TWI819225B - 作為eed抑制劑之咪唑并嘧啶及其用途 - Google Patents
作為eed抑制劑之咪唑并嘧啶及其用途 Download PDFInfo
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- TWI819225B TWI819225B TW109124012A TW109124012A TWI819225B TW I819225 B TWI819225 B TW I819225B TW 109124012 A TW109124012 A TW 109124012A TW 109124012 A TW109124012 A TW 109124012A TW I819225 B TWI819225 B TW I819225B
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- A61P35/00—Antineoplastic agents
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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- C07D487/14—Ortho-condensed systems
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- C07D487/16—Peri-condensed systems
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/16—Peri-condensed systems
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- C07D495/14—Ortho-condensed systems
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- C07D513/22—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 four or more hetero rings
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本揭示案提供由式I
表示之化合物:,
其中R1
、R2
、R3
及R4
如本說明書中所定義,及其鹽及溶劑合物。式I
化合物為EED抑制劑。EED抑制劑可用於治療癌症及其他疾病。
Description
本揭示案提供胚胎外胚層發育(EED)抑制劑、用於製備EED抑制劑之合成中間物以及治療抑制EED蛋白提供益處之病況及疾病(例如癌症)之治療方法。
多梳家族(PcG)蛋白為在許多人類癌症中失調之染色質修飾酶。多梳抑制複合物2 (PRC2)包括SUZ12 (zeste 12之抑制因子)、EED及催化次單位EZH2 (zeste同源物2之強化子),藉由使靶基因啟動子區及周圍之核心組蛋白H3離胺酸27 (H3K27me3)甲基化來抑制基因。PRC2為參與基因轉錄之表觀遺傳調控之細胞機制的關鍵組分,且在發育、組織分化及再生中發揮關鍵作用。參見例如Moritz及Trievel,
《生物化學雜誌(J. Biol. Chem.
)》293(36)
:13805-13814 (2018);Fiskus等人, 《分子癌症治療學(Mol Cancer Ther
)》5(12)
:3096-3014 (2006)。
PRC2之甲基轉移酶活性至少需要EED及SUZ12。EED、SUZ12及EZH2在許多癌症中過度表現,包括但不限於乳癌、前列腺癌及肝細胞癌。此項技術中存在對抑制EED活性之小分子的需求以治療癌症及其他疾病。
在一個態樣中,本揭示案提供由以下式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者表示之化合物及其醫藥學上可接受之鹽及溶劑合物,例如水合物,統稱為「本揭示案之化合物」。本揭示案之化合物為EED抑制劑及/或可用於製備EED抑制劑之合成中間物。因此,本揭示案之某些化合物可用於治療或預防抑制EED蛋白提供益處之疾病或病況,諸如癌症。
在另一態樣中,本揭示案提供藉由向有需要之個體(例如人類患者)投與治療有效量之本揭示案之化合物來治療或預防病況或疾病之方法。可藉由抑制EED治療或預防之所關注之疾病或病況為例如癌症、慢性自體免疫病症、發炎性病況、增生性病症、敗血症或病毒感染。亦提供防止不想要的增殖性細胞(諸如在癌症中)在個體增殖之方法,其包含向處於罹患以不想要的增殖性細胞為特徵之病況風險下的個體投與治療有效量之本揭示案之化合物。在一些實施例中,本揭示案之化合物可藉由誘導彼等細胞之凋亡來減少不想要的細胞的增殖。在一些實施例中,本揭示案之化合物與視情況選用之治療劑組合投與。
在另一態樣中,本揭示案提供一種抑制個體之EED的方法,其包含向該個體投與治療有效量之本揭示案之化合物。
在另一態樣中,本揭示案提供一種醫藥組合物,其包含本揭示案之化合物及賦形劑及/或醫藥學上可接受之載劑。
在另一態樣中,本揭示案提供一種包含本揭示案之化合物及賦形劑及/或醫藥學上可接受之載劑的組合物,用於治療或預防抑制EED提供益處之疾病或病況,例如癌症。
在另一態樣中,本揭示案提供一種組合物,其包含:(a)本揭示案之化合物;(b)第二治療活性劑;及(c)視情況選用之賦形劑及/或醫藥學上可接受之載劑。
在另一態樣中,本揭示案提供用於治療或預防所關注之疾病或病況(例如癌症)之本揭示案之化合物。
在另一態樣中,本揭示案提供本揭示案之化合物用於製造治療所關注之疾病或病況(例如癌症)之藥物的用途。
在另一態樣中,本揭示案提供一種套組,其包含本揭示案之化合物及視情況選用之封裝組合物,該封裝組合物包含視情況選用之可用於治療所關注之疾病或病況的治療劑,及含有用於治療疾病或病況(例如癌症)之指示的藥品說明書。
在另一態樣中,本揭示案提供製備本揭示案之化合物及本揭示案之中間物的方法。
本揭示案之其他實施例及優點將在下面的描述中部分闡述,且將自描述中流露出,或可藉由本揭示案之實踐而習得。本揭示案之實施例及優點將藉由在隨附申請專利範圍中特別指出之要素及組合來實現及獲得。
應理解,前述發明內容與以下實施方式僅為例示性及解釋性的,而非限制所主張之發明。
I.本揭示案之化合物
本揭示案之化合物為EED抑制劑及/或可用於製備EED抑制劑之合成中間物。
在一個實施例中,本揭示案之化合物為式I
化合物:,
其中:
R1
為芳烷基;
R2
選自由氫及C1
-C4
烷基組成之群組;
R3
及R4
與其所連接之碳原子一起形成式I-A
、I-B
或I-C
之基團:;
X選自由-C(R5a
)(R5b
)-、-C(=O)-及-S(=O)2
-組成之群組;
R5a
及R5b
獨立地選自由氫及C1
-C4
烷基組成之群組;
Y選自由-C(R6a
)(R6b
)-、-S-、-O-及-N(R7
)-組成之群組;或
X及Y一起形成5員伸雜芳基;
Z為-C(R6c
)(R6d
)m
-;
R6a
及R6b
獨立地選自由氫及C1
-C4
烷基組成之群組;
各R6c
及R6d
獨立地選自由氫及C1
-C4
烷基組成之群組;
m為0、1或2;
R7
選自由氫、C1
-C6
烷基、C1
-C6
鹵烷基、視情況經取代之C3
-C8
環烷基、視情況經取代之C4
-C8
雜環基、羥烷基、(烷氧基)烷基、(環烷基)烷基及(雜環基)烷基組成之群組;
R8a
、R8b
及R8c
獨立地選自由氫、鹵基、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C4
烷氧基、甲醯胺基、視情況經取代之C3
-C8
環烷基、視情況經取代之4員至8員雜環基、(雜環基)C1
-C4
烷基及烷基磺醯基組成之群組;
為稠合苯基、稠合5員雜芳基或稠合6員雜芳基;
為視情況經取代之稠合3員至8員環烷基或視情況經取代之稠合4員至8員雜環基;
為視情況經取代之稠合4員至8員雜環基;及
用「」標明之鍵附接在式I
之R3
位置,且用「*」標明之鍵附接在式I
之R4
位置;或
R3
為R3a
;
R4
為R4a
;
R3a
選自由視情況經取代之芳基、視情況經取代之5員至10員雜芳基及視情況經取代之4員至8員雜環基組成之群組;及
R4a
選自由氫、鹵基、C1
-C4
鹵烷基、-S(=O)2
R9
、-P(=O)(R10a
)(R10b
)、-C(=O)OR11a
、-C(=O)NR11b
R11c
及-S(=O)(=NR13a
)R13b
組成之群組;
R9
選自由C1
-C4
烷基及C3
-C6
環烷基組成之群組;
R10a
及R10b
獨立地為C1
-C4
烷基;
R11a
選自由氫及C1
-C4
烷基組成之群組;
R11b
及R11c
獨立地選自由氫及C1
-C4
烷基組成之群組;或
R11b
及R11c
與其所連接之氮原子一起形成視情況經取代之4員至6員雜環基;
R13a
選自由氫、C1
-C6
烷基、C3
-C6
環烷基及羥烷基組成之群組;
R13b
選自由C1
-C6
烷基及C3
-C6
環烷基組成之群組;或
R13a
及R13b
一起形成5員至7員雜環基;及
為單鍵或雙鍵,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
化合物,其中:
X選自由-C(R5a
)(R5b
)-、-C(=O)-及-S(=O)2
-組成之群組;
Y選自由-C(R6a
)(R6b
)-、-S-、-O-及-N(R7
)-組成之群組;及
R8a
、R8b
及R8c
獨立地選自由氫、鹵基、C1
-C4
烷基、C1
-C4
鹵烷基、C1
-C4
烷氧基及烷基磺醯基組成之群組,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
化合物,其中R3
及R4
與其所連接之碳原子一起形成式I-A
、I-B
或I-C
之基團,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式II
化合物:,
其中R1
、R2
、R8a
、R8b
、R8c
、X、Y、Z、及如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式III
化合物:,
其中L選自由-C(R8b
)=及-N=組成之群組;且R1
、R2
、R8a
、R8b
、R8c
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式IV
化合物:,
其中L選自由-C(R8b
)=及-N=組成之群組;且R1
、R2
、R8a
、R8b
、R8c
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式V
化合物:,
其中L選自由-C(R8b
)=及-N=組成之群組;且R1
、R2
、R8a
、R8b
、R8c
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式VI
化合物:,
其中L選自由-C(R8b
)=及-N=組成之群組;且R1
、R2
、R8a
、R8b
、R8c
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式III
-VI
中之任一者之化合物,其中L為-C(R8b
)=,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式III
-VI
中之任一者之化合物,其中L為-N=,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-VI
中之任一者之化合物,其中R8a
、R8b
及R8c
獨立地選自由氫、C1
-C4
烷基、C1
-C4
鹵烷基及C3
-C6
環烷基組成之群組,或其醫藥學上可接受之鹽或溶劑合物。在另一個實施例中,R8a
選自由-CHF2
、-CF3
、-CH3
、-CD3
及環丙基組成之群組;且R8b
及R8c
為氫。在另一個實施例中,R8a
選自由-CF3
或-CH3
組成之群組;且R8b
及R8c
為氫。
在另一個實施例中,本揭示案之化合物為式I
-VI
中之任一者之化合物,其中R8a
選自由C1
-C4
烷基、4員至8員雜環基及(雜環基)C1
-C4
烷基組成之群組;且R8b
及R8c
為氫,或其醫藥學上可接受之鹽或溶劑合物。在另一個實施例中,R8a
為C1
-C4
烷基。在另一個實施例中,R8a
為4員至8員雜環。在另一個實施例中,R8a
為(雜環基)C1
-C4
烷基。在另一個實施例中,R8a
選自由以下組成之群組:。
在另一個實施例中,本揭示案之化合物為式VII
化合物:,
其中:
L1
選自由-S-、-O-及-N(R8a
)-組成之群組;
L2
選自由-C(R8b
)=及-N=組成之群組;
L3
選自由-C(R8c
)=及-N=組成之群組;
R8a
選自由氫及C1
-C4
烷基組成之群組;
R8b
選自由氫、C1
-C4
烷基及C1
-C4
鹵烷基組成之群組;
R8c
選自由氫、C1
-C4
烷基及C1
-C4
鹵烷基組成之群組;及
R1
、R2
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式VIII
化合物:,
其中:
L1
選自由-S-、-O-及-N(R8a
)-組成之群組;
L2
選自由-C(R8b
)=及-N=組成之群組;
L3
選自由-C(R8c
)=及-N=組成之群組;
R8a
選自由氫及C1
-C4
烷基組成之群組;
R8b
選自由氫、C1
-C4
烷基及C1
-C4
鹵烷基組成之群組;
R8c
選自由氫、C1
-C4
烷基及C1
-C4
鹵烷基組成之群組;及
R1
、R2
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式IX
化合物:,
其中:
L1
選自由-S-、-O-及-N(R8a
)-組成之群組;
R8a
選自由氫及C1
-C4
烷基組成之群組;
R8b
選自由氫、C1
-C4
烷基及C1
-C4
鹵烷基組成之群組;
R8c
選自由氫、C1
-C4
烷基及C1
-C4
鹵烷基組成之群組;及
R1
、R2
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式X
化合物:,
其中R1
、R2
、X、Y、Z、及如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XI
化合物:,
其中:
R8d
、R8e
及R8f
獨立地選自由氫、鹵基及C1
-C4
烷基組成之群組;
n為1、2或3;且
R1
、R2
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XI-A
化合物:,
其中R1
、R2
、R8d
、R8e
、R8f
、n、X、Y及Z如關於式XI
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XI-B
化合物:,
其中R1
、R2
、R8d
、R8e
、R8f
、n、X、Y及Z如關於式XI
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XII
化合物:,
其中:
L4
選自由-S-、-O-及-N(R8g
)-組成之群組;
R8g
選自由氫、C1
-C4
烷基、視情況經取代之C3
-C6
環烷基及視情況經取代之4員至8員雜環基組成之群組;
o為0、1、2或3;
p為0、1、2或3;
其中o和p之和為1、2、3、4或5;且
R1
、R2
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XII-A
化合物:,
其中R1
、R2
、L4
、o、p、X、Y及Z如關於式XII
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XII-B
化合物:,
其中R1
、R2
、L4
、o、p、X、Y及Z如關於式XII
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XIII
化合物:,
其中R1
、R2
、X、Y、Z及如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XIII-A
化合物:,
其中R1
、R2
、X、Y、Z及如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XIII-B
化合物:,
其中R1
、R2
、X、Y、Z及如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XIV
化合物:,
其中:
R8d
、R8e
及R8f
獨立地選自由氫及C1
-C4
烷基組成之群組;
q為1、2或3;且
R1
、R2
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XIV-A
化合物:,
其中R1
、R2
、R8d
、R8e
、R8f
、q、X、Y及Z如關於式XIV
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XIV-B
化合物:,
其中R1
、R2
、R8d
、R8e
、R8f
、q、X、Y及Z如關於式XIV
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XV
化合物:,
其中:
L5
選自由-S-、-O-及-N(R8h
)-組成之群組;
R8h
選自由氫、C1
-C4
烷基、視情況經取代之C3
-C6
環烷基、視情況經取代之4員至8員雜環基、-C(=O)R14a
及-S(=O)2
R14b
組成之群組;
R14a
及R14b
獨立地選自由C1
-C6
烷基及視情況經取代之C3
-C8
環烷基組成之群組;
r為1、2或3;
s為1、2或3;且
R1
、R2
、X、Y及Z如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XV-A
化合物:,
其中R1
、R2
、L5
、r、s、X、Y及Z如關於式XV
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XV-B
化合物:,
其中R1
、R2
、L5
、r、s、X、Y及Z如關於式XV
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中Z為-CH2
-,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中X為-CH2
-,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中X為-C(=O)-,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中X為-S(=O)2
-,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中Y為-O-,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中Y為-N(R7
)-,或其醫藥學上可接受之鹽或溶劑合物。在另一個實施例中,R7
選自由C1
-C6
烷基、C1
-C6
鹵烷基及視情況經取代之C3
-C8
環烷基組成之群組,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中Z為-CH2
-,X為-C(=O)-且Y為-N(R7
)-,或其醫藥學上可接受之鹽或溶劑合物。在另一個實施例中,R7
選自由C1
-C6
烷基、C1
-C6
鹵烷基及視情況經取代之C3
-C8
環烷基組成之群組。在另一個實施例中,R7
為C1
-C4
烷基。在另一個實施例中,R7
選自由甲基、乙基、丙基或異丙基組成之群組。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中X-Y一起形成視情況經取代之稠合5員或6員雜芳基,或其醫藥學上可接受之鹽或溶劑合物。在另一個實施例中,X及Y一起形成5員伸雜芳基。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中X及Y一起形成式I-D
之5員伸雜芳基:,
其中:
X1
選自由=CR15a
-及=N-組成之群組;
Y1
選自由-O-、-S-及-NR15c
-組成之群組;
Z1
選自由=CR15b
-及=N-組成之群組;
R15a
及R15b
獨立地選自由氫、C1
-C4
烷基、C1
-C4
鹵烷基及C3
-C6
環烷基組成之群組;
R15c
選自由氫、C1
-C4
烷基及C3
-C6
環烷基組成之群組;及
用「」標明之鍵附接至Z,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中X及Y一起形成式I-E
之5員伸雜芳基:,
其中:
X2
選自由=CR16a
-及=N-組成之群組;
Y2
選自由=CR16b
-及=N-組成之群組;
Z2
選自由=CR16b
-及=N-組成之群組;及
R16a
、R16b
及R16c
獨立地選自由氫、C1
-C4
烷基及C3
-C6
環烷基組成之群組;及
用「」標明之鍵附接至Z,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中之任一者之化合物,其中X及Y一起形成選自由以下組成之群組之5員伸雜芳基:,
其中用「」標明之鍵附接至Z,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XVI
化合物:,
其中R1
、R2
、R3a
及R4a
如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R3a
為視情況經取代之苯基,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R3a
為視情況經取代之5員雜芳基,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R3a
為視情況經取代之6員雜芳基,或其醫藥學上可接受之鹽或溶劑合物。在另一個實施例中,R3a
選自由以下組成之群組:。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R3a
選自由以下組成之群組:。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R3a
選自由以下組成之群組: 。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R3a
為視情況經取代之4員至6員雜環基,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R4a
為C1
-C4
鹵烷基,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R4a
為-S(=O)2
R9
,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R4a
為-P(=O)(R10a
)(R10b
),或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R4a
為-C(=O)OR11a
,或其醫藥學上可接受之鹽或溶劑合物。在另一個實施例中,R11a
為氫。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R4a
為-C(=O)NR11b
R11c
,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式XVI
化合物,其中R4a
為-S(=O)(=NR13a
)R13b
,或其醫藥學上可接受之鹽或溶劑合物。在另一個實施例中,R13a
選自由氫及C1
-C4
烷基組成之群組,且R13b
為C1
-C4
烷基。在另一個實施例中,R13a
及R13b
一起形成6員雜環基,例如,。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中R2
為氫,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中:
R1
為R1
-1:;
R12a
、R12b
及R12c
各自獨立地選自由氫、鹵基、C1
-C4
烷基、C1
-C4
鹵烷基及C1
-C4
烷氧基組成之群組;
W選自由-CH2
-及-C(=O)-組成之群組;及
t為1或2,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中R1
為R1
-1,R12a
為氟;且R12b
及R12c
獨立地選自由氫及氟組成之群組。在另一個實施例中,R12a
為氟;且R12b
及R12c
為氫。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中:
R1
為R1
-2:;
R12a
、R12b
及R12c
各自獨立地選自由氫、鹵基、C1
-C4
烷基、C1
-C4
鹵烷基及C1
-C4
烷氧基組成之群組;及
t為1或2,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中R1
為R1
-2,R12a
為氟;且R12b
及R12c
獨立地選自由氫及氟組成之群組。在另一個實施例中,R12a
為氟;且R12b
及R12c
為氫。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中:
R1
為R1
-3:;且
R12a
、R12b
及R12c
各自獨立地選自由氫、鹵基、C1
-C4
烷基、C1
-C4
鹵烷基及C1
-C4
烷氧基組成之群組,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中R1
為R1
-3,R12a
為氟;且R12b
及R12c
獨立地選自由氫及氟組成之群組。在另一個實施例中,R12a
為氟;且R12b
及R12c
為氫。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中:
R1
為R1
-4:;且
R12a
、R12b
及R12c
各自獨立地選自由氫、鹵基、C1
-C4
烷基、C1
-C4
鹵烷基及C1
-C4
烷氧基組成之群組,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中R1
為R1
-4,R12a
為氟;且R12b
及R12c
獨立地選自由氫及氟組成之群組。在另一個實施例中,R12a
為氟;且R12b
及R12c
為氫。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中R1
選自由以下組成之群組:,
或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中R1
選自由以下組成之群組:
或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
、XV
-B
或XVI
中之任一者之化合物,其中R1
選自由以下組成之群組:,
或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之化合物為表1中列出之任何一或多種化合物,或其醫藥學上可接受之鹽或溶劑合物。
表1
化合物編號 | 結構 | 名稱 |
1 | N-(2-氟-6-甲基苯甲基)-3H,5H-4-氧雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-12-胺 | |
2 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-3H,5H-4-氧雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-12-胺 | |
3 | 11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-2,4,10,11a-四氮雜二苯并[cd,f]薁-3(4H)-酮 | |
4 | 11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-2,4,5,10,11a-五氮雜二苯并[cd,f]薁-3(4H)-酮 | |
5 | 11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-6-(甲基磺醯基)-2,4,10,11a-四氮雜二苯并[cd,f]薁-3(4H)-酮 | |
6 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-3H,5H-4-氧雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
7 | 7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-3H,5H-4-氧雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
8 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-3H,5H-4-氧雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
9 | 12-(((2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-氟-3H,5H-4-氧雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
10 | 12-(((5-氟苯并呋喃-4-基)甲基)胺基)-3H,5H-4-氧雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
11 | 6-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-3H,5H-4-氧雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
12 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-3H,5H-4-氧雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
13 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-3H,5H-4-氧雜-2,8,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
14 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-3H,5H-4-氧雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
15 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
16 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
17 | 7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
18 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-3H,5H-4-氧雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
19 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
20 | 6-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
21 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
22 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
23 | 8-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
24 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(三氟甲基)-3H,5H-4-氧雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
25 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
26 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
27 | 12-((苯并[d][1,3]間二氧雜環戊烯-4-基甲基)胺基)-7-(三氟甲基)-3H,5H-4-氧雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
28 | 12-((2-氟-6-甲氧基苯甲基)胺基)-7-(三氟甲基)-3H,5H-4-氧雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
29 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(三氟甲基)-3H,5H-4-氧雜-2,9,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
30 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(三氟甲基)-3H,5H-4-氧雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
31 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲氧基)-3H,5H-4-氧雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
32 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(三氟甲基)-3H,5H-4-氧雜-2,7,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
33 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-甲基-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
34 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-甲基-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
35 | 4-((1,4-二氧雜環己烷-2-基)甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
36 | 4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
37 | 4-((1,4-二氧雜環己烷-2-基)甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
38 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((1-甲基哌啶-4-基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
39 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-甲基-8-(三氟甲基)-4,5-二氫-3H-2,4,9,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
40 | 4-((1,4-二氧雜環己烷-2-基)甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(三氟甲基)-4,5-二氫-3H-2,4,9,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
41 | 4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
42 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((1-甲基哌啶-4-基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
43 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((1-羥基環丙基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
44 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((1-羥基環丙基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
45 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((四氫-2H-哌喃-4-基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
46 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((四氫-2H-哌喃-4-基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
47 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((3-羥基-3-甲基環丁基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
48 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2-羥基-2-甲基丙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
49 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((3-羥基-3-甲基環丁基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
50 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((3-羥基-3-甲基環丁基)甲基)-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
51 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(四氫-2H-哌喃-4-基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
52 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((四氫呋喃-3-基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
53 | 11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-6-甲基-5,6-二氫-2,4,6,7,10,11a-六氮雜環戊并[4,5]環辛并[1,2,3-cd]茚-3(4H)-酮 | |
54 | 11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-5,7-二氫-3H-4-氧雜-2,6,7,10,11a-五氮雜環戊并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
55 | 4-(環丙基甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
56 | 4-環丙基-11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-6,8-二甲基-5,6-二氫-2,4,6,7,10,11a-六氮雜環戊并[4,5]環辛并[1,2,3-cd]茚-3(4H)-酮 | |
57 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2-甲氧基乙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
58 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2-羥基-2-甲基丙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
59 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
60 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(四氫-2H-哌喃-4-基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
61 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2-氟乙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
62 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2-氟-2-甲基丙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
63 | 4-(2,2-二氟丙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
64 | 4-環丙基-7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
65 | 7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(四氫-2H-哌喃-4-基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
66 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-((四氫-2H-哌喃-4-基)甲基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
67 | 4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
68 | 4-((1,4-二氧雜環己烷-2-基)甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
69 | 4-環丙基-12-((2-氟-6-甲氧基苯甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
70 | 4-環丙基-12-((2-氟-6-甲氧基苯甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
71 | 12-((2-氟-6-甲氧基苯甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
72 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2-氟乙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
73 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
74 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(1-甲基哌啶-4-基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
75 | 7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(1-甲基哌啶-4-基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
76 | 4-(2,2-二氟丙基)-7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
77 | 4-(2,2-二氟丙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
78 | 7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2-氟-2-甲基丙基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
79 | 7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2-氟乙基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
80 | 4-(2,2-二氟乙基)-7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
81 | 4-(2,2-二氟乙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
82 | 4-(2,2-二氟丙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
83 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
84 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
85 | 4-(3,3-二氟環丁基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
86 | 4-環丙基-11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4,5-二氫-3H-8-硫雜-2,4,6,10,11a-五氮雜環戊并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
87 | 4-環丙基-11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-8-硫雜-2,4,10,11a-四氮雜環戊并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
88 | 4-環丙基-11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-6-硫雜-2,4,10,11a-四氮雜環戊并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
89 | 4-(2,2-二氟乙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
90 | 4-乙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
91 | 4-環丙基-11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-8-硫雜-2,4,6,10,11a-五氮雜環戊并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
92 | 4-環丙基-8-氟-13-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-5,6-二氫-2,4,12,13a-四氮雜苯并[4,5]環壬并[1,2,3-cd]茚-3(4H)-酮 | |
93 | 4-(2,6-二甲基四氫-2H-哌喃-4-基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
94 | 11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4H-3-硫雜-2,5,10,11a-四氮雜二苯并[cd,f]薁3,3-二氧化物 | |
95 | 11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-6-甲基-4H-3-硫雜-2,5,10,11a-四氮雜二苯并[cd,f]薁3,3-二氧化物 | |
96 | 7-氟-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3-硫雜-2,11,12a-三氮雜苯并[4,5]環辛并[1,2,3-cd]茚3,3-二氧化物 | |
97 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4,5-二氫-3-硫雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚3,3-二氧化物 | |
98 | 4-(2,6-二甲基四氫-2H-哌喃-4-基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
99 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺 | |
100 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)-8-(4 (甲基磺醯基)苯基)咪唑并[1,5-c]嘧啶-5-胺 | |
101 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(2-甲基吡啶-3-基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
102 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)-8-(6-(三氟甲基)吡啶-3-基)咪唑并[1,5-c]嘧啶-5-胺 | |
103 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(6-甲基吡啶-3-基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
104 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(4-氟苯基)-1 (甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
105 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)-8-(6-(甲基磺醯基)吡啶-3-基)咪唑并[1,5-c]嘧啶-5-胺 | |
106 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(1-甲基-1H-吡唑-4-基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
107 | 8-(6-(二氟甲基)吡啶-3-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
108 | 8-(2,6-二甲基吡啶-3-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
109 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(2-甲基-6-(三氟甲基)吡啶-3-基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
110 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(2-甲基-4-(甲基磺醯基)苯基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
111 | 8-(6-環丙基吡啶-3-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
112 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(4-(甲基磺醯基)苯基)-1-(三氟甲基)咪唑并[1,5-c]嘧啶-5-胺 | |
113 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(三氟甲基)-8-(4-(三氟甲基)苯基)咪唑并[1,5-c]嘧啶-5-胺 | |
114 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(4-氟苯基)-1-(三氟甲基)咪唑并[1,5-c]嘧啶-5-胺 | |
115 | 8-(2,6-二甲基吡啶-3-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(三氟甲基)咪唑并[1,5-c]嘧啶-5-胺 | |
116 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(三氟甲基)-8-(6-(三氟甲基)吡啶-3-基)咪唑并[1,5-c]嘧啶-5-胺 | |
117 | (8-(6-(二氟甲基)吡啶-3-基)-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-基)二甲基氧化膦 | |
118 | (5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(4-氟苯基)咪唑并[1,5-c]嘧啶-1-基)二甲基氧化膦 | |
119 | (5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(6-(三氟甲基)吡啶-3-基)咪唑并[1,5-c]嘧啶-1-基)二甲基氧化膦 | |
120 | 二乙基(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(6-(三氟甲基)吡啶-3-基)咪唑并[1,5-c]嘧啶-1-基)氧化膦 | |
121 | 二乙基(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(4-(三氟甲基)苯基)咪唑并[1,5-c]嘧啶-1-基)氧化膦 | |
122 | 二乙基(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(4-(甲基磺醯基)苯基)咪唑并[1,5-c]嘧啶-1-基)氧化膦 | |
123 | (8-(2,6-二甲基吡啶-3-基)-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-基)二甲基氧化膦 | |
124 | 二乙基(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(4-氟苯基)咪唑并[1,5-c]嘧啶-1-基)氧化膦 | |
125 | (8-(2,6-二甲基吡啶-3-基)-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-基)二乙基氧化膦 | |
126 | N-(呋喃-2-基甲基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺 | |
127 | 5-((呋喃-2-基甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯 | |
128 | 5-((呋喃-2-基甲基)胺基)-N-甲基-8-苯基咪唑并[1,5-c]嘧啶-1-甲醯胺 | |
129 | 5-((2-甲氧基苯甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯 | |
130 | 5-((2-氟-6-甲氧基苯甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯 | |
131 | 5-((2,6-二氟-3-甲氧基苯甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯 | |
132 | 5-((2-氟-5-甲氧基苯甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯 | |
133 | 5-((2-氯-6-氟-3-甲氧基苯甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯 | |
134 | 5-((苯并[d][1,3]間二氧雜環戊烯-4-基甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯 | |
135 | 5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯 | |
136 | 5-((2-甲氧基苯甲基)胺基)-N-甲基-8-苯基咪唑并[1,5-c]嘧啶-1-甲醯胺 | |
137 | 5-((2-氟-6-甲氧基苯甲基)胺基)-N-甲基-8-苯基咪唑并[1,5-c]嘧啶-1-甲醯胺 | |
138 | 5-((3,6-二氟-2-甲氧基苯甲基)胺基)-N-甲基-8-苯基咪唑并[1,5-c]嘧啶-1-甲醯胺 | |
139 | 5-((2-氟-5-甲氧基苯甲基)胺基)-N-甲基-8-苯基咪唑并[1,5-c]嘧啶-1-甲醯胺 | |
140 | 5-((2-氯-6-氟-3-甲氧基苯甲基)胺基)-N-甲基-8-苯基咪唑并[1,5-c]嘧啶-1-甲醯胺 | |
141 | 5-((苯并[d][1,3]間二氧雜環戊烯-4-基甲基)胺基)-N-甲基-8-苯基咪唑并[1,5-c]嘧啶-1-甲醯胺 | |
142 | 5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-N-甲基-8-苯基咪唑并[1,5-c]嘧啶-1-甲醯胺 | |
143 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-苯基-1-(三氟甲基)咪唑并[1,5-c]嘧啶-5-胺 | |
144 | (5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-基)二甲基氧化膦 | |
146 | 8-(3,6-二氫-2H-哌喃-4-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
147 | (S )-4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5,5a,6,8,9-六氫-3H-7-氧雜-2,4,9a,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
148 | (S)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-甲基-7-(甲基磺醯基)-5,5a,6,7,8,9-六氫-2,4,7,9a,11,12a-六氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3(4H)-酮 | |
149 | (S)-4-乙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(甲基磺醯基)-5,5a,6,7,8,9-六氫-2,4,7,9a,11,12a-六氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3(4H)-酮 | |
150 | (S)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-(甲基磺醯基)-5,5a,6,7,8,9-六氫-2,4,7,9a,11,12a-六氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3(4H)-酮 | |
151 | (S)-4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(甲基磺醯基)-5,5a,6,7,8,9-六氫-2,4,7,9a,11,12a-六氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3(4H)-酮 | |
152 | (R)-7-(環丙烷羰基)-4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-5,5a,6,7,8,9-六氫-2,4,7,9a,11,12a-六氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3(4H)-酮 | |
153 | (S)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-甲基-4,5,5a,6,8,9-六氫-7-氧雜-3-硫雜-2,4,9a,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚3,3-二氧化物 | |
154 | (S)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-甲基-7-(甲基磺醯基)-5,5a,6,7,8,9-六氫-4H-3-硫雜-2,4,7,9a,11,12a-六氮雜苯并[4,5]環辛并[1,2,3-cd]茚3,3-二氧化物 | |
155 | (S)-4-乙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5,5a,6,8,9-六氫-7-氧雜-3-硫雜-2,4,9a,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚3,3-二氧化物 | |
156 | (R)-4-乙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(甲基磺醯基)-5,5a,6,7,8,9-六氫-4H-3-硫雜-2,4,7,9a,11,12a-六氮雜苯并[4,5]環辛并[1,2,3-cd]茚3,3-二氧化物 | |
157 | (S)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5,5a,6,8,9-六氫-7-氧雜-3-硫雜-2,9a,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚3,3-二氧化物 | |
158 | (S)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(甲基磺醯基)-5,5a,6,7,8,9-六氫-4H-3-硫雜-2,7,9a,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚3,3-二氧化物 | |
169 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)-8-(四氫-2H-哌喃-4-基)咪唑并[1,5-c]嘧啶-5-胺 | |
160 | 8-(3,6-二氫-2H-硫代哌喃-4-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺 | |
161 | 4-(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-8-基)四氫-2H-硫代哌喃1,1-二氧化物 | |
162 | 12-(((6-氟苯并二氫哌喃-5-基)甲基)胺基)-4-異丙基-7-甲基-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
163 | 12-(((6-氟苯并二氫哌喃-5-基)甲基)胺基)-4-異丙基-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
164 | 12-(((6-氟苯并二氫哌喃-5-基)甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
165 | 12-(((6-氟苯并二氫哌喃-5-基)甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
166 | 12-(((5-氟-3-側氧基-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-甲基-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
167 | 12-(((5-氟-3-側氧基-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
168 | 12-(((5-氟-3-側氧基-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
169 | 12-(((5-氟-3-側氧基-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
170 | 4-乙基-12-(((6-氟苯并二氫哌喃-5-基)甲基)胺基)-7-甲基-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
171 | 4-乙基-12-(((6-氟苯并二氫哌喃-5-基)甲基)胺基)-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
172 | 4-乙基-12-(((6-氟苯并二氫哌喃-5-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
173 | 4-乙基-12-(((6-氟苯并二氫哌喃-5-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
174 | 4-乙基-12-(((5-氟-3-側氧基-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
175 | 4-乙基-12-(((5-氟-3-側氧基-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
176 | 4-乙基-12-(((5-氟-3-側氧基-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
177 | 4-乙基-12-(((5-氟-3-側氧基-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
178 | (5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-基)(亞胺基)(甲基)-l6-碸酮 | |
179 | (8-(2,6-二甲基吡啶-3-基)-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-基)(亞胺基)(甲基)-碸酮 | |
180 | (5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(2-甲基吡啶-3-基)咪唑并[1,5-c]嘧啶-1-基)(亞胺基)(甲基)-碸酮 | |
181 | (5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(2-(三氟甲基)吡啶-3-基)咪唑并[1,5-c]嘧啶-1-基)(亞胺基)(甲基)-l6-碸酮 | |
182 | (5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-基)(甲基)(甲基亞胺基)-l6-碸酮 | |
183 | (8-(2,6-二甲基吡啶-3-基)-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-基)(甲基)(甲基亞胺基)-l6-碸酮 | |
184 | (5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(2-甲基吡啶-3-基)咪唑并[1,5-c]嘧啶-1-基)(甲基)(甲基亞胺基)-l6-碸酮 | |
185 | (5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(2-(三氟甲基)吡啶-3-基)咪唑并[1,5-c]嘧啶-1-基)(甲基)(甲基亞胺基)-l6-碸酮 | |
186 | 1-(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-基)-3,4,5,6-四氫-1,2-噻嗪1-氧化物 | |
187 | 1-(8-(2,6-二甲基吡啶-3-基)-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-基)-3,4,5,6-四氫-1,2-噻嗪1-氧化物 | |
188 | 1-(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(2-甲基吡啶-3-基)咪唑并[1,5-c]嘧啶-1-基)-3,4,5,6-四氫-1,2-噻嗪1-氧化物 | |
189 | 1-(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(2-(三氟甲基)吡啶-3-基)咪唑并[1,5-c]嘧啶-1-基)-3,4,5,6-四氫-1,2-噻嗪1-氧化物 | |
E 1 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 2 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-甲基-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 3 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 4 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-3-側氧基-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-7-甲腈 | |
E 5 | 4-環丁基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 6 | 4-(2,2-二氟乙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 7 | 4-(2,2-二氟丙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 8 | 4-(2,2-二氟乙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 9 | 4-(2,2-二氟乙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 10 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-5-甲基-8-(三氟甲基)-6H-2,3,5a,9,12,13a-六氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 11 | 7-(二氟甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 12 | 7-乙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 13 | 4-(2,2-二氟乙基)-7-乙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 14 | 7-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 15 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-異丙基-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 16 | 4-(2,2-二氟丙基)-7-乙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 17 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-5-甲基-6H-2,3,5a,7,12,13a-六氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 18 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-5,8-二甲基-6H-2,3,5a,7,12,13a-六氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 19 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(甲基-d3)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 20 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基-d2)胺基)-7-甲基-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 21 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基-d2)胺基)-7-(甲基-d3)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 22 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基-2,3-d2)甲基-d2)胺基)-7-甲基-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 23 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基-2,3-d2)甲基-d2)胺基)-7-(甲基-d3)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 24 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基-d2)胺基)-N,N-二甲基-3-側氧基-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-7-甲醯胺 | |
E 25 | 8-(2,6-二甲基吡啶-3-基)-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-1-(甲基磺醯基)咪唑并[1,5-a]吡啶-6-甲腈 | |
E 26 | 8-(6-環丙基吡啶-3-基)-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-1-(甲基磺醯基)咪唑并[1,5-a]吡啶-6-甲腈 | |
E 27 | 5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-(2-甲基吡啶-3-基)-1-(甲基磺醯基)咪唑并[1,5-a]吡啶-6-甲腈 | |
E 28 | 13-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-5,6-二氫-2,4,12,13a-四氮雜苯并[4,5]環壬并[1,2,3-cd]茚-3(4H)-酮 | |
E 29 | 13-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-甲基-5,6-二氫-2,4,7,12,13a-五氮雜苯并[4,5]環壬并[1,2,3-cd]茚-3(4H)-酮 | |
E 30 | 13-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-甲基-4-(2,2,2-三氟乙基)-5,6-二氫-2,4,7,12,13a-五氮雜苯并[4,5]環壬并[1,2,3-cd]茚-3(4H)-酮 | |
E 31 | 13-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-8-(三氟甲基)-5,6-二氫-2,4,9,12,13a-五氮雜苯并[4,5]環壬并[1,2,3-cd]茚-3(4H)-酮 | |
E 32 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(三氟甲基)-6H-2,3,5a,7,12,13a-六氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 33 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(三氟甲基)-6H-2,3,5a,9,12,13a-六氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 34 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-甲基-6H-2,3,5a,7,12,13a-六氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 35 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-5-甲基-8-(三氟甲基)-6H-4-氧雜-2,3,9,12,13a-五氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 36 | N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-甲基-6H-4-氧雜-2,3,7,12,13a-五氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 37 | 5-乙基-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-(三氟甲基)-6H-2,3,5a,9,12,13a-六氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 38 | 5-乙基-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-甲基-6H-2,3,5a,7,12,13a-六氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺 | |
E 39 | 12-(((6-氟苯并二氫哌喃-5-基)甲基)胺基)-7-甲基-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 40 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 41 | 4-(2,2-二氟丙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-甲基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 42 | 7-(二氟甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 43 | 7-(二氟甲基)-4-(2,2-二氟丙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 44 | 4-(2,2-二氟乙基)-7-(二氟甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 45 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(四氫-2H-哌喃-4-基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 46 | 7-(第三丁基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 47 | 4-(2,2-二氟乙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-異丙基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 48 | 7-(1,4-二氧雜環己烷-2-基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 49 | 7-((1,4-二氧雜環己烷-2-基)甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 50 | 7-(第三丁基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 51 | 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(氧雜環丁-3-基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 | |
E 52 | 7-環丁基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮 |
在另一個實施例中,本揭示案之化合物為選自由以下組成之群組的式I
化合物:
4-乙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮;
12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮;
4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮;
12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮;及
11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-6-甲基-4H-3-硫雜-2,5,10,11a-四氮雜二苯并[cd,f]薁3,3-二氧化物,
或其醫藥學上可接受之鹽或溶劑合物。
本揭示案涵蓋本揭示案之化合物之鹽的製備及用途。如本文所用,藥物「醫藥學上可接受之鹽」係指本揭示案之化合物之鹽或兩性離子形式。本揭示案之化合物之鹽可在化合物之最終分離及純化期間製備,或藉由使化合物與適合之酸反應而單獨製備。本揭示案之化合物之醫藥學上可接受之鹽可為與醫藥學上可接受之酸形成的酸加成鹽。可用於形成醫藥學上可接受之鹽之酸的實例包括無機酸,諸如硝酸、硼酸、鹽酸、氫溴酸、硫酸及磷酸;以及有機酸,諸如草酸、馬來酸、琥珀酸及檸檬酸。本揭示案之化合物之鹽的非限制性實例包括但不限於鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、硫酸氫鹽、2-羥基乙烷磺酸鹽、磷酸鹽、磷酸氫鹽、乙酸鹽、己二酸鹽、褐藻酸鹽、天冬胺酸鹽、苯甲酸鹽、硫酸氫鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡糖酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、甲酸鹽、琥珀酸鹽、富馬酸鹽、馬來酸鹽、抗壞血酸鹽、羥乙磺酸鹽、水楊酸鹽、甲烷磺酸鹽、均三甲苯磺酸鹽、萘磺酸鹽、菸鹼酸鹽、2-萘磺酸鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、三氯乙酸鹽、三氟乙酸鹽、磷酸鹽、麩胺酸鹽、碳酸氫鹽、對甲苯磺酸鹽、十一烷酸鹽、乳酸鹽、檸檬酸鹽、酒石酸鹽、葡糖酸鹽、甲烷磺酸鹽、乙烷二磺酸鹽、苯磺酸鹽及對甲苯磺酸鹽。另外,存在於本揭示案之化合物中之可用胺基可用甲基、乙基、丙基及丁基氯化物、溴化物及碘化物;二甲基、二乙基、二丁基及二戊基硫酸鹽;癸基、月桂基、肉豆蔻基及固醇氯化物、溴化物及碘化物;以及苯甲基及苯乙基溴化物四級銨化。鑒於前述內容,本文中出現的任何參考的本揭示案之化合物意欲包括以下化合物:本揭示案之化合物以及其醫藥學上可接受之鹽、水合物或溶劑合物。
本揭示案涵蓋本揭示案之化合物之溶劑合物的製備及用途。溶劑合物通常不會顯著改變化合物之生理活性或毒性,且因此可充當藥理學等效物。如本文所用,術語「溶劑合物」為本揭示案之化合物與溶劑分子之組合、物理締合及/或溶合,例如二溶劑合物、單溶劑合物或半溶劑合物,其中溶劑分子與本揭示案之化合物之比率分別為約2:1、約1:1或約1:2。此物理締合涉及不同程度的離子及共價鍵結,包括氫鍵結。在某些情況下,可分離溶劑合物,諸如當一或多個溶劑分子併入結晶固體之晶格中時。因此,「溶劑合物」涵蓋溶液相及可分離的溶劑合物。本揭示案之化合物可與醫藥學上可接受之溶劑(諸如水、甲醇及乙醇)一起以溶劑化形式存在,且本揭示案意欲包括本揭示案之化合物的溶劑化形式及非溶劑化形式。一種類型之溶劑合物為水合物。「水合物」係指溶劑合物之特定亞組,其中溶劑分子為水。溶劑合物通常可充當藥理學等效物。溶劑合物之製備為此項技術中已知的。參見例如M. Caira等人, 《醫藥科學雜誌(J. Pharmaceut.Sci.
)》, 93(3)
:601-611 (2004),其描述氟康唑與乙酸乙酯及與水之溶劑合物的製備。溶劑合物、半溶劑合物、水合物及其類似物之類似製備由E.C. van Tonder等人, 《美國藥學科學家協會醫藥科技(AAPS Pharm. Sci. Tech.
)》, 5(1)
:Article 12 (2004)及A.L. Bingham等人, 《化學通訊(Chem. Commun.
)》603-604 (2001)描述。製備溶劑合物之典型的非限制性方法涉及在高於20℃至約25℃之溫度下,將本揭示案之化合物溶解於所需溶劑(有機溶劑、水或其混合物)中,隨後以足以形成晶體之速率冷卻溶液,且藉由已知方法(例如過濾)分離晶體。可使用諸如紅外光譜法之分析技術來確認溶劑合物晶體中溶劑合物之存在。
II.本揭示案之中間物
本揭示案亦提供可用於製備本揭示案之化合物的合成中間物,統稱為「本揭示案之中間物」。
在一個實施例中,本揭示案之中間物為式I
化合物,其中:
R3
為R3a
;
R4
為R4a
;
R3a
選自由經取代之芳基、經取代之5員至10員雜芳基及經取代之4員至8員雜環組成之群組;
其中芳基、5員至10員雜芳基或4員至8員雜環取代基中之至少一者為胺基、羥烷基或(胺基)烷基;且
R4a
為鹵基或-C(=O)OR11a
,或其醫藥學上可接受之鹽或溶劑合物。
在一個實施例中,本揭示案之中間物為式XVII
化合物:,
其中為苯基、5員雜芳基或6員雜芳基;且R1
、R2
、R7
、R8a
、R8b
、R8c
及如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之中間物為式XVIII
化合物:,
其中為視情況經取代之3員至8員環烷基或視情況經取代之4員至8員雜環基;且R1
、R2
、R7
及如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之中間物為式XIX
化合物:,
其中為視情況經取代之4員至8員雜環基;且R1
、R2
及R7
如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在一個實施例中,本揭示案之中間物為式XX
化合物:,
其中為苯基、5員雜芳基或6員雜芳基;且R1
、R2
、R8a
、R8b
、R8c
及如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之中間物為式XXI
化合物:,
其中為視情況經取代之3員至8員環烷基或視情況經取代之4員至8員雜環基;且R1
、R2
及如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
在另一個實施例中,本揭示案之中間物為式XXII
化合物:,
其中為視情況經取代之4員至8員雜環基;且R1
及R2
如關於式I
所定義,或其醫藥學上可接受之鹽或溶劑合物。
本揭示案之例示性中間物包括但不限於實例1之E 12-8及E 12-9、實例2之E 16-1及E-16-2、實例3之E 3-1、實例4之E 36-6及E 36-7、實例5之E 10-8、實例6之E 95-3、實例26之E-2211.2及E-2211.3、實例27之E-2189.1及E-2189.2以及實例28之E-2206.2及E-2206.3。
III.本揭示案之化合物及中間物的製備方法
本揭示案亦提供製備本揭示案之化合物及/或本揭示案之中間物的方法。
實例1-6及17提供製備本揭示案之化合物及/或本揭示案之中間物的例示性方法。
IV.用本揭示案之化合物治療疾病之方法
本揭示案之化合物抑制EED,因此可用於治療或預防多種疾病及病況。特別地,本揭示案之化合物可用於治療或預防抑制EED提供益處之疾病或病況的方法。此等疾病及病況中最重要的為癌症及增生性疾病。在一個實施例中,此類癌症稱為「EED介導之癌症」。「EED介導之癌症」為此項技術中已知的。本揭示案之治療方法包含向有需要之個體(例如人類)投與治療有效量之本揭示案之化合物。除本揭示案之化合物之外,本發明方法亦涵蓋視情況向個體投與視情況選用之治療劑。視情況選用之治療劑係選自已知可用於治療折磨有需要之個體之疾病或病況的藥物,例如已知可用於治療特定癌症之化學治療劑及/或輻射。
在另一個實施例中,本發明係關於一種治療罹患抑制EED提供益處之疾病或病況之個體的方法,該方法包含投與治療有效量之本揭示案之化合物。
由於本揭示案之化合物為EED蛋白之抑制劑,因此可藉由採用此等化合物來治療由EED介導之許多疾病及病況。因此,本揭示案大體上係關於一種用於治療個體(例如人類個體)之對EED抑制有反應之病況或病症的方法,該個體罹患該病況或病症或處於罹患該病況或病症之風險下,該方法包含向該個體投與有效量之一或多種本揭示案之化合物。
在另一個實施例中,本揭示案係關於一種在有需要之個體中抑制EED的方法,該方法包含向該個體投與有效量之至少一種本揭示案之化合物。
本揭示案之方法可藉由以純化合物或以醫藥組合物形式投與本揭示案之化合物來實現。本揭示案之化合物之醫藥組合物或純化合物之投與可在所關注之疾病或病況發作期間或之後進行。通常,醫藥組合物為無菌的,且不含有會在投與時引起不良反應之毒性、致癌或誘變化合物。進一步提供套組,其包含單獨或一起封裝之本揭示案之化合物及視情況選用之治療劑,以及具有使用此等活性劑之說明的說明書。
在一個實施例中,本揭示案之化合物與視情況選用之治療劑一起投與,該治療劑可用於治療抑制EED提供益處之疾病或病況。視情況選用之治療劑不同於本揭示案之化合物。本揭示案之化合物及視情況選用之治療劑可同時或依次投與以達到所需效果。另外,本揭示案之化合物及視情況選用之治療劑可由單個組合物或兩個單獨的組合物投與。
視情況選用之治療劑係以提供其所需治療效果之量投與。各視情況選用之治療劑的有效劑量範圍為此項技術中已知的,且在此類確定的範圍內向有需要之個體投與視情況選用之治療劑。
本揭示案之化合物及視情況選用之治療劑可作為單個單位劑量一起投與或作為多個單位劑量分開投與,其中本揭示案之化合物在視情況選用之治療劑之前投與或反之亦然。可投與一或多個劑量之本揭示案之化合物及/或一或多個劑量之視情況選用之治療劑。因此,本揭示案之化合物可與一或多種視情況選用之治療劑(例如但不限於抗癌劑)結合使用。
藉由本揭示案之方法可治療之疾病及病況包括但不限於癌症及其他增生性病症、炎性疾病、敗血症、自體免疫疾病及病毒感染。在一個實施例中,用本揭示案之化合物或包含本揭示案之化合物的醫藥組合物治療人類個體,其中該化合物以足以抑制個體之EED蛋白的量投與。
在另一態樣中,本揭示案提供一種治療個體之癌症的方法,其包含投與治療有效量之本揭示案之化合物。儘管不限於特定機制,但在一些實施例中,本揭示案之化合物藉由抑制EED來治療癌症。可治療癌症之實例包括但不限於表3之任何一或多種癌症。
表3
腎上腺癌 | 腺泡細胞癌 | 聽神經瘤 | 肢端雀斑樣痣原位黑素瘤 |
肢端汗腺瘤 | 急性嗜酸性球性白血病 | 急性類紅血球性白血病 | 急性淋巴母細胞性白血病 |
急性巨核母細胞性白血病 | 急性單核球性白血病 | 急性前髓細胞性白血病 | 腺癌 |
腺樣囊性癌 | 腺瘤 | 腺瘤樣牙源性腫瘤 | 腺鱗癌 |
脂肪組織贅瘤 | 腎上腺皮質癌 | 成人T細胞白血病/淋巴瘤 | 侵襲性NK細胞白血病 |
AIDS相關淋巴瘤 | 腺泡狀橫紋肌肉瘤 | 腺泡狀軟組織肉瘤 | 成釉細胞纖維瘤 |
間變性大細胞淋巴瘤 | 未分化甲狀腺癌 | 血管免疫母細胞性T細胞淋巴瘤 | 血管肌脂瘤 |
血管肉瘤 | 星形細胞瘤 | 非典型畸胎樣橫紋肌樣瘤 | B細胞慢性淋巴細胞性白血病 |
B細胞前淋巴細胞性白血病 | B細胞淋巴瘤 | 基底細胞癌 | 膽道癌 |
膀胱癌 | 母細胞瘤 | 骨癌 | 布倫納瘤 |
棕色瘤 | 伯基特氏淋巴瘤 | 乳癌 | 腦癌 |
癌 | 原位癌 | 癌肉瘤 | 軟骨腫瘤 |
齒堊質瘤 | 骨髓肉瘤 | 軟骨瘤 | 脊索瘤 |
絨毛膜癌 | 脈絡叢乳頭狀瘤 | 腎透明細胞肉瘤 | 顱咽管瘤 |
皮膚T細胞淋巴瘤 | 宮頸癌 | 結腸直腸癌 | 德戈斯病 |
促結締組織增生小型圓形細胞腫瘤 | 彌漫性大B細胞淋巴瘤 | 胚胎發育不良性神經上皮腫瘤 | 無性細胞瘤 |
胚胎性癌 | 內分泌腺腫瘤 | 內胚層竇瘤 | 腸病相關T細胞淋巴瘤 |
食道癌 | 胚內胎 | 纖維瘤 | 纖維肉瘤 |
濾泡性淋巴瘤 | 濾泡性甲狀腺癌 | 神經節細胞瘤 | 胃腸癌 |
生殖細胞腫瘤 | 妊娠絨毛膜癌 | 巨細胞纖維母細胞瘤 | 骨巨細胞瘤 |
膠質瘤 | 多形性膠質母細胞瘤 | 膠質瘤 | 腦膠質瘤病 |
升糖素瘤 | 性腺母細胞瘤 | 粒層細胞瘤 | 半陰陽胚細胞瘤 |
膽囊癌 | 胃癌 | 毛細胞白血病 | 血管母細胞瘤 |
頭頸癌 | 血管外皮瘤 | 血液癌 | 肝母細胞瘤 |
肝脾T細胞淋巴瘤 | 霍奇金氏淋巴瘤 | 非霍奇金氏淋巴瘤 | 侵襲性小葉癌 |
腸癌 | 腎癌 | 喉癌 | 惡性雀斑樣痣 |
致死性中線癌 | 白血病 | 萊迪格細胞瘤 | 脂肪肉瘤 |
肺癌 | 淋巴管瘤 | 淋巴管肉瘤 | 淋巴上皮瘤 |
淋巴瘤 | 急性淋巴細胞性白血病 | 急性骨髓性白血病 | 慢性淋巴細胞性白血病 |
肝癌 | 小細胞肺癌 | 非小細胞肺癌 | MALT淋巴瘤 |
惡性纖維組織細胞瘤 | 惡性周圍神經鞘瘤 | 惡性蠑螈瘤 | 套細胞淋巴瘤 |
邊緣區B細胞淋巴瘤 | 肥大細胞白血病 | 縱隔生殖細胞腫瘤 | 乳房髓質癌 |
甲狀腺髓質癌 | 神經管胚細胞瘤 | 黑素瘤 | 腦膜瘤 |
默克爾細胞癌 | 間皮瘤 | 轉移性尿道上皮癌 | 混合性苗勒氏管腫瘤 |
黏液性腫瘤 | 多發性骨髓瘤 | 肌肉組織腫瘤 | 蕈樣黴菌病 |
黏液樣脂肪肉瘤 | 黏液瘤 | 黏液肉瘤 | 鼻咽癌 |
神經鞘瘤 | 神經母細胞瘤 | 神經纖維瘤 | 神經瘤 |
結節性黑素瘤 | 眼癌 | 少突星形細胞瘤 | 少突膠質細胞瘤 |
嗜酸性腺瘤 | 視神經鞘腦膜瘤 | 視神經腫瘤 | 口腔癌 |
骨肉瘤 | 卵巢癌 | 肺上溝瘤 | 甲狀腺乳頭狀癌 |
副神經節瘤 | 松果體母細胞瘤 | 松果體細胞瘤 | 垂體細胞瘤 |
垂體腺瘤 | 垂體瘤 | 漿細胞瘤 | 多胚瘤 |
前體T淋巴母細胞性淋巴瘤 | 原發性中樞神經系統淋巴瘤 | 原發性滲出性淋巴瘤 | 原發性腹膜癌 |
前列腺癌 | 胰臟癌 | 咽癌 | 腹膜假黏液瘤 |
腎細胞癌 | 腎髓質癌 | 視網膜母細胞瘤 | 橫紋肌瘤 |
橫紋肌肉瘤 | 里希特氏轉化 | 直腸癌 | 肉瘤 |
許旺細胞瘤病 | 精原細胞瘤 | 塞特利氏細胞瘤 | 性索性腺間質瘤 |
印戒細胞癌 | 皮膚癌 | 小藍圓形細胞瘤 | 小細胞癌 |
軟組織肉瘤 | 生長抑素瘤 | 煙塵疣 | 脊髓腫瘤 |
脾邊緣區淋巴瘤 | 鱗狀細胞癌 | 滑膜肉瘤 | 塞薩里氏病 |
小腸癌 | 鱗狀癌 | 胃癌 | T細胞淋巴瘤 |
睾丸癌 | 泡膜細胞瘤 | 甲狀腺癌 | 移行細胞癌 |
咽喉癌 | 臍尿管癌 | 泌尿生殖癌 | 尿道上皮癌 |
葡萄膜黑素瘤 | 子宮癌 | 疣狀癌 | 視覺通路神經膠質瘤 |
外陰癌 | 陰道癌 | 瓦爾登斯特倫氏巨球蛋白血症 | 沃辛氏腫瘤 |
威爾姆斯瘤 |
在另一個實施例中,癌症為實體腫瘤。在另一個實施例中,癌症為血液癌。例示性血液癌包括但不限於表4中列出之癌症。在另一個實施例中,血液癌為急性淋巴細胞性白血病、慢性淋巴細胞性白血病(包括B細胞慢性淋巴細胞性白血病)或急性骨髓性白血病。
表4
急性淋巴細胞性白血病(ALL) | 急性嗜酸性球性白血病 |
急性骨髓性白血病(AML) | 急性類紅血球性白血病 |
慢性淋巴細胞性白血病(CLL) | 急性淋巴母細胞性白血病 |
小淋巴細胞性淋巴瘤(SLL) | 急性巨核母細胞性白血病 |
多發性骨髓瘤(MM) | 急性單核球性白血病 |
霍奇金氏淋巴瘤(HL) | 急性前髓細胞性白血病 |
非霍奇金氏淋巴瘤(NHL) | 急性骨髓性白血病 |
套細胞淋巴瘤(MCL) | B細胞前淋巴細胞性白血病 |
邊緣區B細胞淋巴瘤 | B細胞淋巴瘤 |
脾邊緣區淋巴瘤 | MALT淋巴瘤 |
濾泡性淋巴瘤(FL) | 前體T淋巴母細胞性淋巴瘤 |
瓦爾登斯特倫氏巨球蛋白血症(WM) | T細胞淋巴瘤 |
彌漫性大B細胞淋巴瘤(DLBCL) | 肥大細胞白血病 |
邊緣區淋巴瘤(MZL) | 成人T細胞白血病/淋巴瘤 |
毛細胞白血病(HCL) | 侵襲性NK細胞白血病 |
伯基特氏淋巴瘤(BL) | 血管免疫母細胞性T細胞淋巴瘤 |
里希特氏轉化 |
在另一個實施例中,癌症為白血病,例如選自急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴細胞性白血病及混合系白血病(MLL)之白血病。在另一個實施例中,癌症為NUT-中線癌。在另一個實施例中,癌症為多發性骨髓瘤。在另一個實施例中,癌症為肺癌,諸如小細胞肺癌(SCLC)。在另一個實施例中,癌症為神經母細胞瘤。在另一個實施例中,癌症為伯基特氏淋巴瘤。在另一個實施例中,癌症為宮頸癌。在另一個實施例中,癌症為食道癌。在另一個實施例中,癌症為卵巢癌。在另一個實施例中,癌症為結腸直腸癌。在另一個實施例中,癌症為前列腺癌。在另一個實施例中,癌症為乳癌。
在另一個實施例中,癌症選自由以下組成之群組:急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴細胞性白血病混合系白血病、NUT-中線癌、多發性骨髓瘤、小細胞肺癌、非小細胞肺癌、神經母細胞瘤、伯基特氏淋巴瘤、宮頸癌、食道癌、卵巢癌、結腸直腸癌、前列腺癌、乳癌、膀胱癌、卵巢癌、膠質瘤、肉瘤、食道鱗狀細胞癌及甲狀腺乳頭狀癌。
在另一個實施例中,本揭示案提供一種治療良性增生性病症之方法,該良性增生性病症諸如但不限於良性軟組織腫瘤、骨腫瘤、腦及脊髓腫瘤、眼瞼及眼眶腫瘤、肉芽腫瘤、脂肪瘤、腦膜瘤、多發性內分泌瘤、鼻息肉、垂體腫瘤、促乳素瘤、假腦瘤、皮脂溢性角化症、胃息肉、甲狀腺結節、胰臟囊性贅瘤、血管瘤、聲帶結節、息肉及囊腫、卡斯特萊曼病(Castleman disease)、慢性潛毛疾病、皮膚纖維瘤、毛髮囊腫、化膿性肉芽腫及青少年多發性息肉症候群。
本揭示案之化合物亦可藉由向需要此類治療之哺乳動物,尤其人類投與有效量之本發明化合物來治療感染性及非感染性炎症事件以及自體免疫及其他炎性疾病。使用本文所述之化合物及方法治療之自體免疫及炎性疾病、病症及症候群之實例包括炎性骨盆疾病、尿道炎、皮膚曬傷、鼻竇炎、肺炎、腦炎、腦膜炎、心肌炎、腎炎、骨髓炎、肌炎、肝炎、胃炎、腸炎、皮膚炎、齒齦炎、闌尾炎、胰臟炎、膽囊炎、無γ球蛋白血症、牛皮癬、過敏、克羅恩氏病(Crohn's disease)、腸激躁症候群、潰瘍性結腸炎、休格連氏病(Sjogren's disease)、組織移植排斥反應、移植器官之超急性排斥、哮喘、過敏性鼻炎、慢性阻塞性肺病(COPD)、自體免疫多腺疾病(亦稱為自體免疫多腺症候群)、自體免疫禿髮、惡性貧血、絲球體腎炎、皮肌炎、多發性硬化症、硬皮病、脈管炎、自體免疫溶血性及血小板減少性病況、古巴斯德氏症候群(Goodpasture's syndrome)、動脈粥樣硬化、艾迪森氏病(Addison's disease)、帕金森氏病(Parkinson's disease)、阿茲海默氏病(Alzheimer's disease)、I型糖尿病、敗血性休克、全身性紅斑性狼瘡症(SLE)、類風濕性關節炎、牛皮癬性關節炎、青少年關節炎、骨關節炎、慢性特發性血小板減少性紫癜、瓦爾登斯特倫巨球蛋白血症、重症肌無力、橋本氏甲狀腺炎(Hashimoto's thyroiditis)、異位性皮膚炎、退化性關節病、白斑病、自體免疫垂體機能減退、格-巴二氏症候群(Guillain-Barre syndrome)、白塞氏病(Behcet's disease)、硬腫症、蕈樣黴菌病、急性發炎反應(諸如急性呼吸窘迫症候群及局部缺血/再灌注損傷)及格雷夫氏病(Graves' disease)。
在另一個實施例中,本揭示案提供一種藉由向需要此類治療之哺乳動物,尤其人類投與有效量之本揭示案之化合物來治療全身性炎症反應症候群,諸如LPS誘發之內毒素休克及/或細菌誘發之敗血症的方法。
在另一個實施例中,本揭示案提供一種用於治療病毒感染及疾病之方法。使用本文所述之化合物及方法治療之病毒感染及疾病之實例包括基於游離基因體之DNA病毒,包括但不限於人類乳頭狀瘤病毒、疱疹病毒、埃-巴二氏病毒、人類免疫缺陷病毒、B型肝炎病毒及C型肝炎病毒。
在另一個實施例中,本揭示案提供在上述疾病,尤其癌症、炎性疾病及/或病毒性疾病中,藉由向需要此類療法之個體投與治療有效量之本揭示案之化合物來調節活體內蛋白質甲基化、基因表現、細胞增殖、細胞分化及/或凋亡的治療方法。
在另一個實施例中,本揭示案提供一種藉由使細胞與本揭示案之化合物接觸來調節內源或異源啟動子活性的方法。
在本揭示案之方法中,向有需要之人類投與通常根據醫藥實踐調配之治療有效量之本揭示案之化合物。此類治療是否適用視個體情況而定,且要接受醫學評定(診斷),該評定(診斷)考慮到存在的病徵、症狀及/或功能障礙,出現特定病徵、症狀及/或功能障礙之風險以及其他因素。
本揭示案之化合物可藉由任何適合之途徑投與,例如藉由經口、頰內、吸入、舌下、直腸、陰道、經由腰椎穿刺之腦池內或鞘內、經尿道、經鼻、經皮(亦即透皮)或非經腸(包括靜脈內、肌肉內、皮下、冠狀動脈內、皮內、乳房內、腹膜內、關節內、鞘內、眼球後、肺內注射及/或手術植入特定部位)投與。非經腸投與可使用針頭及注射器或使用高壓技術來完成。
醫藥組合物包括其中以有效量投與本揭示案之化合物以達成其預期目的之彼等組合物。精確調配物、投與途徑及劑量由個別醫師根據所診斷之病況或疾病來確定。可單獨調整劑量及間隔,以提供足以維持治療效果之本揭示案之化合物之水準。
本揭示案之化合物的毒性及治療功效可藉由標準醫藥程序在細胞培養物或實驗動物中確定,例如用於確定化合物之最大耐受劑量(MTD),其定義為在動物體內不產生毒性之最高劑量。最大耐受劑量與治療效果(例如抑制腫瘤生長)之間的劑量比為治療指數。視所採用之劑型及所利用之投與途徑而定,劑量可在此範圍內變化。治療有效量之確定完全在熟習此項技術者之能力範圍內,尤其是根據本文提供之詳細揭示內容。
在療法中使用所需之本揭示案之化合物的治療有效量隨所治療之病況的性質、所需活性之時長及個體之年齡及病況而變化,且最終由主治醫師確定。可單獨調整劑量及間隔,以提供足以維持所需治療效果之本揭示案之化合物的血漿水平。所需劑量可以單次劑量投與,或以適當間隔投與之多次劑量投與,例如每天一次、兩次、三次、四次或更多次子劑量。多次劑量通常為所要或所需的。舉例而言,本揭示案之化合物可按以下頻率投與:遞送四次劑量,每天一次劑量,間隔四天(q4d × 4);遞送四次劑量,每天一次劑量,間隔三天(q3d × 4);每天遞送一次劑量,間隔五天(qd × 5);每週一次劑量,持續三週(qwk3);五次每日劑量,休息兩天,再五次每日劑量(5/2/5);或確定為適合情況之任何劑量方案。
在本揭示案之方法中使用的本揭示案之化合物可以每劑量約0.005至約500毫克、每劑量約0.05至約250毫克或每劑量約0.5至約100毫克之量投與。舉例而言,本揭示案之化合物可以每劑量約0.005、約0.05、約0.5、約5、約10、約20、約30、約40、約50、約100、約150、約200、約250、約300、約350、約400、約450或約500毫克之量投與,包括0.005與500毫克之間的所有劑量。
含有本揭示案之化合物的組合物或含有該化合物之組合物的劑量可為約1 ng/kg至約200 mg/kg,約1 μg/kg至約100 mg/kg,或約1 mg/kg至約50 mg/kg。組合物之劑量可為任何劑量,包括但不限於約1 μg/kg。組合物之劑量可為任何劑量,包括但不限於約1 μg/kg、約10 μg/kg、約25 μg/kg、約50 μg/kg、約75 μg/kg、約100 μg/kg、約125 μg/kg、約150 μg/kg、約175 μg/kg、約200 μg/kg、約225 μg/kg、約250 μg/kg、約275 μg/kg、約300 μg/kg、約325 μg/kg、約350 μg/kg、約375 μg/kg、約400 μg/kg、約425 μg/kg、約450 μg/kg、約475 μg/kg、約500 μg/kg、約525 μg/kg、約550 μg/kg、約575 μg/kg、約600 μg/kg、約625 μg/kg、約650 μg/kg、約675 μg/kg、約700 μg/kg、約725 μg/kg、約750 μg/kg、約775 μg/kg、約800 μg/kg、約825 μg/kg、約850 μg/kg、約875 μg/kg、約900 μg/kg、約925 μg/kg、約950 μg/kg、約975 μg/kg、約1 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約60 mg/kg、約70 mg/kg、約80 mg/kg、約90 mg/kg、約100 mg/kg、約125 mg/kg、約150 mg/kg、約175 mg/kg、約200 mg/kg或更多。上述劑量為平均情況之示例,但可存在值得更高或更低劑量之個別情況,且此類均在本揭示案之範疇內。在實踐中,醫師確定最適合個別個體之實際給藥方案,其可隨特定個體之年齡、體重及反應而變化。
本揭示案之化合物通常與醫藥載劑混合投與,以給出根據預期投與途徑及標準醫藥實踐選擇之醫藥組合物。根據本揭示案使用之醫藥組合物以習知方式使用一或多種生理學上可接受之載劑調配,該等載劑包含便於加工本揭示案之化合物的賦形劑及/或助劑。
此等醫藥組合物可例如藉由習知混合、溶解、造粒、糖衣藥丸製造、乳化、囊封、包覆或凍乾製程來製造。適當的調配物視所選投與途徑而定。當經口投與治療有效量之本揭示案之化合物時,組合物通常呈錠劑、膠囊、散劑、溶液或酏劑之形式。當以錠劑形式投與時,組合物另外可含有固體載劑,諸如明膠或佐劑。錠劑、膠囊及散劑含有約0.01%至約95%,且較佳約1%至約50%之本揭示案之化合物。當以液體形式投與時,可添加液體載劑,諸如水、石油或動植物來源的油。液體形式之組合物可進一步含有生理鹽水溶液、右旋糖或其他醣溶液或二醇。當以液體形式投與時,組合物含有約0.1重量%至約90重量%,且較佳約1重量%至約50重量%之本揭示案之化合物。
當藉由靜脈內、皮膚或皮下注射投與治療有效量之本揭示案之化合物時,組合物呈無熱原質、非經腸可接受之水溶液形式。在適當考慮pH、等張性、穩定性及其類似物之情況下,製備此類非經腸可接受之溶液在此項技術之技術範圍內。用於靜脈內、皮膚或皮下注射之較佳組合物通常含有等張媒劑。
本揭示案之化合物可易於與此項技術中熟知的醫藥學上可接受之載劑組合。標準醫藥學載劑描述於《雷明頓氏醫藥科學(Remington's Pharmaceutical Sciences)》, Mack Publishing Co., Easton, PA, 第19版1995中。此類載劑使活性劑能夠調配為錠劑、丸劑、糖衣藥丸、膠囊、液體、凝膠、糖漿、漿液、懸浮液及其類似物,以供待治療之個體口服。經口使用之醫藥製劑可藉由將本揭示案之化合物添加至固體賦形劑中,視情況研磨所得混合物,且必要時在添加適合之助劑之後加工顆粒混合物,以獲得錠劑或糖衣藥丸芯。適合的賦形劑包括例如填充劑及纖維素製劑。必要時,可添加崩解劑。
本揭示案之化合物可經調配以藉由注射,例如藉由快速注射或連續輸注進行非經腸投與。注射用調配物可以單位劑型呈現,例如在安瓿或多劑量容器中,且添加防腐劑。組合物可採取諸如於油性或水性媒劑中之懸浮液、溶液或乳液之形式,且可含有諸如懸浮劑、穩定劑及/或分散劑之調配劑。
用於非經腸投與之醫藥組合物包括水溶性形式之活性劑的水溶液。另外,本揭示案之化合物的懸浮液可製備為適當的油性注射懸浮液。適合之親脂性溶劑或媒劑包括脂肪油或合成脂肪酸酯。水性注射懸浮液可含有增加懸浮液之黏度的物質。視情況,懸浮液亦可含有適合的穩定劑或增加化合物溶解度且允許製備高度濃縮溶液之試劑。或者,本發明之組合物可呈粉末形式,以便在使用前用適合之媒劑(例如無菌無熱原質水)復原。
本揭示案之化合物亦可調配於直腸組合物中,諸如例如含有習知栓劑基質之栓劑或保留灌腸劑。除先前描述之調配物之外,本揭示案之化合物亦可調配為儲槽式製劑。此類長效調配物可藉由植入(例如皮下或肌肉內)或藉由肌肉內注射投與。因此,例如,本揭示案之化合物可用適合之聚合或疏水性材料(例如,作為可接受之油中之乳液)或離子交換樹脂調配。
特定言之,本揭示案之化合物可以含有賦形劑(諸如澱粉或乳糖)之錠劑形式、或以膠囊或卵形栓劑形式(單獨或與賦形劑混合)或以含有調味劑或著色劑之酏劑或懸浮液形式經口、頰內或舌下投與。此類液體製劑可用醫藥學上可接受之添加劑(諸如懸浮劑)製備。本揭示案之化合物亦可非經腸注射,例如靜脈內、肌肉內、皮下或冠狀動脈內注射。對於非經腸投與,本揭示案之化合物通常以無菌水溶液之形式使用,該水溶液可含有其他物質,例如鹽或單糖,諸如甘露糖醇或葡萄糖,以使溶液與血液等張。
V. 視情況選用之治療劑
在本揭示案之一些治療方法及用途中,將本揭示案之化合物作為單一藥劑投與患有疾病、病症或病況(例如癌症)之個體。在本揭示案之其他治療方法及用途中,將本揭示案之化合物與一或多種視情況選用之治療劑組合投與患有疾病、病症或病況(例如癌症)之個體。在一個實施例中,本揭示案之化合物與一種視情況選用之治療劑組合投與。在另一個實施例中,本揭示案之化合物與兩種視情況選用之治療劑組合投與。在另一個實施例中,本揭示案之化合物與三種視情況選用之治療劑組合投與。可用於治療癌症患者之視情況選用之治療劑包括此項技術中已知的彼等治療劑以及未來開發的彼等治療劑。
視情況選用之治療劑以提供其所需治療效果之量投與。各視情況選用之治療劑的有效劑量範圍為此項技術中已知的,且在此類確定的範圍內向有需要之個體投與視情況選用之治療劑。
本揭示案之化合物及視情況選用之治療劑可作為單個單位劑量一起投與或作為多個單位劑量分開且以任何順序投與,例如其中本揭示案之化合物在視情況選用之治療劑之前投與,或反之亦然。可向個體投與一或多個劑量之本揭示案之化合物及視情況選用之治療劑。
在一個實施例中,視情況選用之治療劑為免疫檢查點抑制劑。免疫檢查點抑制劑為阻斷免疫系統抑制劑檢查點之療法。免疫檢查點可為刺激性的或抑制性的。阻斷抑制性免疫檢查點活化免疫系統功能,且可用於癌症免疫療法。Pardoll, 《自然綜述-癌症(Nature Reviews.Cancer
)》12:
252-64 (2012)。當腫瘤細胞附著於特定的T細胞受體時,腫瘤細胞會關閉活化的T細胞。免疫檢查點抑制劑防止腫瘤細胞附著於T細胞,從而導致T細胞保持活化。實際上,細胞及可溶性組分之協同作用對抗病原體及癌症之傷害。對免疫系統路徑之調節可涉及改變路徑中至少一種組分的表現或功能活性,隨後調節免疫系統之反應。U.S. 2015/0250853。免疫檢查點抑制劑之實例包括PD-1抑制劑、PD-L1抑制劑、CTLA-4抑制劑、LAG3抑制劑、TIM3抑制劑、cd47抑制劑及B7-H1抑制劑。因此,在一個實施例中,免疫檢查點抑制劑選自由PD-1抑制劑、PD-L1抑制劑、CTLA-4抑制劑、LAG3抑制劑、TIM3抑制劑及cd47抑制劑組成之群組。
在另一個實施例中,免疫檢查點抑制劑為計劃性細胞死亡(PD-1)抑制劑。PD-1為一種T細胞共抑制受體,其在腫瘤細胞逃避宿主免疫系統之能力中發揮關鍵作用。阻斷PD-1與PD-L1 (PD-1之配體)之間的相互作用增強免疫功能且介導抗腫瘤活性。PD-1抑制劑之實例包括特異性結合PD-1之抗體。特定抗PD-1抗體包括但不限於尼沃單抗(nivolumab)、派姆單抗(pembrolizumab)、STI-A1014、皮立珠單抗(pidilzumab)及賽咪單抗-rwlc (cemiplimab-rwlc)。關於抗PD-1抗體之可獲得性、生產方法、作用機制及臨床研究的一般論述,參見U.S. 2013/0309250、U.S. 6,808,710、U.S. 7,595,048、U.S. 8,008,449、U.S. 8,728,474、U.S. 8,779,105、U.S. 8,952,136、U.S. 8,900,587、U.S. 9,073,994、U.S. 9,084,776及Naido等人, 《英國癌症雜誌(British Journal of Cancer
)》111:
2214-19 (2014)。
在另一個實施例中,免疫檢查點抑制劑為PD-L1 (亦稱為B7-H1或CD274)抑制劑。PD-L1抑制劑之實例包括特異性結合PD-L1之抗體。特定抗PD-L1抗體包括但不限於阿維魯單抗(avelumab)、阿特珠單抗(atezolizumab)、德瓦魯單抗(durvalumab)及BMS-936559。關於可獲得性、生產方法、作用機制及臨床研究的一般論述,參見U.S. 8,217,149、U.S. 2014/0341917、U.S. 2013/0071403、WO 2015036499及Naido等人, 《英國癌症雜誌》111:
2214-19 (2014)。
在另一個實施例中,免疫檢查點抑制劑為CTLA-4抑制劑。CTLA-4,亦稱為細胞毒性T淋巴細胞抗原4,為一種下調免疫系統之蛋白質受體。CTLA-4表徵為「制動器」,其與抗原呈遞細胞上之共刺激分子結合,阻止與T細胞上之CD28相互作用,且亦生成一種明顯的抑制信號,限制T細胞活化。CTLA-4抑制劑之實例包括特異性結合CTLA-4之抗體。特定的抗CTLA-4抗體包括但不限於伊匹單抗(ipilimumab)及曲美單抗(tremelimumab)。關於可獲得性、生產方法、作用機制及臨床研究的一般論述,參見U.S. 6,984,720、U.S. 6,207,156及Naido等人, 《英國癌症雜誌》111:
2214-19 (2014)。
在另一個實施例中,免疫檢查點抑制劑為LAG3抑制劑。LAG3,亦即淋巴細胞活化基因3,為一種負協同模擬受體,可調節T細胞穩態、增殖及活化。另外,據報導LAG3參與調節性T細胞(Tregs)之遏制功能。大部分LAG3分子保留在細胞中靠近微管組織中心,且僅在抗原特異性T細胞活化後才會被誘導。U.S. 2014/0286935。LAG3抑制劑之實例包括特異性結合LAG3之抗體。特定的抗LAG3抗體包括但不限於GSK2831781。關於可獲得性、生產方法、作用機制及研究之一般論述,參見U.S. 2011/0150892、U.S. 2014/0093511、U.S. 20150259420及Huang等人, 《免疫(Immunity
)》 21:503-13 (2004)。
在另一個實施例中,免疫檢查點抑制劑為TIM3抑制劑。TIM3,亦即T細胞免疫球蛋白及黏蛋白結構域3,為一種免疫檢查點受體,用於限制TH
1及TC
1 T細胞反應之持續時間及幅度。由於TIM3路徑在功能異常之CD8+
T細胞及Tregs上表現,TIM3路徑視為抗癌免疫療法之靶標,而CD8+
T細胞及Tregs為據報導在腫瘤組織中構成免疫抑制的兩個免疫細胞群體。Anderson, 《癌症免疫學研究(Cancer Immunology Research
)》2:
393-98 (2014)。TIM3抑制劑之實例包括特異性結合TIM3之抗體。關於TIM3抑制劑之可獲得性、生產方法、作用機制及研究的一般論述,參見U.S. 20150225457、U.S. 20130022623、U.S. 8,522,156、Ngiow等人, 《癌症研究(Cancer Res
)》71:
6567-71 (2011),Ngiow等人, 《癌症研究》71:
3540-51 (2011)及Anderson
, 《癌症免疫學研究》 2:393-98 (2014)。
在另一個實施例中,免疫檢查點抑制劑為cd47抑制劑。參見Unanue, E.R.,PNAS
110:10886-87 (2013)。
術語「抗體」意欲包括完整單株抗體、多株抗體、由至少兩個完整抗體形成之多特異性抗體及抗體片段,只要其表現出所需的生物活性即可。在另一個實施例中,「抗體」意欲包括不具有抗體之Fc部分的可溶性受體。在一個實施例中,抗體為藉由重組基因工程製得的人類化單株抗體及其片段。
另一類免疫檢查點抑制劑包括結合並阻斷T細胞上之PD-1受體而不觸發抑制劑信號轉導的多肽。此類肽包括B7-DC多肽、B7-H1多肽、B7-1多肽及B7-2多肽及其可溶性片段,如美國專利8,114,845中所揭示。
另一類免疫檢查點抑制劑包括具有抑制PD-1信號傳導之肽部分的化合物。此類化合物之實例揭示於美國專利8,907,053中且具有以下結構:
或其醫藥學上可接受之鹽,其中該化合物包含至少5個可用作能夠抑制PD-1信號傳導路徑之治療劑的胺基酸。
另一類免疫檢查點抑制劑包括某些代謝酶之抑制劑,諸如由浸潤性骨髓細胞及腫瘤細胞表現之吲哚胺2,3雙加氧酶(IDO)及在白血病細胞中突變之異檸檬酸去氫酶(IDH)。IDH酶之突變體導致2-羥基戊二酸(2-HG)之水準增加,從而阻止骨髓細胞分化。Stein等人, 《血液(Blood
)》130:
722-31 (2017);Wouters, 《血液》130:
693-94 (2017)。特定的突變體IDH阻斷劑包括但不限於伊沃西尼(ivosidenib)及甲磺酸依那西尼(enasidenib mesylate)。Dalle及DiNardo, 《血液學治療進展(Ther Adv Hematol
)》9(7):
163-73 (2018);Nassereddine等人, 《腫瘤靶標及療法(Onco Targets Ther
)》12:
303-08 (2018)。IDO酶藉由消耗T細胞合成代謝功能所必需的胺基酸或經由合成能夠改變淋巴細胞功能之胞質受體的特定天然配體來抑制免疫反應。Pardoll, 《自然綜述-癌症》12:
252-64 (2012);Löb, 《癌症免疫學與免疫療法(Cancer Immunol Immunother
)》58:
153-57 (2009)。特定的IDO阻斷劑包括但不限於左-1-甲基色胺酸(L-1MT)及1-甲基-色胺酸(1MT)。Qian等人,
《癌症研究(Cancer Res
)》69:
5498-504 (2009);及Löb等人,
《癌症免疫學與免疫療法》58:
153-7 (2009)。
在一個實施例中,免疫檢查點抑制劑為尼沃單抗、派姆單抗、皮立珠單抗、STI-A1110、阿維魯單抗、阿特珠單抗、德瓦魯單抗、STI-A1014、伊匹單抗、曲美單抗、GSK2831781、BMS-936559或MED14736。
在另一個實施例中,視情況選用之治療劑為表觀遺傳藥物。如本文所用,術語「表觀遺傳藥物」係指靶向表觀遺傳調節因子之治療劑。表觀遺傳調節因子之實例包括組蛋白離胺酸甲基轉移酶、組蛋白精胺酸甲基轉移酶、組蛋白去甲基酶、組蛋白去乙醯基酶、組蛋白乙醯基酶及DNA甲基轉移酶。組蛋白去乙醯基酶抑制劑包括但不限於伏立諾他(vorinostat)及乳酸帕比諾他(panobinostat lactate)。
在另一個實施例中,視情況選用之治療劑為可與本揭示案之化合物組合投與以治療癌症的化學治療劑或其他抗增殖劑。可與本揭示案之化合物組合使用之習知療法及抗癌劑的實例包括手術、放射療法(例如,γ射線、中子束放射療法、電子束放射療法、質子療法、近接療法及全身性放射性同位素)、內分泌療法、生物反應調節劑(例如,干擾素、介白素、腫瘤壞死因子(TNF)、高熱及冷凍療法、減輕任何不良反應之藥劑(例如止吐劑)及任何其他經核准之生物療法或化學療法,例如使用藥物藉由殺死癌細胞或阻止癌細胞分裂來阻止癌細胞生長的治療方案。化學療法可藉由口服、注射或輸注或在皮膚上進行,視所治療癌症之類型及階段而定。
非限制性的例示性抗增殖化合物包括芳香酶抑制劑;抗雌激素;抗雄激素;性腺釋素促效劑;拓樸異構酶I抑制劑;拓樸異構酶II抑制劑;微管活性劑;烷基化劑,例如替莫唑胺(temozolomide);類視黃素、類胡蘿蔔素或生育酚;環加氧酶抑制劑;MMP抑制劑;mTOR抑制劑;抗代謝物;鉑化合物;甲硫胺酸胺基肽酶抑制劑;雙膦酸鹽;抗增殖抗體;肝素酶抑制劑;Ras致癌同功異型物之抑制劑;端粒酶抑制劑;蛋白酶體抑制劑;用於治療血液科惡性疾病之化合物;Flt-3抑制劑;Hsp90抑制劑;驅動蛋白紡錘體蛋白抑制劑;MEK抑制劑;抗腫瘤抗生素;亞硝基脲;靶向/降低蛋白質或脂質激酶活性之化合物、靶向/降低蛋白質或脂質磷酸酶活性之化合物或任何其他抗血管生成化合物。
非限制性的例示性芳香酶抑制劑包括類固醇,諸如阿他美坦(atamestane)、依西美坦(exemestane)及福美司坦(formestane);及非類固醇,諸如胺格魯米特(aminoglutethimide)、羅穀亞胺(roglethimide)、吡魯米特(pyridoglutethimide)、曲洛司坦(trilostane)、睪內酯(testolactone)、酮康唑(ketokonazole)、伏羅唑(vorozole)、法屈唑(fadrozole)、阿那曲唑(anastrozole)及來曲唑(letrozole)。
非限制性抗雌激素包括他莫昔芬(tamoxifen)、氟維司群(fulvestrant)、雷洛昔芬(raloxifene)及鹽酸雷洛昔芬(raloxifene hydrochloride)。抗雄激素包括但不限於比卡魯胺(bicalutamide)及阿帕魯胺(apalutamide)。性腺釋素促效劑包括但不限於阿巴瑞克(abarelix)、戈舍瑞林(goserelin)及乙酸戈舍瑞林(goserelin acetate)。
非限制性的例示性拓樸異構酶I抑制劑包括拓朴替康(topotecan)、吉馬替康(gimatecan)、伊立替康(irinotecan)、喜樹鹼(camptothecin)及其類似物、9-硝基喜樹鹼及大分子喜樹鹼結合物PNU-166148。拓樸異構酶II抑制劑包括但不限於蒽環黴素(anthracycline),諸如阿黴素(doxorubicin)、道諾黴素(daunorubicin)、表柔比星(epirubicin)、艾達黴素(idarubicin)及奈莫柔比星(nemorubicin);蒽醌,諸如米托蒽醌(mitoxantrone)及洛索蒽醌(losoxantrone);及鬼臼毒素(podophillotoxine),諸如依託泊苷(etoposide)及替尼泊苷(teniposide)。
微管活性劑包括微管穩定化、微管去穩定化化合物及微管蛋白聚合抑制劑,包括但不限於紫杉烷(taxane),諸如太平洋紫杉醇(paclitaxel)及多西他賽(docetaxel);圓皮海綿內酯(discodermolide);秋水仙鹼(cochicine)及埃博黴素(epothilone)及其衍生物。
非限制性的例示性烷基化劑包括環磷醯胺(cyclophosphamide)、異環磷醯胺(ifosfamide)、美法侖(melphalan)、曲貝替定(trabectedin)及亞硝基脲,諸如卡莫司汀(carmustine)及洛莫司汀(lomustine)。
非限制性的例示性基質金屬蛋白酶抑制劑(「MMP抑制劑」)包括膠原蛋白肽模擬物及非肽模擬物抑制劑、四環素衍生物、巴馬司他(batimastat)、馬立馬司他(marimastat)、普啉司他(prinomastat)、美他司他(metastat)、BMS-279251、BAY 12-9566、TAA211、MMI270B及AAJ996。
非限制性的例示性mTOR抑制劑包括抑制哺乳動物雷帕黴素靶蛋白(mTOR)且具有抗增殖活性的化合物,諸如西羅莫司(sirolimus)、依維莫司(everolimus)、CCI-779及ABT578。
非限制性的例示性抗代謝物包括5-氟尿嘧啶(5-FU);卡培他濱(capecitabine);吉西他濱(gemcitabine);DNA去甲基化合物,諸如5-氮胞苷及地西他濱(decitabine);甲胺喋呤及依達曲沙(edatrexate);及葉酸拮抗劑,諸如培美曲塞(pemetrexed)。
非限制性的例示性鉑化合物包括卡鉑(carboplatin)、順-鉑(cis-platin)、順鉑(cisplatinum)及奧沙利鉑(oxaliplatin)。
非限制性的例示性甲硫胺酸胺基肽酶抑制劑包括苯胍麥(bengamide)或其衍生物及PPI-2458。
非限制性的例示性雙膦酸鹽包括依替酮酸(etridonic acid)、氯膦酸(clodronic acid)、替魯羅酸(tiludronic acid)、帕米膦酸(pamidronic acid)、阿侖膦酸(alendronic acid)、伊班膦酸(ibandronic acid)、利塞膦酸(risedronic acid)及唑來膦酸(zoledronic acid)。
非限制性的例示性肝素酶抑制劑包括靶向、降低或抑制硫酸肝素降解之化合物,諸如PI-88及OGT2115。
靶向、降低或抑制Ras致癌活性之非限制性的例示性化合物包括法呢基轉移酶抑制劑,諸如L-744832、DK8G557、替吡法尼(tipifarnib)及洛那法尼(lonafarnib)。
非限制性的例示性端粒酶抑制劑包括靶向、降低或抑制端粒酶活性之化合物,諸如抑制端粒酶受體之化合物,諸如特羅他汀(telomestatin)。
非限制性的例示性蛋白酶體抑制劑包括靶向、降低或抑制蛋白酶體活性之化合物,包括但不限於硼替佐米(bortezomib)。在一些實施例中,蛋白酶體抑制劑為卡非佐米(carfilzomib)或依薩佐米(ixazomib)。
非限制性的例示性FMS樣酪胺酸激酶抑制劑為靶向、降低或抑制FMS樣酪胺酸激酶受體(Flt-3R)活性之化合物,包括吉列替尼(gilteritinib)、干擾素、Ι-β-D-阿糖呋喃胞嘧啶(ara-c)及白消安(bisulfan);及ALK抑制劑,其為靶向、降低或抑制間變性淋巴瘤激酶之化合物,包括艾樂替尼(alectinib)、布加替尼(brigatinib)及勞拉替尼(lorlatinib)。
非限制性的例示性Flt-3抑制劑包括PKC412、米哚妥林(midostaurin)、星形孢菌素衍生物、SU11248、MLN518及吉列替尼。
非限制性的例示性HSP90抑制劑包括靶向、降低或抑制HSP90之內在ATP酶活性的化合物;或經由泛素蛋白酶體路徑降解、靶向、降低或抑制HSP90客戶蛋白的化合物。靶向、降低或抑制HSP90之內在ATP酶活性的化合物尤其為抑制HSP90之ATP酶活性的化合物、蛋白質或抗體,諸如17-烯丙基胺基,17-去甲氧基格爾德黴素(17AAG)(一種格爾德黴素衍生物);其他格爾德黴素相關化合物;根赤殼菌素(radicicol)及HDAC抑制劑。
非限制性的例示性蛋白酪胺酸激酶及/或絲胺酸及/或蘇胺酸激酶抑制劑或脂質激酶抑制劑包括a)靶向、降低或抑制血小板衍生生長因子受體(PDGFR)活性之化合物,諸如靶向、降低或抑制PDGFR活性之化合物,包括奧拉單抗(olaratumab)及N-苯基-2-嘧啶-胺衍生物,諸如伊馬替尼、SUlOl、SU6668及GFB-111;b)靶向、降低或抑制纖維母細胞生長因子受體(FGFR)活性之化合物,諸如厄達替尼(erdafitinib)及樂伐替尼(lenvatinib);c)靶向、降低或抑制胰島素樣生長因子受體I (IGF-IR)活性之化合物,諸如布加替尼;d)靶向、降低或抑制血管內皮生長因子受體(VEGFR)活性之化合物,諸如樂伐替尼(lenvatinib);e)靶向、降低或抑制Trk受體酪胺酸激酶家族活性之化合物,或ephrin B4抑制劑,諸如拉羅替尼(larotrectinib);f)靶向、降低或抑制Axl受體酪胺酸激酶家族活性之化合物;g)靶向、降低或抑制Ret受體酪胺酸激酶活性之化合物,諸如艾樂替尼;h)靶向、降低或抑制Kit/SCFR受體酪胺酸激酶活性之化合物,諸如伊馬替尼(imatinib);i)靶向、降低或抑制c-Kit受體酪胺酸激酶活性之化合物,諸如伊馬替尼;j)靶向、降低或抑制c-Abl家族成員、其基因融合產物(例如Bcr-Abl激酶)及突變體活性之化合物,諸如N-苯基-2-嘧啶-胺衍生物,諸如伊馬替尼或尼羅替尼(nilotinib);PD180970;AG957;NSC 680410;PD173955;或達沙替尼(dasatinib);k)靶向、降低或抑制蛋白激酶C(PKC)及Raf絲胺酸/蘇胺酸激酶家族成員、MEK、SRC、JAK、FAK、PDK1、PKB/Akt及Ras/MAPK家族成員及/或細胞週期素依賴性激酶家族(CDK)成員活性之化合物,諸如美國專利第5,093,330號中所揭示之星形孢菌素衍生物,諸如米哚妥林(midostaurin);其他化合物之實例包括UCN-01、沙芬戈(safingol)、BAY 43-9006、苔蘚蟲素1、哌立福新(perifosine);伊莫福新(ilmofosine);RO 318220及RO 320432;GO 6976;Isis 3521;LY333531/LY379196;異喹啉化合物;法呢基轉移酶抑制劑;PD184352或QAN697、或AT7519;阿貝西尼(abemaciclib);畢尼替尼(binimetinib);考比替尼(cobimetinib);恩拉非尼(encorafenib);來那替尼(neratinib);帕博西尼(palbociclib);瑞博西尼(ribociclib);l)靶向、降低或抑制蛋白質酪胺酸激酶活性之化合物,諸如阿卡替尼(acalabrutinib)、甲磺酸伊馬替尼或酪胺酸磷酸化抑制劑(tyrphostin),諸如Tyrphostin A23/RG-50810;AG 99;Tyrphostin AG 213;Tyrphostin AG 1748;Tyrphostin AG 490;Tyrphostin B44;Tyrphostin B44 (+)對映異構體;Tyrphostin AG 555;AG 494;Tyrphostin AG 556、AG957及阿達斯汀(adaphostin)(4-{[(2,5-二羥基苯基)甲基]胺基}-苯甲酸金剛烷基酯;NSC 680410,阿達斯汀);m)靶向、降低或抑制受體酪胺酸激酶之表皮生長因子家族(呈均二聚體或雜二聚體之EGFR、ErbB2、ErbB3、ErbB4)及其突變體活性之化合物,諸如布加替尼、CP 358774、ZD 1839、ZM 105180;曲妥珠單抗(trastuzumab)、西妥昔單抗(cetuximab)、吉非替尼(gefitinib)、埃羅替尼(erlotinib)、奧希替尼(osimertinib)、達可替尼(dacomitinib)、萊西單抗(necitumumab)、來那替尼(neratinib)、OSI-774、Cl-1033、EKB-569、GW-2016、抗體El.l、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3及E7.6.3及7H-吡咯并-[2,3-d]嘧啶衍生物;n)靶向、降低或抑制磷脂醯肌醇3-激酶(PI3K)活性之化合物,諸如艾培昔布(alpelisib)、考班昔布(copanlisib)及杜維昔布(duvelisib);及o)靶向、降低或抑制c-Met受體活性之化合物。
靶向、降低或抑制蛋白質或脂質磷酸酶活性之非限制性的例示性化合物包括磷酸酶1、磷酸酶2A或CDC25之抑制劑,諸如岡田井酸(okadaic acid)或其衍生物。
其他抗血管生成化合物包括具有與蛋白質或脂質激酶抑制作用無關的另一種活性機制的化合物,例如沙立度胺(thalidomide)及TNP-470。
額外的非限制性的例示性化學治療性化合物,其中之一或多者可與本揭示案之化合物組合使用,包括:阿瓦斯汀(avastin)、道諾黴素、阿德力黴素(adriamycin)、Ara-C、VP-16、替尼泊苷、米托蒽醌、艾達黴素、卡鉑、PKC412、6-巰基嘌呤(6-MP)、磷酸氟達拉濱(fludarabine phosphate)、奧曲肽(octreotide)、SOM230、FTY720、6-硫鳥嘌呤、克拉屈濱(cladribine)、6-巰基嘌呤、噴司他丁(pentostatin)、羥基脲、2-羥基-lH-異吲哚-l,3-二酮衍生物、l-(4-氯苯胺基)-4-(4-吡啶基甲基)酞嗪或其醫藥學上可接受之鹽、1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞嗪琥珀酸鹽、血管生長抑素、內皮生長抑素、鄰胺基苯甲酸醯胺、ZD4190、ZD6474、SU5416、SU6668、貝伐珠單抗(bevacizumab)、rhuMAb、rhuFab、馬庫剛(macugon);FLT-4抑制劑、FLT-3抑制劑、VEGFR-2 IgGI抗體、RPI 4610、卟吩姆鈉(porfimer sodium)、阿奈可他(anecortave)、曲安西龍(triamcinolone)、氫皮質酮、11-a-表氫化皮質醇、皮質酮、17a-羥基孕酮、皮質固酮、去氧皮質固酮、睪固酮、雌酮、地塞米松(dexamethasone)、膚輕鬆(fluocinolone)、植物生物鹼、激素化合物及/或拮抗劑、生物反應調節劑(諸如淋巴介質或干擾素)、反義寡核苷酸或寡核苷酸衍生物、shRNA及siRNA。
設想在本文提供之治療方法中使用許多適合的視情況選用之治療劑,例如抗癌劑。實際上,本文所提供之方法可包括但不限於投與許多視情況選用之治療劑,諸如:誘導細胞凋亡之藥劑;多核苷酸(例如,反義、核酶、siRNA);多肽(例如,酶及抗體);生物模擬物(例如,棉籽酚或BH3模擬物);與Bcl-2家族蛋白諸如Bax結合(例如,寡聚或複合)之藥劑;生物鹼;烷基化劑;抗腫瘤抗生素;抗代謝物;激素;鉑化合物;單株或多株抗體(例如,與抗癌藥物、毒素、防禦素結合之抗體)、毒素;放射核種;生物反應調節劑(例如,干擾素(例如IFN-α)及介白素(例如IL-2));授受免疫療法劑;造血生長因子;誘導腫瘤細胞分化之藥劑(例如全反式視黃酸);基因療法試劑(例如反義治療試劑及核苷酸);腫瘤疫苗;血管生成抑制劑;蛋白酶體抑制劑:NF-КB調節劑;抗CDK化合物;HDAC抑制劑;及其類似物。適合與所揭示之化合物共同投與的視情況選用之治療劑之許多其他實例,諸如化學治療性化合物及抗癌療法,為熟習此項技術者已知的。
在某些實施例中,抗癌劑包含誘導或刺激細胞凋亡之藥劑。誘導或刺激細胞凋亡之藥劑包括例如與DNA相互作用或修飾DNA,諸如藉由嵌入、交聯、烷基化或以其他方式破壞或化學修飾DNA之藥劑。誘導細胞凋亡之藥劑包括但不限於輻射(例如,X射線、γ射線、UV);腫瘤壞死因子(TNF)相關因子(例如,TNF家族受體蛋白、TNF家族配體、TRAIL、TRAIL-R1或TRAIL-R2之抗體);激酶抑制劑(例如,表皮成長因子受體(EGFR)激酶抑制劑)。其他抗癌劑包括:血管生長因子受體(VGFR)激酶抑制劑、纖維母細胞生長因子受體(FGFR)激酶抑制劑、血小板衍生生長因子受體(PDGFR)激酶抑制劑及Bcr-Abl激酶抑制劑(諸如GLEEVEC));反義分子;抗體(例如,HERCEPTIN、RITUXAN、ZEVALIN及AVASTIN);抗雌激素(例如,雷洛昔芬及他莫昔芬);抗雄激素(例如,氟他胺(flutamide)、阿帕魯胺、比卡魯胺、非那雄安(finasteride)、胺魯米特(aminoglutethamide)、酮康唑及皮質類固醇);BCL-2抑制劑(例如,維納妥拉(venetoclax));環加氧酶2 (COX-2)抑制劑(例如,塞內昔布(celecoxib)、美洛昔康(meloxicam)、NS-398及非類固醇抗炎藥(NSAID));抗炎藥(例如,保泰松(butazolidin)、DECADRON、DELTASONE、地塞米松(dexamethasone)、地塞米松英特生(dexamethasone intensol)、DEXONE、HEXADROL、羥基氯奎(hydroxychloroquine)、METICORTEN、ORADEXON、ORASONE、羥布宗(oxyphenbutazone)、PEDIAPRED、苯基丁氮酮(phenylbutazone)、PLAQUENIL、潑尼松龍(prednisolone)、潑尼松(prednisone)、PRELONE及TANDEARIL);及癌症化學治療藥物(例如,伊立替康(CAMPTOSAR)、CPT-11、氟達拉濱(FLUDARA)、達卡巴嗪(DTIC)、地塞米松、米托蒽醌、MYLOTARG、VP-16、順鉑、卡鉑、奧沙利鉑、5-FU、阿黴素、吉西他濱、硼替佐米、吉非替尼、貝伐珠單抗、TAXOTERE或TAXOL);細胞信號傳導分子;神經醯胺及細胞介素;星形孢菌素及其類似物。
在其他實施例中,本文提供之治療方法包括向患有癌症之個體(癌症患者)投與治療有效量之本揭示案之化合物、免疫檢查點抑制劑及至少一種額外的視情況選用之治療劑,例如選自烷基化劑、抗代謝物及天然產物(例如,草藥及其他植物及/或動物衍生之化合物)之抗過度增生性或抗贅生性劑。
適用於本發明方法之烷基化劑包括但不限於:1)氮芥(例如,二氯甲基二乙胺(mechlorethamine)、環磷醯胺、異環磷醯胺、美法侖(L-溶肉瘤素);及苯丁酸氮芥(chlorambucil));2)乙烯亞胺及甲基三聚氰胺(例如,六甲基三聚氰胺及噻替派(thiotepa);3)磺酸烷基酯(例如,白消安);4)亞硝基脲(例如,卡莫司汀(BCNU);洛莫司汀(CCNU);司莫司汀(甲基-CCNU);及鏈佐星(鏈佐黴素));及5)三氮烯(例如,達卡巴嗪(DTIC;二甲基三氮烯醯亞胺-唑甲醯胺)。
在一些實施例中,適用於本發明方法之抗代謝物包括但不限於:1)葉酸類似物(例如,甲胺喋呤(胺甲喋呤));2)嘧啶類似物(例如,氟尿嘧啶(5-氟尿嘧啶;5-FU)、氟尿苷(氟脫氧尿苷;FudR)及阿糖胞苷(胞嘧啶阿拉伯糖苷));及3)嘌呤類似物(例如,巰基嘌呤(6-巰基嘌呤;6-MP)、硫鳥嘌呤(6-硫鳥嘌呤;TG)及噴司他丁(2'-去氧助間型黴素))。
在其他實施例中,適用於本揭示案之方法的化學治療劑包括但不限於:1)長春花生物鹼(例如,長春花鹼(VLB)、長春新鹼);2)表鬼臼毒素(例如,依託泊苷及替尼泊苷);3)抗生素(例如,更生黴素(放線菌素D)、道諾黴素(柔紅黴素;紅比黴素)、阿黴素、博萊黴素、普卡黴素(光神黴素)及絲裂黴素(絲裂黴素C));4)酶(例如,L-天冬醯胺酶);5)生物反應調節劑(例如,干擾素-α);6)鉑配位複合物(例如,順鉑(cis-DDP)及卡鉑);7)蒽二酮(例如,米托蒽醌);8)經取代之脲(例如,羥基脲);9)甲基肼衍生物(例如,丙卡巴肼(N-甲基肼;MIH));10)腎上腺皮質抑制劑(例如,米托坦(o,p'-DDD)及胺魯米特);11)腎上腺皮質類固醇(例如,潑尼松);12)孕激素(例如,己酸羥孕酮、乙酸甲羥孕酮及乙酸甲地孕酮);13)雌激素(例如,己烯雌酚及乙炔基雌二醇);14)抗雌激素(例如,他莫昔芬);15)雄激素(例如,丙酸睪固酮及氟甲睾酮);16)抗雄激素(例如,氟他胺):及17)促性腺激素釋放激素類似物(例如,亮丙立德)。
在癌症療法背景下常規使用之任何溶瘤劑均可用於本揭示案之治療方法。舉例而言,美國食品與藥物管理局(FDA)維持獲准在美國使用之溶瘤劑的處方集。FDA之國際對應機構維持類似的處方集。熟習此項技術者應瞭解,所有美國批准之化學治療劑上所要求的「產品標籤」描述例示性藥劑之經批准之適應症、給藥資訊、毒性資料及其類似物。
抗癌劑進一步包括已確定具有抗癌活性之化合物。實例包括但不限於3-AP、12-O-十四醯基佛波醇-13-乙酸酯、17AAG、852A、ABI-007、ABR-217620、ABT-751、ADI-PEG 20、AE-941、AG-013736、AGRO100、丙胺菌素(alanosine)、AMG 706、抗體G250、抗瘤酮(antineoplaston)、AP23573、阿帕茲醌(apaziquone)、APC8015、阿替莫德(atiprimod)、ATN-161、阿曲生坦(atrasenten)、阿紮胞苷(azacitidine)、BB-10901、BCX-1777、貝伐珠單抗、BG00001、比卡魯胺、BMS 247550、硼替佐米、苔蘚蟲素-1、布舍瑞林、長效聚乙二醇化天冬醯胺酶(calaspargase pegol-mknl)、促鈣三醇、CCI-779、CDB-2914、頭孢克肟(cefixime)、西妥昔單抗、CG0070、西侖吉肽(cilengitide)、氯法拉濱(clofarabine)、磷酸考布他汀A4 (combretastatin A4 phosphate)、CP-675,206、CP-724,714、CpG 7909、薑黃素、達土木單抗(daratumumab)、地西他濱(decitabine)、DENSPM、迪奴圖單抗(dinutuximab)、度骨化醇(doxercalciferol)、E7070、E7389、海鞘素743 (ecteinascidin 743)、乙丙昔羅(efaproxiral)、依氟鳥胺酸(eflornithine)、EKB-569、埃羅妥珠單抗(elotuzumab)、恩紮妥林(enzastaurin)、埃羅替尼(erlotinib)、依昔舒林(exisulind)、非瑞替尼(fenretinide)、夫拉平度(flavopiridol)、氟達拉濱、氟他胺、福莫司汀(fotemustine)、FR901228、G17DT、加利昔單抗(galiximab)、吉非替尼、金雀異黃酮(genistein)、格拉吉伯(glasdegib)、葡磷醯胺(glufosfamide)、GTI-2040、組胺瑞林(histrelin)、HKI-272、高粗榧鹼(homoharringtonine)、HSPPC-96、hu14.18-介白素-2融合蛋白、HuMax-CD4、伊洛前列素(iloprost)、咪喹莫特(imiquimod)、英利昔單抗(infliximab)、奧英妥珠單抗(inotuzumab ozogamicin)、介白素-12、IPI-504、伊洛福芬(irofulven)、伊沙匹隆(ixabepilone)、拉帕替尼(lapatinib)、來那度胺(lenalidomide)、來他替尼(lestaurtinib)、亮丙立德、LMB-9免疫毒素、洛那法尼、魯昔單抗(luniliximab)、多塔塔特鎦Lu 177、馬磷醯胺(mafosfamide)、MB07133、MDX-010、MLN2704、莫格利珠單抗(mogamulizumab-kpkc)、單株抗體3F8、單株抗體J591、莫特沙芬(motexafin)、帕西妥莫單抗(moxetumomab pasudotox-tdfk)、MS-275、MVA-MUC1-IL2、尼魯米特(nilutamide)、尼拉帕尼(niraparib)、硝基喜樹鹼、諾拉曲特二鹽酸鹽(nolatrexed dihydrochloride)、諾瓦得士(nolvadex)、NS-9、O6-苯甲基鳥嘌呤、奧利默森鈉(oblimersen sodium)、ONYX-015、奧戈伏單抗(oregovomab)、OSI-774、帕尼單抗(panitumumab)、鉑爾定(paraplatin)、PD-0325901、培美曲塞、PHY906、吡格列酮(pioglitazone)、吡非尼酮(pirfenidone)、匹蒽醌(pixantrone)、保納珠單抗維多汀(polatuzumab vedotin-piiq)、PS-341、PSC 833、PXD101、吡唑啉吖啶(pyrazoloacridine)、R115777、RAD001、豹蛙酶(ranpirnase)、蝴蝶黴素(rebeccamycin)類似物、重組人類血管生成抑制素蛋白(rhuAngiostatin protein)、rhuMab 2C4、羅格列酮(rosiglitazone)、魯比替康(rubitecan)、蘆卡帕尼(rucaparib)、S-1、S-8184、沙鉑(satraplatin)、SB-15992、SGN-0010、SGN-40、索尼得吉(sonidegib)、索拉非尼(sorafenib)、SR31747A、ST1571、SU011248、辛二醯苯胺異羥肟酸(suberoylanilide hydroxamic acid)、蘇拉明(suramin)、塔格索夫(tagraxofusp-erzs)、塔拉司他(talabostat)、他侖帕奈(talampanel)、塔拉佐帕瑞(talazoparib)、塔利奎達(tariquidar)、坦羅莫司(temsirolimus)、TGFa-PE38免疫毒素、沙立度胺、胸腺法新(thymalfasin)、替吡法尼(tipifarnib)、替拉紮明(tirapazamine)、TLK286、曲貝替定(trabectedin)、曲氟尿苷及鹽酸替吡嘧啶(trifluridine and tipiracil hydrochloride)、葡糖醛酸曲美沙特(trimetrexate glucuronate)、TroVax、UCN-1、丙戊酸、長春氟寧(vinflunine)、VNP40101M、沃洛昔單抗(volociximab)、伏立諾他(vorinostat)、VX-680、ZD1839、ZD6474、齊留通(zileuton)及唑蘇達三鹽酸鹽(zosuquidar trihydrochloride)。
在一個實施例中,視情況選用之治療劑包含表5中所列之抗癌藥或抗癌藥組合中之一者。
表5
阿貝西尼 | 乙酸阿比特龍 | Abraxane (白蛋白穩定化太平洋紫杉醇奈米粒子調配物) | ABVD |
ABVE | ABVE-PC | AC | 阿卡替尼 |
AC-T | Actemra (托珠單抗) | Adcetris (貝倫妥單抗維多汀) | ADE |
曲妥珠單抗-美坦新偶聯物 | 阿德力黴素(鹽酸阿黴素) | 雙馬來酸阿法替尼 | Afinitor (依維莫司) |
Akynzeo (奈妥吡坦及鹽酸帕洛諾司瓊) | Aldara (咪喹莫特) | 阿地介白素 | Alecensa (艾樂替尼) |
艾樂替尼 | 阿侖單抗 | Alimta (培美曲塞二鈉) | Aliqopa (鹽酸考班昔布) |
Alkeran注射劑(鹽酸美法侖) | Alkeran錠劑(美法侖) | Aloxi (鹽酸帕洛諾司瓊) | Alunbrig (布加替尼) |
Ameluz (胺基乙醯丙酸) | 阿米福汀 | 胺基乙醯丙酸 | 阿那曲唑 |
阿帕魯胺 | 阿瑞匹坦 | Aranesp (阿法達貝泊汀) | Aredia (帕米膦酸二鈉) |
Arimidex (阿那曲唑) | Aromasin (依西美坦) | Arranon (奈拉濱) | 三氧化二砷 |
Arzerra (奧法木單抗) | 菊歐文氏菌天冬醯胺酶 | 阿特珠單抗 | Avastin (貝伐珠單抗) |
阿維魯單抗 | 西卡思羅 | 阿西替尼 | 阿紮胞苷 |
Azedra (碘苄胍I 131) | Bavencio (阿維魯單抗) | BEACOPP | Beleodaq (貝利司他) |
貝利司他 | 鹽酸苯達莫司汀 | Bendeka (鹽酸苯達莫司汀) | BEP |
Besponsa (奧英妥珠單抗) | 貝伐珠單抗 | 貝瑟羅汀 | 比卡魯胺 |
BiCNU (卡莫司汀) | 畢尼替尼 | 博萊黴素 | 布林莫單抗 |
Blincyto (布林莫單抗) | 硼替佐米 | Bosulif (伯舒替尼) | 伯舒替尼 |
Braftovi (恩拉非尼) | 貝倫妥單抗維多汀 | 布加替尼 | BuMel |
白消安 | Busulfex (白消安) | 卡巴他賽 | Cabometyx (卡博替尼-S-蘋果酸鹽) |
卡博替尼-S-蘋果酸鹽 | CAF | Calquence (阿卡替尼) | Campath (阿侖單抗) |
Camptosar (鹽酸伊立替康) | 卡培他濱 | CAPOX | Carac (氟尿嘧啶--局部用) |
卡鉑 | 卡鉑-紫杉醇 | 卡非佐米 | 卡莫司汀 |
卡莫司汀植入物 | Casodex (比卡魯胺) | CEM | 賽咪單抗-rwlc |
色瑞替尼 | Cerubidine (鹽酸道諾黴素) | Cervarix (重組HPV二價疫苗) | 西妥昔單抗 |
CEV | 苯丁酸氮芥 | 苯丁酸氮芥-潑尼松 | CHOP |
順鉑 | 克拉屈濱 | 氯法拉濱 | Clolar (氯法拉濱) |
CMF | 考比替尼 | Cometriq (卡博替尼-S-蘋果酸鹽) | 鹽酸考班昔布 |
COPDAC | Copiktra (杜維昔布) | COPP | COPP-ABV |
Cosmegen (更生黴素) | Cotellic (考比替尼) | 克唑替尼 | CVP |
環磷醯胺 | Cyramza (雷莫蘆單抗) | 阿糖胞苷 | 阿糖胞苷脂質體 |
Cytosar-U (阿糖胞苷) | 達拉非尼 | 達卡巴嗪 | Dacogen (地西他濱) |
達可替尼 | 更生黴素 | 達土木單抗 | 阿法達貝泊汀 |
Darzalex (達土木單抗) | 達沙替尼 | 鹽酸道諾黴素 | 鹽酸道諾黴素及阿糖胞苷脂質體 |
地西他濱 | 去纖苷鈉 | Defitelio (去纖苷鈉) | 地加瑞克 |
地尼介白素 | 德諾單抗 | DepoCyt (阿糖胞苷脂質體) | 地塞米松 |
鹽酸右雷佐生 | 迪奴圖單抗 | 多西他賽 | Doxil (鹽酸阿黴素脂質體) |
鹽酸阿黴素 | 鹽酸阿黴素脂質體 | Dox-SL (鹽酸阿黴素脂質體) | 德瓦魯單抗 |
杜維昔布 | Efudex (氟尿嘧啶--局部用) | Eligard (乙酸亮丙立德) | Elitek (拉布立酶) |
Ellence (鹽酸表柔比星) | 埃羅妥珠單抗 | Eloxatin (奧沙利鉑) | 艾曲波帕乙醇胺 |
Emend (阿瑞匹坦) | Empliciti (埃羅妥珠單抗) | 甲磺酸依那西尼 | 恩拉非尼 |
恩雜魯胺 | 鹽酸表柔比星 | EPOCH | 阿法依泊汀 |
Epogen (阿法依泊汀) | Erbitux (西妥昔單抗) | 甲磺酸艾日布林 | Erivedge (維莫德吉) |
Erleada (阿帕魯胺) | 鹽酸埃羅替尼 | Erwinaze (菊歐文氏菌天冬醯胺酶) | Ethyol (阿米福汀) |
Etopophos (磷酸依託泊苷) | 依託泊苷 | 磷酸依託泊苷 | Evacet (鹽酸阿黴素脂質體) |
依維莫司 | Evista (鹽酸雷洛昔芬) | Evomela (鹽酸美法侖) | 依西美坦 |
5-FU (氟尿嘧啶注射劑) | 5-FU (氟尿嘧啶--局部用) | Fareston (托瑞米芬) | Farydak (乳酸帕比諾他) |
Faslodex (氟維司群) | FEC | Femara (來曲唑) | 非格司亭 |
Firmagon (地加瑞克) | 磷酸氟達拉濱 | Fluoroplex (氟尿嘧啶--局部用) | 氟尿嘧啶注射劑 |
氟尿嘧啶--局部用 | 氟他胺 | FOLFIRI | FOLFIRI-貝伐珠單抗 |
FOLFIRI-西妥昔單抗 | FOLFIRINOX | FOLFOX | Folotyn (普拉曲沙) |
福他替尼二鈉 | FU-LV | 氟維司群 | Fusilev (甲醯四氫葉酸鈣) |
Gardasil (重組HPV四價疫苗) | Gardasil 9 (重組HPV九價疫苗) | Gazyva (奧比珠單抗) | 吉非替尼 |
鹽酸吉西他濱 | 吉西他濱-順鉑 | 吉西他濱-奧沙利鉑 | 吉妥珠單抗奧佐米星 |
Gemzar (鹽酸吉西他濱) | Gilotrif (雙馬來酸阿法替尼) | Gleevec (甲磺酸伊馬替尼) | Gliadel Wafer (卡莫司汀植入物) |
穀卡匹酶 | 乙酸戈舍瑞林 | 格拉司瓊 | 鹽酸格拉司瓊 |
Granix (非格司亭) | Halaven (甲磺酸艾日布林) | Hemangeol (鹽酸普萘洛爾) | Herceptin (曲妥珠單抗) |
重組HPV二價疫苗 | 重組HPV九價疫苗 | 重組HPV四價疫苗 | Hycamtin (鹽酸拓朴替康) |
Hydrea (羥基脲) | 羥基脲 | Hyper-CVAD | Ibrance (帕博西尼) |
替伊莫單抗 | 依魯替尼 | ICE | Iclusig (鹽酸普納替尼) |
鹽酸伊達比星 | 艾德昔布 | Idhifa (甲磺酸依那西尼) | Ifex (異環磷醯胺) |
異環磷醯胺 | IL-2 (阿地介白素) | 甲磺酸伊馬替尼 | Imbruvica (依魯替尼) |
Imfinzi (德瓦魯單抗) | 咪喹莫特 | Imlygic (塔里穆尼拉赫韋克) | Inlyta (阿西替尼) |
奧英妥珠單抗 | 重組干擾素α-2b | 介白素-2 (阿地介白素) | Intron A (重組干擾素α-2b) |
碘苄胍I 131 | 伊匹單抗 | Iressa (吉非替尼) | 鹽酸伊立替康 |
鹽酸伊立替康脂質體 | Istodax (羅米地辛) | 艾維頓尼 | 伊沙匹隆 |
檸檬酸依薩佐米 | Ixempra (伊沙匹隆) | Jakafi (磷酸蘆可替尼) | JEB |
Jevtana (卡巴他賽) | Kadcyla (曲妥珠單抗-美坦新偶聯物) | Kepivance (帕利夫明) | Keytruda (派姆單抗) |
Kisqali (瑞博西尼) | Kymriah (替沙津魯) | Kyprolis (卡非佐米) | 乙酸蘭瑞肽 |
二甲苯磺酸拉帕替尼 | 硫酸拉羅替尼 | Lartruvo (奧拉單抗) | 來那度胺 |
甲磺酸樂伐替尼 | Lenvima (甲磺酸樂伐替尼) | 來曲唑 | 甲醯四氫葉酸鈣 |
Leukeran (苯丁酸氮芥) | 乙酸亮丙立德 | Levulan Kerastik (胺基乙醯丙酸) | Libtayo (賽咪單抗-rwlc) |
LipoDox (鹽酸阿黴素脂質體) | 洛莫司汀 | Lonsurf (曲氟尿苷及鹽酸替吡嘧啶) | Lorbrena (勞拉替尼) |
勞拉替尼 | Lumoxiti (帕西妥莫單抗) | Lupron (乙酸亮丙立德) | Lupron Depot (乙酸亮丙立德) |
Lutathera (多塔塔特鎦Lu 177) | Lutetium (多塔塔特Lu 177) | Lynparza (奧拉帕尼) | Marqibo (硫酸長春新鹼脂質體) |
Matulane (鹽酸丙卡巴肼) | 鹽酸二氯甲基二乙胺 | 乙酸甲地孕酮 | Mekinist (曲美替尼) |
Mektovi (畢尼替尼) | 美法侖 | 鹽酸美法侖 | 巰基嘌呤 |
美司鈉 | Mesnex (美司鈉) | 甲胺喋呤 | 溴化甲基納曲酮 |
米哚妥林 | 絲裂黴素C | 鹽酸米托蒽醌 | 莫格利珠單抗-kpkc |
帕西妥莫單抗-tdfk | Mozobil (普樂沙福) | Mustargen (鹽酸二氯甲基二乙胺) | MVAC |
Myleran (白消安) | Mylotarg (吉妥珠單抗奧佐米星) | 太平洋紫杉醇奈米粒子(白蛋白穩定化太平洋紫杉醇奈米粒子調配物) | Navelbine (酒石酸長春瑞賓) |
萊西單抗 | 奈拉濱 | 馬來酸來那替尼 | Nerlynx (馬來酸來那替尼) |
奈妥吡坦及鹽酸帕洛諾司瓊 | Neulasta (培非格司亭) | Neupogen (非格司亭) | Nexavar (甲苯磺酸索拉非尼) |
Nilandron (尼魯米特) | 尼羅替尼 | 尼魯米特 | Ninlaro (檸檬酸依薩佐米) |
尼拉帕尼甲苯磺酸鹽單水合物 | 尼沃單抗 | Nplate (羅米司亭) | 奧比珠單抗 |
Odomzo (索尼得吉) | OEPA | 奧法木單抗 | OFF |
奧拉帕尼 | 奧拉單抗 | 高三尖杉酯鹼 | Oncaspar (培門冬酶) |
鹽酸昂丹司瓊 | Onivyde (鹽酸伊立替康脂質體) | Ontak (地尼白介素) | Opdivo (尼沃單抗) |
OPPA | 奧希替尼 | 奧沙利鉑 | 太平洋紫杉醇 |
白蛋白穩定化太平洋紫杉醇奈米粒子調配物 | PAD | 帕博西尼 | 帕利夫明 |
鹽酸帕洛諾司瓊 | 鹽酸帕洛諾司瓊及奈妥吡坦 | 帕米膦酸二鈉 | 帕尼單抗 |
乳酸帕比諾他 | 鹽酸帕唑帕尼 | PCV | PEB |
培門冬酶 | 培非格司亭 | 聚乙二醇化干擾素α-2b | PEG-Intron (聚乙二醇化干擾素α-2b) |
派姆單抗 | 培美曲塞二鈉 | Perjeta (帕妥珠單抗) | 帕妥珠單抗 |
普樂沙福 | 泊利度胺 | Pomalyst (泊利度胺) | 鹽酸普納替尼 |
Portrazza (萊西單抗) | Poteligeo (莫格利珠單抗-kpkc) | 普拉曲沙 | 潑尼松 |
鹽酸丙卡巴肼 | Procrit (阿法依泊汀) | Proleukin (阿地介白素) | Prolia (德諾單抗) |
Promacta (艾曲波帕乙醇胺) | 鹽酸普萘洛爾 | Provenge (西普魯塞-T) | Purinethol (巰基嘌呤) |
Purixan (巰基嘌呤) | 二氯化鐳223 | 鹽酸雷洛昔芬 | 雷莫蘆單抗 |
拉布立酶 | R-CHOP | R-CVP | 重組人類乳頭狀瘤病毒(HPV)二價疫苗 |
重組人類乳頭狀瘤病毒(HPV)九價疫苗 | 重組人類乳頭狀瘤病毒(HPV)四價疫苗 | 重組干擾素α-2b | 瑞戈非尼 |
Relistor (溴化甲基納曲酮) | R-EPOCH | Retacrit (阿法依泊汀) | Revlimid (來那度胺) |
Rheumatrex (甲胺喋呤) | 瑞博西尼 | R-ICE | Rituxan (利妥昔單抗) |
Rituxan Hycela (利妥昔單抗及人類玻尿酸酶) | 利妥昔單抗 | 利妥昔單抗及人類玻尿酸酶 | 鹽酸羅拉匹坦 |
羅米地辛 | 羅米司亭 | 紅比黴素(鹽酸道諾黴素) | Rubraca (樟腦磺酸蘆卡帕尼) |
樟腦磺酸蘆卡帕尼 | 磷酸蘆可替尼 | Rydapt (米哚妥林) | Sancuso (格拉司瓊) |
司蘭索胸膜內氣溶膠(滑石) | 司妥昔單抗 | 西普魯塞-T | Somatuline Depot (乙酸蘭瑞肽) |
索尼得吉 | 甲苯磺酸索拉非尼 | Sprycel (達沙替尼) | STANFORD V |
無菌滑石粉(滑石) | Steritalc (滑石) | Stivarga (瑞戈非尼) | 蘋果酸舒尼替尼 |
Sustol (格拉司瓊) | Sutent (蘋果酸舒尼替尼) | Sylatron (聚乙二醇化干擾素α-2b) | Sylvant (司妥昔單抗) |
Synribo (高三尖杉酯鹼) | Tabloid (硫鳥嘌呤) | TAC | Tafinlar (達拉非尼) |
Tagrisso (奧希替尼) | 滑石 | 塔里穆尼拉赫韋克 | 檸檬酸他莫昔芬 |
Tarabine PFS (阿糖胞苷) | Tarceva (鹽酸埃羅替尼) | Targretin (貝瑟羅汀) | Tasigna (尼羅替尼) |
Tavalisse (福他替尼二鈉) | 紫杉醇(太平洋紫杉醇) | Taxotere (多西他賽) | Tecentriq (阿特珠單抗) |
Temodar (替莫唑胺) | 替莫唑胺 | 坦羅莫司 | 沙立度胺 |
Thalomid (沙立度胺) | 硫鳥嘌呤 | 噻替派 | Tibsovo (艾維頓尼) |
替沙津魯 | 托珠單抗 | Tolak (氟尿嘧啶--局部用) | 鹽酸拓朴替康 |
托瑞米芬 | Torisel (坦羅莫司) | Totect (鹽酸右雷佐生) | TPF |
曲貝替定 | 曲美替尼 | 曲妥珠單抗 | Treanda (鹽酸苯達莫司汀) |
Trexall (甲胺喋呤) | 曲氟尿苷及鹽酸替吡嘧啶 | Trisenox (三氧化二砷) | Tykerb (二甲苯磺酸拉帕替尼) |
Unituxin (迪奴圖單抗) | 三乙酸尿苷 | VAC | 戊柔比星 |
Valstar (戊柔比星) | 凡德他尼 | VAMP | Varubi (鹽酸羅拉匹坦) |
Vectibix (帕尼單抗) | VeIP | Velcade (硼替佐米) | 維羅非尼 |
Venclexta (維納妥拉) | 維納妥拉 | Verzenio (阿貝西尼) | Vidaza (阿紮胞苷) |
硫酸長春花鹼 | 硫酸長春新鹼 | 硫酸長春新鹼脂質體 | 酒石酸長春瑞賓 |
VIP | 維莫德吉 | Vistogard (三乙酸尿苷) | Vitrakvi (硫酸拉羅替尼) |
Vizimpro (達可替尼) | Voraxaze (穀卡匹酶) | 伏立諾他 | Votrient (鹽酸帕唑帕尼) |
Vyxeos (鹽酸道諾黴素及阿糖胞苷脂質體) | Xalkori (克唑替尼) | Xeloda (卡培他濱) | XELIRI |
XELOX | Xgeva (德諾單抗) | Xofigo (二氯化鐳223) | Xtandi (恩雜魯胺) |
Yervoy (伊匹單抗) | Yescarta (西卡思羅) | Yondelis (曲貝替定) | Zaltrap (Ziv-阿柏西普) |
Zarxio (非格司亭) | Zejula (尼拉帕尼甲苯磺酸鹽單水合物) | Zelboraf (維羅非尼) | Zevalin (替伊莫單抗) |
Zinecard (鹽酸右雷佐生) | Ziv-阿柏西普 | Zofran (鹽酸昂丹司瓊) | Zoladex (乙酸戈舍瑞林) |
唑來膦酸 | Zolinza (伏立諾他) | Zometa (唑來膦酸) | Zydelig (艾德昔布) |
Zykadia (色瑞替尼) | Zytiga (乙酸阿比特龍) |
本揭示案提供與治療個體之疾病有關之以下特定實施例。
實施例I. 一種治療個體之方法,該方法包含向該個體投與治療有效量之本揭示案之化合物,其中該個體患有癌症、慢性自體免疫病症、發炎性病況、增生性病症、敗血症或病毒感染。
實施例II.如實施例I之方法,其中該個體患有癌症。
實施例III.如實施例II之方法,其中該癌症為表3之任一或多種癌症。
實施例IV.如實施例II之方法,其中該癌症選自由以下組成之群組:急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴細胞性白血病混合系白血病、NUT中線癌、多發性骨髓瘤、小細胞肺癌、非小細胞肺癌、神經母細胞瘤、伯基特氏淋巴瘤、宮頸癌、食道癌、卵巢癌、結腸直腸癌、前列腺癌、乳癌、膀胱癌、卵巢癌、神經膠質瘤、肉瘤、食道鱗狀細胞癌及甲狀腺乳頭狀癌。
實施例V.如實施例II之方法,其中該癌症為表4之任一或多種癌症。
實施例VI.如實施例I-V中任一項之方法,其進一步包含投與治療有效量之可用於治療疾病或病況之視情況選用之治療劑,例如免疫檢查點抑制劑或其他抗癌劑。
實施例VII.如實施例I-VI中任一項之方法,其中本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中任一者之化合物或其醫藥學上可接受之鹽或溶劑合物。
實施例VIII.如實施例I-VI中任一項之方法,其中本揭示案之化合物為式XVI
化合物或其醫藥學上可接受之鹽或溶劑合物。
實施例IX.一種醫藥組合物,其包含本揭示案之化合物及醫藥學上可接受之賦形劑,用於治療癌症、慢性自體免疫病症、發炎性病況、增生性病症、敗血症或病毒感染。
實施例X.如實施例IX之醫藥組合物,其用於治療癌症。
實施例XI.如實施例X之醫藥組合物,其中該癌症為表3之任一或多種癌症。
實施例XII.如實施例X之醫藥組合物,其中該癌症選自由以下組成之群組:急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴細胞性白血病混合系白血病、NUT-中線癌、多發性骨髓瘤、小細胞肺癌、非小細胞肺癌、神經母細胞瘤、伯基特氏淋巴瘤、宮頸癌、食道癌、卵巢癌、結腸直腸癌、前列腺癌、乳癌、膀胱癌、卵巢癌、神經膠質瘤、肉瘤、食道鱗狀細胞癌及甲狀腺乳頭狀癌。
實施例XIII.如實施例X之醫藥組合物,其中該癌症為表4之任一或多種癌症。
實施例XIV.如實施例IX-XIII中任一項之醫藥組合物,其中本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中任一者之化合物或其醫藥學上可接受之鹽或溶劑合物。
實施例XV.如實施例IX-XIII中任一項之醫藥組合物,其中本揭示案之化合物為式XVI
化合物或其醫藥學上可接受之鹽或溶劑合物。
實施例XVI.一種本揭示案之化合物,其用於治療癌症、慢性自體免疫病症、發炎性病況、增生性病症、敗血症或病毒感染。
實施例XVII.如實施例XVI之化合物,其用於治療癌症。
實施例XVIII.如實施例XVII之化合物,其中該癌症為表3之任一或多種癌症。
實施例XIX.如實施例XVII之化合物,其中該癌症選自由以下組成之群組:急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴細胞性白血病混合系白血病、NUT中線癌、多發性骨髓瘤、小細胞肺癌、非小細胞肺癌、神經母細胞瘤、伯基特氏淋巴瘤、宮頸癌、食道癌、卵巢癌、結腸直腸癌、前列腺癌、乳癌、膀胱癌、卵巢癌、神經膠質瘤、肉瘤、食道鱗狀細胞癌及甲狀腺乳頭狀癌。
實施例XX.如實施例XVII之化合物,其中該癌症為表4之任一或多種癌症。
實施例XXI.如實施例XVI-XX中任一項之化合物,其中本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中任一者之化合物或其醫藥學上可接受之鹽或溶劑合物。
實施例XXII.如實施例XVI-XX中任一項之化合物,其中本揭示案之化合物為式XVI
化合物或其醫藥學上可接受之鹽或溶劑合物。
實施例XXIII.一種本揭示案之化合物用於製造治療癌症、慢性自體免疫病症、發炎性病況、增生性病症、敗血症或病毒感染之藥物的用途。
實施例XXIV.如實施例XXIII之用途,其用於治療癌症。
實施例XXV.如實施例XXIV之用途,其中該癌症為表3之任一或多種癌症。
實施例XXVI.如實施例XXIII之用途,其中該癌症選自由以下組成之群組:急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴細胞性白血病混合系白血病、NUT中線癌、多發性骨髓瘤、小細胞肺癌、非小細胞肺癌、神經母細胞瘤、伯基特氏淋巴瘤、宮頸癌、食道癌、卵巢癌、結腸直腸癌、前列腺癌、乳癌、膀胱癌、卵巢癌、神經膠質瘤、肉瘤、食道鱗狀細胞癌及甲狀腺乳頭狀癌。
實施例XXVII.如實施例XXIV之用途,其中該癌症為表4之任一或多種癌症。
實施例XXVIII.如實施例XXIII-XXVII中任一項之用途,其中本揭示案之化合物為式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中任一者之化合物或其醫藥學上可接受之鹽或溶劑合物。
實施例XXIX.如實施例XXIII-XXVII中任一項之用途,其中本揭示案之化合物為式XVI
化合物或其醫藥學上可接受之鹽或溶劑合物。
實施例XXX. 一種抑制有需要之個體之細胞內之EED蛋白的方法,該方法包含向該個體投與式I
-XI
、XI
-A
、XI
-B
、XII
、XII
-A
、XII
-B
、XIII
、XIII
-A
、XIII
-B 、 XIV
、XIV
-A
、XIV
-B
、XV
、XV
-A
或XV
-B
中任一者之化合物或其醫藥學上可接受之鹽或溶劑合物。
實施例XXXI. 一種抑制有需要之個體之細胞內之EED蛋白的方法,該方法包含向該個體投與式XVI
化合物或其醫藥學上可接受之鹽或溶劑合物。
V.本揭示案之套組
在另一個實施例中,本揭示案提供包含本揭示案之化合物(或包含本揭示案之化合物之組合物)的套組,該等套組以有助於其用於實踐本揭示案之方法的方式封裝。在一個實施例中,該套組包括封裝在容器諸如密封之瓶或器皿中之本揭示案之化合物(或包含本揭示案之化合物之組合物),以及貼附至容器或包括在套組中之標籤,該標籤描述使用該化合物或組合物來實踐本揭示案之方法,例如如實施例I-VI中任一項之方法。在一個實施例中,該化合物或組合物以單位劑型封裝。該套組可進一步包括適合於根據預期投與途徑投與該組合物之裝置。
VI.定義
術語「抑制EED提供益處之疾病或病況」及其類似術語涉及EED例如對於疾病或病況之發作、進展、表現為重要或必需之疾病或病況,或已知由EED抑制劑治療之疾病或病況。此類病況之實例包括但不限於癌症、慢性自體免疫疾病、炎性疾病、增生性疾病、敗血症及病毒感染。一般熟習此項技術者能夠容易地判定化合物是否治療由EED抑制劑介導之任何特定細胞類型的疾病或病況,例如藉由可方便地用於評定特定化合物活性之分析。參見例如Yue及Turkson, 《調研藥物專家評論(Expert Opinion Invest Drugs
)》18
:45-56 (2009)。
術語「EED」係指胚胎外胚層發育蛋白。參見Moritz及Trievel, 《生物化學雜誌(J. Biol. Chem.
)》293(36)
:13805-13814 (2018)。
術語「視情況選用之治療劑」係指不同於本揭示案之化合物且已知治療所關注之疾病或病況的治療劑。舉例而言,當癌症為所關注之疾病或病況時,視情況選用之治療劑可為已知的化學治療藥物,例如紫杉醇,或輻射。
術語「疾病」或「病況」表示通常視為病理病況或功能且本身可以特定病徵、症狀及/或功能障礙之形式顯現的紊亂及/或異常。本揭示案之化合物為EED之抑制劑,且可用於治療或預防抑制EED提供益處之疾病及病況。
如本文所用,術語「治療(treat/treating/treatment)」及其類似者係指消除、減輕或改善疾病或病況及/或與其相關之症狀。儘管不排除,但治療疾病或病況無需將疾病、病況或與其相關之症狀完全消除。術語「治療」及同義詞涵蓋向需要此類治療之個體投與治療有效量之本揭示案之化合物。治療可根據症狀定向,例如以抑制症狀。其可在短期內實現、在中期內定向或可為長期治療,例如在維持療法之情形下。
如本文所用,術語「預防(prevent/preventing/prevention)」係指預防疾病或病況及/或其伴隨症狀發作或防止個體患病之方法。如本文所用,「預防」亦包括延遲疾病及/或其伴隨症狀發作及降低個體患病之風險。術語「預防」可包括「預防性治療」,其係指降低個體再次罹患疾病或病況或先前控制之疾病或病況復發的機率,該個體未患但處於再次罹患疾病或病況或疾病或病況復發之風險下,或容易再次罹患疾病或病況或疾病或病況復發。
如本文所用,術語「治療有效量」或「有效劑量」係指當藉由本揭示案之方法投與時足以向有需要之個體有效遞送活性成分以治療所關注之病況或疾病的活性成分之量。在癌症或其他增殖病症之情況下,治療有效量之藥劑可減少(亦即,在一定程度上延緩或停止)不想要的細胞增殖;減少癌細胞之數量;減小腫瘤尺寸;抑制(亦即,在一定程度上延緩或停止)癌細胞浸潤至外周器官中;抑制(亦即,在一定程度上延緩或停止)腫瘤轉移;在一定程度上抑制腫瘤生長;及/或在一定程度上緩解與癌症相關之一或多種症狀。在所投與之化合物或組合物阻止生長及/或殺死現有癌細胞之情況下,其可為細胞抑制性的及/或細胞毒性的。
術語「容器」意謂因此適合於儲存、運送、分配及/或操縱醫藥產品之任何盛器及封閉件。
術語「說明書」意謂隨附醫藥產品之資訊,該資訊提供關於如何投與產品之描述,以及使醫師、藥劑師及個體就產品之使用做出知情決策所需的安全性及功效資料。藥品說明書一般視為醫藥產品之「標籤」。
「並行投與」、「組合投與」、「同時投與」及類似片語意謂向所治療之個體並行投與兩種或更多種藥劑。「並行」意謂同時或在不同的時間點以任何順序依次投與各藥劑。然而,若不同時投與,則意味著其按順序且在時間上足夠接近地投與個體,以提供所需治療效果且可協同作用。舉例而言,本揭示案之化合物可作為視情況選用之治療劑在同一時間或在不同時間點以任何順序依次投與。本揭示案之化合物及視情況選用之治療劑可以任何適當形式及藉由任何適合途徑分開投與。當本揭示案之化合物及視情況選用之治療劑不並行投與時,應理解其可以任何順序向有需要之個體投與。舉例而言,本揭示案之化合物可在視情況選用之治療劑治療模式(例如放射療法)投與之前(例如,之前5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週4週、5週、6週、8週或12週)、同時或之後(例如,之後5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週、4週、5週、6週、8週或12週)向有需要之個體投與。在各種實施例中,本揭示案之化合物及視情況選用之治療劑相隔1分鐘、相隔10分鐘、相隔30分鐘、相隔少於1小時、相隔1小時、相隔1小時至2小時、相隔2小時至3小時、相隔3小時至4小時、相隔4小時至5小時、相隔5小時至6小時、相隔6小時至7小時、相隔7小時至8小時、相隔8小時至9小時、相隔9小時至10小時、相隔10小時至11小時、相隔11小時至12小時、相隔不超過24小時或相隔不超過48小時進行投與。在一個實施例中,組合療法之組分相隔約1分鐘至約24小時投與。
在描述本揭示案之上下文中(尤其在申請專利範圍之上下文中),除非另外指明,否則術語「一(a/an)」、「該」及類似指代之使用應解釋為涵蓋單數及複數兩者。除非本文中另外指明,否則本文中對數值範圍之引述僅意欲充當單獨提及屬於該範圍內之各單獨數值的速記方法,且各單獨數值併入本說明書中,如同其在本文中單獨引述一般。除非另外主張,否則本文提供之任何及所有實例或例示性語言(例如,「諸如」)之使用旨在更好地說明本揭示案,而非對本揭示案之範疇的限制。本說明書之語言均不應解釋為指示任何非主張之要素對於本揭示案之實踐為必不可少的。
如本文所用,術語「鹵基」本身或作為另一基團之一部分係指-Cl、-F、-Br或-I。
如本文所用,術語「硝基」本身或作為另一基團之一部分係指-NO2
。
如本文所用,術語「氰基」本身或作為另一基團之一部分係指-CN。
如本文所用,術語「羥基」本身或作為另一基團之一部分係指-OH。
如本文所用,術語「烷基」本身或作為另一基團之一部分係指含有一至十二個碳原子(亦即C1
-C12
烷基)或指定碳原子數(例如C1
烷基,諸如甲基,C2
烷基,諸如乙基等)之直鏈或分支鏈脂族烴。在一個實施例中,烷基為C1
-C10
烷基。在另一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。在另一個實施例中,烷基為C1
-C3
烷基,亦即甲基、乙基、丙基或異丙基。非限制性的例示性C1
-C12
烷基包括甲基、乙基、丙基、異丙基、丁基、第二丁基、第三丁基、異丁基、3-戊基、己基、庚基、辛基、壬基及癸基。在另一個實施例中,烷基之一或多個氫原子經氘原子置換,亦即烷基經氘同位素標記。非限制性的例示性氘代烷基為-CD3
。
如本文所用,術語「視情況經取代之烷基」本身或作為另一基團之一部分係指未經取代或經一個、兩個或三個取代基取代之烷基,其中各取代基獨立地為硝基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、芳基磺醯基、脲基、胍基、胺基甲酸酯基、羧基、烷氧基羰基、羧基烷基、-N(R56a
)C(=O)R56b
、-N(R56c
)S(=O)2
R56d
、-C(=O)R57
、-S(=O)R56e
或-S(=O)2
R58
;其中:
R56a
為氫或烷基;
R56b
為烷基、鹵烷基、視情況經取代之環烷基、烷氧基、(烷氧基)烷基、(芳基)烷基、(雜芳基)烷基、(胺基)烷基、(羥基)烷基、(氰基)烷基、視情況經取代之烯基、視情況經取代之炔基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之C6
-C10
芳基或視情況經取代之雜芳基;
R56c
為氫或烷基;
R56d
為烷基、鹵烷基、視情況經取代之環烷基、烷氧基、(烷氧基)烷基、(芳基)烷基、(雜芳基)烷基、(胺基)烷基、(羥基)烷基、(氰基)烷基、視情況經取代之烯基、視情況經取代之炔基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之C6
-C10
芳基或視情況經取代之雜芳基;
R56e
為烷基、鹵烷基、視情況經取代之環烷基、烷氧基、(烷氧基)烷基、(芳基)烷基、(雜芳基)烷基、(胺基)烷基、(羥基)烷基、(氰基)烷基、視情況經取代之烯基、視情況經取代之炔基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之C6
-C10
芳基或視情況經取代之雜芳基;
R57
為鹵烷基、視情況經取代之環烷基、烷氧基、(烷氧基)烷基、(芳基)烷基、(雜芳基)烷基、(胺基)烷基、(羥基)烷基、(氰基)烷基、視情況經取代之烯基、視情況經取代之炔基、視情況經取代之環烷基、視情況經取代之雜環或視情況經取代之雜芳基;及
R58
為鹵烷基、視情況經取代之環烷基、烷氧基、(烷氧基)烷基、(芳基)烷基、(雜芳基)烷基、(胺基)烷基、(羥基)烷基、(氰基)烷基、視情況經取代之烯基、視情況經取代之炔基、視情況經取代之環烷基、視情況經取代之雜環或視情況經取代之雜芳基。非限制性的例示性視情況經取代之烷基包括-CH(CO2
Me)CH2
CO2
Me及-CH(CH3
)CH2
N(H)C(=O)O(CH3
)3
。
如本文所用,術語「烯基」本身或作為另一基團之一部分係指含有一個、兩個或三個碳-碳雙鍵之烷基。在一個實施例中,烯基為C2
-C6
烯基。在另一個實施例中,烯基為C2
-C4
烯基。在另一個實施例中,烯基具有一個碳-碳雙鍵。非限制性的例示性烯基包括乙烯基、丙烯基、異丙烯基、丁烯基、第二丁烯基、戊烯基及己烯基。
如本文所用,術語「視情況經取代之烯基」本身或作為另一基團之一部分係指未經取代或經一個、兩個或三個取代基取代之烯基,其中各取代基獨立地為鹵基、硝基、氰基、羥基、胺基(例如,烷基胺基、二烷基胺基)、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、芳基磺醯基、脲基、胍基、羧基、羧基烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基或視情況經取代之雜環。非限制性的例示性視情況經取代之烯基包括-CH=CHPh。
如本文所用,術語「炔基」本身或作為另一基團之一部分係指含有一個、兩個或三個碳-碳參鍵之烷基。在一個實施例中,炔基為C2
-C6
炔基。在另一個實施例中,炔基為C2
-C4
炔基。在另一個實施例中,炔基具有一個碳-碳參鍵。非限制性的例示性炔基包括乙炔基、丙炔基、丁炔基、2-丁炔基、戊炔基及己炔基。
如本文所用,術語「視情況經取代之炔基」本身或作為另一基團之一部分係指未經取代或經一個、兩個或三個取代基取代之炔基,其中各取代基獨立地為鹵基、硝基、氰基、羥基、胺基(例如烷基胺基、二烷基胺基)、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、芳基磺醯基、脲基、胍基、羧基、羧基烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基或視情況經取代之雜環。非限制性的例示性視情況經取代之炔基包括-C≡CPh及-CH(Ph)C≡CH。
如本文所用,術語「鹵烷基」本身或作為另一基團之一部分係指經一或多個氟、氯、溴及/或碘原子取代之烷基。在一個實施例中,烷基經一個、兩個或三個氟及/或氯原子取代。在另一個實施例中,烷基經一個、兩個或三個氟原子取代。在另一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。在另一個實施例中,烷基為C1
或C2
烷基。非限制性的例示性鹵烷基包括氟甲基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、3,3,3-三氟丙基、4,4,4-三氟丁基及三氯甲基。
如本文所用,術語「羥烷基」或「(羥基)烷基」本身或作為另一基團之一部分係指經一個、兩個或三個羥基取代之烷基。在一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。在另一個實施例中,烷基為C1
或C2
烷基。在另一個實施例中,羥烷基為單羥基烷基,亦即經一個羥基取代。在另一個實施例中,羥基烷基為二羥基烷基,亦即經兩個羥基取代。非限制性的例示性(羥基)烷基包括羥甲基、羥乙基、羥丙基及羥丁基,諸如1-羥乙基、2-羥乙基、1,2-二羥基乙基、2-羥丙基、3-羥丙基、3-羥丁基、4-羥丁基、2-羥基-1-甲基丙基及1,3-二羥基丙-2-基。
如本文所用,術語「烷氧基」本身或作為另一基團之一部分係指連接至末端氧原子之烷基。在一個實施例中,烷基為C1
-C6
烷基,所得烷氧基因此稱為「C1
-C6
烷氧基」。在另一個實施例中,烷基為C1
-C4
烷基。非限制性的例示性烷氧基包括甲氧基、乙氧基及第三丁氧基。
如本文所用,術語「鹵烷氧基」本身或作為另一基團之一部分係指連接至末端氧原子之鹵烷基。在一個實施例中,鹵烷基為C1
-C6
鹵烷基。在另一個實施例中,鹵烷基為C1
-C4
鹵烷基。非限制性的例示性鹵烷氧基包括氟甲氧基、二氟甲氧基、三氟甲氧基及2,2,2-三氟乙氧基。
如本文所用,術語「烷硫基」本身或作為另一基團之一部分係指連接至末端硫原子之烷基。在一個實施例中,烷基為C1
-C4
烷基。非限制性的例示性烷硫基包括-SCH3
及-SCH2
CH3
。
如本文所用,術語「烷氧基烷基」或「(烷氧基)烷基」本身或作為另一基團之一部分係指經一個烷氧基取代之烷基。在一個實施例中,烷氧基為C1
-C6
烷氧基。在另一個實施例中,烷氧基為C1
-C4
烷氧基。在另一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。非限制性的例示性烷氧基烷基包括甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基、丙氧基甲基、異丙氧基甲基、丙氧基乙基、丙氧基丙基、丁氧基甲基、第三丁氧基甲基、異丁氧基甲基、第二丁氧基甲基及戊氧基甲基。
單獨或另一基團之一部分使用之術語「雜烷基」係指含有三至二十個鏈原子(亦即3員至20員雜烷基)或指定鏈原子數之未經取代之直鏈或分支鏈脂族烴,其中至少一個-CH2
-經-O-、-N(H)-、-N(C1
-C4
烷基)-或-S-中之至少一者置換。-O-、-N(H)-、-N(C1
-C4
烷基)-或-S-可獨立地置於脂族烴鏈之任何內部位置,只要各-O-、-N(H)-、-N(C1
-C4
烷基)-或-S-基團由至少兩個-CH2
-基團隔開。在一個實施例中,一個-CH2
-基團經一個-O-基團置換。在另一個實施例中,兩個-CH2
-基團經兩個-O-基團置換。在另一個實施例中,三個-CH2
-基團經三個-O-基團置換。在另一個實施例中,四個-CH2
-基團經四個-O-基團置換。非限制性的例示性雜烷基包括-CH2
OCH3
、-CH2
OCH2
CH2
CH3
、-CH2
CH2
CH2
OCH3
、-CH2
CH2
OCH2
CH2
OCH2
CH3
、- CH2
CH2
OCH2
CH2
OCH2
CH2
OCH2
CH3
。
如本文所用,術語「環烷基」本身或作為另一基團之一部分係指含有三至十二個碳原子(亦即C3-12
環烷基)或指定碳數(例如C3
環烷基,諸如環丙基,C4
環烷基,諸如環丁基等)之飽和及部分不飽和(例如含有一或兩個雙鍵)的單環、雙環或三環脂族烴。在一個實施例中,環烷基為雙環的,亦即其具有兩個環。在另一個實施例中,環烷基為單環的,亦即其具有一個環。在另一個實施例中,環烷基為C3-8
環烷基。在另一個實施例中,環烷基為C3-6
環烷基,亦即環丙基、環丁基、環戊基或環己基。在另一個實施例中,環烷基為C5
環烷基,亦即環戊基。在另一個實施例中,環烷基為C6
環烷基,亦即環己基。非限制性的例示性C3-12
環烷基包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、降冰片烷基、十氫萘、金剛烷基、環己烯基及螺[3.3]庚烷。
如本文所用,術語「視情況經取代之環烷基」本身或作為另一基團之一部分係指未經取代或經一個、兩個或三個取代基取代之環烷基,其中各取代基獨立地為鹵基、硝基、氰基、羥基、胺基(例如,-NH2
、烷基胺基、二烷基胺基、芳烷基胺基、羥基烷胺基或(雜環基)烷基胺基)、雜烷基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、芳基磺醯基、脲基、胍基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧基烷基、(胺基)烷基、(氰基)烷基、(甲醯胺基)烷基、巰基烷基、(雜環基)烷基、(雜芳基)烷基、-N(R56a
)C(=O)R56b
、-N(R56c
)S(=O)2
R56d
、-C(=O)R57
、-S(=O)R56e
、-S(=O)2
R58
或-OR59
,其中R56a
、R56b
、R56c
、R56d
、R56e
、R57
及R58
如關於術語「視情況經取代之烷基」所定義,且R59
為(羥基)烷基或(胺基)烷基。術語視情況經取代之環烷基亦包括具有稠合的視情況經取代之芳基或視情況經取代之雜芳基的環烷基,諸如。
非限制性的例示性視情況經取代之環烷基包括:。
如本文所用,術語「雜環基」本身或作為另一基團之一部分係指含有三至十四個環成員(亦即3員至14員雜環基)之飽和及部分不飽和(例如含有一或兩個雙鍵)的單環、雙環或三環基團,其包含一個、兩個、三個或四個雜原子。各雜原子獨立地為氧、硫或氮。各硫原子獨立地經氧化以得到亞碸,亦即S(=O),或碸,亦即S(=O)2
。
術語雜環包括一或多個-CH2
-基團經一或多個-C(=O)-基團置換的基團,包括環脲基諸如咪唑啶基-2-酮,環醯胺基諸如吡咯啶-2-酮或哌啶-2-酮,及環胺基甲酸酯基諸如噁唑啶基-2-酮。
術語雜環亦包括具有稠合的視情況經取代之芳基或視情況經取代之雜芳基的基團,諸如吲哚啉、吲哚啉-2-酮、2,3-二氫-1H-吡咯并[2,3-c]吡啶、2,3,4,5-四氫-1H-苯并[d]氮呯或1,3,4,5-四氫-2H-苯并[d]氮呯-2-酮。
在一個實施例中,雜環基為含有一個環及一或兩個氧原子(例如四氫呋喃或四氫哌喃)或一或兩個氮原子(例如吡咯啶、哌啶或哌嗪)或一個氧及一個氮原子(例如嗎啉),且視情況一個-CH2
-經一個-C(=O)-基團置換(例如吡咯啶-2-酮或哌嗪-2-酮)之4員至8員環狀基團。在另一個實施例中,雜環基為含有一個環及一或兩個氮原子且視情況一個-CH2
-基團經一個-C(=O)-基團置換的5員至8員環狀基團。在另一個實施例中,雜環基為含有一個環及一或兩個氮原子且視情況一個-CH2
-基團經一個-C(=O)-基團置換的5員或6員環狀基團。在另一個實施例中,雜環基為含有兩個環及一或兩個氮原子之8員至12員環狀基團。雜環可經由任何可用的碳或氮原子連接至分子之其餘部分。非限制性的例示性雜環基包括:。
如本文所用,術語「視情況經取代之雜環」本身或作為另一基團之一部分係指未經取代或經一至四個取代基取代之雜環基,其中各取代基獨立地為鹵基、硝基、氰基、羥基、胺基(例如,-NH2
、烷基胺基、二烷基胺基、芳烷基胺基、羥基烷胺基或(雜環基)烷基胺基)、雜烷基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、芳基磺醯基、脲基、胍基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧基烷基、(胺基)烷基、(氰基)烷基、(甲醯胺基)烷基、巰基烷基、(雜環基)烷基、(雜芳基)烷基、-N(R56a
)C(=O)R56b
、-N(R56c
)S(=O)2
R56d
、-C(=O)R57
、-S(=O)R56e
、-S(=O)2
R58
或-OR59
,其中R56a
、R56b
、R56c
、R56d
、R56e
、R57
、R58
及R59
如關於術語「視情況經取代之環烷基」所定義。取代可發生在雜環基之任何可用的碳或氮原子上。非限制性的例示性視情況經取代之雜環基包括:。
如本文所用,術語「芳基」本身或作為另一基團之一部分係指具有六至十四個碳原子之芳族環系統,亦即C6
-C14
芳基。非限制性的例示性芳基包括苯基(縮寫為「Ph」)、萘基、菲基、蒽基、茚基、薁基、聯苯基、伸聯苯基及茀基。在一個實施例中,芳基為苯基或萘基。在另一個實施例中,芳基為苯基。
如本文所用,術語「視情況經取代之芳基」本身或作為另一基團之一部分係指未經取代或經一至五個取代基取代之芳基,其中該等取代基各自獨立地為鹵基、硝基、氰基、羥基、胺基(例如,-NH2
、烷基胺基、二烷基胺基、芳烷基胺基、羥基烷胺基或(雜環基)烷基胺基)、雜烷基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、芳基磺醯基、脲基、胍基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧基烷基、(胺基)烷基、(氰基)烷基、(甲醯胺基)烷基、巰基烷基、(雜環基)烷基、(雜芳基)烷基、-N(R56a
)C(=O)R56b
、-N(R56c
)S(=O)2
R56d
、-C(=O)R57
、-S(=O)R56e
、-S(=O)2
R58
或-OR59
,其中R56a
、R56b
、R56c
、R56d
、R56e
、R57
、R58
及R59
如關於術語「視情況經取代之環烷基」所定義。
在一個實施例中,視情況經取代之芳基為視情況經取代之苯基。在另一個實施例中,視情況經取代之苯基具有四個取代基。在另一個實施例中,視情況經取代之苯基具有三個取代基。在另一個實施例中,視情況經取代之苯基具有兩個取代基。在另一個實施例中,視情況經取代之苯基具有一個取代基。非限制性的例示性視情況經取代之芳基包括2-甲基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、3-甲基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、4-甲基苯基、4-乙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、2,6-二氟苯基、2,6-二氯苯基、2-甲基,3-甲氧基苯基、2-乙基,3-甲氧基苯基、3,4-二甲氧基苯基、3,5-二氟苯基3,5-二甲基苯基、3,5-二甲氧基,4-甲基苯基、2-氟-3-氯苯基、3-氯-4-氟苯基及2-苯基丙-2-胺。術語視情況經取代之芳基包括具有稠合的視情況經取代之環烷基及稠合的視情況經取代之雜環基的芳基。非限制性實例包括:2,3-二氫-1H-茚-1-基、1,2,3,4-四氫萘-1-基、1,3,4,5-四氫-2H-苯并[c]氮呯-2-基、1,2,3,4-四氫異喹啉-1-基及2-側氧基-2,3,4,5-四氫-1H-苯并[d]氮呯-1-基。
如本文所用,術語「雜芳基」本身或作為另一基團之一部分係指具有五至14十四個環成員(亦即5員至14員雜芳基)之單環及雙環芳族環系統,其包含一個、兩個、三個或四個雜原子。各雜原子獨立地為氧、硫或氮。在一個實施例中,雜芳基具有三個雜原子。在另一個實施例中,雜芳基具有兩個雜原子。在另一個實施例中,雜芳基具有一個雜原子。在另一個實施例中,雜芳基為5員至10員雜芳基。在另一個實施例中,雜芳基具有5個環原子,例如噻吩基,一種具有四個碳原子及一個硫原子之5員雜芳基。在另一個實施例中,雜芳基具有6個環原子,例如吡啶基,一種具有五個碳原子及一個氮原子之6員雜芳基。非限制性的例示性雜芳基包括噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻嗯基、呋喃基、苯并呋喃基、哌喃基、異苯并呋喃基、苯并噁酮基、苯并哌喃基、二苯并哌喃基、2H
-吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、噠嗪基、異吲哚基、3H
-吲哚基、吲哚基、吲唑基、嘌呤基、異喹啉基、喹啉基、酞嗪基、萘啶基、噌啉基、喹唑啉基、喋啶基、4aH
-咔唑基、咔唑基、β-咔啉基、啡啶基、吖啶基、嘧啶基、啡啉基、啡嗪基、噻唑基、異噻唑基、苯并噻唑基、異噁唑基、呋呫基及啡噁嗪基。在一個實施例中,雜芳基係選自噻吩基(例如,噻吩-2-基及噻吩-3-基)、呋喃基(例如,2-呋喃基及3-呋喃基)、吡咯基(例如,1H-吡咯-2-基及1H-吡咯-3-基)、咪唑基(例如,2H-咪唑-2-基及2H-咪唑-4-基)、吡唑基(例如,1H-吡唑-3-基、1H-吡唑-4-基及1H-吡唑-5-基)、吡啶基(例如,吡啶-2-基、吡啶-3-基及吡啶-4-基)、嘧啶基(例如,嘧啶-2-基、嘧啶-4-基及嘧啶-5-基)、噻唑基(例如,噻唑-2-基、噻唑-4-基及噻唑-5-基)、異噻唑基(例如,異噻唑-3-基、異噻唑-4-基及異噻唑-5-基)、噁唑基(例如,噁唑-2-基、噁唑-4-基及噁唑-5-基)及異噁唑基(例如,異噁唑-3-基、異噁唑-4-基及異噁唑-5-基)。術語雜芳基亦包括N-氧化物。非限制性的例示性N-氧化物為吡啶基N-氧化物。
如本文所用,術語「視情況經取代之雜芳基」本身或作為另一基團之一部分係指未經取代或經一至四個取代基取代之雜芳基,其中該等取代基獨立地為鹵基、硝基、氰基、羥基、胺基(例如,-NH2
、烷基胺基、二烷基胺基、芳烷基胺基、羥基烷胺基或(雜環基)烷基胺基)、雜烷基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、芳基磺醯基、脲基、胍基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧基烷基、(胺基)烷基、(氰基)烷基、(甲醯胺基)烷基、巰基烷基、(雜環基)烷基、(雜芳基)烷基、-N(R56a
)C(=O)R56b
、-N(R56c
)S(=O)2
R56d
、-C(=O)R57
、-S(=O)R56e
、-S(=O)2
R58
或-OR59
,其中R56a
、R56b
、R56c
、R56d
、R56e
、R57
、R58
及R59
如關於術語「視情況經取代之環烷基」所定義。
在一個實施例中,視情況經取代之雜芳基具有兩個取代基。在另一個實施例中,視情況經取代之雜芳基具有一個取代基。任何可用的碳或氮原子可經取代。
如本文所用,術語「5員伸雜芳基」本身或作為另一基團之一部分係指視情況經取代之5員雜芳基的二價形式。在一個實施例中,伸雜芳基為經取代之5員伸雜芳基。在一個實施例中,伸雜芳基為未經取代之5員伸雜芳基。非限制性的例示性5員伸雜芳基包括:。
如本文所用,術語「芳氧基」本身或作為另一基團之一部分係指連接至末端氧原子之視情況經取代之芳基。非限制性的例示性芳氧基為PhO-。
如本文所用,術語「雜芳基氧基」本身或作為另一基團之一部分係指連接至末端氧原子之視情況經取代之雜芳基。非限制性的例示性芳氧基為吡啶基-O-。
如本文所用,術語「芳烷氧基」本身或作為另一基團之一部分係指連接至末端氧原子之芳烷基。非限制性的例示性芳烷氧基為PhCH2
O-。
如本文所用,術語「(氰基)烷基」本身或作為另一基團之一部分係指經一個、兩個或三個氰基取代之烷基。在一個實施例中,烷基經一個氰基取代。在另一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。非限制性的例示性(氰基)烷基包括-CH2
CH2
CN及-CH2
CH2
CH2
CN。
如本文所用,術語「(環烷基)烷基」本身或作為另一基團之一部分係指經一或兩個視情況經取代之環烷基取代之烷基。在一個實施例中,環烷基為視情況經取代之C3
-C6
環烷基。在另一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。在另一個實施例中,烷基為C1
或C2
烷基。在另一個實施例中,烷基經一個視情況經取代之環烷基取代。在另一個實施例中,烷基經兩個視情況經取代之環烷基取代。非限制性的例示性(環烷基)烷基包括:。
如本文所用,術語「磺醯胺基」本身或作為另一基團之一部分係指式-SO2
NR50a
R50b
之基團,其中R50a
及R50b
各自獨立地為氫、烷基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之芳基或視情況經取代之雜芳基;或R50a
及R50b
與其所連接之氮一起形成視情況經取代之3員至8員雜環基。非限制性的例示性磺醯胺基包括-SO2
NH2
、-SO2
N(H)CH3
及-SO2
N(H)Ph。
如本文所用,術語「甲醯胺基」本身或作為另一基團之一部分係指式-C(=O)NR50c
R50d
之基團,其中R50c
及R50d
各自獨立地為氫、烷基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之芳基或視情況經取代之雜芳基;或R50c
及R50d
與其所連接之氮一起形成視情況經取代之3員至8員雜環基。非限制性的例示性甲醯胺基包括-C(=O)NH2
、-C(=O)(H)CH3
及-C(=O)N(CH3
)2
。
如本文所用,術語「烷基羰基」本身或作為另一基團之一部分係指經烷基取代之羰基,亦即-C(=O)-。在一個實施例中,烷基為C1
-C4
烷基。非限制性的例示性烷基羰基為-COCH3
。
如本文所用,術語「芳基羰基」本身或作為另一基團之一部分係指經視情況經取代之芳基取代的羰基,亦即-C(=O)-。非限制性的例示性芳基羰基為-COPh。
如本文所用,術語「烷基磺醯基」本身或作為另一基團之一部分係指經烷基取代之磺醯基,亦即-SO2
-。非限制性的例示性烷基磺醯基為-SO2
CH3
。
如本文所用,術語「芳基磺醯基」本身或作為另一基團之一部分係指經視情況經取代之芳基取代的磺醯基,亦即-SO2
-。非限制性的例示性芳基磺醯基為-SO2
Ph。
如本文所用,術語「巰基烷基」本身或作為另一基團之一部分係指經-SH基團取代之烷基。
單獨或作為另一基團之一部分使用之術語「羧基」係指式-C(=O)OH之基團。
如本文所用,術語「脲基」本身或作為另一基團之一部分係指式-NR51a
-C(=O)-NR51b
R51c
之基團,其中R51a
為氫或烷基;且R51b
及R51c
各自獨立地為氫、烷基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之芳基或視情況經取代之雜芳基,或R51b
及R51c
與其所連接之氮一起形成視情況經取代之4員至8員雜環基。非限制性的例示性脲基包括-NH-C(C=O)-NH2
及-NH-C(C=O)-NHCH3
。
如本文所用,術語「胍基」本身或作為另一基團之一部分係指式-NR52a
-C(=NR53
)-NR52b
R52c
之基團,其中R52a
為氫或烷基;R52b
及R53c
各自獨立地為氫、烷基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之芳基或視情況經取代之雜芳基;或R52b
及R52c
與其所連接之氮一起形成視情況經取代之4員至8員雜環基;且R53
為氫、烷基、氰基、烷基磺醯基、烷基羰基、甲醯胺基或磺醯胺基。非限制性的例示性胍基包括-NH-C(C=NH)-NH2
、-NH-C(C=NCN)-NH2
及-NH-C(C=NH)-NHCH3
。
如本文所用,術語「(雜環基)烷基」本身或作為另一基團之一部分係指經一個、兩個或三個視情況經取代之雜環基取代的烷基。在一個實施例中,烷基經一個視情況經取代之5員至8員雜環基取代。在另一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。雜環基可經由碳或氮原子連接至烷基。非限制性的例示性(雜環基)烷基包括:。
如本文所用,術語「胺基甲酸酯基」本身或作為另一基團之一部分係指式-NR54a
-C(=O)-OR54b
之基團,其中R54a
為氫或烷基,且R54b
為氫、烷基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之芳基或視情況經取代之雜芳基。非限制性的例示性胺基甲酸酯基為-NH-(C=O)-OtBu。
如本文所用,術語「(雜芳基)烷基」本身或作為另一基團之一部分係指經一或兩個視情況經取代之雜芳基取代的烷基。在一個實施例中,烷基經一個視情況經取代之5員至14員雜芳基取代。在另一個實施例中,烷基經兩個視情況經取代之5員至14員雜芳基取代。在另一個實施例中,烷基經一個視情況經取代之5員至9員雜芳基取代。在另一個實施例中,烷基經兩個視情況經取代之5員至9員雜芳基取代。在另一個實施例中,烷基經一個視情況經取代之5員或6員雜芳基取代。在另一個實施例中,烷基經兩個視情況經取代之5員或6員雜芳基取代。在一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。在另一個實施例中,烷基為C1
或C2
烷基。非限制性的例示性(雜芳基)烷基包括:。
如本文所用,術語「芳烷基」或「(芳基)烷基」本身或作為另一基團之一部分係指經一個、兩個或三個視情況經取代之芳基取代的烷基。在一個實施例中,烷基經一個視情況經取代之芳基取代。在另一個實施例中,烷基經兩個視情況經取代之芳基取代。在一個實施例中,芳基為視情況經取代之苯基或視情況經取代之萘基。在另一個實施例中,芳基為視情況經取代之苯基。在一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。在另一個實施例中,烷基為C1
或C2
烷基。非限制性的例示性(芳基)烷基包括苯甲基、苯乙基、-CHPh2
及-CH(4-F-Ph)2
。
如本文所用,術語「醯胺基」本身或作為另一基團之一部分係指式-C(=O)NR60a
R60b
之基團,其中R60a
及R60b
各自獨立地為氫、視情況經取代之烷基、視情況經取代之烯基、視情況經取代之炔基、鹵烷基、(烷氧基)烷基、(羥基)烷基、(氰基)烷基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之芳基、視情況經取代之雜芳基、(芳基)烷基、(環烷基)烷基、(雜環基)烷基或(雜芳基)烷基;或R60a
及R60b
與其所連接之氮一起形成視情況經取代之4員至8員雜環基。在一個實施例中,R60a
及R60b
各自獨立地為氫或C1
-C6
烷基。
單獨或作為另一基團之一部分使用之術語「胺基」係指式-NR55a
R55b
之基團,其中R55a
及R55b
獨立地為氫、視情況經取代之烷基、鹵烷基、(羥基)烷基、(烷氧基)烷基、(胺基)烷基、雜烷基、視情況經取代之環烷基、視情況經取代之雜環基、視情況經取代之芳基、視情況經取代之雜芳基、(芳基)烷基、(環烷基)烷基、(雜環基)烷基或(雜芳基)烷基。
在一個實施例中,胺基為-NH2
。
在另一個實施例中,胺基為「烷基胺基」,亦即R55a
為C1-6
烷基且R55b
為氫之胺基。在一個實施例中,R55a
為C1
-C4
烷基。非限制性的例示性烷基胺基包括-N(H)CH3
及-N(H)CH2
CH3
。
在另一個實施例中,胺基為「二烷基胺基」,亦即R55a
及R55b
各自獨立地為C1-6
烷基之胺基。在一個實施例中,R55a
及R55b
各自獨立地為C1
-C4
烷基。非限制性的例示性二烷基胺基包括-N(CH3
)2
及-N(CH3
)CH2
CH(CH3
)2
。
在另一個實施例中,胺基為「羥基烷胺基」,亦即R55a
為(羥基)烷基且R55b
為氫或C1
-C4
烷基之胺基。
在另一個實施例中,胺基為「環烷基胺基」,亦即R55a
為視情況經取代之環烷基且R55b
為氫或C1
-C4
烷基之胺基。
在另一個實施例中,胺基為「芳烷基胺基」,亦即R55a
為芳烷基且R55b
為氫或C1
-C4
烷基之胺基。非限制性的例示性芳烷基胺基包括-N(H)CH2
Ph、-N(H)CHPh2
及-N(CH3
)CH2
Ph。
在另一個實施例中,胺基為「(環烷基)烷基胺基」,亦即R55a
為(環烷基)烷基且R55b
為氫或C1
-C4
烷基之胺基。非限制性的例示性(環烷基)烷基胺基包括:。
在另一個實施例中,胺基為「(雜環基)烷基胺基」,亦即R55a
為(雜環基)烷基且R55b
為氫或C1
-C4
烷基之胺基。非限制性的例示性(雜環基)烷基胺基包括:。
如本文所用,術語「(胺基)烷基」本身或作為另一基團之一部分係指經一個胺基取代之烷基。在一個實施例中,胺基為-NH2
。在一個實施例中,胺基為烷基胺基。在另一個實施例中,胺基為二烷基胺基。在另一個實施例中,烷基為C1
-C6
烷基。在另一個實施例中,烷基為C1
-C4
烷基。非限制性的例示性(胺基)烷基包括-CH2
NH2
、CH2
CH2
N(H)CH3
、-CH2
CH2
N(CH3
)2
、CH2
N(H)環丙基、-CH2
N(H)環丁基及-CH2
N(H)環己基及-CH2
CH2
CH2
N(H)CH2
Ph及-CH2
CH2
CH2
N(H)CH2
(4-CF3
-Ph)。
本揭示案涵蓋藉由將一或多個原子置換為具有不同原子質量或質量數之原子而經同位素標記(亦即放射性標記)之任何本揭示案之化合物。可併入所揭示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,諸如分別為2
H (或氘(D))、3
H、11
C、13
C、14
C、15
N、18
O、17
O、31
P、32
P、35
S、18
F及36
Cl,例如3
H、11
C及14
C。在一個實施例中,提供在本揭示案之化合物內之某一位置處的基本上所有原子經具有不同原子質量或質量數之原子置換的化合物。在另一個實施例中,提供在本揭示案之化合物內之某一位置處的基本上所有原子經氘原子置換,例如-CH3
基團之所有氫原子經氘原子置換得到-CD3
基團的化合物。在另一個實施例中,提供在本揭示案之化合物內之某一位置處的一部分原子經置換,亦即本揭示案之化合物在某一位置處經具有不同原子質量或質量數之原子富集的化合物。在另一個實施例中,提供本揭示案之化合物之原子均未經具有不同原子質量或質量數之原子置換的化合物。經同位素標記之本揭示案之化合物可藉由此項技術中已知之方法製備。
本揭示案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、非對映異構體及其他立體異構形式。本揭示案涵蓋使用所有此類可能的形式,以及其外消旋及解析形式及其混合物。鑒於本揭示案,個別對映異構體可根據此項技術中已知的方法分離。當本文所述之化合物含有烯烴雙鍵或其他幾何不對稱性中心時,除非另外規定,否則預期其包括E及Z幾何異構體。本揭示案亦涵蓋所有互變異構體。
如本文所用,術語「立體異構體」為僅原子在空間中之取向不同的個別分子的所有異構體的通用術語。其包括具有一個以上對掌性中心之化合物的對映異構體及不為彼此鏡像之異構體(非對映異構體)。
術語「對掌性中心」或「不對稱碳原子」係指與四個不同基團連接之碳原子。
術語「對映異構體」及「對映異構體的」係指不能疊加於其鏡像上且因此具有光學活性的分子,其中對映異構體沿一個方向旋轉偏光平面,其鏡像化合物則沿相反方向旋轉偏光平面。
術語「外消旋」係指等份之對映異構體之混合物且該混合物為光學無活性的。在一個實施例中,本揭示案之化合物為外消旋的。
術語「絕對組態」係指對掌性分子實體(或基團)之原子的空間排列及其立體化學描述,例如R或S。
本說明書中使用之立體化學術語及慣例意欲與《理論化學與應用化學(Pure & Appl.Chem
)》68
:2193 (1996)中所述之立體化學術語及慣例一致,除非另外指明。
術語「對映異構體過量」或「ee」係指一種對映異構體與另一種對映異構體相比存在多少之量度。對於R
及S
對映異構體之混合物,對映異構體過量百分比定義為│R - S
│*100,其中R
及S
為混合物中對映異構體各自的莫耳或重量分數,使得R
+S
= 1。在知道對掌性物質之旋光度的情況下,對映異構體過量百分比定義為([α]obs
/[α]max
)*100,其中[α]obs
為對映異構體混合物之旋光度且[α]max
為純對映異構體之旋光度。對映異構體過量之測定可使用多種分析技術,包括NMR光譜法、對掌性管柱層析或旋光測定法。
如本文所用,術語「約」包括所敍述數目±10%。因此,「約10」意謂9至11。
實例
實例1
合成12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-3H,5H-4-氧雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第12號化合物)
在0℃下,將2-(二苯基亞甲基胺基)乙酸乙酯(18.4 g,69 mmol)於DMSO (50 ml)中之溶液逐滴添加至NaH (60%) (5.0 g,125.5 mmol)於70 ml無水DMSO中之懸浮液中。反應混合物立即變為橙色。5分鐘後,逐滴添加含2-((二苯基亞甲基)胺基)乙酸乙酯(15 g,62.7 mmol)之50 ml DMSO。將混合物在室溫下攪拌2小時。此後,藉由小心地添加NH4
Cl水溶液來淬滅反應混合物。隨後將混合物用乙酸乙酯萃取,用鹽水洗滌,乾燥且濃縮,並用作下一步驟之粗物質。LC-MS: [M+H]+ = 470.01。
在0℃下,向化合物E 12-2 (粗物質,5.0 g,10.6 mmol)於THF (50 ml)中之溶液中添加10 ml 3 N HCl水溶液。將混合物在室溫下攪拌1小時,且將反應混合物濃縮,隨後用Na2
CO3
水溶液鹼化至pH 8~9。將混合物用DCM萃取,用鹽水洗滌。減壓濃縮,隨後藉由急驟層析(0-100% EtOAc/己烷)純化,以80%之總產率得到所需化合物E 12-3。LC-MS: [M+H]+ = 305.95。
將HCOOH (4 ml)及Ac2
O (4 ml)之混合物在50℃下加熱1小時。將反應混合物冷卻至室溫,且添加至2-胺基-2-(甲硫基)嘧啶-4-基)乙酸乙酯(化合物E 12-3,2.0 g,6.55 mmol)於20 ml DCM中之溶液中。將混合物在室溫下攪拌2小時。反應完成後,將混合物濃縮。將混合物用DCM (2 × 50 ml)萃取,依次用水(20 ml)及鹽水(10 ml)洗滌。將有機相乾燥(Na2
SO4
),過濾且濃縮,得到呈油狀之粗標題化合物E 12-4,其未經進一步純化即用於下一步驟。LC-MS: [M+H]+ = 334.05。
向化合物E 12-4 (2.0 g,粗物質)於二噁烷(20 ml)中之溶液中逐滴添加POCl3
(1.5 ml)。將反應混合物在回流下加熱4小時。將混合物冷卻至室溫且濃縮。添加冰冷卻的水(50 ml),且將混合物用飽和的NaHCO3
水溶液調節至pH 8。將混合物用DCM (2 × 50 ml)萃取,用鹽水(10 ml)洗滌,乾燥(Na2
SO4
)且過濾。濃縮濾液,且藉由矽膠管柱層析(用50-100% EtOAc/己烷)溶離純化殘餘物,以70%之總產率分兩步得到呈白色固體狀之標題化合物E 12-5 (1.42 g,4.59 mmol)。LC-MS: [M+H]+ = 315.70。1
H NMR (400 MHz, DMSO d6
): 8.67 (s, 1H), 7.99 (s, 1H), 4.33 (q, 2H), 2.76 (s, 3H), 1.34 (t, 3H)。
在0℃下,向化合物E 12-5 (567 mg,1.8 mmol,1.0 eq.)於DCM (18 ml)中之溶液中添加m-CPBA (464 mg,2.7 mmol,≤77%,1.5 eq.)。45分鐘後,在0℃下添加Et3
N (1 ml,7.6 mmol,4 eq.)且攪拌2分鐘,隨後添加化合物A.1 (300 mg,1.8 mmol)。隨後將反應混合物在室溫下攪拌3小時。此後,濃縮反應混合物且藉由矽膠管柱層析(用50-100% EtOAc/己烷溶離)純化殘餘物,以55%之產率得到E 12-7 (429 mg,0.99 mmol)。LC-MS: [M+H]+ = 434.03。1
H NMR (400 MHz, DMSO-d6
) δ 8.75 (s, 1H), 8.65 (t, J = 5.1 Hz, 1H), 7.68 (s, 1H), 6.94 (t, J = 9.5 Hz, 1H), 6.70 (dd, J = 8.7, 3.9 Hz, 1H), 4.68 (d, J = 5.0 Hz, 2H), 4.54 (t, J = 8.7 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 3.27 (t, J = 8.8 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H)。
將乙酸鈀(II) (70 mg,0.31 mmol,0.1 eq.)及cataCXium A (221 mg,0.62 mmol,0.2 eq.)在DME (2.0 ml,脫氣)中混合在一起,且在70℃下,經由移液管將所得溶液添加至化合物E 12-7 (1.34 g,3.1 mmol,1.0 eq.)、化合物B.1 (1.86 g,6.2 mmol,2.0 eq.)、雙頻哪醇根基二硼(1.6 g,6.2 mmol,2.0 eq.)及K2
CO3
(1.71 g,12.4 mmol,4.0 eq.)於DME/H2
O (10:1,22 ml,脫氣)中之攪拌溶液中。攪拌反應混合物12小時。此後,將反應混合物濃縮且用乙酸乙酯(2×50 ml)萃取,用水及鹽水洗滌,且隨後經Na2
SO4
乾燥。濃縮混合物,且藉由HPLC純化殘餘物,得到所需化合物,其經TFA/DCM處理,以50%之產率得到呈白色固體狀之所需化合物E 12-8 (719 mg,1.55 mmol)。LC-MS: [M+H]+ = 464.16。
將E 12-8 (40 mg,0.090 mmol,1 eq.)及LiOH (20 mg,0.90 mmol,10 eq.)於THF (4 ml)及水(1.0 ml)中之混合物在70℃下加熱隔夜。在0℃下逐滴添加3 N HCl水溶液直至pH 2-3。濃縮混合物,且藉由HPLC純化殘餘物,以90%之產率得到呈白色固體狀之標題化合物E 12-9 (35 mg,0.081 mmol)。LC-MS: [M+H]+ = 436.13。
經由套管向2,4,6-三氯苯甲醯氯(24 mg,0.01 mmol,1.5 eq.)、DIPEA (85 mg,0.66 mmol,10.0 eq.)及DMAP (4 mg,0.033 mmol,0.5 eq.)於甲苯(2 ml)中之混濁混合物中緩慢地添加開環酸E 12-9 (31 mg,0.066 mmol)於甲苯(1 ml)中之澄清溶液。2小時後,濃縮反應混合物。將粗產物用乙酸乙酯(2 ×10 ml)萃取,在鹽水中洗滌且經Na2
SO4
乾燥。濃縮混合物,且藉由HPLC純化殘餘物,以60%之產率得到呈白色固體狀之第12號化合物(16 mg,0.039 mmol)。LC-MS: [M+H]+ = 418.12。1
H NMR (400 MHz, Acetone-d6
) δ 8.77 (s, 1H), 8.66 (d, J = 4.7 Hz, 1H), 8.20 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.56 (dd, J = 8.0, 4.6 Hz, 1H), 6.90 (t, J = 9.4 Hz, 1H), 6.67 (dd, J = 8.6, 3.8 Hz, 1H), 6.04 (s, 1H), 5.08 (s, 1H), 4.90 (s, 2H), 4.59 (t, J = 8.6 Hz, 2H), 3.49 (t, J = 8.6 Hz, 2H)。
實例2
12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第16號化合物):
將乙酸鈀(II) (70 mg,0.31 mmol,0.1 eq.)及cataCXium A (221 mg,0.62 mmol,0.2 eq.)在DME (2.0 ml,脫氣)中混合在一起,且在70℃下,經由移液管將所得溶液添加至化合物E 10-7 (1.34 g,3.1 mmol,1.0 eq.)、化合物B.2 (1.77 g,6.2 mmol,2.0 eq.)、雙頻哪醇根基二硼(1.6 g,6.2 mmol,2.0 eq.)及K2
CO3
(1.71 g,12.4 mmol,4.0 eq.)於DME/H2
O (10:1,22 ml,脫氣)中之攪拌溶液中。攪拌反應混合物12小時。此後,將反應混合物濃縮且用乙酸乙酯(2 × 50 ml)萃取,用水及鹽水洗滌,且隨後經Na2
SO4
乾燥。濃縮混合物,且藉由HPLC純化殘餘物,以50%之產率得到呈白色固體狀之標題化合物E 16-1 (871 mg,1.55 mmol)。LC-MS: [M+H]+ = 563.16。
在室溫下將化合物E 16-1用25% TFA/DCM處理1小時,此後真空移除揮發物。將粗物質用乙酸乙酯稀釋,用飽和Na2
CO3
水溶液洗滌,隨後用鹽水洗滌。有機層經Na2
SO4
且真空濃縮,得到化合物E 16-2,其用作下一步之粗物質。
將E 16-2 (40 mg,0.09 mmol,1 eq.)及LiOH (20 mg,0.90 mmol,10 eq.)於THF (4 ml)及水(1.0 ml)中之混合物在70℃下加熱隔夜。在0℃下逐滴添加3 NHCl水溶液直至pH 2-3。濃縮混合物,且藉由HPLC純化殘餘物,以90%之產率得到呈白色固體狀之第16號化合物。LC-MS: [M+H]+ = 416.14。1
H NMR (400 MHz, DMSO-d6
) δ 8.82 (s, 1H), 8.65 (t, J = 5.1 Hz, 1H), 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.47 (s, 1H), 7.92 (dd, J = 7.8, 1.6 Hz, 1H), 7.53 - 7.48 (m, 2H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 4.98-4.94 (m, 1H), 4.75 (s, 2H), 4.57-4.53 (m, 2H), 4.03 (m, 1H), 3.35 (t, J = 8.7 Hz, 2H)。
實例3
合成11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-2,4,10,11a-四氮雜二苯并[cd,f]薁-3(4H)-酮(第3號化合物):
將乙酸鈀(II) (70 mg,0.31 mmol,0.1 eq.)及cataCXium A (221 mg,0.62 mmol,0.2 eq.)在DME (2.0 ml,脫氣)中混合在一起,且在70℃下,經由移液管將所得溶液添加至化合物E 10-7 (1.34 g,3.1 mmol,1.0 eq.)、化合物B.3 (1.05 g,6.2 mmol,2.0 eq.)、雙頻哪醇根基二硼(1.6 g,6.2 mmol,2.0 eq.)及K2
CO3
(1.71 g,12.4 mmol,4.0 eq.)於DME/H2
O (10:1,22 ml,脫氣)中之攪拌溶液中。攪拌反應混合物12小時。此後,將反應混合物濃縮且用乙酸乙酯(2 × 50 ml)萃取,用水及鹽水洗滌,且隨後經Na2
SO4
乾燥。濃縮混合物,且藉由HPLC純化殘餘物,以50%之產率得到呈白色固體狀之標題化合物E 3-1 (692 mg,1.55 mmol)。LC-MS: [M+H]+ = 563.16。
將E 3-1 (40 mg,0.090 mmol,1 eq.)及LiOH (20 mg,0.90 mmol,10 eq.)於THF (4 ml)及水(1.0 ml)中之混合物在70℃下加熱隔夜。在0℃下逐滴添加3 N HCl水溶液直至pH 2-3。濃縮混合物,且藉由HPLC純化殘餘物,以90%之產率得到呈白色固體狀之第3號化合物(32 mg,0.081 mmol)。LC-MS: [M+H]+ = 402.13。1
H NMR (400 MHz, DMSO-d6
) δ 9.50 (s, 1H), 8.67 (s, 1H), 8.53 (t, J = 5.1 Hz, 1H), 7.99 (s, 1H), 7.88 - 7.80 (m, 1H), 7.19 (dd, J = 6.1, 1.6 Hz, 2H), 7.02 (ddd, J = 8.3, 6.1, 2.4 Hz, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 4.73 (d, J = 4.8 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.31 (d, J = 8.5 Hz, 2H)。
實例4
合成4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第36號化合物)
將(5-溴-2-(三氟甲基)吡啶-4-基)甲醇(E 36-1)之等分試樣溶解於無水DCM (~0.2 M)中,隨後向此溶液中添加1.5 eq. Dess-Martin高碘烷,且使反應混合物攪拌1小時,經由TLC監測。完成後,用飽和NH4
Cl溶液淬滅,隨後用DCM萃取且用水及鹽水洗滌。收集有機層且合併,用鹽水洗滌,經無水Na2
SO4
乾燥,且真空濃縮。在矽膠正相管柱層析上用增加量的乙酸乙酯/己烷進行純化,得到所需醛E 36-2 (產率~90%)。
在冰浴下,向獲得之醛中添加甲醇(~0.2 M),隨後添加2.2 eq.環丙胺、2 eq. Na(CN)BH3
及2 eq.乙酸。隨後移除冰浴且使反應混合物攪拌3小時,經由TLC監測。完成後,濃縮反應混合物,且藉由HPLC純化殘餘物,以70%之產率得到標題化合物E 36-3。LC-MS: [M+H]+ = 294.99。
向獲得之二級胺中添加1.5 eq.由無水DCM (~0.2 M)溶解之(Boc)2
O,隨後添加3 eq TEA,使反應混合物攪拌1小時,經由TLC監測。完成後,將其用飽和NH4
Cl溶液淬滅,隨後用DCM萃取且用鹽水洗滌。收集有機層且合併,經無水Na2
SO4
乾燥,且真空濃縮。在矽膠正相管柱層析上用增加量的乙酸乙酯/己烷進行純化,得到Boc保護之二級胺E 36-4 (產率~90%)。LC-MS: [M+H]+ = 395.10。
將乙酸鈀(II) (0.1 eq.)及cataCXium A (0.2 eq.)在DME (0.5 ml,脫氣)中混合在一起,且在70℃下,經由移液管將所得溶液添加至8-溴-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(1 eq.)、Boc保護之二級胺E 36-4 (2 eq.)、雙頻哪醇根基二硼(2.0 eq.)及K2
CO3
(4.0 eq.)於DME/H2
O (10:1,10 ml,脫氣)中之混合物中。攪拌反應混合物12小時。此後,將反應混合物濃縮且用乙酸乙酯(2 × 50 ml)萃取,用水及鹽水洗滌,且隨後經Na2
SO4
乾燥。濃縮混合物,且藉由HPLC純化殘餘物,以40%之產率得到標題化合物E 36-5。LC-MS: [M+H]+ = 671.25。
將化合物E 36-5在0℃下用25% TFA/DCM處理1小時,此後真空移除揮發物,用作下一步之粗物質(E 36-6)。LC-MS: [M+H]+ = 571.25。
將化合物E 36-6 (1 eq.)及LiOH (10 eq.)於THF (10 ml/mmol)及水(5 ml/mmol)中之混合物在70℃下加熱隔夜。濃縮混合物,且隨後藉由製備型HPLC純化殘餘物,以~1:1之比率得到E 36及化合物E 36-7。
向化合物E 36-7 (1 eq.)及HATU (2 eq.)於DMF (5 ml/mmol)中之混合物中添加DIPEA (5 eq.)。使反應混合物攪拌隔夜。隨後將其濃縮,且藉由製備型HPLC純化殘餘物,得到第36號化合物。兩種化合物之組合產率為~90%。LC-MS: [M+H]+ = 525.15。1
H NMR (400 MHz, 甲醇-d4
) δ 8.84 (s, 1H), 8.74 (s, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 6.86 (t, J = 9.6 Hz, 1H), 6.65 (dd, J = 8.7, 4.0 Hz, 1H), 5.42 (d, J = 14.7 Hz, 1H), 4.81 (d,J
= 6.1 Hz, 2H), 4.59 (t, J = 8.9 Hz, 2H), 4.37 (d, J = 14.9 Hz, 1H), 3.42 (t, J = 8.7 Hz, 2H), 2.55 (s, 1H), 1.16 (s, 1H), 1.00 (d, J = 5.5 Hz, 2H), 0.94 - 0.77 (m, 1H)。
實例5
合成N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-3H,5H-4-氧雜-2,6,11,12a-四氮雜苯并[4,5]環辛并[1,2,3-cd]茚-12-胺(第2號化合物)
在0℃下用LAH (0.2 ml 1M LAH於THF中之溶液)處理2 ml THF中之化合物E 10-8 (25 mg,0.053 mmol)。此後,將溫度升高至50℃且攪拌隔夜。冷卻至室溫後,將反應物用0℃之飽和Na2
SO4
緩慢淬滅。隨後將其過濾且用乙酸乙酯洗滌數次。藉由急驟層析(0-10% MeOH/DCM)純化,以50%之產率得到第2號化合物(10 mg,0.024 mmol)。LC-MS: [M+H]+ = 404.14。
實例6
合成11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-6-甲基-4H-3-硫雜-2,5,10,11a-四氮雜二苯并[cd,f]薁3,3-二氧化物(第95號化合物)
合成8-(2-(((第三丁基二甲基矽烷基)氧基)甲基)-6-甲基吡啶-3-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)咪唑并[1,5-c]嘧啶-5-胺(E 95-1):
在N2
氛圍下,將8-溴-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)咪唑并[1,5-c]嘧啶-5-胺(795 mg,2.19 mmol)、3-溴-2-(((第三丁基二甲基矽烷基)氧基)甲基)-6-甲基吡啶(1.393 g,4.38 mmol)、乙酸鈀(II) (0.1 eq.)、cataCXium A (0.2 eq.)、雙頻哪醇根基二硼(2.0 eq.)及K2
CO3
(5.0 eq.)在DME:水(10:1,17.4 ml,脫氣)中混合在一起。將反應混合物在70℃下攪拌12小時。此後,將反應混合物濃縮且用乙酸乙酯(2 × 200 ml)萃取,用水及鹽水洗滌,且隨後經Na2
SO4
乾燥。濃縮混合物,且藉由HPLC純化殘餘物,以38%之產率得到標題化合物E 95-1 (304 mg,0.585 mmol)。LC-MS: [M+H]+ = 520.30。
合成8-(2-(((第三丁基二甲基矽烷基)氧基)甲基)-6-甲基吡啶-3-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-碘咪唑并[1,5-c]嘧啶-5-胺(E 95-2):
在0℃下,向8-(2-(((第三丁基二甲基矽烷基)氧基)甲基)-6-甲基吡啶-3-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)咪唑并[1,5-c]嘧啶-5-胺(304 mg,0.585 mmol)於DMF (5 ml)中之溶液中添加NIS (125 mg,0.95 mmol),且在室溫下攪拌15分鐘。將混合物用EA (4 × 50 ml)萃取,用鹽水(30 ml)洗滌,乾燥(Na2
SO4
)且過濾。濃縮濾液,且藉由管柱層析(矽膠,用20-80% EtOAc/己烷)溶離純化殘餘物,得到呈黃色固體狀之E 95-2 (190 mg,0.29 mmol,50%)。LC-MS: [M+H]+ = 646.21。
合成(3-(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-1-碘咪唑并[1,5-c]嘧啶-8-基)-6-甲基吡啶-2-基)甲醇(E 95-3):
向8-(2-(((第三丁基二甲基矽烷基)氧基)甲基)-6-甲基吡啶-3-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-碘咪唑并[1,5-c]嘧啶-5-胺(190 mg,0.29 mmol)於THF (6 ml)中之溶液中添加TBAF (3 ml),且在室溫下攪拌隔夜。完成後,將混合物用EA (3 × 60 ml)萃取,用鹽水(30 ml)洗滌,經Na2
SO4
乾燥且過濾。濃縮濾液,且藉由管柱層析(矽膠,用0-15% MeOH/DCM溶離)純化殘餘物,得到E 95-3 (125 mg,0.24 mmol,80%)。LC-MS: [M+H]+ = 532.19。
合成S-((3-(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-1-碘咪唑并[1,5-c]嘧啶-8-基)-6-甲基吡啶-2-基)甲基)硫乙酸酯(E 95-4):
在0℃下,將含MsCl (41 mg,0.352 mmol)之THF (0.5 ml)逐滴添加至(3-(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-1-碘咪唑并[1,5-c]嘧啶-8-基)-6-甲基吡啶-2-基)甲醇(125 mg,0.24 mmol)及Et3
N (36 mg,0.352 mmol)於THF (2 ml)中之溶液中。立即形成白色的Et3
N鹽酸鹽沈澱。將反應混合物攪拌2-3小時,完成後,添加含硫代乙酸鉀(81 mg,0.704 mmol)之DMF (1.0 ml),產生橙色溶液,其在數小時後變成紅色。經由UPLC監測反應,完成後將反應混合物停止且濃縮,隨後溶解於DCM中。將此混合物溶液用飽和LiCl洗滌兩次,隨後用水及鹽水洗滌。將飽和LiCl、鹽水及水洗滌液合併,且分別用乙酸乙酯反萃取。將所有有機層合併,經Na2
SO4
乾燥,過濾且濃縮成深色油狀物。急驟層析(矽膠,用20-100% EtOAc/己烷溶離),得到呈黃色固體狀之E 95-4 (78 mg,0.13 mmol,56%)。LC-MS: [M+H]+ = 590.03。
合成8,8'-((二硫烷二基雙(亞甲基))雙(6-甲基吡啶-2,3-二基))雙(N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-碘咪唑并[1,5-c]嘧啶-5-胺) (E 95-5):
在N2
氛圍下,向S-((3-(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-1-碘咪唑并[1,5-c]嘧啶-8-基)-6-甲基吡啶-2-基)甲基)硫乙酸酯(78 mg,0.13 mmol)於甲醇(5.0 ml,脫氣)中之溶液中添加0.9 eq. NaOMe (7 mg,0.12 mmol)。將反應混合物在80℃下回流一小時。急驟層析(矽膠,用20-100% EtOAc/己烷溶離),得到呈黃色固體狀之E 95-5 (57 mg,0.052 mmol,79%)。LC-MS: [M/2+H]+ = 547.14。
合成N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-6-甲基-4H-3-硫雜-2,5,10,11a-四氮雜二苯并[cd,f]薁-11-胺(E 95-6):
在N2
氛圍下,向8,8'-((二硫烷二基雙(亞甲基))雙(6-甲基吡啶-2,3-二基))雙(N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-碘咪唑并[1,5-c]嘧啶-5-胺) (57 mg,0.052 mmol)於DMF (3.0 ml,脫氣)中之溶液中添加1.2 eq. TCEP (18 mg,0.0626 mmol)。將反應混合物在室溫下攪拌24小時。藉由UPLC監測反應。完成後,將其藉由逆相HPLC純化,得到呈淡黃色固體狀之E 95-6 (38 mg,0.091 mmol,87%)。LC-MS: [M+H]+ = 420.15。
合成11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-6-甲基-4H-3-硫雜-2,5,10,11a-四氮雜二苯并[cd,f]薁3,3-二氧化物(E 95):
向N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-6-甲基-4H-3-硫雜-2,5,10,11a-四氮雜二苯并[cd,f]薁-11-胺(38 mg,0.091 mmol)於MeOH : H2O : THF (4.0 mL,5:5:10)中之溶液中添加5 eq.過硫酸氫鉀(279 mg,0.45 mmol)。將反應混合物攪拌5小時。完成後,逆相HPLC得到呈淡黃色固體狀之第95號化合物(17 mg,0.038 mmol,41%)。LC-MS: [M+H]+ = 452.25。
實例7
合成(5-氟-2,3-二氫苯并呋喃-4-基)甲胺(A.1)
向3-溴-4-氟苯酚(A.1-1,50 g,0.26 mol,1 eq.)及2-溴-1,1-二乙氧基乙烷(67 g,0.34 mol,1.3 eq.)於250 ml DMF中之溶液中一次性添加K2
CO3
(109 g,0.78 mol,3 eq.)。將懸浮液在110℃下加熱且在N2
下攪拌隔夜。冷卻至室溫後,將反應物用水稀釋且用乙酸乙酯(2 × 500 ml)萃取。將合併之有機相用鹽水洗滌且經無水Na2
SO4
乾燥。將殘餘物在矽膠(0-10% EtOAc/己烷)上純化,得到呈黃色油狀之標題化合物(A.1-2) (60.12 g,196 mmol,75%產率)。LC-MS: [M+H]+ = 307.02。1
H NMR (400 MHz, 甲醇-d4
) δ 7.13 (d, 1H), 7.04 (dd, 1H), 6.84 (dd, 1H), 4.82 (t, 1H), 3.97 (d, 2H), 3.78 (q, 2H), 3.65 (q, 2H), 1.27 (t, 6H)。
向在100℃下加熱之PPA (132.4 g,0.39 mol)及甲苯(300 ml)之溶液中緩慢地添加含化合物A.1-2 (81 g,0.26 mol)之50 ml甲苯。將反應混合物在100℃下加熱4小時。冷卻至室溫後,添加400 ml冰水且用己烷萃取兩次。將合併之有機相用鹽水洗滌且經無水Na2
SO4
乾燥。將殘餘物在矽膠(0-10% EtOAc/己烷)上純化,以45%之總產率得到呈不可分離之非對映異構體混合物形式的標題化合物(A.1-3,A.1-4)。LC-MS: [M+H]+ = 214.94。
向A.1-3及A.1-4 (31 g,0.144 mol)及Zn(CN)2
(25.3 g,0.216 mol)於100 ml DMF中之溶液中添加Pd(PPh3
)4
(16.2 g,14 mmol)。將反應混合物用N2
脫氣,且在N2
氛圍下在100℃下攪拌24小時。冷卻至室溫後,添加水且用乙酸乙酯(2 × 100 ml)萃取。將合併之有機相用鹽水洗滌且經無水Na2
SO4
乾燥。將殘餘物在矽膠(0-20% EtOAc/己烷)上純化,以分離呈白色固體狀之所需異構體(A.1-5)。使用NMR確認結構。LC-MS: [M+H]+ = 162.02。化合物A.1-5:1
H NMR (400 MHz, 甲醇-d4
) δ 8.10 (dd, 1H), 7.89 (dd, 1H), 7.30 (dd, 1H), 7.07 (d, 1H)。
含所需異構體A.1-5 (2.3 g,14.55 mmol)之10 ml THF在0℃下用LAH (36 ml LAH於THF中之1M溶液)處理。此後,將溫度升高至50℃且攪拌隔夜。冷卻至室溫後,將反應物用0℃之飽和Na2
SO4
緩慢淬滅。將其過濾且用乙酸乙酯洗滌數次。藉由急驟層析(0-10% MeOH/含有1%三甲胺之DCM)純化,以70%之產率得到所需化合物A.1-7 (1.63 g,10.1 mmol)。LC-MS: [M+H]+ = 166.02。
向化合物A.1-7 (1 g,6.02 mmol)於MeOH (50 ml)中之溶液中添加Pd/C (100 mg, 10% wt)。將反應混合物用H2
脫氣,且在H2
氛圍下在40℃下攪拌6小時。隨後將混合物經由矽藻土過濾,且用MeOH洗滌。減壓濃縮,隨後藉由急驟層析(0-10% MeOH/含有1%三甲胺之DCM)純化,以85%之產率得到所需化合物中間物A.1 (859 mg,5.11 mmol)。LC-MS: [M+H]+ = 168.07。1
H NMR (400 MHz, 甲醇-d4
): 6.81 (dd, 1H), 6.59 (dd, 1H), 4.56 (t, 2H), 3.77 (s, 2H), 3.27 (t, 2H)。
實例8
合成3-溴-2-(((第三丁基二甲基矽烷基)氧基)甲基)-6-甲基吡啶(B.4)
將H2
SO4
(1.2 mL,23.4 mmol,1.0 eq.)添加至3-溴-6-甲基吡啶甲酸(B.4-1,5.0 g,23.4 mmol,1.0 eq.)於MeOH (50 ml)中之溶液中。將所得溶液攪拌14小時,同時在油浴中維持回流之溫度。將混合物冷卻至室溫且真空濃縮。將殘餘物溶解於乙酸乙酯(50 ml)中,且用水及飽和NaCl水溶液(2 × 100 ml)洗滌,經無水Na2
SO4
乾燥且真空濃縮。將殘餘物藉由矽膠管柱純化且用EtOAc/己烷(1:5)溶離,以90%之產率得到3-溴-6-甲基吡啶甲酸甲酯(B.4-2,4.7 g)。LC-MS [M+H]+ = 229.97。
在-60℃下,向3-溴-6-甲基吡啶甲酸甲酯(B.4-2,520 mg,2.28 mmol)於DCM (15 ml)中之溶液中逐滴添加DIBAL-H (4.6 ml,4.60 mmol,1 M於環己烷中)。將反應混合物維持在-60℃至-15℃下30分鐘,隨後使其升溫至室溫且再攪拌12小時。將反應混合物再次冷卻至0℃,且用飽和NH4
Cl水溶液(50 ml)淬滅。將所得混合物用DCM (3 × 100 ml)萃取,用鹽水(50 ml)洗滌,乾燥(Na2
SO4
),過濾且濃縮。將殘餘物藉由矽膠管柱純化且用EtOAc/己烷(1:3)溶離,得到呈無色液體狀之標題化合物(B.4-3) (1.36 mmol,273 mg,60%)。LC-MS [M+H]+ = 201.97。
將(3-溴-6-甲基吡啶-2-基)甲醇(B.4-3,273 mg,1.36 mmol)、咪唑(138 mg,2.04 mmol)及TBSCl (300 mg,2.04 mmol)於DCM (10 ml)中之溶液在室溫下攪拌3小時。添加H2
O (5 ml),且分離各層。將水相用DCM (2 × 20 ml)萃取,且將合併之有機萃取物乾燥(Na2
SO4
),且減壓移除溶劑。將殘餘物藉由矽膠管柱純化且用EtOAc/己烷(1:5)溶離,得到呈無色液體狀之標題化合物(B.4,1.22 mmol,386 mg,90%)。LC-MS [M+H]+ = 316.06。
實例9
合成(2-溴-5-(三氟甲基)苯甲基)胺基甲酸第三丁酯(B.5):
將NaBH4
(0.66 g,14.81mmol)裝入100 ml燒瓶中,隨後裝入20 ml無水THF。將混合物在冰水浴中冷卻。在該溫度下將TFA (1.5 ml)添加至THF (4 ml)中0.5小時。移除冰水浴,且將所得混合物在室溫下攪拌2小時。將2-溴-5-三氟甲基-苯甲腈(B.5-1,2 g,8.0 mmol)溶解於THF (10 mL)中。再次在冰水浴中冷卻TFA/NaBH4
混合物,且經0.5小時添加腈溶液。使混合物達到環境溫度,同時攪拌16小時。對等分試樣之LC分析顯示反應完成。將混合物在冰浴中冷卻,且緩慢添加10 ml甲醇。真空移除揮發物,且添加乙酸乙酯(50 ml)。用水(10 ml)洗滌此混合物。將水層用乙酸乙酯(10 ml)洗滌,且將合併之有機層用鹽水(10 ml)洗滌,經Na2
SO4
乾燥,過濾且濃縮。藉由逆相combi flash (用1-20%乙腈/H2
O溶離)純化殘餘物,得到呈無色液體狀之標題化合物(B.5-2,1.6 g,80%)。LC-MS [M+H]+ = 256.96。
將化合物(B.5-2,512 mg,2 mmol)與(Boc)2
O (0.51 g,2.4 mmol,1.2 eq.)及Et3
N (2 eq.,4 mmol,380 mg)一起在20 ml DCM中在室溫下攪拌3小時。此後,藉由管柱層析使用0-50% EtOAc/己烷純化殘餘物,得到所需化合物(B.5,560 mg),總產率為80%。LC-MS [M+H]+ = 355.16。
實例10
合成3-溴-2-(((第三丁基二甲基矽烷基)氧基)甲基)-6-(三氟甲基)吡啶(B.6):
在0℃下,向3-溴-6-(三氟甲基)吡啶甲酸甲酯(B.6-1,1 g,3.53 mmol)於MeOH (50 ml)中之溶液中添加NaBH4
(671 mg,17.65 mmol)。將反應混合物在室溫下攪拌隔夜,隨後減壓濃縮。將所得殘餘物溶解於乙酸乙酯(50 ml)中,用NH4
Cl水溶液(3 × 20 ml)洗滌,經Na2
SO4
乾燥,過濾且濃縮,得到標題化合物。將殘餘物藉由管柱層析(用0-50% EtOAc/己烷溶離)純化,得到呈無色液體狀之標題化合物(B.6-2,3.17 mmol,806 mg,90%)。LC-MS [M+H]+ = 255.95。
如實例8中所述完成TBS保護。LC-MS [M+H]+ = 370.03。
實例11
合成((5-溴-2-(三氟甲基)吡啶-4-基)甲基)胺基甲酸第三丁酯(B.7):
向配備有攪拌棒、冷凝器及氮氣入口之500 ml圓底燒瓶中裝入38.9 g (144 mmol) 5-溴-2-三氟甲基-異菸鹼酸。向固體中添加250 ml無水DCM,隨後添加13.2 ml (151 mmol,1.05 eq.)乙二醯氯。向混合物中添加0.5 ml無水DMF,且將混合物在環境溫度下攪拌2小時。真空移除溶劑。在冰浴中向配備有攪拌棒之1公升錐形瓶中裝入500 ml NH4
OH水溶液。向冷卻的溶液中逐滴添加粗醯氯。殘餘物用少量乙腈轉移。添加後將混合物攪拌20分鐘。藉由過濾收集所得沈澱物且用水洗滌。濾餅在45℃下真空乾燥,得到呈灰白色固體狀之5-溴-2-三氟甲基-異菸鹼醯胺(B.7-2,118 mmol,31.52 g,82%產率)。LC-MS [M+H]+ = 269.95。
向配備有攪拌棒、冷凝器及氮氣入口之100 mL圓底中裝入5.2 g (19.3 mmol) 5-溴-2-三氟甲基異菸鹼醯胺(B.7-2)。用12 ml POCl3
稀釋固體。將混合物在70℃下加熱3小時。將混合物冷卻至室溫,且倒於冰上。藉由小心添加50%氫氧化鈉中和混合物。藉由過濾收集所得灰白色固體,用水洗滌且在50℃下真空乾燥18小時。由此以94%之產率得到4.5 g呈灰白色固體狀之5-溴-2-三氟甲基-異菸鹼腈(B.7-3,4.53 g,18.1 mmol)。LC-MS [M+H]+ = 250.95。1
H NMR (CDCl3
): δ, 9.03 (s, 1H), 7.91 (s, 1H)。
如實例9中所述完成腈還原及Boc保護。
實例12
合成((3-溴-6-甲基吡啶-2-基)甲基)胺基甲酸第三丁酯(B.8):
向5-溴-2-甲基吡啶(B.8-1,510 mg,3.0 mmol,1.0 eq.)於CHCl3
(8 ml,0.38 M)中之溶液中添加77% mCPBA (5.44 g,12.0 mmol,4.0 eq.),且在60℃下加熱20小時。冷卻至室溫後,添加Ca(OH)2
(1.5 g,15.9 mmol,5.3 eq.),且將所得沈澱物攪拌30分鐘。過濾沈澱物,且用3:1 CHCl3
/甲醇洗滌。真空濃縮濾液,得到固體,將其在含30%乙酸乙酯之己烷中攪拌且過濾,得到所需N-氧化物。真空濃縮濾液,且藉由管柱層析使用0-100%乙酸乙酯/己烷純化殘餘物,得到更多所需N-氧化物(B.8-2,410 mg,2.4 mmol)。
向5-溴-2-甲基吡啶1-氧化物(B.8-2,372 mg,2.0 mmol)於乙腈(10 ml,0.2 M)中之溶液中添加氰化三甲基矽烷(TMSCN) (793 mg,8.0 mmol,4.0 eq.)及三乙胺(606 mg,6.0 mmol,3.0 eq.)。將反應物在100℃下加熱隔夜。冷卻至室溫後,真空濃縮溶劑,且藉由管柱層析使用0-50%乙酸乙酯/己烷純化殘餘物,得到3-溴-6-甲基吡啶甲腈(B.8-3,273 mg,1.4 mmol,70%產率)。
將3-溴-6-甲基吡啶甲腈(B.8-3,273 mg,1.4 mmol)溶解於15 ml無水THF中。在攪拌溶液的同時,逐滴添加3.5 ml BH3
.DMS複合物(2M) (5 eq.)。隨後將混合物攪拌隔夜,且隨後在0℃下藉由緩慢添加30 ml MeOH淬滅。攪拌1小時後,隨後將有機層減壓濃縮,接著藉由急驟層析(0-10% MeOH/含有1%三甲胺之DCM)純化,得到所需化合物(B.8-4,199 mg,0.98 mmol,70%產率)。
如實例9中所述完成Boc保護。
實例13
合成N-(呋喃-2-基甲基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺(第126號化合物):
(a) CH3
COCl,MeOH,79%;(b) Dibal-H,56%;(c) DIAD,PPh3
,沙立度胺,70% (d) NH2
.NH2
.H2
O,EtOH,80%;(e) HCO2
H,Ac2
O,60.0%;(f) POCl3
,二噁烷,47.0%;(g) (i) mCPBA,DCM,(ii)呋喃-2-基甲胺,rt,3 h,52%;(h)苯基硼酸,Pd(PPh3
)4
,K2
CO3
,二噁烷−H2
O,90℃隔夜,88%。
合成5-溴-2-(甲硫基)嘧啶-4-甲酸甲酯(E 28-1):
在0-5℃下,將乙醯氯(3.1 mL,43.8 mmol)逐滴添加至甲醇(50 ml)中。將所得混合物在此溫度下攪拌5分鐘,且添加5-溴-2-(甲硫基)嘧啶-4-甲酸(5.5 g,22.2 mmol)。將反應混合物加熱至回流1小時,隨後冷卻至室溫。將反應混合物倒入飽和NaHCO3
水溶液(100 ml)中。將混合物用DCM (3 × 100 ml)萃取,用水(50 ml)洗滌,乾燥(Na2
SO4
),過濾且濃縮,且將殘餘物自石油醚再結晶,以79%之產率得到呈黃色固體狀之標題化合物(E 28-1) (4.6 g,34.6 mmol)。LC-MS: [M+H]+ = 263.10。
合成(5-溴-2-(甲硫基)嘧啶-4-基)甲醇(E 28-2):
在-60℃下,向5-溴-2-(甲硫基)嘧啶-4-甲酸甲酯(E 28-1,600 mg,2.28 mmol)於DCM (15 ml)中之溶液中逐滴添加DIBAL-H (4.6 ml,4.60 mmol,1 M於環己烷中)。將反應混合物維持在-60℃至-15℃下30分鐘,隨後使其升溫至室溫且再攪拌12小時。將反應混合物再次冷卻至0℃,且用飽和NH4
Cl水溶液(50 ml)淬滅。將所得混合物用DCM (3 × 100 ml)萃取,用鹽水(50 ml)洗滌,乾燥(Na2
SO4
),過濾且濃縮。將殘餘物藉由管柱層析(用0-50% EtOAc/己烷溶離)純化,以56%之產率得到呈黃色固體狀之標題化合物(E 28-2) (300 mg)。LC-MS: [M+H]+ = 235.02。
合成2-((5-溴-2-(甲硫基)嘧啶-4-基)甲基)異吲哚啉-1,3-二酮(E 28-3):
將(5-溴-2-(甲硫基)嘧啶-4-基)甲醇(1.69 g,7.22 mmol)、鄰苯二甲醯亞胺(1.27 g,8.66 mmol)及三苯基膦(2.19 g,10.84 mmol)之THF溶液(10 ml)與DIAD (1.88 g,10.84 mmol)在用冰冷卻下混合,且在室溫下攪拌隔夜。反應完成後,將其用乙酸乙酯稀釋,且將有機層用飽和鹽水洗滌,經Na2
SO4
乾燥且減壓蒸發。將殘餘物藉由管柱層析(用0-50% EtOAc/己烷溶離)純化,以70%之產率得到所需產物(E 28-3,479 mg)。LC-MS: [M+H]+ = 363.12。
合成(5-溴-2-(甲硫基)嘧啶-4-基)甲胺(E 28-4):
將2-((5-溴-2-(甲硫基)嘧啶-4-基)甲基)異吲哚啉-1,3-二酮(910 mg,2.51 mmol)在乙醇(10 ml)中與NH2
NH2
.H2
O (0.16 ml,5.02 mmol)在室溫下攪拌4小時。反應完成後,將固體用乙醇濾出,且減壓蒸發濾液。將其藉由逆相combi flash (用0-20%乙腈/H2
O溶離)純化,以80%之產率得到呈無色液體狀之標題化合物(E 28-4)。LC-MS: [M+H]+ = 236.10
合成N-((5-溴-2-(甲硫基)嘧啶-4-基)甲基)甲醯胺(E 28-5):
將HCO2
H (4 ml)及Ac2
O (4 ml)之混合物在50℃下加熱1小時。將反應混合物冷卻至室溫,且添加至5-溴-2-(甲硫基)嘧啶-4-基)甲胺(1.52 g,6.55 mmol)於20 ml DCM中之溶液中。將混合物在室溫下攪拌2小時。反應完成後,將混合物濃縮。將混合物用DCM (2 × 50 ml)萃取,依次用水(20 ml)及鹽水(10 ml)洗滌。將有機相乾燥(Na2
SO4
),過濾且濃縮,得到呈油狀之粗標題化合物(E 28-5),其未經進一步純化即用於下一步驟。LC-MS: [M+H]+ =262.12。
合成8-溴-5-(甲硫基)咪唑并[1,5-c]嘧啶(E 28-6):
向N-((5-溴-2-(甲硫基)嘧啶-4-基)甲基)甲醯胺(800 mg,3.06 mmol)於二噁烷(30 ml)中之溶液中逐滴添加POCl3
(0.43 ml,4.60 mmol)。將反應混合物在回流下加熱2小時。添加冰水(50 mL),且將混合物用飽和NaHCO3
水溶液調節至pH 8。將混合物用DCM (4 × 50 ml)萃取,用鹽水(30 ml)洗滌,乾燥(Na2
SO4
)且過濾。濃縮濾液,且藉由管柱層析(矽膠,用0-50% EtOAc/己烷溶離)純化殘餘物,得到呈黃色固體狀之標題化合物(E 28-6) (350 mg,47.0%)。LC-MS: [M+H]+ = 244.0。
合成8-溴-N-(呋喃-2-基甲基)咪唑并[1,5-c]嘧啶-5-胺(E 28-7):
在0℃下,向化合物E 28-6 (439 mg,1.8 mmol,1.0 eq.)於DCM (18 ml)中之溶液中添加m-CPBA (464 mg,2.7 mmol,≤77%,1.5 eq.)。45分鐘後,在0℃下添加Et3
N (1 ml,7.6 mmol,4 eq.)且攪拌2分鐘,隨後添加呋喃-2-基甲胺(175 mg,1.8 mmol)。隨後將反應混合物在室溫下攪拌3小時。此後,濃縮反應混合物,且藉由矽膠管柱層析(用50-100% EtOAc/己烷溶離)純化殘餘物,以52%之產率得到標題化合物E 28-7 (274 mg,0.93 mmol)。LC-MS: [M+H]+ = 294.12。
合成N-(呋喃-2-基甲基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺(第126號化合物):
向8-溴-N-(呋喃-2-基甲基)咪唑并[1,5-c]嘧啶-5-胺(160 mg,0.55 mmol)於混合溶劑(二噁烷/水= 10 ml:2.5 ml)中之溶液中添加碳酸鉀(227 mg,1.64 mmol)、苯基硼酸(168 mg,0.82 mmol)及Pd(PPh3
)4
(63 mg,0.055mmol)。將所得混合物在N2
下在90℃下攪拌隔夜。隨後將混合物冷卻至室溫,且真空移除溶劑。殘餘物用矽膠層析(用0-10% MeOH/DCM溶離)純化,以80%之產率得到第126號化合物(159 mg,0.34 mmol)。LC-MS: [M+H]+ = 291.11;1
H NMR (400 MHz, CDCl3
) δ 10.13 (s, 1H), 7.66 (s, 1H), 7.61 (d, J = 1.0 Hz, 1H), 7.57 - 7.51 (m, 4H), 7.51 - 7.45 (m, 1H), 7.37 (dd, J = 1.8, 0.8 Hz, 1H), 6.41 (dd, J = 3.2, 0.8 Hz, 1H), 6.34 (dd, J = 3.2, 1.8 Hz, 1H), 4.89 (s, 2H)。
實例14
合成N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺(第99號化合物),
N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-苯基-1-(三氟甲基)咪唑并[1,5-c]嘧啶-5-胺(第143號化合物)
及
(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-基)二甲基氧化膦(第144號化合物)
(a) (5-氟-2,3-二氫苯并呋喃-4-基)甲胺,40℃,24 h,60%;(b)苯基硼酸,Pd(PPh3
)4
,K2
CO3
,二噁烷−H2
O,90℃隔夜,88%;(c) NIS,DMF,0℃,70%;(d)2,2-二氟-2-(氟磺醯基)乙酸甲酯,CuI,PdCl2
(dppf)Cl2
,DMF,90℃ 42%;(e)二甲基氧化膦,Pd(dba)3
,xantphos,Et3
N,二噁烷,40%;(f) MeSO2
Na,CuI,DMSO,50%
合成8-溴-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)咪唑并[1,5-c]嘧啶-5-胺(E 28-8):
將8-溴-5-(甲硫基)咪唑并[1,5-c]嘧啶(E 28-6,1.0 g,4.1 mmol)及(5-氟-2,3-二氫苯并呋喃-4-基)甲胺(1.41 g,8.2 mmol)之混合物在40℃下加熱且攪拌24小時。冷卻至室溫後,將粗混合物藉由逆相combi flash (用0-70%乙腈/H2
O溶離)純化,以60%之產率得到呈黃色固體狀之標題化合物(E 28-8)。LC-MS: [M+H]+ = 363.01;1
H NMR (400 MHz, 甲醇-d4
) δ 8.58 (s, 1H), 7.38 (s, 1H), 7.32 (s, 1H), 6.91 - 6.80 (m, 1H), 6.65 (dd, J = 8.7, 3.9 Hz, 1H), 4.74 (s, 2H), 4.62 - 4.52 (m, 2H), 3.37 (s, 2H)。
合成N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺(E 28-9):
向8-溴-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)咪唑并[1,5-c]嘧啶-5-胺(200 mg,0.55 mmol)於混合溶劑(二噁烷:水= 10 ml : 2.5 ml)中之溶液中添加碳酸鉀(227 mg,1.64 mmol)、苯基硼酸(168 mg,0.82 mmol)及Pd(PPh3
)4
(63 mg,0.055 mmol)。將所得混合物在N2
下在90℃下攪拌隔夜。隨後將混合物冷卻至室溫,且真空移除溶劑。將殘餘物藉由矽膠層析用0-10% MeOH/DCM溶離純化,以88%之產率得到標題化合物E 28-9 (174 mg,0.34 mmol)。LC-MS: [M+H]+ = 361.13。
合成N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-碘-8-苯基咪唑并[1,5-c]嘧啶-5-胺(E 28-10):
在0℃下,向N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺(500 mg,1.38 mmol)於DMF (10 ml)中之溶液中添加NIS (278 mg,1.24 mmol),且在室溫下攪拌15分鐘。將混合物用DCM (4 × 50 ml)萃取,用鹽水(30 ml)洗滌,乾燥(Na2
SO4
)且過濾。濃縮濾液,且藉由管柱層析(矽膠,用20-50% EtOAc/己烷溶離)純化殘餘物,得到呈黃色固體狀之標題化合物(E 28-10) (610 mg,1.26 mmol,70%)。LC-MS: [M+H]+ = 487.03
合成N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-苯基-1-(三氟甲基)咪唑并[1,5-c]嘧啶-5-胺(第143號化合物):
將N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-碘-8-苯基咪唑并[1,5-c]嘧啶-5-胺(50 mg,0.1 mmol)於DMF (5 ml)中之溶液添加至碘化銅(I) (190 mg,1.0 mmol)、2,2-二氟-2-(氟磺醯基)乙酸甲酯(192 mg,1.0 mmol)及PdCl2
(dppf)Cl2
(7 mg,0.01 mmol)之混合物中。將反應物在90℃下攪拌隔夜,且隨後冷卻至室溫並藉由倒入水中淬滅。過濾混合物且用乙醚萃取濾液。濃縮醚萃取物,且藉由HPLC純化殘餘物,以42%之產率得到第143號化合物(16 mg,0.04 mmol)。LC-MS: [M+H]+ = 429.12。1
H NMR (400 MHz, DMSO-d6
) δ 8.85 (s, 1H), 8.61 (s, 1H), 7.44-7.31 (m, 6H), 6.94 (t, J = 8.8 Hz, 1H), 6.71 (dd, J = 8.4, 4.0 Hz, 1H), 4.73 (d, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.31 (t, J = 8.8 Hz, 2H)。
合成(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-基)二甲基氧化膦(第144號化合物):
向N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-碘-8-苯基咪唑并[1,5-c]嘧啶-5-胺(50 mg,0.1 mmol)於2 ml二噁烷中之溶液中添加二甲基氧化膦(22 mg,0.3 mmol)、Pd(dba)3
(9 mg,0.01 mmol)、xantphos (6 mg,0.01 mmol)及Et3
N (0.2 ml)。將混合物用氬氣吹掃,且在100℃下加熱隔夜。濃縮混合物,且藉由HPLC純化殘餘物,以40%之產率得到第144號化合物(17 mg,0.04 mmol)。LC-MS: [M+H]+ = 437.14。1
H NMR (400 MHz, DMSO-d6
) δ 8.85 (s, 1H), 8.52 (s, 1H), 7.58-7.56 (m, 2H), 7.42-7.41 (m, 2H), 7.29 (s, 1H), 6.94 (t, J = 9.2 Hz, 1H), 6.70 (dd, J = 8.4, 4.0 Hz, 1H), 4.73 (d, J = 4.0 Hz, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.31 (t, J = 8.8 Hz, 2H), 1.21 (s, 1H), 1.18 (s, 1H)。
N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺(第99號化合物)
將化合物E 28-10 (50 mg,0.1 mmol)、MeSO2
Na (30 mg.0.3 mmol)及CuI (57 mg.0.3 mmol)於DMSO (2 ml)中之混合物用N2
鼓泡5分鐘,隨後將密封管在微波反應器中在120℃下加熱20分鐘,且隨後在100℃下加熱3小時。濃縮混合物,且藉由HPLC純化殘餘物,以50%之產率得到第99號化合物(21 mg,0.05 mmol)。1
H NMR (400 MHz, CDCl3
) δ 8.60 (s, 1H), 7.55 - 7.35 (m, 6H), 6.77 (dd, J = 10.1, 8.7 Hz, 1H), 6.61 (dd, J = 8.7, 3.9 Hz, 1H), 4.82 (s, 2H), 4.61 (t, J = 8.7 Hz, 2H), 3.40 (t, J = 8.7 Hz, 2H), 2.86 (s, 3H)。LC-MS: [M+H]+ = 439.12。
實例15
合成5-((呋喃-2-基甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯(第127號化合物)及5-((呋喃-2-基甲基)胺基)-N-甲基-8-苯基咪唑并[1,5-c]嘧啶-1-甲醯胺(第128號化合物)
(a) 2-(二苯基亞甲基胺基)乙酸乙酯,NaH,rt,2 h;(b)含3 N HCl之THF,rt,1 h,70%;(c) HCO2
H,Ac2
O,rt,2 h;(d) POCl3
,二噁烷,回流,4 h,70%;(e) (i) mCPBA,DCM,(ii)呋喃-2-基甲胺,rt,3 h,55%;(f)苯基硼酸,Pd(PPh3
)4
,K2
CO3
,二噁烷−H2
O,90℃隔夜,90%;(g) Li(OH)2
,THF-H2
O,90%;(h) NHMe.HCl,DIPEA,HATU,90%
合成2-(5-溴-2-(甲硫基)嘧啶-4-基)-2-((二苯基亞甲基)胺基)乙酸乙酯(E 29-1):
在0℃下,將2-(二苯基亞甲基胺基)乙酸乙酯(18.4 g,69 mmol)於DMSO (50 ml)中之溶液逐滴添加至NaH (60%) (5.0 g,125.5 mmol)於70 ml無水DMSO中之懸浮液中。反應混合物立即變為橙色。5分鐘後,逐滴添加含5-溴-4-氯-2-(甲硫基)嘧啶(15 g,62.7 mmol)之50 mL DMSO。隨後將混合物在室溫下攪拌2小時。此後,藉由小心地添加NH4
Cl水溶液來淬滅反應混合物。隨後將混合物用乙酸乙酯萃取,用鹽水洗滌,乾燥且濃縮,並用作下一步驟之粗物質。LC-MS: [M+H]+ = 470.01。
合成2-胺基-2-(5-溴-2-(甲硫基)嘧啶-4-基)乙酸乙酯(E 29-2):
在0℃下,向化合物E 29-1 (粗物質,5.0 g,10.6 mmol)於THF (50 ml)中之溶液中添加10 ml 3 N HCl水溶液。將混合物在室溫下攪拌1小時,且隨後將反應混合物濃縮,接著用Na2
CO3
水溶液鹼化至pH 8~9。將混合物用DCM萃取,用鹽水洗滌。減壓濃縮,隨後藉由急驟層析(0-100% EtOAc/己烷)純化,以70%之總產率得到所需化合物8-2 (2.26 g)。LC-MS: [M+H]+ = 305.95。
合成2-(5-溴-2-(甲硫基)嘧啶-4-基)-2-甲醯胺基乙酸乙酯(E 29-3):
將HCO2
H (4 ml)及Ac2
O (4 ml)之混合物在50℃下加熱1小時。將反應混合物冷卻至室溫,且添加至2-胺基-2-(甲硫基)嘧啶-4-基)乙酸乙酯(2.0 g,6.55 mmol)於20 ml DCM中之溶液中。將混合物在室溫下攪拌2小時。反應完成後,將混合物濃縮。將混合物用DCM (2 × 50 ml)萃取,依次用水(20 ml)及鹽水(10 ml)洗滌。將有機相乾燥(Na2
SO4
),過濾且濃縮,得到呈油狀之粗標題化合物E 29-3,其未經進一步純化即用於下一步驟。LC-MS: [M+H]+ = 334.05。
合成8-溴-5-(甲硫基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(E 29-4):
向化合物E 29-3 (2.0 g,粗物質)於二噁烷(20 ml)中之溶液中逐滴添加POCl3
(1.5 ml)。將反應混合物在回流下加熱4小時。將混合物冷卻至室溫且濃縮。添加冰冷卻的水(50 ml),且將混合物用飽和的NaHCO3
水溶液調節至pH 8。將混合物用DCM (2 × 50 ml)萃取,用鹽水(10 ml)洗滌,乾燥(Na2
SO4
)且過濾。濃縮濾液,且藉由矽膠管柱層析(用50-100% EtOAc/己烷)溶離純化殘餘物,以70%之總產率分兩步得到呈白色固體狀之標題化合物E 29-4 (1.42 g,4.59 mmol)。LC-MS: [M+H]+ = 315.70。1
H NMR (400 MHz, DMSO d6
): 8.67 (s, 1H), 7.99 (s, 1H), 4.33 (q, 2H), 2.76 (s, 3H), 1.34 (t, 3H)。
合成8-溴-5-((呋喃-2-基甲基)胺基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(E 29-5):
在0℃下,向化合物E 29-4 (567 mg,1.8 mmol,1.0 eq.)於DCM (18 ml)中之溶液中添加m-CPBA (464 mg,2.7 mmol,≤77%,1.5 eq.)。45分鐘後,在0℃下添加Et3
N (1 ml,7.6 mmol,4 eq.)且攪拌2分鐘,隨後添加呋喃-2-基甲胺(175 mg,1.8 mmol)。隨後將反應混合物在室溫下攪拌3小時。此後,濃縮反應混合物,且藉由矽膠管柱層析(用50-100% EtOAc/己烷溶離)純化殘餘物,以55%之產率得到標題化合物E 29-5 (361 mg,0.99 mmol)。LC-MS: [M+H]+ = 365.017。1
H NMR (400 MHz, MeOD) δ 8.58 (s, 1H), 7.70 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 1.8, 1.0 Hz, 1H), 6.39 (dt, J = 3.2, 1.1 Hz, 2H), 4.78 (t, J = 0.9 Hz, 2H), 4.46 - 4.36 (m, 2H), 1.43 - 1.35 (m, 3H)。
合成5-((呋喃-2-基甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸乙酯(第127號化合物):
向8-溴-5-((呋喃-2-基甲基)胺基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(200 mg,0.55 mmol)於混合溶劑(二噁烷:水= 10 ml : 2.5 ml)中之溶液中添加碳酸鉀(227 mg,1.64 mmol)、苯基硼酸(168 mg,0.82 mmol)及Pd(PPh3
)4
(63 mg,0.055 mmol)。將所得混合物在N2
下在90℃下攪拌隔夜。隨後將混合物冷卻至室溫,且真空移除溶劑。藉由矽膠層析用0-10% MeOH/DCM溶離純化殘餘物,以80%之產率得到第127號化合物(159 mg,0.34 mmol)。LC-MS: [M+H]+ = 363.017。1
H NMR (400 MHz, CDCl3
) δ 8.81 (s, 1H), 7.49 (d, J = 1.0 Hz, 1H), 7.41 (d, J = 6.7 Hz, 3H), 7.34 (dq, J = 3.3, 1.7 Hz, 3H), 6.35 (d, J = 3.2 Hz, 1H), 6.30 (dt, J = 3.1, 1.4 Hz, 1H), 4.87 (s, 2H), 3.87 (q, J = 7.1 Hz, 2H), 0.88 (t, J = 7.1 Hz, 3H)。
合成5-((呋喃-2-基甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-甲酸(E 29-6):
將E 29 (40 mg,0.11 mmol,1 eq.)及LiOH (26 mg,1.10 mmol,10 eq.)於THF (4 ml)及水(2.0 ml)中之混合物在70℃下加熱隔夜。在0℃下逐滴添加3 NHCl水溶液直至pH 2-3。濃縮混合物,且藉由HPLC純化殘餘物,以90%之產率得到標題化合物E 29-6 (33 mg,0.099 mmol)。LC-MS: [M+H]+ = 335.10。
合成N-(呋喃-2-基甲基)-1-(((甲胺基)氧基)羰基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺(第128號化合物):
向化合物E 29-6 (10 mg,0.029 mmol)於DMF (1 ml)中之溶液中添加甲胺鹽酸鹽(4 mg,0.058 mmol)及二異丙基乙胺(50 µL,0.29 mmol)。將反應混合物在室溫下攪拌10分鐘,且隨後添加HATU (11 mg,0.029 mmol)。將反應混合物升溫至室溫,在室溫下攪拌隔夜。濃縮混合物,且藉由HPLC純化殘餘物,以90%之產率得到第128號化合物(9 mg,0.026 mmol)。LC-MS: [M+H]+ = 348.13。1
H NMR (400 MHz, CDCl3
) δ 9.22 (s, 1H), 7.55 - 7.43 (m, 3H), 7.38 -7.30 (m, 3H), 6.40 (s, 1H), 6.36 (s, 1H), 6.31 (brs, 1H), 4.86 (s, 2H), 2.54 (s, 3H)。
實例16
合成-(3,6-二氫-2H-哌喃-4-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺(第146號化合物)及8-(3,6-二氫-2H-哌喃-4-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺(第169號化合物):
合成8-(3,6-二氫-2H-哌喃-4-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)咪唑并[1,5-c]嘧啶-5-胺(E 47-1):
向溶液(二噁烷:水= 10 ml : 2.5 ml)中添加化合物E 28-8 (250 mg,0.69 mmol)、3,6-二氫-2H-哌喃-4-硼酸頻哪醇酯(290 mg,1.38 mmol)、Pd(PPh3
)4
(80 mg,0.069 mmol)、285 mg Na2
CO3
。將所得混合物在N2
下在90℃下攪拌隔夜。隨後將混合物冷卻至室溫,且真空移除溶劑並藉由管柱層析(DCM: MeOH = 20:1)來純化,以80%之產率獲得呈白色固體狀之標題化合物E 47-1。LC-MS: [M+H]+ = 366.14。
合成8-(3,6-二氫-2H-哌喃-4-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-碘咪唑并[1,5-c]嘧啶-5-胺(E 47-2):
在0℃下,向化合物E 47-1 (160 mg,0.43 mmol)於DMF (4 ml)中之溶液中添加NIS (82 mg,0.4 mmol),且在室溫下攪拌15分鐘。將混合物用DCM (4 × 50 ml)萃取,用鹽水(30 ml)洗滌,乾燥(Na2
SO4
)且過濾。濃縮濾液,且藉由管柱層析(矽膠,用20-50% EtOAc/己烷溶離)純化殘餘物,以60%之產率得到標題化合物(E 47-2) (127 mg,0.25 mmol,70%)。LC-MS: [M+H]+ = 493.04
合成8-(3,6-二氫-2H-哌喃-4-基)-N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)咪唑并[1,5-c]嘧啶-5-胺(第146號化合物):
將化合物E 47-2 (50 mg,0.1 mmol)、MeSO2
Na (30 mg,0.3 mmol)及CuI (57 mg,0.3 mmol)於DMSO (2 ml)中之混合物用N2
鼓泡5分鐘,隨後將密封管在微波反應器中在120℃下加熱20分鐘,且隨後在100℃下加熱3小時。濃縮混合物,且藉由HPLC純化殘餘物,以50%之產率得到第146號化合物(21 mg,0.05 mmol)。LC-MS: [M+H]+ = 445.12。
合成N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-1-(甲基磺醯基)-8-(四氫-2H-哌喃-4-基)咪唑并[1,5-c]嘧啶-5-胺(第169號化合物):
向化合物第146號化合物(10 mg)於MeOH (1 ml)中之溶液中添加Pd/C (2 mg,20% wt)。將反應混合物用H2
脫氣且在H2
氛圍下在室溫下攪拌6小時。隨後將混合物經由矽藻土過濾,且用MeOH洗滌。減壓濃縮,隨後藉由HPLC純化,以定量產率得到第169號化合物(10 mg)。LC-MS: [M+H]+ = 447.14。
實例17
合成(S
)-4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4,5,5a,6,8,9-六氫-3H-7-氧雜-2,4,9a,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第147號化合物)
鈀催化之胺化反應的一般程序:
向烘乾的40 ml小瓶中裝入E 28-8 (1.0 mmol)、Pd(OAc)2
(5 mol%)、DPEphos (10 mol%)、K3
PO4
(2.5 mmol)及必需的胺(1.5 mmol)。將倒置的隔墊置於小瓶上,且插入針頭(作為排氣孔),同時經由第二針頭用氬氣吹掃所得混合物數分鐘。經由隔墊引入二噁烷(4 ml)。將所得懸浮液用氬氣吹掃3分鐘。隨後將小瓶快速加蓋,隨後加熱至85℃隔夜。將混合物吸附於矽膠上,且藉由急驟層析(0-10% MeOH/DCM)純化,以50%之產率得到所需化合物E 1-1 (293 mg)。LC-MS: [M+H]+ = 586.27。
在室溫下,將TBAF (1M於THF中,1 ml,1.0 mmol)逐滴添加至E 1-1 (293 mg,0.5 mmol)於THF (2 ml)中之溶液中。將反應混合物攪拌2小時,之後將其真空濃縮。藉由急驟層析(0-10% MeOH/DCM)純化,以80%之產率得到所需化合物E 99-2 (188 mg,0.4 mmol)。LC-MS: [M+H]+ = 472.19。
將化合物(E 1-2)溶解於無水DCM (~0.2 M)中,隨後向此溶液中添加1.5 eq. DMP,且使反應混合物攪拌1小時,經由TLC監測。完成後,用飽和NH4
Cl溶液淬滅,隨後用DCM萃取且用水及鹽水洗滌。收集有機層且合併,用鹽水洗滌,經無水Na2
SO4
乾燥,且真空濃縮。在矽膠正相管柱層析上用增加量的乙酸乙酯/己烷進行純化,得到所需醛。
在冰浴下,向獲得之醛中添加甲醇(~0.2 M),隨後添加2.2 eq.環丙胺、2 eq. Na(CN)BH3
及2 eq.乙酸。隨後移除冰浴且使反應混合物攪拌3小時,經由TLC監測。完成後,濃縮反應混合物,且藉由HPLC純化殘餘物,經兩步以50%之產率得到化合物E 1-3 (100 mg,0.2 mmol)。LC-MS: [M+H]+ = 511.23。
將化合物E 1-3 (1 eq.)及LiOH (10 eq.)於THF (10 ml/mmol)及水(5 ml/mmol)中之混合物在70℃下加熱隔夜。濃縮混合物,且隨後藉由製備型HPLC純化殘餘物,以80%之產率得到第147號化合物。
實例18
合成(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-基)(亞胺基)(甲基)-l6-碸酮(第178號化合物);(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-基)(甲基)(甲基亞胺基)-l6-碸酮(第182號化合物);1-(5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-8-苯基咪唑并[1,5-c]嘧啶-1-基)-3,4,5,6-四氫-1,2-噻嗪1-氧化物(第186號化合物)
實例19
合成6-氟苯并二氫哌喃-5-基)甲胺(A.2):
向圓底燒瓶中添加2-溴-3-氟-6-羥基苯甲醛(1 eq.)、溴乙酸乙酯(1.5 eq.)、飽和NaHCO3
水溶液(2 ml/mmol)及含PPh3
(1.4 eq.)之(1 ml/mmol) EtOAc。將反應混合物在室溫下劇烈攪拌隔夜。在起始物質耗盡後,將反應物用水稀釋且用EtOAc萃取(×3)。合併有機相,用鹽水洗滌,經MgSO4
乾燥且真空濃縮。將殘餘物在矽膠上純化(0-10% EtOAc/己烷),以80%之產率得到A.2.2。LC-MS: [M+H]+ = 288.97
在氬氣氛圍下,將A.2.2 (1 eq.)、CuCl (1.1 eq.)於20 ml MeOH中之混合物冷卻至0℃。分數份添加NaBH4
(2 eq.)。在起始物質耗盡後,將反應物用水稀釋且用EtOAc萃取(×3)。合併有機相,用鹽水洗滌,經MgSO4
乾燥,真空濃縮,且藉由急驟層析純化,以70%之產率得到呈白色固體狀之A.2.3。LC-MS: [M+H]+ = 290.97
在0℃下,在氬氣氛圍下,向A.2.3 (1 eq.)於THF (4 ml)中之溶液中添加LAH (1 eq.)。將反應混合物在室溫下攪拌2小時,隨後用水淬滅且用EtOAc稀釋。隨後過濾反應混合物,且藉由急驟層析純化,以65%之產率得到A.2.4。LC-MS: [M+H]+ = 248.98。
在0℃下,將碘(1.30 eq.)添加至三苯基膦(1.30 eq.)及咪唑(1.35 eq.)於25 ml二氯甲烷中之溶液中。將反應混合物攪拌15分鐘,隨後添加含化合物A.2.4之二氯甲烷。黃色沈澱物在輕微放熱反應期間消失,且咪唑鹽酸鹽以白色絮狀沈澱物形式出現。將混合物在室溫下攪拌至少1小時,且添加3 ml甲醇。繼續攪拌30分鐘。將溶液用二氯甲烷稀釋且用水及鹽水洗滌。有機相經MgSO4
乾燥且在旋轉蒸發儀上蒸發。粗物質未經進一步純化即用於下一步驟。
向3-溴-4-氟-2-(3-碘丙基)苯酚(1 eq.)於丙酮中之溶液中添加K2
CO3
(2 eq.)。將混合物在50℃下攪拌12小時。將反應混合物過濾且真空濃縮。隨後藉由急驟層析純化反應混合物,以65%之產率總產率得到A.2.5。LC-MS: [M+H]+ = 230.97。
向A.2.5 (1 eq.)及Zn(CN)2
(2 eq.)於DMF (2 ml/mmol)中之溶液中添加Pd(PPh3
)4
(0.1 eq.)。將反應混合物用N2
脫氣,且在N2
氛圍下在100℃下攪拌24小時。冷卻至室溫後,將反應物用水稀釋且用乙酸乙酯(2 × 100 ml)萃取。將合併之有機相用鹽水洗滌且經無水Na2
SO4
乾燥。將殘餘物在矽膠上純化(0-20% EtOAc/己烷),以60%之產率分離得到A.2.6。LC-MS: [M+H]+ = 178.05。
將A.2.6 (1 eq.)於THF中之溶液在0℃下用LAH (2 eq.,1M LAH於THF中之溶液)處理。將溫度升高至50℃且將反應混合物攪拌隔夜。冷卻至室溫後,將反應物用0℃之飽和Na2
SO4
緩慢淬滅。將其過濾且用乙酸乙酯洗滌數次。藉由急驟層析(0-10% MeOH/含有1%三甲胺之DCM)純化,以70%之產率得到所需化合物A.2。LC-MS: [M+H]+ = 182.09。
實例20
合成5-氟-2,3-二氫苯并呋喃-4-基)甲-d2-胺(A.3)
在0℃下,向5-氟苯并呋喃-4-甲腈(2.00 g,12.4 mmol,1.0 eq.)於DMSO (20 ml)中之溶液中添加H2
O2
(7.04 g,62.1 mmol,6 ml)及K2
CO3
(1.72 g,12.4 mmol,1.0 eq.)。將反應混合物在室溫下攪拌1小時,倒入冰水(5.0 ml)中且攪拌10分鐘。將反應混合物過濾且真空濃縮,得到呈白色固體狀之5-氟苯并呋喃-4-甲醯胺(A.3.1,1.80 g,10.1 mmol,80%產率)。LC-MS: [M+H]+ = 180.03。
向化合物A.3.1 (1 g,5.05 mmol)於MeOH (50 ml)中之溶液中添加Pd/C (100 mg,10% wt)。將反應混合物用H2
脫氣,且在H2
氛圍下在40℃下攪拌6小時。隨後將混合物經由矽藻土過濾,且用MeOH洗滌。減壓濃縮,隨後藉由急驟層析(0-10% MeOH/含有1%三甲胺之DCM)純化,以85%之產率得到所需化合物中間物A.3.2 (859 mg,4.71 mmol)。LC-MS: [M+H]+ = 182.05。
將含化合物A.3.2 (2.3 g,12.63 mmol)之15 ml THF在0℃下用LAD (36 ml 1M LAD於THF中之溶液)處理。此後,將溫度升高至50℃且將反應混合物攪拌隔夜。冷卻至室溫後,將反應物用0℃之飽和Na2
SO4
緩慢淬滅。隨後將其過濾且用乙酸乙酯洗滌數次。藉由急驟層析(0-10% MeOH/含有1%三甲胺之DCM)純化,以70%之產率得到所需化合物A.3 (1.50 g,8.84 mmol)。LC-MS: [M+H]+ = 170.08。1
H NMR (400 MHz, CDCl3
): 6.82-6.76 (m, 1H), 6.59 (dd,J
= 8.8, 4.0 Hz, 1H), 4.59 (t, J= 8.8 Hz, 2H), 3.27 (t, J= 8.8 Hz, 2H)。
實例21
合成N-((3-溴-6-甲基吡啶-2-基)甲基)-2,2,2-三氟乙-1-胺(A.4)
向5-溴-2-乙基吡啶(A.4.1,554 mg,3.0 mmol,1.0 eq.)於CHCl3
(8 ml,0.38 M)中之溶液中添加77% mCPBA (5.44 g,12.0 mmol,4.0 eq.),且將反應混合物在室溫下攪拌隔夜。冷卻至室溫後,添加Ca(OH)2
(1.5 g,15.9 mmol,5.3 eq.),且將所得沈澱物攪拌30分鐘。過濾沈澱物,且用3:1 CHCl3
/甲醇洗滌。接著真空濃縮濾液,且藉由管柱層析使用0-100%乙酸乙酯/己烷純化殘餘物,得到所需N-氧化物(A.4.2,482 mg,2.4 mmol)。LC-MS: [M+H]+ = 201.97。
向5-溴-2-乙基吡啶1-氧化物(A.4.2,400 mg,2.0 mmol)於乙腈(10 ml,0.2 M)中之溶液中添加氰化三甲基矽烷(TMSCN) (793 mg,8.0 mmol,4.0 eq.)及三乙胺(606 mg,6.0 mmol,3.0 eq.)。將反應物在100℃下加熱隔夜。冷卻至室溫後,真空濃縮溶劑,且藉由管柱層析使用0-50%乙酸乙酯/己烷純化殘餘物,得到3-溴-6-乙基吡啶甲腈(A.4.3,293 mg,1.4 mmol,70%產率)。LC-MS: [M+H]+ = 210.97。
將3-溴-6-乙基吡啶甲腈(A.4.3,1 g,4.78 mmol)溶解於濃鹽酸(20 ml)中,且在110℃下攪拌2天。使反應混合物冷卻至室溫,且蒸發至乾。粗產物未經進一步純化即用於下一步驟。LC-MS: [M+H]+ = 229.97。
將3-溴-6-乙基吡啶甲酸(A.4.4,5.33 g,23.3 mmol)溶解於MeOH (50 ml)中且冷卻至0℃,並逐滴添加1.0 ml H2
SO4
。隨後將反應物在90℃下攪拌隔夜。將混合物冷卻至室溫且真空濃縮。將殘餘物溶解於乙酸乙酯(50 ml)中,且用水及飽和NaCl水溶液(2 × 100 ml)洗滌,經無水Na2
SO4
乾燥且真空濃縮。藉由矽膠管柱層析純化且用EtOAc/己烷(1:5)溶離殘餘物,以90%之產率產生3-溴-6-乙基吡啶甲酸甲酯(A.4.5,5.09 g,20.97 mmol)。LC-MS [M+H]+ = 243.98
在-60℃下,向3-溴-6-乙基吡啶甲酸甲酯(A.4.5,522 mg,2.15 mmol)於DCM (15 ml)中之溶液中逐滴添加DIBAL-H (4.6 ml,4.60 mmol,1 M於環己烷中)。將反應混合物維持在-60℃至-15℃下30分鐘,隨後升溫至室溫且再攪拌12小時。將反應混合物冷卻至0℃,且用飽和NH4
Cl水溶液(50 ml)淬滅。將所得混合物用DCM (3 × 100 ml)萃取,用鹽水(50 ml)洗滌,乾燥(Na2
SO4
),過濾且濃縮。藉由矽膠管柱層析純化且用EtOAc/己烷(1:3)溶離殘餘物,得到呈無色液體狀之A.4.6 (1.36 mmol,293 mg,60%)。LC-MS [M+H]+ = 215.99
將(3-溴-6-乙基吡啶-2-基)甲醇(A.4.6)之等分試樣溶解於無水DCM (~0.2 M)中,隨後向此溶液中添加1.5 eq. DMP,且使反應混合物攪拌1小時。完成後(藉由TLC監測),將反應物用飽和NH4
Cl溶液淬滅,隨後用DCM萃取且用水及鹽水洗滌。收集有機層且合併,用鹽水洗滌,經無水Na2
SO4
乾燥,且真空濃縮。在矽膠正相管柱層析上用增加量的乙酸乙酯/己烷進行純化,得到所需醛。
在0℃下,向醛中添加甲醇(~0.2 M),隨後添加2.2 eq. 2,2,2-三氟乙-1-胺、2 eq. Na(CN)BH3
及2 eq.乙酸。移除冰浴且使反應混合物攪拌3小時。完成後(藉由TLC監測),濃縮反應混合物,且藉由HPLC純化殘餘物,以70%之產率得到A.4。LC-MS: [M+H]+ = 297.01。
實例22
合成(5-溴-2-(二氟甲基)吡啶-4-基)甲醇(A.6):
在具有攪拌棒之100 mL燒瓶中,添加銅粉(380 mg,5.94 mmol,2.25 eq.)及(2,5-二溴吡啶-4-基)三乙基矽烷基甲醇(A.6.2,1.006 g,2.64 mmol,1.0 eq.)。將燒瓶抽空且用N2
氛圍回填。添加無水DMSO (6 ml)及溴二氟乙酸乙酯(589 mg,2.90 mmol,1.1 eq.)。開始攪拌且將混合物加熱至油浴70℃。2小時後,將反應混合物之等分試樣稀釋至1.27 M KH2
PO4
水溶液中且添加EtOAc。超音波處理後,分離頂部有機層。緩慢添加KH2
PO4
(1.27 M,40 ml),同時保持內部溫度低於10℃。將混合物在0℃下攪拌0.5小時,隨後經由矽藻土過濾。濾餅用EtOAc (40 ml)洗滌。分離兩相濾液層。將有機層用水及鹽水洗滌,隨後濃縮且藉由急驟層析純化,得到化合物A.6.3 (825 mg,74%產率)。
向冷卻至0℃之A.6.3 (825 mg,1.95 mmol)於甲醇(2 ml)中之溶液中逐滴添加6 N NaOH (1 mL,3.0 eq.)。將所得澄清溶液在0℃下攪拌。3小時後,UPLC-MS分析表明已完全轉化為所需產物。在0℃下,將反應混合物用4 N HCl (1.5 mL)酸化至pH 3。HPLC純化得到呈淡黃色固體狀之A.6.4 (412 mg,1.46 mmol,75%)。
在具有攪拌棒之50 mL燒瓶中,添加二氟酸A.6.4 (412 mg,1.46 mmol)。將燒瓶抽空且用N2
氛圍回填。添加NMP (2 ml)及85% H3
PO4
(169 mg,1.46 mmol)。將所得混合物加熱至油浴145℃且攪拌。2小時後,UPLC-MS表明已完全轉化為所需產物。將混合物冷卻至15℃且用1 N NaOH淬滅。藉由HPLC純化混合物,得到呈淡黃色固體狀之所需化合物A.6 (274 mg,1.15 mmol,79%)。
實例23
合成12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(甲基-d3)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第E 19號化合物):
向火焰乾燥的燒瓶中添加3-溴-6-甲基吡啶甲酸(1 g,4.67 mmol),隨後添加第三丁醇鉀(1.0 g,9.34 mmol)及DMSO-d
6 (12 mL),且將混合物在室溫下在氬氣下攪拌12小時。將反應混合物用冷水(10 mL)稀釋且用乙酸乙酯(20 mL)萃取。將乙酸乙酯層用鹽水(20 mL × 2)洗滌,經無水硫酸鈉乾燥且濃縮,以90%之產率產生粗產物(E 19.1)。LC-MS: [M+H]+ = 215.95。
將H2
SO4
(1.0 eq.)添加至3-溴-6-(甲基-d3)吡啶甲酸-d (E 19.1,5.0 g,23.3 mmol,1.0 eq.)於MeOH (50 ml)中之溶液中。將所得溶液攪拌14小時,同時在油浴中維持回流之溫度。將混合物冷卻至室溫且真空濃縮。將殘餘物溶解於乙酸乙酯(50 ml)中,且用水及飽和NaCl水溶液(2 × 100 ml)洗滌,經無水Na2
SO4
乾燥且真空濃縮。藉由矽膠管柱層析純化且用EtOAc/己烷(1:5)溶離殘餘物,以90%之產率產生3-溴-6-甲基吡啶甲酸甲酯(E 19.2,4.7 gm)。LC-MS [M+H]+
= 232.99。
在-60℃下,向3-溴-6-(甲基-d3)吡啶甲酸甲酯(E 19.2,520 mg,2.15 mmol)於DCM (15 ml)中之溶液中逐滴添加DIBAL-H (4.6 ml,4.60 mmol,1 M於環己烷中)。將反應混合物維持在-60℃至-15℃下30分鐘,使其升溫至室溫且再攪拌12小時。將反應混合物再次冷卻至0℃,且用飽和NH4
Cl水溶液(50 ml)淬滅。將所得混合物用DCM (3 × 100 ml)萃取,用鹽水(50 ml)洗滌,乾燥(Na2
SO4
),過濾且濃縮。藉由矽膠管柱層析純化且用EtOAc/己烷(1:3)溶離殘餘物,得到呈無色液體狀之E 19.3 (1.36 mmol,273 mg,60%)。LC-MS [M+H]+ = 204.99。
將(3-溴-6-(甲基-d3)吡啶-2-基)甲醇(E 19.3)之等分試樣溶解於無水DCM (~0.2 M)中。向此溶液中添加1.5 eq. DMP,且使反應混合物攪拌1小時(藉由TLC監測)。完成後,將反應物用飽和NH4
Cl溶液淬滅,用DCM萃取,且用水及鹽水洗滌。收集有機層且合併,用鹽水洗滌,經無水Na2
SO4
乾燥,且真空濃縮。在矽膠正相管柱層析上用增加量的乙酸乙酯/己烷進行純化,得到所需醛。
在0℃下,向醛中添加甲醇(~0.2 M),隨後添加2.2 eq.三氟乙-1-胺、2 eq. Na(CN)BH3
及2 eq.乙酸。移除冰浴且使反應混合物攪拌3小時。完成後,濃縮反應混合物且藉由HPLC純化殘餘物,以70%之產率得到E 19.4。LC-MS: [M+H]+ = 286.01。
將乙酸鈀(II) (0.1 eq.)及cataCXium A (0.2 eq.)在DME (0.5 ml,脫氣)中混合在一起,且在70℃下,經由移液管將所得溶液添加至8-溴-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(1 eq.)、二級胺E 19.4 (2 eq.)、雙頻哪醇根基二硼(2.0 eq.)及K2
CO3
(4.0 eq.)於DME/H2
O (10:1,10 ml,脫氣)中之混合物中。攪拌反應混合物12小時。將反應混合物濃縮且用乙酸乙酯(2 × 50 ml)萃取,用水及鹽水洗滌,且經Na2
SO4
乾燥。濃縮混合物且藉由HPLC純化殘餘物,以50%之產率得到E19.5。LC-MS: [M+H]+ = 561.21。
將化合物E 19.5 (1 eq.)及LiOH (10 eq.)於THF (10 ml/mmol)及水(5 ml/mmol)中之混合物在70℃下加熱隔夜。濃縮混合物,且隨後藉由製備型HPLC純化殘餘物,以80%之產率得到E 19.6。LC-MS: [M+H]+ = 534.18。
向化合物E 19.6 (1 eq.)及HATU (2 eq.)於DMF (5 ml/mmol)中之混合物中添加DIPEA (5 eq.)。使反應混合物攪拌隔夜,且濃縮。藉由製備型HPLC純化殘餘物,以90%之產率得到第E 19號化合物。LC-MS: [M+H]+
= 516.17。1
H NMR (400 MHz, DMSO-d6
) δ 8.85 (s, 1H), 8.71 (t,J
= 5.1 Hz, 1H), 7.93 (d,J
= 8.0 Hz, 1H), 7.54 (s, 1H), 7.44 (d,J
= 8.1 Hz, 1H), 6.96 (dd,J
= 10.3, 8.6 Hz, 1H), 6.71 (dd,J
= 8.7, 3.9 Hz, 1H), 5.46 (d,J
= 15.0 Hz, 1H), 4.75 (d,J
= 4.5 Hz, 2H), 4.71 - 4.61 (m, 1H), 4.56 (t,J
= 8.8 Hz, 2H), 4.19 (d,J
= 15.0 Hz, 1H), 4.08 (dq,J
= 15.2, 9.0 Hz, 1H), 3.34 (t,J
= 8.7 Hz, 2H), 2.57 (s, 3H)。
實例24
合成8-(6-環丙基吡啶-3-基)-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-1-(甲基磺醯基)咪唑并[1,5-a]吡啶-6-甲腈(第E 26號化合物)
使5-溴-6-甲基-2-側氧基-1,2-二氫吡啶-3-甲腈(E 26.1,120 mg,0.55 mmol)及DIPEA (145 mg,1.14 mmol)於POCl3
(2.0 ml)中之混合物回流3小時。真空蒸發所得棕色混合物,且添加10 ml EtOAc及5 ml NaHCO3
水溶液。將混合物用EtOAc (20 ml ×3)萃取,乾燥(Na2
SO4
),過濾且濃縮。藉由急驟層析(矽膠,用PE/EA = 1/3 ~ 1/5溶離)純化殘餘物,得到呈白色固體狀之E 26.2 (70 mg, 54%產率)。LC-MS: [M+H]+ = 230.1。
在室溫下,向5-溴-2-氯-6-甲基菸鹼腈(4.46 g,19.4 mmol)及NBS (3.79 mg,21.3 mmol)於CCl4
(80 ml)中之溶液中添加BPO (469 mg,1.94 mmol)。將所得混合物脫氣且在80℃下在氮氣下攪拌4小時。過濾反應混合物,用鹽水洗滌,乾燥(Na2
SO4
),過濾且濃縮。藉由矽膠管柱層析(用10% EtOAc/石油醚溶離)純化粗產物,得到呈黃色油狀之5-溴-6-(溴甲基)-2-氯菸鹼腈(E 26.3) (4.1 g,74%)。LC-MS: [M+H]+ = 308.83。
向5-溴-6-(溴甲基)-2-氯菸鹼腈(4.46 g,14.5 mmol)於DMF (50 ml)中之溶液中添加NaN3
(1.89 g,29 mmol)。將混合物在室溫下攪拌2小時,倒入水中,且用EtOAc (30 ml × 3)萃取。用鹽水洗滌合併之有機層,乾燥(Na2
SO4
),過濾且濃縮,得到呈黃色油狀之6-(疊氮基甲基)-5-溴-2-氯菸鹼腈(3.4 g,產率:87%),其直接用於下一步驟。LC-MS: [M+H]+ = 271.92。
向6-(疊氮基甲基)-5-溴-2-氯菸鹼腈(3.4 g,12.6 mmol)於THF (50 ml)及H2
O (5 ml)中之溶液中添加PPh3
(4.93 g,18.9 mmol)。將所得混合物在50℃下加熱1小時,且濃縮。將殘餘物溶解於50 ml HCl水溶液中,且用DCM (20 ml × 2)洗滌。藉由添加NaOH水溶液將水層鹼化至pH~8,且用EtOAc (30 ml × 3)萃取。將有機層乾燥(Na2
SO4
),過濾且濃縮,得到呈黃色油狀之所需產物6-(胺基甲基)-5-溴-2-氯菸鹼腈(2.28 g,74%)。LC-MS: [M+H]+ = 245.93。
向6-(胺基甲基)-5-溴-2-氯菸鹼腈(2.25 g,9.3 mmol)於甲酸乙酯(40 ml)中之溶液中添加NaHCO3
(391 mg,4.6 mmol)。將混合物在室溫下攪拌24小時且過濾。濃縮濾液,得到呈棕色油狀之所需化合物(2.1 g,90%),其直接用於下一步驟。LC-MS: [M+H]+ = 273.93。
向粗化合物於二噁烷(30 ml)中之溶液中添加POCl3
(2.59 g,16.8 mmol)。使混合物回流3小時。將反應混合物用NaHCO3
水溶液淬滅且用EtOAc (30 × 3)萃取。有機層用鹽水洗滌,乾燥(Na2
SO4
),過濾且濃縮。藉由矽膠管柱層析(10% EtOAc/石油)純化粗物質,得到呈淡黃色固體狀之所需化合物(E.26.6) (1.6 g,83%)。LC-MS: [M+H]+ = 255.91。
將8-溴-5-氯咪唑并[1,5-a]吡啶-6-甲腈(60 mg,0.24 mmol)、(6-環丙基吡啶-3-基)硼酸(50 mg,0.31 mmol)、Pd(dppf)Cl2
(12 mg,0.015 mmol)及Na2
CO3
(81 mg,0.77 mmol)於H2
O (0.5 ml)及二噁烷(1.5 ml)中之混合物在110℃下在N2
下加熱1小時。將反應混合物過濾且濃縮。藉由製備型HPLC純化粗產物,得到5-氯-8-(6-環丙基吡啶-3-基)咪唑并[1,5-a]吡啶-6-甲腈(E 26.7,74 mg,產率:90%)。LC-MS: [M+H]+ = 295.06。
在室溫下,向5-氯-8-(6-環丙基吡啶-3-基)咪唑并[1,5-a]吡啶-6-甲腈(38 mg,0.13 mmol)及(5-氟-2,3-二氫苯并呋喃-4-基)甲胺(65 mg,0.39 mmol)於NMP (0.5 ml)中之溶液中添加三乙胺(39 mg,0.39 mmol)。藉由微波將所得溶液在130℃下加熱1小時。濃縮反應混合物且藉由矽膠管柱層析(用PE:EA = 1:1溶離)純化,得到黃色固體(E 26.8,66%)。LC-MS (m/z): 426.16 [M+H]+。
在0℃下,向N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-8-苯基咪唑并[1,5-c]嘧啶-5-胺(500 mg,1.38 mmol)於DMF (10 ml)中之溶液中添加NIS (278 mg,1.24 mmol)。將混合物在室溫下攪拌15分鐘。將混合物用DCM (4 × 50 ml)萃取,用鹽水(30 ml)洗滌,乾燥(Na2
SO4
)且過濾。濃縮濾液,且藉由管柱層析(矽膠,用20-50% EtOAc/己烷溶離)純化殘餘物,得到呈黃色固體狀之標題化合物(E 26.9) (610 mg,1.26 mmol,70%)。LC-MS: [M+H]+ = 552.06。
將化合物E 26.9 (50 mg,0.09 mmol)、MeSO2
Na (30 mg.0.3 mmol)及CuI (57 mg,0.3 mmol)於DMSO (2 ml)中之混合物用N2
鼓泡5分鐘,隨後將密封管在微波反應器中在120℃下加熱20分鐘,且隨後在100℃下加熱3小時。濃縮混合物,且藉由HPLC純化殘餘物,以50%之產率得到第E 26號化合物(25 mg,0.05 mmol)。LC-MS: [M+H]+ = 504.14。
實例25
合成N-((5-氟-2,3-二氫苯并呋喃-4-基)甲基)-5-甲基-8-(三氟甲基)-6H-2,3,5a,9,12,13a-六氮雜苯并[4,5]環戊并[7,8]環辛并[1,2,3-cd]茚-13-胺(第E 10號化合物)
向配備有攪拌棒、冷凝器及氮氣入口之500 ml圓底燒瓶中裝入38.9 g (144 mmol) 5-溴-2-三氟甲基-異菸鹼酸(E 10.1)。向固體中添加250 ml無水DCM,隨後添加13.2 ml (151 mmol,1.05 eq.)乙二醯氯。向混合物中添加0.5 ml無水DMF,且將混合物在環境溫度下攪拌2小時。真空移除溶劑。在冰浴中向配備有攪拌棒之1公升錐形瓶中裝入500 ml NH4
OH水溶液。向冷卻的溶液中逐滴添加粗醯氯。殘餘物用少量乙腈轉移。添加後將混合物攪拌20分鐘。藉由過濾收集所得沈澱物且用水洗滌。濾餅在45℃下真空乾燥,得到呈灰白色固體狀之5-溴-2-三氟甲基-異菸鹼醯胺(E 10.2,118 mmol,31.52 g,82%產率)。LC-MS [M+H]+ = 269.95。
向配備有攪拌棒、冷凝器及氮氣入口之100 mL圓底中裝入5.2 g (19.3 mmol) 5-溴-2-三氟甲基異菸鹼醯胺(E 10.2)。用12 ml POCl3
稀釋固體。將混合物在70℃下加熱3小時。將混合物冷卻至室溫,且倒於冰上。藉由小心添加50%氫氧化鈉中和混合物。藉由過濾收集所得灰白色固體,用水洗滌且在50℃下真空乾燥18小時。由此以94%之產率得到4.5 g呈灰白色固體狀之5-溴-2-三氟甲基-異菸鹼腈(E 10.3,4.53 g,18.1 mmol)。LC-MS [M+H]+ = 250.95。1
H NMR (CDCl3
): δ, 9.03 (s, 1H), 7.91 (s, 1H)。
將NaBH4
(0.66 g,14.81mmol)裝入100 ml燒瓶中,隨後裝入20 ml無水THF。將混合物在冰水浴中冷卻。在該溫度下將TFA (1.5 ml)添加至THF (4 ml)中0.5小時。移除冰水浴,且將所得混合物在室溫下攪拌2小時。將5-溴-2-(三氟甲基)異菸鹼腈(E 10.3,2 gm,8.0 mmol)溶解於THF (10 ml)中。再次在冰水浴中冷卻TFA/NaBH4
混合物,且經0.5小時添加腈溶液。使混合物達到環境溫度,同時攪拌16小時。對等分試樣之LC分析顯示反應完成。將混合物在冰浴中冷卻,且緩慢添加10 ml甲醇。真空移除揮發物且添加乙酸乙酯(50 ml)。用水(10 ml)洗滌此混合物。將水層用乙酸乙酯(10 ml)洗滌,且將合併之有機層用鹽水(10 ml)洗滌,經Na2
SO4
乾燥,過濾且濃縮。藉由逆相combi flash (用1-20%乙腈/H2
O溶離)純化殘餘物,得到呈無色液體狀之標題化合物(E 10.4,1.6 g,80%)。LC-MS [M+H]+ = 254.96。
將化合物(E 10.4,512 mg,2 mmol)在室溫下與(Boc)2
O (0.51 g,2.4 mmol,1.2 eq.)及Et3
N (2 eq.,4 mmol,380 mg)在20 ml DCM中攪拌3小時。藉由管柱層析使用0-50% EtOAc/己烷純化殘餘物,得到所需化合物(E 10.5,560 mg),總產率為80%。LC-MS [M+H]+ = 355.16。
將乙酸鈀(II) (0.1 eq.)及cataCXium A (0.2 eq.)在DME (0.5 ml,脫氣)中混合在一起,且在70℃下,經由移液管將所得溶液添加至8-溴-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(1 eq.)、二級胺E 10.5 (2 eq.)、雙頻哪醇根基二硼(2.0 eq.)及K2
CO3
(4.0 eq.)於DME/H2
O (10:1,10 ml,脫氣)中之混合物中。將反應混合物攪拌12小時。將反應混合物濃縮且用乙酸乙酯(2 × 50 ml)萃取,用水及鹽水洗滌,且隨後經Na2
SO4
乾燥。濃縮混合物且藉由HPLC純化殘餘物,以50%之產率得到E 10.6。LC-MS: [M+H]+ = 631.22
將化合物E 10.6 (1 eq.)及LiOH (10 eq.)於THF (10 ml/mmol)及水(5 ml/mmol)中之混合物在70℃下加熱隔夜。濃縮混合物,且隨後藉由製備型HPLC純化殘餘物,以80%之產率得到E 10.7。LC-MS: [M+H]+ = 603.19。
在250 ml圓底燒瓶中,將E 10.7 (3.29 g,5.47 mmol)及丙-2-炔-1-胺(0.601 g,10.94 mmol)於DMF (15 mL)中之攪拌溶液在室溫下在氮氣氛圍下依序用EDCI.HCl (2.28 g,11.94 mmol)、HOBt (1.61 g,11.93 mmol)及Et3
N (2.03 ml,14.92 mmol)處理。將反應混合物在室溫下在氮氣氛圍下攪拌12小時。反應完成後(TLC),將反應混合物用冰冷的水稀釋。濃縮混合物,且隨後藉由製備型HPLC純化殘餘物,以80%之產率得到E 10.8。LC-MS: [M+H]+ = 640.22
在室溫下將化合物E 10.8用25% TFA/DCM處理1小時,且真空移除揮發物。將粗產物用乙酸乙酯稀釋,用飽和Na2
CO3
水溶液及鹽水洗滌。有機層經Na2
SO4
乾燥且真空濃縮,得到化合物E 10.9,其作為粗物質用於下一步驟。LC-MS: [M+H]+ = 540.22。
在20 ml微波小瓶中,將化合物E 10.9 (0.22 g,0.42 mmol)及(2-甲氧基苯基)甲胺(0.086 g,0.63 mmol)於甲苯(5 mL)中之溶液在室溫下在氮氣氛圍下用Zn(OTf)2
(0.009 g,0.021 mmol)處理。在140℃下對反應混合物進行微波輻射1小時。反應完成後(TLC),將反應混合物用水稀釋且用EtOAc (30 mL)萃取。將有機萃取物用飽和NaHCO3
及鹽水洗滌,且經無水Na2
SO4
乾燥。減壓濃縮溶液,且藉由製備型HPLC純化獲得之殘餘物,以40%之產率得到第E 10號化合物。LC-MS: [M+H]+ = 522.15。
實例26
合成12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(四氫-2H-哌喃-4-基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第E 45號化合物)
向5-溴-2-(四氫-2H
-哌喃-4-基)吡啶(5.00 g,20.65 mmol)於DCM (100 ml)中之溶液中緩慢地添加1.5 eqm
CPBA (5.35 g,30.97 mmol)。4小時後,將反應混合物用2.0 eq Ca(OH)2
(3.90 g,41.3 mmol)淬滅,且將所得沈澱物攪拌30分鐘。將沈澱物過濾且用3:1 DCM/甲醇洗滌。真空濃縮濾液,以粗製固體形式得到5-溴-2-(四氫-2H
-哌喃-4-基)吡啶1-氧化物,其未經進一步純化即用於後續反應。
向前一步驟獲得之粗物質5-溴-2-(四氫-2H
-哌喃-4-基)吡啶1-氧化物(4.00 g,15.63 mmol)於乙腈(78 ml,0.2 M)中之溶液中添加6.0 eq氰化三甲基矽烷(TMSCN) (9.48 g,94.00 mmol)及4.5 eq三乙胺(5.26 g,70.34 mmol)。將反應物在100℃下加熱隔夜。冷卻至室溫後,真空濃縮溶劑,且藉由HPLC (乙腈/H2
O,自25% ACN開始,在42% ACN/H2
O獲得化合物)純化殘餘物,得到3-溴-6-(四氫-2H-哌喃-4-基)吡啶甲腈(1.60 g,5.97 mmol,2步產率為29%)。LC-MS [M+H]+
= 266.97/268.96。1
H NMR (400 MHz, DMSO-d6
) δ 8.30 (d,J
= 8.4 Hz, 1H), 7.64 (d,J
= 8.4 Hz, 1H), 3.96 - 3.93 (m, 2H), 3.46 - 3.40 (m, 2H), 3.05 - 2.98 (m, 1H), 1.79 - 1.68 (m, 4H)。
將3-溴-6-(四氫-2H-哌喃-4-基)吡啶甲腈(1.60 g,5.97 mmol)溶解於50 ml無水DCM中且冷卻至-78℃。在攪拌溶液的同時,逐滴添加2 eq DIBAL-H之甲苯溶液(12 ml,11.94 mmol)。將混合物攪拌5小時,藉由緩慢添加飽和羅謝爾鹽(酒石酸鈉鉀)水溶液淬滅,升溫至室溫,用乙酸乙酯稀釋且攪拌,直至形成兩個易於分離之透明層。HPLC純化得到呈液體狀之(3-溴-6-(四氫-2H-哌喃-4-基)吡啶-2-基)甲胺(1.12 g,4.12 mmol,69%)。LC-MS [M+H]+
= 271.04/273.03。1
H NMR (400 MHz, DMSO-d6
) δ 8.29 (s, 寬峰, 2H), 8.07 (d,J
= 8.4 Hz, 1H), 7.29 (d,J
= 8.4 Hz, 1H), 4.53 - 4.22 (m, 2H), 3.48 - 3.42 (m, 2H), 3.00 - 2.93 (m, 1H), 1.91 - 1.69 (m, 4H)。
向(3-溴-6-(四氫-2H-哌喃-4-基)吡啶-2-基)甲胺(181 mg,0.67 mmol)於DCM (10 ml)中之溶液中添加2.0 eq 4-甲基苯磺酸2,2,2-三氟乙酯(311 mg,1.34 mmol)及2.0 eq DIPEA (173 mg,1.34 mmol)。3小時後,將反應混合物用TFA及H2
O淬滅,隨後HPLC純化,得到N-((3-溴-6-(四氫-2H-哌喃-4-基)吡啶-2-基)甲基)-2,2,2-三氟乙-1-胺。LC-MS: [M+H]+
= 354.01。
在經由凍乾冷凍乾燥之後,將化合物在室溫下與2 eq (Boc)2
O (292 mg,1.34 mmol)及3 eq Et3
N (2.01 mmol,203 mg)在4 ml DCM中攪拌5小時。完成後,藉由combi-flash管柱層析使用0-100% EtOAc/己烷純化殘餘物,得到化合物((3-溴-6-(四氫-2H-哌喃-4-基)吡啶-2-基)甲基)(2,2,2-三氟乙基)胺基甲酸第三丁酯(85 mg,0.19 mmol,2步產率為28%)。LC-MS [M+H]+
= 454.07。
將乙酸鈀(II) (0.2 eq.)及cataCXium A (0.4 eq.)在DME (0.5 ml,脫氣)中混合在一起,且在70℃下,經由移液管將所得溶液添加至8-溴-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(1 eq.)、((3-溴-6-(四氫-2H-哌喃-4-基)吡啶-2-基)甲基)(2,2,2-三氟乙基)胺基甲酸第三丁酯(83 mg,0.18 mmol,1.2 eq.)、雙頻哪醇根基二硼(2 eq.)及K2
CO3
(5 eq.)於DME/H2
O (10:1,5.0 ml,脫氣)中之混合物中。將反應混合物攪拌隔夜。隨後,將其濃縮且用乙酸乙酯(2 × 30 ml)萃取,用水及鹽水洗滌,且經無水Na2
SO4
乾燥。濃縮混合物,隨後製備型HPLC純化,得到E-2211.1。LC-MS: [M+H]+ = 729.29。移除E-2211.1之Boc保護基,得到E-2211.2。LC-MS: [M+H]+ = 629.21。
將化合物E-2211.2 (1 eq.)及LiOH (10 eq.)於THF (10 ml/mmol)及水(5 ml/mmol)中之混合物在80℃下加熱隔夜。濃縮混合物,且隨後藉由製備型HPLC純化殘餘物,以50%之產率分3步得到E-2211.3。
向化合物E-2211.3 (1 eq.)及HATU (2 eq.)於DMF (5 ml/mmol)中之混合物中添加DIPEA (5 eq.)。使反應混合物攪拌2小時,且濃縮。藉由製備型HPLC純化殘餘物,以定量產率得到第E 45號化合物。LC-MS: [M+H]+ = 583.09。1
H NMR (400 MHz, DMSO-d6
) δ 8.83 (s, 1H), 8.68 (t,J
= 4.8 Hz, 1H), 7.90 (d,J
= 8.4 Hz, 1H), 7.54 (s, 1H), 7.43 (d,J
= 8.4 Hz, 1H), 6.95 (dd,J
= 9.6, 8.8 Hz, 1H), 6.72 (dd,J
= 8.8, 4.0 Hz, 1H), 5.47 (d, J = 14.8 Hz, 1H), 4.74 (d,J
= 4.8 Hz, 2H), 4.70 - 4.63 (m, 1H), 4.55 (t,J
= 8.8 Hz, 2H), 4.16 (d,J
= 14.8 Hz, 1H), 4.07-4.03 (m, 4H), 3.45-3.51 (m, 2H), 3.33 (t,J
= 8.4 Hz, 2H), 2.97-3.05 (m, 1H), 1.75-1.84 (m, 4H)。
實例27
合成7-(第三丁基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第E 46號化合物)
將H2
SO4
(0.5 mL,9.69 mmol,1.0 eq.)添加至5-溴-2-(第三丁基)異菸鹼酸(2.5 g,9.69 mmol,1.0 eq.)於MeOH (25 ml)中之溶液中。將所得溶液在回流下攪拌14小時。將混合物冷卻至室溫且真空濃縮。將殘餘物溶解於乙酸乙酯(50 ml)中,用水及飽和NaCl水溶液(2 × 50 ml)洗滌,經無水Na2
SO4
乾燥,且真空濃縮。殘餘物藉由矽膠管柱層析純化,用EtOAc/己烷溶離,得到5-溴-2-(第三丁基)異菸鹼酸甲酯。
在-78℃下,向5-溴-2-(第三丁基)異菸鹼酸甲酯於DCM (50 ml)中之溶液中逐滴添加DIBAL-H (18 ml,18.90 mmol,1.05 M於甲苯中)。將反應混合物維持在-78℃至-15℃下30分鐘,隨後升溫至室溫且再攪拌12小時。將反應混合物冷卻至0℃,且用飽和NH4
Cl水溶液(50 ml)淬滅。所得混合物用DCM (3 × 250 ml)萃取,用鹽水(150 ml)洗滌,經無水(Na2
SO4
)乾燥,過濾且濃縮。殘餘物藉由矽膠管柱層析純化,用EtOAc/己烷溶離,得到(5-溴-2-(第三丁基)吡啶-4-基)甲醇(1.78 g,7.28 mmol,75%,分2步)。LC-MS [M+H]+ = 243.98/245.99。
將(5-溴-2-(第三丁基)吡啶-4-基)甲醇(1.78 g,7.28 mmol)之等分試樣溶解於無水DCM (~0.2 M)中,隨後向此溶液中添加1.3 eq. Dess-Martin高碘烷(4.11 g,9.46 mmol),且使反應混合物攪拌1小時,經由TLC監測。完成後,用飽和NH4
Cl溶液淬滅,隨後用DCM萃取。收集有機層且合併,用鹽水洗滌,經無水Na2
SO4
乾燥,且真空濃縮。在矽膠正相管柱層析上用增加量的乙酸乙酯/己烷進行純化,得到所需5-溴-2-(第三丁基)異菸鹼醛。
在冰浴下,向5-溴-2-(第三丁基)異菸鹼醛中添加甲醇(~0.2 M),隨後添加2.2 eq. 2,2,2-三氟乙-1-胺、2 eq. Na(CN)BH3
及2 eq.乙酸。移除冰浴且使反應混合物攪拌3小時,經由TLC監測。完成後,濃縮反應混合物,且藉由HPLC純化殘餘物,得到N-((5-溴-2-(第三丁基)吡啶-4-基)甲基)-2,2,2-三氟乙-1-胺(800 mg,2.27 mmol,31%,分2步)。LC-MS: [M+H]+ = 324.89/326.86。
將乙酸鈀(II) (0.1 eq.)及cataCXium A (0.2 eq.)在DME (0.5 ml,脫氣)中混合在一起,且在70℃下,經由移液管將所得溶液添加至8-溴-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(1 eq.)、N-((5-溴-2-(第三丁基)吡啶-4-基)甲基)-2,2,2-三氟乙-1-胺(2 eq.)、雙頻哪醇根基二硼(2 eq.)及K2
CO3
(5 eq.)於DME/H2
O (10:1,22 ml,脫氣)中之混合物中。將反應混合物攪拌隔夜。將反應混合物濃縮且用乙酸乙酯(2 × 50 ml)萃取,用水及鹽水洗滌,且經Na2
SO4
乾燥。濃縮混合物且藉由HPLC純化殘餘物,以~15%之產率得到E-2189.1。LC-MS: [M+H]+ = 601.20。
將化合物E-2189.1 (1 eq.)及LiOH (10 eq.)於THF (10 ml/mmol)及水(5 ml/mmol)中之混合物在80℃下加熱隔夜。濃縮混合物,且藉由製備型HPLC純化殘餘物,以~5:1之比率得到E-2189.2及第E 46號化合物。LC-MS: [M+H]+ = 573.15。
向化合物E-2189.2 (1 eq.)及HATU (2 eq.)於DMF (5 ml/mmol)中之混合物中添加DIPEA (5 eq.)。使反應混合物攪拌2小時。濃縮反應混合物,且藉由製備型HPLC純化殘餘物,以~90%之組合產率得到第E 46號化合物。LC-MS: [M+H]+ = 555.10。1
H NMR (400 MHz, DMSO-d6
) δ 8.85 (s, 1H), 8.72 (t, 1H), 8.65 (d,J
= 2.4, 1H), 7.91 (d,J
= 7.8 Hz, 1H), 7.58 (d,J
= 1.6 Hz, 1H), 6.96 (t,J
= 8.8 Hz, 1H), 6.71 (dd,J
= 8.8, 4.0 Hz, 1H), 5.34 (d,J
= 14.8 Hz, 1H), 4.75 (d,J
= 4.0 Hz, 2H), 4.56 (t,J
= 8.8 Hz, 2H), 4.29 (d, J = 14.8 Hz, 1H), 4.06 - 4.12 (m, 1H), 3.34 (t, J = 8.8 Hz, 2H),1.40 (s, 9H)。
實例28
合成4-(2,2-二氟乙基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-異丙基-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第E 47號化合物)
向5-溴-2-異丙基吡啶(1.00 g,5.00 mmol)於DCM (20 ml)中之溶液中添加1.5 eqm
CPBA。4小時後,將反應混合物用2.0 eq Ca(OH)2
淬滅,且將所得沈澱物攪拌30分鐘。將沈澱物過濾且用3:1 DCM/甲醇洗滌。真空濃縮濾液,以粗製固體形式得到5-溴-2-異丙基吡啶1-氧化物,其未經進一步純化即用於後續反應。
向前一步驟獲得之粗物質5-溴-2-異丙基吡啶1-氧化物於乙腈中之溶液(20 ml,0.2 M)中添加6.0 eq氰化三甲基矽烷(TMSCN)及4.5 eq三乙胺。將反應物在100℃下加熱隔夜。冷卻至室溫後,真空濃縮溶劑,且藉由製備型HPLC純化殘餘物,得到3-溴-6-異丙基吡啶甲腈(443 mg,1.97 mmol,2步產率為39%)。LC-MS [M+H]+ = 225.01/227.03。
將3-溴-6-異丙基吡啶甲腈(443 mg,1.97 mmol)溶解於10 ml無水DCM中且冷卻至-78℃。在攪拌溶液的同時,逐滴添加2 eq DIBAL-H溶液。將混合物攪拌5小時,隨後藉由緩慢添加飽和羅謝爾鹽(酒石酸鈉鉀)水溶液淬滅。使反應混合物溫熱,用乙酸乙酯稀釋,且攪拌直至形成兩個可容易分離之透明層。HPLC純化,得到呈液體狀之(3-溴-6-異丙基吡啶-2-基)甲胺。LC-MS [M+H]+ = 229.01/230.97。1
H NMR (400 MHz, DMSO-d6
) δ 8.34 (s, 寬峰, 2H), 8.04 (d,J
= 8.4 Hz, 1H), 7.28 (d,J
= 8.4 Hz, 1H), 4.24 - 4.23 (m, 2H), 3.33 - 3.02 (m, 1H), 1.26 (d,J
= 6.8 Hz, 6H)。
向(3-溴-6-異丙基吡啶-2-基)甲胺(107 mg,0.47 mmol)於DCM (10 ml)中之溶液中添加2.0 eq 4-甲基苯磺酸2,2-二氟乙酯(200 mg,0.94 mmol)及2.0 eq DIPEA。3小時後,將反應混合物用TFA及H2
O淬滅。HPLC純化得到N-((3-溴-6-異丙基吡啶-2-基)甲基)-2,2-二氟乙-1-胺。LC-MS [M+H]+ = 293.04/285.09。
在經由凍乾冷凍乾燥之後,將N-((3-溴-6-異丙基吡啶-2-基)甲基)-2,2-二氟乙-1-胺(103 mg,0.35 mmol)在室溫下與2 eq (Boc)2
O (153 mg,0.70 mmol)及3 eq Et3
N (203 mg,1.05 mmol)在3 ml無水DCM攪拌5小時。完成後,藉由combi-flush管柱層析使用0-100% EtOAc/己烷純化殘餘物,得到((3-溴-6-異丙基吡啶-2-基)甲基)(2,2-二氟乙基)胺基甲酸第三丁酯(52 mg,0.13 mmol,2步產率為28%)。
將乙酸鈀(II) (0.2 eq.)及cataCXium A (0.4 eq.)在DME (0.5 ml,脫氣)中混合在一起,且在70℃下,經由移液管將所得溶液添加至8-溴-5-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)咪唑并[1,5-c]嘧啶-1-甲酸乙酯(1 eq.)、((3-溴-6-異丙基吡啶-2-基)甲基)(2,2-二氟乙基)胺基甲酸第三丁酯(52 mg,0.13 mmol,1.2 eq.)、雙頻哪醇根基二硼(2.0 eq.)及K2
CO3
(5.0 eq.)於DME/H2
O (10:1,4.0 ml,脫氣)中之混合物中。將反應混合物攪拌隔夜。隨後,將其濃縮且用乙酸乙酯(2 × 30 ml)萃取,用水及鹽水洗滌,且經Na2
SO4
乾燥。將混合物濃縮且藉由HPLC純化,得到E-2206.1。LC-MS: [M+H]+ = 669.33。移除E-2206.1之Boc保護基,得到E-2206.2。LC-MS: [M+H]+ = 569.17。
將E-2206.2 (1 eq.)及LiOH (10 eq.)於THF (10 ml/mmol)及水(5 ml/mmol)中之混合物在80℃下加熱隔夜。濃縮混合物,且隨後藉由製備型HPLC純化殘餘物,得到E-2206.3。LC-MS: [M+H]+ = 541.10。
向E-2206.3 (1 eq.)及HATU (2 eq.)於DMF (3 ml/mmol)中之混合物中添加DIPEA (5 eq.)。使反應混合物攪拌2小時,且濃縮。藉由製備型HPLC純化殘餘物,以定量產率得到第E 47號化合物。LC-MS: [M+H]+ = 523.15。1
H NMR (400 MHz, DMSO-d6
) δ 8.80 (s, 1H), 8.63 (t, 1H), 7.85 (d,J
= 8.0 Hz, 1H), 7.49 (s, 1H), 7.37 (d,J
= 8.0 Hz, 1H), 6.94 (dd,J
= 9.6, 8.8 Hz, 1H), 6.70 (dd,J
= 8.8, 4.0 Hz, 1H), 6.29 (t,J
= 57.2 Hz, 1H), 5.40 (d,J
= 8.4 Hz, 1H), 4.72 (d,J
= 3.6 Hz, 2H), 4.54 (t,J
= 8.8 Hz, 2H), 4.14 (d,J
= 14.8 Hz, 1H), 4.09 - 4.03 (m, 1H), 3.75 - 3.33 (m, 1H), 3.33 (t,J
= 8.8 Hz, 2H), 3.10 - 3.03 (m, 2H), 1.29 - 1.22 (m, 6H)。
實例29
合成7-(1,4-二氧雜環己烷-2-基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第E 48號化合物)
第E 48號化合物可使用以上實例中所述之方法,以5-溴-2-(1,4-二氧雜環己烷-2-基)吡啶為起始物質來製備。
實例30
合成7-((1,4-二氧雜環己烷-2-基)甲基)-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-4,5-二氫-3H-2,4,6,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮(第E 49號化合物)
第E 49號化合物可使用以上實例中所述之方法,以2-((1,4-二氧雜環己烷-2-基)甲基)-5-溴吡啶為起始物質來製備。
實例31
化合物表徵
表2之化合物使用實例1-17中所述,參見例如「合成方法」行且此項技術中已知的方法來製備。所有化合物均以TFA鹽形式藉由質譜分析及/或1
H NMR來表徵。
表2
實例27
生物分析
化合物編號 | 1 H NMR (400 MHz)/ LC-MS 資料 | 合成方法 |
1 | LC-MS: [M+H]+ = 376.14 | 實例5 |
2 | LC-MS: [M+H]+ = 404.14 | 實例5 |
3 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.50 (s, 1H), 8.67 (s, 1H), 8.53 (t, J = 5.1 Hz, 1H), 7.99 (s, 1H), 7.88 - 7.80 (m, 1H), 7.19 (dd, J = 6.1, 1.6 Hz, 2H), 7.02 (ddd, J = 8.3, 6.1, 2.4 Hz, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 4.73 (d, J = 4.8 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.31 (d, J = 8.5 Hz, 2H)。 LC-MS: [M+H]+ = 402.12 | 實例3 |
4 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.26 (s, 1H), 8.69 (s, 1H), 8.66 (t, J = 5.1 Hz, 1H), 8.32 (dd, J = 8.1, 1.7 Hz, 1H), 8.19 (dd, J = 4.5, 1.6 Hz, 1H), 8.06 (s, 1H), 7.09 (dd, J = 8.0, 4.6 Hz, 1H), 6.96 (dd, J = 10.4, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 4.73 (d, J = 4.9 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.31 (d, J = 8.5 Hz, 2H)。 LC-MS: [M+H]+ = 403.12 | 實例3 |
5 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.77 (s, 1H), 8.76 (t, J = 5.1 Hz, 1H), 8.70 (s, 1H), 8.15 - 8.01 (m, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.47 (dd, J = 8.5, 2.0 Hz, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 4.74 (d, J = 5.0 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.36 (t, J = 8.7 Hz, 2H), 3.21 (s, 3H)。 LC-MS: [M+H]+ = 480.11 | 實例3 |
6 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.87 (s, 1H), 8.73 (t, J = 5.1 Hz, 1H), 7.68 (s, 1H), 7.60 - 7.51 (m, 2H), 7.48 (qd, J = 7.5, 1.7 Hz, 1H), 6.97 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 5.78 (d, J = 12.4 Hz, 1H), 5.04 (d, J = 12.5 Hz, 1H), 4.76 (d, J = 4.8 Hz, 2H), 4.57 (t, J = 8.7 Hz, 2H), 3.36 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 417.13 | 實例1 |
7 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.87 (s, 1H), 8.74 (t, J = 5.1 Hz, 1H), 7.66 (s, 1H), 7.62 (dd, J = 8.7, 5.6 Hz, 1H), 7.48 (dd, J = 9.2, 2.8 Hz, 1H), 7.38 (td, J = 8.6, 2.8 Hz, 1H), 7.02 - 6.91 (m, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 5.76 (d, J = 12.5 Hz, 1H), 5.03 (d, J = 12.5 Hz, 1H), 4.76 (d, J = 4.8 Hz, 2H), 4.57 (t, J = 8.8 Hz, 2H), 3.35 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 435.12 | 實例1 |
8 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.88 (d, J = 9.5 Hz, 2H), 7.98 (d, J = 1.8 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.79 (d, J = 14.4 Hz, 2H), 6.97 (t, J = 9.5 Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 5.87 (d, J = 12.5 Hz, 1H), 5.20 (d, J = 12.7 Hz, 1H), 4.78 (d, J = 4.8 Hz, 2H), 4.57 (t, J = 8.7 Hz, 2H), 3.36 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 485.12 | 實例1 |
9 | LC-MS: [M+H]+ = 417.12 | 實例1 |
10 | LC-MS: [M+H]+ = 416.10 | 實例1 |
11 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.89 (s, 1H), 8.81 (t, J = 5.1 Hz, 1H), 7.75 (s, 1H), 7.57 (td, J = 8.1, 6.0 Hz, 1H), 7.42 (dd, J = 8.0, 1.1 Hz, 1H), 7.35 (ddd, J = 9.4, 8.2, 1.1 Hz, 1H), 6.97 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 5.67 (dd, J = 12.9, 2.6 Hz, 1H), 5.29 (d, J = 13.1 Hz, 1H), 4.86 - 4.66 (m, 2H), 4.57 (t, J = 8.8 Hz, 2H), 3.36 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 435.12 | 實例1 |
13 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.98 (d, J = 2.7 Hz, 2H), 8.92 (s, 1H), 8.16 (s, 1H), 7.92 (s, 1H), 6.97 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 5.91 (brs, 1H), 5.22 (brs, 1H), 4.79 (d, J = 4.8 Hz, 2H), 4.57 (t, J = 8.7 Hz, 2H), 3.36 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 486.11 | 實例1 |
14 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.00 (d, J = 5.1 Hz, 1H), 8.92 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 8.05 (d, J = 8.3 Hz, 1H), 7.83 (s, 1H), 6.97 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 6.12 - 5.96 (m, 1H), 5.06 (d, J = 12.6 Hz, 1H), 4.78 (d, J = 4.9 Hz, 2H), 4.57 (t, J = 8.8 Hz, 2H), 3.36 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 486.11 | 實例1 |
15 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.79 (s, 1H), 8.53 (t, J = 5.1 Hz, 1H), 8.24 (t, J = 7.4 Hz, 1H), 7.53 - 7.35 (m, 4H), 7.33 - 7.24 (m, 1H), 7.03 - 6.90 (m, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 4.83 - 4.70 (m, 3H), 4.57 (t, J = 8.8 Hz, 2H), 4.03 (dd, J = 14.2, 5.7 Hz, 1H), 3.35 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 416.14 | 實例2 |
17 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.79 (s, 1H), 8.57 (t, J = 5.1 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 7.50 (dd, J = 8.6, 5.7 Hz, 1H), 7.41 (s, 1H), 7.24 (td, J = 8.6, 2.7 Hz, 1H), 7.11 (dd, J = 9.2, 2.8 Hz, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.7, 3.8 Hz, 1H), 4.77-4.33 (m, 3H), 4.56 (t, J = 8.7 Hz, 2H), 3.97 (dd, J = 14.6, 5.4 Hz, 1H), 3.35 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 434.14 | 實例2 |
18 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.90 (s, 1H), 8.85 (t, J = 5.1 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 6.96 (t, J = 9.5 Hz, 1H), 6.72 (dd, J = 8.7, 3.8 Hz, 1H), 5.91 (d, J = 12.2 Hz, 1H), 4.95 (d, J = 12.1 Hz, 1H), 4.76 (d, J = 4.2 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.35 (t, J = 8.8 Hz, 2H), 2.57 (s, 3H)。 LC-MS: [M+H]+ = 432.14 | 實例1 |
19 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.82 (s, 1H), 8.69 (t, J = 5.1 Hz, 1H), 8.24 (dd, J = 8.8, 5.7 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.71 - 7.59 (m, 1H), 7.52 (s, 1H), 6.96 (t, J = 9.5 Hz, 1H), 6.72 (dd, J = 8.6, 3.8 Hz, 1H), 4.86 (dd, J = 14.6, 8.8 Hz, 1H), 4.76 (d, J = 4.5 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 4.11 (dd, J = 14.7, 5.5 Hz, 1H), 3.35 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 484.13 | 實例2 |
20 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.84 (s, 1H), 8.64 (s, 1H), 8.49 (t, J = 7.2 Hz, 1H), 7.49 (s, 1H), 7.46 - 7.38 (m, 1H), 7.35 - 7.18 (m, 2H), 6.95 (t, J = 9.4 Hz, 1H), 6.71 (dd, J = 8.7, 3.8 Hz, 1H), 4.74 (s, 2H), 4.58 (dt, J = 17.7, 7.8 Hz, 3H), 4.31 (dd, J = 15.1, 5.8 Hz, 1H), 3.34 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 434.14 | 實例2 |
21 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.84 (s, 1H), 8.64 (d, J = 5.8 Hz, 1H), 8.40 (dd, J = 8.4, 6.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.49 - 7.39 (m, 2H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 4.95 (dd, J = 14.4, 8.5 Hz, 1H), 4.75 (d, J = 4.3 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.05 (dd, J = 14.4, 5.9 Hz, 1H), 3.34 (t, J = 8.7 Hz, 2H), 2.56 (s, 3H)。 LC-MS: [M+H]+ = 431.15 | 實例2 |
22 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.83 (s, 2H), 8.76 (t, J = 5.2 Hz, 1H), 8.23 (dd, J = 8.8, 5.7 Hz, 1H), 7.77 (s, 1H), 7.65 (s, 1H), 6.96 (t, J = 9.5 Hz, 1H), 6.72 (dd, J = 8.7, 3.8 Hz, 1H), 4.93 (dd, J = 14.5, 8.8 Hz, 1H), 4.77 (d, J = 4.8 Hz, 2H), 4.57 (t, J = 8.7 Hz, 2H), 4.17 (dd, J = 14.6, 5.6 Hz, 1H), 3.35 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 485.13 | 實例2 |
23 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.79 (s, 1H), 8.59 (t, J = 5.1 Hz, 1H), 8.21 (dd, J = 8.9, 5.6 Hz, 1H), 7.49 (s, 1H), 7.35 - 7.27 (m, 2H), 7.26 - 7.18 (m, 1H), 6.96 (dd, J = 10.3, 8.6 Hz, 1H), 6.71 (dd, J = 8.7, 3.9 Hz, 1H), 4.75 (q, J = 5.0 Hz, 3H), 4.56 (t, J = 8.8 Hz, 2H), 3.97 (dd, J = 14.7, 5.5 Hz, 1H), 3.35 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 434.14 | 實例2 |
24 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.90 (s, 1H), 8.85 (s, 1H), 7.88 (d, J = 1.7 Hz, 1H), 7.86 - 7.74 (m, 3H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 5.86 (d, J = 12.5 Hz, 1H), 5.15 (d, J = 12.4 Hz, 1H), 4.77 (d, J = 3.8 Hz, 2H), 4.57 (t, J = 8.8 Hz, 2H), 3.37 (dt, J = 9.0, 5.1 Hz, 2H)。 LC-MS: [M+H]+ = 485.12 | 實例1 |
25 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.84 (s, 1H), 8.77 (t, J = 5.1 Hz, 1H), 8.57 - 8.45 (m, 1H), 8.18 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 5.07 (dd, J = 14.4, 8.3 Hz, 1H), 4.77 (d, J = 4.8 Hz, 2H), 4.57 (t, J = 8.8 Hz, 2H), 4.10 (dd, J = 14.4, 6.0 Hz, 1H), 3.35 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 485.12 | 實例2 |
26 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.81 (s, 1H), 8.65 (t, J = 5.1 Hz, 1H), 8.28 (t, J = 7.0 Hz, 1H), 7.76 (dq, J = 3.7, 1.9 Hz, 2H), 7.60 - 7.43 (m, 2H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 4.85 (dd, J = 14.5, 8.8 Hz, 1H), 4.75 (d, J = 4.8 Hz, 2H), 4.57 (t, J = 8.8 Hz, 2H), 4.07 (dd, J = 14.6, 5.5 Hz, 1H), 3.36 (dd, J = 9.6, 7.5 Hz, 2H)。 LC-MS: [M+H]+ = 484.13 | 實例2 |
27 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.02 (t, J = 5.5 Hz, 1H), 8.90 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.86 (dd, J = 8.6, 2.0 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.74 (s, 1H), 6.96 (dd, J = 7.5, 1.6 Hz, 1H), 6.92 - 6.79 (m, 2H), 6.07 (s, 2H), 5.87 (d, J = 12.7 Hz, 1H), 5.20 (d, J = 12.6 Hz, 1H), 4.79 (d, J = 5.3 Hz, 2H)。 LC-MS: [M+H]+ = 469.10 | 實例1 |
28 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.92 (s, 1H), 8.53 (t, J = 4.3 Hz, 1H), 7.98 (s, 1H), 7.94 - 7.83 (m, 1H), 7.83 - 7.71 (m, 2H), 7.50 - 7.33 (m, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.89 (t, J = 8.9 Hz, 1H), 5.87 (d, J = 12.5 Hz, 1H), 5.20 (d, J = 12.4 Hz, 1H), 4.80 (s, 2H), 3.87 (d, J = 1.0 Hz, 3H)。 LC-MS: [M+H]+ = 473.11 | 實例1 |
29 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.05 (t, J = 5.2 Hz, 1H), 8.92 (s, 1H), 8.27 (d, J = 7.9 Hz, 1H), 8.07 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 6.97 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.7, 3.8 Hz, 1H), 5.95 (s, 1H), 5.23 (s, 1H), 4.81 (d, J = 5.0 Hz, 2H), 4.57 (t, J = 8.7 Hz, 2H), 3.36 (dd, J = 9.6, 7.5 Hz, 2H)。 LC-MS: [M+H]+ = 486.11 | 實例1 |
30 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.06 - 8.94 (m, 2H), 8.92 (s, 1H), 8.40 (dd, J = 2.1, 0.8 Hz, 1H), 7.87 (s, 1H), 6.95 (dd, J = 10.3, 8.6 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 6.05 (d, J = 12.2 Hz, 1H), 5.06 (d, J = 12.0 Hz, 1H), 4.86 - 4.67 (m, 2H), 4.57 (t, J = 8.7 Hz, 2H), 3.37 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 486.11 | 實例1 |
31 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.88 (s, 1H), 8.79 (t, J = 5.1 Hz, 1H), 7.71 (t, J = 4.3 Hz, 2H), 7.63 (dd, J = 2.6, 1.1 Hz, 1H), 7.52 (ddd, J = 8.7, 2.6, 1.1 Hz, 1H), 6.96 (dd, J = 10.3, 8.6 Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 5.80 (d, J = 12.5 Hz, 1H), 5.11 (d, J = 12.5 Hz, 1H), 4.77 (d, J = 4.5 Hz, 2H), 4.57 (t, J = 8.7 Hz, 2H), 3.36 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 501.11 | 流程1 |
32 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.08 (t, J = 5.1 Hz, 1H), 8.92 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.03 - 6.90 (m, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 5.95 (s, 1H), 5.26 (s, 1H), 4.79 (d, J = 4.9 Hz, 2H), 4.58 (t, J = 8.7 Hz, 2H), 3.37 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 486.11 | 實例1 |
33 | 1 H NMR (400 MHz, CDCl3 ) δ 9.35 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 6.66 (d, J = 9.2 Hz, 1H), 6.59 - 6.45 (m, 1H), 5.43 (d, J = 14.5 Hz, 1H), 4.81 (d, J = 6.1 Hz, 2H), 4.50 (t, J = 8.4 Hz, 2H), 4.24 (d, J = 14.4 Hz, 1H), 3.33 (t, J = 8.4 Hz, 2H), 3.16 (s, 3H)。 LC-MS: [M+H]+ = 499.14 | 實例4 |
34 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.84 (s, 1H), 8.74 (s, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 6.87 (t, J = 9.5 Hz, 1H), 6.66 (dd, J = 8.8, 3.7 Hz, 1H), 5.54 (d, J = 14.8 Hz, 1H), 4.81 (d, J = 6.1 Hz, 2H), 4.61 (t, J = 8.8 Hz, 2H), 4.28 (d, J = 14.8 Hz, 1H), 3.43 (t, J = 8.8 Hz, 2H), 3.16 (s, 3H)。 LC-MS: [M+H]+ = 499.14 | 實例4 |
35 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.78 (s, 1H), 8.14 (d,J = 8.1 Hz, 1H), 7.88 (d,J = 8.1 Hz, 1H), 7.65 (s, 1H), 6.87 (t,J = 9.4 Hz, 1H), 6.66 (d,J = 8.6 Hz, 1H), 5.54 (d,J = 16.3 Hz, 1H), 4.81 (d, J = 6.1 Hz, 2H), 4.61-4.53 (m, 3H), 4.01 (s, 1H), 3.74 (dq,J = 48.4, 11.0, 10.5 Hz, 5H), 3.60 - 3.45 (m, 2H), 3.42 (t,J = 9.1 Hz, 2H), 3.33-3.30 (m, 1H)。 LC-MS: [M+H]+ = 485.17 | 實例4 |
37 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.82 (t,J = 4.7 Hz, 2H), 7.95 (d,J = 4.3 Hz, 1H), 7.69 (s, 1H), 6.86 (t,J = 9.5 Hz, 1H), 6.71 - 6.58 (m, 1H), 5.47 (dd,J = 15.0, 9.3 Hz, 1H), 4.81 (d, J = 6.1 Hz, 2H), 4.68 - 4.49 (m, 3H), 4.09 - 3.76 (m, 4H), 3.76 - 3.47 (m, 4H), 3.41 (q,J = 8.6 Hz, 3H)。 LC-MS: [M+H]+ = 585.17 | 實例4 |
38 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.85 (s, 1H), 8.75 (s, 1H), 8.00 (s, 1H), 7.69 (s, 1H), 6.87 (t,J = 9.5 Hz, 1H), 6.66 (d,J = 8.9 Hz, 1H), 5.46 (d,J = 14.9 Hz, 1H), 4.81 (d, J = 6.1 Hz, 2H), 4.61 (t,J = 8.7 Hz, 2H), 4.32 (d,J = 15.0 Hz, 1H), 3.92 (dd,J = 13.7, 8.9 Hz, 1H), 3.58 (t,J = 11.7 Hz, 2H), 3.43 (t,J = 8.7 Hz, 2H), 3.11 (dd,J = 13.7, 5.7 Hz, 1H), 2.99 (dd,J = 29.9, 11.6 Hz, 2H), 2.90 (s, 3H), 2.23 (s, 1H), 2.07 (d,J = 14.4 Hz, 1H), 1.98 (d,J = 14.6 Hz, 1H), 1.64 (d,J = 14.1 Hz, 2H)。 LC-MS: [M+H]+ = 596.23 | 實例4 |
39 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.87 (t, J = 4.8 Hz, 1H), 8.83 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.82 (s, 1H), 6.95 (dd, J = 10.3, 8.6 Hz, 1H), 6.70 (dd, J = 8.7, 3.9 Hz, 1H), 5.39 (d, J = 15.0 Hz, 1H), 4.77 (d, J = 4.9 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.20 (d, J = 15.0 Hz, 1H), 3.33 (td, J = 8.5, 4.5 Hz, 2H), 2.98 (s, 3H)。 LC-MS: [M+H]+ = 499.14 | 實例4 |
40 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.89 (s, 1H), 8.85 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.86 - 7.79 (m, 2H), 6.94 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 5.34 (dd, J = 15.2, 6.4 Hz, 1H), 4.84 - 4.69 (m, 2H), 4.54 (t, J = 8.7 Hz, 2H), 4.35 (dd, J = 15.2, 10.1 Hz, 1H), 3.96 - 3.83 (m, 1H), 3.81 - 3.41 (m, 6H), 3.39 - 3.21 (m, 3H), 3.11 - 2.90 (m, 1H)。 LC-MS: [M+H]+ = 585.17 | 實例4 |
41 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.80 (s, 1H), 8.76 (t, J = 5.1 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.57 (s, 1H), 7.01 - 6.92 (m, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 5.38 (d, J = 14.8 Hz, 1H), 4.77 (d, J = 4.9 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.24 (d, J = 14.7 Hz, 1H), 3.42 (t, J = 8.7 Hz, 2H), 2.63 (tt, J = 7.4, 4.2 Hz, 1H), 0.99 (ddd, J = 10.9, 7.0, 5.1 Hz, 1H), 0.92 (ddt, J = 9.4, 7.1, 3.5 Hz, 1H), 0.81 - 0.74 (m, 1H), 0.72 - 0.64 (m, 1H)。 LC-MS: [M+H]+ = 525.15 | 實例4 |
42 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.76 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H), 6.86 (t, J = 9.5 Hz, 1H), 6.65 (dd, J = 8.5, 3.6 Hz, 1H), 5.57 (d, J = 14.7 Hz, 1H), 4.81 (d, J = 6.1 Hz, 2H), 4.59 (t, J = 8.7 Hz, 2H), 4.35 (d, J = 14.7 Hz, 1H), 3.81 (dd, J = 13.5, 8.5 Hz, 1H), 3.57 (d, J = 12.5 Hz, 2H), 3.52 - 3.37 (m, 3H), 2.97 (dd, J = 24.7, 12.5 Hz, 2H), 2.88 (s, 3H), 2.28 (brs, 1H), 1.98 (t, J = 13.7 Hz, 2H), 1.65 (t, J = 13.5 Hz, 2H)。 LC-MS: [M+H]+ = 596.23 | 實例4 |
43 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.82 (s, 1H), 8.76 (s, 1H), 7.99 (s, 1H), 7.67 (s, 1H), 6.89 - 6.79 (m, 1H), 6.63 (dd, J = 8.7, 3.8 Hz, 1H), 5.46 (d, J = 15.0 Hz, 1H), 4.86 (s, 2H), 4.82 (d, J = 14.9 Hz, 1H), 4.58 (td, J = 8.7, 1.2 Hz, 2H), 3.95 (d, J = 14.4 Hz, 1H), 3.49 (d, J = 14.5 Hz, 1H), 3.41 (t, J = 8.7 Hz, 2H), 0.91 (t, J = 2.4 Hz, 1H), 0.86 - 0.72 (m, 3H)。 LC-MS: [M+H]+ = 555.16 | 實例4 |
44 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.75 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.66 (s, 1H), 6.87 (t, J = 9.5 Hz, 1H), 6.66 (dd, J = 8.8, 3.8 Hz, 1H), 5.54 (d, J = 14.8 Hz, 1H), 4.86 (s, 2H), 4.82 (d, J = 14.9 Hz, 1H), 4.60 (t, J = 8.7 Hz, 2H), 4.15 (d, J = 14.1 Hz, 1H), 3.58 (d, J = 14.1 Hz, 1H), 3.42 (t, J = 8.7 Hz, 2H), 0.92 (s, 1H), 0.80 (dd, J = 17.3, 9.1 Hz, 3H)。 LC-MS: [M+H]+ = 555.16 | 實例4 |
45 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.83 (s, 1H), 8.77 (brs, 1H), 8.02 (s, 1H), 7.70 (s, 1H), 6.95 - 6.80 (m, 1H), 6.66 (dd, J = 8.7, 3.9 Hz, 1H), 5.45 (d, J = 14.8 Hz, 1H), 4.60 (t, J = 8.8 Hz, 2H), 4.39 (d, J = 15.0 Hz, 1H), 3.96 (s, 2H), 3.85 (s, 1H), 3.56 - 3.35 (m, 4H), 3.42 (m, 2H), 3.15 -3.10 (m, 1H), 2.32 - 2.22 (m, 1H), 1.57 (dd, J = 24.7, 12.9 Hz, 2H), 1.49 - 1.26 (m, 2H)。 LC-MS: [M+H]+ = 583.20 | 實例4 |
46 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.74 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.65 (s, 1H), 6.86 (t, J = 9.5 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H), 5.56 (d, J = 14.7 Hz, 1H), 4.60 (t, J = 8.7 Hz, 2H), 4.37 (d, J = 14.9 Hz, 1H), 3.94 (d, J = 11.1 Hz, 2H), 3.69 (d, J = 13.7 Hz, 1H), 3.56 - 3.35 (m, 4H), 3.42 (t, J = 8.7 Hz, 2H), 3.34-3.30 (m, 1H), 2.32 - 2.22 (m, 1H), 1.57 (dd, J = 24.7, 12.9 Hz, 2H), 1.49 - 1.26 (m, 2H)。 LC-MS: [M+H]+ = 583.20 | 實例4 |
47 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.74 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H), 6.87 (dd, J = 10.3, 8.7 Hz, 1H), 6.66 (dd, J = 8.7, 3.9 Hz, 1H), 5.52 (d, J = 14.6 Hz, 1H), 4.85 (s, 2H), 4.67 - 4.46 (m, 2H), 4.35 (d, J = 14.6 Hz, 1H), 3.91 (dd, J = 13.4, 6.9 Hz, 1H), 3.57 (dd, J = 13.4, 7.4 Hz, 1H), 3.42 (t, J = 8.7 Hz, 2H), 2.44 - 2.21 (m, 1H), 2.11 (ddt, J = 11.9, 7.6, 4.0 Hz, 2H), 1.98 (q, J = 11.4 Hz, 2H), 1.32 (s, 3H)。 LC-MS: [M+H]+ = 583.20 | 實例4 |
48 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.83 (s, 1H), 8.75 (s, 1H), 8.05 (s, 1H), 7.69 (s, 1H), 6.93 - 6.81 (m, 1H), 6.66 (dd, J = 8.7, 3.9 Hz, 1H), 5.42 (d, J = 14.9 Hz, 1H), 4.84 (d, J = 1.0 Hz, 2H), 4.65 - 4.52 (m, 2H), 4.08 (d, J = 14.2 Hz, 1H), 3.42 (t, J = 8.7 Hz, 2H), 3.08 (d, J = 14.2 Hz, 1H), 2.68 (s, 1H), 1.42 - 1.18 (m, 6H)。 LC-MS: [M+H]+ = 557.18 | 實例4 |
49 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.83 (s, 1H), 8.76 (q, J = 1.5 Hz, 1H), 7.94 (s, 1H), 7.66 (s, 1H), 6.86 (t, J = 9.7 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.41 (d, J = 14.9 Hz, 1H), 4.84 (d, J = 1.0 Hz, 2H), 4.59 (t, J = 8.8 Hz, 2H), 4.34 (d, J = 14.9 Hz, 1H), 4.00 (dd, J = 13.6, 7.3 Hz, 1H), 3.41 (t, J = 8.7 Hz, 2H), 3.26 (dd, J = 13.6, 6.8 Hz, 1H), 2.31 (q, J = 8.1 Hz, 1H), 2.14 (ddt, J = 17.7, 12.2, 5.1 Hz, 2H), 2.05 - 1.87 (m, 2H), 1.33 (s, 3H)。 LC-MS: [M+H]+ = 583.20 | 實例4 |
50 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.77 (s, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.67 - 7.51 (m, 2H), 6.85 (dd, J = 10.3, 8.7 Hz, 1H), 6.64 (dd, J = 8.7, 3.8 Hz, 1H), 5.49 (d, J = 15.1 Hz, 1H), 4.82 (s, 2H), 4.65 - 4.50 (m, 2H), 4.35 (d, J = 15.1 Hz, 1H), 3.98 (dd, J = 13.6, 7.6 Hz, 1H), 3.49 (dd, J = 13.5, 6.4 Hz, 1H), 3.40 (t, J = 8.7 Hz, 2H), 2.72 (s, 3H), 2.33 (q, J = 8.1 Hz, 1H), 2.22 - 2.04 (m, 2H), 1.99 (td, J = 10.2, 3.8 Hz, 2H), 1.33 (s, 3H)。 LC-MS: [M+H]+ = 529.22 | 實例4 |
51 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.81 (s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.66 (s, 1H), 6.94 - 6.82 (m, 1H), 6.66 (dd, J = 8.7, 3.9 Hz, 1H), 5.56 - 5.45 (m, 1H), 4.88 (s, 2H), 4.65 - 4.50 (m, 2H), 4.45-4.41 (m, 1H), 4.12 - 3.93 (m, 2H), 3.55 - 3.39 (m, 4H), 3.39 - 3.36 (m, 2H), 2.58-2.50 (m, 1H), 2.30-2.25 (m, 1H), 1.65-1.60 (m, 1H), 1.38-1.34 (m, 1H)。 LC-MS: [M+H]+ = 569.18 | 實例4 |
52 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.76 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.65 (s, 1H), 6.85 (t, J = 9.4 Hz, 1H), 6.64 (dd, J = 8.6, 3.8 Hz, 1H), 5.54 (dd, J = 14.8, 6.6 Hz, 1H), 4.85 (s, 2H), 4.59 (t, J = 8.8 Hz, 2H), 4.39 (t, J = 14.0 Hz, 1H), 4.00 - 3.84 (m, 2H), 3.79-3.75 (m, 2H), 3.64 - 3.48 (m, 1H), 3.41 (t, J = 8.7 Hz, 2H), 3.24 (q, J = 7.3 Hz, 2H), 2.88 (m, 1H), 2.11 - 1.92 (m, 1H), 1.84 - 1.61 (m, 1H)。 LC-MS: [M+H]+ = 569.18 | 實例4 |
53 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.74 (s, 1H), 8.45 (t, J = 7.2 Hz, 1H), 8.37 (t, J = 5.2 Hz, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 6.93 (dd, J = 10.4, 8.7 Hz, 1H), 6.69 (dd, J = 8.6, 3.9 Hz, 1H), 4.78 - 4.60 (m, 3H), 4.54 (t, J = 8.7 Hz, 2H), 4.18 (dd, J = 16.0, 5.7 Hz, 1H), 3.88 (s, 3H), 3.30 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 420.15 | 實例2 |
54 | 1 H NMR (400 MHz,d4 -MeOD) δ 8.62 (s, 1H), 7.49-7.52 (m, 2H), 6.85 (t,J = 9.6 Hz, 1H), 6.63 (m, 1H), 4.80 (s, 2H), 4.57 (t,J = 8.4 Hz, 2H), 4.44 (s, 2H), 3.90 (s, 3H), 3.37 (t,J = 8.4 Hz, 2H)。 LC-MS: [M+H]+ = 421.15 | 實例1 |
55 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.80 (s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.59 (s, 1H), 6.97 (t, J = 9.4 Hz, 1H), 6.72 (dd, J = 8.8, 3.7 Hz, 1H), 5.44 (s, 1H), 4.76 (s, 2H), 4.57 (t, J = 8.7 Hz, 2H), 4.41 (brs, 1H), 3.73 (brs, 1H), 3.38 (t, J = 8.7 Hz, 2H), 3.10 (brs, 1H), 1.28-1.16 (m, 2H), 0.49 (d, J = 39.7 Hz, 2H), 0.24 (s, 1H)。 LC-MS: [M+H]+ = 539.17 | 實例4 |
56 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.73 (s, 1H), 8.33 (s, 1H), 7.33 (s, 1H), 6.96 (t, J = 9.5 Hz, 1H), 6.71 (dd, J = 8.7, 3.8 Hz, 1H), 4.94 (d, J = 16.2 Hz, 1H), 4.72 (s, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.34 (d, J = 16.2 Hz, 1H), 3.92 (s, 3H), 3.32 (td, J = 8.9, 2.9 Hz, 2H), 2.5 -2.45 (m, 1H), 2.28 (s, 3H), 1.04 (d, J = 7.0 Hz, 1H), 0.82 (dd, J = 9.9, 6.3 Hz, 2H), 0.72 (dd, J = 8.3, 4.4 Hz, 1H)。 LC-MS: [M+H]+ = 474.20 | 實例4 |
57 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.76 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.65 (s, 1H), 6.94 - 6.82 (m, 1H), 6.66 (dd, J = 8.7, 3.8 Hz, 1H), 5.54 (d, J = 14.7 Hz, 1H), 4.87 (s, 2H), 4.64 - 4.57 (m, 2H), 4.52 (d, J = 14.7 Hz, 1H), 4.00 - 3.89 (m, 1H), 3.75-3.68 (m, 3H), 3.43 (d, J = 8.7 Hz, 2H), 3.40 (s, 3H)。 LC-MS: [M+H]+ = 543.16 | 實例4 |
58 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.84 (s, 1H), 8.80 (t, J = 5.1 Hz, 1H), 8.20 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 6.96 (t, J = 9.5 Hz, 1H), 6.72 (dd, J = 8.9, 3.8 Hz, 1H), 5.38 (d, J = 14.6 Hz, 1H), 4.77 (d, J = 4.8 Hz, 2H), 4.68 (d, J = 14.6 Hz, 1H), 4.56 (t, J = 8.7 Hz, 2H), 3.79 (d, J = 13.5 Hz, 1H), 3.34 (t, J = 8.7 Hz, 2H), 3.27 (d, J = 13.5 Hz, 1H), 1.18 (s, 3H), 1.13 (s, 3H)。 LC-MS: [M+H]+ = 557.18 | 實例4 |
59 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.85 (brs, 2H), 8.22 (d, J = 8.1 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.56 (s, 1H), 6.95 (t, J = 9.5 Hz, 1H), 6.71 (dd, J = 8.8, 3.8 Hz, 1H), 5.37 (d, J = 15.0 Hz, 1H), 4.76 (d, J = 3.7 Hz, 2H), 4.53 (dt, J = 20.8, 7.8 Hz, 3H), 4.37 (d, J = 15.0 Hz, 1H), 3.34 (t, J = 8.7 Hz, 2H), 1.27 (d, J = 6.7 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3H)。 LC-MS: [M+H]+ = 527.17 | 實例4 |
60 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.79 (s, 1H), 8.66 (t, J = 5.1 Hz, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.81 - 7.67 (m, 2H), 7.47 (s, 1H), 6.96 (dd, J = 10.3, 8.6 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 5.26 (d, J = 15.1 Hz, 1H), 4.76 (d, J = 4.9 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.38 (d, J = 15.1 Hz, 1H), 4.03 (s, 1H), 3.88 (s, 2H), 3.35-3.30 (m, 3H), 2.47 - 2.21 (m, 3H), 1.59 (d, J = 11.9 Hz, 1H), 0.95 (d, J = 12.2 Hz, 1H)。 LC-MS: [M+H]+ = 568.54 | 實例4 |
61 | LC-MS: [M+H]+ = 530.47 | 實例4 |
62 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.84 (s, 1H), 8.70 (t, J = 5.1 Hz, 1H), 7.85 - 7.69 (m, 3H), 7.52 (s, 1H), 6.96 (dd, J = 10.3, 8.6 Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 5.33 (d, J = 15.1 Hz, 1H), 4.77 (d, J = 4.8 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 4.36 (d, J = 15.1 Hz, 1H), 4.10 (dd, J = 33.2, 14.7 Hz, 1H), 3.34 (t, J = 8.7 Hz, 2H), 3.21 (dd, J = 14.7, 12.3 Hz, 1H), 1.39 (dd, J = 40.0, 21.9 Hz, 6H)。 LC-MS: [M+H]+ = 558.52 | 實例4 |
63 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.85 (s, 1H), 8.72 (t, J = 5.1 Hz, 1H), 7.96 (d, J = 1.9 Hz, 1H), 7.80 (dd, J = 8.3, 1.9 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.53 (s, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.7, 3.9 Hz, 1H), 5.36 (d, J = 15.2 Hz, 1H), 4.77 (d, J = 4.0 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 4.33 (dd, J = 15.3, 3.0 Hz, 2H), 3.53 (td, J = 14.2, 9.4 Hz, 1H), 3.34 (t, J = 8.7 Hz, 2H), 1.66 (t, J = 19.3 Hz, 3H)。 LC-MS: [M+H]+ = 562.48 | 實例4 |
64 | LC-MS: [M+H]+ = 474.48 | 實例4 |
65 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.84 (s, 1H), 8.56 (d, J = 6.1 Hz, 1H), 7.53 (ddd, J = 19.8, 9.1, 4.3 Hz, 2H), 7.38 (s, 1H), 7.27 (td, J = 8.5, 2.8 Hz, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 5.15 (d, J = 15.0 Hz, 2H), 4.77 - 4.71 (m, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.25 (d, J = 15.0 Hz, 1H), 4.03 (ddt, J = 12.2, 7.9, 3.9 Hz, 1H), 3.90 (td, J = 12.2, 4.3 Hz, 2H), 3.39 - 3.28 (m, 4H), 2.30 (qd, J = 12.0, 4.4 Hz, 1H), 1.61 (d, J = 12.3 Hz, 1H), 1.11 (d, J = 12.4 Hz, 1H)。 LC-MS: [M+H]+ = 518.53 | 實例4 |
66 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.81 (s, 1H), 8.67 (d, J = 6.4 Hz, 1H), 7.99 (d, J = 1.9 Hz, 1H), 7.77 (dd, J = 8.3, 1.9 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.48 (s, 1H), 6.95 (dd, J = 10.2, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.8 Hz, 1H), 5.23 (d, J = 14.8 Hz, 1H), 4.74 (d, J = 4.7 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.24 (d, J = 15.0 Hz, 1H), 3.85 (d, J = 11.4 Hz, 2H), 3.66 (dd, J = 12.9, 8.1 Hz, 1H), 3.33 (t, J = 8.7 Hz, 2H), 3.28 - 3.15 (m, 2H), 2.96 (s, 1H), 2.07 (s, 1H), 1.56 - 1.08 (m, 4H)。 LC-MS: [M+H]+ = 582.20 | 實例4 |
67 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.78 (s, 1H), 8.67 (t, J = 5.1 Hz, 1H), 7.82 - 7.67 (m, 3H), 7.53 (s, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 5.21 (d, J = 15.0 Hz, 1H), 4.75 (d, J = 4.5 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.21 (d, J = 15.0 Hz, 1H), 3.33 (d, J = 17.5 Hz, 2H), 2.31-2.20 (m, 1H), 1.02 (tq, J = 6.8, 4.2, 3.4 Hz, 1H), 0.90 - 0.69 (m, 3H)。 LC-MS: [M+H]+ = 524.49 | 實例4 |
68 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.84 (s, 1H), 8.76 - 8.62 (m, 1H), 7.89 (dd, J = 8.1, 1.9 Hz, 1H), 7.78 (dd, J = 8.4, 2.1 Hz, 1H), 7.76 - 7.63 (m, 1H), 7.50 (s, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.7, 3.9 Hz, 1H), 5.27 (d, J = 15.0 Hz, 1H), 4.75 (d, J = 4.3 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.32 (dd, J = 15.1, 9.3 Hz, 1H), 3.91 - 3.38 (m, 7H), 3.38 - 3.25 (m, 3H), 3.09 (ddd, J = 53.1, 13.6, 5.9 Hz, 1H)。 LC-MS: [M+H]+ = 584.54 | 實例4 |
69 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.83 (s, 1H), 8.43 (t, J = 4.4 Hz, 1H), 8.21 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.58 (s, 1H), 7.40 (td, J = 8.4, 6.9 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.88 (ddd, J = 9.3, 8.4, 0.9 Hz, 1H), 5.38 (d, J = 14.7 Hz, 1H), 4.77 (d, J = 4.2 Hz, 2H), 4.24 (d, J = 14.7 Hz, 1H), 3.86 (s, 3H), 2.62 (tt, J = 7.5, 4.2 Hz, 1H), 1.04 - 0.87 (m, 2H), 0.77 (tt, J = 9.4, 6.1 Hz, 1H), 0.72 - 0.62 (m, 1H)。 LC-MS: [M+H]+ = 513.46 | 實例4 |
70 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.07 (s, 2H), 8.88 (s, 1H), 8.68 (s, 1H), 8.54 (t, J = 4.4 Hz, 1H), 8.16 (s, 1H), 7.54 (s, 1H), 7.42 (td, J = 8.4, 6.8 Hz, 1H), 6.97 (d, J = 8.4 Hz, 1H), 6.90 (t, J = 8.9 Hz, 1H), 4.86 - 4.68 (m, 2H), 3.87 (s, 3H), 2.62 (tt, J = 7.5, 4.2 Hz, 1H), 0.82 - 0.48 (m, 4H)。 LC-MS: [M+H]+ = 513.46 | 實例4 |
71 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.85 (s, 1H), 8.44 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.56 (s, 1H), 7.40 (td, J = 8.4, 6.9 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.88 (t, J = 8.9 Hz, 1H), 5.38 (d, J = 15.1 Hz, 1H), 4.83 - 4.71 (m, 2H), 4.49 (p, J = 6.9 Hz, 2H), 4.36 (d, J = 15.1 Hz, 1H), 3.35 (q, J = 8.5 Hz, 2H), 1.26 (d, J = 6.9 Hz, 3H), 1.06 (d, J = 6.7 Hz, 3H)。 LC-MS: [M+H]+ = 515.48 | 實例4 |
72 | LC-MS: [M+H]+ = 531.45 | 實例4 |
73 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.02 - 8.67 (m, 2H), 8.11 (d, J = 7.3 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 6.96 (q, J = 9.1 Hz, 1H), 6.72 (dq, J = 8.4, 3.7 Hz, 1H), 5.26 (dd, J = 15.2, 7.2 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 4.56 (q, J = 8.5 Hz, 2H), 4.39 (dd, J = 15.4, 7.0 Hz, 1H), 4.27 (q, J = 7.3 Hz, 1H), 3.35 (q, J = 8.5 Hz, 2H), 1.41 - 1.23 (m, 3H), 1.23 - 1.06 (m, 3H)。 LC-MS: [M+H]+ = 527.49 | 實例4 |
74 | LC-MS: [M+H]+ = 581.22 | 實例4 |
75 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.45 (s, 1H), 8.78 (s, 1H), 8.60 (t, J = 5.0 Hz, 1H), 7.57 (dd, J = 8.7, 5.7 Hz, 1H), 7.45 (dd, J = 9.3, 2.8 Hz, 1H), 7.38 (s, 1H), 7.29 (td, J = 8.6, 2.8 Hz, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.8 Hz, 1H), 5.19 (d, J = 15.2 Hz, 1H), 4.73 (d, J = 5.0 Hz, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.19 (d, J = 15.2 Hz, 1H), 4.05 - 3.88 (m, 1H), 3.33 (d, J = 8.8 Hz, 4H), 3.04 (m, 4H), 2.81 - 2.64 (m, 4H), 1.91 (d, J = 13.4 Hz, 1H), 1.35 - 1.15 (m, 3H)。 LC-MS: [M+H]+ = 530.22 | 實例4 |
76 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.82 (d, J = 2.3 Hz, 1H), 8.59 (t, J = 5.2 Hz, 1H), 7.54 (td, J = 8.9, 4.2 Hz, 2H), 7.42 (d, J = 1.3 Hz, 1H), 7.31 (td, J = 8.5, 2.7 Hz, 1H), 7.03 - 6.89 (m, 1H), 6.71 (dd, J = 8.7, 3.8 Hz, 1H), 5.24 (d, J = 15.2 Hz, 1H), 4.74 (d, J = 4.7 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 4.35 (q, J = 15.5 Hz, 2H), 4.18 (d, J = 15.2 Hz, 1H), 3.33 (t, J = 8.7 Hz, 2H), 1.67 (t, J = 19.2 Hz, 3H)。 LC-MS: [M+H]+ = 512.48 | 實例4 |
77 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.85 (d, J = 10.4 Hz, 2H), 8.23 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.63 (s, 1H), 7.01 - 6.92 (m, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 5.54 (d, J = 14.9 Hz, 1H), 4.77 (d, J = 4.9 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.30 (dd, J = 13.9, 7.1 Hz, 3H), 3.35 (q, J = 8.5 Hz, 2H), 1.66 (t, J = 19.4 Hz, 3H)。 LC-MS: [M+H]+ = 563.48 | 實例4 |
78 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.82 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 7.55 (dd, J = 8.7, 5.7 Hz, 1H), 7.45 - 7.33 (m, 2H), 7.30 (td, J = 8.5, 2.7 Hz, 1H), 6.95 (dd, J = 10.3, 8.6 Hz, 1H), 6.70 (dd, J = 8.7, 3.8 Hz, 1H), 5.21 (d, J = 15.0 Hz, 1H), 4.82 - 4.67 (m, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.24 (d, J = 15.0 Hz, 1H), 4.08 (dd, J = 33.6, 15.1 Hz, 1H), 3.33 (t, J = 8.9 Hz, 3H), 1.44 (d, J = 21.5 Hz, 3H), 1.31 (d, J = 22.2 Hz, 3H)。 LC-MS: [M+H]+ = 508.52 | 實例4 |
79 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.78 (s, 1H), 8.56 (t, J = 5.1 Hz, 1H), 7.52 (ddd, J = 12.1, 9.0, 4.2 Hz, 2H), 7.39 (s, 1H), 7.28 (td, J = 8.6, 2.8 Hz, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.8 Hz, 1H), 5.19 (d, J = 15.0 Hz, 1H), 4.71 (dd, J = 15.6, 4.8 Hz, 2H), 4.65 - 4.46 (m, 3H), 4.18 (d, J = 15.0 Hz, 1H), 4.12 - 3.93 (m, 1H), 3.47 (td, J = 15.0, 7.5 Hz, 2H), 3.33 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 480.46 | 實例4 |
80 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.80 (s, 1H), 8.58 (t, J = 4.8 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.41(d, J = 2.8 Hz, 1H), 7.41 (s, 1H), 7.26-7.31 (m, 1H), 6.95 (t, J = 9.6 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 6.26 (t, J = 56.4 Hz, 1H), 5.24 (d, J = 14.9 Hz, 1H), 4.73 (d, J = 4.9 Hz, 2H), 4.55 (t, J = 8.9 Hz, 2H), 4.19 (d, J = 15.2 Hz, 1H), 4.04-4.14 (m, 1H), 3.58-3.69 (m, 2H), 3.31-3.35 (m, 2H)。 LC-MS: [M+H]+ = 548.46 | 實例4 |
81 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.83 (s, 1H), 8.72 (t, J = 4.8 Hz, 1H), 8.07 (d, J = 1.2 Hz, 1H), 7.79-7.70 (m, 2H), 7.52 (s, 1H), 6.95 (dd, J = 10.3, 8.6 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 6.24 (t, J = 56.4 Hz, 1H), 5.34 (d, J = 15.2 Hz, 1H), 4.75 (d, J = 4.8 Hz, 2H), 4.56 (t, J = 8.9 Hz, 2H), 4.34 (d, J = 15.1 Hz, 1H), 4.03-4.14 (m, 1H), 3.60-3.71 (m, 2H), 3.31-3.36 (m, 2H)。 LC-MS: [M+H]+ = 548.46 | 實例4 |
82 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.87 (d, J = 2.0 Hz, 2H), 8.83 (s, 1H), 8.18 (s, 1H), 7.67 (s, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.7, 3.9 Hz, 1H), 5.48 - 5.28 (m, 1H), 4.77 (d, J = 4.2 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.41 - 4.20 (m, 2H), 3.62 (td, J = 14.3, 10.0 Hz, 1H), 3.34 (t, J = 8.7 Hz, 2H), 1.66 (t, J = 19.3 Hz, 3H)。 LC-MS: [M+H]+ = 563.15 | 實例4 |
83 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.84 (s, 1H), 8.74 (t, J = 5.1 Hz, 1H), 8.17 (d, J = 1.9 Hz, 1H), 7.80 (dd, J = 8.5, 1.9 Hz, 1H), 7.72 (d, J = 8.2 Hz, 1H), 7.54 (s, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 5.38 (d, J = 15.3 Hz, 1H), 4.76 (d, J = 5.0 Hz, 2H), 4.67 - 4.58 (m, 1H), 4.56 (t, J = 8.8 Hz, 2H), 4.35 (d, J = 15.3 Hz, 1H), 4.17 - 4.03 (m, 1H), 3.34 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 566.13 | 實例4 |
84 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.85 (dd,J = 14.5, 5.1 Hz, 3H), 8.36 (s, 1H), 7.69 (s, 1H), 7.02 - 6.92 (m, 1H), 6.72 (dd,J = 8.6, 3.9 Hz, 1H), 5.43 (d,J = 15.1 Hz, 1H), 4.77 (d,J = 5.0 Hz, 2H), 4.69 - 4.51 (m, 3H), 4.38 (d,J = 15.1 Hz, 1H), 4.21 - 4.11 (m, 1H), 3.34 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 567.13 | 實例4 |
85 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.87 (s, 1H), 8.81 (d, J = 7.0 Hz, 2H), 8.02 (s, 1H), 7.66 (s, 1H), 6.96 (t, J = 9.5 Hz, 1H), 6.72 (dd, J = 8.6, 3.8 Hz, 1H), 5.34 (d, J = 15.2 Hz, 1H), 4.77 (d, J = 4.8 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.36 (d, J = 15.1 Hz, 1H), 4.21 (td, J = 8.3, 3.7 Hz, 1H), 3.34 (t, J = 8.8 Hz, 2H), 3.19 - 3.02 (m, 2H), 2.92 (d, J = 19.6 Hz, 2H)。 LC-MS: [M+H]+ = 575.15 | 實例4 |
86 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.77 (s, 1H), 8.64 (t, J = 5.1 Hz, 1H), 7.42 (s, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 5.03 (d, J = 15.4 Hz, 1H), 4.72 (d, J = 4.9 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.19 (d, J = 15.4 Hz, 1H), 3.30 (t, J = 8.7 Hz, 2H), 2.78 (tt, J = 7.6, 4.1 Hz, 1H), 2.66 (s, 3H), 1.02 (ddt, J = 9.2, 6.8, 4.3 Hz, 1H), 0.89 (dtd, J = 9.6, 7.0, 5.3 Hz, 1H), 0.77 (dtd, J = 9.6, 7.0, 5.1 Hz, 1H), 0.64 (ddt, J = 9.2, 6.9, 4.8 Hz, 1H)。 LC-MS: [M+H]+ = 477.14 | 實例4 |
87 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.76 (s, 1H), 8.58 (t, J = 5.1 Hz, 1H), 7.51 (d, J = 5.1 Hz, 1H), 7.46 (s, 1H), 7.16 (d, J = 5.1 Hz, 1H), 6.95 (dd, J = 10.3, 8.6 Hz, 1H), 6.71 (dd, J = 8.7, 3.9 Hz, 1H), 5.01 (d, J = 15.2 Hz, 1H), 4.72 (d, J = 4.9 Hz, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.10 (d, J = 15.2 Hz, 1H), 3.32 (t, J = 8.7 Hz, 2H), 2.50 (m, 1H), 1.04 - 0.92 (m, 1H), 0.88 - 0.65 (m, 3H)。 LC-MS: [M+H]+ = 462.13 | 實例4 |
88 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.75 (s, 1H), 8.50 (t, J = 5.1 Hz, 1H), 7.63 - 7.50 (m, 2H), 7.32 (d, J = 5.3 Hz, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 5.31 (d, J = 16.1 Hz, 1H), 4.80 - 4.65 (m, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.17 (d, J = 16.1 Hz, 1H), 3.32 (t, J = 8.7 Hz, 2H), 2.72 - 2.59 (m, 1H), 1.04 - 0.93 (m, 1H), 0.77 (dddd, J = 16.2, 10.0, 7.6, 4.4 Hz, 3H)。 LC-MS: [M+H]+ = 462.13 | 實例4 |
89 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.86-8.80 (m, 2H), 8.27 (s, 1H), 7.66 (s, 1H), 6.96 (t, J = 8.8 Hz, 1H), 6.71 (dd, J = 8.6, 3.8 Hz, 1H), 6.24 (t, J = 56.4 Hz, 1H), 5.40 (d, J = 14.8 Hz, 1H), 4.76 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 8.8 Hz, 1H), 4.37 (d, J = 14.8 Hz, 1H), 4.13-4.03 (m, 1H), 3.77-3.68 (m, 2H), 3.36-3.32 (m, 2H)。 LC-MS: [M+H]+ = 549.13 | 實例4 |
90 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.86 (s, 1H), 8.85 - 8.74 (m, 2H), 8.15 (s, 1H), 7.63 (s, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.72 (dd, J = 8.7, 3.9 Hz, 1H), 5.25 (d, J = 14.8 Hz, 1H), 4.77 (d, J = 4.8 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.32 (d, J = 14.8 Hz, 1H), 3.78 (dq, J = 13.8, 6.9 Hz, 1H), 3.34 (t, J = 8.9 Hz, 2H), 3.12 (dq, J = 13.6, 6.7 Hz, 1H), 1.10 (t, J = 7.0 Hz, 3H)。 LC-MS: [M+H]+ = 513.15 | 實例4 |
91 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.89 (t, J = 5.1 Hz, 1H), 8.82 (s, 1H), 7.68 (s, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.7, 3.9 Hz, 1H), 5.22 (d, J = 15.6 Hz, 1H), 4.74 (d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.35 (d, J = 15.6 Hz, 1H), 3.32 (t, J = 8.7 Hz, 2H), 2.76 (tt, J = 7.4, 4.1 Hz, 1H), 1.03 - 0.73 (m, 3H), 0.71 - 0.60 (m, 1H)。 LC-MS: [M+H]+ = 531.11 | 實例4 |
92 | LC-MS: [M+H]+ = 488.15 | 實例4 |
93 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.81 (s, 1H), 8.68 (t, J = 5.0 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.85 - 7.66 (m, 2H), 7.47 (d, J = 3.8 Hz, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 5.30 (d, J = 15.0 Hz, 1H), 4.75 (d, J = 4.5 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.39 (d, J = 15.0 Hz, 1H), 4.07 - 3.88 (m, 3H), 3.33 (t, J = 8.7 Hz, 2H), 2.42 - 2.19 (m, 2H), 1.59 (dt, J = 13.0, 7.7 Hz, 1H), 1.12 (d, J = 6.2 Hz, 3H), 1.08 (dd, J = 15.7, 6.1 Hz, 1H), 1.02 (d, J = 6.3 Hz, 3H), 0.84 (dt, J = 12.2, 5.7 Hz, 1H)。 LC-MS: [M+H]+ = 596.22 | 實例4 |
94 | 1 H NMR (400 MHz, DMSO-d6 ) δ 9.04 (t, J = 4.8 Hz, 1H), 8.88 (s, 1H), 8.61 (dd, J = 3.6, 1.4 Hz, 1H), 8.25 (dd, J = 8.0, 1.6 Hz, 1H), 8.14 (s, 1H), 7.53 (dd, J = 8.0, 4.4 Hz, 1H), 6.96 (t, J = 8.8 Hz, 1H), 6.71 (dd, J = 8.8, 4.0 Hz, 1H), 5.05 (d, J = 14.0 Hz, 1H), 4.79 (t, J = 6.4 Hz, 2H), 4.53-4.58 (m, 3H), 3.34 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 438.09 | 實例6 |
95 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.98 (t, J = 4.8 Hz, 1H), 8.86 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.96 (t, J = 8.8 Hz, 1H), 6.71 (dd, J = 8.4, 4.0 Hz, 1H), 5.01 (d, J = 14.0 Hz, 1H), 4.78 (d, J = 5.6 Hz, 2H), 4.57-4.53 (m, 3H), 3.33 (t, J = 8.8 Hz, 2H), 2.55 (s, 3H)。 LC-MS: [M+H]+ = 452.11 | 實例6 |
96 | LC-MS: [M+H]+ = 469.10 | 實例6 |
97 | LC-MS: [M+H]+ = 466.12 | 實例6 |
98 | LC-MS: [M+H]+ = 597.21 | 實例4 |
99 | 1 H NMR (400 MHz, CDCl3 ) δ 8.60 (s, 1H), 7.55 - 7.35 (m, 6H), 6.77 (dd, J = 10.1, 8.7 Hz, 1H), 6.61 (dd, J = 8.7, 3.9 Hz, 1H), 4.82 (s, 2H), 4.61 (t, J = 8.7 Hz, 2H), 3.40 (t, J = 8.7 Hz, 2H), 2.86 (s, 3H)。 LC-MS: [M+H]+ = 439.12。 | 實例14 |
100 | 1 H NMR (400 MHz, CDCl3 ) δ 8.12 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.49 (s, 1H), 6.95 - 6.83 (m, 1H), 6.72 (dd, J = 8.7, 4.0 Hz, 1H), 5.68 (s, 1H), 4.88 (d, J = 4.9 Hz, 2H), 4.66 (t, J = 8.7 Hz, 2H), 3.45 (t, J = 8.7 Hz, 2H), 3.16 (s, 3H), 3.14 (s, 3H)。 LC-MS: [M+H]+ = 517.09 | 實例14 |
101. | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.78 (d, J = 1.5 Hz, 1H), 8.73 (dd, J = 5.9, 1.8 Hz, 1H), 8.44 (dt, J = 7.9, 1.5 Hz, 1H), 7.95 (dd, J = 7.8, 6.0 Hz, 1H), 7.59 (d, J = 0.9 Hz, 1H), 6.88 (td, J = 9.5, 9.1, 1.9 Hz, 1H), 6.67 (dd, J = 8.6, 4.0 Hz, 1H), 4.88 (d, J = 4.9 Hz, 2H), 4.60 (td, J = 8.7, 1.5 Hz, 2H), 3.43 (t, J = 8.7 Hz, 2H), 3.11 - 3.00 (m, 3H), 2.63 (s, 3H)。 LC-MS: [M+H]+ = 454.12。 | 實例14 |
102 | 1 H NMR (400 MHz, CDCl3 ) δ 8.74 (d, J = 2.1 Hz, 1H), 8.39 (s, 1H), 8.05 - 7.91 (m, 1H), 7.78 (dd, J = 8.1, 0.7 Hz, 1H), 7.49 (s, 1H), 6.89 - 6.72 (m, 1H), 6.65 (dd, J = 8.7, 3.9 Hz, 1H), 6.46 (s, 1H), 4.85 (s, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.41 (t, J = 8.7 Hz, 2H), 3.08 (s, 3H)。 LC-MS: [M+H]+ = 508.09。 | 實例14 |
103 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.87 - 8.80 (m, 1H), 8.76 (d, J = 0.9 Hz, 1H), 8.51 (dd, J = 8.3, 2.1 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 0.8 Hz, 1H), 6.91 - 6.82 (m, 1H), 6.66 (dt, J = 9.0, 3.4 Hz, 1H), 4.85 (s, 2H), 4.60 (td, J = 8.7, 1.4 Hz, 2H), 3.41 (t, J = 8.7 Hz, 2H), 3.18 (s, 3H), 2.86 (s, 3H)。 LC-MS: [M+H]+ = 454.12 | 實例14 |
104 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.68 (s, 1H), 7.52 - 7.31 (m, 3H), 7.18 - 7.04 (m, 2H), 6.92 - 6.81 (m, 1H), 6.66 (dd, J = 8.6, 3.8 Hz, 1H), 4.84 (d, J = 1.0 Hz, 2H), 4.59 (t, J = 8.7 Hz, 2H), 3.39 (t, J = 8.7 Hz, 2H), 3.00 (s, 3H)。 LC-MS: [M+H]+ = 457.10 | 實例14 |
105 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.79 (dd, J = 2.0, 1.0 Hz, 1H), 8.75 (s, 1H), 8.23 - 8.01 (m, 2H), 7.57 (s, 1H), 6.93 - 6.80 (m, 1H), 6.67 (dd, J = 8.6, 3.9 Hz, 1H), 4.84 (d, J = 1.0 Hz, 2H), 4.60 (t, J = 8.7 Hz, 2H), 3.41 (t, J = 8.8 Hz, 2H), 3.28 (s, 3H), 3.14 (s, 3H)。 LC-MS: [M+H]+ = 518.08 | 實例14 |
106 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.63 (s, 1H), 7.76 (s, 1H), 7.59 (s, 1H), 7.44 (s, 1H), 6.85 (t, J = 9.6 Hz, 1H), 6.64 (dd, J = 8.4, 3.6 Hz, 1H), 4.81 (s, 2H), 4.57 (t, J = 8.4 Hz, 2H), 3.94 (s, 3H), 3.36 (t, J = 8.8 Hz, 2H), 3.00 (s, 3H), 2.66 (s, 2H)。 LC-MS: [M+H]+ = 443.12 | 實例14 |
107 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.74 (s, 1H), 8.73 - 8.67 (m, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.54 (s, 1H), 6.96 - 6.77 (m, 2H), 6.73 - 6.61 (m, 1H), 4.86 (d, J = 1.1 Hz, 2H), 4.60 (t, J = 8.7 Hz, 2H), 3.41 (t, J = 8.7 Hz, 2H), 3.11 (s, 3H)。 LC-MS: [M+H]+ = 490.10 | 實例14 |
108 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.54 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.33 (s, 1H), 6.65 (t, J = 9.2 Hz, 1H), 6.44 (dd, J = 8.6, 3.6 Hz, 1H), 4.63 (t, J = 6.4 Hz, 2H), 4.37 (t, J = 8.8 Hz, 1H), 3.20 (t, J = 8.8 Hz, 2H), 2.85 (s, 3H), 2.60 (s, 3H), 2.36 (s, 3H)。 LC-MS: [M+H]+ = 468.14 | 實例14 |
109 | LC-MS: [M+H]+ = 522.11 | 實例14 |
110 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.92 (s, 1H), 8.73 (s, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.73 (dd, J = 7.9, 2.0 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.36 (s, 1H), 6.96 (dd, J = 10.3, 8.6 Hz, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 4.75 (q, J = 14.4 Hz, 2H), 4.56 (t, J = 8.7 Hz, 2H), 3.41 - 3.29 (m, 2H), 3.23 (s, 3H), 2.99 (s, 3H), 2.20 (s, 3H)。 LC-MS: [M+H]+ = 531.10。 | 實例14 |
111 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.94 (d, J = 2.0 Hz, 1H), 8.91 (s, 1H), 8.65 (s, 1H), 8.15 (d, J = 8.4 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.03 - 6.91 (m, 1H), 6.72 (dt, J = 8.4, 2.9 Hz, 1H), 4.76 (d, J = 4.2 Hz, 2H), 4.56 (td, J = 8.8, 2.0 Hz, 2H), 3.33 (t, J = 8.7 Hz, 2H), 3.13 (s, 3H), 2.36 - 2.25 (m, 1H), 1.26 (d, J = 8.1 Hz, 2H), 1.18 - 1.03 (m, 2H)。 LC-MS: [M+H]+ = 480.14 | 實例14 |
112 | 1 H NMR (400 MHz, CDCl3 ) δ 8.32 (s, 1H), 8.03 (d, J = 7.9 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.40 (s, 1H), 6.87 (t, J = 9.4 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 4.87 (s, 2H), 4.65 (t, J = 8.7 Hz, 2H), 3.44 (t, J = 8.7 Hz, 2H), 3.14 (s, 3H)。 LC-MS: [M+H]+ = 507.10 | 實例14 |
113 | 1 H NMR (400 MHz, CDCl3 ) δ 7.72 (d, J = 7.8 Hz, 2H), 7.52 (d, J = 7.9 Hz, 2H), 7.40 (s, 1H), 6.89 (t, J = 9.5 Hz, 1H), 6.71 (dd, J = 8.6, 3.8 Hz, 1H), 4.86 (s, 2H), 4.66 (t, J = 8.6 Hz, 2H), 3.45 (t, J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 497.11 | 實例14 |
114 | 1 H NMR (400 MHz, DMSO) δ 8.86 (s, 1H), 8.66 (s, 1H), 7.41-7.38 (m, 2H), 7.31 (s, 1H), 7.24 (t, J = 8.8 Hz, 2H), 6.94 (t, J = 9.6 Hz, 1H), 6.71 (dd, J = 8.4, 3.6 Hz, 1H), 4.72 (d, J = 4.0 Hz, 1H), 4.54 (t, J = 8.8 Hz, 2H), 3.32 (t, J = 8.4 Hz, 2H)。 LC-MS: [M+H]+ = 447.11 | 實例14 |
115 | 1 H NMR (400 MHz, DMSO) δ 8.92-8.91 (m, 2H), 8.28 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 6.95 (t, J = 9.6 Hz, 1H), 6.71 (dd, J = 8.4, 3.6 Hz, 1H), 4.80-4.68 (m, 2H), 4.55 (t, J = 8.4 Hz, 2H), 3.35-3.31 (m, 2H), 2.76 (s, 3H), 2.48 (s, 3H)。 LC-MS: [M+H]+ = 458.15 | 實例14 |
116 | 1 H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.84 (t, J = 4.8 Hz, 1H), 8.78 (d, J = 1.2 Hz, 1H), 8.11 (dd, J = 8.0, 1.2 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.49 (s, 1H), 6.95 (t, J = 9.6 Hz, 1H), 6.70 (dd, J = 8.4, 3.6 Hz, 1H), 4.75 (d, J = 4.4 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.33 (t, J = 8.4 Hz, 2H)。 LC-MS: [M+H]+ = 498.10 | 實例14 |
117 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.76 (t, J = 1.5 Hz, 2H), 8.14 (dd, J = 8.0, 2.2 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.43 (s, 1H), 6.97 - 6.77 (m, 2H), 6.69 - 6.59 (m, 1H), 4.85 (d, J = 1.1 Hz, 2H), 4.59 (t, J = 8.7 Hz, 2H), 3.40 (t, J = 8.7 Hz, 2H), 1.58 (d, J = 13.7 Hz, 6H)。 LC-MS: [M+H]+ = 488.13 | 實例14 |
118 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.72 (d, J = 1.1 Hz, 1H), 7.65 - 7.53 (m, 2H), 7.36 (s, 1H), 7.22 (t, J = 8.8 Hz, 2H), 6.93 - 6.81 (m, 1H), 6.66 (dd, J = 8.7, 3.9 Hz, 1H), 4.83 (d, J = 1.0 Hz, 2H), 4.59 (t, J = 8.7 Hz, 2H), 3.38 (t, J = 8.7 Hz, 2H), 1.46 (s, 3H), 1.42 (s, 3H)。 LC-MS: [M+H]+ = 455.13 | 實例14 |
119 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.82 (d, J = 2.1 Hz, 1H), 8.77 (d, J = 1.2 Hz, 1H), 8.17 (ddd, J = 8.1, 2.2, 0.7 Hz, 1H), 7.88 (dd, J = 8.1, 0.8 Hz, 1H), 7.45 (s, 1H), 6.92 - 6.81 (m, 1H), 6.66 (dd, J = 8.6, 3.9 Hz, 1H), 4.85 (d, J = 1.1 Hz, 2H), 4.59 (t, J = 8.7 Hz, 2H), 3.40 (t, J = 8.6 Hz, 2H), 1.62 (s, 3H), 1.58 (s, 3H)。 LC-MS: [M+H]+ = 506.12 | 實例14 |
120 | 1 H NMR (400 MHz, CDCl3 ) δ 8.81 (s, 1H), 8.60 (s, 1H), 8.04 (d,J = 7.9 Hz, 1H), 7.83 (d,J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.29 (d,J = 1.4 Hz, 1H), 6.87 (t,J = 9.4 Hz, 1H), 6.71 (dd,J = 8.6, 3.8 Hz, 1H), 4.88 (s, 2H), 4.66 (t,J = 8.4 Hz, 2H), 3.45 (t,J = 8.7 Hz, 2H), 1.98 (ddq,J = 27.6, 14.5, 7.6 Hz, 4H), 1.01 (dt,J = 18.4, 7.6 Hz, 6H)。 LC-MS: [M+H]+ = 534.06 | 實例14 |
121 | 1 H NMR (400 MHz, CDCl3 ) δ 8.32 (s, 1H), 7.72 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 7.9 Hz, 2H), 7.37 (s, 1H), 6.87 (t, J = 9.5 Hz, 1H), 6.69 (dd, J = 8.7, 3.9 Hz, 1H), 4.85 (s, 2H), 4.64 (t, J = 8.7 Hz, 2H), 3.45 (t, J = 8.7 Hz, 2H), 1.91 (s, 2H), 1.64 (td, J = 14.2, 7.4 Hz, 2H), 0.96 (dt, J = 17.0, 7.6 Hz, 6H)。 LC-MS: [M+H]+ = 533.06 | 實例14 |
122 | 1 H NMR (400 MHz, CDCl3 ) δ 8.30 (s, 1H), 8.07 - 7.94 (m, 2H), 7.68 - 7.58 (m, 2H), 7.39 (d, J = 1.5 Hz, 1H), 6.89 (t, J = 9.5 Hz, 1H), 6.76 - 6.62 (m, 1H), 4.87 (s, 2H), 4.66 (t, J = 8.6 Hz, 2H), 3.47 (t, J = 8.7 Hz, 2H), 3.15 (d, J = 1.5 Hz, 3H), 2.06 (dq, J = 13.8, 7.4 Hz, 2H), 1.89 (dq, J = 14.4, 7.3 Hz, 2H), 1.00 (dt, J = 18.8, 7.6 Hz, 6H)。 LC-MS: [M+H]+ = 543.15 | 實例14 |
123 | 1 H NMR (400 MHz, DMSO) δ 8.96 (s, 1H), 8.29 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 6.94 (t, J = 8.8 Hz, 1H), 6.70 (dd, J = 8.4, 3.6 Hz, 1H), 4.80-4.68 (m, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.34 (t, J = 8.0 Hz, 2H), 2.71 (s, 3H), 2.48 (s, 3H), 1.63 (d, J = 14.0 Hz, 3H), 1.31 (d, J = 14.0 Hz, 3H)。 LC-MS: [M+H]+ = 466.17 | 實例14 |
124 | 1 H NMR (400 MHz, DMSO) δ 8.95 (s, 1H), 8.76 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 6.96 (t, J = 8.8 Hz, 1H), 6.72 (dd, J = 8.4, 3.6 Hz, 1H), 4.74-4.70 (m, 2H), 4.57 (t, J = 8.4 Hz, 2H), 3.36 (t, J = 8.0 Hz, 2H), 2.74 (s, 2H), 2.069-1.983 (m,1H), 1.845-1.759 (m,1H), 1.52-1.49 (m, 2H), 0.97-0.89 (m, 3H), 0.67-0.59 (m, 3H)。 LC-MS: [M+H]+ = 483.16 | 實例14 |
125 | 1 H NMR (400 MHz, DMSO) δ 8.87 (s, 1H), 8.53 (s, 1H), 7.53-7.51 (m, 2H), 6.94 (t, J = 8.8 Hz, 1H), 6.70 (dd, J = 8.4, 3.6 Hz, 1H), 4.71 (d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 3.33 (t, J = 8.4 Hz, 2H), 1.77-1.68 (m, 2H), 1.44-1.33 (m, 2H), 0.83-0.75 (m, 6H)。 LC-MS: [M+H]+ = 493.20 | 實例14 |
126 | 1 H NMR (400 MHz, CDCl3 ) δ 10.13 (s, 1H), 7.66 (s, 1H), 7.61 (d, J = 1.0 Hz, 1H), 7.57 - 7.51 (m, 4H), 7.51 - 7.45 (m, 1H), 7.37 (dd, J = 1.8, 0.8 Hz, 1H), 6.41 (dd, J = 3.2, 0.8 Hz, 1H), 6.34 (dd, J = 3.2, 1.8 Hz, 1H), 4.89 (s, 2H)。 LC-MS: [M+H]+ = 291.11 | 實例13 |
127 | 1 H NMR (400 MHz, CDCl3 ) δ 8.81 (s, 1H), 7.49 (d, J = 1.0 Hz, 1H), 7.41 (d, J = 6.7 Hz, 3H), 7.34 (dq, J = 3.3, 1.7 Hz, 3H), 6.35 (d, J = 3.2 Hz, 1H), 6.30 (dt, J = 3.1, 1.4 Hz, 1H), 4.87 (s, 2H), 3.87 (q, J = 7.1 Hz, 2H), 0.88 (t, J = 7.1 Hz, 3H)。 LC-MS: [M+H]+ = 363.017 | 實例13 |
128 | 1 H NMR (400 MHz, CDCl3 ) δ 9.22 (s, 1H), 7.55 - 7.43 (m, 3H), 7.38 -7.30 (m, 3H), 6.40 (s, 1H), 6.36 (s, 1H), 6.31 (brs, 1H), 4.86 (s, 2H), 2.54 (s, 3H)。 LC-MS: [M+H]+ = 348.13。 | 實例15 |
129 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.71 (s, 1H), 7.46 - 7.33 (m, 7H), 7.33 - 7.26 (m, 1H), 7.03 (dd, J = 8.3, 1.1 Hz, 1H), 6.94 (td, J = 7.5, 1.1 Hz, 1H), 4.84 (s, 2H), 3.91 (s, 3H), 3.80 (q, J = 7.2 Hz, 2H), 0.86 (t, J = 7.1 Hz, 3H)。 LC-MS: [M+H]+ = 403.16 | 實例15 |
130 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.70 (s, 1H), 7.48 - 7.31 (m, 7H), 6.90 (dt, J = 8.4, 0.9 Hz, 1H), 6.80 (ddd, J = 9.3, 8.4, 0.9 Hz, 1H), 4.88 (s, 2H), 3.91 (s, 3H), 3.79 (q, J = 7.1 Hz, 2H), 0.86 (t, J = 7.1 Hz, 3H)。LC-MS: [M+H]+ = 421.16 | 實例15 |
131 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.66 (s, 1H), 7.52 - 7.23 (m, 6H), 7.11 (td, J = 9.2, 5.1 Hz, 1H), 6.96 (td, J = 9.2, 2.0 Hz, 1H), 4.92 (s, 2H), 3.88 (s, 3H), 3.79 (q, J = 7.1 Hz, 2H), 0.86 (t, J = 7.1 Hz, 3H)。LC-MS: [M+H]+ = 439.15 | 實例15 |
132 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.70 (s, 1H), 7.50 - 7.29 (m, 6H), 7.15 - 6.98 (m, 2H), 6.91 - 6.77 (m, 1H), 4.86 (s, 2H), 3.85 - 3.77 (m, 2H), 3.76 (s, 3H), 0.86 (t, J = 7.1 Hz, 3H)。 LC-MS: [M+H]+ = 421.15 | 實例15 |
133 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.73 (s, 1H), 7.52 - 7.31 (m, 6H), 7.21 - 7.05 (m, 2H), 4.99 (d, J = 1.7 Hz, 2H), 3.90 (s, 3H), 3.79 (q, J = 7.1 Hz, 2H), 0.85 (t, J = 7.1 Hz, 3H)。 LC-MS: [M+H]+ = 455.12 | 實例15 |
134 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.70 (s, 1H), 7.47 - 7.31 (m, 6H), 6.95 (ddt, J = 7.7, 1.4, 0.7 Hz, 1H), 6.88 - 6.75 (m, 2H), 5.99 (s, 2H), 4.84 (s, 2H), 3.80 (q, J = 7.1 Hz, 2H), 0.86 (t, J = 7.1 Hz, 3H)。 LC-MS: [M+H]+ = 417.14 | 實例15 |
135 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.70 (s, 1H), 7.50 - 7.25 (m, 6H), 6.91 - 6.83 (m, 1H), 6.67 (dd, J = 8.6, 3.9 Hz, 1H), 4.84 (d, J = 1.1 Hz, 2H), 4.59 (t, J = 8.7 Hz, 2H), 3.80 (q, J = 7.2 Hz, 2H), 3.44 - 3.35 (m, 2H), 0.86 (t, J = 7.1 Hz, 3H)。LC-MS: [M+H]+ = 433.15 | 實例15 |
136 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.80 (s, 1H), 7.50 - 7.30 (m, 7H), 7.23 (s, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.04 - 6.91 (m, 1H), 4.89 (s, 2H), 3.91 (s, 3H), 2.52 (s, 3H)。 LC-MS: [M+H]+ = 388.16 | 實例15 |
137 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.80 (s, 1H), 7.42 (m, 6H), 7.30 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.84 (ddd, J = 9.4, 8.4, 0.9 Hz, 1H), 4.89 (s, 2H), 3.92 (s, 3H), 2.51 (s, 3H)。 LC-MS: [M+H]+ = 406.16 | 實例15 |
138 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.70 (s, 1H), 7.50 - 7.36 (m, 5H), 7.34 (s, 1H), 7.14 (dt, J = 9.5, 4.7 Hz, 1H), 7.06 - 6.88 (m, 1H), 4.93 (s, 2H), 3.89 (d, J = 1.0 Hz, 3H), 2.50 (s, 3H)。 LC-MS: [M+H]+ = 424.15 | 實例15 |
139 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.75 (s, 1H), 7.55 - 7.35 (m, 5H), 7.30 (s, 1H), 7.16 - 7.02 (m, 2H), 6.91 (dd, J = 8.6, 4.2 Hz, 1H), 4.93 (s, 2H), 3.78 (d, J = 1.4 Hz, 3H), 2.51 (s, 3H)。 LC-MS: [M+H]+ = 406.16 | 實例15 |
140 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.66 (s, 1H), 7.51 - 7.31 (m, 6H), 7.23 - 7.02 (m, 2H), 4.99 (d, J = 1.8 Hz, 2H), 3.91 (s, 3H), 2.50 (s, 3H)。 LC-MS: [M+H]+ = 440.12 | 實例15 |
141 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 9.02 (s, 1H), 7.55 - 7.35 (m, 5H), 7.21 (s, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.97 - 6.83 (m, 2H), 6.03 (s, 2H), 4.90 (s, 2H), 2.52 (s, 3H)。 LC-MS: [M+H]+ = 402.14 | 實例15 |
142 | 1 H NMR (400 MHz, 甲醇-d4 ) δ 8.64 (s, 1H), 7.50 - 7.29 (m, 6H), 6.92 - 6.81 (m, 1H), 6.67 (dd, J = 8.7, 3.9 Hz, 1H), 4.83 (d, J = 1.2 Hz, 2H), 4.59 (t, J = 8.7 Hz, 2H), 3.38 (t, J = 8.7 Hz, 2H), 2.51 (s, 3H)。 LC-MS: [M+H]+ = 418.16 | 實例15 |
143 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.85 (s, 1H), 8.61 (s, 1H), 7.44-7.31 (m, 6H), 6.94 (t, J = 8.8 Hz, 1H), 6.71 (dd, J = 8.4, 4.0 Hz, 1H), 4.73 (d, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.31 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 429.12 | 實例14 |
144 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.85 (s, 1H), 8.52 (s, 1H), 7.58-7.56 (m, 2H), 7.42-7.41 (m, 2H), 7.29 (s, 1H), 6.94 (t, J = 9.2 Hz, 1H), 6.70 (dd, J = 8.4, 4.0 Hz, 1H), 4.73 (d, J = 4.0 Hz, 2H), 4.54 (t, J = 8.8 Hz, 2H), 3.31 (t, J = 8.8 Hz, 2H), 1.21 (s, 1H), 1.18 (s, 1H)。 LC-MS: [M+H]+ = 437.14 | 實例14 |
E 1 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.85 (s, 1H), 8.62 (t, J = 4.9 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.96 (dd, J = 10.3, 8.6 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 5.23 (d, J = 14.9 Hz, 1H), 4.74 (d, J = 4.5 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.46 (p, J = 6.9 Hz, 1H), 4.24 (d, J = 14.9 Hz, 1H), 3.33 (t, J = 8.7 Hz, 2H), 2.53 (s, 3H), 1.27 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.7 Hz, 3H)。 LC-MS: [M+H]+ = 473.20 | |
E 2 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.79 (d, J = 14.9 Hz, 3H), 7.80 (s, 1H), 7.52 (s, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 5.22 (d, J = 14.9 Hz, 1H), 4.75 (d, J = 4.7 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.27 (d, J = 14.9 Hz, 1H), 4.19 (p, J = 6.8 Hz, 1H), 3.32 (t, J = 8.7 Hz, 2H), 2.64 (s, 3H), 1.24 (dd, J = 35.6, 6.8 Hz, 6H)。 LC-MS: [M+H]+ = 473.20 | |
E 3 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.85 (s, 1H), 8.71 (t,J = 5.1 Hz, 1H), 7.93 (d,J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.44 (d,J = 8.1 Hz, 1H), 6.96 (dd,J = 10.3, 8.6 Hz, 1H), 6.71 (dd,J = 8.7, 3.9 Hz, 1H), 5.46 (d,J = 15.0 Hz, 1H), 4.75 (d,J = 4.5 Hz, 2H), 4.71 - 4.61 (m, 1H), 4.56 (t,J = 8.8 Hz, 2H), 4.19 (d,J = 15.0 Hz, 1H), 4.08 (dq,J = 15.2, 9.0 Hz, 1H), 3.34 (t,J = 8.7 Hz, 2H), 2.57 (s, 3H)。 LC-MS: [M+H]+ = 513.15 | |
E 4 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.79 (s, 1H), 8.71 (t, J = 5.1 Hz, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.88 (dd, J = 8.1, 1.8 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.46 (s, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 5.19 (d, J = 15.1 Hz, 1H), 4.80 - 4.69 (m, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.23 (d, J = 15.3 Hz, 1H), 4.17 (q, J = 6.8 Hz, 1H), 3.33 (t, J = 8.7 Hz, 2H), 1.29 (d, J = 6.7 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H)。 LC-MS: [M+H]+ = 483.19 | |
E 5 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.86 (s, 1H), 8.84 - 8.70 (m, 2H), 7.86 (s, 1H), 7.62 (s, 1H), 6.96 (dd, J = 10.3, 8.6 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 5.22 (d, J = 15.0 Hz, 1H), 4.77 (d, J = 4.9 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.40 (d, J = 15.1 Hz, 1H), 4.35 - 4.17 (m, 1H), 3.33 (t, J = 8.7 Hz, 2H), 2.62 - 2.54 (m, 1H), 2.34 - 2.27 (m, 1H), 2.27 - 2.09 (m, 2H), 1.70 (ddt, J = 25.8, 10.6, 7.5 Hz, 2H)。 LC-MS: [M+H]+ = 539.17 | |
E 6 | 1 H NMR (400 MHz, DMSO-d6 ) δ 8.86 (d, J = 4.0 Hz, 1H), 8.74 (d, J = 6.5 Hz, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.58 - 7.42 (m, 2H), 6.94 (dd, J = 10.2, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.8 Hz, 1H), 6.47 - 6.09 (m, 1H), 5.46 (d, J = 15.1 Hz, 1H), 4.74 (d, J = 3.5 Hz, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.26 (dt, J = 15.3, 5.5 Hz, 1H), 4.12 (dddd, J = 23.0, 13.9, 10.0, 3.2 Hz, 1H), 3.80 (qd, J = 12.9, 4.7 Hz, 1H), 3.33 (t, J = 8.7 Hz, 2H), 2.59 (t, J = 2.9 Hz, 3H)。 LC-MS: [M+H]+ = 495.47 | |
E 7 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.87 (d,J = 4.6 Hz, 1H), 8.70 (d,J = 5.9 Hz, 1H), 7.99 (d,J = 7.9 Hz, 1H), 7.63 - 7.43 (m, 2H), 6.96 (t,J = 9.4 Hz, 1H), 6.71 (dd,J = 8.5, 3.9 Hz, 1H), 5.42 (d,J = 15.1 Hz, 1H), 4.76 (d,J = 4.1 Hz, 2H), 4.56 (t,J = 8.7 Hz, 2H), 4.36 - 4.17 (m, 2H), 3.80 (td,J = 14.1, 7.1 Hz, 1H), 3.34 (t,J = 8.6 Hz, 2H), 2.59 (s, 3H), 1.66 (dd,J = 21.1, 17.6 Hz, 3H)。 LC-MS: [M+H]+ = 509.18 | |
E 8 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.84 (d, J = 3.6 Hz, 2H), 8.22 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.62 (s, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.8 Hz, 1H), 6.54 (brs, 1H), 5.56 (d, J = 14.9 Hz, 1H), 4.76 (d, J = 5.0 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.28 (d, J = 14.9 Hz, 1H), 4.10 (dt, J = 22.2, 11.0 Hz, 1H), 3.65 (qd, J = 13.1, 5.2 Hz, 1H), 3.34 (t,J = 8.6 Hz, 2H)。 LC-MS: [M+H]+ = 549.13 | |
E 9 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.83 (d, J = 10.8 Hz, 2H), 8.73 (s, 1H), 7.86 (s, 1H), 7.57 (s, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 6.47 - 6.09 (m, 1H), 5.36 (d, J = 14.9 Hz, 1H), 4.75 (d, J = 4.2 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.25 (d, J = 14.9 Hz, 1H), 4.10 (dddd, J = 22.8, 13.5, 9.2, 3.3 Hz, 1H), 3.68 - 3.45 (m, 1H), 3.33 (t, J = 8.7 Hz, 2H), 2.63 (s, 3H)。 LC-MS: [M+H]+ = 495.16 | |
E 10 | 1 H NMR (400 MHz, DMSO- d6 ) δ 9.08 (s, 1H), 9.01 (s, 1H), 8.85 (s, 1H), 8.06 (s, 1H), 7.80 (s, 1H), 7.47 (d,J = 1.3 Hz, 1H), 6.98 (dd,J = 10.3, 8.7 Hz, 1H), 6.74 (dd,J = 8.6, 3.9 Hz, 1H), 5.79 (d,J = 14.7 Hz, 1H), 5.57 (d,J = 14.8 Hz, 1H), 4.88 - 4.72 (m, 2H), 4.59 (t,J = 8.9 Hz, 3H), 3.34 (t,J = 8.6 Hz, 2H), 2.56 - 2.53 (m, 3H)。 LC-MS: [M+H]+ = 522.16 | |
E 11 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.79 (d, J = 8.1 Hz, 2H), 8.70 (t, J = 5.1 Hz, 1H), 7.86 (s, 1H), 7.56 (s, 1H), 7.08 (d, J = 55.0 Hz, 1H), 6.99 - 6.85 (m, 1H), 6.70 (dd, J = 8.7, 3.9 Hz, 1H), 5.20 (d, J = 14.9 Hz, 1H), 4.75 (d, J = 4.7 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.36 (d, J = 15.0 Hz, 1H), 4.25 (q, J = 6.8 Hz, 1H), 3.33 (t, J = 8.7 Hz, 2H), 1.27 (d, J = 6.7 Hz, 3H), 1.17 (d, J = 6.8 Hz, 3H)。 LC-MS: [M+H]+ = 509.18 | |
E 12 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.83 (s, 1H), 8.66 (brs, 1H), 7.88 (d,J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.40 (d,J = 8.1 Hz, 1H), 6.96 (dd,J = 10.3, 8.7 Hz, 1H), 6.71 (dd,J = 8.6, 3.8 Hz, 1H), 5.46 (d,J = 14.9 Hz, 1H), 4.75 (d,J = 4.9 Hz, 2H), 4.67 (dd,J = 15.2, 9.5 Hz, 1H), 4.56 (t,J = 8.8 Hz, 2H), 4.17 (d,J = 14.9 Hz, 1H), 4.14 - 3.99 (m, 1H), 3.34 (t,J = 8.6 Hz, 2H), 2.82 (q,J = 7.6 Hz, 2H), 1.28 (td,J = 7.6, 1.3 Hz, 3H)。 LC-MS: [M+H]+ = 527.49 | |
E 13 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.82 (s, 1H), 8.64 (t, J = 5.2 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 10.3, 8.7 Hz, 1H), 6.71 (dd, J = 8.6, 3.9 Hz, 1H), 5.41 (d, J = 14.7 Hz, 2H), 4.75 (d, J = 4.9 Hz, 2H), 4.56 (t, J = 8.8 Hz, 2H), 4.20-4.14 (m, 2H), 3.80-3.76 (m, 1H), 3.34 (t,J = 8.6 Hz, 2H), 2.82 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H)。 LC-MS: [M+H]+ = 509.50 | |
E 14 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.83 (s, 1H), 8.65 (t,J = 5.1 Hz, 1H), 7.80 (d,J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.41 (d,J = 8.1 Hz, 1H), 6.95 (dd,J = 10.3, 8.7 Hz, 1H), 6.71 (dd,J = 8.7, 3.9 Hz, 1H), 5.41 (d,J = 14.8 Hz, 1H), 4.75 (d,J = 4.8 Hz, 2H), 4.68 (dd,J = 15.2, 9.6 Hz, 1H), 4.56 (t,J = 8.8 Hz, 2H), 4.08 (d,J = 14.8 Hz, 1H), 3.96 (dt,J = 15.3, 9.2 Hz, 1H), 3.34 (t,J = 8.7 Hz, 2H), 2.28-2.21 (m, 1H), 1.32 - 1.15 (m, 1H), 1.16-0.99 (m, 3H)。 LC-MS: [M+H]+ = 539.17 | |
E 15 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.83 (s, 1H), 8.66 (t,J = 5.1 Hz, 1H), 7.88 (d,J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.41 (d,J = 8.1 Hz, 1H), 6.96 (dd,J = 10.3, 8.7 Hz, 1H), 6.71 (dd,J = 8.7, 3.9 Hz, 1H), 5.47 (d,J = 14.9 Hz, 1H), 4.75 (d,J = 4.9 Hz, 2H), 4.67 (dd,J = 15.0, 9.5 Hz, 1H), 4.56 (t,J = 8.8 Hz, 2H), 4.17 (d,J = 14.8 Hz, 1H), 4.13 - 3.98 (m, 1H), 3.34 (t,J = 8.7 Hz, 2H), 3.09 (p,J = 6.9 Hz, 1H), 1.29 (dd,J = 6.9, 5.4 Hz, 6H)。 LC-MS: [M+H]+ = 541.18 | |
E 16 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.85 (s, 1H), 8.65 (d,J = 5.4 Hz, 1H), 7.91 (d,J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.43 (d,J = 8.1 Hz, 1H), 6.96 (dd,J = 10.3, 8.7 Hz, 1H), 6.71 (dd,J = 8.6, 3.9 Hz, 1H), 5.40 (d,J = 14.8 Hz, 1H), 4.75 (d,J = 4.4 Hz, 2H), 4.56 (t,J = 8.8 Hz, 2H), 4.27-4.12 (m, 3H), 3.34 (t,J = 8.7 Hz, 2H), 2.84 (q,J = 7.6 Hz, 2H), 1.67 (t,J = 19.3 Hz, 3H), 1.29 (t,J = 7.6 Hz, 3H)。 LC-MS: [M+H]+ = 523.19 | |
E 17 | 1 H NMR (400 MHz, DMSO- d6 ) δ 9.06 (s, 1H), 8.88 (t,J = 5.1 Hz, 1H), 8.60 (dd,J = 4.8, 1.6 Hz, 1H), 7.92 (dd,J = 8.0, 1.6 Hz, 1H), 7.67 (s, 1H), 7.57 (dd,J = 7.9, 4.8 Hz, 1H), 7.45 (d,J = 1.3 Hz, 1H), 6.98 (t,J = 9.5 Hz, 1H), 6.73 (dd,J = 8.6, 3.9 Hz, 1H), 5.82 (d,J = 14.4 Hz, 1H), 5.34 (d,J = 14.3 Hz, 1H), 4.78 (t,J = 4.6 Hz, 2H), 4.59 (t,J = 8.8 Hz, 2H), 3.34 (t,J = 8.7 Hz, 2H), 2.60 (s, 3H)。 LC-MS: [M+H]+ = 454.17 | |
E 18 | 1 H NMR (400 MHz, DMSO- d6 ) δ 9.04 (s, 1H), 8.85 (s, 1H), 7.78 (d,J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.42 (d,J = 7.8 Hz, 2H), 7.03 - 6.91 (m, 1H), 6.72 (dd,J = 8.7, 3.9 Hz, 1H), 5.76 (d,J = 14.3 Hz, 1H), 5.27 (d,J = 14.2 Hz, 1H), 4.76 (d,J = 3.9 Hz, 2H), 4.58 (t,J = 8.8 Hz, 2H), 3.34 (t,J = 8.7 Hz, 2H), 2.61 (s, 3H), 2.53 (s, 3H)。 LC-MS: [M+H]+ = 468.18 | |
E 19 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.85 (s, 1H), 8.71 (t,J = 5.1 Hz, 1H), 7.93 (d,J = 8.0 Hz, 1H), 7.54 (s, 1H), 7.44 (d,J = 8.1 Hz, 1H), 6.96 (dd,J = 10.3, 8.6 Hz, 1H), 6.71 (dd,J = 8.7, 3.9 Hz, 1H), 5.46 (d,J = 15.0 Hz, 1H), 4.75 (d,J = 4.5 Hz, 2H), 4.71 - 4.61 (m, 1H), 4.56 (t,J = 8.8 Hz, 2H), 4.19 (d,J = 15.0 Hz, 1H), 4.08 (dq,J = 15.2, 9.0 Hz, 1H), 3.34 (t,J = 8.7 Hz, 2H), 2.57 (s, 3H)。 LC-MS: [M+H]+ = 516.15 | |
E 20 | LC-MS: [M+H]+ = 515.18 | |
E 21 | LC-MS: [M+H]+ = 518.18 | |
E 22 | LC-MS: [M+H]+ = 517.18 | |
E 23 | LC-MS: [M+H]+ = 520.20 | |
E 24 | LC-MS: [M+H]+ = 571.19 | |
E 25 | LC-MS: [M+H]+ = 492.14 | |
E 26 | LC-MS: [M+H]+ = 504.14 | |
E 27 | LC-MS: [M+H]+ = 478.12 | |
E 28 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.74 (s, 1H), 8.44 (t, J = 5.1 Hz, 1H), 7.48 (t, J = 6.7 Hz, 1H), 7.38 (td, J = 7.4, 1.6 Hz, 1H), 7.29 (td, J = 7.4, 1.4 Hz, 1H), 7.22 (td, J = 7.5, 1.4 Hz, 2H), 7.10 (s, 1H), 6.96 (dd, J = 10.3, 8.6 Hz, 1H), 6.72 (dd, J = 8.6, 3.9 Hz, 1H), 4.85 - 4.62 (m, 2H), 4.56 (t, J = 8.8 Hz, 2H), 3.38 - 3.20 (m, 4H), 2.82 (dd, J = 8.9, 6.2 Hz, 2H)。 LC-MS: [M+H]+ = 430.16 | |
E 29 | LC-MS: [M+H]+ = 445.17 | |
E 30 | LC-MS: [M+H]+ = 527.17 | |
E 31 | LC-MS: [M+H]+ = 541.18 | |
E 32 | LC-MS: [M+H]+ = 508.14 | |
E 33 | LC-MS: [M+H]+ = 508.14 | |
E 34 | LC-MS: [M+H]+ = 454.17 | |
E 35 | LC-MS: [M+H]+ = 523.14 | |
E 36 | LC-MS: [M+H]+ = 455.15 | |
E 37 | LC-MS: [M+H]+ = 536.17 | |
E 38 | LC-MS: [M+H]+ = 482.20 | |
E 39 | LC-MS: [M+H]+ = 527.17 | |
E 40 | 1 H NMR (400 MHz, DMSO- d6 ) δ 9.02 - 8.67 (m, 2H), 8.11 (d, J = 7.3 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 6.96 (q, J = 9.1 Hz, 1H), 6.72 (dq, J = 8.4, 3.7 Hz, 1H), 5.26 (dd, J = 15.2, 7.2 Hz, 2H), 4.78 (d, J = 6.4 Hz, 2H), 4.56 (q, J = 8.5 Hz, 2H), 4.39 (dd, J = 15.4, 7.0 Hz, 1H), 4.27 (q, J = 7.3 Hz, 1H), 3.35 (q, J = 8.5 Hz, 2H), 1.41 - 1.23 (m, 3H), 1.23 - 1.06 (m, 3H)。 LC-MS: [M+H]+ = 527.17 | |
E 41 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.86 (s, 1H), 8.68 (t, J = 5.1 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.52 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H), 6.95 (dd, J = 10.3, 8.7 Hz, 1H), 6.70 (dd, J = 8.6, 3.9 Hz, 1H), 5.40 (d, J = 14.9 Hz, 1H), 4.75 (d, J = 4.2 Hz, 2H), 4.55 (t, J = 8.7 Hz, 2H), 4.27 (dd, J = 17.6, 13.4 Hz, 2H), 3.78 (td, J = 14.0, 6.8 Hz, 1H), 3.33 (t, J = 8.7 Hz, 2H), 2.57 (s, 3H), 1.65 (t, J = 19.3 Hz, 3H)。 LC-MS: [M+H]+ = 509.18 | |
E 42 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.85 (s, 1H), 8.78 (d,J = 8.3 Hz, 2H), 8.10 (s, 1H), 7.64 (s, 1H), 7.16 - 6.83 (m, 2H), 6.71 (dd,J = 8.6, 3.9 Hz, 1H), 5.39 (d,J = 15.2 Hz, 1H), 4.76 (d,J = 4.8 Hz, 2H), 4.69 - 4.48 (m, 3H), 4.35 (d,J = 15.1 Hz, 1H), 4.06 (dt,J = 15.1, 9.1 Hz, 1H), 3.34 (t,J = 8.7 Hz, 2H)。 LC-MS: [M+H]+ = 549.13 | |
E 43 | LC-MS: [M+H]+ = 545.16 | |
E 44 | 1 H NMR (400 MHz, DMSO- d6 ) δ 8.81 (d, J = 25.3 Hz, 3H), 8.02 (s, 1H), 7.63 (s, 1H), 7.19 - 6.81 (m, 2H), 6.71 (dd, J = 8.6, 3.8 Hz, 1H), 6.44 - 6.03 (m, 1H), 5.36 (d, J = 15.0 Hz, 1H), 4.76 (d, J = 4.8 Hz, 2H), 4.55 (t, J = 8.8 Hz, 2H), 4.35 (d, J = 14.9 Hz, 1H), 4.06 (dt,J = 15.1, 9.1 Hz, 1H), 3.66 (td, J = 13.0, 10.9, 4.6 Hz, 1H), 3.34 (t, J = 8.8 Hz, 2H)。 LC-MS: [M+H]+ = 531.14 | |
E 48 | LC-MS: [M+H]+ = 585.18 | 實例26 |
E 49 | LC-MS: [M+H]+ = 599.20 | 實例26 |
E 50 | LC-MS: [M+H]+ = 555.21 | 實例26 |
E 51 | LC-MS: [M+H]+ = 555.21 | 實例26 |
E 52 | LC-MS: [M+H]+ = 553.19 | 實例26 |
在EED Alpha篩選結合分析中測試本揭示案之代表性化合物,且在Karpas 422及Pfeiffer細胞株中測定7天處理之抗增殖活性(IC50
值)。「N/A」表示「未評定」。
細胞增殖分析:
人類B細胞淋巴瘤細胞KARPAS422係購自美國菌種保藏中心(ATCC),且使用標準細胞培養條件在補充有10% FBS (Invitrogen,目錄號10099-141)之RPMI-1640 (Invitrogen,目錄號11875)中在37℃、5% CO2
之含濕氣培育箱中培養。為了評定PRC2抑制對細胞生長之影響,將細胞以2 000-3 000個細胞/孔之密度接種於96孔細胞培養盤之200 μL培養基中,且在37℃下在5% CO2
之氛圍中用連續稀釋之化合物處理7天。使用Tecan Infinite M1000多模式微量盤讀取器(Tecan,Morrisville,NC),藉由基於乳酸脫氫酶之WST-8分析(Dojindo Molecular Technologies)評估細胞生長。將WST-8試劑添加至培養盤,培育1-4小時,且在450 nm下讀取。將讀數相對於經DMSO處理之細胞標準化,且使用GraphPad Prism 6軟體藉由非線性回歸分析來計算IC50
藉由AlphaScreen (α-篩選)進行EED-H3K27Me3肽競爭結合分析:
為了評定在EED-H3K27Me3競爭結合分析中之效力,將本揭示案之代表性化合物在DMSO中連續稀釋3倍,以獲得總共十二個濃度。將各濃度之化合物(各2.5 µl)轉移至384孔Perkin Elmer OptiPlate-384白色培養盤中。將5 µl在緩衝液(25 mM HEPES,pH 8,0.02% Tween-20,0.5% BSA)中含有20 nM EED (1-441)-His蛋白之溶液添加至孔中,且隨後與化合物培育15分鐘。將2.5 µl在緩衝液(25 mM HEPES,pH 8,0.02% Tween-20,0.5% BSA)中含有20 nM生物素-H3K27Me3 (19-33)肽之溶液添加至孔中,且隨後與化合物培育30分鐘。AlphaScreen偵測珠粒混合物係在即將使用之前藉由將鎳螯合劑受體珠粒及抗生蛋白鏈菌素供體珠粒以1:1之比率(Perkin Elmer,產品編號6760619C/M/R)混合至上述緩衝液中來製備。隨後將10 µl偵測珠粒混合物添加至培養盤,且在黑暗中在室溫下培育1小時。供體及受體珠粒之最終濃度各為10 µg/ml。在680 nm激發樣品後,使用適合於用615 nm濾光片進行最佳信號偵測之AlphaScreen設置,在CLARIOStar盤讀取器(BMG Labtech)上讀取培養盤。615 nm處之發射信號用於量化化合物抑制。基於來自陽性(最大信號對照)及陰性對照(最小信號對照)之讀數對AlphaScreen信號進行標準化,得到剩餘活性之百分比。隨後將資料擬合至劑量反應方程式,得到IC50
值。
結果列於表2A及2B。
表2A
表2B
IC50
定義:A = < 10 nM;B = > 10 nM-< 100 nM;及C = > 100 nM
實例28
活體內功效
化合物編號 | Pfeiffer 細胞株 (nM) | Karpas 細胞株 (nM) | Alpha screen (nM) |
1 | > 100 | > 100 | > 10 |
2 | > 100 | > 100 | > 10 |
3 | 83.95 | N/A | 6.88 |
4 | > 100 | > 100 | > 10 |
5 | 18.05 | 32.23 | 0.26 |
6 | 0.22 | 1.98 | 0.19 |
7 | 0.68 | 3.35 | 0.61 |
8 | 0.57 | 2.91 | 1.97 |
9 | 1.81 | 5.60 | 0.84 |
10 | 2.93 | 15.82 | 1.11 |
11 | 1.22 | 4.61 | 0.75 |
12 | 0.65 | 3.84 | 0.34 |
13 | 1.99 | 9.03 | 1.09 |
14 | 0.36 | 3.49 | 3.35 |
15 | 1.25 | 4.36 | 0.52 |
16 | 3.39 | 14.67 | 0.70 |
17 | 4.17 | 20.51 | 0.66 |
18 | 0.73 | 15.28 | 0.70 |
19 | 0.79 | 9.60 | 1.13 |
20 | 0.90 | 13.88 | 0.61 |
21 | 0.61 | 14.95 | 0.55 |
22 | 4.88 | 45.57 | 0.67 |
23 | 9.95 | 89.21 | 1.18 |
24 | 38.38 | > 100 | 4.75 |
25 | 0.29 | 16.46 | 3.31 |
26 | 32.91 | 41.4 | 9.84 |
27 | > 100 | > 100 | 5.87 |
28 | > 100 | > 100 | 2.58 |
29 | N/A | N/A | 20.73 |
30 | N/A | N/A | 2.03 |
31 | N/A | 3.68 | 0.6041 |
32 | 11.6 | 84.41 | 1.84 |
33 | 0.22 | 1.11 | 1.06 |
34 | 0.35 | 2.64 | 0.67 |
35 | 0.12 | 1.23 | 1.16 |
36 | 1.04 | 5.66 | 1.44 |
37 | 0.25 | 1.79 | 0.94 |
38 | 3.22 | 15.71 | 1.25 |
39 | 22.67 | > 100 | 26.14 |
40 | 38.78 | > 100 | 10.48 |
41 | 1.03 | 1.69 | 0.60 |
42 | 4.19 | 4.01 | 0.84 |
43 | 1.05 | 5.46 | 1.05 |
44 | 1.03 | 2.44 | 1.34 |
45 | 0.61 | 6.15 | 3.39 |
46 | N/A | 0.57 | 1.07 |
47 | N/A | 0.65 | 0.91 |
48 | N/A | 0.74 | 1.65 |
49 | N/A | 2.78 | 1.81 |
50 | N/A | 0.71 | 1.16 |
51 | N/A | 2.08 | 0.70 |
52 | N/A | 0.54 | 0.70 |
53 | N/A | > 100 | 3.96 |
54 | N/A | > 100 | 0.95 |
55 | N/A | 8.08 | 2.14 |
56 | N/A | 21.01 | 4.49 |
57 | N/A | 2.63 | 4.20 |
58 | N/A | N/A | 2.74 |
59 | N/A | 39.86 | 2.14 |
60 | N/A | 1.18 | N/A |
61 | N/A | 1.63 | 1.19 |
62 | N/A | 4.86 | 1.44 |
63 | N/A | 3.69 | 1.89 |
64 | N/A | 2.44 | N/A |
65 | N/A | 0.69 | N/A |
66 | N/A | 0.74 | 3.61 |
67 | N/A | 7.78 | 2.87 |
68 | N/A | 1.35 | 3.86 |
69 | N/A | >100 | 19.83 |
70 | N/A | >100 | >100 |
71 | N/A | >100 | 8.94 |
72 | N/A | 3.86 | 2.69 |
73 | N/A | 11.33 | 0.50 |
74 | N/A | 46.98 | 1.67 |
75 | N/A | 11.06 | 1.72 |
76 | N/A | 14.53 | 0.97 |
77 | N/A | 22.46 | 1.90 |
78 | N/A | 34.46 | 3.23 |
79 | N/A | 15.28 | 1.61 |
80 | N/A | 2.42 | 1.61 |
81 | N/A | 1.43 | 1.70 |
82 | 0.074 | 3.51 | 10.49 |
83 | 0.304 | 6.32 | 9.95 |
84 | 0.048 | 1.48 | 3.07 |
85 | 0.13 | 2.71 | 9.82 |
86 | 0.021 | 2.29 | 2.56 |
87 | 0.018 | 8.67 | 11.15 |
88 | 0.035 | 25.68 | 12.32 |
89 | N/A | N/A | N/A |
90 | 0.044 | 0.078 | N/A |
91 | 0.043 | 5.23 | N/A |
92 | N/A | N/A | N/A |
93 | 0.55 | 3.71 | N/A |
94 | 0.20 | 13.9 | 14.00 |
95 | 0.023 | 0.89 | 13.12 |
96 | 0.056 | 21.19 | 21.88 |
97 | 0.058 | 1.847 | N/A |
98 | N/A | N/A | N/A |
99 | 0.19 | 0.88 | 3.25 |
100 | 1.05 | 0.26 | 0.24 |
101 | 1.76 | 5.59 | 0.56 |
102 | 0.59 | 0.94 | 0.62 |
103 | N/A | 1.88 | 0.59 |
104 | N/A | 8.1 | 0.59 |
105 | N/A | 10.81 | 1.01 |
106 | N/A | 10.6 | 0.556 |
107 | N/A | 2.84 | 0.215 |
108 | N/A | 6.89 | 0.421 |
109 | N/A | 10.87 | 0.53 |
110 | N/A | 3.93 | 0.47 |
111 | N/A | 1.42 | 0.34 |
112 | N/A | 20.32 | 0.83 |
113 | N/A | >100 | 0.98 |
114 | N/A | > 100 | 1.48 |
115 | N/A | 50.09 | 2.35 |
116 | N/A | > 100 | 1.98 |
117 | N/A | 19.49 | 0.19 |
118 | N/A | 28.38 | 0.27 |
119 | N/A | 27.93 | 0.20 |
120 | N/A | >100 | 1.15 |
121 | N/A | >100 | 0.31 |
122 | N/A | >100 | 0.31 |
123 | N/A | 22.88 | 4.74 |
124 | N/A | 72.03 | 8.04 |
125 | N/A | 91.65 | 27.64 |
126 | N/A | >100 | N/A |
127 | N/A | >100 | N/A |
128 | N/A | >100 | N/A |
129 | N/A | >100 | N/A |
130 | N/A | >100 | N/A |
131 | N/A | >100 | N/A |
132 | N/A | >100 | N/A |
133 | N/A | >100 | N/A |
134 | N/A | >100 | N/A |
135 | N/A | 7.07 | N/A |
136 | N/A | >100 | N/A |
137 | N/A | >100 | N/A |
138 | N/A | >100 | N/A |
139 | N/A | >100 | N/A |
140 | N/A | >100 | N/A |
141 | N/A | >100 | N/A |
142 | N/A | >100 | N/A |
143 | N/A | >100 | N/A |
144 | N/A | >10 | N/A |
化合物編號 | Pfeiffer細胞株(nM) | Karpas細胞株(nM) | Alpha screen (nM) |
E 1 | A | A | A |
E 2 | A | A | A |
E 3 | A | A | A |
E 4 | A | A | A |
E 5 | A | A | A |
E 6 | A | A | A |
E 7 | A | A | A |
E 8 | A | A | A |
E 9 | A | A | A |
E 10 | B | B | A |
E 11 | A | A | A |
E 12 | A | A | A |
E 13 | A | A | A |
E 14 | A | A | A |
E 15 | A | A | A |
E 16 | A | A | A |
E 17 | B | B | A |
E 18 | A | B | A |
E 19 | A | A | A |
E 20 | A | A | A |
E 21 | A | A | A |
E 22 | A | A | A |
E 23 | A | A | A |
E 24 | B | B | B |
E 25 | B | B | A |
E 26 | A | B | B |
E 27 | A | B | B |
E 28 | B | C | B |
E 29 | B | B | B |
E 30 | B | B | B |
E 31 | B | B | B |
E 32 | A | B | B |
E 33 | B | B | B |
E 34 | A | B | B |
E 35 | B | B | B |
E 36 | B | B | B |
E 37 | B | B | B |
E 38 | B | B | B |
E 39 | A | B | B |
E 40 | A | A | A |
E 45 | A | A | A |
E 46 | A | A | A |
E 47 | A | A | A |
E 48 | A | A | A |
E 49 | A | A | A |
E 50 | A | A | A |
E 51 | A | A | A |
E 52 | A | A | A |
在密歇根大學動物使用及護理委員會之指導下,使用經核准之動物方案進行動物實驗。異種移植腫瘤係藉由在自Charles River獲得之嚴重聯合免疫缺陷(SCID)小鼠的背側皮下注射含1×107
個Karpas 422人類B細胞淋巴瘤細胞之50%基質膠來建立,每隻小鼠一個腫瘤。當腫瘤達到~100 mm3
時,將小鼠隨機分配至處理組及媒劑對照組。每日監測動物是否有任何毒性跡象,且在治療期間每週稱重2-3次,治療結束後至少每週稱重一次。在治療期間每週2-3次且在治療結束後至少每週一次,利用電子測徑規量測腫瘤大小。腫瘤體積計算為V=L×W2
/2,其中L為腫瘤的長度,W為腫瘤的寬度。將化合物調配為在PEG 200中之懸浮液,且藉由管飼以特定劑量經口投與。適用時,結果以平均值± SEM表示。使用GraphPad Prism 7.00 (GraphPad軟體)進行繪圖及統計分析。
圖1中提供本揭示案之代表性化合物的抗腫瘤活性。圖2提供經處理之動物的體重。
現已完整描述本文之方法、化合物及組合物,熟習此項技術者應理解,在不影響本文中或其任一實施例所提供之方法、化合物及組合物之範疇的情況下,該等方法、化合物及組合物可在條件、調配物及其他參數之廣泛且等效範圍內執行。
本文中所引用之所有專利、專利申請案及公開案均全部以全文引用之方式併入本文中。
圖1為顯示在小鼠之KARPAS422腫瘤模型中,本揭示案之代表性化合物之抗腫瘤功效的線圖。
圖2為顯示在小鼠之KARPAS422腫瘤模型中,用本揭示案之代表性化合物處理之荷瘤小鼠之體重變化的線圖。
Claims (27)
- 一種式I化合物,
- 如請求項1之化合物,其中:R8a選自由-CF3、-CH3、-CHF2、-CD3及環丙基組成之群組;及R8b及R8c為氫,或其醫藥學上可接受之鹽或水合物或其立體異構體。
- 如請求項2之化合物,其具有式VII:
- 如請求項1之化合物,其中W為-C(=O)-且t為1,或其醫藥學上可接受之鹽或水合物或其立體異構體。
- 如請求項1之化合物,其中:R12a為氟;及R12b及R12c獨立地選自由氫及氟組成之群組,或其醫藥學上可接受之鹽或水合物或立體異構體。
- 如請求項15之化合物,其選自由以下組成之群組:4-乙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮; 12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-(2,2,2-三氟乙基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮;4-環丙基-12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮;12-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-4-異丙基-7-(三氟甲基)-4,5-二氫-3H-2,4,8,11,12a-五氮雜苯并[4,5]環辛并[1,2,3-cd]茚-3-酮;及11-(((5-氟-2,3-二氫苯并呋喃-4-基)甲基)胺基)-6-甲基-4H-3-硫雜-2,5,10,11a-四氮雜二苯并[cd,f]薁3,3-二氧化物,或其醫藥學上可接受之鹽或水合物或其立體異構體。
- 一種式I化合物,
- 一種醫藥組合物,其包含如請求項1至17中任一項之化合物或其醫藥學上可接受之鹽或水合物或其立體異構體及醫藥學上可接受之載劑。
- 一種如請求項1至17中任一項之化合物或其醫藥學上可接受之鹽或水合物或其立體異構體、或如請求項18之醫藥組合物用於製造藥物之用途,其中該藥物係用於治療有需要之個體之癌症。
- 如請求項19之用途,其中該癌症係選自白血病、小細胞肺癌及非小細胞肺癌。
- 如請求項19之用途,其中該癌症係選自急性嗜酸性球性白血病、急性類紅血球性白血病、急性淋巴母細胞性白血病、急性巨核母細胞性白血病、急性單核球性白血病、急性前髓細胞性白血病、成人T細胞白血病/淋巴瘤、侵襲性NK細胞白血病、B細胞慢性淋巴細胞性白血病、B細胞前淋巴細胞性白血病、毛細胞白血病、急性淋巴細胞性白血病、急性骨髓性白血病、慢性淋巴細胞性白血病及肥大細胞白血病。
- 一種如請求項1至17中任一項之化合物或其醫藥學上可接受之鹽或水合物或其立體異構體、或如請求項18之醫藥組合物用於製造藥物之用途,其中該藥物係用於抑制有需要之個體之細胞內之EED蛋白。
- 一種套組,其包含如請求項1至17中任一項之化合物或其醫藥學上可接受之鹽或水合物或其立體異構體,及向患有癌症之個體投與該化合物或其醫藥學上可接受之鹽或水合物或其立體異構體的說明書。
- 如請求項24之套組,其中該癌症係選自白血病、小細胞肺癌及非小細胞肺癌。
- 如請求項24之套組,其中該癌症係選自急性嗜酸性球性白血病、急性類紅血球性白血病、急性淋巴母細胞性白血病、急性巨核母細胞性白血病、急性單核球性白血病、急性前髓細胞性白血病、成人T細胞白血病/淋巴瘤、侵襲性NK細胞白血病、B細胞慢性淋巴細胞性白血病、B細胞前淋巴細胞性白血病、毛細胞白血病、急性淋巴細胞性白血病、急性骨髓性白血病、慢性淋巴細胞性白血病及肥大細胞白血病。
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CN115028631A (zh) * | 2021-03-05 | 2022-09-09 | 中国科学院上海药物研究所 | 三氮唑并嘧啶衍生物、其药物组合物及用途 |
WO2022222932A1 (en) * | 2021-04-19 | 2022-10-27 | Ascentage Pharma (Suzhou) Co., Ltd. | A pharmaceutical combination and use thereof |
WO2023016511A1 (zh) * | 2021-08-11 | 2023-02-16 | 上海青煜医药科技有限公司 | 氮杂芳基化合物、其制备方法及应用 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017221100A1 (en) * | 2016-06-20 | 2017-12-28 | Novartis Ag | Imidazopyrimidine compounds useful for the treatment of cancer |
Family Cites Families (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5093330A (en) | 1987-06-15 | 1992-03-03 | Ciba-Geigy Corporation | Staurosporine derivatives substituted at methylamino nitrogen |
JP2001523958A (ja) | 1997-03-21 | 2001-11-27 | ブライハム アンド ウィミンズ ホスピタル,インコーポレイテッド | 免疫療法のctla−4結合ペプチド |
JP4896327B2 (ja) | 1999-08-23 | 2012-03-14 | ダナ−ファーバー キャンサー インスティテュート,インコーポレイテッド | Pd−1、b7−4の受容体、およびその使用 |
EP1792991A1 (en) | 1999-08-24 | 2007-06-06 | Medarex, Inc. | Human CTLA-4 antibodies and their uses |
ES2654064T3 (es) | 2002-07-03 | 2024-03-13 | Ono Pharmaceutical Co | Composiciones inmunopotenciadoras que comprenden anticuerpos anti-PD-L1 |
CN101213297B (zh) | 2005-05-09 | 2013-02-13 | 小野药品工业株式会社 | 程序性死亡-1(pd-1)的人单克隆抗体及单独使用或与其它免疫治疗剂联合使用抗pd-1抗体来治疗癌症的方法 |
KR101586617B1 (ko) | 2007-06-18 | 2016-01-20 | 머크 샤프 앤 도메 비.브이. | 사람 프로그램된 사멸 수용체 pd-1에 대한 항체 |
AR072999A1 (es) | 2008-08-11 | 2010-10-06 | Medarex Inc | Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos |
NZ591130A (en) | 2008-08-25 | 2012-09-28 | Amplimmune Inc | Compositions comprising a PD-1 antagonists and cyclophosphamide and methods of use thereof |
PE20120341A1 (es) | 2008-12-09 | 2012-04-24 | Genentech Inc | Anticuerpos anti-pd-l1 y su uso para mejorar la funcion de celulas t |
JP4965623B2 (ja) | 2009-09-30 | 2012-07-04 | インターナショナル・ビジネス・マシーンズ・コーポレーション | 所定のソフトウェアの実行パラメータを入力フィールドへ入力することを支援するための方法、システム、およびプログラム |
US8907053B2 (en) | 2010-06-25 | 2014-12-09 | Aurigene Discovery Technologies Limited | Immunosuppression modulating compounds |
WO2013006490A2 (en) | 2011-07-01 | 2013-01-10 | Cellerant Therapeutics, Inc. | Antibodies that specifically bind to tim3 |
AU2013201121A1 (en) | 2011-09-20 | 2013-04-04 | Vical Incorporated | Synergistic anti-tumor efficacy using alloantigen combination immunotherapy |
RS61033B1 (sr) | 2011-11-28 | 2020-12-31 | Merck Patent Gmbh | Antitela na pd-l1 i njihova upotreba |
BR122022015975B1 (pt) | 2012-05-15 | 2024-01-02 | Bristol-Myers Squibb Company | Anticorpos monoclonais, kit para o tratamento de um indivíduo afligido com um câncer, processo para medir pd-l1 membranoso em células tumorais isoladas e uso do anticorpo ou uma porção que se liga ao antígeno do mesmo |
AR091649A1 (es) | 2012-07-02 | 2015-02-18 | Bristol Myers Squibb Co | Optimizacion de anticuerpos que se fijan al gen de activacion de linfocitos 3 (lag-3) y sus usos |
JP2015525781A (ja) | 2012-07-31 | 2015-09-07 | ザ ブリガム アンド ウィメンズ ホスピタル インコーポレイテッドThe Brigham and Women’s Hospital, Inc. | 免疫応答の調節 |
JP6224739B2 (ja) | 2013-03-15 | 2017-11-01 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドGlaxosmithkline Intellectual Property Development Limited | 抗lag−3結合タンパク質 |
DK3043816T3 (da) | 2013-09-11 | 2019-10-14 | Medimmune Ltd | Anti-b7-h1-antistoffer til behandling af tumorer |
WO2015132675A2 (en) | 2014-03-07 | 2015-09-11 | University Health Network | Methods and compositions for modifying the immune response |
US20150259420A1 (en) | 2014-03-14 | 2015-09-17 | Novartis Ag | Antibody molecules to lag-3 and uses thereof |
ES2798424T3 (es) * | 2016-06-20 | 2020-12-11 | Novartis Ag | Compuestos de triazolopiridina y usos de estos |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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