中添加吡啶(1.0 g,8.5 mmol)及乙酸酐(1.3 g,8.5 mmol)。將混合物在室溫下攪拌48小時,繼而蒸發溶劑。將殘餘物溶解於乙酸乙酯中且用水洗滌。濃縮有機層,得到粗製物酐62-1
。
步驟 2 :
將於CH2
Cl2
中之酐62-1
(2.0 gr,3.6 mmol)之經攪拌溶液冷卻至0℃。在劇烈攪拌下向此混合物中逐滴添加SOCl2
(2 mL)。在0℃下攪拌混合物,且使其緩慢地升溫至室溫。在反應完成之後,將其蒸發以移除過量SOCl2
,得到酸氯化物中間物62-2
,其緊接著在下一步驟使用。
步驟 3 :
向於室溫下攪拌5 min之於乙腈中之62-2
(200 mg,0.38 mmol)及噠嗪(30 mg,0.38 mmol)之溶液中添加(S)-N'-(第三丁基二甲基矽烷基)戊-4-烯-1-磺醯咪醯胺及(R)-N'-(第三丁基二甲基矽烷基)戊-4-烯-1-磺醯咪醯胺(99 mg,0.38 mmol)之外消旋混合物。在反應完成之後,將殘餘物溶解於乙酸乙酯中且用水洗滌。將有機層濃縮且藉由逆相層析法乙腈-水50%-90%純化30 min,得到中間物IV
之非對映異構體混合物。
步驟 4 :
將磺醯咪醯胺中間物IV
(150 mg,0.23 mmol)、丙醯氯(26 mg,0.29 mmol)及三乙胺(0.29 mmol)之混合物在室溫下在CH2
Cl2
中攪拌一小時。將反應混合物在減壓下蒸發,溶解於DMF中且藉由逆相層析法乙腈-水50-90%純化30 min,得到62-3
。
步驟 5 :
將酯中間物62-3
(25 mg,0.036 mmol)及哈維達-格拉布第2代催化劑(2.2 mg,0.004 mmol)密封於微波小瓶中且用氬氣吹掃,且隨後添加1,2-DCE。將微波小瓶加熱至60℃達1小時。在反應完成之後,將反應混合物在減壓下蒸發,溶解於DMF中且藉由逆相層析法乙腈-水50%-90%純化30 min,得到呈非對映異構體混合物形式之巨環中間物62-4
。
步驟 6 :
將中間物(62-4
)溶解於甲醇(3 mL)及水(0.3 mL)中。向此溶液中添加K2
CO3
(10.8 mg,0.08 mmol)且在室溫下攪拌7 hr。將混合物溶解於乙酸乙酯中且用水洗滌。將有機層濃縮且藉由逆相層析法乙腈-水50%-90%純化30 min ,得到實例 62 (
較低極性溶離份)及實例 63 (
較高極性溶離份)。
實例 62
:1
H NMR (400 MHz,氘代氯仿) δ 7.72 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.9 Hz, 2H), 7.17 (dd, J = 8.5, 2.3 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.00 (dd, J = 15.8, 7.6 Hz, 1H), 5.80 (dt, J = 15.8, 5.2 Hz, 1H), 4.20 - 3.95 (m, 4H), 3.78 (t, J = 14.7 Hz, 3H), 3.53 - 3.40 (m, 3H), 3.34 (d, J = 14.4 Hz, 2H), 3.15 - 3.00 (m, 2H), 2.88 - 2.67 (m, 3H), 2.45 (q, J = 7.5 Hz, 3H), 2.24 (dt, J = 12.7, 6.3 Hz, 2H), 2.12 - 1.63 (m, 4H), 1.40 (d, J = 13.3 Hz, 1H), 1.26 (t, J = 7.1 Hz, 1H), 1.17 (t, J = 7.4 Hz, 2H)。LCMS-ESI+ (m/z):C33
H40
ClN3
O5
S [M+H]+計算值:626.2;實驗值:626.2。
實例 63 : 1
H NMR (400 MHz,氘代氯仿) δ 8.05 (s, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.44 - 7.33 (m, 2H), 7.18 (d, J = 8.2 Hz, 1H), 7.08 (s, 1H), 6.91 (t, J = 8.1 Hz, 1H), 5.91 - 5.71 (m, 2H), 4.15 - 4.00 (m, 3H), 3.99 - 3.85 (m, 1H), 3.71 (d, J = 14.7 Hz, 2H), 3.58 (d, J = 14.9 Hz, 1H), 3.43 (d, J = 14.7 Hz, 1H), 3.27 (s, 2H), 3.00 (s, 2H), 2.95 - 2.87 (m, 2H), 2.80 (d, J = 19.0 Hz, 3H), 2.46 (tt, J = 7.4, 3.4 Hz, 3H), 1.90-1.60 (m, 6H), 1.23 (dt, J = 18.1, 7.3 Hz, 4H)。LCMS-ESI+ (m/z):C33
H40
ClN3
O5
S [M+H]+計算值:626.2;實驗值:626.2。實例 64 及 65.
步驟 1 :製備 (R)-N-( 第三丁基二甲基矽烷基 ) 庚 -6- 烯 -3- 磺醯胺:
向於THF中之(R)-庚-6-烯-3-磺醯胺(根據國際公開案第WO17/147410號中之程序製備,1.5 g,9.2 mmol)之經攪拌溶液中添加於冰浴中之Et3
N (1.8 g,18.3 mmol),繼而添加於THF中之第三丁基氯二甲基矽烷(1.7 g,11.5 mmol)。將所得混合物在室溫下攪拌24 hr。將沈澱物過濾掉且用醚洗滌。將濾液濃縮且進行正相層析法己烷/EtOAc = 3:1純化,得到(R)-N-(第三丁基二甲基矽烷基)庚-6-烯-3-磺醯胺。
步驟 2 :
製備(3R)-N'-(第三丁基二甲基矽烷基)庚-6-烯-3-磺醯咪醯胺:在氮氣氛圍下向於CH2
Cl2
中之Ph3
PCl2
(4.2 g,12.6 mmol)之經攪拌懸浮液中添加三乙胺(1.2 g,12.6 mmol)。將混合物在室溫下攪拌10 min,隨後冷卻至0℃,且添加於CH2
Cl2
中之(R)-N-(第三丁基二甲基矽烷基)庚-6-烯-3-磺醯胺(2.2 g,7.9 mmol)之溶液。將反應混合物在0℃下攪拌1小時。向反應混合物中鼓入氨氣。將混合物在0℃下攪拌2小時,且隨後升溫至室溫達24小時。將沈澱物過濾掉,且用CH2
Cl2
洗滌。將濾液濃縮且進行正相層析法(己烷:EtOAc = 7:3)純化,得到(3R)-N'-(第三丁基二甲基矽烷基)庚-6-烯-3-磺醯咪醯胺。1
H NMR (400 MHz,氘代氯仿) δ 5.78 (ddt,J
= 16.9, 10.5, 6.6 Hz, 1H), 5.13 - 4.85 (m, 2H), 4.38 (s, 2H), 2.75 (tt,J
= 7.0, 4.8 Hz, 1H), 2.32 - 2.10 (m, 2H), 2.06 - 1.86 (m, 2H), 1.79 - 1.54 (m, 2H), 1.03 (td,J
= 7.5, 1.7 Hz, 3H), 0.87 (s, 9H), 0.09 (d,J
= 1.1 Hz, 6H)。
步驟 3 :
以與實例 3
及實例 4
相同之方式使用(3R)-N'-(第三丁基二甲基矽烷基)庚-6-烯-3-磺醯咪醯胺而不使用N'-(第三丁基二甲基矽烷基)戊-4-烯-1-磺醯咪醯胺來製備實例 64
及實例 65
。
實例 64
(較高極性溶離份):1
H NMR (400 MHz,氘代氯仿) δ 7.70 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.16 (t, J = 4.2 Hz, 2H), 7.07 (s, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.86 (s, 1H), 5.59 (dd, J = 15.8, 7.8 Hz, 1H), 4.18 - 3.95 (m, 3H), 3.85 - 3.63 (m, 3H), 3.35 - 3.21 (m, 4H), 3.07 - 2.92 (m, 1H), 2.77 (s, 2H), 2.44 (t, J = 7.9 Hz, 7H), 2.18 - 1.57 (m, 10H), 1.25 (s, 1H), 1.13 (dt, J = 28.4, 7.2 Hz, 6H)。LCMS-ESI+ (m/z):C36
H46
ClN3
O5
S [M+H]+計算值:668.2;實驗值:668.3。
實例 65
(較低極性溶離份):1
H NMR (400 MHz,氘代氯仿) δ 7.70 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 10.5 Hz, 2H), 7.08 (s, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.10-6.00 (m, 1H), 5.50 (dd, J = 15.4, 8.5 Hz, 1H), 4.29 - 3.99 (m, 3H), 3.87 - 3.59 (m, 3H), 3.25 (s, 4H), 3.00 (s, 1H), 2.76 (d, J = 13.4 Hz, 2H), 2.43 (dd, J = 19.8, 12.5 Hz, 6H), 2.24 - 1.54 (m, 11H), 1.41 (s, 1H), 1.28 - 1.05 (m, 6H)。LCMS-ESI+ (m/z):C36
H46
ClN3
O5
S [M+H]+計算值:668.2;實驗值:668.3。實例 66.
步驟 1 :製備 66-1 :
將中間物IV
(900 mg,1.4 mmol)、二碳酸二第三丁酯(429 mg,1.9 mmol)、DMAP (17 mg,0.14 mmol)及三乙胺(0.2 mL)之混合物在室溫下在CH2
Cl2
中攪拌一小時。在反應完成之後,將反應混合物在減壓下蒸發且藉由矽膠層析法(己烷:EtOAc 1:1)純化,得到中間物66-1
。
步驟 2 :
在圓瓶燒瓶中添加66-1
(880 mg,1.26 mmol)及哈維達-格拉布第2代催化劑(78 mg,0.13 mmol)。將燒瓶密封且用氬氣吹掃,且隨後添加1,2-DCE。將燒瓶加熱至60℃達1小時。在反應完成之後,在減壓下蒸發反應混合物,得到中間物66-2
。
步驟 3 :
將中間物66-2
(600 mg,0.84 mmol)溶解於甲醇(6 mL)及水(0.6 mL)中。向此溶液中添加K2
CO3
(406 mg,2.94 mmol)且在室溫下攪拌7小時。將混合物溶解於乙酸乙酯中且用水洗滌。將有機層濃縮且藉由逆相層析法(乙腈-水50%-90%達30 min)純化,得到非對映異構體66-3
(較高極性溶離份)及66-4
(較低極性溶離份)。
步驟 4 :
將中間物66-3
(15 mg,0.024 mmol)溶解於DMF中,且在室溫下添加NaH (4 mg,0.072 mmol),攪拌10 min,且隨後添加三氟甲磺酸2-溴乙酯(12 mg,0.048 mmol)。將反應混合物在室溫下攪拌5小時且溶解於乙酸乙酯中且用水洗滌。濃縮有機層,得到溴中間物66-5
,其不經純化即進一步使用。
步驟 5 :
將溴中間物66-5
(15 mg,0.02 mmol)溶解於嗎啉中且在50℃下攪拌1小時。在減壓下蒸發此混合物,得到66-6
,其不經純化即進一步使用。
步驟 6 :
將嗎啉中間物66-6
(9 mg,0.011 mmol)用CH2
Cl2
(2 mL)及TFA (1 mL)之混合物處理且在室溫下攪拌1 h。將混合物溶解於乙酸乙酯中且用飽和碳酸氫鈉水溶液洗滌。將有機層濃縮且藉由逆相層析法乙腈-水50%-90%持續30 min純化成中間物66-7
。
步驟 7 :
將中間物66-7
(5 mg,0.007 mmol)、丙醯氯(1 mg,0.007 mmol)及三乙胺(0.021 mmol)在室溫下在CH2
Cl2
中攪拌一小時。在反應完成之後,將其在減壓下蒸發,溶解於DMF中且藉由逆相層析法乙腈-水50-90%純化30 min,得到實例 66
。1H NMR (400 MHz,氘代氯仿) δ 7.72 (d, J = 8.5 Hz, 1H), 7.46 - 7.39 (m, 1H), 7.31 (s, 1H), 7.22 - 7.15 (m, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 5.94 (d, J = 15.8 Hz, 1H), 5.73 (dd, J = 15.9, 7.8 Hz, 1H), 4.10 (d, J = 12.0 Hz, 1H), 4.03 - 3.75 (m, 7H), 3.66 (t, J = 13.1 Hz, 5H), 3.51 (d, J = 12.0 Hz, 1H), 3.36 (d, J = 14.4 Hz, 2H), 3.27 (s, 2H), 3.14 - 2.92 (m, 3H), 2.76 (d, J = 14.8 Hz, 3H), 2.53 - 2.39 (m, 3H), 2.32 - 1.64 (m, 10H), 1.41 (d, J = 12.5 Hz, 2H), 1.22 (t, J = 7.5 Hz, 3H)。LCMS-ESI+ (m/z):C39
H51
ClN4
O6
S [M+H]+計算值:739.3;實驗值:739.5。實例 67.
以與實例 66
相同之方式使用中間物66-4
(較低極性溶離份)來合成實例 67
。1H NMR (400 MHz,氘代氯仿) δ 7.74 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.18 (dd, J = 8.6, 2.3 Hz, 1H), 7.08 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.83 (s, 2H), 4.11 (d, J = 12.1 Hz, 1H), 3.99 - 3.75 (m, 6H), 3.61 (dd, J = 37.3, 15.1 Hz, 6H), 3.49 (s, 1H), 3.40 (s, 1H), 3.32 - 3.18 (m, 2H), 3.06 - 2.97 (m, 1H), 2.90 (s, 2H), 2.82 - 2.66 (m, 3H), 2.49 (s, 4H), 2.28 - 1.62 (m, 9H), 1.37 (s, 2H), 1.27 - 1.11 (m, 4H)。LCMS-ESI+ (m/z):C39
H51
ClN4
O6
S [M+H]+計算值:739.3;實驗值:739.5。實例 68.
以與實例 67
相同之方式使用中間物67-4
(較低極性溶離份)及1-甲基哌嗪而不使用嗎啉來合成實例 68
。1
H NMR (400 MHz,氘代氯仿) δ 7.74 (d, J = 8.5 Hz, 1H), 7.47 - 7.30 (m, 2H), 7.21 - 7.13 (m, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 1H), 6.11 (dd, J = 15.9, 9.0 Hz, 1H), 5.75 (d, J = 15.9 Hz, 1H), 4.12 - 3.93 (m, 4H), 3.85 - 3.49 (m, 8H), 3.36 (t, J = 14.1 Hz, 4H), 3.16 - 3.00 (m, 3H), 2.87 (d, J = 10.7 Hz, 4H), 2.82 - 2.60 (m, 4H), 2.09 (td, J = 15.4, 14.9, 8.0 Hz, 6H), 1.98 - 1.59 (m, 6H), 1.46 (d, J = 3.0 Hz, 1H), 1.42 - 1.20 (m, 2H), 1.12 (t, J = 7.1 Hz, 2H)。LCMS-ESI+ (m/z):C40
H54
ClN5
O5
S [M+H]+計算值:752.3;實驗值:752.4。實例 69.
步驟 1 :
以與實例 1
(步驟4及步驟5)相同之方式使用己-5-烯-1-磺醯胺而不使用(2R,3S)-3-甲基己-5-烯-2-磺醯胺來製備N'-(第三丁基二甲基矽烷基)己-5-烯-1-磺醯咪醯胺。1
H NMR (400 MHz,氘代氯仿) δ 5.87 - 5.63 (m, 1H), 5.07 - 4.84 (m, 2H), 4.71 - 4.01 (m, 2H), 3.04 (dddd,J
= 13.4, 10.0, 8.5, 5.0 Hz, 2H), 2.13 - 2.01 (m, 2H), 1.92 - 1.71 (m, 2H), 1.57 - 1.45 (m, 2H), 0.88 (d,J
= 5.9 Hz, 9H), 0.11 - 0.2 (m, 6H)。
步驟 2 :
製備中間物69-2
:向於室溫下攪拌5 min之於乙腈中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-碳醯氯(來自實例 1
步驟3,
200 mg,0.40 mmol)及噠嗪(32 mg,0.40 mmol)之混合物中添加N'-(第三丁基二甲基矽烷基)己-5-烯-1-磺醯咪醯胺70-1 (121 mg,0.44 mmol)。在反應完成之後,將殘餘物溶解於乙酸乙酯中且用水洗滌。將有機層濃縮且藉由正相層析法己烷:AtOAc 1:1純化,得到呈非對映異構體混合物形式之69-2
。
步驟 3 :
製備中間物69-3
:將非對映異構體混合物69-2
(160 mg,0.25 mmol)、丙醯氯(28 mg,0.30 mmol)及三乙胺(0.56 mmol)在室溫下在CH2
Cl2
中攪拌一小時。在反應完成之後,將反應混合物在減壓下蒸發,溶解於DMF中且藉由逆相層析法乙腈-水50-90%純化30 min,得到呈非對映異構體混合物形式之69-3
。
步驟 4
:製備實例69:在微波小瓶中添加中間物69-3
(25 mg,0.037 mmol)及哈維達-格拉布II (2.2 mg,0.004 mmol)。將小瓶密封且用氬氣吹掃,且隨後添加1,2-DCE。將微波小瓶加熱至60℃達一小時。在反應完成之後,將反應混合物在減壓下蒸發,溶解於DMF中且藉由逆相層析法乙腈-水50-90%純化30 min,得到實例 69
(較低極性溶離份)。1
H NMR (400 MHz,氘代氯仿) δ 7.67 (dd, J = 8.6, 4.6 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.32 - 7.05 (m, 3H), 6.96 (dd, J = 18.1, 8.1 Hz, 1H), 5.63 - 5.30 (m, 2H), 4.25 - 4.01 (m, 2H), 3.86 - 3.56 (m, 4H), 3.49 - 3.27 (m, 5H), 3.22 (d, J = 10.0 Hz, 2H), 2.76 (d, J = 10.8 Hz, 2H), 2.58 - 2.37 (m, 4H), 2.15 - 1.74 (m, 10H), 1.63 (dt, J = 18.7, 9.4 Hz, 6H), 1.23 (t, J = 7.5 Hz, 2H)。LCMS-ESI+ (m/z):C35
H44
ClN3
O5
S [M+H]+計算值:654.4;實驗值:654.2。實例 70 及 71.
實例70 | 實例71 |
以與實例 3 及 4
相同之方式使用(3R)-N'-(第三丁基二甲基矽烷基)庚-6-烯-3-磺醯咪醯胺(實例 64 及 65
步驟1)及3-(1-甲基-1H-吡唑-5-基)丙酸來合成實例 71 及 72
。
實例 70 : 1
H NMR (400 MHz,氘代氯仿) δ 7.69 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 2.2 Hz, 1H), 7.16 (td, J = 8.5, 2.3 Hz, 1H), 7.09 - 7.01 (m, 2H), 7.00 - 6.87 (m, 2H), 6.16 (d, J = 2.1 Hz, 1H), 5.94 - 5.80 (m, 1H), 5.51 (dd, J = 15.3, 8.7 Hz, 1H), 4.31 (s, 1H), 4.12 - 4.02 (m, 2H), 3.93 (s, 2H), 3.78 (t, J = 13.6 Hz, 1H), 3.71 - 3.59 (m, 4H), 3.25 (d, J = 15.2 Hz, 3H), 3.05 - 2.89 (m, 6H), 2.87 - 2.72 (m, 4H), 2.48 - 2.19 (m, 4H), 2.16 - 1.57 (m, 11H), 1.49 - 1.30 (m, 1H), 1.16 (t, J = 7.5 Hz, 2H)。LCMS-ESI+ (m/z):C40
H50
ClN5
O5
S [M+H]+計算值:748.2;實驗值:748.3。
實例 71 : 1
H NMR (400 MHz,氘代氯仿) δ 7.70 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 2.1 Hz, 1H), 7.49 - 7.31 (m, 2H), 7.16 (dd, J = 8.5, 2.4 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.91 (dd, J = 11.6, 8.3 Hz, 2H), 6.15 (d, J = 2.1 Hz, 1H), 5.72 (td, J = 10.8, 5.0 Hz, 1H), 5.37 (t, J = 10.3 Hz, 1H), 4.10 (q, J = 9.0, 8.0 Hz, 3H), 3.98 - 3.55 (m, 5H), 3.48 - 3.35 (m, 1H), 3.35 - 3.14 (m, 4H), 3.11 - 2.63 (m, 9H), 2.46 - 2.14 (m, 5H), 2.12 - 1.52 (m, 10H), 1.45 - 1.34 (m, 1H), 1.14 (q, J = 5.1, 2.9 Hz, 1H), 1.03 - 0.82 (m, 2H)。LCMS-ESI+ (m/z):C40
H50
ClN5
O5
S [M+H]+計算值:748.2;實驗值:748.3。實例 72.
以與實例 18
相同之方式使用(S)-3-羥基-3-苯基丙酸而不使用3-甲氧基丙酸來合成實例 72
。1
H NMR (400 MHz,氘代氯仿) δ 7.61 (d, J = 8.5 Hz, 1H), 7.44 - 7.27 (m, 6H), 7.16 (d, J = 1.7 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.3 Hz, 2H), 5.88 - 5.66 (m, 2H), 5.25 (dd, J = 9.9, 2.7 Hz, 1H), 3.99 (q, J = 12.0 Hz, 3H), 3.71 (dd, J = 27.2, 14.6 Hz, 3H), 3.56 (dd, J = 7.5, 3.2 Hz, 1H), 3.32 (s, 4H), 3.03 (dd, J = 15.6, 10.2 Hz, 2H), 2.87 - 2.64 (m, 4H), 2.47 - 2.06 (m, 5H), 2.06 - 1.66 (m, 5H), 1.29 (d, J = 30.9 Hz, 4H)。LCMS-ESI+ (m/z):C40
H46
ClN3
O6
S [M+H]+計算值:732.2;實驗值:732.0。實例 73.
向實例 5
(12 mg,0.021 mmol)及於3 mL二氯甲烷中之二異丙基乙胺(0.041 mmol)之溶液中逐滴添加於1 mL二氯甲烷中之1,1-二氧化硫代嗎啉-4-碳醯氯(8 mg,0.041 mmol)之溶液,且使混合物在回流下攪拌16 hr。LC/MS顯示反應完成。在減壓下蒸發溶劑,且將殘餘物溶解於3 mL 甲醇中且使用HPLC進行純化,獲得實例 73
。1
H NMR (400 MHz,氘代氯仿) δ 7.77 - 7.62 (m, 1H), 7.23 - 7.11 (m, 2H), 7.08 (d, J = 2.3 Hz, 1H), 7.04 - 6.81 (m, 2H), 5.93 - 5.74 (m, 1H), 5.53 (dd, J = 15.5, 8.4 Hz, 1H), 4.28 - 3.85 (m, 7H), 3.79 - 3.49 (m, 4H), 3.40 - 3.20 (m, 4H), 2.99 (d, J = 34.6 Hz, 4H), 2.85 - 2.61 (m, 2H), 2.55 - 2.20 (m, 4H), 2.20 - 1.58 (m, 9H), 1.42 (t, J = 12.8 Hz, 2H)。LCMS-ESI+ (m/z):C36
H45
ClN4
O7
S2
[M+H]+計算值:745.25;實驗值:745.96。實例 74.
以與實例 73
相同之方式使用實例 6
來合成實例 74
。LCMS-ESI+ (m/z):C36
H45
ClN4
O7
S2
[M+H]+計算值:745.25;實驗值:745.96。實例 75.
使於3 mL乙腈中之實例 5
(12 mg,0.021 mmol)、碳酸二苯酯(5 mg,0.023 mmol)及DMAP (15 mg,0.123 mmol)之溶液在rt下攪拌16 hr。添加(1-甲基-1H-吡唑-5-基)甲胺(6.8 mg,0.062 mmol),且將混合物在rt下進一步攪拌1 hr。LC/MS顯示反應完成。在減壓下蒸發溶劑,且將殘餘物溶解於3 mL 甲醇中且使用HPLC進行純化,獲得實例 75
。1
H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.49 - 7.20 (m, 3H), 7.20 - 7.03 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.37 (d, J = 1.9 Hz, 1H), 6.00 - 5.68 (m, 2H), 5.38 - 5.16 (m, 2H), 4.21 - 3.90 (m, 2H), 3.82 - 3.47 (m, 3H), 3.46 - 3.18 (m, 11H), 3.10 (dd, J = 15.0, 10.7 Hz, 1H), 2.93 - 2.60 (m, 3H), 2.58 - 2.15 (m, 3H), 2.15 - 1.64 (m, 6H), 1.52 - 1.17 (m, 2H)。LCMS-ESI+ (m/z):C37
H45
ClN6
O5
S [M+H]+計算值:721.29;實驗值:721.91。實例 76.
以與實例 75
相同之方式使用實例 6
及N
-甲基乙胺來合成實例 76
。LCMS-ESI+ (m/z):C35
H45
ClN4
O5
S [M+H]+計算值:669.28;實驗值:669.88。實例 77.
以與實例 77
相同之方式使用N
-甲基乙胺來合成實例 77
。LCMS-ESI+ (m/z):C35
H45
ClN4
O5
S [M+H]+計算值:669.28;實驗值:669.88。實例 78.
以與實例 76
相同之方式使用(1-甲基-1H-吡唑-5-基)甲醇來合成實例 78
。LCMS-ESI+ (m/z):C37
H44
ClN5
O6
S [M+H]+計算值:722.27;實驗值:723.24。實例 79.
以與實例 76
相同之方式使用吡啶-4-基甲胺來合成實例 79
。1H NMR (400 MHz,甲醇-d4) δ 8.70 (d, J = 6.0 Hz, 2H), 7.96 (d, J = 6.0 Hz, 2H), 7.68 (dd, J = 8.9, 6.4 Hz, 1H), 7.41 - 7.16 (m, 2H), 7.18 - 6.98 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 5.89 (dt, J = 15.8, 5.3 Hz, 1H), 5.76 (t, J = 12.0 Hz, 1H), 4.64 (s, 2H), 4.21 - 3.46 (m, 6H), 3.39 (d, J = 14.5 Hz, 1H), 3.34 (s, 6H), 3.10 (dd, J = 15.1, 10.8 Hz, 1H), 2.97 - 2.58 (m, 3H), 2.35 (d, J = 58.3 Hz, 3H), 2.19 - 1.68 (m, 6H), 1.54 - 1.17 (m, 2H)。LCMS-ESI+ (m/z):C38
H44
ClN5
O5
S [M+H]+計算值:718.28;實驗值:719.76。實例 80.
以與實例 76
相同之方式使用吡嗪-2-基甲胺來合成實例 80
。1
H NMR (400 MHz,甲醇-d4) δ 8.64 (s, 1H), 8.60 - 8.41 (m, 2H), 7.74 (dd, J = 8.5, 5.2 Hz, 1H), 7.29 (dd, J = 12.5, 8.1 Hz, 2H), 7.23 - 7.00 (m, 2H), 6.86 (dd, J = 16.3, 8.1 Hz, 1H), 5.89 (dt, J = 15.8, 5.3 Hz, 1H), 5.76 (t, J = 12.0 Hz, 1H), 4.64 (s, 2H), 4.21 - 3.46 (m, 6H), 3.39 (d, J = 14.5 Hz, 1H), 3.34 (s, 6H), 3.10 (dd, J = 15.1, 10.8 Hz, 1H), 2.97 - 2.58 (m, 3H), 2.35 (d, J = 58.3 Hz, 3H), 2.19 - 1.68 (m, 6H), 1.54 - 1.17 (m, 2H)。LCMS-ESI+ (m/z):C37
H43
ClN6
O5
S [M+H]+計算值:719.27;實驗值:719.71。實例 81.
以與實例 18
相同之方式使用3-環丙基丙酸而不使用3-甲氧基丙酸來合成實例 81
。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 8.3, 1.9 Hz, 1H), 7.18 - 7.05 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 5.93 - 5.76 (m, 2H), 4.06 (d, J = 12.1 Hz, 1H), 4.02 - 3.89 (m, 2H), 3.78 (d, J = 14.9 Hz, 1H), 3.71 (d, J = 14.3 Hz, 1H), 3.67 - 3.46 (m, 2H), 3.40 (d, J = 14.4 Hz, 1H), 3.34 (s, 1H), 3.25 (s, 3H), 3.11 (dd, J = 15.3, 10.8 Hz, 1H), 2.82 - 2.72 (m, 2H), 2.47 (t, J = 7.3 Hz, 3H), 2.26 - 2.17 (m, 1H), 2.13 - 1.98 (m, 3H), 1.93 (s, 1H), 1.77 (t, J = 6.3 Hz, 2H), 1.53 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 13.1 Hz, 2H), 1.28 (s, 2H), 0.89 (t, J = 6.6 Hz, 1H), 0.80 - 0.68 (m, 1H), 0.48 - 0.39 (m, 2H), 0.08 (t, J = 4.7 Hz, 2H)。LCMS-ESI+ (m/z):C37
H46
ClN3
O5
S [M+H]+計算值:680.29;實驗值:680.98。實例 82.
以與實例 18
相同之方式使用3-環戊基丙酸而不使用3-甲氧基丙酸來合成實例 82
。LCMS-ESI+ (m/z):C39
H50
ClN3
O5
S [M+H]+計算值:709.32;實驗值:709.36。實例 83 及 84.
步驟 1 :製備 2-(1- 甲基 -1H- 吡唑 -5- 基 ) 環丙烷 -1- 甲酸反 -(±)- 乙酯:
將氫化鈉(0.22 g,9.1 mmol)及三甲基氧化鋶碘(1.4 g,18.1 mmol)在室溫下在7 mL DMSO中攪拌一小時。將(E)-3-(1-甲基-1H-吡唑-5-基)丙烯酸乙酯(0.65 g,3.6 mmol)溶解於5 mL DMSO/THF (1:1)中且添加至反應混合物中。在反應完成(3 h,LC/MS)之後,添加1 N HCl,且將反應混合物用二乙醚萃取。使合併有機層經MgSO4
乾燥,移除溶劑,且粗產物不經進一步純化即使用。
步驟 2 :製備反 (±)-2-(1- 甲基 -1H- 吡唑 -5- 基 ) 環丙烷 -1- 甲酸:
向於10 mL甲醇中之2-(1-甲基-1H-吡唑-5-基)環丙烷-1-甲酸反-(±)-乙酯(0.4 g,2.4 mmol)之溶液中添加2 mL 1 N NaOH,且將反應物在rt下攪拌3 hr。在減壓下移除甲醇,且使用濃HCl將水溶液酸化至pH 4。藉由過濾收集所形成之沈澱物,用水洗滌且進行空氣乾燥,得到酸,其不經進一步純化即使用。
步驟 3 :製備實例 83 及實例 84
:以與實例 18
相同之方式使用反(±)-2-(1-甲基-1H-吡唑-5-基)環丙烷-1-甲酸及實例 5
來合成兩個非對映異構體實例 83
及實例 84
。藉由超臨界流體層析法(Chiralpak AD-H,5 M,21×250 mm,50% MeOH,流量65 mL/min,100巴)分離兩個非對映異構體。
實例 83 ( 較低極性溶離份 ) : 1
H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.55 - 7.24 (m, 3H), 7.24 - 7.02 (m, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.01 (d, J = 2.0 Hz, 1H), 5.85 (qd, J = 15.8, 9.5 Hz, 2H), 4.19 - 3.82 (m, 5H), 3.84 - 3.36 (m, 6H), 3.34 (s, 3H), 3.21 - 3.00 (m, 2H), 2.93 - 2.67 (m, 3H), 2.46 (dt, J = 10.6, 5.6 Hz, 3H), 2.24 (d, J = 8.1 Hz, 2H), 2.15 - 1.94 (m, 4H), 1.85 - 1.54 (m, 3H), 1.50 - 1.14 (m, 4H)。LCMS-ESI+ (m/z):C39
H46
ClN5
O5
S [M+H]+計算值:732.29;實驗值:732.00。
實例 84 ( 較高極性溶離份 ) : 1
H NMR (400 MHz,甲醇-d4) δ 7.78 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.2, 1.8 Hz, 1H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.11 (dt, J = 15.5, 6.4 Hz, 1H), 5.98 (d, J = 2.0 Hz, 1H), 5.61 (dd, J = 15.4, 9.0 Hz, 1H), 4.19 - 4.12 (m, 1H), 4.01 (dd, J = 21.8, 11.8 Hz, 2H), 3.94 - 3.85 (m, 5H), 3.74 - 3.66 (m, 3H), 3.50 (p, J = 1.6 Hz, 1H), 3.34 - 3.31 (m, 2H), 3.27 (s, 3H), 3.15 (p, J = 1.6 Hz, 1H), 3.08 - 3.01 (m, 1H), 2.88 - 2.74 (m, 3H), 2.56 - 1.70 (m, 10H), 1.59 - 1.54 (m, 1H), 1.46 - 1.39 (m, 1H), 1.18 - 1.36 (m, 1H)。LCMS-ESI+ (m/z):C39
H46
ClN5
O5
S [M+H]+計算值:732.29;實驗值:732.06。實例 85.
以與實例 18
相同之方式使用4-(1H-吡唑-1-基)丁酸而不使用3-甲氧基丙酸來合成實例 85
。1
H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 1.9, 0.7 Hz, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.32 (dd, J = 8.3, 1.9 Hz, 1H), 7.21 - 7.04 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.27 (t, J = 2.1 Hz, 1H), 5.97 - 5.74 (m, 2H), 4.20 (t, J = 6.8 Hz, 2H), 4.12 - 3.88 (m, 3H), 3.74 (dd, J = 26.9, 14.7 Hz, 2H), 3.66 - 3.47 (m, 2H), 3.38 (d, J = 32.3 Hz, 4H), 3.10 (dd, J = 15.0, 10.9 Hz, 1H), 2.93 - 2.60 (m, 3H), 2.61 - 2.30 (m, 4H), 2.31 - 1.71 (m, 12H), 1.41 (t, J = 13.2 Hz, 1H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O5
S [M+H]+計算值:720.29;實驗值:720.97。實例 86.
以與實例 18
相同之方式使用2-(咪唑并[1,2-a]吡啶-2-基)乙酸而不使用3-甲氧基丙酸來合成實例 86
。LCMS-ESI+ (m/z):C40
H44
ClN5
O5
S [M+H]+計算值:742.28;實驗值:742.10。實例 87.
以與實例 18
相同之方式使用實例5
及3-(2-(三氟甲基)苯基)丙酸而不使用3-甲氧基丙酸來合成實例 87
。LCMS-ESI+ (m/z):C41
H45
ClF3
N3
O5
S [M+H]+計算值:784.2793;實驗值:784.392。實例 88.
以與實例 18
相同之方式使用3-(呋喃-2-基)丙酸而不使用3-甲氧基丙酸來合成實例 88
。1
H NMR (400 MHz,氘代氯仿) δ 7.70 (d, J = 8.5 Hz, 1H), 7.34 - 7.29 (m, 2H), 7.22 (d, J = 1.9 Hz, 1H), 7.12 (dd, J = 8.2, 2.2 Hz, 1H), 7.07 (d, J = 2.3 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 5.85 (dt, J = 15.5, 5.2 Hz, 1H), 5.69 (dd, J = 15.8, 7.9 Hz, 1H), 4.12 - 3.95 (m, 2H), 3.60 (dd, J = 7.8, 3.4 Hz, 1H), 3.30 (d, J = 1.9 Hz, 3H), 3.08 - 2.94 (m, 4H), 2.82 - 2.64 (m, 6H), 2.30 (td, J = 14.7, 13.8, 6.2 Hz, 4H), 2.06 - 1.64 (m, 12H)。LCMS-ESI+ (m/z):C38
H44
ClN3
O6
S計算值:706.2712;實驗值:706.305。實例 89. 製備 3-(1,3- 二甲基 -1H- 吡唑 -5- 基 ) 丙酸:
步驟 1 :
將氫化鈉(70 mg,3 mmol)溶解於THF (6 mL)中且隨後冷卻至0℃,隨後將2-(二甲氧基磷醯基)乙酸乙酯(650 mg,3 mmol)添加至混合物中且攪拌20 min。隨後,將1,3-二甲基-1H-吡唑-5-甲醛(300 mg,2.417 mmol)添加至反應物中且升溫至室溫達30 min。在根據TLC反應完成之後,用乙酸乙酯及氯化銨水溶液稀釋內容物,且隨後使有機層經MgSO4
乾燥,過濾且濃縮。隨後,使粗反應混合物在2/1己烷乙酸乙酯中進行矽膠層析法純化,得到(E)-3-(1,3-二甲基-1H-吡唑-5-基)丙烯酸乙酯(405 mg)。LCMS-ESI+ (m/z):C10
H14
N2
O2
計算值:195.113;實驗值:195.132。
步驟 2 :
將於乙醇(7 mL)中之(E)-3-(1,3-二甲基-1H-吡唑-5-基)丙烯酸乙酯(405 mg,2 mmol)裝填至反應燒瓶中。隨後,添加鈀/碳,且攪拌反應物,且用氮氣吹掃且抽空內容物。隨後,添加來自氣球之氫氣,且將反應物攪拌3小時。LCMS指示向氫化產物之完全轉化。隨後,將內容物經由燒結漏斗過濾且用乙酸乙酯稀釋。用水潤濕鈀熔塊。濃縮內容物,且產物不經進一步純化即用於下一步驟,得到3-(1,3-二甲基-1H-吡唑-5-基)丙酸乙酯。LCMS-ESI+ (m/z):C10
H17
N2
O2
[M+H]計算值:197.129;實驗值:197.090。
步驟 3 :
將3-(1,3-二甲基-1H-吡唑-5-基)丙酸乙酯(404 mg,2 mmol)溶解於THF (2 mL)、乙醇(1 mL)及水(1 mL)中,隨後添加氫氧化鈉(412 mg,10 mmol)。隨後,將反應物攪拌1小時。LCMS指示完全轉化。將反應物用DCM稀釋,且隨後用1N HCl酸化至pH ~4。隨後,使有機層經MgSO4
乾燥且濃縮,得到3-(1,3-二甲基-1H-吡唑-5-基)丙酸。LCMS-ESI+ (m/z):C8
H13
N2
O2
[M+H]計算值:169.0972;實驗值:169.082。
製備實例 89
:以與實例 18
相同之方式使用3-(1,3-二甲基-1H-吡唑-5-基)丙酸而不使用3-甲氧基丙酸來合成實例 89
。1
H NMR (400 MHz,氘代氯仿) δ 7.55 - 7.46 (m, 2H), 7.23 (d, J = 8.2 Hz, 1H), 7.02 (d, J = 2.6 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.77 (d, J = 7.5 Hz, 2H), 3.99 (s, 3H), 3.89 (d, J = 15.3 Hz, 1H), 3.65 (t, J = 12.8 Hz, 2H), 3.56 - 3.50 (m, 1H), 3.39 (d, J = 14.3 Hz, 1H), 3.35 (s, 3H), 3.11 - 2.98 (m, 2H), 2.96 - 2.84 (m, 2H), 2.84 - 2.60 (m, 4H), 2.51 - 2.35 (m, 2H), 2.31 - 2.22 (m, 2H), 2.11 (d, J = 8.7 Hz, 2H), 2.08 (s, 3H), 1.99 (d, J = 17.1 Hz, 4H), 1.89 - 1.73 (m, 3H), 1.36 - 1.20 (m, 3H)。LCMS-ESI+ (m/z):C39
H48
ClN5
O5
S [M+H]計算值:734.3137;實驗值:734.400。實例 90.
以與實例 18
相同之方式使用3-(4-氯苯基)丙酸而不使用3-甲氧基丙酸來合成實例 90
。LCMS-ESI+ (m/z):C39
H45
Cl2
N3
O5
S [M+H]計算值:750.253;實驗值:750.976。實例 91.
以與實例 18
相同之方式使用3-(噻唑-2-基)丙酸而不使用3-甲氧基丙酸來合成實例 91
。1
H NMR (400 MHz,氘代氯仿) δ 7.88 (d, J = 3.6 Hz, 1H), 7.70 - 7.64 (m, 1H), 7.40 (d, J = 3.5 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 7.18 - 7.14 (m, 2H), 7.09 - 7.04 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 5.91 - 5.62 (m, 2H), 4.09 - 3.96 (m, 2H), 3.84 - 3.67 (m, 3H), 3.62 - 3.52 (m, 3H), 3.30 (s, 3H), 3.11 - 2.95 (m, 3H), 2.82 - 2.71 (m, 2H), 2.45 - 2.23 (m, 4H), 2.09 - 1.99 (m, 2H), 1.94 (q, J = 9.6 Hz, 4H), 1.88 - 1.64 (m, 4H), 1.27 (d, J = 9.8 Hz, 2H)。LCMS-ESI+ (m/z):C37
H43
ClN4
O5
S2
[M+H]計算值:723.2436;實驗值:723.971。實例 92. 製備 3-(1-(2,2,2- 三氟乙基 )-1H- 吡唑 -5- 基 ) 丙酸:
步驟 1 :
將(1-(2,2,2-三氟乙基)-1H-吡唑-5-基)甲醇(750 mg,4.16 mmol)裝入圓底燒瓶中且隨後溶解於DCM (10 mL)中。隨後,添加戴斯馬丁高碘烷(Dess Martin Periodinane) (2.2 g,5 mmol)。使反應物攪拌45 min。隨後,LCMS指示反應完成,用碳酸氫鈉水溶液稀釋內容物,且隨後使有機層經MgSO4
乾燥且隨後過濾且濃縮。藉由矽膠層析法在1/1己烷乙酸乙酯中純化粗材料,得到1-(2,2,2-三氟乙基)-1H-吡唑-5-甲醛。LCMS-ESI+ (m/z):C6
H5
F3
N2
O [M+H]計算值:179.043;實驗值:179.016。
步驟 2-4 :
以與實例 90
(步驟1-3)中之3-(1,3-二甲基-1H-吡唑-5-基)丙酸相同之方式來合成3-(1-(2,2,2-三氟乙基)-1H-吡唑-5-基)丙酸。製備實例 92 :
以與實例 18
相同之方式使用3-(1-(2,2,2-三氟乙基)-1H-吡唑-5-基)丙酸而不使用3-甲氧基丙酸來合成實例 92
。1
H NMR (400 MHz,氘代氯仿) δ 7.60 (d, J = 2.1 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.10 - 6.99 (m, 2H), 6.95 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.28 (d, J = 2.1 Hz, 1H), 5.78 (d, J = 7.3 Hz, 2H), 4.91 (q, J = 8.3 Hz, 2H), 3.94 (s, 3H), 3.72 - 3.58 (m, 3H), 3.58 - 3.53 (m, 1H), 3.36 (s, 3H), 3.09 - 2.91 (m, 4H), 2.88 - 2.66 (m, 4H), 2.44 (s, 2H), 2.33 - 2.21 (m, 3H), 2.04 - 1.91 (m, 4H), 1.89 - 1.74 (m, 4H), 1.33 - 1.21 (m, 2H)。LCMS-ESI+ (m/z):C39
H45
ClN5
O5
S2
[M+H]計算值:788.2855;實驗值:788.261。實例 93.
以與實例 18
相同之方式使用3-(4-甲基噻唑-5-基)丙酸而不使用3-甲氧基丙酸來合成實例 93
。LCMS-ESI+ (m/z):C38
H45
ClN4
O5
S2
[M+H]計算值:737.2593;實驗值:737.220。實例 94.
以與實例 18
相同之方式使用4,4,4-三氟丁酸而不使用3-甲氧基丙酸來合成實例 94
。1
H NMR (400 MHz,氘代氯仿) δ 7.64 (d, J = 8.5 Hz, 1H), 7.20 - 7.04 (m, 3H), 7.03 - 6.97 (m, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.91 - 5.64 (m, 2H), 4.01 (q, J = 12.0 Hz, 3H), 3.73 (dd, J = 31.3, 14.6 Hz, 3H), 3.59 (dd, J = 8.1, 3.2 Hz, 1H), 3.31 (s, 3H), 3.18 (dt, J = 12.1, 6.0 Hz, 1H), 3.02 (dd, J = 15.2, 10.7 Hz, 1H), 2.80 - 2.63 (m, 4H), 2.59 - 2.46 (m, 2H), 2.39 - 2.27 (m, 3H), 2.08 - 1.90 (m, 5H), 1.88 - 1.78 (m, 2H), 1.76 - 1.65 (m, 2H), 0.98 - 0.77 (m, 2H)。LCMS-ESI+ (m/z):C35
H41
ClF3
N3
O5
S [M+H]計算值:708.248;實驗值:708.865。實例 95.
以與實例 18
相同之方式使用5,5,5-三氟戊酸而不使用3-甲氧基丙酸來合成實例 95
。1
H NMR (400 MHz,氘代氯仿) δ 7.61 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.14 (s, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.94 (dd, J = 8.6, 4.0 Hz, 2H), 5.89 - 5.66 (m, 2H), 3.99 (q, J = 11.8 Hz, 2H), 3.72 (dd, J = 29.4, 14.8 Hz, 3H), 3.57 (dd, J = 7.6, 3.1 Hz, 1H), 3.32 (s, 3H), 3.02 (dd, J = 15.1, 10.9 Hz, 1H), 2.80 - 2.67 (m, 3H), 2.65 - 2.53 (m, 2H), 2.46 - 2.14 (m, 7H), 1.97 (dq, J = 14.9, 7.4 Hz, 6H), 1.86 - 1.67 (m, 4H), 1.33 (t, J = 12.9 Hz, 2H)。LCMS-ESI+ (m/z):C36
H43
ClF3
N3
O5
S [M+H]計算值:722.264;實驗值:722.274。實例 96.
以與實例 18
相同之方式使用2-苯氧基乙酸而不使用3-甲氧基丙酸來合成實例 96
。1
H NMR (400 MHz,氘代氯仿) δ 7.73 (d, J = 8.3 Hz, 1H), 7.50 - 7.27 (m, 4H), 7.18 (dd, J = 8.5, 2.2 Hz, 1H), 7.12 - 6.97 (m, 4H), 6.93 (dd, J = 8.2, 2.8 Hz, 1H), 5.95 - 5.65 (m, 2H), 4.10 (d, J = 12.0 Hz, 1H), 4.04 - 3.91 (m, 2H), 3.91 - 3.83 (m, 1H), 3.75 (q, J = 14.1, 13.1 Hz, 2H), 3.61 (dd, J = 7.7, 3.4 Hz, 1H), 3.28 (s, 3H), 3.24 - 3.16 (m, 1H), 3.07 - 2.94 (m, 1H), 2.84 - 2.61 (m, 3H), 2.46 - 2.23 (m, 3H), 2.08 - 1.56 (m, 8H), 1.44 - 1.29 (m, 3H), 0.88 (t, J = 8.1 Hz, 1H)。LCMS-ESI+ (m/z):C39
H44
ClN3
O6
S [M+H]計算值:718.271;實驗值:718.109。實例 97.
以與實例 18
相同之方式使用3-苯基丙酸而不使用3-甲氧基丙酸來合成實例 97
。1
H NMR (400 MHz,氘代氯仿) δ 7.67 (dd, J = 14.8, 8.6 Hz, 1H), 7.34 - 7.27 (m, 3H), 7.25 - 7.16 (m, 4H), 7.10 - 7.00 (m, 2H), 6.91 (d, J = 8.3 Hz, 1H), 5.95 - 5.56 (m, 2H), 4.09 - 3.94 (m, 2H), 3.88 (q, J = 14.4, 11.1 Hz, 1H), 3.74 (dd, J = 25.2, 14.8 Hz, 3H), 3.59 (dd, J = 7.9, 3.3 Hz, 1H), 3.33 (s, 3H), 3.08 - 2.91 (m, 3H), 2.86 - 2.51 (m, 5H), 2.48 - 2.23 (m, 2H), 2.24 - 2.14 (m, 1H), 2.04 (t, J = 10.7 Hz, 2H), 1.98 - 1.63 (m, 6H), 1.41 - 1.23 (m, 2H), 0.86 (t, J = 10.0 Hz, 1H)。LCMS-ESI+ (m/z):C40
H46
ClN3
O5
S [M+H]計算值:716.292;實驗值:716.069。實例 98.
以與實例 18
相同之方式使用1-甲基-1H-吲哚-2-甲酸而不使用3-甲氧基丙酸來合成實例 98
。LCMS-ESI+ (m/z):C41
H45
ClN4
O5
S [M+H]計算值:741.287;實驗值:741.886。實例 99.
以與實例 18
相同之方式使用3-(2-甲基噻唑-4-基)丙酸而不使用3-甲氧基丙酸來合成實例 99
。1
H NMR (400 MHz,氘代氯仿) δ 7.73 (d, J = 8.2 Hz, 1H), 7.38 (dd, J = 25.3, 8.7 Hz, 1H), 7.23 (s, 1H), 7.21 - 7.13 (m, 2H), 7.08 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 5.97 - 5.63 (m, 2H), 4.09 (d, J = 12.1 Hz, 1H), 4.01 (t, J = 10.3 Hz, 1H), 3.84 (t, J = 14.5 Hz, 1H), 3.73 (s, 3H), 3.60 (d, J = 7.4 Hz, 1H), 3.27 (d, J = 3.9 Hz, 3H), 3.06 - 2.91 (m, 1H), 2.78 (s, 2H), 2.65 (s, 2H), 2.28 (d, J = 31.5 Hz, 4H), 2.07 - 1.60 (m, 8H), 1.43 - 1.12 (m, 6H), 0.94 - 0.72 (m, 2H)。LCMS-ESI+ (m/z):C38
H45
ClN4
O5
S2
[M+H]計算值:737.295;實驗值:737.040。實例 100. 製備 2-((1- 甲基 -1H- 吡唑 -5- 基 ) 氧基 ) 乙酸:
步驟 1 :
將1-甲基-1H-吡唑-5-醇(250 mg,3 mmol)裝入圓底燒瓶中,且隨後添加碳酸鉀(387 mg,3 mmol)。隨後,添加THF (5 mL)。添加溴乙酸乙酯(547 mg,3 mmol),隨後將反應物在50℃下攪拌1小時。TLC指示1-甲基-1H-吡唑-5-醇消耗。隨後,用乙酸乙酯及水稀釋內容物,且隨後使有機層經MgSO4
乾燥,過濾且濃縮,得到2-((1-甲基-1H-吡唑-5-基)氧基)乙酸乙酯。
步驟 2 :
隨後,將2-((1-甲基-1H-吡唑-5-基)氧基)乙酸乙酯(0.265 mg,1.44 mmol)稀釋於THF (2 mL)、水(1 mL)及乙醇(1 mL)中,隨後添加氫氧化鈉(115 mg,2.88 mmol)。將反應物攪拌2小時,且隨後用第二丁醇及1N HCl稀釋至pH~4,且使有機層經MgSO4
乾燥,過濾且濃縮,得到2-((1-甲基-1H-吡唑-5-基)氧基)乙酸。LCMS-ESI+ (m/z):C6
H8
N2
O3
[M+H]計算值:157.061;實驗值:157.088。
製備實例 100 :
以與實例 18
相同之方式使用2-((1-甲基-1H-吡唑-5-基)氧基)乙酸而不使用3-甲氧基丙酸來合成實例 100
。1
H NMR (400 MHz,丙酮-d6) δ 7.77 (d, J = 8.6 Hz, 1H), 7.43 (s, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.22 (dd, J = 8.5, 2.3 Hz, 1H), 7.11 (d, J = 2.4 Hz, 2H), 7.04 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.96 - 5.78 (m, 2H), 4.13 - 3.92 (m, 4H), 3.79 (dd, J = 23.4, 14.6 Hz, 2H), 3.63 (dd, J = 13.4, 7.6 Hz, 1H), 3.53 (dd, J = 7.7, 3.0 Hz, 1H), 3.45 (d, J = 14.4 Hz, 1H), 3.26 (s, 3H), 3.04 (t, J = 7.2 Hz, 2H), 2.90 - 2.80 (m, 2H), 2.62 (s, 3H), 2.46 (d, J = 7.2 Hz, 2H), 2.34 - 2.18 (m, 2H), 2.01 - 1.91 (m, 5H), 1.84 - 1.70 (m, 3H), 1.57 - 1.39 (m, 2H)。LCMS-ESI+ (m/z):C37
H44
ClN5
O6
S [M+H]計算值:722.277;實驗值:722.907。實例 101.
以與實例 18
相同之方式使用3-(5-甲基噻唑-4-基)丙酸而不使用3-甲氧基丙酸來合成實例 101
。LCMS-ESI+ (m/z):C38
H45
ClN4
O5
S2
[M+H]計算值:737.2953;實驗值:737.894。實例 102.
以與實例 18
相同之方式使用3-(5-甲基-1,3,4-噻二唑-2-基)丙酸(以與如5-甲基-1,3,4-噻二唑-2-甲醛之實例 89
之3-(1,3-二甲基-1H-吡唑-5-基)丙酸相同之方式製備)來合成實例 102
。1
H NMR (400 MHz,氘代氯仿) δ 7.64 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.91 - 5.64 (m, 2H), 4.01 (q, J = 12.1 Hz, 2H), 3.89 (s, 1H), 3.83 - 3.65 (m, 3H), 3.59 (dd, J = 8.2, 3.1 Hz, 1H), 3.50 - 3.35 (m, 2H), 3.32 (s, 3H), 3.04 (dd, J = 16.7, 9.6 Hz, 3H), 2.78 (s, 3H), 2.76 - 2.62 (m, 3H), 2.47 - 2.22 (m, 4H), 2.09 - 1.91 (m, 4H), 1.81 (p, J = 9.9 Hz, 2H), 1.71 (t, J = 9.3 Hz, 1H), 1.43 - 1.14 (m, 3H)。LCMS-ESI+ (m/z):C37
H44
ClN5
O5
S2
[M+H]計算值:738.255;實驗值:738.054。實例 103.
以與實例 18
相同之方式使用3-(1,4-二甲基-1H-吡唑-5-基)丙酸(以與5-甲基-1,3,4-噻二唑-2-甲醛之實例 89
中之3-(1,3-二甲基-1H-吡唑-5-基)丙酸相同之方式製備)來合成實例 103
。1
H NMR (400 MHz,氘代氯仿) δ 7.54 (d, J = 7.0 Hz, 2H), 7.22 (d, J = 7.3 Hz, 1H), 7.14 - 6.99 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 5.90 - 5.66 (m, 2H), 4.06 - 3.94 (m, 4H), 3.85 (s, 1H), 3.66 (dd, J = 22.7, 14.0 Hz, 2H), 3.58 - 3.50 (m, 1H), 3.37 (d, J = 23.2 Hz, 3H), 3.04 (t, J = 12.4 Hz, 2H), 2.99 - 2.65 (m, 5H), 2.40 (d, J = 19.5 Hz, 2H), 2.24 (d, J = 11.3 Hz, 2H), 2.11 (s, 2H), 2.09 (s, 3H), 1.99 (d, J = 12.9 Hz, 4H), 1.90 - 1.65 (m, 3H), 1.37 - 1.20 (m, 3H), 0.80 (dd, J = 55.2, 11.8 Hz, 1H)。LCMS-ESI+ (m/z):C39
H48
ClN5
O5
S [M+H]計算值:734.314;實驗值:734.132。 實例 104.
以與實例 18
相同之方式使用1-乙基-1H-吡唑-4-甲酸而不使用3-甲氧基丙酸來合成實例 104
。1
H NMR (400 MHz,甲醇-d4) δ 8.43 (s, 1H), 7.93 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.26 (s, 1H), 7.06 (s, 1H), 6.93 (dd, J = 13.2, 8.6 Hz, 2H), 5.97 - 5.78 (m, 2H), 4.22 (q, J = 7.3 Hz, 2H), 3.98 (d, J = 15.3 Hz, 3H), 3.83 - 3.62 (m, 2H), 3.58 (dd, J = 8.3, 2.9 Hz, 1H), 3.52 - 3.40 (m, 2H), 3.35 (s, 3H), 3.19 - 2.99 (m, 2H), 2.86 - 2.68 (m, 3H), 2.49 (s, 2H), 2.37 - 2.24 (m, 2H), 2.08 (d, J = 12.7 Hz, 3H), 1.94 (s, 3H), 1.83 (t, J = 6.7 Hz, 2H), 1.46 (t, J = 7.3 Hz, 3H)。LCMS-ESI+ (m/z):H+C37
H44
ClN5
O5
S計算值:706.22824;實驗值:706.194。實例 105.
以與實例 18
相同之方式使用2-((四氫-2H-哌喃-4-基)氧基)乙酸而不使用3-甲氧基丙酸來合成實例 105
。1H NMR (400 MHz,氘代氯仿) δ 7.73 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.3, 1.8 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.86 (dt, J = 15.8, 5.2 Hz, 1H), 5.73 (dd, J = 15.9, 7.5 Hz, 1H), 4.15 (s, 2H), 4.12 - 3.92 (m, 4H), 3.92 - 3.63 (m, 4H), 3.55 (dddd, J = 20.5, 11.9, 6.3, 3.2 Hz, 3H), 3.32-3.25 (m, 4H), 3.01 (dd, J = 14.9, 11.0 Hz, 1H), 2.84 - 2.66 (m, 3H), 2.50 - 2.18 (m, 4H), 2.14 - 1.56 (m, 12H), 1.47 - 1.18 (m, 2H)。LCMS-ESI+ (m/z):C38
H48
ClN3
O7
S [M+H]+計算值:726.29;實驗值:726.22。 實例 106.
步驟 1 :
以與實例 1
(步驟4及步驟5)相同之方式使用(S)-2-甲基戊-4-烯-1-磺醯胺而不使用(2R,3S)-3-甲基己-5-烯-2-磺醯胺來製備N'-(第三丁基二甲基矽烷基)己-5-烯-1-磺醯咪醯胺。1
H NMR (400 MHz,氘代氯仿) δ 5.75 (ddt,J
= 19.5, 9.5, 7.0 Hz, 1H), 5.06 (d,J
= 1.4 Hz, 1H), 5.03 (dq,J
= 5.1, 1.7 Hz, 1H), 4.75 (d,J
= 7.7 Hz, 2H), 3.13 (ddd,J
= 18.6, 13.7, 4.6 Hz, 1H), 2.91 (ddd,J
= 22.5, 13.8, 7.1 Hz, 1H), 2.32 - 2.16 (m, 2H), 2.16 - 2.02 (m, 2H), 1.10 (dd,J
= 6.6, 4.2 Hz, 3H), 0.88 (s, 9H), 0.10 (d,J
= 3.0 Hz, 6H)。
步驟 2 :
製備中間物106-2
:向於乙腈(30 mL)中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-碳醯氯(1.56 g,3.11 mmol)之經攪拌溶液中添加於乙腈(6 mL)中之噠嗪(0.22 ml,3.11 mmol),繼而添加於乙腈(6 mL)中之(2S)-N'-(第三丁基二甲基矽烷基)-2-甲基戊-4-烯-1-磺醯咪醯胺(0.9 g,3.27 mmol)。將所得混合物在rt下攪拌過夜。濃縮反應混合物,且藉由矽膠管柱(0-50%於己烷中之EtOAc)純化殘餘物。
步驟 3 :
製備中間物106-3 :
向於CH2
Cl2
(15 mL)中之中間物106-2
(1.54 g,2.46 mmol)之經攪拌溶液中添加於冰浴中之三乙胺(0.69 mL,4.92 mmol),繼而添加二碳酸二第三丁酯(0.81 g,3.69 mmol)及4-(二甲基胺基)-吡啶(120.17 mg,0.98 mmol)。將所得混合物在rt下攪拌3 h。濃縮反應混合物,且藉由矽膠管柱純化殘餘物。將溶離份濃縮,溶解於EtOAc中且用1% HCl溶液洗滌,隨後用飽和NaHCO3
水溶液洗滌。使有機相經MgSO4
乾燥,過濾,濃縮,且藉由矽膠管柱再次純化殘餘物,得到所需產物。
步驟 4 :
製備中間物106-4
:用氬氣使於1,2-二氯乙烷(150 mL)中之反應混合物中間物106-3
(330 mg,0.45 mmol)、哈維達-格拉布第2代催化劑(85.18 mg,0.14 mmol)脫氣。將反應混合物在60℃下攪拌過夜。濃縮反應混合物,且藉由矽膠管柱純化殘餘物。分離兩個非對映異構體(較低極性產物為106-4
)。
步驟 5 :
製備實例 106
:以與實例 18
相同之方式使用2-((四氫-2H-哌喃-4-基)氧基)乙酸(3.61 mg,0.023 mmol)而不使用3-甲氧基丙酸及較低極性非對映異構體中間物106-4
(9 mg,0.015 mmol)來合成實例 106
。1
H NMR (400 MHz,甲醇-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.10 (dt, J = 14.7, 7.0 Hz, 1H), 5.63 (dd, J = 15.3, 8.4 Hz, 1H), 4.22 (s, 2H), 4.15 (dd, J = 14.8, 6.9 Hz, 1H), 4.11 - 4.01 (m, 2H), 4.00 - 3.92 (m, 2H), 3.92 - 3.81 (m, 2H), 3.77 (d, J = 8.0 Hz, 1H), 3.71 (td, J = 10.0, 9.4, 4.9 Hz, 2H), 3.53 - 3.45 (m, 2H), 3.29 (s, 3H), 3.07 (dd, J = 15.1, 9.7 Hz, 2H), 2.93 - 2.69 (m, 3H), 2.48 (d, J = 21.0 Hz, 3H), 2.37 - 2.06 (m, 4H), 2.06 - 1.88 (m, 4H), 1.88 - 1.73 (m, 3H), 1.65 (dtt, J = 13.4, 9.0, 4.3 Hz, 2H), 1.45 (t, J = 12.1 Hz, 1H), 1.15 (d, J = 6.8 Hz, 3H)。LCMS-ESI+:C39
H50
ClN3
O7
S計算值:740.3 (M+H);實驗值:740.0 (M+H)。實例 107.
以與實例 75
相同之方式使用來自實例 106
之中間物106-4
及環丙基甲胺來合成實例 107
。1H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 11.4 Hz, 2H), 7.02 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.06 (dd, J = 14.6, 7.3 Hz, 1H), 5.60 (dd, J = 15.3, 8.8 Hz, 1H), 4.25 (dd, J = 14.9, 6.7 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.84 (d, J = 15.1 Hz, 2H), 3.78 (dd, J = 8.9, 3.5 Hz, 1H), 3.67 (d, J = 14.2 Hz, 1H), 3.28 (s, 3H), 3.13 - 3.01 (m, 3H), 2.88 - 2.69 (m, 2H), 2.46 (dt, J = 23.9, 13.6 Hz, 3H), 2.18 (ddd, J = 36.0, 20.5, 10.7 Hz, 3H), 1.99 - 1.89 (m, 3H), 1.79 (dt, J = 17.4, 9.2 Hz, 3H), 1.43 (t, J = 11.9 Hz, 1H), 1.31 (s, 1H), 1.14 (d, J = 6.6 Hz, 3H), 1.08 - 0.97 (m, 1H), 0.57 - 0.47 (m, 2H), 0.25 (dt, J = 5.9, 4.4 Hz, 2H)。LCMS-ESI+:C37
H47
ClN4
O5
S計算值:695.3 (M+H);實驗值:694.8 (M+H)。實例 108.
以與實例 18
相同之方式使用2-((四氫-2H-哌喃-4-基)氧基)乙酸而不使用3-甲氧基丙酸及中間物49-3
來合成實例 108
。1
H NMR (400 MHz,甲醇-d4
) δ 7.75 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4, 2.4 Hz, 1H), 7.16 - 7.12 (m, 2H), 7.00 (s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.00 - 5.93 (m, 1H), 5.59 (dd, J = 15.2, 9.2 Hz, 1H), 4.38 - 4.32 (m, 1H), 4.18 (s, 2H), 4.00 - 3.93 (m, 2H), 3.83 (d, J = 14.8 Hz, 1H), 3.76 - 3.65 (m, 3H), 3.52 - 3.45 (m, 3H), 3.37 - 3.34 (m, 3H), 3.24 (s, 3H), 3.16 - 3.06 (m, 1H), 2.86 - 2.73 (m, 3H), 2.49 - 1.72 (m, 12H), 1.67 - 1.58 (m, 2H), 1.54 (d, J = 6.8 Hz, 3H), 1.50 - 1.42 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C40
H52
ClN3
O7
S [M+H]+計算值:754.4;實驗值:754.2。實例 109 方法 1
步驟1:將(4S
)-5-[S-胺基-N-[第三丁基(二甲基)矽烷基]磺醯亞胺醯基]-4-甲基-戊-1-烯(106-1
,14.9 g,53.9 mmol)與無水甲苯(3×50 mL)一起共沸,且在氬氣氛圍下溶解於無水四氫呋喃(250 mL)中。將溶液冷卻至-50℃ (內部溫度探針)。在5 min內逐滴添加於己烷(46.3 mL,116 mmol)中之2.5 M n-BuLi之溶液。將此混合物攪拌15 min。同時,將(4-硝基苯基) [(1S)-1-苯基乙基]碳酸酯(5-3-1
,20.1 g,70.1 mmol)與甲苯(3×50 mL)一起共沸。在氬氣氛圍下將材料溶於無水四氫呋喃(50 mL)中。在5 min內經由套管將溶液添加至反應物中。反應物起初為黃色,但變為極深色(綠色)。在15 min之後,將反應物升溫至0℃ (冰浴)。反應物變為黃色,同時變得溫熱。在1 h之後,TLC (經KMnO4
色料顯影之20%乙酸乙酯/己烷)顯示反應完成。在0℃下用水(150 mL)淬滅反應物。添加乙酸乙酯(150 mL)。分離各相且將水相用乙酸乙酯(2×75 mL)萃取。將合併有機相用飽和NaHCO3
(150 mL)及鹽水(150 mL)洗滌。使有機相經硫酸鈉乾燥且在減壓下移除溶劑,得到粗製物[(1S
)-1-苯基乙基] N-[N-[第三丁基(二甲基)矽烷基]-S-[(2S)-2-甲基戊-4-烯基]磺醯亞胺醯基]胺基甲酸酯(109-1-1
)。
步驟2:在0℃下將於四氫呋喃(1.0 M,63.6 mL,63.6 mmol)中之四丁基氟化銨之溶液添加至於無水四氫呋喃中之109-1-1
(22.5 g,53.0 mmol)之溶液中。在於0℃下90 min之後,反應完成。在減壓下移除溶劑。用水(150 mL)及乙酸乙酯(150 mL)稀釋殘餘物。分離各相且將水相用乙酸乙酯(3×100 mL)萃取。將合併有機相用鹽水洗滌且經硫酸鈉乾燥。壓力移除溶劑,且使殘餘物經受急驟層析法(0-65%乙酸乙酯/己烷,具有固體負載物之120 g金Teledyne ISCO管柱)。蒸發光散射偵測器(ELSD)以及UV用於峰偵測。組合含有產物之溶離份,且在減壓下移除溶劑,得到呈在硫下之非對映異構體混合物形式之((2S)-2-甲基戊-4-烯-1-基磺醯亞胺醯基)胺基甲酸酯。使固體經受使用ChiralPak IC管柱之具有作為共溶劑之乙醇之手性SFC分離。可替代地,在ChiralPak AD-H管柱上使用甲醇作為共溶劑。組合含有相同非對映異構體之溶離份,且在減壓下移除溶劑,得到呈兩種非對映異構體形式之((2S)-2-甲基戊-4-烯-1-基磺醯亞胺醯基)胺基甲酸(S)-1-苯基乙酯。
第一經溶析非對映異構體(109-1-2 ,
在具有15%乙醇共溶劑之ChiralPak IC上Rt = 3.05 min,如圖所示暫行指定之絕對立體化學):1
H NMR (400 MHz,氘代氯仿) δ 7.43 - 7.33 (m, 4H), 7.33 - 7.29 (m, 1H), 5.74 (q, J = 6.7 Hz, 1H), 5.62 (ddt, J = 16.0, 11.0, 7.1 Hz, 1H), 5.05 (d, J = 1.3 Hz, 1H), 5.04 - 4.99 (m, 1H), 3.43 (dd, J = 14.4, 4.5 Hz, 1H), 3.06 (dd, J = 14.4, 7.9 Hz, 1H), 2.30 - 2.20 (m, 1H), 2.20 - 2.04 (m, 2H), 1.59 (d, J = 6.7 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H)。
第二經溶析非對映異構體 (109-1-3 ,
在具有15%乙醇共溶劑之ChiralPak IC上Rt = 4.92 min,如圖所示暫行指定之絕對立體化學):1
H NMR (400 MHz,氘代氯仿) δ 7.44 - 7.32 (m, 4H), 7.32 - 7.30 (m, 1H), 5.79 - 5.73 (m, 1H), 5.73 - 5.66 (m, 1H), 5.16 - 5.05 (m, 2H), 3.38 (dd, J = 14.5, 4.4 Hz, 1H), 3.20 (dd, J = 14.4, 7.7 Hz, 1H), 2.27 (dq, J = 12.5, 6.8 Hz, 1H), 2.22 - 2.10 (m, 2H), 1.59 (d, J = 6.7 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H)。
步驟3:i) 製備(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(109-1-4) :
將(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸甲酯1-3
(11.2 g,22.5 mmol)在2 N NaOH水溶液(10 mL)及MeOH/THF混合物(1/1) (200 mL)中在60℃下攪拌過夜。在冷卻之後,將混合物用HCl中和且濃縮。將所得固體懸浮於水中且隨後用DCM萃取。使有機相經無水硫酸鎂乾燥且在減壓下移除溶劑,得到109-1-4
,其不經純化即進一步使用。LCMS-ESI+ (m/z):C28
H32
ClNO4
[M+H]+計算值:482.20;實驗值:482.14。
ii)
製備中間物109-1-5
:向於DCM (200 mL)中之中間物109-1-4
(9.68 g,20.1 mmol)之經攪拌溶液中添加中間物109-1-2
(第一溶析非對映異構體) (6.17 g,19.9 mmol)、1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (7.62 g,39.75 mmol)及4-(二甲基胺基)吡啶(4.21 g,34.46 mmol)。將反應混合物在rt下攪拌過夜。隨後,將反應混合物用DCM稀釋,用1 N HCl及鹽水洗滌。使有機相經MgSO4
乾燥,過濾,濃縮,得到109-1-5
,其不經純化即進一步使用。
步驟4:向於DCM (130 mL)中之中間物109-1-5
(12.7 g,16.4 mmol)之溶液中添加TFA (25 mL)。將反應混合物在rt下攪拌。在反應結束之後,在真空下移除溶劑。將殘餘物溶解於DCM中,用飽和NaHCO3
溶液洗滌。將有機相分離,經MgSO4
乾燥,過濾,且濃縮,得到109-1-6
,其不經純化即進一步使用。
步驟5:向於DCM中之中間物109-1-6
(10 g,15.97 mmol)之溶液中添加三乙胺(4.45 mL,31.94 mmol)、4-(二甲基胺基)-吡啶(500 mg,4.09 mmol)及二碳酸二第三丁酯(5.23 g,23.95 mmol)。將反應混合物在rt下攪拌過夜。將反應混合物用1N HCl (水溶液)及鹽水洗滌。將有機相分離,經MgSO4
乾燥,過濾,濃縮且進行矽膠管柱層析法(0-100% EtOAc/己烷)純化,得到中間物109-1-7
。
步驟6:用氬氣使於1,2-二氯乙烷(400 mL)中之中間物109-1-7
(1 g,1.38 mmol)、哈維達-格拉布II (258.13 mg,0.41 mmol)脫氣。將反應混合物在60℃下攪拌過夜。濃縮反應混合物,且藉由管柱層析法(SiO2
,0-70% EtOAc/己烷)純化殘餘物,得到實例 109
。1
H NMR (400 MHz,氘代氯仿) δ 7.76 (d,J
= 8.5 Hz, 1H), 7.43 (dd,J
= 8.2, 1.9 Hz, 1H), 7.32 (d,J
= 2.0 Hz, 1H), 7.20 (dd,J
= 8.5, 2.3 Hz, 1H), 7.10 (d,J
= 2.3 Hz, 1H), 6.93 (d,J
= 8.2 Hz, 1H), 6.27 (ddd,J
= 15.1, 7.9, 5.2 Hz, 1H), 5.99 (s, 2H), 5.56 (dd,J
= 15.3, 8.2 Hz, 1H), 4.20 (s, 2H), 4.06 (t,J
= 11.4 Hz, 2H), 3.92 - 3.82 (m, 1H), 3.82 - 3.69 (m, 2H), 3.47 (d,J
= 5.6 Hz, 2H), 3.36 (d,J
= 14.6 Hz, 1H), 3.28 (s, 3H), 3.02 (dd,J
= 15.0, 11.0 Hz, 1H), 2.80 (dt,J
= 11.3, 5.1 Hz, 2H), 2.63 - 2.53 (m, 1H), 2.47 - 2.36 (m, 2H), 2.26 (dt,J
= 14.4, 7.3 Hz, 2H), 2.03 - 1.84 (m, 3H), 1.84 - 1.57 (m, 4H), 1.41 (t,J
= 13.4 Hz, 1H), 1.16 (d,J
= 6.1 Hz, 3H)。LCMS-ESI+ (m/z):C32
H40
ClN3
O4
S [M+H]+計算值:598.2;實驗值:598.1。方法 2
步驟1:在0℃下向於DCM (50 mL)中之中間物109-1-3
(來自實例 109- 方法 1- 步驟 2
之第二溶析非對映異構體,1.1 g,3.54 mmol)之溶液中添加三乙胺(1.48 mL,10.63 mmol)及三氟乙酸酐(1 mL,7.08 mmol)。將反應混合物在0℃下攪拌30 min。用鹽水淬滅反應物。隨後,將反應混合物用DCM稀釋,用飽和NaHCO3
溶液洗滌。將有機相分離,經MgSO4
乾燥,過濾,且濃縮,得到中間物109-2-1
,其不經純化即進一步使用。
步驟2:向於DCM (30 mL)中之中間物109-2-1
(1.4 g,3.44 mmol)之溶液中添加TFA (10 mL)。將反應混合物在rt下攪拌。在完成之後,濃縮反應混合物,且藉由矽膠管柱層析法(0-50% EtOAc/己烷)純化殘餘物,得到中間物109-2-2
。
步驟3:向於DCM (200 mL)中之中間物109-1-4
(1.5 g,3.11 mmol)之經攪拌溶液中添加中間物109-2-2
(790 mg,3.06 mmol)、1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (1.5 g,7.78 mmol)及4-(二甲基胺基)吡啶(760 mg,6.22 mmol)。將反應混合物在rt下攪拌過夜。隨後,將反應混合物用DCM稀釋,用1 N HCl及鹽水洗滌。使有機相經MgSO4
乾燥,過濾,濃縮,且藉由矽膠管柱層析法(0-100% EtOAc/己烷)純化殘餘物,得到中間物109-2-3
。
步驟4:向於DCE (10 mL)中之中間物109-2-3
(72 mg,0.1 mmol)之溶液中添加TFA (0.02 mL,0.2 mmol)及哈維達-格拉布第2代催化劑(12.46 mg,0.02 mmol)。用氬氣使反應混合物脫氣,且隨後在60℃下攪拌過夜。濃縮反應混合物,且藉由矽膠管柱層析法(0-100% EtOAc/己烷)純化殘餘物,得到中間物109-2-4
。
步驟5:向於MeOH (10 mL)及H2
O (2 mL)中之中間物109-2-4
(130 mg,0.19 mmol)之溶液中添加碳酸鉀(129.4 mg,0.94 mmol)。將反應混合物在60℃下攪拌過夜。將反應混合物濃縮,溶解於乙酸乙酯中,用水洗滌,用乙酸乙酯反萃取。將有機相分離,經MgSO4
乾燥,過濾,濃縮,且藉由矽膠管柱層析法(0-70% EtOAc/己烷)純化,得到實例 109
。方法 3
步驟1:在-40℃下向於THF (10 mL)中之中間物106-1
(690 mg,2.5 mmol)之溶液中添加正丁基鋰(於己烷中1.6 M,1.87 mL)。將所得混合物在-40℃下攪拌20 min。隨後,逐滴添加於THF (6 mL)中之(4-硝基苯基) [(1S)-1-苯基乙基]碳酸酯(5-3-1
,1.43 g,4.99 mmol)之溶液,且使反應混合物升溫至rt且攪拌3 h。將反應物用水淬滅且用EtOAc萃取。將有機層分離,經MgSO4
乾燥,過濾,且濃縮。藉由矽膠管柱(0-20% EtOAc/己烷)純化殘餘物。分離兩個非對映異構體。
第一經溶析非對映異構體(109-3-1
,如圖所示暫行指定之絕對立體化學):1
H NMR (400 MHz,氘代氯仿) δ 7.49 - 7.29 (m, 5H), 5.84 (dq,J
= 23.2, 6.6 Hz, 1H), 5.74 - 5.47 (m, 1H), 5.08 - 4.93 (m, 2H), 3.32 (dd,J
= 14.1, 4.6 Hz, 1H), 3.18 - 2.95 (m, 1H), 2.29 - 2.10 (m, 2H), 2.03 (ddt,J
= 13.8, 6.9, 1.3 Hz, 1H), 1.59 (d,J
= 6.6 Hz, 3H), 1.09 (d,J
= 6.6 Hz, 3H), 0.93 (s, 9H), 0.21 (d,J
= 3.1 Hz, 6H)。
第二經溶析非對映異構體(109-3-2
,如圖所示暫行指定之絕對立體化學):1
H NMR (400 MHz,氘代氯仿) δ 7.45 - 7.25 (m, 5H), 5.81 (t,J
= 6.6 Hz, 1H), 5.78 - 5.63 (m, 1H), 5.11 - 4.95 (m, 2H), 3.40 (dd,J
= 13.9, 4.2 Hz, 1H), 3.07 (dd,J
= 14.0, 7.5 Hz, 1H), 2.27 - 2.13 (m, 2H), 2.13 - 2.07 (m, 1H), 1.59 (d,J
= 6.6 Hz, 3H), 1.09 (dd,J
= 6.7, 3.2 Hz, 3H), 0.88 (s, 9H), 0.17 - 0.09 (m, 6H)。
步驟2:在冰浴中向於THF (5 mL)中之中間物 109-3-1
(40 mg,0.094 mmol)之經攪拌溶液中緩慢地添加四丁基氟化銨(1.0 M THF,0.14 ml)。將反應混合物在0℃下攪拌20 min,且隨後使其緩慢地升溫至rt。將反應混合物在rt下攪拌2.5 h。濃縮反應混合物,且藉由矽膠管柱(0-60% EtOAc/己烷)純化殘餘物,得到中間物 109-1-2
。1H NMR (400 MHz,氘代氯仿) δ 7.42 - 7.37 (m, 2H), 7.37 - 7.24 (m, 3H), 5.72 (q, J = 6.6 Hz, 1H), 5.62 (ddt, J = 15.9, 11.1, 7.1 Hz, 1H), 5.51 (s, 2H), 5.07 - 4.97 (m, 2H), 3.42 (dd, J = 14.4, 4.5 Hz, 1H), 3.06 (dd, J = 14.4, 7.9 Hz, 1H), 2.33 - 2.01 (m, 3H), 1.57 (d, J = 6.7 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H)。方法 4
步驟1:亦以與方法3-步驟2( 實例 109)
類似之方式使用中間物109-3-2
而不使用中間物109-3-1
來製備中間物109-1-3
。以與實例 109 (
方法2)相同之方式使用中間物109-1-3
來合成實例 109
。實例 110 方法 1
步驟1:將1-[S-胺基-N-[第三丁基(二甲基)矽烷基]磺醯亞胺醯基]己烷(1-5
,5.9 g,20.1 mmol)與無水甲苯 (3×20 mL)一起共沸,且在氬氣氛圍下溶解於無水四氫呋喃(150 mL)中。將溶液冷卻至-50℃ (內部溫度探針)。在5 min內逐滴添加於己烷(17.3 mL,43.3 mmol)中之2.5 M n-BuLi之溶液。將此混合物攪拌15 min。同時,將(4-硝基苯基) [(1S)-1-苯基乙基]碳酸酯(5-3-1
,7.5 g,26.2 mmol)與甲苯(3×20 mL)一起共沸。在氬氣氛圍下將材料溶於無水四氫呋喃(60 mL)中。在5 min內經由套管將溶液添加至反應物中。反應物起初為黃色,但變為極深色(綠色)。在15 min之後,將反應物升溫至0℃ (冰浴)。反應物變為黃色,同時變得溫熱。在1 h之後,TLC (經KMnO4
色料顯影之20% EtOAc/己烷)顯示反應完成。在0℃下將反應物用水(75 mL)淬滅。添加EtOAc (50 mL)。分離各相且將水相用EtOAc (2×50 mL)萃取。將合併有機相用飽和NaHCO3
(75 mL)及鹽水(75 mL)洗滌。使有機相經硫酸鈉乾燥,且在減壓下移除溶劑,得到粗製物[(1S)-1-苯基乙基] N-[N-[第三丁基(二甲基)矽烷基]-S-[(1R,2S)-1,2-二甲基戊-4-烯基]磺醯亞胺醯基]胺基甲酸酯(110-1-1
)。
步驟2:在0℃下將TBAF (1.0 M,19.7 mL,19.7 mmol)之溶液添加至於無水THF中之110-1-1
(6.64 g,15.1 mmol)之溶液中。在於0℃下1 h之後,反應完成。在減壓下移除THF。用水(80 mL)及EtOAc (80 mL)稀釋殘餘物。分離各相,且將水相用EtOAc (3×50 mL)萃取。將合併有機相用鹽水洗滌且經硫酸鈉乾燥。壓力移除溶劑,且使殘餘物經受急驟層析法(0-65% EtOAc/己烷,具有固體負載物之120 g金isco管柱)。ELSD以及UV用於峰偵測。組合含有產物之溶離份,且在減壓下移除溶劑,得到呈在硫下之非對映異構體混合物形式之[(1S)-1-苯基乙基] N-[[(1R,2S)-1,2-二甲基戊-4-烯基]磺醯亞胺醯基]胺基甲酸酯。使固體經受使用ChiralPak IC管柱之具有作為共溶劑之甲醇之手性SFC分離。
第一經溶析非對映異構體(110-1-2
,在具有15%甲醇共溶劑之ChiralPak IC上RT = 2.37 min,如圖所示暫行指定之絕對立體化學)。1H NMR (400 MHz,氘代氯仿) δ 7.45 - 7.33 (m, 4H), 7.33 - 7.30 (m, 1H), 5.73 (q, J = 6.7 Hz, 1H), 5.48 (dddd, J = 16.4, 10.1, 8.2, 6.0 Hz, 1H), 5.06 - 4.93 (m, 2H), 3.41 (qd, J = 7.0, 2.2 Hz, 1H), 2.53 - 2.39 (m, 1H), 2.07 (dt, J = 14.0, 6.2 Hz, 1H), 2.00 - 1.86 (m, 1H), 1.59 (d, J = 6.7 Hz, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.02 (d, J = 6.8 Hz, 3H)。
第二經溶析非對映異構體(110-1-3
,在具有15%甲醇共溶劑之ChiralPak IC上Rt = 3.92 min,如圖所示暫行指定之絕對立體化學)。1H NMR (400 MHz,氘代氯仿) δ 7.43 - 7.32 (m, 4H), 7.33 - 7.29 (m, 1H), 5.75 (q, J = 6.6 Hz, 1H), 5.71 - 5.62 (m, 1H), 5.13 - 5.03 (m, 2H), 3.38 (qd, J = 7.1, 2.3 Hz, 1H), 2.47 (dtd, J = 8.9, 6.9, 2.2 Hz, 1H), 2.11 (dtt, J = 13.1, 6.5, 1.4 Hz, 1H), 2.07 - 1.96 (m, 1H), 1.59 (d, J = 6.7 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H)。
以與實例 109 ( 方法 1-
步驟3-6)相同之方式使用中間物110-1-2
而不使用中間物109-1-2
來合成實例 110
。1H NMR (400 MHz,氘代氯仿) δ 7.778 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.3, 1.9 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.5, 2.3 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.91 (dt, J = 15.8, 5.8 Hz, 1H), 5.69 (dd, J = 15.8, 6.8 Hz, 1H), 4.18 - 3.95 (m, 2H), 3.87 (dd, J = 14.9, 3.4 Hz, 1H), 3.73 (s, 5H), 3.41 - 3.23 (m, 4H), 3.01 (dd, J = 15.0, 10.9 Hz, 1H), 2.89 - 2.72 (m, 2H), 2.62 (s, 2H), 2.46 (s, 1H), 2.31 - 2.01 (m, 3H), 1.99 - 1.64 (m, 6H), 1.46 (s, 3H), 1.11 (d, J = 6.9 Hz, 3H)。LCMS-ESI+ (m/z): H+ C33
H42
ClN3
O4
S計算值:612.26;實驗值:612.06。方法 2:
步驟1:在氬氣下向於無水二氯甲烷中之中間物110-1-3
(來自實例 110-
方法1-步驟2之第二溶析非對映異構體,3.6 g,11.10 mmol)及三氟乙酸酐(3.5 g,16.64 mmol)之冰冷溶液中添加TEA (2.32 mL,16.64 mmol),且隨後將溶液攪拌30 min。濃縮反應混合物,得到中間物110-2-1
。
步驟2:向二氯甲烷/三氟乙酸(3/1) (200 mL)之經攪拌混合物中添加中間物110-2-1
(4.2 g,9.98 mmol)。將混合物在室溫下攪拌過夜。在減壓下移除溶劑。隨後,添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑。藉由正相層析法(SiO2
,1: 2己烷:EtOAc)純化如此獲得之殘餘物,得到中間物110-2-2
。1H NMR (400 MHz,氘代氯仿) δ 5.70 (dddd, J = 17.0, 10.2, 8.3, 5.8 Hz, 1H), 5.58 (s, 2H), 5.22 - 5.01 (m, 2H), 3.56 (qd, J = 7.0, 2.2 Hz, 1H), 2.63 - 2.42 (m, 1H), 2.19 (dtt, J = 15.1, 6.0, 1.6 Hz, 1H), 2.05 - 1.91 (m, 1H), 1.43 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 6.8 Hz, 3H)。
步驟3:向於DCM中之中間物109-1-4
(4.0 g,8.29 mmol)之經攪拌溶液中添加EDCI (2.5 g,16.6 mmol)及DMAP (2.0 g,16.6 mmol)。將反應混合物在室溫下攪拌10 min。添加中間物110-2-2
(2.4 g,9.13 mmol),且將所得懸浮液在室溫下攪拌過夜。將反應混合物用水淬滅,且用DCM、NaHCO3
水溶液、1 N HCl水溶液及鹽水洗滌。用Mg2
SO4
乾燥有機層,且在減壓下移除溶劑,獲得粗殘餘物,使其經受管柱層析法(SiO2
,50-90%己烷/EtOAc),得到所需中間物110-2-3
。
步驟4:將中間物110-2-3
(1.2 g,1.57 mmol)、TFA (360 mg,3.15 mmol)及哈維達格拉布第2代催化劑(196 mg,0.32 mmol)在1,2-二氯乙烷(150 mL)中在60℃下攪拌2 h。添加更多催化劑(196 mg,0.32 mmol),且將混合物在60℃下攪拌24 hr。在濃縮之後,藉由矽膠管柱層析法(5-95%己烷/EtOAc)純化殘餘物,獲得中間物110-2-4
。
步驟5:向於MeOH (10 mL)中之中間物110-2-4
(200 mg,0.28 mmol)之經攪拌溶液中添加水(2 mL),且隨後添加K2
CO3
(195 mg,1.41 mmol)。將反應混合物在60℃下攪拌24 hr。將混合物在減壓下蒸發且隨後溶解於DCM中。添加水,且隨後用DCM萃取混合物。將合併有機層用鹽水洗滌,經Mg2
SO4
乾燥,過濾,濃縮,且藉由矽膠管柱層析法(50-90%己烷/EtOAc)純化,得到實例 110
。方法 3:
步驟1:在5 min內在-50℃下向於THF (50 mL)中之中間物1-5
(實例 1
-步驟5,1 g,3.44 mmol)之溶液中逐滴添加正丁基鋰(於己烷中1.6 M,4.6 mL,7.40 mmol)。將混合物攪拌15 min。同時,將(4-硝基苯基) [(1S)-1-苯基乙基]碳酸酯(5-3-1,1.3 g,4.47 mmol)與甲苯(3×20 mL)一起共沸。在氬氣氛圍下將材料溶於無水四氫呋喃(30 mL)中。在5 min內經由套管將溶液添加至反應物中。反應物起初為黃色,但變為極深色(綠色)。在15 min之後,將反應物升溫至0℃ (冰浴)。反應物變為黃色,同時變得溫熱。在3 h之後,TLC (經KMnO4
色料顯影之20% EtOAc/己烷)顯示反應完成。在0℃下將反應物用水淬滅(75 mL)。添加EtOAc (50 mL)。分離各相,且將水相用EtOAc (2×50 mL)萃取。用飽和NaHCO3
(75 mL)及鹽水(75 mL)洗滌合併有機相。使有機相經硫酸鈉乾燥,且在減壓下移除溶劑。將所得粗產物再溶解於己烷中且藉由急驟管柱層析法(矽膠,0至100%於己烷中之二氯甲烷,ELSD偵測器)純化。藉由矽膠TLC (3:1己烷:乙酸乙酯,KMnO4
色料)分析ELSD-活性溶離份;且在70-100%二氯甲烷下共溶析非對映異構體產物。將粗產物混合物再溶解於己烷中且再次藉由急驟管柱層析法(矽膠,0至20%於己烷中之乙酸乙酯,ELSD偵測器)純化。藉由矽膠TLC (3:1己烷:乙酸乙酯,KMnO4
色料)分析ELSD-活性溶離份。在10%乙酸乙酯下溶析之第一溶析峰(110-3-1
,如圖所示暫行指定之絕對立體化學),同時在15%乙酸乙酯下溶析之後一溶析峰(110-3-2
,如圖所示暫行指定之絕對立體化學)。
步驟2:在0℃下將TBAF (1.0 M,2.84 mL,2.84 mmol)之溶液添加至於無水THF中之中間物110-3-1
(830 mg,1.89 mmol)之溶液中。在於0℃下60 min之後,反應完成。在減壓下移除溶劑。用水(80 mL)及EtOAc (80 mL)稀釋殘餘物。分離各相,且將水相用EtOAc (3×50 mL)萃取。將合併有機相用鹽水洗滌,且經硫酸鈉乾燥。壓力移除溶劑,且使殘餘物經受急驟層析法(0-50% EtOAc/己烷,80 g矽膠)。ELSD以及UV用於峰偵測。組合含有產物之溶離份,且在減壓下移除溶劑,得到中間物110-1-2
。
製備實例 110 :
以與實例 110
(方法1)相同之方式使用中間物110-1-2
來合成實例 110
。方法 4 :
步驟 1 :
亦以與方法3-步驟2( 實例 110)
類似之方式使用中間物110-3-2
而不使用中間物110-3-1
來製備中間物 110-1-3
。
製備實例 110 :
以與實例 109 (
方法2)相同之方式使用中間物110-1-3
來合成實例 110
。實例 111
在rt下向於DCM (0.6 mL)中之實例 109
(10 mg,0.0167 mmol)之混合物中添加ACN (1.7 mL)。隨後,將4-二甲基胺基吡啶(10.2 mg,0.0836 mmol)及碳酸二苯酯(28.6 mg,0.134 mmol)添加至混合物中且在室溫下攪拌。在5小時之後,添加嘧啶-2-胺(12.7 mg,0.134 mmol),且將反應物在60℃下加熱5小時,且隨後在室溫下加熱過夜。將反應物濃縮,再溶解於DMF (1.2 mL)中,過濾,且藉由Gilson逆相製備型HPLC純化,用60-100% ACN/H2
O及0.1% TFA溶析。1
H NMR (400 MHz,甲醇-d4) δ 8.73 (d, J = 5.1 Hz, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.38 - 6.82 (m, 7H), 6.14 (dq, J = 14.4, 6.6 Hz, 1H), 5.62 (dd, J = 15.4, 8.3 Hz, 1H), 4.21 (dd, J = 14.8, 6.3 Hz, 1H), 4.12 - 4.01 (m, 3H), 3.91 - 3.64 (m, 3H), 3.29 (s, 3H), 3.08 (dd, J = 15.2, 10.0 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.60 - 2.37 (m, 3H), 2.32 - 2.06 (m, 3H), 2.02 - 1.67 (m, 7H), 1.45 (t, J = 11.1 Hz, 1H), 1.15 (dd, J = 8.4, 6.3 Hz, 3H)。LCMS-ESI+ (m/z):C37
H43
ClN6
O5
S [M+H]+計算值:719.2;實驗值:719.5。實例 112
以與實例 111
相同之方式使用(3S)-四氫呋喃-3-胺鹽酸鹽而不使用嘧啶-2-胺來合成實例 112
,亦將休尼格氏鹼(Hunig's base) (8.64 mg,0.0669 mmol)添加至此反應物中。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.24 - 7.10 (m, 3H), 7.03 - 6.88 (m, 2H), 6.23 - 5.97 (m, 1H), 5.64 - 5.50 (m, 1H), 4.37 - 4.21 (m, 2H), 4.11 - 4.01 (m, 2H), 3.98 - 3.75 (m, 6H), 3.72 - 3.48 (m, 3H), 3.28 (s, 3H), 3.08 (dd, J = 15.3, 10.2 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.57 - 2.33 (m, 3H), 2.31 - 2.09 (m, 3H), 1.98 - 1.73 (m, 8H), 1.44 (t, J = 11.8 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S [M+H]+計算值:711.3;實驗值:710.8。實例 113
向於DCM (1.0 mL)中之1-甲基吡唑-4-甲酸(3.76 mg,0.0298 mmol)之混合物中添加1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (5.71 mg,0.0298 mmol)及4-二甲基胺基吡啶(3.64 mg,0.0298 mmol)。將混合物在rt下攪拌5分鐘,隨後添加實例 5
(8.7 mg,0.0149 mmol),且將反應物在室溫下攪拌過夜。隨後,將反應混合物濃縮,再溶解於DMF (1.2 mL)中,過濾,且藉由Gilson逆相製備型HPLC純化,用60-100% ACN/H2
O及0.1% TFA溶析,得到實例 113
。1
H NMR (400 MHz,甲醇-d4) δ 8.42 (s, 1H), 7.91 (s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.07 (d, J = 2.1 Hz, 1H), 6.99 - 6.83 (m, 2H), 5.98 - 5.90 (m, 1H), 5.86 (dd, J = 16.0, 8.2 Hz, 1H), 3.97 (d, J = 29.0 Hz, 6H), 3.77 (d, J = 15.0 Hz, 1H), 3.71 - 3.65 (m, 2H), 3.62 - 3.55 (m, 2H), 3.47 (d, J = 14.3 Hz, 1H), 3.37 (s, 3H), 3.16 (d, J = 26.2 Hz, 1H), 2.88 - 2.74 (m, 3H), 2.50 (s, 2H), 2.30 (d, J = 9.2 Hz, 2H), 2.10 (d, J = 14.0 Hz, 3H), 2.00 - 1.84 (m, 4H), 1.41 (d, J = 11.9 Hz, 1H)。LCMS-ESI+ (m/z):C36
H42
ClN5
O5
S [M+H]+計算值:692.2;實驗值:691.973。實例 114
以與實例 75
相同之方式使用實例 109
及3-胺基氮雜環丁烷-1-甲酸甲酯來合成實例 114
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.72 (d,J
= 8.5 Hz, 1H), 7.17 - 7.12 (m, 2H), 7.09 (d,J
= 2.3 Hz, 1H), 6.94 (s, 1H), 6.90 (d,J
= 8.2 Hz, 1H), 6.07 - 5.89 (m, 1H), 5.57 (dd,J
= 15.3, 9.0 Hz, 1H), 4.60 - 4.41 (m, 1H), 4.25 (t,J
= 8.5 Hz, 3H), 4.13 - 3.98 (m, 2H), 3.96 - 3.79 (m, 3H), 3.75 (dd,J
= 9.0, 3.7 Hz, 1H), 3.69 - 3.62 (m, 1H), 3.66 (s, 3H), 3.29 - 3.23 (m, 1H), 3.25 (s, 3H), 3.06 (dd,J
= 15.3, 10.3 Hz, 1H), 2.88 - 2.66 (m, 2H), 2.53 - 2.28 (m, 3H), 2.24 - 2.05 (m, 3H), 2.00 - 1.65 (m, 7H), 1.42 (t,J
= 12.4 Hz, 1H), 1.12 (d,J
= 6.5 Hz, 3H)。LCMS-ESI+:C38
H48
ClN5
O7
S計算值:754.29 (M+H);實驗值:753.97 (M+H)。實例 115
以與實例 75
相同之方式使用實例 109
及(1S,2R)-2-氟環丙胺來合成實例 115
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.75 (d,J
= 8.5 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.12 (d,J
= 2.3 Hz, 1H), 7.03 - 6.97 (m, 1H), 6.91 (d,J
= 8.2 Hz, 1H), 6.03 (dd,J
= 15.0, 7.6 Hz, 1H), 5.59 (dd,J
= 15.2, 8.9 Hz, 1H), 4.79 - 4.54 (m, 1H), 4.29 (dd,J
= 14.9, 6.4 Hz, 1H), 4.14 - 4.01 (m, 2H), 3.91 - 3.73 (m, 3H), 3.68 (d,J
= 14.5 Hz, 1H), 3.31 - 3.24 (m, 1H), 3.27 (s, 3H), 3.07 (dd,J
= 15.2, 10.3 Hz, 1H), 2.89 - 2.72 (m, 2H), 2.68 (dt,J
= 10.2, 5.5 Hz, 1H), 2.57 - 2.31 (m, 3H), 2.28 - 2.07 (m, 3H), 2.03 - 1.65 (m, 6H), 1.44 (t,J
= 12.5 Hz, 1H), 1.24 - 1.07 (m, 4H), 1.01 - 0.84 (m, 1H)。LCMS-ESI+:C36
H44
ClFN4
O5
S計算值:699.27 (M+H);實驗值:698.73 (M+H)。實例 116
以與實例 75
相同之方式使用實例 109
及(1R,2S)-2-氟環丙胺來合成實例 116
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.75 (d,J
= 8.5 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.12 (d,J
= 2.3 Hz, 1H), 7.00 (s, 1H), 6.91 (d,J
= 8.2 Hz, 1H), 6.11 - 5.97 (m, 1H), 5.58 (dd,J
= 15.3, 8.9 Hz, 1H), 4.66 (dtd,J
= 64.4, 5.7, 3.2 Hz, 1H), 4.30 (dd,J
= 14.9, 6.3 Hz, 1H), 4.15 - 3.99 (m, 2H), 3.86 (d,J
= 14.8 Hz, 2H), 3.78 (dd,J
= 9.0, 3.7 Hz, 1H), 3.68 (d,J
= 14.6 Hz, 1H), 3.31 - 3.28 (m, 1H), 3.27 (s, 3H), 3.07 (dd,J
= 15.2, 10.3 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.67 (dt,J
= 9.4, 5.3 Hz, 1H), 2.55 - 2.30 (m, 3H), 2.26 - 2.08 (m, 3H), 2.01 - 1.67 (m, 6H), 1.44 (t,J
= 12.2 Hz, 1H), 1.21 - 1.06 (m, 4H), 1.02 - 0.87 (m, 1H)。LCMS-ESI+:C36
H44
ClFN4
O5
S計算值:699.27 (M+H);實驗值:698.65 (M+H)。實例 117
以與實例 75
類似之方式使用(1S, 2R)-2-甲基環丙-1-胺鹽酸鹽、三乙胺及實例 109
來製備實例 117
。1H NMR (400 MHz,甲醇-d4) δ 7.76 (d, J = 8.5 Hz, 2H), 7.38 (s, 2H), 7.18 (d, J = 9.3 Hz, 2H), 7.12 (s, 2H), 6.85 (s, 2H), 6.24 (s, 2H), 5.59 (s, 2H), 4.60 (s, 1H), 4.11 - 3.97 (m, 4H), 3.83 - 3.66 (m, 9H), 2.80 (d, J = 19.4 Hz, 4H), 2.63 (s, 3H), 2.32 (s, 4H), 2.20 - 2.03 (m, 5H), 1.96 (s, 6H), 1.77 (s, 6H), 1.46 (s, 3H), 1.31 (s, 1H), 1.07 (d, J = 6.1 Hz, 23H), 0.83 (ddt, J = 12.2, 6.1, 3.0 Hz, 3H), 0.61 (ddd, J = 9.0, 5.1, 3.6 Hz, 4H), 0.51 - 0.39 (m, 6H)。LCMS -ESI+ (m/z):C37
H47
ClN4
O5
S [M+H]計算值:695.32;實驗值694.99。實例 118
合成5-氯-1-甲基-1H-吡咯-3-甲酸:向於1.0 mL DMSO中之5-氯-1H-吡咯-3-甲酸(0.075 g;0.515 mmol)之溶液中添加新研磨之氫氧化鉀(KOH (固體);0.231 g;4.12 mmol)。在添加碘甲烷(MeI;0.048 mL;0.109 g;0.773 mmol)之前,將異質漿液攪拌50分鐘。在用各10 mL CH2
Cl2
及1 N HCl (水溶液)稀釋反應混合物之前,使混合物在周圍溫度下攪拌4小時。在分離各層之前,將雙相混合物攪拌至少十分鐘。用各10 mL之乙酸異丙酯及乙酸乙酯反萃取水層。將合併有機相用10 mL H2
O洗滌且經無水Na2
SO4
乾燥。將有機相在真空中濃縮至乾且直接用於下一步驟中(參見下文) (62 mg;82.7 %產率) (1
H NMR (400 MHz,DMSO-d 6
) δ 11.98 (s, 1H), 7.47 (d,J
= 2.1 Hz, 1H), 6.39 (d,J
= 2.1 Hz, 1H), 3.60 (s, 3H), 2.55 (s, 1H)。LCMS-ESI+(m/z):C6
H6
ClNO2
[M+H]計算值:160.01;實驗值160.07。
以與實例 106
類似之方式使用5-氯-1-甲基-1H-吡咯-3-甲酸及實例 109
來製備實例 118
。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.38 - 7.27 (m, 2H), 7.15 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.81 (d, J = 8.1 Hz, 1H), 6.48 (s, 1H), 6.17 (dd, J = 14.8, 7.4 Hz, 1H), 5.51 (dd, J = 15.4, 8.7 Hz, 1H), 4.15 (s, 1H), 4.10 (d, J = 7.1 Hz, 0H), 4.09 - 3.95 (m, 2H), 3.86 - 3.70 (m, 2H), 3.60 (s, 4H), 3.25 (s, 4H), 3.03 (dd, J = 15.0, 9.8 Hz, 1H), 2.86 - 2.67 (m, 2H), 2.59 (d, J = 10.4 Hz, 1H), 2.41 (s, 3H), 2.22 - 2.05 (m, 4H), 1.99 (d, J = 9.6 Hz, 2H), 1.91 (d, J = 7.5 Hz, 2H), 1.79 (dd, J = 19.5, 8.7 Hz, 1H), 1.73 (s, 2H), 1.69 (d, J = 8.8 Hz, 0H), 1.41 (t, J = 12.7 Hz, 1H), 1.33 - 1.19 (m, 2H), 1.06 (d, J = 6.5 Hz, 3H), 0.89 (dd, J = 7.3, 3.8 Hz, 1H)。LCMS-ESI+(m/z):C38
H44
Cl2
N4
O5
S [M+H]計算值:739.24;實驗值:739.75 (M+H)。實例 119
以與實例 18
類似之方式使用1-(二氟甲基)-1H-吡唑-4-甲酸及實例 109
來製備實例 119
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.48 (s, 1H), 8.09 (s, 1H), 7.77 (d,J
= 8.5 Hz, 1H), 7.66 (s, 0H), 7.52 (s, 1H), 7.40 - 7.32 (m, 1H), 7.18 (dd,J
= 8.5, 2.4 Hz, 1H), 7.10 (dd,J
= 6.4, 2.1 Hz, 2H), 6.84 (d,J
= 8.2 Hz, 1H), 6.22 (dt,J
= 14.4, 6.9 Hz, 1H), 5.56 (dd,J
= 15.4, 8.6 Hz, 1H), 4.22 - 3.98 (m, 3H), 3.87 - 3.74 (m, 2H), 3.78 - 3.61 (m, 4H), 3.55 (dt,J
= 11.6, 2.8 Hz, 0H), 3.35 (s, 0H), 3.28 (s, 3H), 3.06 (dd,J
= 15.2, 10.2 Hz, 1H), 2.88 - 2.70 (m, 2H), 2.70 - 2.61 (m, 1H), 2.52 - 2.38 (m, 1H), 2.29 (s, 1H), 2.21 (dt,J
= 14.1, 7.0 Hz, 1H), 2.12 (d,J
= 13.7 Hz, 1H), 1.94 (d,J
= 7.0 Hz, 3H), 1.88 - 1.69 (m, 2H), 1.44 (t,J
= 11.9 Hz, 1H), 1.31 (s, 0H), 1.11 (d,J
= 6.8 Hz, 3H)。19
F NMR (376 MHz,甲醇-d 4
) δ -97.35。LCMS-ESI+(m/z):C37
H42
ClF2
N5
O5
S [M+H]計算值:742.26;實驗值742.13。實例 120
以與實例 18
類似之方式使用1-(2-甲氧基乙基)-1H-吡唑-4-甲酸及實例 109
來製備實例 118
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.11 (s, 1H), 7.92 (s, 1H), 7.77 (d,J
= 8.6 Hz, 1H), 7.41 - 7.24 (m, 3H), 7.18 (dd,J
= 8.4, 2.3 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.83 (d,J
= 8.2 Hz, 1H), 6.22 (dt,J
= 14.4, 6.8 Hz, 1H), 5.75 - 5.67 (m, 0H), 5.55 (dd,J
= 15.4, 8.7 Hz, 1H), 5.07 (s, 0H), 4.31 (t,J
= 5.1 Hz, 2H), 4.22 - 3.97 (m, 3H), 3.84 (d,J
= 14.8 Hz, 1H), 3.82 - 3.63 (m, 7H), 3.61 - 3.51 (m, 0H), 3.29 (d,J
= 12.4 Hz, 5H), 3.06 (dd,J
= 15.0, 10.0 Hz, 1H), 2.88 - 2.74 (m, 2H), 2.64 (d,J
= 13.8 Hz, 1H), 2.43 (s, 2H), 2.27 (s, 1H), 2.23 - 2.08 (m, 3H), 1.94 (d,J
= 6.3 Hz, 3H), 1.88 - 1.68 (m, 2H), 1.52 (d,J
= 6.6 Hz, 1H), 1.50 - 1.38 (m, 1H), 1.31 (s, 3H), 1.10 (dd,J
= 6.7, 3.6 Hz, 4H), 0.93 (d,J
= 5.7 Hz, 0H), 0.90 (s, 2H), 0.12 (s, 1H)。LCMS-ESI+(m/z):C39
H48
ClN5
O6
S [M+H]計算值:750.30;實驗值750.08。實例 121
以與實 例 18
相同之方式使用(S)-2-羥基-3-苯基丙酸及實例 109
來合成實例 121
。1H NMR (400 MHz,乙腈-d3) δ 7.72 (d, J = 8.5 Hz, 1H), 7.36 - 7.21 (m, 6H), 7.19 (dd, J = 8.6, 2.4 Hz, 1H), 7.16 - 7.10 (m, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.01 (dt, J = 14.0, 6.5 Hz, 1H), 5.57 (dd, J = 15.5, 7.9 Hz, 1H), 4.43 (dd, J = 8.1, 4.2 Hz, 1H), 4.06 (d, J = 12.1 Hz, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.86 (s, 1H), 3.80 (d, J = 15.3 Hz, 1H), 3.74 - 3.66 (m, 2H), 3.34 (d, J = 14.3 Hz, 1H), 3.20 (s, 3H), 3.17 (dd, J = 14.1, 4.2 Hz, 1H), 3.05 (dd, J = 15.2, 10.1 Hz, 1H), 2.94 (dd, J = 14.0, 8.2 Hz, 1H), 2.86 - 2.68 (m, 2H), 2.52 - 2.34 (m, 3H), 2.14 (t, J = 8.5 Hz, 2H), 2.10 - 2.00 (m, 1H), 1.90 - 1.59 (m, 9H), 1.41 (dt, J = 14.6, 7.8 Hz, 1H), 1.05 (d, J = 6.3 Hz, 3H)。19
F NMR (376 MHz,乙腈-d3) δ -77.38。LCMS-ESI+ (m/z):C41
H48
ClN3
O6
S [M+H]+計算值:746.3;實驗值:746.0。實例 122
以與實 例 18
相同之方式使用(R
)-2-羥基-3-苯基丙酸及實例 109
來合成實例 122
。1H NMR (400 MHz,乙腈-d3) δ 7.73 (d, J = 8.5 Hz, 1H), 7.36 - 7.27 (m, 4H), 7.28 - 7.22 (m, 1H), 7.20 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (dd, J = 9.3, 2.2 Hz, 2H), 6.88 (d, J = 8.3 Hz, 1H), 6.00 (dt, J = 14.6, 6.9 Hz, 1H), 5.55 (dd, J = 15.6, 7.9 Hz, 1H), 4.49 (dd, J = 7.6, 4.1 Hz, 1H), 4.06 (d, J = 12.1 Hz, 1H), 4.00 (d, J = 12.1 Hz, 1H), 3.83 - 3.75 (m, 2H), 3.75 - 3.64 (m, 2H), 3.34 (d, J = 14.3 Hz, 1H), 3.20 (s, 3H), 3.15 (dd, J = 14.1, 4.1 Hz, 1H), 3.04 (dd, J = 15.1, 10.3 Hz, 1H), 2.96 (dd, J = 14.1, 7.6 Hz, 1H), 2.86 - 2.64 (m, 2H), 2.49 - 2.32 (m, 3H), 2.11 - 1.99 (m, 2H), 1.92 - 1.57 (m, 10H), 1.40 (dt, J = 15.1, 8.0 Hz, 1H), 0.99 (d, J = 6.9 Hz, 3H)。19F NMR (376 MHz,乙腈-d3) δ -77.38。LCMS-ESI+ (m/z):C41
H48
ClN3
O6
S [M+H]+計算值:746.3;實驗值:746.0。實例 123
以與實 例 18
相同之方式使用1-環丙基-1H-吡唑-4-甲酸及實例 109
來合成實例 123
。1
H NMR (400 MHz,乙腈-d3) δ 8.29 (s, 1H), 7.90 (d, J = 0.6 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.23 (dd, J = 8.2, 1.9 Hz, 1H), 7.08 (d, J = 2.3 Hz, 1H), 7.04 - 6.92 (m, 2H), 6.83 (d, J = 8.2 Hz, 1H), 6.01 (dt, J = 13.7, 6.6 Hz, 1H), 5.60 (dd, J = 15.4, 8.4 Hz, 1H), 4.54 (hept, J = 6.6 Hz, 1H), 4.12 (dd, J = 14.8, 6.3 Hz, 1H), 3.97 (s, 2H), 3.86 - 3.67 (m, 3H), 3.63 (d, J = 14.4 Hz, 1H), 3.35 (d, J = 14.4 Hz, 1H), 3.21 (s, 3H), 3.06 (dd, J = 15.2, 10.2 Hz, 1H), 2.86 - 2.65 (m, 2H), 2.59 (d, J = 13.3 Hz, 1H), 2.47 - 2.32 (m, 2H), 2.19 (dq, J = 14.5, 7.2 Hz, 2H), 2.08 - 1.97 (m, 2H), 1.90 (d, J = 4.0 Hz, 2H), 1.83 - 1.63 (m, 3H), 1.46 (t, J = 6.8 Hz, 6H), 1.34 (dt, J = 13.3, 8.0 Hz, 1H), 1.08 (d, J = 6.4 Hz, 3H)。19
F NMR (376 MHz,乙腈-d3) δ -77.37。LCMS-ESI+ (m/z):C39
H48
ClN5
O5
S [M+H]+計算值:734.3;實驗值:733.8。實例 124
以與實 例 18
相同之方式使用2-((4-甲基四氫-2H-哌喃-4-基)氧基)乙酸及實例 109
來合成實例 124
。1
H NMR (400 MHz,乙腈-d3) δ 7.72 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.2, 1.9 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.04 (dt, J = 14.7, 6.7 Hz, 1H), 5.58 (ddd, J = 15.5, 7.5, 1.4 Hz, 1H), 4.08 (d, J = 1.0 Hz, 2H), 4.05 (d, J = 12.1 Hz, 1H), 3.99 (d, J = 12.1 Hz, 1H), 3.90 (dd, J = 15.0, 5.3 Hz, 1H), 3.81 (d, J = 7.1 Hz, 1H), 3.79 - 3.75 (m, 1H), 3.75 - 3.66 (m, 3H), 3.61 (dt, J = 11.6, 4.2 Hz, 2H), 3.36 (d, J = 14.5 Hz, 1H), 3.21 (s, 3H), 3.05 (dd, J = 15.1, 10.8 Hz, 1H), 2.85 - 2.66 (m, 2H), 2.57 - 2.45 (m, 2H), 2.45 - 2.34 (m, 1H), 2.33 - 2.21 (m, 1H), 2.15 (dt, J = 14.7, 7.4 Hz, 1H), 2.09 - 1.99 (m, 1H), 1.92 - 1.85 (m, 3H), 1.84 - 1.56 (m, 8H), 1.40 (dt, J = 14.9, 7.6 Hz, 1H), 1.25 (s, 3H), 1.07 (d, J = 6.9 Hz, 3H)。19
F NMR (376 MHz,乙腈-d3) δ -77.38。LCMS-ESI+ (m/z):C40
H52
ClN3
O7
S [M+H]+計算值:754.3;實驗值:753.9。實例 125
以與實 例 18
相同之方式使用6-氧雜螺[3.4]辛烷-2-甲酸及實例 109
來合成實例 125
。1
H NMR (400 MHz,乙腈-d 3
) δ 7.59 (d,J
= 8.5 Hz, 1H), 7.28 (dd,J
= 8.2, 1.9 Hz, 1H), 7.09 (d,J
= 2.3 Hz, 1H), 7.04 (d,J
= 2.0 Hz, 1H), 6.94 (dd,J
= 8.6, 2.3 Hz, 1H), 6.80 (d,J
= 8.3 Hz, 1H), 6.15 - 5.99 (m, 1H), 5.64 (dd,J
= 15.5, 8.2 Hz, 1H), 4.01 - 3.90 (m, 3H), 3.85 (ddd,J
= 14.7, 4.9, 3.1 Hz, 1H), 3.79 - 3.64 (m, 6H), 3.61 (d,J
= 5.6 Hz, 2H), 3.45 - 3.29 (m, 2H), 3.26 (s, 4H), 3.07 (dd,J
= 15.2, 10.1 Hz, 1H), 2.75 (dtt,J
= 43.7, 17.9, 8.8 Hz, 4H), 2.51 - 2.13 (m, 7H), 2.10 - 1.99 (m, 3H), 1.95 - 1.89 (m, 2H), 1.88 - 1.63 (m, 2H), 1.43 - 1.23 (m, 2H), 1.10 (dd,J
= 6.8, 1.1 Hz, 3H)。LCMS-ESI+ (m/z):H+C40
H50
ClN3
O6
S計算值:736.3;實驗值:736.12。實例 126
以與實 例 18
相同之方式使用3-氯-1-甲基-1H-吡唑-4-甲酸及實例 109
來合成實例 126
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.23 (s, 1H), 7.72 (d,J
= 8.3 Hz, 1H), 7.18 (dd,J
= 8.1, 1.9 Hz, 1H), 7.13 (s, 1H), 7.11 (s, 2H), 7.00 - 6.87 (m, 2H), 6.04 (dd,J
= 15.0, 7.3 Hz, 1H), 5.62 (dd,J
= 15.2, 8.9 Hz, 1H), 4.37 (dd,J
= 14.8, 6.4 Hz, 1H), 4.07 (s, 2H), 3.89 (s, 3H), 3.88 - 3.75 (m, 3H), 3.67 (d,J
= 14.2 Hz, 1H), 3.28 (s, 3H), 3.19 - 3.00 (m, 1H), 2.91 - 2.70 (m, 2H), 2.62 - 2.45 (m, 1H), 2.44 - 2.07 (m, 4H), 2.05 - 1.73 (m, 3H), 1.44 (t,J
= 12.7 Hz, 1H), 1.31 (s, 1H), 1.17 (d,J
= 6.3 Hz, 3H)。LCMS-ESI+ (m/z):C37
H43
Cl2
N5
O5
S計算值:739.24;實驗值:739.99。實例 127
以與實例 18
相同之方式使用順-3-甲氧基環丁烷甲酸及實例 109
來合成實例 127
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.75 (d,J
= 8.5 Hz, 1H), 7.30 (dd,J
= 8.2, 1.9 Hz, 1H), 7.17 (dd,J
= 8.5, 2.4 Hz, 1H), 7.10 (dd,J
= 9.1, 2.1 Hz, 2H), 6.88 (d,J
= 8.2 Hz, 1H), 6.13 (dt,J
= 14.4, 6.9 Hz, 1H), 5.61 (dd,J
= 15.4, 8.5 Hz, 1H), 4.17 (dd,J
= 14.8, 6.7 Hz, 1H), 4.11 - 4.00 (m, 2H), 3.96 (dd,J
= 14.8, 5.3 Hz, 1H), 3.91 - 3.80 (m, 2H), 3.76 (d,J
= 8.6 Hz, 1H), 3.68 (d,J
= 14.2 Hz, 1H), 3.27 (d,J
= 13.7 Hz, 7H), 3.06 (dd,J
= 15.1, 9.8 Hz, 1H), 2.88 - 2.70 (m, 3H), 2.58 - 2.47 (m, 3H), 2.45 (s, 2H), 2.34 - 2.19 (m, 2H), 2.14 (dd,J
= 19.5, 10.9 Hz, 3H), 1.95 (s, 3H), 1.90 - 1.70 (m, 3H), 1.44 (t,J
= 12.4 Hz, 1H), 1.13 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+:C38
H48
ClN3
O6
S計算值:710.3 (M+H);實驗值:710.1 (M+H)。實 例 128
以與實例 18
相同之方式使用反-3-甲氧基環丁烷甲酸及實例 109
來合成實例 128
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.76 (d,J
= 8.5 Hz, 1H), 7.31 (dd,J
= 8.1, 1.9 Hz, 1H), 7.18 (dd,J
= 8.5, 2.4 Hz, 1H), 7.11 (dd,J
= 4.1, 2.2 Hz, 2H), 6.88 (d,J
= 8.2 Hz, 1H), 6.14 (dt,J
= 14.5, 6.9 Hz, 1H), 5.62 (dd,J
= 15.4, 8.4 Hz, 1H), 4.20 - 4.08 (m, 2H), 4.06 (dd,J
= 7.6, 3.7 Hz, 2H), 4.03 - 3.93 (m, 2H), 3.85 (d,J
= 15.0 Hz, 1H), 3.77 (dd,J
= 8.5, 2.8 Hz, 1H), 3.69 (d,J
= 14.2 Hz, 1H), 3.36 (s, 1H), 3.30 (s, 3H), 3.26 (s, 3H), 3.21 - 3.12 (m, 1H), 3.07 (dd,J
= 15.2, 9.8 Hz, 1H), 2.89 - 2.70 (m, 2H), 2.57 (qd,J
= 8.1, 4.1 Hz, 2H), 2.46 (s, 2H), 2.36 - 2.17 (m, 3H), 2.12 (d,J
= 13.9 Hz, 2H), 2.02 - 1.67 (m, 6H), 1.45 (t,J
= 12.5 Hz, 1H), 1.14 (d,J
= 6.9 Hz, 3H)。LCMS-ESI+:C38
H48
ClN3
O6
S計算值:710.3 (M+H);實驗值:710.1 (M+H)。實 例 129
以與實例 75
相同之方式使用實例 109
及反-外消旋-(1R,2S)-2-(1-甲基吡唑-4-基)環丙胺氯化氫以及三乙胺來合成實例 129
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.67 (d,J
= 8.6 Hz, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 7.22 (d,J
= 8.2 Hz, 1H), 7.09 (s, 1H), 6.98 (s, 2H), 6.88 (d,J
= 8.2 Hz, 1H), 6.10 - 6.01 (m, 1H), 5.70 - 5.59 (m, 1H), 4.23 (dd,J
= 14.8, 6.8 Hz, 1H), 4.02 (s, 2H), 3.83 (s, 5H), 3.65 (d,J
= 14.2 Hz, 1H), 3.37 (s, 1H), 3.30 (s, 4H), 3.08 (dd,J
= 15.2, 9.9 Hz, 1H), 2.92 - 2.51 (m, 5H), 2.45 (s, 2H), 2.23 (s, 2H), 2.08 (t,J
= 11.5 Hz, 2H), 2.02 - 1.85 (m, 4H), 1.81 (d,J
= 7.5 Hz, 2H), 1.40 (t,J
= 12.9 Hz, 1H), 1.19 - 1.12 (m, 3H), 1.03 (q,J
= 6.3 Hz, 1H)。LCMS-ESI+:C40
H49
ClN6
O5
S計算值:761.3 (M+H);實驗值:760.8 (M+H)。實 例 130
以與實例 18
相同之方式使用1-乙基吡咯-3-甲酸及實例 109
來合成實例 130
。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.4 Hz, 1H), 7.62 (t, J = 1.9 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.18 - 7.08 (m, 3H), 6.90 (d, J = 8.2 Hz, 1H), 6.81 (dd, J = 3.0, 2.1 Hz, 1H), 6.64 (dd, J = 2.9, 1.8 Hz, 1H), 6.12 (dt, J = 14.4, 6.6 Hz, 1H), 5.62 (dd, J = 15.4, 8.5 Hz, 1H), 4.24 (dd, J = 14.6, 6.3 Hz, 1H), 4.12 - 3.98 (m, 4H), 3.86 (d, J = 15.0 Hz, 1H), 3.82 - 3.75 (m, 1H), 3.69 (d, J = 14.3 Hz, 1H), 3.38 (s, 1H), 3.29 (s, 3H), 3.08 (dd, J = 15.1, 10.0 Hz, 1H), 2.89 - 2.70 (m, 2H), 2.57 (dd, J = 12.9, 6.5 Hz, 1H), 2.46 (s, 2H), 2.32 - 2.15 (m, 2H), 2.12 (d, J = 13.7 Hz, 1H), 1.96 (d, J = 6.2 Hz, 3H), 1.88 - 1.69 (m, 3H), 1.46 (t, J = 7.3 Hz, 4H), 1.31 (s, 1H), 1.14 (d, J = 6.5 Hz, 3H)。LCMS-ESI+:C39
H47
ClN4
O5
S計算值:719.3 (M+H);實驗值:718.8 (M+H)。實 例 131
以與實例 75
相同之方式使用實例 109
及1-(甲氧基甲基)環丙胺來合成實例 131
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.25 - 7.14 (m, 2H), 7.11 (d, J = 2.3 Hz, 1H), 7.01 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.03 (dd, J = 14.7, 7.4 Hz, 1H), 5.59 (dd, J = 15.3, 8.9 Hz, 1H), 4.31 - 4.22 (m, 1H), 4.13 - 4.00 (m, 2H), 3.90 - 3.73 (m, 3H), 3.68 (d, J = 14.2 Hz, 1H), 3.46 (d, J = 8.2 Hz, 1H), 3.39 (s, 3H), 3.27 (s, 4H), 3.07 (dd, J = 15.3, 10.2 Hz, 1H), 2.92 - 2.70 (m, 3H), 2.48 (d, J = 7.6 Hz, 2H), 2.39 (d, J = 9.2 Hz, 1H), 2.19 (dt, J = 14.1, 7.0 Hz, 1H), 2.12 (d, J = 13.1 Hz, 2H), 2.01 - 1.87 (m, 3H), 1.77 (tq, J = 17.6, 9.3, 8.8 Hz, 3H), 1.44 (t, J = 11.6 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H), 0.83 (d, J = 12.6 Hz, 3H)。LCMS-ESI+:C38
H49
ClN4
O6
S計算值:725.3 (M+H);實驗值:724.8 (M+H)。實 例 132
以與實例 75
相同之方式使用實例 109
及2-甲氧基乙-1-胺來合成實例 132
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.06 (dd, J = 15.0, 6.9 Hz, 1H), 5.58 (dd, J = 15.3, 8.9 Hz, 1H), 4.27 (dd, J = 14.7, 6.5 Hz, 1H), 4.14 - 3.96 (m, 2H), 3.91 - 3.62 (m, 4H), 3.49 (d, J = 5.3 Hz, 2H), 3.38 (s, 3H), 3.27 (s, 3H), 3.07 (dd, J = 15.2, 10.2 Hz, 1H), 2.91 - 2.66 (m, 3H), 2.57 - 2.28 (m, 3H), 2.28 - 2.04 (m, 3H), 2.02 - 1.87 (m, 3H), 1.87 - 1.66 (m, 3H), 1.54 - 1.36 (m, 2H), 1.31 (s, 1H), 1.13 (d, J = 6.6 Hz, 3H)。LCMS-ESI+:C36
H47
ClN4
O6
S計算值:699.3 (M+H);實驗值:698.6 (M+H)。實 例 133
以與實例 18
相同之方式使用2-(((3R,4S)-3-氟四氫-2H-哌喃-4-基)氧基)乙酸及實例 110
來合成實例 133
。1H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.8 Hz, 1H), 7.37 (dd, J = 8.2, 1.8 Hz, 1H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 7.08 (d, J = 2.0 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 6.12 - 6.05 (m, 1H), 5.56 (dd, J = 15.2, 8.8 Hz, 1H), 4.18 - 4.11 (m, 2H), 4.08 - 3.83 (m, 4H), 3.81 - 3.72 (m, 2H), 3.68 (s, 2H), 3.61 (d, J = 14.4 Hz, 1H), 3.55 - 3.40 (m, 3H), 3.37 - 3.31 (m, 2H), 3.26 (s, 3H), 3.16 - 3.08 (m, 1H), 2.88 - 2.69 (m, 3H), 2.51 - 1.61 (m, 12H), 1.54 - 1.46 (m, 1H), 1.43 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.8 Hz, 3H)。LCMS-ESI+:C40
H51
ClFN3
O7
S計算值:772.3 (M+H);實驗值:772.2 (M+H)。實例 134
以與實例 18
相同之方式使用1-乙基-1H-吡唑-4-甲酸及實例 109
來合成實例 134
。1H NMR (400 MHz,甲醇-d4) δ 8.29 (s, 1H), 7.96 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.23 (dd, J = 8.2, 1.8 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.99 (d, J = 1.9 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.07 (dt, J = 14.3, 6.7 Hz, 1H), 5.62 (dd, J = 15.3, 8.8 Hz, 1H), 4.34 (dd, J = 14.8, 6.5 Hz, 1H), 4.24 (q, J = 7.3 Hz, 2H), 4.06 (d, J = 1.5 Hz, 2H), 3.92 (dd, J = 14.7, 5.2 Hz, 1H), 3.84 (d, J = 15.1 Hz, 1H), 3.78 (dd, J = 8.8, 3.3 Hz, 1H), 3.67 (d, J = 14.3 Hz, 1H), 3.36 (d, J = 2.5 Hz, 1H), 3.29 (s, 3H), 3.09 (dd, J = 15.2, 9.9 Hz, 1H), 2.93 - 2.65 (m, 3H), 2.56 (d, J = 10.0 Hz, 1H), 2.43 (dd, J = 17.5, 8.9 Hz, 2H), 2.25 (dt, J = 26.4, 9.7 Hz, 2H), 2.11 (d, J = 13.5 Hz, 1H), 1.98 (dd, J = 16.3, 5.2 Hz, 2H), 1.82 (dt, J = 23.0, 9.3 Hz, 4H), 1.50 (t, J = 7.3 Hz, 3H), 1.16 (d, J = 6.6 Hz, 3H)。LCMS-ESI+:C38
H46
ClN5
O5
S計算值:720.3 (M+H);實驗值:719.0 (M+H)。實例 135
步驟1:製備3-(2-甲醯基-1H-吡咯-1-基)丙酸甲酯:在氮氣氛圍下將於無水DMF (10 mL)中之吡咯甲醛(5.0 g,0.053 mol)之溶液逐滴添加至於無水DMF (40 mL)中之60%氫化鈉(油分散液) (2.56 g,0.063 mol)之經攪拌懸浮液中。將混合物之溫度維持在0℃下。在完成添加之後,在相同溫度下繼續攪拌30 min。隨後,逐滴添加3-溴丙酸甲酯溶液(13.17 g,0.079 mol),且使溫度升高至室溫。將反應混合物在此溫度下攪拌48 h。隨後,添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且將溶劑在減壓下移除且藉由正相層析法(矽膠管柱,0-80% EtOAc/己烷)純化,得到3-(2-甲醯基-1H-吡咯-1-基)丙酸甲酯。
步驟2:製備3H-吡-6-甲酸甲酯:向於MeOH (20 mL)中之3-(2-甲醯基-1H-吡咯-1-基)丙酸甲酯(2.0 g,11.04 mmol)之溶液中添加NaOMe (2.62 g,12.14 mmol)。將反應混合物在45℃下攪拌48 h。隨後,添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且將溶劑在減壓下移除且藉由正相層析法(矽膠管柱,0-80% EtOAc/己烷)純化,得到中間物3H-吡-6-甲酸甲酯。1
H NMR (400 MHz,氘代氯仿) δ 7.58 (p,J
= 1.2 Hz, 1H), 6.60 (dtd,J
= 6.1, 2.2, 0.7 Hz, 1H), 6.36 (q,J
= 0.9 Hz, 1H), 6.31 - 6.21 (m, 1H), 4.50 (tt,J
= 2.2, 1.0 Hz, 2H), 3.83 (s, 3H)。
步驟3:製備3H-吡-6-甲酸:向於甲醇(6 mL)中之3H-吡-6-甲酸甲酯(0.3 g,1.8 mmol)之經攪拌溶液中添加2N LiOH (1 mL),且將反應混合物在rt下攪拌3 h。向反應混合物中添加2N HCl (1 mL)且濃縮。添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑,得到3H-吡-6-甲酸。
步驟4:以與實 例 18
相同之方式使用3H-吡-6-甲酸及實例 109
來合成實例 135
。1H NMR (400 MHz,氘代氯仿) δ 7.86 - 7.61 (m, 2H), 7.40 (d, J = 8.3 Hz, 1H), 7.20 (d, J = 6.6 Hz, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.63 (d, J = 6.1 Hz, 1H), 6.44 (s, 1H), 6.34 (d, J = 6.1 Hz, 1H), 6.04 - 5.86 (m, 1H), 5.62 (dd, J = 15.7, 7.7 Hz, 1H), 4.56 (s, 2H), 4.20 - 3.94 (m, 3H), 3.82 (dd, J = 42.9, 13.7 Hz, 3H), 3.58 - 3.39 (m, 1H), 3.29 (s, 3H), 3.11 - 2.88 (m, 2H), 2.88 - 2.69 (m, 2H), 2.46 (t, J = 30.6 Hz, 4H), 2.16 - 1.66 (m, 7H), 1.28 (s, 2H), 1.13 (d, J = 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C40
H45
ClN4
O5
S [M+H]+計算值:729.26;實驗值:729.30。實例 136
步驟1:製備2,3-二氫-1H-吡-6-甲酸甲酯:將3H-吡-6-甲酸甲酯(300 mg,1.85 mmol)及銠(於氧化鋁上5%)混合在乙醇(10 mL)中。使混合物脫氣,注入氫氣,且隨後將混合物攪拌5 h。使混合物經由二氧化矽過濾且濃縮。隨後,添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑,得到2,3-二氫-1H-吡-6-甲酸甲酯。1
H NMR (400 MHz,氘代氯仿) δ 7.21 (d,J
= 1.4 Hz, 1H), 6.22 (q,J
= 1.2 Hz, 1H), 3.99 - 3.86 (m, 2H), 3.78 (s, 3H), 2.80 (ddd,J
= 7.7, 6.7, 1.2 Hz, 2H), 2.48 (tt,J
= 8.0, 6.8 Hz, 2H)。
步驟2:以與實例 133 ( 步驟 3)
相同之方式使用2,3-二氫-1H-吡-6-甲酸甲酯而不使用3H-吡-6-甲酸甲酯來合成2,3-二氫-1H-吡-6-甲酸。
步驟3:以與實 例 18
相同之方式使用2,3-二氫-1H-吡-6-甲酸及實例 109
來合成實例 136
。1H NMR (400 MHz,氘代氯仿) δ 7.76 (d, J = 8.5 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.25 - 7.15 (m, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.35 (d, J = 1.4 Hz, 1H), 6.05 - 5.89 (m, 1H), 5.62 (dd, J = 15.6, 7.5 Hz, 1H), 4.18 - 3.69 (m, 7H), 3.30 (s, 4H), 3.08 - 2.94 (m, 1H), 2.92 - 2.74 (m, 3H), 2.61 - 2.32 (m, 5H), 2.21 - 1.62 (m, 13H), 1.41 (t, J = 12.9 Hz, 1H), 1.13 (d, J = 6.8 Hz, 2H)。LCMS-ESI+ (m/z):C40
H47
ClN4
O5
S [M+H]+計算值:731.30;實驗值:731.22。實例 137
以與實例 18
相同之方式使用3,4-二氫-1H-吡咯并[2,1-c][1,4]噁嗪-7-甲酸及實例 110
來合成實例 137
。1H NMR (400 MHz,氘代氯仿) δ 7.74 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 1.7 Hz, 1H), 7.21 (dd, J = 8.4, 2.5 Hz, 2H), 7.11 (d, J = 2.3 Hz, 1H), 7.04 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 1.6 Hz, 1H), 5.99 (d, J = 11.2 Hz, 1H), 5.52 (dd, J = 15.2, 8.9 Hz, 1H), 4.81 (dd, J = 3.3, 1.1 Hz, 2H), 4.57 (s, 1H), 4.18 - 3.96 (m, 3H), 3.92 - 3.79 (m, 2H), 3.76 - 3.65 (m, 2H), 3.26 (s, 3H), 3.02 (dd, J = 15.2, 9.9 Hz, 1H), 2.87 - 2.70 (m, 3H), 2.42 (dt, J = 25.8, 9.3 Hz, 3H), 2.29 - 1.93 (m, 5H), 1.82 (q, J = 9.2 Hz, 3H), 1.72 - 1.55 (m, 4H), 1.41 (t, J = 12.8 Hz, 1H), 1.28 (s, 2H), 1.01 (d, J = 6.2 Hz, 3H)。LCMS-ESI+ (m/z):C41
H49
ClN4
O6
S [M+H]+計算值:761.29;實驗值:761.22。實例 138
以與實例 18
相同之方式使用1-甲基-1H-吡唑-4-甲酸及實例 110
來合成實例 138
。1H NMR (400 MHz,氘代氯仿) δ 8.01 (d, J = 0.7 Hz, 1H), 7.93 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.5, 2.3 Hz, 1H), 7.18 - 7.07 (m, 2H), 7.06 - 6.89 (m, 2H), 5.96 (dd, J = 15.1, 8.6 Hz, 1H), 5.53 (dd, J = 15.2, 9.0 Hz, 1H), 4.67 (d, J = 7.3 Hz, 2H), 4.12 (s, 2H), 3.99 (s, 2H), 3.86 (d, J = 15.0 Hz, 2H), 3.76 - 3.61 (m, 2H), 3.26 (s, 3H), 3.02 (dd, J = 15.2, 10.2 Hz, 2H), 2.79 (d, J = 15.3 Hz, 3H), 2.41 (dt, J = 45.0, 9.2 Hz, 3H), 2.27 - 1.92 (m, 5H), 1.84 (t, J = 8.9 Hz, 2H), 1.70 - 1.58 (m, 3H), 1.41 (t, J = 12.4 Hz, 2H), 0.96 (d, J = 6.2 Hz, 2H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O5
S [M+H]+計算值:720.29;實驗值:720.23。實例 139
以與實例 18
相同之方式使用3,4-二氫-1H-吡咯并[2,1-c][1,4]噁嗪-7-甲酸及實例 109
來合成實例 139
。1H NMR (400 MHz,氘代氯仿) δ 7.74 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 15.0, 1.8 Hz, 2H), 7.18 (dd, J = 8.4, 2.3 Hz, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 6.37 (q, J = 1.2 Hz, 1H), 5.99 (dt, J = 13.7, 6.5 Hz, 1H), 5.62 (dd, J = 15.6, 7.7 Hz, 1H), 4.84 (d, J = 1.1 Hz, 2H), 4.18 - 3.95 (m, 6H), 3.94 - 3.69 (m, 4H), 3.31 (s, 4H), 3.09 - 2.95 (m, 2H), 2.90 - 2.68 (m, 2H), 2.59 - 2.25 (m, 4H), 2.21 - 2.03 (m, 2H), 2.02 - 1.82 (m, 3H), 1.81 - 1.60 (m, 3H), 1.41 (t, J = 12.7 Hz, 1H), 1.13 (d, J = 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C40
H47
ClN4
O6
S [M+H]+計算值:747.29;實驗值:747.04。實例 140
將於DCM (1.0 mL)中之3-羥基-3-甲基-環丁烷甲酸(2.61 mg,0.02 mmol)及實例 109
(8.0 mg,0.0134 mmol)之混合物冷卻至0℃。添加1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (5.11 mg,0.0268 mmol),繼而添加DMAP (3.27 mg,0.0267 mmol)。將反應物自冷卻浴中移除且在周圍下攪拌過夜。隨後,將反應物藉由移除DCM來濃縮,用DMF (1 mL)稀釋,過濾,且藉由Gilson逆相製備型HPLC (60-100% ACN/H2
O及0.1% TFA)純化,得到實例 140
。1H NMR (400 MHz,甲醇-d4) δ 7.76 - 7.67 (m, 1H), 7.31 (dd, J = 8.2, 1.9 Hz, 1H), 7.14 - 7.04 (m, 3H), 6.86 (d, J = 8.2 Hz, 1H), 6.14 (dt, J = 14.6, 7.0 Hz, 1H), 5.63 (dd, J = 15.4, 8.4 Hz, 1H), 4.14 (dd, J = 14.8, 6.9 Hz, 1H), 4.08 - 3.93 (m, 3H), 3.88 - 3.73 (m, 2H), 3.67 (d, J = 14.3 Hz, 1H), 3.30 (s, 3H), 3.12 - 2.98 (m, 1H), 2.92 - 2.70 (m, 3H), 2.59 - 2.20 (m, 8H), 2.16 - 2.03 (m, 2H), 2.03 - 1.71 (m, 7H), 1.38 (s, 4H), 1.14 (d, J = 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C38
H48
ClN3
O6
S計算值[M+H]+計算值:710.3;實驗值:710.1。實例 141
以與實例 140
相同之方式使用外消旋1-甲基-4,5,6,7-四氫吲唑-6-甲酸而不使用3-羥基-3-甲基-環丁烷甲酸來合成實例 141
。將來自逆相製備型HPLC之後一溶析峰任意指定為「S」,未測定到實際立體化學。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.40 (s, 1H), 7.29 (dd, J = 8.2, 1.8 Hz, 1H), 7.16 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (dd, J = 8.5, 2.1 Hz, 2H), 6.90 (d, J = 8.2 Hz, 1H), 6.14 (dt, J = 14.6, 7.0 Hz, 1H), 5.64 (dd, J = 15.4, 8.3 Hz, 1H), 4.15 (dd, J = 14.8, 7.0 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.96 (dd, J = 14.8, 4.9 Hz, 1H), 3.88 - 3.64 (m, 6H), 3.30 (s, 3H), 3.13 - 3.02 (m, 1H), 2.99 - 2.66 (m, 6H), 2.65 - 2.29 (m, 5H), 2.26 - 2.06 (m, 3H), 2.01 - 1.69 (m, 8H), 1.51 - 1.38 (m, 1H), 1.18 (d, J = 6.9 Hz, 3H)。LCMS-ESI+ (m/z):計算值[M+H] C41
H50
ClN5
O5
S:760.3;實驗值:760.1。實例 142
以與實例 140
相同之方式使用3-(1-甲基吡唑-4-基)丙酸而不使用3-羥基-3-甲基-環丁烷甲酸來合成實例 142
,其中亦添加DMF (1.0 mL)作為共溶劑以用於此反應。1H NMR (400 MHz,甲醇-d4) δ 7.75 - 7.69 (m, 1H), 7.51 (s, 1H), 7.45 - 7.41 (m, 1H), 7.31 (dd, J = 8.3, 1.9 Hz, 1H), 7.14 - 7.05 (m, 3H), 6.86 (d, J = 8.2 Hz, 1H), 6.18 - 6.06 (m, 1H), 5.62 (dd, J = 15.5, 8.4 Hz, 1H), 4.14 - 3.97 (m, 3H), 3.92 (dd, J = 14.8, 4.8 Hz, 1H), 3.87 - 3.73 (m, 5H), 3.67 (d, J = 14.2 Hz, 1H), 3.30 (s, 3H), 3.11 - 3.00 (m, 1H), 2.90 - 2.74 (m, 4H), 2.74 - 2.66 (m, 2H), 2.57 - 2.38 (m, 3H), 2.31 - 2.19 (m, 1H), 2.14 - 2.05 (m, 1H), 2.03 - 1.71 (m, 8H), 1.47 - 1.36 (m, 1H), 1.07 (d, J = 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C39
H48
ClN5
O5
S [M+H]+計算值734.35;實驗值:734.07。實例 143
以與實例 140
相同之方式使用異𠳭烷-3-甲酸而不使用3-羥基-3-甲基-環丁烷甲酸來合成實例 143
。將來自逆相製備型HPLC之前一溶析峰任意指定為「R」,未測定到實際立體化學。1H NMR (400 MHz,甲醇-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.2, 1.9 Hz, 1H), 7.25 - 7.15 (m, 4H), 7.14 - 7.05 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.10 (dt, J = 14.5, 6.9 Hz, 1H), 5.64 (dd, J = 15.4, 8.3 Hz, 1H), 5.06-4.89 (m, 2H) 4.44 (dd, J = 9.7, 4.7 Hz, 1H), 4.22 - 4.01 (m, 3H), 3.95 (dd, J = 14.9, 5.0 Hz, 1H), 3.85 (d, J = 14.9 Hz, 1H), 3.77 (dd, J = 8.4, 3.0 Hz, 1H), 3.70 (d, J = 14.3 Hz, 1H), 3.30 (s, 3H), 3.18 - 3.02 (m, 3H), 2.90 - 2.75 (m, 2H), 2.56 - 2.40 (m, 3H), 2.34 - 2.22 (m, 1H), 2.22 - 2.07 (m, 2H), 2.00 - 1.71 (m, 7H), 1.51 - 1.39 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C42
H48
ClN3
O6
S [M+H]+計算值:758.37;實驗值:758.07。實例 144
在rt下將實例 109
(350 mg,0.59 mmol)溶解於DCM (5.9 mL)中,添加三乙胺(0.24 g,2.34 mmol),繼而添加於DCM (1 mL)中之異氰酸基環丙烷(107 mg,1.3 mmol)。在藉由移除DCM濃縮反應物之前,將所得混合物在rt下攪拌2 hr,將所得殘餘物再溶解於EtOAc (30 mL)中,且用1N HCl (15 mL)洗滌。用EtOAc (2×10 mL)萃取水層。將合併有機層用飽和NaHCO3
(15 mL)、鹽水(15 mL)洗滌,經硫酸鈉乾燥,過濾,濃縮,再溶解於DCM中,與矽膠混合,濃縮至乾,且藉由combiflash (12 g矽膠,0-10%於MeOH中之DCM/2.0 N NH3
,乾負載物)純化兩次。將所需溶離份組合且濃縮,得到實例 144
。1
H NMR (400 MHz,丙酮-d 6
) δ 7.75 (d,J
= 8.5 Hz, 1H), 7.32 - 7.05 (m, 4H), 6.84 (d,J
= 8.2 Hz, 1H), 6.14 (dt,J
= 14.2, 6.6 Hz, 1H), 5.56 (dd,J
= 15.4, 8.4 Hz, 1H), 4.04 (q,J
= 11.9 Hz, 3H), 3.85 (d,J
= 15.1 Hz, 1H), 3.71 (d,J
= 14.8 Hz, 2H), 3.39 (d,J
= 14.2 Hz, 1H), 3.23 (s, 3H), 3.12 (dd,J
= 15.0, 9.8 Hz, 1H), 2.89 - 2.71 (m, 3H), 2.69 - 2.60 (m, 1H), 2.58 - 2.40 (m, 3H), 2.20 - 2.10 (m, 3H), 2.00 - 1.89 (m, 3H), 1.83 - 1.69 (m, 3H), 1.51 - 1.34 (m, 1H), 1.08 (d,J
= 6.3 Hz, 3H), 0.66 (d,J
= 6.9 Hz, 2H), 0.56 - 0.48 (m, 2H)。LCMS-ESI+ (m/z):C36
H45
ClN4
O5
S [M+H]+計算值:681.28;實驗值:680.81。實例 145
步驟1:在2 min內在0℃下經由注射器將丁-3-烯酸第三丁酯(1.40 mL,5.75 mmol)添加至經攪拌之9-硼雜雙環[3.3.1]壬烷溶液(於四氫呋喃中0.5 M,17.2 mL,9 mmol)中,且將所得混合物升溫至室溫。在4.5 h之後,依序添加5-溴-1H-吡咯-3-甲醛(1.00 g,5.75 mmol)、[1,1′-雙(二苯膦基)二茂鐵]二氯鈀(II) (210 mg,0.287 mmol)、碳酸鉀(1.59 g,11.5 mmol)及N
,N
-二甲基甲醯胺(30 mL),且將所得混合物加熱至75℃。在50 min之後,將反應混合物加熱至100℃。在23 h之後,將所得混合物冷卻至室溫,且依序添加二乙醚(400 mL)及飽和氯化銨水溶液(50 mL)。將有機層用水(2×350 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至80%於己烷中之乙酸乙酯)純化殘餘物,得到145-1
。
步驟2:在室溫下經由注射器將氫氧化鋰水溶液(2.0 M,11.0 mL,22 mmol)添加至於四氫呋喃(17 mL)、水(5.0 mL)及甲醇(5.0 mL)中之145-1
(517 mg,2.18 mmol)之經劇烈攪拌溶液中。在1 h之後,將所得混合物加熱至70℃。在3.5 h之後,將所得混合物冷卻至室溫,且依序添加氯化氫水溶液(2.0 M,20 mL)及乙酸乙酯(100 mL)。將有機層用水及鹽水之混合物(1:1 v:v,2×80 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於二氯甲烷(24 mL)及N
,N
-二甲基甲醯胺(4.0 mL)中,添加4-二甲基胺基吡啶(400 mg,3.27 mmol),且在室溫下攪拌所得混合物。在2 min之後,添加N
-(3-二甲基胺基丙基)-N
'-乙基碳化二亞胺鹽酸鹽(774 mg,4.36 mmol)。在14 h之後,添加二乙醚(120 mL)。將有機層依序用氯化氫水溶液(0.05 M,100 mL)及水(100 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至80%於己烷中之乙酸乙酯)純化殘餘物,得到145-2
。
步驟3:在室溫下經由注射器將亞氯酸鈉水溶液(2.0 M,469 mL,0.94 mmol)及單水合磷酸二氫鈉(120 mg,0.868 mmol)之混合物添加至於第三丁醇(0.4 mL)中之145-2
(22 mg,0.14 mmol)及2-甲基-2-丁烯(143 mL,1.35 mmol)之經劇烈攪拌混合物中。在16.5 h之後,依序添加氯化氫水溶液(2.0 M,20 mL)及乙酸乙酯(100 mL)。將有機層用水及鹽水之混合物(1:1 v:v,2×80 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮,得到145-3
。
步驟4:製備實例 145
:以與實例 18
相同之方式使用145-3
及實例 109
來合成實例 145
。1
H NMR (400 MHz,丙酮-d 6
) δ 7.88 (s, 1H), 7.78 (d,J
= 8.5 Hz, 1H), 7.32 - 7.21 (m, 2H), 7.19 - 7.12 (m, 2H), 6.91 (d,J
= 8.2 Hz, 1H), 6.39 (d,J
= 1.7 Hz, 1H), 6.20 - 6.06 (m, 1H), 5.60 (dd,J
= 15.4, 8.4 Hz, 1H), 4.11 (d,J
= 12.1 Hz, 1H), 4.05 (d,J
= 12.1 Hz, 1H), 3.93 - 3.65 (m, 3H), 3.40 (d,J
= 14.2 Hz, 1H), 3.24 (s, 3H), 3.24 − 3.08 (m, 1H), 2.96 - 1.22 (m, 23H), 1.13 (d,J
= 6.2 Hz, 3H)。LCMS-ESI+:C41
H48
ClN4
O6
S計算值:759.3 (M+H);實驗值:759.0 (M+H)。實例 146
以與實 例 18
相同之方式使用2-甲基噻唑-4-甲酸及實例 109
來合成實例 146
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.28 (s, 1H), 7.74 (d,J
= 8.5 Hz, 1H), 7.22 (dd,J
= 8.2, 1.9 Hz, 1H), 7.17 (dd,J
= 8.5, 2.3 Hz, 1H), 7.10 (d,J
= 2.3 Hz, 1H), 7.03 (d,J
= 2.0 Hz, 1H), 6.94 (d,J
= 8.2 Hz, 1H), 6.04 (dt,J
= 14.4, 6.8 Hz, 1H), 5.60 (dd,J
= 15.4, 8.7 Hz, 1H), 4.34 (dd,J
= 15.0, 6.4 Hz, 1H), 4.13 - 4.03 (m, 2H), 3.98 (dd,J
= 15.0, 5.7 Hz, 1H), 3.85 (d,J
= 15.0 Hz, 1H), 3.76 (dd,J
= 8.8, 3.5 Hz, 1H), 3.69 (d,J
= 14.3 Hz, 1H), 3.33 (s, 1H), 3.26 (s, 3H), 3.07 (dd,J
= 15.3, 10.0 Hz, 1H), 2.77 (s, 3H), 2.53 - 2.35 (m, 3H), 2.24 (tt,J
= 14.3, 7.2 Hz, 1H), 2.11 (d,J
= 13.9 Hz, 2H), 1.97 - 1.88 (m, 1H), 1.79 (dt,J
= 20.3, 8.5 Hz, 2H), 1.49 - 1.38 (m, 1H), 1.29 (s, 1H), 1.11 (d,J
= 6.7 Hz, 3H)。LCMS-ESI+ (m/z):H+C37
H43
ClN4
O5
S2
計算值:723.248;實驗值:723.221。實例 147
以與實 例 18
相同之方式使用1-甲基-1H-吡咯-3-甲酸及實例 109
來合成實例 147
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.74 (d,J
= 8.5 Hz, 1H), 7.49 (s, 1H), 7.30 (d,J
= 8.3 Hz, 1H), 7.15 (d,J
= 8.4 Hz, 1H), 7.09 (s, 2H), 6.89 (d,J
= 8.2 Hz, 1H), 6.72 (d,J
= 2.7 Hz, 1H), 6.66 - 6.53 (m, 1H), 6.16 - 6.00 (m, 1H), 5.59 (dd,J
= 15.3, 8.5 Hz, 1H), 4.23 (dd,J
= 16.1, 5.8 Hz, 1H), 4.10 - 3.98 (m, 2H), 3.85 (d,J
= 14.9 Hz, 1H), 3.77 (d,J
= 8.5 Hz, 1H), 3.72 (s, 3H), 3.68 (d,J
= 14.3 Hz, 1H), 3.27 (s, 3H), 3.10 - 3.00 (m, 1H), 2.80 (s, 2H), 2.44 (s, 2H), 2.28 - 2.15 (m, 1H), 2.10 (d,J
= 15.0 Hz, 1H), 1.76 (s, 2H), 1.49 - 1.38 (m, 1H), 1.29 (s, 2H), 1.12 (d,J
= 6.5 Hz, 3H)。LCMS-ESI+ (m/z):H+C38
H45
ClN4
O5
S計算值:705.288;實驗值:705.295。實例 148
以與實 例 18
相同之方式使用1-甲基-1H-吡唑-4-甲酸及實例 109
來合成實例 148
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.74 (d,J
= 8.5 Hz, 1H), 7.17 (t,J
= 9.6 Hz, 2H), 7.09 (d,J
= 6.8 Hz, 2H), 6.85 (d,J
= 7.6 Hz, 1H), 6.35 - 6.01 (m, 1H), 5.55 (dd,J
= 15.2, 8.6 Hz, 1H), 4.03 (q,J
= 12.1 Hz, 2H), 3.84 (d,J
= 14.9 Hz, 1H), 3.78 (d,J
= 8.6 Hz, 1H), 3.67 (d,J
= 14.3 Hz, 1H), 3.42 (s, 2H), 3.27 (d,J
= 1.4 Hz, 3H), 3.11 - 2.99 (m, 1H), 2.89 (s, 6H), 2.80 (s, 1H), 2.60 (s, 0H), 2.43 (s, 2H), 2.23 - 2.08 (m, 1H), 2.06 - 1.97 (m, 1H), 1.92 (d,J
= 10.7 Hz, 2H), 1.76 (d,J
= 6.9 Hz, 3H), 1.42 (t,J
= 13.0 Hz, 1H), 1.23 (d,J
= 7.5 Hz, 3H), 1.09 (d,J
= 6.5 Hz, 3H)。LCMS-ESI+ (m/z):H+C37
H44
ClN5
O5
S計算值:706.28;實驗值:706.27。實例 149
以與實例 75
相同之方式使用實例 109
及順 -
3-甲氧基環丁-1-胺鹽酸鹽來合成實例 149
。1H NMR (400 MHz,丙酮-d6) δ 7.75 (d, J = 8.5 Hz, 1H), 7.39 (br s, 1H), 7.31 - 7.15 (m, 2H), 7.10 (s, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.23 (br s, 1H), 5.57 (br s, 1H), 4.05 (q, J = 10.0 Hz, 2H), 4.00 (m, 2H) 3.88 - 3.61 (m, 4H), 3.44 (d, J = 14.4 Hz, 1H), 3.26 (s, 3H), 3.19 (s, 3H), 3.13 (dd, J = 15.2, 10.3 Hz, 1H), 2.89 - 2.68 (m, 2H), 2.67 - 2.37 (m, 2H), 2.37 - 2.16 (m, 7H), 2.16 -2.07 (m, 3H), 1.95 (m, 2H), 1.88 (m, 2H), 1.74 (m, 1H), 1.48 - 1.33 (m, 1H), 1.29 (s, 1H), 1.14 (d, J = 6.4 Hz, 3H)。LCMS-ESI+:C38
H50
ClN4
O6
S計算值:725.3 (M+H);實驗值:724.8 (M+H)。實例 150
以與實例 75
相同之方式使用實例 109
及反 -
3-甲氧基環丁-1-胺鹽酸鹽來合成實例 150
。1H NMR (400 MHz,丙酮-d6) δ 7.64 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.07 (m, 2H), 6.97 (d, J = 8.2 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.16 - 6.02 (m, 1H), 5.67 (dd, J = 15.5, 8.3 Hz, 1H), 4.31 (q, J = 7.1 Hz, 1H), 4.00 (m, 2H) 3.88 - 3.61 (m, 4H), 3.44 (d, J = 14.4 Hz, 1H), 3.26 (s, 3H), 3.19 (s, 3H), 3.13 (dd, J = 15.2, 10.3 Hz, 1H), 2.89 - 2.68 (m, 2H), 2.67 - 2.37 (m, 2H), 2.37 - 2.16 (m, 7H), 2.16 - 2.07 (m, 3H), 1.95 (m, 2H), 1.88 (m, 2H), 1.74 (m, 1H), 1.48 - 1.33 (m, 1H), 1.29 (s, 1H), 1.14 (d, J = 6.4 Hz, 3H)。LCMS-ESI+:C38
H50
ClN4
O6
S計算值:725.3 (M+H);實驗值:724.5 (M+H)。實例 151
以與實 例 18
相同之方式使用1-環丙基-1H-吡唑-4-甲酸及實例 109
來合成實例 151
。LCMS-ESI+ (m/z):C39
H46
ClN5
O5
S [M+H]+計算值:732.3;實驗值:732.3。實例 152
以與實 例 18
相同之方式使用1-(氧雜環丁烷-3-基)-1H-吡唑-4-甲酸及實例 110
來合成實例 152
。1
H NMR (400 MHz,甲醇-d4
) δ 8.11 (s, 1H), 7.96 (s, 1H), 7.76 (d,J
= 8.4 Hz, 1H), 7.32 (dd,J
= 8.0, 2.0 Hz, 1H), 7.17 (dd,J
= 8.4, 2.4 Hz, 1H), 7.10 (d,J
= 2.4 Hz, 1H), 7.03 (d,J
= 2.0 Hz, 1H), 6.79 (d,J
= 8.0 Hz, 1H), 6.16 - 6.09 (m, 1H), 5.59 - 5.50 (m, 2H), 5.05 (d,J
= 6.8 Hz, 4H), 4.31 - 4.25 (m, 1H), 4.15 - 4.00 (m, 3H), 3.84 (d,J
= 14.8 Hz, 1H), 3.78 (d,J
= 8.4 Hz, 1H), 3.62 (d,J
= 14.4 Hz, 1H), 3.37 - 3.30 (m, 2H), 3.24 (s, 3H), 3.10 - 3.04 (m, 1H), 2.85 - 2.72 (m, 2H), 2.47 - 1.68 (m, 10H), 1.51 (d,J
= 6.8 Hz, 3H), 1.48 - 1.41 (m, 1H), 1.18 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C40
H48
ClN5
O6
S [M+H]+計算值:762.3;實驗值:762.1。實例 153
以與實 例 18
相同之方式使用1-乙基-1H-吡唑-4-甲酸而不使用3-甲氧基丙酸及實例 110
來合成實例 153
。1
H NMR (400 MHz,甲醇-d4
) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.72 (d,J
= 8.4 Hz, 1H), 7.38 (dd,J
= 8.0, 1.6 Hz, 1H), 7.16 (dd,J
= 8.6, 2.2 Hz, 1H), 7.11 (d,J
= 2.0 Hz, 2H), 6.77 (d,J
= 8.0 Hz, 1H), 6.15 - 6.08 (m, 1H), 5.57 (dd,J
= 15.6, 8.8 Hz, 1H), 4.18 (q,J
= 7.2 Hz, 2H), 4.12 (q,J
= 7.0 Hz, 2H), 4.07 - 4.00 (m, 2H), 3.78 - 3.75 (m, 2H), 3.60 (d,J
= 14.4 Hz, 1H), 3.39 - 3.33 (m, 2H), 3.25 (s, 3H), 3.16 - 3.09 (m, 1H), 2.86 - 2.73 (m, 2H), 2.50 - 1.71 (m, 10H), 1.52 - 1.44 (m, 7H), 1.21 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):H+C39
H48
ClN5
O5
S [M+H]+計算值:734.4;實驗值:734.2。實例 154
以與實 例 18
相同之方式使用3-甲氧基-1-甲基-1H-吡唑-4-甲酸及實例 109
來合成實例 154
。將實例 109
(620 mg,1.04 mmol)溶解於二氯甲烷(12 mL)中。添加3-甲氧基-1-甲基-1H-吡唑-4-甲酸(324 mg,2.08 mmol,2當量)及N
-(3-二甲基胺基丙基)-N
′-乙基碳化二亞胺鹽酸鹽(400 mg,2.08 mmol,2當量)。在一次性添加DMAP (253 mg,2.08 mmol,2當量)之前,將反應混合物在室溫下攪拌5分鐘。將反應混合物在室溫下攪拌過夜,且藉由LCMS監視反應進程。在完成之後,在減壓下濃縮反應混合物,且藉由Gilson逆相製備型HPLC (60-100% ACN/H2
O及0.1% TFA)純化殘餘物,得到實例 154
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.07 (s, 1H), 7.76 (d,J
= 8.6 Hz, 1H), 7.34 (d,J
= 8.2 Hz, 1H), 7.22 - 7.10 (m, 3H), 6.92 (d,J
= 8.2 Hz, 1H), 6.20 - 6.05 (m, 1H), 5.63 (dd,J
= 15.5, 8.0 Hz, 1H), 4.10 (d,J
= 12.0 Hz, 1H), 4.06 (s, 4H), 3.91 - 3.83 (m, 1H), 3.82 (s, 3H), 3.79 (s, 1H), 3.72 (d,J
= 14.4 Hz, 1H), 3.38 (d,J
= 14.5 Hz, 1H), 3.30 (s, 3H), 3.09 (dd,J
= 15.1, 10.0 Hz, 1H), 2.89 - 2.72 (m, 2H), 2.51 (d,J
= 26.7 Hz, 2H), 2.24 (dd,J
= 10.9, 6.0 Hz, 2H), 2.12 (d,J
= 13.7 Hz, 1H), 2.02 - 1.70 (m, 4H), 1.54 - 1.40 (m, 1H), 1.14 (d,J
= 6.1 Hz, 3H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O6
S計算值:735.28;實驗值:735.94。實例 155
以與實例 75
相同之方式使用實例 109
及(3R)-四氫呋喃-3-胺來合成實例 155
。1H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 6.9 Hz, 1H), 7.17 - 7.09 (m, 2H), 6.99 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.10 - 5.98 (m, 1H), 5.60 (dd, J = 15.4, 8.8 Hz, 1H), 4.35 - 4.23 (m, 2H), 4.10 - 4.01 (m, 2H), 3.96 - 3.75 (m, 6H), 3.72 - 3.62 (m, 3H), 3.28 (s, 3H), 3.08 (dd, J = 15.1, 10.2 Hz, 1H), 2.84 - 2.72 (m, 2H), 2.55 - 2.37 (m, 3H), 2.32 - 2.07 (m, 3H), 1.97 - 1.76 (m, 8H), 1.43 (t, J = 12.6 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S計算值H+,計算值:711.29;實驗值:710.79。實例 156
以與實例18
相同之方式使用實例109
而不使用實例5
且使用1-環丙基-1H-吡咯-3-甲酸而不使用3-甲氧基丙酸來合成實例156
。1H NMR (400 MHz,甲醇-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.62 (t, J = 2.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.18 (dd, J = 8.5, 2.3 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.95 - 6.84 (m, 2H), 6.61 (dd, J = 3.0, 1.8 Hz, 1H), 6.11 (dt, J = 14.5, 6.8 Hz, 1H), 5.61 (dd, J = 15.4, 8.6 Hz, 1H), 4.27 (dd, J = 14.8, 6.4 Hz, 1H), 4.14 - 3.94 (m, 3H), 3.87 (d, J = 15.1 Hz, 1H), 3.79 (d, J = 7.5 Hz, 1H), 3.70 (d, J = 14.2 Hz, 1H), 3.56 - 3.46 (m, 1H), 3.36 (s, 1H), 3.29 (s, 3H), 3.08 (dd, J = 15.0, 9.4 Hz, 2H), 2.89 - 2.71 (m, 2H), 2.60 - 2.35 (m, 3H), 2.32 - 2.06 (m, 3H), 1.94 (d, J = 11.6 Hz, 3H), 1.88 - 1.66 (m, 3H), 1.45 (t, J = 12.1 Hz, 1H), 1.13 (d, J = 6.7 Hz, 3H), 1.08 - 0.93 (m, 4H)。LCMS-ESI+ (m/z):C40
H47
ClN4
O5
S [M+H]+計算值:731.35;實驗值:729.83。實例 157
以與實例 18
類似之方式使用3,4-二氫-1H-2-苯并哌喃-7-甲酸及實例 109
來製備實例 157
。1
H NMR (400 MHz,乙腈-d3
) δ 7.87 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.96 (s, 1H), 6.93 (d, J = 8.1 Hz, 1H), 5.92 (dt, J = 14.2, 6.5 Hz, 1H), 5.55 (dd, J = 15.3, 8.9 Hz, 1H), 4.77 (s, 2H), 4.33 (dd, J = 15.3, 5.6 Hz, 1H), 4.05 (d, J = 2.2 Hz, 2H), 3.94 (t, J = 5.7 Hz, 2H), 3.84 - 3.64 (m, 3H), 3.26 (d, J = 14.3 Hz, 1H), 3.18 (s, 3H), 3.05 (dd, J = 15.3, 10.4 Hz, 1H), 2.89 (t, J = 5.7 Hz, 2H), 2.84 - 2.65 (m, 3H), 2.50 - 2.21 (m, 3H), 2.19 - 2.00 (m, 3H), 1.91 - 1.81 (m, 3H), 1.79 - 1.63 (m, 3H), 1.47 - 1.35 (m, 1H), 1.05 (d, J = 6.3 Hz, 3H)。LCMS-ESI+
(m/z):C42
H48
ClN3
O6
S [M+H]+
計算值:758.33;實驗值:758.0。實例 158
以與實例 18
類似之方式使用1,4,6,7-四氫哌喃并[4,3-b]吡咯-2-甲酸及實例 109
來製備實例 158
。1
H NMR (400 MHz,乙腈-d3
) δ 9.87 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.09 (s, 1H), 7.06 (d, J = 8.7 Hz, 1H), 7.01 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.78 (s, 1H), 5.98 (dt, J = 13.9, 6.5 Hz, 1H), 5.58 (dd, J = 15.4, 8.4 Hz, 1H), 4.56 (d, J = 2.7 Hz, 2H), 4.13 (dd, J = 15.0, 5.9 Hz, 1H), 4.00 (s, 2H), 3.87 (t, J = 5.6 Hz, 2H), 3.82 - 3.70 (m, 3H), 3.66 (d, J = 15.1 Hz, 1H), 3.32 (d, J = 14.6 Hz, 1H), 3.20 (s, 3H), 3.05 (dd, J = 15.3, 10.1 Hz, 1H), 2.84 - 2.65 (m, 3H), 2.52 (dd, J = 11.6, 5.3 Hz, 1H), 2.40 (dt, J = 16.5, 6.2 Hz, 2H), 2.27 - 2.08 (m, 3H), 2.07 - 1.98 (m, 1H), 1.91 - 1.81 (m, 3H), 1.81 - 1.62 (m, 3H), 1.37 (dt, J = 15.1, 7.8 Hz, 1H), 1.06 (d, J = 6.3 Hz, 3H)。LCMS-ESI+
(m/z):C40
H47
ClN4
O6
S [M+H]+
計算值:747.30;實驗值:747.0。實例 159
將實例 109
(11 mg,0.018 mmol)、(1S,2R)-2-甲基環丙烷-1-甲酸(0.014 mL,0.147 mmol)、二苯基磷醯基疊氮化物(0.032 mL,0.147 mmol)及三甲胺(0.028 mL,0.202 mmol)懸浮於MeCN (2 mL)中。將反應混合物加熱至50℃過夜,隨後冷卻至RT。添加i
-PrOAc (10 mL)及飽和NH4
Cl (8 mL),且將混合物攪拌10 min。分離各層,且將水相用i
-PrOAc萃取。將有機相組合且用水洗滌兩次,隨後經MgSO4
乾燥,過濾,且在減壓下濃縮。藉由二氧化矽管柱層析法(50% EtOAc/己烷至40% MeOH/EtOAc)純化粗殘餘物,獲得實例 159
(6 mg)。1H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 2H), 7.41 (s, 1H), 7.29 (s, 1H), 7.19 - 7.06 (m, 4H), 6.82 (d, J = 8.1 Hz, 2H), 6.17 (s, 2H), 5.56 (s, 2H), 4.08 - 3.95 (m, 3H), 3.86 - 3.77 (m, 4H), 3.69 (d, J = 32.3 Hz, 4H), 3.27 (s, 3H), 3.08 (d, J = 12.6 Hz, 1H), 2.77 (d, J = 21.0 Hz, 3H), 2.62 (s, 3H), 2.50 (td, J = 7.3, 4.1 Hz, 1H), 2.38 (s, 2H), 2.26 (s, 1H), 2.19 (s, 1H), 2.09 (d, J = 13.6 Hz, 2H), 1.93 (s, 5H), 1.78 - 1.70 (m, 2H), 1.41 (d, J = 13.7 Hz, 1H), 1.29 (s, 1H), 1.06 (dd, J = 18.0, 10.9 Hz, 14H), 0.89 (ddd, J = 15.2, 8.9, 4.2 Hz, 6H), 0.15 - 0.06 (m, 4H)。LCMS-ESI+:C37
H47
ClN4
O5
S計算值:695.3 (M+H);實驗值:695.2 (M+H)。實例 160
以與實例 364
相同之方式使用實例 109
及外消旋-(1S*,2S*)-2-甲氧基環丙烷-1-甲酸來合成呈非對映異構體混合物形式之實例 160
。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S [M+H]+
計算值:711.2978;實驗值:710.68。1
H NMR (400 MHz,甲醇-d 4
) δ 7.72 (dd,J
= 8.4, 2.3 Hz, 1H), 7.22 - 7.04 (m, 3H), 7.00 - 6.84 (m, 2H), 6.10 - 5.92 (m, 1H), 5.58 (dd,J
= 15.2, 8.9 Hz, 1H), 4.25 (d,J
= 15.3 Hz, 1H), 4.12 - 3.96 (m, 2H), 3.90 - 3.71 (m, 3H), 3.66 (d,J
= 14.3 Hz, 1H), 3.43 (d,J
= 1.8 Hz, 3H), 3.29 - 3.24 (m, 1H), 3.26 (s, 3H), 3.06 (dd,J
= 15.2, 10.2 Hz, 1H), 2.88 - 2.69 (m, 2H), 2.62 (s, 1H), 2.55 - 2.28 (m, 3H), 2.26 - 2.04 (m, 3H), 2.01 - 1.67 (m, 7H), 1.41 (t,J
= 12.8 Hz, 1H), 1.12 (d,J
= 6.5 Hz, 3H), 1.06 - 0.97 (m, 1H), 0.86 - 0.76 (m, 1H)。實例 161
以與實例 364
相同之方式使用實例 109
及(1R)-2,2-二氟環丙烷甲酸來合成實例 161
。LCMS-ESI+ (m/z):C36
H43
ClF2
N4
O5
S [M+H]+
計算值:717.2684;實驗值:716.58。1
H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.20 - 7.07 (m, 3H), 7.00 - 6.86 (m, 2H), 5.98 (dd, J = 14.7, 7.7 Hz, 1H), 5.58 (dd, J = 15.2, 9.0 Hz, 1H), 4.30 (dd, J = 15.1, 6.2 Hz, 1H), 4.16 - 3.98 (m, 2H), 3.92 - 3.59 (m, 4H), 3.29 - 3.24 (m, 1H), 3.25 (s, 3H), 3.06 (dd, J = 15.3, 10.3 Hz, 1H), 2.89 - 2.64 (m, 2H), 2.56 - 2.25 (m, 3H), 2.26 - 2.05 (m, 3H), 2.00 - 1.66 (m, 6H), 1.52 - 1.34 (m, 2H), 1.12 (d, J = 6.4 Hz, 3H)。實例 162
以與實例 159
類似之方式使用(1R,2S)-2-甲基環丙烷-1-甲酸(0.014 mL,0.147 mmol)、二苯基磷醯基疊氮化物、三乙胺及實例 109
來製備實例 162
。LCMS-ESI+:C37
H47
ClN4
O5
S計算值:695.3 (M+H);實驗值:695.2 (M+H)。實例 163
以與實例 18
類似之方式使用吡咯并[1,2-c]嘧啶-6-甲酸及實例 109
來製備實例 163
。1
H NMR (400 MHz,乙腈-d3
) δ 8.97 (s, 1H), 8.12 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 6.6 Hz, 1H), 7.36 (d, J = 6.5 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.6 Hz, 1H), 7.12 (s, 1H), 7.00 (d, J = 1.8 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.85 (s, 1H), 6.03 - 5.90 (m, 1H), 5.57 (dd, J = 15.3, 8.6 Hz, 1H), 4.26 (d, J = 15.1 Hz, 1H), 4.04 (s, 2H), 3.79 (d, J = 15.2 Hz, 2H), 3.74 - 3.64 (m, 2H), 3.30 (d, J = 14.3 Hz, 1H), 3.19 (s, 3H), 3.06 (dd, J = 15.3, 10.4 Hz, 2H), 2.85 - 2.66 (m, 3H), 2.52 - 2.27 (m, 4H), 2.22 - 2.13 (m, 2H), 2.05 (d, J = 13.9 Hz, 1H), 1.83 - 1.64 (m, 3H), 1.39 (dt, J = 14.5, 7.4 Hz, 1H), 1.09 (d, J = 6.1 Hz, 2H)。LCMS-ESI+
(m/z):C40
H44
ClN5
O5
S [M+H]+
計算值:742.28;實驗值:742.0。實例 164
以與實例 18
相同之方式使用3-環丙基-1-甲基-1H-吡唑-4-甲酸及實例 109
來合成實例 164
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.28 (s, 1H), 7.65 (d,J
= 8.5 Hz, 1H), 7.28 (d,J
= 8.1 Hz, 1H), 7.07 (d,J
= 2.2 Hz, 1H), 6.99 (d,J
= 1.9 Hz, 1H), 6.86 (d,J
= 8.3 Hz, 1H), 6.19 - 6.05 (m, 1H), 5.66 (dd,J
= 15.3, 8.7 Hz, 1H), 4.25 (s, 1H), 4.02 (s, 2H), 3.82 (s, 5H), 3.65 (d,J
= 14.3 Hz, 1H), 3.39 (d,J
= 14.5 Hz, 1H), 3.31 (s, 3H), 3.18 - 3.03 (m, 1H), 2.90 - 2.62 (m, 3H), 2.52 (d,J
= 39.0 Hz, 3H), 2.28 (d,J
= 10.7 Hz, 2H), 2.16 - 2.04 (m, 2H), 1.96 (m, 4H), 1.83 (s, 3H), 1.40 (t,J
= 12.5 Hz, 1H), 1.18 (d,J
= 6.2 Hz, 3H), 1.01 - 0.79 (m, 5H)。LCMS-ESI+ (m/z):C40
H48
ClN5
O5
S [M+H]+計算值:746.3;實驗值:746.0。實例 165
以與實例 18
相同之方式使用實例 109
及順-3-羥基-3-甲基-環丁烷甲酸來合成實例 165
。1H NMR (400 MHz,甲醇-d4) δ 7.72 (d, J = 9.1 Hz, 1H), 7.31 (dd, J = 8.2, 1.8 Hz, 1H), 7.09 (dt, J = 7.5, 2.0 Hz, 3H), 6.86 (d, J = 8.3 Hz, 1H), 6.14 (dt, J = 14.6, 7.0 Hz, 1H), 5.63 (dd, J = 15.4, 8.4 Hz, 1H), 4.14 (dd, J = 14.8, 7.0 Hz, 1H), 4.08 - 3.93 (m, 3H), 3.87 - 3.74 (m, 2H), 3.67 (d, J = 14.3 Hz, 1H), 3.30 (s, 3H), 3.11 - 3.02 (m, 1H), 2.92 - 2.70 (m, 3H), 2.58 - 2.23 (m, 8H), 2.15 - 2.05 (m, 2H), 2.04 - 1.72 (m, 7H), 1.38 (s, 4H), 1.14 (d, J = 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C38
H48
ClN3
O6
S計算值H+:710.30;實驗值:710.05。實例 166
以與實例 18
相同之方式使用實例 110
及順-3-羥基-3-甲基-環丁烷甲酸來合成實例 166
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.25 - 7.15 (m, 2H), 7.12 (d, J = 2.3 Hz, 1H), 7.10 - 7.02 (m, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.03 - 5.92 (m, 1H), 5.61 (dd, J = 15.3, 8.7 Hz, 1H), 4.38 - 4.27 (m, 1H), 4.13 - 4.03 (m, 2H), 3.83 (d, J = 15.1 Hz, 1H), 3.77 - 3.71 (m, 1H), 3.68 (d, J = 14.3 Hz, 1H), 3.25 (s, 3H), 3.18 - 3.08 (m, 1H), 2.90 - 2.71 (m, 3H), 2.50 - 2.20 (m, 9H), 2.16 - 2.07 (m, 1H), 2.01 - 1.72 (m, 7H), 1.55 (d, J = 7.1 Hz, 3H), 1.52 - 1.41 (m, 1H), 1.38 (s, 3H), 1.14 - 1.05 (m, 3H)。LCMS-ESI+ (m/z):C39
H50
ClN3
O6
S計算值H+:724.31;實驗值:723.99。實例 167
步驟1:將於乙腈(6.0 mL)及甲醇(2.0 mL)中之5-甲醯基-1H-吡咯-3-甲酸甲酯(500 mg,3.27 mmol)、(S
)-2-甲基環氧乙烷(458 µL,6.53 mmol)及碳酸銫(2.13 g,6.53 mmol)之經劇烈攪拌混合物加熱至60℃。在45 min之後,使反應混合物冷卻至室溫,且添加乙酸乙酯(60 mL)。將有機層用水及鹽水之混合物(1:1 v:v,40 mL)洗滌,經無水硫酸鈉乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至70%於己烷中之乙酸乙酯)純化殘餘物,得到167-1
。
步驟2:在室0℃下經由注射器將三氟乙酸(163 µL,2.13 mmol)添加至於二氯甲烷(40 mL)中之167-1
(150 mg,0.710 mmol)之經攪拌溶液中。在2 min之後,經由注射器添加三乙基矽烷(343 µL,2.15 mmol),且將所得混合物升溫至室溫。在45 min之後,經由注射器添加三乙胺(1.0 mL),且在減壓下濃縮所得混合物。藉由矽膠急驟管柱層析法(0至40%於己烷中之乙酸乙酯)純化殘餘物,得到167-2
。
步驟3:在室溫下經由注射器將氫氧化鈉水溶液(2.0 M,800 µL,1.6 mmol)添加至於四氫呋喃(1.0 mL)及甲醇(3.0 mL)中之167-2
(53.6 mg,0.275 mmol)之經攪拌溶液中,且將所得混合物加熱至60℃。在3 h之後,使所得混合物冷卻至室溫,且依序添加氯化氫水溶液(2.0 M,1.0 mL)及乙酸乙酯(30 mL)。將有機層用鹽水洗滌,經無水硫酸鈉乾燥,過濾,且在減壓下濃縮,得到167-3
。
步驟4:製備實例 167
:以與實例 109
類似之方式使用167-3
而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸來合成實例 167
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.4 Hz, 1H), 7.45 - 7.21 (m, 4H), 7.13 (d, J = 2.3 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.32 - 5.99 (m, 2H), 5.70 - 5.58 (m, 1H), 4.89 (d, J = 14.4 Hz, 1H), 4.71 (d, J = 14.3 Hz, 1H), 4.23 - 3.59 (m, 9H), 3.43 (d, J = 14.3 Hz, 1H), 3.24 (s, 3H), 3.21 - 3.10 (m, 1H), 2.85 - 1.17 (m, 19H), 1.12 (d, J = 6.8 Hz, 3H)。LCMS: 761.0。實例 168
以與實例 167
類似之方式使用步驟1中之(R)-2-甲基環氧乙烷而不使用(S)-2-甲基環氧乙烷來合成實例 168
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 7.3 Hz, 2H), 7.24 (d, J = 7.4 Hz, 2H), 7.14 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.27 (s, 1H), 6.24 - 6.11 (m, 1H), 5.59 (dd, J = 15.4, 7.9 Hz, 1H), 4.89 (d, J = 14.4 Hz, 1H), 4.71 (d, J = 14.4 Hz, 1H), 4.17 - 3.59 (m, 9H), 3.42 (d, J = 14.4 Hz, 1H), 3.24 (s, 3H), 3.13 (dd, J = 15.2, 10.4 Hz, 1H), 2.84 - 1.15 (m, 19H), 1.12 (d, J = 6.8 Hz, 3H)。LCMS: 761.0。實例 169
製備3-甲氧基-3-甲基-環丁烷甲酸:將3-羥基-3-甲基-環丁烷甲酸(116 mg,0.891 mmol)溶解於DMF (2.0 mL)中,將所得溶液冷卻至0℃。向此經攪拌混合物中添加於礦物油(61.4 mg,1.47 mmol)中之55%氫化鈉分散液。在添加MeI (758 mg,5.37 mmol)之前,將新形成之混合物在0℃下攪拌30 min。隨後,將反應物自冷卻浴中移除且在室溫下攪拌過夜。將反應物用冰驟冷,分配於EtOAc (15.0 mL)與水(5.0 mL)之間。將有機層用鹽水(5.0 mL)洗滌,經硫酸鈉乾燥,過濾,且濃縮成粗產物。隨後,將粗產物溶解於MeOH (2.0 mL)及THF (2.0 mL)之混合物中,且用1 N NaOH (4.45 mL,4.45 mmol)處理。將所得混合物在50℃下加熱1 hr。濃縮反應物。將所得殘餘物用EtOAc (20.0 mL)稀釋,用1N HCl (5.0 mL)酸化,且將有機層用鹽水(2×5.0 mL)洗滌,經硫酸鈉乾燥,過濾,且濃縮,得到標題化合物。1H NMR (400 MHz,氘代氯仿) δ 3.21 (s, 3H), 2.83 - 2.69 (m, 1H), 2.49 - 2.41 (m, 2H), 2.23 - 2.14 (m, 2H), 1.37 (s, 3H)。
以與實例 18
類似之方式使用實例 109
及3-甲氧基-3-甲基-環丁烷甲酸來合成實例 169
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.31 (dd, J = 8.3, 1.8 Hz, 1H), 7.18 - 7.13 (m, 1H), 7.10 (dd, J = 9.2, 2.1 Hz, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.14 (dt, J = 14.4, 7.0 Hz, 1H), 5.62 (dd, J = 15.4, 8.5 Hz, 1H), 4.16 (dd, J = 14.8, 6.8 Hz, 1H), 4.10 - 3.92 (m, 3H), 3.84 (d, J = 15.0 Hz, 1H), 3.77 (d, J = 8.0 Hz, 1H), 3.68 (d, J = 14.2 Hz, 1H), 3.30 (s, 3H), 3.21 (s, 3H), 3.12 - 3.01 (m, 1H), 2.96 - 2.70 (m, 3H), 2.54 - 2.24 (m, 6H), 2.22 - 2.05 (m, 4H), 2.00 - 1.72 (m, 7H), 1.39 (s, 4H), 1.14 (d, J = 6.9 Hz, 3H)。C39
H50
ClN3
O6
S [M+H]+計算值:724.35;實驗值:724.09。實例 170
將PtO2
(1.33 mg)懸浮於於EtOH (5.0 mL)中之實例 144
(20 mg)之溶液中,由玻璃移液管之尖端添加一滴TFA。使氛圍經氫氣(氣球)更換。將混合物攪拌3小時。使反應物脫氣且用氮氣沖洗,經由Nalgene PTFE濾片過濾,且濃縮。隨後,將所得殘餘物溶解於DMF (1.2 mL)中,過濾且藉由Gilson逆相製備型HPLC純化。將所需溶離份組合且濃縮,用ACN/H2
O混合物再處理,且冷凍乾燥,得到實例 170
(6.30 mg)。1H NMR (400 MHz,甲醇-d4) δ 7.77 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.21 - 7.09 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 4.15 - 4.02 (m, 3H), 3.88 - 3.80 (m, 1H), 3.68 (d, J = 14.2 Hz, 1H), 3.40 - 3.34 (m, 5H), 3.16 - 3.07 (m, 1H), 2.88 - 2.72 (m, 2H), 2.68 - 2.57 (m, 2H), 2.46 - 2.34 (m, 1H), 2.15 - 1.86 (m, 5H), 1.81 - 1.61 (m, 4H), 1.60 - 1.29 (m, 7H), 1.12 (d, J = 6.7 Hz, 3H), 0.75 (d, J = 7.1 Hz, 2H), 0.60 - 0.49 (m, 2H)。C36
H47
ClN4
O5
S [M+H]+計算值:683.30;實驗值:682.85。實例 171
以與實例 75
相同之方式使用實例 109
及[外消旋-(1R*,2R*)-2-胺基環丙基]甲醇來合成呈非對映異構體混合物形式之實例 171
。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S [M+H]+
計算值:711.2978;實驗值:710.93。1
H NMR (400 MHz,甲醇-d4) δ 7.72 (d, J = 8.5 Hz, 1H), 7.24 - 7.04 (m, 3H), 6.97 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.01 (dd, J = 14.9, 7.5 Hz, 1H), 5.58 (dd, J = 15.3, 8.9 Hz, 1H), 4.24 (dd, J = 14.9, 6.5 Hz, 1H), 4.12 - 3.97 (m, 2H), 3.89 - 3.71 (m, 3H), 3.71 - 3.60 (m, 1H), 3.51 - 3.40 (m, 2H), 3.29 - 3.24 (m, 1H), 3.26 (s, 3H), 3.05 (dd, J = 15.2, 10.2 Hz, 1H), 2.88 - 2.67 (m, 2H), 2.56 - 2.30 (m, 4H), 2.26 - 2.05 (m, 3H), 2.00 - 1.67 (m, 6H), 1.42 (t, J = 12.3 Hz, 1H), 1.24 - 1.16 (m, 1H), 1.12 (d, J = 6.5 Hz, 3H), 0.83 - 0.65 (m, 2H)。實例 172
以與實例 75
相同之方式使用實例 109
及反-3-胺基-1-甲基環丁-1-醇HCl鹽以及DIEA來合成實例 172
。1H NMR (400 MHz,甲醇-d4) δ 7.67 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.08 (s, 1H), 7.04 - 6.95 (m, 2H), 6.87 (d, J = 8.1 Hz, 1H), 6.12 - 6.01 (m, 1H), 5.71 - 5.58 (m, 1H), 4.40 - 4.28 (m, 1H), 4.27 - 4.15 (m, 1H), 4.05 - 3.99 (m, 2H), 3.85 - 3.76 (m, 3H), 3.65 (d, J = 14.3 Hz, 1H), 3.30 (s, 3H), 3.13 - 3.03 (m, 1H), 2.89 - 2.70 (m, 2H), 2.63 - 2.36 (m, 5H), 2.33 - 1.74 (m, 13H), 1.45 - 1.35 (m, 4H), 1.15 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C38
H49
ClN4
O6
S計算值H+:725.31;實驗值:724.80。實例 173
以與實例 18
類似之方式使用3-胺基-1-甲基-1H-吡唑-4-甲酸及實例 109
來製備實例 173
。1
H NMR (400 MHz,乙腈-d3
) δ 8.01 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7.03 (s, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 6.04 - 5.88 (m, 1H), 5.59 (dd, J = 15.3, 8.8 Hz, 1H), 4.23 (dd, J = 19.5, 8.9 Hz, 1H), 4.00 (s, 2H), 3.80 - 3.71 (m, 2H), 3.70 (s, 3H), 3.63 (s, 2H), 3.32 (d, J = 14.2 Hz, 1H), 3.20 (s, 3H), 3.06 (dd, J = 15.3, 10.5 Hz, 1H), 2.88 - 2.64 (m, 3H), 2.59 - 2.33 (m, 3H), 2.18 (d, J = 10.6 Hz, 2H), 2.03 (d, J = 13.9 Hz, 2H), 1.91 (d, J = 4.1 Hz, 1H), 1.84 - 1.65 (m, 3H), 1.38 (t, J = 7.3 Hz, 1H), 1.08 (d, J = 6.1 Hz, 3H)。LCMS-ESI+
(m/z):C37
H45
ClN6
O5
S [M+H]+
計算值:721.29;實驗值:721.0。實例 174
步驟1:製備174-1
:向於DCM (12 mL)中之3,4-二氫-1H-吡咯并[2,1-c][1,4]噁嗪-7-甲酸(1.1 g,6.9 mmol)之溶液中逐滴添加草醯氯(1.3 g,10.41 mmol),且隨後逐滴添加DMF (0.5 mL)。將混合物之溫度維持在0℃下。在完成添加之後,在相同溫度下繼續攪拌60 min。隨後,在減壓下蒸發溶劑。將所得殘餘物溶解於於DCM (5 mL)中之2-甲基丙-2-醇(1.5 g,20.8 mmol)之溶液中,且隨後在室溫下攪拌30 min。在反應完成之後,將溶劑在減壓下移除且藉由正相層析法(矽膠管柱,0-100% EtOAc/己烷)純化,得到174-1
。
步驟2:製備174-2
:在0℃下向於ACN (10 mL)中之174-1
(0.4 g,1.79 mmol)中添加選擇氟(0.63 g,1.79 mmol)。將反應混合物在0℃下攪拌2 h。添加飽和NaHCO3
水溶液,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,在減壓下移除溶劑,且藉由正相層析法(矽膠管柱,0-100% EtOAc/己烷)純化殘餘物,得到174-2
。
步驟3:製備174-3
:向於DMC (4 mL)中之174-2
(40 mg,0.16 mmol)中添加TFA (2 mL)且在rt下攪拌1 h。將反應混合物蒸發且用作用於下一步驟之粗製物。
步驟4:合成實例 174
:向於DCM (5 mL)中之174-3
(4.6 mg,0.025 mmol)之經攪拌溶液中添加1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (5.1 mg,0.033 mmol)及4-(二甲基胺基)吡啶(4 mg,0.033 mmol)。將反應混合物在室溫下攪拌10分鐘,且隨後添加實例 109
(10 mg,0.017 mmol)。將反應混合物在室溫下攪拌4 hr。隨後,將反應混合物用DCM稀釋,用1 N HCl及鹽水洗滌。使有機相經MgSO4
乾燥,過濾,且濃縮,得到實例 174
。1H NMR (400 MHz,氘代氯仿) δ 7.76 (d,J
= 8.5 Hz, 1H), 7.39 (d,J
= 8.5 Hz, 2H), 7.24 -7.14 (m, 2H), 7.08 (s, 1H), 6.95 (d,J
= 8.3 Hz, 1H), 6.19 (d,J
= 3.9 Hz, 1H), 6.06 - 5.89 (m, 1H), 5.61 (dd,J
= 15.5, 7.6 Hz, 1H), 4.74 (s, 1H), 4.17 - 3.99 (m, 3H), 3.98 - 3.68 (m, 5H), 3.29 (s, 1H),3.01 (dd,J
= 15.1, 10.2 Hz, 2H), 2.79 (d,J
= 15.2 Hz, 2H), 2.59 - 2.25 (m, 3H), 2.19 - 1.59 (m, 9H), 1.41 (t,J
= 12.5 Hz, 1H), 1.28 (s, 1H), 1.13 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C40
H46
ClFN4
O6
S [M+H]+計算值:765.27;實驗值:765.25。實例 175
步驟1:將7-側氧基-5,6,7,8-四氫吲哚嗪-2-甲酸甲酯(50 mg,0.26 mmol)溶解於MeOH (2.6 mL)中,且將反應混合物冷卻至0℃。一次性添加呈固體形式之硼氫化鈉(過量)。藉由TLC監視反應。在完成之後,在減壓下濃縮反應混合物,且經由矽膠層析法純化殘餘物,獲得7-羥基-5,6,7,8-四氫吲哚嗪-2-甲酸甲酯。
步驟2:將7-羥基-5,6,7,8-四氫吲哚嗪-2-甲酸甲酯(20 mg,0.1 mmol)溶解於DMF中,且一次性添加氫化鈉(60%油分散液,10 mg)。在經由移液管添加碘甲烷(過量)之前,將反應混合物攪拌5 min。藉由TLC監視反應進程。在完成之後,將反應混合物用EtOAc稀釋。將有機層用飽和NH4
Cl (1×)洗滌,繼而用鹽水(2×)洗滌。將有機層經硫酸鈉乾燥,過濾,且在減壓下濃縮。粗殘餘物不經進一步純化即用於下一步驟中。
步驟3:將7-甲氧基-5,6,7,8-四氫吲哚嗪-2-甲酸甲酯溶解於二噁烷/1 N NaOH之1:1混合物中。將反應混合物加熱至80℃達1小時,之後使其冷卻至室溫。將反應混合物用1 N HCl洗滌且用EtOAc稀釋。將有機層分離,經硫酸鈉乾燥,過濾,且在減壓下濃縮。殘餘物不經進一步純化即用於下一步驟中。
步驟4:以與實例 18
相同之方式使用7-甲氧基-5,6,7,8-四氫吲哚嗪-2-甲酸及實例 109
來合成實例 175
。1
H NMR (400 MHz,氘代氯仿) δ 7.73 (d,J
= 8.5 Hz, 1H), 7.37 (d,J
= 8.6 Hz, 1H), 7.31 (t,J
= 1.8 Hz, 1H), 7.17 (d,J
= 10.9 Hz, 2H), 7.08 (d,J
= 2.3 Hz, 1H), 6.93 (d,J
= 8.2 Hz, 1H), 6.36 (s, 1H), 5.98 (dt,J
= 14.1, 6.4 Hz, 1H), 5.59 (dd,J
= 15.5, 7.6 Hz, 1H), 4.21 - 3.91 (m, 6H), 3.92 - 3.71 (m, 4H), 3.41 (s, 3H), 3.29 (m, 4H), 3.05 - 2.68 (m, 5H), 2.56 - 2.26 (m, 5H), 2.13 (m, 4H), 2.01 - 1.79 (m, 3H), 1.80 - 1.61 (m, 3H), 1.39 (t,J
= 12.8 Hz, 1H), 1.09 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C42
H51
ClN4
O6
S [M+H]+計算值:775;實驗值:774.9。實例 176
以與實例 18
相同之方式使用實例 109
及1-環丁基-1H-吡唑-4-甲酸來合成實例 176
。1
H NMR (400 MHz,甲醇-d4) δ 8.21 (s, 1H), 7.97 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.1, 1.7 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 1.8 Hz, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.18 (dt, J = 13.9, 6.4 Hz, 1H), 5.49 (dd, J = 15.2, 9.3 Hz, 1H), 4.84 (, J = 8.3 Hz, 1H), 4.48 (dd, J = 14.0, 6.5 Hz, 1H), 4.09 - 3.99 (m, 2H), 3.99 - 3.87 (m, 2H), 3.82 (dd, J = 9.4, 3.5 Hz, 1H), 3.66 (d, J = 14.1 Hz, 1H), 3.29 - 3.22 (m, 4H), 3.02 (dd, J = 15.1, 10.0 Hz, 1H), 2.88 - 2.69 (m, 2H), 2.67 - 2.45 (m, 5H), 2.39 (m, 1H), 2.13 (d, J = 13.8 Hz, 1H), 2.09 - 2.00 (m, 2H), 2.00 - 1.85 (m, 5H), 1.85 - 1.64 (m, 3H), 1.43 (t, J = 12.4 Hz, 1H), 1.04 (d, J = 6.0 Hz, 3H)。LCMS-ESI+:C40
H49
ClN5
O5
S計算值:746.31 (M+H);實驗值:746.17 (M+H)。實例 177
步驟1:將於乙腈(20.0 mL)中之5-甲醯基-1H-吡咯-3-甲酸甲酯(1.50 g,9.80 mmol)、溴化乙烯(10.0 mL,188 mmol)及碳酸鉀(1.62 g,11.8 mmol)之經劇烈攪拌混合物加熱至80℃。在60 min之後,使反應混合物冷卻至室溫,且添加乙酸乙酯(60 mL)。將有機層用水及鹽水之混合物(1:1 v:v,40 mL)洗滌,經無水硫酸鈉乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至35%於己烷中之乙酸乙酯)純化殘餘物,得到177-1
。
步驟2:將於二甲亞碸(3.0 mL)中之177-1
(600 mg,2.31 mmol)及疊氮化鈉(240 mg,3.69 mmol)之經劇烈攪拌混合物加熱至85℃。在45 min之後,使所得混合物冷卻至室溫,且添加二乙醚(120 mL)。將有機層用水(3×100 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於四氫呋喃(20 mL)中且在室溫下攪拌。經由注射器添加三甲基膦溶液(於四氫呋喃中1.0 M,3.46 mL,3.5 mmol)。在39 min之後,使所得混合物冷卻至0℃。依序添加硼氫化鈉(349 mg,9.23 mmol)及乙醇(20 mL),且使所得混合物升溫至室溫。在20 min之後,添加二乙醚(100 mL)。用水及鹽水之混合物(1:1 v:v,2×100 mL)萃取有機層。在室溫下將四氫呋喃(80 mL)及二碳酸二第三丁酯(1.51 g,6.92 mmol)依序添加至經劇烈攪拌之合併水層中。在60 min之後,用二氯甲烷(4×150 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至50%於己烷中之乙酸乙酯)純化殘餘物,得到177-2
。
步驟3:在室溫下經由注射器將氫氧化鈉水溶液(2.0 M,1.47 mL,2.9 mmol)添加至於甲醇(2.5 mL)及四氫呋喃(3.0 mL)中之177-2
(514 mg,1.83 mmol)之經攪拌溶液中,且將所得混合物加熱至70℃。在2 h之後,使所得混合物冷卻至室溫,且依序添加氯化氫水溶液(2.0 M,5 mL)、鹽水(30 mL)及水(10 mL)。用二氯甲烷(2×60 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於苯(30 mL)中,且在減壓下濃縮所得混合物。在室溫下將殘餘物溶解於二氯甲烷(6 mL)中,經由注射器添加2,6-二甲基吡啶(854 µL,7.33 mmol),且攪拌所得混合物。經由注射器添加三氟甲烷磺酸三甲基矽烷酯(995 µL,5.50 mmol)。在10 min之後,經由注射器添加甲醇(10.0 mL)。在10 min之後,在減壓下濃縮所得混合物,且將殘餘物溶解於苯(10 mL)中。在減壓下濃縮所得混合物,得到177-3
。
步驟4:在室溫下經由注射器將氯甲酸甲酯(50.5 µL,791 µmol)添加至於二氯甲烷中之177-3
(50.0 mg,158 µmol)及三乙胺(353 µL,2.53 mmol)之經攪拌混合物中。在10 min之後,添加三氟乙酸(0.2 mL),且藉由矽膠急驟管柱層析法(0至8%於二氯甲烷中之甲醇)純化所得混合物,得到177-4
。
步驟5:製備實例 177
:以與實例 109
類似之方式使用177-4
而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸來合成實例 177
。1H NMR (400 MHz,丙酮-d6) δ 7.77 (d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.29 - 7.19 (m, 2H), 7.14 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.43 (s, 1H), 6.21 - 6.07 (m, 1H), 5.64 (dd, J = 15.5, 7.9 Hz, 1H), 4.66 (s, 2H), 4.17 (s, 2H), 4.11 (d, J = 12.0 Hz, 1H), 4.04 (d, J = 12.1 Hz, 1H), 4.01 - 3.65 (m, 6H), 3.72 (s, 3H), 3.44 (d, J = 14.4 Hz, 1H), 3.25 (s, 3H), 3.15 (dd, J = 15.2, 10.2 Hz, 1H), 2.89 - 1.21 (m, 16H), 1.14 (d, J = 6.4 Hz, 3H)。LCMS: 804.0。實例 178
以與實例 18
相同之方式使用實例 109
及3-(1-羥基-1-甲基-乙基)環丁烷甲酸來合成實例 178
。1H NMR (400 MHz,甲醇-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 8.2, 1.8 Hz, 1H), 7.22 - 7.15 (m, 1H), 7.14 - 7.07 (m, 2H), 6.88 (d, J = 8.2 Hz, 1H), 6.14 (dt, J = 14.5, 6.9 Hz, 1H), 5.61 (dd, J = 15.3, 8.5 Hz, 1H), 4.17 (dd, J = 14.7, 6.7 Hz, 1H), 4.11 - 4.01 (m, 2H), 3.98 (dd, J = 14.9, 5.2 Hz, 1H), 3.85 (d, J = 15.0 Hz, 1H), 3.77 (d, J = 8.9 Hz, 1H), 3.69 (d, J = 14.3 Hz, 1H), 3.29 (s, 3H), 3.11 - 3.00 (m, 2H), 2.89 - 2.75 (m, 2H), 2.51 - 2.40 (m, 3H), 2.36 - 2.23 (m, 4H), 2.18 - 2.06 (m, 4H), 2.01 - 1.72 (m, 7H), 1.49 - 1.40 (m, 1H), 1.14 - 1.09 (m, 9H)。LCMS-ESI+ (m/z):C40
H52
ClN3
O6
S計算值H+:738.33;實驗值:738.03。實例 179
以與實例 75
相同之方式使用實例 109
及反-2-甲氧基環丁胺HCl鹽以及DIEA來合成實例 179
。1H NMR (400 MHz,甲醇-d4) δ 7.77 - 7.67 (m, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.17 - 7.07 (m, 2H), 6.99 (s, 1H), 6.90 (dd, J = 8.1, 3.6 Hz, 1H), 6.11 - 5.99 (m, 1H), 5.60 (t, J = 12.5 Hz, 1H), 4.31 - 4.21 (m, 1H), 4.09 - 4.01 (m, 3H), 3.88 - 3.64 (m, 6H), 3.28 (s, 3H), 3.08 (dd, J = 15.2, 10.1 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.56 - 2.33 (m, 3H), 2.25 - 2.02 (m, 6H), 2.02 - 1.71 (m, 7H), 1.59 - 1.36 (m, 4H), 1.13 (d, J = 6.5 Hz, 3H)。LCMS-ESI+ (m/z):C38
H49
ClN4
O6
S計算值H+:725.31;實驗值:724.85。實例 180
步驟1:在室溫下經由注射器將乙酸酐(74.7 µL,791 µmol)添加至於二氯甲烷中之177-3
(50.0 mg,158 µmol)及三乙胺(353 µL,2.53 mmol)之經攪拌混合物中。在10 min之後,在減壓下濃縮所得混合物。藉由逆相製備型hplc (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到180-1
。
步驟2:以與實例 109
類似之方式使用180-1
而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸來合成實例 180
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.34 (d, J = 8.3 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.14 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 6.19 - 6.06 (m, 1H), 5.64 (dd, J = 15.4, 7.9 Hz, 1H), 4.80 (s, 0.92H), 4.69 (s, 1.08H), 4.34 - 3.60 (m, 10H), 3.44 (d, J = 14.5 Hz, 1H), 3.25 (s, 3H), 3.15 (dd, J = 15.1, 10.2 Hz, 1H), 2.90 - 1.23 (m, 19H), 1.18 - 1.09 (m, 3H)。LCMS: 788.0。實例 181
以與實例 75
相同之方式使用實例 109
及(1R,2S)-2-四氫哌喃-4-基環丙胺HCl鹽以及DIEA來合成實例 181
。1H NMR (400 MHz,甲醇-d4) δ 7.75 - 7.67 (m, 1H), 7.26 - 7.16 (m, 1H), 7.13 - 7.05 (m, 2H), 6.99 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.12 - 6.00 (m, 1H), 5.62 (dd, J = 15.3, 8.9 Hz, 1H), 4.30 - 4.19 (m, 1H), 4.10 - 4.00 (m, 2H), 4.00 - 3.91 (m, 2H), 3.83 (d, J = 14.8 Hz, 1H), 3.78 (dd, J = 8.9, 3.4 Hz, 1H), 3.67 (d, J = 14.2 Hz, 1H), 3.44 - 3.37 (m, 1H), 3.29 (s, 3H), 3.12 - 3.03 (m, 1H), 2.88 - 2.73 (m, 2H), 2.57 - 2.37 (m, 4H), 2.28 - 2.07 (m, 3H), 2.01 - 1.72 (m, 8H), 1.71 - 1.62 (m, 1H), 1.57 - 1.36 (m, 4H), 1.14 (d, J = 6.6 Hz, 3H), 1.03 - 0.90 (m, 2H), 0.86 - 0.75 (m, 1H), 0.75 - 0.62 (m, 2H)。LCMS-ESI+ (m/z):C41
H53
ClN4
O6
S計算值H+:765.34;實驗值:764.86。實例 182
步驟1:製備((1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙基)胺基甲酸外消旋-第三丁酯:將於甲苯(1.0 mL)中之反-外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙烷-1-甲酸(70 mg,0.42 mmol)、二苯基磷醯基疊氮化物(0.095 mL,0.44 mmol)及三乙胺(0.065 mL,0.46 mmol)之反應混合物在100℃下加熱2 h。隨後,將反應混合物冷卻至rt,且向混合物中添加第三丁醇(0.2 mL,2 mmol)。將混合物在rt下攪拌過夜。濃縮反應混合物,且藉由矽膠管柱層析法(0-100% EtOAc/己烷)純化殘餘物,得到產物(25 mg)。
步驟2:製備外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙烷-1-胺:在rt下攪拌於DCM (2.0 mL)及TFA (0.5 mL)中之((1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙基)胺基甲酸外消旋-第三丁酯(85 mg,0.36 mmol)之反應混合物。在反應結束之後,濃縮反應混合物,且殘餘物不經純化即用於下一步驟中。
步驟3:製備實例182
:將於ACN (1.5 mL)中之實例 109
(16 mg,0.027 mmol)、碳酸二苯酯(36 mg,0.168 mmol)及4-二甲基胺基吡啶(13.07 mg,0.107 mol)之反應混合物在rt下攪拌7 h。向混合物中添加三乙胺(0.19 mL,1.34 mmol)及外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙-1-胺(36.7 mg,0.27 mmol)。將反應混合物在45℃下攪拌過夜。濃縮反應混合物,藉由逆相HPLC (60-100% CAN/H2O,及0.1% TFA)純化殘餘物,得到產物(10 mg)。1H NMR (400 MHz,甲醇-d4) δ 7.69 (t, J = 8.8 Hz, 1H), 7.37 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 7.10 (s, 2H), 6.97 (s, 1H), 6.94 - 6.76 (m, 1H), 6.19 - 5.94 (m, 2H), 5.62 (d, J = 13.6 Hz, 1H), 4.38 - 4.18 (m, 1H), 4.13 - 3.92 (m, 4H), 3.80 (dd, J = 22.8, 12.1 Hz, 3H), 3.66 (d, J = 14.3 Hz, 1H), 3.29 (d, J = 3.7 Hz, 3H), 3.08 (dd, J = 15.3, 9.9 Hz, 1H), 2.81 (q, J = 14.8, 11.3 Hz, 3H), 2.50 (d, J = 35.6 Hz, 3H), 2.34 - 2.14 (m, 2H), 2.14 - 1.87 (m, 5H), 1.80 (d, J = 8.1 Hz, 3H), 1.56 - 1.18 (m, 5H), 1.23 - 1.03 (m, 3H)。LCMS-ESI+ (m/z):C40
H49
ClN6
O5
S [M+H]+計算值:761.32;實驗值:760.53。實例 183
及實例 184
以與實例 182
相同之方式使用外消旋-(1R,2S)-2-(1-甲基吡唑-4-基)環丙胺而不使用外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙-1-胺來合成實例183
及實例184
。藉由手性SFC分離來分離HPLC純化產物之混合物,得到實例183
及實例184
。任意指定各化合物之結構。
實例183
:1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.6 Hz, 1H), 7.45 (s, 1H), 7.36 (s, 1H), 7.24 - 7.09 (m, 3H), 6.99 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.02 (s, 1H), 5.59 (dd, J = 15.2, 8.9 Hz, 1H), 4.27 (dd, J = 15.0, 6.4 Hz, 1H), 4.17 - 4.01 (m, 2H), 3.85 (s, 3H), 3.77 (dd, J = 8.9, 3.6 Hz, 2H), 3.68 (d, J = 14.1 Hz, 1H), 3.27 (s, 3H), 3.08 (dd, J = 15.2, 10.2 Hz, 1H), 2.89 - 2.70 (m, 3H), 2.65 (s, 1H), 2.48 (d, J = 7.8 Hz, 2H), 2.39 (d, J = 9.2 Hz, 1H), 2.28 - 2.08 (m, 3H), 2.08 - 1.99 (m, 1H), 1.96 (s, 2H), 1.80 (ddd, J = 29.3, 20.8, 9.4 Hz, 4H), 1.44 (t, J = 12.3 Hz, 1H), 1.34 - 1.22 (m, 1H), 1.14 (s, 3H), 1.04 (q, J = 6.3 Hz, 2H)。LCMS-ESI+ (m/z):C40
H49
ClN6
O5
S [M+H]+計算值:761.32;實驗值:760.96。
實例184
:1H NMR (400 MHz,甲醇-d4) δ 7.71 (d, J = 8.3 Hz, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.10 (s, 2H), 6.98 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.05 (d, J = 15.1 Hz, 1H), 5.62 (dd, J = 14.8, 8.6 Hz, 1H), 4.25 (dd, J = 14.5, 6.5 Hz, 1H), 4.18 - 3.96 (m, 2H), 3.90 - 3.72 (m, 4H), 3.67 (d, J = 14.2 Hz, 1H), 3.29 (s, 3H), 3.08 (dd, J = 15.1, 10.0 Hz, 1H), 2.92 - 2.70 (m, 2H), 2.66 (dt, J = 7.5, 3.9 Hz, 1H), 2.46 (dd, J = 30.1, 19.3 Hz, 3H), 2.32 - 2.14 (m, 2H), 2.14 - 1.93 (m, 4H), 1.93 - 1.66 (m, 4H), 1.50 - 1.23 (m, 4H), 1.23 - 1.09 (m, 3H), 1.04 (q, J = 6.3 Hz, 2H)。LCMS-ESI+ (m/z):C40
H49
ClN6
O5
S [M+H]+計算值:761.32;實驗值:761.90。實例 185
將3-(乙基亞胺基亞甲基胺基)-N,N-二甲基-丙-1-胺鹽酸鹽(9.6 mg,0.050 mmol)及4-(二甲基胺基)吡啶(6.1 mg,0.050 mmol)添加至於二氯甲烷(1 mL)中之5-甲醯基-1-甲基-吡咯-3-甲酸(5.1 mg,0.033 mmol)之溶液中。在5分鐘之後,添加實例 109
(10 mg,0.016 mmol)。在17 h之後,將反應物用乙酸乙酯(8 mL)稀釋,且用水(5 mL)及飽和氯化銨(5 mL)洗滌。使有機相經硫酸鈉乾燥,且在減壓下移除溶劑。將殘餘物溶於甲醇(2 mL)中,且添加硼氫化鈉(1.0 mg,0.024 mmol)。在3 h之後,將反應物用乙酸乙酯(8 mL)稀釋,且用飽和碳酸氫鈉(5 mL)及飽和氯化銨(5 mL)洗滌。使有機相經硫酸鈉乾燥。在減壓下移除溶劑。使殘餘物經受急驟層析法(0-100%乙酸乙酯/己烷,繼之以20%甲醇/乙酸乙酯沖洗)。組合含有產物之清潔溶離份,且在減壓下移除溶劑。將殘餘物與乙腈一起共蒸發。將殘餘物溶於乙腈(2 mL)及水(2 mL)中。使溶液經受凍乾,得到實例 185
。1
H NMR (400 MHz,甲醇-d4) δ 7.78 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.30 (dd, J = 8.1, 1.8 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.07 - 6.98 (m, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.58 (t, J = 1.7 Hz, 1H), 6.16 (dt, J = 13.9, 6.5 Hz, 1H), 5.53 (dd, J = 15.3, 9.0 Hz, 1H), 4.56 (d, J = 10.2 Hz, 2H), 4.48 - 4.30 (m, 1H), 4.12 - 3.99 (m, 2H), 3.96 (d, J = 13.5 Hz, 1H), 3.88 (d, J = 14.9 Hz, 1H), 3.81 (dd, J = 9.0, 3.1 Hz, 1H), 3.72 (d, J = 2.1 Hz, 3H), 3.67 (d, J = 14.2 Hz, 1H), 3.27 (s, 4H), 3.04 (dd, J = 15.1, 9.5 Hz, 1H), 2.89 - 2.69 (m, 2H), 2.57 (m, 1H), 2.51 - 2.35 (m, 2H), 2.12 (d, J = 12.1 Hz, 3H), 2.04 - 1.86 (m, 2H), 1.77 (ddt, J = 24.2, 17.1, 9.1 Hz, 3H), 1.51 - 1.35 (m, 1H), 1.07 (d, J = 5.9 Hz, 3H), 0.91 (d, J = 6.3 Hz, 1H)。LCMS-ESI+:C39
H48
ClN4
O6
S計算值:735.29 (M+H);實驗值:735.07 (M+H)。實例 186
以與實例 75
相同之方式使用實例 109
及順-3-胺基-1-甲基環丁-1-醇以及DIEA來合成實例 186
。1H NMR (400 MHz,甲醇-d4) δ 7.69 (d, J = 9.0 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.98 (s, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.08 - 5.97 (m, 1H), 5.58 (dd, J = 15.4, 8.7 Hz, 1H), 4.26 - 4.16 (m, 1H), 4.06 - 3.97 (m, 2H), 3.85 - 3.71 (m, 4H), 3.64 (d, J = 14.1 Hz, 1H), 3.26 (s, 3H), 3.09 - 3.01 (m, 1H), 2.86 - 2.71 (m, 2H), 2.52 - 2.36 (m, 5H), 2.23 - 1.90 (m, 9H), 1.81 - 1.70 (m, 3H), 1.45 - 1.37 (m, 1H), 1.33 (s, 3H), 1.11 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C38
H49
ClN4
O6
S計算值H+:725.31,實驗值:724.78。實例 187
以與實例 18
相同之方式使用3-乙基-1-甲基-1H-吡唑-4-甲酸及實例 109
來合成實例 187
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.39 (s, 1H), 7.62 (d,J
= 8.4 Hz, 1H), 7.29 (d,J
= 8.3 Hz, 1H), 7.06 (s, 1H), 6.98 (d,J
= 1.9 Hz, 1H), 6.91 (s, 1H), 6.84 (d,J
= 8.2 Hz, 1H), 6.12 (d,J
= 15.4 Hz, 1H), 5.67 (dd,J
= 15.4, 8.5 Hz, 1H), 4.22 (s, 1H), 4.00 (s, 2H), 3.87 (s, 3H), 3.80 (d,J
= 10.8 Hz, 2H), 3.64 (d,J
= 14.4 Hz, 1H), 3.41 (d,J
= 14.5 Hz, 1H), 3.35 (m, 2H), 3.32 (s, 3H), 3.11 (dt,J
= 15.0, 8.3 Hz, 1H), 2.80 (tdd,J
= 22.6, 15.1, 8.6 Hz, 5H), 2.47 (s, 2H), 2.29 (s, 2H), 2.25 - 2.05 (m, 2H), 1.90 (d,J
= 47.6 Hz, 4H), 1.38 (t,J
= 12.9 Hz, 1H), 1.26 - 1.10 (m, 6H)。LCMS-ESI+ (m/z):C39
H48
ClN5
O5
S [M+H]+計算值:734.3;實驗值:734.0。 實例 188
以與實例 18
相同之方式使用3-甲氧基-1-甲基-1H-吡唑-4-甲酸及實例 110
來合成實例 188
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.93 (s, 1H), 7.75 (d,J
= 8.5 Hz, 1H), 7.18 (dd,J
= 8.5, 2.5 Hz, 1H), 7.12 (d,J
= 2.3 Hz, 1H), 6.99 (d,J
= 16.9 Hz, 1H), 6.93 (d,J
= 8.2 Hz, 1H), 6.00 (m, 1H), 5.58 (dd,J
= 15.3, 8.9 Hz, 1H), 4.38 (d,J
= 7.5 Hz, 1H), 4.09 (s, 2H), 3.96 (s, 3H), 3.84 (d,J
= 15.0 Hz, 1H), 3.78 (s, 3H), 3.72 (dd,J
= 8.9, 3.1 Hz, 1H), 3.66 (d,J
= 14.3 Hz, 1H), 3.35 (m, 2H), 3.24 (s, 3H), 3.17 - 3.05 (m, 1H), 2.89 - 2.72 (m, 2H), 2.52 - 2.06 (m, 6H), 2.05 - 1.70 (m, 6H), 1.60 (d,J
= 7.0 Hz, 3H), 1.52 - 1.41 (m, 1H), 1.19 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C39
H48
ClN5
O6 S
[M+H]+計算值:750.3;實驗值:749.9。實例 189
以與實例 75
相同之方式使用反 -
(3-胺基環丁基)甲醇及實例 109
來合成實例 189
。1
H NMR (400 MHz,丙酮-d6
) δ 7.69 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 10.1 Hz, 4H), 6.87 (d, J = 8.2 Hz, 1H), 6.08 (d, J = 14.8 Hz, 1H), 5.72 - 5.54 (m, 1H), 4.32 (q, J = 7.8 Hz, 1H), 4.18 - 3.95 (m, 3H), 3.90 - 3.65 (m, 4H), 3.60 (d, J = 6.7 Hz, 2H), 3.41 (d, J = 14.5 Hz, 1H), 3.24 (s, 3H), 3.13 (dd, J = 15.2, 10.0 Hz, 1H), 2.78 (dt, J = 25.3, 16.7 Hz, 2H), 2.51 (d, J = 33.4 Hz, 3H), 2.40 - 1.65 (m, 9H), 1.45 - 1.35 (m, 1H), 1.13 (d, J = 6.2 Hz, 3H)。LCMS-ESI+ (m/z):C38
H50
ClN4
O6
S [M+H]+計算值:725.31;實驗值:724.79。 實例 190
步驟1:將1H-吡咯-3-甲酸甲酯(1.0 g,7.99 mmol)溶解於DMF (15 mL)中,且經由冰浴將反應混合物冷卻至0℃。分批添加氫化鈉(480 mg,60%油分散液,12 mmol,1.5當量)。將反應混合物在彼溫度下攪拌15 min,且隨後加熱至55℃達一小時。經由注射器添加4-溴丁酸第三丁酯(2.23 g,10 mmol,1.25當量)。將反應混合物加熱至60℃,且藉由TLC (1:2 EtOAc:己烷)監視反應進程。在完成之後,將反應物冷卻至室溫。將反應混合物用EtOAc (100 mL)稀釋,且用水(40 mL)洗滌,隨後用鹽水(40 mL)洗滌。將有機層經硫酸鈉乾燥,過濾且在減壓下濃縮。經由管柱層析法(100%己烷à 1:1 EtOAc:己烷)純化殘餘物,獲得1-(4-(第三丁氧基)-4-側氧基丁基)-1H-吡咯-3-甲酸甲酯。
步驟2:在室溫下將1-(4-(第三丁氧基)-4-側氧基丁基)-1H-吡咯-3-甲酸甲酯(1 g,3.7 mmol)溶解於三氟乙酸(5 mL)及二氯甲烷(15 mL)之1:3溶液中。將反應混合物在室溫下攪拌24小時,隨後在減壓下濃縮。將殘餘物與甲苯(40 mL)一起共沸,獲得4-(3-(甲氧基羰基)-1H-吡咯-1-基)丁酸(785 mg,99%)。
步驟3:向於THF (12 mL)中之4-(3-(甲氧基羰基)-1H-吡咯-1-基)丁酸(900 mg,4.26 mmol)及HATU (1620 mg,4.26 mmol,1當量)之懸浮液中添加三甲胺(1293 mg,12.78 mmol,3當量)。將反應混合物在室溫下攪拌24小時。在獨立容器中,經由金屬塊將三甲基氯化亞碸(1.64 g,12.78 mmol,3當量)及第三丁醇鉀(1.43 g,12.78 mmol,3當量)之懸浮液加熱至60℃達1.5 h。隨後,移除加熱塊,且經由冰浴將反應混合物冷卻至0℃達15 min。隨後,在10 min內經由注射器逐滴添加HATU加成物,在此期間反應混合物變為深紅色。在於減壓下將其濃縮之前,將反應混合物在0℃下再攪拌1 h。經由矽膠層析法(5% MeOH/DCM)純化粗材料,獲得1-(5-(二甲基(側氧基)-λ6
-硫酮)-4-側氧基戊基)-1H-吡咯-3-甲酸甲酯。
步驟4:將1-(5-(二甲基(側氧基)-λ6
-硫酮)-4-側氧基戊基)-1H-吡咯-3-甲酸甲酯(315 mg,1.104 mmol)及氯(1,5-環辛二烯)銥(I)二聚體(74 mg,0.11 mmol,0.1當量)溶解於1,2-二氯乙烷(25 mL)中。在將反應混合物加熱至80℃達約10 min之前,使其充氣有氬氣大氣流達10 min,在此期間反應混合物變為綠色。在減壓下濃縮反應混合物,且經由矽膠層析法純化粗殘餘物,獲得8-側氧基-6,7,8,9-四氫-5H-吡咯并[1,2-a]氮呯-2-甲酸甲酯。
步驟5:將8-側氧基-6,7,8,9-四氫-5H-吡咯并[1,2-a]氮呯-2-甲酸甲酯(50 mg,0.24 mmol)溶解於MeOH (2.4 mL)中,且將反應混合物冷卻至0℃。一次性添加呈固體形式之硼氫化鈉(過量)。藉由TLC監視反應。在完成之後,在減壓下濃縮反應混合物,且經由矽膠層析法純化殘餘物,獲得8-羥基-6,7,8,9-四氫-5H-吡咯并[1,2-a]氮呯-2-甲酸甲酯。
步驟6:將8-羥基-6,7,8,9-四氫-5H-吡咯并[1,2-a]氮呯-2-甲酸酯(23 mg,0.11 mmol)溶解於DMF中,且一次性添加氫化鈉(60%油分散液,10 mg)。在經由移液管添加碘甲烷(過量)之前,將反應混合物攪拌5 min。藉由TLC監視反應進程。在完成之後,用EtOAc稀釋反應混合物。用飽和NH4
Cl (1×)、繼而用鹽水(2×)洗滌有機層。將有機層經硫酸鈉乾燥,過濾,且在減壓下濃縮。粗殘餘物不經進一步純化即用於下一步驟中。
步驟7:將8-甲氧基-6,7,8,9-四氫-5H-吡咯并[1,2-a]氮呯-2-甲酸甲酯溶解於二噁烷/1 N NaOH之1:1混合物中。將反應混合物加熱至80℃達1小時,之後使其冷卻至室溫。將反應混合物用1 N HCl洗滌且用EtOAc稀釋。將有機層分離,經硫酸鈉乾燥,過濾,且在減壓下濃縮。殘餘物不經進一步純化即用於下一步驟中。
步驟8:以與實例 18
相同之方式使用8-甲氧基-6,7,8,9-四氫-5H-吡咯并[1,2-a]氮呯-2-甲酸及實例 109
來合成實例 190
。LCMS-ESI+ (m/z):C43
H53
ClN4
O6
S [M+H]+計算值:789.3,實驗值:789.2。實例 191
步驟1:在2 min內在室溫下經由注射器將丙炔酸乙酯(421 µL,4.16 mmol)添加至於四氫呋喃(24 mL)及乙醇(16 mL)中之嗎啉-3-甲酸(545 mg,4.16 mmol)及N
,N
-二異丙基乙胺(2.17 mL,12.5 mmol)之經攪拌混合物中。在2 h之後,在減壓下濃縮所得混合物。藉由在減壓下進行甲苯(2×20 mL)濃縮來共沸乾燥殘餘物。將殘餘物溶解於二氯甲烷(77 mL)中。依序添加4-(二甲基胺基)吡啶(254 mg,2.08 mmol)、N
,N
-二異丙基乙胺(1.59 mL,9.14 mmol)及三苯膦(1.28 g,4.86 mmol),且將所得混合物攪拌且冷卻至0℃。添加碘(1.21 g,4.78 mmol)。在5 min之後,使所得混合物升溫至室溫。在33 min之後,將所得混合物加熱至50℃。在1 h之後,使所得混合物冷卻至室溫,且添加乙酸乙酯(250 mL)。將有機層依序用氯化氫水溶液(200 mL)及鹽水(150 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於丙酮(30 mL)中,添加碳酸銫(5.42 g,16.6 mmol),且在室溫下攪拌所得混合物。經由注射器添加硫酸甲酯(1.97 mL,20.8 mmol)。在1 h之後,過濾所得混合物,且用二氯甲烷(75 mL)萃取濾餅。將矽膠(12 g)添加至合併濾液中,且在減壓下濃縮所得漿液。藉由矽膠急驟管柱層析法(0至35%於己烷中之乙酸乙酯)純化殘餘物,得到191-1
。
步驟2:在室溫下經由注射器將氫氧化鈉水溶液(2.0 M,5.22 mL,10 mmol)添加至於甲醇(1.5 mL)及四氫呋喃(1.5 mL)中之191-1
(338.3 mg,1.50 mmol)之經攪拌溶液中,且將所得混合物加熱至70℃。在1 h之後,使所得混合物冷卻至室溫,且依序添加氯化氫水溶液(2.0 M,6 mL)及鹽水(20 mL)。依序用二氯甲烷(2×30 mL)及乙酸乙酯(30 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由逆相製備型HPLC (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到191-2
。
步驟3:以與實例 109
類似之方式使用191-2
而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸來合成實例 191
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.2, 1.9 Hz, 1H), 7.36 - 7.29 (m, 2H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.19 (dt, J = 14.4, 6.8 Hz, 1H), 5.66 (dd, J = 15.6, 7.6 Hz, 1H), 4.97 (d, J = 14.1 Hz, 1H), 4.92 (d, J = 14.1 Hz, 1H), 4.21 - 3.57 (m, 10H), 3.97 (s, 3H), 3.47 (d, J = 14.4 Hz, 1H), 3.26 (s, 3H), 3.15 (dd, J = 15.1, 11.0 Hz, 1H), 3.02 - 1.39 (m, 16H), 1.13 (d, J = 6.8 Hz, 3H)。LCMS: 777.0。實例 192
除在步驟 1
使用反-3-胺基-1-甲基-環丁醇HCl鹽以外,以與實例 225
相同之順序來製造實例 192
。1H NMR (400 MHz,甲醇-d4) δ 7.66 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.08 (s, 1H), 7.03 - 6.95 (m, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.12 - 6.01 (m, 1H), 5.70 - 5.59 (m, 1H), 4.27 - 4.14 (m, 2H), 4.05 - 3.99 (m, 2H), 3.84 - 3.75 (m, 3H), 3.66 (d, J = 14.3 Hz, 1H), 3.30 (s, 3H), 3.22 (s, 3H), 3.13 - 3.03 (m, 1H), 2.87 - 2.75 (m, 2H), 2.57 - 2.43 (m, 5H), 2.26 - 1.77 (m, 12H), 1.44 - 1.38 (m, 1H), 1.35 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H)。C39
H51
ClN4
O6
S [M+H]+計算值:739.36;實驗值:738.74。實例 193
除在步驟2中使用碘甲烷代替碘乙烷以外,以與實例 225
相同之順序來製造實例 193
。1H NMR (400 MHz,甲醇-d4) δ 7.72 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 7.6 Hz, 2H), 6.99 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.04 (dd, J = 15.2, 7.5 Hz, 1H), 5.61 (dd, J = 15.3, 8.9 Hz, 1H), 4.25 (dd, J = 15.0, 6.5 Hz, 1H), 4.05 (d, J = 2.4 Hz, 2H), 3.96 - 3.73 (m, 4H), 3.67 (d, J = 14.3 Hz, 1H), 3.28 (s, 3H), 3.20 (s, 3H), 3.08 (dd, J = 15.2, 10.1 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.55 - 2.32 (m, 5H), 2.26 - 1.91 (m, 9H), 1.80 (dt, J = 17.1, 9.2 Hz, 3H), 1.43 (t, J = 12.0 Hz, 1H), 1.35 (s, 3H), 1.13 (d, J = 6.5 Hz, 3H)。C39
H51
ClN4
O6
S [M+H]+計算值:739.36;實驗值:738.79。實例 194
步驟1:將3-羥基-1-甲基-1H-吡唑-4-甲酸(100 mg,0.704 mmol)溶解於DMF (3 mL)中,且一次性添加氫化鈉(60%分散液,84 mg,2.1 mmol,3當量)。經由移液管添加碘乙烷(2.1 mmol,328 mg,3當量)。將反應混合物加熱至80℃直至TLC指示起始材料完全消耗為止。將反應混合物用飽和NH4
Cl (3 mL)淬滅,隨後用EtOAc (10 mL)稀釋。將有機層用飽和NaHCO3
(10 mL)及鹽水(10 mL)洗滌。將有機層經Na2
SO4
乾燥,過濾,且在減壓下濃縮。經由管柱層析法純化殘餘物,獲得3-乙氧基-1-甲基-1H-吡唑-4-甲酸乙酯。
步驟2:將3-乙氧基-1-甲基-1H-吡唑-4-甲酸乙酯(20 mg,0.1 mmol)溶解於1,2-二噁烷(1 mL)及1 N NaOH溶液(1 mL)之1:1混合物中。將反應混合物加熱至80℃達4小時(藉由TLC及LCMS監視反應)。隨後,將反應混合物冷卻至室溫,且用1 M HCl (1.5 mL)淬滅,隨後用EtOAc (5 mL)稀釋。用飽和NaHCO3
(5 mL)及鹽水(5 mL)洗滌有機層。將有機層經Na2
SO4
乾燥,過濾,且在減壓下濃縮,獲得3-乙氧基-1-甲基-1H-吡唑-4-甲酸,其不經進一步純化即使用。
步驟3:以與實例 18
相同之方式使用3-乙氧基-1-甲基-1H-吡唑-4-甲酸及實例 109
來合成實例 194
。LCMS-ESI+ (m/z):C39
H48
ClN5
O6
S [M+H]+計算值:750.3;實驗值:750.1。實例 195
及實例 196
藉由手性SFC分離自實例 160
中純化實例 195
及實例 196
,且暫行指定立體化學。
實例 195
:1H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 9.0 Hz, 2H), 7.02 - 6.95 (m, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.10 - 6.01 (m, 1H), 5.59 (dd, J = 15.2, 8.8 Hz, 1H), 4.26 (s, 1H), 4.04 (d, J = 4.7 Hz, 2H), 3.89 - 3.74 (m, 3H), 3.67 (d, J = 14.3 Hz, 1H), 3.45 (s, 3H), 3.37 (s, 2H), 3.27 (d, J = 4.3 Hz, 3H), 3.07 (dd, J = 15.2, 10.2 Hz, 1H), 2.87 - 2.72 (m, 2H), 2.64 (s, 1H), 2.48 (ddd, J = 34.7, 22.9, 8.1 Hz, 3H), 2.17 (ddd, J = 33.0, 21.9, 10.5 Hz, 3H), 1.97 (d, J = 14.6 Hz, 3H), 1.85 - 1.72 (m, 3H), 1.43 (t, J = 12.3 Hz, 1H), 1.13 (d, J = 6.4 Hz, 3H), 1.02 (ddd, J = 8.9, 6.8, 3.8 Hz, 1H), 0.87 - 0.79 (m, 1H)。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S [M+H]+計算值:711.29;實驗值:710.76。
實例 196
:1H NMR (400 MHz,甲醇-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.23 - 7.07 (m, 3H), 6.97 (s, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.11 - 6.02 (m, 1H), 5.56 (dd, J = 15.2, 9.0 Hz, 1H), 4.31 (dd, J = 14.6, 6.4 Hz, 1H), 4.14 - 4.00 (m, 2H), 3.91 - 3.74 (m, 3H), 3.67 (d, J = 14.1 Hz, 1H), 3.44 (s, 3H), 3.27 (s, 3H), 3.21 (s, 1H), 3.06 (dd, J = 15.3, 10.3 Hz, 1H), 2.91 - 2.69 (m, 3H), 2.63 (s, 1H), 2.51 (d, J = 20.7 Hz, 2H), 2.37 (t, J = 8.9 Hz, 1H), 2.14 (t, J = 15.4 Hz, 3H), 2.02 - 1.87 (m, 3H), 1.78 (tt, J = 16.9, 9.3 Hz, 3H), 1.43 (t, J = 12.5 Hz, 1H), 1.12 (d, J = 6.3 Hz, 3H), 1.02 (ddd, J = 8.8, 6.7, 3.8 Hz, 1H), 0.85 - 0.78 (m, 1H)。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S [M+H]+計算值:711.29;實驗值:710.92。實例 197
以與實例18
相同之方式使用實例 109
而不使用實例 5
且使用6,7-二氫-5H-吡唑并[5,1-b][1,3]噁嗪-2-甲酸而不使用3-甲氧基丙酸來合成實例197
。1H NMR (400 MHz,甲醇-d4) δ 7.77 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.2, 1.9 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.09 (t, J = 7.3 Hz, 1H), 6.04 (s, 1H), 5.62 (dd, J = 15.3, 8.6 Hz, 1H), 4.40 - 4.36 (m, 1H), 4.29 (dt, J = 13.4, 6.6 Hz, 2H), 4.15 - 3.95 (m, 3H), 3.90 - 3.69 (m, 3H), 3.37 (s, 3H), 3.28 (s, 2H), 3.09 (dd, J = 15.2, 9.7 Hz, 2H), 2.90 - 2.71 (m, 3H), 2.47 (s, 3H), 2.33 (p, J = 5.9 Hz, 2H), 2.28 - 2.08 (m, 3H), 1.95 (d, J = 3.7 Hz, 3H), 1.79 (q, J = 11.1, 9.0 Hz, 3H), 1.46 (t, J = 13.1 Hz, 1H), 1.12 (d, J = 6.7 Hz, 3H)。LCMS-ESI+ (m/z):C39
H46
ClN5
O6
S [M+H]+計算值:748.29;實驗值:746.89。實例 198
以與實例 18
相同之方式使用3-羥基-3-(三氟甲基)環丁烷-1-甲酸及實例 109
來合成實例 198
。1H NMR (400 MHz,乙腈-d3) δ 7.73 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.2, 1.9 Hz, 1H), 7.19 (dd, J = 8.4, 2.3 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.09 (d, J = 1.9 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 6.04 (dt, J = 14.5, 6.9 Hz, 1H), 5.60 (dd, J = 15.4, 8.3 Hz, 1H), 4.14 - 3.96 (m, 3H), 3.88 - 3.64 (m, 4H), 3.33 (d, J = 14.3 Hz, 1H), 3.23 (s, 3H), 3.04 (dq, J = 17.7, 9.3, 8.7 Hz, 2H), 2.87 - 2.66 (m, 4H), 2.46 (dq, J = 24.9, 8.8, 7.2 Hz, 4H), 2.06 (s, 4H), 1.91 (t, J = 4.9 Hz, 3H), 1.84 - 1.63 (m,4H), 1.42 (dt, J = 14.9, 7.7 Hz, 1H), 1.09 (d, J = 6.8 Hz, 3H)。LCMS -ESI+ (m/z):C38
H45
ClF3
N3
O6
S [M+H]+計算值:764.26;實驗值:764.09。實例 199
以與實例 75
相同之方式使用實例 109
及反 -
2-乙基環丙-1-胺鹽酸鹽來合成實例 199
。1
H NMR (400 MHz,甲醇-d4) δ 7.77 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 8.4, 2.5 Hz, 2H), 7.11 (d, J = 2.3 Hz, 1H), 6.97 (s, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.20 - 6.04 (m, 1H), 5.52 (dd, J = 15.2, 9.1 Hz, 1H), 4.30 (d, J = 14.3 Hz, 1H), 4.12 - 3.98 (m, 2H), 3.87 (d, J = 15.0 Hz, 1H), 3.80 (dd, J = 9.1, 3.4 Hz, 1H), 3.66 (d, J = 14.1 Hz, 1H), 3.27 (s, 4H), 3.03 (dd, J = 15.2, 9.9 Hz, 1H), 2.88 - 2.70 (m, 2H), 2.55 (m, 1H), 2.42 (m, 1H), 2.32 (s, 1H), 2.22 (dt, J = 7.0, 3.4 Hz, 1H), 2.12 (d, J = 12.4 Hz, 3H), 2.03 - 1.85 (m, 2H), 1.77 (ddt, J = 25.7, 17.3, 9.2 Hz, 3H), 1.40 (dd, J = 14.0, 70 Hz, 2H), 1.23 (dt, J = 14.5, 7.2 Hz, 1H), 1.12 - 1.06 (m, 3H), 1.04 (d, J = 2.7 Hz, 1H), 1.02 (d, J = 2.7 Hz, 2H), 1.00 (d, J = 2.8 Hz, 1H), 0.89 - 0.77 (m, 1H), 0.69 - 0.55 (m, 2H), 0.50 (m, 2H)。LCMS-ESI+:C38
H50
ClN4
O5
S計算值:709.31 (M+H);實驗值:709.38 (M+H)。實例 200
在rt下用氫化鈉(75.0 mg,60%於礦物油中之分散液)及於THF中之碘甲烷(12 mg,0.008 mmol,10當量)處理實例 189
(6.0 mg)。用水(30 mL)淬滅反應混合物,且用EtOAc (30 mL)萃取整體。將所獲得之有機層用鹽水(30 mL)洗滌且經Na2
SO4
乾燥。在減壓下移除溶劑。藉由矽膠製備型TLC (5% MeOH / DCM,展開兩次)純化所獲得之粗混合物,得到實例 200
。1H NMR (400 MHz,丙酮-d6
) δ 7.74 (d, J = 8.5 Hz, 1H), 7.39 - 7.08 (m, 4H), 6.92 - 6.84 (m, 1H), 6.13 - 6.03 (m, 1H), 5.55 - 5.64 (m, 1H), 4.36 - 4.24 (m, 1H), 4.12 - 4.00 (m, 2H), 3.88 - 3.77 (m, 1H), 3.71 (d, J = 14.6 Hz, 2H), 3.40 (d, J = 7.0 Hz, 2H), 3.31 (s, 3H), 3.23 (s, 3H), 3.00 - 2.10 (m, 19H), 2.00 - 1.64 (m, 4H), 1.50 - 1.40 (m, 1H), 1.11 (d, J = 6.3 Hz, 3H)。LCMS-ESI+ (m/z):C39
H52
ClN4
O6
S [M+H]+計算值:739.32;實驗值:738.65。實例 201
以與實例 109- 方法 1
類似之方式使用(2S)-N'-(第三丁基二甲基矽烷基)-2-乙基戊-4-烯-1-磺醯咪醯胺(由(S)-2-乙基戊-4-烯-1-磺醯胺製備)而不使用(4S
)-5-[S-胺基-N-[第三丁基(二甲基)矽烷基]磺醯亞胺醯基]-4-甲基-戊-1-烯來製備中間物 201-1
。1
H NMR (400 MHz,氘代氯仿) δ 7.76 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 8.2, 1.9 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.33 (dt, J = 14.8, 7.1 Hz, 1H), 5.89 (s, 2H), 5.53 (dd, J = 15.3, 8.4 Hz, 1H), 4.11 - 4.01 (m, 2H), 3.87 (d, J = 14.7 Hz, 1H), 3.84 - 3.75 (m, 1H), 3.71 (dd, J = 8.5, 3.9 Hz, 1H), 3.61 (dd, J = 14.5, 3.6 Hz, 1H), 3.42 (d, J = 9.5 Hz, 1H), 3.39 (d, J = 9.5 Hz, 1H), 3.27 (s, 3H), 3.01 (dd, J = 15.0, 11.1 Hz, 1H), 2.88 - 2.71 (m, 2H), 2.58 (d, J = 9.6 Hz, 1H), 2.46 (dq, J = 20.6, 10.6, 9.1 Hz, 1H), 2.32 (dt, J = 14.3, 6.9 Hz, 1H), 2.07 (s, 2H), 1.99 - 1.85 (m, 1H), 1.74 (dq, J = 33.7, 9.2, 8.8 Hz, 2H), 1.50 (t, J = 7.2 Hz, 2H), 1.42 (q, J = 13.3, 12.9 Hz, 1H), 0.96 (t, J = 7.4 Hz, 3H)。LCMS-ESI+ (m/z):C33
H42
ClN3
O4
S [M+H]+計算值:612.3;實驗值:612.5。
以與實例 18
相同之方式使用中間物 201-1
及1-甲基-1H
-吡唑-4-甲酸來合成實例 201
。1
H NMR (400 MHz,甲醇-d4) δ 8.07 (s, 1H), 7.94 (d, J = 0.6 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 8.0, 1.7 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.83 (d, J = 8.1 Hz, 1H), 6.17 (ddd, J = 14.6, 9.0, 5.1 Hz, 1H), 5.48 (dd, J = 15.3, 9.3 Hz, 1H), 4.50 (dd, J = 14.1, 9.3 Hz, 1H), 4.11 - 3.96 (m, 3H), 3.95 - 3.86 (m, 4H), 3.82 (dd, J = 9.4, 3.8 Hz, 1H), 3.67 (d, J = 14.1 Hz, 1H), 3.25 (m, 4H), 3.00 (dd, J = 15.2, 10.1 Hz, 1H), 2.90 - 2.75 (m, 2H), 2.71 (d, J = 15.0 Hz, 1H), 2.53 - 2.41 (m, 1H), 2.37 (m, 1H), 2.19 - 2.05 (m, 2H), 2.05 - 1.82 (m, 4H), 1.82 - 1.64 (m, 2H), 1.49 - 1.27 (m, 4H), 0.90 (t, J = 7.4 Hz, 3H)。LCMS-ESI+:C38
H47
ClN5
O5
S計算值:720.19 (M+H);實驗值:720.31 (M+H)。實例 202
以與實例 18
相同之方式使用中間物 201-1
及3,4-二氫-1H-吡咯并[2,1-c][1,4]噁嗪-7-甲酸來合成實例 202
。1
H 1H NMR (400 MHz,甲醇-d4) δ 7.77 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.16 (d, J = 8.9 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.01 (s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 6.15 (d, J = 7.8 Hz, 1H), 5.61 - 5.49 (m, 1H), 4.78 (s, 2H), 4.34 (s, 1H), 4.04 (m, 6H), 3.87 (d, J = 15.0 Hz, 1H), 3.83 - 3.75 (m, 1H), 3.68 (d, J = 14.2 Hz, 1H), 3.27 (s, 3H), 3.04 (dd, J = 15.1, 9.4 Hz, 1H), 2.79 (m, 2H), 2.68 (m, 1H), 2.41 (m, 2H), 2.24 (m, 1H), 2.12 (m, 1H), 1.98 (m, 3H), 1.86 - 1.64 (m, 3H), 1.57 - 1.38 (m, 2H), .33 (m, 4H), 0.94 (t, J = 7.3 Hz, 3H)。LCMS-ESI+:C41
H50
ClN4
O6
S計算值:761.31 (M+H);實驗值:761.34 (M+H)。實例 203
以與實例 18
類似之方式使用4-甲基呋喃-2-甲酸及實例 109
來製備實例 203
。1
H NMR (400 MHz,丙酮-d6
) δ 7.75 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.31 - 7.15 (m, 3H), 7.12 (d, J = 2.5 Hz, 2H), 6.93 (d, J = 8.2 Hz, 1H), 6.04 (dd, J = 14.7, 7.3 Hz, 1H), 5.61 (dd, J = 14.8, 8.8 Hz, 1H), 4.17 - 3.99 (m, 2H), 3.88 (d, J = 15.0 Hz, 2H), 3.80 - 3.68 (m, 2H), 3.38 (d, J = 14.3 Hz, 1H), 3.22 (s, 3H), 3.14 (dd, J = 15.1, 9.9 Hz, 1H), 2.93 - 2.67 (m, 2H), 2.61 - 2.36 (m, 3H), 2.33 - 2.18 (m, 2H), 2.16- 2.07 (m, 3H), 2.08 (s, 3H) 2.00 - 1.85 (m, 2H), 1.84 - 1.65 (m, 3H), 1.46 (dt, J = 15.2, 7.5 Hz, 1H), 1.14 (d, J = 6.2 Hz, 3H)。LCMS-ESI+ (m/z):C38
H45
ClN3
O6
S [M+H]+計算值:706.26;實驗值:705.95。實例 204
以與實例 18
類似之方式使用5-甲基呋喃-3-甲酸及實例 109
來製備實例 204
。1
H NMR (400 MHz,丙酮-d6
) δ 8.09 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.20 (dt, J = 8.4, 3.2 Hz, 2H), 7.15 - 7.05 (m, 2H), 6.92 (d, J = 8.2 Hz, 1H), 6.43 (s, 1H), 6.06 (dt, J = 14.3, 6.6 Hz, 1H), 5.61 (dd, J = 15.5, 8.5 Hz, 1H), 4.27 (d, J = 15.9 Hz, 1H), 4.15 - 4.00 (m, 2H), 3.85 (t, J = 15.3 Hz, 2H), 3.77 - 3.67 (m, 2H), 3.38 (d, J = 14.3 Hz, 1H), 3.22 (s, 3H), 3.13 (dd, J = 15.3, 9.9 Hz, 1H), 2.91 - 2.68 (m, 2H), 2.49 (d, J = 20.3 Hz, 4H), 2.31 (d, J = 1.1 Hz, 3H), 2.29 - 2.07 (m, 3H), 2.09 (s, 4H), 2.02 - 1.89 (m, 3H), 1.77 (ddt, J = 25.6, 15.2, 7.9 Hz, 3H), 1.45 (dt, J = 15.0, 7.6 Hz, 1H), 1.14 (d, J = 6.5 Hz, 3H)。LCMS-ESI+ (m/z):C38
H45
ClN3
O6
S [M+H]+計算值:706.26;實驗值:706.06。實例 205
步驟1:在氮氣氛圍下將於無水DMF (10 mL)中之1H-吡咯-3-甲酸甲酯(4.3 g,0.034 mol)之溶液逐滴添加至於無水DMF (40 mL)中之NaH 60% (油分散液) (1.6 g,0.041 mol)之經攪拌懸浮液中。將混合物之溫度維持在0℃下。在完成添加之後,在相同溫度下繼續攪拌30 min。隨後,逐滴添加2-溴乙酸第三丁酯(10.1 g,0.052 mol)之溶液,且使溫度升高至室溫。將反應混合物在此溫度下攪拌48 h。隨後,添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑,隨後藉由正相層析法(矽膠管柱,0-100% EtOAc/己烷)純化殘餘物,得到205-1
。
步驟2:向於DCM (45 mL)中之205-1
(7.2 g,0.30 mol)之溶液中添加TFA (15 mL),且在室溫下攪拌過夜。隨後,添加水,且分離各層。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑,得到205-2
。
步驟3:用TEA (7.2 mL,0.070 mol)處理於THF (60 mL)中之205-2
(4.3 g,0.023 mol)及HATU (8.9 g,0.023 mol)之懸浮液,且將所得溶液在rt下攪拌約16 h。單獨地,將於THF (70 mL)中之第三丁醇鉀(7.4 g,0.066 mol)及三甲基氯化亞碸(8.4 g,0.066 mol)之懸浮液在約60℃下加熱約2 h,且隨後在冰水浴中冷卻約15 min。隨後,在約45 min之時段內在約0℃下逐滴添加活化酯溶液。將反應混合物進一步攪拌約1 h,在此之後在減壓下濃縮反應物。將殘餘物分配於DCM與水之間。在分離各層之後,將有機相用飽和NaCl水溶液洗滌,經Mg2
SO4
乾燥,過濾,且在減壓下濃縮。使用0-100%於己烷中之EtOAc之梯度矽膠(80 g)純化粗材料。使於DCE (80 mL)中之活化酸及氯(l,5-環辛二烯)銥(I)二聚體(60 mg)之溶液脫氣。將混合物在uw中在約80℃下加熱約10 min,且隨後冷卻至rt。在減壓下濃縮反應混合物。矽膠5-80%於己烷中之EtOAc純化殘餘物,得到205-3
。
步驟4:在0℃下向於甲醇(5 mL)中之205-3
(50 mg,0.27 mmol)之經攪拌溶液中小份添加NaBH4
(11 mg,0.27 mmol),且在0℃下攪拌1 h,且用10%氯化銨水溶液稀釋。使用蒸發器移除有機溶劑。使剩餘水溶液經受兩次利用乙酸乙酯進行之萃取。將有機層用飽和鹽水洗滌,隨後經硫酸鈉乾燥,且隨後濃縮。藉由逆相層析法ACN/水15-90%用0.1% TFA純化殘餘物達15 min,得到205-4
。
步驟5:製備205-5
:向於DMF (3 mL)中之205-4
(32 mg,0.17 mmol)之經攪拌溶液中添加NaH 60% (7 mg,0.17 mmol),且在室溫下攪拌1 h。使反應混合物經受兩次利用DCM進行之萃取。將有機層用飽和鹽水洗滌,隨後經硫酸鈉乾燥,且隨後濃縮。殘餘物用於下一步。
步驟6:向於甲醇(3 mL)中之205-5
(30 mg,0.15 mmol)之經攪拌溶液中添加1N NaOH (1 mL),且在rt下攪拌1 h。向反應混合物中添加1N HCl (1 mL),且濃縮反應混合物。添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑,得到205-6
。
步驟7:以與實例 174
相同之方式使用中間物 205-6
及實例 109
來合成實例 205
。1
H NMR (400 MHz,氘代氯仿) δ 7.75 (dd,J
= 8.5, 1.7 Hz, 1H), 7.46 - 7.35 (m, 2H), 7.19 (d,J
= 9.2 Hz, 2H), 7.10 (d,J
= 2.2 Hz, 1H), 6.95 (dt,J
= 8.2, 1.5 Hz, 1H), 6.38 (s, 1H), 6.00 (dt,J
= 13.6, 6.4 Hz, 1H), 5.62 (dd,J
= 15.6, 7.6 Hz, 1H), 4.57 (dt,J
= 6.1, 3.0 Hz, 1H), 4.21 (ddd,J
= 11.9, 5.9, 2.5 Hz, 1H), 4.14 - 3.95 (m, 3H), 3.93 - 3.65 (m, 3H), 3.43 (s, 3H), 3.31 (s, 3H), 3.20 - 2.66 (m, 5H), 2.58 - 2.26 (m, 3H), 2.19 - 1.61 (m, 6H), 1.28 (m, 5H), 1.12 (d,J
= 6.8 Hz, 3H), 0.95 - 0.63 (m, 2H).LCMS-ESI+ (m/z):C41
H49
ClN4
O6
S [M+H]+計算值:761.31;實驗值:761.59。實例 206
以與實例 75
相同之方式使用(1R
, 5S
, 6R)-3-氧雜雙環[3.1.0]己-6-胺及實例 109
來合成實例 206
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.73 (d,J
= 8.5 Hz, 1H), 7.18 (d,J
= 8.3 Hz, 1H), 7.13 (d,J
= 14.6 Hz, 2H), 6.97 (s, 1H), 6.91 (d,J
= 8.2 Hz, 1H), 6.03 (d,J
= 14.8 Hz, 1H), 5.60 (dd,J
= 15.2, 8.9 Hz, 1H), 4.26 (br, 1H), 4.06 (m, 2H), 3.98 (d,J
= 8.5 Hz, 2H), 3.84 (d,J
= 15.0 Hz, 1H), 3.81 - 3.71 (m, 3H), 3.67 (d,J
= 14.2 Hz, 1H), 3.35 - 3.32 (m, 4H), 3.27 (s, 3H), 3.07 (dd,J
= 15.2, 10.3 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.45 (d,J
= 28.6 Hz, 4H), 2.29 - 2.06 (m, 3H), 2.03 - 1.69 (m, 5H), 1.43 (t,J
= 12.8 Hz, 1H), 1.14 (d,J
= 6.5 Hz, 3H)。LCMS-ESI+ (m/z):C38
H47
ClN4
O6
S [M+H]+計算值:723.3;實驗值:722.9。實例 207
以與實例 75
相同之方式使用實例 109
及反 -
2-(二氟甲基)環丙-1-胺鹽酸鹽來合成實例 207
。1
H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 2.3 Hz, 1H), 6.97 (s, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.08 - 5.99 (m, 1H), 5.99 - 5.67 (m, 1H), 5.59 (dd, J = 15.3, 8.9 Hz, 1H), 4.33 - 4.22 (m, 1H), 4.11 - 4.01 (m, 2H), 3.85 (d, J = 15.1 Hz, 1H), 3.77 (dd, J = 9.0, 3.7 Hz, 1H), 3.68 (d, J = 14.3 Hz, 1H), 3.27 (s, 4H), 3.08 (dd, J = 15.3, 10.3 Hz, 1H), 2.79 (ddd, J = 22.7, 17.7, 9.6 Hz, 3H), 2.48 (d, J = 8.1 Hz, 2H), 2.37 (t, J = 8.3 Hz, 1H), 2.28 - 2.04 (m, 3H), 2.04 - 1.88 (m, 2H), 1.79 (m, 2H), 1.69 - 1.49 (m, 1H), 1.44 (t, J = 12.9 Hz, 1H), 1.33 (d, J = 17.3 Hz, 2H), 1.14 (d, J = 6.4 Hz, 3H), 1.09 (q, J = 6.4 Hz, 1H), 0.95 (m, 2H)。LCMS-ESI+:C37
H46
ClF2
N4
O5
S計算值:731.28 (M+H);實驗值:731.05 (M+H)。實例 208 及實例 209
步驟1:將1H-吡咯-3-甲酸甲酯(2.0 g,15.98 mmol)溶解於乙腈(30 mL)中,且經由注射器添加丙烯酸第三丁酯(2.46 g,19.18 mmol,1.2當量)。在2 min內在室溫下逐滴添加1,8-二氮雜雙環[5.4.0]十一-7-烯(2.43 g,15.98 mmol,1當量)。將反應混合物加熱至80℃,且藉由TLC (1:2 EtOAc:己烷)監視反應進程。在完成之後,將反應物冷卻至室溫且在減壓下濃縮。將殘餘物用EtOAc (40 mL)稀釋,且用飽和氯化銨(40 mL)洗滌,隨後用鹽水(40 mL)洗滌。將有機層經硫酸鈉乾燥,過濾,且在減壓下濃縮。經由管柱層析法(100%己烷à 1:1 EtOAc:己烷)純化殘餘物,獲得1-(3-(第三丁氧基)-3-側氧基丙基)-1H-吡咯-3-甲酸甲酯(4.05 g,94%)。
步驟2:在室溫下將1-(3-(第三丁氧基)-3-側氧基丙基)-1H-吡咯-3-甲酸甲酯(3.8 g,15 mmol)溶解於三氟乙酸(10 mL)及二氯甲烷(30 mL)之1:3溶液中。將反應混合物在室溫下攪拌24小時,隨後在減壓下濃縮。將殘餘物與甲苯(40 mL)一起共沸,獲得3-(3-(甲氧基羰基)-1H-吡咯-1-基)丙酸(2.95 g,99%)。
步驟3:向於THF (30 mL)中之3-(3-(甲氧基羰基)-1H-吡咯-1-基)丙酸(2.00 g,10.14 mmol)及HATU (3.86 g,10.14 mmol,1當量)之懸浮液中添加三甲胺(3.91 g,30.43 mmol,3當量)。將反應混合物在室溫下攪拌24小時。在單獨容器中,經由金屬塊將三甲基氯化亞碸(3.91 g,30.43 mmol,3當量)及第三丁醇鉀(3.41 g,30.43 mmol,3當量)之懸浮液加熱至60℃達1.5 h。隨後,移除加熱塊,且經由冰浴將反應混合物冷卻至0℃達15 min。隨後,在10 min內經由注射器逐滴添加HATU加成物,在此期間反應混合物變為深紅色。在於減壓下將其濃縮之前,將反應混合物在0℃下再攪拌1 h。經由矽膠層析法(5% MeOH/DCM)純化粗材料,獲得1-(4-(二甲基(側氧基)-λ6
-硫酮)-3-側氧基丁基)-1H-吡咯-3-甲酸甲酯。
步驟4:將1-(4-(二甲基(側氧基)-λ6
-硫酮)-3-側氧基丁基)-1H-吡咯-3-甲酸甲酯(150 mg,0.553 mmol)及氯(1,5-環辛二烯)銥(I)二聚體(37 mg,0.00553 mmol,0.1當量)溶解於1,2-二氯乙烷(15 mL)中。在將反應混合物加熱至80℃達約10 min之前,使其充氣有氬氣大氣流達10 min,在此期間反應混合物變為綠色。在減壓下濃縮反應混合物,且經由矽膠層析法純化粗殘餘物,獲得7-側氧基-5,6,7,8-四氫吲哚嗪-2-甲酸甲酯。
步驟5:將7-側氧基-5,6,7,8-四氫吲哚嗪-2-甲酸甲酯(40 mg,0.207 mmol)溶解於DMF-DMA/EtOH (0.5 mL/0.5 mL)中,且將反應混合物加熱至約80℃達16小時,之後使其冷卻至室溫,且隨後在減壓下濃縮。殘餘物不經進一步純化即用於下一步驟中。
步驟6:將8-((二甲基胺基)亞甲基)-7-側氧基-5,6,7,8-四氫吲哚嗪-2-甲酸甲酯(15 mg)溶解於EtOH (0.5 mL)中,且添加甲肼(0.1 mL)。使反應混合物回流2小時,之後使其冷卻至室溫,且在減壓下濃縮。用矽膠層析法純化殘餘物,獲得2-甲基-4,5-二氫-2H-吡唑并[3,4-g]吲哚嗪-8-甲酸甲酯及3-甲基-4,5-二氫-3H-吡唑并[3,4-g]吲哚嗪-8-甲酸甲酯。
步驟7:將2-甲基-4,5-二氫-2H-吡唑并[3,4-g]吲哚嗪-8-甲酸甲酯及3-甲基-4,5-二氫-3H-吡唑并[3,4-g]吲哚嗪-8-甲酸甲酯(10 mg)溶解於二噁烷/1 N NaOH之1:1混合物中。將反應混合物加熱至80℃達1小時,之後使其冷卻至室溫。將反應混合物用1 N HCl洗滌,且用EtOAc稀釋。將有機層分離,經硫酸鈉乾燥,過濾且在減壓下濃縮。殘餘物不經進一步純化即用於下一步驟中。
步驟8:以與實例 18
相同之方式將區位異構體、2-甲基-4,5-二氫-2H-吡唑并[3,4-g]吲哚嗪-8-甲酸甲酯及3-甲基-4,5-二氫-3H-吡唑并[3,4-g]吲哚嗪-8-甲酸甲酯之混合物偶合至實例 109
,且藉由逆相層析法分離,分別得到實例 208 及實例 209
。暫行指定區位化學。LCMS-ESI+ (m/z):C43
H49
ClN6
O5
S [M+H]+計算值:797.3;實驗值:797.0。實例 210
以與實例 75
相同之方式使用順 -
3-(甲氧基甲基)環丁-1-胺鹽酸及實例 109
來合成實例 210
。1
H NMR (400 MHz,丙酮-d6
) δ 7.69 (d, J = 8.6 Hz, 1H), 7.23 (br, 1H), 7.09 (br, 3H), 6.87 (d, J = 8.0 Hz, 1H), 6.07 (m, 1H), 5.63 (dd, J = 15.4, 8.4 Hz, 1H), 4.23 - 3.96 (m, 4H), 3.88 - 3.79 (m, 2H), 3.71 (t, J = 11.3 Hz, 2H), 3.41 (d, J = 13.0 Hz, 1H), 3.31 (d, J = 6.0 Hz, 2H), 3.26 (s, 3H), 3.24 (s, 3H), 3.13 (dd, J = 15.2, 10.1 Hz, 1H), 2.90 - 2.67 (m, 3H), 2.61 - 2.07 (m, 9H), 2.01 - 1.66 (m, 6H), 1.42 (s, 1H), 1.13 (d, J = 6.4 Hz, 3H)。LCMS-ESI+ (m/z):C39
H52
ClN4
O6
S [M+H]+計算值:739.32;實驗值:738.87。實例 211
以與實 例 75
相同之方式使用3-(甲氧基甲基)雙環[1.1.1]戊-1-胺鹽酸及實例 109
來合成實例 211
。1
H NMR (400 MHz,丙酮-d6
) δ 7.66 (d, J = 8.5 Hz, 1H), 7.33 - 7.17 (m, 2H), 7.05 (d, J = 22.1 Hz, 2H), 6.87 (d, J = 8.2 Hz, 1H), 6.06 (s, 1H), 5.66 (dd, J = 15.5, 8.5 Hz, 1H), 4.18 - 3.92 (m, 3H), 3.89 -3.62 (m, 3H), 3.44 (s, 2H), 3.42 (d, J = 10.2 Hz, 1H), 3.29 (s, 3H), 3.25 (s, 3H), 3.13 (dd, J = 15.2, 10.2 Hz, 1H), 2.79 - 2.06 (m, 11H), 1.99 (s, 6H), 1.97 - 1.67 (m, 3H), 1.48 - 1.33 (m, 1H), 1.14 (d, J = 6.5 Hz, 3H)。LCMS-ESI+ (m/z):C40
H52
ClN4
O6
S [M+H]+計算值:751.32;實驗值:750.72。實例 212
步驟1:製備1-甲基-3-(甲基胺基)-1H-吡唑-4-甲酸乙酯:使圓底燒瓶裝填有3-胺基-1-甲基-吡唑-4-甲酸乙酯(267 mg,1.58 mmol)。將燒瓶置放在高真空下達5 min,隨後回填有氮氣氛圍。在20℃下添加THF (8 mL,0.2 M限制試劑),繼而添加氫化鈉(60%於礦物油中之分散液,73 mg,1.89 mmol)。將反應混合物在20℃下攪拌45 min,且隨後添加碘甲烷(0.20 mL,3.1 mmol)。將反應物在20℃下攪拌19 hr。添加更多碘甲烷(0.10 mL,1.6 mmol)。在氮氣氛圍下安裝回流冷凝器,且在金屬加熱塊中將反應物升溫至70℃達2 hr。藉由LCMS監視反應直至觀測到1-甲基-3-(甲基胺基)-1H-吡唑-4-甲酸乙酯及3-(二甲基胺基)-1-甲基-1H-吡唑-4-甲酸乙酯兩者形成為止。將反應物自加熱塊中移除且允許冷卻至20℃。將反應物用水淬滅且萃取至乙酸乙酯中。將合併有機相用鹽水洗滌,經硫酸鎂乾燥,過濾,且在真空中濃縮。將所得殘餘物溶解於二氯甲烷中,且藉由急驟管柱層析法(矽膠,24 g,0至100%於己烷中之乙酸乙酯)純化。在40%乙酸乙酯下溶析第一UV-活性產物,在50%乙酸乙酯下溶析第二UV-活性產物,且在70%乙酸乙酯下溶析第三UV-活性產物。收集含有第二UV-活性產物之溶離份且在真空中濃縮,獲得1-甲基-3-(甲基胺基)-1H-吡唑-4-甲酸乙酯(135 mg)。1H NMR (400 MHz,氘代氯仿) δ 7.53 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.72 (s, 3H), 2.93 (s, 3H), 1.29 (t, J = 7.1 Hz, 3H)。
步驟2:製備1-甲基-3-(甲基胺基)-1H-吡唑-4-甲酸:向裝填有1-甲基-3-(甲基胺基)-1H-吡唑-4-甲酸乙酯(135 mg,0.74 mmol)之玻璃螺旋蓋小瓶中添加THF (7 mL),隨後添加甲醇(3.5 mL),接著添加氫氧化鈉(於水中2 M,1.8 mL,3.6 mmol)。將所得混合物在20℃下劇烈攪拌16 hr。將反應物用乙酸乙酯稀釋,且用水洗滌,隨後用鹽水洗滌。將有機相經硫酸鎂乾燥,過濾,且在真空中濃縮。將所得粗產物溶解於THF (3.8 mL)中,隨後添加氫氧化鈉(於水中2 M,0.96 mL,1.92 mmol)。將所得混合物在20℃下劇烈攪拌21 hr。添加更多氫氧化鈉(於水中2 M,0.96 mL,1.92 mmol),繼而添加甲醇(0.1 mL)。在金屬加熱塊中將反應物升溫至60℃達4 hr。藉由矽膠TLC (1:1己烷:乙酸乙酯)監視反應直至觀測到起始酯完全消耗為止。將小瓶自加熱塊中移除且允許冷卻至20℃。用2 N HCl淬滅反應物,該HCl係逐滴添加直至根據pH紙pH <3為止。用乙酸乙酯萃取所得混合物三次。將合併有機相經硫酸鎂乾燥,過濾,且在真空中濃縮。在至少95%純度(50 mg)方面,NMR與1-甲基-3-(甲基胺基)-1H-吡唑-4-甲酸一致。1H NMR (400 MHz,甲醇-d4) δ 7.76 (s, 1H), 3.71 (s, 3H), 2.87 (s, 3H)。
步驟3:以與實例 18
相同之方式使用1-甲基-3-(甲基胺基)-1H-吡唑-4-甲酸及實例 109
來合成實例 212
。1H NMR (400 MHz,乙腈-d3) δ 8.18 (s, 1H), 7.54 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.97 - 6.84 (m, 2H), 6.80 (d, J = 8.2 Hz, 1H), 6.04 - 5.93 (m, 1H), 5.61 (dd, J = 15.3, 8.6 Hz, 1H), 4.24 - 4.08 (m, 1H), 3.95 (d, J = 3.0 Hz, 2H), 3.81 - 3.65 (m, 2H), 3.74 (s, 3H), 3.59 (d, J = 14.4 Hz, 1H), 3.36 (d, J = 14.4 Hz, 1H), 3.21 (s, 3H), 3.07 (dd, J = 15.4, 10.4 Hz, 1H), 2.89 (s, 3H), 2.83 - 2.57 (m, 3H), 2.48 - 2.33 (m, 2H), 2.29 - 2.05 (m, 3H), 2.05 - 1.97 (m, 1H), 1.92 - 1.66 (m, 7H), 1.33 (dd, J = 14.6, 8.2 Hz, 1H), 1.08 (d, J = 6.3 Hz, 3H)。LCMS-ESI+
(m/z):C38
H47
ClN6
O5
S [M+H]+
計算值:735.31;實驗值:735.05。實例 213
步驟1:製備3-(二甲基胺基)-1-甲基-1H-吡唑-4-甲酸乙酯:使圓底燒瓶裝填有3-胺基-1-甲基-吡唑-4-甲酸乙酯(267 mg,1.58 mmol)。將燒瓶置於高真空下達5 min,隨後回填有氮氣氛圍。在20℃下添加THF (8 mL,0.2 M限制試劑),繼而添加氫化鈉(60%於礦物油中之分散液,73 mg,1.89 mmol)。將燒瓶在20℃下攪拌45 min,隨後添加碘甲烷(0.20 mL,3.1 mmol)。將反應物在20℃下攪拌19 hr。添加更多碘甲烷(0.10 mL,1.6 mmol)。在氮氣氛圍下安裝回流冷凝器,且在金屬加熱塊中將反應物升溫至70℃達2 hr。藉由LCMS監視反應直至觀測到1-甲基-3-(甲基胺基)-1H-吡唑-4-甲酸乙酯及3-(二甲基胺基)-1-甲基-1H-吡唑-4-甲酸乙酯兩者形成為止。將反應物自加熱塊中移除且允許冷卻至20℃。將反應物用水淬滅且萃取至乙酸乙酯中。將合併有機相用鹽水洗滌,經硫酸鎂乾燥,過濾,且在真空中濃縮。將所得殘餘物溶解於二氯甲烷中,且藉由急驟管柱層析法(矽膠,24 g,0至100%於己烷中之乙酸乙酯)純化。在40%乙酸乙酯下溶析第一UV-活性產物,在50%乙酸乙酯下溶析第二UV-活性產物,且在70%乙酸乙酯下溶析第三UV-活性產物。收集主要含有第一UV-活性產物之溶離份,且在真空中濃縮,獲得3-(二甲基胺基)-1-甲基-1H-吡唑-4-甲酸乙酯(35 mg)。1H NMR (400 MHz,氘代氯仿) δ 7.69 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 3.72 (s, 3H), 2.89 (s, 6H), 1.29 (t, J = 7.1 Hz, 3H)。
步驟2:製備3-(二甲基胺基)-1-甲基-1H-吡唑-4-甲酸:向裝填有起始材料之玻璃螺旋蓋小瓶中添加THF,隨後添加甲醇,接著添加氫氧化鈉(於水中2 M)。將所得混合物在20℃下劇烈攪拌16 hr。藉由謹慎添加2 N HCl水溶液來淬滅反應物,直至根據pH紙pH <3為止。將混合物用乙酸乙酯萃取,且用水洗滌,隨後用鹽水洗滌。使有機相經硫酸鎂乾燥,過濾,且在真空中濃縮。將所得殘餘物再溶解於THF (1.4 mL)中,隨後添加氫氧化鈉(於水中2 M,0.34 mL)。將所得混合物在20℃下劇烈攪拌18 hr。隨後,添加更多氫氧化鈉(於水中2 M,0.34 mL),繼而添加甲醇(100 μL)。在金屬加熱塊中將反應物升溫至60℃達12 hr。藉由矽膠TLC (1:1己烷:乙酸乙酯)監視反應直至所有起始材料均消耗掉為止。將反應物用2 N HCl淬滅,該HCl係逐滴添加直至根據pH紙pH <3為止。用乙酸乙酯萃取所得混合物三次。將合併有機相經硫酸鎂乾燥,過濾,且在真空中濃縮,得到3-(二甲基胺基)-1-甲基-1H-吡唑-4-甲酸(20 mg),其不經任何進一步純化即用於下一步驟中。1H NMR (400 MHz,甲醇-d4) δ 7.93 (s, 1H), 3.74 (s, 3H), 2.86 (s, 6H)。
步驟3:以與實例 18
相同之方式使用3-(二甲基胺基)-1-甲基-1H-吡唑-4-甲酸及實例 109
來合成實例 213
。1H NMR (400 MHz,乙腈-d3) δ 8.04 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 8.2, 1.9 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 5.90 (dt, J = 14.2, 6.7 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 4.41 (dd, J = 15.0, 6.3 Hz, 1H), 4.05 (s, 2H), 3.88 (s, 3H), 3.79 (dd, J = 15.0, 4.0 Hz, 2H), 3.72 - 3.59 (m, 2H), 3.24 (s, 6H), 3.17 (s, 3H), 3.06 (dd, J = 15.3, 10.5 Hz, 1H), 2.84 - 2.65 (m, 2H), 2.51 - 2.31 (m, 2H), 2.25 (t, J = 8.6 Hz, 1H), 2.19 - 2.10 (m, 1H), 2.05 (d, J = 13.8 Hz, 2H), 1.89 (d, J = 7.1 Hz, 4H), 1.81 - 1.61 (m, 4H), 1.46 - 1.35 (m, 1H), 1.07 (d, J = 6.7 Hz, 3H)。LCMS-ESI+
(m/z):C39
H49
ClN6
O5
S [M+H]+
計算值:749.32;實驗值:749.18。實例 214
以與實例 167
類似之方式使用(R)-2-(甲氧基甲基)環氧乙烷而不使用(S)-2-甲基環氧乙烷及實例 109
來合成實例 214
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.29 - 7.20 (m, 2H), 7.14 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.33 (s, 1H), 6.26 - 6.00 (m, 1H), 5.70 - 5.56 (m, 1H), 4.95 (d, J = 14.4 Hz, 1H), 4.74 (d, J = 14.4 Hz, 1H), 4.26 - 3.68 (m, 9H), 3.64 (dd, J = 10.4, 5.4 Hz, 1H), 3.55 (dd, J = 10.4, 4.8 Hz, 1H), 3.44 (d, J = 14.3 Hz, 1H), 3.39 (s, 3H), 3.25 (s, 3H), 3.15 (dd, J = 15.2, 10.3 Hz, 1H), 2.90 - 1.40 (m, 16H), 1.14 (d, J = 6.4 Hz, 3H)。LCMS: 813.2 (M+Na)+。實例 215
以與實例 214
類似之方式使用實例 110
而不使用109
來合成實例 215
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.51 - 7.19 (m, 4H), 7.14 (s, 1H), 7.05 - 6.92 (m, 1H), 6.34 - 6.21 (m, 1H), 6.09 - 5.95 (m, 1H), 5.63 - 5.53 (m, 1H), 4.91 (d, J = 14.3 Hz, 1H), 4.72 (d, J = 14.4 Hz, 1H), 4.64 - 3.60 (m, 10H), 3.54 (dd, J = 10.5, 4.9 Hz, 1H), 3.46 - 3.11 (m, 2H), 3.39 (s, 3H), 3.19 (s, 3H), 2.93 - 0.81 (m, 21H)。LCMS: 827.1 (M+Na)+。實例 216
步驟1:將3-羥基-1-甲基-1H-吡唑-4-甲酸(100 mg,0.704 mmol)溶解於DMF (3 mL)中,且一次性添加氫化鈉(60%分散液,84 mg,2.1 mmol,3當量)。經由移液管添加1-碘基-2-甲氧基乙烷(2.1 mmol,391 mg,3當量)。將反應混合物加熱至80℃直至TLC指示起始材料完全消耗為止。將反應混合物用飽和NH4
Cl (3 mL)淬滅,隨後用EtOAc (10 mL)稀釋。用飽和NaHCO3
(10 mL)及鹽水(10 mL)洗滌有機層。將有機層經Na2
SO4
乾燥,過濾,且在減壓下濃縮。經由管柱層析法純化殘餘物,獲得3-(2-甲氧基乙氧基)-1-甲基-1H-吡唑-4-甲酸2-甲氧基乙酯。
步驟2:將3-(2-甲氧基乙氧基)-1-甲基-1H-吡唑-4-甲酸2-甲氧基乙酯(20 mg,0.08 mmol)溶解於1,2-二噁烷(1 mL)及1 N NaOH溶液(1 mL)之1:1混合物中。將反應混合物加熱至80℃達4小時(藉由TLC及LCMS監視反應)。隨後,將反應混合物冷卻至室溫,且用1 M HCl (1.5 mL)淬滅,隨後用EtOAc (5 mL)稀釋。用飽和NaHCO3
(5 mL)及鹽水(5 mL)洗滌有機層。將有機層經Na2
SO4
乾燥,過濾,且在減壓下濃縮,獲得3-(2-甲氧基乙氧基)-1-甲基-1H-吡唑-4-甲酸,其不經進一步純化即使用。
步驟3:以與實例 18
相同之方式使用3-(2-甲氧基乙氧基)-1-甲基-1H-吡唑-4-甲酸及實例 109
來合成實例 216
。LCMS-ESI+ (m/z):C40
H49
ClN5
O7
S [M+H]+計算值:780.3;實驗值:780.0。實例 217
以與實例 75
相同之方式使用2-氧雜螺[3.3]庚-6-胺鹽酸及實例 109
來合成實例 217
。1
H NMR (400 MHz,丙酮-d6
) δ 7.59 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 3.8 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H), 6.08 (d, J = 13.1 Hz, 1H), 5.73 (d, J = 12.7 Hz, 1H), 4.65 (s, 2H), 4.55 - 4.47 (AB q, 2H), 4.17 - 4.01 (m, 2H), 3.86 - 3.70 (m, 2H), 3.66 (d, J = 14.3 Hz, 1H), 3.46 (d, J = 14.4 Hz, 1H), 3.27 (s, 3H), 3.20 - 3.07 (m, 1H), 3.03 - 2.08 (m, 12H), 2.02 - 1.67 (m, 3H), 1.15 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C39
H50
ClN4
O6
S [M+H]+計算值:737.31;實驗值:737.05。實例 218
以與實例 167
類似之方式使用實例 110
而不使用實例 109
來合成實例 218
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 7.28 - 7.24 (m, 1H), 7.24 - 7.20 (m, 1H), 7.17 - 7.07 (m, 2H), 7.01 (d, J = 8.1 Hz, 1H), 6.29 (d, J = 1.5 Hz, 1H), 6.04 - 5.95 (m, 1H), 5.57 (dd, J = 15.3, 8.7 Hz, 1H), 4.89 (dd, J = 14.3, 0.9 Hz, 1H), 4.71 (dd, J = 14.4, 1.3 Hz, 1H), 4.54 - 4.38 (m, 1H), 4.19 - 4.06 (m, 3H), 4.04 - 3.92 (m, 1H), 3.92 - 3.81 (m, 1H), 3.79 - 3.60 (m, 3H), 3.39 (d, J = 14.2 Hz, 1H), 3.26 - 3.11 (m, 1H), 3.17 (s, 3H), 2.91 - 1.67 (m, 15H), 1.58 (d, J = 7.1 Hz, 3H), 1.54 - 1.41 (m, 1H), 1.32 (d, J = 6.1 Hz, 3H), 1.05 (d, J = 6.8 Hz, 3H)。LCMS: 775.0。實例 219
以與實例 18
相同之方式使用實例 109
而不使用實例 5
且使用2,3-二氫吡唑并[5,1-b]噁唑-6-甲酸而不使用3-甲氧基丙酸來合成實例219
。1H NMR (400 MHz,甲醇-d4) δ 7.77 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.3, 1.8 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.08 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.07 (dt, J = 14.2, 6.8 Hz, 1H), 5.96 (s, 1H), 5.62 (dd, J = 15.3, 8.7 Hz, 1H), 5.16 (t, J = 8.1 Hz, 2H), 4.49 - 4.37 (m, 2H), 4.29 (dd, J = 15.0, 6.3 Hz, 2H), 4.15 - 3.94 (m, 3H), 3.87 (d, J = 15.0 Hz, 1H), 3.83 - 3.75 (m, 1H), 3.71 (d, J = 14.3 Hz, 1H), 3.29 (s, 3H), 3.09 (dd, J = 15.3, 9.6 Hz, 2H), 2.90 - 2.71 (m, 3H), 2.47 (s, 3H), 2.33 - 2.07 (m, 3H), 2.05 - 1.88 (m, 3H), 1.81 (dd, J = 21.4, 8.9 Hz, 3H), 1.46 (t, J = 11.8 Hz, 1H), 1.13 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C38
H44
ClN5
O6
S [M+H]+計算值:734.27;實驗值:733.75。實例 220
以與實例 18
相同之方式使用中間物 201-1
及3-甲氧基-1-甲基-1H-吡唑-4-甲酸來合成實例 220
。1
H NMR (400 MHz,甲醇-d4) δ 7.98 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.25 (s, 1H), 7.19 (d, J = 9.1 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.99 (s, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.17 (s, 1H), 5.52 (s, 1H), 4.10 - 3.99 (m, 2H), 3.95 (d, J = 3.3 Hz, 2H), 3.89 (d, J = 15.1 Hz, 1H), 3.84 - 3.79 (m, 1), 3.77 (s, 3H), 3.68 (d, J = 14.2 Hz, 1H), 3.26 (s, 4H), 3.07 - 2.89 (m, 1H), 2.89 - 2.73 (m, 2H), 2.69 (d, J = 17.0 Hz, 1H), 2.43 (s, 2H), 2.13 (m, 3H), 1.97 (m, 3H), 1.76 (d, J = 9.2 Hz, 3H), 1.53 - 1.32 (m, 4), 0.93 (t, J = 7.3 Hz, 3H)。LCMS-ESI+:C39
H49
ClN5
O6
S計算值:750.30 (M+H);實驗值:750.80 (M+H)。實例 221
步驟1:將3-羥基-1-甲基-1H-吡唑-4-甲酸(100 mg,0.704 mmol)溶解於DMF (3 mL)中,且一次性添加氫化鈉(60%分散液,84 mg,2.1 mmol,3當量)。經由移液管添加(碘甲基)環丙烷(2.1 mmol,382 mg,3當量)。將反應混合物加熱至80℃直至TLC指示起始材料完全消耗為止。將反應混合物用飽和NH4
Cl (3 mL)淬滅,隨後用EtOAc (10 mL)稀釋。用飽和NaHCO3
(10 mL)及鹽水(10 mL)洗滌有機層。將有機層經Na2
SO4
乾燥,過濾,且在減壓下濃縮。經由管柱層析法純化殘餘物,獲得3-(環丙基甲氧基)-1-甲基-1H-吡唑-4-甲酸環丙基甲酯。
步驟2:將3-(環丙基甲氧基)-1-甲基-1H-吡唑-4-甲酸環丙基甲酯(20 mg,0.08 mmol)溶解於1,2-二噁烷(1 mL)及1 N NaOH溶液(1 mL)之1:1混合物中。將反應混合物加熱至80℃達4小時(藉由TLC及LCMS監視反應)。隨後,將反應混合物冷卻至室溫,用1 M HCl (1.5 mL)淬滅,隨後用EtOAc (5 mL)稀釋。用飽和NaHCO3
(5 mL)及鹽水(5 mL)洗滌有機層。將有機層經Na2
SO4
乾燥,過濾,且在減壓下濃縮,獲得3-(環丙基甲氧基)-1-甲基-1H-吡唑-4-甲酸,其不經進一步純化即使用。
步驟3:以與實例 18
相同之方式使用3-(環丙基甲氧基)-1-甲基-1H-吡唑-4-甲酸及實例 109
來合成實例 221
。LCMS-ESI+ (m/z) [M+H]+: C41
H50
ClN5
O6
S計算值:776.3,實驗值:776.0。實例 222
以與實例 75
類似之方式使用(1R,3R)-3-胺基環戊-1-醇、三乙胺及實例 109
來製備實例 222
。1H NMR (400 MHz, DMSO-d6) δ 7.63 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 8.5, 2.3 Hz, 1H), 7.18 - 7.08 (m, 2H), 6.96 (s, 1H), 6.86 (d, J = 8.0 Hz, 2H), 6.06 - 5.86 (m, 1H), 5.47 (dd, J = 15.3, 8.7 Hz, 1H), 4.20 - 3.97 (m, 4H), 3.92 (d, J = 12.2 Hz, 1H), 3.84 (d, J = 13.7 Hz,1H), 3.73 (d, J = 14.8 Hz, 1H), 3.66 - 3.48 (m, 2H), 3.31 (s, 6H), 3.20 (d, J = 14.2 Hz, 1H), 3.12 (s, 3H), 3.05 - 2.92 (m, 1H), 2.86 - 2.58 (m, 3H), 2.43 - 2.17 (m, 2H), 2.15 - 1.55 (m, 8H), 1.55 - 1.24 (m, 2H), 0.98 (d, J = 6.8 Hz, 3H)。LCMS -ESI+ (m/z):C38
H49
ClN4
O6
S [M+H]+計算值:725.31;實驗值:724.82。實例 223
步驟1:向於DCM (100 mL)中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸(1140 mg,2.4 mmol)之經攪拌溶液中添加109-2-2
(703 mg,2.55 mmol)、1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (756 mg,4.87 mmol)及4-(二甲基胺基)吡啶(595 mg,4.87 mmol)。將反應混合物在室溫下攪拌4 hr。隨後,將反應混合物用DCM稀釋,用1 N HCl及鹽水洗滌。使有機相經MgSO4
乾燥,過濾,且濃縮,得到中間物223-1
。
步驟2:向於甲醇(50 mL)中之223-1
(1300 mg,1.83 mmol)之經攪拌溶液中添加水(5 mL)、K2
CO3
(899 mg,9.17 mmol),且將反應混合物在60℃下攪拌24 hr。添加更多水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑,得到223-2
。
步驟3:向於DCM (25 mL)中之223-2
(1000 mg,1.63 mmol)之經攪拌溶液中添加3-甲氧基-1-甲基-1H-吡唑-4-甲酸(280 mg,1.79 mmol)、1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (507 mg,3.26 mmol)及4-(二甲基胺基)吡啶(399 mg,3.26 mmol)。將反應混合物在室溫下攪拌24 h。隨後,將反應混合物用DCM稀釋,且用1 N HCl及鹽水洗滌。使有機相經MgSO4
乾燥,過濾,濃縮,且進行正相層析法0-10% DCM/MeOH純化,得到223-3
。
步驟4:用氬氣使於1,2-二氯乙烷(370 mL)中之223-3
(1000 mg,1.33 mmol)、哈維達-格拉布II (339 mg,0.40 mmol)及TFA (455 mg,3.99 mmol)之經攪拌溶液脫氣。將反應混合物在80℃下攪拌1 hr。將反應混合物濃縮且進行逆相層析法0.1% TFA 70-95%乙腈純化,得到實例 223
。1H NMR (400 MHz,氘代氯仿) δ 7.83 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.2, 1.9 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 5.64 (t, J = 7.3 Hz, 2H), 4.74 - 4.64 (m, 1H), 4.21 - 4.01 (m, 4H), 3.96 (d, J = 15.1 Hz, 1H), 3.86 - 3.63 (m, 4H), 3.35 (d, J = 14.4 Hz, 1H), 3.16 (dd, J = 15.3, 9.1 Hz, 1H), 2.79 (dd, J = 10.0, 5.3 Hz, 2H), 2.67 - 2.48 (m, 2H), 2.45 - 2.21 (m, 5H), 1.46 (td, J = 14.8, 6.9 Hz, 2H), 1.28 (s, 4H), 1.13 (d, J = 7.1 Hz, 4H), 0.96 - 0.77 (m, 3H)。LCMS-ESI+ (m/z):C37
H44
ClN5
O6
S [M+H]+計算值:722.27;實驗值:722.33。實例 224
步驟1:在2 min內在室溫下向於THF (48 mL)及EtOH (32 mL)中之(2S,4R)-4-甲氧基吡咯啶-2-甲酸(1.5 g,10.33 mmol)、DIPEA (5.4 mL,31.0 mmol)之經攪拌溶液中添加丙炔酸乙酯(1.0 g,10.33 mmol)。將反應物在室溫下攪拌2小時,且隨後在減壓下濃縮。將固體與150 mL DCM一起溶解,且隨後添加DMAP (0.63 g,5.2 mmol)、DIPEA (3.9 mL,22.7 mmol)及三苯膦(3.1 g,12.0 mmol)。使混合物冷卻至0℃,且添加碘(3.0 g,11.9 mmol)。在40 min內劇烈攪拌混合物以達到室溫,且隨後在50℃下加熱1 hr。添加DCM、0.2M HCl及鹽水,將有機相萃取,經Mg2
SO4
乾燥,且在減壓下濃縮。將所得殘餘物溶解於丙酮(60 mL)中,且與Cs2
CO3
(13.5 g,41.3 mmol)及硫酸甲酯(6.5 g,51.7 mmol)組合,在室溫下攪拌60 min。將固體過濾掉,且使有機層進行正相層析法(0至35% EtOAc/己烷)純化,得到224-1
。
步驟2:向於甲醇(3 mL)中之224-1
(120 mg,0.53 mmol)之經攪拌溶液中添加THF (3 mL)及2 N NaOH (1 mL),且在室溫下攪拌48 h。向反應混合物中添加2 N HCl (1 mL),且濃縮反應混合物。添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑,得到224-2
。
步驟3:以與實例 174
(步驟3)相同之方式使用(R)-2,7-二甲氧基-2,3-二氫-1H-吡-6-甲酸及實例 109
來合成實例 224
。1H NMR (400 MHz,氘代氯仿) δ 7.76 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 8.2, 1.8 Hz, 1H), 7.24 - 7.15 (m, 3H), 7.10 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.11 (dt, J = 14.0, 6.6 Hz, 1H), 5.60 (dd, J = 15.6, 7.8 Hz, 1H), 4.53 (tt, J = 6.2, 3.5 Hz, 1H), 4.22 - 3.92 (m, 6H), 3.91 - 3.68 (m, 3H), 3.43 (m, 3H), 3.37 - 3.22 (m, 6H), 3.18 - 2.92 (m, 3H), 2.90 - 2.70 (m, 2H), 2.66 - 2.27 (m, 4H), 2.23 - 1.61 (m, 6H), 1.28 (m, 4H), 1.11 (d, J = 6.8 Hz, 3H), 0.96 - 0.72 (m, 1H)..LCMS-ESI+ (m/z):C42
H51
ClN4
O7
S [M+H]+計算值:791.32;實驗值:791.35。實例 225
步驟1:合成225-1
:在室溫下用DCM (3.0 mL)及DMF (1.5 mL)處理順 -
3-胺基-1-甲基-環丁醇HCl鹽(340 mg,3.36 mmol)。添加DIEA (1.303 g,10.1 mmol),繼而添加二碳酸二第三丁酯(880 mg,4.03 mmol)。將所得混合物在rt下攪拌4 hr。隨後,將反應物用EtOAc (15.0 mL)稀釋,用1 N HCl (3.0 mL)、飽和NaHCO3
(3.0 mL)、鹽水(3.0 mL)洗滌,經硫酸鈉乾燥,過濾,且濃縮,得到粗製物225-1
以用於直接使用。
步驟2:合成225-2
:將於THF (1.5 mL)及DMF (1.5 mL)之混合物中之225-1
(147 mg,0.73 mmol)冷卻至0℃,添加NaH (60 wt%於礦物油中之分散液,42 mg,1.10 mmol)。在攪拌20 min之後,添加EtI (137 mg,0.876 mmol)。將反應物緩慢地升溫至rt,且在室溫下攪拌3 hr。隨後,將反應物分配於EtOAc (15.0 mL)與水(3.0 mL)之間。將有機層用鹽水(3.0 mL)洗滌,經硫酸鈉乾燥,過濾,且濃縮,得到粗產物,藉由combiflash (4 g矽膠,0-43% EtOAc/己烷)將其純化。第2溶析峰為所需產物。1H NMR (400 MHz,氘代氯仿) δ 4.71 - 4.61 (m, 1H), 3.90 - 3.80 (m, 1H), 3.35 (q, J = 7.0 Hz, 2H), 2.44 - 2.35 (m, 2H), 1.97 - 1.88 (m, 2H), 1.45 (s, 9H), 1.32 (d, J = 0.9 Hz, 3H), 1.19 (t, J = 7.0 Hz, 3H)。
步驟3:製備225-3
:在室溫下將來自前一步驟之225-2
溶解於DCM (2.4 mL)中,逐滴添加於1,4-二噁烷(0.8 mL)中之4 N HCl。將反應物在rt下攪拌1 hr。將反應物濃縮,且與EtOAc (3×)一起共蒸發,得到225-3
。
步驟4:以與實例 75
相同之方式用實例 109
及225-3
以及DIEA來合成實例 225
。1H NMR (400 MHz,甲醇-d4) δ 7.69 (d, J = 8.5 Hz, 1H), 7.24 - 7.17 (m, 1H), 7.11 - 7.05 (m, 2H), 6.99 (s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.10 - 5.99 (m, 1H), 5.62 (dd, J = 15.4, 8.9 Hz, 1H), 4.23 (dd, J = 14.8, 7.0 Hz, 1H), 4.07 - 4.00 (m, 2H), 3.96 - 3.86 (m, 1H), 3.86 - 3.74 (m, 3H), 3.66 (d, J = 14.3 Hz, 1H), 3.42 (q, J = 7.0 Hz, 2H), 3.29 (s, 3H), 3.12 - 3.02 (m, 1H), 2.89 - 2.73 (m, 2H), 2.57 - 2.31 (m, 6H), 2.28 - 2.02 (m, 7H), 1.86 - 1.73 (m, 4H), 1.41 (t, J = 11.0 Hz, 1H), 1.31 (s, 3H), 1.19 (t, J = 7.0 Hz, 3H), 1.14 (d, J = 6.7 Hz, 3H)。C40
H53
ClN4
O6
S [M+H]+計算值:753.39;實驗值:752.79。實例 226
以與實例 75
相同之方式使用二乙基胺基甲酸反 -
3-胺基環丁酯肆-三氟乙酸及實例 109
來合成實例 226
。1H NMR (400 MHz,甲醇-d4) δ 7.72 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 5.7 Hz, 2H), 6.95 - 6.86 (m, 2H), 5.95 (dt, J = 14.3, 6.9 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 5.15 - 5.05 (m, 1H), 4.45 - 4.22 (m, 3H), 4.15 - 3.89 (m, 4H), 3.83 (d, J = 15.1 Hz, 1H), 3.74 (dd, J = 9.2, 3.6 Hz, 1H), 3.70 - 3.54 (m, 2H), 3.35 (m, 4H), 3.27 (d, J = 14.8 Hz, 1H), 3.24 (s, 3H), 3.06 (dd, J = 15.3, 10.3 Hz, 1H), 2.89 - 2.66 (m, 2H), 2.54 - 2.39 (m, 2H), 2.33 (q, J = 9.1 Hz, 1H), 2.24 - 2.03 (m, 3H), 2.01 - 1.65 (m, 6H), 1.43 (t, J = 13.4 Hz, 1H), 1.13 (d, J = 6.6)。實例 227
以與實例 237
相同之方式使用中間物 375-2
及(1S,2R)-2-(二氟甲基)環丙-1-胺鹽酸鹽來合成實例 227
。1
H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.24 - 7.14 (m, 2H), 7.12 (d, J = 2.3 Hz, 1H), 7.00 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.02 - 5.91 (m, 1H), 5.86 - 5.66 (m, 2H), 4.23 (dd, J = 15.1, 3.3 Hz, 1H), 4.08 (s, 2H), 3.95 - 3.76 (m, 2H), 3.72 (d, J = 8.1 Hz, 1H), 3.67 (d, J = 14.3 Hz, 1H), 3.31 (d, J = 1.2 Hz, 7H), 3.15 - 3.05 (m, 1H), 2.92 - 2.69 (m, 3H), 2.54 (d, J = 9.7 Hz, 1H), 2.46 - 2.29 (m, 1H), 2.17 - 2.00 (m, 2H), 2.00 - 1.91 (m, 2H), 1.91 - 1.68 (m, 2H), 1.54 (m, 1H), 1.45 (t, J = 13.2 Hz, 1H), 1.31 (s, 1H), 1.25 (d, J = 6.8 Hz, 3H), 1.10 (q, J = 6.6 Hz, 1H), 0.93 (m, 2H)。LCMS-ESI+:C38
H48
ClF2
N4
O6
S計算值:761.29 (M+H);實驗值:761.26 (M+H)。實例 228
製備中間物 228-1
:80℃加熱於1,2-二氯乙烷(485 mL)中之106-2
(2.14 g,3.42 mmol)、氧化鎂(413 mg,10.3 mmol)及(1,3-雙-(2,4,6-三甲基苯基)-2-咪唑啶亞基)二氯(鄰異丙氧基苯基亞甲基)釕(449 mg,717 µmol)之經攪拌混合物。在18.5 h之後,將所得混合物冷卻至室溫,經由矽藻土過濾,且在減壓下濃縮。將殘餘物溶解於乙酸乙酯(50 mL)及甲苯(100 mL)之混合物中。添加矽膠(40 g),且在減壓下濃縮所得漿液。藉由矽膠急驟管柱層析法(0至65%於己烷中之乙酸乙酯)純化殘餘物,得到中間物106-4
及中間物 228-1
之混合物。藉由逆相製備型hplc (0.1%於乙腈/水中之三氟乙酸)純化混合物,得到中間物 228-1
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.31 (dd, J = 8.2, 1.9 Hz, 1H), 7.24 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.07 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.82 (td, J = 9.8, 6.1 Hz, 1H), 5.54 - 5.43 (m, 1H), 4.28 - 4.17 (m, 1H), 4.11 (d, J = 12.1 Hz, 1H), 4.01 (d, J = 12.1 Hz, 1H), 3.94 (d, J = 15.1 Hz, 1H), 3.78 (d, J = 14.3 Hz, 1H), 3.64 (dd, J = 14.3, 3.4 Hz, 1H), 3.49 (d, J = 14.3 Hz, 1H), 3.40 (dd, J = 14.3, 8.1 Hz, 1H), 3.28 (dd, J = 15.2, 10.7 Hz, 1H), 3.23 (s, 3H), 2.88 - 1.27 (m, 15H), 1.17 (d, J = 6.9 Hz, 3H)。LCMS: 598.2。
以與實例 18
相同之方式使用中間物 228-1
及3-甲氧基-1-甲基-吡唑-4-甲酸來合成實例 228
。1H NMR (400 MHz,甲醇-d4) δ 8.14 (s, 1H), 7.78 - 7.68 (m, 1H), 7.37 (dd, J = 8.2, 1.9 Hz, 1H), 7.32 (d, J = 2.0 Hz, 1H), 7.16 - 7.09 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 5.88 - 5.76 (m, 1H), 5.55 - 5.45 (m, 1H), 4.31 - 4.24 (m, 1H), 4.14 - 3.98 (m, 6H), 3.95 - 3.88 (m, 1H), 3.82 (s, 3H), 3.79 - 3.66 (m, 2H), 3.48 (d, J = 14.3 Hz, 1H), 3.30 (s, 3H), 3.27 - 3.19 (m, 1H), 2.97 - 2.72 (m, 3H), 2.57 - 2.35 (m, 3H), 2.34 - 2.23 (m, 1H), 2.17 - 2.08 (m, 1H), 2.02 - 1.90 (m, 3H), 1.89 - 1.79 (m, 3H), 1.53 - 1.42 (m, 1H), 1.14 (d, J = 7.0 Hz, 3H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O6
S計算值H+:736.29;實驗值:736.08。實例 229
步驟1:將於N
,N
-二甲基甲醯胺(18 mL)中之5-甲醯基-1H-吡咯-3-甲酸甲酯(700 mg,4.57 mmol)、(S)-4-(碘甲基)-2,2-二甲基-1,3-二氧雜環戊烷(2.12 g,8.76 mmol)及碳酸鉀(1.58 g,11.4 mmol)之經攪拌混合物加熱至85℃。在16 h之後,使所得混合物冷卻至室溫,且依序添加二乙醚(250 mL)、乙酸乙酯(150 mL)及飽和氯化銨水溶液(20 mL)。將有機層用水(2×400 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至45%於己烷中之乙酸乙酯)純化殘餘物,得到229-1
。
步驟2:在室溫下經由注射器將氯化氫水溶液(6.0 M,2.87 mL,17 mmol)添加至於甲醇(11.5 mL)中之229-1
(766 mg,2.87 mmol)之經攪拌溶液中。在30 min之後,依序添加飽和碳酸鈉水溶液(9 mL)、鹽水(30 mL)及水(20 mL)。用二氯甲烷(4×60 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於二氯甲烷(200 mL)及甲醇(1.16 mL)中,且在室溫下攪拌混合物。經由注射器添加三氟乙酸(2.19 mL,28.7 mmol)。在1 min之後,經由注射器添加三乙基矽烷(4.81 mL,30.1 mmol)。在40 min之後,經由注射器依序添加三氟乙酸(4.38 mL,57.4 mmol)及三乙基矽烷(9.6 mL,60.2 mmol)。在30 min之後,依序添加飽和碳酸鈉水溶液(43 mL)及鹽水(100 mL)。分離有機層,且用二氯甲烷(100 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至75%於己烷中之乙酸乙酯)純化殘餘物,得到229-2
。
步驟3:在室溫下將碘(37.7 mg,148 µmol)添加至於四氫呋喃(1.0 mL)中之229-2
(15 mg,71 µmol)、三苯膦(38.9 mg,148 µmol)及咪唑(14.5 mg,213 µmol)之經攪拌混合物中。在50 min之後,依序添加(R)-八氫吡嗪并[2,1-c][1,4]噁嗪二鹽酸鹽(153 mg,710 µmol)、碳酸鉀(294 mg,2.13 mmol)及乙腈(1.0 mL),且將所得混合物加熱至60℃。在135 min之後,使所得混合物冷卻至室溫,且依序添加水(15 mL)及鹽水(15 mL)。將水層依序用二氯甲烷(30 mL)及乙酸乙酯(30 mL)萃取。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至9%於二氯甲烷中之甲醇)純化殘餘物,得到229-3
。
步驟4:製備實例 229
:在室溫下經由注射器將氫氧化鈉水溶液(2.0 M,54 µL,108 µmol)添加至於四氫呋喃(0.7 mL)及甲醇(0.2 mL)中之229-3
(3.0 mg,14 µmol)之經攪拌混合物中。將所得混合物加熱至80℃。在17.5 h之後,將所得混合物冷卻至室溫,且在減壓下濃縮。藉由在減壓下進行甲苯(2 mL)濃縮來共沸乾燥殘餘物。依序添加四氫呋喃(2 mL)及氯化氫溶液(於1,4-二噁烷中2.0 M,27.2 µL),且在減壓下濃縮所得混合物。藉由在減壓下進行甲苯(2 mL)濃縮來共沸乾燥殘餘物。依序添加中間物 359-4
(6.5 mg,11 µmol)、4-二甲基胺吡啶(4.0 mg,33 µmol)、三甲胺(6.1 µL,43 µmol)及二氯甲烷(1.0 mL),且在室溫下攪拌所得混合物。添加3-(((乙基亞胺基)亞甲基)胺基)-N,N-二甲基丙-1-胺鹽酸鹽(2.7 mg,14 µmol),且將所得混合物加熱至45℃。在60 min之後,將所得混合物冷卻至室溫,且在減壓下濃縮。藉由逆相製備型HPLC (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到實例 229
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.3 Hz, 1H), 7.42 (s, 1H), 7.31 - 7.17 (m, 3H), 7.15 (d, J = 2.6 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 5.93 - 5.79 (m, 1H), 5.74 (dd, J = 15.3, 7.3 Hz, 1H), 4.93 (d, J = 14.6 Hz, 1H), 4.79 (d, J = 14.5 Hz, 1H), 4.54 - 1.66 (m, 40H), 1.56 (d, J = 7.1 Hz, 3H), 1.54 - 1.43 (m, 1H), 1.10 - 0.98 (m, 3H)。LCMS: 901.3。實例 230
以與實例 75
類似之方式使用1-氧雜-6-氮雜螺[3.3]庚烷、三乙胺及實例 109
來製備實例 230
。1
H NMR (400 MHz, DMSO-d 6
) δ 7.65 (d,J
= 8.5 Hz, 1H), 7.28 (dd,J
= 8.5, 2.4 Hz, 1H), 7.18 (d,J
= 2.4 Hz, 1H), 7.05 (dd,J
= 8.2, 1.8 Hz, 1H), 6.92 (d,J
= 8.1 Hz, 1H), 6.85 (d,J
= 1.9 Hz, 1H), 5.88 (dt,J
= 14.3, 6.8 Hz, 1H), 5.49 (dd,J
= 15.2, 8.8 Hz, 1H), 4.40 (t,J
= 7.4 Hz, 2H), 4.27 - 3.91 (m, 5H), 3.86 - 3.53 (m, 4H), 3.19 (dd,J
= 13.7, 10.6 Hz, 1H), 3.13 (s, 3H), 3.01 (dd,J
= 15.2, 10.4 Hz, 1H), 2.89 - 2.58 (m, 4H), 2.41 - 2.29 (m, 3H), 2.29 - 2.04 (m, 2H), 2.02 - 1.59 (m, 7H), 1.36 (d,J
= 9.7 Hz, 1H), 1.24 (s, 1H), 1.01 (d,J
= 6.8 Hz, 3H)。LCMS -ESI+ (m/z):C38
H47
ClN4
O6
S [M+H]計算值:723.21;實驗值722.71。實例 231
以與實例 75
類似之方式使用5-氧雜-2-氮雜螺[3.4]辛烷、三乙胺及實例 109
來製備實例 231
。1
H NMR (400 MHz, DMSO-d 6
) δ 7.65 (d,J
= 8.5 Hz, 1H), 7.28 (dd,J
= 8.5, 2.4 Hz, 1H), 7.18 (d,J
= 2.4 Hz, 1H), 7.06 (dd,J
= 8.2, 1.8 Hz, 1H), 6.92 (d,J
= 8.1 Hz, 1H), 6.86 (d,J
= 1.9 Hz, 1H), 5.89 (dt,J
= 14.3, 6.8 Hz, 1H), 5.49 (dd,J
= 15.2, 8.8 Hz, 1H), 4.14 - 3.84 (m, 5H), 3.75 (t,J
= 6.7 Hz, 3H), 3.66 - 3.54 (m, 2H), 3.20 (d,J
= 14.2 Hz, 1H), 3.13 (s, 3H), 3.01 (dd,J
= 15.3, 10.4 Hz, 1H), 2.86 - 2.60 (m, 3H), 2.43 - 2.28 (m, 2H), 2.29 - 2.08 (m, 2H), 2.07 - 1.91 (m, 4H), 1.84 (dq,J
= 11.3, 5.4, 4.1 Hz, 4H), 1.70 (ddt,J
= 23.7, 15.0, 7.1 Hz, 3H), 1.48 - 1.17 (m, 2H), 1.02 (d,J
= 6.8 Hz, 3H)。LCMS -ESI+ (m/z):C39
H49
ClN4
O6
S [M+H]計算值:737.31;實驗值736.84。實例 232
以與實例 75
相同之方式用實例 109
及(2S)-2-(甲氧基甲基)嗎啉;鹽酸鹽以及DIEA來合成實例 232
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.00 - 5.90 (m, 1H), 5.58 (dd, J = 15.2, 9.3 Hz, 1H), 4.39 (dd, J = 14.9, 6.4 Hz, 1H), 4.27 - 4.02 (m, 4H), 3.89 (dd, J = 28.9, 13.1 Hz, 2H), 3.76 (dd, J = 9.3, 3.7 Hz, 1H), 3.67 (d, J = 14.6 Hz, 1H), 3.63 - 3.41 (m, 4H), 3.39 (s, 3H), 3.28 - 3.23 (m, 4H), 3.12 - 3.02 (m, 1H), 2.88 - 2.70 (m, 3H), 2.55 - 2.41 (m, 2H), 2.38 - 2.26 (m, 1H), 2.23 - 2.07 (m, 3H), 2.00 - 1.69 (m, 7H), 1.50 - 1.36 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H)。LCMS-ESI+ (m/z):C39
H51
ClN4
O7
S計算值H+:755.32;實驗值:754.99。實例 233
以與實例 75
相同之方式使用實例 109
及3-氰基氮雜環丁烷氯化氫以及三乙胺來合成實例 233
。1
H NMR (400 MHz,乙腈-d3
) δ 7.71 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.2, 1.9 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 1.9 Hz, 1H), 5.84 (dt, J = 14.1, 6.7 Hz, 1H), 5.53 (dd, J = 15.2, 9.2 Hz, 1H), 4.32 (dd, J = 15.1, 6.4 Hz, 1H), 4.24 (s, 2H), 4.14 (s, 2H), 4.05 (d, J = 1.9 Hz, 2H), 3.79 (d, J = 15.5 Hz, 1H), 3.70 (d, J = 14.1 Hz, 1H), 3.67 - 3.61 (m, 1H), 3.55 (tt, J = 9.1, 6.0 Hz, 1H), 3.39 (dd, J = 15.0, 4.9 Hz, 1H), 3.22 (d, J = 14.2 Hz, 1H), 3.16 (s, 3H), 3.03 (dd, J = 15.4, 10.3 Hz, 1H), 2.85 - 2.66 (m, 2H), 2.42 (dd, J = 9.4, 5.6 Hz, 1H), 2.33 (dd, J = 14.3, 5.9 Hz, 1H), 2.22 (p, J = 9.4 Hz, 1H), 2.14 - 1.97 (m, 3H), 1.90 - 1.61 (m, 6H), 1.45 - 1.33 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H)。LCMS-ESI+
(m/z):C37
H44
ClN5
O5
S [M+H]+
計算值:706.28;實驗值:705.8。實例 234
以與實例 75
相同之方式用實例 109
及4-(2-甲氧基乙氧基)哌啶來合成實例 234
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.6 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 - 7.06 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.02 - 5.89 (m, 1H), 5.63 - 5.52 (m, 1H), 4.37 (dd, J = 14.9, 6.3 Hz, 1H), 4.13 - 4.04 (m, 2H), 4.04 - 3.80 (m, 3H), 3.76 (dd, J = 9.3, 3.7 Hz, 1H), 3.71 - 3.51 (m, 7H), 3.39 (s, 3H), 3.30 (s, 1H), 3.28 - 3.23 (m, 4H), 3.08 (dd, J = 15.3, 10.3 Hz, 1H), 2.89 - 2.69 (m, 2H), 2.55 - 2.40 (m, 2H), 2.38 - 2.26 (m, 1H), 2.23 - 2.03 (m, 3H), 2.01 - 1.68 (m, 8H), 1.61 - 1.29 (m, 4H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C41
H55
ClN4
O7
S計算值H+:783.35;實驗值:783.61。實例 235
以與實例 182
相同之方式使用3-乙氧基氮雜環丁烷而不使用外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙-1-胺來合成實例 235
。1H NMR (400 MHz,甲醇-d4) δ 7.76 (d, J = 8.6 Hz, 1H), 7.28 - 7.04 (m, 3H), 7.01 - 6.77 (m, 2H), 6.03 (s, 1H), 5.54 (dd, J = 15.1, 9.4 Hz, 1H), 4.46 - 4.10 (m, 4H), 4.06 (d, J = 2.2 Hz, 2H), 3.86 (d, J = 14.6 Hz, 2H), 3.78 (dd, J = 9.1, 3.5 Hz, 1H), 3.66 (d, J = 13.9 Hz, 2H), 3.57 - 3.41 (m, 2H), 3.26 (s, 3H), 3.05 (dd, J = 15.1, 10.3 Hz, 2H), 2.79 (d, J = 18.0 Hz, 2H), 2.48 (s, 2H), 2.36 (d, J = 9.8 Hz, 2H), 2.12 (d, J = 13.4 Hz, 2H), 1.94 (d, J = 12.1 Hz, 2H), 1.77 (tt, J = 17.9, 9.5 Hz, 2H), 1.43 (t, J = 13.0 Hz, 1H), 1.31 (s, 3H), 1.22 (t, J = 7.0 Hz, 2H), 1.12 (d, J = 6.2 Hz, 2H), 0.95 - 0.88 (m, 1H)。LCMS-ESI+ (m/z):C38
H44
ClN5
O6
S [M+H]+計算值:725.31;實驗值:724.71。實例 236
以與實例 75
相同之方式使用實例 109
及3-氧雜-6-氮雜雙環[3.1.1]庚烷甲苯磺酸酯來合成實例 236
。1
H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.6 Hz, 1H), 7.21 - 7.17 (m, 1H), 7.12 (d, J = 2.3 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 5.98 (dd, J = 14.8, 7.4 Hz, 1H), 5.59 (dd, J = 15.2, 8.9 Hz, 1H), 4.33 (m, 2H), 4.27 (m, 3H), 4.13 - 4.01 (m, 2H), 3.89 - 3.80 (m, 3H), 3.77 (dd, J = 9.2, 3.7 Hz, 1H), 3.67 (d, J = 14.1 Hz, 2H), 3.27 (d, J = 5.6 Hz, 4H), 3.08 (dd, J = 15.4, 10.3 Hz, 1H), 2.88 - 2.74 (m, 2H), 2.66 (q, J = 6.9 Hz, 1H), 2.56 - 2.43 (m, 3H), 2.35 (t, J = 9.1 Hz, 1H), 2.25 - 2.07 (m, 4H), 2.04 - 1.87 (m, 2H), 1.87 - 1.70 (m, 3H), 1.45 (t, J = 12.6 Hz, 1H), 1.14 (d, J = 6.5 Hz, 3H)。LCMS-ESI+:C38
H48
ClN4
O6
S計算值:723.29 (M+H);實驗值:722.97 (M+H)。實例 237
向於二氯甲烷(2 mL)中之實例 109
(10 mg,0.017 mmol)之混合物中添加氯甲酸4-
硝基苯酯(6.7 mg,0.033 mmol)、DMAP (8 mg,0.067 mmol)及三乙胺。在室溫下攪拌反應混合物。在4小時之後,添加2-(氮雜環丁烷-3-基)丙-2-醇(6.7 mg,0.059 mmol),且將混合物連續攪拌30分鐘。將反應物濃縮,溶解於MeOH (2 mL)中,過濾,且藉由逆相製備型HPLC純化,用60-100% ACN/H2O及0.1% TFA溶析,獲得實例 237
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.72 (d,J
= 8.5 Hz, 1H), 7.25 - 7.02 (m, 3H), 6.90 (d,J
= 8.3 Hz, 2H), 5.95 (dd,J
= 14.9, 7.6 Hz, 1H), 5.56 (dd,J
= 15.2, 9.0 Hz, 1H), 4.27 (dd,J
= 14.9, 6.3 Hz, 1H), 4.11 - 3.87 (m, 7H), 3.85 - 3.69 (m, 2H), 3.63 (t,J
= 15.5 Hz, 2H), 3.24 (s, 3H), 3.14 - 2.98 (m, 1H), 2.88 - 2.54 (m, 3H), 2.54 - 2.23 (m, 3H), 2.23 - 2.00 (m, 3H), 2.00 - 1.62 (m, 7H), 1.42 (t,J
= 12.8 Hz, 1H), 1.20 - 1.06 (m, 9H)。LCMS -ESI+ (m/z):C39
H51
ClN4
O6
S [M+H]計算值:739.33;實驗值738.98。實例 238
除以下以外,以與實例 284
相同之順序來合成實例 238
:在步驟1中,使用(9aS)-1,3,4,6,7,8,9,9a-八氫吡嗪并[2,1-c][1,4]噁嗪;二鹽酸鹽,且在添加STAB之前,亦將三乙胺(2當量)添加至反應混合物中。1
H NMR (400 MHz,甲醇-d4) δ 7.71 (d, J = 1.9 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.35 (dd, J = 8.3, 1.8 Hz, 1H), 7.03 (dd, J = 10.5, 2.2 Hz, 2H), 6.86 - 6.75 (m, 3H), 6.22 - 6.11 (m, 1H), 5.69 (dd, J = 15.4, 8.2 Hz, 1H), 4.17 - 4.08 (m, 1H), 4.05 - 3.90 (m, 7H), 3.84 - 3.73 (m, 7H), 3.63 (d, J = 14.7 Hz, 1H), 3.46 (d, J = 14.0 Hz, 1H), 3.24 - 3.07 (m, 5H), 3.05 - 2.68 (m, 8H), 2.59 - 2.38 (m, 4H), 2.34 - 2.21 (m, 3H), 2.07 (d, J = 13.7 Hz, 1H), 2.01 - 1.92 (m, 3H), 1.90 - 1.81 (m, 3H), 1.40 - 1.30 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H)。LCMS-ESI+ (m/z):C46
H59
ClN6
O6
S計算值H+:859.39;實驗值:859.15。實例 239
步驟1:在5 min內在0℃下將二-第三丁基-二氮烯-1,2-二甲酸酯(4.51 g,19.6 mmol)以三等份添加至於四氫呋喃(120 mL)中之5-甲醯基-1H-吡咯-3-甲酸甲酯(2.00 g,13.1 mmol)、2-亞甲基丙烷-1,3-二醇(5.32 mL,65.3 mmol)及三苯膦(6.17 g,23.5 mmol)之經攪拌混合物中,且使反應混合物緩慢地升溫至室溫。在42 h之後,在減壓下濃縮所得混合物。藉由矽膠急驟管柱層析法(0至43%於己烷中之乙酸乙酯)純化殘餘物,得到239-1
。
步驟2:在室溫下將AD-混合-β (14.9 g)添加至於第三丁基醇(55 mL)及水(55 mL)中之239-1
(2.06 g,9.24 mmol)之經劇烈攪拌溶液中。在21 h之後,添加飽和亞硫酸氫鈉水溶液(34 mL)。在30 min之後,依序添加鹽水(50 mL)及水(20 mL)。將水層依序用乙酸乙酯(2×200 mL)及二氯甲烷(200 mL)萃取。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將甲醇(300 mL)添加至水層中,且將所得不均勻混合物過濾且在減壓下濃縮。將濾液與來自合併有機層濃縮之殘餘物組合,且在減壓下濃縮所得混合物。依序添加甲醇(300 mL)及四氫呋喃(200 mL),且劇烈濕磨且隨後劇烈攪拌所得不均勻層。在15 min之後,將所得混合物過濾且在減壓下濃縮。依序添加甲醇(100 mL)及四氫呋喃(200 mL)。添加矽膠(24 g),且在減壓下濃縮所得漿液。藉由矽膠急驟管柱層析法(0至20%於二氯甲烷中之甲醇)純化殘餘物,得到239-2
。
步驟3:在室溫下經由注射器將三氟乙酸(3.65 mL,47.7 mmol)添加至於二氯甲烷(300 mL)及甲醇(3.87 mL)中之239-2
(1.23 g,4.77 mmol)之經攪拌溶液中。在1 min之後,經由注射器添加三乙基矽烷(8.00 mL,50.1 mmol)。在7 min之後,經由注射器依序添加三氟乙酸(9.13 mL,119 mmol)及三乙基矽烷(19.0 mL,119 mmol)。在7 h之後,添加鹼性氧化鋁(35 g),且在減壓下濃縮所得漿液。藉由矽膠急驟管柱層析法(0至9%於二氯甲烷中之甲醇)純化殘餘物,得到239-3
。
步驟4:在室溫下經由注射器將二-異-丙基-二氮烯-1,2-二甲酸酯(147 µL, 746 µmol)添加至於甲苯(3.0 mL)中之239-3
(60.0 mg,249 µmol)及三苯膦(209 mg,796 µmol)之經攪拌混合物中,且在微波反應器中將所得混合物加熱至140℃。在30 min之後,將所得混合物冷卻至室溫,且藉由矽膠急驟管柱層析法(0至48%於己烷中之乙酸乙酯)純化,得到239-4
。
步驟5:在室溫下經由注射器將氫氧化鈉水溶液(2.0 M,400 µL,800 µmol)添加至於四氫呋喃(0.6 mL)及甲醇(0.4 mL)中之239-4
(16 mg,69 µmol)之經攪拌溶液中,且將所得混合物加熱至75℃。在110 min之後,使所得混合物冷卻至室溫,且依序添加氯化氫水溶液(2.0 M,0.7 mL)及鹽水(5 mL)。依序用二氯甲烷(2×15 mL)及乙酸乙酯(15 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮,得到239-5
。
步驟6:以與實例 106
類似之方式使用中間物 359-4
而不使用實例 109
且使用239-5
而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸來合成實例 239
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.29 - 7.13 (m, 4H), 7.00 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 5.93 - 5.80 (m, 1H), 5.74 (dd, J = 15.3, 7.4 Hz, 1H), 4.90 (s, 2H), 4.71 (d, J = 7.0 Hz, 2H), 4.51 (dd, J = 7.1, 2.8 Hz, 2H), 4.47 - 4.04 (m, 5H), 3.88 (d, J = 15.2 Hz, 1H), 3.74 (d, J = 14.3 Hz, 1H), 3.40 (d, J = 14.3 Hz, 1H), 3.19 (dd, J = 15.3, 8.9 Hz, 1H), 2.97 - 1.63 (m, 15H), 1.56 (d, J = 7.1 Hz, 3H), 1.54 - 1.45 (m, 1H), 1.12 - 0.99 (m, 3H)。LCMS:789.0。實例 240
步驟1:在室溫下將於乙醇(1.5 mL)中之106-4
(30.0 mg,50.2 µmol)及氧化鉑(IV) (5.7 mg,25.1 µmol)之經劇烈攪拌混合物置於氫氣氛圍(1 atm)下。在220 min之後,將所得混合物經由矽藻土過濾且在減壓下濃縮,得到240-1
。
步驟2:以與實例 106
類似之方式使用240-1
而不使用106-4
來合成實例 240
。1H NMR (400 MHz,丙酮-d6) δ 8.13 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.46 (dd, J = 8.2, 1.9 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.26 (dd, J = 8.5, 2.4 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 4.13 (d, J = 12.1 Hz, 1H), 4.08 (s, 3H), 4.05 (d, J = 12.1 Hz, 1H), 3.91 (d, J = 14.6 Hz, 1H), 3.86 (s, 3H), 3.74 (t, J = 16.3 Hz, 2H), 3.46 (d, J = 14.4 Hz, 1H), 3.40 - 3.30 (m, 1H), 3.32 (s, 3H), 3.19 (dd, J = 15.1, 9.7 Hz, 1H), 3.07 - 1.33 (m, 20H), 1.07 (d, J = 6.6 Hz, 3H)。LCMS:738.1。實例 241
步驟1:在兩天內在室溫下攪拌於DCE (10 mL)中之5-甲醯基-1-甲基-1H-吡咯-3-甲酸(150 mg,0.98 mmol)、N-甲基四氫-2H-哌喃-4-胺(118 mg,1.03 mmol)及乙酸(0.11 mL,1.96 mmol)之混合物。添加硼氫化鈉(74 mg,1.96 mmol),且將反應混合物在室溫下再攪拌16 h。添加5 mL水以淬滅反應物。隨後,將其濃縮至乾。將粗殘餘物負載至矽膠上且藉由管柱層析法使用10-50%於DCM中之MeOH純化,獲得中間物241-1
。LCMS-ESI+:C13
H20
N2
O3
[M+H]+
計算值:253.16;實驗值:252.82。
步驟2:以與實例 18
相同之方式使用中間物241-1
及實例 109
來合成實例 241
。1
H NMR (400 MHz,甲醇-d
4) δ 8.12 (d,J
= 7.6 Hz, 1H), 7.66 (s, 2H), 7.29 (d,J
= 8.2 Hz, 1H), 7.09 (s, 1H), 7.01 (d,J
= 8.3 Hz, 2H), 6.86 (d,J
= 8.2 Hz, 1H), 6.14 (d,J
= 14.7 Hz, 1H), 5.65 (t,J
= 12.0 Hz, 1H), 4.63 (s, 2H), 4.27 (s, 2H), 4.14 (d,J
= 11.5 Hz, 2H), 4.03 (s, 1H), 3.97 - 3.90 (m, 1H), 3.79 (s, 3H), 3.66 (d,J
= 14.2 Hz, 2H), 3.53 (d,J
= 12.7 Hz, 2H), 3.31 (s, 3H), 3.27 (s, 2H), 3.19 (s, 2H), 2.83 (s, 4H), 2.66 (s, 1H), 2.47 (s, 2H), 2.23 (d,J
= 7.8 Hz, 2H), 2.11 (d,J
= 11.6 Hz, 2H), 2.00 - 1.89 (m, 3H), 1.82 (s, 2H), 1.41 (s, 2H), 1.31 (s, 3H), 1.15 (d,J
= 6.3 Hz, 2H), 0.98 - 0.85 (m, 2H)。LCMS-ESI+ C45
H58
ClN5
O6
S [M+H]+
計算值:832.39;實驗值:832.40。實例 242
以與實例 75
相同之方式使用實例 109
及3-乙基氮雜環丁烷來合成實例 242
。1H NMR (400 MHz,氘代氯仿) δ 7.70 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.12 - 7.06 (m, 2H), 6.94 - 6.89 (m, 2H), 5.92 (dt, J = 13.6, 6.4 Hz, 1H), 5.53 (dd, J = 15.2, 8.9 Hz, 1H), 4.40 (d, J = 14.8 Hz, 1H), 4.18 - 4.01 (m, 4H), 3.82 (d, J = 15.3 Hz, 1H), 3.77 - 3.61 (m, 4H), 3.25 (s, 4H), 2.96 (dd, J = 15.2, 10.3 Hz, 1H), 2.76 (dd, J = 11.6, 4.4 Hz, 2H), 2.63 - 2.21 (m, 2H), 2.18 - 1.89 (m, 5H), 1.78 (dq, J = 17.1, 9.6 Hz, 2H), 1.69 - 1.57 (m, 3H), 1.38 (q, J = 12.9, 11.5 Hz, 1H), 1.25 (s, 1H), 1.09 (d, J = 6.4 Hz, 3H), 0.89 (t, J = 7.3 Hz, 3H)。LCMS-ESI+
(m/z):C38
H49
ClN4
O5
S [M+H]+
計算值:709.31;實驗值:708.95。實例 243
以與實例 75
相同之方式使用實例 109
及(1S
,2S
)-2-(三氟甲基)環丙-1-胺鹽酸鹽來合成實例 243
。1
H NMR (400 MHz,甲醇-d4) δ 7.77 - 7.67 (m, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.10 (s, 2H), 6.96 - 6.87 (m, 2H), 6.02 (t, J = 7.9 Hz, 1H), 5.61 (dd, J = 15.1, 8.9 Hz, 1H), 4.26 (d, J = 13.3 Hz, 1H), 4.05 (s, 2H), 3.87 - 3.68 (m, 2H), 3.66 (d, J = 14.2 Hz, 1H), 3.28 (m, 4H), 3.12 - 3.06 (m, 1H), 3.03 (dd, J = 7.9, 4.6 Hz, 1H), 2.84 (d, J = 16.2 Hz, 1H), 2.79 - 2.69 (m, 1H), 2.48 (d, J = 15.1 Hz, 2H), 2.38 (s, 1H), 2.32 - 2.15 (m, 1H), 2.10 (d, J = 13.6 Hz, 1H), 2.06 - 1.92 (m, 2H), 1.87 (d, J = 10.6 Hz, 1H), 1.80 (q, J = 6.8, 5.7 Hz, 1H), 1.62 (m, 1H), 1.40 (dd, J = 25.6, 13.0 Hz, 2H), 1.31 (d, J = 3.7 Hz, 2H), 1.20 (dt, J = 7.6, 6.1 Hz, 1H), 1.15 (m, 4H)。LCMS-ESI+:C37
H45
ClF3
N4
O5
S計算值:749.27 (M+H);實驗值:749.40 (M+H)。實例 244
在室溫下將碳酸二苯酯(29.4 mg,137 µmol)添加至於乙腈(0.6 mL)中之240-1
(9.5 mg,16 µmol)及4-(二甲基胺基)吡啶(9.7 mg,79 µmol)之經攪拌混合物中。在21 h之後,依序添加4-甲氧基氮雜環丁烷鹽酸鹽(48.9 mg,396 µmol)及N
,N
-二異丙基乙胺(152 µL,871 µmol),且將所得混合物加熱至55℃。在150 min之後,將所得混合物冷卻至室溫且藉由逆相製備型HPLC (0.1%於乙腈/水中之三氟乙酸)純化,得到實例 244
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.6 Hz, 1H), 7.31 - 7.21 (m, 2H), 7.17 - 7.11 (m, 2H), 6.98 (d, J = 8.1 Hz, 1H), 4.35 - 3.78 (m, 7H), 3.73 (d, J = 14.3 Hz, 1H), 3.49 - 3.22 (m, 4H), 3.30 (s, 3H), 3.24 (s, 3H), 3.16 (dd, J = 15.4, 8.6 Hz, 1H), 2.92 - 1.25 (m, 16H), 1.12 (d, J = 6.7 Hz, 3H)。LCMS:713.1。實例 245
以與實例 75
相同之方式使用實例 109
及哌嗪-1-甲酸甲酯來合成實例 245
。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.6 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 - 7.06 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 6.00 - 5.89 (m, 1H), 5.58 (dd, J = 15.2, 9.3 Hz, 1H), 4.39 (dd, J = 14.9, 6.4 Hz, 1H), 4.12 - 4.02 (m, 2H), 3.85 (d, J = 15.1 Hz, 1H), 3.79 - 3.71 (m, 4H), 3.70 - 3.56 (m, 5H), 3.53 - 3.43 (m, 4H), 3.27 - 3.24 (m, 4H), 3.08 (dd, J = 15.3, 10.3 Hz, 1H), 2.87 - 2.71 (m, 2H), 2.54 - 2.41 (m, 2H), 2.37 - 2.26 (m, 1H), 2.23 - 2.07 (m, 3H), 2.00 - 1.86 (m, 3H), 1.86 - 1.68 (m, 4H), 1.50 - 1.37 (m, 1H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C39
H50
ClN5
O7
S計算值H+:768.31;實驗值:767.73。實例 246
以與實例 237
相同之方式使用實例 109
及3-甲氧基-3-(三氟甲基)氮雜環丁烷鹽酸鹽來合成實例 246
。1
H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.4, 2.4 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.1, 1.9 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 5.96 (dt, J = 14.3, 6.8 Hz, 1H), 5.59 (dd, J = 15.2, 9.2 Hz, 1H), 4.35 (dd, J = 14.9, 6.4 Hz, 1H), 4.15 (d, J = 24.8 Hz, 5H), 4.09 (d, J = 1.2 Hz, 2H), 3.85 (d, J = 15.1 Hz, 1H), 3.76 (dd, J = 9.2, 3.7 Hz, 1H), 3.64 (dd, J = 23.7, 14.6 Hz, 2H), 3.53 (d, J = 1.1 Hz, 3H), 3.26 (m, 4H), 3.08 (dd, J = 15.3, 10.3 Hz, 1H), 2.90 - 2.65 (m, 2H), 2.46 (dd, J = 14.8, 5.5 Hz, 2H), 2.33 (p, J = 9.1 Hz, 1H), 2.19 (dt, J = 14.6, 7.2 Hz, 1H), 2.12 (d, J = 12.9 Hz, 2H), 2.03 - 1.86 (m, 1H), 1.79 (tt, J = 17.7, 9.6 Hz, 3H), 1.45 (t, J = 12.5 Hz, 1H), 1.33 (d, J = 16.3 Hz, 1H), 1.15 (d, J = 6.7 Hz, 3H)。LCMS-ESI+:C38
H47
ClF3
N4
O6
S計算值:779.28 (M+H);實驗值:779.62 (M+H)。實例 247
以與實例 237
類似之方式使用1-(哌嗪-1-基)乙-1-酮、三乙胺及實例109來製備實例 247
。LCMS -ESI+ (m/z):C39
H50
ClN5
O6
S [M+H]計算值:752.32;實驗值751.80。實例 248
以與實例 237
類似之方式使用5,8-二氧雜-2-氮雜螺[3.5]壬烷、三乙胺及實例 109
來製備實例 248
。LCMS -ESI+ (m/z):C39
H49
ClN4
O7
S [M+H]計算值:753.30;實驗值752.88。實例 249
將於乙酸酐(10 mL)中之實例 359
(60 mg,0.081 mmol)之經攪拌溶液在60℃下加熱4小時。添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑,且進行逆相層析法0.1% TFA 70-95%乙腈純化,得到實例 249
。1H NMR (400 MHz,氘代氯仿) δ 7.86 - 7.61 (m, 3H), 7.35 - 7.15 (m, 3H), 7.10 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.83 (s, 1H), 5.60 (dd, J = 15.4, 6.7 Hz, 1H), 5.37 - 5.17 (m, 1H), 4.21 - 3.96 (m, 5H), 3.92 (d, J = 15.2 Hz, 1H), 3.82 (d, J = 12.5 Hz, 3H), 3.75 - 3.63 (m, 2H), 3.26 (d, J = 14.7 Hz, 1H), 3.01 (dd, J = 15.6, 7.5 Hz, 1H), 2.78 (dd, J = 10.7, 5.1 Hz, 2H), 2.63 - 2.46 (m, 2H), 2.16 (d, J = 16.3 Hz, 3H), 2.01 - 1.82 (m, 4H), 1.82 - 1.63 (m, 3H), 1.57 (d, J = 7.2 Hz, 3H), 1.42 (d, J = 9.3 Hz, 2H), 1.26 (d, J = 13.1 Hz, 4H)。LCMS-ESI+ (m/z):C40
H48
ClN5
O7
S [M+H]+計算值:778.30;實驗值:778.35。實例 250
步驟1:向於無水THF (1.3 mL)中之(2R,3S)-3-羥基-2-甲基氮雜環丁烷-1-甲酸第三丁酯(50 mg,0.267 mmol)之溶液中添加60%氫化鈉(油分散液) (15 mg,0.401 mmol)。將混合物之溫度維持在0℃下。在完成添加之後,在相同溫度下繼續攪拌10 min。隨後,逐滴添加碘甲烷(0.02 mL,0.321 mmol),且使溫度升高至rt。將反應混合物在此溫度下攪拌1 h。在減壓下移除溶劑,得到(2R,3S)-3-甲氧基-2-甲基氮雜環丁烷-1-甲酸第三丁酯。
步驟2:向於異丙醇(1.65 mL)中之(2R,3S)-3-甲氧基-2-甲基氮雜環丁烷-1-甲酸第三丁酯(53.7 mg,0.267 mmol)之溶液中添加於二噁烷(4 M,0.2 mL,0.8 mmol)中之氯化氫溶液。將反應混合物在50℃下攪拌25 h。在減壓下移除溶劑,得到(2R,3S)-3-甲氧基-2-甲基氮雜環丁烷鹽酸鹽。
步驟3:向於DCM (0.4 mL)中之實例 109
(10 mg,0.0167 mmol)、氯甲酸硝基苯酯(4.04 mg,0.0201 mmol)及DMAP (4.08 mg,0.0334 mmol)之溶液中添加三乙胺(0.04 mL,0.29 mmol),且在rt下攪拌4 h。添加於DCM (0.4 mL)中之(2R,3S)-3-甲氧基-2-甲基氮雜環丁烷鹽酸鹽(11.5 mg,0.0836 mmol)及三乙胺(0.05 mL,0.359 mmol)之溶液,且攪拌1 h。在減壓下移除溶劑,將殘餘物再溶解於DMSO (2 mL)中,且藉由Gilson逆相製備型HPLC純化,且用50-100% ACN/H2
O及0.1% TFA溶析,獲得實例 250
。1H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 7.12 - 7.07 (m, 2H), 6.91 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 5.95 (dt, J = 14.4, 6.6 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 4.31 (dd, J = 14.8, 6.2 Hz, 1H), 4.23 - 4.11 (m, 2H), 4.06 (d, J = 1.8 Hz, 2H), 3.83 (d, J = 15.1 Hz, 1H), 3.77 - 3.71 (m, 3H), 3.65 (d, J = 14.2 Hz, 1H), 3.61 - 3.52 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J = 15.3, 10.3 Hz, 1H), 2.90 - 2.62 (m, 2H), 2.54 - 2.39 (m, 2H), 2.39 - 2.22 (m, 1H), 2.22 - 2.02 (m, 3H), 1.97 - 1.63 (m, 6H), 1.50 - 1.38 (m, 4H), 1.13 (d, J = 6.4 Hz, 3H)。LCMS-ESI+
(m/z):C38
H49
ClN4
O6
S [M+H]+
計算值:725.31;實驗值:724.92。實例 251
以與實例 362
相同之方式用實例 109
及3-(2-甲氧基乙氧基)氮雜環丁烷鹽酸鹽來製備實例 251
。LCMS-ESI+ (m/z):C39
H51
ClN4
O7
S [M+H]+
計算值:755.3240;實驗值:754.79。1
H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.6, 2.4 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.95 - 6.85 (m, 2H), 5.96 (dt, J = 14.1, 6.7 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 4.40 - 4.13 (m, 4H), 4.12 - 4.00 (m, 2H), 3.98 - 3.80 (m, 3H), 3.74 (dd, J = 9.2, 3.7 Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.62 - 3.52 (m, 5H), 3.37 (s, 3H), 3.29 - 3.25 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J = 15.3, 10.3 Hz, 1H), 2.87 - 2.69 (m, 2H), 2.52 - 2.41 (m, 2H), 2.32 (p, J = 8.6, 7.9 Hz, 1H), 2.24 - 2.04 (m, 3H), 2.00 - 1.66 (m, 6H), 1.42 (t, J = 12.7 Hz, 1H), 1.13 (d, J = 6.6 Hz, 3H)。實例 252
步驟1:向於二噁烷(1 mL)及水(0.7 mL)中之3-甲氧基-1H-吡唑-4-甲酸乙酯(350 mg,2.05 mmol)之懸浮液中添加KOH (346 mg,6.17 mmol)。在30 min內向經攪拌混合物中鼓入CHIF2
氣體。兩種區位異構體產物形成有在221下之相同質量(RT = 0.39及0.49)。將反應混合物用醚(50 mL)稀釋,用水洗滌,繼而用鹽水溶液洗滌。使有機萃取物經硫酸鈉乾燥,得到粗產物,其不經純化即進行下一步驟。LCMS -ESI+ (m/z):C8
H11
F2
N3
O2
[M+H]計算值:220.08;實驗值220.90。
步驟2:向於MeOH (3 mL)、THF (10 mL)中之1-(二氟甲基)-3-甲氧基-1H-吡唑-4-甲酸乙酯(300 mg,1.36 mmol)之懸浮液中添加2 N NaOH溶液(3 mL)。將反應混合物在50℃下攪拌90 min。濃縮溶劑,且將粗殘餘物溶解於水(30 mL)中。藉由逐滴添加將此溶液用1.5 N HCl酸化以維持pH ~2-3且攪拌5 min。將產物過濾,用水洗滌,且乾燥。粗產物1-(二氟甲基)-3-甲氧基-1H-吡唑-4-甲酸用於下一步驟。LCMS -ESI+ (m/z):C6
H6
F2
N2
O3
[M+H]計算值:193.03;實驗值193.02。
步驟-3:以與實例 18
相同之方式使用1-(二氟甲基)-3-甲氧基-1H-吡唑-4-甲酸及實例 109
來合成實例 252
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.50 (s, 1H), 7.75 (d,J
= 8.5 Hz, 1H), 7.57 - 7.23 (m, 1H), 7.23 - 7.20 (m, 1H), 7.17 (dd,J
= 8.5, 2.4 Hz, 1H), 7.11 (d,J
= 2.3 Hz, 1H), 7.04 (d,J
= 2.0 Hz, 1H), 6.94 (d,J
= 8.2 Hz, 1H), 6.05 (dt,J
= 14.2, 6.5 Hz, 1H), 5.61 (dd,J
= 15.3, 8.6 Hz, 1H), 4.29 (dd,J
= 14.9, 6.0 Hz, 1H), 4.07 (d,J
= 2.4 Hz, 5H), 3.99 - 3.62 (m, 5H), 3.36 (s, 1H), 3.28 (s, 3H), 3.16 - 3.00 (m, 1H), 2.79 (dddd,J
= 22.7, 16.7, 11.7, 5.2 Hz, 2H), 2.60 - 2.33 (m, 2H), 2.32 - 2.04 (m, 3H), 2.03 - 1.86 (m, 3H), 1.78 (qd,J
= 9.4, 8.5, 5.3 Hz, 3H), 1.44 (ddd,J
= 14.2, 11.7, 3.1 Hz, 1H), 1.15 (d,J
= 6.2 Hz, 3H)。LCMS-ESI+ (m/z):C38
H44
ClF2
N5
O6
S [M+H]+計算值:772.27;實驗值:772.04。實例 253
以與實例 250
相同之方式使用(2S,3R)-3-羥基-2-甲基氮雜環丁烷-1-甲酸第三丁酯及實例 109
來合成實例 253
。1H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.5, 2.3 Hz, 1H), 7.09 (dd, J = 7.8, 2.0 Hz, 2H), 6.92 (d, J = 8.1 Hz, 1H), 6.88 (s, 1H), 5.94 (dt, J = 14.2, 6.7 Hz, 1H), 5.56 (dd, J = 15.2, 9.2 Hz, 1H), 4.30 (dd, J = 14.9, 6.2 Hz, 1H), 4.19 - 4.13 (m, 1H), 4.06 (d, J = 1.2 Hz, 2H), 3.83 (d, J = 15.2 Hz, 1H), 3.77 - 3.69 (m, 3H), 3.65 (d, J = 14.1 Hz, 1H), 3.24 (s, 3H), 3.16 - 2.99 (m, 1H), 2.88 - 2.69 (m, 2H), 2.66 (s, 0H), 2.52 - 2.37 (m, 1H), 2.33 (q, J = 9.0 Hz, 1H), 2.23 - 2.02 (m, 3H), 2.00 - 1.64 (m, 4H), 1.47 (d, J = 6.5 Hz, 3H), 1.44 - 1.24 (m, 2H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+
(m/z):C38
H49
ClN4
O6
S [M+H]+
計算值:725.31;實驗值:724.93。實例 254
將實例 359
(10 mg,0.14 mmol)、(((9H-芴-9-基)甲氧基)羰基)-L-纈胺酸(9.21 mg,0.02 mmol)、EDCI.HCl (6.5 mg,0.034 mmol)及DMAP (3.3 mg,0.027 mmol)組合在8 mL小瓶中,且添加DCM (3 mL)。將此混合物音波處理3 min以用於完全溶解,且在0℃下攪拌2 h。濃縮溶劑,且向粗產物中添加於DMF (2 mL)中之20%哌啶。將此溶液在rt下攪拌20 min。將反應混合物過濾且藉由逆相製備型HPLC純化,用60-100% ACN/H2
O及0.1% TFA溶析,獲得實例 254
。1
H NMR (400 MHz, DMSO-d 6
) δ 8.26 (s, 3H), 7.98 (s, 1H), 7.63 (d,J
= 8.5 Hz, 1H), 7.26 (dd,J
= 8.4, 2.3 Hz, 1H), 7.16 (d,J
= 2.3 Hz, 1H), 7.05 (d,J
= 8.2 Hz, 1H), 6.95 (d,J
= 8.1 Hz, 1H), 6.89 (s, 1H), 6.51 (s, 2H), 5.98 (t,J
= 12.5 Hz, 1H), 5.79 (dd,J
= 15.1, 8.7 Hz, 1H), 5.42 (dd,J
= 8.7, 3.3 Hz, 1H), 4.15 - 3.94 (m, 3H), 3.95 - 3.85 (m, 2H), 3.81 (s, 4H), 3.70 (s, 3H), 3.58 (d,J
= 14.0 Hz, 1H), 3.25 - 2.94 (m, 2H), 2.85 - 2.59 (m, 2H), 2.35 (d,J
= 35.9 Hz, 1H), 2.21 - 1.60 (m, 10H), 1.42 (d,J
= 7.0 Hz, 4H), 1.03 (d,J
= 5.9 Hz, 3H), 0.96 (dd,J
= 12.0, 6.9 Hz, 6H)。LCMS-ESI+ (m/z):C43
H55
ClN6
O7
S [M+H]+計算值:835.35;實驗值:834.95。實例 255
步驟1:將於乙腈(6 mL)中之5-甲醯基-1H-吡咯-3-甲酸酯(500 mg,3.27 mmol)、1-氯-2-甲基-2-丙烯(639 µL,6.53 mmol)及碳酸銫(2.03 g,6.24 mmol)之經攪拌混合物加熱至65℃。在150 min之後,使所得混合物冷卻至室溫,且依序添加水(30 mL)、鹽水(20 mL)及飽和氯化銨水溶液(10 mL)。用二氯甲烷(2×60 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至25%於己烷中之乙酸乙酯)純化殘餘物,得到255-1
。
步驟2:在1 min內在室溫下經由注射器將四氧化鋨溶液(於第三丁基醇中2.5% wt.,234 µL,19 µmol)添加至於第三丁基醇(3.0 mL)、水(1.0 mL)及四氫呋喃(1.0 mL)中之255-1
(387 mg,1.87 mmol)、4-(二甲基胺基)吡啶(6.9 mg,56 µmol)及4-甲基嗎啉-N
-氧化物(328 mg,2.80 mmol)之經攪拌混合物中。在74 min之後,將所得混合物加熱至90℃。在76 min之後,使所得混合物冷卻至室溫,且依序添加亞硫酸鈉(471 mg)及水(1.0 mL)。在20 min之後,經由矽藻土過濾所得混合物,且用乙酸乙酯(100 mL)萃取濾餅。將合併濾液經硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至100%於二氯甲烷中之乙酸乙酯)純化殘餘物,得到255-2
。
步驟3:在室溫下經由注射器將三氟乙酸(1.43 mL,18.7 mmol)添加至於二氯甲烷(117 mL)及甲醇(1.52 mL)中之255-2
(451 mg,1.87 mmol)之經攪拌溶液中。在1 min之後,經由注射器添加三乙基矽烷(3.14 mL,19.6 mmol)。在19 min之後,經由注射器依序添加三氟乙酸(3.58 mL,46.8 mmol)及三乙基矽烷(7.48 mL,46.7 mmol)。在55 min之後,添加飽和碳酸鈉水溶液(55 mL),且劇烈攪拌所得雙相混合物。在15 min之後,添加鹽水(30 mL),且分離各層。用二氯甲烷(60 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至70%於己烷中之乙酸乙酯)純化殘餘物,得到255-3
。
步驟4:在0℃下經由注射器將鉀雙(三甲基矽烷基)醯胺溶液(於四氫呋喃中1.0 M,466 µL,466 µmol)添加至於四氫呋喃中之255-3
(35.0 mg,155 µmol)之經攪拌溶液中。在6 min之後,經由注射器添加碘甲烷(48.5 µL,777 µmol),且使所得混合物升溫至室溫。在25 min之後,依序添加飽和氯化銨水溶液(5 mL)及乙酸乙酯(30 mL)。將有機層用水(20 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至40%於己烷中之乙酸乙酯)純化殘餘物,得到255-4
。
步驟5:在室溫下經由注射器將氫氧化鈉水溶液(2.0 M,900 µL,1.80 mmol)添加至於四氫呋喃(0.65mL)及甲醇(1.5 mL)中之255-4
(37.0 mg,155 µmol)之經攪拌溶液中,且將所得混合物加熱至70℃。在16 h之後,使所得混合物冷卻至室溫,且依序添加氯化氫水溶液(2.0 M,1.0 mL)及鹽水(10 mL)。依序用二氯甲烷(2×15 mL)及乙酸乙酯(15 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮,得到255-5
。
步驟6:製備實例 255
:以與實例 106
類似之方式使用中間物 359-4
而不使用106-4
且使用255-5
而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸來合成實例 255
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.6 Hz, 1H), 7.45 - 7.12 (m, 5H), 6.97 (s, 1H), 6.30 (s, 1H), 5.99 - 5.83 (m, 1H), 5.83 - 5.69 (m, 1H), 4.80 (s, 2H), 4.24 - 3.38 (m, 11H), 3.36 (s, 3H), 3.19 (dd, J = 15.4, 9.0 Hz, 1H), 2.98 - 1.14 (m, 21H), 1.14 - 1.04 (m, 3H)。LCMS:805.1。實例 256
以與實例 237
相同之方式使用實例 109
及(R)-3-(甲氧基甲基)吡咯啶來合成實例 256
。1
H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.12 (td, J = 3.8, 1.8 Hz, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 2.0 Hz, 1H), 5.97 (dt, J = 14.1, 6.5 Hz, 1H), 5.58 (dd, J = 15.2, 9.1 Hz, 1H), 4.33 (dd, J = 14.8, 5.9 Hz, 1H), 4.08 (d, J = 1.8 Hz, 2H), 3.90 - 3.81 (m, 1H), 3.76 (dd, J = 9.2, 3.7 Hz, 1H), 3.67 (m, 2H), 3.63 - 3.52 (m, 2H), 3.42 (d, J = 8.1 Hz, 1H), 3.37 (m, 4H), 3.26 (s, 4H), 3.22 - 3.14 (m, 1H), 3.08 (dd, J = 15.2, 10.3 Hz, 1H), 2.90 - 2.70 (m, 2H), 2.59 - 2.40 (m, 4H), 2.35 (q, J = 9.0 Hz, 1H), 2.17 (m, 3H), 2.07 (m, 1H), 2.01 - 1.86 (m, 4H), 1.77 (m, 4H), 1.44 (t, J = 12.5 Hz, 1H), 1.15 (d, J = 6.3 Hz, 3H)。LCMS-ESI+:C39
H52
ClN4
O6
S計算值:739.32 (M+H);實驗值:739.80 (M+H)。實例 257
以與實例 237
相同之方式使用實例 109
及6-甲氧基-2-氮雜螺[3.3]庚烷鹽酸鹽來合成實例 257
。1
H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 (dd, J = 6.4, 2.1 Hz, 2H), 6.96 - 6.87 (m, 2H), 5.98 (dt, J = 14.3, 6.8 Hz, 1H), 5.58 (dd, J = 15.2, 9.1 Hz, 1H), 4.29 (dd, J = 14.9, 6.4 Hz, 1H), 4.15 - 4.04 (m, 2H), 4.00 (m, 4H), 3.90 - 3.79 (m, 2H), 3.76 (dd, J = 9.1, 3.7 Hz, 1H), 3.67 (d, J = 14.2 Hz, 1H), 3.65 - 3.57 (m, 1H), 3.26 (m, 4H), 3.24 (s, 3H), 3.08 (dd, J = 15.2, 10.3 Hz, 1H), 2.89 - 2.70 (m, 2H), 2.57 - 2.42 (m, 4H), 2.35 (q, J = 9.0 Hz, 1H), 2.24 - 2.15 (m, 1H), 2.15 - 2.06 (m, 3H), 1.93 (m, 3H), 1.77 (m, 4H), 1.44 (t, J = 12.5 Hz, 1H), 1.33 (d, J = 16.3 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+:C40
H52
ClN4
O6
S計算值:752.32 (M+H);實驗值:751.53 (M+H)。實例 258
以與實例 237
相同之方式使用實例 109
及4-(二氟甲基)哌啶鹽酸鹽來合成實例 258
。1
H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.1, 1.9 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 5.95 (dt, J = 14.2, 6.7 Hz, 1H), 5.89 - 5.61 (m, 1H), 5.61 - 5.53 (m, 1H), 4.45 (s, 2H), 4.38 (dd, J = 14.9, 6.3 Hz, 1H), 4.09 (s, 2H), 3.85 (d, J = 15.2 Hz, 1H), 3.76 (dd, J = 9.3, 3.7 Hz, 1H), 3.67 (d, J = 14.2 Hz, 1H), 3.60 (dd, J = 14.9, 5.8 Hz, 1H), 3.28 (m, 6H), 3.08 (dd, J = 15.3, 10.3 Hz, 1H), 2.98 - 2.68 (m, 4H), 2.46 (dd, J = 14.4, 5.3 Hz, 1H), 2.32 (p, J = 9.2 Hz, 1H), 2.19 (q, J = 7.6 Hz, 1H), 2.12 (d, J = 15.9 Hz, 2H), 2.01 - 1.86 (m, 1H), 1.86 - 1.65 (m, 7H), 1.52 - 1.28 (m, 2H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+:C39
H50
ClF2
N4
O5
S計算值:759.31 (M+H);實驗值:759.33 (M+H)。實例 259
步驟1:在室溫下將戴斯-馬丁高碘烷(85.4 mg,201 µmol)添加至於二氯甲烷(1.0 mL)中之255-3
(32.4 mg,144 µmol)之經攪拌溶液中。在45 min之後,依序添加硫代硫酸鈉水溶液(1.0 M,1.0 mL)、飽和碳酸氫鈉溶液(5.0 mL)、二乙醚(60 mL)及乙酸乙酯(60 mL)。將有機層依序用水(50 mL)、水及飽和碳酸氫鈉水溶液(1:1 v:v,50 mL)之混合物及水(50 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於二氯甲烷(2.0 mL)中且在室溫下攪拌。依序添加嗎啉(88.1 µL,1.01 mmol)、乙酸(57.6 µL,1.01 mmol)及三乙醯氧基硼氫化鈉(213 mg,1.01 mmol),且將所得混合物加熱至45℃。在45 min之後,使所得混合物冷卻至室溫,且依序添加飽和碳酸鈉水溶液(6.0 mL)及乙酸乙酯(75 mL)。將有機層用水及鹽水之混合物(3:1 v:v,50 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至9%於二氯甲烷中之甲醇)純化殘餘物,得到259-1
。
步驟2:製備實例 259
:以與實例 229
類似之方式使用259-1
而不使用229-3
來合成實例 259
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.5 Hz, 1H), 7.44 (s, 1H), 7.28 - 7.16 (m, 3H), 7.15 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.33 (s, 1H), 5.95 - 5.82 (m, 1H), 5.74 (dd, J = 15.3, 7.3 Hz, 1H), 4.90 - 4.76 (m, 2H), 4.48 - 3.59 (m, 16H), 3.40 (d, J = 14.3 Hz, 1H), 3.19 (dd, J = 15.2, 8.9 Hz, 1H), 3.10 - 1.42 (m, 15H), 1.56 (d, J = 7.1 Hz, 3H), 1.32 (d, J = 1.5 Hz, 3H), 1.05 (s, 3H)。LCMS:860.1。實例 260
以與實例 75
相同之方式使用實例 359
及(1R,2R)-2-(二氟甲基)環丙-1-胺鹽酸鹽來合成實例 260
。1
H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 6.99 - 6.92 (m, 2H), 5.99 - 5.79 (m, 2H), 5.79 - 5.65 (m, 1H), 4.42 - 4.26 (m, 1H), 4.20 (dd, J = 8.5, 3.3 Hz, 1H), 4.10 (s, 2H), 3.84 (d, J = 15.1 Hz, 1H), 3.66 (d, J = 14.3 Hz, 1H), 3.29 (m, 1H), 3.15 - 3.06 (m, 1H), 2.96 - 2.68 (m, 3H), 2.50 - 2.35 (m, 1H), 2.31 (t, J = 9.0 Hz, 1H), 2.17 (s, 2H), 2.11 (m, 2H), 2.03 - 1.91 (m, 2H), 1.91 - 1.81 (m, 2H), 1.75 (q, J = 9.2 Hz, 1H), 1.66 - 1.42 (m, 5H), 1.23 - 1.00 (m, 4H), 1.00 - 0.88 (m, 1H)。LCMS-ESI+:C37
H46
ClF2
N4
O5
S計算值:731.28 (M+H);實驗值:731.11 (M+H)。實例 261
以與實例 182
相同之方式使用3-(氧雜環丁烷-3-基)氮雜環丁烷而不使用外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙-1-胺來合成實例 261
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.12 (dt, J = 4.3, 1.9 Hz, 2H), 7.00 - 6.86 (m, 2H), 5.98 (dt, J = 14.2, 6.7 Hz, 1H), 5.58 (dd, J = 15.2, 9.1 Hz, 1H), 4.45 (t, J = 6.0 Hz, 2H), 4.37 - 4.12 (m, 3H), 4.08 (d, J = 2.1 Hz, 2H), 3.92 - 3.71 (m, 3H), 3.71 - 3.55 (m, 2H), 3.26 (s, 3H), 3.08 (dd, J = 15.2, 10.3 Hz, 2H), 3.01 (s, 2H), 2.91 - 2.66 (m, 3H), 2.47 (dd, J = 12.2, 7.9 Hz, 2H), 2.38 - 2.29 (m, 1H), 2.26 - 2.05 (m, 3H), 1.97 - 1.88 (m, 2H), 1.78 (tt, J = 17.1, 9.5 Hz, 3H), 1.45 (t, J = 11.8 Hz, 2H), 1.31 (s, 2H), 1.15 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C39
H49
ClN4
O6
S [M+H]+計算值:737.31;實驗值:737.06。實例 262
步驟1:製備1-環丙基-3-甲氧基-1H-吡唑-4-甲酸乙酯:將於甲苯(5 mL)中之3-甲氧基-1H-吡唑-4-甲酸乙酯(113 mg,0.66 mmol)、環丙基硼酸(114 mg,1.33 mmol)、乙酸銅(II) (120.61 mg,0.66 mmol)、2,2'-雙吡啶基化物(103.71 mg,0.66 mmol)及碳酸鈉(140.76 mg,1.33 mmol)之反應混合物在60℃下加熱過夜且暴露於空氣。將反應混合物冷卻且過濾。將濾液濃縮,且藉由矽膠層析法(用0-100% EtOAc/己烷溶析)純化,得到標題化合物(105 mg)。
步驟2:製備1-環丙基-3-甲氧基-1H-吡唑-4-甲酸:將於MeOH (1.0 mL)及水(0.5 mL)中之1-環丙基-3-甲氧基-吡唑-4-甲酸乙酯(12 mg,0.057 mmol)、2 M NaOH (0.057 mL)之反應混合物在45℃下攪拌過夜。將反應混合物濃縮且不經純化即用於下一步驟中。
步驟3:以與實例 18
相同之方式使用實例 109
而不使用實例 5
且使用2,3-二氫吡唑并[5,1-b]噁唑-6-甲酸而不使用3-甲氧基丙酸來合成實例 262
。1H NMR (400 MHz,甲醇-d4) δ 8.14 (s, 1H), 7.77 (d, J = 8.6 Hz, 1H), 7.37 - 7.30 (m, 1H), 7.23 - 7.09 (m, 3H), 6.92 (d, J = 8.2 Hz, 1H), 6.11 (dt, J = 14.1, 6.4 Hz, 1H), 5.62 (dd, J = 15.3, 8.2 Hz, 1H), 4.19 - 3.95 (m, 6H), 3.87 (d, J = 15.0 Hz, 1H), 3.79 (dd, J = 8.1, 3.3 Hz, 1H), 3.71 (d, J = 14.3 Hz, 1H), 3.63 (tt, J = 7.4, 3.8 Hz, 1H), 3.38 (d, J = 14.2 Hz, 1H), 3.29 (s, 3H), 3.08 (dd, J = 15.0, 9.9 Hz, 1H), 2.92 - 2.71 (m, 3H), 2.51 (ddd, J = 22.6, 9.8, 5.5 Hz, 3H), 2.30 - 2.19 (m, 2H), 2.12 (d, J = 13.6 Hz, 1H), 1.94 (d, J = 13.6 Hz, 3H), 1.78 (d, J = 6.7 Hz, 3H), 1.51 - 1.40 (m, 1H), 1.17 - 1.07 (m, 5H), 1.07 - 1.00 (m, 2H)。LCMS-ESI+ (m/z):C40
H48
ClN5
O6
S [M+H]+計算值:762.30;實驗值:760.83。實例 263
以與實例 182
相同之方式使用3-(環丙氧基)氮雜環丁烷鹽酸鹽而不使用外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙-1-胺來合成實例 263
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.6 Hz, 1H), 7.19 (dd, J = 8.6, 2.4 Hz, 1H), 7.12 (dt, J = 4.3, 2.6 Hz, 2H), 6.93 (d, J = 8.2 Hz, 2H), 5.97 (dt, J = 14.2, 6.8 Hz, 1H), 5.58 (dd, J = 15.2, 9.1 Hz, 1H), 4.48 - 4.39 (m, 1H), 4.38 - 4.15 (m, 3H), 4.08 (d, J = 1.9 Hz, 2H), 4.01 - 3.80 (m, 3H), 3.76 (dd, J = 9.1, 3.6 Hz, 1H), 3.67 (d, J = 14.3 Hz, 2H), 3.36 (d, J = 3.1 Hz, 1H), 3.26 (s, 3H), 3.08 (dd, J = 15.3, 10.3 Hz, 1H), 2.88 - 2.70 (m, 2H), 2.52 - 2.42 (m, 2H), 2.35 (q, J = 9.2 Hz, 1H), 2.25 - 2.04 (m, 3H), 2.01 - 1.69 (m, 5H), 1.44 (t, J = 12.5 Hz, 1H), 1.31 (s, 3H), 1.15 (d, J = 6.6 Hz, 2H), 0.96 - 0.88 (m, 1H), 0.68 - 0.58 (m, 2H), 0.58 - 0.46 (m, 2H)。LCMS-ESI+ (m/z):C39
H49
ClN4
O6
S [M+H]+計算值:737.31;實驗值:735.76。實例 264
步驟1:在室溫下將二(1H-咪唑-1-基)甲硫酮(58.6 mg,329 µmol)添加至於四氫呋喃中之255-3
(37.0 mg,164 µmol)及4-(二甲基胺基)吡啶(10 mg,82 µmol)之經攪拌混合物中。在5 min之後,將所得混合物加熱至65℃。在35 min之後,將所得混合物加熱至80℃。在23 h之後,使所得混合物冷卻至室溫,且經由矽藻土過濾。用乙酸乙酯(20 mL)萃取濾餅,且在減壓下濃縮合併濾液。將殘餘物再溶解於甲苯(14 mL)及1,4-二噁烷(12 mL)中,添加三丁基錫烷(221 µL,821 µmol),且攪拌所得混合物且加熱至100℃。在30 min內經由注射泵添加於甲苯(1.6 mL)中之2,2'-(二氮烯-1,2-二基)雙(2-甲基丙烷腈) (8.1 mg,49 µmol)之溶液。在20 min之後,將所得混合物冷卻至室溫且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至27%於己烷中之乙酸乙酯)純化殘餘物,得到264-1
。
步驟2:以與實例 255
類似之方式使用264-1
而不使用255-4
來合成實例 264
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.39 (s, 1H), 7.29 - 7.10 (m, 4H), 6.99 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 5.95 - 5.82 (m, 1H), 5.74 (dd, J = 15.3, 7.2 Hz, 1H), 4.91 - 3.81 (m, 12H), 3.74 (d, J = 14.2 Hz, 1H), 3.40 (d, J = 14.4 Hz, 1H), 3.19 (dd, J = 15.3, 9.2 Hz, 1H), 3.09 - 1.13 (m, 24H), 1.05 (s, 3H)。LCMS:775.1。實例 265
以與實例 250
相同之方式使用3-(2-羥基丙-2-基)氮雜環丁烷-1-甲酸第三丁酯及實例 109
來合成實例 265
。1H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.6, 2.3 Hz, 1H), 7.14 - 7.08 (m, 2H), 6.91 (d, J = 8.1 Hz, 2H), 5.97 (dt, J = 14.2, 6.6 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 4.28 (dd, J = 14.8, 6.3 Hz, 1H), 4.06 (d, J = 2.3 Hz, 2H), 4.03 - 3.87 (m, 5H), 3.83 (d, J = 15.2 Hz, 1H), 3.74 (dd, J = 9.0, 3.7 Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.24 (d, J = 1.5 Hz, 6H), 3.15 - 2.97 (m, 1H), 2.74 (ddd, J = 28.0, 14.0, 7.8 Hz, 3H), 2.52 - 2.40 (m, 2H), 2.34 (q, J = 9.0 Hz, 1H), 2.23 - 2.05 (m, 3H), 2.00 - 1.85 (m, 1H), 1.76 (tt, J = 17.1, 9.4 Hz, 2H), 1.43 (t, J = 10.4 Hz, 1H), 1.29 (s, 2H), 1.13 (d, J = 6.4 Hz, 9H)。LCMS-ESI+
(m/z):C40
H53
ClN4
O6
S [M+H]+
計算值:753.34;實驗值:752.98。實例 266
步驟1:在室溫下經由注射器將氫氧化鈉水溶液(2.0 M,3.1 mL,6.2 mmol)添加至於甲醇(14.8 mL)中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-甲酸甲酯(500 mg,1.04 mmol)之經攪拌溶液中,且將所得混合物加熱至60℃。在27.5 h之後,使所得混合物冷卻至室溫,藉由添加氯化氫水溶液(1.0 M)酸化,且在減壓下濃縮。將殘餘物溶解於二氯甲烷中,且將有機層用水洗滌,經無水硫酸鎂乾燥,且在減壓下濃縮。將殘餘物溶解於二氯甲烷(52 mL)中,添加109-2-2
(536 mg,2.08 mmol)及4-(二甲基胺基)吡啶(423 mg,3.46 mmol),且在室溫下攪拌所得混合物。添加3-(((乙基亞胺基)亞甲基)胺基)-N,N-二甲基丙-1-胺鹽酸鹽(498 mg,2.60 mmol)。在18 h之後,添加乙酸乙酯及氯化氫水溶液(1.0 M)。將有機層依序用水及鹽水洗滌,經無水硫酸鎂乾燥,且在減壓下濃縮。將殘餘物溶解於四氫呋喃(2.5 mL)、甲醇(29 mL)及水(0.16 mL)中,且在室溫下攪拌所得混合物。添加碳酸鉀(2.39 g,17.3 mmol),且將所得混合物加熱至60℃。在攪拌過夜之後,使所得混合物冷卻至室溫,且添加鹽水(8 mL)及於水(10 mL)中之檸檬酸(1.0 g)之混合物。依序用二氯甲烷(30 mL)及乙酸乙酯(30 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至30%於己烷中之乙酸乙酯)純化殘餘物,得到中間物 266-1
。
步驟2:將於1,2-二氯乙烷(272 mL)中之中間物 266-1
(500 mg,817 µmol)及(1,3-雙-(2,4,6-三甲基苯基)-2-咪唑啶亞基)二氯(鄰異丙氧基苯基亞甲基)釕(102 mg,163 µmol)之經攪拌混合物加熱至75℃。在2.5天之後,使所得混合物冷卻至室溫且在減壓下濃縮。藉由矽膠急驟管柱層析法純化殘餘物,得到中間物 266-2
。1
H NMR (400 MHz,氘代氯仿) δ 7.76 (d,J
= 8.5 Hz, 1H), 7.50 - 7.38 (m, 2H), 7.26 - 7.17 (m, 1H), 7.16 - 7.06 (m, 1H), 6.93 (d,J
= 8.1 Hz, 1H), 6.52 - 5.95 (m, 2H), 6.06 (dt,J
= 14.2, 6.6 Hz, 1H), 5.79 - 5.65 (m, 1H), 4.21 (t,J
= 5.8 Hz, 1H), 4.13 - 4.02 (m, 2H), 3.90 - 3.81 (m, 1H), 3.81 - 3.72 (m, 1H), 3.49 - 3.25 (m, 2H), 3.07 (dd,J
= 15.2, 9.1 Hz, 1H), 2.92 - 1.56 (m, 15H), 1.42 (t,J
= 13.0 Hz, 1H), 1.20 (d,J
= 6.5 Hz, 3H)。LCMS:584.2。
步驟3:使4打蘭小瓶裝填有中間物 266-2
(1當量,0.041 mmol,24 mg)、碳酸二苯酯(1.3當量,0.053 mmol,11 mg)、N,N-二甲基胺基吡啶(2.5當量,0.103 mmol,13 mg)、CH2
Cl2
(2 mL)及三乙胺(10當量,0.411 mmol,57 mL),隨後密封且在50℃下攪拌15小時。在單獨小瓶中,用CH2
Cl2
(0.5 mL)及三乙胺(20當量,0.822 mmol,115 mL)處理3-甲氧基氮雜環丁烷鹽酸鹽(10當量,0.411 mmol,51 mg)。隨後,組合反應混合物且加熱至60℃過夜。將反應混合物濃縮,且藉由製備型HPLC (10-100%於水中之MeCN,0.1% TFA)部分純化。將藉由LCMS得到之含有所需產物之溶離份濃縮,溶解於EtOAc中且用水洗滌。用EtOAc反萃取有機層,且使合併有機層經硫酸鈉乾燥,過濾且濃縮。將粗材料藉由製備型TLC在5:1 EtOAc:MeOH中純化,經矽藻土過濾(用4:1 EtOAc:MeOH溶析),隨後濃縮且藉由製備型HPLC (10-100%於水中之MeCN,0.1% TFA)再次純化。凍乾合併之清潔溶離份,獲得所需產物實例 266
。LCMS-ESI+ (m/z):C36
H45
ClN4
O6
S (M)+
計算值:696.2748;實驗值:695.92。1
H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.5, 2.3 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.94 (s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 5.92 (dt, J = 14.0, 6.7 Hz, 1H), 5.72 (dd, J = 15.2, 8.5 Hz, 1H), 4.28 - 4.12 (m, 5H), 4.12 - 4.01 (m, 2H), 3.94 - 3.74 (m, 3H), 3.70 - 3.53 (m, 2H), 3.37 - 3.20 (m, 1H), 3.30 (s, 3H), 3.06 (dd, J = 15.3, 10.0 Hz, 1H), 2.88 - 2.68 (m, 2H), 2.46 - 2.24 (m, 3H), 2.19 - 1.78 (m, 8H), 1.72 (q, J = 9.0 Hz, 1H), 1.43 (t, J = 12.8 Hz, 1H), 1.14 (d, J = 6.6 Hz, 3H)。實例 267
以與實例 362
相同之方式用實例 109
及(3-甲氧基氮雜環丁烷-3-基)甲醇鹽酸鹽來製備實例 267
。LCMS-ESI+ (m/z):C38
H49
ClN4
O7
S (M)+
計算值:740.3010;實驗值:739.79。1
H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.6, 2.3 Hz, 1H), 7.10 (q, J = 3.8 Hz, 2H), 6.94 - 6.88 (m, 2H), 5.96 (dt, J = 14.2, 6.7 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 4.30 (dd, J = 14.9, 6.2 Hz, 1H), 4.12 - 4.01 (m, 2H), 4.02 - 3.79 (m, 5H), 3.78 - 3.71 (m, 3H), 3.69 - 3.53 (m, 2H), 3.33 (s, 3H), 3.30 - 3.28 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J = 15.2, 10.3 Hz, 1H), 2.88 - 2.68 (m, 2H), 2.53 - 2.40 (m, 2H), 2.38 - 2.26 (m, 1H), 2.22 - 2.05 (m, 3H), 2.00 - 1.68 (m, 6H), 1.43 (t, J = 12.9 Hz, 1H), 1.13 (d, J = 6.6 Hz, 3H)。實例 268
以與實例 362
相同之方式用實例 109
及3-(甲氧基甲基)氮雜環丁烷-3-醇三氟乙酸來製備實例 268
。LCMS-ESI+ (m/z):C38
H49
ClN4
O7
S [M+H]+
計算值:741.3083;實驗值:740.83。1
H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 - 7.06 (m, 2H), 6.94 - 6.87 (m, 2H), 5.96 (dt, J = 14.3, 6.7 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 4.30 (dd, J = 14.8, 6.4 Hz, 1H), 4.15 - 3.95 (m, 4H), 3.93 - 3.70 (m, 4H), 3.70 - 3.57 (m, 2H), 3.48 - 3.46 (m, 2H), 3.43 (s, 3H), 3.30 - 3.27 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J = 15.2, 10.3 Hz, 1H), 2.89 - 2.68 (m, 2H), 2.52 - 2.40 (m, 2H), 2.38 - 2.27 (m, 1H), 2.22 - 2.05 (m, 3H), 2.01 - 1.67 (m, 6H), 1.42 (t, J = 12.9 Hz, 1H), 1.13 (d, J = 6.7 Hz, 3H)。實例 269
以與實例 18
相同之方式使用4-甲氧基苯甲酸及實例 109
來合成實例 269
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.18 - 7.99 (m, 2H), 7.75 (d,J
= 8.5 Hz, 1H), 7.18 (ddd,J
= 8.6, 3.6, 2.1 Hz, 2H), 7.12 (d,J
= 2.3 Hz, 1H), 7.04 - 6.99 (m, 3H), 6.97 (d,J
= 1.9 Hz, 1H), 6.94 (d,J
= 8.1 Hz, 1H), 6.03 (dt,J
= 14.3, 6.5 Hz, 1H), 5.60 (dd,J
= 15.2, 9.0 Hz, 1H), 4.43 (dd,J
= 14.8, 6.1 Hz, 1H), 4.08 (d,J
= 1.7 Hz, 2H), 3.89 (s, 3H), 3.87 - 3.82 (m, 2H), 3.78 (dd,J
= 9.0, 3.6 Hz, 1H), 3.68 (d,J
= 14.2 Hz, 1H), 3.30 - 3.25 (m, 2H), 3.27 (s, 3H), 3.08 (dd,J
= 15.3, 10.3 Hz, 1H), 2.91 - 2.70 (m, 2H), 2.48 (td,J
= 12.7, 5.0 Hz, 2H), 2.39 (q,J
= 9.0 Hz, 1H), 2.28 - 2.07 (m, 3H), 2.05 - 1.70 (m, 5H), 1.44 (t,J
= 12.7 Hz, 1H), 1.16 (d,J
= 6.4 Hz, 3H)。LCMS-ESI+ (m/z):C40
H46
ClN3
O6
S [M+H]+計算值:732.3;實驗值:732.2。實例 270
以與實例 237
相同之方式使用實例 109
及2-(哌嗪-1-基)乙腈來合成實例 270
。1
H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.1, 1.9 Hz, 1H), 6.95 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 5.95 (dt, J = 14.1, 6.7 Hz, 1H), 5.58 (dd, J = 15.2, 9.3 Hz, 1H), 4.39 (dd, J = 14.9, 6.4 Hz, 1H), 4.09 (s, 2H), 3.92 - 3.80 (m, 1H), 3.80 - 3.72 (m, 3H), 3.67 (d, J = 14.1 Hz, 1H), 3.64 - 3.55 (m, 1H), 3.50 (m, 4H), 3.26 (m, 4H), 3.08 (dd, J = 15.2, 10.4 Hz, 1H), 2.91 - 2.71 (m, 3H), 2.61 (s, 4H), 2.47 (dd, J = 14.1, 5.3 Hz, 2H), 2.33 (q, J = 9.2 Hz, 1H), 2.20 (q, J = 7.6 Hz, 1H), 2.16 - 2.04 (m, 3H), 2.04 - 1.85 (m, 1H), 1.77 (m, 3H), 1.45 (t, J = 12.8 Hz, 1H), 1.15 (d, J = 6.6 Hz, 3H)。LCMS-ESI+:C39
H50
ClN6
O5
S計算值:749.32 (M+H);實驗值:749.26 (M+H)。實例 271
以與實例 106
類似之方式使用2,4-二甲氧基嘧啶-5-甲酸而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸來合成實例 271
。1H NMR (400 MHz,丙酮-d6) δ 9.00 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.54 - 7.47 (m, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.18 (dt, J = 14.2, 6.6 Hz, 1H), 5.67 (dd, J = 15.6, 7.4 Hz, 1H), 4.27 (s, 3H), 4.13 (d, J = 12.1 Hz, 1H), 4.09 (s, 3H), 4.04 (d, J = 12.1 Hz, 1H), 4.02 - 3.72 (m, 4H), 3.49 (d, J = 14.4 Hz, 1H), 3.26 (s, 3H), 3.16 (dd, J = 15.1, 11.0 Hz, 1H), 2.97 - 1.37 (m, 16H), 1.14 (d, J = 6.9 Hz, 3H)。LCMS:764.1。實例 272
以與實例 237
相同之方式使用實例 109
及7-甲基-5-氧雜-2,7-二氮雜螺[3.4]辛-6-酮鹽酸鹽來合成實例 272
。1
H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 5.96 (dt, J = 14.3, 6.7 Hz, 1H), 5.58 (dd, J = 15.1, 9.2 Hz, 1H), 4.43 - 4.15 (m, 6H), 4.09 (d, J = 1.6 Hz, 2H), 3.84 (d, J = 7.0 Hz, 3H), 3.76 (dd, J = 9.2, 3.6 Hz, 1H), 3.67 (d, J = 14.2 Hz, 1H), 3.26 (m, 4H), 3.08 (dd, J = 15.3, 10.3 Hz, 1H), 2.88 (s, 3H), 2.84 - 2.72 (m, 2H), 2.55 - 2.42 (m, 3H), 2.33 (m, 1H), 2.27 - 2.06 (m, 3H), 1.94 (t, J = 6.9 Hz, 2H), 1.78 (m, 3H), 1.45 (t, J = 12.7 Hz, 1H), 1.15 (d, J = 6.6 Hz, 3H)。LCMS-ESI+:C39
H49
ClN5
O7
S計算值:766.30 (M+H);實驗值:766.10 (M+H)。實例 273
以與實例 18
相同之方式使用2-甲氧基嘧啶-5-甲酸及實例 109
來合成實例 273
。1
H NMR (400 MHz,氘代氯仿) δ 9.21 (d,J
= 5.1 Hz, 2H), 7.70 (d,J
= 8.5 Hz, 1H), 7.19 (dd,J
= 8.5, 2.4 Hz, 1H), 7.09 (s, 2H), 6.99 (dd,J
= 8.4, 3.8 Hz, 1H), 6.92 (d,J
= 9.4 Hz, 1H), 5.94 - 5.85 (m, 1H), 5.53 (dd,J
= 15.2, 9.1 Hz, 1H), 5.37 (s, 1H), 4.69 (d,J
= 14.9 Hz, 1H), 4.14 (d,J
= 1.5 Hz, 4H), 4.09 (s, 3H), 3.83 (d,J
= 15.3 Hz, 1H), 3.75 - 3.66 (m, 2H), 3.24 (s, 2H), 3.12 (s, 1H), 2.98 (dd,J
= 15.3, 10.3 Hz, 1H), 2.78 (dd,J
= 16.4, 11.7 Hz, 3H), 2.53 - 2.18 (m, 2H), 2.16 - 1.99 (m, 1H), 1.95 (d,J
= 10.5 Hz, 2H), 1.85 - 1.77 (m, 2H), 1.63 (t,J
= 9.5 Hz, 1H), 1.39 (t,J
= 12.7 Hz, 1H), 1.27 - 1.19 (m, 1H), 1.15 (d,J
= 6.1 Hz, 1H), 1.08 (d,J
= 6.1 Hz, 3H)。LCMS-ESI+ (m/z):H+C38
H44
ClN5
O6
S計算值:733.27;實驗值:734.050 (M+H)。實例 274
使2打蘭小瓶裝填有實例 267
(1當量,0.013 mmol,10 mg)及THF (0.5 mL)。添加氫化鈉(60%於油中之分散液,2當量,0.027 mmol,1.1 mg),且將反應混合物攪拌10分鐘。隨後,添加碘甲烷(5當量,0.067 mmol,4.2 mL),且將反應混合物再攪拌30分鐘,在此時將其用甲醇淬滅,濃縮,隨後再溶解於甲醇中,且藉由製備型HPLC (60-100%於水中之MeCN,0.1% TFA)純化。凍乾合併之清潔溶離份,獲得所需產物實例 274
。LCMS-ESI+ (m/z):C39
H51
ClN4
O7
S (M)+
計算值:754.3167;實驗值:754.07。1
H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 7.10 (td, J = 3.9, 1.9 Hz, 2H), 6.96 - 6.88 (m, 2H), 5.96 (dt, J = 14.2, 6.7 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 4.30 (dd, J = 14.9, 6.3 Hz, 1H), 4.13 - 4.02 (m, 2H), 4.01 - 3.78 (m, 5H), 3.74 (dd, J = 9.2, 3.7 Hz, 1H), 3.69 - 3.54 (m, 4H), 3.42 (s, 3H), 3.32 (s, 3H), 3.31 - 3.28 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J = 15.2, 10.3 Hz, 1H), 2.87 - 2.69 (m, 2H), 2.54 - 2.40 (m, 2H), 2.32 (p, J = 9.0 Hz, 1H), 2.23 - 2.05 (m, 3H), 2.00 - 1.66 (m, 6H), 1.43 (t, J = 12.8 Hz, 1H), 1.13 (d, J = 6.7 Hz, 3H)。實例 275
以與實例 362
相同之方式使用實例 109
及4-(氮雜環丁烷-3-基氧基)吡啶二鹽酸鹽來合成實例 275
。LCMS-ESI+ (m/z):C41
H48
ClN5
O6
S [M+H]+
計算值:774.3087;實驗值:773.81。1
H NMR (400 MHz,甲醇-d4) δ 8.69 (d, J = 7.4 Hz, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.17 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.96 - 6.86 (m, 2H), 5.96 (dt, J = 14.3, 6.8 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 5.39 (tt, J = 6.6, 3.5 Hz, 1H), 4.56 (s, 2H), 4.32 (dd, J = 14.9, 6.4 Hz, 1H), 4.26 - 3.96 (m, 4H), 3.83 (d, J = 15.1 Hz, 1H), 3.74 (dd, J = 9.2, 3.7 Hz, 1H), 3.70 - 3.55 (m, 2H), 3.30 - 3.27 (m, 1H), 3.24 (s, 3H), 3.06 (dd, J = 15.3, 10.3 Hz, 1H), 2.89 - 2.69 (m, 2H), 2.53 - 2.39 (m, 2H), 2.32 (q, J = 9.0 Hz, 1H), 2.23 - 2.06 (m, 3H), 2.01 - 1.66 (m, 6H), 1.43 (t, J = 12.6 Hz, 1H), 1.13 (d, J = 6.6 Hz, 3H)。實例 276
以與實例 237
相同之方式使用實例 109
及2-(3-甲氧基氮雜環丁烷-3-基)-1-甲基-1H-咪唑二鹽酸鹽來合成實例 276
。1
H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 1.9 Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.08 (dd, J = 8.1, 1.8 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 2.0 Hz, 1H), 5.97 (dt, J = 14.3, 6.6 Hz, 1H), 5.58 (dd, J = 15.2, 9.2 Hz, 1H), 4.59 (s, 2H), 4.49 - 4.28 (m, 3H), 4.09 (d, J = 1.7 Hz, 2H), 3.88 (s, 3H), 3.76 (dd, J = 9.2, 3.7 Hz, 1H), 3.73 - 3.62 (m, 1H), 3.26 (m, 4H), 3.21 (s, 3H), 3.14 - 3.05 (m, 1H), 2.87 - 2.63 (m, 2H), 2.48 (m, 3H), 2.33 (t, J = 9.1 Hz, 1H), 2.27 - 2.08 (m, 3H), 2.07 - 1.86 (m, 3H), 1.79 (tt, J = 17.4, 9.5 Hz, 3H), 1.45 (t, J = 12.7 Hz, 1H), 1.15 (d, J = 6.5 Hz, 3H)。LCMS-ESI+:C41
H52
ClN6
O6
S計算值:791.33 (M+H);實驗值:791.43 (M+H)。實例 277
以與實例 237
相同之方式使用實例 109
及5-(3-甲氧基氮雜環丁烷-3-基)-1-甲基-1H-1,2,4-三唑二鹽酸鹽來合成實例 277
。1
H NMR (400 MHz,甲醇-d4) δ 7.94 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 5.96 (dt, J = 14.2, 6.6 Hz, 1H), 5.58 (dd, J = 15.2, 9.2 Hz, 1H), 4.56 (m, 4H), 4.34 (dd, J = 14.8, 6.3 Hz, 1H), 4.08 (d, J = 1.5 Hz, 2H), 3.91 (s, 3H), 3.85 (d, J = 15.1 Hz, 1H), 3.76 (dd, J = 9.3, 3.7 Hz, 1H), 3.67 (d, J = 14.2 Hz, 1H), 3.59 (d, J = 14.0 Hz, 1H), 3.26 (m, 4H), 3.13 (s, 3H), 3.11 - 3.01 (m, 1H), 2.89 - 2.70 (m, 2H), 2.56 - 2.42 (m, 3H), 2.34 (q, J = 9.2 Hz, 1H), 2.24 - 2.05 (m, 4H), 2.05 - 1.86 (m, 1H), 1.78 (m, 3H), 1.45 (t, J = 12.6 Hz, 1H), 1.15 (d, J = 6.3 Hz, 3H)。LCMS-ESI+:C41
H52
ClN6
O6
S計算值:792.32 (M+H);實驗值:792.25 (M+H)。實例 278
以與實例 106
類似之方式使用3,6-二甲氧基噠嗪-4-甲酸而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸來合成實例 278
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.29 - 7.20 (m, 2H), 7.14 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.23 - 6.08 (m, 1H), 5.65 (dd, J = 15.3, 7.9 Hz, 1H), 4.22 (s, 3H), 4.13 (d, J = 12.1 Hz, 1H), 4.08 (s, 3H), 4.07 - 3.57 (m, 5H), 3.45 (d, J = 14.4 Hz, 1H), 3.25 (s, 3H), 3.16 (dd, J = 15.2, 10.5 Hz, 1H), 2.95 - 1.54 (m, 15H), 1.53 - 1.43 (m, 1H), 1.16 (d, J = 6.8 Hz, 3H)。LCMS:764.2。實例 279
將實例 154
(500 mg,0.68 mmol)與二氧化硒(377 mg,5當量)組合,且添加1,4-二噁烷(7 mL)。將反應混合物加熱至回流,且藉由LCMS監視反應進程。在4小時之後(約50%轉化),將反應物冷卻至室溫且在減壓下濃縮。藉由Gilson逆相製備型HPLC (50-100% ACN/H2
O及0.1% TFA)純化殘餘物,得到實例 279
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.15 (s, 1H), 7.72 (d,J
= 9.1 Hz, 1H), 7.37 (dd,J
= 8.3, 1.8 Hz, 1H), 7.19 (s, 1H), 7.16 - 7.07 (m, 2H), 6.89 (d,J
= 8.2 Hz, 1H), 6.15 (dd,J
= 15.5, 5.3 Hz, 1H), 5.83 (ddd,J
= 15.5, 8.0, 1.5 Hz, 1H), 4.54 (s, 1H), 4.05 (m, 7H), 3.90 - 3.82 (m, 3H), 3.81 (s, 3H), 3.69 (d,J
= 14.3 Hz, 1H), 3.41 (d,J
= 14.4 Hz, 1H), 3.29 (s, 3H), 3.18 - 3.04 (m, 1H), 2.92 - 2.69 (m, 2H), 2.51 (br, 2H), 2.44 - 2.25 (m, 1H), 2.16 - 2.03 (m, 1H), 2.02 - 1.92 (m, 3H), 1.88 - 1.74 (m, 3H), 1.43 (t,J
= 11.9 Hz, 1H), 1.15 (d,J
= 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O7
S [M+H]+計算值:752.3;實驗值:751.9。實例 280
將實例 223
(10 mg,0.014 mmol)與PtO2
(15 mg,0.028 mmol)組合,且添加乙醇(0.5 mL)。將接合至玻璃配接器之氫氣球(1 atm)連接至圓底燒瓶。將反應物在大氣氫氣下攪拌5小時,且藉由LCMS監視反應進程。在完成之後,用氬氣流吹掃反應容器。將固體過濾掉,且用額外乙醇洗滌。隨後,在減壓下濃縮反應混合物,且藉由Gilson逆相製備型HPLC (50-100% ACN/H2
O及0.1% TFA)純化殘餘物,得到實例 280
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.08 (s, 1H), 7.77 (d,J
= 8.5 Hz, 1H), 7.39 (d,J
= 8.5 Hz, 1H), 7.28 (s, 1H), 7.18 (dd,J
= 8.5, 2.3 Hz, 1H), 7.12 (d,J
= 2.3 Hz, 1H), 6.94 (d,J
= 8.2 Hz, 1H), 4.15 - 4.01 (m, 5H), 4.01 - 3.84 (m, 3H), 3.81 (s, 3H), 3.78 - 3.68 (m, 2H), 3.19 - 3.07 (m, 1H), 2.89 - 2.76 (m, 2H), 2.58 - 2.21 (m, 3H), 2.12 (d,J
= 13.4 Hz, 1H), 2.01 - 1.92 (m, 4H), 1.88 - 1.41 (m, 11H), 1.10 (d,J
= 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C37
H46
ClN5
O6
S [M+H]+計算值:724.3;實驗值:724.1。實例 281
及實例 282
步驟1:在0℃下在氬氣下向於DCM (23 mL)中之(1S,2R)-2-(2-羥基乙基) 環丙烷-1-甲酸甲酯(0.5 g,3.46 mmol)之經充分攪拌溶液中添加一次戴斯馬丁高碘烷(1.76 g,4.16 mmol),升溫至室溫(20 min),且攪拌2 h。將反應物冷卻至0℃,且用1 N Na2
S2
O3
水溶液及飽和NaHCO3
(40 mL)之1:1混合物淬滅。用DCM (2×20 mL)萃取水溶液。向合併之DCM溶液中再添加1 N Na2
SO2
O3
水溶液及飽和NaHCO3
(20 mL)之1:1混合物。將DCM層組合且用鹽水溶液洗滌一次,經Na2
SO4
乾燥,濃縮且用於下一步驟。
步驟2:在-78℃下向於DCM (17.5 mL)中之(1S,2R)-2-(2-側氧基乙基)環丙烷-1-甲酸甲酯之溶液中逐滴添加三氟化二乙基胺基硫(DAST) (1.7 g,10.55 mmol),且移除冷卻浴。將混合物在室溫下攪拌過夜。將反應物用Na2
HCO3
淬滅,分配有水及DCM。用DCM (2×20 mL)萃取水溶液。將合併之DCM溶液經Na2
SO4
乾燥,過濾,濃縮且用於下一步驟。
步驟3:向粗製物(1S,2R)-2-(2,2-二氟乙基)環丙烷-1-甲酸甲酯(300 mg,1.82 mmol)中添加THF (15 mL)、MeOH (3 mL)及1 N LiOH (3 mL)。將此混合物在65℃下攪拌90 min。使反應物冷卻至室溫,且在減壓下移除溶劑。將粗殘餘物溶解於水(20 mL)中,且藉由逐滴添加用1.5 N HCl酸化以維持pH ~2-3,且攪拌5 min。形成沈澱物,過濾,用水洗滌,且乾燥,得到用於下一步驟之粗產物(1S,2R)-2-(2,2-二氟乙基)環丙烷-1-甲酸。1
H NMR (400 MHz, DMSO-d 6
) δ 12.15 (s, 1H), 6.09 (tt,J
= 56.5, 4.5 Hz, 1H), 1.84 (tdd,J
= 17.5, 7.2, 4.5 Hz, 2H), 1.43 (ddt,J
= 13.1, 9.8, 7.3 Hz, 2H), 0.97 (dt,J
= 8.8, 4.3 Hz, 1H), 0.77 (dddd,J
= 17.6, 8.1, 6.2, 3.9 Hz, 1H)。
步驟4:向於乙腈(2 mL)中之反-2-(2,2-二氟乙基)環丙烷-1-甲酸(40 mg,0.26 mmol)之混合物中添加三乙胺(118 uL,0.84 mmol)及二苯基磷醯基疊氮化物(73.6 mg,0.26 mmol)。隨後,將混合物在60℃下加熱2 h。使反應混合物冷卻至室溫。向此混合物中添加一次實例 109
,且在60℃下攪拌24 h。將反應物濃縮,溶解於MeOH (3 mL)中,過濾且藉由逆相製備型HPLC純化,用60-100% ACN/H2
O及0.1% TFA溶析,獲得兩種異構體實例 281
及實例 282
,且任意指定立體化學。
實例 281 : 1
H NMR (400 MHz,甲醇-d 4
) δ 7.66 (d,J
= 8.5 Hz, 1H), 7.30 (d,J
= 8.1 Hz, 1H), 7.18 (d,J
= 8.3 Hz, 1H), 7.06 (d,J
= 2.2 Hz, 1H), 6.98 - 6.91 (m, 1H), 6.84 (dd,J
= 8.2, 4.9 Hz, 1H), 6.15-5.87 (m, 2H), 5.61 (dt,J
= 15.6, 8.8 Hz, 1H), 4.18 (td,J
= 16.0, 6.9 Hz, 2H), 3.99 (d,J
= 5.9 Hz, 2H), 3.87 - 3.70 (m, 4H), 3.63 (d,J
= 14.3 Hz, 1H), 3.27 (d,J
= 4.1 Hz, 4H), 3.05 (dd,J
= 15.2, 9.8 Hz, 1H), 2.90 - 2.64 (m, 2H), 2.49 (d,J
= 38.4 Hz, 4H), 2.31 - 1.63 (m, 5H), 1.52 - 1.22 (m, 3H), 1.12 (d,J
= 6.6 Hz, 4H), 0.96 (d,J
= 7.7 Hz, 1H), 0.83 (dt,J
= 9.5, 4.8 Hz, 1H), 0.70 (q,J
= 6.2 Hz, 1H)。LCMS-ESI+ (m/z):C38
H47
ClF2
N4
O5
S [M+H]+計算值:745.29;實驗值:744.75。
實例 282 : 1
H NMR (400 MHz,甲醇-d 4
) δ 7.78 - 7.52 (m, 1H), 7.40 - 7.10 (m, 1H), 7.10 - 6.91 (m, 2H), 6.85 (d,J
= 8.0 Hz, 1H), 6.22 - 5.76 (m, 1H), 5.67 - 5.51 (m, 1H), 4.16 (ddd,J
= 25.1, 15.0, 8.3 Hz, 1H), 4.00 (s, 2H), 3.90 - 3.70 (m, 2H), 3.63 (d,J
= 14.2 Hz, 1H), 3.27 (d,J
= 3.1 Hz, 3H), 3.15 - 2.94 (m, 1H), 2.90 - 2.62 (m, 2H), 2.61 - 1.63 (m, 15H), 1.33 (d,J
= 39.5 Hz, 3H), 1.12 (t,J
= 6.3 Hz, 3H), 0.98 (d,J
= 6.8 Hz, 1H), 0.90 - 0.77 (m, 1H), 0.69 (q,J
= 6.3 Hz, 1H)。LCMS-ESI+ (m/z):C38
H47
ClF2
N4
O5
S [M+H]+計算值:745.29;實驗值:744.76。實例 283
將實例 279
(200 mg,0.27 mmol)溶解於DMF (2.7 mL)中,且一次性添加氫化鈉(60%於油中之分散液,22 mg,0.53 mmol,2當量)。在添加碘甲烷(76 mg,0.53 mmol,2當量)之前,將混合物在室溫下攪拌5 min。隨後,將反應物加熱至50℃,且藉由LCMS監視反應進程。在觀測到大量轉化(約4:1產物:起始材料)之時,使反應物冷卻至0℃,且添加水(約5滴)。隨後,直接藉由Gilson逆相製備型HPLC (60-100% ACN/H2
O及0.1% TFA)純化殘餘物,得到實例 283 。 1
H NMR (400 MHz,甲醇-d 4
) δ 8.08 (s, 1H), 7.76 (d,J
= 8.5 Hz, 1H), 7.36 (d,J
= 7.9 Hz, 1H), 7.24 - 7.15 (m, 2H), 7.12 (d,J
= 2.3 Hz, 1H), 6.92 (d,J
= 8.2 Hz, 1H), 6.01 (dd,J
= 15.4, 7.8 Hz, 1H), 5.83 (dd,J
= 15.3, 8.6 Hz, 1H), 4.06 (m, 6H), 3.9 - 3.8 (m, 7H), 3.73 (d,J
= 14.5 Hz, 1H), 3.41 (d,J
= 14.4 Hz, 1H), 3.31 (s, 3H), 3.30 (s, 3H), 3.19 - 3.06 (m, 1H), 2.92 - 2.70 (m, 2H), 2.52 (br, 2H), 2.24 (m, 1H), 2.05 (m, 2H), 1.96 (m, 3H), 1.83 (m, 3H), 1.46 (m, 1H), 1.19 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C39
H48
ClN5
O7
S [M+H]+計算值:766.3;實驗值:766.0。實例 284
步驟1:合成5-[[(3R)-4-異丙基-3-甲基-哌嗪-1-基]甲基]-1-甲基-吡咯-3-甲酸甲酯雙TFA鹽:在添加三乙醯氧基硼氫化鈉(95.1 mg,0.449 mmol)之前,將於DCE (0.5 mL)中之5-甲醯基-1-甲基-吡咯-3-甲酸甲酯(50.0 mg,0.299 mmol)及(2R)-1-異丙基-2-甲基-哌嗪(42.5 mg,0.299 mmol)之混合物在室溫下攪拌10分鐘。將所得混合物攪拌過夜。將反應物濃縮,再溶解於水:DMF (5:1 V:V)之混合物中,過濾且藉由Gilson逆相製備型HPLC純化,用2-50% ACN/H2
O及0.1% TFA溶析。將所需溶離份組合且冷凍乾燥,得到5-[[(3R)-4-異丙基-3-甲基-哌嗪-1-基]甲基]-1-甲基-吡咯-3-甲酸甲酯;2,2,2-三氟乙酸(60.0 mg)。LCMS-ESI+ (m/z):C16
H27
N3
O2
計算值H+:294.21;實驗值:293.99。
步驟2:合成5-[[(3R)-4-異丙基-3-甲基-哌嗪-1-基]甲基]-1-甲基-吡咯-3-甲酸;雙TFA鹽:在rt下將5-[[(3R)-4-異丙基-3-甲基-哌嗪-1-基]甲基]-1-甲基-吡咯-3-甲酸甲酯;雙TFA鹽(60.0 mg, 0.115 mmol)溶解於MeOH (1.0 mL)及THF (1.0 mL)之混合物中。添加1N NaOH (1.15 mL,1.15 mmol)。隨後,將所得混合物加熱至50℃達8 hr。將反應物濃縮,再溶解於1N HCl (1.0 mL)溶液中,過濾且藉由逆相製備型HPLC純化,用2-50% ACN/H2
O及0.1% TFA溶析。將所需溶離份組合且冷凍乾燥,得到標題化合物。LCMS-ESI+ (m/z):C15
H25
N3
O2
計算值H+:280.19;實驗值:280.20。
步驟3:合成實例 284
:遵循與使用實例 109
及中間物 284-2
之實例 18
相同之程序。1H NMR (400 MHz,甲醇-d4) δ 7.70 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.2, 1.8 Hz, 1H), 7.12 - 7.03 (m, 3H), 6.88 (d, J = 8.3 Hz, 1H), 6.62 - 6.57 (m, 1H), 6.20 - 6.07 (m, 1H), 5.64 (dd, J = 15.4, 8.4 Hz, 1H), 4.19 (dd, J = 14.8, 6.4 Hz, 1H), 4.08 - 3.92 (m, 4H), 3.87 - 3.77 (m, 2H), 3.75 (s, 3H), 3.68 (d, J = 14.3 Hz, 1H), 3.64 - 3.54 (m, 2H), 3.49 - 3.42 (m, 1H), 3.39 (d, J = 14.3 Hz, 1H), 3.30 (s, 3H), 3.18 - 3.04 (m, 4H), 2.89 - 2.70 (m, 2H), 2.67 - 2.58 (m, 1H), 2.53 - 2.33 (m, 3H), 2.33 - 2.17 (m, 3H), 2.15 - 2.06 (m, 1H), 2.04 - 1.91 (m, 3H), 1.86 - 1.73 (m, 3H), 1.46 - 1.34 (m, 8H), 1.29 (d, J = 6.6 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H)。LCMS-ESI+ (m/z):C47
H63
ClN6
O5
S計算值H+:859.43;實驗值:859.13。實例 285
步驟1:合成(3S)-4-[(2S)-2-(甲氧基羰基胺基)-3-甲基-丁醯基]-3-甲基-哌嗪-1-甲酸第三丁酯:在室溫下向於DCM (6.0 mL)中之(3R)-3-甲基哌嗪-1-甲酸第三丁酯(250 mg,1.25 mmol)及(2R)-2-(甲氧基羰基 胺基)-3-甲基-丁酸(241 mg,1.37 mmol)之混合物中添加EDCI.HCl (358 mg,1.87 mmol),繼而添加DMAP (229 mg,1.87 mmol)。在用DCM稀釋所得混合物之前,將其在室溫下攪拌過夜。將有機層依序用飽和NH4
Cl、飽和NaHCO3
及鹽水洗滌,隨後使其經硫酸鈉乾燥,過濾且濃縮,得到粗產物,藉由combiflash (0-100% EtOAc/己烷)將其純化。將所需溶離份組合且濃縮,得到所需產物(446 mg)。LCMS-ESI+ (m/z):C17
H31
N3
O5
計算值H+:358.23;實驗值:358.20。
步驟2:合成N-[(1S)-2-甲基-1-[(2S)-2-甲基哌嗪-1-羰基]丙基]胺基甲酸甲酯;二HCl鹽:隨後,將來自步驟 1
之(3S)-4-[(2S)-2-(甲氧基羰基 胺基)-3-甲基-丁醯基]-3-甲基-哌嗪-1-甲酸第三丁酯(446 mg,1.25 mmol)溶解於DCM (3.0 mL)中,且在室溫下用於1,4-二噁烷(1.25 mL)中之4 N HCl處理3 hr。將反應物濃縮,與EtOAc (3×4.0 mL)一起共蒸發,得到標題化合物(270 mg)。LCMS-ESI+ (m/z):C12
H23
N3
O3
計算值H+:258.17;實驗值:258.17。
步驟3:合成實例 285
:遵循與使用實例 109
、中間物 285-2
及DIEA之實例 75
之合成相同之程序。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 - 7.05 (m, 2H), 6.95 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 1.9 Hz, 1H), 6.00 - 5.90 (m, 1H), 5.58 (dd, J = 15.2, 9.3 Hz, 1H), 4.47 - 4.31 (m, 3H), 4.13 - 4.04 (m, 2H), 3.85 (d, J = 15.1 Hz, 1H), 3.76 (dd, J = 9.3, 3.7 Hz, 1H), 3.71 - 3.62 (m, 5H), 3.31 - 3.24 (m, 5H), 3.12 - 3.04 (m, 2H), 2.88 - 2.70 (m, 2H), 2.54 - 2.41 (m, 2H), 2.38 - 2.24 (m, 1H), 2.23 - 1.67 (m, 12H), 1.49 - 1.30 (m, 3H), 1.23 - 1.08 (m, 5H), 1.03 - 0.89 (m, 7H)。LCMS-ESI+ (m/z):C45
H61
ClN6
O8
S計算值H+:881.40;實驗值:880.97。實例 286
以與實例 182
相同之方式使用1-(氮雜環丁烷-3-基)-3-甲氧基-氮雜環丁烷而不使用外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙-1-胺來合成實例 286
。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 8.9 Hz, 1H), 7.11 (dd, J = 9.6, 1.9 Hz, 2H), 6.96 - 6.87 (m, 2H), 6.02 (dt, J = 14.2, 6.6 Hz, 1H), 5.56 (dd, J = 15.2, 9.2 Hz, 1H), 4.45 (s, 1H), 4.34 (q, J = 8.4, 7.5 Hz, 4H), 4.28 (s, 1H), 4.12 (d, J = 13.1 Hz, 2H), 4.07 (d, J = 1.9 Hz, 2H), 4.02 (d, J = 15.2 Hz, 2H), 3.86 (d, J = 15.2 Hz, 1H), 3.77 (dd, J = 9.2, 3.7 Hz, 1H), 3.66 (d, J = 14.0 Hz, 2H), 3.39 (s, 3H), 3.26 (s, 4H), 3.07 (dd, J = 15.3, 10.2 Hz, 1H), 2.89 - 2.69 (m, 2H), 2.55 - 2.41 (m, 2H), 2.41 - 2.24 (m, 1H), 2.18 (t, J = 7.5 Hz, 1H), 2.09 (t, J = 14.3 Hz, 3H), 2.03 - 1.87 (m, 3H), 1.78 (tt, J = 17.7, 9.5 Hz, 3H), 1.44 (t, J = 12.8 Hz, 1H), 1.12 (d, J = 6.5 Hz, 3H)。LCMS-ESI+ (m/z):C40
H52
ClN5
O6
S [M+H]+計算值:766.33;實驗值:766.11。實例 287
以與實例 182
相同之方式使用1-(氮雜環丁烷-3-基)-4-甲氧基-哌啶而不使用外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙-1-胺來合成實例 286
。1H NMR (400 MHz,甲醇-d4) δ 7.73 (d, J = 8.5 Hz, 1H), 7.24 - 7.06 (m, 3H), 6.90 (d, J = 7.2 Hz, 2H), 6.00 (dd, J = 14.7, 7.6 Hz, 1H), 5.57 (dd, J = 15.2, 9.2 Hz, 1H), 4.34 (dd, J = 14.6, 6.7 Hz, 3H), 4.21 (s, 2H), 4.07 (d, J = 1.9 Hz, 3H), 3.93 - 3.55 (m, 6H), 3.40 (s, 3H), 3.26 (s, 3H), 3.08 (dd, J = 15.3, 10.3 Hz, 3H), 2.90 - 2.70 (m, 3H), 2.58 - 2.42 (m, 3H), 2.34 (t, J = 9.5 Hz, 2H), 2.15 (dd, J = 25.4, 10.7 Hz, 4H), 2.04 - 1.60 (m, 8H), 1.44 (t, J = 12.7 Hz, 1H), 1.13 (d, J = 6.5 Hz, 3H)。LCMS-ESI+ (m/z):C42
H56
ClN5
O6
S [M+H]+計算值:794.36;實驗值:794.05。實例 288
以與實例 283
相同之方式使用2-氟吡嗪及實例 279
來合成實例 288
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.25 (d,J
= 1.4 Hz, 1H), 8.12 (s, 1H), 8.08 (d,J
= 2.8 Hz, 1H), 7.95 (dd,J
= 2.8, 1.4 Hz, 1H), 7.75 (d,J
= 8.5 Hz, 1H), 7.43 (dd,J
= 8.3, 1.8 Hz, 1H), 7.25 (s, 1H), 7.15 (d,J
= 8.8 Hz, 1H), 7.11 (d,J
= 2.3 Hz, 1H), 6.91 (d,J
= 8.3 Hz, 1H), 6.24 (dd,J
= 15.6, 5.4 Hz, 1H), 6.15 (s, 1H), 5.88 (dd,J
= 15.5, 8.1 Hz, 1H), 4.24 (t,J
= 5.8 Hz, 2H), 4.06 (d,J
= 6.0 Hz, 5H), 3.81 (m, 6H), 3.72 (d,J
= 14.4 Hz, 1H), 3.40 (d,J
= 14.4 Hz, 1H), 3.16 (s, 3H), 3.08 (dd,J
= 15.2, 10.4 Hz, 1H), 2.91 - 2.61 (m, 3H), 2.49 (dd,J
= 27.4, 14.6 Hz, 2H), 2.10 (d,J
= 13.7 Hz, 1H), 2.03 - 1.81 (m, 2H), 1.73 (dq,J
= 15.0, 8.1, 7.7 Hz, 2H), 1.59 - 1.39 (m, 2H), 1.22 (d,J
= 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C42
H48
ClN7
O7
S [M+H]+計算值:830.3;實驗值:829.7。實例 289
以本文所描述之類似方法合成實例 289
。LCMS-ESI+ (m/z):C36
H45
ClN4
O6
S [M+H]+
計算值:697.2821;實驗值:696.81。實例 290
合成中間物 290-1
:在室溫下將中間物 359-4
(35.0 mg,0.0585 mmol)溶解於EtOH (10.0 mL)中,添加PtO2
(16.0 mg),使所得混合物脫氣,且在氫氣球下氫化1 hr。隨後,經由0.45 µm PTFE盤過濾器過濾反應物。將濾液濃縮,再溶解於DMF (1.2 mL)中,過濾,且藉由逆相製備型HPLC純化。將所需溶離份組合且冷凍乾燥,得到359-4
。1H NMR (400 MHz,甲醇-d4) δ 7.78 (d, J = 8.5 Hz, 1H), 7.41 (dd, J = 8.2, 1.9 Hz, 1H), 7.23 - 7.14 (m, 2H), 7.11 (d, J = 2.3 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 4.11 - 3.97 (m, 3H), 3.86 (d, J = 15.0 Hz, 1H), 3.80 - 3.72 (m, 1H), 3.69 - 3.62 (m, 1H), 3.28 (d, J = 14.1 Hz, 1H), 3.05 (dd, J = 15.2, 9.2 Hz, 1H), 2.86 - 2.69 (m, 2H), 2.50 - 2.31 (m, 2H), 2.31 - 2.22 (m, 1H), 2.13 - 2.05 (m, 1H), 2.01 - 1.84 (m, 3H), 1.83 - 1.74 (m, 2H), 1.74 - 1.52 (m, 4H), 1.51 - 1.23 (m, 7H), 1.04 (d, J = 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C32
H42
ClN3
O4
計算值H+:600.26;實驗值:600.14。
合成實例 290
:在室溫下將中間物290-2
(10.0 mg,0.0137 mmol)及3-甲氧基-1-甲基-吡唑-4-甲酸(2.79 mg,0.0179 mmol)混合在DCM (1.0 mL)中。向此經攪拌混合物中添加EDCI.HCl (3.41 mg,0.0179 mmol)及DMAP (2.18 mg,0.0179 mmol),繼而添加DIEA (5.32 mg,0.041 mmol)。將新形成之混合物在室溫下攪拌2天,且隨後將其濃縮,再溶解於DMF (1.2 mL)中,過濾且藉由逆相製備型HPLC純化。1H NMR (400 MHz,甲醇-d4) δ 7.95 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.16 - 7.10 (m, 2H), 6.95 (d, J = 8.2 Hz, 1H), 4.19 - 4.06 (m, 3H), 3.99 (s, 3H), 3.85 (d, J = 15.0 Hz, 1H), 3.79 (s, 3H), 3.74 - 3.65 (m, 2H), 3.18 - 3.08 (m, 1H), 2.88 - 2.71 (m, 2H), 2.51 - 2.20 (m, 3H), 2.15 - 2.06 (m, 1H), 2.04 - 1.87 (m, 3H), 1.87 - 1.77 (m, 2H), 1.77 - 1.33 (m, 12H), 1.14 (d, J = 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C38
H48
ClN5
O6
S計算值H+:738.30;實驗值:737.88。實例 291
以與實例 283
相同之方式使用1-碘基-2-甲氧基乙烷及實例 279
來合成實例 291
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.09 (s, 1H), 7.76 (d,J
= 8.6 Hz, 1H), 7.36 (d,J
= 8.8 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.12 (d,J
= 2.3 Hz, 1H), 6.92 (d,J
= 8.2 Hz, 1H), 6.04 (dd,J
= 15.4, 7.2 Hz, 1H), 5.84 (dd,J
= 15.5, 8.5 Hz, 1H), 4.08 (m, 8H), 3.82 (m, 5H), 3.76 - 3.64 (m, 2H), 3.58 - 3.38 (m, 4H), 3.34 (s, 3H), 3.30 (s, 3H), 3.19 - 3.06 (m, 2H), 2.91 - 2.71 (m, 2H), 2.51 (m, 2H), 2.26 (m, 1H), 2.12 (m, 1H), 1.96 (m, 2H), 1.82 (d,J
= 6.3 Hz, 3H), 1.46 (t,J
= 13.1 Hz, 1H), 1.20 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C41
H51
ClFN5
O8
S [M+H]+計算值:810.3;實驗值:810.0。實例 292
以與實例 75
相同之方式使用氮雜環丁烷-3-基-二甲基胺基甲酸酯雙-鹽酸(以與反 -
3-胺基環丁基二甲基胺基甲酸酯雙-鹽酸(實例 360
-步驟1/2)相同之方式以3-羥基氮雜環丁烷-1-甲酸第三丁酯而不使用二甲基胺基甲酸反 -
3-((第三丁氧基羰基)胺基)環丁酯為起始物來製備)及實例 109
來合成實例 292
。1
H NMR (400 MHz,甲醇-d4) δ 7.72 (d,J
= 8.5 Hz, 1H), 7.16 (d,J
= 8.8 Hz, 1H), 7.12 - 7.05 (m, 2H), 6.95 - 6.86 (m, 2H), 5.96 (dq,J
= 14.1, 7.2 Hz, 1H), 5.56 (dd,J
= 15.2, 9.1 Hz, 1H), 5.15 - 5.00 (m, 1H), 4.30 (dd,J
= 15.5, 6.9 Hz, 4H), 4.13 - 3.90 (m, 4H), 3.83 (d,J
= 15.2 Hz, 1H), 3.74 (dd,J
= 9.1, 3.6 Hz, 1H), 3.69 - 3.54 (m, 2H), 3.24 (s, 3H), 3.06 (dd,J
= 15.3, 10.3 Hz, 1H), 2.98 (s, 3H), 2.90 (s, 3H), 2.87 - 2.68 (m, 2H), 2.44 (dd,J
= 14.2, 6.7 Hz, 2H), 2.39 - 2.26 (m, 1H), 2.23 - 2.03 (m, 3H), 2.02 - 1.65 (m, 6H), 1.43 (t,J
= 12.9 Hz, 1H), 1.13 (d,J
= 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C39
H51
ClN5
O7
S [M+H]+計算值:768.31;實驗值:767.73。實例 293
步驟1:製備N
-(第三丁基甘胺醯基)-N
-甲基甘胺酸(293-1
)。在0℃下向於DCM (10 mL)中之N
-(N
-(第三丁氧基羰基)-N
-(第三丁基)甘胺醯基)-N-甲基甘胺酸(600 mg,1.98 mmol)之溶液中緩慢地添加TFA (2 mL)。將反應混合物升溫至室溫,且攪拌過夜。隨後,將其濃縮至乾,且不經進一步純化即用於下一步驟中。LCMS-ESI+:C9
H18
N2
O3
[M+H]+
計算值:203.14;實驗值:203.10。
步驟2:向粗製物中間物293-1
(0.4 g,1.98 mmol)中添加1.0 M Na2
CO3
水溶液(6 mL)。將反應混合物冷卻至0℃,且逐漸添加於二噁烷(12 mL)中之9-芴基甲氧基碳醯氯(Fmoc-Cl) (1.03 g,3.97 mmol)。將反應混合物在室溫下攪拌14小時,且隨後用1.0 N HCl (13 mL)水溶液中和至pH值2。隨後,將其用EtOAc (50 mL×2)萃取。將有機層組合,乾燥且濃縮。藉由管柱層析法使用0-10%於DCM中之MeOH純化粗殘餘物,獲得中間物293-2
。LCMS-ESI+:C24
H28
N2
O5
[M+H]+
計算值:425.21;實驗值:425.19。
步驟3:以與實例 18
相同之方式使用中間物293-2
及實例 359
來合成中間物293-3
。LCMS-ESI+:C62
H72
ClN7
O10
S [M+H]+
計算值:1142.48;實驗值:1142.08。
步驟4:向於DMF (1.2 mL)中之中間物293-3
(22 mg,0.20 mmol)之溶液中添加哌啶(0.3 mL)。將反應混合物攪拌20 min,且LC/MS顯示其即將完成。添加0.5 ml水以淬滅反應物。將粗混合物用MeOH (2 mL)稀釋,且藉由RP-HPLC (30-100%梯度,0.1%TFA)純化,獲得實例 293
。1
H NMR (400 MHz,甲醇-d
4) δ 7.94 (d,J
= 4.3 Hz, 1H), 7.76 (t,J
= 8.1 Hz, 1H), 7.26 - 7.03 (m, 4H), 6.94 (t,J
= 7.7 Hz, 1H), 5.99 (d,J
= 15.0 Hz, 1H), 5.77 (td,J
= 16.8, 15.4, 8.2 Hz, 1H), 5.44 (ddd,J
= 37.1, 8.0, 3.8 Hz, 1H), 4.28 (d,J
= 28.4 Hz, 1H), 4.10 (t,J
= 4.4 Hz, 5H), 4.03 - 3.84 (m, 5H), 3.79 (d,J
= 1.5 Hz, 3H), 3.69 (t,J
= 12.5 Hz, 1H), 3.16 (t,J
= 5.5 Hz, 1H), 3.11 (s, 3H), 2.88 - 2.72 (m, 2H), 2.59 - 2.42 (m, 2H), 2.20 (s, 3H), 2.09 (d,J
= 13.7 Hz, 1H), 2.01 - 1.84 (m, 5H), 1.83 - 1.70 (m, 2H), 1.57 (d,J
= 7.0 Hz, 3H), 1.49 (d,J
= 12.7 Hz, 1H), 1.41 (d,J
= 9.4 Hz, 9H), 1.17 (q,J
= 3.1 Hz, 3H)。LCMS-ESI+ C47
H62
ClN7
O8
S [M+H]計算值:920.41;實驗值:920.20。實例 294
以本文所描述之類似方法合成實例 294
。LCMS-ESI+ (m/z):C37
H48
ClN5
O5
S [M+H]+
計算值:710.3137;實驗值:710.03。實例 295
以與實例 283
相同之方式使用4-(2-碘基乙基)嗎啉及實例 279
來合成實例 291
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.09 (s, 1H), 7.76 (d,J
= 8.5 Hz, 1H), 7.39 (dd,J
= 8.2, 1.9 Hz, 1H), 7.25 (s, 1H), 7.19 (dd,J
= 8.5, 2.3 Hz, 1H), 7.13 (d,J
= 2.3 Hz, 1H), 6.93 (d,J
= 8.2 Hz, 1H), 6.21 (dd,J
= 15.3, 8.7 Hz, 1H), 5.93 (dd,J
= 15.3, 8.8 Hz, 1H), 4.27 (dd,J
= 14.9, 5.5 Hz, 1H), 4.08 (m, 9H), 3.99 - 3.76 (m, 8H), 3.76 - 3.57 (m, 4H), 3.59 - 3.38 (m, 4H), 3.36 - 3.20 (m, 2H), 3.30 (s, 3H), 3.20 - 3.08 (m, 2H), 2.89 - 2.73 (m, 2H), 2.54 (m, 2H), 2.33 (m, 1H), 2.12 (d,J
= 13.2 Hz, 1H), 1.96 (m, 2H), 1.83 (m, 3H), 1.47 (t,J
= 12.4 Hz, 1H), 1.25 (d,J
= 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C44
H57
ClFN6
O8
S [M+H]+計算值:865.4;實驗值:865.4。實例 296
以與實例 283
相同之方式使用碘乙烷及實例 279
來合成實例 296
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.10 (s, 1H), 7.75 (d,J
= 8.5 Hz, 1H), 7.42 - 7.31 (m, 1H), 7.19 (s, 1H), 7.18 - 7.10 (m, 2H), 6.91 (d,J
= 8.2 Hz, 1H), 6.04 (dd,J
= 15.4, 7.6 Hz, 1H), 5.80 (dd,J
= 15.4, 8.6 Hz, 1H), 4.12 - 4.02 (m, 5H), 3.98 (d,J
= 7.5 Hz, 1H), 3.82 (m, 5H), 3.72 (d,J
= 14.4 Hz, 1H), 3.61 (dq,J
= 9.5, 7.0 Hz, 1H), 3.45 - 3.25 (m, 3H), 3.31 (m, 2H), 3.29 (s, 3H), 3.18 - 3.06 (m, 1H), 2.87 - 2.71 (m, 3H), 2.51 (s, 2H), 2.24 (d,J
= 7.7 Hz, 1H), 2.11 (d,J
= 13.7 Hz, 1H), 1.96 (m, 2H), 1.82 (d,J
= 7.2 Hz, 3H), 1.45 (t,J
= 11.8 Hz, 1H), 1.23 - 1.12 (m, 6H)。LCMS-ESI+ (m/z):C40
H50
ClN5
O7
S [M+H]+計算值:780.3;實驗值:780.1。實例 297
步驟1:在室溫下向於DCE (1.0 mL)中之3-側氧基氮雜環丁烷-1-甲酸第三丁酯(50.0 mg,0.292 mmol)及(9aS)-1,3,4,6,7,8,9,9a-八氫吡嗪并[2,1-c][1,4]噁嗪二鹽酸鹽(62.8 mg,0.292 mmol)之混合物中添加三乙胺(59.1 mg,0.584 mmol)。將所得混合物在室溫下攪拌10 min,且添加三乙醯氧基硼氫化鈉(92.9 mg,0.438 mmol)。將所得混合物在室溫下攪拌過夜。隨後,將反應物與MeOH混合,過濾沈澱物,藉由combiflash (4g矽膠,0-10% 2.0N MeOH/EtOAc)純化濾液。將所需溶離份組合且濃縮,得到297-1
。1H NMR (400 MHz,氘代氯仿) δ 3.94 - 3.75 (m, 5H), 3.73 - 3.62 (m, 2H), 3.24 (t, J = 10.7 Hz, 1H), 3.11 - 3.02 (m, 1H), 2.82 - 2.71 (m, 2H), 2.68 (d, J = 11.5 Hz, 1H), 2.54 (dt, J = 10.8, 2.3 Hz, 1H), 2.44 - 2.30 (m, 3H), 2.20 - 2.10 (m, 1H), 1.68 (t, J = 10.5 Hz, 1H), 1.41 (s, 9H)。LCMS-ESI+ (m/z):C15
H27
N3
O3
計算值H+:298.21;實驗值:297.98。
步驟2:在室溫下將中間物297-1
(53.2 mg,0.179 mmol)溶解於DCM (1.0 mL)中。緩慢地添加於1,4-二噁烷(0.224 mL,0.894 mmol)中之4 N HCl。將所得混合物在室溫下攪拌2 hr。將反應物濃縮,且與EtOAc (3×2.0 mL)一起共蒸發,得到297-2
。1H NMR (400 MHz,甲醇-d4) δ 4.22 - 4.00 (m, 7H), 3.94 (t, J = 12.4 Hz, 1H), 3.71 - 3.50 (m, 5H), 3.46 (d, J = 12.6 Hz, 1H), 3.18 - 3.02 (m, 2H), 2.60 (t, J = 12.7 Hz, 1H), 2.24 (t, J = 11.7 Hz, 1H)。LCMS-ESI+ (m/z):C10
H19
N3
O計算值H+:198.15;實驗值:198.15。
步驟3:合成實例 297
:向於DCM (0.4 mL)中之實例 109
(10.0 mg,0.0167 mmol)之溶液中添加乙腈(2.0 mL)。向混合物中添加DMAP (10.2 mg,0.084 mmol)及碳酸二苯酯(28.6 mg,0.134 mmol)。將反應混合物在室溫下攪拌3 hr。向經攪拌混合物中添加(9aS)-8-(氮雜環丁烷-3-基)-3,4,6,7,9,9a-六氫-1H-吡嗪并[2,1-c][1,4]噁嗪三鹽酸鹽(20.5 mg,0.069 mmol),繼而添加DIEA (32.4 mg,0.25 mmol)。隨後,將反應物在50℃下加熱5 hr,之後將其濃縮,再溶解於DMF (1.2 mL)中,過濾且藉由Gilson逆相製備型HPLC純化。將所需溶離份組合且濃縮。將殘餘物用水稀釋且冷凍乾燥,得到標題化合物。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.6 Hz, 1H), 7.18 (dd, J = 8.4, 2.3 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.96 - 6.89 (m, 2H), 6.02 - 5.92 (m, 1H), 5.58 (dd, J = 15.3, 9.0 Hz, 1H), 4.31 (dd, J = 14.9, 6.4 Hz, 1H), 4.21 - 3.97 (m, 5H), 3.89 - 3.81 (m, 1H), 3.76 (dd, J = 9.1, 3.8 Hz, 1H), 3.71 - 3.63 (m, 1H), 3.54 - 3.46 (m, 1H), 3.45 - 3.36 (m, 1H), 3.32 - 3.17 (m, 13H), 3.13 - 3.04 (m, 2H), 2.87 - 2.73 (m, 2H), 2.55 - 2.41 (m, 3H), 2.40 - 2.29 (m, 1H), 2.25 - 2.04 (m, 4H), 2.00 - 1.68 (m, 7H), 1.50 - 1.34 (m, 2H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C43
H57
N6
O6
S計算值H+:821.37;實驗值:821.07。實例 298
以與實例 280
相同之方式使用實例 279
來合成實例 298
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.08 (s, 1H), 8.00 (s, 1H), 7.77 (d,J
= 8.5 Hz, 1H), 7.39 (t,J
= 7.5 Hz, 1H), 7.29 (s, 1H), 7.18 (d,J
= 8.5 Hz, 1H), 7.12 (d,J
= 2.3 Hz, 1H), 6.93 (d,J
= 8.3 Hz, 1H), 4.09 (m, 6H), 3.82 (m, 5H), 3.71 (d,J
= 14.4 Hz, 1H), 3.61 (s, 1H), 3.37 (d,J
= 4.2 Hz, 2H), 3.18 - 3.04 (m, 1H), 3.02 (s, 3H), 2.88 (s, 3H), 2.80 (m, 2H), 2.56 (m, 2H), 2.26 (s, 1H), 2.11 (d,J
= 13.5 Hz, 1H), 2.01 - 1.9 (m, 2H), 1.76 (m, 4H), 1.67 - 1.39 (m, 4H), 1.19 (d,J
= 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C38
H48
ClN5
O7
S [M+H]+計算值:754.3;實驗值:754.1。實例 298
以與實例 280
相同之方式使用實例 279
來合成實例 299
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.10 (s, 1H), 7.77 (d,J
= 8.5 Hz, 1H), 7.41 (dd,J
= 8.3, 1.8 Hz, 1H), 7.25 (s, 1H), 7.17 (dd,J
= 8.5, 2.3 Hz, 1H), 7.12 (d,J
= 2.3 Hz, 1H), 6.94 (d,J
= 8.2 Hz, 1H), 4.08 (m, 7H), 3.82 (m, 5H), 3.71 (d,J
= 14.2 Hz, 1H), 3.40 (m, 4H), 3.35 (m, 2H), 3.31 (s, 3H), 3.21 (d,J
= 7.2 Hz, 1H), 3.18 - 3.07 (m, 1H), 2.90 - 2.71 (m, 2H), 2.62 (m, 1H), 2.48 (m, 1H), 2.36 (m, 1H), 2.11 (d,J
= 13.5 Hz, 1H), 1.96 (m, 3H), 1.77 (d,J
= 7.4 Hz, 3H), 1.50 (q,J
= 11.3, 9.2 Hz, 4H), 1.16 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C39
H50
ClN5
O7
S [M+H]+計算值:768.3;實驗值:768.1。實例 300
向於DCM (5 mL)中之3-甲氧基-1-甲基-1H-吡唑-4-甲酸(6 mg,0.038 mmol)、1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (10.75 mg,0.069 mmol)及4-(二甲基胺基)吡啶(8.45 mg,0.069 mmol)之經攪拌溶液中添加實例 223
(25 mg,0.035 mmol)。將反應混合物在室溫下攪拌24 hr。隨後,將反應混合物用DCM及水稀釋,且在DCM中萃取。將有機相經MgSO4
乾燥,過濾,濃縮且進行逆相層析法0.1% TFA 70-95%乙腈純化,得到實例 300
。1H NMR (400 MHz,氘代氯仿) δ 11.16 (s, 1H), 7.97 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.28 - 7.17 (m, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.11 (dd, J = 14.9, 7.7 Hz, 1H), 5.74 (dd, J = 15.6, 6.2 Hz, 1H), 5.33 (t, J = 5.3 Hz, 1H), 4.11 (d, J = 5.5 Hz, 3H), 4.07 - 3.88 (m, 3H), 3.82 (s, 2H), 3.76 (d, J = 14.4 Hz, 1H), 3.57 (d, J = 61.0 Hz, 2H), 3.42 - 3.18 (m, 3H), 3.13 - 2.58 (m, 6H), 2.48 - 2.21 (m, 3H), 2.07 - 1.47 (m, 13H), 1.40 (t, J = 12.8 Hz, 1H), 1.28 (s, 2H), 1.19 (d, J = 6.2 Hz, 2H), 0.96 - 0.70 (m, 2H)。LCMS-ESI+ (m/z):C44
H55
ClN6
O8
S [M+H]+計算值:862.35;實驗值:862.95。實例 301
以與實例 404
相同之方式使用二甲基甘胺酸及實例 223
來合成實例 301
。1H NMR (400 MHz,氘代氯仿) δ 8.10 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.2 Hz, 1H), 7.25 - 7.12 (m, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.37 - 6.21 (m, 1H), 5.85 (dd, J = 15.7, 5.7 Hz, 1H), 5.33 (s, 1H), 4.55 (d, J = 18.1 Hz, 1H), 4.35 (d, J = 14.4 Hz, 1H), 4.15 - 3.87 (m, 5H), 3.90 - 3.66 (m, 4H), 3.29 (dd, J = 28.4, 13.1 Hz, 3H), 3.04 (s, 5H), 2.78 (d, J = 12.3 Hz, 5H), 2.49 - 2.15 (m, 5H), 2.11 - 1.91 (m, 3H), 1.89 - 1.62 (m, 4H), 1.38 - 1.13 (m, 4H)。LCMS-ESI+ (m/z):C41
H51
ClN6
O7
S [M+H]+計算值:807.32;實驗值:806.99。實例 302
以與實例 18
相同之方式使用實例 109
而不使用實例 5
且使用7-甲氧基-5,6,7,8-四氫咪唑并[1,2-a]吡啶-2-甲酸而不使用3-甲氧基丙酸來合成實例 302
。1H NMR (400 MHz,甲醇-d4) δ 7.93 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.16 (ddd, J = 19.0, 8.6, 2.3 Hz, 3H), 6.99 - 6.88 (m, 2H), 6.07 (dt, J = 14.2, 6.5 Hz, 1H), 5.56 (dd, J = 15.2, 9.3 Hz, 1H), 4.47 (dd, J = 14.6, 6.2 Hz, 1H), 4.27 (dd, J = 8.2, 4.3 Hz, 2H), 4.08 (d, J = 1.8 Hz, 3H), 3.91 - 3.76 (m, 3H), 3.67 (d, J = 14.2 Hz, 1H), 3.46 (s, 3H), 3.27 (s, 4H), 3.07 (dd, J = 15.3, 10.3 Hz, 1H), 2.91 - 2.69 (m, 3H), 2.57 - 2.28 (m, 5H), 2.17 (dt, J = 30.1, 13.2 Hz, 4H), 2.03 - 1.85 (m, 3H), 1.77 (dq, J = 17.4, 9.1 Hz, 3H), 1.44 (t, J = 12.2 Hz, 1H), 1.16 - 1.05 (m, 3H)。LCMS-ESI+ (m/z):C41
H50
ClN5
O6
S [M+H]+計算值:776.32;實驗值:776.29。實例 303
步驟1:製備(1S,2S)-2-(甲氧基甲基)環丙烷-1-甲酸:將(1S,2S)-2-(羥基甲基)環丙烷-1-甲酸乙酯(640 mg,4.44 mmol)之溶液懸浮於THF (44 mL)中,冷卻至0℃,且用NaH (213 mg,8.88 mmol)處理。在15分鐘之後,添加甲基碘化物(1.38 mL,22.2 mmol),且使反應混合物升溫至RT。在攪拌1 h之後,謹慎添加EtOH (22 mL),繼而添加2M NaOH (22 mL,44 mmol)。隨後,將反應混合物升溫至65℃且在此溫度下攪拌18 h。隨後,將混合物冷卻至RT,且傾入含有10% HCl之分液漏斗中。用DCM萃取水層3×。將合併有機物經MgSO4
乾燥,隨後過濾,且在減壓下濃縮,得到(1S,2S)-2-(甲氧基甲基)環丙烷-1-甲酸(282 mg),其不經進一步純化即繼續。1
H NMR (400 MHz,氘代氯仿) δ 3.43 - 3.30 (m, 4H), 3.26 (dd,J
= 10.4, 6.7 Hz, 1H), 1.76 (dddd,J
= 12.8, 10.4, 7.8, 5.2 Hz, 1H), 1.56 (dt,J
= 8.6, 4.4 Hz, 1H), 1.32 - 1.21 (m, 1H), 0.93 (ddd,J
= 8.2, 6.3, 4.3 Hz, 1H)。
步驟2:製備實例 303 :
將(1S,2S)-2-(甲氧基甲基) 環丙烷-1-甲酸(112 mg,0.861 mmol)懸浮於PhMe (1 mL)中,隨後用二苯基磷醯基疊氮化物(0.18 mL,0.84 mmol)及三甲胺(0.14 mL,1.0 mmol)處理。將經攪拌之反應混合物加熱至80℃,隨後冷卻至RT。添加實例 109
(50 mg,0.084 mmol),且將經攪拌之反應混合物加熱至50℃達4 h。在完成之後,用EtOAc稀釋反應混合物。將有機相用飽和NaHCO3
溶液、5%檸檬酸及鹽水洗滌,隨後經MgSO4
乾燥,過濾,且在減壓下濃縮。藉由二氧化矽管柱層析法(0%至40% MeOH/EtOAc)純化粗殘餘物,隨後藉由HPLC再純化,獲得實例 303
。1
H NMR (400 MHz,氘代氯仿) δ 7.80 - 7.34 (m, 1H), 7.23 - 6.57 (m, 5H), 6.00 (dt,J
= 14.0, 6.7 Hz, 1H), 5.63 (ddd,J
= 41.7, 15.4, 8.5 Hz, 1H), 4.40 - 3.88 (m, 3H), 3.88 - 3.49 (m, 5H), 3.42 (s, 3H), 3.38 - 3.18 (m, 5H), 3.18 - 2.89 (m, 1H), 2.89 - 2.52 (m, 3H), 2.52 - 2.08 (m, 5H), 2.08 - 1.49 (m, 7H), 1.48 - 1.19 (m, 3H), 1.13 (d,J
= 6.3 Hz, 3H), 0.98 (dt,J
= 10.6, 5.4 Hz, 1H), 0.92 - 0.80 (m, 1H), 0.75 (q,J
= 6.6 Hz, 1H)。LCMS-ESI+:C38
H49
ClN4
O6
S計算值:725.3 (M+H);實驗值:725.8 (M+H)。實例 304
步驟1:將硼氫化鈉(494 mg,13.1 mmol)添加至於甲醇(10 mL)中之5-甲醯基-1-甲基-吡咯-3-甲酸(500 mg,3.27 mmol)之溶液中。在2小時之後,添加更多硼氫化鈉(494 mg,13.1 mmol)。在5小時之後,用水(5 mL)淬滅反應物。在減壓下移除甲醇。用乙酸乙酯(3×5 mL)萃取水相。將水相用ACN稀釋且經受凍乾,得到5-(羥基甲基)-1-甲基-1H-吡咯-3-甲酸鈉鹽。
步驟2:將來自上文之5-(羥基甲基)-1-甲基-1H-吡咯-3-甲酸鈉鹽(507 mg,3.27 mmol)懸浮於四氫呋喃(25 mL)及N
-甲基-2-吡咯啶酮(10 mL)中。添加氫化鈉60%於礦物油中之懸浮液(250 mg,6.54 mmol)。在5分鐘之後,添加碘甲烷(0.61 mL,9.8 mmol)。在16 h之後,添加氫化鈉60%於礦物油中之懸浮液(250 mg,6.54 mmol)。在5分鐘之後,添加碘甲烷(0.61 mL,9.8 mmol)。在4天之後,將反應物用乙酸乙酯(100 mL)稀釋,且用水(50 mL)、5%氯化鋰(2×)及鹽水(50 mL)洗滌。使有機相經硫酸鈉乾燥,且在減壓下移除溶劑。使殘餘物經受急驟層析法(0-100 %乙酸乙酯/己烷)。組合含有產物之溶離份,且在減壓下移除溶劑,得到5-(甲氧基甲基)-1-甲基-1H-吡咯-3-甲酸甲酯。1
H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 1.9 Hz, 1H), 6.43 (d, J = 1.8 Hz, 1H), 4.33 (s, 2H), 3.68 (s, 3H), 3.61 (s, 3H), 3.20 (s, 3H)。
步驟3:將1 N氫氧化鋰 (2.0 mL,2.0 mmol)之溶液添加至於甲醇(10 mL)中之5-(甲氧基甲基)-1-甲基-1H-吡咯-3-甲酸甲酯(138 mg,0.75 mmol)之溶液中。將溶液在40℃下攪拌18小時。使反應物冷卻,且用1 N鹽酸將pH調整至2。用乙酸乙酯(3×15 mL)萃取混合物。將有機相組合且用鹽水洗滌,且經硫酸鈉乾燥。在減壓下移除溶劑,得到5-(羥基甲基)-1-甲基-1H-吡咯-3-甲酸。1
H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.38 (d, J = 1.9 Hz, 1H), 6.38 (d, J = 1.9 Hz, 1H), 4.32 (s, 2H), 3.60 (s, 3H), 3.20 (s, 3H)。
以與實例 18
相同之方式使用5-(甲氧基甲基)-1-甲基-1H-吡咯-3-甲酸及實例 109
來合成實例 304
。1H NMR (400 MHz,甲醇-d4) δ 7.77 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.17 (dd, J = 8.5, 2.3 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 7.02 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.66 - 6.59 (m, 1H), 6.22 - 6.08 (m, 1H), 5.60 - 5.46 (m, 2H), 4.47 - 4.33 (m, 3H), 4.12 - 4.00 (m, 2H), 3.96 (d, J = 11.9 Hz, 0H), 3.88 (d, J = 15.1 Hz, 1H), 3.81 (dd, J = 9.1, 3.2 Hz, 1H), 3.73 - 3.62 (m, 4H), 3.27 (m, 4H), 3.04 (dd, J = 15.2, 9.6 Hz, 1H), 2.88 - 2.70 (m, 2H), 2.57 (m, 1H), 2.42 (m, 3H), 2.12 (m, 4H), 1.94 (m, 3H), 1.77 (m, 3H), 1.49 - 1.28 (m, 1H), 1.08 (d, J = 5.9 Hz, 3H)。LCMS-ESI+:C40
H49
ClN4
O6
S計算值:749.31 (M+H);實驗值:749.85 (M+H)。實例 305
步驟1:合成305-1
:在室溫下向於MeOH (1.0 mL)中之3-胺基-1-甲基-環丁烷甲酸(250 mg,1.94 mmol)之混合物中添加於1,4-二噁烷(1.94 mL,7.74 mmol)中之4 N HCl。將所得混合物在室溫下攪拌2天。將反應物濃縮,與EtOAc (3×)一起共蒸發,且進一步經真空管線乾燥,得到305-1
。1H NMR (400 MHz,甲醇-d4) δ 3.95 - 3.80 (m, 1H), 3.74 (s, 3H), 2.65 - 2.52 (m, 2H), 2.40 - 2.25 (m, 2H), 1.46 (s, 3H)。
步驟2:以與實例 75
相同之方式使用實例 109
及305-1
以及DIEA來合成實例 305
。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.4 Hz, 1H), 7.23 - 7.09 (m, 3H), 6.99 (s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.10 - 5.98 (m, 1H), 5.65 - 5.54 (m, 1H), 4.37 - 4.22 (m, 2H), 4.11 - 4.01 (m, 2H), 3.89 - 3.74 (m, 3H), 3.73 - 3.65 (m, 4H), 3.27 (s, 3H), 3.12 - 3.02 (m, 1H), 2.89 - 2.71 (m, 2H), 2.53 - 2.35 (m, 5H), 2.32 - 2.23 (m, 2H), 2.23 - 2.16 (m, 1H), 2.16 - 2.08 (m, 2H), 2.00 - 1.71 (m, 7H), 1.48 - 1.40 (m, 4H), 1.13 (d, J = 6.7 Hz, 3H)。LCMS-ESI+ (m/z):C40
H51
ClN4
O7
S計算值H+:767.32;實驗值:766.77。實例 306
以與實例 214
類似之方式使用(S)-2-(甲氧基甲基)環氧乙烷而不使用(R)-2-(甲氧基甲基)環氧乙烷來合成實例 306
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.50 - 7.38 (m, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.27 - 7.21 (m, 2H), 7.14 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.31 (s, 1H), 6.23 - 6.10 (m, 1H), 5.62 (dd, J = 15.5, 8.0 Hz, 1H), 4.93 (d, J = 14.4 Hz, 1H), 4.74 (d, J = 14.5 Hz, 1H), 4.26 - 3.94 (m, 5H), 3.94 - 3.81 (m, 2H), 3.81 - 3.71 (m, 2H), 3.64 (dd, J = 10.4, 5.4 Hz, 1H), 3.55 (dd, J = 10.4, 4.8 Hz, 1H), 3.43 (d, J = 14.4 Hz, 1H), 3.39 (s, 3H), 3.24 (s, 3H), 3.14 (dd, J = 15.1, 10.4 Hz, 1H), 2.96 - 1.39 (m, 16H), 1.13 (d, J = 6.6 Hz, 3H)。LCMS:791.0。實例 307
以與實例 75
相同之方式使用(1R,2R)-2-(甲氧基甲基)環丁-1-胺及實例 109
來合成實例 307 。
1H NMR (400 MHz,甲醇-d4) δ 7.76 (d, J = 8.4 Hz, 1H), 7.20 (dd, J = 20.9, 8.3 Hz, 2H), 7.13 (s, 1H), 7.03 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.08 (d, J = 15.2 Hz, 1H), 5.59 (dd, J = 15.4, 9.0 Hz, 1H), 4.25 (s, 1H), 4.04 (dd, J = 19.9, 7.0 Hz, 3H), 3.91 - 3.63 (m, 4H), 3.46 (dd, J = 11.2, 5.8 Hz, 2H), 3.36 (s, 3H), 3.27 (s, 3H), 3.09 (dd, J = 15.1, 10.2 Hz, 1H), 2.89 - 2.73 (m, 2H), 2.44 (d, J = 35.2 Hz, 4H), 2.20 (dd, J = 23.2, 5.7 Hz, 2H), 1.96 (s, 3H), 1.89 - 1.70 (m, 4H), 1.56 - 1.40 (m, 3H), 1.13 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 7.1 Hz, 1H), 0.61 (s, 1H), 0.12 (d, J = 12.1 Hz, 1H)。LCMS-ESI+
C39
H51
ClN4
O6
S [M+H]+
計算值:739.32;實驗值:738.84。實例 308
以與實例 18
相同之方式使用實例 109
及1-甲基-5-(嗎啉基甲基)-1H-吡咯-3-甲酸(使用與實例 309
-步驟1類似之程序由5-甲醯基-1-甲基-吡咯-3-甲酸及嗎啉製備)來合成實例 308
。1
H NMR (400 MHz,甲醇-d4) δ 7.71 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.01 (dd, j = 12.9, 2.1 Hz, 2H), 6.77 (d, J = 8.3 Hz, 1H), 6.70 (s, 1H), 6.20 (dd, J = 15.1, 7.7 Hz, 1H), 5.73 (dd, J = 15.4, 8.2 Hz, 1H), 4.44 (s, 2H), 4.15 (dd, J = 14.7, 7.1 Hz, 1H), 4.02-3.85 (m, 3H), 3.80 (s, 4H), 3.78-3.71 (m, 1H), 3.61 (d, J = 14.4 Hz, 1H), 3.50 (d, J = 14.5 Hz, 1H), 3.14 (dd, J = 15.2, 10.7 Hz, 1H), 3.02-2.82 (m, 2H), 2.82-2.65 (m, 1H), 2.65-2.44 (m, 1H), 2.34 (d, J = 15.2 Hz, 3H), 2.12-1.96 (m, 1H), 1.96-1.79 (m, 3H), 1.32 (d, J = 10.5 Hz, 2H), 1.19 (d, J = 6.2 Hz, 3H)。LCMS-ESI+:C43
H54
ClN5
O6
S計算值:804.35 (M+H);實驗值:804.56 (M+H)。實例 309
步驟1:將1-(氧雜環丁烷-3-基)哌嗪添加至於四氫呋喃(3 mL)中之5-甲醯基-1-甲基-吡咯-3-甲酸(50 mg,0.327 mmol)之溶液中。將溶液在室溫下攪拌2小時。添加硼氫化鈉(346 mg,9 mmol)及甲醇(0.5 mL)。在2 h之後,用水(2 mL)及三氟乙酸(0.3 mL)淬滅反應物。使溶液經受製備型HPLC。將含有產物之溶離份組合且經受凍乾,得到1-甲基-5-((4-(氧雜環丁烷-3-基)哌嗪-1-基)甲基)-1H-吡咯-3-甲酸。1
H NMR (400 MHz,甲醇-d4) δ 7.49 (d, J = 1.8 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 4.76 (t, J = 6.9 Hz, 2H), 4.64 (dd, J = 7.0, 5.6 Hz, 2H), 4.23 (s, 2H), 3.83 (t, J = 6.1 Hz, 1H), 3.77 (s, 3H), 3.29 - 3.10 (m, 4H), 2.81 (s, 5H)。
步驟2:以與實例 18
相同之方式使用實例 109
及1-甲基-5-((4-(氧雜環丁烷-3-基)哌嗪-1-基)甲基)-1H-吡咯-3-甲酸來合成實例 308
。1H NMR (400 MHz,甲醇-d4) δ 7.68 (d, J = 1.8 Hz, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.05 (dd, J = 14.4, 2.1 Hz, 2H), 6.98 (s, 3H), 6.93 (s, 2H), 6.84 (d, J = 8.2 Hz, 1H), 6.14 (dd, J = 15.0, 7.6 Hz, 1H), 5.68 (dd, J = 15.4, 8.3 Hz, 1H), 4.78 (t, J = 6.9 Hz, 2H), 4.66 (t, J = 6.3 Hz, 2H), 4.20 (d, J = 14.2 Hz, 3H), 4.01 (s, 2H), 4.00 - 3.90 (m, 0H), 3.65 (d, J = 14.5 Hz, 1H), 3.43 (d, J = 14.4 Hz, 1H), 3.20 - 3.02 (m, 1H), 2.86 (d, J = 16.7 Hz, 1H), 2.76 (dq, J = 16.7, 8.7, 7.4 Hz, 2H), 2.49 (s, 2H), 2.30 (d, J = 15.5 Hz, 2H), 2.22 - 2.05 (m, 1H), 1.97 (d, J = 9.0 Hz, 1H), 1.84 (s, 0H), 1.40 (t, J = 12.3 Hz, 1H), 1.17 (d, J = 6.1 Hz, 3H)。LCMS-ESI+:C46
H59
ClN6
O6
S計算值:859.39 (M+H);實驗值:859.46 (M+H)。實例 310
以與實例75類似之方式使用(1R,2R)-2-(二氟甲基)環丙-1-胺、三乙胺及實例 109
來製備實例 310
。1H NMR (400 MHz,甲醇-d4) δ 7.72 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.15 - 7.05 (m, 2H), 6.96 (s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.10 - 6.00 (m, 1H), 5.83 (td, J = 57.3, 4.2 Hz, 1H), 5.61 (dd, J = 15.3, 9.0 Hz, 1H), 4.27 (d, J = 14.4 Hz, 1H), 4.06 (d, J = 1.8 Hz, 2H), 3.84 (d, J = 15.1 Hz, 1H), 3.77 (dd, J = 9.0, 3.6 Hz, 1H), 3.67 (d, J = 14.2 Hz, 1H), 3.30 - 3.23 (m, 4H), 3.08 (dd, J = 15.2, 10.2 Hz, 1H), 2.78 (ddd, J = 22.7, 18.6, 10.0 Hz, 3H), 2.45 (dt, J = 34.4, 13.8 Hz, 3H), 2.21 (dd, J = 14.9, 6.4 Hz, 1H), 2.15 - 2.04 (m, 1H), 2.04 - 1.87 (m, 2H), 1.82 (dt, J = 21.0, 8.2 Hz, 2H), 1.59 - 1.48 (m, 1H), 1.43 (t, J = 11.9 Hz, 1H), 1.31 (s, 2H), 1.14 (d, J = 6.5 Hz, 3H), 1.09 (q, J = 6.3 Hz, 1H), 1.04 - 0.85 (m, 1H)。LCMS-ESI+:LCMS-ESI+計算值:C37
H45
ClF2
N4
O5
S計算值:731.28 (M+H);實驗值:731.13 (M+H)。實例 311
以與實例 75
類似之方式使用(1S,2S)-2-(二氟甲基)環丙-1-胺、三乙胺及實例 109
來製備實例 311
。1H NMR (400 MHz,甲醇-d4) δ 7.78 (d, J = 8.5 Hz, 1H), 7.18 (dt, J = 9.2, 3.1 Hz, 2H), 7.10 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.17 (dd, J = 14.9, 7.4 Hz, 1H), 5.84 (td, J = 57.6, 4.0 Hz, 1H), 5.48 (dd, J = 15.2, 9.3 Hz, 1H), 4.38 (dd, J = 14.1, 6.9 Hz, 1H), 4.08 - 3.97 (m, 2H), 3.88 (d, J = 15.0 Hz, 1H), 3.85 - 3.74 (m, 2H), 3.65 (d, J = 14.1 Hz, 1H), 3.26 (m, 4H), 3.01 (dd, J = 15.2, 10.0 Hz, 1H), 2.91 - 2.69 (m, 3H), 2.58 (dd, J = 12.3, 6.2 Hz, 1H), 2.41 (dq, J = 27.3, 9.2, 8.2 Hz, 2H), 2.18 - 2.01 (m, 3H), 1.99 - 1.85 (m, 2H), 1.76 (ddt, J = 28.8, 18.5, 9.4 Hz, 2H), 1.55 - 1.30 (m, 3H), 1.06 (m, 4H), 0.92 - 0.79 (m, 1H)。LCMS-ESI+:C37
H45
ClF2
N4
O5
S計算值:731.28 (M+H);實驗值:731.02 (M+H)。實例 312
以與實例 75
類似之方式使用(1R,2S)-2-甲氧基-2-甲基環丙-1-胺、三乙胺及實例 109
來製備實例 312
。任意指定立體化學但不指定絕對立體化學。1H NMR (400 MHz,甲醇-d4) δ 7.76 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.18 (dd, J = 8.5, 2.3 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.02 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.06 (dt, J = 14.3, 6.8 Hz, 1H), 5.58 (dd, J = 15.3, 8.9 Hz, 1H), 4.28 (dd, J = 14.9, 6.5 Hz, 1H), 4.13 - 4.00 (m, 2H), 3.86 (d, J = 14.9 Hz, 1H), 3.78 (dd, J = 8.9, 3.7 Hz, 1H), 3.68 (d, J = 14.2 Hz, 1H), 3.38 (s, 3H), 3.30 - 3.25 (m, 4H), 3.07 (dd, J = 15.2, 10.2 Hz, 1H), 2.90 - 2.74 (m, 2H), 2.70 (dd, J = 8.0, 4.8 Hz, 1H), 2.54 - 2.43 (m, 1H), 2.38 (t, J = 9.1 Hz, 1H), 2.20 (dt, J = 14.6, 7.3 Hz, 1H), 2.12 (d, J = 13.4 Hz, 2H), 2.01 - 1.87 (m, 2H), 1.87 - 1.69 (m, 3H), 1.45 (d, J = 12.1 Hz, 1H), 1.39 (s, 3H), 1.31 (s, 1H), 1.13 (d, J = 6.7 Hz, 3H), 0.93 - 0.84 (m, 1H), 0.72 (t, J = 5.7 Hz, 1H)。LCMS-ESI+:C38
H49
ClN4
O6
S計算值:725.31 (M+H);實驗值:726.03 (M+H)。實例 313
以與實例312類似之方式使用(1S,2R)-2-甲氧基-2-甲基環丙-1-胺、三乙胺及實例 109
來製備實例 313
。任意指定立體化學但不指定絕對立體化學。LCMS-ESI+:C38
H49
ClN4
O6
S計算值:725.31 (M+H);實驗值:726.20 (M+H)。實例 314
步驟1:合成314-1
:在室溫下向於DCM (6.0 mL)中之3-胺基-1-甲基-環丁烷甲酸甲酯HCl鹽(248 mg,1.38 mmol)之混合物中添加DIEA (537 mg,4.15 mmol),繼而添加二碳酸二第三丁酯(362 mg,1.66 mmol)。將所得混合物在室溫下攪拌過夜。將反應物濃縮,再溶解於EtOAc中,用1N HCl、飽和NaHCO3
、鹽水洗滌,經硫酸鈉乾燥,過濾,且濃縮,進一步經真空管線乾燥,得到314-1
。1H NMR (400 MHz,氘代氯仿) δ 4.88 - 4.68 (m, 1H), 4.38 - 4.20 (m, 1H), 3.71 (s, 3H), 2.36 - 2.24 (m, 4H), 1.45 (s, 9H), 1.42 (s, 3H)。
步驟2:合成314-2
:將314-1
(337 mg,1.39 mmol)溶解於THF (7.0 mL)中,冷卻至0℃,添加於THF (2.77 mL,2.77 mmol)中之1.0 N超氫化物。當進行冰融化過夜時,使反應物升溫至室溫。將反應物緩慢地用飽和NH4
Cl淬滅,且用EtOAc稀釋。將有機層用鹽水洗滌,經硫酸鈉乾燥,過濾,且濃縮,得到粗產物。將粗產物藉由combiflash (12 g矽膠,0-100% EtOAc/己烷)純化,藉由ELS偵測器偵測。將所需溶離份組合且濃縮,得到314-2
(110.0 mg)。1H NMR (400 MHz,氘代氯仿) δ 4.18 - 4.08 (m, 1H), 3.54 (d, 1H), 3.36 (d, J = 2.0 Hz, 1H), 2.09 - 1.99 (m, 2H), 1.92 - 1.78 (m, 2H), 1.43 (s, 9H), 1.15 - 1.09 (m, 3H)。
步驟3:合成314-3
:在rt下用DCM (2.0 mL)及於1,4-二噁烷(0.5 mL)中之4 N HCl處理314-2
(110 mg,0.51 mmol)達1 hr。將反應物濃縮,與EtOAc (3×3.0 mL)一起共蒸發,且進一步經真空管線乾燥,得到314-3
。
步驟4:以與實例 75
相同之方式使用實例 109
及314-3
以及DIEA來合成實例 314
。1H NMR (400 MHz,甲醇-d4) δ 7.70 (d, J = 8.6 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.12 - 7.03 (m, 2H), 7.00 (s, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.12 - 6.00 (m, 1H), 5.68 - 5.56 (m, 1H), 4.32 - 4.18 (m, 2H), 4.08 - 3.98 (m, 2H), 3.87 - 3.74 (m, 3H), 3.66 (d, J = 14.2 Hz, 1H), 3.35 (s, 2H), 3.29 (s, 3H), 3.08 (dd, J = 15.2, 9.9 Hz, 1H), 2.89 - 2.70 (m, 2H), 2.59 - 2.39 (m, 3H), 2.25 - 2.01 (m, 6H), 1.98 - 1.74 (m, 8H), 1.46 - 1.35 (m, 1H), 1.18 (s, 3H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C39
H51
ClN4
O6
S計算值H+:739.32;實驗值:738.88。實例 315
以與實例 316
相同之方式使用中間物316-3
及實例 109
來合成實例 315
。順式環丙烷立體異構中心之絕對組態尚未確定,且任意指示。LCMS-ESI+ (m/z):C38
H49
ClN4
O6
S [M+H]+
計算值:725.3134;實驗值:724.89。1
H NMR (400 MHz,甲醇-d
4) δ 7.73 (d,J
= 8.5 Hz, 1H), 7.20 (d,J
= 8.2 Hz, 1H), 7.15 (d,J
= 8.6 Hz, 1H), 7.09 (d,J
= 2.2 Hz, 1H), 6.99 (s, 1H), 6.88 (d,J
= 8.1 Hz, 1H), 6.03 (dd,J
= 14.9, 7.5 Hz, 1H), 5.57 (dd,J
= 15.2, 8.9 Hz, 1H), 4.26 (dd,J
= 14.8, 6.6 Hz, 1H), 4.10 - 3.98 (m, 2H), 3.83 (d,J
= 15.0 Hz, 2H), 3.76 (dd,J
= 8.9, 3.7 Hz, 1H), 3.66 (d,J
= 14.2 Hz, 1H), 3.54 - 3.36 (m, 2H), 3.34 (s, 3H), 3.33 - 3.25 (m, 1H), 3.26 (s, 3H), 3.05 (dd,J
= 15.2, 10.2 Hz, 1H), 2.87 - 2.68 (m, 3H), 2.54 - 2.29 (m, 3H), 2.25 - 2.04 (m, 3H), 2.02 - 1.67 (m, 6H), 1.42 (t,J
= 12.6 Hz, 1H), 1.35 - 1.22 (m, 1H), 1.12 (d,J
= 6.4 Hz, 3H), 1.02 (ddd,J
= 9.0, 7.4, 5.7 Hz, 1H), 0.53 (td,J
= 6.0, 4.4 Hz, 1H)。實例 316
步驟1:用(4-硝基苯基) [(1S)-1-苯基乙基]碳酸酯(1當量,3.44 mmol,989 mg)處理於三乙胺(4當量,13.8 mmol,1.92 mL)及THF (15 mL)中之外消旋-[(1R*,2S*)-2-胺基環丙基]甲醇(1當量,3.44 mmol,300 mg)之溶液。將反應混合物在室溫下攪拌過夜,隨後濃縮且藉由矽膠層析法(EtOAc/己烷)純化,獲得呈非對映異構體混合物形式之所需產物316-2
/316-3
(375 mg)。藉由手性SFC (IC管柱,15% EtOH)純化非對映異構體混合物,獲得316-2
(RT
= 1.52 min;186 mg)及316-3
(RT
= 1.14 min;191 mg)。316-2
及316-3
之絕對立體化學尚未測定,且任意指示。
中間物 316-2 : 1
H NMR (400 MHz,氘代氯仿) δ 7.41 - 7.27 (m, 5H), 5.81 (q,J
= 6.6 Hz, 1H), 5.03 (s, 1H), 3.96 (d,J
= 11.8 Hz, 1H), 3.32 (s, 1H), 3.18 (t,J
= 11.2 Hz, 1H), 2.62 (q,J
= 6.9, 6.5 Hz, 1H), 1.53 (d,J
= 6.6 Hz, 3H), 1.39 (q,J
= 7.6 Hz, 1H), 0.93 (ddd,J
= 9.3, 7.2, 5.7 Hz, 1H), 0.28 (td,J
= 6.3, 4.2 Hz, 1H)。
中間物 316-3 : 1
H NMR (400 MHz,氘代氯仿) δ 7.43 - 7.29 (m, 5H), 5.82 (q,J
= 6.6 Hz, 1H), 5.02 (s, 1H), 3.87 (d,J
= 12.2 Hz, 1H), 3.20 - 2.94 (bs, 1H), 3.03 (t,J
= 11.2 Hz, 1H), 2.67 (d,J
= 5.4 Hz, 1H), 1.56 (d,J
= 6.6 Hz, 3H), 1.37 (ddp,J
= 13.6, 6.7, 4.0, 3.4 Hz, 1H), 0.93 (dt,J
= 9.4, 6.7 Hz, 1H), 0.25 (d,J
= 5.5 Hz, 1H)。
步驟2:向於CH2
Cl2
(0.75 mL)中之中間物316-2
(1當量,0.149 mmol,35 mg)之溶液中依序添加粉末狀分子篩、4 Å (1 wt當量,35 mg)、1,8-雙(二甲基胺基)萘(2.5當量,0.372 mmol,79.7 mg)及1,8-雙(二甲基胺基)萘(2當量,0.298 mmol,44.0 mg)。將反應混合物在室溫下攪拌5小時,經矽藻土過濾,且用EtOAc溶析。將濾液用1 N HCl、水及鹽水洗滌,隨後用硫酸鈉乾燥,過濾且濃縮。藉由矽膠層析法(EtOAc/己烷)純化粗反應混合物,獲得所需中間物316-4
。1
H NMR (400 MHz,氘代氯仿) δ 7.42 - 7.26 (m, 5H), 5.82 (q,J
= 6.7 Hz, 1H), 5.26 - 4.88 (m, 1H), 3.60 (dd,J
= 10.4, 6.1 Hz, 1H), 3.38 - 3.22 (m, 1H), 3.35 (s, 3H), 2.72 (tdd,J
= 6.9, 4.1, 2.0 Hz, 1H), 1.54 (d,J
= 6.6 Hz, 3H), 1.28 (ddt,J
= 15.1, 8.6, 6.3 Hz, 1H), 1.00 (q,J
= 7.2 Hz, 1H), 0.50 (q,J
= 5.4 Hz, 1H)。
步驟3:將中間物316-4
用4 N HCl/二噁烷(1.5 mL)處理,密封且在室溫下攪拌過夜。將反應混合物在氬氣流下濃縮,隨後進一步在高真空下乾燥30分鐘,獲得粗製物中間物316-5
,其繼續直接用於步驟4。
步驟4:使4打蘭小瓶裝填有實例 109
(1當量,0.017 mmol,10 mg)、碳酸二苯酯(6當量,0.10 mmol,21.5 mg)、N,N-二甲基胺基吡啶(4當量,0.067 mmol,8.2 mg)及MeCN (0.75 mL)。將反應小瓶密封,且在室溫下攪拌過夜。隨後,將反應混合物用三乙胺(25當量,0.42 mmol,0.06 mL)處理,與來自步驟3之粗製物中間物316-5
組合,且加熱至50℃達3小時。將反應混合物冷卻至室溫,濃縮且藉由製備型HPLC (60-100%於水中之MeCN,0.1% TFA)純化,獲得實例 316
。順式環丙烷立體異構中心之絕對組態尚未確定,且任意指示。LCMS-ESI+ (m/z):C38
H49
ClN4
O6
S [M+H]+
計算值:725.3134;實驗值:724.74。1
H NMR (400 MHz,甲醇-d 4
) δ 7.73 (d,J
= 8.5 Hz, 1H), 7.25 - 7.12 (m, 2H), 7.10 (d,J
= 2.2 Hz, 1H), 6.99 (s, 1H), 6.89 (d,J
= 8.1 Hz, 1H), 6.09 - 5.96 (m, 1H), 5.57 (dd,J
= 15.3, 8.9 Hz, 1H), 4.26 (dd,J
= 14.8, 6.4 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.89 - 3.78 (m, 2H), 3.76 (dd,J
= 8.9, 3.6 Hz, 1H), 3.66 (d,J
= 14.2 Hz, 1H), 3.60 - 3.45 (m, 1H), 3.46 - 3.37 (m, 1H), 3.35 (s, 3H), 3.30 - 3.25 (m, 1H), 3.25 (s, 3H), 3.05 (dd,J
= 15.2, 10.2 Hz, 1H), 2.88 - 2.67 (m, 3H), 2.54 - 2.29 (m, 3H), 2.26 - 2.04 (m, 3H), 2.01 - 1.66 (m, 6H), 1.42 (t,J
= 12.3 Hz, 1H), 1.29 (p,J
= 7.5 Hz, 1H), 1.12 (d,J
= 6.7 Hz, 3H), 1.02 (ddd,J
= 9.1, 7.5, 5.7 Hz, 1H), 0.50 (q,J
= 5.6 Hz, 1H)。實例 317
以與實例 75
相同之方式使用實例 109
及(1S,2R)-2-甲氧基環丙胺鹽酸鹽來合成實例 317
。亦將三乙胺(40當量)添加至反應混合物中(步驟2)。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S [M+H]+
計算值:711.2978;實驗值:710.98。1
H NMR (400 MHz,甲醇-d
4) δ 7.74 (d,J
= 8.5 Hz, 1H), 7.20 (d,J
= 8.2 Hz, 1H), 7.16 (dd,J
= 8.5, 2.3 Hz, 1H), 7.10 (d,J
= 2.3 Hz, 1H), 7.00 (s, 1H), 6.88 (d,J
= 8.2 Hz, 1H), 6.03 (dd,J
= 14.9, 7.4 Hz, 1H), 5.57 (dd,J
= 15.3, 8.9 Hz, 1H), 4.26 (dd,J
= 14.8, 6.5 Hz, 1H), 4.12 - 3.97 (m, 2H), 3.84 (d,J
= 14.9 Hz, 2H), 3.76 (dd,J
= 8.9, 3.7 Hz, 1H), 3.66 (d,J
= 14.2 Hz, 1H), 3.42 (s, 3H), 3.30 - 3.26 (m, 2H), 3.25 (s, 3H), 3.05 (dd,J
= 15.2, 10.2 Hz, 1H), 2.87 - 2.69 (m, 3H), 2.55 - 2.29 (m, 3H), 2.25 - 2.04 (m, 3H), 2.02 - 1.64 (m, 6H), 1.42 (t,J
= 12.2 Hz, 1H), 1.12 (d,J
= 6.6 Hz, 3H), 0.96 (dt,J
= 8.2, 6.8 Hz, 1H), 0.55 (q,J
= 4.6 Hz, 1H)。實例 318
以與實例 75
相同之方式使用實例 109
及(1R,2S)-2-甲氧基環丙胺鹽酸鹽來合成實例 318
。亦將三乙胺(40當量)添加至反應混合物中(步驟2)。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S [M+H]+
計算值:711.2978;實驗值:710.64。1
H NMR (400 MHz,甲醇-d 4
) δ 7.73 (d,J
= 8.5 Hz, 1H), 7.20 (d,J
= 8.1 Hz, 1H), 7.15 (dd,J
= 8.5, 2.3 Hz, 1H), 7.09 (d,J
= 2.3 Hz, 1H), 6.99 (s, 1H), 6.88 (d,J
= 8.2 Hz, 1H), 6.03 (dd,J
= 14.9, 7.6 Hz, 1H), 5.57 (dd,J
= 15.3, 8.9 Hz, 1H), 4.26 (dd,J
= 14.8, 6.5 Hz, 1H), 4.11 - 3.97 (m, 2H), 3.83 (d,J
= 14.9 Hz, 2H), 3.76 (dd,J
= 8.9, 3.7 Hz, 1H), 3.66 (d,J
= 14.2 Hz, 1H), 3.41 (s, 3H), 3.29 - 3.26 (m, 2H), 3.25 (s, 3H), 3.05 (dd,J
= 15.2, 10.2 Hz, 1H), 2.87 - 2.66 (m, 3H), 2.56 - 2.29 (m, 3H), 2.25 - 2.04 (m, 3H), 2.01 - 1.66 (m, 6H), 1.41 (t,J
= 12.4 Hz, 1H), 1.11 (d,J
= 6.4 Hz, 3H), 0.97 (q,J
= 7.0 Hz, 1H), 0.59 (dd,J
= 7.5, 4.0 Hz, 1H)。實例 319
步驟1:使圓底燒瓶 裝填有起始3-羥基-1-甲基-4-吡唑甲酸乙酯(100 mg,0.588 mmol)。將燒瓶置於高真空下達5 min,隨後回填有氮氣氛圍。在20℃下添加DMF (3 mL),繼而添加氫化鈉(60%於礦物油中之分散液,27 mg,1.2當量)。將燒瓶在20℃下攪拌60 min,隨後添加4-(2-碘基乙基)嗎啉(184 mg,1.3當量)。將反應物在80℃下攪拌16 hr。將反應物自加熱中移除且允許冷卻至20℃,隨後將反應物用水淬滅,且五次萃取至乙酸乙酯中。將合併有機相用鹽水洗滌,經硫酸鎂乾燥,過濾且在真空中濃縮,得到120 mg 粗產物。粗產物之矽膠TLC (95:5二氯甲烷:甲醇)指示起始胺基吡唑(Rf ~0.60)及一種新型UV-活性產物(Rf 0.50)之完全消耗。將所得殘餘物溶解於二氯甲烷中,且藉由急驟管柱層析法(矽膠,12 g,0至10%於二氯甲烷中之甲醇)純化。在5%二氯甲烷下溶析主要UV-活性產物。藉由矽膠TLC分析溶離份。收集含有主要UV-活性產物之溶離份且在真空中濃縮,得到1-甲基-3-(2-嗎啉基乙氧基)-1H-吡唑-4-甲酸乙酯(120 mg)。1
H NMR (400 MHz,氘代氯仿) δ 7.63 (s, 1H), 4.37 (t, J = 5.7 Hz, 2H), 4.21 (q, J = 7.1 Hz, 2H), 3.71 (s, 3H), 3.72-3.69 (m, 4H), 2.82 (t, J = 5.7 Hz, 2H), 2.61 (t, J = 4.7 Hz, 4H), 1.28 (t, J = 7.1 Hz, 3H)。LCMS-ESI+
(m/z):C13
H21
N3
O4
[M+H]+
計算值:284.2;實驗值:284.1。
步驟2:向裝填有1-甲基-3-(2-嗎啉基乙氧基)-1H-吡唑-4-甲酸乙酯(120 mg,0.424 mmol)之玻璃螺旋蓋小瓶中添加THF (4.2 mL),隨後添加氫氧化鈉(於水中2 M,0.96 mL)。將所得混合物在升溫至60℃之金屬加熱塊中劇烈攪拌12 hr,在此時矽膠TLC (95:5二氯甲烷:甲醇)指示起始乙酯之近乎完全消耗。用逐滴添加之1 N HCl (約2 mL)淬滅反應物直至根據pH紙pH 4-5為止。用乙酸乙酯萃取三次所得混合物。隨後,在真空中濃縮水相,得到混雜有未經辨識量之氯化鈉(60 mg)之呈根據NMR至少95%純度之1-甲基-3-(2-嗎啉基乙氧基)-1H-吡唑-4-甲酸。1
H NMR (400 MHz,甲醇-d4
) δ 7.80 (s, 1H), 4.49 (t, J = 4.9 Hz, 2H), 3.88 (t, J = 4.6 Hz, 4H), 3.74 (s, 3H), 3.27 (t, J = 5.0 Hz, 2H), 3.11 (t, J = 4.5 Hz, 4H)。LCMS-ESI+
(m/z):C11
H17
N3
O4
[M+H]+
計算值:256.1;實驗值:256.1。
步驟3:以與實例 18
類似之方式使用1-甲基-3-(2-嗎啉基乙氧基)-1H-吡唑-4-甲酸及實例 109
來製備實例 319
。1
H NMR (400 MHz,乙腈-d3
) δ 7.98 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.30 (dd, J = 8.2, 1.9 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.04 (dt, J = 14.5, 6.9 Hz, 1H), 5.58 (dd, J = 15.6, 7.6 Hz, 1H), 4.66 (dtt, J = 13.0, 9.4, 4.6 Hz, 2H), 4.06 (d, J = 12.2 Hz, 1H), 4.04 - 3.97 (m, 2H), 3.88 (dd, J = 14.8, 7.3 Hz, 1H), 3.83 - 3.77 (m, 1H), 3.75 (s, 3H), 3.71 (d, J = 14.3 Hz, 5H), 3.60 (s, 2H), 3.38 (d, J = 14.4 Hz, 1H), 3.21 (s, 3H), 3.07 (dd, J = 15.2, 10.8 Hz, 3H), 2.86 - 2.63 (m, 3H), 2.52 (dt, J = 18.7, 7.6 Hz, 2H), 2.41 (td, J = 9.0, 4.2 Hz, 1H), 2.34 - 2.21 (m, 1H), 2.16 (dt, J = 15.0, 7.6 Hz, 1H), 2.09 - 2.00 (m, 1H), 1.90 (dd, J = 9.1, 5.1 Hz, 3H), 1.84 - 1.60 (m, 5H), 1.41 (dt, J = 14.8, 7.7 Hz, 1H), 1.06 (d, J = 6.9 Hz, 3H)。LCMS-ESI+
(m/z):C43
H55
ClN6
O7
S [M+H]+
計算值:835.4;實驗值:835.3。實例 320
以與實例 75
相同之方式使用實例 109
及4-甲氧基哌啶來合成實例 320
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 5.96 (dt, J = 14.2, 6.7 Hz, 1H), 5.58 (dd, J = 15.2, 9.3 Hz, 1H), 4.38 (dd, J = 14.9, 6.3 Hz, 1H), 4.13 - 4.04 (m, 2H), 4.04 - 3.89 (m, 2H), 3.85 (d, J = 15.2 Hz, 1H), 3.76 (dd, J = 9.3, 3.7 Hz, 1H), 3.67 (d, J = 14.1 Hz, 1H), 3.63 - 3.54 (m, 1H), 3.52 - 3.43 (m, 1H), 3.39 (s, 3H), 3.31 - 3.30 (m, 1H), 3.28 - 3.24 (m, 4H), 3.08 (dd, J = 15.3, 10.3 Hz, 1H), 2.87 - 2.71 (m, 2H), 2.54 - 2.42 (m, 2H), 2.38 - 2.27 (m, 1H), 2.22 - 2.06 (m, 3H), 1.99 - 1.69 (m, 9H), 1.58 - 1.39 (m, 3H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C39
H51
ClN4
O6
S計算值H+:739.32;實驗值:738.84。實例 321
以與實例 75
相同之方式使用反-2-(二氟甲基)環丙-1-胺鹽酸鹽及中間物 266-2
來合成實例 321
。1H NMR (400 MHz,甲醇-d4) δ 7.72 (d, J = 8.5 Hz, 1H), 7.15 (t, J = 9.9 Hz, 2H), 7.09 (s, 1H), 6.99 (s, 1H), 6.89 (d, J = 8.2 Hz, 1H), 5.94 (d, J = 13.4 Hz, 1H), 5.81 (d, J = 4.2 Hz, 1H), 5.78 - 5.64 (m, 1H), 4.18 (t, J = 10.8 Hz, 2H), 4.10 - 3.99 (m, 2H), 3.74 (dd, J = 66.1, 14.7 Hz, 3H), 3.17 - 2.97 (m, 1H), 2.77 (d, J = 22.1 Hz, 4H), 2.36 (s, 4H), 2.21 - 2.02 (m, 3H), 1.96 (d, J = 21.9 Hz, 3H), 1.86 - 1.65 (m, 1H), 1.59 - 1.36 (m, 2H), 1.13 (d, J = 6.3 Hz, 4H), 1.06 (q, J = 6.5 Hz, 1H), 0.92 (s, 1H)。LCMS -ESI+ (m/z):C36
H43
ClF2
N4
O5
S [M+H]+計算值:717.26;實驗值:716.77。實例 322
以與實例 75
相同之方式使用(1R,3R)-3-甲氧基環戊-1-胺鹽酸鹽及實例 109
來合成實例 322
。1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 5.86 (dt, J = 14.4, 6.8 Hz, 1H), 5.49 (dd, J = 15.2, 8.9 Hz, 1H), 4.20 - 3.87 (m, 4H), 3.84 - 3.53 (m, 8H), 3.24 (s, 4H), 3.13 (s, 3H), 3.02 (dd, J = 15.3, 10.4 Hz, 1H), 2.89 - 2.60 (m, 2H), 2.44 - 2.30 (m, 2H), 2.29 - 2.05 (m, 2H), 2.04 - 1.56 (m, 9H), 1.39 (td, J = 17.2, 14.6, 9.7 Hz, 1H), 1.02 (d, J = 6.8 Hz, 3H)。LCMS -ESI+ (m/z):C39
H51
ClN4
O6
S [M+H]+計算值:739.32;實驗值:738.81。實例 323
以與實例 244
類似之方式使用106-4
而不使用240-1
且使用3,3-二氟氮雜環丁烷鹽酸鹽而不使用3-甲氧基氮雜環丁烷鹽酸鹽來合成實例 323
。1H NMR (400 MHz,丙酮-d6) δ 7.77 (d, J = 8.6 Hz, 1H), 7.28 - 7.20 (m, 1H), 7.17 - 6.92 (m, 4H), 6.05 - 5.88 (m, 1H), 5.58 (dd, J = 15.3, 9.0 Hz, 1H), 4.36 (t, J = 12.5 Hz, 4H), 4.12 (d, J = 12.1 Hz, 1H), 4.08 (d, J = 12.0 Hz, 1H), 3.88 (d, J = 15.1 Hz, 1H), 3.82 - 3.61 (m, 2H), 3.54 (d, J = 13.5 Hz, 1H), 3.35 (d, J = 14.2 Hz, 1H), 3.21 (s, 3H), 3.15 (dd, J = 15.4, 10.3 Hz, 1H), 2.89 - 1.53 (m, 15H), 1.53 - 1.38 (m, 1H), 1.13 (d, J = 6.6 Hz, 3H)。LCMS:717.5。實例 324
以與實例 244
類似之方式使用106-4
而不使用240-1
且使用1,1-二氟-5-氮雜螺[2.3]己烷鹽酸鹽而不使用3-甲氧基氮雜環丁烷鹽酸鹽來合成實例 324
。1H NMR (400 MHz,丙酮-d6) δ 7.77 (d, J = 8.6 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 6.97 (d, J = 8.1 Hz, 1H), 5.98 (dt, J = 14.1, 6.6 Hz, 1H), 5.58 (dd, J = 15.3, 8.9 Hz, 1H), 4.45 - 3.94 (m, 6H), 3.89 (d, J = 15.1 Hz, 1H), 3.80 - 3.67 (m, 2H), 3.58 - 3.40 (m, 1H), 3.35 (d, J = 14.2 Hz, 1H), 3.21 (s, 3H), 3.15 (dd, J = 15.4, 10.4 Hz, 1H), 2.96 - 0.77 (m, 18H), 1.14 (d, J = 6.5 Hz, 3H)。LCMS:742.9。實例 325
以與實例 214
類似之方式使用中間物 359-4
而不使用106-4
來合成實例 325
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.41 - 7.32 (m, 2H), 7.25 (dd, J = 8.5, 2.3 Hz, 1H), 7.15 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.35 (s, 1H), 6.09 - 5.97 (m, 1H), 5.87 (dd, J = 15.8, 6.2 Hz, 1H), 4.96 (d, J = 14.5 Hz, 1H), 4.75 (d, J = 14.5 Hz, 1H), 4.32 - 3.42 (m, 12H), 3.39 (s, 3H), 3.15 (dd, J = 15.2, 10.5 Hz, 1H), 2.88 - 1.39 (m, 16H), 1.15 (d, J = 6.4 Hz, 3H)。LCMS:777.1。實例 326
以與實例 214
類似之方式使用中間物 359-4
而不使用106-4
且使用(S)-2-(甲氧基甲基)環氧乙烷而不使用(R)-2-(甲氧基甲基)環氧乙烷來合成實例 326
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.6 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.39 - 7.32 (m, 2H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.35 (s, 1H), 6.10 - 5.95 (m, 1H), 5.87 (dd, J = 15.7, 6.3 Hz, 1H), 4.96 (d, J = 14.5 Hz, 1H), 4.75 (d, J = 14.6 Hz, 1H), 4.35 - 3.85 (m, 8H), 3.75 (d, J = 14.5 Hz, 1H), 3.65 (dd, J = 10.4, 5.3 Hz, 1H), 3.56 (dd, J = 10.4, 4.8 Hz, 1H), 3.45 (d, J = 14.4 Hz, 1H), 3.39 (s, 3H), 3.15 (dd, J = 15.2, 10.5 Hz, 1H), 2.84 - 1.65 (m, 15H), 1.53 - 1.42 (m, 1H), 1.15 (d, J = 6.4 Hz, 3H)。LCMS:777.1。實例 327
以與實例 229
類似之方式使用嗎啉而不使用(R)-八氫吡嗪并[2,1-c][1,4]噁嗪二鹽酸鹽來合成實例 327
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.44 (s, 1H), 7.29 - 7.17 (m, 3H), 7.15 (d, J = 2.4 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.32 (s, 1H), 5.95 - 5.80 (m, 1H), 5.74 (dd, J = 15.4, 7.3 Hz, 1H), 4.94 (d, J = 14.5 Hz, 1H), 4.84 (d, J = 14.5 Hz, 1H), 4.67 - 1.71 (m, 35H), 1.55 (d, J = 7.0 Hz, 3H), 1.54 - 1.42 (m, 1H), 1.08 - 1.00 (m, 3H)。LCMS:846.1。實例 328
步驟1:製備(1S,2S)-2-甲醯基環丙烷-1-甲酸乙酯:將於DCM (4.0 mL)中之外消旋-(1S,2S)-2-(羥基甲基)環丙烷甲酸乙酯(110 mg,0.76 mmol)、戴斯-馬丁高碘烷(388.34 mg,0.92 mmol)之反應混合物在rt下攪拌過夜。將反應混合物用1% Na2
S2
O4
、飽和NaHCO3
洗滌,用DCM萃取,經MgSO4
乾燥,過濾,濃縮,且藉由矽膠管柱(0-50% EtOAc/己烷)純化殘餘物,得到產物。
步驟2:製備(1S,2S)-2-(嗎啉基甲基)環丙烷-1-甲酸乙酯:在0℃下向於DCM (3.0 mL)中之(1S,2S)-2-甲醯基環丙烷-1-甲酸乙酯(100 mg,0.7 mmol)之溶液中添加嗎啉(0.08 mL,0.93 mmol)。隨後,向混合物中添加三乙醯氧基硼氫化鈉(0.22 g,1.06 mmol)。將反應混合物在rt下攪拌過夜。藉由矽膠層析法(0-100% EtOAc/己烷,隨後0-15% DCM/MeOH)純化反應混合物,得到產物。
步驟3:製備(1S,2S)-2-(嗎啉基甲基)環丙烷-1-甲酸:將於MeOH (2 mL)及H2
O (0.5 mL)中之(1S,2S)-2-(嗎啉基甲基) 環丙烷甲酸乙酯(80 mg,0.375 mol)、2 M NaOH (0.38 mL)之反應混合物在45℃下加熱過夜。將反應混合物濃縮,與甲苯(×3)一起共沸以移除水分,且不經純化即進行下一步驟。
步驟4:製備實例 328
:將於甲苯(1.0 mL)中之(1S,2S)-2-(嗎啉基甲基)環丙烷-1-甲酸(60 mg,0.32 mmol)、二苯基磷醯基疊氮化物(94 mg,0.341 mmol)、三甲胺(35 mg,0.352 mmol)之反應混合物在100℃下攪拌2 h。隨後,使反應混合物冷卻至rt。向混合物中添加實例 109
,且將反應混合物在45℃下攪拌過夜。濃縮反應混合物,藉由逆相HPLC (10-100%乙腈/H2
O,含有0.1% TFA)純化殘餘物,得到產物。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.12 (q, J = 2.9, 2.2 Hz, 2H), 6.97 (d, J = 2.0 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.01 (dt, J = 14.4, 6.8 Hz, 1H), 5.59 (dd, J = 15.3, 9.0 Hz, 1H), 4.30 (dd, J = 14.9, 6.5 Hz, 1H), 4.18 - 3.99 (m, 4H), 3.84 (dd, J = 14.0, 8.7 Hz, 3H), 3.80 - 3.61 (m, 4H), 3.53 - 3.41 (m, 2H), 3.27 (s, 4H), 3.08 (dd, J = 15.2, 10.3 Hz, 1H), 2.95 - 2.61 (m, 4H), 2.58 - 2.29 (m, 4H), 2.28 - 2.06 (m, 3H), 2.04 - 1.69 (m, 6H), 1.45 (t, J = 12.1 Hz, 1H), 1.39 - 1.23 (m, 2H), 1.12 (dd, J = 15.0, 5.6 Hz, 3H), 0.92 (dt, J = 7.9, 5.8 Hz, 1H)。LCMS-ESI+ (m/z):C41
H54
ClN5
O6
S [M+H]+計算值:780.35;實驗值:780.39。實例 329
以與實例 167
類似之方式使用229-2
而不使用167-2
且使用中間物 359-4
而不使用106-4
來合成實例 329
。1H NMR (400 MHz,丙酮-d6) δ 7.77 (d, J = 8.6 Hz, 1H), 7.50 - 6.85 (m, 6H), 6.28 (s, 1H), 6.06 - 5.56 (m, 2H), 4.91 (d, J = 14.5 Hz, 1H), 4.71 (d, J = 14.5 Hz, 1H), 4.49 - 2.97 (m, 13H), 2.81 - 1.13 (m, 19H), 1.13 - 0.96 (m, 3H)。LCMS:777.4。實例 330
以與實例 75
相同之方式使用實例 109
及4-(二氟甲氧基)哌啶來合成實例 330
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.15 - 7.06 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 5.97 (dt, J = 14.2, 6.7 Hz, 1H), 5.58 (dd, J = 15.2, 9.2 Hz, 1H), 4.44 - 4.33 (m, 2H), 4.12 - 4.03 (m, 2H), 4.00 - 3.81 (m, 3H), 3.76 (dd, J = 9.3, 3.7 Hz, 1H), 3.70 - 3.55 (m, 2H), 3.28 - 3.24 (m, 4H), 3.08 (dd, J = 15.3, 10.3 Hz, 1H), 2.89 - 2.71 (m, 2H), 2.54 - 2.42 (m, 2H), 2.39 - 2.27 (m, 1H), 2.22 - 2.06 (m, 3H), 1.97 - 1.87 (m, 5H), 1.86 - 1.62 (m, 6H), 1.51 - 1.38 (m, 1H), 1.14 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C39
H49
ClF2
N4
O6
S計算值H+:775.30;實驗值:774.79。實例 331
以與實例 255
類似之方式使用239-3
而不使用255-3
來合成實例 331
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.5 Hz, 1H), 7.61 - 6.91 (m, 8H), 6.34 (s, 1H), 6.17 - 5.58 (m, 2H), 4.79 (s, 2H), 4.24 - 2.88 (m, 12H), 4.05 (s, 4H), 3.35 (s, 6H), 2.82 - 1.25 (m, 18H), 1.11 - 1.03 (m, 3H)。LCMS:835.3。實例 332
步驟1:向於甲醇(5 mL)中之實例 358
(25 mg,0.033 mmol)之經攪拌溶液中添加1N NaOH (1 mL),且在rt下攪拌24 h。將1 N HCl (1 mL)添加至反應混合物中,且在減壓下濃縮反應混合物。添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑,得到中間物332-1
。
步驟2:藉由使用於DCM中之EDCI/DMAP偶合中間物332-1與二甲基胺來合成實例 332
。1H NMR (400 MHz,氘代氯仿) δ 7.75 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.21 (dd, J = 8.4, 2.3 Hz, 1H), 7.11 (d, J = 2.4 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 1.8 Hz, 1H), 5.96 (dt, J = 13.8, 6.4 Hz, 1H), 5.59 (dd, J = 15.4, 8.1 Hz, 1H), 4.37 - 4.00 (m, 2H), 3.86 (s, 2H), 3.75 (d, J = 12.3 Hz, 1H), 3.38 - 2.90 (m, 5H), 2.87 - 2.66 (m, 1H), 2.45 (s, 2H), 2.29 - 1.47 (m, 9H), 1.28 (s, 14H), 1.11 (d, J = 6.7 Hz, 2H), 0.90 (t, J = 6.7 Hz, 3H)。LCMS-ESI+ (m/z):C41
H50
ClN5
O6
S [M+H]+計算值:776.32;實驗值:776.12。實例 333
以與實例 362
相同之方式使用實例 109
及N,N-二甲基氮雜環丁烷-3-胺二鹽酸鹽來合成實例 333
。LCMS-ESI+ (m/z):C38
H50
ClN5
O5
S [M+H]+
計算值:724.3294;實驗值:724.08。1
H NMR (400 MHz,甲醇-d 4
) δ 7.71 (d,J
= 8.5 Hz, 1H), 7.14 (d,J
= 8.6 Hz, 1H), 7.10 (d,J
= 2.2 Hz, 1H), 7.07 (dd,J
= 8.2, 1.9 Hz, 1H), 6.93 - 6.86 (m, 2H), 5.97 (dt,J
= 14.3, 6.7 Hz, 1H), 5.56 (dd,J
= 15.2, 9.2 Hz, 1H), 4.39 - 4.24 (m, 3H), 4.24 - 4.13 (m, 2H), 4.13 - 3.99 (m, 3H), 3.83 (d,J
= 15.1 Hz, 1H), 3.74 (dd,J
= 9.2, 3.7 Hz, 1H), 3.69 - 3.54 (m, 2H), 3.28 - 3.25 (m, 1H), 3.24 (s, 3H), 3.06 (dd,J
= 15.3, 10.3 Hz, 1H), 2.91 (s, 6H), 2.87 - 2.69 (m, 2H), 2.46 (dd,J
= 13.0, 7.5 Hz, 2H), 2.32 (p,J
= 8.9 Hz, 1H), 2.23 - 2.03 (m, 3H), 2.01 - 1.65 (m, 6H), 1.42 (t,J
= 12.3 Hz, 1H), 1.12 (d,J
= 6.5 Hz, 3H)。實例 334
以與實例 362
相同之方式使用實例 109
及(R)-八氫吡嗪并[2,1-c][1,4]噁嗪二鹽酸鹽來合成實例 334
。LCMS-ESI+ (m/z):C40
H52
ClN5
O6
S [M+H]+
計算值:766.3400;實驗值:766.10。1
H NMR (400 MHz,甲醇-d
4) δ 7.72 (d,J
= 8.5 Hz, 1H), 7.17 (dd,J
= 8.5, 2.4 Hz, 1H), 7.11 (d,J
= 2.3 Hz, 1H), 7.05 (dd,J
= 8.1, 1.9 Hz, 1H), 6.93 (d,J
= 8.1 Hz, 1H), 6.86 (d,J
= 2.0 Hz, 1H), 5.94 (dt,J
= 14.3, 6.7 Hz, 1H), 5.56 (dd,J
= 15.2, 9.3 Hz, 1H), 4.57 (s, 2H), 4.39 (dd,J
= 14.9, 6.7 Hz, 1H), 4.20 - 3.94 (m, 4H), 3.84 (d,J
= 15.0 Hz, 2H), 3.75 (dd,J
= 9.4, 3.7 Hz, 1H), 3.70 - 3.60 (m, 2H), 3.61 - 3.36 (m, 4H), 3.30 - 3.25 (m, 3H), 3.24 (s, 3H), 3.21 - 3.12 (m, 1H), 3.07 (dd,J
= 15.4, 10.2 Hz, 1H), 2.87 - 2.69 (m, 3H), 2.54 - 2.38 (m, 2H), 2.29 (p,J
= 8.9, 8.4 Hz, 1H), 2.23 - 2.02 (m, 3H), 2.01 - 1.66 (m, 6H), 1.43 (t,J
= 12.6 Hz, 1H), 1.11 (d,J
= 6.5 Hz, 3H)。實例 335
步驟1:將於吡啶中之(反 -
3-(羥基甲基)環丁基)胺基甲酸第三丁酯(368 mg,1.83 mmol)及N
,N
-二甲基胺甲醯氯(0.20 mL,2.19 mmol)之反應混合物在90℃下加熱過夜。在冷卻至室溫之後,添加5 mL冰水,且將反應混合物用EtOAc (70 mL)稀釋,用水(30 mL)、鹽水洗滌,乾燥且濃縮,且藉由管柱層析法使用0-60%於己烷中之EtOAc純化,獲得中間物335-1
。1
H NMR (400 MHz,丙酮-d 6
) δ 6.27 (s, 1H), 4.21 (m, 1H), 4.12 - 4.00 (m, 2H), 2.92 (s, 3H), 2.86 (s, 3H), 2.54 - 2.38 (m, 1H), 2.21 - 2.10 (m, 4H), 1.40 (s, 9H)。
步驟2:將中間物335-2
(130 mg,0.48 mmol)溶解於EtOAc (1 mL)中,且隨後添加於二噁烷(4 mL)中之4 N HCl。將反應混合物在室溫下攪拌4 hr。鼓入通過氮氣以驅出HCl,且移除溶劑,得到335-2
。其不經進一步純化即用於下一 步驟中。
步驟3:以與實例 75
相同之方式使用中間物335-2
及實例 109
來合成實例 335
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.67 (d, J = 9.0 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.06 (s, 1H), 6.97 (s, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.03 (d, J = 15.4 Hz, 1H), 5.57 (dd, J = 15.3, 8.7 Hz, 1H), 4.34 - 4.27 (m, 1H), 4.20 (d, J = 13.9 Hz, 1H), 4.11 (d, J = 6.8 Hz, 2H), 4.03 (s, 2H), 3.79 (dd, J = 23.6, 12.1 Hz, 3H), 3.68 (d, J = 14.1 Hz, 1H), 3.27 (s, 3H), 3.06 - 3.00 (m, 1H), 2.94 (s, 3H), 2.92 (s, 3H), 2.77 (d, J = 18.8 Hz, 2H), 2.56 (s, 2H), 2.45 (d, J = 18.0 Hz, 2H), 2.29 - 2.21 (m, 3H), 2.15 (q, J = 11.8, 10.2 Hz, 4H), 2.03 (d, J = 7.4 Hz, 2H), 1.95 (d, J = 11.5 Hz, 2H), 1.79 (d, J = 5.1 Hz, 2H), 1.39 (d, J = 13.8 Hz, 2H), 1.11 (d, J = 6.2 Hz, 3H)。LCMS-ESI+
C41
H54
ClN5
O7
S [M+H]+
計算值:796.34;實驗值:795.87。實例 336
步驟1:將於吡啶中之(順 -
3-(羥基甲基)環丁基)胺基甲酸第三丁酯(515 mg,2.56 mmol)及N
,N
-二甲基胺甲醯氯(0.31 mL,3.33 mmol)之反應混合物在90℃下加熱過夜。在冷卻至室溫之後,添加5 mL冰水,且將反應混合物用乙醚(70 mL)稀釋,用水(30 mL)、鹽水洗滌,乾燥且濃縮,且藉由管柱層析法使用30-80%於己烷中之EtOAc純化,獲得中間物336-1
。1
H NMR (400 MHz,丙酮-d 6
) δ 6.24 (s, 1H), 3.98 (m, 3H), 2.90 (s, 3H), 2.87 (s, 3H), 2.34 (m, 2H), 2.29 - 2.19 (m, 1H), 1.78 (m, 2H), 1.39 (s, 9H)。
步驟2:製備中間物336-2
。將中間物336-1
(165 mg,0.61 mmol)溶解於EtOAc (1 mL)中,且隨後添加於二噁烷(4 mL)中之4 N HCl。將反應混合物在室溫下攪拌4 hr。鼓入通過氮氣以驅出HCl,且移除溶劑,得到336-2
。其不經進一步純化即用於下一步驟中。
步驟3:以與實例 75
相同之方式使用中間物336-2
及實例 109
來合成實例 336
。1
H NMR (400 MHz,甲醇-d 4
/氘代氯仿 (3/1)) δ 7.66 (d, 1H), 7.21 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 2.1 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 6.97 (s, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.03 (dd, J = 14.6, 7.6 Hz, 1H), 5.59 (dd, J = 15.4, 8.7 Hz, 1H), 4.20 - 4.09 (m, 2H), 4.05 - 3.99 (m, 4H), 3.79 (dd, J = 19.0, 12.5 Hz, 3H), 3.71 - 3.63 (m, 1H), 3.28 (s, 3H), 3.03 (dd, J = 15.1, 9.7 Hz, 1H), 2.93 (s, 3H), 2.91 (s, 3H), 2.85 - 2.73 (m, 2H), 2.55 - 2.39 (m, 5H), 2.35 - 2.28 (m, 1H), 2.21 (d, J = 17.3 Hz, 2H), 2.07 (d, J = 13.7 Hz, 2H), 1.96 (d, J = 5.2 Hz, 1H), 1.77 (dd, J = 19.6, 9.7 Hz, 6H), 1.41 - 1.32 (m, 2H), 1.12 (d, J = 6.3 Hz, 3H)。LCMS-ESI+
C41
H54
ClN5
O7
S [M+H]+
計算值:796.34;實驗值:795.84。實例 337
步驟1:80℃於乙腈(8.0 mL)中之5-甲醯基-1H-吡咯-3-甲酸甲酯(400 mg,2.61 mmol)、1-溴-2-甲氧基乙烷(982 µL,10.5 mmol)及碳酸鉀(722 mg,5.22 mmol)之經劇烈攪拌混合物。在210 min之後,將反應混合物冷卻至室溫,經由矽藻土過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至45%於己烷中之乙酸乙酯)純化殘餘物,得到337-1
。
步驟2:在0℃下將硼氫化鈉(274 mg,7.24 mmol)添加至於甲醇(10 mL)及四氫呋喃(5.0 mL)中之337-1
(510 mg,2.41 mmol)之經攪拌溶液中,且使所得混合物升溫至室溫。在20 min之後,添加乙酸乙酯(125 mL)。將有機層用水及鹽水之混合物(1:1 v:v,2×80 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於N
,N
-二甲基甲醯胺(6.0 mL)中,且將所得混合物攪拌且冷卻至−20℃。經由注射器添加鉀雙(三甲基矽烷基)醯胺溶液(於四氫呋喃中1.0 M,4.11 mL,4.1 mmol)。在10 min之後,經由注射器添加碘甲烷(342 µL,5.48 mmol),且使所得混合物升溫至室溫。在60 min之後,依序添加飽和氯化銨水溶液(5 mL)、二乙醚(65 mL)及乙酸乙酯(65 mL)。將有機層依序用水及鹽水之混合物(2:1 v:v,100 mL)及水(100 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至45%於己烷中之乙酸乙酯)純化殘餘物,得到337-2
。
步驟3:在室溫下經由注射器將氫氧化鈉水溶液(2.0 M,3.18 mL,6.4 mmol)添加至於四氫呋喃(1.0 mL)及甲醇(3.0 mL)中之337-3
(248 mg,1.09 mmol)之經攪拌溶液中,且將所得混合物加熱至70℃。在2 h之後,使所得混合物冷卻至室溫,且依序添加氯化氫水溶液(2.0 M,3.5 mL)、水(5 mL)及鹽水(20 mL)。依序用二氯甲烷(2×)及乙酸乙酯(30 mL)萃取水層,且將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮,得到337-3
。
步驟4:在室溫下將3-(((乙基亞胺基)亞甲基)胺基)-N,N-二甲基丙-1-胺鹽酸鹽(6.7 mg,35 µmol)添加至於二氯甲烷(1.0 mL)中之106-4 (7.0 mg,12 µmol)、X-3 (5.0 mg,23 µmol)及4-(二甲基胺基)吡啶(4.3 mg,35 µmol)之經攪拌混合物中,且將所得混合物加熱至45℃。在60 min之後,添加乙酸乙酯(30 mL)。將有機層依序用檸檬酸水溶液(5% wt.,30 mL)及水(30 mL)洗滌,經硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至10%於二氯甲烷中之甲醇)純化殘餘物,得到不純實例 337
。使不純產物進行C18-逆相矽膠(0至100%於水中之乙腈)純化,得到實例 337
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.27 - 7.21 (m, 2H), 7.14 (s, 1H), 7.02 - 6.79 (m, 1H), 6.57 (s, 1H), 6.32 - 6.06 (m, 1H), 5.75 - 5.44 (m, 1H), 4.72 - 3.02 (m, 14H), 3.32 (s, 3H), 3.27 (s, 3H), 3.24 (s, 3H), 2.86 - 1.18 (m, 16H), 1.13 (d, J = 6.6 Hz, 3H)。LCMS:815.1 (M+Na)+。實例 338
以與實例337類似之方式使用1-溴-3-甲氧基丙烷而不使用1-溴-2-甲氧基乙烷來合成實例 338
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.6 Hz, 1H), 7.33 (d, J = 8.3 Hz, 1H), 7.30 - 7.18 (m, 2H), 7.13 (d, J = 2.3 Hz, 1H), 7.01 - 6.76 (m, 1H), 6.52 (s, 1H), 6.37 - 6.06 (m, 1H), 5.69 - 5.46 (m, 1H), 4.57 - 2.97 (m, 14H), 3.31 (s, 3H), 3.26 (s, 3H), 3.24 (s, 3H), 2.96 - 1.18 (m, 18H), 1.12 (d, J = 6.6 Hz, 3H)。LCMS:829.1 (M+Na)+。實例 339
以與實例 106
類似之方式使用5-(甲氧基甲基)-4-甲基呋喃-2-甲酸及實例 109
來製備實例 339
。1
H NMR (400 MHz,丙酮-d6
) δ 7.76 (d, J = 8.5 Hz, 1H), 7.28 - 7.18 (m, 2H), 7.11 (d, J = 8.8 Hz, 3H), 6.93 (d, J = 8.1 Hz, 1H), 6.08 (br s, 1H), 5.61 (dd, J = 15.4, 8.5 Hz, 1H), 4.43 (s, 2H), 4.16 - 3.99 (m, 2H), 3.88 (d, J = 14.9 Hz, 1H), 3.73 (d, J = 13.1 Hz, 2H), 3.38 (d, J = 14.6 Hz, 2H), 3.33 (s, 3H), 3.22 (s, 3H), 3.20 - 3.10 (m, 2H) 2.87 - 2.69 (m, 2H), 2.47 (s, 4H), 2.25 (d, J = 14.5 Hz, 4H), 2.11 (s, 3H), 2.00 - 1.66 (m, 5H), 1.14 (d, J = 6.2 Hz, 3H)。LCMS-ESI+ (m/z):C40
H49
ClN3
O7
S [M+H]+計算值:750.29;實驗值:749.94。實例 340
以與實例 281
相同之方式使用1-甲基-2-氧雜雙環[2.1.1]己烷-4-甲酸及實例 109
來合成實例 340
。1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H), 7.27 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.95 (s, 1H), 6.90 (d, J = 8.1 Hz, 1H), 5.96 (dt, J = 14.4, 6.8 Hz, 1H), 5.49 (dd, J = 15.2, 8.7 Hz, 1H), 4.15 - 3.88 (m, 3H), 3.78 (t, J = 16.6 Hz, 2H), 3.70 - 3.52 (m, 8H), 3.22 (d, J = 14.2 Hz, 1H), 3.14 (s, 3H), 3.01 (dd, J = 15.2, 10.5 Hz, 1H), 2.88 - 2.60 (m, 2H), 2.46 - 2.20 (m, 3H), 2.18 - 2.07 (m, 1H), 2.05 - 1.91 (m, 4H), 1.90 - 1.78 (m, 2H), 1.77 - 1.55 (m, 4H), 1.35 (s, 3H), 1.01 (d, J = 6.8 Hz, 3H)。LCMS -ESI+ (m/z):C39
H49
ClN4
O6
S [M+H]+計算值:737.31;實驗值:736.75。實例 341
以與實例 281
相同之方式使用5-氧雜螺[2.4]庚烷-1-甲酸及實例109來合成實例 341
。分離兩種異構體之混合物,且任意指定立體化學,但不指定絕對立體化學。1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.5, 2.4 Hz, 1H), 7.16 (dd, J = 14.5, 5.3 Hz, 2H), 6.97 (d, J = 12.0 Hz, 2H), 6.89 (d, J = 8.2 Hz, 1H), 6.55 (s, 1H), 6.07 - 5.85 (m, 1H), 5.49 (dd, J = 15.3, 8.7 Hz, 1H), 4.17 - 4.01 (m, 2H), 3.95 (d, J = 12.2 Hz, 1H), 3.91 - 3.72 (m, 3H), 3.69 - 3.47 (m, 3H), 3.27 - 3.17 (m, 6H), 3.14 (d, J = 1.8 Hz, 3H), 3.01 (dd, J = 15.2, 10.5 Hz, 1H), 2.87 - 2.58 (m, 3H), 2.44 - 2.31 (m, 2H), 2.31 - 2.06 (m, 1H), 2.00 (d, J = 14.3 Hz, 1H), 1.74 (ddt, J = 55.6, 20.6, 8.8 Hz, 6H), 1.36 (d, J = 10.0 Hz, 1H), 1.08 (t, J = 6.9 Hz, 1H), 1.00 (dd, J = 6.8, 4.2 Hz, 3H), 0.70 (dt, J = 21.3, 5.1 Hz, 1H. LCMS -ESI+ (m/z):C39
H49
ClN4
O6
S [M+H]+計算值:737.31;實驗值:736.87。實例 342
以與實例 281
相同之方式使用5-氧雜螺[2.4]庚烷-1-甲酸及實例 109
來合成實例 342
。任意指定立體化學,但不指定絕對立體化學。1H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.5, 2.4 Hz, 1H), 7.16 (dd, J = 13.4, 5.2 Hz, 2H), 6.98 (d, J = 16.0 Hz, 2H), 6.89 (dd, J = 8.2, 2.5 Hz, 1H), 6.55 (s, 1H), 5.96 (s, 1H), 5.50 (dd, J = 15.3, 8.6 Hz, 1H), 4.04 (d, J = 12.3 Hz, 2H), 3.95 (d, J = 12.3 Hz, 1H), 3.90 - 3.71 (m, 3H), 3.71 - 3.60 (m, 2H), 3.59 - 3.46 (m, 2H), 3.22 (d, J = 14.5 Hz, 4H), 3.14 (d, J = 1.8 Hz, 3H), 3.01 (dd, J = 15.2, 10.5 Hz, 1H), 2.87 - 2.58 (m, 4H), 2.44 - 2.32 (m, 2H), 2.20 (d, J = 54.6 Hz, 1H), 1.99 (d, J = 14.0 Hz ,2H), 1.91 - 1.57 (m, 5H), 1.40 (d, J = 13.8 Hz, 1H), 1.12 - 0.93 (m, 4H), 0.70 (dt, J = 20.0, 5.1 Hz, 1H)。LCMS -ESI+ (m/z):C39
H49
ClN4
O6
S [M+H]+計算值:737.31;實驗值:736.87。實例 343
步驟1:製備中間物343-1
:向於甲醇(20 mL)中之中間物359-2
(1.4 g,1.83 mmol)之經攪拌溶液中添加水(2 mL)、K2
CO3
(1.7 g,18.3 mmol),且在60℃下攪拌24 hr。添加更多水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑。
步驟2:向於DCM (5 mL)中之中間物184-1 (0.72 g,1.1 mmol)之經攪拌溶液中添加3-甲氧基-1-甲基-1H-吡唑-4-甲酸(200 mg,1.2 mmol)、1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (397 mg,2.5 mmol)及4-(二甲基胺基)吡啶(312 mg,2.5 mmol)。將反應混合物在室溫下攪拌24 hr。隨後,將反應混合物用DCM稀釋,且用1 N HCl及鹽水洗滌。將有機相經MgSO4
乾燥,過濾,濃縮,且進行正相層析法0-10% DCM/MeOH純化,得到中間物343-2
。
步驟3:用氬氣使於1,2-二氯乙烷(38 mL)中之中間物343-2
(100 mg,0.13 mmol)、哈維達-格拉布II (33 mg,0.039 mmol)及TFA (44 mg,0.39 mmol)之經攪拌溶液脫氣。將反應混合物在60℃下攪拌過夜。將反應混合物濃縮且進行逆相層析法0.1% TFA 70-95%乙腈純化,得到實例 343
。1H NMR (400 MHz,氘代氯仿) δ7.84 - 7.70 (m, 2H), 7.52 (dd, J = 8.2, 1.9 Hz, 1H), 7.39 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.5, 2.3 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 8.3 Hz, 1H), 5.64 (t, J = 10.0 Hz, 1H), 5.49 (td, J = 10.8, 4.1 Hz, 1H), 4.75 (d, J = 8.4 Hz, 1H), 4.48 (dt, J = 7.7, 3.9 Hz, 1H), 4.11 (d, J = 18.9 Hz, 4H), 3.92 (d, J = 15.1 Hz, 1H), 3.83 (s, 3H), 3.49 (d, J = 14.7 Hz, 1H), 3.28 (dd, J = 15.3, 10.1 Hz, 2H), 2.93 - 2.53 (m, 4H), 2.39 (s, 2H), 2.18 - 1.72 (m, 10H), 1.48 (d, J = 6.9 Hz, 2H), 1.40 (d, J = 7.2 Hz, 3H), 1.28 (s, 2H), 0.93 - 0.72 (m, 2H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O6
S [M+H]+計算值:736.29;實驗值:736.16。實例 344
以與實例 344
類似之方式使用中間物 359-4
而不使用106-4
來合成實例 344
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 7.30 - 7.17 (m, 3H), 7.15 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.30 (s, 1H), 5.95 - 5.81 (m, 1H), 5.74 (dd, J = 15.1, 7.2 Hz, 1H), 4.92 (d, J = 14.5 Hz, 1H), 4.80 - 4.67 (m, 1H), 4.44 - 3.31 (m, 12H), 3.39 (s, 3H), 3.19 (dd, J = 15.2, 8.7 Hz, 1H), 3.13 - 1.40 (m, 15H), 1.55 (d, J = 7.2 Hz, 3H), 1.11 - 0.99 (m, 3H)。LCMS:791.0。實例 345
以與實例 214
類似之方式使用中間物 359-4
而不使用106-4
且使用(S)-2-(甲氧基甲基)環氧乙烷而不使用(R)-2-(甲氧基甲基)環氧乙烷來合成實例 345
。1H NMR (400 MHz,丙酮-d6) δ 7.79 (d, J = 8.5 Hz, 1H), 7.44 (s, 1H), 7.29 - 7.17 (m, 3H), 7.15 (d, J = 2.3 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 5.96 - 5.82 (m, 1H), 5.74 (dd, J = 15.2, 7.3 Hz, 1H), 4.92 (d, J = 14.4 Hz, 1H), 4.73 (d, J = 14.4 Hz, 1H), 4.47 - 3.33 (m, 12H), 3.39 (s, 3H), 3.19 (dd, J = 15.1, 8.7 Hz, 1H), 3.05 - 1.41 (m, 15H), 1.56 (d, J = 7.1 Hz, 2H), 1.11 - 0.98 (m, 3H)。LCMS:791.0。實例 346
以與實例 75
類似之方式使用3-(甲氧基甲基)氮雜環丁烷鹽酸鹽、三乙胺及實例 109
來製備實例 346
。1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.07 (dd, J = 8.2, 1.8 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 2.0 Hz, 1H), 5.90 (dt, J = 14.4, 6.8 Hz, 1H), 5.49 (dd, J = 15.2, 8.8 Hz, 1H), 4.17 - 3.87 (m, 4H), 3.83 - 3.68 (m, 2H), 3.68 - 3.53 (m, 2H), 3.51 (s, 6H), 3.28 (s, 3H), 3.20 (d, J = 14.1 Hz, 1H), 3.13 (s, 4H), 3.01 (dd, J = 15.3, 10.4 Hz, 1H), 2.87 - 2.59 (m, 4H), 2.45 - 2.31 (m, 2H), 2.29 - 2.06 (m, 2H), 2.04 - 1.57 (m, 7H), 1.45 - 1.32 (m, 1H), 1.01 (d, J = 6.8 Hz, 3H)。LCMS -ESI+ (m/z):LCMS -ESI+ (m/z):C38
H49
ClN4
O6
S [M+H]+計算值:725.31;實驗值:725.06。實例 347
以與實例 75
類似之方式使用(S)-3-甲氧基吡咯啶、三乙胺及實例 109
來製備實例 347
。1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.84 (d, J = 2.0 Hz, 1H), 5.86 (dt, J = 14.4, 6.8 Hz, 1H), 5.49 (dd, J = 15.2, 8.9 Hz, 1H), 4.20 - 3.87 (m, 4H), 3.84 - 3.53 (m, 8H), 3.24 (s, 4H), 3.13 (s, 3H), 3.02 (dd, J = 15.3, 10.4 Hz, 1H), 2.89 - 2.60 (m, 2H), 2.44 - 2.30 (m, 2H), 2.29 - 2.05 (m, 2H), 2.04 - 1.56 (m, 8H), 1.39 (td, J = 17.2, 14.6, 9.7 Hz, 1H), 1.02 (d, J = 6.8 Hz, 3H)。LCMS -ESI+ (m/z):C38
H49
ClN4
O6
S [M+H]+計算值:725.31;實驗值:725.00。實例 348
以與實例 362
相同之方式使用實例 109
及1-(氮雜環丁烷-3-基)咪唑二鹽酸鹽來合成實例 348
。LCMS-ESI+ (m/z):C39
H47
ClN6
O5
S [M+H]+
計算值:747.3090;實驗值:747.13。1
H NMR (400 MHz,甲醇-d 4
) δ 9.16 (s, 1H), 7.94 (t,J
= 1.8 Hz, 1H), 7.72 (d,J
= 8.5 Hz, 1H), 7.68 (t,J
= 1.8 Hz, 1H), 7.16 (dd,J
= 8.4, 2.3 Hz, 1H), 7.12 - 7.05 (m, 2H), 6.96 - 6.87 (m, 2H), 5.97 (dt,J
= 14.3, 6.5 Hz, 1H), 5.57 (dd,J
= 15.2, 9.1 Hz, 1H), 5.35 (td,J
= 8.0, 4.0 Hz, 1H), 4.68 - 4.51 (m, 2H), 4.43 - 4.20 (m, 3H), 4.13 - 4.00 (m, 2H), 3.84 (d,J
= 15.1 Hz, 1H), 3.75 (dd,J
= 9.2, 3.6 Hz, 1H), 3.70 - 3.57 (m, 2H), 3.28 - 3.26 (m, 1H), 3.24 (s, 3H), 3.07 (dd,J
= 15.2, 10.3 Hz, 1H), 2.88 - 2.68 (m, 2H), 2.52 - 2.40 (m, 2H), 2.32 (p,J
= 8.6 Hz, 1H), 2.24 - 2.03 (m, 3H), 2.00 - 1.67 (m, 6H), 1.43 (t,J
= 12.7 Hz, 1H), 1.14 (d,J
= 6.5 Hz, 3H)。實例 349
以與實例 362
相同之方式使用實例 109
及4-(氮雜環丁烷-3-基)嗎啉二鹽酸鹽來合成實例 349
。LCMS-ESI+ (m/z):C40
H52
ClN5
O6
S [M+H]+
計算值:766.3400;實驗值:765.95。1
H NMR (400 MHz,甲醇-d
4) δ 7.70 (d,J
= 8.5 Hz, 1H), 7.18 - 7.03 (m, 3H), 6.97 - 6.82 (m, 2H), 5.96 (dt,J
= 14.1, 6.6 Hz, 1H), 5.57 (dd,J
= 15.2, 9.1 Hz, 1H), 4.39 - 4.15 (m, 5H), 4.11 - 3.99 (m, 4H), 3.93 (s, 3H), 3.83 (d,J
= 15.2 Hz, 1H), 3.74 (dd,J
= 9.2, 3.6 Hz, 1H), 3.69 - 3.59 (m, 2H), 3.31 - 3.25 (m, 5H), 3.24 (s, 3H), 3.07 (dd,J
= 15.3, 10.3 Hz, 1H), 2.87 - 2.68 (m, 2H), 2.53 - 2.40 (m, 2H), 2.33 (p,J
= 8.3, 7.4 Hz, 1H), 2.23 - 2.04 (m, 3H), 2.01 - 1.67 (m, 6H), 1.42 (t,J
= 12.6 Hz, 1H), 1.13 (d,J
= 6.5 Hz, 3H)。實例 350
以與實例 75
相同之方式使用實例 109
及(3R)-3-甲氧基吡咯啶;鹽酸鹽及DIEA來合成實例 350
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.14 - 7.08 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.01 - 5.91 (m, 1H), 5.58 (dd, J = 15.2, 9.2 Hz, 1H), 4.39 - 4.29 (m, 1H), 4.13 - 4.05 (m, 2H), 4.05 - 4.00 (m, 1H), 3.85 (d, J = 15.4 Hz, 1H), 3.76 (dd, J = 9.3, 3.6 Hz, 1H), 3.71 - 3.49 (m, 5H), 3.48 - 3.39 (m, 1H), 3.36 (s, 3H), 3.26 (s, 3H), 3.13 - 3.03 (m, 1H), 2.88 - 2.71 (m, 2H), 2.54 - 2.43 (m, 2H), 2.39 - 2.28 (m, 1H), 2.24 - 1.67 (m, 12H), 1.50 - 1.39 (m, 1H), 1.18 - 1.11 (m, 3H)。LCMS-ESI+ (m/z):C38
H49
ClN4
O6
S計算值H+:725.31;實驗值:724.95。實例 351
以與實例 75
相同之方式使用3-(二氟甲基)氮雜環丁烷及實例 109
來合成實例 351
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.75 (d,J
= 8.5 Hz, 1H), 7.19 (dd,J
= 8.5, 2.4 Hz, 1H), 7.11 (dd,J
= 8.4, 2.0 Hz, 2H), 6.96 - 6.89 (m, 2H), 6.32 - 5.87 (m, 2H), 5.58 (dd,J
= 15.2, 9.1 Hz, 1H), 4.33 (dd,J
= 14.9, 6.4 Hz, 1H), 4.24 - 3.93 (m, 5H), 3.85 (d,J
= 15.2 Hz, 1H), 3.76 (dd,J
= 9.2, 3.6 Hz, 1H), 3.65 (m, 2H), 3.27 (m, 2H), 3.26 (s, 3H), 3.18 - 3.00 (m, 2H), 2.92 - 2.71 (m, 2H), 2.55 - 2.29 (m, 3H), 2.25 - 2.07 (m, 3H), 1.97 - 1.70 (m, 5H), 1.44 (t,J
= 12.2 Hz, 1H), 1.15 (d,J
= 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C37
H45
ClF2
N4
O5
S [M+H]+計算值:731.3;實驗值:730.8。實例 352
以與實例 362
相同之方式使用實例 109
及3-(氮雜環丁烷-3-基氧基)吡啶二鹽酸鹽來合成實例 352
。LCMS-ESI+ (m/z):C41
H48
ClN5
O6
S [M+H]+
計算值:774.3087;實驗值:773.82。1
H NMR (400 MHz,甲醇-d 4
) δ 8.41 (d,J
= 16.0 Hz, 2H), 7.76 (dd,J
= 27.1, 11.3 Hz, 3H), 7.16 (dd,J
= 8.5, 2.3 Hz, 1H), 7.13 - 7.03 (m, 2H), 6.95 - 6.86 (m, 2H), 5.95 (dt,J
= 14.3, 6.7 Hz, 1H), 5.56 (dd,J
= 15.2, 9.1 Hz, 1H), 5.20 (s, 1H), 4.51 (s, 2H), 4.32 (dd,J
= 14.9, 6.3 Hz, 1H), 4.14 - 4.01 (m, 4H), 3.83 (d,J
= 15.1 Hz, 1H), 3.74 (dd,J
= 9.2, 3.7 Hz, 1H), 3.68 - 3.55 (m, 2H), 3.29 - 3.25 (m, 1H), 3.24 (s, 3H), 3.06 (dd,J
= 15.2, 10.3 Hz, 1H), 2.87 - 2.66 (m, 2H), 2.54 - 2.38 (m, 2H), 2.32 (q,J
= 9.0 Hz, 1H), 2.23 - 2.04 (m, 3H), 2.00 - 1.65 (m, 6H), 1.42 (t,J
= 12.7 Hz, 1H), 1.13 (d,J
= 6.5 Hz, 3H)。實例 353
步驟1:在冰水浴中向於DCM (5 mL)中之中間物343-2
(145 mg,0.19 mmol)之經攪拌溶液中一次性添加戴斯-馬丁高碘烷(241 mg,0.56 mmol)。使反應物在室溫下升溫且攪拌30 min。將反應混合物用DCM稀釋,且用1 N HCl及鹽水洗滌。將有機相經MgSO4
乾燥,過濾,濃縮且進行逆相層析法0.1% TFA 70-95%乙腈純化,得到中間物353-1
。
步驟2:用氬氣使於1,2-二氯乙烷(19 mL)中之中間物353-1
(50 mg,0.06 mmol)、哈維達-格拉布II (16.6 mg,0.020 mmol)及TFA (22 mg,0.19 mmol)之經攪拌溶液脫氣。將反應混合物在60℃下攪拌過夜。將反應混合物濃縮且進行正相層析法0-10% DCM/MeOH純化,得到中間物353-2
。
步驟3:在0℃下向於甲醇(2 mL)中之中間物174-2 (16 mg,0.022 mmol)及CeCl3
(16 mg,0.065 mmol)之經攪拌溶液中小份添加NaBH4
(1.2 mg,0.033 mmol),且在0℃下攪拌1 h。用10%氯化銨水溶液稀釋混合物。使用蒸發器移除有機溶劑。使剩餘水溶液經受兩次利用乙酸乙酯進行之萃取。將有機層用飽和鹽水洗滌,隨後經硫酸鈉乾燥且隨後濃縮。使殘餘物進行逆相層析法0.1% TFA 70-95%乙腈純化,得到實例 353
。1
H NMR (400 MHz,氘代氯仿) δ 7.84 - 7.72 (m, 2H), 7.63 (s, 1H), 7.33 (d,J
= 7.7 Hz, 2H), 7.21 (dd,J
= 8.5, 2.4 Hz, 1H), 7.10 (d,J
= 2.3 Hz, 1H), 6.95 (d,J
= 8.2 Hz, 1H), 5.58 (dd,J
= 15.5, 7.5 Hz, 1H), 5.51 - 5.40 (m, 1H), 4.11 (d,J
= 15.5 Hz, 4H), 3.96 (d,J
= 16.1 Hz, 1H), 3.84 - 3.68 (m, 3H), 3.26 (d,J
= 14.3 Hz, 1H), 3.08 - 2.90 (m, 1H), 2.85 - 2.72 (m, 2H), 2.59 (s, 2H), 2.09 (d,J
= 15.0 Hz, 5H), 1.98 - 1.67 (m, 4H), 1.56 (d,J
= 7.3 Hz, 3H), 1.28 (m, 2H), 1.02 (d,J
= 6.9 Hz, 2H), 0.92 - 0.78 (m, 3H), 0.72 - 0.45 (m, 2H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O6
S [M+H]+計算值:736.29;實驗值:736.16。實例 354
以與實例 182
相同之方式使用3-(二氟甲氧基)氮雜環丁烷而不使用外消旋-(1R,2R)-2-(1-甲基-1H-吡唑-5-基)環丙-1-胺來合成實例 354
。1H NMR (400 MHz,甲醇-d4) δ 7.75 (d, J = 8.5 Hz, 1H), 7.19 (dd, J = 8.6, 2.4 Hz, 1H), 7.11 (dd, J = 8.2, 2.0 Hz, 2H), 7.00 - 6.88 (m, 2H), 6.49 (t, J = 74.0 Hz, 1H), 5.97 (dt, J = 14.4, 6.8 Hz, 1H), 5.58 (dd, J = 15.2, 9.2 Hz, 1H), 4.32 (dd, J = 14.7, 6.6 Hz, 2H), 4.09 (d, J = 1.8 Hz, 3H), 3.85 (d, J = 15.2 Hz, 1H), 3.76 (dd, J = 9.2, 3.6 Hz, 1H), 3.72 - 3.54 (m, 3H), 3.26 (s, 3H), 3.08 (dd, J = 15.2, 10.3 Hz, 2H), 2.88 - 2.67 (m, 3H), 2.55 - 2.43 (m, 2H), 2.35 (q, J = 8.9 Hz, 2H), 2.25 - 2.08 (m, 3H), 1.96 (s, 3H), 1.79 (tt, J = 17.5, 9.5 Hz, 3H), 1.45 (t, J = 12.5 Hz, 1H), 1.15 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C37
H45
ClF2
N4
O6
S [M+H]+計算值:747.27;實驗值:746.28。實例 355
以與實例 75
相同之方式使用3-(2,2-二氟乙基)氮雜環丁烷及實例 109
來合成實例 355
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.75 (d,J
= 8.5 Hz, 1H), 7.19 (dd,J
= 8.5, 2.4 Hz, 1H), 7.12 (d,J
= 2.3 Hz, 2H), 6.92 (d,J
= 2.6 Hz, 2H), 6.02 - 5.93 (m, 1H), 5.58 (dd,J
= 15.2, 9.0 Hz, 1H), 4.30 (dd,J
= 14.8, 6.4 Hz, 1H), 4.21 (br, 3H), 4.08 (d,J
= 2.5 Hz, 2H), 3.97 - 3.70 (m, 2H), 3.73 - 3.57 (m, 2H), 3.3 - 3.26 (m, 2H), 3.26 (s, 2H), 3.17 - 3.02 (m, 1H), 2.97 - 2.75 (m, 4H), 2.56 - 2.43 (m, 1H), 2.35 (q,J
= 9.3, 8.2 Hz, 1H), 2.28 - 2.07 (m, 3H), 2.01 - 1.78 (m, 4H), 1.45 (t,J
= 12.7 Hz, 1H), 1.15 (d,J
= 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C38
H47
ClF2
N4
O5
S [M+H]+計算值:745.3;實驗值:744.8。實例 356
步驟1:合成356-1
:在室溫下向於THF (5.0 mL)中之3-羥基-1-甲基-吡唑-4-甲酸乙酯(200.0 mg,1.18 mmol)及1,3-二氧雜環戊烷-2-基甲醇(159 mg,1.53 mmol)之混合物中添加三-N-丁基膦(309 mg,1.53 mmol),繼而逐滴添加偶氮二甲酸二異丙酯(309 mg,1.53 mmol)。將所得混合物在室溫下攪拌3小時,且隨後在70℃下加熱過夜。將反應物冷卻至室溫,濃縮,藉由combiflash (12 g矽膠,0-50% EtOAc/己烷)純化。濃縮所需溶離份,得到標題化合物。1H NMR (400 MHz,氘代氯仿) δ 7.80 (s, 1H), 5.24 (t, J = 3.9 Hz, 1H), 4.51 (d, J = 3.9 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.07 - 3.99 (m, 2H), 3.99 - 3.93 (m, 2H), 3.76 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H)。
步驟2:合成356-2
:於EtOH中且經1N NaOH (0.21 mL,0.21 mmol)在60℃下處理1 hr之中間物356-1
(44.0 mg,0.172 mmol)。添加額外之1 N NaOH (1.72 mL,1.72 mmol),將反應混合物連續加熱5 hr。將反應物冷卻至室溫,濃縮,用EtOAc稀釋,用1 N HCl、鹽水洗滌,經硫酸鈉乾燥,過濾且濃縮,得到356-2
。1H NMR (400 MHz,氘代氯仿) δ 7.85 (s, 1H), 5.24 (t, J = 3.9 Hz, 1H), 4.51 (d, J = 3.9 Hz, 2H), 4.08 - 3.91 (m, 4H), 3.75 (s, 3H)。
步驟3:以與實例 18
相同之方式使用實例 109
及356-2
來合成實例 356
。1H NMR (400 MHz,甲醇-d4) δ 7.87 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.12 (d, J = 2.3 Hz, 1H), 6.99 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.11 - 5.99 (m, 1H), 5.61 (dd, J = 15.2, 8.9 Hz, 1H), 5.23 (t, J = 3.7 Hz, 1H), 4.56 - 4.45 (m, 2H), 4.37 (dd, J = 14.8, 6.4 Hz, 1H), 4.13 - 4.04 (m, 2H), 4.02 - 3.96 (m, 2H), 3.96 - 3.83 (m, 4H), 3.78 (dd, J = 8.9, 3.6 Hz, 1H), 3.73 - 3.66 (m, 4H), 3.28 (s, 3H), 3.09 (dd, J = 15.3, 10.2 Hz, 1H), 2.89 - 2.75 (m, 2H), 2.54 - 2.36 (m, 3H), 2.29 - 2.09 (m, 4H), 1.97 - 1.71 (m, 6H), 1.50 - 1.40 (m, 1H), 1.16 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C41
H50
ClN5
O8
S計算值H+:808.31;實驗值:807.99。實例 357
以與實例 75
相同之方式使用(1r
,3r
)-3-氟環丁-1-胺鹽酸鹽及實例 109
來合成實例 357
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.69 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 7.05 (d, J = 8.4 Hz, 1H), 6.97 (s, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.06 (d, J = 15.4 Hz, 1H), 5.62 (dd, J = 15.4, 8.9 Hz, 1H), 4.41 (s, 1H), 4.23 (d, J = 12.7 Hz, 1H), 4.03 (s, 2H), 3.89 - 3.71 (m, 3H), 3.66 (d, J = 14.2 Hz, 1H), 3.36 (s, 1H), 3.29 (s, 4H), 3.07 (dd, J = 15.2, 9.9 Hz, 1H), 2.89 - 2.70 (m, 3H), 2.64 - 2.50 (m, 3H), 2.50 - 2.31 (m, 5H), 2.20 (s, 2H), 2.10 (d, J = 13.6 Hz, 1H), 1.96 (s, 2H), 1.80 (d, J = 6.9 Hz, 2H), 1.41 (t, J = 13.1 Hz, 1H), 1.14 (d, J = 6.4 Hz, 3H)。LCMS-ESI+ C37
H46
ClFN4
O5
S [M+H]計算值:713.29;實驗值:712.75。實例 358
以與實例 18
相同之方式使用5-(甲氧基羰基)-1-甲基-1H-吡咯-3-甲酸及實例 109
來合成實例 358
。1
H NMR (400 MHz,氘代氯仿) δ 7.74 (d,J
= 8.5 Hz, 1H), 7.51 (d,J
= 1.9 Hz, 1H), 7.41 (dd,J
= 6.4, 1.8 Hz, 1H), 7.20 (dd,J
= 8.5, 2.3 Hz, 1H), 7.11 (d,J
= 2.4 Hz, 2H), 6.97 (d,J
= 8.2 Hz, 2H), 5.96 (dt,J
= 14.6, 6.6 Hz, 1H), 5.59 (dd,J
= 15.5, 8.2 Hz, 1H), 4.17 - 4.03 (m, 2H), 4.00 (s, 2H), 3.91 - 3.69 (m, 7H), 3.29 (d,J
= 5.6 Hz, 4H), 3.06 - 2.90 (m, 2H), 2.88 - 2.68 (m, 3H), 2.45 (d,J
= 10.3 Hz, 2H), 2.32 - 1.57 (m, 8H), 1.48 - 1.23 (m, 3H), 1.11 (d,J
= 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C40
H47
ClN4
O7
S [M+H]+計算值:763.29;實驗值:763.12。實例 359 方法 1:
步驟1:向於四氫呋喃中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b] [1,4]噁氮呯-3,1'-萘]-7-甲酸(500 mg,1.068 mmol)之經攪拌溶液中添加吡啶(337 mg,4.24 mmol)及乙酸酐(545 mg,5.34 mmol)。將混合物在60℃下攪拌過夜,繼而蒸發溶劑。將殘餘物溶解於乙酸乙酯中且用水洗滌。濃縮有機層。將固體溶解於CH2
Cl2
中且冷卻至0℃。在劇烈攪拌下向此混合物中逐滴添加SOCl2
(2 mL)。在0℃下攪拌混合物,且使其緩慢地升溫至室溫。在反應完成之後,將水添加至混合物中且劇烈攪拌過夜。在DCM中萃取所需產物。將有機相經Mg2
SO4
乾燥且在減壓下蒸發,得到中間物359-1
。
步驟2:向於DCM (10 mL)中之359-1
(200 mg,0.39 mmol)之經攪拌溶液中添加N-((S)-胺基((2R,3S)-3-甲基己-5-烯-2-基)(側氧基)-l6-硫酮)-2,2,2-三氟乙醯胺(110-2-2)
(110 mg,0.41 mmol)、1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (122 mg,0.78 mmol)及4-(二甲基胺基)吡啶(96 mg,0.78 mmol)。將反應混合物在室溫下攪拌4 hr。隨後,將反應混合物用DCM稀釋,用1 N HCl及鹽水洗滌。將有機相經MgSO4
乾燥,過濾,濃縮且藉由正相層析法20-80% EtOAc/己烷純化,得到中間物359-2
。
步驟3:合成中間物359-3
:用氬氣使於1,2-二氯乙烷(90 mL)中之中間物359-2
(250 mg,0.33 mmol)、哈維達-格拉布II (61 mg,0.098 mmol)之經攪拌溶液脫氣。將反應混合物在60℃下攪拌過夜。濃縮反應混合物,且殘餘物用於下一步驟。
步驟4:製備中間物359-4
:向於甲醇(10 mL)中之中間物359-3
(58 mg,0.079 mmol)之經攪拌溶液中添加水(1 mL)及K2
CO3
(38 mg,0.39 mmol),且在60℃下攪拌24 hr。添加水,且用二氯甲烷萃取混合物。使有機相經無水硫酸鎂乾燥,且在減壓下移除溶劑。
步驟5:以與實例 18
相同之方式使用3-甲氧基-1-甲基-1H-吡唑-4-甲酸及中間物359-4
來合成實例 359
。1H NMR (400 MHz,氘代氯仿) δ 7.83 - 7.66 (m, 3H), δ 7.33 (s, 1H), 7.21 (dd,J
= 8.5, 2.3 Hz, 1H), 7.10 (d,J
= 2.3 Hz, 1H), 6.95 (d,J
= 8.3 Hz, 1H), 5.85 - 5.74 (m, 1H), 5.70 - 5.62 (m, 1H), 4.19 - 4.00 (m, 3H), 3.80 (s, 3H), 3.31 (d,J
= 14.2 Hz, 2H), 3.07 (d,J
= 15.7 Hz, 2H), 2.89 - 2.69 (m, 3H), 2.61 - 2.35 (m, 3H), 2.25 - 1.67 (m, 10H), 1.58 (d,J
= 7.2 Hz, 3H), 1.44 (t,J
= 12.5 Hz, 2H), 1.28 (s, 2H), 1.02 (d,J
= 6.7 Hz, 3H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O6
S [M+H]+計算值:736.29;實驗值:736.10。方法 2
步驟1:將第三丁基氯二甲基矽烷(4.5 g,1.2當量)添加至於DMF (60 mL)中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-羥基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b] [1,4]噁氮呯-3,1'-萘]-7-甲酸(12 g,24.9 mmol)及咪唑(2.2 g,1.3當量)之溶液中。在2 hr之後,將反應物用EtOAc稀釋且用水、5% LiCl水溶液及鹽水洗滌。使有機相經硫酸鈉乾燥,且在減壓下移除溶劑。使殘餘物經受急驟管柱層析法(矽膠,0-100% EtOAc/己烷)。組合含有產物之溶離份,且在減壓下移除溶劑,得到359-2-1
(14.5 g,97%)。1
H NMR (400 MHz,氘代氯仿) δ 7.69 (d, J = 8.5 Hz, 1H), 7.46 - 7.38 (m, 2H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.97 - 6.90 (m, 1H), 5.82 (ddd, J = 16.7, 10.4, 6.0 Hz, 1H), 5.23 (dt, J = 17.1, 1.6 Hz, 1H), 5.05 (dt, J = 10.5, 1.5 Hz, 1H), 4.20 - 4.03 (m, 4H), 3.90 (s, 3H), 3.59 (d, J = 14.2 Hz, 1H), 3.48 (dd, J = 14.5, 4.0 Hz, 1H), 3.38 - 3.21 (m, 2H), 2.79 (q, J = 5.3 Hz, 2H), 2.69 (td, J = 8.7, 3.9 Hz, 1H), 2.22 - 2.10 (m, 1H), 2.10 - 1.86 (m, 2H), 1.77- 1.68 (m, 2H), 1.65 - 1.49 (m, J = 9.3 Hz, 3H), 0.91 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H)。LCMS-ESI+
(m/z):C34
H46
ClNO4
Si [M+H]+
計算值:596.3;實驗值:596.2。
步驟2:將中間物 359-2-1
(14.5 g,24.3 mmol)與氫氧化鋰(2.3 g,4當量)、水(97 mL)、甲醇(100 mL)及四氫呋喃(150 mL)組合。將混合物在60℃下加熱5 hr。在真空中濃縮反應物,隨後用1 N HCl水溶液(120 mL)酸化剩餘溶液。用EtOAc萃取混合物,且將合併有機相經硫酸鈉乾燥且在減壓下濃縮,得到中間物 359-2-2
。1
H NMR (400 MHz,氘代氯仿) δ 7.70 (d, J = 8.5 Hz, 1H), 7.52 - 7.46 (m, 2H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 8.7 Hz, 1H), 5.80 (ddd, J = 16.8, 10.4, 6.0 Hz, 1H), 5.24 (dt, J = 17.2, 1.6 Hz, 1H), 5.05 (dt, J = 10.6, 1.5 Hz, 1H), 4.19 - 4.04 (m, 4H), 3.61 (d, J = 14.3 Hz, 1H), 3.51 (dd, J = 14.5, 4.0 Hz, 1H), 3.36 (d, J = 14.3 Hz, 1H), 3.28 (dd, J = 14.5, 9.5 Hz, 1H), 2.79 (d, J = 4.5 Hz, 2H), 2.71 (td, J = 8.7, 4.0 Hz, 1H), 2.20 - 2.11 (m, 1H), 2.06 - 1.83 (m, 1H), 1.77 (q, J = 8.4, 7.8 Hz, 2H), 1.65 (q, J = 9.3 Hz, 2H), 1.55 (q, J = 12.9, 12.2 Hz, 2H), 0.91 (s, 9H), 0.05 (d, J = 4.5 Hz, 6H)。LCMS-ESI+
(m/z):C33
H44
ClNO4
Si [M+H]+
計算值:582.3;實驗值:582.5。
步驟3:將中間物 359-2-2
(13.2 g,22.7 mmol)與中間物 110-1-2
(7.72 g,1.05當量)組合,組合1-乙基-3-(3-二甲基胺基丙基)碳化二亞胺鹽酸鹽(3.87 g,1.10當量)、4-二甲基胺基吡啶(3.05 g,1.10當量)及DCM (160 mL)且在室溫下攪拌2 hr。將反應物用DCM (200 mL)稀釋,且用水(150 mL)、飽和NaHCO3
(150 mL)及飽和NH4
Cl (150 mL)洗滌。使有機相經硫酸鈉乾燥,且在減壓下移除溶劑。使殘餘物經受急驟管柱層析法(矽膠,0-100% EtOAc/己烷)。組合含有產物之溶離份,且在減壓下移除溶劑,得到中間物 359-2-3
。LCMS-ESI+
(m/z):C49
H66
ClN3
O6
SSi [M+H]+
計算值:888.4;實驗值:889.6。
步驟4:將中間物 359-2-3
(16.2 g,18.2 mmol)與DCM (300 mL)及三氟乙酸(100 mL)組合且在室溫下攪拌16 hr。組合以上試劑且在RT下攪拌16 h。在減壓下移除多數揮發物。用DCM (100 mL)稀釋殘餘物。用飽和NaHCO3
(2×300 mL)洗滌此溶液。用DCM (50 mL)洗滌水溶液。將合併有機相用鹽水洗滌且經硫酸鈉乾燥,且在減壓下移除溶劑。使殘餘物經受急驟層析法(0-100 % EtOAc/己烷)。組合含有產物之溶離份,且在減壓下移除溶劑,得到中間物 359-2-4
。1
H NMR (400 MHz,氘代氯仿) δ 7.83 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 8.2, 1.9 Hz, 1H), 7.19 (dd, J = 8.5, 2.2 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 5.85 (ddt, J = 16.2, 11.4, 5.7 Hz, 1H), 5.75 (dt, J = 10.4, 7.3 Hz, 1H), 5.33 - 5.23 (m, 1H), 5.15 - 5.06 (m, 3H), 4.21 - 4.03 (m, 1H), 3.94 (d, J = 14.8 Hz, 1H), 3.66 (d, J = 14.2 Hz, 1H), 3.60 - 3.48 (m, 1H), 3.26 (d, J = 14.2 Hz, 1H), 3.12 (dd, J = 14.8, 8.9 Hz, 1H), 2.81- 2.71 (m, 3H), 2.58 (dt, J = 18.8, 8.5 Hz, 2H), 2.18 (dd, J = 13.9, 6.6 Hz, 1H), 2.11 - 1.99 (m, 5H), 1.99 - 1.89 (m, 1H), 1.85 (q, J = 9.2, 8.6 Hz, 2H), 1.74 - 1.43 (m, 3H), 1.37 (d, J = 7.0 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H)。LCMS-ESI+
(m/z):C34
H44
ClN3
O4
S [M+H]+
計算值:626.3;實驗值:626.8。
步驟5:用氬氣使於DCE (20 mL)中之中間物 359-2-4
(300 mg,0.48 mmol)之溶液脫氣5 min。添加MgO (60 mg,3.0當量)及哈維達-格拉布II催化劑(60 mg,0.20當量)。攪拌混合物且脫氣10 min。將混合物在70℃下加熱2 hr。冷卻反應物且添加ACN。在減壓下移除溶劑。使殘餘物經受急驟管柱層析法(矽膠,20-100% (20% MeOH/EtOAc)/己烷)。組合含有產物之溶離份,且在減壓下移除溶劑,得到中間物 359-4
。1
H NMR (400 MHz,氘代氯仿) δ 7.77 (d, J = 8.5 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.20 (dd, J = 8.5, 2.3 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 6.42 (s, 2H), 5.81 (dd, J = 16.1, 4.2 Hz, 1H), 5.77 - 5.65 (m, 1H), 4.20 (s, 1H), 4.10 (d, J = 6.5 Hz, 2H), 3.83 (dd, J = 15.3, 5.8 Hz, 1H), 3.77 (d, J = 14.5 Hz, 1H), 3.57 (t, J = 7.2 Hz, 1H), 3.37 (d, 1H), 3.15 - 3.07 (m, 1H), 2.83 - 2.73 (m, 3H), 2.73 - 2.60 (m, 1H), 2.51 (dt, J = 17.1, 9.6 Hz, 2H), 2.16 (t, J = 14.5 Hz, 1H), 2.08 - 2.02 (m, 1H), 2.01 - 1.77 (m, 4H), 1.72 - 1.47 (dd, J = 18.1, 9.2 Hz, 4H), 1.41 (m, 4H), 1.11 (d, J = 6.9 Hz, 3H)。LCMS-ESI+
(m/z):C32
H40
ClN3
O4
S [M+H]+
計算值:598.3;實驗值:598.5。
步驟6:以與實例 18
類似之方式使用中間物 359-4
及1-甲基-1H-吡唑-4-甲酸來製備實例 359
。實例 360
步驟1:製備二甲基胺基甲酸反 -
3-((第三丁氧基
羰基)胺基)環丁酯:在60℃下在存在DMAP (1957.5 mg,16.02 mmol,3當量)及於DCE (20 mL)中之DIPEA (3451.4 mg,26.70 mmol,5當量)之情況下用二甲基胺基甲酸氯化物(1723.0 mg,16.02 mmol,3.0當量)處理反 -
(3-羥基環丁基)胺基甲酸第三丁酯(1000.0 mg,5.341 mmol)達15 h。用水(30 mL)淬滅反應混合物,且用EtOAc (30 mL×3)萃取整體。將所獲得之有機層用鹽水(30 mL)洗滌且經Na2
SO4
乾燥。在減壓下移除溶劑。藉由矽膠管柱層析法(13-50% EtOAc/己烷)純化所獲得之粗混合物,得到二甲基胺基甲酸反 -
3-((第三丁氧基羰基)胺基)環丁酯。
步驟2:製備二甲基胺基甲酸反 -
3-胺基環丁酯雙-鹽酸:在rt下用4 N-HCl (6 mL)處理二甲基胺基甲酸反 -
3-((第三丁氧基羰基)胺基)環丁酯(114.2 mg,0.442 mmol)。在2 h之後,在減壓下移除溶劑,得到二甲基胺基甲酸反 -
3-胺基環丁酯雙-鹽酸。
步驟3:以與實例 75
相同之方式使用二甲基胺基甲酸反 -
3-胺基環丁酯雙-鹽酸及實例 109
來合成實例 360
。1
H NMR (400 MHz,丙酮-d6
) δ 7.70 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.28 (s, 1H), 7.12 (dd, J = 8.5, 2.3 Hz, 1H), 7.04 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 8.2 Hz, 1H), 6.10 (br s, 1H), 5.48 (br s, 1H), 4.96 (brs, 1H), 4.30 (br s, 1H), 4.00 (s, 2H), 3.94 - 3.55 (m, 3H), 3.51 - 3.16 (m, 7H), 2.89 (d, J = 13.0 Hz, 6H), 2.75 (d, J = 16.5 Hz, 2H), 2.64 - 1.55 (m, 16H), 1.38 (t, J = 12.6 Hz, 1H), 1.02 (d, J = 6.7 Hz, 3H)。LCMS-ESI+ (m/z):C40
H53
ClN5
O7
S [M+H]+計算值:782.33;實驗值:781.74。實例 361
以與實例 75
相同之方式使用3-甲氧基雙環[1.1.1]戊-1-胺鹽酸及實例 109
來合成實例 361
。1
H NMR (400 MHz,甲醇-d4
) 7.69 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.25 (br s, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.07 - 6.96 (m, 2H), 6.80 (d, J = 8.2 Hz, 1H), 6.08 (m, 1H), 5.50 (m, 1H), 4.05 - 3.92 (m, 3H), 3.89 -3.62 (m, 3H), 3.42 (d, J = 10.2 Hz, 1H), 3.29 (s, 3H), 3.25 (s, 3H), 3.13 (dd, J = 15.2, 10.2 Hz, 1H), 2.79 - 2.06 (m, 11H), 1.99 (s, 6H), 1.97 - 1.67 (m, 3H), 1.48 - 1.33 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C39
H50
ClN4
O6
S [M+H]+計算值:737.31;實驗值:736.72。實例 362
使4打蘭小瓶裝填有實例 109
(1當量,0.025 mmol,15 mg)、碳酸二苯酯(8當量,0.201 mmol,43.0 mg)、N,N-二甲基胺基吡啶(5當量,0.125 mmol,15.3 mg)及MeCN (0.75 mL)。將反應小瓶密封且在室溫下攪拌過夜。在單獨小瓶中,用MeCN (0.5 mL)及三乙胺(40當量,1.0 mmol,0.14 mL)處理3-甲氧基氮雜環丁烷鹽酸鹽(10當量,0.251 mmol,31.0 mg),隨後與反應混合物組合,密封且加熱至50℃達3小時。將反應混合物濃縮且藉由製備型HPLC (60-100%於水中之MeCN,0.1% TFA)純化且凍乾,獲得所需產物實例 362
。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S [M+H]+
計算值:711.2978;實驗值:710.79。1
H NMR (400 MHz,甲醇-d 4
) δ 7.73 (d,J
= 8.5 Hz, 1H), 7.17 (dd,J
= 8.5, 2.4 Hz, 1H), 7.14 - 7.02 (m, 2H), 6.96 - 6.85 (m, 2H), 5.96 (dt,J
= 14.2, 6.7 Hz, 1H), 5.56 (dd,J
= 15.2, 9.1 Hz, 1H), 4.29 (dd,J
= 14.9, 6.3 Hz, 1H), 4.20 (s, 3H), 4.06 (d,J
= 2.2 Hz, 2H), 3.83 (d,J
= 15.2 Hz, 3H), 3.74 (dd,J
= 9.2, 3.7 Hz, 1H), 3.63 (t,J
= 17.6 Hz, 2H), 3.30 (s, 3H), 3.30 - 3.25 (m, 1H), 3.24 (s, 3H), 3.06 (dd,J
= 15.2, 10.3 Hz, 1H), 2.87 - 2.66 (m, 2H), 2.45 (dd,J
= 12.6, 7.9 Hz, 2H), 2.32 (p,J
= 9.1 Hz, 1H), 2.14 (ddd,J
= 27.8, 14.4, 8.6 Hz, 3H), 2.01 - 1.63 (m, 6H), 1.42 (dd,J
= 14.2, 10.8 Hz, 1H), 1.13 (d,J
= 6.6 Hz, 3H)。實例 363
以與實例 362
相同之方式使用實例 109
及3-甲氧基-3-甲基-氮雜環丁烷鹽酸鹽來合成實例 363
。LCMS-ESI+ (m/z):C38
H49
ClN4
O6
S [M+H]+
計算值:725.3134;實驗值:724.90。1
H NMR (400 MHz,甲醇-d 4
) δ 7.73 (d,J
= 8.5 Hz, 1H), 7.17 (dd,J
= 8.5, 2.3 Hz, 1H), 7.13 - 7.05 (m, 2H), 6.95 - 6.86 (m, 2H), 5.96 (dt,J
= 14.2, 6.7 Hz, 1H), 5.56 (dd,J
= 15.2, 9.1 Hz, 1H), 4.29 (dd,J
= 14.9, 6.3 Hz, 1H), 4.11 - 4.02 (m, 2H), 3.97 (s, 2H), 3.88 - 3.54 (m, 6H), 3.31 - 3.29 (m, 1H), 3.26 (s, 3H), 3.24 (s, 3H), 3.06 (dd,J
= 15.3, 10.3 Hz, 1H), 2.87 - 2.69 (m, 2H), 2.52 - 2.40 (m, 2H), 2.33 (q,J
= 9.0 Hz, 1H), 2.23 - 2.03 (m, 3H), 1.98 - 1.66 (m, 6H), 1.48 (s, 3H), 1.45 - 1.36 (m, 1H), 1.13 (d,J
= 6.6 Hz, 3H)。實例 364
使經烘箱乾燥之4打蘭小瓶裝填有(1S,2R)-2-氟環丙烷甲酸(15當量,0.376 mmol,39.2 mg)、甲苯(0.75 mL)、三乙胺(16.5當量,0.414 mmol,0.058 mL)及二苯基磷醯基疊氮化物(15當量,0.376 mmol,0.081 mL)。將小瓶密封且在預加熱砂浴中加熱至85℃達2小時。隨後,將反應混合物冷卻至室溫,用實例 109
(1當量,0.025 mmol,15 mg)處理,密封且加熱至45℃達3小時。將反應混合物冷卻至室溫,用EtOAc稀釋,用半飽和NaHCO3
水溶液洗滌,用1 N HCl中和,且用鹽水洗滌。將有機層經硫酸鈉乾燥,過濾且濃縮。藉由製備型HPLC (60-100%於水中之MeCN,0.1% TFA)純化粗反應混合物且凍乾,獲得所需產物實例 364
。LCMS-ESI+ (m/z):C36
H44
ClFN4
O5
S [M+H]+
計算值:699.2778;實驗值:698.72。1
H NMR (400 MHz,甲醇-d
4) δ 7.71 (d,J
= 8.5 Hz, 1H), 7.19 - 7.05 (m, 3H), 6.98 - 6.84 (m, 2H), 5.99 (dd,J
= 14.6, 7.5 Hz, 1H), 5.58 (dd,J
= 15.2, 9.0 Hz, 1H), 4.69 - 4.46 (m, 1H), 4.26 (dd,J
= 14.9, 6.4 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.86 - 3.61 (m, 4H), 3.30 - 3.26 (m, 1H), 3.25 (s, 3H), 3.05 (dd,J
= 15.2, 10.3 Hz, 1H), 2.95 (ddd,J
= 20.9, 10.0, 5.1 Hz, 1H), 2.87 - 2.68 (m, 2H), 2.55 - 2.41 (m, 2H), 2.41 - 2.29 (m, 1H), 2.25 - 2.04 (m, 3H), 2.01 - 1.67 (m, 6H), 1.41 (t,J
= 12.2 Hz, 1H), 1.37 - 1.22 (m, 1H), 1.12 (d,J
= 6.4 Hz, 3H), 0.96 (dddd,J
= 11.9, 7.8, 6.7, 5.3 Hz, 1H)。實例 365
以與實例 316
相同之方式使用中間物316-3
(直接在步驟3中)及實例 109
來合成實例 365
。順式環丙烷立體異構中心之絕對組態尚未確定,且任意指示。LCMS-ESI+ (m/z):C37
H47
ClN4
O6
S [M+H]+
計算值:711.2978;實驗值:710.84。1
H NMR (400 MHz,甲醇-d 4
) δ 7.73 (d,J
= 8.5 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.10 (d,J
= 2.2 Hz, 1H), 6.95 (s, 1H), 6.90 (d,J
= 8.1 Hz, 1H), 6.01 (dt,J
= 14.3, 6.8 Hz, 1H), 5.57 (dd,J
= 15.3, 8.9 Hz, 1H), 4.26 (td,J
= 15.5, 6.5 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.89 - 3.60 (m, 5H), 3.44 - 3.36 (m, 1H), 3.31 - 3.26 (m, 1H), 3.25 (s, 3H), 3.05 (dd,J
= 15.2, 10.4 Hz, 1H), 2.87 - 2.63 (m, 3H), 2.54 - 2.41 (m, 2H), 2.35 (dt,J
= 17.7, 9.6 Hz, 1H), 2.25 - 2.03 (m, 3H), 2.01 - 1.66 (m, 6H), 1.42 (t,J
= 13.8 Hz, 1H), 1.35 - 1.21 (m, 1H), 1.12 (d,J
= 6.3 Hz, 3H), 0.99 (q,J
= 7.4 Hz, 1H), 0.44 (q,J
= 5.6 Hz, 1H)。實例 366
以與實例 367
相同之方式使用實例 223
及4-(2-碘基乙基)嗎啉而不使用碘乙烷來合成實例 366
。LCMS-ESI+ (m/z):C43
H55
ClN6
O7
S [M+H]+計算值:835.4;實驗值:835.0。實例 367
將實例 223
(10 mg,0.014 mmol)溶解於DMF (0.1 mL)中。在室溫下添加NaH,繼而添加碘乙烷(10當量)。經由金屬加熱塊將反應混合物加熱至80℃。藉由LCMS監視反應進程。在觀測到起始材料之完全消耗之後,使殘餘物直接進行Gilson逆相HPLC (60:40 à 100 MeCN/H2
O,0.1% TFA)純化,獲得實例 367
。LCMS-ESI+ (m/z):C39
H48
ClN5
O6
S [M+H]+計算值:750.3;實驗值:750.0。實例 368
步驟1:在室溫下向於乙腈(12 mL)中之(S)-6'-氯-5-(((1R,2R)-2-((S)-1-甲氧基烯丙基)環丁基)甲基)-3',4,4',5-四氫-2H,2'H-螺[苯并[b][1,4]噁氮呯-3,1'-萘]-7-碳醯氯(600 mg,1.19 mmol)之經攪拌溶液中添加噠嗪(105 mg,1.31 mmol),且攪拌10 min。添加於乙腈中之非對映異構體混合物(3R)-N'-(第三丁基二甲基矽烷基)庚-6-烯-3-磺醯咪醯胺(383 mg,1.31 mmol)之溶液,且在室溫下攪拌過夜。隨後,將反應混合物用DCM稀釋,用水及鹽水洗滌。將有機相經MgSO4
乾燥,過濾,且濃縮,得到368-1
。
步驟2:向於DCM (14 mL)中之368-1
(700 g,1.09 mmol)之經攪拌溶液中添加二碳酸二第三丁酯(334 mg,1.53 mmol)、三甲胺(132 mg,1.3 mmol)及4-(二甲基胺基)吡啶(13 mg,0.10 mmol)。將反應混合物在室溫下攪拌1 hr。隨後,將反應混合物用DCM稀釋,用1N HCl、鹽水洗滌,且隨後用飽和NaHCO3
水溶液洗滌。將有機相經MgSO4
乾燥,過濾,且濃縮,得到368-2
。
步驟3:用氬氣使於1,2-二氯乙烷(270 mL)中之368-2
(600 mg,0.81 mmol)及哈維達-格拉布II (50.6 mg,0.08 mmol)之經攪拌溶液脫氣。將反應混合物在60℃下攪拌過夜。使反應混合物濃縮且進行逆相層析法0.1% TFA 65-95%乙腈純化,得到368-3
。
步驟4:向於DCM (5 mL)中之368-3
(80 mg,0.13 mmol)之經攪拌溶液中添加2-((四氫-2H-哌喃-4-基)氧基)乙酸(31 mg,0.196 mmol)、1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl (40 mg,0.26 mmol)及4-(二甲基胺基)吡啶(31.9 mg,0.26 mmol)。將反應混合物在室溫下攪拌24 hr。隨後,將反應混合物用DCM稀釋,且用1N HCl及鹽水洗滌。將有機相經MgSO4
乾燥,過濾,濃縮,且進行逆相層析法0.1% TFA 70-95%乙腈純化,得到實例 368
。1H NMR (400 MHz,氘代氯仿) δ 7.71 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 8.3, 1.9 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.75 (td, J = 11.0, 5.2 Hz, 1H), 5.38 (t, J = 10.3 Hz, 1H), 4.16 (s, 3H), 4.11 - 3.92 (m, 5H), 3.84 (d, J = 15.3 Hz, 1H), 3.78 - 3.67 (m, 2H), 3.55 (ddd, J = 11.8, 8.7, 4.1 Hz, 3H), 3.41 (d, J = 14.7 Hz, 2H), 3.31 (s, 5H), 2.96 - 2.64 (m, 3H), 2.39 (q, J = 8.8 Hz, 1H), 2.28 (t, J = 13.7 Hz, 2H), 2.19 - 1.58 (m, 15H), 1.42 (t, J = 12.8 Hz, 1H), 1.25 (s, 2H), 1.02 (t, J = 7.4 Hz, 3H)。LCMS-ESI+ (m/z):C40
H52
ClN3
O7
S [M+H]+計算值:754.32;實驗值:754.15。實例 369
步驟1:在-78℃下用於THF (15 mL)中之KHMDS (於THF中1.0 M,4.16 mL,4.16 mmol)處理(3R,4S)-3-氟四氫-2H-哌喃-4-醇(500 mg,4.162 mmol)及2-溴乙酸苄酯(1.049 g,4.579 mmol,1.1當量)達2 h。藉由移除THF來濃縮所得混合物,且使殘餘物懸浮於CH2
Cl2
中。過濾懸浮液,且濃縮濾液,得到粗產物。藉由矽膠管柱層析法(0-40% EtOAc/己烷)純化粗產物,得到2-(((3R,4S)-3-氟四氫-2H-哌喃-4-基)氧基)乙酸苄酯。1H NMR (400 MHz,甲醇-d4) δ 7.41 - 7.29 (m, 5H), 5.21 (s, 2H), 4.30 (s, 2H), 4.03 - 3.96 (m, 1H), 3.92 - 3.87 (m, 1H), 3.81 - 3.70 (m, 1H), 3.61 - 3.41 (m, 3H), 2.02 - 1.92 (m, 1H), 1.86 - 1.80 (m, 1H)。
步驟2:在氫氣氛圍之大氣壓下用於EtOAc (5 mL)中之10% Pd/C (1.9 mg)處理2-(((3R,4S)-3-氟四氫-2H-哌喃-4-基)氧基)乙酸苄酯(50.0 mg,1.983 mg)達2 h。經由矽藻土過濾掉催化劑,且濃縮所獲得之濾液。粗製物2-(((3R,4S)-3-氟四氫-2H-哌喃-4-基)氧基)乙酸不經進一步純化及表徵即緊接著用於後續步驟。
步驟3:以與實例 21
相同之方式使用2-(((3R,4S)-3-氟四氫-2H-哌喃-4-基)氧基)乙酸來合成實例 369
。1H NMR (400 MHz,氘代氯仿) δ 7.74 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 8.2, 1.8 Hz, 1H), 7.30 (s, 1H), 7.18 (dd, J = 8.5, 2.3 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 5.93 - 5.64 (m, 2H), 4.98 - 4.77 (m, 1H), 4.35 - 4.20 (m, 2H), 4.15 - 3.97 (m, 4H), 3.88 (p, J = 9.4 Hz, 3H), 3.81 - 3.51 (m, 5H), 3.29 (s, 3H), 3.06 - 2.96 (m, 1H), 2.81 - 2.69 (m, 3H), 2.47 - 2.21 (m, 4H), 2.14 - 2.02 (m, 4H), 1.92 (p, J = 8.6 Hz, 3H), 1.77 - 1.69 (m,3H), 1.38 (t, J = 12.9 Hz, 2H)。LCMS-ESI+ (m/z):C38
H47
ClFN3
O7
S [M+H]+計算值:744.28;實驗值:744.28。實例 370
1
H NMR (400 MHz,甲醇-d4
) δ 7.75 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 8.4, 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.09 (dd, J = 8.2, 1.8 Hz, 1H), 6.95 - 6.93 (m, 2H), 5.99 - 5.92 (m, 1H), 5.59 (dd, J = 15.2, 9.2 Hz, 1H), 4.54 - 4.49 (m, 1H), 4.13 - 4.07 (m, 2H), 3.84 (d, J = 15.2 Hz, 1H), 3.73 (dd, J = 9.4, 3.4 Hz, 1H), 3.65 (d, J = 14.0 Hz, 1H), 3.37 - 3.29 (m, 2H), 3.24 (s, 3H), 3.16 - 3.06 (m, 1H), 2.88 - 2.73 (m, 3H), 2.50 - 1.72 (m, 10H), 1.57 (d, J = 7.2 Hz, 3H), 1.45 (t, J = 13.0 Hz, 1H), 1.16 (d, J = 6.8 Hz, 3H)。LCMS-ESI+
(m/z):C35
H41
ClF3
N3
O5
S [M+H]+
計算值:708.25;實驗值:708.2。實例 371
將於DCM (1.0 mL)中之3-羥基-3-甲基-環丁烷甲酸(2.6 mg,0.0196 mmol)及實例 110
(8.0 mg,0.0131 mmol)之混合物冷卻至0℃。添加1-(3-二甲基胺基丙基)-3-乙基碳化二亞胺HCl鹽(5.0 mg,0.0261 mmol),繼而添加DMAP (3.2 mg,0.0261 mmol)。將反應物自冷卻浴中移除且在室溫下攪拌過夜。濃縮反應物以移除DCM,用DMF (1 mL)稀釋,過濾且藉由Gilson逆相製備型HPLC (60-100% ACN/H2
O及0.1% TFA)純化。彙集所需溶離份且進行冷凍乾燥,得到實例 371
。LCMS-ESI+ (m/z):C39
H50
ClN3
O6
S計算值H+:724.31;實驗值:723.99。 實例 372
以與實例 18
相同之方式使用7-羥基-5,6,7,8-四氫吲哚嗪-2-甲酸及實例 109
來合成實例 306
。LCMS-ESI+ (m/z):C41
H49
ClN4
O6
S [M+H]+計算值:761.3;實驗值:761.0。實例 373
步驟 1
:合成373-1
:將3-(羥基甲基)氮雜環丁烷-1-甲酸第三丁酯(139 mg,0.742 mmol)溶解於DCM (5.0 mL)中且冷卻至0℃,添加戴斯-馬丁高碘烷(409 mg,0.965 mmol)。將反應物自冷卻浴中移除且在室溫下攪拌1 hr。隨後,用1N硫代硫酸鈉(10.0 mL)及飽和NaHCO3
(10.0 mL)處理反應物,劇烈攪拌15 min。隨後,用DCM (20.0 mL)稀釋混合物,分離各層,且將有機層用鹽水洗滌,經硫酸鈉乾燥,過濾,且濃縮,得到373-1
。
步驟 2
:合成373-2
:在室溫下使(9aS)-1,3,4,6,7,8,9,9a-八氫吡嗪并[2,1-c][1,4]噁嗪;二鹽酸鹽(713 mg,3.31 mmol)懸浮於DCM (10.0 mL)中,逐滴添加於MeOH (1.55 mL)中之25 wt% NaOMe。將所得乳白懸浮液在rt下攪拌2 hr。將反應物濃縮,在rt下用EtOAc處理1 hr,隨後過濾。將濾液濃縮,且經真空管線乾燥過夜。在室溫下將游離鹼材料(57.6 mg,0.405 mmol)溶解於DCM (4.0 mL)中。添加373-1
(50.0 mg,0.27 mmol)。在添加STAB (85.8 mg,0.405 mmol)之前,將混合物攪拌2 hr。將新形成之混合物攪拌1 h。將反應物藉由移除DCM來濃縮,再溶解於EtOAc中,且用1N NaOH處理,分離各層。用EtOAc萃取水層兩次。將合併有機層經硫酸鈉乾燥,過濾,且濃縮,得到373-2
。LCMS-ESI+ (m/z):C16
H29
N3
O3
計算值H+:312.22;實驗值:312.23。
步驟 3
:合成373-3
:在室溫下將373-2
(84.0 mg,0.27 mmol)溶解於DCM (1.0 mL)中,添加於1,4-二噁烷(0.27 mL,1.08 mmol)中之4 N HCl。將反應物在室溫下攪拌1 hr。將反應物濃縮,與EtOAc一起共蒸發三次,進一步經真空管線乾燥,得到373-3
。
步驟 4
:以與實例 75
相同之方式使用實例 109
及373-3
以及DIEA來合成實例 373
。LCMS-ESI+ (m/z):C44
H59
ClN6
O6
S計算值H+:835.39;實驗值:835.26。實例 374
以與實例 279
相同之方式使用實例 188
及二氧化硒(40 eq)來合成實例 374
。1H NMR (400 MHz,甲醇-d4) δ 7.97 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.25 - 7.16 (m, 2H), 7.12 (d, J = 2.3 Hz, 2H), 6.92 (dd, J = 8.2, 2.1 Hz, 1H), 6.18 - 6.06 (m, 1H), 5.82 - 5.74 (m, 1H), 4.43 - 4.26 (m, 2H), 4.10 (s, 2H), 3.99 (s, 3H), 3.86 - 3.76 (m, 6H), 3.70 - 3.61 (m, 1H), 3.27 (s, 3H), 3.18 - 3.08 (m, 1H), 2.91 - 2.72 (m, 2H), 2.57 - 2.27 (m, 3H), 2.14 - 2.05 (m, 1H), 1.99 - 1.79 (m, 6H), 1.71 (d, J = 7.0 Hz, 3H), 1.53 - 1.41 (m, 1H), 1.27 (d, J = 8.8, 7.0 Hz, 3H)。LCMS-ESI+ (m/z):C39
H48
ClN5
O7
S計算值H+:766.30;實驗值:765.05。 實例 375
步驟1:將實例 109
(445 mg,0.744 mmol)溶解於二噁烷(7 mL)中。一次性添加二氧化硒(330 mg,4當量)。將混合物加熱至回流直至LCMS指示向對應烯丙醇之約50%轉化為止。隨後,使反應混合物冷卻至室溫,且藉由Gilson逆相製備型HPLC (40-90% ACN/H2
O及0.1% TFA)純化殘餘物,得到中間物 375-1
。1
H NMR (400 MHz,甲醇-d 4
) δ 7.76 (d,J
= 8.6 Hz, 1H), 7.29 (dd,J
= 8.2, 1.9 Hz, 1H), 7.18 (dd,J
= 8.6, 2.3 Hz, 1H), 7.11 (d,J
= 2.4 Hz, 1H), 7.07 (d,J
= 1.9 Hz, 1H), 6.84 (d,J
= 8.2 Hz, 1H), 6.25 (dd,J
= 15.3, 6.1 Hz, 1H), 5.76 (dd,J
= 15.5, 9.0 Hz, 1H), 4.38 (d,J
= 6.0 Hz, 1H), 4.26 (dd,J
= 15.0, 6.1 Hz, 1H), 4.09 - 4.00 (m, 2H), 3.93 - 3.81 (m, 2H), 3.65 (d,J
= 14.1 Hz, 1H), 3.30 (m, 6H), 3.10 - 3.03 (m, 1H), 2.87 - 2.70 (m, 3H), 2.57 - 2.30 (m, 2H), 2.25 - 2.09 (m, 2H), 2.01 - 1.66 (m, 7H), 1.43 (t,J
= 12.7 Hz, 1H), 1.21 (d,J
= 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C32
H40
ClN3
O5
S [M+H]+計算值:614.3;實驗值:614.1。
步驟2:在0℃下將二碳酸二第三丁酯(16.9 mg,77.4 µmol)添加至於四氫呋喃(3.0 mL)中之中間物 375-1
(31.7 mg,51.6 µmol)、三乙胺(21.6 µL,155 µmol)、4-(二甲基胺基)吡啶(18.9 mg,155 µmol)及水(4.6 µL,260 µmol)之經攪拌混合物中,且使所得混合物升溫至室溫。在40 min之後,添加於水(5 mL)中之檸檬酸(200 mg)之溶液。添加乙酸乙酯(60 mL)。將有機層依序用水(30 mL)及水及鹽水之混合物(1:1 v:v,30 mL)洗滌,隨後經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於四氫呋喃(1.0 mL)中,攪拌,且冷卻至−40℃。經由注射器添加碘甲烷(32.2 µL,516 µmol)。在1 min之後,在1 min內經由注射器添加鉀雙(三甲基矽烷基)醯胺溶液(於四氫呋喃中1.0 M)。在1 min之後,使所得混合物升溫至室溫。在30 min之後,添加於水(10 mL)中之磷酸(260 mg)及磷酸二氫鈉脫水物(90 mg)之溶液。添加乙酸乙酯(60 mL)。將有機層依序用水及鹽水之混合物(1:1 v:v,30 mL)及鹽水(2×30 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於二氯甲烷(10 mL)中,且在室溫下攪拌所得混合物。添加三氟乙酸(1.0 mL)。在20 min之後,添加三氟乙酸(0.55 mL)。在30 min之後,添加於水(15 mL)中之磷酸二氫鈉脫水物(6.3 g)之溶液。添加鹽水(10 mL),且用二氯甲烷(2×30 mL)萃取水層。將合併有機層經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。藉由矽膠急驟管柱層析法(0至70%於二氯甲烷中之乙酸乙酯)純化殘餘物,得到375-2
。
步驟2:以與實例 244
類似之方式使用375-2
而不使用240-1
來合成實例 375
。1H NMR (400 MHz,丙酮-d6) δ 7.77 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.18 - 7.03 (m, 3H), 6.96 (d, J = 8.1 Hz, 1H), 5.94 (dd, J = 15.3, 8.1 Hz, 1H), 5.80 (dd, J = 15.3, 9.0 Hz, 1H), 4.35 - 4.16 (m, 4H), 4.13 (d, J = 12.2 Hz, 1H), 4.08 (d, J = 12.1 Hz, 1H), 3.97 - 3.44 (m, 6H), 3.39 (d, J = 14.2 Hz, 1H), 3.30 (s, 3H), 3.28 (s, 3H), 3.25 (s, 3H), 3.18 (dd, J = 15.3, 10.4 Hz, 1H), 3.05 - 1.38 (m, 14H), 1.23 (d, J = 6.8 Hz, 3H)。LCMS:741.2。實例 376
以與實例 283
相同之方式使用1-碘基-2-(2-甲氧基乙氧基)乙烷及實例 279
來合成實例 376
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.09 (s, 1H), 7.75 (d,J
= 8.6 Hz, 1H), 7.41 - 7.31 (m, 1H), 7.23 - 7.14 (m, 2H), 7.12 (m, 1H), 6.92 (d,J
= 8.2 Hz, 1H), 6.05 (dd,J
= 15.4, 7.3 Hz, 1H), 5.85 (dd,J
= 15.4, 8.5 Hz, 1H), 4.15 - 4.01 (m, 9H), 3.82 (m, 5H), 3.76 - 3.58 (m, 6H), 3.54 - 3.44 (m, 4H), 3.41 (d,J
= 14.4 Hz, 1H), 3.35 (s, 3H), 3.30 (s, 3H), 3.19 - 3.06 (m, 1H), 2.89 - 2.73 (m, 2H), 2.51 (br, 2H), 2.27 (m, 1H), 2.11 (m, 1H), 2.0 - 1.89 (m, 2H), 1.82 (m, 3H), 1.46 (t,J
= 11.7 Hz, 1H), 1.20 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C43
H56
ClN5
O9
S [M+H]+計算值:854.3;實驗值:854.1。實例 377 及實例 378
在0℃下將2-(2-甲苯磺醯基亞肼基)乙醯氯(34.4 mg,132 µmol)及N
,N
-二甲苯胺(33.5 µL,264 µmol)依序添加至於二氯甲烷(0.9 mL)中之實例 279
(33.1 mg,44.0 µmol)之經攪拌溶液中。在7 min之後,使所得混合物升溫至室溫。在55 min之後,依序添加2-(2-甲苯磺醯基亞肼基)乙醯氯(80.0 mg,307 µmol)及N
,N
-二甲苯胺(80.0 µL,630 µmol)。在13 min之後,使所得混合物冷卻至0℃,且經由注射器添加三乙胺(163 µL,1.17 mmol)。在20 min之後,依序添加甲苯(60 mL)及於水(100 mL)中之單水合磷酸二氫鈉(160 mg)及磷酸氫鈉七水合物(1.04 g)之混合物。攪動雙相混合物,且分離各層。將有機層依序用於水(50 mL)中之單水合磷酸二氫鈉(80 mg)及磷酸氫鈉七水合物(502 mg)之混合物、於水(50 mL)中之檸檬酸(100 mg)之溶液及水(50 mL)洗滌;經無水硫酸鈉乾燥;過濾;且在減壓下濃縮至8.5 mL之體積。在90 min內在100℃下經由注射泵將含有粗製物377-1
之所得混合物添加至三氟甲磺酸銅(I)甲苯複合物(6.7 mg,22 µmol)及甲苯(5.0 mL)之經劇烈攪拌混合物中。在15 min之後,將所得混合物冷卻至室溫,經由矽藻土過濾,且在減壓下濃縮。藉由逆相製備型hplc (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到呈1:1非對映異構體混合物形式之實例 377
。1H NMR (400 MHz,丙酮-d6) δ 8.21 - 6.64 (m, 11H), 6.20 - 5.79 (m, 1H), 5.74 - 5.14 (m, 2H), 4.25 - 2.99 (m, 17H), 2.99 - 1.17 (m, 17H), 1.13 (d, J = 6.9 Hz, 1.5H), 1.06 (d, J = 6.9 Hz, 1.5H)。LCMS:890.1。進一步溶析,得到實例 378
。1H NMR (400 MHz,丙酮-d6) δ 8.10 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.53 - 6.32 (m, 10H), 6.32 - 5.21 (m, 3H), 4.29 - 2.84 (m, 8H), 4.08 (s, 3H), 3.85 (s, 3H), 3.23 (s, 3H), 2.83 - 1.21 (m, 18H), 1.15 (d, J = 6.8 Hz, 3H)。LCMS:884.2。實例 379
步驟1:製備3-(3-甲氧基氮雜環丁烷-1-基)-1-甲基-1H-吡唑-4-甲酸乙酯:將於N-甲基-2-吡咯啶酮(3 mL)中之3-溴-1-甲基-吡唑-4-甲酸乙酯(150 mg,0.64 mmol)、3-甲氧基氮雜環丁烷鹽酸鹽(119.3 mg,0.97 mmol)、Cs2
CO3
(629.09 mg,1.93 mmol)及XtanTphos Pd G3 (122.07 mg,0.13 mmol)之反應混合物在120℃下加熱過夜。將反應混合物冷卻,用水洗滌,用EtOAc萃取,經MgSO4
乾燥,過濾,濃縮,且藉由矽膠管柱(用0-100% EtOAc/己烷溶析)純化,得到產物。
步驟2:製備3-(3-甲氧基氮雜環丁烷-1-基)-1-甲基-1H-吡唑-4-甲酸:將於EtOH (1.0 mL)及水(0.5 mL)中之3-(3-甲氧基氮雜環丁烷-1-基)-1-甲基-吡唑-4-甲酸乙酯(14 mg,0.06 mmol)、2M NaOH (0.06 mL)之反應混合物在45℃下攪拌過夜。將反應混合物冷卻,濃縮,與甲苯一起共蒸發以移除水分,且不經純化即進行下一步驟。
步驟3:以與實例 18
相同之方式使用實例 109
而不使用實例 5
且使用3-(3-甲氧基氮雜環丁烷-1-基)-1-甲基-1H-吡唑-4-甲酸而不使用3-甲氧基丙酸來合成實例 379
。1H NMR (400 MHz,甲醇-d4) δ 7.82 - 7.70 (m, 2H), 7.29 (d, J = 8.3 Hz, 1H), 7.19 (dd, J = 8.6, 2.3 Hz, 1H), 7.14 - 7.04 (m, 2H), 6.91 (d, J = 8.2 Hz, 1H), 6.10 (dt, J = 14.2, 6.7 Hz, 1H), 5.61 (dd, J = 15.4, 8.6 Hz, 1H), 4.56 (dd, J = 8.8, 6.3 Hz, 1H), 4.51 - 4.45 (m, 1H), 4.33 - 4.23 (m, 2H), 4.19 (dd, J = 8.7, 4.4 Hz, 1H), 4.13 - 4.02 (m, 3H), 4.02 - 3.91 (m, 2H), 3.86 (d, J = 15.1 Hz, 1H), 3.78 (dd, J = 8.5, 2.8 Hz, 1H), 3.74 (s, 2H), 3.69 (d, J = 14.3 Hz, 1H), 3.29 (s, 3H), 3.08 (dd, J = 14.9, 9.3 Hz, 2H), 2.92 - 2.70 (m, 3H), 2.49 (d, J = 26.9 Hz, 4H), 2.33 - 2.19 (m, 2H), 2.19 - 2.05 (m, 2H), 2.02 - 1.73 (m, 6H), 1.46 (d, J = 11.8 Hz, 1H), 1.16 (d, J = 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C41
H51
ClN6
O6
S [M+H]+計算值:791.33;實驗值:791.13。實例 380
步驟1:製備3-(4-甲氧基-1-哌啶基)-1-甲基-吡唑-4-甲酸乙酯:將於二甲基乙醯胺(5 mL)中之3-溴-1-甲基-吡唑-4-甲酸乙酯(200 mg,0.86 mmol)、4-甲氧基哌啶(197.67 mg,1.72 mmol)、Cs2
CO3
(838.79 mg,2.57 mmol)及XtanTphos Pd G3 (162.76 mg,0.17 mmol)之反應混合物在120℃下加熱過夜。將反應混合物冷卻,用水洗滌,用EtOAc萃取,經MgSO4
乾燥,過濾,濃縮,且藉由矽膠層析法(0-100% EtOAc/己烷)純化,得到產物(14 mg)。
步驟2:製備3-(4-甲氧基-1-哌啶基)-1-甲基-吡唑-4-甲酸:將於EtOH (1 mL)及水(0.5 mL)中之3-(4-甲氧基-1-哌啶基)-1-甲基-吡唑-4-甲酸乙酯(14 mg,0.05 mmol)、2M NaOH (0.05 ml)之反應混合物在45℃下加熱過夜。隨後,將反應混合物冷卻,濃縮,與甲苯一起共蒸發以移除水分,且不經純化即進行下一步驟。
步驟3:以與實例 18
相同之方式使用實例 109
而不使用實例 5
且使用3-(4-甲氧基-1-哌啶基)-1-甲基-吡唑-4-甲酸而不使用3-甲氧基丙酸來合成實例380
。1H NMR (400 MHz,甲醇-d4) δ 7.92 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.27 (dd, J = 8.2, 1.9 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.07 (s, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.11 (dt, J = 14.5, 6.9 Hz, 1H), 5.62 (dd, J = 15.3, 8.7 Hz, 1H), 4.32 (dd, J = 14.8, 6.4 Hz, 1H), 4.14 - 3.97 (m, 3H), 3.91 - 3.74 (m, 5H), 3.70 (d, J = 14.3 Hz, 1H), 3.52 - 3.45 (m, 1H), 3.42 (s, 2H), 3.29 (s, 3H), 3.27 - 3.22 (m, 3H), 3.13 - 3.00 (m, 2H), 2.90 - 2.69 (m, 3H), 2.46 (s, 3H), 2.36 - 2.20 (m, 2H), 2.10 (t, J = 17.1 Hz, 4H), 1.94 (d, J = 5.1 Hz, 2H), 1.91 - 1.65 (m, 6H), 1.45 (t, J = 11.8 Hz, 1H), 1.15 (d, J = 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C43
H55
ClN6
O6
S [M+H]+計算值:819.36;實驗值:819.20。實例 381
以與實例 223
相同之方式使用3-甲基丁酸及中間物 266-2
來合成實例 381
。1H NMR (400 MHz,氘代氯仿) δ 7.84 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.3, 1.9 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 8.5, 2.3 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 5.93 (dt, J = 13.6, 6.6 Hz, 1H), 5.73 (dd, J = 15.7, 6.1 Hz, 1H), 5.33 (t, J = 5.7 Hz, 1H), 4.21 - 3.97 (m, 6H), 3.96 - 3.62 (m, 6H), 3.32 (d, J = 14.4 Hz, 1H), 3.04 (dd, J = 15.2, 9.6 Hz, 1H), 2.88 - 2.70 (m, 2H), 2.61 (d, J = 18.4 Hz, 1H), 2.55 - 2.23 (m, 3H), 2.20 - 1.99 (m, 4H), 1.97 - 1.60 (m, 5H), 1.34 (d, J = 52.1 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 0.94 (dd, J = 6.4, 5.2 Hz, 6H)。LCMS-ESI+ (m/z):C42
H52
ClN5
O7
S [M+H]+計算值:807.42;實驗值:807.17。實例 382
以與實例 75
相同之方式使用實例 109
及(2R)-2-甲基哌嗪-1-甲酸第三丁酯來合成實例 382
。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.6 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 - 7.07 (m, 2H), 6.95 (dd, J = 8.1, 1.7 Hz, 1H), 6.88 (d, J = 2.0 Hz, 1H), 6.01 - 5.90 (m, 1H), 5.58 (dd, J = 15.2, 9.3 Hz, 1H), 4.40 (dd, J = 14.8, 6.3 Hz, 1H), 4.35 - 4.23 (m, 1H), 4.18 - 4.02 (m, 3H), 3.85 (d, J = 14.6 Hz, 2H), 3.76 (dd, J = 9.3, 3.7 Hz, 1H), 3.71 - 3.56 (m, 2H), 3.27 - 3.24 (m, 4H), 3.17 - 2.98 (m, 3H), 2.89 - 2.70 (m, 2H), 2.55 - 2.41 (m, 2H), 2.38 - 2.23 (m, 1H), 2.23 - 2.06 (m, 4H), 2.01 - 1.68 (m, 7H), 1.49 (s, 9H), 1.46 - 1.38 (m, 1H), 1.24 - 1.09 (m, 6H)。LCMS-ESI+ (m/z):C43
H58
ClN5
O7
S計算值H+:824.37;實驗值:823.89。實例 383
以與實例 75
相同之方式使用實例 109
及1,2,3,4-四氫吡咯并[1,2-a]吡嗪-8-甲酸甲酯來合成實例 383
。1H NMR (400 MHz,甲醇-d4) δ 7.74 (d, J = 8.5 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 - 7.06 (m, 2H), 6.94 (d, J = 8.1 Hz, 1H), 6.90 - 6.84 (m, 1H), 6.68 (d, J = 3.0 Hz, 1H), 6.54 (d, J = 3.0 Hz, 1H), 6.02 - 5.89 (m, 1H), 5.58 (dd, J = 15.2, 9.3 Hz, 1H), 4.44 - 4.29 (m, 1H), 4.12 - 4.00 (m, 5H), 3.88 - 3.53 (m, 8H), 3.28 - 3.23 (m, 4H), 3.13 - 3.02 (m, 1H), 2.88 - 2.71 (m, 2H), 2.55 - 2.40 (m, 2H), 2.37 - 2.24 (m, 1H), 2.24 - 2.06 (m, 4H), 2.01 - 1.66 (m, 7H), 1.50 - 1.37 (m, 1H), 1.20 - 1.14 (m, 3H)。LCMS-ESI+ (m/z):C42
H50
ClN5
O7
S計算值H+:804.31;實驗值:803.76。實例 384
在0℃下向於DCM (5 mL)中之實例 223
(10 mg,0.014 mmol)之經攪拌溶液中添加氯甲酸異丙酯(16.97 mg,0.138 mmol),且攪拌30 min,且隨後升溫至室溫過夜。將反應混合物蒸發且進行逆相層析法0.1% TFA 70-95%乙腈純化,得到實例 384
。1H NMR (400 MHz,氘代氯仿) δ 7.84 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.50 (dd, J = 8.3, 1.8 Hz, 1H), 7.20 (dd, J = 8.5, 2.5 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.04 (dt, J = 14.3, 6.5 Hz, 1H), 5.74 (dd, J = 15.8, 6.8 Hz, 1H), 5.17 (t, J = 5.8 Hz, 1H), 4.86 (p, J = 6.3 Hz, 1H), 4.21 - 3.96 (m, 5H), 3.82 (s, 6H), 3.32 (d, J = 14.5 Hz, 1H), 3.04 (dd, J = 15.2, 10.0 Hz, 1H), 2.86 - 2.24 (m, 9H), 2.20 - 1.58 (m, 8H), 1.42 (t, J = 10.3 Hz, 1H), 1.30 (dd, J = 7.3, 6.2 Hz, 6H), 1.11 (d, J = 6.8 Hz, 2H)。LCMS-ESI+ (m/z):C41
H50
ClN5
O8
S [M+H]+計算值:808.31;實驗值:808.60。實例 385
以與實例 75
相同之方式使用哌啶-1-甲酸反 -
氮雜環丁烷-3-基酯雙-三氟乙酸及實例 109
來合成實例 385
。1H NMR (400 MHz,甲醇-d4) δ 7.72 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 9.2 Hz, 1H), 7.09 (d, J = 6.2 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 5.95 (dt, J = 14.2, 6.7 Hz, 1H), 5.56 (dd, J = 15.2, 9.1 Hz, 1H), 5.14 - 5.02 (m, 1H), 4.38 - 4.25 (m, 3H), 4.14 - 4.01 (m, 2H), 3.97 (s, 1H), 3.83 (d, J = 15.1 Hz, 1H), 3.74 (dd, J = 9.3, 3.6 Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.59 (dd, J = 15.0, 5.7 Hz, 1H), 3.55 - 3.35 (m, 4H), 3.27 (d, J = 14.4 Hz, 1H), 3.24 (s, 3H), 3.06 (dd, J = 15.3, 10.3 Hz, 1H), 2.85 - 2.65 (d, J = 18.2 Hz, 2H), 2.54 - 2.39 (m, 2H), 2.39 - 2.25 (m, 1H), 2.24 - 2.05 (m, 3H), 1.99 - 1.49 (m, 8H), 1.44 (d, J = 12.8 Hz, 1H), 1.13 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C42
H55
ClN5
O7
S [M+H]+計算值:808.34;實驗值:807.90。實例 386
步驟1:在1 min內在−40℃下經由注射器將鉀雙(三甲基矽烷基)醯胺溶液(於四氫呋喃中1.0 M,199 µL,199 µmol)添加至於四氫呋喃(2.0 mL)中之實例 279
(30 mg,40 µmol)及溴丙烯(20.7 µL,239 µmol)之經攪拌混合物中。在2 min之後,使所得混合物升溫至室溫。在40 min之後,添加於水(10 mL)中之檸檬酸(100 mg)之溶液。添加乙酸乙酯(35 mL),且將有機層依序用水(10 mL)及水及鹽水之混合物(1:1 v:v,20 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於第三丁基醇(1.0 mL)、水(0.5 mL)及四氫呋喃(0.3 mL)中。在室溫下攪拌所得混合物,且依序添加4-甲基嗎啉-N
-氧化物(9.9 mg,85 µmol)及四氧化鋨溶液(於第三丁基醇中2.5% wt.,50 µL,4 µmol)。在90 min之後,添加亞硫酸鈉(83.2 mg,808 µmol),且劇烈攪拌所得混合物。在10 min之後,經由矽藻土過濾所得混合物,且用乙酸乙酯(25 mL)及二氯甲烷(10 mL)萃取濾餅。將合併濾液依序用於水(10 mL)中之檸檬酸(100 mg)及鹽水(10 mL)之混合物以及水及鹽水之混合物(1:1 v:v,10 mL)洗滌,經無水硫酸鎂乾燥,經由矽藻土過濾,且在減壓下濃縮,得到386-1
。
步驟2:在室溫下將過碘酸鈉(23.3 mg,109 µmol)添加至386-1
(12 mg,15 µmol)、四氫呋喃(1.0 mL)及水(0.5 mL)之經劇烈攪拌混合物中。在45 min之後,依序添加乙酸乙酯(30 mL)及於水(10 mL)中之檸檬酸(100 mg)之溶液。將有機層用水及鹽水之混合物(1:1 v:v,2×15 mL)洗滌,經無水硫酸鎂乾燥,過濾,且在減壓下濃縮。將殘餘物溶解於甲苯(3.0 mL)中,添加經精細研磨之肌胺酸(25.9 mg,290 µmol),且劇烈攪拌所得混合物且加熱至120℃。在45 min之後,將所得混合物冷卻至室溫且在減壓下濃縮。藉由逆相製備型HPLC (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到實例 386
。1H NMR (400 MHz,甲醇-d4) δ 8.07 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 8.3, 1.8 Hz, 1H), 7.26 - 7.16 (m, 2H), 7.13 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.12 (dd, J = 15.4, 8.3 Hz, 1H), 5.92 (dd, J = 15.4, 8.6 Hz, 1H), 4.37 - 4.00 (m, 5H), 4.07 (s, 3H), 3.95 - 3.77 (m, 2H), 3.83 (s, 3H), 3.72 (d, J = 14.4 Hz, 1H), 3.56 (ddd, J = 10.2, 6.0, 3.8 Hz, 1H), 3.42 (d, J = 14.4 Hz, 1H), 3.38 - 3.19 (m, 2H), 3.18 - 3.07 (m, 1H), 2.93 - 1.59 (m, 13H), 2.77 (s, 3H), 1.55 - 1.41 (m, 1H), 1.25 (d, J = 6.9 Hz, 3H)。LCMS:809.3。實例 387
以與實例 75
相同之方式使用嗎啉-4-甲酸反 -
氮雜環丁烷-3-基酯雙-三氟乙酸及實例 109
來合成實例 387
。1H NMR (400 MHz, MeOH-d4) δ 7.72 (d, J = 8.5 Hz, 1H), 7.16 (dd, J = 8.5, 2.4 Hz, 1H), 7.09 (dt, J = 5.0, 2.1 Hz, 2H), 6.94 - 6.86 (m, 2H), 5.95 (dt, J = 14.3, 6.7 Hz, 1H), 5.56 (dd, J = 15.3, 9.1 Hz, 1H), 5.12 (tt, J = 6.9, 4.0 Hz, 1H), 4.30 (m, 3H), 4.03 (dd, J = 25.5, 6.3 Hz, 4H), 3.83 (d, J = 15.0 Hz, 1H), 3.74 (dd, J = 9.2, 3.6 Hz, 1H), 3.71 - 3.56 (m, 6H), 3.48 (d, J = 24.7 Hz, 4H), 3.27 (d, J = 14.4 Hz, 1H), 3.24 (s, 3H), 3.05 (dd, J = 15.3, 10.3 Hz, 1H), 2.89 - 2.67 (m, 2H), 2.55 - 2.39 (m, 2H), 2.33 (q, J = 9.0 Hz, 1H), 2.23 - 2.05 (m, 3H), 1.99 - 1.65 (m, 5H), 1.42 (t, J = 13.8 Hz, 1H), 1.13 (d, J = 6.6 Hz, 3H)。LCMS-ESI+ (m/z):C41
H53
ClN5
O8
S [M+H]+計算值:810.32;實驗值:809.82。實例 388
步驟1:合成中間物388-1
:在室溫下用EDCI.HCl (159 mg,0.830 mmol)、繼而用DMAP (101mg,0.83 mmol)處理於DCM (3.0 mL)中之109-1-3
(155.0 mg,0.498 mmol)及109-1-4
(200 mg,0.415 mmol)之混合物。在於室溫下攪拌過夜之後,且濃縮反應混合物。將殘餘物溶解於EtOAc (100.0 mL)中,用飽和NH4
Cl、飽和NaHCO3
、鹽水洗滌,經硫酸鈉乾燥,過濾且濃縮,得到388-1
。LCMS-ESI+ (m/z):C43
H52
ClN3
O6
S計算值H+:774.33;實驗值:774.02。
步驟2:合成388-2
:在室溫下用TFA (2.0 mL)及DCM (4.0 mL)之混合物處理388-1
達1 hr。隨後,將反應物用EtOAc稀釋,用飽和NaHCO3
中和直至pH~7為止,用鹽水洗滌,經硫酸鈉乾燥,過濾且濃縮,得到粗製物388-2
,藉由combiflash (12 g矽膠,0-50% EtOAc/己烷)純化。將所需溶離份組合且濃縮,且用MeOH處理,得到388-2
。1H NMR (400 MHz,甲醇-d4) δ 7.67 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.2, 1.9 Hz, 1H), 7.17 - 7.05 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 5.78 (ddt, J = 16.1, 10.8, 6.9 Hz, 1H), 5.57 (ddd, J = 17.1, 10.5, 7.9 Hz, 1H), 5.21 - 5.02 (m, 4H), 4.10 - 3.96 (m, 2H), 3.62 (dd, J = 14.3, 4.4 Hz, 1H), 3.58 - 3.48 (m, 3H), 3.37 - 3.34 (m, 1H), 3.31 (s, 1H), 2.84 - 2.66 (m, 2H), 2.53 (pd, J = 8.0, 4.0 Hz, 1H), 2.35 - 2.21 (m, 2H), 2.21 - 2.09 (m, 2H), 2.08 - 1.92 (m, 3H), 1.91 - 1.81 (m, 2H), 1.81 - 1.47 (m, 4H), 1.13 (d, J = 6.3 Hz, 3H)。
步驟3:合成388-3
:用氮氣使於DCE (35.0 mL)中之388-2
(173 mg,0.277 mmol)之溶液脫氣。添加哈維達=格拉布II催化劑(26.0 mg,0.0415 mmol),使所得混合物充有氮氣達超過3分鐘,且隨後將其封蓋,且在80℃下在氮氣球下加熱過夜。將反應物冷卻至室溫,與矽膠混合,濃縮至乾,且藉由combiflash (12 g矽膠,0-60% EtOAc/己烷,乾負載物)純化。將所需溶離份組合且濃縮,得到388-3
。1H NMR (400 MHz,甲醇-d4) δ 7.77 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.2, 1.9 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.12 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 1.9 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 6.02 (dt, J = 14.1, 6.7 Hz, 1H), 5.56 (dd, J = 15.4, 8.7 Hz, 1H), 4.21 (dd, J = 14.1, 6.8 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.85 (d, J = 14.9 Hz, 1H), 3.77 (dd, J = 8.8, 3.3 Hz, 1H), 3.69 (d, J = 14.2 Hz, 1H), 3.27 (s, 3H), 3.19 - 3.11 (m, 1H), 3.11 - 3.03 (m, 1H), 2.89 - 2.71 (m, 2H), 2.58 - 2.37 (m, 3H), 2.29 - 2.20 (m, 1H), 2.17 - 2.08 (m, 2H), 2.00 - 1.87 (m, 4H), 1.84 - 1.70 (m, 3H), 1.50 - 1.39 (m, 1H), 1.14 (d, J = 6.8 Hz,3H)。LCMS-ESI+ (m/z):C32
H40
ClN3
O4
S計算值H+:598.24;實驗值:598.03。
步驟4:在室溫下向於DCM (2.0 mL)中之388-3
(70.0 mg,0.117 mmol)及3-甲氧基-1-甲基-吡唑-4-甲酸(36.5 mg,0.234 mmol)之混合物中添加EDCI.HCl (44.7 mg,0.234 mmol),繼而添加DMAP (28.6 mg,0.234 mmol)。將所得混合物在室溫下攪拌過夜。隨後,將反應物濃縮,再溶解於DMF (3.6 mL)中,過濾且藉由Gilson逆相製備型HPLC純化。將所需溶離份組合且濃縮,冷凍乾燥,與乙腈一起濕磨,且過濾,得到實例 388
。1H NMR (400 MHz,甲醇-d4) δ 8.04 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 7.13 (s, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.16 - 6.04 (m, 1H), 5.64 (dd, J = 15.5, 8.1 Hz, 1H), 4.25 - 4.13 (m, 1H), 4.11 - 3.99 (m, 6H), 3.83 - 3.74 (m, 6H), 3.30 (s, 3H), 3.17 - 3.13 (m, 1H), 2.91 - 2.76 (m, 2H), 2.66 - 2.40 (m, 5H), 2.30 - 2.21 (m, 1H), 2.17 - 2.08 (m, 1H), 1.99 - 1.91 (m, 3H), 1.84 - 1.73 (m, 3H), 1.53 - 1.41 (m, 1H), 1.20 (d, J = 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C38
H46
ClN5
O6
S計算值H+:736.29;實驗值:735.97。實例 389
以與實例 106
類似之方式使用3-甲氧基-1-甲基-1H-吡唑-4-甲酸而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸且使用實例 5
而不使用106-4
來合成實例 389
。1H NMR (400 MHz,丙酮-d6) δ 8.11 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.2, 1.9 Hz, 1H), 7.26 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.97 (dt, J = 15.7, 5.1 Hz, 1H), 5.85 (dd, J = 15.9, 8.0 Hz, 1H), 4.13 (d, J = 12.1 Hz, 1H), 4.07 (s, 3H), 4.05 - 3.93 (m, 2H), 3.89 (d, J = 13.5 Hz, 1H), 3.85 (s, 3H), 3.80 (d, J = 14.3 Hz, 1H), 3.59 (dd, J = 7.9, 3.2 Hz, 1H), 3.49 (d, J = 14.3 Hz, 1H), 3.27 (s, 3H), 3.23 - 3.14 (m, 1H), 3.01 - 1.55 (m, 16H), 1.54 - 1.41 (m, 1H)。LCMS:722.1。實例 390
以與實例 244
類似之方式使用實例 5
而不使用240-1
來合成實例 390
。1H NMR (400 MHz,丙酮-d6) δ 7.78 (d, J = 8.5 Hz, 1H), 7.32 - 7.21 (m, 3H), 7.14 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 5.98 - 5.87 (m, 1H), 5.79 - 5.69 (m, 1H), 4.36 - 4.16 (m, 3H), 4.12 (d, J = 12.1 Hz, 1H), 4.03 (d, J = 12.1 Hz, 1H), 3.99 - 3.22 (m, 7H), 3.30 (s, 3H), 3.24 (s, 3H), 3.17 (dd, J = 15.2, 10.8 Hz, 1H), 2.95 - 1.55 (m, 16H), 1.52 - 1.41 (m, 1H)。LCMS:697.1。實例 391
步驟1:在室溫下將二氧化硒(261 mg,2.36 mmol)添加至於1,4-二噁烷(6.7 mL)中之實例 5
(393 mg,673 µmol)之經劇烈攪拌溶液中,且將所得混合物加熱至80℃。在10 min之後,將所得混合物加熱至100℃。在60 min之後,將所得混合物冷卻至室溫,且經由矽藻土過濾。用二氯甲烷(10 mL)萃取濾餅,且在減壓下濃縮合併濾液。藉由逆相製備型HPLC (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到391-1
及391-2
。
步驟2:以與實例 106
類似之方式使用3-甲氧基-1-甲基-1H-吡唑-4-甲酸而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸且使用391-1
而不使用106-4
來合成實例 391
。1H NMR (400 MHz,丙酮-d6) δ 8.11 (s, 1H), 7.94 (s, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.51 - 7.43 (m, 2H), 7.25 (dd, J = 8.5, 2.4 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 8.7 Hz, 1H), 6.17 - 6.01 (m, 2H), 5.72 (d, J = 4.8 Hz, 1H), 4.26 (dd, J = 14.2, 7.0 Hz, 1H), 4.13 (d, J = 12.1 Hz, 1H), 4.10 - 3.70 (m, 4H), 4.08 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H), 3.69 (s, 3H), 3.48 (d, J = 14.4 Hz, 1H), 3.27 (s, 3H), 3.15 (dd, J = 15.0, 10.9 Hz, 1H), 2.93 - 1.54 (m, 14H), 1.54 - 1.43 (m, 1H)。LCMS:898.0 (M+Na)+。實例 392
在1 min內在−40℃下經由注射器將鉀雙(三甲基矽烷基)醯胺溶液(於四氫呋喃中1.0 M,27 µL,27 µmol)添加至於四氫呋喃(1.0 mL)中之中間物 391-3
(4.0 mg,5.4 µmol)及碘甲烷(3.4 µL,54 µmol)之經攪拌混合物中。在2 min之後,使所得混合物升溫至室溫。在7 min之後,添加三氟乙酸(50 µL),且在減壓下濃縮所得混合物。藉由逆相製備型HPLC (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到實例 392
。1H NMR (400 MHz,丙酮-d6) δ 8.11 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.42 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 1.3 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.00 (dd, J = 15.7, 7.2 Hz, 1H), 5.89 (dd, J = 15.7, 8.0 Hz, 1H), 4.14 (d, J = 11.9 Hz, 1H), 4.11 - 4.04 (m, 1H), 4.06 (s, 3H), 4.01 (d, J = 12.1 Hz, 1H), 3.94 - 3.43 (m, 5H), 3.30 (s, 3H), 3.26 (s, 3H), 3.16 (dd, J = 14.8, 10.9 Hz, 1H), 2.96 - 1.63 (m, 14H), 1.56 - 1.46 (m, 1H)。LCMS:752.2。實例 393
在室溫下經由注射器將乙酸酐(5.0 µL,53 µmol)添加至於二氯甲烷(0.6 mL)中之實例 279
(4 mg,5 µmol)及4-(二甲基胺基)吡啶(7.8 mg,64 µmol)之經攪拌混合物中,且將所得混合物加熱至45℃。在30 min之後,將所得混合物冷卻至室溫且在減壓下濃縮。藉由逆相製備型HPLC (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到實例 393
。1H NMR (400 MHz,丙酮-d6) δ 8.14 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 8.3, 1.9 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.4, 2.4 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.13 (dd, J = 15.8, 5.4 Hz, 1H), 5.90 (dd, J = 15.7, 7.4 Hz, 1H), 5.72 (s, 1H), 4.18 (dd, J = 15.2, 6.8 Hz, 1H), 4.11 - 4.03 (m, 2H), 4.09 (s, 3H), 4.01 - 3.88 (m, 2H), 3.87 (s, 3H), 3.77 (d, J = 14.4 Hz, 1H), 3.49 (d, J = 14.3 Hz, 1H), 3.23 (s, 2H), 3.18 (dd, J = 15.2, 10.4 Hz, 1H), 2.96 - 1.18 (m, 17H), 1.12 (d, J = 6.9 Hz, 3H)。LCMS:794.1。實例 394
以與實例 106
類似之方式使用3-甲氧基-1-甲基-1H-吡唑-4-甲酸而不使用2-((四氫-2H-哌喃-4-基)氧基)乙酸且使用391-2
而不使用106-4
來合成實例 394
。1H NMR (400 MHz,丙酮-d6) δ 8.09 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.45 - 7.39 (m, 2H), 7.24 (dd, J = 8.6, 2.4 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.05 (dd, J = 16.3, 7.9 Hz, 1H), 5.83 (dd, J = 15.9, 5.0 Hz, 1H), 4.31 - 3.68 (m, 6H), 4.05 (s, 3H), 3.83 (s, 3H), 3.58 (dd, J = 8.3, 3.0 Hz, 1H), 3.45 (d, J = 14.4 Hz, 1H), 3.36 (s, 3H), 3.28 (s, 3H), 3.23 - 3.14 (m, 1H), 2.85 - 1.54 (m, 14H), 1.53 - 1.39 (m, 1H)。LCMS:752.1。實例 395 及實例 396
製備實例 395
及實例 396
:在1 min內在−40℃下經由注射器將鉀雙(三甲基矽烷基)醯胺溶液(於四氫呋喃中1.0 M,66.5 µL,66.5 µmol)添加至於四氫呋喃(0.6 mL)中之實例 279
(5.0 mg,6.6 µmol)之經攪拌溶液中。在1 min之後,經由注射器添加N
,N
-二甲基胺甲醯氯(12.2 µL,133 µmol)。在2 min之後,使所得混合物升溫至室溫。在40 min之後,依序添加乙酸(50 µL)及甲醇(100 µL),且在減壓下濃縮所得混合物。藉由逆相製備型hplc (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到實例 395
。1H NMR (400 MHz,丙酮-d6) δ 8.43 - 7.66 (m, 2H), 7.48 - 7.05 (m, 4H), 7.04 - 6.82 (m, 1H), 6.13 - 5.42 (m, 2H), 5.38 - 5.15 (m, 1H), 4.34 - 3.10 (m, 17H), 3.10 - 1.18 (m, 28H)。LCMS:894.6。進一步溶析,得到實例 396
。1H NMR (400 MHz,丙酮-d6) δ 8.20 - 6.65 (m, 7H), 6.34 - 5.38 (m, 3H), 4.51 - 3.22 (m, 17H), 3.22 - 1.12 (m, 20H), 1.05 (d, J = 7.1 Hz, 3H)。LCMS:823.0。實例 397
步驟1:在室溫下經由注射器將二硫酸甲酯(8.54 mL,90.2 mmol)添加至於氯仿(20 mL)中之4-碘基-1H-吡唑-1-醇(3.79 g,18.0 mmol)之經攪拌溶液中。在16 h之後,將所得混合物傾入二乙醚(150 mL)中,且使所得非均勻混合物劇烈旋流。傾析上清液,且將殘餘膠溶解於乙醇(19 mL)中且在室溫下攪拌。依序添加三乙胺(8.33 mL,59.8 mmol)及[1,1′-雙(二苯膦基)二茂鐵]二氯鈀(II) (375 mg,512 µmol)。將所得混合物置於一氧化碳氛圍(1 atm)下,且加熱至90℃。在28 h之後,將所得混合物冷卻至室溫且經由矽藻土過濾。用甲醇(25 mL)及二氯甲烷(50 mL)之混合物萃取濾餅。將磷酸鉀(14.5 g,68.3 mmol)添加至合併濾液中,且劇烈攪拌所得不均勻混合物。在15 min之後,將所得混合物經由矽藻土過濾且在減壓下濃縮。將殘餘物溶解於二氯甲烷(50 mL)及甲苯(25 mL)之混合物中,添加鹼性氧化鋁(30 g),且在減壓下濃縮所得漿液。藉由矽膠急驟管柱層析法(0至6%於二氯甲烷中之甲醇)純化殘餘物,得到397-1
。
步驟2:在−40℃下經由注射器將2,2,6,6-四甲基哌啶基氯化鎂氯化鋰複合物溶液(於四氫呋喃/甲苯中1.0 M,3.85 mL,3.85 mmol)添加至於四氫呋喃(40 mL)中之397-1
(131 mg,770 µmol)之經攪拌溶液中。在3 h之後,經由套管添加於四氫呋喃(15 mL)中之六氯乙烷(1.28 g,5.39 mmol)之溶液。在3 min之後,使所得混合物升溫至室溫。在4.5 h之後,添加矽膠(12 g),且在減壓下濃縮所得漿液。藉由矽膠急驟管柱層析法(0至5%於二氯甲烷中之甲醇)純化殘餘物,得到不純397-2
。藉由逆相製備型HPLC (0.1%於乙腈/水中之三氟乙酸)純化不純材料,得到397-2
。
步驟3:在室溫下經由注射器將甲醇鈉溶液(於甲醇中25% wt.,121 µL,528 µmol)添加至於甲醇(0.5 mL)中之397-2
(21.6 mg,106 µmol)之經攪拌溶液中,且將所得混合物加熱至70℃。在22 min之後,經由注射器添加氫氧化鈉水溶液(2.0 M,158 µL,317 µmol)。在15 min之後,,使所得混合物冷卻至室溫,且經由注射器添加氯化氫溶液(於1,4-二噁烷中4.0 M,211 µL,844 µmol)。在減壓下濃縮所得混合物。將殘餘物溶解於二氯甲烷(1.0 mL)中且在室溫下攪拌。依序添加106-4
(10.0 mg,16.7 µmol)、4-(二甲基胺基)吡啶(20.4 mg,167 µmol)及3-(((乙基亞胺基)亞甲基)胺基)-N,N-二甲基丙-1-胺鹽酸鹽(12.8 mg,66.9 µmol),且將所得混合物加熱至45℃。在1 h之後,將所得混合物冷卻至室溫且在減壓下濃縮。藉由逆相製備型hplc (0.1%於乙腈/水中之三氟乙酸)純化殘餘物,得到實例 397
。1H NMR (400 MHz,丙酮-d6) δ 7.96 - 7.61 (m, 2H), 7.42 - 6.87 (m, 5H), 6.15 - 6.00 (m, 1H), 5.69 - 5.50 (m, 1H), 4.27 (s, 3H), 4.25 - 3.24 (m, 7H), 3.23 (s, 3H), 3.21 - 3.10 (m, 1H), 2.94 - 1.19 (m, 16H), 1.14 (d, J = 6.1 Hz, 3H)。LCMS:752.2。實例 398
步驟1:合成398-1
:在室溫下向於DMF (1.0 mL)中之實例 279
(20.0 mg,0.0266 mmol)之溶液中添加溴丙烯(19.3 mg,0.16 mmol),繼而添加60%於礦物油中之NaH分散液(6.38 mg,0.16 mmol)。將反應物在50℃下加熱90 min。LCMS顯示約~50%轉化。添加額外之溴丙烯(19.3 mg,0.16 mmol)及60%於礦物油中之NaH分散液(6.38 mg,0.16 mmol),再在50℃下加熱90 min。將反應物用飽和NH4
Cl淬滅,用鹽水洗滌,經硫酸鈉乾燥,過濾,且濃縮,得到398-1
。LCMS-ESI+ (m/z):C41
H50
ClN5
O7
S計算值H+:792.31;實驗值:792.03。
步驟2:合成398-2
:在室溫下將398-1
(21.0 mg,0.0265 mmol)溶解於tBuOH (1.0 mL)、THF (0.3 mL)及水(0.5 mL)之混合物中。添加NaIO4 (42.5 mg,0.199 mmol),繼而添加2.5%於tBuOH中之OsO4 (33.2 uL,0.0027 mmol)。將所得混合物在室溫下攪拌90分鐘。將反應物用1 N硫代硫酸鈉淬滅,在室溫下劇烈攪拌10 min,用EtOAc (2×20 mL)萃取。將合併有機層用鹽水洗滌,經硫酸鈉乾燥,過濾,且濃縮,得到398-2
。LCMS-ESI+ (m/z):C40
H48
ClN5
O8
S計算值H+:794.29;實驗值:793.96。
步驟3:合成實例 398
:在室溫下向於DCE (1.0 mL)中之398-2
及(9aS)-1,3,4,6,7,8,9,9a-八氫吡嗪并[2,1-c][1,4]噁嗪;二鹽酸鹽(11.4 mg,0.053 mmol)之混合物中添加DIEA (6.83 mg,0.053 mmol)。將所得混合物攪拌5分鐘,添加STAB (11.2 mg,0.053 mmol),且將反應物攪拌過夜。將反應物濃縮,再溶解於DMF (1.2 mL)及水(0.6 mL)中,過濾且藉由逆相製備型HPLC (40-90% ACN/H2O及0.1% TFA)純化。將所需溶離份組合且冷凍乾燥,得到實例 398
。1H NMR (400 MHz,甲醇-d4) δ 8.08 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.38 (dd, J = 8.2, 1.9 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.4 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.18 (dd, J = 15.4, 8.5 Hz, 1H), 5.92 (dd, J = 15.4, 8.8 Hz, 1H), 4.26 (dd, J = 15.0, 5.1 Hz, 1H), 4.13 - 4.04 (m, 7H), 3.94 - 3.78 (m, 9H), 3.75 - 3.59 (m, 4H), 3.46 - 3.36 (m, 4H), 3.31 (s, 3H), 3.23 - 3.09 (m, 3H), 2.90 - 2.76 (m, 4H), 2.70 - 2.47 (m, 5H), 2.36 - 2.25 (m, 1H), 2.12 (d, J = 13.6 Hz, 1H), 2.02 - 1.88 (m, 3H), 1.83 (d, J = 7.4 Hz, 3H), 1.53 - 1.41 (m, 1H), 1.24 (d, J = 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C47
H62
ClN7
O8
S計算值H+:920.41;實驗值:920.45。實例 399
步驟1:合成399-1
:在室溫下將中間物 399-1
(22.0 mg,0.0358 mmol)及5-甲醯基-1-甲基-吡咯-3-甲酸(11.0 mg,0.0716 mmol)溶解於DCM (2.0 mL)中,添加EDCI.HCl (13.7 mg,0.0716 mmol),繼而添加DMAP (8.75 mg,0.0716 mmol)。將所得混合物攪拌1 hr。將反應物濃縮,再溶解於EtOAc中,將有機層依序用飽和NH4
Cl、飽和NaHCO3
及鹽水洗滌,經硫酸鈉乾燥,過濾,且濃縮,得到399-1
。LCMS-ESI+ (m/z):C39
H45
ClN4
O7
S計算值H+:749.27;實驗值:748.96。
步驟2:合成399-2
:在室溫下將399-1
溶解於DMF (1.0 mL)中;添加MeI (21.4 mg,0.151 mmol),繼而添加60%於礦物油中之NaH分散液(6.02 mg,0.151 mmol)。將所得混合物在50℃下加熱30 min,且隨後將反應物冷卻至室溫,用DMF (0.5 mL)稀釋,過濾,且藉由逆相製備型HPLC純化。將所需溶離份組合且冷凍乾燥,得到399-2
。LCMS-ESI+ (m/z):C40
H47
ClN4
O7
S計算值H+ 763.29;實驗值:762.98。
步驟3:在室溫下向於DCE (1.0 mL)中之399-2
(28 mg,0.037 mmol)及(9aS)-1,3,4,6,7,8,9,9a-八氫吡嗪并[2,1-c][1,4]噁嗪;二鹽酸鹽(11.8 mg,0.055 mmol)之經攪拌混合物中添加DIEA (16.6 mg,0.128 mmol)。在添加STAB (11.7 mg,0.055 mmol)之前,將所得混合物攪拌5分鐘。隨後,將新形成之混合物在室溫下攪拌過夜,且隨後濃縮,再溶解於DMF (1.2 mL)中,過濾,且藉由逆相製備型HPLC純化。將所需溶離份組合且冷凍乾燥,得到實例 399
。LCMS-ESI+ (m/z):C47
H61
ClN6
O7
S計算值H+:889.40;實驗值:889.19。1H NMR (400 MHz,甲醇-d4) δ 7.69 (d, J = 1.9 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.3, 1.8 Hz, 1H), 7.05 (dd, J = 9.9, 2.1 Hz, 2H), 6.91 - 6.78 (m, 3H), 6.21 - 6.11 (m, 1H), 5.68 (dd, J = 15.3, 8.3 Hz, 1H), 4.14 (dd, J = 14.7, 6.7 Hz, 1H), 4.06 - 3.88 (m, 7H), 3.84 - 3.72 (m, 7H), 3.64 (d, J = 14.5 Hz, 1H), 3.47 - 3.42 (m, 1H), 3.25 - 3.09 (m, 5H), 3.06 - 2.65 (m, 8H), 2.58 - 2.34 (m, 3H), 2.34 - 2.14 (m, 4H), 2.08 (d, J = 13.6 Hz, 1H), 2.02 - 1.78 (m, 6H), 1.42 - 1.35 (m, 1H), 1.16 (d, J = 6.2 Hz, 3H)。實例 400
將實例 279
(10 mg,0.014 mmol)溶解於二氯甲烷及H2
O之1:1混合物中(0.15 mL: 0.15 mL)。添加呈固體形式之酸式氟化鉀(15 mg)。在添加(溴二氟甲基)三甲基矽烷(50 µL)之前,將反應物在室溫下攪拌2 min。將反應物加熱至50℃達8小時,之後使其冷卻至室溫。直接藉由Gilson逆相製備型HPLC (60-100% ACN/H2
O及0.1% TFA)純化反應混合物,得到實例 400
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.09 (s, 1H), 7.77 (d,J
= 8.4 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.24 (s, 1H), 7.21 - 7.14 (m, 1H), 7.12 (d,J
= 2.2 Hz, 2H), 6.92 (t,J
= 7.9 Hz, 1H), 6.44 (s, 1H), 6.18 (dd,J
= 15.5, 6.1 Hz, 1H), 5.93 (dd,J
= 15.2, 8.2 Hz, 1H), 4.16 - 3.99 (m, 8H), 3.89 (m, 2H), 3.82 (m, 4H), 3.73 (d,J
= 13.9 Hz, 1H), 3.41 (d,J
= 14.3 Hz, 1H), 3.28 (s, 3H), 3.15 (m, 1H), 2.83 (m, 2H), 2.52 (m, 1H), 2.40 (m, 1H), 2.08 (m, 1H), 1.92 (m, 2H), 1.79 (m, 3H), 1.33 (m, 1H), 1.19 (d,J
= 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C39
H45
ClF2
N5
O7
S [M+H]+計算值:802.3;實驗值:802.5。實例 401
以與實例 283
相同之方式使用2-溴-N,N
-二甲基乙醯胺及實例 279
來合成實例 401
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.11 (s, 1H), 7.75 (d,J
= 8.5 Hz, 1H), 7.36 (dd,J
= 8.2, 1.9 Hz, 1H), 7.23 - 7.08 (m, 3H), 6.91 (d,J
= 8.2 Hz, 1H), 6.06 (dd,J
= 15.5, 7.6 Hz, 1H), 5.89 (dd,J
= 15.5, 8.5 Hz, 1H), 4.26 (d,J
= 13.9 Hz, 1H), 4.19 - 4.00 (m, 9H), 3.92 - 3.84 (m, 2H), 3.82 (s, 3H), 3.72 (d,J
= 14.3 Hz, 1H), 3.41 (d,J
= 14.4 Hz, 1H), 3.35 (m, 2H), 3.31 (s, 3H), 3.17 - 3.07 (m, 1H), 2.99 (s, 3H), 2.88 (s, 3H), 2.86 - 2.71 (m, 1H), 2.52 (m, 2H), 2.36 (m, 1H), 2.11 (d,J
= 13.6 Hz, 1H), 1.96 (m, 2H), 1.82 (d,J
= 7.0 Hz, 3H), 1.47 (d,J
= 13.6 Hz, 1H), 1.23 (d,J
= 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C42
H53
ClN6
O8
S [M+H]+計算值:837.3;實驗值:837.9。實例 402
以與實例 283
相同之方式使用2-(氯甲基)吡啶及實例 279
來合成實例 402
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.71 (d,J
= 5.7 Hz, 1H), 8.37 (t,J
= 8.4 Hz, 1H), 8.08 (s, 1H), 7.94 (d,J
= 7.9 Hz, 1H), 7.85 - 7.80 (m, 1H), 7.77 (d,J
= 8.5 Hz, 1H), 7.40 - 7.35 (m, 1H), 7.23 - 7.11 (m, 4H), 6.94 (d,J
= 8.2 Hz, 1H), 6.15 (dd,J
= 15.6, 7.6 Hz, 1H), 5.99 (dd,J
= 15.5, 8.3 Hz, 1H), 4.82 - 4.69 (m, 1H), 4.32 - 4.10 (m, 4H), 4.07 (s, 3H), 3.92 - 3.84 (m, 3H), 3.83 (s, 3H), 3.79 - 3.68 (m, 2H), 3.41 (d,J
= 14.3 Hz, 1H), 3.28 (s, 3H), 3.21 - 3.01 (m, 2H), 2.87 - 2.75 (m, 2H), 2.66-2.34 (m, 3H), 2.11 (m, 1H), 1.96 (m, 2H), 1.83 (m, 3H), 1.47 (s, 1H), 1.26 (d,J
= 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C44
H51
ClN6
O7
S [M+H]+計算值:843.3;實驗值:843.2。實例 403
將實例 279
(10 mg,0.014 mmol)溶解於DMF (0.15 mL)中。添加呈固體形式之氫氧化鈉(過量,1丸粒)。將反應物加熱至50℃達8小時,之後使其冷卻至室溫。直接藉由Gilson逆相製備型HPLC (40-90% ACN/H2
O及0.1% TFA)純化反應混合物,得到實例 403
。1
H NMR (400 MHz,甲醇-d 4
) δ 8.08 (s, 1H), 7.76 (d,J
= 8.6 Hz, 1H), 7.37 (dd,J
= 8.2, 1.8 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.13 (d,J
= 2.3 Hz, 1H), 6.93 (d,J
= 8.3 Hz, 1H), 6.15 (dd,J
= 15.4, 8.7 Hz, 1H), 5.94 (dd,J
= 15.3, 8.7 Hz, 1H), 4.23 (dd,J
= 14.9, 4.3 Hz, 1H), 4.16 - 4.02 (m, 8H), 3.86 (d,J
= 9.8 Hz, 6H), 3.82 (s, 3H), 3.75 - 3.61 (m, 2H), 3.46 - 3.38 (m, 2H), 3.33 - 3.28 (m, 2H), 3.20 - 3.09 (m, 1H), 2.96 (m, 6H), 2.89 - 2.75 (m, 2H), 2.62 - 2.46 (m, 2H), 2.29 (m, 1H), 2.12 (d,J
= 13.7 Hz, 1H), 1.96 (m, 2H), 1.84 (m, 3H), 1.46 (d,J
= 10.5 Hz, 1H), 1.26 (d,J
= 6.9 Hz, 3H)。LCMS-ESI+ (m/z):C42
H55
ClN6
O7
S [M+H]+計算值:823.4;實驗值:823.4。實例 404
向於二甲基胺基甲酸氯化物(2 mL)中之實例 223
(10 mg,0.014 mmol)之經攪拌溶液中添加DMAP (16 mg,0.138 mmol),且在80℃下攪拌過夜。蒸發溶劑,且使反應混合物進行逆相層析法0.1% TFA 70-95%乙腈純化,得到實例 404
。1
H NMR (400 MHz,氘代氯仿) δ 7.83 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 8.2, 1.9 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.5, 2.3 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 5.89 (dt, J = 13.3, 6.4 Hz, 1H), 5.73 (dd, J = 15.7, 5.4 Hz, 1H), 5.26 (t, J = 5.6 Hz, 1H), 4.18 - 3.97 (m, 5H), 3.82 (s, 3H), 3.71 (d, J = 14.5 Hz, 2H), 3.33 (d, J = 14.6 Hz, 1H), 3.06 (dd, J = 15.3, 9.0 Hz, 1H), 2.93 - 2.63 (m, 7H), 2.61 - 2.47 (m, 2H), 2.43 - 1.55 (m, 11H), 1.41 (dd, J = 23.1, 10.6 Hz, 2H), 1.28 (s, 1H), 1.14 (d, J = 6.8 Hz, 3H)。LCMS-ESI+ (m/z):C40
H49
ClN6
O7
S [M+H]+計算值:793.31;實驗值:792.58。
藉由本文所描述之方法來合成實例 405-464
。
MCL-1/Bim結合AlphaLISA分析.
實例 | 結構 | LCMS-ESI+ (m/z) : [M+H]+ 計算值 | LCMS-ESI+ (m/z) : [M+H]+ 實驗值 |
405 | 706.28 | 706.19 | |
406 | 754.3 | 754.3 | |
407 | 726.3 | 726.1 | |
408 | 762.3 | 762.1 | |
409 | 693.24 | 692.92 | |
410 | 746.3 | 746.1 | |
411 | 709.22 | 708.96 | |
412 | 743.3 | 743.15 | |
413 | 719.3 | 719 | |
414 | 695.3 | 694.7 | |
415 | 745.31 | 745.31 | |
416 | 758.34 | 758.82 | |
417 | 796.34 | 796.2 | |
418 | 811.34 | 811.05 | |
419 | 746.3 | 746.1 | |
420 | 733.31 | 734.33 | |
421 | 669.28 | 668.76 | |
422 | 721.3 | 720.98 | |
423 | 695.3 | 694.78 | |
424 | 748.293 | 747.68 | |
425 | 746.31 | 746.03 | |
426 | 743.3 | 743.11 | |
427 | 696.2869 | 695.95 | |
428 | 697.2821 | 696.92 | |
429 | 764.25 | 763.93 | |
430 | 758.3 | 758.2 | |
431 | 746.28 | 745.97 | |
432 | 743.29 | 743.24 | |
433 | 695.3 | 695.2 | |
434 | 722.24 | 721.86 | |
435 | 750.33 | 750.14 | |
436 | 720.3 | 720.4 | |
437 | 771.31 | 770.75 | |
438 | 753.3083 | 753.02 | |
439 | 753.3083 | 753.07 | |
440 | 717.2684 | 716.71 | |
441 | 718.28 | 718.01 | |
442 | 725.31 | 724.69 | |
443 | 732.29 | 732.21 | |
444 | 722.24 | 723.209 | |
445 | 696.3 | 695.9 | |
446 | 708.28 | 708.23 | |
447 | 708.28 | 708.23 | |
448 | 756.3 | 756.9 | |
449 | 723.3 | 723.6 | |
450 | 757.2933 | 757.1 | |
451 | 791.32 | 791.2 | |
452 | 711.3 | 710.66 | |
453 | 779.28 | 778.68 | |
454 | 655.26 | 655.79 | |
455 | 846.2732 | 846.1 | |
456 | 737.31 | 736.79 | |
457 | 746.31 | 745.82 | |
458 | 734.2774 | 734.1 | |
459 | 794.2985 | 794.1 | |
460 | 748.293 | 748.2 | |
461 | 718.2824 | 718.1 | |
462 | 819.3301 | 819.1 | |
463 | 774.3087 | 774.61 | |
464 | 791.33 | 791.28 |
在以下AlphaLISA分析中量測MCL-1及Bim相互作用之抑制。材料
重組人類MCL-1蛋白(含有殘基171-327之C端6×His標籤Mcl-1)係在Gilead Sciences, Inc. (Foster City, CA)處生成。來源於人類Bim (殘基51-76)之生物素標記肽係購自CPC Scientific (Sunnyvale, CA) (CPC 834113)。AlphaLISA抗6His受體微珠(AL128R)、AlphaScreen抗生蛋白鏈菌素供體微珠(6760002B)及Proxiplate-384 Plus (6008289)係購自PerkinElmer。方法
AlphaLISA分析係在總體積為40 μL之384孔Proxiplate中執行。反應混合物含有0.0625 nM 6× His-Mcl-1 (171-327)、0.0625 nM生物素標記-Bim肽、10 μg/mL AlphaLISA抗6×His-AlphaLISA受體微珠、40 µg/mL AlphaScreen抗生蛋白鏈菌素供體微珠及含經連續稀釋之測試化合物之結合緩衝劑(20 mM Hepes,pH 7.5 (Teknova H1035);150 mM NaCl (Promega V4221);0.002% Brij 35 (Thermo Scientific 20150);1 mM二硫蘇糖醇(DTT)溶液(Affymetrix 70726);0.01% BSA (BioLabs B9000S))。藉由Echo 555液體處置器(Labcyte Inc., San Jose, CA)將1,000×種測試化合物預點樣至384孔Proxiplate (Labcyte Echo)上,繼而培育5 µl Mcl-1 (171-327)達1小時。隨後,添加5 µL Bim (51-76)且培育2小時。隨後,添加5 µL AlphaLISA抗6His-AlphaLISA受體微珠達1小時,繼而添加5 µL AlphaScreen抗生蛋白鏈菌素供體微珠達1小時。隨後,在Envision多模讀取器(PerkinElmer)上使用AlphaScreen配置讀取反應盤。計算IC50
值且報導在表 1
中。比較實例 1
為來自國際公開案第WO 2016/033486號之實例4。如下文所示計算抑制百分比:
抑制% = 100% × (良好 - Neg) / (Pos - Neg)
Neg:陰性對照,DMSO
Pos:陽性對照,無Mcl-1蛋白,無生物素標記-Bim肽表 1 . MCL - 1 / Bim IC50 ( nM )
SKBR3細胞生存力分析材料
實例 | IC50 (nM) | 實例 | IC50 (nM) | 實例 | IC50 (nM) | 實例 | IC50 (nM) | 實例 | IC50 (nM) |
1 | 0.9 | 94 | 0.9 | 187 | 0.107 | 280 | 0.044 | 373 | |
2 | 1.5 | 95 | 1.1 | 188 | 0.069 | 281 | 0.154 | 374 | 0.058 |
3 | 4.1 | 96 | 0.4 | 189 | 0.033 | 282 | 0.086 | 375 | 0.046 |
4 | 0.7 | 97 | 0.6 | 190 | 0.055 | 283 | 0.029 | 376 | 0.031 |
5 | 60.2 | 98 | 0.3 | 191 | 0.103 | 284 | 0.061 | 377 | 0.106 |
6 | 27.3 | 99 | 0.2 | 192 | 0.054 | 285 | 0.131 | 378 | 1.152 |
7 | 1.2 | 100 | 0.2 | 193 | 0.046 | 286 | 0.037 | 379 | 0.834 |
8 | 0.7 | 101 | 1.4 | 194 | 0.030 | 287 | 0.029 | 380 | 4.539 |
9 | 6.6 | 102 | 0.3 | 195 | 0.036 | 288 | 0.144 | 381 | 0.769 |
10 | 3.6 | 103 | 1.0 | 196 | 0.040 | 289 | 0.053 | 382 | 1.400 |
11 | 6.5 | 104 | 0.1 | 197 | 0.041 | 290 | 0.030 | 383 | 0.659 |
12 | 1.7 | 105 | 0.1 | 198 | 0.043 | 291 | 0.039 | 384 | 0.340 |
13 | 1.8 | 106 | 0.1 | 199 | 0.117 | 292 | 0.020 | 385 | 0.128 |
14 | 0.3 | 107 | 0.1 | 200 | 0.064 | 293 | 0.058 | 386 | 0.048 |
15 | 7.4 | 108 | 0.1 | 201 | 0.042 | 294 | 0.129 | 387 | 0.102 |
16 | 4.2 | 109 | 10.643 | 202 | 0.082 | 295 | 0.040 | 388 | 1.065 |
17 | 11.3 | 110 | 2.634 | 203 | 0.073 | 296 | 0.053 | 389 | 0.075 |
18 | 0.3 | 111 | 0.093 | 204 | 0.048 | 297 | 0.033 | 390 | 0.061 |
19 | 1.1 | 112 | 0.047 | 205 | 0.075 | 298 | 0.016 | 391 | 0.702 |
20 | 0.5 | 113 | 0.046 | 206 | 0.047 | 299 | 0.039 | 392 | 0.070 |
21 | 0.8 | 114 | 0.043 | 207 | 0.162 | 300 | 0.026 | 393 | 0.062 |
22 | 0.1 | 115 | 0.068 | 208 | 0.136 | 301 | 0.040 | 394 | 1.718 |
23 | 0.8 | 116 | 0.08 | 209 | 0.202 | 302 | 0.091 | 395 | 5.267 |
24 | 0.2 | 117 | 0.113 | 210 | 0.071 | 303 | 0.045 | 396 | |
25 | 0.6 | 118 | 0.103 | 211 | 0.082 | 304 | 0.129 | 397 | 0.045 |
26 | 1.8 | 119 | 0.145 | 212 | 0.040 | 305 | 0.088 | 398 | |
27 | 1.6 | 120 | 0.167 | 213 | 0.076 | 306 | 0.057 | 399 | 0.070 |
28 | 0.2 | 121 | 0.163 | 214 | 0.185 | 307 | 0.120 | 400 | 0.058 |
29 | 0.6 | 122 | 0.161 | 215 | 0.203 | 308 | 0.031 | 401 | 0.044 |
30 | 0.6 | 123 | 0.071 | 216 | 0.196 | 309 | 0.029 | 402 | 0.098 |
31 | 3.1 | 124 | 0.066 | 217 | 0.065 | 310 | 0.074 | 403 | 0.059 |
32 | 1.4 | 125 | 0.074 | 218 | 0.345 | 311 | 0.024 | 404 | 0.092 |
33 | 2.9 | 126 | 0.099 | 219 | 0.099 | 312 | 0.039 | 405 | 0.113 |
34 | 2.0 | 127 | 0.085 | 220 | 0.122 | 313 | 0.064 | 406 | 0.103 |
35 | 0.2 | 128 | 0.068 | 221 | 0.046 | 314 | 0.054 | 407 | 0.113 |
36 | 8.1 | 129 | 0.077 | 222 | 0.044 | 315 | 0.127 | 408 | 0.054 |
37 | 1.4 | 130 | 0.18 | 223 | 0.039 | 316 | 0.056 | 409 | 0.147 |
38 | 0.2 | 131 | 0.046 | 224 | 0.195 | 317 | 0.034 | 410 | 0.194 |
39 | 0.1 | 132 | 0.038 | 225 | 0.043 | 318 | 0.066 | 411 | 0.178 |
40 | 0.1 | 133 | 0.051 | 226 | 0.095 | 319 | 0.038 | 412 | 0.072 |
41 | 0.1 | 134 | 0.072 | 227 | 0.076 | 320 | 0.035 | 413 | 0.478 |
42 | 0.1 | 135 | 0.213 | 228 | 0.069 | 321 | 0.037 | 414 | 0.217 |
43 | 1.6 | 136 | 0.183 | 229 | 0.030 | 322 | 0.057 | 415 | 0.526 |
44 | 0.1 | 137 | 0.491 | 230 | 0.027 | 323 | 0.158 | 416 | 0.047 |
45 | 0.1 | 138 | 0.112 | 231 | 0.051 | 324 | 0.058 | 417 | 0.092 |
46 | 0.1 | 139 | 0.116 | 232 | 0.052 | 325 | 0.100 | 418 | 0.197 |
47 | 0.1 | 140 | 0.043 | 233 | 0.016 | 326 | 0.076 | 419 | 0.186 |
48 | 3.7 | 141 | 0.086 | 234 | 0.053 | 327 | 0.051 | 420 | 0.237 |
49 | 0.1 | 142 | 0.097 | 235 | 0.035 | 328 | 0.049 | 421 | 0.081 |
50 | 1.4 | 143 | 0.173 | 236 | 0.055 | 329 | 0.087 | 422 | 0.035 |
51 | 0.1 | 144 | 0.05 | 237 | 0.044 | 330 | 0.030 | 423 | 0.056 |
52 | 0.9 | 145 | 0.037 | 238 | 0.033 | 331 | 0.075 | 424 | 0.037 |
53 | 0.2 | 146 | 0.062 | 239 | 0.042 | 332 | 0.071 | 425 | 0.078 |
54 | 0.2 | 147 | 0.051 | 240 | 0.018 | 333 | 0.039 | 426 | 0.091 |
55 | 0.2 | 148 | 0.043 | 241 | 0.087 | 334 | 0.041 | 427 | 0.104 |
56 | 0.6 | 149 | 0.109 | 242 | 0.074 | 335 | 0.235 | 428 | 0.069 |
57 | 0.2 | 150 | 0.071 | 243 | 0.059 | 336 | 0.100 | 429 | 0.129 |
58 | 0.2 | 151 | 0.036 | 244 | 0.032 | 337 | 0.050 | 430 | 0.170 |
59 | 0.1 | 152 | 0.057 | 245 | 0.066 | 338 | 0.090 | 431 | 0.121 |
60 | 0.2 | 153 | 0.086 | 246 | 0.096 | 339 | 0.070 | 432 | 0.070 |
61 | 0.1 | 154 | 0.05 | 247 | 0.042 | 340 | 0.031 | 433 | 0.133 |
62 | 0.4 | 155 | 0.060 | 248 | 0.042 | 341 | 0.032 | 434 | 0.446 |
63 | 1.4 | 156 | 0.111 | 249 | 0.140 | 342 | 0.029 | 435 | 0.114 |
64 | 5.2 | 157 | 0.234 | 250 | 0.029 | 343 | 0.019 | 436 | 0.886 |
65 | 1.8 | 158 | 0.135 | 251 | 0.037 | 344 | 0.049 | 437 | 0.301 |
66 | 2.7 | 159 | 0.087 | 252 | 0.043 | 345 | 0.037 | 438 | 0.187 |
67 | 1.2 | 160 | 0.031 | 253 | 0.037 | 346 | 0.031 | 439 | 0.138 |
68 | 46.9 | 161 | 0.025 | 254 | 0.126 | 347 | 0.084 | 440 | 0.051 |
69 | 4.0 | 162 | 0.180 | 255 | 0.096 | 348 | 0.041 | 441 | 0.223 |
70 | 0.2 | 163 | 0.263 | 256 | 0.162 | 349 | 0.026 | 442 | 0.134 |
71 | 0.7 | 164 | 0.141 | 257 | 0.083 | 350 | 0.055 | 443 | 0.187 |
72 | 0.1 | 165 | 0.035 | 258 | 0.117 | 351 | 0.035 | 444 | 0.101 |
73 | 0.3 | 166 | 0.067 | 259 | 0.098 | 352 | 0.046 | 445 | 0.091 |
74 | 7.3 | 167 | 0.141 | 260 | 0.061 | 353 | 0.103 | 446 | 0.149 |
75 | 0.3 | 168 | 0.222 | 261 | 0.053 | 354 | 0.039 | 447 | 0.132 |
76 | 10.5 | 169 | 0.048 | 262 | 0.056 | 355 | 0.062 | 448 | 0.117 |
77 | 5.3 | 170 | 0.060 | 263 | 0.073 | 356 | 0.081 | 449 | 0.131 |
78 | 0.8 | 171 | 0.033 | 264 | 0.263 | 357 | 0.113 | 450 | 0.234 |
79 | 0.4 | 172 | 0.022 | 265 | 0.046 | 358 | 0.114 | 451 | 0.520 |
80 | 0.3 | 173 | 0.087 | 266 | 0.085 | 359 | 0.038 | 452 | 0.045 |
81 | 0.5 | 174 | 0.153 | 267 | 0.030 | 360 | 0.052 | 453 | 0.092 |
82 | 1.1 | 175 | 0.140 | 268 | 0.058 | 361 | 0.055 | 454 | 0.098 |
83 | 0.1 | 176 | 0.138 | 269 | 0.081 | 362 | 0.024 | 455 | 0.147 |
84 | 0.1 | 177 | 0.129 | 270 | 0.041 | 363 | 0.042 | 456 | 0.099 |
85 | 0.6 | 178 | 0.141 | 271 | 0.100 | 364 | 0.064 | 457 | 0.085 |
86 | 1.8 | 179 | 0.102 | 272 | 0.018 | 365 | 0.040 | 458 | 0.079 |
87 | 3.2 | 180 | 0.092 | 273 | 0.077 | 366 | 0.086 | 459 | 0.085 |
88 | 1.5 | 181 | 0.146 | 274 | 0.043 | 367 | 0.063 | 460 | 0.089 |
89 | 0.5 | 182 | 0.144 | 275 | 0.053 | 368 | 461 | 0.087 | |
90 | 0.5 | 183 | 0.132 | 276 | 0.068 | 369 | 462 | 0.251 | |
91 | 0.1 | 184 | 0.108 | 277 | 0.061 | 370 | 463 | 0.219 | |
92 | 0.1 | 185 | 0.041 | 278 | 0.089 | 371 | 464 | 0.209 | |
93 | 51.0 | 186 | 0.066 | 279 | 0.041 | 372 | 比較實例 1 | 0.5 |
SKBR3細胞(ATCC HTB-30)係獲自ATCC (Manassas,VA),且在McCoy 5A培養基(ATCC 30-2007) + 10%胎牛血清(SH30071.03,HyClone,Pittsburgh,PA)加上1×青黴素-鏈黴素L-麩醯胺酸(Corning 30-009-Cl,Corning,NY))中培養。方法
細胞生存力分析係在總體積為70 μL之384孔組織培養盤(Grenier 781086,Monroe,NC)中進行。測試化合物係以1,000×種製備,連續稀釋,且藉由Echo 555液體處置器(Labcyte Inc., San Jose, CA)預點樣至384孔組織培養盤中。將70 μl 6,000個SKBR3細胞分配至該盤之各孔中,且在37℃下在5% CO2
之情況下培育72小時。在培育結束時,製備2× CellTiter Glo (CTG)試劑(1份緩衝劑及2份受質) (Promega, Madison, WI),且將該盤及試劑平衡至室溫達30分鐘。在移液5次之情況下藉由Biomek FX以20 μL/孔將CTG試劑添加至各盤中,且混合以誘導細胞溶解。藉由Envision多模讀取器(PerkinElmer)讀取發光。計算EC50
值且報導在表 2
中。比較實例 1
為來自國際公開案第WO 2016/033486號之實例4。如下計算抑制百分比:
抑制% = 100% × (良好 - Neg) / (Pos - Neg)
Neg,陰性對照,DMSO
Pos,陽性對照,10 μM嘌呤黴素表 2. MCL-1 CV SKBR3 EC50
(nM)
實例 | EC50 (nM) | 實 例 | EC50 (nM) | 實 例 | EC50 (nM) | 實 例 | EC50 (nM) | 實 例 | EC50 (nM) |
1 | 1701.8 | 94 | 901.6 | 187 | 43.096 | 280 | 50 | 373 | |
2 | 792.2 | 95 | 1103.0 | 188 | 78.259 | 281 | 183.521 | 374 | 47.482 |
3 | N.D. | 96 | 603.6 | 189 | 64.255 | 282 | 28.657 | 375 | 22.367 |
4 | 899.1 | 97 | 787.7 | 190 | 283 | 84.797 | 376 | 26.706 | |
5 | 10000.0 | 98 | 2188.5 | 191 | 123.213 | 284 | 54.672 | 377 | 33.992 |
6 | 8731.8 | 99 | 2091.9 | 192 | 39.714 | 285 | 79.68 | 378 | 1182.46 |
7 | 4800.1 | 100 | 2260.5 | 193 | 286 | 65.07 | 379 | 1663.07 | |
8 | N.D. | 101 | 2586.5 | 194 | 287 | 25.014 | 380 | 3401.06 | |
9 | 7776.1 | 102 | 891.3 | 195 | 29.64 | 288 | 169.57 | 381 | 534.464 |
10 | N.D. | 103 | 10000.0 | 196 | 99.186 | 289 | 588.134 | 382 | 562.153 |
11 | 10000.0 | 104 | N.D. | 197 | 129.808 | 290 | 26.375 | 383 | 1195.62 |
12 | 4464.8 | 105 | 351.4 | 198 | 103.987 | 291 | 384 | 153.799 | |
13 | 3274.3 | 106 | N.D. | 199 | 58.219 | 292 | 45.095 | 385 | 221.972 |
14 | 356.3 | 107 | N.D. | 200 | 293 | 69.205 | 386 | 83.761 | |
15 | 7734.0 | 108 | N.D. | 201 | 103.304 | 294 | 260.141 | 387 | 161.643 |
16 | 10000.0 | 109 | 202 | 90.982 | 295 | 21.969 | 388 | 1395.31 | |
17 | 10000.0 | 110 | 203 | 76.148 | 296 | 64.086 | 389 | 303.742 | |
18 | 894.5 | 111 | 721.43 | 204 | 136.301 | 297 | 68.966 | 390 | 86.369 |
19 | 1084.8 | 112 | 73.25 | 205 | 58.879 | 298 | 71.896 | 391 | 4557.45 |
20 | 2060.5 | 113 | 206 | 299 | 59.742 | 392 | 142.343 | ||
21 | 1303.0 | 114 | 154.23 | 207 | 43.957 | 300 | 26.776 | 393 | 33.351 |
22 | 259.4 | 115 | 208 | 45.025 | 301 | 41.854 | 394 | 4745.65 | |
23 | 1451.0 | 116 | 141.46 | 209 | 302 | 301.941 | 395 | 6177.74 | |
24 | 891.2 | 117 | 82.89 | 210 | 43.444 | 303 | 22.84 | 396 | |
25 | 2005.9 | 118 | 184.35 | 211 | 54.2 | 304 | 21.302 | 397 | |
26 | 1685.9 | 119 | 93.75 | 212 | 37.619 | 305 | 139.57 | 398 | |
27 | 2080.3 | 120 | 106.06 | 213 | 56.973 | 306 | 43.594 | 399 | 19.98 |
28 | 8407.1 | 121 | 71.54 | 214 | 55.876 | 307 | 96.799 | 400 | 530.34 |
29 | 1838.6 | 122 | 112.69 | 215 | 308 | 16.109 | 401 | 117.941 | |
30 | 1835.7 | 123 | 114.49 | 216 | 309 | 10.548 | 402 | 90.153 | |
31 | 2585.3 | 124 | 95.85 | 217 | 83.199 | 310 | 230.419 | 403 | 13.758 |
32 | 1478.8 | 125 | 88.65 | 218 | 85.531 | 311 | 13.432 | 404 | 196.712 |
33 | 7436.2 | 126 | 122.98 | 219 | 145.684 | 312 | 43.55 | 405 | 195.953 |
34 | 3354.6 | 127 | 157.55 | 220 | 97.761 | 313 | 94.474 | 406 | 332.427 |
35 | 265.7 | 128 | 96.44 | 221 | 103.725 | 314 | 32.934 | 407 | |
36 | 10000.0 | 129 | 64.66 | 222 | 80.097 | 315 | 164.107 | 408 | 240.875 |
37 | 1612.6 | 130 | 152.35 | 223 | 37.34 | 316 | 115.522 | 409 | 297.308 |
38 | 280.0 | 131 | 161.74 | 224 | 83.461 | 317 | 48.506 | 410 | 145.606 |
39 | 261.6 | 132 | 71.99 | 225 | 51.277 | 318 | 74.379 | 411 | 174.67 |
40 | 328.0 | 133 | 130.07 | 226 | 71.326 | 319 | 19.879 | 412 | 179.346 |
41 | 255.5 | 134 | 59.56 | 227 | 21.252 | 320 | 36.615 | 413 | 129.529 |
42 | 3338.7 | 135 | 131.91 | 228 | 69.861 | 321 | 47.093 | 414 | 153.743 |
43 | 2410.8 | 136 | 76.42 | 229 | 322 | 64.447 | 415 | 104.739 | |
44 | 375.6 | 137 | 103.58 | 230 | 47.091 | 323 | 169.714 | 416 | 130.943 |
45 | 191.2 | 138 | 60.54 | 231 | 39.981 | 324 | 37.906 | 417 | 403.335 |
46 | 512.3 | 139 | 94.07 | 232 | 242.625 | 325 | 50.295 | 418 | 335.297 |
47 | 758.2 | 140 | 38.59 | 233 | 47.175 | 326 | 52.579 | 419 | 135.182 |
48 | 8453.2 | 141 | 65.32 | 234 | 73.857 | 327 | 28.609 | 420 | 124.328 |
49 | 207.2 | 142 | 416.33 | 235 | 39.785 | 328 | 72.183 | 421 | 152.44 |
50 | 3320.5 | 143 | 218.95 | 236 | 151.512 | 329 | 56.983 | 422 | 187.244 |
51 | 705.4 | 144 | 50.76 | 237 | 120.97 | 330 | 56.423 | 423 | 168.533 |
52 | 1951.8 | 145 | 147.42 | 238 | 23.352 | 331 | 68.944 | 424 | 147.23 |
53 | 388.1 | 146 | 184.91 | 239 | 332 | 51.133 | 425 | 170.703 | |
54 | 3809.1 | 147 | 110.61 | 240 | 91.536 | 333 | 38.306 | 426 | 316.412 |
55 | 685.2 | 148 | 37.17 | 241 | 334 | 48.609 | 427 | 331.872 | |
56 | 1180.4 | 149 | 95.28 | 242 | 83.993 | 335 | 66.239 | 428 | 164.693 |
57 | 596.5 | 150 | 39.26 | 243 | 41.72 | 336 | 60.424 | 429 | 260.617 |
58 | 663.5 | 151 | 244 | 116.254 | 337 | 86.397 | 430 | 139.281 | |
59 | 873.9 | 152 | 55.70 | 245 | 60.739 | 338 | 123.754 | 431 | 233.147 |
60 | 1090.8 | 153 | 69.50 | 246 | 176.397 | 339 | 53.182 | 432 | 171.684 |
61 | 774.8 | 154 | 24.1 | 247 | 84.985 | 340 | 37.086 | 433 | 394.987 |
62 | 2427.2 | 155 | 43.01 | 248 | 55.287 | 341 | 39.429 | 434 | 402.832 |
63 | 9713.3 | 156 | 145.374 | 249 | 221.575 | 342 | 33.638 | 435 | 167.159 |
64 | 5825.9 | 157 | 64.776 | 250 | 44.38 | 343 | 17.328 | 436 | 752.744 |
65 | 1971.3 | 158 | 47.436 | 251 | 39.574 | 344 | 18.544 | 437 | 122.588 |
66 | 5828.7 | 159 | 144.479 | 252 | 82.721 | 345 | 22.56 | 438 | 278.341 |
67 | 1040.8 | 160 | 35.036 | 253 | 39.167 | 346 | 30.944 | 439 | 789.246 |
68 | 6299.0 | 161 | 168.251 | 254 | 154.781 | 347 | 79.756 | 440 | 284.088 |
69 | 7800.5 | 162 | 136.473 | 255 | 348 | 84.676 | 441 | 373.917 | |
70 | 373.6 | 163 | 98.741 | 256 | 160.518 | 349 | 33.724 | 442 | 122.053 |
71 | 1385.7 | 164 | 106.452 | 257 | 89.674 | 350 | 75.591 | 443 | 161.763 |
72 | 262.0 | 165 | 45.503 | 258 | 194.681 | 351 | 58.806 | 444 | 171.572 |
73 | 2449.3 | 166 | 79.778 | 259 | 352 | 54.429 | 445 | 209.764 | |
74 | 10000.0 | 167 | 58.568 | 260 | 353 | 256.743 | 446 | 175.783 | |
75 | 691.7 | 168 | 74.154 | 261 | 72.01 | 354 | 36.948 | 447 | 161.434 |
76 | 6330.5 | 169 | 60.981 | 262 | 85.774 | 355 | 67.355 | 448 | 250.704 |
77 | 6036.1 | 170 | 209.553 | 263 | 62.236 | 356 | 233.261 | 449 | 146.579 |
78 | 4068.4 | 171 | 129.805 | 264 | 357 | 206.237 | 450 | 167.379 | |
79 | 3031.6 | 172 | 125.128 | 265 | 96.236 | 358 | 95.129 | 451 | 160.647 |
80 | 1059.2 | 173 | 67.868 | 266 | 53.788 | 359 | 19.022 | 452 | 282.052 |
81 | 612.3 | 174 | 102.675 | 267 | 184.308 | 360 | 139.487 | 453 | 96.749 |
82 | 2315.0 | 175 | 33.867 | 268 | 88.772 | 361 | 44 | 454 | 146.083 |
83 | 460.5 | 176 | 79.254 | 269 | 264.075 | 362 | 17.259 | 455 | 145.824 |
84 | 783.2 | 177 | 46.373 | 270 | 61.679 | 363 | 46.531 | 456 | 174.228 |
85 | 3092.7 | 178 | 143.607 | 271 | 175.649 | 364 | 258.689 | 457 | 391.672 |
86 | 4913.7 | 179 | 82.519 | 272 | 47.923 | 365 | 145.67 | 458 | 376.136 |
87 | 10000.0 | 180 | 134.333 | 273 | 81.006 | 366 | 53.129 | 459 | 194.159 |
88 | 2571.9 | 181 | 37.915 | 274 | 82.551 | 367 | 100.501 | 460 | |
89 | 854.8 | 182 | 136.147 | 275 | 90.367 | 368 | 461 | 151.118 | |
90 | 4557.9 | 183 | 195.116 | 276 | 64.262 | 369 | 462 | 344.509 | |
91 | 616.1 | 184 | 47.24 | 277 | 60.866 | 370 | 5795.45 | 463 | |
92 | 245.0 | 185 | 99.209 | 278 | 80.523 | 371 | 464 | 222.449 | |
93 | 4822.2 | 186 | 167.95 | 279 | 372 | 比較實例 1 | 2190.4 |
包括公開案、專利及專利文獻之所有參考文獻均以引用之方式併入本文中,如同單獨地以引用之方式併入一般。本發明提供對各種實施例及技術之提及。然而,應理解,可作出許多變化及修改,同時該等變化及修改保持在本發明之精神及範疇內。在理解描述視為所主張主題之例證說明之情況下作出描述,且該描述不意欲將隨附申請專利範圍限於所說明之特定實施例。為方便起見,提供在本發明通篇使用之標題,且不解釋為該等標題以任何方式限制申請專利範圍。在任何標題下說明之實施例可與在任何其他標題下說明之實施例組合。
Claims (10)
- 如請求項1之用途,其中該癌症為非小細胞肺癌。
- 如請求項1之用途,其中該癌症為乳癌。
- 如請求項1之用途,其中該癌症為多發性骨髓瘤。
- 如請求項1之用途,其中該癌症為白血病。
- 如請求項6之用途,其中該癌症為非小細胞肺癌。
- 如請求項6之用途,其中該癌症為乳癌。
- 如請求項6之用途,其中該癌症為多發性骨髓瘤。
- 如請求項6之用途,其中該癌症為白血病。
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