TW202304467A - 作為新穎sos1抑制劑之磷衍生物 - Google Patents
作為新穎sos1抑制劑之磷衍生物 Download PDFInfo
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- TW202304467A TW202304467A TW111114329A TW111114329A TW202304467A TW 202304467 A TW202304467 A TW 202304467A TW 111114329 A TW111114329 A TW 111114329A TW 111114329 A TW111114329 A TW 111114329A TW 202304467 A TW202304467 A TW 202304467A
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- Prior art keywords
- ethyl
- pyrimidin
- methyl
- amino
- fluorophenyl
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- 150000003017 phosphorus Chemical class 0.000 title abstract description 4
- 239000003112 inhibitor Substances 0.000 title description 13
- 101100421901 Caenorhabditis elegans sos-1 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 418
- 238000000034 method Methods 0.000 claims abstract description 121
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 44
- 201000010099 disease Diseases 0.000 claims abstract description 26
- 239000004480 active ingredient Substances 0.000 claims abstract description 22
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- -1 4-({(1R)-1-[3-(1,1-difluoro-2-hydroxy-2-methylpropyl)-2-fluorophenyl]ethyl} Amino)-6-(dimethylphosphoryl)-2-methylpyrido[3,4-d]pyrimidin-8-ol Chemical compound 0.000 claims description 392
- 239000000203 mixture Substances 0.000 claims description 221
- 150000003839 salts Chemical class 0.000 claims description 186
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- 150000001204 N-oxides Chemical class 0.000 claims description 130
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 88
- 150000004677 hydrates Chemical class 0.000 claims description 88
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 52
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 51
- 125000004432 carbon atom Chemical group C* 0.000 claims description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 150000001412 amines Chemical class 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 239000000126 substance Substances 0.000 claims description 29
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- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 22
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- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 20
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- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
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- 150000002367 halogens Chemical class 0.000 claims description 16
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
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- 125000004437 phosphorous atom Chemical group 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 9
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Classifications
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- 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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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
- C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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Abstract
Description
本發明涵蓋如本文描述及定義之通式(I)新穎SOS1抑制劑、製備該等化合物之方法、適用於製備該等化合物之中間化合物、包含該等化合物之醫藥組合物及組合,及該等化合物於製造用於治療或預防疾病,特別是過度增生性疾患,尤其與SOS1相關聯之疾病之醫藥組合物中之用途,其作為唯一藥劑或與其他活性成分組合。
US 2011/0054173 A1揭示某些1-或2-(4-(芳氧基)-苯基)乙胺基-、氧基-或氫硫基)喋啶及1-或2-(4-(雜芳氧基)-苯基)乙胺基-、氧基-或氫硫基)喋啶及其作為農業化學及動物健康產品之用途。
2-位置取代之喹唑啉化合物描述(例如)於EP 0326328、EP 0326329、WO93/007124、WO2003/087098及US 5,236,925中。不將此等化合物描述為醫藥活性化合物,或若將其等描述為醫藥活性化合物,則將其等描述為對表皮生長因子受體(EGFR)具有親和力之化合物。
在大多數(45至100%)接受EGFR抑制劑之病患中,皮膚毒性係類特異性副作用,其通常表現為丘膿皰性皮疹。該皮膚毒性係與皮膚中EGFR之抑制相關,EGFR對表皮之正常發育及生理至關重要。
然而,目前最新技術不描述:
如本文描述及定義之本發明之通式(I)磷衍生物,即攜載含磷官能基並有效且選擇性抑制Ras-Sos1相互作用之衍生物。
Ras蛋白在人類癌症中發揮重要作用。Ras蛋白中之突變可存在於所有人類腫瘤之20至30%中並識別為致瘤驅動因素,尤其於肺癌、結腸直腸癌及胰臟癌中(Malumbres & Barbacid 2002 Nature Reviews Cancer, Pylayeva-Gupta等人,2011 Nature Reviews Cancer)。已知三種人類Ras基因編碼21 kDa大小之四種不同Ras蛋白:H-Ras、N-Ras,及K-Ras之兩種剪接變體,即K-Ras 4A及K-Ras-4B。所有Ras同功型於GTP結合域內均係高度保守的且主要於高變C端區域中不同。該等不同Ras同功型之C端係藉由脂質化(法尼基化、棕櫚醯化)進行轉譯後修飾以促進膜錨定。Ras蛋白於細胞質膜處之定位提供跨膜生長受體之附近且已顯示對傳遞來自與細胞內下游途徑之細胞外生長因子結合之生長信號而言必不可少。取決於細胞環境,多種上游信號可活化Ras蛋白,諸如表皮生長因子受體(EGFR)、血小板衍生之生長因子受體(PDGFR)、神經生長因子受體(NGFR)等。經活化之Ras可透過多種下游途徑(例如Raf-MEK-ERK或PI3K-PDK1-Akt途徑)傳訊。
在分子水準上,Ras蛋白發揮分子開關之作用。藉由結合GTP及GDP,其等以活性(結合GTP)及無活性(結合GDP)狀態存在於細胞中。負載活性GTP之Ras藉由其同源Ras結合域(RBD)之結合募集其他蛋白質,導致效應蛋白之活化,接著不同功能之下游傳訊事件,例如細胞骨架重排或轉錄活化。Ras之活性狀態受鳥嘌呤核苷酸交換因子(GEF)及GTP酶活化蛋白(GAP)嚴格調節。GEF藉由促進自GDP至GTP之核苷酸交換來充當Ras之活化劑。GAP藉由催化結合之GTP水解為GDP而將使Ras-GTP去活化。在癌細胞中,通常於GTP結合區內於密碼子12處之點突變消除RAS高效水解結合之GTP,甚至在GAP之存在下之能力。因此,癌細胞包含增加含量之活性突變Ras-GTP,認為其係用於驅動癌細胞增生之關鍵因素。
迄今為止,已鑑別RAS特異性GEF之三種主要家族(於Vigil 2010 Nature Reviews Cancer;Rojas等人,2011, Genes & Cancer 2(3) 298-305中回顧)。存在無七(sevenless)蛋白之兩個子代(SOS1及SOS2)、Ras鳥嘌呤核苷酸釋放蛋白之4種不同同功型(Ras-GRP1-4)及兩種Ras鳥嘌呤核苷酸釋放因子(Ras-GRF1及2)。該等SOS蛋白係經普遍表現及募集至經活化之生長因子之位點。Ras-GRF主要表現於神經系統中,在神經系統中,其等參與Ras之鈣依賴性活化。相反,Ras GRP蛋白表現於造血細胞中並與非受體酪胺酸激酶協同作用。在癌症之情境中,已發現涉及主要SOS蛋白。
自1990年代以來,用於癌症療法之靶向Ras一直係夢想(Downward 2002 Nature Reviews Cancer, Krens等人,2010 Drug Discovery Today)。由於緊湊性質、對GDP及GTP之高親和力與高細胞內GTP濃度之組合,因此一直認為Ras蛋白本身係不可成藥的,即鑑別將結合並抑制活性Ras之小化學分子之幾率係經評為極低。已採取替代方法來減少Ras傳訊,例如藉由解決更具前景之藥物標靶,諸如參與Ras蛋白之轉譯後修飾之酵素,尤其法尼基轉移酶及香葉基香葉基轉移酶(Berndt 2011 Nature Reviews Cancer)。於臨床前模型中經鑑別及開發具有頗具前景之抗腫瘤效應之法尼基轉移酶之抑制劑(FTI)。出乎意料地,在臨床試驗中,此等抑制劑已具有有限之效用。靶向涉及Ras傳訊途徑之上游及下游激酶已更成功。數種藥物正在及已在抑制不同激酶,例如EGFR、Raf、MEK、Akt、PI3K的臨床試驗中(Takashima & Faller 2013 Expert Opin. Ther. Targets)。可獲得抑制Raf、EGFR或MEK之市售癌症藥物。
儘管如此,對當前療法耐藥之Ras依賴性腫瘤之治療仍存在較大之未滿足需求。許多研究小組一直在積極鑑別直接靶向Ras之小分子(Ras小分子已以下於中回顧:Cox等人,2014 Nature Reviews Drug Discovery、Spiegel等人,2014 Nature Chemical Biology, Cromm 2015 Angewandte Chemie、Marin-Ramos等人,Seminars in Cancer Biology)。一組抑制劑包含抑制Ras與其效應物Raf或PI3K之相互作用之小分子。另一組化合物充當K-Ras之特異性半胱胺酸突變形式之共價抑制劑(甘胺酸至半胱胺酸點突變G12C)。Ras-G12C突變體之特異性靶向可具有減少副作用之益處,因為野生型Ras蛋白應不受影響。此外,數個報導顯示中斷GEF輔助之Ras活化之小分子及肽(Hillig等人,2019 PNAS;Gray等人,2019 Angewandte Chemie)。似乎存在數種不同之可導致此作用模式的結合位點。抑制劑可以變構或正構方式結合至Ras或結合至GEF。所有此等直接靶向Ras之方法均處於臨床前研究階段。已顯示穩定之肽在奈米莫耳範圍內具有活性。(Leshchiner等人,2015 PNAS)。必須等待其等於臨床環境中作為藥物之用途。
表皮生長因子受體(EGFR)係酪胺酸激酶(TK)受體,其一經結合至表皮生長因子及其他生長因子配體即經活化,觸發數個下游途徑,包括RAS/MAPK、PI3K/Akt及STAT,該等途徑調節不同細胞過程,包括DNA合成及增生(Russo A, Oncotarget.4254, 2015)。HER (ErbB)受體酪胺酸激酶家族由四個成員構成,即,表皮生長因子受體[EGFR (HER1或ErbB1)、HER2 (ErbB2、neu)、HER3 (ErbB3)及HER4 (ErbB4)]。此等受體之過表現、突變或異常活性已涉及各種類型之癌症(Feldinger K,Breast Cancer (Dove Med Press), 2015, 7, 147)。
第一代抑制劑
埃羅替尼(Erlotinib)及吉非替尼(Gefitinib)係EGFR/HER-1 (人類表皮生長因子受體)酪胺酸激酶之小分子抑制劑。埃羅替尼及吉非替尼已開發為可逆且高度特異性小分子酪胺酸激酶抑制劑,其等競爭性阻斷三磷酸腺苷對EGFR之酪胺酸激酶域中之其結合位點之結合,藉此抑制自體磷酸化並阻斷下游傳訊(Cataldo VD, N Engl J Med, 2011, 364, 947)。
第二代抑制劑
阿法替尼(Afatinib)係經批准用於患有NSCLC之病患之一線治療之經口酪胺酸激酶抑制劑(TKI),該等病患之腫瘤受活化編碼表皮生長因子受體(EGFR)之基因之突變驅動。阿法替尼亦係特異性EGFR突變(T790M)之抑制劑,該突變於約一半接受彼等藥物之病患中引起對第一代EGFR靶向TKI之耐藥性。(Engle JA, Am J Health Syst Pharm 2014, 71 (22), 1933)。
來那替尼(Neratinib)(一種泛HER抑制劑,不可逆酪胺酸激酶抑制劑)結合並抑制表皮生長因子受體EGFR (或HER1)、HER2及HER4之酪胺酸激酶活性,此導致下游傳訊途徑之磷酸化及活化減少。已顯示來那替尼活體外及活體內有效對抗HER2過表現或突變腫瘤。來那替尼當前正於乳癌及其他實體瘤(包括彼等具有HER2突變者)之各種臨床試驗中進行研究(Feldinger K,Breast Cancer (Dove Med Press), 2015, 7, 147)。
達克替尼(Dacomitinib)係EGFR、HER2及HER4之不可逆抑制劑。在臨床前細胞系及異種移植研究中,達克替尼證實抗活化EGFR突變及EGFR T790M兩者之活性(Liao BC, Curr Opin Oncol. 2015, 27(2), 94)。
第三代抑制劑
第三代EGFR-TKI係經設計以抑制EGFR T790M同時保留野生型EGFR。
AZD9291 (AstraZeneca, Macclesfield, UK)(一種單苯胺基嘧啶化合物)係不可逆突變選擇性EGFR-TKI。此藥物在結構上不同於第一代及第二代EGFR-TKI。在臨床前研究中,其強效抑制具有活化EGFR突變(EGFR del19及EGFR L858R)及EGFR T790M之細胞系中EGFR之磷酸化。AZD9291亦於具有活化EGFR突變及EGFR T790M之腫瘤異種移植及轉基因小鼠模型中引起深刻且持續之腫瘤消退。AZD9291在抑制野生型EGFR細胞系之磷酸化方面之效力降低(Liao BC, Curr Opin Oncol. 2015, 27(2), 94)。
羅西替尼(Rociletinib) (CO-1686) (Clovis Oncology, Boulder, Colo) (一種2,4-二取代之嘧啶分子)係不可逆突變選擇性EGFR-TKI。在臨床前研究中,CO-1686於具有活化EGFR突變及EGFR T790M之細胞系、異種移植模型及轉基因小鼠模型中導致腫瘤消退(Walter AO, Cancer Discov, 2013, 3(12), 1404)。
HM61713 (Hanmi Pharmaceutical Company Ltd, Seoul, South Korea)係用於活化EGFR突變及EGFR T790M之經口投與、選擇性抑制劑。其對野生型EGFR具有低活性(Steuer CE, Cancer. 2015, 121(8), E1)。
更有趣之文獻係
Hofmann等人,Cancer Discov 2021;11:142-5及
Hillig RC, Bader B. Adv Cancer Res. 2022;153:169-203。
現已發現且此構成本發明之基礎,本發明之化合物具有令人驚訝且有利之性質。
特別是,已驚訝地發現本發明之化合物有效且選擇性抑制Ras-Sos1相互作用並可因此用於治療或預防過度增生性疾患,特別是癌症。
根據第一態樣,本發明涵蓋通式(I)化合物:
(I)
其中
X
1表示CH或N;
X
2表示CR
a或N
X
3表示CR
a或N
X
4表示CH或N
Y表示O或S;
R
1、R
2係彼此獨立地選自C
1-4烷基、OR
b或NR
cR
d;或
R
1、R
2連同其等結合之磷原子一起形成4至7員雜環烷基,其中一或多個碳原子可經-O-、-NR
e-、-S-、-S(O)-、S(O)
2-或-S(O)NR
f-置換;且其中各殘餘碳原子可視需要經一或兩個CH
3或經一個-CH
2-CH
3取代,
R
3係選自-H、-OH、-OMe、-CN、-NR
pR
q,或視需要經OH、OMe、CN或鹵素取代之C
1-2-烷基
R
4係選自-F、-Cl、-Br、-OH、-NH
2、-N(CH
3)H、-CH
3或-CF
2H;
R
5表示-A-B-E,其中
A表示-CR
jR
k-或不存在,及
B表示-CR
lR
m-或不存在,及
E 表示-H、-F、-OH、-OCH
3、-NH
2、-NH-CH
3、-N(CH
3)
2、-N(CH
3)-OCH
3、-CN、-SO
2-CH
3、-NH-SO
2-CH
3、-N(CH
3)-SO
2-CH
3、-NH-C(O)-CH
3、-N(CH
3)-C(O)-CH
3、-S(=NH)(=O)-CH
3、-S(=N-CH
3)(=O)-CH
3、-C(O)-NH
2、-C(O)-NH(CH
3)、-C(O)-N(CH
3)
2,或
R
5表示-SO
2-NR
nR
o,
R
6係選自-H、鹵素或-CH
3;
R
a係選自-H、鹵素、-OH、-OCH
3、-CN、環丙基、-NH
2、-NH(CH
3)、-N(CH
3)
2,或視需要經鹵素、-OH或-OCH
3、-CH
3、-CF
3、-NH
2、-NH(CH
3)、-N(CH
3)
2或-CN取代一或多次之C
1-2烷基
R
b係選自-H (在以下條件下:若R
1及R
2兩者均為OR
b,則僅一個R
b可為H)、-CH
3、-CH
2-CH
3、-CH(CH
3)
2或環丙基,
R
c係選自-CH
3、-CH
2-CH
3、-CH(CH
3)
2或環丙基,
R
d係選自-H、-CH
3、-CH
2-CH
3、-CH(CH
3)
2或環丙基,
R
e係選自H、視需要經一或多個F取代之C
1-C
3-烷基、環丙基、-C(O)-R
g、-SO
2-CH
3或視需要經-CH
3、鹵素、-CF
3或-CF
2H取代之5員雜芳基
R
f係選自H、-CH
3或-CH
2-CH
3,
R
g係選自視需要經-OH、-OCH
3、-CH
3、鹵素取代之C
1-4烷基;或
係選自視需要經-CH
3、CH
2CH
3、CF
2H、CF
3或鹵素取代之5員雜芳基;或
係選自NR
hR
i;
R
h係選自H或-CH
3,及
R
i係選自視需要經鹵素取代之C
1-3烷基或選自環丙基,
R
j及R
k係彼此獨立地選自H、F或-CH
3,或連同其等結合之碳原子一起形成環丙基;
R
l及R
m係彼此獨立地選自H、氘或-CH
3、-CH
2-CH
3、環丙基;
或連同其等結合之碳原子一起形成環丙基;
R
n及R
o係獨立地選自H或視需要經-OH、-OCH
3取代之C
1-4烷基,或
R
n及R
o連同其等結合之氮一起形成4至7員雜環烷基,其視需要含有其他選自N或O之雜原子,其中此雜環烷基之碳原子可視需要經H或C
1-4烷基取代且其中此C
1-4烷基可再次經鹵素、=O、-OH、-OCH
3、-NH
2、-NH-CH
3或-N(CH
3)
2取代,且其中此雜環烷基之氮原子可視需要經-C(O)-環丙基或-C(O)-C
1-4-烷基取代,兩者均視需要經F取代一或多次;
R
p及R
q係獨立地選自H、-CH
3或-CH
2-CH
3;
或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一態樣,本發明涵蓋通式(Ia)化合物(上文式(I)之子組)
(Ia)
其中
X
1表示CH;
X
2表示CR
a或N
X
3表示CR
a或N
X
4表示CH或N
Y表示O;
R
1、R
2係彼此獨立地選自-CH
3、-CH
2-CH
3或-CH(CH
3)
2;或
R
1、R
2連同其等結合之磷原子一起形成
;
或
;
R
3係選自-CH
3、-CHF
2、-CF
3或-Cl;
R
4係選自-H、-NH
2或-CH
3;
R
5係選自-Br、-CF
2-H、-CF
2-F、-CF
2-CH
3、-CF
2-CH
2-OH、-CF
2-CD
2-OH、-CF
2-CH
2-OCH
3、-CF
2-CH(CH
3)-OH、-CF
2-CH(CH
2-CH
3)-OH、-CF
2-C(CH
3)
2-OH、CF
2-C(CH
3)
2-OCH
3、-CF
2-CH(CH(CH
3)
2)-OH、-CF
2-CH(C(CH
3)
3)-OH、-CF
2-C(CH
3)(CH
2-CH
2-CH
2-CH
3)-OH、-CF
2-C(=O)-CH(CH
3)
2、-CF
2-C(=O)-C(CH
3)
3、-CF
2-C(=O)-OH、-CF
2-C(=O)-NH
2、-CF
2-C(=O)-N(CH
3)
2、-CF
2-C(=O)-NH-CH
3、-CF
2-C(=O)-NH-CH
2-CH
3、-CF
2-C(=O)-NH-環丙基、-CF
2-CH
2-NH-SO
2-CH
3、-CF
2-CH
2-N(CH
3)-SO
2-CH
3、-CF
2-CH
2-NH-C(=O)-CH
3或-CF
2-CH
2-N(CH
3);
R
6係選自-H、-CH
3、-Fl或-Cl;
R
a係選自-H、-CH
3、-CH
2-CH
3、-CF
3、-CHF
2、-CH
2-OH、-CH
2-O-CH
3、-OH、-OCH
3或環丙基,
R
r係選自-H、-CH
3、-CH(CH
3)
2、-CH
2-苯基、-C(=O)-H、-C(=O)-CH
3、-C(=O)-CH
2F、-C(=O)-CH(CH
3)
2、-C(=O)-CH(CH
3)-OH、-C(=O)-CH(CH
3)-O-CH
3、
、
、
、
、
、
、
、
、
、-C(=O)-CH
2-CN、-C(=O)-CH
2-O-CH
3、-C(=O)-O-C(CH
3)
3、-C(=O)-O-CH
2-CH
3、-C(=O)-NH
2、-C(=O)-N(CH
3)
2、-C(=O)-CH
2-CHF
2、-C(=O)-NH-環丙基、-C(=S)-CH
3、-SO
2-CH
3、
或
;
R
s係選自-CH
3或-CD
3;
R
t係選自-H或D;
或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
定義
術語「經取代」意謂指定原子或基團上之一或多個氫原子係經選自指示基團之基團置換,前提條件為不超過該指定原子在現有情況下之正常化合價。取代基及/或變量之組合係可允許的。
術語「視需要經取代」意謂取代基之數量可等於或不同於零。除非另有指示,否則視需要經取代之基團可經儘可能多的任選取代基取代,任選取代基可藉由用任何可用碳或氮或磷原子上之非氫取代基置換氫原子來容納。通常,任選取代基(當存在時)之數量可係1、2、3、4或5,特別是1、2或3。
如本文使用,術語「一或多個」,例如在本發明之通式(I)化合物之取代基之定義中,意謂「1、2、3、4或5,特別1、2、3或4,更特別1、2或3,甚至更特別1或2」。
除非另有規定,否則當根據本發明之化合物中之基團係經取代時,該等基團可經取代基單取代或多取代。於本發明之範圍內,重複出現之所有基團之含義均彼此獨立。根據本發明之化合物中之基團可經一、二或三個相同或不同取代基,特別經一個取代基取代。
如本文使用,側氧基取代基表示氧原子,其經由雙鍵結合至碳原子或硫原子。
術語「環取代基」意謂結合至芳環或非芳環之取代基,其置換該環上可用之氫原子。
複合取代基應包含多於一個部分,例如(C
1-C
4-烷氧基)-(C
1-C
4-烷基)-,給定部分之位置可於該複合取代基之任何合適位置處,即該C
1-C
4-烷氧基部分可結合至該(C
1-C
4-烷氧基)-(C
1-C
4-烷基)-基團之C
1-C
4-烷基部分之任何碳原子。此複合取代基之開端或末端之連字元指示該複合取代基結合至分子之剩餘部分之結合點。包含碳原子及視需要一或多個雜原子(諸如氮、氧或硫原子)之環應(例如)經取代基取代,該取代基可結合於該環之任何合適位置,其可結合至合適之碳原子及/或合適之雜原子。
術語「包含」當用於本說明書中時包括「由……構成」。
若於本內文中將任何項目稱為「如本文提及」,則意謂其可於本內文中之任何處提及。
如本內文中提及之術語具有下列含義:
術語「鹵素原子」意謂氟、氯、溴或碘原子,特別是氟、氯或溴原子。
術語「C
1-C
6-烷基」意謂具有1、2、3、4、5或6個碳原子之直鏈或分支鏈、飽和、單價烴基,例如甲基、乙基、丙基、異丙基、丁基、二級丁基、異丁基、三級丁基、戊基、異戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、4-甲基戊基、1-乙基丁基、2-乙基丁基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、2,3-二甲基丁基、1,2-二甲基丁基或1,3-二甲基丁基,或其異構體。特別是,該基團具有1、2、3或4個碳原子(「C
1-C
4-烷基」),例如甲基、乙基、丙基、異丙基、丁基、二級丁基異丁基或三級丁基,更特別1、2或3個碳原子(「C
1-C
3-烷基」),例如甲基、乙基、正丙基或異丙基。
術語「C
1-C
6-羥基烷基」意謂直鏈或分支鏈、飽和、單價烴基,其中術語「C
1-C
6-烷基」係如上文定義,且其中1、2或3個氫原子係經羥基置換,例如羥甲基、1-羥乙基、2-羥乙基、1,2-二羥乙基、3-羥丙基、2-羥丙基、1-羥丙基、1-羥基丙-2-基、2-羥基丙-2-基、2,3-二羥丙基、1,3-二羥基丙-2-基、3-羥基-2-甲基-丙基、2-羥基-2-甲基-丙基、1-羥基-2-甲基-丙基。
術語「C
1-C
6-烷基氫硫基」意謂式(C
1-C
6-烷基)-S-之直鏈或分支鏈、飽和、單價基團,其中術語「C
1-C
6-烷基」係如上文定義,例如甲基氫硫基、乙基氫硫基、丙基氫硫基、異丙基氫硫基、丁基氫硫基、二級丁基氫硫基、異丁基氫硫基、三級丁基氫硫基、戊基氫硫基、異戊基氫硫基、己基氫硫基。
術語「C
1-C
6-鹵烷基」意謂直鏈或分支鏈、飽和、單價烴基,其中術語「C
1-C
6-烷基」係如上文定義,且其中氫原子中之一或多者係相同或不同地經鹵素原子置換。特別是,該鹵素原子係氟原子。該C
1-C
6-鹵烷基係(例如)氟甲基、二氟甲基、三氟甲基、2-氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、五氟乙基、3,3,3-三氟丙基或1,3-二氟丙-2-基。
術語「C
1-C
6-烷氧基」意謂式(C
1-C
6-烷基)-O-之直鏈或分支鏈、飽和、單價基團,其中術語「C
1-C
6-烷基」係如上文定義,例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、二級丁氧基、異丁氧基、三級丁氧基、戊氧基、異戊氧基或正己氧基,或其異構體。
術語「C
1-C
6-鹵烷氧基」意謂如上文定義之直鏈或分支鏈、飽和、單價C
1-C
6-烷氧基,其中氫原子中之一或多者係相同或不同地經鹵素原子置換。特別是,該鹵素原子係氟原子。該C
1-C
6-鹵烷氧基係(例如)氟甲氧基、二氟甲氧基、三氟甲氧基、2,2,2-三氟乙氧基或五氟乙氧基。
術語「C
2-C
6-烯基」意謂直鏈或分支鏈、單價烴基,其含有一或兩個雙鍵,且其具有2、3、4、5或6個碳原子,特別2或3個碳原子(「C
2-C
3-烯基」),應瞭解在其中該烯基含有多於一個雙鍵之情況下,則該等雙鍵可彼此分離或結合。該烯基係(例如)乙烯基(ethenyl) (或「乙烯基(vinyl)」)、丙-2-烯-1-基(或「烯丙基」)、丙-1-烯-1-基、丁-3-烯基、丁-2-烯基、丁-1-烯基、戊-4-烯基、戊-3-烯基、戊-2-烯基、戊-1-烯基、己-5-烯基、己-4-烯基、己-3-烯基、己-2-烯基、己-1-烯基、丙-1-烯-2-基(或「異丙烯基」)、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、2-甲基丁-2-烯基、1-甲基丁-2-烯基、3-甲基丁-1-烯基、2-甲基丁-1-烯基、1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-異丙基乙烯基、4-甲基戊-4-烯基、3-甲基戊-4-烯基、2-甲基戊-4-烯基、1-甲基戊-4-烯基、4-甲基戊-3-烯基、3-甲基戊-3-烯基、2-甲基戊-3-烯基、1-甲基戊-3-烯基、4-甲基戊-2-烯基、3-甲基戊-2-烯基、2-甲基戊-2-烯基、1-甲基戊-2-烯基、4-甲基戊-1-烯基、3-甲基戊-1-烯基、2-甲基戊-1-烯基、1-甲基戊-1-烯基、3-乙基丁-3-烯基、2-乙基丁-3-烯基、1-乙基丁-3-烯基、3-乙基丁-2-烯基、2-乙基丁-2-烯基、1-乙基丁-2-烯基、3-乙基丁-1-烯基、2-乙基丁-1-烯基、1-乙基丁-1-烯基、2-丙基丙-2-烯基、1-丙基丙-2-烯基、2-異丙基丙-2-烯基、1-異丙基丙-2-烯基、2-丙基丙-1-烯基、1-丙基丙-1-烯基、2-異丙基丙-1-烯基、1-異丙基丙-1-烯基、3,3-二甲基丙-1-烯基、1-(1,1-二甲基乙基)乙烯基、丁-1,3-二烯基、戊-1,4-二烯基或己-1,5-二烯基。特別是,該基團係乙烯基或烯丙基。
術語「C
2-C
6-炔基」意謂直鏈或分支鏈、單價烴基,其含有一個三鍵,且其含有2、3、4、5或6個碳原子,特別是2或3個碳原子(「C
2-C
3-炔基」)。該C
2-C
6-炔基係(例如)乙炔基、丙-1-炔基、丙-2-炔基(或「炔丙基」)、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-異丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特別是,該炔基係乙炔基、丙-1-炔基或丙-2-炔基。
術語「C
3-C
8-環烷基」意謂飽和、單價、單環或雙環烴環,其含有3、4、5、6、7或8個碳原子(「C
3-C
8-環烷基」)。該C
3-C
8-環烷基係(例如)單環烴環,例如環丙基、環丁基、環戊基、環己基、環庚基或環辛基,或雙環烴環,例如雙環[4.2.0]辛基或八氫戊烯基。
術語「C
4-C
8-環烯基」意謂單價、單環或雙環烴環,其含有4、5、6、7或8個碳原子及一個雙鍵。特別是,該環含有4、5或6個碳原子(「C
4-C
6-環烯基」)。該C
4-C
8-環烯基係(例如)單環烴環,例如環丁烯基、環戊烯基、環己烯基、環庚烯基或環辛烯基,或雙環烴環,例如雙環[2.2.1]庚-2-烯基或雙環[2.2.2]辛-2-烯基。
術語「C
3-C
8-環烷氧基」意謂式(C
3-C
8-環烷基)-O-之飽和、單價、單環或雙環基團,其含有3、4、5、6、7或8個碳原子,其中術語「C
3-C
8-環烷基」係如上文定義,例如環丙氧基、環丁氧基、環戊氧基、環己氧基、環庚氧基或環辛氧基。
術語「螺環烷基」意謂飽和、單價雙環烴基,其中兩個環共用一個共同之環碳原子,且其中該雙環烴基含有5、6、7、8、9、10或11個碳原子,該螺環烷基可經由除螺碳原子外之碳原子中之任一者結合至分子之剩餘部分。該螺環烷基係(例如)螺[2.2]戊基、螺[2.3]己基、螺[2.4]庚基、螺[2.5]辛基、螺[2.6]壬基、螺[3.3]庚基、螺[3.4]辛基、螺[3.5]壬基、螺[3.6]癸基、螺[4.4]壬基、螺[4.5]癸基、螺[4.6]十一基或螺[5.5]十一基。
術語「4至7員雜環烷基」及「4至6員雜環烷基」意謂具有分別4、5、6或7,又或總計4、5或6個環原子之單環、飽和雜環,其含有一或兩個來自系列N、O及S之相同或不同環雜原子,該雜環烷基可經由該等碳原子中之任一者或(若存在)氮原子結合至分子之剩餘部分。
該雜環烷基(但不限於此)可為4員環,諸如,舉例而言,氮雜環丁烷基、氧雜環丁烷基或硫雜環丁烷基;或5員環,諸如,舉例而言,四氫呋喃基、1,3-二氧雜環戊烷基、硫雜環戊烷基、吡咯啶基、咪唑啶基、吡唑啶基、1,1-二氧負離子基硫雜環戊烷基、1,2-噁唑啶基、1,3-噁唑啶基或1,3-噻唑啶基;或6員環,諸如,舉例而言,四氫哌喃基、四氫噻喃基、哌啶基、嗎啉基、二噻烷基、硫嗎啉基、哌嗪基、1,3-二氧雜環己烷基、1,4-二氧雜環己烷基或1,2-噁嗪烷基,或7員環,諸如,舉例而言,氮雜環庚烷基、1,4-二氮雜環庚烷基或1,4-氧氮雜環庚烷基。
特別是,「4至6員雜環烷基」意謂如上文定義之4至6員雜環烷基,其含有一個環氮原子及視需要來自系列:N、O、S之另一環雜原子。更特別是,「5或6員雜環烷基」意謂具有總計5或6個環原子之單環、飽和雜環,其含有一個環氮原子及視需要來自系列:N、O之另一環雜原子。
術語「5至8員雜環烯基」意謂具有總計5、6、7或8個環原子之單環、不飽和、非芳族雜環,其含有一或兩個雙鍵及一或兩個來自序列:N、O、S之相同或不同環雜原子;該雜環烯基可經由該等碳原子中之任一者或(若存在)氮原子結合至分子之剩餘部分。
該雜環烯基係(例如) 4H-哌喃基、2H-哌喃基、2,5-二氫-1H-吡咯基、[1,3]二氧雜環戊烯基、4H-[1,3,4]噻二嗪基、2,5-二氫呋喃基、2,3-二氫呋喃基、2,5-二氫噻吩基、2,3-二氫噻吩基、4,5-二氫噁唑基或4H-[1,4]噻嗪基。
術語「雜螺環烷基」意謂具有總計6、7、8、9、10或11個環原子之雙環、飽和雜環,其中兩個環共用一個共同之環碳原子,該「雜螺環烷基」含有一或兩個來自系列:N、O、S之相同或不同環雜原子;該雜螺環烷基可經由除螺碳原子外之碳原子中之任一者或(若存在)氮原子結合至分子之剩餘部分。
該雜螺環烷基係(例如)氮雜螺[2.3]己基、氮雜螺[3.3]庚基、氧氮雜螺[3.3]庚基、硫雜螺[3.3]庚基、氧雜螺[3.3]庚基、氧氮螺[5.3]壬基、氧氮螺[4.3]辛基、氮雜螺[4.5]癸基、氧氮螺[5.5]十一基、二氮雜螺[3.3]庚基、硫雜螺[3.3]庚基、硫雜螺[4.3]辛基、氮雜螺[5.5]十一基,或其他同源支架中之一者,諸如螺[3.4]-、螺[4.4]-、螺[2.4]-、螺[2.5]-、螺[2.6]-、螺[3.5]-、螺[3.6]-、螺[4.5]-及螺[4.6]-。
術語「稠合雜環烷基」意謂具有總計6、7、8、9或10個環原子之雙環、飽和雜環,其中兩個環共用兩個相鄰之環原子,該「稠合雜環烷基」含有一或兩個來自系列:N、O、S之相同或不同環雜原子;該稠合雜環烷基可經由該等碳原子中之任一者或(若存在)氮原子結合至分子之剩餘部分。
該稠合雜環烷基係(例如)氮雜雙環[3.3.0]辛基、氮雜雙環[4.3.0]壬基、二氮雜雙環[4.3.0]壬基、氧氮雜雙環[4.3.0]壬基、硫雜雙環[4.3.0]壬基或氮雜雙環[4.4.0]癸基。
術語「橋接雜環烷基」意謂具有總計7、8、9或10個環原子之雙環、飽和雜環,其中兩個環共用兩個非相鄰之共同環原子,該「橋接雜環烷基」含有一或兩個來自系列:N、O、S之相同或不同環雜原子;該橋接雜環烷基可經由除螺碳原子外之碳原子中之任一者或(若存在)氮原子結合至分子之剩餘部分。
該橋接雜環烷基係(例如)氮雜雙環[2.2.1]庚基、氧氮雜雙環[2.2.1]庚基、硫雜雙環[2.2.1]庚基、二氮雜雙環[2.2.1]庚基、氮雜雙環[2.2.2]辛基、二氮雜雙環[2.2.2]辛基、氧氮雜雙環[2.2.2]辛基、硫雜雙環[2.2.2]辛基、氮雜雙環[3.2.1]辛基、二氮雜雙環[3.2.1]辛基、氧氮雜雙環[3.2.1]辛基、硫雜雙環[3.2.1]辛基、氮雜雙環[3.3.1]壬基、二氮雜雙環[3.3.1]壬基、氧氮雜雙環[3.3.1]壬基、硫雜雙環[3.3.1]壬基、氮雜雙環[4.2.1]壬基、二氮雜雙環[4.2.1]壬基、氧氮雜雙環[4.2.1]壬基、硫雜雙環[4.2.1]壬基、氮雜雙環[3.3.2]癸基、二氮雜雙環[3.3.2]癸基、氧氮雜雙環[3.3.2]癸基、硫雜雙環[3.3.2]癸基或氮雜雙環[4.2.2]癸基。
術語「雜芳基」意謂具有5、6、8、9、10、11、12、13或14個環原子(「5至14員雜芳基」基團),特別5、6、9或10個環原子之單價、單環、雙環或三環芳環,其含有至少一個環雜原子及視需要一、二或三個來自系列:N、O及/或S之其他環雜原子,且其經由環碳原子或視需要經由環氮原子(若化合價容許)結合。
該雜芳基可為5員雜芳基,諸如,舉例而言,噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、異噁唑基、異噻唑基、噁二唑基、三唑基、噻二唑基或四唑基;或6員雜芳基,諸如,舉例而言,吡啶基、噠嗪基、嘧啶基、吡嗪基或三嗪基;或三環雜芳基,諸如,舉例而言,哢唑基、吖啶基或吩嗪基;或9員雜芳基,諸如,舉例而言,苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并異噁唑基、苯并咪唑基、苯并噻唑基、苯并三唑基、吲唑基、吲哚基、異吲哚基、吲哚嗪基或嘌呤基;或10員雜芳基,諸如,舉例而言,喹啉基、喹唑啉基、異喹啉基、噌啉基、酞嗪基、喹喔啉基或喋啶基。
一般而言,且除非另有提及,否則雜芳基或伸雜芳基包括其所有可能之異構形式,例如:關於對分子之剩餘部分之連接點之互變異構體及位置異構體。因此,針對一些說明性非限制性實例,術語吡啶基包括吡啶-2-基、吡啶-3-基及吡啶-4-基;或術語噻吩基包括噻吩-2-基及噻吩-3-基。
術語「C
1-C
6」,如用於本內文中,例如用於「C
1-C
6-烷基」、「C
1-C
6-鹵烷基」、「C
1-C
6-羥基烷基」、「C
1-C
6-烷氧基」或「C
1-C
6-鹵烷氧基」之定義之內文中,意謂具有有限數量1至6個碳原子,即1、2、3、4、5或6個碳原子之烷基。
此外,如本文使用,術語「C
3-C
8」,如用於本內文中,例如用於「C
3-C
8-環烷基」之定義之內文中,意謂具有有限數量3至8個碳原子,即3、4、5、6、7或8個碳原子之環烷基。
當給定值之範圍時,該範圍包含於該範圍內之各值及子範圍。
例如:
「C
1-C
6」包含C
1、C
2、C
3、C
4、C
5、C
6、C
1-C
6、C
1-C
5、C
1-C
4、C
1-C
3、C
1-C
2、C
2-C
6、C
2-C
5、C
2-C
4、C
2-C
3、C
3-C
6、C
3-C
5、C
3-C
4、C
4-C
6、C
4-C
5及C
5-C
6;
「C
2-C
6」包含C
2、C
3、C
4、C
5、C
6、C
2-C
6、C
2-C
5、C
2-C
4、C
2-C
3、C
3-C
6、C
3-C
5、C
3-C
4、C
4-C
6、C
4-C
5及C
5-C
6;
「C
3-C
10」包含C
3、C
4、C
5、C
6、C
7、C
8、C
9、C
10、C
3-C
10、C
3-C
9、C
3-C
8、C
3-C
7、C
3-C
6、C
3-C
5、C
3-C
4、C
4-C
10、C
4-C
9、C
4-C
8、C
4-C
7、C
4-C
6、C
4-C
5、C
5-C
10、C
5-C
9、C
5-C
8、C
5-C
7、C
5-C
6、C
6-C
10、C
6-C
9、C
6-C
8、C
6-C
7、C
7-C
10、C
7-C
9、C
7-C
8、C
8-C
10、C
8-C
9及C
9-C
10;
「C
3-C
8」包含C
3、C
4、C
5、C
6、C
7、C
8、C
3-C
8、C
3-C
7、C
3-C
6、C
3-C
5、C
3-C
4、C
4-C
8、C
4-C
7、C
4-C
6、C
4-C
5、C
5-C
8、C
5-C
7、C
5-C
6、C
6-C
8、C
6-C
7及C
7-C
8;
「C
3-C
6」包含C
3、C
4、C
5、C
6、C
3-C
6、C
3-C
5、C
3-C
4、C
4-C
6、C
4-C
5及C
5-C
6;
「C
4-C
8」包含C
4、C
5、C
6、C
7、C
8、C
4-C
8、C
4-C
7、C
4-C
6、C
4-C
5、C
5-C
8、C
5-C
7、C
5-C
6、C
6-C
8、C
6-C
7及C
7-C
8;
「C
4-C
7」包含C
4、C
5、C
6、C
7、C
4-C
7、C
4-C
6、C
4-C
5、C
5-C
7、C
5-C
6及C
6-C
7;
「C
4-C
6」包含C
4、C
5、C
6、C
4-C
6、C
4-C
5及C
5-C
6;
「C
5-C
10」包含C
5、C
6、C
7、C
8、C
9、C
10、C
5-C
10、C
5-C
9、C
5-C
8、C
5-C
7、C
5-C
6、C
6-C
10、C
6-C
9、C
6-C
8、C
6-C
7、C
7-C
10、C
7-C
9、C
7-C
8、C
8-C
10、C
8-C
9及C
9-C
10;
「C
6-C
10」包含C
6、C
7、C
8、C
9、C
10、C
6-C
10、C
6-C
9、C
6-C
8、C
6-C
7、C
7-C
10、C
7-C
9、C
7-C
8、C
8-C
10、C
8-C
9及C
9-C
10。
如本文使用,術語「脫離基」意謂於化學反應中作為穩定物種而經取代之原子或原子團,其具有成鍵電子。特別是,此脫離基係選自包含以下之基團:鹵離子,特別是氟離子、氯離子、溴離子或碘離子、(甲基磺醯基)氧基、[(三氟甲基)磺醯基]氧基、[(九氟丁基)磺醯基]氧基、(苯基磺醯基)氧基、[(4-甲基苯基)磺醯基]氧基、[(4-溴苯基)磺醯基]氧基、[(4-硝基苯基)磺醯基]氧基、[(2-硝基苯基)磺醯基]氧基、[(4-異丙基苯基)磺醯基]氧基、[(2,4,6-三異丙基苯基)磺醯基]氧基、[(2,4,6-三甲基苯基)磺醯基]氧基、[(4-三級丁基苯基)磺醯基]氧基及[(4-甲氧基苯基)磺醯基]氧基。
除非另有規定,否則在本發明之內文中,取代基及殘基具有下列含義:
(C
1-C
4)-
烷基於本發明之內文中意謂具有1、2、3或4個碳原子之直鏈或分支鏈烷基,諸如:例如,甲基、乙基、正丙基、異丙基、正丁基、異丁基、二級丁基及三級丁基。
(C
1-C
4)-
烷氧基於本發明之內文中意謂具有1、2、3或4個碳原子之直鏈或分支鏈烷氧基,諸如:例如,甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、二級丁氧基及三級丁氧基。
單 (C
1-C
4)-
烷基胺基於本發明之內文中意謂具有一個含有1、2、3或4個碳原子之直鏈或分支鏈烷基取代基之胺基,諸如:例如,甲胺基、乙胺基、正丙胺基、異丙胺基、正丁基胺基及三級丁基胺基。
二 (C
1-C
4)-
烷基胺基於本發明之內文中意謂具有兩個各含有1、2、3或4個碳原子之相同或不同直鏈或分支鏈烷基取代基之胺基,諸如:例如,N,N-二甲胺基、N,N-二乙胺基、N-乙基-N-甲胺基、N-甲基-N-正丙胺基、N-異丙基-N-甲胺基、N-異丙基-N-正丙胺基、N,N-二異丙胺基、N-正丁基-N-甲胺基及N-三級丁基-N-甲胺基。
(C
1-C
4)-
烷基羰基於本發明之內文中意謂經由羰基[-C(=O)-]結合至分子之剩餘部分之具有1、2、3或4個碳原子之直鏈或分支鏈烷基,諸如:例如,乙醯基、丙醯基、正丁醯基、異丁醯基、正戊醯基及新戊醯基。
(C
1-C
4)-
烷氧基羰基於本發明之內文中意謂經由羰基[-C(=O)-]結合至分子之剩餘部分之具有1、2、3或4個碳原子之直鏈或分支鏈烷氧基,諸如:例如,甲氧基羰基、乙氧基羰基、正丙氧基羰基、異丙氧基羰基、正丁氧基羰基及三級丁氧基羰基。
單 (C
1-C
4)-
烷基胺基羰基於本發明之內文中意謂經由羰基[-C(=O)-]結合至分子之剩餘部分且具有一個具有1、2、3或4個碳原子之直鏈或分支鏈烷基取代基之胺基,諸如:例如,甲胺基羰基、乙胺基羰基、正丙胺基羰基、異丙胺基羰基、正丁基胺基羰基及三級丁基胺基羰基。
二 (C
1-C
4)-
烷基胺基羰基於本發明之內文中意謂經由羰基[-C(=O)-]結合至分子之剩餘部分且具有兩個在各情況下具有1、2、3或4個碳原子之相同或不同直鏈或分支鏈烷基取代基之胺基,諸如:例如,N,N-二甲胺基羰基、N,N-二乙胺基羰基、N-乙基-N-甲胺基羰基、N-甲基-N-正丙胺基羰基、N-異丙基-N-甲胺基羰基、N,N-二異丙胺基羰基、N-正丁基-N-甲胺基羰基及N-三級丁基-N-甲胺基羰基。
(C
3-C
6)-
環烷基於本發明之內文中意謂具有3、4、5或6個環碳原子之單環、飽和碳環,諸如:環丙基、環丁基、環戊基及環己基,例如,特別是環丙基及環丁基,
4 至 7 員雜環烷基及
4 至 6 員雜環烷基於本發明之內文中意謂具有分別4、5、6或7,或總計4、5或6個環原子之單環、飽和雜環,其含有一或兩個來自系列N、O、S、S(O)及S(O)
2之相同或不同環雜原子,且其可經由環碳原子或經由環氮原子(若存在)結合,諸如:氮雜環丁烷基、氧雜環丁烷基、硫雜環丁烷基、吡咯啶基、吡唑啶基、咪唑啶基、四氫呋喃基、硫雜環戊烷基、1,1-二氧負離子基硫雜環戊烷基、1,2-噁唑啶基、1,3-噁唑啶基、1,3-噻唑啶基、哌啶基、哌嗪基、四氫哌喃基、四氫噻喃基、1,3-二氧雜環己烷基、1,4-二氧雜環己烷基、1,2-噁嗪烷基、嗎啉基、硫嗎啉基、1,1-二氧負離子基硫嗎啉基、氮雜環庚烷基、1,4-二氮雜環庚烷基及1,4-氧氮雜環庚烷基,例如,特別是含有一個環氮原子及視需要來自系列N、O或S(O)
2之另一環雜原子之4至6員雜環烷基及含有一個環氮原子及視需要來自系列N或O之另一環雜原子之5或6員雜環烷基:諸如:氮雜環丁烷基、吡咯啶基、吡唑啶基、咪唑啶基、1,2-噁唑啶基、1,3-噁唑啶基、哌啶基、哌嗪基、1,2-噁嗪烷基、嗎啉基及硫嗎啉基,特別是吡咯啶基、哌啶基、哌嗪基及嗎啉基。
5 員氮雜雜芳基於本發明之內文中意謂具有總計5個環原子之芳族雜環基(雜芳族),其含有至少一個環氮原子及視需要一或兩個選自N、O及S之其他環雜原子,且其經由環碳原子或視需要經由環氮原子(若化合價容許)結合,特別是含有一個環氮原子及一或兩個選自N及O之其他環雜原子之5員氮雜雜芳基,諸如:吡咯基、吡唑基、咪唑基、噁唑基、噻唑基、異噁唑基、異噻唑基、三唑基、噁二唑基及噻二唑基,例如,特別是吡唑基、咪唑基、噁唑基、異噁唑基及噁二唑基。
側氧基取代基於本發明之內文中意謂氧原子,其經由雙鍵結合至碳原子。
通式(I)化合物可能作為同位素變體存在。因此,本發明包括通式(I)化合物之一或多種同位素變體,特別是通式(I)之含氘化合物。
化合物或試劑之術語「同位素變體」定義為顯示構成此化合物之一或多種同位素之非天然比例之化合物。
術語「通式(I)化合物之同位素變體」定義為顯示構成此化合物之一或多種同位素之非天然比例之通式(I)化合物。
表達「非天然比例」意謂此同位素之高於其天然豐度之比例。待應用於此內文中之同位素之天然豐度係描述於「Isotopic Compositions of the Elements 1997」, Pure Appl. Chem., 70(1), 217-235, 1998中。
此等同位素之實例包括氫、碳、氮、氧、磷、硫、氟、氯、溴及碘之穩定及放射性同位素,諸如分別
2H (氘)、
3H (氚)、
11C、
13C、
14C、
15N、
17O、
18O、
32P、
33P、
33S、
34S、
35S、
36S、
18F、
36Cl、
82Br、
123I、
124I、
125I、
129I及
131I。
關於本文指定疾患之治療及/或預防,通式(I)化合物之同位素變體較佳含有氘(「通式(I)之含氘化合物」)。通式(I)化合物之併入一或多種放射性同位素諸如
3H或
14C的同位素變體適用(例如)於藥物及/或受質組織分佈研究中。此等同位素係特別佳,因為其等易於併入及可偵測性。正電子發射同位素(諸如
18F或
11C)可併入通式(I)化合物內。通式(I)化合物之此等同位素變體適用於活體內成像應用。通式(I)之含氘及含
13C化合物可用於臨床前或臨床研究之內文之質譜法分析中。
通式(I)化合物之同位素變體的製備可一般藉由熟習此項技術者已知的方法,諸如彼等描述於本文之方案及/或實例中者,藉由用一種試劑代替該試劑之同位素變體,較佳代替含氘試劑。取決於氘化之所需位點,在一些情況下來自D
2O之氘可直接併入化合物內或併入適用於合成此等化合物之試劑內。氘氣亦係適用於將氘併入分子內之試劑。烯鍵及炔鍵之催化氘化係用於併入氘之快速途徑。金屬觸媒(即Pd、Pt及Rh)在氘氣之存在下可用以將氘直接交換為官能基中含有之氫。多種氘化試劑及合成建構組元可自諸如以下之公司購買獲得:例如C/D/N Isotopes, Quebec, Canada;Cambridge Isotope Laboratories Inc., Andover, MA, USA;及CombiPhos Catalysts, Inc., Princeton, NJ, USA。
術語「通式(I)之含氘化合物」定義為通式(I)化合物,其中一或多個氫原子係經一或多個氘原子置換,且其中於通式(I)化合物之各氘化位置之氘豐度高於氘之天然豐度,其係約0.015%。特別是,於通式(I)之含氘化合物中,於該通式(I)化合物之各氘化位置之氘豐度係高於在該(等)位置之10%、20%、30%、40%、50%、60%、70%或80%,較佳高於90%、95%、96%或97%,甚至更佳高於98%或99%。應瞭解於各氘化位置之氘豐度係獨立於其他氘化位置之氘豐度。
將一或多個氘原子選擇性併入通式(I)化合物內可改變物理化學性質(諸如,舉例而言酸度[C. L. Perrin等人,J. Am. Chem. Soc., 2007, 129, 4490]、鹼度[C. L. Perrin等人,J. Am. Chem. Soc., 2005, 127, 9641]、親脂性[B. Testa等人,Int. J. Pharm., 1984, 19(3), 271])及/或分子之代謝概況且可導致親體化合物對代謝物之比率或形成代謝物之量的改變。此等改變可導致某些治療優勢及因此在一些情況下可較佳。已報導,代謝物之比率改變時,代謝速率及代謝轉換率降低(A. E. Mutlib等人,Toxicol. Appl. Pharmacol., 2000, 169, 102)。曝露於親體藥物及代謝物之此等變化可關於通式(I)之含氘化合物之藥效學、耐受性及效用具有重要影響。在一些情況下,氘取代減少或消除非所需或毒性代謝物之形成及增強所需代謝物之形成(例如奈韋拉平(Nevirapine):A. M. Sharma等人,Chem. Res. Toxicol., 2013, 26, 410;依法韋侖(Efavirenz):A. E. Mutlib等人,Toxicol. Appl. Pharmacol., 2000, 169, 102)。在其他情況下,氘化之主要效應係降低全身清除率。因此,該化合物之生物半衰期增加。潛在臨床益處將包括維持類似之全身曝露與降低之峰值水準及增加之谷值水準之能力。取決於特定化合物之藥物動力學/藥效學關係,此可導致更低之副作用及增強之效用。ML-337 (C. J. Wenthur等人,J. Med. Chem., 2013, 56, 5208)及奧達那替尼(Odanacatib) (K. Kassahun等人,WO2012/112363)係此氘效應之實例。又其他情況已報導,其中代謝速率降低導致藥物曝露增加而不改變全身清除率(例如羅非昔布(Rofecoxib):F. Schneider等人,Arzneim. Forsch. / 藥物. Res., 2006, 56, 295;特拉匹韋(Telaprevir):F. Maltais等人,J. Med. Chem., 2009, 52, 7993)。顯示此效應之氘化藥物可具有減少之給藥需求(例如達成所需效應之劑量數減少或劑量減少)及/或可產生更低之代謝物負荷。
通式(I)化合物可具有多個用於代謝之潛在攻擊位點。為最佳化對物理化學性質及代謝概況之上述效應,可選擇具有一或多種氘-氫交換中之某一模式的通式(I)之含氘化合物。特別是,通式(I)之含氘化合物之氘原子係結合至碳原子及/或位於通式(I)化合物之彼等位置,該等位置係用於代謝酵素(諸如,舉例而言細胞色素P
450)之攻擊位點。
在本文使用字組化合物、鹽、多晶型物、水合物、溶劑合物及類似物之複數形式之情況下,此亦用以意謂單一化合物、鹽、多晶型物、異構體、水合物、溶劑合物或類似物。
「穩定化合物」或「穩定結構」意謂足夠穩健以可自反應混合物分離至有用純度,並調配成有效治療劑之化合物。
本發明之化合物視需要含有一或多個非對稱中心,取決於所需之各種取代基之位置及性質。一或多個非對稱碳原子可能以(R)或(S)構型存在,其在單一非對稱中心之情況下可導致外消旋混合物,及在多個非對稱中心之情況下可導致非對映異構體混合物。在某些情況下,由於給定鍵(例如,與指定化合物之兩個經取代之芳環相鄰之中心鍵)之受限旋轉亦可能存在非對稱性。
較佳化合物係彼等產生更所需生物活性者。本發明之化合物之經分離、純或經部分純化之異構體及立體異構體或外消旋或非對映異構體混合物亦包括於本發明之範圍內。此等材料之純化及分離可藉由此項技術中已知的標準技術進行。
較佳異構體係彼等產生更所需生物活性者。本發明之化合物之此等經分離、純或經部分純化之異構體或外消旋混合物亦包括於本發明之範圍內。此等材料之純化及分離可藉由此項技術中已知的標準技術進行。
光學異構體可藉由根據習知方法拆分外消旋混合物獲得,例如,藉由使用光學活性酸或鹼形成非對映異構體鹽或形成共價非對映異構體。適當酸之實例係酒石酸、二乙醯酒石酸、二甲苯醯酒石酸及樟腦磺酸。非對映異構體之混合物可基於其物理及/或化學差異藉由此項技術中已知的方法,例如藉由層析術或分級結晶分離成其等個別非對映異構體。然後自經分離之非對映異構體鹽釋放光學活性鹼或酸。用於分離光學異構體之不同方法涉及使用對掌性層析術(例如,使用對掌性相之HPLC管柱),有或沒有習知衍生化,經最佳化選擇以將該等對映異構體之分離最大化。使用對掌性相之合適HPLC管柱可購買獲得,諸如彼等由Daicel製造者,例如,尤其例如Chiracel OD及Chiracel OJ,其等均為例行性可選擇的。有或沒有衍生化的酶促分離亦係有用的。本發明之光學活性化合物可同樣藉由對掌性合成利用光學活性起始材料獲得。
為將不同類型之異構體彼此區分,參考IUPAC規則部分E (Pure Appl Chem 45, 11-30, 1976)。
本發明包括呈單一立體異構體或呈該等立體異構體(例如(R)-或(S)-異構體)之任何比率的任何混合物的本發明之化合物之所有可能立體異構體。本發明之化合物之單一立體異構體,例如單一對映異構體或單一非對映異構體之分離係例如藉由任何合適之最先進方法(諸如層析術,尤其對掌性層析術)達成。
此外,本發明之化合物可能呈互變異構體存在。例如,含有咪唑并吡啶部分作為雜芳基之本發明之任何化合物(例如)可呈1H互變異構體,或3H互變異構體,或甚至任何量之兩種互變異構體之混合物存在,即:
本發明包括呈單一互變異構體,或呈該等互變異構體之任何比率之任何混合物之本發明之化合物之所有可能互變異構體。
此外,本發明之化合物可呈N-氧化物存在,其等定義為本發明之化合物中之至少一個氮係經氧化。本發明包括所有此等可能之N-氧化物。
本發明亦涵蓋本發明之化合物之有用形式,諸如代謝物、水合物、溶劑合物、前藥、鹽,特別是醫藥上可接受之鹽,及/或共沈澱物。
本發明之化合物可呈水合物,或呈溶劑合物存在,其中本發明之化合物含有極性溶劑,特別是水、甲醇或乙醇,例如,呈該等化合物之晶格之結構元素。極性溶劑(特別是水)之量可以化學計量或非化學計量比率存在。在化學計量溶劑合物(例如水合物)之情況下,一半、(半)、單、倍半、二、三、四、五等溶劑合物或水合物分別係可能的。本發明包括所有此等水合物或溶劑合物。
此外,本發明之化合物可以游離形式存在,例如呈游離鹼,或呈游離酸,或呈兩性離子,或以鹽之形式存在。該等鹽可為任何鹽,有機或無機加成鹽,特別是任何醫藥上可接受之有機或無機加成鹽,其通常用於藥學中,或其(例如)用於分離或純化本發明之化合物。
術語「醫藥上可接受之鹽」係指本發明之化合物之無機或有機酸加成鹽。例如,參見S. M. Berge等人,「Pharmaceutical Salts」,J. Pharm. Sci. 1977, 66, 1-19。
本發明之化合物之合適之醫藥上可接受之鹽可為(例如)鏈中或環中攜載氮原子之例如具有足夠鹼性之本發明之化合物之酸加成鹽,諸如與無機酸,或「礦物酸」形成之酸加成鹽,諸如鹽酸、氫溴酸、氫碘酸、硫酸、磺醯胺酸、重硫酸、磷酸或硝酸,例如,或與有機酸形成之酸加成鹽,諸如,舉例而言,甲酸、乙酸、乙醯乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一酸、月桂酸、苯甲酸、水楊酸、2-(4-羥基苯甲醯基)-苯甲酸、樟腦酸、肉桂酸、環戊烷丙酸、雙葡萄糖酸、3-羥基-2-萘甲酸、菸鹼酸、棕櫚酸、果膠酸、3-苯基丙酸、新戊酸、2-羥基乙磺酸、衣康酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、對甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟腦磺酸、檸檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、蘋果酸、己二酸、海藻酸、馬來酸、富馬酸、D-葡萄糖酸、扁桃酸、抗壞血酸、葡萄糖庚酸、甘油磷酸、天冬胺酸、磺基水楊酸或硫氰酸。
此外,具有足夠酸性之本發明之化合物之另一適當醫藥上可接受之鹽係鹼金屬鹽(例如鈉或鉀鹽)、鹼土金屬鹽(例如鈣、鎂或鍶鹽或鋁或鋅鹽),或來源於氨或具有1至20個碳原子之有機一級、二級或三級胺之銨鹽,諸如乙胺、二乙胺、三乙胺、乙基二異丙胺、單乙醇胺、二乙醇胺、三乙醇胺、二環己基胺、二甲胺基乙醇、二乙胺基乙醇、參(羥甲基)胺基甲烷、普魯卡因、二苄基胺、N-甲基嗎啉、精胺酸、離胺酸、1,2-乙二胺、N-甲基哌啶、N-甲基-還原葡糖胺、N,N-二甲基-還原葡糖胺、N-乙基-還原葡糖胺、1,6-己二胺、葡萄胺糖、肌胺酸、絲胺醇、2-胺基-1,3-丙二醇、3-胺基-1,2-丙二醇、4-胺基-1,2,3-丁三醇,或與具有1至20個碳原子之三級銨離子形成之鹽,諸如四甲基銨、四乙基銨、四(正丙基)銨、四(正丁基)銨、N-苄基-N,N,N-三甲基銨、膽鹼或殺藻胺。
熟習此項技術者將進一步知曉可藉由經由許多已知方法中之任一者使化合物與適當之無機或有機酸反應製備所主張化合物之酸加成鹽。或者,本發明之酸性化合物之鹼及鹼土金屬鹽係藉由經由各種已知方法使本發明之化合物與適當之鹼反應製備。
本發明包括呈單一鹽,或呈該等鹽之任何比率之任何混合物之本發明之化合物之所有可能的鹽。
在本內文中,特別是在實驗部分中,針對中間物及本發明實例之合成,當化合物作為與相應之鹼或酸之鹽形式提及時,如藉由各別製備及/或純化方法獲得之該鹽形式之精確化學計量組成在大多數情況下係未知的。
除非另有規定,否則與鹽諸如例如「鹽酸鹽」、「三氟乙酸鹽」、「鈉鹽」或「x HCl」、「x CF
3COOH」、「x Na
+」相關之化學名稱或結構式之後綴意謂鹽形式,該鹽形式之化學計量未經指定。
此類似適用於已藉由所述製備及/或純化方法獲得,作為呈具有(若定義)未知化學計量組成的溶劑合物(諸如水合物)的合成中間物或示例性化合物或其鹽之情況。
如本文使用,術語「活體內可水解酯」意謂含有羧基或羥基之本發明之化合物之活體內可水解酯,例如,在人體或動物體內水解以產生親體酸或醇之醫藥上可接受之酯。適用於羧基之醫藥上可接受之酯包括(例如)烷基、環烷基及視需要經取代之苯基烷基,特別是苄基酯、C
1-C
6烷氧基甲基酯,例如甲氧基甲基、C
1-C
6烷醯氧基甲基酯,例如新戊醯氧基甲基、鄰苯二甲酸酯、C
3-C
8環烷氧基-羰基氧基-C
1-C
6烷基酯,例如1-環己基羰氧基乙基;1,3-二氧雜戊烯-2-酮基甲基酯,例如5-甲基-1,3-二氧雜戊烯-2-酮基甲基;及C
1-C
6-烷氧基羰氧基乙基酯,例如1-甲氧基羰氧基乙基,該等酯可於本發明之化合物中於任何羧基處形成。
含有羥基之本發明之化合物之活體內可水解酯包括無機酯諸如磷酸酯及[α]-醯氧基烷基醚及由於酯分解以產生親體羥基之活體內水解所得的相關化合物。[α]-醯氧基烷基醚之實例包括乙醯氧基甲氧基及2,2-二甲基丙醯氧基甲氧基。用於羥基之活體內可水解酯形成基團之選擇包括烷醯基、苯甲醯基、苯基乙醯基及經取代之苯甲醯基及苯基乙醯基、烷氧基羰基(以產生碳酸烷基酯)、二烷基胺甲醯基及N-(二烷基胺基乙基)-N-烷基胺甲醯基(以產生胺基甲酸酯)、二烷基胺基乙醯基及羧基乙醯基。本發明涵蓋所有此等酯。
此外,本發明包括本發明之化合物之所有可能結晶形式,或多晶型物,呈單一多晶型物,或呈多於一種多晶型物之任何比率之混合物。
此外,本發明亦包括根據本發明之化合物之前藥。術語「前藥」此處指定本身可具有生物活性或無生物活性,但在其等於體內停留時間期內轉化(例如代謝或水解)為根據本發明之化合物之化合物。
根據另一實施例,本發明涵蓋通式(I)化合物,其中X
1、X
2、X
3或X
4中之僅一者係N,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一實施例,本發明涵蓋通式(I)化合物,其中Y表示O,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一實施例,本發明涵蓋通式(I)化合物,其中R
1及R
2係選自C
1-4烷基,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一實施例,本發明涵蓋通式(I)化合物,其中R
3係選自視需要經1至3個F取代之C
1-2-烷基,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一實施例,本發明涵蓋通式(I)化合物,其中R
6係選自-F、-Cl、-H或-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一實施例,本發明涵蓋通式(I)化合物,其中R
a係選自-H、-Cl、-CH
3、-CF
3或-CF
2H,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一實施例,本發明涵蓋通式(I)化合物,其中R
j及R
k連同其等結合之碳原子一起形成環丙基或係選自兩個-F、兩個-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一實施例,本發明涵蓋通式(I)化合物,其中R
n及R
o連同其等結合之氮一起形成嗎啉或N-乙醯基哌嗪,兩者均視需要經1或2個-CH
3、-CF
3或-CF
2H取代,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一實施例,本發明涵蓋通式(I)化合物,其中上文實施例之任何取代基可與來自上文實施例中之一或多者之任何其他一或多個取代基組合,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
根據另一實施例,本發明涵蓋下列化合物:
6-(二甲基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺
1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇
1-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
1-苄基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-苄基-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2,8-二甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇
1-{3-[(1R)-1-({6-[二(丙-2-基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇
6-(二甲基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺
1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[2,3-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇
1-{3-[(1R)-1-({6-[二(丙-2-基)磷醯基]-2-甲基吡啶并[2,3-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇
1-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[2,3-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
6-(二甲基磷醯基)-2,7-二甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2,7-二甲基吡啶并[2,3-d]嘧啶-4-胺
1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2,7-二甲基吡啶并[2,3-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇
1-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2,7-二甲基吡啶并[2,3-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
1-{3-[(1R)-1-({6-[二(丙-2-基)磷醯基]-2,7-二甲基吡啶并[2,3-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇
6-(二甲基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺
(2RS)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基己-2-醇(非對映異構體之混合物)
6-(二甲基磷醯基)-2-甲基-N-{1-[2-(三氟甲基)吡啶-4-基]乙基}吡啶并[3,4-d]嘧啶-4-胺(對映異構體1)
6-(二甲基磷醯基)-2-甲基-N-{1-[2-(三氟甲基)吡啶-4-基]乙基}吡啶并[3,4-d]嘧啶-4-胺(對映異構體2)
4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-8-醇
1-乙醯基-4-[8-羥基-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-甲醛
1-硫代乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基喹唑啉-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇
1-乙醯基-4-[8-(羥甲基)-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[8-環丙基-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[8-(二氟甲基)-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[8-(甲氧基甲基)-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
(2RS)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-8-乙基-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丁-2-醇(非對映異構體之混合物)
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-4-基)-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-3-基)-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(甲磺醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸
2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-N-環丙基-2,2-二氟乙醯胺
2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N,N-二甲基乙醯胺
2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙醯胺
2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N-甲基乙醯胺
2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙醯胺
2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-N-乙基-2,2-二氟乙醯胺
2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N,N-二甲基乙醯胺
2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N-甲基乙醯胺
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-甲基-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(丙-2-基)-1,4λ
5-氮雜磷雜環己烷-4-酮
1-苄基-4-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
6-(二甲基磷醯基)-N-{(1R)-1-[2-氟-3-(三氟甲基)苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺
N-[(1R)-1-(3-溴-2-氟苯基)乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺
1-乙醯基-4-[4-({(1R)-1-[3-(二氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[4-({(1R)-1-[2,5-二甲基-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-[4-({(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-2,5-二氫-1H-1λ
5-磷雜環戊烯-1-酮
2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟(
2H
2)乙-1-醇
1-(4-{[(1R)-1-{3-[1,1-二氟-2-羥基(
2H
2)乙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ
5-磷雜環戊烷-1-酮
2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇
1-[4-({(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
2-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇
(2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丁-2-醇(非對映異構體1)
(2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-醇(非對映異構體1)
1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇(非對映異構體之混合物)
1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇(非對映異構體1)
1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇(非對映異構體2)
1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}-2-甲基丙-2-醇(非對映異構體之混合物)
1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}-2-甲基丙-2-醇(非對映異構體1)
1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}-2-甲基丙-2-醇(非對映異構體2)
(2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體之混合物)
(2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體1)
(2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體2)
(2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體之混合物)
(2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體3)
(2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體4)
(2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體之混合物)
(2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體1)
(2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體2)
(2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇
(2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體3)
(2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體4)
1-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-2,5-二氫-1H-1λ
5-磷雜環戊烯-1-酮
(2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丙-2-醇
(2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-醇(非對映異構體2)
(2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丁-2-醇(非對映異構體2)
(2R*)-1-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體2)
4-[2,8-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯
6-(二乙基磷醯基)-N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺
1-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
N-{(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺
1-[4-({(1R)-1-[3-胺基-5-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
6-(二乙基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺
N-{(1R)-1-[3-胺基-5-(三氟甲基)苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺
6-[二(丙-2-基)磷醯基]-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺
1-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
1-[2,7-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
6-(二甲基磷醯基)-7-甲氧基-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺
6-[二(丙-2-基)磷醯基]-2,7-二甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺
1-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[2,3-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇
1-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1λ
5-磷雜環戊烷-1-酮
1-苄基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
6-(二甲基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}喹唑啉-4-胺
1-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[二(丙-2-基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺
1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-酮
1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-酮
1-(4-{[(1R)-1-{3-[(2R*)-1,1-二氟-2-羥丙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ
5-磷雜環戊烷-1-酮(非對映異構體1)
1-(4-{[(1R)-1-{3-[(2R*)-1,1-二氟-2-羥丙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ
5-磷雜環戊烷-1-酮(非對映異構體2)
(2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體2)
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物)
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體1)
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體2)
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物)
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體1)
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體2)
N-{(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺
N-{(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺
1-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
1-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇
2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2,8-二甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺
1-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2,7-二甲基吡啶并[2,3-d]嘧啶-6-基]-1λ
5-磷雜環戊烷-1-酮
1-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基喹唑啉-6-基]-1λ
5-磷雜環戊烷-1-酮
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基喹唑啉-4-胺
N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[二(丙-2-基)磷醯基]-2,7-二甲基吡啶并[2,3-d]嘧啶-4-胺
2-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙-1-醇(非對映異構體之混合物)
2-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙-1-醇(非對映異構體1)
2-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙-1-醇(非對映異構體2)
2,2-二氟-2-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}乙-1-醇(非對映異構體之混合物)
2,2-二氟-2-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}乙-1-醇(非對映異構體1)
2,2-二氟-2-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}乙-1-醇(非對映異構體2)
(2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-醇(非對映異構體1)
(2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-醇(非對映異構體2)
1-乙醯基-4-(2-甲基-4-{[(1S)-1-[2-甲基-3-(三氟甲基)苯基](
2H
4)乙基]胺基}吡啶并[3,4-d]嘧啶-6-基)-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟乙基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[4-({(1R)-1-[2-氟-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[7-甲氧基-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[2,7-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
(R)-1-(4-(2,8-二甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d]嘧啶-6-基)-4-氧離子基-1,4-氮雜磷雜環己烷-1-基)乙-1-酮
1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2S)-2-甲氧基丙醯基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2R)-2-羥基丙醯基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(1-氟環丙烷-1-羰基)-1,4λ
5-氮雜磷雜環己烷-4-酮
1-{4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羰基}環丙烷-1-甲腈
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(2-甲基丙醯基)-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(甲氧基乙醯基)-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2R)-2-甲氧基丙醯基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(1-羥基環丙烷-1-羰基)-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2S)-2-羥基丙醯基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(氧雜環丁烷-3-羰基)-1,4λ
5-氮雜磷雜環己烷-4-酮
1-[1-(二氟甲基)環丙烷-1-羰基]-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(3,3-二氟環丁烷-1-羰基)-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-4-羰基)-1,4λ
5-氮雜磷雜環己烷-4-酮
3-{4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-基}-3-側氧基丙腈
1-(環丙烷羰基)-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(氧雜環丁烷-3-羰基)-1,4λ
5-氮雜磷雜環己烷-4-酮
1-[(2S)-2-羥基丙醯基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-[(2R)-2-羥基丙醯基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-{4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羰基}環丙烷-1-甲腈
1-(1-氟環丙烷-1-羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-[1-(二氟甲基)環丙烷-1-羰基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(3,3-二氟環丁烷-1-羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(2-甲基丙醯基)-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(環丙烷羰基)-4-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(1-羥基環丙烷-1-羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(環丙烷羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-4-羰基)-1,4λ
5-氮雜磷雜環己烷-4-酮
1-[(2S)-2-甲氧基丙醯基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(甲氧基乙醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-[1-(羥甲基)環丙烷-1-羰基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)甲磺醯胺
N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)乙醯胺
N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基甲磺醯胺
N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基乙醯胺
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-甲醯胺
N-環丙基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-甲醯胺
N-(2,2-二氟乙基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-甲醯胺
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-甲醯胺
4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸乙酯
N,N-二甲基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-甲醯胺
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸乙酯
1-乙醯基-4-[4-({(1R)-1-[3-(二氟甲基)-2-甲基苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[4-({(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[2-甲基-4-({(1R)-1-[3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
(R)-1-(4-(4-((1-(3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基)乙基)胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)-4-氧離子基-1,4-氮雜磷雜環己烷-1-基)乙-1-酮
1-乙醯基-4-[4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)-2-(三氟甲基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[2-(二氟甲基)-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[2-氯-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)甲磺醯胺
N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)乙醯胺
N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基甲磺醯胺
N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基乙醯胺
N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)-N-環丙基乙醯胺
1-(二氟乙醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
4-[4-({(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(二氟乙醯基)-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(二氟乙醯基)-4-[2-甲基-4-({(1R)-1-[3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(二氟乙醯基)-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
1-(二氟乙醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中X
1表示CH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中X
2表示CR
a,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中X
2表示N,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中:X
3表示CR
a,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中X
3表示N,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中X
4表示CH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中X
4表示N,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中Y表示O,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
1係-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
1係-CH
2-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
1係-CH(CH
3)
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
2係-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
2係-CH
2-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
2係-CH(CH
3)
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
3係-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
3係-CHF
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
3係-CF
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
3係-Cl,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
4係-H,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
4係-NH
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
4係-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-Br,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-H,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-F,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH
2-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CD
2-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH
2-OCH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH(CH
3)-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH(CH
2-CH
3)-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(CH
3)
2-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(CH
3)
2-OCH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH(CH(CH
3)
2)-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH(C(CH
3)
3)-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(CH
3)(CH
2-CH
2-CH
2-CH
3)-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(=O)-CH(CH
3)
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(=O)-C(CH
3)
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(=O)-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(=O)-NH
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(=O)-N(CH
3)
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(=O)-NH-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(=O)-NH-CH
2-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-C(=O)-NH-環丙基,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH
2-NH-SO
2-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH
2-N(CH
3)-SO
2-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH
2-NH-C(=O)-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
2-CH
2-N(CH
3),或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
6係-H,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
6係-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
6係-Fl,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
6係-Cl,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-H,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-CH
2-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-CF
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-CHF
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-CH
2-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-CH
2-O-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-OCH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
a係-環丙基,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-H,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-CH(CH
3)
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-CH
2-苯基,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-H,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-CH
2F,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-CH(CH
3)
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-CH(CH
3)-OH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-CH(CH
3)-O-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-CH
2-CN,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-CH
2-O-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-O-C(CH
3)
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-O-CH
2-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-NH
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-N(CH
3)
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-CH
2-CHF
2,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=O)-NH-環丙基,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-C(=S)-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
r係-SO
2-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
s係-CD
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
s係-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
t係-H,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
t係D,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
1及R
2兩者均為-CH
3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中R
5係-CF
3且R
6係-F,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
本發明之另一實施例涵蓋式(I)或式(Ia)化合物,同上,其中X
2係N且X
3係CH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
在第一態樣之另一特定實施例中,本發明在「本發明之第一態樣之其他實施例」之標題下涵蓋上文提及之實施例中之兩者或更多者之組合。
本發明涵蓋本發明之通式(I)化合物之任何實施例或態樣內之任何子組合,同上。
本發明涵蓋本發明之中間化合物之任何實施例或態樣內之任何子組合。
本發明涵蓋此內文之實例部分中揭示之通式(I)化合物,同下。
根據本發明之通式(I)化合物可根據下列方案1至12製備。下文描述之方案及程序闡述本發明之通式(I)化合物之合成途徑且無意為限制性。熟習此項技術者應清楚如方案1至12中例示之轉化順序可以各種方式修飾。因此此等方案中例示之轉化順序無意為限制性。另外,取代基R
1、R
2、R
3、R
4、R
5、R
6或Y中任一者之相互轉變可在本文例示之轉化之前及/或之後達成。此等修飾可為諸如保護基之引入、保護基之裂解、官能基之還原或氧化、鹵化、金屬化、取代或熟習此項技術者已知的其他反應。此等轉化包括彼等引入容許取代基進一步相互轉變之官能基者。適當之保護基及其引入及裂解為熟習此項技術者熟知(參見例如T.W. Greene及P.G.M. Wuts,Protective Groups in Organic Synthesis,第3版,Wiley 1999)。特定實例描述於隨後段落中。
用於製備通式(I)化合物之數種途徑描述於方案1至12中。
本發明涵蓋此內文之實例部分中揭示之中間化合物,同下。
本發明涵蓋本發明之中間化合物之任何實施例或態樣內之任何子組合,同上。
本發明之通式(I)化合物可藉由熟習此項技術者已知的任何方法轉化為如本文描述的任何鹽,較佳醫藥上可接受之鹽。同樣,本發明之通式(I)化合物之任何鹽可藉由熟習此項技術者已知的任何方法轉化為游離化合物。
本發明之通式(I)化合物證實無法預測之有價值之藥理學作用譜。已驚訝地發現本發明之化合物有效抑制SOS1且因此該該等化合物可用於在人類及動物中治療或預防疾病,較佳過度增生性疾患。
本發明之化合物可用以抑制、阻斷、減少、降低等細胞增生及/或細胞分裂,及/或產生細胞凋亡。此方法包括對有需要哺乳動物(包括人類)投與一量之本發明之通式(I)化合物,或其醫藥上可接受之鹽、異構體、多晶型物、代謝物、水合物、溶劑合物或酯,其有效治療疾患。
過度增生性疾患包括(但不限於),例如:牛皮廯、瘢瘤,及影響皮膚之其他過度增生、良性前列腺增生(BPH)、實體瘤,諸如乳房、呼吸道、腦、生殖器官、消化道、尿路、眼、肝、皮膚、頭及頸、甲狀腺、副甲狀腺之癌症及其遠端轉移。彼等疾患亦包括淋巴瘤、肉瘤及白血病。
乳癌之實例包括(但不限於)侵襲性導管癌、侵襲性小葉癌、導管原位癌及小葉原位癌。
呼吸道癌症之實例包括(但不限於)小細胞及非小細胞肺癌,及支氣管腺瘤及胸膜肺母細胞瘤。
腦癌之實例包括(但不限於)腦幹及腦下垂體神經膠質瘤(hypophtalmic glioma)、小腦及腦星形細胞瘤、髓母細胞瘤、室管膜瘤,及神經外胚層及松果體腫瘤。
男性生殖器官之腫瘤包括(但不限於)前列腺及睪丸癌。
女性生殖器官之腫瘤包括(但不限於)子宮內膜、宮頸、卵巢、陰道及外陰癌,及子宮之肉瘤。
消化道之腫瘤包括(但不限於)肛門、結腸、結腸直腸、食道、膽囊、胃、胰臟、直腸、小腸及唾液腺癌。
尿路之腫瘤包括(但不限於)膀胱、陰莖、腎、腎盂、輸尿管、尿道及人乳頭狀腎癌。
眼癌包括(但不限於)眼內黑色素瘤及視網膜母細胞瘤。
肝癌之實例包括(但不限於)肝細胞癌(伴或不伴纖維板層變體之肝細胞癌)、膽管癌(肝內膽管癌)及混合肝細胞膽管癌。
皮膚癌包括(但不限於)鱗狀細胞癌、卡波西肉瘤(Kaposi’s sarcoma)、惡性黑色素瘤、默克爾(Merkel)細胞皮膚癌及非黑色素瘤皮膚癌。
頭及頸癌包括(但不限於)喉、下咽、鼻咽、口咽癌、唇及口腔癌及鱗狀細胞。
淋巴瘤包括(但不限於) AIDS相關淋巴瘤、非何傑金氏淋巴瘤(non-Hodgkin’s lymphoma)、皮膚T細胞淋巴瘤、伯奇氏淋巴瘤(Burkitt lymphoma)、何傑金氏病,及中樞神經系統之淋巴瘤。
肉瘤包括(但不限於)軟組織肉瘤、骨肉瘤、惡性纖維組織細胞瘤、淋巴肉瘤及橫紋肌肉瘤。
白血病包括(但不限於)急性骨髓性白血病、急性淋巴母細胞白血病、慢性淋巴球性白血病、慢性骨髓性白血病及毛細胞白血病。
本發明亦提供治療血管生成障礙(包括與過度及/或異常血管生成相關聯之疾病)之方法。
血管生成之不適當及異位表現可對生物體有害。許多病理狀態係與外來血管之生長相關聯。此等包括(例如)糖尿病視網膜病變、缺血性視網膜靜脈阻塞及早產兒視網膜病變[Aiello等人,New Engl. J. Med., 1994, 331, 1480;Peer等人,Lab. Invest., 1995, 72, 638]、年齡相關性黃斑變性(AMD) [Lopez等人,Invest. Opththalmol. Vis. Sci., 1996, 37, 855]、新生血管性青光眼、牛皮廯、晶狀體後纖維組織增生、血管纖維瘤、發炎、類風濕性關節炎(RA)、再狹窄、支架內再狹窄、血管移植再狹窄等。另外,與癌性及腫瘤組織相關聯之血液供應增加促進生長,導致腫瘤迅速增大及轉移。此外,腫瘤中新血管及淋巴管之生長為叛逆細胞提供逃避途徑,促進該癌症之轉移及隨後擴散。因此,本發明之通式(I)化合物可用以治療及/或預防前述血管生成疾患中之任一者,例如藉由抑制及/或減少血管形成;藉由抑制、阻斷、減少、降低等內皮細胞增生,或參與血管生成之其他類型,及引起此等細胞類型之細胞死亡或細胞凋亡。
此等疾患已於人類中經良好表徵,但於其他哺乳動物中亦存在類似病因,且可藉由投與本發明之醫藥組合物治療。
如整個本檔案中說明之術語「治療(treating或treatment)」係按常規使用,例如出於對抗、減輕、減少、緩解、改善疾病或疾患(諸如癌)之病症之目的管理或護理個體。
本發明之化合物可用於特別是治療及防止(即預防)腫瘤生長及轉移,尤其於所有適應症及階段之實體瘤中,在有或無預治療該腫瘤生長之情況下。
一般而言,化學治療劑及/或抗癌劑與本發明之化合物或醫藥組合物之組合使用將發揮以下作用:
1. 相較於單獨投與藥劑,於減少腫瘤生長或甚至消除該腫瘤中產生更佳效用,
2. 提供較少量投與之化學治療劑之投與,
3. 提供於病患中耐受性良好之化學治療劑治療,相比於以單一藥劑化學療法及某些其他組合療法觀測者,有害之藥理學併發症更少,
4. 於哺乳動物(尤其人類)中提供範圍更廣泛之不同癌症類型之治療,
5. 於經治療之病患中提供更高之反應率,
6. 相較於標準化學療法治療,於經治療之病患中提供更長之存活時間,
7. 為腫瘤進展提供更長時間,及/或
8. 相較於其他癌症藥劑組合產生拮抗效應之已知情況,產生至少與彼等與單獨使用該等藥劑者一樣好的效用及耐受性結果。
另外,本發明之通式(I)化合物亦可與射療法及/或手術干預組合使用。
在本發明之另一實施例中,本發明之通式(I)化合物可用以使細胞對輻射敏感,即在對該細胞進行輻射治療之前,用本發明之化合物治療細胞使該細胞比未用本發明之化合物進行任何治療時之該細胞更易受DNA損傷及細胞死亡。在一項態樣中,用至少一種本發明之通式(I)化合物治療該細胞。
因此,本發明亦提供一種殺死細胞之方法,其中對細胞投與一或多種本發明之化合物與習知輻射療法之組合。
本發明亦提供一種使細胞對細胞死亡更敏感之方法,其中在治療該細胞以引起或誘導細胞死亡之前用一或多種本發明之通式(I)化合物治療該細胞。在一項態樣中,在用一或多種本發明之通式(I)化合物治療該細胞之後,用至少一種化合物,或至少一種方法,或其組合治療該細胞,以出於抑制正常細胞之功能或殺死該細胞之目的引起DNA損傷。
在本發明之其他實施例中,藉由用至少一種DNA損傷劑治療細胞殺死該細胞,即在用一或多種本發明之通式(I)化合物治療細胞以使該細胞對細胞死亡敏感之後,用至少一種DNA損傷劑治療該細胞以殺死該細胞。適用於本發明中之DNA損傷劑包括(但不限於)化學治療劑(例如順鉑)、電離輻射(X射線、紫外輻射)、致癌劑及誘變劑。
在其他實施例中,藉由用至少一種方法治療細胞以引起或誘導DNA損傷殺死該細胞。此等方法包括(但不限於)活化細胞傳訊途徑,當該途徑係經活化時其導致DNA損傷,抑制細胞傳訊途徑,當該途徑係經抑制時其導致DNA損傷,及於細胞中誘導生物化學變化,其中該變化導致DNA損傷。僅以非限制性實例說明之,可抑制細胞中之DNA修復途徑,藉此防止DNA損傷之修復並導致細胞中DNA損傷之異常累積。
在本發明之一項態樣中,在細胞中DNA損傷之輻射或其他誘導之前對該細胞投與本發明之通式(I)化合物。在本發明之另一態樣中,伴隨細胞中DNA損傷之輻射或其他誘導對該細胞投與本發明之通式(I)化合物。在本發明之又另一態樣中,已開始細胞中DNA損傷之輻射或其他誘導後立即對該細胞投與本發明之通式(I)化合物。
在另一態樣中,該細胞係活體外的。在另一實施例中,該細胞係活體內的。
根據另一態樣,本發明涵蓋上述通式(I)化合物,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特別其醫藥上可接受之鹽,或其混合物,用以治療或預防疾病,特別是過度增生性疾患。
根據本發明之化合物之醫藥活性可由其作為SOS1抑制劑之活性解釋。
根據另一態樣,本發明涵蓋上述通式(I)化合物,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特別其醫藥上可接受之鹽,或其混合物之用途,用於治療或預防疾病,特別是過度增生性疾患,尤其與SOS1相關聯之疾病。
根據另一態樣,本發明涵蓋上述式(I)化合物,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,特別其醫藥上可接受之鹽,或其混合物之用途,用於預防或治療疾病,特別是過度增生性疾患,尤其與SOS1相關聯之疾病。
根據另一態樣,本發明涵蓋上述通式(I)化合物,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特別其醫藥上可接受之鹽,或其混合物之用途,用於治療或預防疾病之方法中,特別是過度增生性疾患,尤其與SOS1相關聯之疾病。
根據另一態樣,本發明涵蓋上述通式(I)化合物,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特別其醫藥上可接受之鹽,或其混合物之用途,用於製備用於預防或治療疾病,特別是過度增生性疾患,尤其與SOS1相關聯之疾病的醫藥組合物,較佳藥劑。
根據另一態樣,本發明涵蓋一種使用有效量之上述通式(I)化合物,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物及鹽,特別其醫藥上可接受之鹽,或其混合物治療或預防疾病,特別是過度增生性疾患,尤其與SOS1相關聯之疾病之方法。
根據另一態樣,本發明涵蓋醫藥組合物,特別是藥劑,其包含上述通式(I)化合物,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物、鹽,特別醫藥上可接受之鹽,或其混合物,及一或多種賦形劑,特別是一或多種醫藥上可接受之賦形劑。可利用用於以適當劑型製備此等醫藥組合物之習知程序。
此外,本發明涵蓋醫藥組合物,特別是藥劑,其等包含至少一種根據本發明之化合物,通常連同一或多種醫藥上合適之賦形劑一起,及係關於其等出於上述目的之用途。
根據本發明之化合物可能具有全身及/或局部活性。出於此目的,其等可以合適之方式投與,諸如,舉例而言,經由經口、非經腸、非肺、經鼻、舌下、經舌、經頰、經直腸、經陰道、經真皮、透皮、經結膜、經耳道或作為植入物或支架。
針對此等投與途徑,根據本發明之化合物可以合適之投與形式投與。
針對經口投與,可將根據本發明之化合物調配為此項技術中已知快速及/或以經修飾之方式遞送本發明之化合物之劑型,諸如,舉例而言,錠劑(未包衣或包衣錠劑,例如具有延遲溶解或不溶之腸溶性或控釋包衣),經口崩解之錠劑、薄膜/薄片、薄膜/凍乾粉、膠囊(例如硬質或軟質明膠膠囊)、糖包衣錠劑、顆粒、小丸、粉末、乳液、懸浮液、噴霧劑或溶液。可能以結晶及/或非晶型及/或溶解形式將根據本發明之化合物併入該等劑型內。
非經腸投與可以避免吸收步驟(例如靜脈內、動脈內、心內、脊柱內或腰腔內)或以包括吸收(例如肌內、皮下、皮內、經皮或腹膜內)實現。適用於非經腸投與之投與形式係(尤其)用於以溶液、懸浮液、乳液、凍乾粉或無菌粉末之形式注射及輸注之製劑。
適用於其他投與途徑之實例係用於吸入之醫藥形式[尤其粉末吸入器、霧化器]、滴鼻劑、鼻用溶液、噴鼻劑;用於經舌、舌下或經頰投與之錠劑/薄膜/薄片/膠囊;栓劑;眼藥水、眼藥膏、眼浴、眼部插入物、滴耳劑、耳噴劑、耳用粉末、洗耳劑、耳用棉球;陰道膠囊、水性懸浮液(洗劑、攪拌混合物)、親脂性懸浮液、乳液、軟膏、乳膏、透皮治療系統(諸如,舉例而言,貼劑)、乳液、糊劑、泡沫、除塵粉、植入物或支架。
根據本發明之化合物可併入規定投與形式內。此可以本身已知的方式藉由與醫藥上合適之賦形劑混合實現。醫藥上合適之賦形劑包括(尤其),
填充劑及載劑(例如纖維素、微晶纖維素(諸如,舉例而言,Avicel
®)、乳糖、甘露醇、澱粉、磷酸鈣(諸如,舉例而言,Di-Cafos
®)),
軟膏基質(例如石油膠、石蠟、三酸甘油酯、蠟、羊毛蠟、羊毛蠟醇、羊毛脂、親水性軟膏、聚乙二醇),
用於栓劑之基質(例如聚乙二醇、可可脂、硬質脂肪),
溶劑(例如水、乙醇、異丙醇、甘油、丙二醇、中等鏈長三酸甘油酯脂肪油、液體聚乙二醇、石蠟),
表面活性劑、乳化劑、分散劑或潤濕劑(例如十二烷基硫酸鈉)、卵磷脂、磷脂、脂肪醇(諸如,舉例而言,Lanette
®)、山梨醇脂肪酸酯(諸如,舉例而言,Span
®)、聚氧乙烯山梨醇脂肪酸酯(諸如,舉例而言,Tween
®)、聚氧乙烯脂肪酸甘油酯(諸如,舉例而言,Cremophor
®)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(諸如,舉例而言,Pluronic
®),
緩衝劑、酸及鹼(例如磷酸鹽、碳酸鹽、檸檬酸、乙酸、鹽酸、氫氧化鈉溶液、碳酸銨、氨丁三醇、三乙醇胺),
等滲劑(例如葡萄糖、氯化鈉),
吸附劑(例如高度分散之二氧化矽),
增黏劑、凝膠形成劑、增稠劑及/或黏合劑(例如聚乙烯吡咯啶酮、甲基纖維素、羥丙基甲基纖維素、羥丙基纖維素、羧甲基纖維素鈉、澱粉、卡波姆、聚丙烯酸(諸如,舉例而言,Carbopol
®);海藻酸鹽、明膠),
崩解劑(例如經修飾之澱粉、羧甲基纖維素鈉、羥基乙酸澱粉鈉(諸如,舉例而言,Explotab
®)、交聯聚乙烯吡咯啶酮、交聯羧甲基纖維素鈉(諸如,舉例而言,AcDiSol
®)),
流動調節劑、潤滑劑、助流劑及脫模劑(例如硬脂酸鎂、硬脂酸、滑石、高度分散之二氧化矽(諸如,舉例而言,Aerosil
®)),
包衣材料(例如糖、蟲膠)及用於快速或以經修飾之方式溶解之薄膜或擴散膜之成膜劑(例如聚乙烯吡咯啶酮(諸如,舉例而言,Kollidon
®)、聚乙烯醇、羥丙基甲基纖維素、羥丙基纖維素、乙基纖維素、鄰苯二甲酸羥丙基甲基纖維素、乙酸纖維素、乙酸鄰苯二甲酸纖維素、聚丙烯酸酯、聚甲基丙烯酸酯,諸如,舉例而言,Eudragit
®)),
膠囊材料(例如明膠、羥丙基甲基纖維素),
合成聚合物(例如聚乳酸、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(諸如,舉例而言,Eudragit
®)、聚乙烯吡咯啶酮(諸如,舉例而言,Kollidon
®)、聚乙烯醇、聚乙酸乙烯酯、聚環氧乙烷、聚乙二醇及其共聚物及嵌段共聚物),
塑化劑(例如聚乙二醇、丙二醇、甘油、三乙酸甘油酯、檸檬酸三乙醯酯、鄰苯二甲酸二丁酯),
滲透增強劑,
穩定劑(例如抗氧化劑,諸如,舉例而言,抗壞血酸、抗壞血酸棕櫚酸酯、抗壞血酸鈉、丁基羥基苯甲醚、丁基羥基甲苯、沒食子酸丙酯),
防腐劑(例如對羥基苯甲酸酯、山梨酸、硫柳汞、苯紮氯銨、乙酸氯己定、苯甲酸鈉),
著色劑(例如無機顏料,諸如,舉例而言,氧化鐵、二氧化鈦),
調味劑、甜味劑、味道及/或氣味掩蔽劑。
此外,本發明係關於一種醫藥組合物,其包含至少一種根據本發明之化合物,通常連同一或多種醫藥上合適之賦形劑一起,及係關於其根據本發明之用途。
根據另一態樣,本發明涵蓋醫藥組合,特別是藥劑,其包含至少一種本發明之通式(I)化合物及至少一種或多種其他活性成分,特別是用於治療及/或預防過度增生性疾患,尤其與SOS1相關聯之疾病。
特別是,本發明涵蓋一種醫藥組合,其包含:
一或多種第一活性成分,特定言如上文定義之通式(I)化合物,及
一或多種適用於治療過度增生性疾患,尤其與SOS1相關聯之疾病之其他活性成分。
本發明中之術語「組合」係如熟習此項技術者已知使用,該組合可能係固定組合、非固定組合或多劑式套組。
本發明中之「固定組合」係如熟習此項技術者已知使用並定義為一種組合,其中例如第一活性成分諸如一或多種本發明之通式(I)化合物,及另一活性成分係以一個單位劑量或以一個單一實體共同存在。「固定組合」之一項實例係一種醫藥組合物,其中第一活性成分及另一活性成分係以用於同時投與之混合物,諸如以調配物存在。「固定組合」之另一實例係一種醫藥組合,其中該第一活性成分及另一活性成分係以一個單元而非以混合物存在。
本發明中之非固定組合或「多劑式套組」係如熟習此項技術者已知使用並定義為一種組合,其中第一活性成分及另一活性成分係以多於一個單元存在。非固定組合或多劑式套組之一項實例係一種組合,其中該第一活性成分及另一活性成分係分別存在。該非固定組合或多劑式套組之組分可分別、循序、同時、伴隨或時間交錯投與。
本發明之化合物可作為單獨藥劑或與一或多種其他醫藥活性成分組合投與,其中該組合不引起不可接受之不良效應。本發明亦涵蓋此等醫藥組合。例如,本發明之化合物可與已知抗癌劑組合。
抗癌劑之實例包括:
131I-chTNT、阿巴瑞克(abarelix)、阿貝西利(abemaciclib)、阿比特龍(abiraterone)、阿卡替尼(acalabrutinib)、阿柔比星(aclarubicin)、阿達木單抗(adalimumab)、阿多曲妥珠單抗-恩他新(ado-trastuzumab emtansine)、阿法替尼、阿柏西普(aflibercept)、阿地白介素(aldesleukin)、艾樂替尼(alectinib)、阿崙單抗(alemtuzumab)、阿崙膦酸(alendronic acid)、阿曲諾英(alitretinoin)、阿爾法拉丁(alpharadin)、六甲蜜胺(altretamine)、胺磷汀(amifostine)、胺麩精(aminoglutethimide)、胺基乙醯丙酸己酯(hexyl aminolevulinate)、氨柔比星(amrubicin)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、安塞司亭(ancestim)、茴香腦二硫雜環戊二烯硫酮(anethole dithiolethione)、雷星-阿奈妥單抗(anetumab ravtansine)、血管收縮素II (angiotensin II)、抗凝血酶III (antithrombin III)、阿帕魯胺(apalutamide)、阿瑞匹坦(aprepitant)、阿西莫單抗(arcitumomab)、阿格拉賓(arglabin)、三氧化二砷(arsenic trioxide)、天冬醯胺酸酶(asparaginase)、阿特珠單抗(atezolizumab)、阿維魯單抗(avelumab)、阿基侖賽(axicabtagene ciloleucel)、阿西替尼(axitinib)、阿紮胞苷(azacitidine)、巴厘昔單抗(basiliximab)、貝洛替康(belotecan)、苯達莫司汀(bendamustine)、貝西索單抗(besilesomab)、貝利司他(belinostat)、貝伐單抗(bevacizumab)、貝沙羅汀(bexarotene)、比卡魯胺(bicalutamide)、比生群(bisantrene)、博來黴素(bleomycin)、博納吐單抗(blinatumomab)、硼替佐米(bortezomib)、博舒替尼(bosutinib)、布舍瑞林(buserelin)、貝倫妥單抗維多汀(brentuximab vedotin)、布加替尼(brigatinib)、白消安(busulfan)、卡巴他賽(cabazitaxel)、卡博替尼(cabozantinib)、降鈣素(calcitonine)、亞葉酸鈣(calcium folinate)、左亞葉酸鈣(calcium levofolinate)、卡培他濱(capecitabine)、卡羅單抗(capromab)、卡馬西平卡鉑(carbamazepine carboplatin)、卡波醌(carboquone)、卡非佐米(carfilzomib)、卡莫氟(carmofur)、卡莫司汀(carmustine)、卡妥索單抗(catumaxomab)、塞來昔布(celecoxib)、西莫白介素(celmoleukin)、西米普利單抗(cemiplimab)、色瑞替尼(ceritinib)、西妥昔單抗(cetuximab)、氮芥苯丁酸(chlorambucil)、氯地孕酮(chlormadinone)、氮芥(chlormethine)、西多福韋(cidofovir)、西那卡塞(cinacalcet)、順鉑(cisplatin)、克拉屈濱(cladribine)、氯膦酸(clodronic acid)、氯法拉濱(clofarabine)、考比替尼(cobimetinib)、庫潘尼西(copanlisib)、克立他酶(crisantaspase)、克唑替尼(crizotinib)、環磷醯胺(cyclophosphamide)、環丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、達卡巴嗪(dacarbazine)、更生黴素(dactinomycin)、達雷木單抗(daratumumab)、阿法達貝泊汀(darbepoetin alfa)、達拉非尼(dabrafenib)、達洛魯胺(darolutamide)、達沙替尼(dasatinib)、道諾黴素(daunorubicin)、地西他濱(decitabine)、地加瑞克(degarelix)、地尼白介素迪夫托斯(denileukin diftitox)、地諾單抗(denosumab)、地普奧肽(depreotide)、德舍瑞林(deslorelin)、雙脫水半乳糖醇(dianhydrogalactitol)、右雷佐生(dexrazoxane)、二溴螺氯銨(dibrospidium chloride)、雙脫水半乳糖醇、雙氯芬酸(diclofenac)、地努妥昔單抗(dinutuximab)、多西他賽(docetaxel)、朵拉司瓊(dolasetron)、去氧氟尿苷(doxifluridine)、阿黴素(doxorubicin)、阿黴素+雌酮(doxorubicin + estrone)、屈大麻酚(dronabinol)、杜瓦魯單抗(durvalumab)、依庫珠單抗(eculizumab)、依決洛單抗(edrecolomab)、依利醋銨(elliptinium acetate)、埃羅妥珠單抗(elotuzumab)、艾曲波帕(eltrombopag)、恩西地平(enasidenib)、內皮抑素(endostatin)、依諾西他濱(enocitabine)、恩雜魯胺(enzalutamide)、表柔比星(epirubicin)、環硫雄醇(epitiostanol)、阿法依伯汀(epoetin alfa)、倍他依泊汀(epoetin beta)、仄他依泊汀 (epoetin zeta)、依鉑(eptaplatin)、艾日布林(eribulin)、埃羅替尼、埃索美拉唑(esomeprazole)、雌二醇(estradiol)、雌莫司汀(estramustine)、炔雌醇(ethinylestradiol)、依託泊苷(etoposide)、依維莫司(everolimus)、依西美坦(exemestane)、法曲唑(fadrozole)、芬太尼(fentanyl)、非格司亭(filgrastim)、氟甲睪酮(fluoxymesterone)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟尿嘧啶(fluorouracil)、氟他胺(flutamide)、亞葉酸(folinic acid)、福美坦(formestane)、福沙匹坦(fosaprepitant)、福莫司汀(fotemustine)、氟維司群(fulvestrant)、釓布醇(gadobutrol)、釓特醇(gadoteridol)、釓特酸葡甲胺(gadoteric acid meglumine)、釓弗塞胺(gadoversetamide)、釓塞酸(gadoxetic acid)、硝酸鎵(gallium nitrate)、加尼瑞克(ganirelix)、吉非替尼、吉西他濱(gemcitabine)、吉妥珠單抗(gemtuzumab)、穀卡匹酶(Glucarpidase)、氧化型麩胱甘肽(glutoxim)、GM-CSF、戈舍瑞林(goserelin)、格拉司瓊(granisetron)、顆粒性白血球群落刺激因子(granulocyte colony stimulating factor)、組胺二鹽酸鹽(histamine dihydrochloride)、組胺瑞林(histrelin)、羥基脲(hydroxycarbamide)、I-125核種、蘭索拉唑(lansoprazole)、伊班膦酸(ibandronic acid)、替伊莫單抗(ibritumomab tiuxetan)、依魯替尼(ibrutinib)、伊達比星(idarubicin)、異環磷醯胺(ifosfamide)、伊馬替尼(imatinib)、咪喹莫特(imiquimod)、英丙舒凡(improsulfan)、吲地司瓊(indisetron)、英卡膦酸(incadronic acid)、巨大戟醇甲基丁烯酸酯(ingenol mebutate)、奧英妥珠單抗(inotuzumab ozogamicin)、干擾素α (interferon alfa)、干擾素β (interferon beta)、干擾素γ (interferon gamma)、碘比醇(iobitridol)、碘苄胍(iobenguane) (123I)、碘美普爾(iomeprol)、伊匹單抗(ipilimumab)、伊立替康(irinotecan)、伊曲康唑(Itraconazole)、伊沙匹隆(ixabepilone)、艾沙佐米(ixazomib)、蘭瑞肽(lanreotide)、蘭索拉唑、拉帕替尼(lapatinib)、阿索氯林(Iasocholine)、來那度胺(lenalidomide)、樂伐替尼(lenvatinib)、來格司亭(lenograstim)、香菇多醣(lentinan)、來曲唑(letrozole)、亮丙瑞林(leuprorelin)、左旋咪唑(levamisole)、左炔諾孕酮(levonorgestrel)、左甲狀腺素鈉(levothyroxine sodium)、麥角乙脲(lisuride)、洛鉑(lobaplatin)、洛莫司汀(lomustine)、氯尼達明(lonidamine)、多他酸鑥Lu 177 (lutetium Lu 177 dotatate)、馬索羅酚(masoprocol)、甲羥孕酮(medroxyprogesterone)、甲地孕酮(megestrol)、美拉胂醇(melarsoprol)、美法侖(melphalan)、美雄烷(mepitiostane)、巰基嘌呤(mercaptopurine)、美司鈉(mesna)、美沙酮(methadone)、胺甲喋呤(methotrexate)、甲氧沙林(methoxsalen)、甲胺基乙醯丙酸鹽(methylaminolevulinate)、甲基普賴蘇濃(methylprednisolone)、甲基睪固酮(methyltestosterone)、甲酪胺酸(metirosine)、米哚妥林(midostaurin)、米伐木肽(mifamurtide)、米替福新(miltefosine)、米鉑(miriplatin)、二溴甘露醇(mitobronitol)、米托胍腙(mitoguazone)、二溴衛矛醇(mitolactol)、絲裂黴素(mitomycin)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、莫加木單抗(mogamulizumab)、莫格莫司亭(molgramostim)、莫匹達莫(mopidamol)、鹽酸嗎啡(morphine hydrochloride)、硫酸嗎啡(morphine sulfate)、姆瓦西(mvasi)、大麻隆(nabilone)、納比西莫(nabiximols)、那法瑞林(nafarelin)、納洛酮+噴他佐辛(naloxone + pentazocine)、納曲酮(naltrexone)、那托司亭(nartograstim)、耐昔妥珠單抗(necitumumab)、奈達鉑(nedaplatin)、奈拉濱(nelarabine)、來那替尼、奈立膦酸(neridronic acid)、奈妥吡坦(netupitant)/帕洛諾司瓊(palonosetron)、納武單抗(nivolumab)、噴曲肽(pentetreotide)、尼羅替尼(nilotinib)、尼魯米特(nilutamide)、尼莫唑(nimorazole)、尼妥珠單抗(nimotuzumab)、尼莫司汀(nimustine)、尼達尼布(nintedanib)、尼拉帕尼(niraparib)、二胺硝吖啶(nitracrine)、納武單抗、奧比妥珠單抗(obinutuzumab)、奧曲肽(octreotide)、奧法木單抗(ofatumumab)、奧拉帕尼(olaparib)、奧拉木單抗(olaratumab)、美琥他辛(omacetaxine mepesuccinate)、奧美拉唑(omeprazole)、昂丹司瓊(ondansetron)、奧普瑞白介素(oprelvekin)、奧古蛋白(orgotein)、奧瑞莫德(orilotimod)、奧希替尼(osimertinib)、奧沙利鉑(oxaliplatin)、羥考酮(oxycodone)、羥甲烯龍(oxymetholone)、奧佐米辛(ozogamicine)、p53基因療法、紫杉醇(paclitaxel)、帕博西尼(palbociclib)、帕利夫明(palifermin)、鈀-103核種、帕洛諾司瓊、帕米膦酸(pamidronic acid)、帕尼單抗(panitumumab)、帕比司他(panobinostat)、泮托拉唑(pantoprazole)、培唑帕尼(pazopanib)、培門冬酶(pegaspargase)、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、派姆單抗(pembrolizumab)、聚乙二醇化非格司亭(pegfilgrastim)、聚乙二醇干擾素α-2b (peginterferon alfa-2b)、派姆單抗、培美曲塞(pemetrexed)、噴他佐辛(pentazocine)、噴司他丁(pentostatin)、佩洛黴素(peplomycin)、全氟丁烷(Perflubutane)、培磷醯胺(perfosfamide)、帕妥珠單抗(Pertuzumab)、畢西巴尼(picibanil)、匹魯卡品(pilocarpine)、吡柔比星(pirarubicin)、匹杉瓊(pixantrone)、普樂沙福(plerixafor)、普卡黴素(plicamycin)、聚胺葡糖(poliglusam)、聚雌二醇磷酸酯(polyestradiol phosphate)、聚乙烯吡咯啶酮+玻尿酸鈉(sodium hyaluronate)、多醣-K、泊馬度胺(pomalidomide)、普納替尼(ponatinib)、卟吩姆鈉(porfimer sodium)、普拉曲沙(pralatrexate)、潑尼莫司汀(prednimustine)、強體松(prednisone)、丙卡巴肼(procarbazine)、丙考達唑(procodazole)、普萘洛爾(propranolol)、喹高利特(quinagolide)、雷貝拉唑(rabeprazole)、雷妥莫單抗(racotumomab)、氯化鐳-223 (radium-223 chloride)、雷多替尼(radotinib)、雷洛昔芬(raloxifene)、雷替曲塞(raltitrexed)、雷莫司瓊(ramosetron)、雷莫蘆單抗(ramucirumab)、雷尼莫司汀(ranimustine)、拉布裡酶(rasburicase)、雷佐生(razoxane)、瑞法替尼(refametinib)、瑞戈非尼(regorafenib)、瑞博西尼(ribociclib)、利塞膦酸(risedronic acid)、依替膦酸錸-186 (rhenium-186 etidronate)、利妥昔單抗(rituximab)、羅拉吡坦(rolapitant)、羅米地辛(romidepsin)、羅米司亭(romiplostim)、羅莫肽(romurtide)、魯卡帕尼(rucaparib)、來克西德南釤(153Sm) (samarium (153Sm) lexidronam)、沙格司亭(sargramostim)、沙利魯單抗(sarilumab)、沙妥莫單抗(satumomab)、胰泌素(secretin)、司妥昔單抗(siltuximab)、普列威(sipuleucel-T)、西佐喃(sizofiran)、索布佐生(sobuzoxane)、甘胺雙唑鈉(sodium glycididazole)、索尼德吉(sonidegib)、索拉非尼(sorafenib)、司坦唑醇(stanozolol)、鏈脲佐菌素(streptozocin)、舒尼替尼(sunitinib)、他拉泊芬(talaporfin)、拉赫他利莫近(talimogene laherparepvec)、他米巴羅汀(tamibarotene)、他莫昔芬(tamoxifen)、他噴他多(tapentadol)、他索納明(tasonermin)、替西白介素(teceleukin)、諾非妥莫單抗鍀(99mTc) (technetium (99mTc) nofetumomab merpentan)、99mTc-HYNIC-[Tyr3]-奧曲肽、替加氟(tegafur)、替加氟+吉美西(gimeracil) +奧替西林(oteracil)、替莫泊芬(temoporfin)、替莫唑胺(temozolomide)、替西羅莫司(temsirolimus)、替尼泊苷(teniposide)、睪固酮、替曲磷(tetrofosmin)、沙利度胺(thalidomide)、噻替哌(thiotepa)、胸腺法新(thymalfasin)、促甲狀腺素α (thyrotropin alfa)、硫鳥嘌呤(tioguanine)、替沙侖賽(tisagenlecleucel)、替雷利珠單抗(tislelizumab)、托珠單抗(tocilizumab)、拓撲替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲貝替定(trabectedin)、曲美替尼(trametinib)、曲馬多(tramadol)、曲妥珠單抗(trastuzumab)、曲妥珠單抗恩他新(trastuzumab emtansine)、曲奧舒凡(treosulfan)、視網酸(tretinoin)、曲氟尿苷(trifluridine) +替吡嘧啶(tipiracil)、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、曲美替尼(trametinib)、曲磷胺(trofosfamide)、血小板生成素、色胺酸、烏苯美司(ubenimex)、瓦拉替尼(valatinib)、戊柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽(vapreotide)、威羅非尼(vemurafenib)、長春花鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、長春氟寧(vinflunine)、長春瑞濱(vinorelbine)、維莫德吉(vismodegib)、伏立諾他(vorinostat)、伏氯唑(vorozole)、釔-90玻璃微球體、淨司他丁(zinostatin)、淨司他丁斯酯(zinostatin stimalamer)、唑來膦酸(zoledronic acid)、佐柔比星(zorubicin)。
基於已知評估適用於治療過度增生型疾患之化合物之標準實驗室技術,藉由標準毒性測試及藉由標準藥理學分析來用於確定治療哺乳動物中上文鑑別之病症,及藉由比較此等結果與用以治療此等病症之已知活性成分或藥劑之結果,可容易確定用於治療各所需適應症之本發明之化合物之有效劑量。欲投與以治療此等病症中之一者之活性成分之量可根據諸如特定化合物及採用之劑量單位、投與模式、治療期、治療病患之年齡及性別,及治療病症之性質及程度之考慮因素廣泛變化。
欲投與之活性成分之總量將一般在約0.001 mg/kg至約200 mg/kg體重每天,及較佳約0.01 mg/kg至約20 mg/kg體重每天之範圍內。臨床上有用之給藥時間表將在一天一至三次給藥至每四週一次給藥之範圍內。另外,「藥物假期」係可能的,其中在某一時間週期內未對病患給藥,以有利於在藥理學效應與耐受性之間達成整體平衡。單位劑量可能含有約0.5 mg至約1500 mg活性成分,且可投與每天一或多次或一天少於一次。用於藉由注射,包括靜脈內、肌內、皮下及非經腸注射,及使用輸注技術投與之平均每日劑量將較佳係0.01至200 mg/kg總體重。平均每日直腸劑量方案將較佳係0.01至200 mg/kg總體重。平均每日陰道劑量方案將較佳係0.01至200 mg/kg總體重。平均每日局部劑量方案將較佳係0.1至200 mg,投與介於每天一至四次之間。透皮濃度將較佳係維持0.01至200 mg/kg之每日劑量所需之濃度。平均每日吸入劑量方案將較佳係0.01至100 mg/kg總體重。
當然用於各病患之特定初始及持續劑量方案將根據如由主治醫師確定之病症之性質及嚴重程度、採用之特定化合物之活性、病患之年齡及一般情況、投與時間、投與途徑、藥物之排泄率、藥物組合,及類似物而變化。本發明之化合物或其醫藥上可接受之鹽或酯或組合物之所需治療模式及給藥次數可由熟習此項技術者使用習知治療測試確定。
實驗部分
NMR峰形式係如其等出現於光譜中般規定,未考慮可能之高階效應。
選定化合物之
1H-NMR資料係以
1H-NMR峰表形式列舉。其中,針對各信號峰,δ值係以ppm給定,接著圓括號中報導之信號強度。來自不同峰之δ值-信號強度對由逗號隔開。因此,峰表係由一般形式描述:δ
1(強度
1)、δ
2(強度
2)、…、δ
i(強度
i)、…、δ
n(強度
n)。
尖銳信號之強度與印刷NMR光譜中信號之高度(以cm計)相關。當與其他信號比較時,此資料可與信號強度之實際比率相關。在寬信號之情況下,相較於該光譜中顯示之最強信號,顯示多於一個峰,或該信號之中心連同其等相關強度一起。
1H-NMR峰表類似於經典
1H-NMR讀數,且因此通常含有經典NMR解釋中列舉之所有峰。此外,類似於經典
1H-NMR印出,峰表可顯示溶劑信號、來源於特定標靶化合物之立體異構體之信號、雜質峰、
13C衛星峰及/或旋轉邊帶。相較於該標靶化合物(例如,具有>90%之純度)的峰,立體異構體峰及/或雜質峰係通常以更低強度顯示。此等立體異構體及/或雜質對特定製造方法而言可為典型的,且因此其等峰可有助於基於「副產物指紋」鑑別製造方法之再現。藉由已知方法(MestReC、ACD模擬,或藉由使用經驗評估之預期值)計算該標靶化合物峰之專家可視需要分離該標靶化合物之峰,視需要使用另外強度過濾器。此操作將類似於經典
1H-NMR解釋中之峰拾取。呈峰表形式報告之NMR資料之詳細說明可參見公開案「Citation of NMR Peaklist Data within Patent Applications」 (參考http://www.researchdisclosure.com/searching-disclosures,研究揭示內容資料庫編號605005, 2014, 01 Aug 2014)。在峰拾取例行中,如研究揭示內容資料庫編號605005中描述,參數「最小高度」可經調整介於1%至4%之間。然而,取決於量測化合物之化學結構及/或取決於其濃度,將該參數「最小高度」設定為<1%可為合理的。
使用來自ACD/Labs之ACD/名稱軟體產生化學名稱。在一些情況下,使用市售試劑之一般公認名稱代替ACD/名稱產生之名稱。
下表1列舉此段及實例部分中使用之縮寫,只要其等於本內文主體內未解釋。其他縮寫具有熟習此項技術者本身慣用之其等含義。
表1:縮寫
下表列舉本文使用之縮寫。
縮寫 | 含義 |
Ac 2O | 乙酸酐 |
AcOH | 乙酸(醋酸) |
aq. | 水性 |
Boc | 三級丁氧基羰基 |
BOP | (苯并三唑-1-氧基)參(二甲胺基)六氟磷酸鏻 |
cat. | 催化 |
conc. | 濃 |
CI | 化學電離 |
DAD | 二極體陣列偵測器 |
DBU | 1,8-二氮雜雙環(5.4.0)十一碳-7-烯 |
DCC | N,N‘-二環己基碳二亞胺 |
DCM | 二氯甲烷 |
DIPEA | 二異丙基乙胺 |
DMA | N,N-二甲基乙醯胺 |
DMF | N,N-二甲基甲醯胺 |
DMSO | 二甲基亞碸 |
EDC | 1-乙基-3-(3-二甲胺基丙基)碳二亞胺 |
ELSD | 蒸發光散射偵測器 |
EtOAc | 乙酸乙酯 |
EtOH | 乙醇 |
eq. | 當量 |
ESI | 電灑(ES)電離 |
h | 小時 |
HATU | 3-氧化六氟磷酸1-[雙(二甲胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓 |
HCl | 鹽酸 |
HPLC | 高效液相層析術 |
LC-MS | 液相層析質譜法 |
min | 分鐘 |
MeCN | 乙腈 |
MeOH | 甲醇 |
MS | 質譜法 |
NCS | N-氯琥珀醯亞胺 |
NMR | 核磁共振譜法:化學位移(δ)係以ppm給定。除非另有說明,否則藉由將DMSO信號設定為2.50 ppm校正化學位移。 |
PDA | 光二極體陣列 |
Pd/C | 活性炭載鈀 |
PdCl 2(dppf) | [1,1'-雙(二苯基膦基)二茂鐵]-二氯化鈀(II) |
Pd 2(dba) 3 | 參-(二亞芐基丙酮)-二鈀(0) |
PyBOP | (苯并三唑-1-氧基)三吡咯啶基六氟磷酸鏻 |
r.t.或rt或RT | 室溫 |
rac | 外消旋 |
Rt | 以分鐘計之滯留時間(如用HPLC或UPLC量測) |
sat. | 飽和 |
SM | 起始材料 |
SPhos | 2-二環己基膦基-2',6'-二甲氧基聯苯 |
SQD | 單四極桿-偵測器 |
T3P | 丙基膦酸酐 |
TEA | 三乙胺 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
TLC | 薄層層析術 |
UPLC | 超高效液相層析術 |
Xantphos | 4,5-雙(二苯基膦基)-9,9-二甲基呫噸 |
其他縮寫具有熟習此項技術者本身慣用之其等含義。
本申請案中描述之本發明之各種態樣係由下列實例闡述,該等實例無意以任何方式限制本發明。
本文描述之示例性測試實驗用以闡述本發明且本發明不限於給定實例。
實驗部分-一般部分
實驗部分中未描述合成的所有試劑均可購買獲得,或係已知化合物或可由已知化合物藉由熟習此項技術者已知的方法形成。
根據本發明之方法產生之化合物及中間物可需純化。有機化合物之純化為熟習此項技術者熟知且可存在數種純化相同化合物之方法。在一些情況下,可無需純化。在一些情況下,該等化合物可藉由結晶化純化。在一些情況下,可使用合適溶劑攪拌出雜質。在一些情況下,該等化合物的純化可藉由層析術,特別是急驟管柱層析術,使用例如預包裝矽膠匣例如Biotage SNAP匣KP-Sil
®或KP-NH
®與Biotage自動純化器系統(SP4
®或Isolera Four
®)及溶析液諸如己烷/乙酸乙酯或DCM/甲醇梯度之組合。在一些情況下,該等化合物可藉由製備型HPLC使用例如配備二極體陣列偵測器及/或在線電灑電離質譜儀與合適預包裝反相管柱及溶析液諸如可含有添加劑(諸如三氟乙酸、甲酸或氨水)之水及乙腈梯度之組合之Waters自動純化器純化。
在一些情況下,如上文描述之純化方法可提供呈鹽形式之具有足夠鹼性或酸性官能基之本發明之彼等化合物,諸如,在具有足夠鹼性之本發明之化合物之情況下,例如,三氟乙酸鹽或甲酸鹽,或在具有足夠酸性之本發明之化合物之情況下,例如,銨鹽。此類型之鹽可藉由熟習此項技術者已知的各種方法分別轉化為其游離鹼或游離酸形式,或在隨後生物分析中以鹽的形式使用。應瞭解如本文分離並描述之本發明之化合物之特定形式(例如鹽、游離鹼等)不一定係該化合物可適用於生物分析以定量特定生物活性之唯一形式。
實驗部分-一般程序
本發明之化合物可如下列部分中描述般製備。下文描述之方案及程序闡述本發明之通式(I)化合物之一般合成途徑且無意限制本發明。熟習此項技術者應清楚如該等方案中例示之轉化順序可以各種方式修飾。因此,該等方案中例示之轉化順序無意為限制性。另外,取代基中之任一者之相互轉變可在例示性轉化之前及/或之後達成。此等修飾可為諸如保護基之引入;保護基之裂解;官能基之交換、還原或氧化;鹵化;金屬化;取代或熟習此項技術者已知的其他反應。此等轉化包括彼等引入容許取代基之進一步相互轉變之官能基者。適當之保護基及其引入及裂解為熟習此項技術者熟知(參見例如P.G.M. Wuts及T.W. Greene,「Protective Groups in Organic Synthesis」,4'"版,Wiley 2006)。特定實例描述於隨後段落中。此外,可能的是,可進行兩個或更多個連續步驟,而無需在該等步驟之間進行後處理,例如「一鍋」反應,如熟習此項技術者熟知。
本發明之化合物之合成較佳根據方案1至12中顯示之一般合成順序進行。
方案1
方案1:用於製備通式(IX)化合物之合成途徑,其中X
1、X
2、X
3具有如針對通式(I)給定之含義,同上,R
a*係脫離基,例如(不限於)鹵離子,較佳氯、溴及R
b*表示保護基。R
b*可為例如(不限於)氫、甲基、乙基、丙基、異丙基、丁基、三級丁基及苄基。R
3係例如(不限於) H、(氟化)烷基。LG表示脫離基,諸如,舉例而言,鹵離子,較佳氯、烷基磺醯基、烷基磺酸酯及芳基磺酸酯,如繪示。
步驟1 à通式(IX) (方案1)
雙環嘧啶形成:在第一步驟中,通式(II)之鹵素取代之苯甲酸衍生物(其可購買獲得或描述於文獻中)可類似於文獻程序轉化為相應之雙環嘧啶(IX)。通常,使衍生物(II)與氨較佳在高溫下,視需要在高壓下,於水或有機溶劑或其混合物諸如舉例而言1,2-二氯乙烷、THF、甲醇、乙醇中反應以形成通式(III)衍生物。例如,參見WO2017069275、US20030199511及US20030187026及其中之參考文獻。或者,衍生物(II)可用例如亞硫醯氯、草醯氯於有機溶劑中,視需要用一滴DMF,視需要在高溫下於有機溶劑中轉化為相應之酸氯。該相應之酸氯可用亞胺或其鹽,用無機鹼,諸如,舉例而言,碳酸銫、碳酸鈉、碳酸鉀,或有機鹼,諸如,舉例而言三乙胺、二異丙基乙胺或吡啶,有或無DMAP,視需要使用金屬催化之反應,視需要在配體之存在下,於有機溶劑諸如,舉例而言DMF、甲苯、1,4-二噁烷/水中,在高溫下處理。例如,參見WO2007134986, Bioorg. Med. Chem. Lett., 2015, 23, 3013及其中之參考文獻。
步驟2 à通式(IX) (方案1)
雙環嘧啶形成:或者,通式(III)之胺基取代之苯甲酸衍生物(其可購買獲得或描述於文獻中)可類似於文獻程序轉化為相應之雙環嘧啶(IX)。通常,使衍生物(III)與乙脒或亞胺,視需要與鹼諸如舉例而言碳酸鉀或氫氧化鈉或三乙胺、二異丙基乙胺、1,8-二氮雜雙環[5.4.0]十一碳-7-烯或吡啶於有機溶劑諸如舉例而言DMF中在高溫下反應。例如,參見WO2004071460、WO2015155306及Chem. Med. Chem., 2014, 9, 2516。
步驟3 à通式(IX) (方案1)
雙環嘧啶形成:或者,通式(IV)之鹵素取代之苯甲酸酯衍生物(其可購買獲得或描述於文獻中)可類似於文獻轉化為相應之雙環嘧啶(IX)。通常,衍生物(IV)可與亞胺或其鹽、無機鹼,諸如,舉例而言,碳酸銫、碳酸鈉、碳酸鉀,或有機鹼,諸如,舉例而言,三乙胺、二異丙基乙胺、1,8-二氮雜雙環[5.4.0]十一碳-7-烯或吡啶,有或無DMAP,視需要使用金屬催化之反應,視需要在配體之存在下,於有機溶劑諸如,舉例而言DMF、甲苯、1,4-二噁烷/水中,在高溫下反應。例如,參見Chem. Commun., 2008, 6333;Bioorg. Med. Chem. Lett., 2013, 23, 3325;WO2018118735、WO2007134986及其中之參考文獻。
步驟4 à通式(IX) (方案1)
雙環嘧啶形成:或者,通式(V)之胺基取代之苯甲酸酯衍生物(其可購買獲得或描述於文獻中)可類似於文獻程序轉化為相應之雙環嘧啶(IX)。通常,衍生物(V)可與腈、羧酸氯化物、羧酸酐、亞胺或其鹽在酸或鹼之存在下,於水或有機溶劑,或其混合物諸如舉例而言DMF、甲苯、1,4-二噁烷/水中,在高溫下反應。例如,參見J. Med. Chem., 2018, 61, 3389;J. Med. Chem., 2019, 62, 9772;WO2004071460、WO2007134986及其中之參考文獻。
步驟5 à通式(IX) (方案1)
雙環嘧啶形成:或者,通式(VI)之苯并噁嗪酮衍生物(其可購買獲得或可類似於文獻程序製備)可類似於文獻程序轉化為相應之雙環嘧啶(IX)。通常,衍生物(VI)可與乙酸銨於有機溶劑中在高溫下反應。例如,參見J. Med. Chem., 2019, 62, 9772;J. Med. Chem., 2011, 54, 6734;Bioorg. Med. Chem., 2014, 22, 5487或WO2005105760及其中之參考文獻。
步驟6 à通式(IX) (方案1)
雙環嘧啶形成:或者,通式(VII)之苯甲酸醯胺衍生物 (其可購買獲得或描述於文獻中)可類似於文獻程序轉化為相應之雙環嘧啶(IX)。通常,衍生物(VII)可與鹼諸如舉例而言氫氧化鈉於溶劑諸如舉例而言水中,在高溫下反應。例如,參見Monatshefte Für Chemie, 1987, 118, 399;WO2007134986、WO2013016999;WO2012028578及其中之參考文獻。
步驟7 à通式(IX) (方案1)
雙環嘧啶形成:或者,通式(VIII)之胺基苯甲酸醯胺衍生物(其可購買獲得或描述於文獻中)可類似於文獻程序轉化為相應之雙環嘧啶(IX)。通常,衍生物(VIII)可與有機酸在高溫下,有機酸醯胺或羧酸酐或使用銅催化之反應,視需要與鹼、水或有機溶劑或其混合物,較佳在高溫下反應。例如,參見Eur. J. Org. Chem., 2020, 2730;Polish Journal of Pharmacology and Pharmacy, 1985, 37, 541;Heterocycles, 2015, 90, 857;Yakugaku Zasshi, 1977, 97, 1022及其中之參考文獻。
步驟(IX) à (X) (方案1)
羥基轉化為脫離基
在下一步驟(方案1)中,化合物(IX)可類似於文獻程序轉化為攜載脫離基(LG)之相應衍生物(X)。
針對LG =氯或溴,通常分別與三氯氧化磷或三溴三氧化磷一起,在有或無N,N-二甲基苯胺或N,N-二異丙基乙胺,有或無有機溶劑(諸如,舉例而言甲苯)之情況下在高溫下使用。例如,參見US2012/53174;WO2012/30912或WO2012/66122及其中之參考文獻。
針對LG = 2,4,6-三異丙基苯磺酸酯,通常2,4,6-三異丙基苯磺醯氯,使用於有機溶劑(諸如,舉例而言二氯甲烷)中之鹼(諸如,舉例而言三乙胺及/或DMAP)。例如,參見WO2010/99379、US2012/53176及其中之參考文獻。
針對LG =甲苯磺酸酯,通常4-甲基苯-1-磺醯氯,使用於有機溶劑(諸如,舉例而言二氯甲烷或乙腈)中之鹼(諸如,舉例而言三乙胺或碳酸鉀及/或DMAP)。例如,參見Org. Lett., 2011, 4374或Bioorg. Med. Chem. Lett., 2013, 2663及其中之參考文獻。
針對LG =三氟甲磺酸酯,通常N,N-雙(三氟甲基磺醯基)苯胺或三氟甲磺酸酐,使用於有機溶劑(諸如,舉例而言二氯甲烷)中之鹼(諸如,舉例而言三乙胺或1,8-二氮雜雙環[5.4.0]十一碳-7-烯及/或DMAP)。例如,參見J. Am. Chem. Soc., 2015, 13433或WO2014/100501及其中之參考文獻。
方案2:用於製備通式(I)化合物之合成途徑,其中R
a*表示脫離基,例如(不限於)鹵離子,較佳氯或溴及R
c*表示R
5之受保護衍生物。R
d*及R
e*係如通式(I)或其(受保護)衍生物中之R
1及R
2。R
f*係H或脫離基,諸如,例如氯。LG表示脫離基,諸如,舉例而言,鹵離子,較佳氯、烷基磺醯基、烷基磺酸酯或芳基磺酸酯,如方案1中繪示。
通式(XII)化合物為公共領域中熟知且可由通式(IX)化合物與通式(XI)化合物使用脫水結合方法形成。已知此等方法使用偶合試劑,諸如苯并三唑-1-氧基參(二甲胺基)六氟磷酸鏻(BOP)及苯并三唑-1-基-氧基三吡咯啶基六氟磷酸鏻(pyBOP),參見J. Org. Chem., 2007, 72, 10194;Advanced Synthesis & Catalysis, 2018, 360, 4764;Bioorg. Med. Chem., 2019, 27, 931;WO 2011028741 A1之教示;係於公共領域中。
或者,通式(XII)化合物可以兩步驟方法形成,藉此使用標準充分記錄之方法將通式(IX)化合物轉化為通式(X)化合物,諸如,當LG = Cl時使用三氯氧化磷,或當LG = Br時使用三溴三氧化磷,或當LG =甲苯磺酸酯,通常4-甲基苯-1-磺醯氯時使用於有機溶劑(諸如,舉例而言二氯甲烷或乙腈)中之鹼(諸如,舉例而言三乙胺或碳酸鉀及/或DMAP)。例如,參見Org. Lett., 2011, 4374或Bioorg. Med. Chem. Lett., 2013, 2663及其中之參考文獻。
隨後,使用親核取代反應(S
NAr)以通式(XI)化合物,可將通式(X)化合物轉化為通式(XII)化合物,該等通式(XI)化合物於公共領域中經充分記錄且為熟習此項技術者已知。
通式(XIV)化合物可由通式(XII)化合物,以通式(XIII)化合物使用文獻已知的方法形成。通式(XIII)化合物為公共領域中熟知、可購買獲得或可藉由已知合成途徑合成。例如(不限於)當R
f*係H時,可進行金屬催化之反應。例如,參見US2019/270704, 2019, A1;US2015/225436, 2015, A1或J. Med. Chem. 2020, 63, 7081及其中之參考文獻之教示。當R
f*係脫離基(不限於)諸如,舉例而言,氯時,可進行親核取代反應。例如,參見WO2008/110611, 2008, A1或J. Med. Chem. 2020, 63, 7081及其中之參考文獻。
隨後,藉由使用標準充分記錄之方法(諸如(不限於)官能基操縱)可將通式(XIV)化合物轉化為通式(I)化合物。例如(不限於)當R
c*係通式(I)中R
5之受保護衍生物時,可進行保護基之移除。針對R
d*及R
e*之其他官能基操縱可類似於文獻進行,參見例如J. Med. Chem. 2020, 63, 7081及其中之參考文獻。當Y = S時,參見例如CN109776607, 2019, A或Synthesis 2020, 52, 141。
方案3:用於製備通式(XVI)化合物之合成途徑,其中X’
3表示X
3(其中X
3不為N)之子集及X
4、R
4、R
5及R
6具有如針對通式(I),同上給定之含義。R
c*係如通式(I)中之R
5或R
5之受保護衍生物。
方案3中顯示之反應可使用熟習此項技術者已知的不同化學反應進行。
例如,市售化合物(A1)可藉由已知程序(例如,參見WO2008/130021, 2008, A2)轉化為化合物(A2)。化合物(A2)可如方案1中描述環化為化合物(A3)。化合物(A4)可藉由於有機溶劑(諸如,舉例而言DMSO)中在室溫下與NaSMe之親核芳族取代(SnAr)獲自化合物(A3) (例如,參見US2014/336190, 2014, A1, Tetrahedron 2002, 58, 4931、WO2010/24451, 2010, A1)。通式(XV)化合物可如方案2中描述獲自化合物(A4)。通式(XV)化合物可使用熟習此項技術者已知的不同化學反應轉化為通式(XVI)化合物。例如,可進行鈀催化之反應(例如,參見WO2012/52167, 2012, A1)、親核芳族取代(例如,參見WO2012/52167, 2012, A1)或氧化/親核芳族取代順序(例如,參見KR2016/37198, 2016, A)。通式(XVI)化合物可如方案2中描述轉化為通式(I)化合物。
方案4:用於製備通式(XII)化合物之合成途徑,其中R
a*表示如方案2中繪示之P(O)R
d*R
e*或脫離基,例如(不限於)鹵離子,較佳氯或溴,及R
c*係如通式(I)中之R
5,同上,或R
5之受保護衍生物。
通式(XVIII)化合物為公共領域中熟知、可購買獲得或可藉由已知合成途徑合成,例如,經由形成雜芳環,經由通式(XVII)化合物與脲在不同條件下反應(例如,參見Luo等人,CN 102584828之教示)或如Brogi等人,J. Med. Chem., 2018, 61, 2124;Bergeron等人,WO 2010014939 A1之教示中闡述之多步驟合成。
通式(XVIII)化合物轉化為通式(XIX)化合物為公共領域中熟知。例如,當LG =氯,通常三氯磷酸鹽或亞硫醯氯時,在有或無N,N-二甲基苯胺或N,N-二異丙基乙胺,有或無有機溶劑(諸如,舉例而言,甲苯)之情況下在高溫下可使用。例如,參見Cantin等人,Bioorg. Med. Chem. Lett., 2012, 2565;Bayrakdarian等人,WO 2008136756 A1;Luo等人,CN 102584828;Zhou等人,J. Med. Chem., 2015, 58, 9480。
針對LG =溴,通常三溴三氧化磷,在有或無鹼,有或無有機溶劑(諸如,舉例而言甲苯)之情況下,在高溫下可使用。例如,參見Kim等人,J. Org. Chem., 2004, 69, 5638。
用通式(XI)化合物將通式(XIX)化合物轉化為通式(XX)化合物為公共領域中熟知且針對(X)轉化為(XII)類似闡述於方案2中。例如,此等親核取代係經充分記錄,參見Liwicki等人,WO 2018066718 A1;Gelin等人,WO 2013016197 A1;Jiang等人,J. Med. Chem., 2016, 59, 10498之教示。
使用不同合成方法,諸如,舉例而言,鈴木(Suzuki)反應(Liwicki等人,WO 2018066718 A1;Pulipati等人,Synth. Commun., 2017, 47, 1142)、斯蒂勒(Stille)反應(Johnson等人,WO 2011028741 A1;Labadie等人,Bioorg. Med. Chem. Lett., 2013, 23, 5923)或其他方法,參見Finlay等人,ACS Med. Chem. Letters, 2016, 7, 831之教示,可將通式(XX)化合物轉化為通式(XII)化合物。
方案4內自通式(XII)化合物至通式(I)化合物之其餘步驟遵循與方案2中描述相同之途徑及方法。
方案5:用於製備通式(XXV)化合物之合成途徑,其中X
4及R
6具有如通式(I)中之含義,同上,R
c*係如通式(I)中之R
5,同上,或R
5之受保護衍生物。
步驟(XXI) à (XXII) (方案5)
在第一步驟(方案5)中,溴衍生物(XXI) (其等可購買獲得)或描述於文獻中)可類似於許多文獻程序轉化為相應之乙醯基化合物(XXII)。例如,該反應可使用熟習此項技術者已知的不同化學反應進行,例如,使用於有機溶劑(諸如,舉例而言THF)中之鎂,透過將芳基鎂格氏試劑添加至魏因雷布(Weinreb)醯胺之格氏(Grignard)化學反應;或鈀催化之化學反應或斯蒂勒化學反應。針對此等轉化,參見(格氏:Fillon等人,Tetahedron 2003, 59, 8199;Leazer等人,Org. Synth. 2005, 82, 115;鈀:WO2005/5382;斯蒂勒:WO2019/122129及其中之參考文獻)之教示。
步驟(XXII) à (XXIII) (方案5)
乙醯基衍生物(XXII) (其等可購買獲得或描述於文獻中或由(XXI)製備)可類似於許多文獻程序轉化為相應之對掌性亞磺醯亞胺(XXIII)。例如該反應可在周圍溫度下使用乙醇鈦(IV)或異丙醇鈦(IV)於有機溶劑(諸如,舉例而言THF)中進行。例如,參見Chem. Rev. 2010, 110, 3600-3740;Chem. Soc. Rev. 2009, 38, 1162-1186;Tetrahedron 2004, 60, 8003或WO2019/122129及其中之參考文獻。
步驟(XXIII) à (XXIV) (方案5)
(R)-亞磺醯亞胺(XXIII)可類似於許多文獻程序轉化為相應之(R)-亞磺醯胺(XXIV)。例如,該反應可使用還原劑(例如,硼氫化鈉或硼烷-THF)於有機溶劑(諸如,舉例而言乙醇、甲醇或THF)中進行。此等轉化為熟習此項技術者已知,參見Pan等人,Tetrahedron Asym., 2011, 22, 329;WO2019/122129;Li等人,Chem. Med. Chem., 2018, 13, 1363;Ghosh等人,Eur. J. Med. Chem., 2018, 160, 171之教示。或者,該反應可使用還原劑(諸如,舉例而言二異丙基氫化鋁),於質子惰性溶劑(例如,甲苯)中進行。此等轉化為熟習此項技術者已知,參見WO2017/6282;Lee等人,Synlett., 2019, 30, 401之教示。或者,(R)-亞磺醯胺(XXIV)可使用鋰硼化物(L-selectride)於有機溶劑(諸如THF)中獲自相應之(S)-亞磺醯亞胺(XXIII)。此等轉化為熟習此項技術者已知。例如,參見J. Org. Chem. 2006, 71, 6859及/或J. Org. Chem. 2007, 72, 626及其中之參考文獻。
步驟(XXIV) à (XXV) (步驟5):
(R)-亞磺醯胺(XXIV)可類似於許多文獻程序轉化為相應之(R)-胺(XXV)。例如,該反應可使用氫氯化物(HCl)於質子惰性有機溶劑(諸如二噁烷)中進行以產生相應之HCl鹽。鹼性水溶液後處理產生游離之NH
2胺。針對有關亞磺醯亞胺及磺醯胺化學反應之回顧,參見例如Chem. Rev. 2010, 110, 3600-3740;Chem. Soc. Rev. 2009, 38, 1162-1186;Tetrahedron 2004, 60, 8003或WO2013030138及其中之參考文獻。
方案6:用於製備通式(XXV)化合物之替代合成途徑,其中X
4及R
6具有與通式(I)中相同之含義,同上,及R
c*係如通式(I)中之R
5,同上,或R
5之受保護衍生物。
步驟(XXII) à (XXVI) (方案6)
在第一步驟(方案6)中,通式(XXII)之酮衍生物(其等可購買獲得或描述於文獻中或如方案5中描述製備)可類似於許多文獻程序轉化為相應之對掌性(S)-醇(XXVI)。例如,對映選擇性還原可使用催化氫化,用氫氣在壓力下用觸媒,例如BINAP衍生之觸媒,例如(R)-或(S)-RUCY-Xyl-BINAP (參見WO2019/122129第140頁或WO2013/185103第81頁)或使用CBS還原(Corey-Bakshi-Shibata還原)程序進行。此等轉化為熟習此項技術者已知,關於參考文獻,參見J. Org. Chem. 1988, 53, 2861。
步驟(XXVI) à (XXVII) (方案6)
對掌性(S)-醇(XXVI)可類似於許多文獻程序轉化為相應之(R)-疊氮化物(XXVII)。例如,該反應可使用二苯基膦疊氮化物及鹼(例如,DBU)於質子惰性有機溶劑(諸如,舉例而言甲苯)中進行(參見WO2019/122129第144頁之教示)。關於有關疊氮化物化學合成之回顧,參見例如Chem. Rev. 1988, 88, 297及其中之參考文獻。
步驟(XXVII) à (XXV) (方案6)
(R)-疊氮化物(XXVII)可類似於許多文獻程序轉化為相應之(R)-胺(XXV)。例如,該反應可使用施陶丁格(Staudinger)還原條件,用膦(例如,三苯基膦),於具有多種不同有機溶劑(例如甲醇、乙醇或THF)之水中進行。或者,該疊氮化物還原可使用催化氫化方法,使用金屬觸媒(例如,碳載鈀),在氫之加壓氣氛下進行(參見WO2019/122129第144頁之教示)。關於有關疊氮化物化學合成之回顧,參見例如Chem. Rev. 1988, 88, 297及其中之參考文獻。
方案7:用於製備通式(XXV)化合物之替代合成途徑,其中X
4及R
6具有與通式(I)中相同之含義,同上,及R
c*係如通式(I)中之R
5,同上,或R
5之受保護衍生物。
對熟習此項技術者而言,可進行方案7中描述之化學反應,其中(XXVIII)立體異構體可使用熟習此項技術者已知的各種方法分離,諸如,舉例而言,使用對掌性HPLC純化進行分離。此等立體異構體之分離可於通式(XXVIII)化合物上進行以獲得具有一般結構(XXV)之化合物。
方案8:用於具有各種官能基之對掌性受N-Boc保護之胺之合成途徑,其用於製備通式(XXXIII至XL)化合物,其中X
4、R
6、R
j及R
k具有與通式(I)中相同之含義,同上,及R
g*及R
h*係彼此獨立地選自-CH
3或-H。R
i*可選自-CH
3、-CH
2CH
3或環丙基。
步驟(XXX) à (XXXI) (方案8)
乙醯基芳烴(XXX) (其等可購買獲得或可由文獻程序製備)可遵循如方案5至7中繪示之合成途徑及程序轉化為相應之對掌性(R)-Boc胺(XXXI)。
步驟(XXXI) à (XXXII) (方案8)
芳基碘化物(XXXI)可轉化為酯(XXXII)以透過文獻程序形成新C-C鍵。此等轉化為熟習此項技術者已知的「烏爾曼(Ullmann)反應」或「根岸(Negishi)偶合」。例如,該等芳基碘化物(XXXII)及氟烷基溴化物(XXXIa)係在過量Cu(0)粉末之存在下在高溫下反應。或者,烷基溴化物可透過文獻程序轉化為相應之鋅試劑。例如,此轉化可使用鋅粉末及烷基溴化物(XXXIa)於質子惰性有機溶劑(諸如DMA或THF)中達成。該鋅試劑與該等芳基鹵化物(XXXI)之偶合可使用標準鈀催化條件達成。例如,此轉化可使用參(二亞苄基丙酮)二鈀(0)用適當之配體(諸如SPhos)於質子惰性有機溶劑(諸如DMA或THF)中在高溫下達成。例如,參見Adv. Synth. Catal. 2018, 360, 1605、Chem. Commun. 2012, 48, 7738、E. J. Org. Chem. 2016, 33, 5529、J. Org. Chem 2013, 78, 8250及/或Chem. Lett. 2015, 44, 818及其中之參考文獻。
步驟(XXXII) à (XXXIII) (方案8)
酯(XXXII)可使用標準文獻程序還原為一級醇(XXXIII)。此等轉化為熟習此項技術者已知,例如,該反應可藉由使用還原劑(諸如硼氫化鈉)於質子有機溶劑(諸如甲醇或乙醇)中或於質子惰性有機溶劑(諸如THF)中進行。例如,參見Adv. Synth. Catal. 2018, 360, 1605或US2005/54658, 2005, A1,第18頁及/或Bioorg. Med. Chem. 2017, 25, 496。
步驟(XXXII) à (XXXIV) (方案8)
酯(XXXII)可使用標準文獻程序轉化為三級醇(XXXIV)。此等轉化為熟習此項技術者已知,例如,該反應可藉由使用格氏試劑(諸如甲基溴化鎂或甲基氯化鎂)於質子惰性有機溶劑(諸如THF)中進行。例如,參見J. Am. Chem. Soc. 2020, 142, 2984及/或Q. Rev. Chem. Soc. 1967, 21, 259及其中之參考文獻。
步驟(XXXII) à (XXXV) (方案8)
酯(XXXII)可使用標準文獻程序轉化為環丙基醇(XXXV)。此等轉化為熟習此項技術者已知的名稱「庫林科維奇(Kulinkovich)反應」,例如,該反應可藉由用催化量之異丙醇鈦(IV)或乙醇鈦(IV)及格氏試劑(諸如乙基溴化鎂或乙基氯化鎂)於質子惰性有機溶劑(諸如THF、乙醚或甲苯)中處理酯進行。關於此化學及培訓及程序之參考文獻,參見Org. Lett. 2013, 15, 4968, Adv. Synth. Catal. 2004, 346, 760及/或J. Am. Chem. Soc. 2001, 123, 5777及其中之參考文獻。
步驟(XXXII) à (XXXVI) (方案8)
酯(XXXII)可使用標準文獻程序水解為羧酸(XXXVI)。此等轉化為熟習此項技術者已知,例如,該反應可藉由用氫氧化鋰於水及THF或甲醇混合物中或用氫氧化鈉於水及二噁烷中處理酯進行。例如,參見US2013/303798, 2013, A1及/或WO2014/153667, A1及其中之參考文獻。
步驟(XXXVI) à (XXXVII) (方案8)
羧酸(XXXVI)可使用標準文獻程序轉化為魏因雷布醯胺(XXXVII)。此等轉化為熟習此項技術者已知。例如,此等轉化可使用HATU、DCC、EDC*HCl、T3P、SOCl
2及/或草醯氯於有機溶劑(諸如二氯甲烷或N,N-二甲基甲醯胺)中,使用N,O-二甲基羥基胺作為偶合搭配物達成。例如,參見EP1007514, 2006, B1、E. J. Org. Chem. 2017, 25, 3584、Org. Lett. 2018, 20, 4691及/或Adv. Synth. Catal. 2020, 362, 1106及其中之參考文獻。
步驟(XXXVII) à (XXXVIII) (方案8)
魏因雷布醯胺(XXXVII)可使用標準文獻程序轉化為酮(XXXVIII)。此等轉化為熟習此項技術者已知。例如,此轉化可藉由使用甲基溴化鎂或乙基氯化鎂或環丙基氯化鎂於THF中達成。例如,參見Bioorg. Med. Chem. 2016, 24, 2707、Adv. Synth. Catal. 2020, 362, 1106及/或CN104803954, 2018, B及其中之參考文獻。
步驟(XXXVIII) à (XXXIX) (方案8)
酮(XXXVIII)可使用標準文獻程序轉化為二級醇(XXXIX)。此等轉化為熟習此項技術者已知。例如,此等轉化可使用硼氫化鈉於質子有機溶劑(諸如甲醇或乙醇)中或於質子惰性有機溶劑(諸如THF)中達成。或者,氫化鋁鋰可用於質子惰性有機溶劑(諸如乙醚)中。例如,參見Angew. Chem. Int. Ed. 2019, 58, 17393、J. Am. Chem. Soc. 1996, 118, 5952及/或J. Org. Chem. 1989, 54, 661及其中之參考文獻。
步驟(XXXVI) à (XL) (方案8)
羧酸(XXXVI)可使用標準文獻程序轉化為醯胺(XL)。此等轉化為熟習此項技術者已知。例如,此轉化可使用HATU、DCC、EDC*HCl、T3P、SOCl
2及/或草醯氯於有機溶劑(諸如二氯甲烷或N,N-二甲基甲醯胺)中,使用一級或二級胺或氨(衍生物)作為偶合搭配物達成。例如,參見EP1007514, 2006, B1、E. J. Org. Chem. 2017, 25, 3584、Org. Lett. 2018, 20, 4691及/或Adv. Synth. Catal. 2020, 362, 1106及其中之參考文獻。
方案9:用於通式(XLII至XLVI)之具有各種官能基之對掌性受N-Boc保護之胺之合成途徑,其中X
4、R
6、R
j、R
k、R
l及R
m具有與通式(I)中相同之含義,同上,及R
j*及R
k*可獨立地選自-H或-CH
3。
步驟( XLa) à (XLI) (方案9)
可遵循如方案8中繪示之合成途徑及程序製備之醇(XLa)可使用標準文獻程序轉化為三氟甲磺酸酯(XLI)。此等轉化為熟習此項技術者已知。例如,該轉化可使用三氟甲磺酸酐與三乙胺或吡啶之組合於質子惰性有機溶劑(諸如二氯甲烷)中達成。例如,參見Angew. Chem. Int. Ed. 2014, 53, 6473、Adv. Synth. Catal. 2018, 360, 3667及/或Org. Lett. 2020, 22, 6568及其中之參考文獻。
步驟(XLI) à (XLII) (方案9)
三氟甲磺酸酯(XLI)可使用標準文獻程序轉化為胺(XLII)。此等轉化為熟習此項技術者已知。例如,此等轉化可使用二級或一級胺或氨作為親核劑於極性有機溶劑(諸如乙腈或N,N-二甲基乙醯胺)中在高溫下達成。例如,參見WO2016/49048, 2016, A1;WO2016/44323, 2016, A1及其中之參考文獻。
步驟(XLI) à (XLIII) (方案9)
三氟甲磺酸酯(XLI)可使用標準文獻程序轉化為腈(XLIII)。此等轉化為熟習此項技術者已知。例如,此等轉化可使用氰化鈉作為親核劑於極性有機溶劑(諸如乙腈、N,N-二甲基乙醯胺或二甲基亞碸)中在高溫下達成。例如,參見US2014/194431, 2014, A1;WO2016/44429, 2016, A1及其中之參考文獻。
步驟(XLI) à (XLIV) (方案9)
三氟甲磺酸酯(XLI)可使用標準文獻程序轉化為碸(XLIV)。此等轉化為熟習此項技術者已知。例如,此等轉化可使用甲基亞磺酸鈉作為親核劑於極性有機溶劑(諸如乙腈、N,N-二甲基乙醯胺或二甲基亞碸)中在高溫下達成。例如,參見Green Chem. 2020, 22, 322及其中之參考文獻。
步驟(XLII) à (XLV) (方案9)
針對j*或k* = H,胺(XLII)可使用標準文獻程序轉化為磺醯胺(XLV)。此等轉化為熟習此項技術者已知。例如,該反應可使用甲磺醯氯或甲磺酸酐與三乙胺或碳酸鉀之組合於有機溶劑(諸如二氯甲烷)中達成。例如,參見WO2005/123747, 2005, A1、ChemMedChem 2014, 9, 614、Eur. J. Med. Chem. 2021, 211, 113053及其中之參考文獻。
步驟(XLII) à (XLVI) (方案9)
針對j*或k* = H,胺(XLII)可使用標準文獻程序轉化為醯胺(XLVI)。此等轉化為熟習此項技術者已知。例如,該反應可使用乙醯氯或乙酸酐與三乙胺或吡啶之組合於有機溶劑(諸如二氯甲烷)中達成。例如,參見Bioorg. Med. Chem. Lett. 2008, 18, 6429、Org. Lett. 2015, 17, 2478;WO2006/45498, 2006, A1及其中之參考文獻。
方案10:用於通式(XLIX至LVI)之對掌性受N-Boc保護之胺之合成途徑,其中X
4及R
6具有與通式(I)中相同之含義,同上,及R
c*係如通式(I)中之R
5,同上,或R
5之受保護衍生物。
步驟(XLVII) à (XLVIII) (方案10)
可遵循如方案5及6中繪示之合成途徑及程序製備或可購買獲得或可藉由文獻程序製備之受Boc保護之胺(XLVII)可使用文獻程序轉化為硼化化合物(XLVIII)。此等轉化為熟習此項技術者已知,稱為哈特維希-宮浦-硼化。例如,該反應可使用環辛二烯甲醇銥二聚體([Ir(cod)(OMe)]
2)作為觸媒以適當之配體(諸如4,4’-二-三級丁基-2,2’-二吡啶)與雙(頻哪醇合)二硼之組合於質子惰性有機溶劑(諸如THF)中在高溫下達成。例如,參見J. Am. Chem. Soc. 2007, 129, 15343、J. Am. Chem. Soc. 2002, 124, 390、Science 2002, 295, 305及其中之參考文獻。
步驟(XLVIII) à (XLIX) (方案10)
硼化化合物(XLVIII)可使用文獻程序轉化為氯化化合物(XLIX)。此等轉化為熟習此項技術者已知,例如,該轉化可使用過量氯化銅(II)於甲醇及水之混合物中在高溫下達成。例如,參見J. Am. Chem. Soc. 2007, 129, 15343及其中之參考文獻。
步驟(XLVIII) à (L) (方案10)
硼化化合物(XLVIII)可使用文獻程序轉化為溴化化合物(L)。此等轉化為熟習此項技術者已知,例如,該轉化可使用過量溴化銅(II)於甲醇及水之混合物中在高溫下達成。例如,參見J. Am. Chem. Soc. 2007, 129, 15343及其中之參考文獻。
步驟(L) à (LI) (方案10)
溴化化合物(L)可使用文獻程序轉化為甲醯化化合物(LI)。此等轉化為熟習此項技術者已知。例如,該轉化可使用鹵素-鋰-交換以有機鋰試劑(諸如,舉例而言正丁基鋰)於質子惰性有機溶劑(諸如THF)中在低溫下產生芳基鋰物種來達成,芳基鋰係用維爾斯邁爾(Vilsmeier)試劑((氯亞甲基)二甲基亞胺氯化物)捕獲。例如,參見J. Organomet. Chem. 1988, 352, 1及/或Org. Prep. Proc. Int. 2010, 42, 503及其中之參考文獻。
步驟(LI) à (LII) (方案10)
甲醯化化合物(LI)可使用文獻程序轉化為二氟烷基化化合物(LII)。此等轉化為熟習此項技術者已知。例如,此等轉化可使用DAST (N,N-二乙胺基三氟化硫)於有機溶劑(諸如二氯甲烷)中達成。例如,參見J. Org. Chem. 1999, 64, 7048、WO2009/121939, 2009, A1;J. Org. Chem. 1975, 40, 574及其中之參考文獻。
步驟(L) à (LIII) (方案10)
溴化化合物(L)可使用文獻程序轉化為氟化化合物(LIII)。此等轉化為熟習此項技術者已知,例如,此轉化可使用鈀觸媒前體與受阻、富電子膦配體(諸如AdBrettPhos (2-(二-1-金剛烷基膦基)-3,6-二甲氧基-2',4',6'-三-異丙基-1,1'-聯苯)之組合於有機溶劑(諸如甲苯或環己烷)中及氟化銀作為氟化物源達成。例如,參見J. Am. Chem. Soc. 2014, 136, 3792及其中之參考文獻。
步驟(L) à (LIV) (方案10)
溴化化合物(L)可使用文獻程序轉化為羥基化化合物(LIV)。此等轉化為熟習此項技術者已知,例如,此等轉化可使用銅觸媒與啡啉配體及鹼之組合於作為溶劑之水中達成。或者,可使用於極性、質子惰性溶劑(諸如NMP)中之鈀觸媒(諸如乙酸鈀)與膦配體(諸如tBuBrettPshos (二-三級丁基(2',4',6'-三異丙基-3,6-二甲氧基聯苯-2-基)膦))、鹼及硼酸之組合。例如,參見Org. Lett. 2020, 22, 8470、J. Org. Chem. 2013, 78, 5804、Green Chem. 2015, 17, 3910及其中之參考文獻。
步驟(L) à (LV) (方案10)
溴化化合物(L)可使用文獻程序轉化為胺化化合物(LV)。此等轉化為熟習此項技術者已知。例如,此轉化可使用鈀觸媒諸如Pd
2dba
3(參(二亞苄基丙酮)二鈀(0))及適當之膦配體及氨於有機溶劑(諸如二噁烷)中在高溫下達成。或者,銅催化之轉化可使用例如碘化銅於液氨中進行。例如,參見Chem. Eur. J. 2009, 15, 4528、J. Org. Chem. 2012, 77, 7471、 Chem. Soc. Rev. 2010, 39, 4130及其中之參考文獻。
步驟(L) à (LVI) (方案10)
溴化化合物(L)可使用文獻程序轉化為甲基化化合物(LVI)。此等轉化為熟習此項技術者已知。例如,此等轉化可藉由使用鈀觸媒諸如(Pd(PPh
3)
4)及TMB (三甲基硼氧烴三聚物)作為親核劑使用鹼(諸如碳酸鉀)於水及有機溶劑(諸如二噁烷)之混合物中達成。或者,可進行鎳催化之轉化。例如,參見Tetrahedron Lett. 2000, 41, 6237、Chem. Commun. 2017, 53, 10183及其中之參考文獻。
方案11:用於通式(LIX)之對掌性受N-Boc保護之胺之合成途徑,其中X
4、R
6、R
n及R
o具有與通式(I)中相同之含義,同上。
通式(XXXI)化合物可遵循文獻程序或遵循先前方案中繪示之合成途徑製備。
步驟(XXXI) à (LVII) (方案11):
芳基碘化物(XXXI)可使用文獻程序轉化為硫醚(LVII)。此等轉化為熟習此項技術者已知。例如,此等轉化可藉由使用鈀觸媒(諸如參(二亞苄基丙酮)-二鈀(0))與適當之配體(諸如Xantphos)之組合,及苯基甲烷硫醇及鹼(諸如DIPEA)於質子惰性有機溶劑(諸如二噁烷)在高溫下達成。或者,此種轉化亦已使用銅催化描述。例如,參見Appl. Organomet. Chem. 2013, 27, 501及Tetrahedron Lett. 2006, 47, 5781及其中之參考文獻。
步驟(LVII) à (LVIII) (方案11)
硫醚(LVII)可使用文獻程序轉化為磺醯氯(LVIII)。此等轉化為熟習此項技術者已知。例如,此等轉化可藉由使用氧化劑(諸如NCS)或其相近類似物(諸如1,3-二氯-5,5-二甲基乙內醯脲)在酸性條件下使用例如乙酸及水達成。磺醯氯(LVIII)可用於下一步驟中而無需純化。例如,參見Tetrahedron Lett. 2010, 51, 418及J. Org. Chem. 1996, 61, 9289及其中之參考文獻。
步驟(LVIII) à (LIX) (方案11)
磺醯氯(LVIII)可使用文獻程序轉化為磺醯胺(LIX)。此等轉化為熟習此項技術者已知。例如,此等轉化可藉由使用游離一級或二級胺在鹼性條件下用有機鹼(諸如DIPEA或TEA)於質子惰性有機溶劑(諸如二氯甲烷)中達成。例如,參見US2014/200277, 2014, A1;Bioorg. Med. Chem. Lett. 2006, 16, 1134、J. Med. Chem. 2010, 53, 1048及其中之參考文獻。
方案12:用於通式(LXI或LXII)之對掌性胺之脫保護之合成途徑,其中X
4、R
4及R
6具有與通式(I)中相同之含義,同上,及R
c*係如通式(I)中之R
5,同上,或R
5之受保護衍生物。
受Boc保護之胺(LX) (其等可遵循方案5至11中繪示之合成途徑製備)可使用標準文獻程序轉化為HCl鹽(LXI)或游離胺(LXII)。此等轉化為熟習此項技術者已知。例如,此轉化可使用氯化氫於二噁烷中於有機溶劑(諸如二噁烷)中之溶液達成。該等HCl鹽(LXI)可在移除揮發物後獲得。鹼性水溶液後處理遞送游離胺(LXII)。或者,於有機溶劑(諸如二氯甲烷)中之三氟乙酸可用於該脫保護。例如,參見J. Med. Chem. 2016, 59, 9150、Eur. J. Med. Chem. 2018, 145, 413、WO2012/78915, 2012, A1及其中之參考文獻。
一般方法
一般程 序 1 :
在氬下向受質(1當量)、相應氧化膦(1當量)及Et
3N (3.5當量)於MeCN (0.2 M)中之溶液添加Pd(PPh
3)
4(0.15當量)並在90℃下將該混合物加熱指示時間。將該反應混合物過濾,在減壓下濃縮並藉由製備型HPLC純化(鹼性方法)。
一般程 序 2 :向6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(1當量)及2,4,6-三(丙-2-基)苯-1-磺醯氯(1.1當量)於DMF (0.2M)中之溶液添加Et
3N (2.5當量)及DMAP (0.15當量)並在室溫下將該混合物攪拌1 h。然後,添加相應胺(1.2當量)並攪拌該混合物直至觀測到起始材料之完全轉化。該混合物用DCM及H
2O稀釋,有機相用H
2O及鹽水清洗,經Na
2SO
4乾燥,過濾並在減壓下濃縮。在藉由急驟管柱層析術純化後獲得所需產物。
一般程 序 3 :向受Boc保護之胺(1當量)於DCM (0.2M)中之溶液添加TFA (10當量)並在室溫下攪拌該混合物直至觀測到起始材料之完全轉化。該混合物用甲苯稀釋並在減壓下濃縮。該化合物無需進一步純化即可用於下一步驟。
一般程 序 4 :在室溫下向[(1R)-1-(3-{1,1-二氟-2-[甲氧基(甲基)胺基]-2-側氧基乙基}-2-氟苯基)乙基]胺基甲酸三級丁酯(1當量)於THF (0.1M)中之溶液添加相應格氏試劑(3當量)。在室溫下攪拌該反應混合物直至觀測到起始材料之完全轉化,藉由緩慢添加飽和NH
4Cl水溶液淬滅並用EtOAc萃取。有機相用鹽水清洗,乾燥並在減壓下濃縮。殘餘物藉由急驟管柱層析術純化。
一般程 序 5 :在0℃下向醇(1當量)於DCM (0.2M)中之溶液添加2,6-二甲吡啶并將該混合物攪拌5 min。然後,緩慢添加TESOTf並在室溫下將該混合物攪拌整夜。該反應藉由添加飽和NaHCO
3水溶液淬滅,有機相經Na
2SO
4乾燥並在減壓下濃縮。殘餘物藉由急驟管柱層析術純化。
一般程 序 6 :向羥基嘧啶衍生物(1當量)及苄基胺(1.1當量)於DMF (0.2 M)中之溶液添加PyBOP (1.3當量)及1,8-二氮雜雙環(5.4.0)十一碳-7-烯(4當量)並在室溫下將該混合物攪拌整夜。該混合物用乙酸乙酯稀釋,用水及用飽和氯化鈉水溶液清洗兩次,經硫酸鈉乾燥,並濃縮。殘餘物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以獲得相應N-芳基化苄基胺。
一般程 序 7 :在室溫下向1,4λ
5-氮雜磷雜環己烷-4-酮衍生物(A,1.0當量)於二氯甲烷(~1 ml / µmol A)中之溶液添加N,N-二異丙基乙胺(2.5當量)及乙酸酐(1.1當量)。在室溫下將該混合物攪拌通常3 h (直至完全反應,如藉由分析型HPLC指示)。然後濃縮該混合物,及殘餘物藉由製備型HPLC純化。
一般程 序 8 :向酸衍生物(1.2當量)於DMF (0.25 M)中之溶液添加HATU (1.5當量),並在室溫下將該混合物攪拌5 min。然後,隨後添加胺衍生物(1當量)及N,N-二異丙基乙胺(2.5當量),並在室溫下將該混合物攪拌整夜。然後濃縮該混合物及殘餘物藉由製備型HPLC純化。
一般程 序 9 :向胺衍生物(1當量)於DMF (0.15 M)中之溶液添加各別異氰酸酯(1.1當量),並在室溫下將該混合物攪拌整夜。濃縮該混合物及殘餘物藉由製備型HPLC純化。
一般程 序 10 :向胺衍生物(1當量)於DMF (0.15 M)中之溶液添加N,N-二異丙基乙胺(2.5當量)及各別醯氯(1當量),並在室溫下將該混合物攪拌整夜。該混合物用甲醇稀釋,濃縮,及殘餘物藉由製備型HPLC純化。
一般程 序 11 :向二氟乙酸(10當量)於二氯甲烷(1 M)中之溶液添加三乙胺(15當量)、3-{[(乙基亞胺基)亞甲基]胺基}-N,N-二甲基丙-1-胺(2.2當量)及1-羥基-1H-苯并三唑-水合物(2.2當量),並在室溫下將該混合物攪拌15 min。添加於二氯甲烷(0.1 M)中之各別胺(1當量),並在室溫下將該混合物攪拌整夜。濃縮該混合物,及殘餘物藉由製備型HPLC純化。
分析型
LC-MS
方法
1
:
儀器:Waters Acquity UPLCMS SingleQuad;管柱:Acquity UPLC BEH C18 1.7 µm,50x2.1 mm;溶析液A:水+ 0.1體積%甲酸(99%),溶析液B:乙腈;梯度:0至1.6 min 1至99% B,1.6至2.0 min 99% B;流量0.8 ml/min;溫度:60℃;DAD掃描:210至400 nm。
方法 2 :儀器:Waters Acquity UPLCMS SingleQuad;管柱:Acquity UPLC BEH C18 1.7 µm,50x2.1 mm;溶析液A:水+ 0.2體積%氨水(32%),溶析液B:乙腈;梯度:0至1.6 min 1至99% B,1.6至2.0 min 99% B;流量0.8 ml/min;溫度:60℃;DAD掃描:210至400 nm。
方法 3 :儀器:Waters Acquity UPLCMS SingleQuad;管柱:Acquity UPLC BEH C18 1.7 µm,50x2.1 mm;溶析液A:水+ 0.2體積%氨水(32%),溶析液B:乙腈;梯度:0至1.7 min 1至45% B,1.7至1.72 min 45至99% B,1.72至2.0 min 99% B;流量0.8 ml/min;溫度:60℃;ELSD。
方法 4 :儀器:Waters Acquity UPLCMS SingleQuad;管柱:Acquity UPLC BEH C18 1.7 50x2.1 mm;溶析液A:水+ 0.1體積%甲酸(99%),溶析液B:乙腈;梯度:0至1.6 min 1至99% B,1.6至2.0 min 99% B;流量0.8 ml/min;溫度:60℃;DAD掃描:210至400 nm。
方法 5 :儀器:Waters Acquity UPLCMS SingleQuad;管柱:Acquity UPLC BEH C18 1.7 50x2.1 mm;溶析液A:水+ 0.2體積%氨水(32%),溶析液B:乙腈;梯度:0至1.6 min 1至99% B,1.6至2.0 min 99% B;流量0.8 ml/min;溫度:60℃;DAD掃描:210至400 nm。
製備型 HPLCa) 自動純化器:酸性條件
b) 自動純化器:鹼性條件
系統: | Waters自動純化系統:泵2545,樣本管理器2767, CFO, DAD 2996, ELSD 2424, SQD |
管柱: | XBrigde C18 5.0 µm 100x30 mm |
溶劑: | A = H 2O + 0.1體積% HCOOH (99%) |
B =乙腈 | |
梯度: | 0至0.5 min 5% B 25 mL/min,0.51至5.5 min 10至100% B 70 mL/min,5.51至6.5 min 100% B 70 mL/min |
溫度: | 室溫 |
溶液: | 最大250 mg /最大2.5 mL DMSO或DMF |
注射: | 1 x 2.5 mL |
偵測: | DAD掃描範圍210至400 nm,MS ESI+,ESI-,掃描範圍160至1000 m/z |
系統: | Waters自動純化系統:泵2545,樣本管理器2767, CFO, DAD 2996, ELSD 2424, SQD |
管柱: | XBrigde C18 5.0 µm 100x30 mm |
溶劑: | A = H 2O + 0.2體積% NH 3(32%) |
B =乙腈 | |
梯度: | 0至0.5 min 5% B 25 mL/min,0.51至5.5 min 10至100% B 70 mL/min,5.51至6.5 min 100% B 70 mL/min |
溫度: | 室溫 |
溶液: | 最大250 mg /最大2.5 mL DMSO或DMF |
注射: | 1 x 2.5 mL |
偵測: | DAD掃描範圍210至400 nm,MS ESI+,ESI-,掃描範圍160至1000 m/z |
將1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇-鹽酸鹽(1/1) (5.00 g,17.6 mmol)溶解於二氯甲烷(100 mL)中並在氬氣氛下冷卻至0℃。添加2,6-二甲基吡啶(14 mL)並將該懸浮液攪拌5分鐘。滴加三乙基矽基三氟甲磺酸酯(16 ml,70 mmol)及容許將該混合物升溫至室溫並攪拌16小時。在0℃下該混合物用飽和碳酸氫鈉水溶液淬滅。將有機相分離並經硫酸鈉乾燥,隨後將其濾除。蒸發溶劑以產生無色油(6.37 g),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 1.65 min;MS (M+H)
+: m/z = 362
在室溫下向5-胺基-2-氯吡啶-4-羧酸(100 g,579 mmol)及乙脒鹽酸鹽(164 g,1.74 mol)於2-甲氧基乙醇(1.2 L)中之溶液添加乙酸鈉(143 g,1.74 mol)。在130℃下將該反應混合物攪拌48小時。濃縮該反應混合物以在減壓下移除約400 ml 2-甲氧基乙醇。將殘餘物倒入水中,沈澱棕色固體。將沈澱過濾,在減壓下由油泵乾燥以產生呈棕色固體之7-氯-2-甲基吡啶并[4,3-d]嘧啶-4-醇(16.6 g,69%)。
LC-MS (方法2): R
t= 0.64 min;MS (M+H)
+: m/z = 196
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.384 (16.00), 2.518 (0.89), 2.523 (0.59), 7.928 (4.21), 7.930 (4.17), 8.817 (3.76), 8.819 (3.55)。
將2-胺基-5-溴吡啶-3-羧酸(5.00 g,23.0 mmol)及乙脒胺-鹽酸鹽(1/1) (7.62 g,80.6 mmol)溶解於2-甲氧基乙醇(60 mL)中。添加乙酸鈉(6.61 g,80.6 mmol)並將該混合物加熱至150℃歷時三天。將該混合物冷卻至室溫並倒於冰水混合物上。所得固體藉由過濾收集並用水清洗。乾燥固體以產生呈淺棕色固體之標題化合物(4.60 g,83%產率)。
LC-MS (方法3): R
t= 0.43 min;MS (M+H)
+: m/z = 240
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.392 (16.00), 2.518 (0.46), 8.554 (3.20), 8.561 (3.45), 8.986 (3.45), 8.993 (3.08), 12.659 (0.48)。
將2-氯-6-甲基吡啶-3-羧酸(20.0 g,117 mmol)及碳酸鉀(43.5 g,315 mmol)溶解於二甲基甲醯胺(200 mL)中。將氣氛交換為氬並添加碘甲烷(33 ml,520 mmol)。在室溫下將該混合物攪拌16小時。過濾該混合物並部分蒸發溶劑。添加乙酸乙酯(200 mL)及所得有機相用水清洗,然後分離並用硫酸鈉乾燥以產生呈棕色油之標題化合物(21 g,97%產率)。
LC-MS (方法1): R
t= 0.90 min;MS (M+H)
+: m/z = 186
1H-NMR (400 MHz,氯仿-d) δ [ppm]: 2.590 (10.33), 2.884 (0.62), 2.959 (0.69), 3.941 (16.00), 7.157 (1.41), 7.176 (1.48), 8.078 (2.26), 8.098 (2.17)。
在室溫下在氬下將2-(三級丁基胺基)-6-甲基吡啶-3-羧酸(7.60 g,36.5 mmol)及碳酸鉀(13.6 g,98.5 mmol)溶解於二甲基甲醯胺(95 mL)中。滴加碘甲烷(10 ml,160 mmol)並將該混合物攪拌16小時。過濾該混合物並添加乙酸乙酯。所得有機相用水及鹽水清洗及然後分離並用硫酸鈉乾燥。該化合物藉由biotage急驟管柱層析術於矽膠上使用己烷及乙酸乙酯之混合物作為溶析液純化以獲得標題化合物(1.75 g,22%產率)。
LC-MS (方法2): R
t= 1.55 min;MS (ESIpos): m/z = 223 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.450 (16.00), 2.342 (6.03), 2.518 (0.58), 3.772 (7.79), 6.443 (0.97), 6.464 (1.00), 7.940 (1.22), 7.960 (1.20), 8.007 (0.63)。
將2-(三級丁基胺基)-6-甲基吡啶-3-羧酸甲酯(20.1 g,90.4 mmol)溶解於乙腈(450 mL)中並在氬下冷卻至0℃。添加N-溴琥珀醯亞胺(24.1 g,136 mmol)並將該混合物攪拌1.5小時。添加飽和硫代硫酸鈉水溶液且其用二氯甲烷萃取。有機相用硫酸鈉乾燥。該化合物藉由biotage急驟管柱層析術於矽膠上使用己烷及乙酸乙酯之混合物作為溶析液純化以獲得標題化合物(12.3 g,45%產率)。
LC-MS (方法2): R
t= 1.74 min;MS (ESIpos): m/z = 301 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.440 (16.00), 2.468 (7.06), 2.518 (0.75), 2.523 (0.55), 3.324 (0.46), 3.796 (8.22), 7.957 (0.65), 8.086 (2.37)。
向5-溴-2-(三級丁基胺基)-6-甲基吡啶-3-羧酸甲酯(12.3 g,40.8 mmol)添加三氟乙酸(120 ml,1.5 mol)並在120℃下使用微波將該混合物攪拌45分鐘。添加甲苯並蒸發溶劑以產生粗固體(15.1 g,103%產率),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 1.10 min;MS (ESIpos): m/z = 245 [M+H]
+
在室溫下在氬下將三氟乙酸-2-胺基-5-溴-6-甲基吡啶-3-羧酸甲酯(1/1) (15.1 g,92%純度,38.7 mmol)溶解於甲醇(180 mL)中。添加氫氧化鈉溶液(150 ml,5重量%,190 mmol)並將所得懸浮液攪拌16小時。蒸發甲醇,添加鹽酸水溶液(2.5 M)直至形成固體。添加乙酸直至達成4之pH。將固體濾除並用水及醚清洗及然後在70℃下在真空下乾燥以產生標題化合物(7.5 g,84%產率)。
LC-MS (方法1): R
t= 0.67 min;MS (ESIpos): m/z = 231 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.907 (0.20), 2.251 (0.08), 2.412 (16.00), 2.518 (1.53), 2.523 (1.06), 2.570 (0.09), 3.324 (0.67), 4.399 (0.08), 7.291 (0.14), 8.042 (6.41)。
在135℃下將受質2-胺基-5-溴-6-甲基吡啶-3-羧酸(3.50 g,15.1 mmol)、乙脒鹽酸鹽(6.44 g,68.2 mmol)及乙酸鈉(1.24 g,15.1 mmol)於2-甲氧基乙醇(30 mL)中之混合物加熱4天。添加另外2-甲氧基乙醇(30 ml)及乙脒鹽酸鹽(1.43 g,15.1 mmol)及乙酸鈉(1.24 g,15.1 mmol),在140℃下再加熱2天。添加另外2-甲氧基乙醇(20 ml)及乙脒鹽酸鹽(2.86 g,30.3 mmol)及乙酸鈉(2.49 g,30.3 mmol),在140℃下再加熱一天。將該反應混合物倒入冰水中並過濾所得懸浮液。殘餘物用水清洗並在減壓下在65℃下乾燥三天以產生呈淺棕色固體之標題化合物(2.95 g,77%產率)。
LC-MS (方法1): R
t= 0.70 min;MS (ESIneg): m/z = 252 [M-H]
-
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (0.08), 1.752 (0.07), 1.899 (0.37), 2.208 (0.08), 2.318 (0.14), 2.322 (0.31), 2.327 (0.42), 2.331 (0.32), 2.336 (0.17), 2.371 (16.00), 2.518 (4.96), 2.522 (3.84), 2.659 (0.25), 2.665 (0.44), 2.669 (0.72), 2.678 (13.68), 2.838 (0.08), 3.239 (0.41), 8.479 (4.79), 12.596 (0.05)。
向2-胺基-5-溴-6-(三氟甲基)吡啶-3-羧酸甲酯(920 mg,3.08 mmol)於Ac
2O (61 ml,650 mmol)中之溶液添加DMAP (3.76 mg,30.8 µmol)並在100℃下將該混合物攪拌2天。然後,在室溫下添加甲苯並在減壓下濃縮該混合物。粗產物在真空下乾燥且無需進一步純化即可用於下一步驟中(1.05 g,100%產率)。
LC-MS (方法2): R
t= 1.12 min;MS (ESIpos): m/z = 341 [M+H]
+
在室溫下將2-乙醯胺基-5-溴-6-(三氟甲基)吡啶-3-羧酸甲酯(1.05 g,3.08 mmol)於NH
4OH水溶液(28至30%,93 ml)中之溶液攪拌整夜。將該混合物在減壓下濃縮,用H
2O稀釋並用EtOAc萃取。經組合之有機相用鹽水清洗,經Na
2SO
4乾燥,過濾並在減壓下濃縮。在藉由二氧化矽層析術(己烷/EtOAc)純化後獲得標題化合物(630 mg,66%產率)。
LC-MS (方法1): R
t= 0.93 min;MS (ESIpos): m/z = 308 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.810 (0.52), 1.850 (0.73), 1.987 (0.66), 2.422 (16.00), 2.518 (0.95), 2.523 (0.66), 8.827 (2.58), 12.878 (0.47)。
向6-溴-2-甲基-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-醇(250 mg,812 µmol)、(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙-1-胺(594 mg,2.92 mmol)及PyBOP (1.65 g,3.16 mmol)於DMF (6.3 mL)中之溶液添加1,8-二氮雜雙環(5.4.0)十一碳-7-烯(1.5 ml,9.7 mmol)並在50℃下將該反應混合物攪拌整夜。添加水及該混合物用乙酸乙酯萃取。經組合之有機相用水及鹽水清洗,經Na
2SO
4乾燥,過濾並在減壓下濃縮。在藉由二氧化矽層析術(己烷/EtOAc)純化後獲得標題化合物(258 mg,64%產率)。
LC-MS (方法2): R
t= 1.51 min;MS (ESIpos): m/z = 495 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.85), 1.172 (1.60), 1.189 (0.74), 1.562 (4.55), 1.579 (4.46), 1.987 (3.19), 2.323 (0.52), 2.327 (0.73), 2.331 (0.51), 2.406 (16.00), 2.518 (2.67), 2.523 (1.91), 2.605 (5.08), 2.665 (0.53), 2.669 (0.74), 2.673 (0.50), 4.017 (0.63), 4.035 (0.64), 5.687 (0.66), 5.705 (1.02), 5.722 (0.64), 5.759 (0.56), 7.352 (0.57), 7.372 (1.28), 7.391 (0.78), 7.558 (1.39), 7.576 (1.11), 7.754 (1.22), 7.773 (1.09), 9.188 (1.03), 9.206 (1.00), 9.480 (3.55)。
將6-氯-2-甲基吡啶并[3,4-d]嘧啶-4-醇(2.87 g,14.7 mmol)懸浮於N,N-二甲基甲醯胺(29 mL)中。在室溫下添加2,4,6-三異丙基苯磺醯氯(4.89 g,16.2 mmol),接著添加三乙胺(7.2 ml,51 mmol)。將該混合物攪拌1小時。添加(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙胺(6.37 g,17.6 mmol)並在室溫下將所得混合物攪拌16小時。部分蒸發溶劑並將殘餘物重新溶解於二氯甲烷及水中。有機相用水(兩次)及鹽水清洗。該有機相透過疏水性過濾乾燥。蒸發溶劑及化合物透過急驟管柱層析術於具有矽膠之Biotage上且己烷及乙酸乙酯作為溶析液純化以產生標題化合物(6.00 g,97%純度,74%產率)。
LC-MS (方法2): R
t= 1.77 min;MS (ESIneg): m/z = 537 [M-H]
-
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.382 (1.24), 0.385 (1.24), 0.404 (5.28), 0.424 (7.14), 0.442 (2.59), 0.662 (7.85), 0.672 (0.86), 0.681 (16.00), 0.689 (0.81), 0.701 (5.46), 1.233 (0.41), 1.321 (4.11), 1.329 (4.29), 1.577 (3.02), 1.594 (3.00), 2.332 (1.09), 2.336 (0.51), 2.382 (10.57), 2.518 (7.29), 2.522 (4.80), 2.673 (1.12), 2.678 (0.48), 5.751 (0.46), 5.768 (0.74), 5.786 (0.46), 7.204 (0.43), 7.223 (1.04), 7.242 (0.74), 7.281 (0.48), 7.297 (0.63), 7.622 (0.63), 8.548 (2.57), 8.550 (2.59), 8.835 (2.82), 8.847 (0.79), 8.865 (0.76)。
在圓形燒瓶中將6-氯-N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(1.35 g,2.50 mmol)溶解於二甲基亞碸(20 mL)中。添加1,8-二氮雜雙環(5.4.0)十一碳-7-烯(750 µl,5.0 mmol),接著添加硝甲烷(680 µl,13 mmol)。在室溫下將該混合物攪拌16小時。添加乙酸乙酯及水,分離相且有機相透過疏水性過濾乾燥。該化合物透過biotage急驟管柱層析術於矽膠上使用己烷及乙酸乙酯作為溶析液純化以產生標題化合物(1.00 g,72%產率)。
LC-MS (方法2): R
t= 1.91 min;MS (ESIpos): m/z = 553 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.365 (1.71), 0.384 (6.14), 0.404 (7.75), 0.423 (3.26), 0.651 (8.53), 0.670 (16.00), 0.691 (6.74), 1.293 (5.37), 1.305 (5.88), 1.565 (3.47), 1.582 (3.58), 2.361 (9.67), 2.680 (8.64), 5.720 (0.61), 5.737 (0.95), 5.748 (1.31), 5.755 (0.69), 7.165 (0.54), 7.185 (1.29), 7.204 (0.93), 7.246 (0.70), 7.263 (0.95), 7.278 (0.47), 7.567 (0.54), 7.584 (0.92), 7.599 (0.53), 8.319 (2.76), 8.687 (1.06), 8.704 (1.05)。
向6-溴-2-甲基吡啶并[2,3-d]嘧啶-4-醇(2.00 g,8.33 mmol)、(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙-1-胺(2.03 g,10.0 mmol)及PyBOP (5.64 g,10.8 mmol)於DMF (60 mL)中之溶液添加DBU (5.0 ml,33 mmol)並在室溫下將該反應混合物攪拌整夜。在減壓下濃縮該混合物並在藉由二氧化矽層析術純化及隨後自CH
2Cl
2/MTBE中再結晶後獲得標題化合物(1.37 g,39%產率)。
LC-MS (方法2): R
t= 1.32 min;MS (ESIpos): m/z = 425 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.12), 1.171 (2.50), 1.189 (1.28), 1.470 (1.34), 1.487 (1.36), 1.551 (5.16), 1.569 (5.23), 1.986 (4.69), 2.396 (16.00), 2.448 (1.37), 2.518 (3.22), 2.522 (2.12), 2.606 (5.94), 2.673 (0.56), 4.016 (0.99), 4.034 (0.97), 5.695 (0.73), 5.713 (1.12), 5.730 (0.71), 7.350 (0.66), 7.369 (1.45), 7.389 (0.85), 7.551 (1.60), 7.569 (1.29), 7.756 (1.42), 7.775 (1.29), 9.003 (3.41), 9.009 (3.59), 9.198 (2.97), 9.204 (2.69)。
向6-溴-2-甲基吡啶并[2,3-d]嘧啶-4-醇(3.89 g,16.2 mmol)、(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙-1-胺(16.1 g,17.8 mmol)及PyBOP (10.0 g,17.8 mmol)於DMF (120 mL)中之溶液添加DBU (9.7 ml,64.8 mmol)並在室溫下將該反應混合物攪拌整夜。該混合物用EtOAc稀釋,用H
2O (2x)及鹽水清洗,並經Na
2SO
4乾燥。將該混合物過濾,在減壓下濃縮並在藉由二氧化矽層析術(鹼性相,己烷/EtOAc)純化後獲得標題化合物(5.55 g,59%)。
LC-MS (方法2): R
t= 1.72 min;MS (ESIpos): m/z = 583 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.384 (1.14), 0.387 (1.21), 0.405 (5.21), 0.417 (0.57), 0.425 (7.62), 0.434 (0.56), 0.444 (2.69), 0.663 (7.57), 0.674 (0.88), 0.682 (16.00), 0.691 (1.14), 0.703 (5.64), 1.323 (3.86), 1.332 (4.28), 1.566 (2.95), 1.584 (2.98), 2.367 (11.84), 2.518 (5.24), 2.523 (3.80), 3.321 (0.48), 5.753 (0.44), 5.770 (0.71), 5.788 (0.46), 7.199 (0.41), 7.218 (1.02), 7.238 (0.73), 7.272 (0.40), 7.276 (0.50), 7.293 (0.64), 7.622 (0.62), 8.790 (0.76), 8.808 (0.74), 8.991 (2.74), 8.998 (2.85), 9.199 (2.02), 9.205 (1.92)。
在室溫下向6-溴-N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2-甲基吡啶并[2,3-d]嘧啶-4-胺(1.00 g,1.71 mmol)及三乙基矽烷(27 µl,170 µmol)於二氯甲烷(15 mL)中之溶液滴加三氟乙酸(2.0 ml,26 mmol)。在室溫下將該混合物攪拌整夜。然後,添加甲苯並在減壓下移除揮發物。在藉由二氧化矽層析術(己烷/EtOAc)純化後獲得標題化合物(815 mg,100%產率)。
LC-MS (方法2): R
t= 1.15 min;MS (ESIpos): m/z = 469 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.58), 1.171 (3.21), 1.189 (1.98), 1.202 (6.11), 1.226 (6.29), 1.563 (4.70), 1.580 (4.70), 1.986 (5.14), 2.326 (1.01), 2.332 (0.75), 2.368 (16.00), 2.518 (4.79), 2.522 (3.16), 2.669 (1.01), 2.673 (0.75), 4.017 (1.19), 4.034 (1.19), 5.338 (2.24), 5.731 (0.75), 5.748 (1.14), 5.766 (0.70), 7.197 (0.70), 7.216 (1.67), 7.235 (1.05), 7.299 (0.66), 7.303 (0.75), 7.321 (1.05), 7.336 (0.53), 7.340 (0.44), 7.588 (0.62), 7.604 (1.05), 7.620 (0.53), 8.803 (1.23), 8.821 (1.19), 8.995 (3.69), 9.002 (3.65), 9.196 (3.16), 9.202 (2.99)。
向6-溴-2,7-二甲基吡啶并[2,3-d]嘧啶-4-醇(1.50 g,5.90 mmol)、(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙-1-胺(1.44 g,7.08 mmol)及PyBOP (3.99 g,7.67 mmol)於DMF (46 mL)中之溶液添加1,8-二氮雜雙環(5.4.0)十一碳-7-烯(3.5 ml,24 mmol)並在室溫下將該反應混合物攪拌整夜。添加水並用二氯甲烷萃取水相。經組合之有機相用鹽水清洗,經硫酸鈉乾燥,過濾並在減壓下濃縮。在藉由二氧化矽層析術(己烷/EtOAc)純化後獲得標題化合物(1.45 g,56%產率)。
LC-MS (方法2): R
t= 1.37 min;MS (ESIpos): m/z = 441 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (3.17), 1.171 (6.28), 1.189 (3.01), 1.560 (5.52), 1.578 (5.54), 1.986 (12.05), 2.414 (14.52), 2.518 (1.28), 2.523 (0.82), 2.596 (6.89), 2.706 (16.00), 3.998 (0.85), 4.016 (2.49), 4.034 (2.51), 4.052 (0.83), 5.720 (0.79), 5.738 (1.19), 5.758 (1.89), 7.363 (0.74), 7.383 (1.65), 7.402 (0.97), 7.562 (1.81), 7.580 (1.46), 7.758 (1.63), 7.777 (1.46), 9.192 (4.67), 9.315 (0.41)。
向6-溴-2,7-二甲基吡啶并[2,3-d]嘧啶-4-醇(500 mg,1.97 mmol)、(1R)-1-[3-(二氟甲基)-2-氟苯基]乙-1-胺鹽酸鹽(1/1) (511 mg,2.26 mmol)及PyBOP (1.33 g,2.56 mmol)於N,N-二甲基甲醯胺(17 mL)中之溶液添加1,8-二氮雜雙環(5.4.0)十一碳-7-烯(1.2 ml,7.9 mmol)並在室溫下將該反應混合物攪拌整夜。添加水及乙酸乙酯,有機相用水及鹽水清洗,經硫酸鈉乾燥,過濾並在減壓下濃縮。在藉由二氧化矽層析術(己烷/EtOAc)純化後獲得標題化合物(625 mg,75%產率)。
LC-MS (方法2): R
t= 1.24 min;MS (ESIpos): m/z = 427 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (1.83), 1.172 (3.84), 1.190 (1.87), 1.579 (4.53), 1.597 (4.51), 1.988 (6.18), 2.337 (0.44), 2.364 (16.00), 2.518 (4.31), 2.523 (2.92), 2.673 (0.93), 2.678 (0.58), 2.691 (14.37), 3.999 (0.46), 4.017 (1.37), 4.035 (1.31), 4.053 (0.42), 5.732 (0.68), 5.750 (1.03), 5.767 (0.68), 7.101 (1.05), 7.237 (2.17), 7.275 (0.72), 7.294 (1.57), 7.313 (0.93), 7.373 (0.91), 7.494 (0.54), 7.511 (0.91), 7.529 (0.44), 7.659 (0.52), 7.678 (0.89), 7.695 (0.46), 8.763 (0.48), 8.778 (0.48), 9.144 (4.57)。
向6-溴-2,7-二甲基吡啶并[2,3-d]嘧啶-4-醇(120 mg,472 µmol)、(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙-1-胺(196 mg,543 µmol)及PyBOP (320 mg,614 µmol)於DMF (4.0 mL)中之溶液添加DBU (280 µl,1.9 mmol)並在室溫下將該反應混合物攪拌整夜。該混合物用H
2O及EtOAc稀釋,有機相用H
2O (2x)及鹽水清洗,並經Na
2SO
4乾燥。將該混合物過濾,在減壓下濃縮並在藉由二氧化矽層析術(己烷/EtOAc)純化後獲得標題化合物(122 mg,43%)。
LC-MS (方法2): R
t= 1.74 min;MS (ESIpos): m/z = 567 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.388 (1.44), 0.389 (1.44), 0.409 (5.84), 0.429 (7.47), 0.448 (2.94), 0.664 (8.29), 0.683 (16.00), 0.704 (5.90), 1.325 (5.42), 1.331 (5.67), 1.556 (3.40), 1.574 (3.39), 1.987 (0.45), 2.343 (10.70), 2.522 (1.42), 2.684 (9.83), 5.745 (0.54), 5.763 (0.84), 5.781 (0.53), 7.195 (0.49), 7.214 (1.23), 7.233 (0.88), 7.271 (0.61), 7.287 (0.81), 7.591 (0.47), 7.608 (0.79), 7.624 (0.43), 8.711 (0.95), 8.729 (0.91), 9.149 (3.42)。
在室溫下向6-溴-N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2,7-二甲基吡啶并[2,3-d]嘧啶-4-胺(400 mg,669 µmol)及三乙基矽烷(11 µl,67 µmol)於CH
2Cl
2(5.9 mL)中之溶液滴加TFA (770 µl,10 mmol)。在室溫下將該混合物攪拌整夜。然後,添加甲苯並在減壓下移除揮發物。在藉由二氧化矽層析術(己烷/EtOAc)純化後獲得標題化合物(320 mg,99%)。
LC-MS (方法2): R
t= 1.19 min;MS (ESIpos): m/z = 485 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.20), 1.172 (4.73), 1.190 (2.99), 1.202 (6.97), 1.217 (6.94), 1.625 (4.90), 1.643 (4.87), 1.907 (0.47), 1.987 (6.92), 2.327 (0.94), 2.331 (0.65), 2.518 (4.10), 2.523 (2.67), 2.669 (0.98), 2.673 (0.65), 2.761 (16.00), 3.999 (0.58), 4.017 (1.68), 4.035 (1.67), 4.053 (0.53), 5.361 (0.81), 5.838 (0.76), 5.856 (1.17), 5.874 (0.73), 7.261 (0.76), 7.280 (1.82), 7.299 (1.17), 7.358 (0.72), 7.362 (0.81), 7.379 (1.15), 7.395 (0.55), 7.399 (0.48), 7.654 (0.64), 7.671 (1.11), 7.686 (0.58), 9.321 (4.32)。
將6-氯-2-甲基吡啶并[3,4-d]嘧啶-4-醇(6.00 g,30.7 mmol)及2,4,6-三(丙-2-基)苯-1-磺醯氯(10.2 g,33.7 mmol)溶解於N,N-二甲基甲醯胺(60 mL)中。添加三乙胺(11 ml),接著添加4-(二甲胺基)吡啶(562 mg,4.60 mmol)。在室溫下將該混合物攪拌一小時。然後,添加(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙-1-胺(7.48 g,36.8 mmol)並將該混合物攪拌16小時。添加二氯甲烷及水,有機相用水及鹽水清洗,用硫酸鈉乾燥並蒸發溶劑。該化合物藉由biotage急驟管柱層析術於矽膠上使用己烷及乙酸乙酯之混合物作為溶析液純化以產生標題化合物(9.98 g,85%產率)。
LC-MS (方法2): R
t= 1.39 min;MS (ESIneg): m/z = 379 [M-H]
-
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.44), 1.171 (0.97), 1.189 (0.51), 1.553 (4.57), 1.570 (4.57), 1.986 (1.77), 2.386 (16.00), 2.518 (1.28), 2.523 (0.86), 2.609 (4.97), 5.668 (0.57), 5.685 (0.88), 5.703 (0.57), 7.343 (0.55), 7.362 (1.24), 7.382 (0.72), 7.544 (1.33), 7.561 (1.07), 7.751 (1.18), 7.770 (1.07), 8.525 (3.73), 8.527 (3.64), 8.818 (3.98), 8.820 (3.79), 8.967 (0.86), 8.984 (0.84)。
將6-氯-2-甲基吡啶并[3,4-d]嘧啶-4-醇(433 mg,2.22 mmol)及2,4,6-三(丙-2-基)苯-1-磺醯氯(738 mg,2.44 mmol)溶解於N,N-二甲基甲醯胺(4.3 mL)中。添加三乙胺(770 µl),接著添加4-(二甲胺基)吡啶(40.6 mg,332 µmol)。在室溫下將該混合物攪拌一小時。添加(1R)-1-[3-(二氟甲基)-2-氟苯基]乙-1-胺-鹽酸鹽(1/1) (600 mg,2.66 mmol)並將該混合物攪拌16小時。添加二氯甲烷及水,有機相用水及鹽水清洗,用硫酸鈉乾燥並蒸發溶劑。該化合物藉由biotage急驟管柱層析術於矽膠上使用己烷及乙酸乙酯之混合物作為溶析液純化以產生標題化合物(0.57 g,70%產率)。
LC-MS (方法2): R
t= 1.25 min;MS (ESIpos): m/z = 367 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (3.83), 1.172 (7.69), 1.190 (3.67), 1.598 (4.72), 1.615 (4.75), 1.988 (12.40), 2.397 (16.00), 2.518 (1.81), 2.523 (1.25), 4.000 (0.93), 4.017 (2.87), 4.035 (2.88), 4.053 (0.94), 5.732 (0.71), 5.750 (1.11), 5.759 (2.44), 5.768 (0.70), 7.102 (1.04), 7.238 (2.18), 7.280 (0.73), 7.299 (1.60), 7.318 (0.92), 7.373 (0.94), 7.499 (0.54), 7.516 (0.92), 7.534 (0.44), 7.670 (0.50), 7.687 (0.92), 7.706 (0.45), 8.537 (3.84), 8.539 (3.82), 8.841 (4.23), 8.867 (1.04), 8.885 (1.01)。
在氬下向6-氯-N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(100 mg,185 µmol)、二甲基-λ5-膦酮(14.5 mg,185 µmol)及三乙胺(90 µl,650 µmol;CAS-RN:[121-44-8])於乙腈(1.3 ml)中之溶液添加肆(三苯基膦)鈀(0) (42.9 mg,37.1 µmol;CAS-RN:[14221-01-3])並在100℃下將該混合物加熱兩天。將該混合物過濾,濃縮及粗產物直接用於下一步驟。
LC-MS (方法2): Rt = 1.59 min;MS (ESIpos): m/z = 581.6 [M+1]+
遵循一般程序1,使6-氯-N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2,8-二甲基吡啶并[3,4-d]嘧啶-4-胺(83.0 mg,150 µmol)與於乙腈(1.0 mL)中之二甲基-λ
5-膦酮(11.7 mg,150 µmol)、肆(三苯基膦)鈀(0) (27.5 mg,30.0 µmol,0.20當量)及三乙胺(73 µl,530 µmol)在90℃下反應20小時。將該混合物冷卻至室溫並添加乙酸乙酯及水,分離相及有機相透過疏水性過濾乾燥。蒸發溶劑以產生淺黃色油,其無需進一步純化且以粗混合物使用。
LC-MS (方法2): R
t= 1.78 min;MS (ESIpos): m/z = 595 [M+H]
+
反應分兩批平行進行:在20℃下將(S)-2-甲基丙烷-2-亞磺醯胺(200 g,1.65 mol)、乙醛(500 ml,5 M於THF中)及MgSO
4(750 g,6.23 mol)於DCM (1.5 L)中之混合物攪拌28 h。將兩種反應混合物組合並過濾。濾餅用DCM (1000 ml x 2)清洗。在真空中濃縮經組合之濾液。殘餘物藉由層析術於矽膠(3% EA於PE中)上純化以產生呈淡黃色油之(S,E)-N-亞乙基-2-甲基丙烷-2-亞磺醯胺(410 g,84.37%產率)。
1H NMR (CDCl
3400MHz) 8.07(q, 1H), 2.23 (d, 2H), 1.16 (s, 9H)。
反應分四批平行進行:在-20℃下向n-BuLi (320 ml,2.5 M於己烷中)之溶液滴加於THF (300 ml)中之N-異丙基丙-2-胺(120 ml,849.10 mmol),然後將其攪拌1 h並冷卻至-60℃。將1-氟-2-碘-苯(180 g,810.82 mmol)於THF (300 ml)中之溶液滴加至該反應。在攪拌2 h後,在-60℃下在N
2下滴加於THF (300 ml)中之(S,E)-N-亞乙基-2-甲基丙烷-2-亞磺醯胺(100 g,679.17 mmol)。將該混合物升溫至20℃並攪拌16 h。將各反應溶液倒入飽和NH
4Cl水溶液(3 L)中並用MTBE (800 ml x 3)萃取。經組合之有機溶液用鹽水(500 ml)清洗,經Na2SO4乾燥,過濾並在真空中濃縮。將該等四批組合並藉由層析術於矽膠(PE: EA = 10: 1至1: 2)上純化三次以產生呈淡棕色油(含有~0.04當量異構體)之所需產物(94 g,254.58 mmol)。
1H NMR (CDCl
3400MHz) 7.63-7.67 (m, 1H), 7.30-7.33 (m, 1H), 6.86-6.91 (m, 1H), 4.81-4.86 (m, 1H), 3.41 (d, 1H), 1.57 (d, 2H), 1.23 (s, 9H)。
在20℃下向(S)-N-[(1R)-1-(2-氟-3-碘-苯基)乙基]-2-甲基-丙烷-2-亞磺醯胺(94 g,254.58 mmol)於二噁烷(140 ml)中之溶液添加HCl/二噁烷(4 M,140 ml),然後將該反應攪拌2 h。TLC (PE: EA = 1:1)顯示該反應完成。向該混合物添加MTBE (300 ml)並過濾。濾餅用MTBE (50 ml x 2)清洗並在真空中乾燥以產生呈淡黃色固體之(R)-1-(2-氟-3-碘苯基)乙胺鹽酸鹽(67 g,87.28%產率)。
1H NMR (DMSO-d6 400 MHz) 8.70 (s, 1H), 7.84-7.88 (m, 1H), 7.66-7.69 (m, 1H), 7.08-7.12 (m, 1H), 4.58-4.61 (m, 1H), 1.52 (d, 3H)。
向(R)-1-(2-氟-3-碘苯基)乙胺鹽酸鹽(67 g,222.20 mmol)於H2O (300 ml)及THF (300 ml)中之溶液添加NaHCO3 (70 g,833.27 mmol),然後添加Boc2O (52 g,238.26 mmol)並在25℃下將該反應攪拌1 h。TLC (DCM: MeOH = 10: 1)顯示該反應完成。該混合物用MTBE (300 ml x 3)萃取。經組合之有機溶液用鹽水(300 ml)清洗,經Na2SO4乾燥,過濾並在真空中濃縮。殘餘物用PE (100 ml)研磨並過濾。在真空中乾燥濾餅以產生呈淡黃色固體之(R)-(1-(2-氟-3-碘苯基)乙基)胺基甲酸三級丁酯(75 g,92.43%產率)。
1H NMR (MeOD 400 MHz) 7.64-7.68 (m, 1H), 7.31-7.35 (m, 1H), 6.90-6.95 (m, 1H), 4.86-4.94 (m, 1H), 1.51 (d, 3H), 1.25 (s, 9H)。
在20℃下將2-溴-2,2-二氟乙酸乙酯(40 ml,311.36 mmol)及Cu (40 g,629.43 mmol)於DMSO (300 ml)中之混合物攪拌1 h,然後添加(R)-(1-(2-氟-3-碘苯基)乙基)胺基甲酸三級丁酯(75 g,205.38 mmol)並將該反應在80℃下攪拌加熱5 h。TLC (PE: EA = 3:1)顯示反應完成。將該反應冷卻並用MTBE (500 ml x 4)直接萃取。經組合之MTBE溶液用飽和NH
4Cl (300 ml x 2)清洗,經Na
2SO
4乾燥,過濾並在真空中濃縮。殘餘物藉由層析術於矽膠(PE: EA = 20: 1 ~ 5: 1)上純化以產生呈淡黃色油之(R)-2-(3-(1-((三級丁氧基羰基)胺基)乙基)-2-氟苯基)-2,2-二氟乙酸乙酯(45 g,60.64%產率)。
1H NMR (CDCl
3400 MHz) 7.52-7.56 (m, 1H), 7.44-7.48 (m, 1H), 7.20-7.25 (m, 1H), 4.97 (br s, 3H), 4.33-4.39 (m, 2H), 1.51 (d, 3H), 1.19-1.45 (m, 12H)。
在氬下在-15℃下向(3-{(1R)-1-[(三級丁氧基羰基)胺基]乙基}-2-氟苯基)(二氟)乙酸乙酯(16.4 g,45.4 mmol)及N-甲氧基甲胺鹽酸鹽(1/1) (6.64 g,68.1 mmol)於四氫呋喃(330 ml)中之溶液添加N,N-二異丙基乙胺(12 ml),並將該溶液攪拌5 min。然後,滴加2-丙基氯化鎂(2 M於THF中,110 ml,2.0 M,230 mmol)並在-15℃至-10℃下將所得溶液攪拌1 h。該反應用飽和氯化銨水溶液淬滅,並用乙酸乙酯萃取。有機相用飽和氯化鈉水溶液清洗,過濾乾燥並濃縮。粗產物藉由急驟管柱層析術純化以產生標題化合物(13.8 g,81%產率)。
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (2.54), 1.172 (5.05), 1.190 (2.60), 1.274 (5.68), 1.291 (5.71), 1.342 (16.00), 1.987 (8.09), 2.327 (0.45), 2.518 (1.66), 2.523 (1.17), 2.669 (0.46), 3.198 (8.59), 3.223 (1.92), 3.999 (0.58), 4.017 (1.73), 4.035 (1.69), 4.053 (0.53), 4.843 (0.49), 4.862 (0.68), 4.880 (0.45), 7.333 (0.89), 7.353 (2.11), 7.372 (1.30), 7.483 (0.91), 7.500 (1.41), 7.516 (0.65), 7.545 (0.77), 7.562 (1.35), 7.584 (1.27), 7.605 (0.76)。
向5-胺基-2-溴異菸鹼酸(CAS 1242336-80-6,50 g,230 mmol)及乙脒鹽酸鹽(1:1) (65 g,691 mmol)於2-甲氧基乙醇(300 ml)中之溶液添加乙酸鈉(57 g,691 mmol),在160℃下攪拌48小時。將該混合物冷卻至室溫,用水稀釋並攪拌1小時。將所得沈澱濾除並在真空中乾燥以產生標題化合物(44 g,76%產率)。
LC-MS (方法2): Rt = 0.48 min;MS (ESIpos): m/z = 240 [M+H]
+
向2-胺基-6-甲氧基吡啶-3-甲醯胺(19.0 g,114 mmol)於DMF (160 ml)中之溶液添加NBS (22.3 g,125 mmol)並在25℃下將該反應混合物攪拌2小時。濃縮該混合物,殘餘物用水(200 ml)研磨並在減壓下乾燥所得固體以產生呈棕色固體之標題化合物(20.0 g,64%產率),其無需進一步純化即可使用。
在120℃下將2-胺基-5-溴-6-甲氧基吡啶-3-甲醯胺(中間物33,52 g,90%純度,211 mmol)及原乙酸三乙酯(165 g,1.02 mol)於2-甲氧基乙醇(520 ml)中之溶液攪拌2小時。過濾所得懸浮液及取沈澱物自2-丙醇中再結晶,以產生呈棕色固體之6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-醇(27.8 g,96%純度,49%產率)。
LC-MS (方法2): R
t= 0.54 min;MS (ESIpos): m/z = 272 [M+H]
+
1H NMR (400 MHz, DMSO-d
6) δ ppm 12.55 (br s, 1 H), 8.45 (s, 1 H), 4.00 - 4.07 (m, 3 H), 2.52 - 2.55 (m, 1 H), 2.36 (s, 3 H)。
根據一般程序6,自6-溴-7-甲氧基-2-甲基吡啶并[2,3-d]嘧啶-4-醇(中間物34,900 mg,3.33 mmol)及(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙-1-胺鹽酸鹽(1/1) (879 mg,3.67 mmol)開始,獲得標題化合物(1.22 g,80%產率)。
LC-MS (方法2): R
t= 1.40 min;MS (ESIpos): m/z = 455 [M+H]
+
1H NMR (400 MHz, DMSO-d6) δ ppm 1.53 (d, J=6.84 Hz, 3 H) 2.33 (s, 3 H) 2.60 (s, 3 H) 4.00 (s, 3 H) 5.57 - 5.74 (m, 1 H) 7.27 - 7.40 (m, 1 H) 7.45 - 7.60 (m, 1 H) 7.71 - 7.80 (m, 1 H) 8.58 - 8.70 (m, 1 H) 9.12 (s, 1 H)。
遵循一般程序4:[(1R)-1-(3-{1,1-二氟-2-[甲氧基(甲基)胺基]-2-側氧基乙基}-2-氟苯基)乙基]胺基甲酸三級丁酯(4.00 g,10.6 mmol)、溴(甲基)鎂(32 ml,1.0 M,32 mmol)於THF (120 ml)中,自-10℃至0℃反應1.5 h。處理水溶液後,獲得標題化合物(3.63 g,定量)且無需進一步純化即可用於下一步驟中。
LC-MS (方法2): R
t= 1.29 min;MS (ESIpos): m/z = 332 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.87), 1.172 (0.63), 1.190 (0.40), 1.272 (6.20), 1.289 (6.20), 1.353 (16.00), 2.443 (8.06), 2.518 (1.59), 2.523 (1.09), 4.851 (0.45), 4.869 (0.62), 4.887 (0.42), 5.759 (0.88), 7.356 (0.72), 7.376 (1.65), 7.395 (1.01), 7.533 (0.89), 7.550 (1.41), 7.566 (0.73), 7.569 (0.74), 7.596 (1.11), 7.614 (1.59), 7.633 (0.67)。
在0℃下向{(1R)-1-[3-(1,1-二氟-2-側氧基丙基)-2-氟苯基]乙基}胺基甲酸三級丁酯(3.63 g,97%純度,10.6 mmol)於EtOH (42 ml)中之溶液分批添加NaBH
4。在室溫下將該混合物攪拌2 h,然後在0℃下倒入飽和NH
4Cl水溶液中。該混合物用EtOAc萃取,有機相用鹽水清洗,經Na
2SO
4乾燥並在減壓下濃縮。藉由急驟管柱層析術純化產生非對映異構體之混合物(3.32 g,94%產率),其等藉由對掌性HPLC分離。
製備方法:SFC
儀器:Sepiatec:Prep SFC100;管柱:Chiralpak IG 5 µ 250x30 mm;溶析液A:CO2;溶析液B:甲醇;等度:10% B;流量:100 ml/min;溫度:40℃;BPR:150 bar;UV:210 nm
LC-MS (方法2): R
t= 1.16 min;MS (ESIpos): m/z = 351 [M+NH
4 +]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.135 (3.55), 1.147 (3.69), 1.171 (1.70), 1.189 (1.04), 1.277 (4.65), 1.281 (4.31), 1.294 (4.89), 1.361 (16.00), 1.986 (1.18), 4.126 (0.44), 4.147 (0.63), 4.164 (0.64), 4.183 (0.45), 4.909 (0.69), 5.555 (1.07), 5.571 (1.11), 5.588 (0.80), 5.604 (0.72), 7.247 (0.77), 7.266 (1.87), 7.286 (1.30), 7.348 (1.08), 7.364 (1.60), 7.381 (0.74), 7.493 (0.89), 7.509 (1.57), 7.528 (0.85), 7.547 (0.60), 7.565 (0.90), 7.583 (0.56)。
非對映異構體1:1.71 g
1H NMR (400 MHz, DMSO-d
6) δ ppm 1.10 - 1.23 (m, 4 H), 1.29 (d, 4 H), 1.36 (s, 8 H), 4.16 (td, 1 H), 4.91 (br t, 1 H), 5.60 (br d, 1 H), 7.27 (t, 1 H), 7.36 (t, 1 H), 7.48 - 7.61 (m, 2 H)。
非對映異構體2:1.67 g
1H NMR (400 MHz, DMSO-d
6) δ ppm 1.15 (br d, 5 H), 1.29 (d, 4 H), 1.36 (s, 7 H), 2.52 - 2.55 (m, 1 H), 4.10 - 4.21 (m, 1 H), 4.91 (br t, 1 H), 5.56 (d, 1 H), 7.17 - 7.30 (m, 1 H), 7.36 (t, 1 H), 7.48 - 7.59 (m, 2 H)。
遵循一般程序3:[(1R)-1-{3-[1,1-二氟-2-羥丙基]-2-氟苯基}乙基]胺基甲酸三級丁酯(中間物37,非對映異構體1) (1.70 g,5.10 mmol)及TFA (5.9 ml,76 mmol)於DCM (30 ml)中產生標題化合物(2.07 g),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 0.83 min;MS (ESIpos): m/z = 234 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.145 (11.32), 1.161 (11.34), 1.223 (2.34), 1.394 (1.43), 1.409 (1.41), 1.501 (16.00), 1.519 (15.96), 1.734 (0.86), 2.296 (3.25), 2.518 (3.45), 2.523 (2.51), 4.121 (0.61), 4.139 (0.86), 4.159 (1.08), 4.175 (0.89), 4.196 (0.56), 4.669 (1.26), 4.684 (1.63), 4.699 (1.26), 7.160 (0.67), 7.164 (0.59), 7.180 (0.86), 7.230 (0.74), 7.248 (0.76), 7.388 (2.16), 7.408 (5.07), 7.428 (3.08), 7.478 (0.57), 7.522 (1.72), 7.526 (2.00), 7.544 (2.97), 7.559 (1.42), 7.563 (1.33), 7.693 (1.62), 7.710 (2.85), 7.726 (1.45), 8.383 (4.21)。
遵循一般程序3:[(1R)-1-{3-[1,1-二氟-2-羥丙基]-2-氟苯基}乙基]胺基甲酸三級丁酯(中間物37,非對映異構體2) (1.66 g,4.98 mmol)、TFA (5.8 ml)於DCM (30 ml)中產生標題化合物(2.03 g),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 0.82 min;MS (ESIpos): m/z = 234 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (11.70), 1.169 (11.66), 1.223 (2.96), 1.406 (1.47), 1.423 (1.47), 1.491 (2.28), 1.503 (16.00), 1.520 (15.65), 1.734 (1.13), 2.297 (4.13), 2.336 (0.41), 2.518 (4.38), 2.523 (3.26), 2.678 (0.41), 4.132 (0.63), 4.151 (0.96), 4.169 (1.21), 4.188 (0.98), 4.207 (0.59), 4.678 (1.30), 4.695 (1.70), 4.708 (1.36), 7.142 (0.42), 7.162 (0.88), 7.164 (0.80), 7.180 (1.03), 7.185 (0.62), 7.230 (0.91), 7.248 (0.94), 7.391 (2.19), 7.411 (5.20), 7.430 (3.18), 7.484 (0.59), 7.527 (2.00), 7.544 (3.07), 7.560 (1.44), 7.564 (1.36), 7.699 (1.66), 7.716 (2.97), 7.732 (1.51), 8.360 (4.29)。
遵循一般程序5:(1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟丙-2-醇三氟乙酸(1/1) (中間物38,1.57 g,3.84 mmol)、三乙基矽基三氟甲磺酸酯(4.3 ml,19 mmol)、2,6-二甲吡啶(3.1 ml)於DCM (25 ml)中產生標題化合物(1.17 g,88%產率)。
LC-MS (方法2): R
t= 1.58 min;MS (ESIpos): m/z = 349 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.362 (0.65), 0.379 (0.91), 0.383 (0.83), 0.400 (2.30), 0.407 (0.91), 0.420 (2.51), 0.427 (2.43), 0.435 (0.77), 0.440 (1.17), 0.447 (2.63), 0.455 (0.72), 0.466 (1.40), 0.484 (0.72), 0.765 (6.97), 0.772 (0.52), 0.776 (0.71), 0.785 (16.00), 0.793 (0.72), 0.804 (5.14), 0.873 (0.60), 0.892 (1.24), 0.913 (0.51), 1.189 (2.09), 1.204 (2.12), 1.248 (3.35), 1.265 (3.31), 2.518 (0.53), 4.241 (0.63), 4.257 (0.62), 7.255 (0.93), 7.274 (0.66), 7.311 (0.43), 7.325 (0.50), 7.329 (0.53), 7.707 (0.51)。
遵循一般程序3:三氟乙酸/(1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟丙-2-醇(1/1) (中間物39,1.53 g,85%純度,3.73 mmol)、三乙基矽基三氟甲磺酸酯(4.2 ml,19 mmol)、2,6-二甲吡啶(3.0 ml)於DCM (25 mL)中產生標題化合物(1.14 g,87%產率)。
LC-MS (方法2): R
t= 1.58 min;MS (ESIpos): m/z = 349 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.306 (0.93), 0.323 (0.90), 0.326 (1.14), 0.343 (2.11), 0.363 (2.20), 0.383 (1.34), 0.402 (2.03), 0.421 (2.25), 0.436 (0.67), 0.440 (1.43), 0.455 (0.72), 0.459 (1.02), 0.478 (0.46), 0.736 (7.05), 0.748 (0.73), 0.756 (16.00), 0.765 (0.69), 0.776 (5.43), 0.873 (0.54), 0.893 (1.13), 0.913 (0.51), 1.222 (4.18), 1.234 (2.60), 1.238 (3.91), 1.962 (0.54), 2.518 (0.61), 2.523 (0.43), 4.280 (0.61), 4.296 (0.63), 7.261 (0.91), 7.280 (0.68), 7.327 (0.50), 7.747 (0.50)。
遵循一般程序2:6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(350 mg,1.46 mmol)、(1R)-1-(3-{1,1-二氟-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙-1-胺(中間物40,608 mg,1.75 mmol)、2,4,6-三(丙-2-基)苯-1-磺醯氯(486 mg,1.60 mmol)、三乙胺(510 µl)及DMAP (26.7 mg,219 µmol)於DMF (4.4 ml)中在急驟管柱層析術後產生標題化合物(600 mg,72%產率)。
LC-MS (方法2): R
t= 1.70 min;MS (ESIpos): m/z = 572 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.244 (0.78), 0.261 (0.83), 0.264 (0.99), 0.282 (2.07), 0.302 (2.20), 0.305 (0.85), 0.322 (1.12), 0.326 (2.11), 0.345 (2.27), 0.364 (1.37), 0.383 (0.88), 0.402 (0.40), 0.639 (6.53), 0.647 (0.50), 0.650 (0.73), 0.658 (16.00), 0.666 (0.70), 0.678 (5.04), 1.172 (0.76), 1.189 (0.41), 1.218 (1.90), 1.234 (1.94), 1.589 (2.23), 1.606 (2.23), 1.987 (1.18), 2.411 (7.93), 2.518 (0.70), 2.523 (0.47), 5.846 (0.52), 7.270 (0.86), 7.289 (0.54), 7.379 (0.49), 7.687 (0.48), 8.658 (1.98), 8.805 (2.35), 8.838 (0.59), 8.857 (0.57)。
遵循一般程序2:使(1R)-1-(3-{1,1-二氟-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙-1-胺(中間物41,507 mg,1.46 mmol)、2,4,6-三(丙-2-基)苯-1-磺醯氯(486 mg,1.60 mmol)、三乙胺(510 µl)、DMAP (26.7 mg,219 µmol)於DMF (3.7 ml)中反應整夜以產生標題化合物(500 mg,60%產率)。
LC-MS (方法2): R
t= 1.72 min;MS (ESIpos): m/z = 572 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.211 (0.97), 0.228 (0.82), 0.230 (1.11), 0.248 (1.98), 0.268 (1.99), 0.288 (0.80), 0.296 (0.62), 0.316 (1.76), 0.336 (1.97), 0.354 (1.32), 0.373 (1.00), 0.392 (0.44), 0.645 (6.51), 0.653 (0.40), 0.656 (0.65), 0.665 (16.00), 0.673 (0.67), 0.684 (5.07), 1.223 (1.89), 1.239 (1.86), 1.594 (2.22), 1.612 (2.22), 2.371 (7.61), 2.518 (0.43), 5.669 (0.54), 7.244 (0.85), 7.263 (0.52), 7.371 (0.48), 7.642 (0.47), 8.689 (1.85), 8.797 (2.10), 8.895 (0.54), 8.912 (0.52)。
遵循一般程序3:6-溴-N-[(1R)-1-(3-{1,1-二氟-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物42,125 mg,219 µmol)及TFA (250 µl)於DCM (1.4 ml)中在藉由急驟管柱層析術純化後產生標題化合物(99.0 mg,99%產率)。
LC-MS (方法2): R
t= 1.14 min;MS (ESIpos): m/z = 455 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.144 (3.59), 1.154 (1.90), 1.161 (3.59), 1.172 (2.26), 1.190 (1.16), 1.578 (4.44), 1.596 (4.37), 1.987 (4.51), 2.399 (16.00), 2.518 (1.66), 2.523 (1.24), 3.320 (0.64), 4.017 (0.96), 4.034 (0.94), 5.563 (2.34), 5.579 (2.28), 5.747 (0.68), 5.758 (6.34), 5.765 (1.06), 5.782 (0.65), 7.230 (0.72), 7.249 (1.65), 7.269 (0.99), 7.363 (0.54), 7.367 (0.61), 7.384 (0.92), 7.400 (0.45), 7.404 (0.41), 7.617 (0.52), 7.634 (0.90), 7.651 (0.45), 8.668 (3.75), 8.670 (3.84), 8.807 (4.39), 8.858 (1.09), 8.875 (1.05)。
遵循一般程序3:6-溴-N-[(1R)-1-(3-{1,1-二氟-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物43,490 mg,860 µmol)及TFA (990 µl)於DCM (5.0 ml)中在藉由急驟管柱層析術純化後產生標題化合物(351 mg,90%產率)。
LC-MS (方法2): R
t= 1.11 min;MS (ESIpos): m/z = 455 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.131 (3.39), 1.147 (3.45), 1.154 (2.16), 1.171 (3.70), 1.189 (1.77), 1.582 (4.17), 1.600 (4.21), 1.986 (5.52), 2.377 (16.00), 2.518 (1.96), 2.523 (1.38), 4.016 (1.11), 4.034 (1.08), 5.578 (2.44), 5.594 (2.37), 5.703 (0.65), 5.720 (1.01), 5.738 (0.64), 5.756 (2.12), 7.221 (0.70), 7.240 (1.60), 7.259 (0.96), 7.358 (0.51), 7.362 (0.58), 7.380 (0.88), 7.395 (0.44), 7.599 (0.49), 7.615 (0.86), 7.632 (0.44), 8.666 (3.67), 8.668 (3.68), 8.805 (4.24), 8.875 (1.05), 8.893 (1.00)。
遵循一般程序5:1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟丙-2-醇三氟乙酸(1/1) (中間物38,1.93 g,81%純度,4.47 mmol)、三級丁基(二甲基)矽基三氟甲磺酸酯(4.1 ml,18 mmol)及2,6-二甲吡啶(3.6 ml)於DCM (25 ml)中在藉由急驟管柱層析術純化後產生標題化合物(1.04 g,67%產率)。
LC-MS (方法2): R
t= 1.58 min;MS (ESIpos): m/z = 349 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.225 (4.64), 0.718 (1.04), 0.726 (16.00), 0.733 (1.01), 1.209 (1.33), 1.225 (1.36), 1.260 (2.06), 1.276 (2.02), 7.265 (0.56), 7.284 (0.40)。
遵循一般程序2:6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(425 mg,1.77 mmol)、(1R)-1-{3-[2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟丙基]-2-氟苯基}乙-1-胺(中間物46,738 mg,2.12 mmol)、2,4,6-三(丙-2-基)苯-1-磺醯氯(590 mg,1.95 mmol)、Et
3N (620 µl)、DMAP (32.4 mg,266 µmol)於DMF (5.0 ml)中產生標題化合物(796 mg,79%產率)。
LC-MS (方法2): R
t= 1.73 min;MS (ESIneg): m/z = 567 [M-H]
-
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.319 (4.72), 0.670 (1.01), 0.678 (16.00), 1.285 (1.28), 1.300 (1.25), 1.643 (1.43), 1.659 (1.43), 2.044 (0.75), 2.460 (5.07), 2.575 (0.79), 2.580 (0.56), 7.320 (0.54), 8.714 (1.25), 8.864 (1.44)。
遵循一般程序5:1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇鹽酸鹽(1/1) [CAS 2569698-46-8] (6.00 g,21.1 mmol)、三乙基矽基三氟甲磺酸酯(17 ml,76 mmol)、2,6-二甲吡啶(17 ml)於DCM (140 ml)中產生標題化合物(7.29 g,95%產率)。
LC-MS (方法2): R
t= 1.66 min;MS (ESIpos): m/z = 363 [M+H]
+
¹H-NMR (400 MHz,氯仿-d) δ [ppm]: 0.641 (1.70), 0.662 (6.54), 0.671 (0.47), 0.673 (0.46), 0.682 (7.49), 0.701 (2.64), 0.958 (8.28), 0.969 (0.74), 0.978 (16.00), 0.986 (0.76), 0.998 (6.12), 1.544 (4.94), 1.560 (4.89), 1.699 (2.91), 4.560 (1.04), 4.577 (1.02), 7.251 (0.47), 7.290 (0.64), 7.407 (1.68), 7.438 (0.48), 7.443 (0.52), 7.460 (0.77), 7.475 (0.42), 7.480 (0.41), 7.632 (0.74)。
遵循一般程序2:6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(2.50 g,10.4 mmol)、(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙-1-胺(中間物48,4.52 g,12.5 mmol)、2,4,6-三(丙-2-基)苯-1-磺醯氯(3.47 g,11.5 mmol)、Et
3N (5.1 ml,36 mmol)、DMAP (191 mg,1.56 mmol)於DMF (25 ml)中產生標題化合物(5.30 g,87%產率)。
LC-MS (方法1): R
t= 1.79 min;MS (ESIneg): m/z = 581, 583 [M-H]
-。
1H NMR (400 MHz, DMSO-d
6) δ ppm 8.87 (d, 1 H), 8.80 (s, 1 H), 8.68 (s, 1 H), 7.62 (t, 1 H), 7.20 - 7.32 (m, 2 H), 5.73 - 5.80 (m, 1 H), 2.52 - 2.53 (m, 1 H), 2.33 - 2.39 (m, 3 H), 1.58 (d, 3 H), 1.33 (br d, 6 H), 1.23 (br s, 1 H), 0.65 - 0.73 (m, 9 H), 0.38 - 0.48 (m, 6 H)。
在-78℃下向[(1R)-1-(3-{1,1-二氟-2-[甲氧基(甲基)胺基]-2-側氧基乙基}-2-氟苯基)乙基]胺基甲酸三級丁酯(中間物31,4.34 g,11.5 mmol)於THF (120 ml)中之溶液緩慢添加三級丁基鋰(15 ml,1.7 M,25 mmol)。在-78℃下將該混合物攪拌1 h並藉由在-78℃下添加飽和NH
4Cl水溶液淬滅。在室溫下該混合物用水稀釋,用EtOAc萃取,有機相用鹽水清洗,經Na
2SO
4乾燥,過濾並在減壓下濃縮。藉由急驟管柱層析術純化產生標題化合物(1.51 g,35%產率)。
LC-MS (方法2): R
t= 1.51 min;MS (ESIpos): m/z = 374 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.792 (0.90), 1.154 (0.43), 1.172 (0.79), 1.190 (0.44), 1.264 (16.00), 1.279 (3.14), 1.351 (6.23), 1.987 (0.76), 2.518 (2.00), 2.523 (1.36), 5.758 (1.57), 7.358 (0.71), 7.377 (0.45), 7.520 (0.55), 7.581 (0.59), 7.600 (0.77)。
將4-乙氧基-1,4λ
5-氮雜磷雜環己烷-4-酮[CAS 1042425-93-3] (20.8 g,102 mmol)溶解於CH
2Cl
2(300 mL)中。添加三乙胺(43 ml,310 mmol),接著添加二碳酸二-三級丁酯(26 ml,110 mmol)。在室溫下將該混合物攪拌一夜。有機相用飽和NaHCO
3水溶液及鹽水清洗。將該有機相乾燥,過濾並蒸發溶劑以產生標題化合物(30.7 g,定量),其無需純化即可用於下一步驟。
LC-MS (方法2): R
t= 0.86 min;MS (ESIpos): m/z = 264 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.239 (1.89), 1.257 (4.04), 1.275 (1.87), 1.405 (16.00), 3.977 (0.99), 3.994 (1.01), 3.996 (1.06), 4.014 (0.90)。
將4-乙氧基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯(中間物51,26.9 g,102 mmol)溶解於THF (300 mL)中並冷卻至0℃。滴加氫化鋁鋰(82 ml,1.0 M於THF中,82 mmol)。在0℃下將該混合物攪拌45分鐘。TLC分析指示起始材料之完全消耗。滴加半飽和洛瑟耳(Rochelles)鹽水溶液。添加乙酸乙酯並在室溫下將該混合物攪拌1小時。過濾該懸浮液並分離有機相。水相用另外乙酸乙酯萃取。乾燥經組合之有機相並蒸發溶劑。將殘餘物溶解於CH
2Cl
2(350 mL)中並冷卻至0℃。滴加過氧化氫(10 ml,30%純度,100 mmol)。容許將該混合物升溫至室溫並攪拌0.5小時。將該混合物冷卻至0℃並緩慢添加Na
2S
2O
3溶液(10重量%)。在室溫下將該混合物攪拌5分鐘。將該有機相分離,過濾並蒸發溶劑。標題化合物藉由急驟管柱層析術於矽膠上使用CH
2Cl
2/EtOH (0%至10% EtOH)純化。獲得呈白色固體之標題化合物(21.6 g,97%產率)。
1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (s, 9 H) 1.63 - 1.88 (m, 2 H) 2.05 - 2.27 (m, 2 H) 3.00 - 3.26 (m, 2 H) 3.78 - 4.09 (m, 2 H) 6.21 - 7.59 (m, 1 H)。
向{(1R)-1-[3-(1,1-二氟-3,3-二甲基-2-側氧基丁基)-2-氟苯基]乙基}胺基甲酸三級丁酯(中間物50,1.24 g,3.32 mmol)於EtOH (15 ml)中之溶液添加NaBH
4(159 mg,4.21 mmol)並在室溫下將該混合物攪拌2 h。在0℃下將該混合物倒入飽和NH
4Cl水溶液中,用EtOAc萃取及有機相用鹽水清洗,經Na
2O
4乾燥,過濾並在減壓下濃縮。非對映異構體藉由急驟管柱層析術分離。
非對映異構體 1:411 mg (33%產率)
LC-MS (方法2): R
t= 1.37 min;MS (ESIpos): m/z = 393.6 [M+NH
4 +]
+
1H NMR (400 MHz, DMSO-d
6) δ ppm 7.59 (br d, 1 H), 7.49 (t, 1 H), 7.38 (br t, 1 H), 7.25 (t, 1 H), 5.61 (d, 1 H), 4.86 - 4.96 (m, 1 H), 3.66 - 3.77 (m, 1 H), 2.52 - 2.54 (m, 1 H), 1.37 (s, 9 H), 1.28 (d, 4 H), 0.97 - 1.23 (m, 2 H), 0.94 (s, 9 H), 0.73 - 0.87 (m, 1 H)。
非對映異構體 2:554 mg (44%產率)
LC-MS (方法2): R
t= 1.36 min;MS (ESIpos): m/z = 393.6 [M+NH
4 +]
+
1H NMR (400 MHz, DMSO-d
6) δ ppm 7.45 - 7.56 (m, 2 H), 7.36 (br t, 1 H), 7.17 - 7.29 (m, 1 H), 5.53 (d, 1 H), 4.91 (br t, 1 H), 3.66 - 3.77 (m, 1 H), 1.26 - 1.38 (m, 11 H), 1.07 - 1.22 (m, 2 H), 0.96 (s, 9 H)。
遵循GP 3:[(1R)-1-{3-[1,1-二氟-2-羥基-3,3-二甲基丁基]-2-氟苯基}乙基]胺基甲酸三級丁酯(中間物53 (非對映異構體1),409 mg,1.09 mmol)及TFA (1.3 ml,16 mmol)於DCM (7.0 ml)中產生標題化合物(626 mg),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 1.10 min;MS (ESIpos): m/z = 276 [M+H]
+
遵循一般程序3:[(1R)-1-{3-[1,1-二氟-2-羥基-3,3-二甲基丁基]-2-氟苯基}乙基]胺基甲酸三級丁酯(中間物53 (非對映異構體2),552 mg,1.47 mmol)及TFA (1.7 ml,22 mmol)於DCM (9.0 ml)中產生標題化合物(787 mg),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 1.08 min;MS (ESIpos): m/z = 276 [M+H]
+
遵循GP 6:1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-醇三氟乙酸(1/1) (中間物54,626 mg,1.09 mmol)、三乙基矽基三氟甲磺酸酯(1.2 ml,5.4 mmol)及2,6-二甲吡啶(880 µl)於DCM (7.0 ml)中產生標題化合物(702 mg),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 1.78 min;MS (ESIpos): m/z = 390 [M+H]
+
遵循一般程序5:1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-醇三氟乙酸(1/1) (中間物55,787 mg,1.47 mmol)、三乙基矽基三氟甲磺酸酯(1.7 ml,7.3 mmol)、2,6-二甲吡啶(1.2 ml)於DCM (10 ml)中產生標題化合物(786 mg),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 1.78 min;MS (ESIpos): m/z = 390 [M+H]
+
遵循一般程序2:(1R)-1-(3-{1,1-二氟-3,3-二甲基-2-[(三乙基矽基)氧基]丁基}-2-氟苯基)乙-1-胺(中間物56,702 mg,1.08 mmol)、6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(286 mg,1.19 mmol)、2,4,6-三(丙-2-基)苯-1-磺醯氯(394 mg,1.30 mmol)、Et
3N (380 µl)、DMAP (19.9 mg,163 µmol)於DMF (3.5 ml)中產生標題化合物(399 mg,60%產率)。
LC-MS (方法2): R
t= 1.89 min;MS (ESIpos): m/z = 611 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.382 (0.45), 0.399 (0.83), 0.419 (2.32), 0.434 (2.46), 0.440 (2.56), 0.453 (2.53), 0.459 (1.07), 0.473 (1.14), 0.491 (0.45), 0.814 (11.81), 0.820 (10.17), 0.831 (1.20), 0.839 (16.00), 0.847 (1.16), 0.859 (5.87), 1.154 (0.64), 1.172 (1.37), 1.190 (0.71), 1.583 (2.69), 1.600 (2.66), 1.987 (2.29), 2.331 (0.66), 2.388 (9.60), 2.518 (2.97), 2.523 (2.15), 2.673 (0.65), 4.017 (0.69), 4.035 (0.62), 4.047 (0.55), 5.746 (0.42), 5.763 (0.64), 5.782 (0.40), 7.261 (0.52), 7.280 (1.12), 7.299 (0.66), 7.446 (0.58), 7.676 (0.58), 8.670 (2.35), 8.809 (2.60), 8.847 (0.71), 8.865 (0.69)。
遵循一般程序2:(1R)-1-(3-{1,1-二氟-3,3-二甲基-2-[(三乙基矽基)氧基]丁基}-2-氟苯基)乙-1-胺(中間物57,786 mg,1.47 mmol)、6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(388 mg,1.62 mmol)、2,4,6-三(丙-2-基)苯-1-磺醯氯(534 mg,1.76 mmol)、Et
3N (510 µl)、DMAP (26.9 mg,220 µmol)於DMF (5.0 ml)中產生標題化合物(683 mg,76%產率)。
LC-MS (方法2): R
t= 1.89 min;MS (ESIpos): m/z = 611 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.323 (0.62), 0.342 (0.86), 0.360 (2.06), 0.369 (0.83), 0.380 (2.24), 0.389 (2.16), 0.400 (1.00), 0.409 (2.27), 0.428 (1.19), 0.447 (0.71), 0.795 (7.39), 0.807 (1.10), 0.815 (16.00), 0.824 (1.10), 0.835 (6.59), 0.850 (11.81), 1.154 (0.73), 1.172 (1.60), 1.190 (0.83), 1.591 (2.84), 1.609 (2.81), 1.987 (2.97), 2.361 (9.68), 2.518 (2.34), 2.523 (1.67), 4.017 (0.68), 4.035 (0.96), 4.072 (0.56), 5.630 (0.45), 5.648 (0.69), 5.666 (0.44), 7.237 (0.56), 7.256 (1.21), 7.275 (0.71), 7.432 (0.62), 7.641 (0.61), 8.699 (2.47), 8.802 (2.82), 8.915 (0.73), 8.933 (0.71)。
遵循一般程序3:6-溴-N-[(1R)-1-(3-{1,1-二氟-3,3-二甲基-2-[(三乙基矽基)氧基]丁基}-2-氟苯基)乙基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物58,197 mg,322 µmol)及TFA (500 µl)於DCM (3.0 ml)中產生標題化合物(162 mg,定量)。
LC-MS (方法2): R
t= 1.35 min;MS (ESIpos): m/z = 497 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.928 (16.00), 1.154 (1.39), 1.172 (3.14), 1.190 (1.63), 1.572 (3.80), 1.590 (3.78), 1.987 (5.39), 2.382 (0.46), 2.411 (13.54), 2.518 (2.04), 2.523 (1.45), 4.017 (1.23), 4.035 (1.23), 4.053 (0.40), 5.537 (1.83), 5.556 (1.82), 5.749 (0.61), 5.759 (6.90), 5.767 (0.94), 5.784 (0.58), 7.219 (0.68), 7.238 (1.51), 7.258 (0.88), 7.383 (0.52), 7.400 (0.83), 7.416 (0.40), 7.605 (0.45), 7.621 (0.80), 7.638 (0.41), 8.681 (3.21), 8.683 (3.31), 8.811 (3.75), 8.850 (0.98), 8.869 (0.96)。
遵循一般程序3:6-溴-N-[(1R)-1-(3-{1,1-二氟-3,3-二甲基-2-[(三乙基矽基)氧基]丁基}-2-氟苯基)乙基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物59,340 mg,556 µmol)及TFA (860 µl)於DCM (5.0 ml)中產生標題化合物(285 mg,定量)。
LC-MS (方法2): R
t= 1.34 min;MS (ESIpos): m/z = 497 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (10.60), 1.154 (1.12), 1.172 (2.25), 1.189 (1.06), 1.583 (2.52), 1.600 (2.50), 1.987 (3.85), 2.084 (16.00), 2.382 (8.95), 2.518 (0.89), 2.523 (0.62), 4.016 (0.79), 4.034 (0.76), 5.570 (1.00), 5.589 (0.99), 5.737 (0.56), 5.759 (1.82), 7.203 (0.46), 7.222 (1.01), 7.241 (0.60), 7.398 (0.55), 7.591 (0.53), 8.672 (2.13), 8.805 (2.45), 8.860 (0.61), 8.878 (0.59)。
遵循一般程序3:{(1R)-1-[3-(1,1-二氟-3,3-二甲基-2-側氧基丁基)-2-氟苯基]乙基}胺基甲酸三級丁酯(中間物50,200 mg,536 µmol)、TFA (410 µl,5.4 mmol)於DCM (4 ml)中產生標題化合物(284 mg)。
LC-MS (方法2): R
t= 1.20 min;MS (ESIpos): m/z = 274 [M+H]
+
遵循一般程序2:6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物32,141 mg,589 µmol)、1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-酮三氟乙酸(1/1) (中間物62,284 mg,535 µmol)、2,4,6-三(丙-2-基)苯-1-磺醯氯(195 mg,642 µmol)、Et
3N (220 µl,1.6 mmol)、DMAP (13.1 mg,107 µmol)及另外DIPEA (370 µl,2.1 mmol)於DMF (3 ml)中產生標題化合物(217 mg,74%產率)。
LC-MS (方法2): R
t= 144.00 min;MS (ESIpos): m/z = 495 [M+H]
+
1H NMR (400 MHz, DMSO-d
6) δ ppm 8.90 (d, 1 H), 8.81 (s, 1 H), 8.66 (d, 1 H), 7.70 (t, 1 H), 7.54 (t, 1 H), 7.30 - 7.38 (m, 1 H), 5.60 - 5.72 (m, 1 H), 2.52 - 2.54 (m, 2 H), 2.33 - 2.39 (m, 3 H), 1.58 (d, 3 H), 1.15 - 1.28 (m, 9 H), 0.73 (s, 1 H)。
向1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇鹽酸鹽(1/1) (500 mg,1.76 mmol)、Et
3N (980 µl,7.0 mmol)及DMAP (10.8 mg,0.088 mmol)於THF (50 ml)中之溶液添加2-苯并呋喃-1,3-二酮(313 mg,2.11 mmol)。在室溫下將該混合物攪拌整夜及然後加熱至70℃整夜。然後,在室溫下添加Ac
2O (170 µl,1.8 mmol)並將該混合物加熱至70℃歷時3天。該混合物用飽和NaHCO
3水溶液及鹽水清洗,經Na
2SO
4乾燥,過濾並在減壓下濃縮。藉由急驟管柱層析術純化產生標題化合物(584 mg,88%產率)。
LC-MS (方法2): R
t= 1.21 min;MS (ESIpos): m/z = 378 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.101 (7.88), 1.151 (7.99), 1.172 (2.27), 1.190 (1.14), 1.786 (6.84), 1.804 (6.76), 1.987 (3.89), 2.518 (2.26), 2.523 (1.58), 4.017 (0.90), 4.035 (0.89), 5.311 (9.06), 5.658 (0.42), 5.677 (1.47), 5.694 (1.44), 5.713 (0.41), 5.759 (1.22), 7.280 (0.84), 7.299 (2.09), 7.319 (1.40), 7.365 (0.86), 7.369 (0.98), 7.386 (1.33), 7.402 (0.61), 7.406 (0.57), 7.742 (0.72), 7.759 (1.30), 7.775 (0.66), 7.839 (1.58), 7.848 (16.00), 7.851 (8.12), 7.856 (1.47)。
向2-{(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]-乙基}-1H-異吲哚-1,3(2H)-二酮(中間物64,580 mg,1.54 mmol)於DMF (10 ml)中之溶液添加NaH (61.5 mg,60%純度,1.54 mmol)並在室溫下將該混合物攪拌30 min。添加碘甲烷(190 µl,3.1 mmol)並將該反應攪拌1 h。添加更多碘甲烷(190 µl,3.1 mmol)並在室溫下將該混合物攪拌整夜。在減壓下濃縮該混合物,將殘餘物溶解於DCM中,用鹽水清洗,經Na
2SO
4乾燥,過濾並在減壓下濃縮。藉由急驟管柱層析術純化產生標題化合物(443 mg,74%產率)。
LC-MS (方法2): R
t= 1.39 min;MS (ESIpos): m/z = 392 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.151 (7.38), 1.177 (7.28), 1.190 (0.91), 1.784 (6.43), 1.802 (6.39), 1.987 (1.73), 2.074 (1.51), 2.518 (5.25), 2.523 (3.51), 2.678 (0.40), 3.078 (16.00), 4.017 (0.41), 5.673 (1.28), 5.691 (1.25), 5.759 (2.25), 7.283 (0.72), 7.303 (1.86), 7.322 (1.29), 7.357 (0.80), 7.362 (0.95), 7.379 (1.20), 7.395 (0.55), 7.399 (0.50), 7.747 (0.61), 7.764 (1.13), 7.780 (0.58), 7.838 (1.39), 7.847 (13.01), 7.849 (12.83), 7.851 (7.10), 7.857 (1.46)。
向2-{(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}-1H-異吲哚-1,3(2H)-二酮(中間物65,440 mg,1.12 mmol)於EtOH (5.5 ml)及THF (5.5 ml)中之溶液添加水合肼(550 µl,11 mmol)並在室溫下將該混合物攪拌整夜。過濾所得懸浮液及殘餘物用EtOH/DCM清洗。將殘餘物溶解於DCM/H
2O中及有機相用飽和NaHCO
3水溶液、鹽水清洗,經Na
2SO
4乾燥,過濾,在減壓下濃縮並與濃縮濾液組合。藉由急驟管柱層析術純化產生標題化合物(270 mg,92%產率)。
LC-MS (方法2): R
t= 1.10 min;MS (ESIpos): m/z = 262 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.225 (15.13), 1.240 (15.59), 2.332 (0.42), 2.518 (1.96), 2.523 (1.37), 2.673 (0.41), 3.185 (16.00), 4.242 (0.44), 4.258 (1.39), 4.275 (1.37), 4.291 (0.43), 7.214 (0.53), 7.233 (1.74), 7.251 (2.39), 7.255 (2.00), 7.265 (1.15), 7.270 (1.36), 7.285 (0.55), 7.290 (0.42), 7.688 (0.53), 7.694 (0.62), 7.705 (1.02), 7.711 (1.05), 7.723 (0.56), 7.728 (0.56)。
遵循一般程序2:6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物32,205 mg,854 µmol)、(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙-1-胺(中間物66,268 mg,1.02 mmol)、2,4,6-三(丙-2-基)苯-1-磺醯氯(284 mg,939 µmol)、Et
3N (360 µl,2.6 mmol)、DMAP (20.9 mg,171 µmol)於DMF (3.0 ml)中產生標題化合物(285 mg,69%產率)。
LC-MS (方法2): R
t= 1.39 min;MS (ESIpos): m/z = 483 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.171 (0.71), 1.247 (5.99), 1.255 (6.17), 1.572 (4.29), 1.589 (4.32), 1.987 (0.99), 2.332 (0.46), 2.370 (16.00), 2.518 (2.44), 2.523 (1.71), 2.673 (0.47), 3.174 (12.80), 3.349 (0.96), 5.704 (0.65), 5.722 (1.03), 5.740 (0.65), 7.202 (0.60), 7.221 (1.45), 7.240 (0.97), 7.291 (0.58), 7.295 (0.68), 7.312 (0.91), 7.328 (0.44), 7.590 (0.50), 7.606 (0.87), 7.622 (0.45), 8.678 (3.74), 8.805 (4.39), 8.877 (1.04), 8.895 (1.00)。
將1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇鹽酸鹽(1/1) (2.00 g,7.05 mmol)溶解於CH2Cl2 (40 mL)中並在氬氣氛下冷卻至0℃。添加二甲吡啶(5.7 ml)並將所得混合物攪拌5分鐘。滴加三級丁基(二甲基)矽基三氟甲磺酸酯(6.5 ml,28 mmol)並容許整夜將該混合物緩慢升溫至室溫。添加飽和NaHCO3水溶液並將該混合物攪拌10分鐘。將有機相分離並乾燥。在高溫下蒸發溶劑。添加甲苯並再次蒸發該溶劑。標題化合物藉由急驟管柱層析術於矽膠上純化以產生標題化合物(2.07 g,81%產率)。
LC-MS (方法2): R
t= 1.65 min;MS (ESIpos): m/z = 363 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.013 (0.48), 0.766 (1.23), 0.773 (16.00), 0.780 (0.95), 0.839 (1.21), 1.222 (2.07), 1.238 (2.05), 1.316 (3.78), 2.518 (0.79), 2.523 (0.53), 7.229 (0.50), 7.248 (0.42)。
6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物32,200 mg,833 µmol)及(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟-2-甲基丙基)-2-氟苯基]-乙-1-胺(中間物68,452 mg,1.25 mmol)溶解於DMF (6.4 mL)中。添加PyBop (564 mg,1.08 mmol),接著添加DBU (500 µl,3.3 mmol)並在室溫下將所得混合物攪拌一夜。添加乙酸乙酯。有機相用水(兩次)及鹽水清洗並乾燥。蒸發溶劑。標題化合物藉由急驟管柱層析術於矽膠上純化以產生標題化合物(330 mg,68%產率)。
LC-MS (方法2): R
t= 1.79 min;MS (ESIpos): m/z = 586 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.804 (1.02), 0.811 (16.00), 0.819 (0.90), 1.249 (0.87), 1.267 (1.83), 1.285 (0.89), 1.434 (2.40), 1.668 (1.48), 1.685 (1.48), 2.083 (3.06), 2.455 (5.25), 2.614 (0.63), 2.618 (0.44), 4.112 (0.67), 4.130 (0.65), 7.310 (0.51), 8.771 (1.25), 8.773 (1.27), 8.897 (1.48)。
在室溫下將6-溴-N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)-乙基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物69,400 mg,685 µmol)溶解於CH2Cl2 (6 mL)中。添加三乙基矽烷(11 µl,69 µmol),接著滴加三氟乙酸(790 µl,10 mmol)。在室溫下將所得混合物攪拌一夜。添加甲苯並蒸發溶劑。標題化合物藉由急驟管柱層析術於矽膠上純化以產生標題化合物(340 mg,106%產率)。
LC-MS (方法2): R
t= 1.21 min;MS (ESIpos): m/z = 471 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.201 (9.34), 1.221 (9.52), 1.599 (6.66), 1.616 (6.61), 2.442 (16.00), 2.518 (6.01), 2.523 (3.93), 3.165 (6.91), 4.016 (0.42), 4.035 (0.41), 5.759 (8.13), 5.770 (1.06), 5.788 (1.58), 5.806 (1.01), 7.228 (1.02), 7.247 (2.42), 7.266 (1.56), 7.331 (1.09), 7.348 (1.57), 7.363 (0.73), 7.614 (0.88), 7.631 (1.55), 7.646 (0.78), 8.744 (4.93), 8.845 (6.52)。
將6-氯-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物32,5.00 g,25.6 mmol)及肆(4.68 g,5.11 mmol)溶解於乙腈(130 mL)中。添加三乙胺(12 ml,89 mmol),接著添加二甲基-λ
5-膦酮(2.00 g,25.6 mmol)。將該混合物加熱至90℃歷時48小時。形成之固體藉由過濾收集並用MTBE清洗以產生呈淺灰色固體之標題化合物(6.68 g,82%純度,90%產率)。
LC-MS (方法1): R
t= 0.50 min;MS (ESIpos): m/z = 238 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.103 (3.14), 1.675 (15.74), 1.708 (16.00), 2.075 (0.76), 2.426 (14.14), 2.518 (2.02), 2.523 (1.48), 3.073 (1.07), 8.385 (1.83), 8.388 (1.88), 8.400 (1.88), 8.402 (1.79), 9.108 (3.17)。
在室溫下在氮氣氛下將[(1R)-1-(3-{1,1-二氟-2-[甲氧基(甲基)胺基]-2-側氧基乙基}-2-氟苯基)乙基]胺基甲酸三級丁酯(中間物31,501 mg,1.33 mmol)溶解於THF (15 mL)中。緩慢添加乙基溴化鎂溶液(1.2 ml,3.2 M,4.0 mmol)並在室溫下將該混合物攪拌3小時。添加飽和NH
4Cl水溶液。該混合物用乙酸乙酯萃取。經組合之有機相用鹽水清洗。乾燥該有機相並蒸發溶劑以產生呈黃色油之標題化合物(440 mg,96%產率)。
LC-MS (方法2): R
t= 1.34 min;MS (ESIpos): m/z = 363 [M+NH
4]
+
將{(1R)-1-[3-(1,1-二氟-2-側氧基丁基)-2-氟苯基]乙基}胺基甲酸三級丁酯(2.76 g,7.99 mmol)溶解於乙醇(31 mL)中。將氣氛交換為氬並將該混合物冷卻至0℃。分批添加硼氫化鈉(453 mg,12.0 mmol)。容許將該混合物升溫至室溫。將該混合物添加至半飽和NH4Cl水溶液。及在室溫下攪拌1小時。該混合物用乙酸乙酯萃取。經組合之有機相用鹽水清洗。將該有機相分離,乾燥並蒸發溶劑以產生無色油。標題化合物藉由HPLC分離純化以產生無色油(1.09 g,39%產率)。
LC-MS (方法2): R
t= 1.24 min;MS (ESIpos): m/z = 365 [M+NH
4]
+
中間物72之兩種非對映異構體藉由對掌性HPLC分離。
分析方法:儀器:Agilent:1260, Aurora SFC-Modul;管柱:Chiralpak IG 3 µ 100x4.6 mm;溶析液A:CO2;溶析液B:甲醇+ 0.2體積%氨水(32%);等度:7%B;梯度:無;流量:4 ml/min;溫度:37.5℃;BPR:100 bar;UV:262 nm
製備方法:SFC
儀器:Sepiatec:Prep SFC100;管柱:Chiralpak IG 5 µ 250x30 mm;溶析液A:CO2;溶析液B:甲醇;等度:7%B;梯度:無;流量:100 ml/min;溫度:40℃;BPR:150 bar;UV:262 nm
中間物 73[(1R)-1-{3-[1,1-二氟-2-羥基丁基]-2-氟苯基}乙基]胺基甲酸三級丁酯(非對映異構體1)
中間物72之非對映異構體1:
Rt (分析方法) = 0.80 min
中間物 75[(1R)-1-{3-[1,1-二氟-2-羥基丁基]-2-氟苯基}乙基]胺基甲酸三級丁酯(非對映異構體2)
中間物72之非對映異構體2:
Rt (分析方法) = 1.17 min
在室溫下將[(1R)-1-{3-[1,1-二氟-2-羥基丁基]-2-氟苯基}乙基]胺基甲酸三級丁酯(中間物74,549 mg,1.58 mmol)溶解於CH
2Cl
2(5 mL)中。添加三氟乙酸(2.0 ml,26 mmol)並在室溫下將該混合物攪拌3小時。添加甲苯並蒸發溶劑以產生無色油(615 mg),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 0.90 min;MS (ESIpos): m/z = 248 [M+H]
+
將[(1R)-1-{3-[1,1-二氟-2-羥基丁基]-2-氟苯基}乙基]胺基甲酸三級丁酯(中間物75,692 mg,1.99 mmol)溶解於CH
2Cl
2(5 mL)中。添加三氟乙酸(2.0 ml,26 mmol)並在室溫下將該混合物攪拌3小時。將甲苯添加至該混合物並蒸發溶劑以產生呈無色油之標題化合物(859 mg),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 0.88 min;MS (ESIpos): m/z = 248 [M+H]
+
將1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟丁-2-醇三氟乙酸(1/1) (中間物76,615 mg,1.70 mmol)溶解於CH
2Cl
2(7.6 mL)中並添加2,6-二甲吡啶(1.4 mL)。在室溫下將該混合物攪拌10分鐘。滴加三乙基矽基三氟甲磺酸酯(2.25 g,8.51 mmol)並在室溫下在氮氣氛下將所得混合物攪拌6小時。添加飽和NaHCO
3水溶液。分離相並乾燥有機相及蒸發溶劑。添加甲苯並再次蒸發該溶劑。重複此步驟。標題化合物藉由急驟管柱層析術於矽膠上使用己烷/乙酸乙酯(9/1至0/10)作為溶析液純化。獲得呈淺黃色油之標題化合物(387 mg,63%產率)。
LC-MS (方法2): R
t= 1.66 min;MS (ESIpos): m/z = 362.5 [M+H]
+
將1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟丁-2-醇三氟乙酸(1/1) (中間物77,859 mg,2.38 mmol)溶解於CH
2Cl
2(11 mL)中。添加2,6-二甲吡啶(1.9 mL)。滴加三乙基矽基三氟甲磺酸酯(3.14 g,11.9 mmol)並在室溫下在氮氣氛下將該混合物攪拌6小時。添加飽和NaHCO
3水溶液並將該混合物攪拌10分鐘。將有機相分離並乾燥。蒸發溶劑。添加甲苯並蒸發溶劑。再次重複該步驟。標題化合物藉由急驟管柱層析術於矽膠上使用己烷/乙酸乙酯(9/1至0/10)作為溶析液純化。獲得呈淺黃色油之標題化合物(466 mg,54%產率)。
LC-MS (方法2): R
t= 1.63 min;MS (ESIpos): m/z = 362.9 [M+H]
+
在氬下將正丁基鋰(1.6 ml,2.5 M,4.0 mmol)稀釋於THF (4 mL)中並冷卻至-78℃及攪拌15分鐘。將[(1R)-1-(3-{1,1-二氟-2-[甲氧基(甲基)胺基]-2-側氧基乙基}-2-氟苯基)乙基]胺基甲酸三級丁酯(中間物31,500 mg,1.33 mmol)溶解於THF (4 mL)中並添加至此溶液。在-78℃下將該混合物攪拌1小時及然後容許整夜緩慢升溫至室溫。滴加飽和NH4Cl水溶液。該混合物用乙酸乙酯萃取兩次。經組合之有機相用鹽水清洗。乾燥該有機相並蒸發溶劑。標題化合物藉由急驟管柱層析術於矽膠上純化。獲得該標題化合物(300 mg,60%產率)。
LC-MS (方法2): R
t= 1.72 min;MS (ESIpos): m/z = 490 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.818 (5.29), 0.836 (13.01), 0.854 (6.33), 1.154 (0.98), 1.212 (0.67), 1.230 (1.83), 1.248 (2.89), 1.253 (1.78), 1.265 (8.18), 1.282 (7.11), 1.305 (0.92), 1.349 (16.00), 1.488 (0.69), 1.505 (1.88), 1.525 (2.29), 1.543 (1.66), 1.560 (0.50), 2.073 (0.65), 2.327 (0.63), 2.331 (0.45), 2.518 (2.99), 2.523 (1.95), 2.669 (0.63), 2.673 (0.45), 2.784 (1.93), 2.801 (3.60), 2.819 (1.77), 4.841 (0.51), 4.859 (0.69), 4.876 (0.47), 7.355 (0.79), 7.374 (1.80), 7.394 (1.12), 7.534 (0.96), 7.551 (1.56), 7.571 (1.07), 7.578 (0.95), 7.595 (1.42), 7.610 (1.61), 7.628 (0.74)。
在氬氣氛下將{(1R)-1-[3-(1,1-二氟-2-側氧基己基)-2-氟苯基]乙基}胺基甲酸三級丁酯(中間物80,297 mg,795 µmol)溶解於THF (12 mL)中並冷卻至0℃。滴加甲基溴化鎂溶液(700 µl,3.4 M,2.4 mmol)。在0℃下將該混合物攪拌30分鐘及然後容許整夜緩慢升溫至室溫。將該混合物冷卻至0℃並緩慢添加飽和NH
4Cl水溶液。該混合物用乙酸乙酯萃取兩次。經組合之有機相用鹽水清洗。乾燥該有機相並蒸發溶劑。標題化合物藉由急驟管柱層析術於矽膠上純化。獲得該標題化合物(278 mg,90%產率)。
LC-MS (方法2): R
t= 1.40 min;MS (ESIpos): m/z = 407 [M+H]+NH3
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.834 (1.53), 0.841 (1.59), 0.852 (4.39), 0.859 (2.93), 0.869 (2.28), 0.876 (1.42), 1.116 (3.42), 1.132 (3.59), 1.154 (0.68), 1.172 (1.35), 1.190 (1.01), 1.232 (1.31), 1.250 (1.90), 1.267 (5.23), 1.284 (4.60), 1.359 (16.00), 1.421 (0.51), 1.461 (0.92), 1.482 (0.74), 1.987 (1.03), 2.518 (2.06), 2.523 (1.39), 4.879 (0.48), 4.897 (0.65), 4.915 (0.44), 5.176 (3.63), 5.185 (2.26), 5.758 (5.62), 7.220 (0.60), 7.239 (1.59), 7.258 (1.29), 7.284 (0.93), 7.299 (1.19), 7.316 (0.51), 7.465 (0.69), 7.480 (1.21), 7.497 (0.65), 7.528 (0.50), 7.538 (0.62), 7.547 (0.60), 7.558 (0.52)。
在氬氣氛下在室溫下將[(1R)-1-{3-[(2RS)-1,1-二氟-2-羥基-2-甲基己基]-2-氟苯基}乙基]胺基甲酸三級丁酯(50.0 mg,128 µmol)溶解於CH
2Cl
2(1 mL)中。添加三氟乙酸(99 µl,1.3 mmol)並在室溫下將該混合物攪拌整夜。添加甲苯並蒸發溶劑。再次添加甲苯並蒸發溶劑以產生標題化合物(64.0 mg),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 1.14 min;MS (ESIpos): m/z = 290 [M+H]
+
遵循一般程序4:[(1R)-1-(3-{1,1-二氟-2-[甲氧基(甲基)胺基]-2-側氧基乙基}-2-氟苯基)乙基]胺基甲酸三級丁酯(中間物31,2.76 g,7.34 mmol)及氯(丙-2-基)鎂(11 ml,2.0 M,22 mmol)反應5 h以產生呈油之標題化合物(773 mg,29%產率)。
LC-MS (方法2): R
t= 1.38 min;MS (ESIneg): m/z = 358.5 (M-H)
-.
1H NMR (400 MHz,氯仿-d) δ ppm 1.14 - 1.63 (m, 22 H), 3.20 - 3.38 (m, 1 H), 4.81 - 5.07 (m, 2 H), 7.18 - 7.25 (m, 1 H), 7.39 - 7.47 (m, 1 H), 7.48 - 7.57 (m, 1 H)。
遵循一般程序3:{(1R)-1-[3-(1,1-二氟-3-甲基-2-側氧基丁基)-2-氟苯基]乙基}胺基甲酸三級丁酯(中間物83,288 mg,801 µmol)及TFA (620 µl,8.0 mmol)呈油之產生標題化合物(312 mg,定量),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 1.17 min;MS (ESIpos): m/z = 260.4 [M+H]
+.
遵循一般程序2:6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(204 mg,852 µmol)、三氟乙酸/1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-酮(1/1) (289 mg,774 µmol)、2,4,6-三(丙-2-基)苯-1-磺醯氯(281 mg,929 µmol)、DMAP (18.9 mg,155 µmol)及另外DIPEA (540 µl,3.1 mmol)於DMF (3.0 ml)中在藉由急驟管柱層析術(己烷/EtOAc)純化後產生呈白色固體之標題化合物(259.0 mg,63%)。
LC-MS (方法2): R
t= 1.38 min;MS (ESIpos): m/z = 481.5, 483.4 [M+H]
+
將{(1R)-1-[3-(1,1-二氟-3-甲基-2-側氧基丁基)-2-氟苯基]乙基}胺基甲酸三級丁酯(中間物85,5.96 g,16.6 mmol)溶解於乙醇(65 mL)中。將氣氛交換為氬並將該混合物冷卻至0℃。分批添加NaBH
4(942 mg,24.9 mmol)。容許將該混合物升溫至室溫。將該混合物添加至半飽和NH
4Cl水溶液並在室溫下攪拌1小時。該混合物用乙酸乙酯萃取。經組合之有機相用鹽水清洗。將該有機相分離,乾燥並蒸發溶劑以產生無色油。標題化合物藉由HPLC分離純化以產生無色油(3.37 g,56%產率)。
兩種非對映異構體藉由對掌性HPLC分離。獲得作為第一溶析異構體之非對映異構體1。
LC-MS (方法2): R
t= 1.28 min;MS (ESIpos): m/z = 379.6 [M+NH
4]
+
在分離中間物86之兩種非對映異構體後,獲得作為第二溶析異構體之非對映異構體2。
LC-MS (方法2): R
t= 1.26 min;MS (ESIpos): m/z = 379.6 [M+NH
4]
+
在室溫下將[(1R)-1-{3-[1,1-二氟-2-羥基-3-甲基丁基]-2-氟苯基}乙基]-胺基甲酸三級丁酯(中間物86,286 mg,791 µmol)溶解於CH
2Cl
2(5 mL)中。添加三氟乙酸(2.0 ml,26 mmol)並在室溫下將該混合物攪拌3小時。添加甲苯並蒸發溶劑以產生呈無色油之標題化合物(295 mg,99%產率)。
LC-MS (方法2): R
t= 1.01 min;MS (ESIpos): m/z = 262.6 [M+H]
+
在室溫下將[(1R)-1-{3-[1,1-二氟-2-羥基-3-甲基丁基]-2-氟苯基}乙基]-胺基甲酸三級丁酯(中間物87,297 mg,822 µmol)溶解於CH
2Cl
2(5 mL)中。添加三氟乙酸(2.0 ml,26 mmol)並將該混合物攪拌3小時。添加甲苯並蒸發溶劑以產生無色油(339 mg),其無需進一步純化即可使用。
LC-MS (方法2): R
t= 0.99 min;MS (ESIpos): m/z = 262.6 [M+H]
+
將1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-醇三氟乙酸(1/1) (中間物88,295 mg,786 µmol)溶解於CH
2Cl
2(3.5 mL)中並添加2,6-二甲吡啶(0.64 mL)。在室溫下將該混合物攪拌10分鐘。滴加三乙基矽基三氟甲磺酸酯(1.04 g,3.93 mmol)並在室溫下在氮氣氛下將所得混合物攪拌6小時。添加飽和NaHCO
3水溶液。分離相並乾燥有機相及蒸發溶劑。添加甲苯並再次蒸發該溶劑。重複此步驟。標題化合物藉由急驟管柱層析術於矽膠上使用己烷/乙酸乙酯(9/1至0/10)作為溶析液純化。獲得呈淺黃色油之標題化合物(197 mg,67%產率)。
LC-MS (方法2): R
t= 1.73 min;MS (ESIpos): m/z = 376.9 [M+H]
+
將1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-醇三氟乙酸(1/1) (中間物89,339 mg,903 µmol)溶解於CH
2Cl
2(4 mL)中並添加二甲吡啶(0.74 mL)。在室溫下將該混合物攪拌10分鐘。滴加三乙基矽基三氟甲磺酸酯(1.19 g,4.52 mmol)並在室溫下在氮氣氛下將所得混合物攪拌6小時。添加飽和NaHCO
3水溶液。分離相並乾燥有機相及蒸發溶劑。添加甲苯並再次蒸發該溶劑。重複此步驟。標題化合物藉由急驟管柱層析術於矽膠上使用己烷/乙酸乙酯(9/1至0/10)作為溶析液純化。獲得呈淺黃色油之標題化合物(201 mg,59%產率)。
LC-MS (方法2): R
t= 1.72 min;MS (ESIpos): m/z = 376.8 [M+H]
+
在-78℃下向[(1R)-1-(3-{1,1-二氟-2-[甲氧基(甲基)胺基]-2-側氧基乙基}-2-氟苯基)乙基]胺基甲酸三級丁酯(500 mg,1.33 mmol)於THF (8.0 ml)中之溶液滴加丁基鋰(1.6 ml,2.5 M,4.0 mmol)。在-78℃下將該反應攪拌1 h並容許整夜升溫至室溫。該反應藉由添加氯化銨水溶液淬滅。該混合物用乙酸乙酯萃取兩次,有機相用飽和氯化鈉水溶液清洗,經硫酸鈉乾燥並濃縮。粗產物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以產生標題化合物(300 mg,95%純度,60%產率)。
LC-MS (方法2): R
t= 1.72 min;MS (ESIpos): m/z = 490 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.818 (5.29), 0.836 (13.01), 0.854 (6.33), 1.154 (0.98), 1.212 (0.67), 1.230 (1.83), 1.248 (2.89), 1.253 (1.78), 1.265 (8.18), 1.282 (7.11), 1.305 (0.92), 1.349 (16.00), 1.488 (0.69), 1.505 (1.88), 1.525 (2.29), 1.543 (1.66), 1.560 (0.50), 2.073 (0.65), 2.327 (0.63), 2.331 (0.45), 2.518 (2.99), 2.523 (1.95), 2.669 (0.63), 2.673 (0.45), 2.784 (1.93), 2.801 (3.60), 2.819 (1.77), 4.841 (0.51), 4.859 (0.69), 4.876 (0.47), 7.355 (0.79), 7.374 (1.80), 7.394 (1.12), 7.534 (0.96), 7.551 (1.56), 7.571 (1.07), 7.578 (0.95), 7.595 (1.42), 7.610 (1.61), 7.628 (0.74)。
在0℃下向{(1R)-1-[3-(1,1-二氟-2-側氧基己基)-2-氟苯基]乙基}胺基甲酸三級丁酯(中間物92,297 mg,795 µmol)於THF (8.0 ml)中之溶液滴加溴(甲基)鎂(700 µl,3.4 M,2.4 mmol)。在0℃下將該反應攪拌30 min並容許整夜升溫至室溫。將該反應再次冷卻至0℃並藉由添加氯化銨水溶液淬滅。該混合物用乙酸乙酯萃取兩次,有機相用飽和氯化鈉水溶液清洗,經硫酸鈉乾燥並濃縮。粗產物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以產生標題化合物(300 mg,95%純度,60%產率)。
LC-MS (方法2): R
t= 1.40 min;MS (ESIpos): m/z = 407 [M+H]+NH3
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.834 (1.53), 0.841 (1.59), 0.852 (4.39), 0.859 (2.93), 0.869 (2.28), 0.876 (1.42), 1.116 (3.42), 1.132 (3.59), 1.154 (0.68), 1.172 (1.35), 1.190 (1.01), 1.232 (1.31), 1.250 (1.90), 1.267 (5.23), 1.284 (4.60), 1.359 (16.00), 1.421 (0.51), 1.461 (0.92), 1.482 (0.74), 1.987 (1.03), 2.518 (2.06), 2.523 (1.39), 4.879 (0.48), 4.897 (0.65), 4.915 (0.44), 5.176 (3.63), 5.185 (2.26), 5.758 (5.62), 7.220 (0.60), 7.239 (1.59), 7.258 (1.29), 7.284 (0.93), 7.299 (1.19), 7.316 (0.51), 7.465 (0.69), 7.480 (1.21), 7.497 (0.65), 7.528 (0.50), 7.538 (0.62), 7.547 (0.60), 7.558 (0.52)。
向[(1R)-1-{3-[(2RS)-1,1-二氟-2-羥基-2-甲基己基]-2-氟苯基}乙基]胺基甲酸三級丁酯(中間物93,50.0 mg,128 µmol)於二氯甲烷(1.0 ml)中之溶液添加三氟乙酸(99 µl,1.3 mmol)並在室溫下將該混合物攪拌整夜。然後向該混合物兩次添加甲苯並濃縮該混合物。粗產物用於下一反應中。
LC-MS (方法2): R
t= 1.14 min;MS (ESIpos): m/z = 290 [M+H]
+
使用一般方法1,自(1RS)-1-[2-(三氟甲基)吡啶-4-基]乙-1-胺(310 mg,1.63 mmol)及6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物32,587 mg,2.45 mmol)開始,產生標題化合物469 mg (95%純度,66%產率)。
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.151 (0.63), 1.169 (1.23), 1.187 (0.59), 1.609 (5.87), 1.627 (5.96), 1.985 (2.66), 2.381 (16.00), 2.518 (1.00), 2.522 (0.67), 4.014 (0.55), 4.032 (0.54), 5.556 (0.67), 5.574 (1.04), 5.591 (0.68), 7.747 (1.29), 7.760 (1.33), 7.984 (2.58), 8.622 (3.74), 8.692 (2.07), 8.704 (1.99), 8.819 (3.71), 8.889 (1.04), 8.906 (1.02)。
中間物 966-溴-2-甲基-N-{(1S*)-1-[2-(三氟甲基)吡啶-4-基]乙基}吡啶并[3,4-d]嘧啶-4-胺(對映異構體1)
中間物95之對映異構體藉由對掌性HPLC分離:
分析方法:
儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SC 3 μ,100x4.6;溶析液A:己烷+ 0.1體積%二乙胺;溶析液B:乙醇;等度:80%A+20%B;流量:1.4 ml/min;溫度:25℃;UV:280 nm
製備方法:
儀器:PrepCon Labomatic HPLC-2;管柱:YMC Cellulose SC 10 μ,250x50;溶析液A:己烷+ 0.1體積%二乙胺;溶析液B:乙醇;等度:80%A+20%B;流量:90 ml/min;溫度:25℃;UV:280 nm
R
t(分析方法)對映異構體1:1.66 min
中間物 976-溴-2-甲基-N-{(1R*)-1-[2-(三氟甲基)吡啶-4-基]乙基}吡啶并[3,4-d]嘧啶-4-胺(對映異構體2)
中間物95之對映異構體藉由對掌性HPLC分離:
分析方法:
儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SC 3 μ,100x4.6;溶析液A:己烷+ 0.1體積%二乙胺;溶析液B:乙醇;等度:80%A+20%B;流量:1.4 ml/min;溫度:25℃;UV:280 nm
製備方法:
儀器:PrepCon Labomatic HPLC-2;管柱:YMC Cellulose SC 10 μ,250x50;溶析液A:己烷+ 0.1體積%二乙胺;溶析液B:乙醇;等度:80%A+20%B;流量:90 ml/min;溫度:25℃;UV:280 nm
R
t(分析方法)對映異構體1: 2.59 min
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.082 (0.49), 1.258 (0.70), 1.609 (4.88), 1.627 (4.92), 2.382 (16.00), 2.518 (1.19), 2.523 (0.83), 5.557 (0.65), 5.575 (1.01), 5.592 (0.65), 7.748 (1.05), 7.761 (1.08), 7.985 (2.13), 8.623 (3.57), 8.692 (1.69), 8.705 (1.63), 8.823 (4.02), 8.889 (1.00), 8.907 (0.97)。
在室溫下將3-胺基-2-溴-6-氯-4-吡啶羧酸(CAS 1073182-69-0,67 g,85%純度,226.5 mmol)添加至乙酸酐(700 ml)。然後在100℃下將該反應加熱16 h。濃縮該反應混合物且殘餘物直接用於下一步驟。
在120℃下將8-溴-6-氯-2-甲基-4H-吡啶并[3,4-d][1,3]噁嗪-4-酮(70 g,79%純度,200.8 mmol)及乙酸銨(中間物98,61.9 g,802 mmol)於2-甲氧基乙醇(700 ml)中之溶液攪拌16 h。然後濃縮該反應混合物並將殘餘物添加至水及在室溫下攪拌30 min。將該混合物過濾並濃縮以產生呈棕色固體之標題化合物,其直接用於下一反應。
在室溫下向8-溴-6-氯-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物99,12 g,91%純度,39.7 mmol)及(4-甲氧基苯基)甲醇(11.0 g,79.6 mmol)於二甲基亞碸中之溶液添加氫氧化鉀。在80℃下將該反應混合物攪拌16 h。將該溶液冷卻至室溫,倒入水中並沈澱黃色固體。過濾該混合物以產生粗固體。將該固體添加至石油醚/乙酸乙酯(1:1)之混合物並在室溫下攪拌30 min。過濾該混合物並在減壓下由油泵乾燥以產生呈棕色固體之6-氯-8-[(4-甲氧基苄基)氧基]-2-甲基吡啶并[3,4-d]嘧啶-4-醇。將該固體添加至乙腈(70 ml)並在70℃下再結晶30 min。過濾該混合物在減壓下由油泵乾燥以產生棕色固體(9.10 g,90%純度,62%產率)。
LC-MS (方法1): R
t= 1.08 min;MS (ESIneg): m/z = 330 [M-H]
-
中間物 1016-氯-N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-8-[(4-甲氧基苯基)甲氧基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺
使用一般方法1,自(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙-1-胺(中間物48,783 mg,2.17 mmol)及6-氯-8-[(4-甲氧基苯基)甲氧基]-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物100,599 mg,1.80 mmol)開始,獲得呈黃色油之標題化合物(590 mg,48%產率)。
LC-MS (方法2): R
t= 1.88 min;MS (ESIpos): m/z = 675.6 [M+H]
+
中間物 102N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-6-(二甲基磷醯基)-8-[(4-甲氧基苯基)甲氧基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺
向6-氯-N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-8-[(4-甲氧基苯基)甲氧基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物101,300 mg,444 µmol)之溶液,添加肆(三苯基膦)鈀(0) (77.0 mg,66.6 µmol),接著添加乙腈(5 mL)、三乙胺(220 µl,1.6 mmol)及二甲基-λ
5-膦酮(34.7 mg,444 µmol)。將氣氛交換為氬並將小瓶密封及加熱至90℃歷時24 h。蒸發溶劑,及殘餘物藉由急驟層析術(二氧化矽、二氯甲烷、甲醇)純化以獲得呈無色油之標題化合物(208 mg,65%產率)。
LC-MS (方法2): R
t= 1.73 min;MS (ESIpos): m/z = 717.9 [M+H]
+
在130℃(回流)下將5-胺基-2-溴吡啶-4-羧酸(640 mg,2.95 mmol)及三氟乙脒胺(583 mg,85%純度,4.42 mmol)於2-甲氧基乙醇(9.6 ml)中之溶液攪拌整夜。將該混合物冷卻至室溫,濃縮,及殘餘物藉由急驟層析術(二氧化矽、二氯甲烷、甲醇)純化以產生呈棕色固體之標題化合物(809 mg,99%純度,93%產率)。
LC-MS (方法1): R
t= 0.92 min;MS (ESIpos): m/z = 296 [M+H]
+
向6-溴-2-(三氟甲基)吡啶并[3,4-d]嘧啶-4(3H)-酮(中間物103,314 mg,1.07 mmol)於1,2-二氯乙烷(2.9 ml)中之懸浮液添加3滴DMF亞硫醯氯(230 µl,3.2 mmol),隨後,及在100℃下將該混合物攪拌3 h。然後將該混合物冷卻,濃縮,及殘餘物藉由急驟層析術(二氧化矽、二氯甲烷、甲醇)純化以產生呈黃色油之標題化合物(311 mg,94%純度,88%產率)。
LC-MS (方法1): R
t= 1.27 min;MS (ESIpos): m/z = 310.9 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.518 (3.31), 2.523 (2.19), 8.077 (0.65), 8.079 (0.63), 8.188 (15.97), 8.190 (16.00), 9.030 (12.25), 9.032 (12.35), 9.063 (0.46), 9.065 (0.44)。
隨後向6-溴-4-氯-2-(三氟甲基)吡啶并[3,4-d]嘧啶(中間物105,208 mg,666 µmol)於N,N-二甲基乙醯胺(2.7 ml)中之溶液添加三乙胺(240 µl,1.7 mmol)及(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙-1-胺鹽酸鹽(1/1) (168 mg,699 µmol),並在室溫下將該混合物攪拌整夜。濃縮粗化合物且殘餘物經過急驟層析術(二氧化矽、己烷、乙酸乙酯)以產生呈深黃色固體之標題化合物(317 mg,99%純度,99%產率)。
LC-MS (方法1): R
t= 1.55 min;MS (ESIpos): m/z = 481 [M+H]
+
如針對中間物103描述,自5-胺基-2-溴吡啶-4-羧酸(139 mg,638 µmol)及二氟乙脒胺鹽酸鹽(1/1) (100 mg,766 µmol)開始,獲得標題化合物。
LC-MS (方法1): R
t= 0.78 min;MS (ESIpos): m/z = 276 [M+H]
+
如針對中間物104描述,自6-溴-2-(二氟甲基)吡啶并[3,4-d]嘧啶-4(3H)-酮(中間物106,114 mg,413 µmol)及亞硫醯氯(90 µl,1.2 mmol)開始,獲得標題化合物。
LC-MS (方法1): R
t= 1.14 min;MS (ESIpos): m/z = 296 [M+H]
+
向6-溴-4-氯-2-(二氟甲基)吡啶并[3,4-d]嘧啶(中間物107,113 mg,384 µmol)於N,N-二甲基乙醯胺(1.5 ml)中之溶液添加三乙胺(140 µl,1000 µmol),接著添加(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙-1-胺鹽酸鹽(1/1) (101 mg,422 µmol),並在室溫下將該混合物攪拌整夜。濃縮該混合物及殘餘物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以產生呈白色固體之標題化合物(142 mg,94%純度,75%產率)。
LC-MS (方法1): R
t= 1.45 min;MS (ESIpos): m/z = 463 [M+H]
+
在170℃下將5-胺基-2-溴吡啶-4-羧酸(488 mg,2.25 mmol)及脲(540 mg,8.99 mmol)之混合物攪拌整夜。然後冷卻,用水稀釋並加熱至回流歷時40 min。在冷卻至室溫後,標題化合物部分沈澱(214 mg,58%純度,23%產率)並藉由過濾收集。濃縮濾液並藉由急驟層析術(二氧化矽、二氯甲烷、甲醇)純化濾液以產生該標題化合物之另一溶離份(365 mg,82%純度,55%產率)。
LC-MS (方法1): R
t= 0.60 min;MS (ESIneg): m/z = 240 [M-H]
-
在100℃下將6-溴吡啶并[3,4-d]嘧啶-2,4(1H,3H)-二酮(中間物109,210 mg,868 µmol)、三氯化磷醯(2.1 ml,23 mmol)及N,N-二異丙基乙胺(760 µl,4.3 mmol)之混合物攪拌整夜。向該混合物添加冰乙酸,所得混合物用乙酸乙酯萃取,有機相用飽和碳酸氫鈉水溶液清洗,經硫酸鈉乾燥,並濃縮。粗產物無需純化即可用於下一反應中。
LC-MS (方法1): R
t= 1.17 min;MS (ESIpos): m/z = 280 [M+H]
+
如針對中間物108描述進行反應,自6-溴-2,4-二氯吡啶并[3,4-d]嘧啶(中間物110,120 mg,430 µmol)及(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙-1-胺(96.2 mg,473 µmol)開始。在藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化後獲得呈橙色油之標題化合物(120 mg,94%純度,59%產率)。
LC-MS (方法1): R
t= 1.49 min;MS (ESIpos): m/z = 447 [M+H]
+
使用一般方法1,自6-氯-8-[(4-甲氧基苯基)甲氧基]-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物116,1.01 g,3.05 mmol)及(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙-1-胺(744 mg,3.66 mmol)開始,獲得標題化合物。
LC-MS (方法2): R
t= 1.53 min;MS (ESIpos): m/z = 517.6 [M+H]
+
中間物 1134-{8-[(4-甲氧基苯基)甲氧基]-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基}-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯
如針對中間物102描述進行反應,自6-氯-8-[(4-甲氧基苯基)甲氧基]-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-吡啶并[3,4-d]嘧啶-4-胺(中間物112,409 mg,791 µmol)及4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯(中間物52,208 mg,949 µmol)開始以獲得呈黃色油之標題化合物(105 mg,19%產率)。
LC-MS (方法2): R
t= 1.47 min;MS (ESIpos): m/z = 701.0 [M+H]
+
如針對中間物22描述,使用6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物32,20 g,83.3 mmol)製備標題化合物(28.77 g,81%產率)。
LC-MS (方法2): R
t= 1.40 min;MS (ESIpos): m/z = 425, 427 [M+H]
+
如針對中間物28描述進行反應,自(R)-2-(3-(1-((三級丁氧基羰基)胺基)乙基)-2-氟苯基)-2,2-二氟乙酸乙酯(中間物30,4.2 g,11.62 mmol)開始,以獲得標題化合物(2.8 g,95%純度,76%產率)。
LC-MS (方法2): R
t= 1.07 min;MS (ESIpos): m/z = 262.3 [M+H]
+
向(3-{(1R)-1-[(三級丁氧基羰基)胺基]乙基}-2-氟苯基)(二氟)乙酸乙酯(15.1 g,41.7 mmol)於四氫呋喃(1.2.ml)中之溶液分批添加四氫硼酸鈉(3.31 g,87.6 mmol),並在室溫下將所得混合物攪拌整夜。向該混合物添加鹽酸水溶液(1 M),直至該溶液已達成~pH6,並將該混合物攪拌15 min。然後該混合物用乙酸乙酯萃取,有機相用飽和氯化鈉水溶液清洗,經硫酸鈉乾燥並濃縮。殘餘物無需純化即可用於下一反應。
¹H-NMR (400 MHz,氯仿-d) δ [ppm]: 1.116 (0.42), 1.133 (0.81), 1.151 (0.43), 1.243 (0.69), 1.249 (5.05), 1.261 (0.77), 1.267 (10.29), 1.285 (5.04), 1.429 (10.00), 1.439 (8.97), 1.451 (7.32), 1.468 (5.81), 1.496 (0.41), 1.861 (0.54), 2.054 (16.00), 3.753 (0.45), 4.065 (2.36), 4.102 (4.56), 4.120 (3.70), 4.138 (4.61), 4.155 (1.17), 5.005 (0.87), 7.179 (1.53), 7.198 (3.18), 7.218 (1.84), 7.405 (1.36), 7.423 (1.95), 7.442 (0.95), 7.454 (1.47), 7.458 (1.30), 7.473 (2.13), 7.490 (1.15), 7.495 (1.00)。
向{(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]-乙基}胺基甲酸三級丁酯(中間物130,14.3 g,44.8 mmol)於二氯甲烷(530 ml)中之溶液添加三氟乙酸(52 ml,670 mmol),並在室溫下將該混合物攪拌2 h。濃縮該混合物及隨後用甲苯稀釋並濃縮兩次以產生粗標題化合物(17.6 g,91%純度,定量),其無需純化即可用於下一步驟。
LC-MS (方法2): R
t= 0.74 min;MS (ESIpos): m/z = 220 [M+H]
+
在0℃下向2-{3-[(1R)-1-胺基乙基]-2-氟苯基}-2,2-二氟乙-1-醇三氟乙酸(1/1) (中間物131,17.6 g,91%純度,48.1 mmol)於二氯甲烷(270 ml)中之溶液添加2,6-二甲基吡啶(39 ml),接著添加三級丁基(二甲基)矽基三氟甲磺酸酯(44 ml,190 mmol),並在室溫下將該混合物攪拌3 h。該混合物用飽和碳酸氫鈉水溶液淬滅,將有機相分離,用硫酸鈉乾燥,並濃縮。殘餘物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以產生呈黃色油之標題化合物(9.09 g,60%產率)。
LC-MS (方法2): R
t= 1.50 min;MS (ESIpos): m/z = 335 [M+H]
+
¹H-NMR (400 MHz,氯仿-d) δ [ppm]: -0.008 (3.80), 0.787 (0.44), 0.791 (0.79), 0.799 (16.00), 0.806 (0.60), 1.414 (1.58), 1.430 (1.56), 4.108 (0.68), 4.111 (0.66)。
如針對中間物141描述進行反應,使用四氘硼酸鈉(982 mg,23.5 mmol),以產生標題化合物(2.79 g,92%產率)。
LC-MS (方法2): R
t= 1.26 min;MS (ESIpos): m/z = 339.4 [M+H
2O+H]
+
中間物134係分兩步如針對類同位素異構分子中間物117描述,自氘化中間物133開始製備。獲得呈黃色固體之標題化合物(741 mg,66%產率)。
LC-MS (方法2): R
t= 1.67 min;MS (ESIpos): m/z = 557.5 [M+H]
+
1H NMR (400 MHz, DMSO-d6) δ ppm -0.14 - -0.07 (m, 6 H) 0.68 (s, 9 H) 1.55 - 1.64 (m, 3 H) 2.38 (s, 3 H) 5.64 - 5.80 (m, 1 H) 7.22 - 7.31 (m, 1 H) 7.36 - 7.46 (m, 1 H) 7.59 - 7.72 (m, 1 H) 8.64 - 8.68 (m, 1 H) 8.79 - 8.81 (m, 1 H) 8.84 - 8.90 (m, 1 H)。
向1-[2-甲基-3-(三氟甲基)苯基]乙-1-酮(2.50 g,12.4 mmol)於1,4-二噁烷(19 ml)及氧化氘(19 ml,1.0 mol)中之溶液添加吡咯啶(100 µl,1.2 mmol),並在室溫下將該混合物攪拌整夜。該混合物用甲基-三級丁基醚萃取,用飽和氯化鈉水溶液清洗,經硫酸鈉乾燥,並濃縮。粗產物(2.37 g,93%產率)無需純化即可用於下一反應。
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.417 (16.00), 2.421 (15.91), 2.518 (1.50), 2.523 (0.98), 7.499 (1.87), 7.519 (4.13), 7.538 (2.36), 7.817 (4.10), 7.837 (3.58), 7.928 (3.82), 7.948 (3.49)。
標題化合物係如針對其類同位素異構分子中間物117描述,自氘化中間物135開始,使用參考文獻已知的程序製備,以獲得標題化合物(143 mg,81%產率)。
LC-MS (方法2): R
t= 1.39 min;MS (ESIpos): m/z = 429 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.171 (0.66), 1.517 (0.48), 1.986 (1.40), 2.379 (16.00), 2.518 (1.13), 2.523 (0.81), 2.606 (4.93), 7.345 (0.56), 7.364 (1.26), 7.383 (0.73), 7.544 (1.32), 7.561 (1.05), 7.746 (1.18), 7.766 (1.06), 8.649 (3.33), 8.651 (3.52), 8.785 (3.92), 8.787 (4.04), 8.967 (1.85)。
在90℃下將6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物32,5.00 g,95%純度,19.8 mmol)、4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯(中間物52,4.34 g,19.8 mmol)、肆(三苯基膦)鈀(0) (3.62 g,3.96 mmol)及三乙胺(9.7 ml,69 mmol)於乙腈(100 ml)中之混合物攪拌22 h。然後將該混合物冷卻,過濾,並濃縮以產生標題化合物(7.63 g,86%純度,88%產率),其無需純化即可用於下一步驟。
LC-MS (方法2): R
t= 0.58 min;MS (ESIpos): m/z = 379.5 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.438 (16.00), 2.074 (2.99), 2.432 (5.35), 2.518 (0.81), 2.523 (0.53), 8.434 (0.71), 8.436 (0.73), 8.449 (0.72), 8.451 (0.71), 9.128 (1.42)。
向4-(4-羥基-2-甲基吡啶并[3,4-d]嘧啶-6-基)-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯(中間物137,2.50 g,86%純度,5.68 mmol)於1,4-二噁烷(15 ml)中之溶液添加於1,4-二噁烷中之鹽酸鹽(4 M於1,4-二噁烷中,15 ml,85 mmol)並在室溫下將該混合物攪拌22 h。濃縮該混合物,並在室溫下將殘餘物攪拌於甲基-三級丁基醚(50 ml)中。過濾所得懸浮液並收集固體以獲得呈淡棕色固體之標題化合物(2.34 g,90%純度,定量),其無需純化即可用於下一反應。
LC-MS (方法1): R
t= 1.09 min;MS (ESIpos): m/z = 279.5 [M+H]
+
使用一般程序7,自4-(4-羥基-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1,4λ
5-氮雜磷雜環己烷-4-酮鹽酸鹽(1/1) (中間物138,2.34 g,7.44 mmol)開始,獲得呈棕色固體之標題化合物(3.46 g,84%純度,122%產率),其無需純化即可用於下一反應。
LC-MS (方法1): R
t= 0.50 min;MS (ESIneg): m/z = 319.5 [M-H]
-
向6-溴-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-吡啶并[3,4-d]嘧啶-4-胺(中間物117,200 mg,470 µmol)於DMSO (3.3 ml)中之混合物添加1,8-二氮雜雙環(5.4.0)十一碳-7-烯(140 µl,940 µmol),並在室溫下將該混合物攪拌整夜。然後該混合物用水稀釋,用二氯甲烷萃取,並將有機相分離,用硫酸鈉乾燥,並濃縮。粗產物藉由製備型TLC (二氧化矽、己烷、乙酸乙酯)純化以產生標題化合物(170 mg,82%產率)。
LC-MS (方法2): R
t= 1.52 min;MS (ESIpos): m/z = 439 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.543 (4.55), 1.560 (4.58), 2.327 (0.48), 2.385 (16.00), 2.518 (1.89), 2.523 (1.30), 2.605 (5.15), 2.669 (0.52), 2.702 (11.32), 5.651 (0.67), 5.668 (1.04), 5.686 (0.65), 5.758 (1.26), 7.338 (0.58), 7.357 (1.28), 7.377 (0.74), 7.538 (1.38), 7.555 (1.11), 7.736 (1.23), 7.755 (1.10), 8.472 (3.27), 8.857 (1.05), 8.874 (1.00)。
向6-溴-N-{(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟乙基)-2-氟苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物131,300 mg,540 µmol)於二氯甲烷(2.0 ml)中之溶液添加三氟乙酸(620 µl,8.1 mmol),並在室溫下將該混合物攪拌整夜。然後該混合物用甲苯稀釋並濃縮。殘餘物藉由急驟層析術(Biotage
®Sfär Amino、己烷、乙酸乙酯)純化以獲得標題化合物(208 mg,87%產率)。
LC-MS (方法2): R
t= 1.07 min;MS (ESIpos): m/z = 441 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (1.80), 1.171 (3.55), 1.189 (1.70), 1.586 (4.91), 1.603 (4.85), 1.986 (6.51), 2.332 (0.41), 2.395 (16.00), 2.518 (2.20), 2.523 (1.49), 3.358 (1.84), 3.372 (0.44), 3.888 (0.48), 3.903 (0.53), 3.924 (0.95), 3.939 (0.98), 3.960 (0.48), 3.974 (0.45), 3.998 (0.50), 4.016 (1.48), 4.034 (1.47), 4.052 (0.48), 5.706 (0.66), 5.722 (1.62), 5.727 (1.17), 5.737 (0.77), 5.745 (1.26), 5.756 (0.78), 5.763 (0.75), 7.241 (0.83), 7.261 (1.87), 7.280 (1.08), 7.411 (0.68), 7.428 (1.09), 7.444 (0.53), 7.630 (0.59), 7.648 (1.06), 7.665 (0.53), 8.665 (4.08), 8.805 (4.52), 8.868 (1.23), 8.886 (1.17)。
如針對中間物140描述進行反應,自2-(3-{(1R)-1-[(6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-2,2-二氟乙-1-醇(中間物141,200 mg,453 µmol)開始。產物(208 mg,定量)無需純化即可用於下一反應。
LC-MS (方法2): R
t= 1.21 min;MS (ESIpos): m/z = 455 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.96), 1.171 (2.06), 1.189 (1.00), 1.577 (4.34), 1.594 (4.37), 1.986 (3.33), 2.402 (16.00), 2.518 (2.69), 2.523 (2.11), 2.718 (11.43), 3.359 (1.74), 3.385 (0.49), 3.886 (0.48), 3.901 (0.52), 3.922 (0.94), 3.938 (1.00), 3.957 (0.45), 3.974 (0.45), 4.016 (0.68), 4.034 (0.64), 5.704 (1.16), 5.720 (3.01), 5.736 (2.02), 5.756 (2.21), 7.234 (0.76), 7.254 (1.69), 7.273 (0.98), 7.404 (0.59), 7.422 (0.93), 7.438 (0.47), 7.613 (0.52), 7.630 (0.91), 7.646 (0.46), 8.481 (3.26), 8.756 (1.11), 8.774 (1.06)。
在0℃下向2-(3-{(1R)-1-[(6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-2,2-二氟乙-1-醇(中間物141,757 mg,1.72 mmol)於二氯甲烷(8.5 ml)中之溶液添加三乙胺(960 µl,6.9 mmol)及三氟甲磺酸酐(410 µl,2.4 mmol),並在室溫下將該混合物攪拌2 h。添加另一三氟甲磺酸酐(145 µl),並在室溫下將該混合物攪拌整夜。然後該混合物用二氯甲烷(60 ml)稀釋,用水清洗,並分離有機相,透過分離漏斗過濾並濃縮。殘餘物經過急驟層析術(二氧化矽、己烷、乙酸乙酯)以產生標題化合物(577 mg,80%純度,47%產率)。
LC-MS (方法2): R
t= 1.43 min;MS (ESIpos): m/z = 573.5 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (5.16), 1.172 (10.62), 1.189 (5.94), 1.206 (0.47), 1.580 (0.54), 1.597 (3.00), 1.614 (2.64), 1.986 (16.00), 2.370 (1.69), 2.381 (8.60), 2.518 (1.73), 2.523 (1.19), 3.999 (1.27), 4.016 (3.86), 4.034 (3.80), 4.052 (1.21), 5.366 (0.54), 5.404 (0.52), 5.700 (0.44), 5.717 (0.64), 5.735 (0.41), 7.325 (0.52), 7.344 (1.06), 7.364 (0.60), 7.503 (0.67), 7.523 (0.57), 7.731 (0.43), 7.748 (0.57), 8.664 (2.61), 8.809 (3.33), 8.897 (0.61), 8.913 (0.59)。
向(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟乙基)-2-氟苯基]-乙-1-胺(中間物132,750 mg,2.25 mmol)、三乙胺(940 µl,6.7 mmol)及4-(二甲胺基)吡啶(54 mg,0.45 mmol)於四氫呋喃(50 ml)中之溶液添加2-苯并呋喃-1,3-二酮(400 mg,2.70 mmol),並在80℃下將該混合物攪拌整夜。然後,添加乙酸酐(320 µl,3.4 mmol),並在80℃下持續攪拌整夜。將該混合物冷卻,並添加飽和碳酸氫鈉水溶液。將有機相分離,用飽和氯化鈉水溶液清洗,用硫酸鈉乾燥,並濃縮。殘餘物經過急驟層析術(二氧化矽、己烷、乙酸乙酯)以獲得標題化合物(833 mg,80%產率)。
LC-MS (方法2): R
t= 1.67 min;MS (ESIpos): m/z = 464 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: -0.242 (4.60), -0.173 (4.75), 0.587 (0.83), 0.595 (16.00), 0.602 (0.84), 1.791 (1.45), 1.809 (1.44), 2.518 (0.72), 2.523 (0.49), 4.042 (0.40), 7.347 (0.47), 7.842 (6.00)。
向2-{(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟乙基)-2-氟苯基]-乙基}-1H-異吲哚-1,3(2H)-二酮(中間物144,830 mg,1.79 mmol)於二氯甲烷(10 ml)中之溶液添加三氟乙酸(2.8 ml)並在室溫下將該混合物攪拌整夜。濃縮該混合物,用二氯甲烷(2 ml)稀釋,並再攪拌3 h。然後該混合物用甲苯稀釋,濃縮,及粗產物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以產生標題化合物(472 mg,75%產率)。
LC-MS (方法1): R
t= 1.12 min;MS (ESIpos): m/z = 350 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.791 (9.26), 1.809 (9.13), 2.518 (2.54), 2.523 (1.80), 3.811 (0.72), 3.821 (0.77), 3.847 (1.44), 3.858 (1.45), 3.883 (0.74), 3.893 (0.70), 5.658 (1.80), 5.674 (1.09), 5.693 (1.92), 5.711 (1.85), 5.729 (0.53), 5.758 (2.00), 7.316 (1.30), 7.335 (2.94), 7.355 (1.73), 7.472 (0.96), 7.476 (1.09), 7.493 (1.75), 7.509 (0.84), 7.512 (0.79), 7.792 (0.93), 7.809 (1.71), 7.827 (1.36), 7.829 (1.47), 7.837 (0.79), 7.842 (2.05), 7.851 (15.68), 7.853 (16.00), 7.857 (6.30), 7.862 (2.01), 7.866 (0.76), 7.872 (0.45), 7.875 (0.63), 7.877 (0.52)。
向2-{(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}-1H-異吲哚-1,3(2H)-二酮(中間物145,470 mg,1.35 mmol)於DMF (8.0 ml)中之溶液添加氫化鈉(108 mg,60%純度,2.69 mmol),並在室溫下將該混合物攪拌30 min。然後,添加碘甲烷(420 µl,6.7 mmol)並持續攪拌1 h。添加更多碘甲烷(420 µl,6.7 mmol)並持續攪拌整夜。然後濃縮該混合物及殘餘物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以產生標題化合物(386 mg,79%產率)。
LC-MS (方法1): R
t= 1.31 min;MS (ESIpos): m/z = 364 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.789 (5.17), 1.807 (5.22), 2.518 (2.09), 2.523 (1.40), 3.272 (16.00), 3.865 (1.14), 3.900 (2.03), 3.935 (0.99), 5.696 (1.03), 5.714 (1.01), 5.758 (1.19), 7.331 (0.71), 7.350 (1.61), 7.370 (0.95), 7.493 (0.60), 7.511 (0.97), 7.526 (0.47), 7.530 (0.44), 7.808 (0.52), 7.826 (1.23), 7.828 (1.11), 7.837 (0.52), 7.842 (1.47), 7.851 (9.53), 7.852 (9.56), 7.856 (3.87), 7.861 (1.16)。
向2-{(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}-1H-異吲哚-1,3(2H)-二酮(中間物146,384 mg,1.06 mmol)於THF (5.0 ml)及乙醇(5.0 ml)中之溶液添加水合肼(510 µl,11 mmol),並在室溫下將該混合物攪拌整夜。過濾該混合物,及固體用乙醇清洗。將該固體溶解於二氯甲烷及水中,將有機相分離並用飽和碳酸氫鈉水溶液清洗,用飽和氯化鈉水溶液清洗,經硫酸鈉乾燥,並濃縮。殘餘物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以獲得標題化合物(231 mg,94%產率)。
LC-MS (方法2): R
t= 0.95 min;MS (ESIpos): m/z = 234 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.037 (0.43), 1.045 (0.86), 1.064 (0.45), 1.236 (16.00), 1.253 (15.56), 1.717 (1.32), 1.725 (0.44), 1.914 (0.50), 2.024 (1.31), 2.225 (0.42), 2.518 (3.20), 2.523 (2.21), 3.350 (1.22), 3.908 (3.02), 3.911 (2.99), 3.944 (6.20), 3.946 (5.96), 3.979 (2.95), 3.982 (2.86), 4.258 (0.86), 4.274 (2.69), 4.291 (2.65), 4.308 (0.83), 7.263 (1.66), 7.282 (4.00), 7.301 (2.53), 7.372 (1.44), 7.377 (1.60), 7.391 (2.23), 7.395 (2.31), 7.410 (1.11), 7.414 (1.06), 7.741 (1.22), 7.758 (2.18), 7.775 (1.10), 7.778 (1.07)。
4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮鹽酸鹽(1/1) (中間物164,1.20 g,81%純度,1.94 mmol)藉由急驟層析術(SNAP NH 55 g,己烷、乙酸乙酯)純化以獲得呈游離鹼之標題化合物831 mg (92%產率)。
LC-MS (方法2): R
t= 1.08 min;MS (ESIpos): m/z = 464 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.572 (5.11), 1.590 (5.12), 1.753 (0.44), 1.795 (0.87), 1.835 (0.49), 2.256 (0.52), 2.270 (0.76), 2.280 (1.01), 2.292 (0.81), 2.304 (1.02), 2.318 (0.98), 2.323 (1.13), 2.327 (1.47), 2.331 (1.14), 2.336 (0.76), 2.416 (16.00), 2.518 (4.05), 2.523 (2.72), 2.622 (6.51), 2.665 (0.73), 2.669 (0.99), 2.673 (0.69), 3.008 (0.56), 3.023 (0.89), 3.034 (0.76), 3.056 (0.60), 3.070 (1.11), 3.102 (0.79), 3.110 (0.77), 3.133 (0.72), 3.140 (0.71), 5.701 (0.80), 5.718 (1.24), 5.736 (0.79), 7.346 (0.74), 7.365 (1.60), 7.385 (0.92), 7.542 (1.73), 7.559 (1.40), 7.783 (1.55), 7.802 (1.40), 8.948 (1.84), 8.963 (1.83), 9.091 (4.44), 9.329 (1.32), 9.346 (1.27)。
向氨(1.9 ml,7.0 M於甲醇中,13 mmol)之溶液添加2-(3-{(1R)-1-[(6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-2,2-二氟乙基三氟甲磺酸酯(中間物143,750 mg,1.31 mmol)於乙腈(17 ml)中之溶液並在50℃下將該混合物攪拌2 h。將該混合物濃縮,用二氯甲烷稀釋,並用水清洗。分離相,及水相用乙酸乙酯萃取。濃縮經組合之有機相,及殘餘物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯、乙醇)純化以獲得標題化合物300 mg (90%純度,47%產率)。
LC-MS (方法2): R
t= 1.09 min;MS (ESIpos): m/z = 440 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (4.17), 1.172 (8.19), 1.189 (3.89), 1.586 (3.23), 1.603 (3.18), 1.987 (16.00), 2.213 (0.52), 2.393 (10.67), 2.518 (2.96), 2.523 (1.98), 3.186 (0.72), 3.224 (1.39), 3.262 (0.66), 3.999 (1.09), 4.017 (3.32), 4.035 (3.36), 4.053 (1.11), 5.724 (0.50), 5.741 (0.75), 5.759 (0.48), 7.236 (0.59), 7.255 (1.25), 7.275 (0.70), 7.403 (0.44), 7.421 (0.69), 7.635 (0.67), 8.665 (2.63), 8.807 (2.93), 8.865 (0.76), 8.883 (0.73)。
向N-{(1R)-1-[3-(2-胺基-1,1-二氟乙基)-2-氟苯基]乙基}-6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物149,150 mg,341 µmol)於1,2-二氯乙烷(3.1 ml)中之溶液添加三乙胺(240 µl,1.7 mmol)及DMAP (420 µg,3.4 µmol),接著添加甲磺醯氯(32 µl,410 µmol),並在室溫下將該混合物攪拌1 h。該混合物用水稀釋,用二氯甲烷萃取,及有機相用飽和碳酸氫鈉水溶液、飽和硫酸鈉水溶液清洗,並濃縮。獲得粗產物(158 mg,85%產率)。
LC-MS (方法2): R
t= 1.09 min;MS (ESIpos): m/z = 518 [M+H]
+
¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.587 (1.92), 1.601 (1.91), 2.398 (5.48), 2.514 (0.66), 2.518 (0.62), 2.522 (0.50), 2.820 (0.56), 2.829 (6.29), 2.976 (0.62), 3.212 (0.44), 3.349 (1.07), 3.403 (0.59), 3.901 (16.00), 5.749 (0.46), 7.284 (0.73), 7.300 (0.41), 7.781 (0.59), 8.671 (1.58), 8.808 (1.20), 8.870 (0.46), 8.884 (0.45)。
根據一般程序7,自N-{(1R)-1-[3-(2-胺基-1,1-二氟乙基)-2-氟苯基]乙基}-6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物149,150 mg,341 µmol)開始,獲得標題化合物(170 mg,85%產率)。
LC-MS (方法2): R
t= 1.07 min;MS (ESIpos): m/z = 482 [M+H]
+
¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.959 (1.07), 1.044 (0.55), 1.058 (0.51), 1.114 (0.47), 1.128 (0.47), 1.157 (0.50), 1.171 (0.73), 1.186 (0.54), 1.229 (0.43), 1.484 (0.42), 1.586 (5.06), 1.600 (4.97), 1.788 (16.00), 1.796 (1.45), 1.905 (3.25), 1.986 (0.79), 2.215 (3.41), 2.218 (0.86), 2.397 (15.68), 2.514 (2.47), 2.518 (2.14), 2.522 (1.70), 3.852 (0.42), 3.869 (0.44), 3.934 (0.44), 5.731 (0.81), 5.746 (1.21), 5.760 (0.80), 7.236 (0.99), 7.252 (1.96), 7.267 (1.14), 7.385 (0.68), 7.399 (1.09), 7.412 (0.55), 7.632 (0.62), 7.646 (1.06), 7.660 (0.55), 8.328 (0.69), 8.340 (1.37), 8.353 (0.68), 8.674 (3.98), 8.806 (4.43), 8.863 (1.04), 8.878 (1.04)。
如針對中間物149描述製備標題化合物,自2-(3-{(1R)-1-[(6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-2,2-二氟乙基三氟甲磺酸酯(中間物143,570 mg,994 µmol)開始:290 mg。
LC-MS (方法2): R
t= 1.18 min;MS (ESIpos): m/z = 454 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.052 (1.00), 1.069 (0.87), 1.153 (3.66), 1.171 (7.33), 1.189 (3.56), 1.582 (5.32), 1.600 (5.27), 1.986 (14.81), 2.249 (12.32), 2.384 (16.00), 2.518 (1.36), 2.523 (0.94), 3.183 (0.73), 3.191 (0.66), 3.221 (1.31), 3.228 (1.32), 3.258 (0.64), 3.266 (0.73), 3.998 (1.08), 4.016 (3.28), 4.034 (3.24), 4.052 (1.04), 5.718 (0.82), 5.736 (1.26), 5.753 (0.80), 7.225 (0.90), 7.244 (1.98), 7.264 (1.18), 7.398 (0.73), 7.416 (1.19), 7.431 (0.58), 7.607 (0.65), 7.624 (1.16), 7.641 (0.59), 8.667 (4.24), 8.804 (4.09), 8.865 (1.24), 8.883 (1.21)。
如針對中間物150描述獲得標題化合物,自6-溴-N-[(1R)-1-{3-[1,1-二氟-2-(甲胺基)乙基]-2-氟苯基}乙基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物152,145 mg,319 µmol)開始:187 mg (95%純度,定量)。
LC-MS (方法2): R
t= 1.20 min;MS (ESIpos): m/z = 532 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.578 (1.98), 1.596 (1.96), 2.386 (6.74), 2.518 (1.84), 2.523 (1.32), 2.854 (9.21), 2.956 (0.90), 3.350 (0.44), 3.903 (16.00), 5.730 (0.47), 5.758 (0.50), 7.281 (0.79), 7.300 (0.45), 7.454 (0.43), 7.665 (0.43), 8.677 (1.70), 8.810 (1.93), 8.867 (0.52), 8.884 (0.49)。
如針對中間物151描述製備標題化合物,自6-溴-N-[(1R)-1-{3-[1,1-二氟-2-(甲胺基)乙基]-2-氟苯基}乙基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物152,145 mg,319 µmol)開始:130 mg (95%純度,78%產率)。
LC-MS (方法2): R
t= 1.16 min;MS (ESIpos): m/z = 496 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.224 (1.30), 1.241 (4.54), 1.256 (6.01), 1.272 (3.08), 1.582 (4.92), 1.590 (4.51), 1.600 (5.16), 1.608 (4.27), 1.838 (0.55), 1.912 (10.22), 1.924 (15.66), 1.938 (0.41), 2.216 (1.87), 2.337 (0.83), 2.385 (13.71), 2.391 (16.00), 2.518 (9.91), 2.523 (7.14), 2.679 (0.84), 2.838 (7.49), 3.019 (10.10), 3.125 (0.40), 3.136 (0.41), 3.143 (0.44), 4.014 (0.47), 4.056 (0.48), 4.114 (0.52), 4.130 (0.46), 4.153 (0.75), 4.166 (0.81), 4.183 (0.59), 4.206 (0.51), 4.216 (0.72), 4.258 (0.54), 5.710 (1.04), 5.727 (1.59), 5.744 (1.02), 5.759 (2.82), 7.223 (0.80), 7.243 (1.77), 7.262 (1.06), 7.287 (0.68), 7.307 (1.48), 7.326 (0.89), 7.379 (0.64), 7.396 (1.00), 7.412 (0.52), 7.436 (0.56), 7.452 (0.85), 7.469 (0.43), 7.616 (0.56), 7.634 (0.98), 7.649 (0.51), 7.675 (0.48), 7.692 (0.84), 7.710 (0.42), 8.679 (6.80), 8.809 (4.68), 8.812 (4.06), 8.855 (1.12), 8.873 (1.13), 8.893 (1.00), 8.911 (0.92)。
中間物 1552-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基三氟甲磺酸酯
如針對中間物143描述獲得標題化合物,自1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(實例42,320 mg,614 µmol)開始:94.0 mg (22%純度,5%產率)。
LC-MS (方法2): R
t= 1.11 min;MS (ESIpos): m/z = 654 [M+H]
+
中間物 1561-乙醯基-4-(4-{[(1R)-1-{3-[2-(環丙胺基)-1,1-二氟乙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1,4λ
5-氮雜磷雜環己烷-4-酮
如針對中間物149描述獲得標題化合物,自2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基三氟甲磺酸酯(中間物155,90.0 mg,138 µmol)開始:7.00 mg (95%純度,9%產率)。
LC-MS (方法2): R
t= 0.99 min;MS (ESIpos): m/z = 561.6 [M+H]
+
中間物 1574-[4-({(1R)-1-[3-(2-乙氧基-1,1-二氟-2-側氧基乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯
如針對中間物102描述製備標題化合物,自(3-{(1R)-1-[(6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)(二氟)乙酸乙酯(中間物174,1.68 g,3.88 mmol),及4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯(中間物52,850 mg,3.88 mmol)開始:1.45 g (80%純度,48%產率)。
LC-MS (方法2): R
t= 1.22 min;MS (ESIpos): m/z = 622.5 [M+H]
+
如針對中間物138描述進行反應,自4-[4-({(1R)-1-[3-(2-乙氧基-1,1-二氟-2-側氧基乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯開始。
LC-MS (方法2): R
t= 1.01 min;MS (ESIpos): m/z = 522.5 [M+H]
+
根據一般程序7製備標題化合物,自二氟{2-氟-3-[(1R)-1-{[2-甲基-6-(4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]苯基}乙酸乙酯鹽酸鹽(1/1) (中間物158,1.34 g,2.40 mmol)開始,以獲得622 mg (80%純度,37%產率)。
LC-MS (方法2): R
t= 1.03 min;MS (ESIpos): m/z = 564.5 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.034 (0.73), 1.052 (1.52), 1.069 (0.74), 1.085 (1.28), 1.102 (1.28), 1.149 (0.78), 1.170 (3.29), 1.187 (6.72), 1.205 (3.21), 1.605 (3.17), 1.623 (3.13), 2.118 (9.00), 2.323 (0.47), 2.327 (0.51), 2.392 (9.43), 2.518 (1.30), 2.523 (0.95), 3.159 (16.00), 3.172 (14.99), 3.439 (0.43), 3.452 (0.49), 3.895 (0.44), 4.087 (1.27), 4.099 (3.87), 4.113 (3.84), 4.126 (1.23), 4.320 (0.56), 4.323 (0.60), 4.338 (1.53), 4.342 (1.61), 4.347 (0.50), 4.356 (1.55), 4.360 (2.00), 4.373 (0.71), 4.377 (0.48), 5.724 (0.51), 5.741 (0.78), 5.758 (6.79), 6.939 (0.46), 7.326 (0.56), 7.345 (1.21), 7.365 (0.69), 7.565 (0.48), 7.582 (0.80), 7.730 (0.40), 7.749 (0.73), 9.166 (0.71), 9.183 (0.67), 9.260 (1.74), 9.267 (1.56), 9.272 (1.37), 9.297 (0.71)。
在0℃下向{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸(實例43,133 mg,248 µmol)於二氯甲烷(6.9 ml)中之溶液添加草醯二氯(84 µl,990 µmol)及DMF (0.38 µl),並在室溫下將該混合物攪拌2 h。該酸氯溶液直接用於下一反應。
根據一般程序1進行反應,自6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-醇(中間物71,172 mg,725 µmol)及{3-[(1R)-1-胺基乙基]-2-氟苯基}(二氟)乙酸乙酯三氟乙酸(1/1) (中間物321 mg,855 µmol)開始以獲得標題化合物(417 mg,定量)。
LC-MS (方法2): R
t= 1.08 min;MS (ESIpos): m/z = 481.5 [M+H]
+
向(3-{(1R)-1-[(三級丁氧基羰基)胺基]乙基}-2-氟苯基)(二氟)乙酸乙酯(935 mg,2.59 mmol)添加甲基胺(6.5 ml,2.0 M於甲醇中,13 mmol),並在室溫下將該混合物攪拌3 h。濃縮該混合物,並將殘餘物懸浮於三級丁基甲基醚中。濾除固體並乾燥以產生呈灰白色固體之標題化合物(768 mg,86%產率)。
LC-MS (方法1): R
t= 1.08 min;MS (ESIpos): m/z = 364.7 [M+NH
4]
+
如針對中間物138描述進行反應,自[(1R)-1-{3-[1,1-二氟-2-(甲胺基)-2-側氧基乙基]-2-氟苯基}乙基]胺基甲酸三級丁酯(中間物162,768 mg,2.22 mmol)開始,以獲得標題化合物(600 mg,96%產率)。
LC-MS (方法2): R
t= 0.74 min;MS (ESIpos): m/z = 247 [M+H]
+
如針對中間物138描述進行反應,自4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯(中間物187,400 mg,710 µmol)開始,以獲得標題化合物(430 mg,121%產率)。
LC-MS (方法2): R
t= 1.10 min;MS (ESIpos): m/z = 464.5 [M+H]
+
表1中顯示之中間物係根據一般程序2自各別嘧啶-4-醇衍生物及各別胺製備。
中間物表
1
編號 | 結構 IUPAC名稱 分析資料 | 起始材料 產率 |
165 | 6-溴-N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.596 (4.78), 1.613 (4.78), 1.986 (0.66), 2.389 (16.00), 2.518 (1.02), 2.523 (0.77), 5.727 (0.70), 5.744 (1.09), 5.761 (0.70), 7.102 (1.07), 7.237 (2.22), 7.280 (0.73), 7.298 (1.61), 7.318 (0.94), 7.373 (0.95), 7.499 (0.54), 7.516 (0.92), 7.533 (0.45), 7.667 (0.49), 7.685 (0.92), 7.703 (0.46), 8.666 (3.67), 8.807 (3.93), 8.875 (1.03), 8.893 (1.01)。 LC-MS (方法2): R t= 1.25 min;MS (ESIpos): m/z = 413 [M+H]⁺ | 中間物32及CAS 1389852-29-2 5.20 g (87%產率) |
166 | 6-溴-N-{(1R)-1-[3-(二氟甲基)-2-甲基苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (0.96), 1.171 (2.00), 1.189 (0.96), 1.534 (4.60), 1.551 (4.56), 1.955 (10.11), 1.986 (3.29), 2.397 (15.94), 2.518 (0.73), 2.523 (0.66), 2.781 (9.53), 2.940 (16.00), 4.016 (0.68), 4.034 (0.69), 5.691 (0.67), 5.708 (1.05), 5.726 (0.67), 7.076 (0.86), 7.214 (1.83), 7.282 (0.59), 7.301 (1.43), 7.321 (0.95), 7.351 (0.77), 7.390 (1.39), 7.408 (0.93), 7.632 (1.12), 7.651 (0.98), 8.658 (3.73), 8.783 (4.30), 8.914 (1.03), 8.932 (1.00)。 LC-MS (方法2): R t= 1.30 min;MS (ESIpos): m/z = 408 [M+H]⁺ | 中間物32及CAS 2230840-56-7 1.10 g (81%產率) |
167 | 6-溴-N-{(1R)-1-[3-(1,1-二氟乙基)苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (4.12), 1.172 (8.62), 1.189 (4.23), 1.591 (4.87), 1.609 (4.85), 1.912 (4.39), 1.959 (8.40), 1.987 (15.25), 2.006 (3.83), 2.331 (0.40), 2.430 (16.00), 2.518 (2.36), 2.523 (1.67), 2.673 (0.40), 3.999 (1.10), 4.016 (3.30), 4.034 (3.21), 4.052 (1.01), 5.579 (0.67), 5.596 (1.00), 5.615 (0.65), 7.434 (2.45), 7.436 (3.49), 7.443 (1.19), 7.451 (1.65), 7.563 (0.93), 7.575 (0.66), 7.578 (0.82), 7.664 (1.89), 8.626 (3.66), 8.798 (4.04), 8.819 (1.07), 8.838 (1.04)。 LC-MS (方法2): R t= 1.31 min;MS (ESIpos): m/z = 407 [M+H]⁺ | 中間物32及CAS 2359690-78-9 92.0 mg (31%產率) |
168 | 6-氯-N-{(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 LC-MS (方法2): R t= 1.39 min;MS (ESIpos): m/z = 303 [M+H]⁺ | 中間物2及CAS 1213555-38-4 1.11 g (90%產率) |
16 | 6-氯-2-甲基-N-{(1R)-1-[3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52 - 1.67 (m, 3 H) 2.42 (s, 3 H) 5.43 - 5.68 (m, 1 H) 7.48 - 7.65 (m, 2 H) 7.72 - 7.78 (m, 1 H) 7.80 - 7.86 (m, 1 H) 8.46 (s, 1 H) 8.81 (s, 2 H) | 中間物2及CAS 127852-30-6 26.0 g (97%純度,47%產率) |
170 | 6-溴-N-{(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟乙基)-2-氟苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz,氯仿-d) δ [ppm]: -0.079 (4.14), -0.062 (4.05), 0.727 (0.75), 0.735 (16.00), 0.743 (0.67), 1.249 (0.47), 1.266 (0.90), 1.285 (0.45), 1.714 (1.28), 1.731 (1.26), 2.056 (1.73), 2.589 (4.87), 4.112 (0.63), 4.140 (0.44), 5.306 (1.43), 7.186 (0.44), 7.485 (0.41), 7.720 (0.83), 8.948 (0.98)。 | 中間物32及中間物132 2.72 g (64%產率) |
171 | 6-溴-N-{(1R)-1-[2-氟-3-(三氟甲基)苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 LC-MS (方法2): R t= 1.37 min;MS (ESIpos): m/z = 429 [M+H]⁺ | 中間物32及CAS 1079656-93-1 442 mg (85%產率) |
172 | 6-溴-N-{(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.585 (3.87), 1.603 (3.86), 1.715 (0.69), 2.331 (0.57), 2.383 (13.23), 2.518 (3.27), 2.523 (2.20), 2.673 (0.56), 3.331 (16.00), 3.374 (0.54), 3.947 (0.96), 3.982 (1.82), 4.016 (0.89), 5.709 (0.58), 5.726 (0.91), 5.744 (0.59), 7.250 (0.66), 7.270 (1.45), 7.289 (0.84), 7.425 (0.52), 7.443 (0.84), 7.459 (0.41), 7.641 (0.46), 7.659 (0.80), 7.674 (0.40), 8.667 (3.23), 8.807 (3.62), 8.883 (0.93), 8.901 (0.89)。 LC-MS (方法2): R t= 1.28 min;MS (ESIpos): m/z = 455 [M+H]⁺ | 中間物32及中間物147 362 mg (97%產率) |
173 | {3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基喹唑啉-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸乙酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (2.26), 1.052 (4.77), 1.070 (2.65), 1.087 (16.00), 1.104 (15.81), 1.151 (9.60), 1.158 (1.01), 1.168 (10.19), 1.172 (3.11), 1.190 (4.59), 1.208 (2.16), 1.600 (1.93), 1.617 (1.91), 1.724 (6.51), 1.757 (6.37), 2.323 (0.42), 2.327 (0.59), 2.331 (0.49), 2.346 (5.96), 2.518 (2.34), 2.523 (1.48), 2.669 (0.54), 2.774 (0.50), 2.791 (0.66), 2.808 (0.48), 3.422 (1.08), 3.435 (1.12), 3.440 (0.95), 3.452 (0.98), 4.337 (0.90), 4.341 (0.96), 4.347 (0.84), 4.354 (0.96), 4.360 (2.18), 4.372 (0.97), 4.553 (1.07), 4.570 (1.45), 4.587 (1.04), 5.758 (0.48), 6.942 (5.50), 7.336 (0.79), 7.355 (0.45), 7.564 (0.48), 7.650 (0.55), 7.657 (0.56), 7.672 (0.61), 7.678 (0.61), 7.755 (0.45), 8.014 (0.66), 8.018 (0.41), 8.802 (0.51), 8.805 (0.51), 8.834 (0.53), 8.836 (0.53), 8.859 (0.45), 8.877 (0.43)。 | 中間物183及中間物118 92.0 mg (85%純度,11%產率) |
174 | (3-{(1R)-1-[(6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)(二氟)乙酸乙酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.085 (0.99), 1.102 (1.00), 1.147 (0.66), 1.151 (1.48), 1.165 (0.86), 1.170 (5.44), 1.189 (10.57), 1.206 (4.89), 1.580 (4.76), 1.598 (4.75), 1.984 (5.40), 2.366 (16.00), 2.518 (0.68), 2.523 (0.51), 2.735 (0.45), 3.996 (0.41), 4.014 (1.22), 4.032 (1.20), 4.317 (0.69), 4.322 (0.72), 4.334 (2.09), 4.339 (2.12), 4.352 (2.11), 4.357 (2.06), 4.370 (0.72), 4.375 (0.64), 5.664 (0.75), 5.682 (1.16), 5.699 (0.74), 7.319 (0.89), 7.339 (1.92), 7.358 (1.09), 7.557 (0.58), 7.561 (0.67), 7.578 (1.10), 7.594 (0.54), 7.598 (0.52), 7.714 (0.58), 7.732 (1.06), 7.750 (0.54), 8.654 (4.01), 8.802 (4.50), 8.893 (1.20), 8.910 (1.15)。 | 中間物183及中間物118 2.20 g (90%純度,49%產率) |
175 | {3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基喹唑啉-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸乙酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (2.26), 1.052 (4.77), 1.070 (2.65), 1.087 (16.00), 1.104 (15.81), 1.151 (9.60), 1.158 (1.01), 1.168 (10.19), 1.172 (3.11), 1.190 (4.59), 1.208 (2.16), 1.600 (1.93), 1.617 (1.91), 1.724 (6.51), 1.757 (6.37), 2.323 (0.42), 2.327 (0.59), 2.331 (0.49), 2.346 (5.96), 2.518 (2.34), 2.523 (1.48), 2.669 (0.54), 2.774 (0.50), 2.791 (0.66), 2.808 (0.48), 3.422 (1.08), 3.435 (1.12), 3.440 (0.95), 3.452 (0.98), 4.337 (0.90), 4.341 (0.96), 4.347 (0.84), 4.354 (0.96), 4.360 (2.18), 4.372 (0.97), 4.553 (1.07), 4.570 (1.45), 4.587 (1.04), 5.758 (0.48), 6.942 (5.50), 7.336 (0.79), 7.355 (0.45), 7.564 (0.48), 7.650 (0.55), 7.657 (0.56), 7.672 (0.61), 7.678 (0.61), 7.755 (0.45), 8.014 (0.66), 8.018 (0.41), 8.802 (0.51), 8.805 (0.51), 8.834 (0.53), 8.836 (0.53), 8.859 (0.45), 8.877 (0.43)。 | 中間物 92.0 mg (85%純度,11%產率) |
176 | N-[(1R)-1-(3-{(2R*)-1,1-二氟-3-甲基-2-[(三乙基矽基)氧基]丁基}-2-氟苯基)乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 (非對映異構體1) LC-MS (方法1): R t= 1.69 min;MS (ESIpos): m/z = 596 [M+H]⁺ | 中間物71及中間物90 115 mg (48%純度,100%產率) |
177 | N-[(1R)-1-(3-{(2R*)-1,1-二氟-3-甲基-2-[(三乙基矽基)氧基]丁基}-2-氟苯基)乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 (非對映異構體2) LC-MS (方法1): R t= 1.68 min;MS (ESIpos): m/z = 596 [M+H]⁺ | 中間物71及中間物91 90.0 mg (61%純度,100%產率) |
178 | N-[(1R)-1-(3-{(2R*)-1,1-二氟-2-[(三乙基矽基)氧基]丁基}-2-氟苯基)乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體1) LC-MS (方法1): R t= 1.59 min;MS (ESIpos): m/z = 582 [M+H]⁺ | 中間物71及中間物78 95.0 mg (58%純度,99%產率) |
179 | N-[(1R)-1-(3-{(2R*)-1,1-二氟-2-[(三乙基矽基)氧基]丁基}-2-氟苯基)乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體2) LC-MS (方法1): R t= 1.59 min;MS (ESIpos): m/z = 582 [M+H]⁺ | 中間物71及中間物79 90.0 mg (62%純度,100%產率) |
表2中顯示之中間物係根據一般程序6自各別嘧啶-4-醇衍生物及各別胺製備。
中間物表
2
編號 | 結構 IUPAC名稱 分析資料 | 起始材料 產率 |
180 | 6-溴-N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (4.68), 1.172 (9.71), 1.190 (4.72), 1.607 (4.41), 1.624 (4.39), 1.988 (16.00), 2.331 (0.79), 2.415 (14.99), 2.518 (3.72), 2.523 (2.44), 2.673 (0.77), 3.999 (1.20), 4.017 (3.59), 4.035 (3.50), 4.053 (1.11), 5.744 (0.67), 5.759 (2.95), 5.779 (0.66), 7.107 (1.01), 7.243 (2.09), 7.285 (0.71), 7.305 (1.55), 7.324 (0.89), 7.379 (0.89), 7.511 (0.54), 7.528 (0.92), 7.547 (0.50), 7.687 (0.49), 7.704 (0.89), 7.723 (0.45), 9.109 (1.02), 9.126 (0.98), 9.497 (3.52)。 LC-MS (方法2): R t= 1.36 min;MS (ESIpos): m/z = 479 [M+H]⁺ | 中間物11及CAS 1389852-29-2 270 mg (87%產率) |
181 | 6-溴-N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基喹唑啉-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.51), 1.172 (1.07), 1.190 (0.53), 1.584 (4.65), 1.602 (4.63), 1.988 (1.72), 2.318 (0.45), 2.323 (0.99), 2.327 (1.45), 2.331 (1.34), 2.338 (16.00), 2.518 (4.41), 2.523 (3.05), 2.665 (0.91), 2.669 (1.26), 2.673 (0.86), 5.753 (0.68), 5.770 (1.05), 5.788 (0.66), 7.101 (1.04), 7.237 (2.17), 7.270 (0.71), 7.289 (1.57), 7.308 (0.90), 7.373 (0.93), 7.482 (0.52), 7.498 (0.89), 7.523 (3.02), 7.545 (3.32), 7.662 (0.48), 7.679 (0.89), 7.697 (0.44), 7.836 (1.90), 7.842 (2.02), 7.858 (1.61), 7.864 (1.78), 8.562 (1.04), 8.580 (1.01), 8.721 (2.42), 8.727 (2.37)。 LC-MS (方法2): R t= 1.35 min;MS (ESIpos): m/z = 410 [M+H]⁺ | CAS 5426-59-5及CAS 1389852-29-2 388 mg (90%產率) |
182 | 6-溴-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}喹唑啉-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.536 (5.07), 1.554 (5.06), 2.326 (16.00), 2.616 (5.95), 5.670 (0.76), 5.687 (1.17), 5.704 (0.75), 7.322 (0.67), 7.341 (1.46), 7.361 (0.86), 7.495 (3.08), 7.517 (4.78), 7.533 (1.31), 7.759 (1.43), 7.778 (1.28), 7.806 (1.97), 7.811 (2.05), 7.828 (1.66), 7.834 (1.79), 8.659 (1.13), 8.677 (1.10), 8.705 (2.60), 8.711 (2.66)。 LC-MS (方法2): R t= 1.50 min;MS (ESIpos): m/z = 425 [M+H]⁺ | CAS 5426-59-5及CAS 1212862-77-5 3.90 g (88%產率) |
表3中顯示之中間物係根據一般程序1自各別嘧啶-4-醇衍生物及各別胺製備。
中間物表
3
編號 | 結構 IUPAC名稱 分析資料 | 起始材料 產率 |
183 | 6-(二甲基磷醯基)-2-甲基喹唑啉-4-醇 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (1.94), 1.052 (3.81), 1.069 (2.10), 1.357 (0.48), 1.390 (0.48), 1.683 (15.94), 1.716 (16.00), 2.376 (13.54), 2.518 (1.08), 2.523 (0.71), 3.422 (1.00), 3.434 (1.03), 3.439 (0.87), 3.452 (0.91), 4.345 (0.74), 4.357 (1.44), 4.370 (0.71), 7.656 (1.08), 7.661 (1.07), 7.677 (1.19), 7.682 (1.16), 8.069 (0.82), 8.074 (0.82), 8.090 (0.78), 8.095 (1.55), 8.099 (0.83), 8.116 (0.74), 8.120 (0.75), 8.439 (1.15), 8.443 (1.13), 8.469 (1.16), 8.473 (1.11), 12.397 (0.67)。 LC-MS (): R t= min;MS (): m/z = | CAS 5426-59-5 94.0 mg (19%產率) |
184 | 4-(2-甲基-4-{[(1S)-1-[2-甲基-3-(三氟甲基)苯基]( 2H 4)乙基]胺基}吡啶并[3,4-d]嘧啶-6-基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.447 (16.00), 2.327 (0.41), 2.422 (4.78), 2.518 (1.14), 2.523 (0.80), 2.621 (1.97), 7.367 (0.52), 7.542 (0.53), 7.559 (0.43), 7.785 (0.48), 7.804 (0.43), 9.000 (0.55), 9.016 (0.54), 9.087 (1.29), 9.373 (0.75)。 LC-MS (方法2): R t= 135.00 min;MS (ESIpos): m/z = 568 [M+H]⁺ | 中間物136及中間物52 169 mg (91%產率) |
185 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.446 (16.00), 1.615 (1.79), 1.633 (1.78), 2.432 (4.24), 2.518 (0.83), 2.523 (0.55), 5.756 (0.89), 5.795 (0.40), 7.103 (0.43), 7.238 (0.89), 7.303 (0.67), 7.514 (0.41), 9.002 (0.57), 9.019 (0.57), 9.106 (1.37), 9.285 (0.40)。 LC-MS (方法2): R t= 1.24 min;MS (ESIpos): m/z = 550 [M+H]⁺ | 中間物165及中間物52 2.09 g (89%產率) |
186 | 4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.25 min;MS (ESIpos): m/z = 595 [M+H]⁺ | 中間物172及中間物52 192 mg (147%產率) |
187 | 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.38 min;MS (ESIpos): m/z = 564.5 [M+H]⁺ | 中間物117及中間物52 290 mg (粗,87%產率) |
188 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-甲基苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.26 min;MS (ESIpos): m/z = 546.7 [M+H]⁺ | 中間物166及中間物52 210 mg (粗,105%產率) |
189 | 4-[4-({(1R)-1-[2-氟-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.448 (16.00), 1.631 (1.99), 1.649 (1.98), 2.323 (0.51), 2.327 (0.58), 2.331 (0.45), 2.414 (5.37), 2.522 (1.57), 2.669 (0.41), 5.758 (0.49), 7.369 (0.69), 7.659 (0.52), 7.834 (0.51), 9.001 (0.72), 9.017 (0.72), 9.109 (1.77), 9.324 (0.55), 9.341 (0.55)。 LC-MS (方法2): R t= 1.34 min;MS (ESIpos): m/z = 568 [M+H]⁺ | 中間物171及中間物52 108 mg (95%純度,39%產率) |
190 | 4-[4-({(1R)-1-[3-(1,1-二氟乙基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.28 min;MS (ESIpos): m/z = 546.5 [M+H]⁺ | 中間物167及中間物52 190 mg (粗) |
191 | 4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.250 (2.57), 1.258 (2.72), 1.410 (0.58), 1.448 (16.00), 1.593 (1.64), 1.610 (1.65), 2.323 (0.48), 2.327 (0.59), 2.331 (0.46), 2.413 (4.44), 2.518 (1.75), 2.523 (1.19), 2.669 (0.45), 3.174 (5.17), 5.759 (2.91), 5.772 (0.41), 7.225 (0.61), 7.245 (0.41), 7.595 (0.46), 7.608 (0.44), 7.612 (0.58), 7.621 (0.58), 7.625 (0.71), 7.641 (0.40), 7.645 (0.44), 9.014 (0.58), 9.029 (0.57), 9.105 (1.34), 9.282 (0.41)。 LC-MS (方法2): R t= 1.35 min;MS (ESIpos): m/z = 622 [M+H]⁺ | 中間物67及中間物52 185 mg (115%產率) |
192 | 4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.25 min;MS (ESIpos): m/z = 576.5 [M+H]⁺ | 中間物172及中間物52 !無TS! |
193 | 4-(4-{[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.76 min;MS (ESIpos): m/z = 722 [M+H]⁺ | 中間物49及中間物52 300 mg (81%產率) |
194 | 1-苄基-4-[4-({(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.052 (0.41), 1.070 (0.51), 1.592 (5.16), 1.610 (5.24), 1.874 (0.41), 1.914 (0.81), 1.955 (0.47), 2.322 (0.60), 2.327 (0.85), 2.332 (0.75), 2.336 (0.52), 2.385 (16.00), 2.518 (3.45), 2.523 (2.29), 2.665 (0.55), 2.669 (0.81), 2.673 (0.57), 2.807 (0.90), 2.838 (0.98), 2.928 (0.61), 2.942 (0.46), 2.959 (0.46), 2.971 (0.53), 2.983 (0.62), 2.997 (0.46), 3.014 (0.41), 3.660 (6.09), 5.758 (1.08), 5.860 (0.84), 5.877 (1.28), 5.895 (0.82), 7.250 (0.50), 7.257 (0.65), 7.265 (1.02), 7.270 (0.72), 7.273 (0.87), 7.280 (0.90), 7.287 (0.71), 7.326 (0.84), 7.328 (0.66), 7.331 (0.48), 7.340 (0.64), 7.346 (4.32), 7.354 (4.56), 7.361 (11.58), 7.374 (0.62), 7.487 (0.85), 7.507 (1.78), 7.526 (1.02), 7.725 (1.40), 7.728 (1.59), 7.744 (1.27), 7.747 (1.25), 7.846 (1.35), 7.849 (1.36), 7.867 (1.22), 9.005 (1.69), 9.020 (1.67), 9.126 (4.27), 9.128 (4.20), 9.387 (1.32), 9.404 (1.27)。 LC-MS (方法2): R t= 1.39 min;MS (ESIpos): m/z = 574 [M+H]⁺ | 中間物168 270 mg (94%產率) |
195 | 1-苄基-4-[2-甲基-4-({(1R)-1-[3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.052 (0.52), 1.070 (0.60), 1.234 (0.45), 1.384 (1.85), 1.619 (5.89), 1.637 (5.94), 1.867 (0.50), 1.909 (0.98), 1.946 (0.57), 2.322 (0.90), 2.327 (1.24), 2.332 (1.11), 2.336 (0.71), 2.367 (0.84), 2.377 (0.83), 2.461 (16.00), 2.518 (4.38), 2.523 (2.96), 2.664 (0.71), 2.669 (1.03), 2.673 (0.73), 2.798 (1.06), 2.829 (1.17), 2.856 (0.48), 2.908 (0.71), 2.922 (0.55), 2.941 (0.57), 2.952 (0.62), 2.962 (0.73), 2.977 (0.53), 2.994 (0.47), 3.651 (7.31), 5.638 (0.88), 5.656 (1.32), 5.674 (0.88), 7.248 (0.57), 7.254 (0.76), 7.261 (1.22), 7.268 (0.94), 7.270 (0.92), 7.276 (1.02), 7.283 (0.80), 7.321 (0.89), 7.324 (0.78), 7.327 (0.54), 7.341 (5.32), 7.348 (5.59), 7.356 (12.47), 7.369 (0.70), 7.549 (0.60), 7.569 (1.83), 7.587 (2.27), 7.596 (2.46), 7.615 (0.75), 7.759 (1.58), 7.778 (1.24), 7.844 (2.59), 8.929 (1.96), 8.944 (1.94), 9.121 (4.75), 9.214 (1.50), 9.233 (1.44)。 LC-MS (方法2): R t= 1.33 min;MS (ESIneg): m/z = 538 [M-H]⁻ | 中間物169 296 mg (101%產率) |
196 | 4-[4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)-2-(三氟甲基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法1): R t= 1.49 min;MS (ESIpos): m/z = 619 [M+H]⁺ | 中間物105及中間物52 537 mg (71%純度,93%產率) |
197 | 4-[2-(二氟甲基)-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法1): R t= 1.42 min;MS (ESIpos): m/z = 601 [M+H]⁺ | 中間物108及中間物52 252 mg (70%純度,96%產率) |
198 | 4-[2-氯-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法1): R t= 1.46 min;MS (ESIpos): m/z = 585 [M+H]⁺ | 中間物111及中間物52 162 mg (29%純度,30%產率) |
199 | 4-[7-甲氧基-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.30 min;MS (ESIpos): m/z = 595 [M+H]⁺ | 中間物35及中間物52 180 mg (110%產率) |
200 | 4-[2,7-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.153 (1.92), 1.172 (3.98), 1.189 (1.95), 1.407 (4.02), 1.429 (16.00), 1.470 (0.83), 1.487 (0.82), 1.589 (1.89), 1.607 (1.84), 2.323 (0.49), 2.327 (0.62), 2.331 (0.50), 2.394 (3.56), 2.449 (1.03), 2.518 (2.71), 2.523 (1.67), 2.601 (2.61), 2.669 (0.50), 2.866 (3.74), 3.084 (0.62), 3.095 (0.64), 3.102 (0.66), 3.113 (0.60), 7.375 (0.58), 7.557 (0.68), 7.575 (0.54), 7.749 (0.59), 7.769 (0.53), 8.843 (0.49), 8.875 (0.48)。 LC-MS (方法2): R t= 1.29 min;MS (ESIpos): m/z = 578 [M+H]⁺ | 中間物18及中間物52 247 mg (75%產率) |
201 | 4-[2,8-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.50 min;MS (ESIpos): m/z = 578 [M+H]⁺ | 中間物140及中間物52 201 mg (153%產率) |
202 | 1-苄基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.797 (0.54), 0.814 (0.53), 0.821 (0.58), 0.904 (0.60), 1.052 (0.46), 1.070 (0.60), 1.155 (7.41), 1.173 (16.00), 1.191 (7.85), 1.581 (5.66), 1.598 (5.67), 1.751 (1.02), 1.907 (0.76), 1.955 (0.72), 1.971 (0.79), 2.011 (0.50), 2.323 (1.24), 2.327 (1.71), 2.332 (1.42), 2.336 (1.00), 2.368 (13.09), 2.411 (0.41), 2.518 (5.36), 2.523 (3.68), 2.629 (7.53), 2.660 (0.46), 2.665 (0.96), 2.669 (1.34), 2.673 (0.97), 2.678 (0.45), 2.727 (0.82), 2.781 (0.70), 2.819 (0.70), 2.888 (1.42), 2.941 (0.88), 3.065 (0.84), 3.077 (0.92), 3.083 (2.57), 3.095 (2.34), 3.102 (2.61), 3.113 (2.21), 3.119 (0.96), 3.131 (0.71), 3.660 (1.36), 5.725 (0.79), 5.742 (1.22), 5.758 (1.42), 7.283 (0.83), 7.342 (1.56), 7.362 (6.15), 7.369 (6.39), 7.381 (1.98), 7.535 (2.04), 7.554 (1.65), 7.662 (1.26), 7.668 (1.29), 7.684 (1.42), 7.689 (1.38), 7.777 (1.80), 7.796 (1.64), 8.039 (0.53), 8.062 (0.92), 8.084 (0.47), 8.824 (1.12), 8.855 (1.18)。 LC-MS (方法2): R t= 1.34 min;MS (ESIpos): m/z = 553 [M+H]⁺ | 中間物182 234 mg (120%產率) |
203 | 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.444 (16.00), 1.574 (1.91), 1.592 (1.93), 2.323 (0.43), 2.327 (0.59), 2.331 (0.50), 2.378 (0.45), 2.406 (2.88), 2.518 (2.31), 2.523 (1.49), 2.618 (2.56), 2.669 (0.48), 5.758 (0.97), 7.369 (0.57), 7.549 (0.70), 7.568 (0.57), 7.765 (0.68), 7.784 (0.57), 9.218 (0.78), 9.224 (0.60), 9.229 (0.57), 9.240 (0.44)。 LC-MS (方法2): R t= 1.26 min;MS (ESIpos): m/z = 564 [M+H]⁺ | 中間物15及中間物52 257 mg (97%產率) |
204 | 4-(4-{[(1R)-1-(3-{1,1-二氟-2-[(甲磺醯基)胺基]乙基}-2-氟苯基)乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (1.74), 1.052 (3.64), 1.070 (1.68), 1.410 (1.13), 1.448 (16.00), 1.605 (1.65), 1.623 (1.60), 2.318 (0.44), 2.323 (0.67), 2.327 (0.86), 2.331 (0.64), 2.441 (4.54), 2.518 (3.23), 2.523 (2.14), 2.665 (0.50), 2.669 (0.71), 2.673 (0.50), 2.829 (5.62), 3.422 (0.54), 3.435 (0.55), 3.440 (0.52), 3.452 (0.52), 4.358 (0.49), 5.800 (0.41), 7.289 (0.71), 7.309 (0.42), 7.445 (0.40), 7.782 (0.63), 9.007 (0.59), 9.023 (0.58), 9.110 (1.40), 9.271 (0.41), 9.288 (0.40)。 | 中間物150及中間物52 136 mg (90%純度,62%產率) |
205 | 4-[4-({(1R)-1-[3-(2-乙醯胺基-1,1-二氟乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.09 min;MS (ESIpos): m/z = 621.8 [M+H]⁺ | 中間物151及中間物52 168 mg (90%純度,70%產率) |
206 | 4-(4-{[(1R)-1-(3-{1,1-二氟-2-[(甲磺醯基)(甲基)胺基]乙基}-2-氟苯基)乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.053 (1.02), 1.071 (0.96), 1.159 (0.46), 1.409 (0.83), 1.448 (16.00), 1.599 (1.59), 1.617 (1.59), 2.323 (0.40), 2.327 (0.45), 2.430 (3.95), 2.518 (1.22), 2.523 (0.84), 2.855 (8.91), 3.363 (0.66), 7.286 (0.69), 7.305 (0.40), 9.012 (0.57), 9.029 (0.56), 9.110 (1.21)。 | 中間物153及中間物52 182 mg (95%純度,81%產率) |
207 | 4-(4-{[(1R)-1-(3-{2-[乙醯基(甲基)胺基]-1,1-二氟乙基}-2-氟苯基)乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.052 (0.99), 1.070 (0.69), 1.159 (0.55), 1.165 (0.67), 1.408 (2.69), 1.447 (16.00), 1.602 (1.03), 1.610 (0.96), 1.620 (1.06), 1.628 (0.87), 1.915 (2.46), 1.926 (3.60), 2.323 (0.46), 2.327 (0.54), 2.332 (0.41), 2.428 (2.47), 2.433 (2.88), 2.518 (1.45), 2.523 (1.02), 2.840 (1.67), 3.020 (2.21), 9.013 (0.62), 9.029 (0.61), 9.107 (0.95)。 | 中間物154及中間物52 139 mg (95%純度,81%產率) |
208 | 1-[4-({(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-2,5-二氫-1H-1λ 5-磷雜環戊烯-1-酮 LC-MS (方法2): R t= 1.53 min;MS (ESIpos): m/z = 577.7 [M+H]⁺ | 中間物170 120 mg (116%產率) |
209 | N-[(1R)-1-{3-[2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟( 2H 2)乙基]-2-氟苯基}乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 LC-MS (方法2): R t= 1.48 min;MS (ESIpos): m/z = 555 [M+H]⁺ | 中間物135 121 mg (122%產率) |
210 | 1-(4-{[(1R)-1-{3-[2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟( 2H 2)乙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ 5-磷雜環戊烷-1-酮 LC-MS (方法2): R t= 1.60 min;MS (ESIpos): m/z = 581 [M+H]⁺ | 中間物134 157 mg (151%產率) |
211 | N-{(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟乙基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 LC-MS (方法2): R t= 1.49 min;MS (ESIpos): m/z = 553 [M+H]⁺ | 中間物170 65.0 mg (131%產率) |
212 | 1-[4-({(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 LC-MS (方法2): R t= 1.57 min;MS (ESIpos): m/z = 579 [M+H]⁺ | 中間物170 113 mg (145%產率) |
213 | N-{(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟乙基)-2-氟苯基]乙基}-6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 LC-MS (方法2): R t= 1.57 min;MS (ESIpos): m/z = 581 [M+H]⁺ | 中間物170 115 mg (147%產率) |
216 | N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物) LC-MS (方法1): R t= 1.64 min;MS (ESIpos): m/z = 596 [M+H]⁺ | 中間物49 240 mg (112%產率) |
219 | N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物) LC-MS (方法1): R t= 1.68 min;MS (ESIpos): m/z = 610 [M+H]⁺ | 中間物49 270 mg (114%產率) |
220 | N-[(1R)-1-(3-{(2R*)-1,1-二氟-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺 無需純化即可使用。 | 中間物42 260 mg (102%產率) |
221 | N-[(1R)-1-(3-{(2R*)-1,1-二氟-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物) 無需純化即可使用。 | 中間物43 230 mg (103%產率) |
222 | N-[(1R)-1-(3-{(2R*)-1,1-二氟-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物1.1及1.2) 無需純化即可使用。 | 中間物42 265 mg (102%產率) |
223 | N-[(1R)-1-(3-{(2R*)-1,1-二氟-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物2.1及2.2) 無需純化即可使用。 | 中間物43 240 mg (104%產率) |
224 | 1-(4-{[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-2,5-二氫-1H-1λ 5—磷雜環戊烯-1-酮 LC-MS (方法2): R t= 1.66 min;MS (ESIpos): m/z = 605 [M+H]⁺ | 中間物49 350 mg (169%產率) |
225 | N-[(1R)-1-{3-[(2R*)-2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟丙基]-2-氟苯基}乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體1) LC-MS (方法2): R t= 1.56 min;MS (ESIpos): m/z = 567 [M+H]⁺ | 中間物47 150 mg (151%產率) |
表4中顯示之中間物係根據一般程序3自各別受N-Boc保護之衍生物及各別胺製備。
中間物表
4
編號 | 結構 IUPAC名稱 分析資料 | 起始材料 產率 |
226 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.617 (5.02), 1.635 (5.00), 1.758 (0.40), 1.797 (0.80), 1.838 (0.44), 2.284 (0.81), 2.296 (0.81), 2.309 (0.86), 2.318 (1.10), 2.322 (1.33), 2.327 (1.44), 2.331 (1.23), 2.428 (16.00), 2.518 (3.30), 2.523 (2.24), 2.665 (0.59), 2.669 (0.83), 2.673 (0.58), 3.013 (0.70), 3.070 (0.75), 3.079 (0.71), 3.094 (0.49), 3.103 (0.70), 3.112 (0.72), 3.119 (0.66), 3.134 (0.68), 3.142 (0.66), 5.775 (0.78), 5.793 (1.20), 5.811 (0.76), 7.104 (1.18), 7.240 (2.45), 7.284 (0.86), 7.303 (1.89), 7.322 (1.08), 7.376 (1.04), 7.496 (0.64), 7.513 (1.08), 7.531 (0.53), 7.685 (0.59), 7.702 (1.07), 7.721 (0.54), 8.949 (1.75), 8.965 (1.76), 9.111 (4.36), 9.240 (1.26), 9.257 (1.21)。 LC-MS (方法2): R t= 0.98 min;MS (ESIpos): m/z = 451 [M+H]⁺ | 中間物185 1.23 g (95%純度,90%產率) |
227 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-甲基苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮鹽酸鹽(1/1) LC-MS (方法2): R t= 0.98 min;MS (ESIpos): m/z = 446.6 [M+H]⁺ | 中間物188 210 mg (113%產率) |
228 | 三氟乙酸4-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮(1/1) LC-MS (方法2): R t= 0.93 min;MS (ESIpos): m/z = 508 [M+H]⁺ | 中間物193 154 mg (102%產率) |
229 | 4-[4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)-2-(三氟甲基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 LC-MS (方法2): R t= 1.35 min;MS (ESIneg): m/z = 516 [M-H]⁻ | 中間物196 690 mg (153%產率) |
230 | 4-[2-(二氟甲基)-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 LC-MS (方法2): R t= 1.26 min;MS (ESIneg): m/z = 498 [M-H]⁻ | 中間物197 316 mg (151%產率) |
231 | 4-[2-氯-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 LC-MS (方法2): R t= 1.18 min;MS (ESIpos): m/z = 485 [M+H]⁺ | 中間物198 134 mg (50%純度,50%產率) |
232 | N-(2,2-二氟-2-{2-氟-3-[(1R)-1-{[2-甲基-6-(4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]苯基}乙基)甲磺醯胺鹽酸鹽(1/1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.662 (3.40), 1.679 (3.15), 2.336 (1.47), 2.518 (11.64), 2.523 (7.39), 2.559 (5.10), 2.827 (16.00), 3.164 (5.95), 3.232 (1.17), 3.312 (1.23), 3.385 (3.70), 3.469 (10.73), 3.565 (5.13), 3.643 (1.54), 3.650 (1.07), 3.662 (0.99), 3.674 (0.94), 3.699 (0.84), 3.713 (0.84), 3.724 (1.04), 3.740 (1.02), 3.759 (1.29), 3.776 (1.30), 3.796 (0.83), 3.813 (0.78), 4.132 (0.44), 5.759 (2.21), 5.872 (0.56), 5.889 (0.76), 5.906 (0.48), 7.308 (0.70), 7.327 (1.57), 7.346 (0.93), 7.462 (0.66), 7.479 (1.11), 7.496 (0.54), 7.757 (0.61), 7.771 (1.54), 7.787 (2.15), 7.804 (0.90), 9.250 (2.18)。 | 中間物204 129 mg (90%純度,96%產率) |
233 | N-(2,2-二氟-2-{2-氟-3-[(1R)-1-{[2-甲基-6-(4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]苯基}乙基)乙醯胺鹽酸鹽(1/1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.184 (0.82), 1.201 (0.43), 1.248 (3.55), 1.265 (3.95), 1.273 (2.95), 1.289 (2.49), 1.675 (2.55), 1.692 (1.95), 1.764 (9.37), 2.331 (1.98), 2.336 (1.23), 2.518 (10.05), 2.523 (6.21), 2.589 (2.73), 2.673 (1.97), 2.706 (0.69), 3.114 (0.51), 3.124 (0.53), 3.132 (0.53), 3.142 (0.54), 3.164 (16.00), 3.232 (0.67), 3.311 (0.94), 3.384 (3.19), 3.565 (7.78), 3.643 (2.28), 3.662 (1.60), 3.674 (1.40), 3.699 (1.13), 3.709 (0.94), 3.713 (0.95), 3.838 (0.62), 3.860 (0.68), 3.882 (0.76), 3.898 (0.87), 3.911 (0.81), 3.928 (0.50), 3.951 (0.43), 5.759 (2.99), 5.885 (0.48), 5.903 (0.55), 7.280 (0.52), 7.300 (1.16), 7.320 (0.66), 7.419 (0.58), 7.436 (0.96), 7.453 (0.45), 7.765 (0.56), 8.335 (0.64), 8.351 (1.33), 8.366 (0.63), 9.285 (1.36)。 | 中間物205 152 mg (90%純度,92%產率) |
234 | N-(2,2-二氟-2-{2-氟-3-[(1R)-1-{[2-甲基-6-(4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]苯基}乙基)-N-甲基甲磺醯胺鹽酸鹽(1/1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.672 (3.33), 1.689 (3.25), 2.318 (0.48), 2.322 (0.92), 2.327 (1.25), 2.332 (1.01), 2.336 (0.61), 2.373 (0.61), 2.413 (0.40), 2.518 (3.31), 2.523 (2.39), 2.580 (5.80), 2.665 (0.75), 2.669 (1.08), 2.673 (0.80), 2.678 (0.45), 2.724 (0.66), 2.747 (0.62), 2.841 (16.00), 2.854 (12.11), 3.164 (2.28), 3.232 (0.75), 3.311 (0.84), 3.384 (2.03), 3.441 (0.87), 3.446 (0.96), 3.452 (1.01), 3.457 (1.32), 3.459 (1.17), 3.463 (1.02), 3.468 (1.38), 3.469 (1.45), 3.479 (0.99), 3.486 (1.64), 3.488 (1.56), 3.490 (1.44), 3.496 (1.46), 3.499 (1.55), 3.501 (1.34), 3.510 (1.19), 3.514 (1.16), 3.597 (1.34), 3.604 (1.30), 3.644 (2.41), 3.651 (1.34), 3.658 (1.33), 3.662 (1.55), 3.667 (1.50), 3.675 (1.56), 3.677 (1.70), 3.690 (1.17), 3.699 (1.57), 3.701 (1.59), 3.709 (1.40), 3.713 (1.49), 3.717 (1.24), 3.724 (1.18), 3.729 (1.12), 3.731 (1.05), 3.834 (0.64), 3.872 (0.99), 3.903 (1.24), 3.939 (1.33), 3.974 (0.77), 4.018 (0.61), 4.132 (0.84), 5.882 (0.53), 5.900 (0.77), 5.917 (0.49), 7.310 (0.76), 7.330 (1.64), 7.350 (0.95), 7.478 (0.61), 7.494 (1.03), 7.511 (0.51), 7.782 (0.50), 7.798 (0.81), 7.816 (0.42), 9.301 (1.90), 9.354 (1.40)。 | 中間物206 175 mg (90%純度,96%產率) |
235 | N-(2,2-二氟-2-{2-氟-3-[(1R)-1-{[2-甲基-6-(4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]苯基}乙基)-N-甲基乙醯胺鹽酸鹽(1/1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.103 (0.71), 1.166 (3.50), 1.185 (7.34), 1.203 (3.76), 1.249 (1.23), 1.266 (1.35), 1.275 (0.83), 1.290 (0.76), 1.671 (2.63), 1.686 (3.26), 1.897 (16.00), 2.318 (0.85), 2.322 (1.53), 2.327 (2.11), 2.332 (1.69), 2.336 (1.06), 2.370 (0.88), 2.518 (5.71), 2.523 (3.98), 2.573 (2.70), 2.660 (0.60), 2.665 (1.29), 2.669 (1.87), 2.673 (1.40), 2.678 (0.78), 2.732 (0.90), 2.836 (6.00), 3.029 (9.03), 3.058 (1.37), 3.070 (1.74), 3.072 (1.51), 3.076 (1.37), 3.088 (1.41), 3.105 (0.51), 3.164 (0.89), 3.232 (0.95), 3.242 (0.56), 3.247 (0.71), 3.299 (0.62), 3.311 (1.36), 3.384 (5.55), 3.441 (2.06), 3.446 (2.23), 3.452 (2.44), 3.457 (3.16), 3.459 (2.88), 3.468 (3.49), 3.469 (3.64), 3.486 (4.19), 3.488 (4.02), 3.497 (3.96), 3.499 (4.31), 3.504 (3.84), 3.510 (4.01), 3.514 (4.11), 3.644 (3.23), 3.651 (2.71), 3.658 (2.59), 3.662 (2.96), 3.667 (2.77), 3.674 (2.82), 3.677 (2.96), 3.698 (2.54), 3.701 (2.50), 3.708 (2.07), 3.713 (2.25), 3.717 (1.73), 3.724 (1.54), 3.728 (1.44), 3.840 (0.58), 3.860 (0.54), 4.018 (0.71), 4.033 (0.59), 4.076 (0.64), 4.114 (0.51), 4.133 (0.88), 4.150 (0.97), 4.171 (0.79), 4.183 (1.02), 4.204 (0.54), 4.223 (0.61), 5.881 (0.71), 5.897 (0.70), 7.268 (0.48), 7.287 (1.07), 7.307 (0.65), 7.356 (0.62), 7.418 (0.52), 7.436 (0.86), 7.455 (0.42), 7.496 (0.59), 7.750 (0.44), 9.273 (1.16), 9.311 (1.32)。 | 中間物207 142 mg (90%純度,102%產率) |
236 | 二氟{2-氟-3-[(1R)-1-{[2-甲基-6-(4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]苯基}乙酸乙酯鹽酸鹽(1/1) LC-MS (方法2): R t= 1.01 min;MS (ESIpos): m/z = 522.5 [M+H]⁺ | 中間物157 1.34 g (103%產率) |
表5中顯示之中間物係自其等各別N-苄基衍生物藉由氫化製備:將N-苄基化合物(1當量)溶解於乙醇(0.1 M)中,添加Pd/C (10% Pd,0.9當量),並在氫氣氛下在室溫下將該混合物攪拌整夜。將該混合物過濾,濃縮,及獲得之粗產物無需純化即可用於下一反應。
中間物表
5
編號 | 結構 IUPAC名稱 分析資料 | 起始材料 產率 |
237 | 4-[4-({(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 LC-MS (方法2): R t= 1.10 min;MS (ESIpos): m/z = 484 [M+H]⁺ | 中間物194 218 mg (97%產率) |
238 | 4-[2-甲基-4-({(1R)-1-[3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 LC-MS (方法2): R t= 1.03 min;MS (ESIneg): m/z = 448 [M-H]⁻ | 中間物195 235 mg (96%產率) |
239 | 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 LC-MS (方法2): R t= 1.10 min;MS (ESIneg): m/z = 461 [M-H]⁻ | 中間物202 207 mg (111%產率) |
如針對中間物141描述自中間物43製備標題化合物,以獲得351 mg (90%產率)。
LC-MS (方法2): R
t= 1.11 min;MS (ESIpos): m/z = 455 [M+H]⁺
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.131 (3.39), 1.147 (3.45), 1.154 (2.16), 1.171 (3.70), 1.189 (1.77), 1.582 (4.17), 1.600 (4.21), 1.986 (5.52), 2.377 (16.00), 2.518 (1.96), 2.523 (1.38), 4.016 (1.11), 4.034 (1.08), 5.578 (2.44), 5.594 (2.37), 5.703 (0.65), 5.720 (1.01), 5.738 (0.64), 5.756 (2.12), 7.221 (0.70), 7.240 (1.60), 7.259 (0.96), 7.358 (0.51), 7.362 (0.58), 7.380 (0.88), 7.395 (0.44), 7.599 (0.49), 7.615 (0.86), 7.632 (0.44), 8.666 (3.67), 8.668 (3.68), 8.805 (4.24), 8.875 (1.05), 8.893 (1.00)。
根據一般程序2製備標題化合物,自中間物32 (1.0 g,4.2 mmol)及(R)-3-胺基-α-甲基-5-(三氟甲基)苯甲胺(CAS 1213552-98-7,1.2 g,5.0 mmol))開始以獲得標題化合物(1.47 g,82%產率)。
LC-MS (方法2): Rt = 1.21 min;MS (ESIpos): m/z = 426 [M+H]⁺
向(R)-1-(2-甲基-3-(三氟甲基)苯基)乙-1-胺鹽酸鹽(2.0 g,9.84 mmol)於二氯甲烷(50 ml)中之懸浮液添加N,N-二異丙基乙胺(3.43 ml,19.6 mmol),接著添加二碳酸二-三級丁酯(2.58 g,11.8 mmol),並在室溫下將該混合物攪拌20 h。該混合物用飽和氯化鈉水溶液稀釋並用乙酸乙酯萃取。將有機相乾燥並濃縮,並將殘餘物重新溶解於乙醇中,添加咪唑(335 mg),及在室溫下將該混合物攪拌2 h。然後該混合物用飽和氯化鈉水溶液稀釋並用乙酸乙酯萃取。將有機相乾燥並濃縮,及殘餘物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以產生標題化合物(2.78 g,92%產率)。
1H NMR (400 MHz,氯仿-d) δ ppm 1.40 (br s, 12 H) 2.46 (s, 3 H) 4.70 - 5.26 (m, 2 H) 7.20 - 7.34 (m, 1 H) 7.39 - 7.57 (m, 2 H)。
向雙(1,5-環辛二烯)二甲氧基二銥(49 mg,74 µmol)及4,4'-二-三級丁基-2,2’-聯吡啶(39 mg,148 µmol)於四氫呋喃(15 ml)中之溶液添加(R)-(1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基甲酸三級丁酯(中間物242,1.5 g,4.95 mmol)及雙(頻哪醇合)二硼(1.26 g,4.95 mmol),並在80℃下將該混合物攪拌20 h。然後濃縮該混合物並將殘餘物重新溶解於甲醇(60 ml)中。然後向該混合物添加至於水(60 ml)中之溴化銅(II) (3.31 g,14.8 mmol),並在90℃下將所得混合物加熱6 h。然後將該混合物冷卻,用飽和碳酸氫鈉水溶液稀釋,及用乙酸乙酯萃取。將有機相乾燥並濃縮,以產生標題化合物(1.31 g,69%產率)。
LC-MS (方法2): R
t= 1.51 min;MS (ESIneg): m/z = 380 [M-H]
-
將(R)-(1-(5-溴-2-甲基-3-(三氟甲基)苯基)乙基)-胺基甲酸三級丁酯(粗中間物243,300 mg,784 µmol)、碳酸銫(511 mg,1.57 mmol)、三甲基硼氧烴三聚物(147 mg,1.18 mmol)及[1,1'雙(二苯基膦基)二茂鐵]二氯化鈀(II) (57.4 mg,78.5 µmol)之混合物加熱至110℃,歷時20 h。將該混合物冷卻,濃縮,及殘餘物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯)純化以產生標題化合物(180 mg,72%產率)。
LC-MS (方法2): R
t= 1.49 min;MS (ESIneg): m/z = 316 [M-H]
-
如針對中間物28描述製備標題化合物,自(R)-(1-(2,5-二甲基-3-(三氟甲基)苯基)乙基)胺基甲酸三級丁酯(中間物244,180 mg,567 µmol)開始以產生標題化合物(105 mg,72%產率)。
1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 - 1.53 (m, 3 H) 2.38 (m, 6 H) 4.49 - 4.85 (m, 1 H) 7.44 - 7.59 (m, 1 H) 7.60 - 7.79 (m, 1 H) 8.13 - 8.66 (m, 3 H)。
遵循一般程序1,在氬下向6-氯-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺(60.0 mg,158 µmol)、二甲基-λ5-膦酮(12.3 mg,158 µmol)及三乙胺(77 µl,550 µmol)於乙腈(800 µl)中之溶液添加肆(三苯基膦)鈀(0) (28.9 mg,31.5 µmol)並在90℃下將該混合物加熱整夜。將該混合物過濾,濃縮並藉由HPLC (鹼性方法)純化,以產生標題化合物(17 mg,95%純度,24%產率)。
LC-MS (方法2): Rt = 1.17 min;MS (ESIneg): m/z = 421 [M-H]-
1H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.58 (d, 3H), 1.68 - 1.73 (m, 6H), 2.42 (s, 3H), 2.63 (s, 3H), 5.72 (t, 1H), 7.37 (t, 1H), 7.55 (d, 1H), 7.81 (d, 1H), 8.96 (dd, 1H), 9.07 (s, 1H), 9.38 (d, 1H)。
在氬下向6-氯-N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺(70.0 mg,191 µmol)、二甲基-λ5-膦酮(14.9 mg,191 µmol)及三乙胺(93 µl,670 µmol)於乙腈(970 µl)中之溶液添加肆(三苯基膦)鈀(0) (35.0 mg,38.2 µmol)並在90℃下將該混合物加熱整夜。將該混合物過濾,濃縮並藉由HPLC (鹼性方法)純化。將含有標題化合物之溶離份濃縮並藉由製備型薄層層析術(矽膠、CH
2Cl
2/EtOH 95:5)進一步純化以產生呈白色固體之標題化合物(35 mg,95%純度,43%產率)。
LC-MS (方法2): Rt = 1.01 min;MS (ESIneg): m/z = 407 [M-H]-
1H NMR (DMSO-d6) δ:9.30 (d, J=7.4 Hz, 1H), 9.09 (s, 1H), 8.96 (d, J=6.1 Hz, 1H), 7.71 (s, 1H), 7.42-7.57 (m, 1H), 7.09-7.39 (m, 2H), 5.70-5.87 (m, 1H), 2.43 (s, 3H), 1.67-1.75 (m, 6H), 1.59-1.65 (m, 3H)。
在室溫下向N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺(107 mg,184 µmol)及三乙基矽烷(2.9 µl,18 µmol)於二氯甲烷中之溶液滴加三氟乙酸(210 µl,2.8 mmol)並將該混合物整夜。然後,添加另一三氟乙酸(210 µl,2.8 mmol)並將該反應混合物再次攪拌整夜,然後該混合物用甲苯稀釋,濃縮並藉由製備型HPLC (酸性方法)純化以產生標題化合物(16 mg,98%純度,18%產率)。
LC-MS (方法4): Rt = 0.82 min;MS (ESIpos): m/z = 467.46 [M+H]+
1H NMR (DMSO-d6) δ:9.21-9.35 (m, 1H), 9.09 (s, 1H), 8.98 (d, J=6.6 Hz, 1H), 7.54-7.73 (m, 1H), 7.30-7.40 (m, 1H), 7.14-7.26 (m, 1H), 5.71-5.85 (m, 1H), 5.34 (s, 1H), 2.39-2.43 (m, 3H), 1.68-1.75 (m, 6H), 1.57-1.63 (m, 3H), 1.18-1.25 (m, 7H)。
在氬下向1-(3-{(1R)-1-[(6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇(80.0 mg,170 µmol)、1λ5-磷雜環戊烷-1-酮(17.7 mg,170 µmol)及三乙胺(83 µl,600 µmol;CAS-RN:[121-44-8])於乙腈(1.8 ml)中之溶液添加肆(三苯基膦)鈀(0) (29.5 mg,25.6 µmol;CAS-RN:[14221-01-3])並在90℃下將該混合物攪拌整夜。將該混合物冷卻,過濾並濃縮。殘餘物藉由製備型薄層層析術(矽膠、二氯甲烷、乙醇9:1)純化以產生標題化合物(60.7 mg,95%純度,69%產率)。
LC-MS (方法2): Rt = 1.07 min;MS (ESIpos): m/z = 493 [M+H]+
1H NMR (DMSO-d6) δ:9.32 (d, J=7.4 Hz, 1H), 9.07-9.12 (m, 1H), 9.00-9.06 (m, 1H), 7.59-7.67 (m, 1H), 7.27-7.36 (m, 1H), 7.18-7.26 (m, 1H), 5.76-5.86 (m, 1H), 5.27-5.39 (m, 1H), 2.41 (s, 3H), 1.93-2.21 (m, 6H), 1.75-1.90 (m, 2H), 1.53-1.63 (m, 3H), 1.12-1.32 (m, 6H)。
在氬下向受質6-溴-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺(100 mg,235 µmol)、1-苄基-1,4λ5-氮雜磷雜環己烷-4-酮(49.2 mg,235 µmol)及三乙胺(110 µl,820 µmol)於乙腈(1.2 ml)中之溶液添加肆(三苯基膦)鈀(0) (43.1 mg,47.0 µmol)並在90℃下將該混合物加熱整夜。然後將該混合物冷卻,過濾,濃縮並藉由HPLC (鹼性方法)純化以產生呈白色固體之標題化合物(71 mg,95%純度,52%產率)。
LC-MS (方法2): Rt = 1.39 min;MS (ESIpos): m/z = 554 [M+H]+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.566 (5.04), 1.584 (5.07), 1.867 (0.43), 1.906 (0.85), 1.947 (0.48), 2.322 (0.81), 2.326 (1.14), 2.332 (0.91), 2.336 (0.67), 2.361 (0.78), 2.372 (0.71), 2.381 (0.76), 2.418 (16.00), 2.518 (3.76), 2.522 (2.40), 2.620 (6.37), 2.664 (0.64), 2.669 (0.90), 2.673 (0.64), 2.801 (0.93), 2.831 (1.02), 2.860 (0.40), 2.917 (0.62), 2.931 (0.48), 2.950 (0.47), 2.961 (0.54), 2.972 (0.66), 2.985 (0.47), 3.003 (0.41), 3.655 (6.52), 5.698 (0.78), 5.715 (1.21), 5.733 (0.76), 7.249 (0.50), 7.255 (0.66), 7.263 (1.07), 7.268 (0.78), 7.271 (0.85), 7.277 (0.91), 7.284 (0.72), 7.323 (0.79), 7.329 (0.48), 7.343 (5.16), 7.350 (5.04), 7.358 (12.53), 7.371 (0.67), 7.380 (0.98), 7.538 (1.74), 7.556 (1.40), 7.779 (1.54), 7.798 (1.38), 8.977 (1.78), 8.992 (1.74), 9.104 (4.69), 9.350 (1.33), 9.368 (1.28)。
向1-苄基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ5-氮雜磷雜環己烷-4-酮(130 mg,235 µmol)於乙醇(2.0 ml)中之溶液添加Pd/C 10% (50.0 mg,47.0 µmol)。將燒瓶抽空並用氬(3x)回填。然後,用氫吹掃該燒瓶並在室溫下在氫氣氛下將該混合物攪拌兩天。然後將該混合物過濾,在減壓下濃縮並藉由管柱層析術(矽膠、二氯甲烷/乙醇)純化。濃縮經組合之溶離份以產生標題化合物35.0 mg (32%產率)。
LC-MS (方法2): R
t= 1.10 min;MS (ESIneg): m/z = 462 [M-H]
-
1H NMR (DMSO-d6) δ:9.28-9.43 (m, 1H), 9.09 (s, 1H), 8.89-9.01 (m, 1H), 7.74-7.87 (m, 1H), 7.48-7.60 (m, 1H), 7.26-7.44 (m, 1H), 5.61-5.84 (m, 1H), 2.96-3.23 (m, 5H), 2.62 (s, 3H), 2.42 (s, 3H), 2.27-2.37 (m, 3H), 1.75-1.88 (m, 2H), 1.54-1.62 (m, 3H)。
在室溫下向4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ5-氮雜磷雜環己烷-4-酮(33.0 mg,71%純度,50.2 µmol)於二氯甲烷(530 µl)中之溶液添加N,N-二異丙基乙胺(10 µl,60 µmol)及乙酸酐(5.2 µl,55 µmol)並在室溫下將該混合物攪拌整夜。然後該混合物用甲苯滴定,濃縮並藉由HPLC (鹼性方法)純化以產生標題化合物(21.5 mg,95%純度,80%產率)。
LC-MS (方法2): R
t= 1.13 min;MS (ESIneg): m/z = 504 [M-H]
-
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.574 (4.69), 1.591 (4.67), 2.054 (0.40), 2.116 (16.00), 2.254 (0.43), 2.274 (0.40), 2.327 (1.12), 2.332 (0.83), 2.382 (0.42), 2.420 (12.71), 2.518 (4.41), 2.523 (3.04), 2.623 (6.24), 2.669 (1.14), 2.673 (0.82), 3.859 (0.59), 3.872 (0.59), 3.885 (0.49), 3.916 (0.41), 5.708 (0.48), 5.724 (0.68), 5.739 (0.45), 7.348 (0.72), 7.367 (1.57), 7.387 (0.90), 7.543 (1.68), 7.561 (1.36), 7.787 (1.50), 7.806 (1.35), 9.010 (1.53), 9.026 (1.52), 9.094 (3.72), 9.375 (0.88), 9.389 (0.84)。
遵循一般程序1,在氬下向6-溴-N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺(300 mg,730 µmol)、1-苄基-1,4λ
5-氮雜磷雜環己烷-4-酮(153 mg,730 µmol)及三乙胺(360 µl,2.6 mmol)於乙腈(3.6 mL)中之溶液添加肆(三苯基膦)鈀(0) (126 mg,109 µmol)並在90℃下將該混合物加熱16小時。將該混合物過濾並濃縮及藉由Biotage-Selekt急驟管柱層析術使用CH
2Cl
2/乙醇(9/1)作為溶析液純化以產生標題化合物1-苄基-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ5-氮雜磷雜環己烷-4-酮(366 mg,95%純度,88%產率)。
LC-MS (方法2): R
t= 1.28 min;MS (ESIpos): m/z = 541 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.035 (0.64), 1.052 (1.44), 1.070 (0.77), 1.234 (0.73), 1.611 (5.60), 1.629 (5.58), 1.870 (0.47), 1.914 (0.90), 1.951 (0.54), 2.323 (0.48), 2.327 (0.73), 2.332 (0.69), 2.370 (0.86), 2.380 (0.76), 2.390 (0.84), 2.401 (0.82), 2.430 (16.00), 2.518 (2.19), 2.523 (1.64), 2.665 (0.45), 2.669 (0.64), 2.673 (0.44), 2.803 (0.98), 2.834 (1.09), 2.860 (0.46), 2.911 (0.69), 2.925 (0.54), 2.943 (0.54), 2.954 (0.60), 2.965 (0.71), 2.980 (0.52), 2.997 (0.45), 3.654 (6.72), 4.356 (0.44), 5.758 (0.41), 5.774 (0.88), 5.792 (1.35), 5.810 (0.87), 7.102 (1.35), 7.238 (2.86), 7.249 (0.59), 7.255 (0.73), 7.263 (1.15), 7.271 (0.92), 7.278 (1.74), 7.284 (0.89), 7.298 (2.23), 7.309 (0.68), 7.317 (1.36), 7.323 (1.06), 7.329 (0.56), 7.343 (4.87), 7.350 (5.10), 7.358 (12.04), 7.374 (1.47), 7.493 (0.73), 7.510 (1.23), 7.528 (0.61), 7.681 (0.67), 7.699 (1.20), 7.717 (0.60), 8.979 (1.85), 8.995 (1.85), 9.124 (4.59), 9.262 (1.39), 9.280 (1.36)。
向1-苄基-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(100 mg,185 µmol)於乙醇(1.6 mL)中之溶液添加碳載鈀(10重量%,158 mg,148 µmol)。將燒瓶抽空並用氬回填(重複三次)。然後用氫氣吹掃該燒瓶並在室溫下在氫氣氛下將該混合物攪拌16小時。然後將粗化合物過濾並在減壓下濃縮。該化合物藉由biotage急驟管柱層析術於矽膠上使用二氯甲烷及乙醇(9/1)作為溶析液純化。獲得標題化合物(31.0 mg,37%產率)。
LC-MS (方法2): R
t= 0.97 min;MS (ESIpos): m/z = 450 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.074 (10.08), 1.094 (0.53), 1.236 (0.48), 1.617 (4.46), 1.635 (4.38), 1.808 (0.72), 1.846 (0.40), 1.955 (11.30), 2.169 (0.61), 2.297 (0.66), 2.318 (1.09), 2.323 (1.67), 2.327 (2.15), 2.332 (1.51), 2.336 (0.88), 2.429 (13.03), 2.518 (6.66), 2.523 (4.59), 2.660 (0.56), 2.665 (1.17), 2.669 (1.65), 2.673 (1.17), 2.678 (0.56), 2.781 (10.75), 2.942 (16.00), 3.029 (0.64), 3.081 (0.80), 3.090 (0.72), 3.113 (0.66), 3.122 (0.64), 3.129 (0.61), 3.144 (0.61), 3.153 (0.61), 5.777 (0.69), 5.794 (1.06), 5.812 (0.69), 7.105 (1.03), 7.240 (2.15), 7.284 (0.80), 7.303 (1.65), 7.322 (0.96), 7.376 (0.90), 7.497 (0.58), 7.514 (0.96), 7.532 (0.48), 7.686 (0.53), 7.703 (0.96), 7.721 (0.48), 8.954 (1.51), 8.969 (1.51), 9.112 (3.69), 9.242 (1.09), 9.259 (1.06)。
在室溫下將4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(33.0 mg,73.4 µmol)溶解於二氯甲烷(0.78 mL)中。添加N,N-二異丙基乙胺(15 µl,88 µmol),接著添加乙酸酐(7.6 µl,81 µmol)。將該混合物攪拌16小時。添加甲苯並將該混合物部分蒸發。該化合物藉由HPLC (鹼性方法)純化以產生標題化合物(23 mg,95%純度,61%產率)。
LC-MS (方法2): R
t= 1.00 min;MS (ESIpos): m/z = 492 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.11), 1.352 (0.11), 1.619 (2.10), 1.636 (2.04), 1.908 (0.17), 2.058 (0.22), 2.118 (6.62), 2.327 (3.48), 2.331 (2.48), 2.433 (5.63), 2.518 (16.00), 2.523 (10.32), 2.669 (3.42), 2.673 (2.43), 2.678 (1.16), 3.707 (0.17), 3.866 (0.33), 4.037 (0.17), 5.784 (0.28), 5.799 (0.39), 5.817 (0.28), 7.106 (0.50), 7.241 (0.99), 7.287 (0.33), 7.306 (0.77), 7.325 (0.44), 7.377 (0.44), 7.500 (0.33), 7.516 (0.50), 7.534 (0.22), 7.688 (0.28), 7.706 (0.50), 7.725 (0.22), 9.014 (0.72), 9.031 (0.77), 9.118 (1.82), 9.282 (0.55), 9.300 (0.50)。
在室溫下將N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-6-(二甲基磷醯基)-2,8-二甲基吡啶并[3,4-d]嘧啶-4-胺(100 mg,168 µmol)溶解於二氯甲烷(2 mL)中。添加三乙基矽烷(2.7 µl,17 µmol),接著添加三氟乙酸(190 µl,2.5 mmol)。在室溫下將所得混合物攪拌20 h。將水及乙酸乙酯添加至該混合物並分離相。透過疏水性過濾乾燥有機相。蒸發溶劑。該化合物藉由HPLC (鹼性方法)純化並隨後藉由製備型薄層層析術使用二氯甲烷及乙醇作為溶析液純化以產生標題化合物(12.0 mg,15%產率)。
LC-MS (方法2): R
t= 1.12 min;MS (ESIpos): m/z = 481 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.202 (6.15), 1.229 (6.43), 1.582 (4.64), 1.599 (4.66), 1.671 (6.95), 1.674 (7.40), 1.705 (7.13), 1.708 (7.21), 2.416 (16.00), 2.518 (0.97), 2.523 (0.64), 2.770 (13.42), 5.335 (7.89), 5.757 (3.57), 5.768 (0.76), 5.786 (1.17), 5.803 (0.74), 7.195 (0.74), 7.214 (1.75), 7.233 (1.13), 7.291 (0.66), 7.295 (0.77), 7.312 (1.09), 7.328 (0.51), 7.332 (0.47), 7.601 (0.61), 7.617 (1.06), 7.633 (0.55), 8.794 (1.93), 8.810 (1.91), 9.162 (1.32), 9.181 (1.26)。
遵循一般程序1,使1-(3-{(1R)-1-[(6-溴-2-甲基吡啶并[3,4-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇(80.0 mg,170 µmol)與二異丙基氧化膦(22.9 mg,170 µmol)在90℃下反應16小時。然後,添加另外肆(三苯基膦)鈀(0) (19.7 mg,17.0 µmol)並在90℃下將該混合物再攪拌16小時。然後將該混合物冷卻至室溫並過濾。該化合物藉由製備型薄層層析術於矽膠盤上使用二氯甲烷及乙醇作為溶劑純化以產生標題化合物(20.1 mg,95%純度,21%產率)。
LC-MS (方法2): R
t= 1.19 min;MS (ESIpos): m/z = 523 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.922 (3.58), 0.929 (3.65), 0.939 (3.78), 0.947 (3.71), 0.960 (3.71), 0.968 (3.78), 0.978 (3.71), 0.986 (3.51), 1.052 (0.95), 1.065 (0.95), 1.070 (1.01), 1.083 (0.95), 1.097 (1.22), 1.105 (3.78), 1.115 (4.25), 1.123 (4.25), 1.133 (3.71), 1.143 (3.65), 1.153 (3.71), 1.161 (3.71), 1.171 (3.51), 1.195 (6.82), 1.222 (7.02), 1.593 (4.86), 1.611 (4.86), 2.318 (0.47), 2.409 (16.00), 2.426 (0.88), 2.444 (1.35), 2.452 (1.15), 2.461 (1.82), 2.470 (2.30), 2.518 (6.75), 2.523 (4.66), 3.378 (0.41), 5.333 (2.23), 5.758 (9.92), 5.769 (0.88), 5.787 (1.28), 5.805 (0.81), 7.211 (0.74), 7.230 (1.82), 7.249 (1.22), 7.300 (0.88), 7.317 (1.22), 7.333 (0.54), 7.618 (0.68), 7.634 (1.15), 7.650 (0.61), 8.898 (1.96), 8.912 (1.89), 9.079 (4.86), 9.081 (4.79), 9.357 (1.42), 9.375 (1.35)。
遵循一般程序1:6-溴-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺(60.0 mg,141 µmol)及二甲基氧化膦(11.0 mg,141 µmol)在藉由製備型TLC (CH
2Cl
2/EtOH 8:1)純化後產生標題化合物(25.1 mg,40%)。
LC-MS (方法2): R
t= 1.08 min;MS (ESIpos): m/z = 423 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.565 (4.57), 1.583 (4.65), 1.782 (14.54), 1.815 (13.99), 2.399 (16.00), 2.518 (3.22), 2.522 (2.15), 2.623 (5.45), 2.673 (0.50), 5.713 (0.69), 5.730 (1.07), 5.748 (0.69), 7.346 (0.63), 7.366 (1.38), 7.385 (0.80), 7.542 (1.46), 7.560 (1.18), 7.784 (1.29), 7.803 (1.18), 9.175 (1.57), 9.180 (1.76), 9.186 (1.60), 9.192 (1.73), 9.230 (1.13), 9.244 (1.98), 9.249 (2.01), 9.274 (1.46), 9.279 (1.24)。
遵循一般程序1:1-(3-{(1R)-1-[(6-溴-2-甲基吡啶并[2,3-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇(60.0 mg,128 µmol)及二甲基氧化膦(9.98 mg,128 µmol)在藉由製備型HPLC (鹼性方法)純化後產生標題化合物(30.0 mg,48%)。
LC-MS (方法5): R
t= 0.87 min;MS (ESIpos): m/z = 467 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.205 (5.76), 1.230 (6.07), 1.588 (4.46), 1.606 (4.51), 1.786 (8.48), 1.819 (8.44), 2.396 (16.00), 2.518 (8.50), 2.523 (6.25), 5.340 (6.99), 5.782 (0.71), 5.800 (1.11), 5.817 (0.72), 7.206 (0.69), 7.225 (1.64), 7.244 (1.08), 7.306 (0.72), 7.323 (1.03), 7.338 (0.50), 7.606 (0.55), 7.622 (0.99), 7.637 (0.53), 9.125 (1.22), 9.143 (1.18), 9.188 (1.57), 9.193 (1.97), 9.200 (1.71), 9.205 (1.81), 9.250 (1.44), 9.255 (1.28), 9.280 (1.41), 9.285 (1.28)。
遵循一般程序1:在90℃下將1-(3-{(1R)-1-[(6-溴-2-甲基吡啶并[2,3-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇(100 mg,213 µmol)、二(丙-2-基)-λ
5-膦酮(28.6 mg,213 µmol)及肆(三苯基膦)鈀(0) (61.5 mg,53.3 µmol)加熱2天。在藉由製備型HPLC (鹼性方法)純化後獲得標題化合物(52.6 mg,45%)。
LC-MS (方法2): R
t= 1.04 min;MS (ESIneg): m/z = 521 [M-H]
-
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.925 (3.35), 0.928 (3.47), 0.942 (3.57), 0.946 (3.47), 0.965 (3.47), 0.969 (3.52), 0.982 (3.54), 0.987 (3.37), 1.088 (2.86), 1.103 (3.69), 1.106 (3.84), 1.120 (3.32), 1.126 (3.30), 1.141 (3.76), 1.143 (3.84), 1.158 (2.93), 1.193 (5.98), 1.219 (6.16), 1.600 (4.45), 1.617 (4.40), 2.397 (16.00), 2.518 (3.84), 2.523 (2.49), 5.335 (4.35), 5.758 (1.91), 5.777 (0.73), 5.795 (1.12), 5.813 (0.71), 7.210 (0.71), 7.229 (1.71), 7.248 (1.10), 7.299 (0.66), 7.304 (0.76), 7.320 (1.05), 7.336 (0.51), 7.341 (0.44), 7.598 (0.59), 7.614 (1.03), 7.629 (0.54), 9.073 (1.47), 9.078 (1.91), 9.080 (1.83), 9.085 (1.49), 9.174 (1.27), 9.179 (1.17), 9.199 (1.27), 9.204 (1.12), 9.241 (1.25), 9.259 (1.20)。
遵循一般程序1:1-(3-{(1R)-1-[(6-溴-2-甲基吡啶并[2,3-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇(100 mg,213 µmol)及磷雜環戊烷1-氧化物(22.2 mg,213 µmol)在藉由製備型TLC (CH
2Cl
2/EtOH 9:1)純化後產生標題化合物(66.6 mg,60%)。
LC-MS (方法2): R
t= 0.95 min;MS (ESIneg): m/z = 491 [M-H]
-
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.205 (6.62), 1.230 (6.90), 1.591 (5.00), 1.609 (4.97), 1.892 (0.48), 1.910 (0.63), 1.947 (1.32), 1.973 (1.37), 1.986 (1.06), 2.017 (1.06), 2.037 (0.99), 2.059 (0.91), 2.077 (0.58), 2.161 (0.48), 2.180 (0.71), 2.195 (0.89), 2.209 (0.89), 2.223 (0.53), 2.327 (0.91), 2.331 (0.66), 2.397 (16.00), 2.518 (3.65), 2.523 (2.48), 2.669 (0.91), 2.673 (0.63), 5.342 (6.39), 5.759 (8.98), 5.784 (0.81), 5.802 (1.24), 5.820 (0.79), 7.202 (0.79), 7.221 (1.85), 7.241 (1.19), 7.300 (0.74), 7.305 (0.84), 7.322 (1.17), 7.337 (0.58), 7.341 (0.53), 7.606 (0.66), 7.622 (1.14), 7.638 (0.61), 9.114 (1.70), 9.119 (1.93), 9.124 (1.80), 9.130 (1.72), 9.177 (1.37), 9.195 (1.29), 9.243 (1.50), 9.248 (1.37), 9.272 (1.50), 9.277 (1.37)。
遵循一般程序1:6-溴-2,7-二甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺(100 mg,228 µmol)、二甲基氧化膦(35.5 mg,455 µmol)及肆(三苯基膦)鈀(0) (52.6 mg,45.5 µmol)在藉由製備型HPLC (鹼性方法)純化後產生標題化合物(24.0 mg,23%)。
LC-MS (方法2): R
t= 1.10 min;MS (ESIneg): m/z = 435 [M-H]
-
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.564 (4.64), 1.582 (4.69), 1.838 (16.00), 1.872 (15.74), 2.336 (0.46), 2.364 (15.23), 2.518 (5.56), 2.523 (3.92), 2.613 (5.61), 2.678 (0.44), 2.832 (12.47), 5.705 (0.71), 5.722 (1.08), 5.739 (0.69), 7.342 (0.64), 7.362 (1.39), 7.381 (0.80), 7.541 (1.51), 7.559 (1.22), 7.765 (1.35), 7.785 (1.20), 8.926 (2.19), 8.958 (2.17), 9.037 (1.17), 9.054 (1.11)。
遵循一般程序1:6-溴-N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2,7-二甲基吡啶并[2,3-d]嘧啶-4-胺(100 mg,235 µmol)、二甲基氧化膦(36.7 mg,470 µmol)及肆(三苯基膦)鈀(0) (54.3 mg,47.0 µmol)在藉由製備型HPLC (鹼性方法)純化後產生標題化合物(31.0 mg,30%)。
LC-MS (方法2): R
t= 0.96 min;MS (ESIpos): m/z = 423 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.611 (4.86), 1.629 (4.84), 1.839 (13.82), 1.872 (13.83), 2.331 (0.48), 2.376 (16.00), 2.518 (2.60), 2.523 (1.81), 2.673 (0.46), 2.845 (13.08), 5.789 (0.74), 5.808 (1.14), 5.825 (0.72), 7.107 (1.09), 7.243 (2.31), 7.280 (0.82), 7.299 (1.78), 7.319 (1.01), 7.379 (0.96), 7.497 (0.61), 7.514 (1.02), 7.532 (0.50), 7.671 (0.56), 7.688 (1.01), 7.706 (0.50), 8.923 (2.23), 8.951 (1.42), 8.956 (2.52), 8.969 (1.21)。
遵循一般程序1:1-(3-{(1R)-1-[(6-溴-2,7-二甲基吡啶并[2,3-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇(100 mg,207 µmol)、二甲基氧化膦(16.1 mg,207 µmol)及肆(三苯基膦)鈀(0) (59.8 mg,51.7 µmol)在藉由製備型HPLC (鹼性方法)純化後產生標題化合物(40.0 mg,38%)。
LC-MS (方法2): R
t= 0.92 min;MS (ESIneg): m/z = 479 [M-H]
-
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.928 (0.41), 1.205 (5.87), 1.229 (6.09), 1.588 (4.60), 1.605 (4.60), 1.839 (12.73), 1.873 (12.58), 2.074 (0.63), 2.331 (1.63), 2.337 (0.74), 2.363 (16.00), 2.518 (8.76), 2.523 (6.16), 2.669 (2.30), 2.673 (1.56), 2.678 (0.71), 2.846 (12.96), 5.344 (7.94), 5.779 (0.71), 5.797 (1.11), 5.815 (0.71), 7.202 (0.71), 7.221 (1.67), 7.240 (1.08), 7.305 (0.74), 7.322 (1.04), 7.338 (0.48), 7.591 (0.56), 7.607 (1.00), 7.624 (0.52), 8.924 (2.30), 8.938 (1.34), 8.957 (3.12)。
遵循一般程序1:1-(3-{(1R)-1-[(6-溴-2,7-二甲基吡啶并[2,3-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇(104 mg,215 µmol)、1λ
5-磷雜環戊烷-1-酮(22.4 mg,215 µmol)及肆(三苯基膦)鈀(0) (62.2 mg,53.8 µmol)在藉由製備型HPLC (鹼性方法)純化後產生標題化合物(23.8 mg,21%)。
LC-MS (方法2): R
t= 0.97 min;MS (ESIpos): m/z = 507 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.202 (6.28), 1.226 (6.50), 1.601 (4.85), 1.619 (4.83), 1.797 (0.56), 1.806 (0.53), 1.820 (0.65), 1.837 (0.60), 1.847 (0.66), 1.863 (0.47), 1.948 (0.55), 1.968 (0.73), 1.983 (0.78), 2.012 (1.21), 2.047 (0.61), 2.064 (0.56), 2.074 (0.50), 2.327 (0.80), 2.332 (0.60), 2.366 (16.00), 2.426 (0.47), 2.444 (0.47), 2.518 (3.71), 2.523 (2.54), 2.669 (0.83), 2.673 (0.58), 2.828 (13.23), 5.344 (5.12), 5.782 (0.76), 5.800 (1.18), 5.817 (0.75), 7.202 (0.75), 7.221 (1.78), 7.240 (1.13), 7.302 (0.66), 7.306 (0.76), 7.323 (1.10), 7.339 (0.53), 7.343 (0.48), 7.584 (0.61), 7.600 (1.08), 7.616 (0.55), 8.907 (2.08), 8.938 (3.17), 8.956 (1.30)。
遵循一般程序1:在90℃下將1-(3-{(1R)-1-[(6-溴-2,7-二甲基吡啶并[2,3-d]嘧啶-4-基)胺基]乙基}-2-氟苯基)-1,1-二氟-2-甲基丙-2-醇(104 mg,215 µmol)、二(丙-2-基)-λ
5-膦酮(28.9 mg,215 µmol)及肆(三苯基膦)鈀(0) (99.5 mg,86.1 µmol)加熱3天。在藉由製備型TLC (CH
2Cl
2/EtOH 9:1)純化後獲得標題化合物(20.5 mg,17%)。
LC-MS (方法2): R
t= 1.05 min;MS (ESIpos): m/z = 537 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.878 (2.79), 0.894 (3.73), 0.896 (3.80), 0.911 (3.03), 0.918 (3.01), 0.934 (3.75), 0.935 (3.73), 0.951 (2.72), 1.021 (0.63), 1.040 (0.76), 1.050 (0.45), 1.052 (0.67), 1.058 (0.83), 1.070 (0.43), 1.077 (1.06), 1.095 (0.61), 1.158 (2.76), 1.176 (6.18), 1.185 (6.61), 1.193 (5.28), 1.213 (9.15), 1.231 (3.30), 1.608 (4.49), 1.626 (4.45), 2.331 (0.99), 2.337 (0.45), 2.367 (16.00), 2.518 (5.28), 2.523 (3.75), 2.558 (0.72), 2.567 (1.08), 2.575 (0.99), 2.584 (0.70), 2.593 (0.92), 2.610 (0.52), 2.673 (0.97), 2.678 (0.43), 2.834 (10.52), 5.331 (6.47), 5.759 (1.84), 5.776 (0.72), 5.794 (1.10), 5.812 (0.70), 7.209 (0.70), 7.229 (1.66), 7.248 (1.12), 7.301 (0.65), 7.305 (0.76), 7.322 (1.03), 7.338 (0.52), 7.342 (0.45), 7.557 (0.56), 7.573 (1.01), 7.589 (0.52), 8.817 (1.10), 8.844 (1.10), 8.988 (1.01), 9.006 (0.99)。
遵循一般程序1:在90℃下將6-溴-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺(70.0 mg,142 µmol)、二甲基氧化膦(15.5 mg,199 µmol)及肆(三苯基膦)鈀(0) (73.8 mg,63.4 µmol)加熱2天。在藉由製備型HPLC (鹼性方法)純化後獲得標題化合物(10.0 mg,14%)。
LC-MS (方法2): R
t= 1.24 min;MS (ESIpos): m/z = 491 [M+H]
+
1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.065 (4.29), 1.154 (0.53), 1.172 (0.53), 1.232 (0.71), 1.590 (3.65), 1.607 (3.65), 1.861 (3.88), 1.895 (3.88), 2.327 (3.41), 2.331 (2.47), 2.430 (11.71), 2.518 (16.00), 2.523 (10.65), 2.618 (4.82), 2.669 (3.53), 2.673 (2.53), 5.730 (0.59), 5.747 (1.00), 5.760 (10.35), 7.353 (0.53), 7.373 (1.12), 7.393 (0.65), 7.556 (1.41), 7.575 (1.18), 7.792 (1.12), 7.811 (1.00), 9.463 (1.35), 9.495 (1.29), 9.575 (0.59), 9.593 (0.59)。
實例 23(2RS)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基己-2-醇(非對映異構體之混合物)
使用一般程序6,自(2RS)-1-{3-[(1R)-1-胺基乙基]-2-氟苯基}-1,1-二氟-2-甲基己-2-醇之三氟乙酸鹽(1/1) (非對映異構體之混合物,中間物82,64.0 mg,81%純度,128 µmol)及6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-醇(33.5 mg,141 µmol) (中間物71)開始。藉由製備型薄層層析術(矽膠盤20 x 20 cm,二氯甲烷、乙醇)純化,以獲得15.5 mg (95%純度,23%產率)標題化合物。
LC-MS (方法2): R
t= 1.18 min;MS (ESIpos): m/z = 509 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.791 (2.29), 0.802 (3.24), 0.809 (6.54), 0.819 (7.45), 0.827 (3.42), 0.837 (3.37), 1.135 (5.66), 1.154 (5.70), 1.176 (1.10), 1.194 (1.96), 1.212 (2.28), 1.228 (2.28), 1.268 (0.77), 1.286 (0.72), 1.299 (0.72), 1.313 (0.68), 1.330 (0.80), 1.346 (0.74), 1.358 (0.80), 1.376 (0.67), 1.413 (0.60), 1.452 (1.14), 1.465 (0.96), 1.481 (1.10), 1.492 (1.09), 1.516 (0.52), 1.586 (6.82), 1.603 (6.76), 1.689 (16.00), 1.723 (15.99), 2.084 (0.45), 2.332 (1.50), 2.336 (0.64), 2.411 (14.13), 2.423 (13.61), 2.518 (7.82), 2.523 (5.56), 2.673 (1.51), 2.678 (0.64), 5.174 (4.52), 5.191 (4.24), 5.758 (2.39), 5.765 (0.68), 5.782 (1.10), 5.801 (1.02), 5.821 (1.05), 5.839 (0.65), 7.200 (0.69), 7.207 (0.70), 7.220 (1.69), 7.226 (1.66), 7.239 (1.16), 7.245 (1.08), 7.295 (0.74), 7.312 (1.17), 7.322 (1.09), 7.338 (0.52), 7.605 (0.90), 7.623 (1.55), 7.641 (0.86), 8.963 (1.72), 8.970 (1.78), 8.979 (1.76), 8.984 (1.75), 9.089 (6.35), 9.263 (1.15), 9.282 (2.12), 9.301 (1.16)。
向6-溴-2-甲基-N-{(1S*)-1-[2-(三氟甲基)吡啶-4-基]乙基}吡啶并[3,4-d]嘧啶-4-胺(對映異構體1) (中間物96,50 mg,121.3 µmol)之溶液添加肆(三苯基膦)鈀(0) (21.0 mg,18.2 µmol),接著添加乙腈(2 mL)、三乙胺(59 µl,420 µmol)及二甲基-λ
5-膦酮(11 µl,150 µmol)。將氣氛交換為氬並將小瓶密封及加熱至90℃,歷時24 h。蒸發溶劑,將殘餘物重新溶解於DMSO (2.5 mL)中並過濾及然後呈遞至HPLC純化(鹼性方法)以獲得呈白色固體之標題化合物22.0 mg (98%純度,43%產率)。
LC-MS (方法2): R
t= 1.02 min;MS (ESIpos): m/z = 410.4 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.627 (5.33), 1.645 (5.36), 1.689 (5.99), 1.696 (6.11), 1.723 (6.04), 1.730 (5.97), 2.427 (16.00), 2.518 (1.11), 2.522 (0.71), 5.611 (0.73), 5.629 (1.13), 5.647 (0.72), 7.761 (1.25), 7.770 (1.26), 7.773 (1.27), 8.004 (2.54), 8.699 (2.00), 8.711 (1.95), 8.919 (1.74), 8.920 (1.80), 8.935 (1.80), 8.937 (1.78), 9.108 (4.03), 9.275 (1.20), 9.293 (1.17)。
向6-溴-2-甲基-N-{(1R*)-1-[2-(三氟甲基)吡啶-4-基]乙基}吡啶并[3,4-d]嘧啶-4-胺(對映異構體2) (中間物97,50 mg,121.3 µmol)之溶液添加肆(三苯基膦)鈀(0) (21.0 mg,18.2 µmol),接著添加乙腈(2 mL)、三乙胺(59 µl,420 µmol)及二甲基-λ
5-膦酮(11 µl,150 µmol)。將氣氛交換為氬並將小瓶密封及加熱至90℃,歷時24 h。蒸發溶劑,將殘餘物重新溶解於DMSO (2.5 mL)中並過濾及然後呈遞至HPLC純化(鹼性方法)以獲得呈白色固體之標題化合物17.0 mg (98%純度,34%產率)。
LC-MS (方法2): R
t= 1.01 min;MS (ESIpos): m/z = 410.4 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.61 - 1.66 (m, 3 H) 1.68 - 1.71 (m, 3 H) 1.71 - 1.75 (m, 3 H) 2.41 - 2.45 (m, 3 H) 5.43 - 5.74 (m, 1 H) 7.69 - 7.84 (m, 1 H) 7.95 - 8.13 (m, 1 H) 8.61 - 8.77 (m, 1 H) 8.85 - 9.00 (m, 1 H) 9.04 - 9.18 (m, 1 H) 9.24 - 9.39 (m, 1 H)。
向N-[(1R)-1-(3-{1,1-二氟-2-甲基-2-[(三乙基矽基)氧基]丙基}-2-氟苯基)乙基]-6-(二甲基磷醯基)-8-[(4-甲氧基苯基)甲氧基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(中間物102,208 mg,290 µmol)於二氯甲烷(3.0 ml)中之溶液緩慢添加三氟乙酸(3.0 ml)並在室溫下將該混合物攪拌2 h。濃縮該反應混合物及殘餘物經過製備型HPLC (儀器:Waters自動純化系統;管柱:XBrigde C18 5 μ,100x30 mm;溶析液A:水+ 0.2體積%氨水(32%);溶析液B:乙腈;梯度:0.0至0.5 min 9% B (35至70 ml/min),0.5至5.5 min 9至29% B;流量:70 ml/min;溫度:RT;DAD掃描:210至400 nm)以產生呈白色固體之標題化合物(52 mg,99%純度,37%產率)。
LC-MS (方法2): R
t= 0.75 min;MS (ESIpos): m/z = 483.7 [M+H]
+
1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 - 1.27 (m, 6 H) 1.50 - 1.61 (m, 3 H) 1.69 - 1.82 (m, 6 H) 2.34 (s, 3 H) 5.21 - 5.44 (m, 1 H) 5.63 - 5.79 (m, 1 H) 7.16 - 7.25 (m, 1 H) 7.27 - 7.34 (m, 1 H) 7.47 - 7.71 (m, 2 H) 8.72 (d, J=7.35 Hz, 1 H) 11.22 - 12.25 (m, 1 H)。
遵循一般程序3,自4-{8-[(4-甲氧基苯基)甲氧基]-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)-吡啶并[3,4-d]嘧啶-6-基}-4-側氧基-1,4λ
5-氮雜磷雜環己烷-1-羧酸三級丁酯(中間物113,105 mg,150 µmol)開始,在藉由製備型HPLC (鹼性方法)純化之後,獲得呈白色固體之標題化合物(10.0 mg,98%純度,13%產率)。
LC-MS (方法2): R
t= 0.74 min;MS (ESIpos): m/z = 522 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (0.42), 1.232 (1.72), 1.315 (0.43), 1.527 (5.25), 1.545 (5.24), 1.844 (1.36), 1.850 (0.63), 1.870 (0.57), 1.908 (0.56), 2.074 (1.44), 2.101 (16.00), 2.259 (0.44), 2.291 (0.60), 2.318 (1.17), 2.323 (2.23), 2.327 (3.04), 2.331 (2.40), 2.344 (14.10), 2.518 (9.95), 2.523 (6.86), 2.603 (7.23), 2.660 (0.81), 2.665 (1.84), 2.669 (2.56), 2.673 (1.79), 2.678 (0.81), 3.234 (0.52), 3.262 (0.63), 3.659 (0.47), 3.685 (0.49), 5.616 (0.60), 5.633 (0.87), 5.646 (0.57), 6.549 (0.51), 7.339 (0.80), 7.358 (1.78), 7.377 (1.06), 7.529 (1.97), 7.547 (1.61), 7.602 (0.56), 7.625 (0.54), 7.768 (1.72), 7.787 (1.56), 8.850 (0.80)。
向4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)-吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(中間物148,50.0 mg,108 µmol)於乙醇(1 ml)中之溶液添加碳酸鉀(14.9 mg,108 µmol)及甲酸乙酯(70 µl,860 µmol),並在室溫下將該混合物攪拌整夜。該混合物用二氯甲烷稀釋,過濾,並濃縮。殘餘物藉由製備型TLC (二氧化矽、二氯甲烷、乙醇)純化以獲得標題化合物(29.1 mg,95%純度,52%產率)。
LC-MS (方法2): R
t= 1.11 min;MS (ESIpos): m/z = 492 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (0.49), 1.575 (6.11), 1.593 (6.07), 1.955 (0.63), 2.061 (0.66), 2.100 (0.40), 2.258 (0.71), 2.281 (0.61), 2.361 (0.53), 2.374 (0.79), 2.396 (0.85), 2.422 (16.00), 2.623 (8.90), 3.659 (0.64), 3.694 (0.68), 3.774 (0.57), 3.785 (0.57), 3.808 (1.03), 3.821 (1.02), 3.834 (0.80), 3.867 (0.70), 3.879 (0.41), 3.939 (0.43), 3.974 (0.61), 3.987 (0.61), 5.707 (0.89), 5.723 (1.34), 5.741 (0.88), 7.349 (0.96), 7.368 (2.03), 7.388 (1.19), 7.544 (2.27), 7.563 (1.86), 7.786 (2.04), 7.806 (1.85), 8.115 (5.54), 9.015 (2.28), 9.032 (2.25), 9.089 (5.45), 9.373 (1.56), 9.389 (1.50)。
向1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(實例7,100 mg,198 µmol)於二氯甲烷(1.3 ml)中之溶液添加勞森(Lawesson's)試劑([CAS 38078-09-0],80.0 mg,198 µmol),及在0℃下將該混合物攪拌2 h並在室溫下整夜。將該混合物過濾,濃縮,及殘餘物藉由製備型TLC (二氧化矽、己烷、甲醇)純化以獲得標題化合物(26.5 mg,95%純度,24%產率)。
LC-MS (方法2): R
t= 1.22 min;MS (ESIpos): m/z = 522 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (0.56), 1.575 (5.41), 1.593 (5.45), 2.107 (0.70), 2.116 (0.52), 2.137 (0.44), 2.173 (0.47), 2.336 (0.42), 2.423 (12.40), 2.425 (12.89), 2.518 (5.66), 2.523 (3.88), 2.624 (7.27), 2.678 (0.56), 2.696 (16.00), 4.143 (0.45), 4.151 (0.41), 4.177 (0.51), 4.299 (0.58), 4.325 (0.71), 4.362 (0.58), 5.706 (0.54), 5.712 (0.58), 5.724 (0.86), 5.729 (0.87), 5.741 (0.59), 5.747 (0.57), 5.758 (11.06), 7.350 (0.80), 7.369 (1.75), 7.389 (1.01), 7.545 (1.93), 7.563 (1.56), 7.789 (1.74), 7.809 (1.57), 9.041 (1.99), 9.059 (1.96), 9.105 (5.48), 9.400 (1.16), 9.415 (1.12)。
向{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基喹唑啉-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸乙酯(中間物173,90.0 mg,188 µmol)於四氫呋喃(1.2.ml)中之溶液分批添加四氫硼酸鈉(35.5 mg,939 µmol),並在室溫下將所得混合物攪拌1 h。向該混合物添加鹽酸水溶液(1 M),直至該溶液已達成~pH6,並將該混合物攪拌15 min。然後該混合物用乙酸乙酯萃取,有機相用飽和氯化鈉水溶液清洗,透過分離漏斗過濾並濃縮。殘餘物藉由製備型HPLC (鹼性方法)純化以產生標題化合物(25.0 mg,95%純度,29%產率)。
LC-MS (方法2): R
t= 0.85 min;MS (ESIpos): m/z = 438.4 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.605 (4.77), 1.623 (4.90), 1.725 (13.70), 1.759 (13.80), 2.372 (16.00), 2.518 (1.60), 2.523 (1.18), 3.895 (0.50), 3.912 (0.55), 3.932 (0.94), 3.948 (0.98), 3.967 (0.47), 3.983 (0.45), 5.709 (0.81), 5.725 (1.91), 5.741 (0.76), 5.806 (0.73), 5.824 (1.13), 5.842 (0.72), 7.235 (0.87), 7.254 (1.91), 7.273 (1.11), 7.396 (0.68), 7.414 (1.05), 7.429 (0.53), 7.649 (1.63), 7.656 (1.91), 7.671 (2.47), 7.677 (2.04), 7.689 (0.52), 7.986 (0.91), 7.990 (0.91), 8.008 (0.86), 8.011 (1.67), 8.015 (0.96), 8.033 (0.76), 8.036 (0.79), 8.806 (1.24), 8.809 (1.22), 8.829 (1.33), 8.837 (1.44), 8.841 (1.44), 8.848 (1.25)。
於微波瓶中,將1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]-乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(實例7,100 mg,70%純度,138 µmol)溶解於甲醇(700 µl)中並用UV光(370 nm)照射該混合物5天。濃縮該混合物,及殘餘物藉由製備型TLC (二氧化矽、二氯甲烷、甲醇)純化,產生標題化合物(5 mg,95%純度,6%產率)。
LC-MS (方法2): R
t= 1.15 min;MS (ESIpos): m/z = 537 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.852 (0.76), 1.233 (2.80), 1.572 (2.33), 1.590 (2.33), 2.121 (7.80), 2.318 (1.51), 2.422 (7.26), 2.518 (16.00), 2.523 (11.33), 2.621 (3.04), 2.678 (1.33), 2.687 (0.93), 3.304 (0.77), 5.007 (0.64), 5.013 (0.85), 5.025 (2.33), 5.047 (1.05), 5.059 (1.28), 5.064 (0.62), 5.721 (0.45), 7.364 (0.76), 7.383 (0.47), 7.540 (0.84), 7.559 (0.66), 7.782 (0.75), 7.801 (0.65), 8.911 (0.92), 8.928 (0.91), 9.335 (0.51), 9.352 (0.50)。
將1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ5-氮雜磷雜環己烷-4-酮(實例7,125 mg,247 µmol)、環丙烷羧酸(39 µl,490 µmol)、過硫酸銨([CAS 7727-54-0],282 mg,1.24 mmol)及硝酸銀(168 mg,989 µmol)於乙腈(1.8 ml)及水(750 µl)中之混合物加熱至80℃,歷時24 h。然後將該混合物冷卻至室溫,用水稀釋並用乙酸乙酯萃取。將有機相分離,乾燥並濃縮。殘餘物經過製備型HPLC (鹼性方法),獲得呈白色固體之標題化合物(12 mg,95%純度,8%產率)。
LC-MS (方法2): R
t= 1.35 min;MS (ESIpos): m/z = 546.5 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.996 (0.72), 1.009 (0.90), 1.024 (0.83), 1.109 (1.30), 1.125 (1.28), 1.565 (4.60), 1.582 (4.63), 2.053 (0.57), 2.062 (0.54), 2.084 (3.60), 2.113 (16.00), 2.284 (0.42), 2.322 (1.24), 2.327 (1.65), 2.332 (1.27), 2.449 (12.76), 2.518 (5.27), 2.523 (3.44), 2.625 (5.99), 2.660 (0.43), 2.664 (0.92), 2.669 (1.31), 2.673 (0.94), 3.306 (0.86), 3.779 (0.63), 3.909 (0.60), 5.706 (0.52), 5.722 (0.76), 5.737 (0.51), 7.341 (0.70), 7.361 (1.54), 7.380 (0.88), 7.540 (1.64), 7.558 (1.33), 7.778 (1.45), 7.798 (1.31), 8.725 (2.00), 8.742 (1.98), 9.217 (1.03), 9.234 (0.97)。
向1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(實例7,200 mg,396 µmol)及雙(二氟甲亞磺酸鋅) (665 mg,95%純度,2.14 mmol)於二氯甲烷(1.6 ml)及水(650 µl)中之混合物添加三氟乙酸(61 µl,790 µmol),接著滴加2-甲基丙烷-2-過氧醇(peroxol)([CAS 75-91-2],570 µl,70%純度,4.0 mmol),並在40℃下將該混合物攪拌22 h。添加另一雙(二氟甲亞磺酸鋅) (665 mg,95%純度,2.14 mmol)及2-甲基丙烷-2-過氧醇(570 µl,70%純度,4.0 mmol)並在室溫下持續攪拌2天。該混合物用飽和碳酸氫鈉水溶液稀釋,用二氯甲烷萃取,及有機相透過分離漏斗過濾並濃縮。殘餘物藉由製備型HPLC (鹼性方法)純化以產生呈白色固體之標題化合物(29.0 mg,99%純度,13%產率)。
LC-MS (方法2): R
t= 1.30 min;MS (ESIpos): m/z = 556.2 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.586 (4.96), 1.604 (4.97), 1.960 (0.40), 2.101 (0.44), 2.121 (16.00), 2.151 (0.43), 2.280 (0.48), 2.291 (0.44), 2.318 (0.64), 2.323 (1.06), 2.327 (1.37), 2.331 (1.08), 2.336 (0.64), 2.360 (0.43), 2.452 (14.03), 2.518 (4.99), 2.523 (3.43), 2.619 (6.67), 2.665 (0.80), 2.669 (1.12), 2.673 (0.81), 3.835 (0.43), 3.861 (0.51), 3.873 (0.58), 3.892 (0.79), 3.905 (0.83), 3.949 (0.71), 3.992 (0.46), 5.720 (0.64), 5.737 (0.96), 5.755 (0.63), 7.355 (0.75), 7.374 (1.64), 7.394 (0.95), 7.522 (1.02), 7.553 (1.78), 7.571 (1.43), 7.657 (2.24), 7.782 (1.64), 7.792 (1.02), 7.801 (1.47), 9.180 (1.76), 9.195 (1.75), 9.558 (1.13), 9.575 (1.09)。
如針對實例35描述進行反應,自1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(實例7,125 mg,247 µmol)及甲氧基乙酸(38 µl,490 µmol)開始。藉由製備型HPLC (鹼性方法)純化以產生標題化合物(23.0 mg)。
LC-MS (方法2): R
t= 1.22 min;MS (ESIpos): m/z = 550.2 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.572 (2.87), 1.589 (2.88), 2.098 (0.41), 2.118 (9.38), 2.283 (0.51), 2.322 (0.44), 2.327 (0.53), 2.332 (0.45), 2.422 (7.73), 2.518 (1.44), 2.523 (0.94), 2.619 (3.95), 3.366 (16.00), 3.373 (1.71), 3.896 (0.68), 3.908 (0.68), 3.920 (0.70), 3.929 (0.75), 3.949 (0.71), 4.967 (5.28), 5.718 (0.50), 7.342 (0.45), 7.362 (0.97), 7.381 (0.56), 7.539 (1.07), 7.558 (0.87), 7.779 (0.95), 7.799 (0.88), 8.946 (1.09), 8.962 (1.06), 9.337 (0.62), 9.354 (0.58)。
實例 38(2RS)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-8-乙基-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丁-2-醇(非對映異構體之混合物)
在-78℃下向{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸乙酯(中間物173,270 mg,75%純度,421 µmol)於四氫呋喃(2.0 ml)中之溶液添加溴(乙基)鎂(530 µl,3.2 M,1.7 mmol),移除冷卻浴,並將該混合物攪拌3 h。然後該反應藉由在室溫下緩慢添加乙醇淬滅並在減壓下濃縮。粗產物藉由製備型HPLC (鹼性方法)純化及隨後藉由製備型TLC (二氧化矽、二氯甲烷、乙醇)純化以產生標題化合物(9 mg,90%純度,4%產率)。
LC-MS (方法2): R
t= 1.22 min;MS (ESIpos): m/z = 495 [M+H]
+
1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 - 0.97 (m, 3 H) 1.27 (d, J=1.52 Hz, 3 H) 1.33 - 1.45 (m, 1 H) 1.47 - 1.63 (m, 4 H) 1.65 - 1.74 (m, 6 H) 2.39 - 2.45 (m, 3 H) 3.16 - 3.28 (m, 2 H) 3.75 - 3.97 (m, 1 H) 5.49 - 5.63 (m, 1 H) 5.70 - 5.87 (m, 1 H) 7.15 - 7.31 (m, 1 H) 7.33 - 7.44 (m, 1 H) 7.56 - 7.76 (m, 1 H) 8.72 - 8.85 (m, 1 H) 9.08 - 9.22 (m, 1 H)。
實例 394-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-4-基)-1,4λ
5-氮雜磷雜環己烷-4-酮
在氬氣氛下向4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(中間物148,75.0 mg,162 µmol)及4-溴-1-甲基-1H-吡唑(33 µl,320 µmol)於甲苯(1.5 ml)中之溶液添加三級丁醇鈉(23.3 mg,243 µmol)、DavePhos [CAS 213697-53-1] (24 mg,65 µmol)及參(亞苄基丙酮)-二鈀(0) (37.0 mg,40.5 µmol),並在120℃下將該混合物攪拌整夜。然後將該混合物冷卻至室溫,過濾,並濃縮。殘餘物藉由製備型TLC (二氧化矽、二氯甲烷、甲醇)純化以產生標題化合物(1.30 mg,95%純度,1%產率)。
LC-MS (方法2): R
t= 1.16 min;MS (ESIneg): m/z = 542 [M-H]
-
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (0.76), 1.572 (4.16), 1.590 (4.11), 1.840 (0.40), 1.878 (0.76), 1.918 (0.47), 2.318 (0.41), 2.323 (0.93), 2.327 (1.32), 2.331 (0.94), 2.337 (0.58), 2.344 (0.62), 2.362 (0.74), 2.382 (0.80), 2.414 (13.02), 2.465 (0.56), 2.470 (0.83), 2.518 (4.05), 2.523 (2.85), 2.622 (5.18), 2.665 (0.81), 2.669 (1.12), 2.673 (0.76), 3.517 (1.35), 3.547 (1.00), 3.560 (1.46), 3.576 (0.90), 3.752 (16.00), 5.703 (0.65), 5.720 (0.98), 5.737 (0.63), 7.221 (3.67), 7.223 (3.63), 7.347 (0.62), 7.367 (1.34), 7.383 (4.03), 7.385 (4.21), 7.542 (1.42), 7.561 (1.14), 7.788 (1.25), 7.807 (1.13), 8.993 (1.43), 9.009 (1.41), 9.067 (3.86), 9.364 (1.08), 9.382 (1.03)。
實例 404-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-3-基)-1,4λ
5-氮雜磷雜環己烷-4-酮
如針對實例39描述進行反應,自4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(中間物148,75.0 mg,162 µmol)及3-溴-1-甲基-1H-吡唑(52.1 mg,324 µmol)開始,以獲得標題化合物(60 mg,95%產率)。
LC-MS (方法2): R
t= 1.17 min;MS (ESIpos): m/z = 544 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.571 (4.35), 1.589 (4.28), 1.872 (0.76), 1.910 (0.43), 2.304 (0.56), 2.316 (0.82), 2.322 (0.71), 2.327 (0.80), 2.332 (0.76), 2.337 (0.77), 2.351 (0.52), 2.411 (14.18), 2.518 (0.95), 2.523 (0.69), 2.619 (5.51), 3.686 (16.00), 3.727 (0.98), 3.739 (1.25), 3.769 (0.97), 3.779 (1.03), 5.698 (0.67), 5.715 (1.03), 5.733 (0.66), 5.779 (3.76), 5.784 (3.72), 7.343 (0.64), 7.362 (1.37), 7.382 (0.80), 7.490 (2.98), 7.495 (2.91), 7.538 (1.50), 7.556 (1.20), 7.789 (1.33), 7.809 (1.20), 8.995 (1.55), 9.011 (1.50), 9.060 (4.13), 9.374 (1.11), 9.391 (1.06)。
在室溫下向4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(中間物148,50.0 mg,108 µmol)於二氯甲烷(1.0 ml)中之溶液添加N,N-二異丙基乙胺(38 µl,220 µmol),接著添加甲磺酸酐(20.7 mg,119 µmol),並在室溫下將該混合物攪拌整夜。該混合物用甲苯稀釋並濃縮。殘餘物藉由製備型HPLC (鹼性方法)純化以獲得標題化合物(37.3 mg,95%純度,61%產率)。
LC-MS (方法2): R
t= 1.14 min;MS (ESIpos): m/z = 542 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.575 (4.39), 1.592 (4.37), 2.085 (0.71), 2.425 (14.72), 2.455 (1.14), 2.518 (4.72), 2.523 (3.36), 2.623 (5.50), 3.015 (16.00), 3.301 (0.60), 3.599 (0.76), 3.632 (0.83), 3.723 (0.53), 3.738 (0.42), 3.759 (0.63), 3.771 (0.69), 3.787 (0.41), 5.708 (0.68), 5.725 (1.06), 5.742 (0.66), 7.350 (0.64), 7.369 (1.38), 7.388 (0.80), 7.545 (1.50), 7.563 (1.20), 7.785 (1.32), 7.804 (1.19), 9.022 (1.57), 9.038 (1.53), 9.101 (4.11), 9.103 (3.96), 9.368 (1.17), 9.385 (1.10)。
作為中間物156之副產物獲得實例42,其藉由製備型HPLC分離:4.00 mg (95%純度,5%產率)。
LC-MS (方法2): R
t= 0.81 min;MS (ESIpos): m/z = 522.7 [M+H]
+
1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 - 1.66 (m, 3 H) 1.87 - 2.39 (m, 2 H) 2.12 (s, 4 H) 2.27 - 2.38 (m, 1 H) 2.53 - 2.55 (m, 5 H) 3.44 - 3.58 (m, 1 H) 3.70 - 3.84 (m, 1 H) 3.93 (br s, 3 H) 4.15 - 4.34 (m, 1 H) 5.73 (s, 1 H) 5.76 - 5.86 (m, 1 H) 7.23 - 7.30 (m, 1 H) 7.40 - 7.48 (m, 1 H) 7.64 - 7.72 (m, 1 H) 9.18 (br d, J=7.10 Hz, 1 H) 9.26 (br d, J=4.31 Hz, 2 H)。
向{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸乙酯(中間物159,150 mg,266 µmol)於乙醇(450 µl)中之溶液添加氫氧化鉀水溶液(670 µl,2.0 M,1.3 mmol),並在室溫下將該混合物攪拌20 min。將該混合物濃縮,用水稀釋並藉由固相萃取層析術(C18 SPE,水、甲醇)純化以獲得標題化合物(135 mg,90%純度,85%產率)。
LC-MS (方法2): R
t= 0.56 min;MS (ESIpos): m/z = 536.5 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.085 (1.87), 1.103 (1.99), 1.151 (1.16), 1.168 (1.21), 1.235 (0.44), 1.617 (4.70), 1.635 (4.71), 2.008 (0.48), 2.117 (16.00), 2.318 (0.66), 2.323 (0.77), 2.327 (1.04), 2.331 (0.75), 2.337 (0.43), 2.456 (13.46), 2.518 (2.45), 2.523 (1.78), 2.665 (0.46), 2.669 (0.61), 2.673 (0.44), 3.165 (1.88), 3.376 (0.65), 3.442 (0.77), 3.502 (0.97), 3.530 (0.58), 3.754 (0.62), 3.783 (0.65), 3.953 (0.42), 5.793 (0.71), 5.810 (1.08), 5.828 (0.69), 6.940 (0.65), 7.280 (0.84), 7.299 (1.80), 7.319 (1.03), 7.502 (0.73), 7.519 (1.20), 7.535 (0.58), 7.678 (0.60), 7.697 (1.05), 7.715 (0.55), 9.289 (1.31), 9.294 (1.74), 9.300 (1.47), 9.305 (1.55), 9.328 (1.24), 9.333 (1.01), 9.357 (1.20), 9.362 (1.01), 9.601 (0.40)。
實例 442-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-N-環丙基-2,2-二氟乙醯胺
向環丙胺(42 µl,600 µmol)之溶液添加{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}(二氟)乙醯氯(中間物160,33.3 mg,60.0 µmol當量)之溶液並在室溫下將該混合物攪拌10 min。濃縮該混合物並藉由製備型HPLC (鹼性方法)純化以獲得標題化合物(10.4 mg,95%純度,29%產率)。
LC-MS (方法2): R
t= 0.87 min;MS (ESIpos): m/z = 575.6 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.561 (0.44), 0.572 (1.02), 0.575 (1.09), 0.582 (1.63), 0.590 (1.99), 0.601 (0.74), 0.663 (0.74), 0.674 (1.37), 0.681 (1.49), 0.693 (1.86), 0.697 (1.04), 0.712 (0.49), 1.107 (16.00), 1.599 (3.42), 1.617 (3.42), 2.117 (10.44), 2.318 (0.51), 2.322 (0.83), 2.327 (0.98), 2.332 (0.72), 2.336 (0.42), 2.414 (11.46), 2.518 (3.11), 2.523 (2.13), 2.664 (0.54), 2.669 (0.75), 2.673 (0.54), 2.762 (0.40), 2.770 (0.62), 2.781 (0.62), 2.789 (0.40), 4.190 (1.06), 5.741 (0.55), 5.758 (1.01), 5.776 (0.55), 7.283 (0.60), 7.302 (1.32), 7.322 (0.76), 7.469 (0.51), 7.487 (0.85), 7.503 (0.41), 7.689 (0.42), 7.707 (0.75), 9.051 (0.94), 9.062 (0.92), 9.147 (0.69), 9.164 (0.67), 9.256 (2.50), 9.262 (1.44), 9.268 (1.40), 9.288 (0.75)。
實例 452-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N,N-二甲基乙醯胺
如針對實例44描述進行反應,使用中間物160及N-甲基甲胺(300 µl,2.0 M,600 µmol),以獲得標題化合物(19.6 mg,95%純度,55%產率)。
LC-MS (方法2): R
t= 0.88 min;MS (ESIpos): m/z = 563.6 [M+H]
+
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (d, J=7.10 Hz, 3 H) 1.95 - 2.09 (m, 1 H) 2.12 (s, 4 H) 2.24 - 2.38 (m, 1 H) 2.40 (s, 3 H) 2.94 - 2.99 (m, 6 H) 3.42 - 3.55 (m, 1 H) 3.77 (q, J=11.83 Hz, 1 H) 3.86 - 4.00 (m, 1 H) 4.18 - 4.32 (m, 1 H) 5.71 - 5.78 (m, 1 H) 7.31 (t, J=7.73 Hz, 1 H) 7.49 (t, J=6.72 Hz, 1 H) 7.71 (br t, J=7.22 Hz, 1 H) 9.17 (br d, J=6.84 Hz, 1 H) 9.24 - 9.31 (m, 2 H)。
如針對實例44描述進行反應,使用中間物160及氨(86 µl,7.0 M,600 µmol),以獲得標題化合物(19.6 mg,95%純度,55%產率)。
LC-MS (方法2): R
t= 0.77 min;MS (ESIpos): m/z = 535.6 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.798 (0.88), 0.802 (0.50), 0.814 (0.96), 0.821 (0.99), 0.840 (0.50), 0.886 (0.50), 0.904 (1.01), 0.923 (0.46), 1.035 (3.23), 1.052 (6.84), 1.070 (3.26), 1.160 (0.44), 1.232 (1.86), 1.602 (4.96), 1.619 (4.95), 1.907 (0.48), 2.005 (0.51), 2.117 (14.61), 2.318 (1.36), 2.323 (2.42), 2.327 (3.20), 2.331 (2.34), 2.336 (1.20), 2.414 (16.00), 2.518 (12.04), 2.523 (8.26), 2.660 (0.93), 2.665 (2.03), 2.669 (2.84), 2.673 (2.01), 2.678 (0.91), 3.159 (0.75), 3.171 (0.80), 3.364 (0.81), 3.404 (0.68), 3.417 (0.64), 3.422 (1.61), 3.435 (1.70), 3.439 (1.62), 3.452 (1.72), 3.457 (0.76), 3.469 (0.71), 3.484 (0.59), 3.511 (0.58), 3.754 (0.53), 3.785 (0.58), 4.347 (1.10), 4.360 (2.10), 4.372 (1.05), 5.758 (10.50), 5.775 (1.27), 5.793 (0.79), 7.282 (0.86), 7.301 (1.87), 7.320 (1.07), 7.483 (0.74), 7.500 (1.26), 7.516 (0.61), 7.686 (0.62), 7.704 (1.12), 7.723 (0.57), 8.137 (1.70), 8.408 (1.98), 9.145 (1.09), 9.162 (1.04), 9.251 (1.00), 9.256 (2.56), 9.262 (2.93), 9.267 (2.52), 9.292 (1.20)。
實例 472-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ
5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N-甲基乙醯胺
如針對實例44描述進行反應,使用中間物160及氨(86 µl,7.0 M,600 µmol),以獲得標題化合物(19.6 mg,95%純度,55%產率)。
LC-MS (方法2): R
t= 0.78 min;MS (ESIpos): m/z = 549.5 [M+H]
+
1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (d, J=6.84 Hz, 3 H) 1.95 - 2.08 (m, 1 H) 2.12 (s, 4 H) 2.27 - 2.37 (m, 1 H) 2.41 (s, 3 H) 2.73 (d, J=4.56 Hz, 3 H) 3.43 - 3.55 (m, 1 H) 3.77 (q, J=12.00 Hz, 1 H) 3.86 - 3.99 (m, 1 H) 4.19 - 4.31 (m, 1 H) 5.71 - 5.78 (m, 1 H) 7.30 (t, J=7.86 Hz, 1 H) 7.50 (t, J=6.84 Hz, 1 H) 7.71 (br t, J=7.35 Hz, 1 H) 8.99 (br d, J=4.56 Hz, 1 H) 9.16 (br d, J=6.84 Hz, 1 H) 9.24 - 9.30 (m, 2 H)。
如針對中間物162描述,使{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸乙酯(中間物161,142 mg,296 µmol)與氨(300 µl,7.0 M,2.1 mmol)反應以產生標題化合物(16.0 mg,91%純度,11%產率)。
LC-MS (方法2): R
t= 0.78 min;MS (ESIpos): m/z = 452.6 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.593 (5.12), 1.610 (5.07), 1.688 (7.43), 1.692 (7.59), 1.722 (7.62), 1.726 (7.34), 2.427 (16.00), 2.518 (0.90), 2.523 (0.62), 5.750 (0.84), 5.767 (1.30), 5.785 (0.83), 7.279 (1.02), 7.298 (2.17), 7.317 (1.23), 7.477 (0.76), 7.494 (1.28), 7.511 (0.63), 7.693 (0.68), 7.710 (1.22), 7.728 (0.62), 8.137 (1.66), 8.407 (1.91), 8.949 (1.98), 8.965 (2.00), 9.087 (4.77), 9.284 (1.47), 9.302 (1.39)。
如針對中間物162描述,使{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸乙酯(中間物161,142 mg,296 µmol)與乙胺(520 µl,2.0 M,1.0 mmol)反應以產生標題化合物(19 mg,95%純度,19%產率)。
LC-MS (方法2): R
t= 0.90 min;MS (ESIpos): m/z = 480.2 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.964 (1.05), 1.045 (1.37), 1.064 (3.26), 1.081 (1.48), 1.105 (16.00), 1.142 (0.68), 1.639 (1.40), 1.657 (1.40), 1.714 (2.83), 1.747 (2.80), 3.185 (0.43), 3.203 (0.61), 3.221 (0.42), 7.341 (0.61), 9.221 (0.89)。
如針對中間物162描述,使{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸乙酯(中間物161,142 mg,296 µmol)與二甲胺(540 µl,2.0 M,1.1 mmol)反應以產生標題化合物(8.00 mg,96%純度,7%產率)。
LC-MS (方法2): R
t= 0.93 min;MS (ESIpos): m/z = 480.5 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.826 (0.64), 0.852 (0.75), 0.967 (1.01), 1.107 (1.04), 1.144 (0.68), 1.232 (2.61), 1.372 (0.57), 1.496 (0.46), 1.605 (3.58), 1.623 (3.54), 1.692 (5.83), 1.694 (5.88), 1.726 (5.94), 1.729 (5.83), 2.331 (3.23), 2.337 (1.41), 2.439 (6.28), 2.518 (16.00), 2.523 (11.18), 2.673 (3.18), 2.678 (1.38), 2.960 (8.48), 2.971 (6.31), 5.743 (0.45), 5.761 (0.70), 5.778 (0.47), 7.301 (0.66), 7.320 (1.41), 7.340 (0.85), 7.478 (0.58), 7.495 (0.93), 7.512 (0.48), 7.710 (0.49), 7.730 (0.83), 8.979 (0.91), 8.995 (0.93), 9.108 (2.71)。
根據一般程序6,自6-(二甲基磷醯基)-2-甲基吡啶并-[3,4-d]嘧啶-4-醇(中間物71,49.0 mg,207 µmol)及2-{3-[(1R)-1-胺基乙基]-2-氟苯基}-2,2-二氟-N-甲基乙醯胺鹽酸鹽(1/1) (中間物163,70.1 mg,248 µmol)開始,獲得標題化合物(5.00 mg,5%產率)。
LC-MS (方法2): R
t= 0.88 min;MS (ESIpos): m/z = 466.6 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.107 (16.00), 1.232 (0.56), 1.590 (1.36), 1.608 (1.34), 1.686 (1.92), 1.690 (1.96), 1.720 (1.91), 1.724 (1.89), 2.331 (1.12), 2.336 (0.51), 2.420 (4.42), 2.518 (6.16), 2.523 (4.16), 2.673 (1.12), 2.678 (0.51), 2.723 (1.64), 2.735 (1.58), 4.191 (1.18), 7.301 (0.54), 8.946 (0.52), 8.962 (0.56), 9.092 (1.16)。
在90℃下將4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(中間物226,51.7 mg,115 µmol)、N,N,N-三丁基丁烷-1-溴化銨(1.85 mg,5.75 µmol)及(S)-(-)-脯胺酸(660 µg,5.8 µmol)於碳酸二甲酯(0.5 ml)中之溶液攪拌2天。將殘餘物濃縮並藉由急驟層析術(二氧化矽、二氯甲烷、甲醇)純化以產生標題化合物(21.0 mg,98%純度,39%產率)。
LC-MS (方法2): R
t= 1.02 min;MS (ESIneg): m/z = 462 [M-H]
-
1H NMR (400 MHz, DMSO-d6) δ ppm 1.62 (d, J=7.10 Hz, 3 H) 1.84 - 1.99 (m, 2 H) 2.29 (s, 3 H) 2.43 (s, 5 H) 2.69 - 2.94 (m, 4 H) 5.63 - 5.86 (m, 1 H) 7.08 - 7.39 (m, 2 H) 7.47 - 7.56 (m, 1 H) 7.66 - 7.76 (m, 1 H) 8.92 - 9.01 (m, 1 H) 9.11 (s, 1 H) 9.23 - 9.30 (m, 1 H)。
向4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)-吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮鹽酸鹽(1/1) (中間物164,430 mg,860 µmol)於乙醇(8.0 ml)中之溶液添加丙酮(12 ml),接著添加氰基硼氫化鈉(81.1 mg,1.29 mmol)及乙酸(120 µl),並在室溫下將該混合物攪拌整夜。然後,添加氫氧化鈉水溶液(1 M),該混合物用水稀釋並用二氯甲烷萃取。濃縮有機相並用DMSO稀釋殘餘物。將形成之固體過濾並乾燥以產生標題化合物(275 mg,90%純度,57%產率)。
LC-MS (方法2): R
t= 1.24 min;MS (ESIpos): m/z = 507 [M+H]
+
1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 - 1.15 (m, 6 H) 1.53 - 1.63 (m, 3 H) 1.92 - 2.14 (m, 1 H) 2.42 (s, 3 H) 2.62 (s, 4 H) 3.01 - 3.15 (m, 1 H) 3.51 - 3.86 (m, 2 H) 4.59 - 4.77 (m, 1 H) 5.65 - 5.79 (m, 1 H) 7.30 - 7.41 (m, 1 H) 7.49 - 7.60 (m, 1 H) 7.74 - 7.84 (m, 1 H) 8.99 - 9.03 (m, 1 H) 9.04 - 9.06 (m, 1 H) 9.37 - 9.46 (m, 1 H)。
實例 541-苄基-4-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮
向1-苄基-4-[4-({(1R)-1-[3-(2-{[三級丁基(二甲基)矽基]氧基}-1,1-二氟-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ
5-氮雜磷雜環己烷-4-酮(150 mg,211 µmol)於THF (1.5 ml)中之溶液添加四丁基氟化銨(840 µl,1.0 M於THF中,840 µmol),並在40℃下將該混合物攪拌整夜。濃縮該混合物及殘餘物藉由急驟層析術(二氧化矽、己烷、乙酸乙酯、二氯甲烷、乙醇)純化以獲得標題化合物(130 mg,90%純度,93%產率)。
LC-MS (方法2): R
t= 1.23 min;MS (ESIpos): m/z = 599 [M+H]
+
¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.914 (0.40), 0.932 (0.67), 1.153 (0.81), 1.171 (1.59), 1.189 (1.47), 1.199 (6.51), 1.224 (6.70), 1.233 (1.48), 1.251 (0.40), 1.587 (4.89), 1.605 (4.81), 1.876 (0.44), 1.907 (1.12), 1.953 (0.48), 1.986 (2.75), 2.322 (0.49), 2.326 (0.68), 2.332 (0.58), 2.336 (0.43), 2.373 (0.82), 2.415 (16.00), 2.518 (1.88), 2.522 (1.24), 2.664 (0.42), 2.668 (0.58), 2.805 (0.92), 2.836 (1.03), 2.863 (0.45), 2.904 (0.65), 2.917 (0.52), 2.958 (0.67), 2.973 (0.50), 2.989 (0.44), 3.158 (0.84), 3.171 (0.78), 3.653 (6.02), 4.016 (0.57), 4.034 (0.57), 4.212 (0.43), 4.216 (0.44), 4.489 (0.44), 4.494 (0.43), 5.334 (8.36), 5.758 (5.35), 5.767 (0.82), 5.785 (1.24), 5.803 (0.79), 7.199 (0.78), 7.219 (1.81), 7.238 (1.25), 7.249 (0.56), 7.255 (0.67), 7.263 (1.07), 7.271 (0.84), 7.278 (0.93), 7.284 (0.72), 7.297 (0.84), 7.301 (0.88), 7.309 (0.79), 7.319 (1.30), 7.322 (1.39), 7.329 (0.72), 7.343 (4.65), 7.350 (4.87), 7.358 (11.05), 7.371 (0.62), 7.480 (0.43), 7.498 (0.40), 7.525 (0.49), 7.553 (0.63), 7.569 (0.43), 7.600 (0.69), 7.617 (1.16), 7.632 (0.62), 8.986 (1.61), 9.002 (1.60), 9.120 (4.22), 9.254 (1.32), 9.272 (1.26)。
表6中顯示之實例係根據一般程序6自各別嘧啶-4-醇衍生物及各別胺製備。
實例表
6
實例 | 結構;IUPAC名稱;分析資料;起始材料;產率 |
55 | 6-(二甲基磷醯基)-N-{(1R)-1-[2-氟-3-(三氟甲基)苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.628 (5.30), 1.646 (5.28), 1.690 (10.69), 1.724 (10.64), 2.412 (16.00), 2.518 (2.92), 2.523 (2.03), 5.747 (0.78), 5.765 (1.22), 5.782 (0.77), 7.351 (0.76), 7.370 (1.62), 7.390 (0.89), 7.641 (0.66), 7.659 (1.15), 7.676 (0.55), 7.823 (0.61), 7.840 (1.12), 7.858 (0.56), 8.953 (1.85), 8.955 (1.87), 8.970 (1.84), 8.972 (1.79), 9.096 (4.24), 9.334 (0.69), 9.350 (0.67)。 LC-MS (方法2): R t= 1.11 min;MS (ESIneg): m/z = 425 [M-H]⁻ 中間物71 35.0 mg (95%純度,12%產率) |
56 | N-[(1R)-1-(3-溴-2-氟苯基)乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.598 (5.02), 1.616 (4.95), 1.689 (7.94), 1.691 (8.11), 1.722 (7.98), 1.724 (7.88), 2.327 (1.00), 2.331 (0.71), 2.433 (16.00), 2.518 (3.47), 2.523 (2.43), 2.669 (1.00), 2.673 (0.69), 5.751 (0.77), 5.769 (1.21), 5.787 (0.76), 7.109 (0.96), 7.129 (2.05), 7.148 (1.13), 7.496 (0.66), 7.500 (0.81), 7.517 (1.28), 7.533 (0.66), 7.536 (0.68), 7.560 (0.92), 7.564 (0.88), 7.576 (1.00), 7.580 (1.57), 7.583 (0.85), 7.596 (0.88), 7.600 (0.74), 8.957 (1.80), 8.958 (1.84), 8.973 (1.80), 8.975 (1.77), 9.096 (4.05), 9.280 (1.20), 9.298 (1.17)。 LC-MS (方法2): R t= 1.09 min;MS (ESIpos): m/z = 439 [M+H]⁺ 中間物71 33.0 mg (95%純度,11%產率) |
57 | 1-乙醯基-4-[4-({(1R)-1-[3-(二氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.615 (4.95), 1.633 (4.93), 2.115 (16.00), 2.318 (0.59), 2.469 (14.23), 2.518 (6.48), 2.523 (4.67), 2.679 (0.52), 3.845 (0.50), 3.857 (0.64), 3.882 (0.45), 5.645 (0.69), 5.663 (1.04), 5.682 (0.68), 6.891 (1.32), 7.031 (2.62), 7.171 (1.18), 7.430 (0.69), 7.449 (1.60), 7.469 (1.27), 7.488 (1.78), 7.507 (0.72), 7.630 (1.17), 7.649 (0.96), 7.681 (1.95), 8.978 (1.58), 8.994 (1.59), 9.110 (4.11), 9.233 (1.12), 9.252 (1.09)。 LC-MS (方法1): R t= 0.86 min;MS (ESIpos): m/z = 474 [M+H]⁺ 中間物139 29.9 mg (95%純度,16%產率) |
58 | 1-乙醯基-4-[4-({(1R)-1-[2,5-二甲基-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56 (d, J=7.10 Hz, 3 H) 1.83 - 1.98 (m, 1 H) 1.99 - 2.14 (m, 4 H) 2.20 - 2.36 (m, 5 H) 2.42 - 2.44 (m, 3 H) 2.54 - 2.59 (m, 3 H) 3.63 - 4.12 (m, 4 H) 5.62 - 5.79 (m, 1 H) 7.37 (s, 1 H) 7.61 (s, 1 H) 8.98 - 9.04 (m, 1 H) 9.09 (s, 1 H) 9.28 - 9.40 (m, 1 H)。 LC-MS (方法2): Rt = 1.18 min;MS (ESIpos): m/z = 520 [M+H]⁺ 中間物139及中間物245 35.0 mg (95%純度,19%產率) |
表7中顯示之實例係如針對實例4描述自各別受矽基保護之醇衍生物製備。
實例表
7
實例 | 結構;IUPAC名稱;分析資料;起始材料;產率 |
59 | 1-[4-({(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-2,5-二氫-1H-1λ 5-磷雜環戊烯-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.606 (4.88), 1.624 (4.87), 2.322 (0.86), 2.327 (1.16), 2.332 (0.86), 2.436 (16.00), 2.518 (4.93), 2.523 (3.23), 2.558 (0.69), 2.601 (1.22), 2.645 (0.92), 2.660 (0.44), 2.664 (0.91), 2.669 (1.22), 2.673 (0.88), 2.878 (1.00), 2.885 (1.00), 2.931 (0.75), 3.892 (0.56), 3.908 (0.63), 3.928 (1.13), 3.944 (1.20), 3.964 (0.55), 3.980 (0.54), 5.704 (1.08), 5.720 (2.61), 5.736 (1.04), 5.783 (0.80), 5.801 (1.23), 5.819 (0.77), 6.008 (2.57), 6.079 (2.54), 7.245 (0.90), 7.264 (2.00), 7.283 (1.15), 7.409 (0.71), 7.426 (1.13), 7.442 (0.55), 7.656 (0.61), 7.674 (1.11), 7.690 (0.56), 9.058 (1.86), 9.074 (2.01), 9.083 (4.72), 9.307 (1.32), 9.325 (1.25)。 LC-MS (方法2): R t= 0.91 min;MS (ESIneg): m/z = 461 [M-H]⁻ 中間物208 54.7 mg (95%純度,63%產率) |
60 | 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟( 2H 2)乙-1-醇 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.602 (4.77), 1.620 (4.73), 1.688 (6.65), 1.692 (6.78), 1.722 (6.79), 1.726 (6.68), 1.890 (0.41), 2.432 (16.00), 2.442 (0.85), 2.518 (2.84), 2.523 (2.16), 5.684 (4.34), 5.758 (6.52), 5.782 (0.76), 5.800 (1.16), 5.817 (0.73), 7.245 (0.87), 7.264 (1.91), 7.284 (1.11), 7.408 (0.69), 7.426 (1.10), 7.442 (0.54), 7.656 (0.59), 7.674 (1.02), 7.691 (0.52), 8.955 (1.72), 8.957 (1.76), 8.971 (1.74), 8.973 (1.68), 9.091 (4.08), 9.276 (1.26), 9.294 (1.17)。 LC-MS (方法2): R t= 0.86 min;MS (ESIpos): m/z = 441 [M+H]⁺ 中間物135 49.4 mg (95%純度,60%產率) |
61 | 1-(4-{[(1R)-1-{3-[1,1-二氟-2-羥基( 2H 2)乙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ 5-磷雜環戊烷-1-酮 LC-MS (方法2): R t= 0.94 min;MS (ESIpos): m/z = 467 [M+H]⁺ 中間物210 36.9 mg (95%純度,42%產率) |
62 | 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.601 (5.28), 1.619 (5.30), 1.689 (8.01), 1.692 (8.24), 1.723 (8.15), 1.726 (8.05), 2.332 (0.40), 2.431 (16.00), 2.518 (2.71), 2.522 (1.77), 3.891 (0.64), 3.907 (0.71), 3.927 (1.27), 3.943 (1.34), 3.963 (0.63), 3.979 (0.60), 5.711 (1.12), 5.727 (2.51), 5.743 (1.08), 5.779 (0.87), 5.797 (1.33), 5.815 (0.85), 7.244 (0.95), 7.263 (2.13), 7.283 (1.24), 7.407 (0.80), 7.424 (1.29), 7.440 (0.62), 7.655 (0.71), 7.672 (1.26), 7.688 (0.63), 8.952 (1.99), 8.967 (1.97), 9.088 (4.67), 9.276 (1.30), 9.293 (1.25)。 LC-MS (方法2): R t= 0.90 min;MS (ESIpos): m/z = 439 [M+H]⁺ 中間物211 32.5 mg (95%純度,52%產率) |
63 | 1-[4-({(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.601 (5.28), 1.619 (5.26), 1.794 (0.47), 1.813 (0.66), 1.832 (0.81), 1.846 (0.70), 1.867 (0.56), 1.959 (0.58), 1.976 (0.90), 1.995 (1.12), 2.012 (1.24), 2.035 (1.03), 2.053 (0.92), 2.069 (0.66), 2.090 (1.04), 2.101 (0.91), 2.118 (1.06), 2.136 (1.00), 2.153 (0.68), 2.437 (16.00), 2.518 (3.71), 2.522 (2.46), 2.673 (0.73), 3.903 (0.53), 3.938 (0.99), 3.967 (0.50), 5.726 (0.66), 5.782 (0.84), 5.800 (1.28), 5.818 (0.80), 7.242 (0.96), 7.261 (2.16), 7.280 (1.24), 7.407 (0.77), 7.424 (1.20), 7.440 (0.58), 7.655 (0.67), 7.672 (1.16), 7.688 (0.59), 9.012 (1.84), 9.027 (1.82), 9.096 (4.77), 9.351 (0.48)。 LC-MS (方法2): R t= 0.99 min;MS (ESIpos): m/z = 465 [M+H]⁺ 中間物212 35.3 mg (95%純度,53%產率) |
64 | 2-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.911 (1.76), 0.930 (4.84), 0.947 (5.16), 0.953 (2.29), 0.966 (2.41), 0.972 (4.79), 0.990 (4.83), 1.009 (1.82), 1.603 (4.72), 1.621 (4.68), 1.952 (0.45), 1.962 (1.11), 1.971 (1.27), 1.981 (1.93), 1.990 (1.80), 1.997 (1.27), 2.000 (1.67), 2.006 (1.56), 2.008 (1.61), 2.022 (1.12), 2.024 (1.19), 2.031 (0.93), 2.040 (0.41), 2.332 (0.64), 2.430 (16.00), 2.518 (3.29), 2.522 (2.15), 2.673 (0.66), 3.312 (0.66), 3.316 (0.67), 3.369 (2.64), 3.385 (0.43), 3.391 (0.41), 3.393 (0.52), 3.401 (0.54), 3.891 (0.52), 3.907 (0.57), 3.927 (1.03), 3.943 (1.09), 3.962 (0.50), 3.978 (0.49), 5.709 (1.07), 5.725 (2.51), 5.741 (1.02), 5.774 (0.76), 5.792 (1.15), 5.810 (0.73), 7.248 (0.86), 7.268 (1.90), 7.287 (1.12), 7.407 (0.68), 7.424 (1.07), 7.440 (0.52), 7.662 (0.58), 7.679 (1.03), 7.696 (0.52), 8.931 (1.74), 8.945 (1.73), 9.087 (4.40), 9.312 (1.26), 9.330 (1.20)。 LC-MS (方法2): R t= 0.99 min;MS (ESIpos): m/z = 467 [M+H]⁺ 中間物213 33.1 mg (95%純度,50%產率) |
65 | (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丁-2-醇(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.899 (2.80), 0.917 (6.56), 0.935 (3.22), 1.358 (0.45), 1.375 (0.54), 1.383 (0.49), 1.393 (0.47), 1.399 (0.55), 1.533 (0.51), 1.552 (0.56), 1.562 (0.53), 1.593 (5.26), 1.610 (5.21), 1.689 (8.38), 1.691 (8.47), 1.723 (8.51), 1.726 (8.39), 2.437 (16.00), 2.518 (4.52), 2.523 (3.08), 3.372 (0.93), 3.858 (0.45), 5.556 (2.71), 5.574 (2.64), 5.797 (0.84), 5.815 (1.28), 5.833 (0.83), 7.232 (0.91), 7.251 (2.09), 7.270 (1.31), 7.358 (0.81), 7.375 (1.24), 7.391 (0.59), 7.638 (0.67), 7.655 (1.21), 7.671 (0.63), 8.956 (1.94), 8.971 (1.97), 9.092 (4.73), 9.259 (1.43), 9.276 (1.39)。 LC-MS (方法2): R t= 0.98 min;MS (ESIpos): m/z = 467 [M+H]⁺ 中間物178 20.0 mg (100%純度,45%產率) |
66 | (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-醇(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.863 (5.11), 0.880 (5.28), 0.903 (5.75), 0.920 (5.91), 1.593 (5.16), 1.610 (5.20), 1.691 (9.95), 1.724 (9.94), 1.769 (0.61), 1.779 (0.60), 1.786 (0.72), 1.795 (0.72), 1.803 (0.54), 1.812 (0.52), 2.434 (16.00), 2.518 (4.58), 2.523 (3.23), 3.828 (0.40), 3.846 (0.44), 3.856 (0.44), 5.523 (2.88), 5.541 (2.78), 5.788 (0.84), 5.805 (1.30), 5.823 (0.83), 7.234 (0.96), 7.253 (2.16), 7.273 (1.28), 7.384 (0.79), 7.402 (1.25), 7.418 (0.64), 7.636 (0.74), 7.653 (1.25), 7.670 (0.66), 8.958 (1.95), 8.973 (1.97), 9.092 (4.74), 9.260 (1.45), 9.278 (1.39)。 LC-MS (方法2): R t= 1.05 min;MS (ESIpos): m/z = 481 [M+H]⁺ 中間物176 17.0 mg (100%純度,38%產率) |
67 | 1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇(非對映異構體之混合物) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.935 (1.40), 0.948 (1.53), 0.954 (3.29), 0.967 (3.37), 0.973 (1.78), 0.979 (1.63), 0.986 (1.70), 0.991 (1.70), 0.997 (3.42), 1.010 (3.25), 1.016 (1.65), 1.029 (1.40), 1.201 (8.48), 1.227 (8.51), 1.589 (6.39), 1.607 (6.39), 1.657 (5.35), 1.665 (5.63), 1.690 (5.42), 1.698 (5.43), 1.953 (0.43), 1.963 (0.73), 1.973 (1.14), 1.978 (0.99), 1.981 (1.02), 1.992 (1.52), 1.998 (1.18), 2.005 (0.93), 2.010 (1.33), 2.018 (0.80), 2.024 (0.74), 2.028 (0.83), 2.331 (0.90), 2.410 (15.83), 2.412 (16.00), 2.518 (4.67), 2.523 (3.22), 2.673 (0.89), 5.336 (9.13), 5.777 (0.76), 5.790 (1.10), 5.795 (1.13), 5.808 (0.74), 5.812 (0.70), 7.203 (0.59), 7.210 (0.62), 7.222 (1.42), 7.229 (1.41), 7.241 (0.94), 7.248 (0.89), 7.301 (1.03), 7.319 (1.56), 7.336 (0.70), 7.610 (0.52), 7.624 (1.01), 7.637 (0.95), 7.652 (0.46), 8.953 (1.37), 8.965 (1.94), 8.979 (1.40), 9.087 (6.40), 9.293 (0.98), 9.310 (1.84), 9.328 (0.97)。 LC-MS (方法2): R t= 1.00 min;MS (ESIpos): m/z = 481 [M+H]⁺ 中間物216 103 mg (95%純度,50%產率) |
實例67之非對映異構體係根據下列方法分離。 分析方法: 儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SB 3 µ,100x4.6;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:90%A+10%B;流量:1.4 ml/min;溫度:25℃;UV:280 nm 製備方法: 儀器:PrepCon Labomatic HPLC-2;管柱:YMC Cellulose SB 5 µ,250x30;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:90%A+10%B;流量:50 ml/min;溫度:25℃;UV:280 nm | |
68 | 1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (0.48), 0.935 (1.92), 0.954 (4.32), 0.973 (2.24), 0.979 (2.10), 0.997 (4.51), 1.016 (2.06), 1.203 (6.64), 1.229 (8.08), 1.590 (4.91), 1.608 (4.87), 1.665 (7.23), 1.698 (7.32), 1.954 (0.45), 1.963 (0.81), 1.973 (1.27), 1.982 (0.93), 1.992 (1.65), 2.005 (1.07), 2.011 (1.09), 2.024 (0.86), 2.029 (0.42), 2.336 (0.49), 2.411 (16.00), 2.518 (6.41), 2.523 (4.34), 2.678 (0.51), 5.336 (7.12), 5.777 (0.78), 5.795 (1.22), 5.813 (0.76), 7.203 (0.77), 7.222 (1.82), 7.242 (1.18), 7.298 (0.71), 7.301 (0.81), 7.319 (1.12), 7.334 (0.55), 7.611 (0.62), 7.626 (1.11), 7.643 (0.58), 8.965 (1.82), 8.979 (1.82), 9.088 (4.10), 9.311 (1.14), 9.330 (1.09)。 LC-MS (方法2): R t= 1.00 min;MS (ESIpos): m/z = 482 [M+H]⁺ 實例67 28.0 mg (95%純度) Rt (分析方法) = 4.92 min;de >99% |
69 | 1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.948 (1.97), 0.967 (4.53), 0.986 (2.30), 0.991 (2.19), 1.011 (4.48), 1.030 (2.18), 1.200 (7.17), 1.225 (7.80), 1.588 (5.17), 1.606 (5.12), 1.657 (7.30), 1.690 (7.30), 1.959 (0.41), 1.970 (0.93), 1.978 (1.12), 1.989 (1.15), 1.998 (1.45), 2.009 (1.16), 2.018 (1.01), 2.029 (0.86), 2.331 (1.67), 2.413 (16.00), 2.518 (9.55), 2.523 (6.26), 2.673 (1.67), 5.335 (7.66), 5.772 (0.84), 5.790 (1.29), 5.808 (0.82), 7.210 (0.80), 7.230 (1.88), 7.249 (1.24), 7.304 (0.87), 7.321 (1.22), 7.336 (0.56), 7.621 (0.68), 7.638 (1.18), 7.653 (0.61), 8.953 (1.92), 8.967 (1.94), 9.087 (4.40), 9.293 (1.40), 9.311 (1.39)。 LC-MS (方法2): R t= 1.00 min;MS (ESIpos): m/z = 482 [M+H]⁺ 實例67 25.0 mg (95%純度) Rt (分析方法) = 6.23 min;de 97% |
70 | 1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}-2-甲基丙-2-醇(非對映異構體之混合物) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (0.54), 0.894 (3.68), 0.902 (4.07), 0.911 (3.97), 0.920 (3.99), 0.934 (3.82), 0.942 (4.12), 0.952 (3.82), 0.960 (3.86), 1.143 (6.03), 1.161 (6.38), 1.184 (7.02), 1.201 (16.00), 1.224 (10.33), 1.594 (9.29), 1.612 (9.20), 1.655 (8.16), 1.663 (8.27), 1.687 (8.19), 1.695 (8.12), 2.182 (0.62), 2.192 (0.70), 2.199 (1.01), 2.204 (0.81), 2.210 (0.99), 2.216 (1.09), 2.223 (0.94), 2.228 (0.80), 2.233 (1.01), 2.240 (0.66), 2.251 (0.59), 2.327 (2.50), 2.331 (1.76), 2.337 (0.79), 2.418 (15.48), 2.423 (15.72), 2.518 (9.17), 2.523 (6.29), 2.673 (1.70), 2.678 (0.76), 5.335 (2.76), 5.779 (1.16), 5.798 (1.75), 5.814 (1.15), 7.206 (0.85), 7.217 (0.97), 7.225 (1.97), 7.237 (2.07), 7.245 (1.40), 7.256 (1.40), 7.304 (1.60), 7.322 (2.35), 7.340 (1.16), 7.609 (0.81), 7.626 (1.86), 7.641 (1.78), 7.657 (0.65), 8.949 (1.72), 8.965 (3.14), 8.981 (1.65), 9.092 (8.46), 9.399 (0.53)。 LC-MS (方法1): R t= 0.95 min;MS (ESIpos): m/z = 496 [M+H]⁺ 中間物219 68.0 mg (95%純度,29%產率) |
實例70之非對映異構體係根據下列方法分離。 分析方法: 儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SB 3 µ,100x4.6;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:70%A+30%B;流量:1.4 ml/min;溫度:25℃;UV:280 nm; 製備方法: 儀器:PrepCon Labomatic HPLC-2;管柱:YMC Cellulose SB 5 µ,250x30;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:70%A+30%B;流量:50 ml/min;溫度:25℃;UV:280 nm; | |
71 | 1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}-2-甲基丙-2-醇(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.892 (3.47), 0.911 (3.52), 0.933 (3.55), 0.951 (3.51), 1.144 (3.48), 1.161 (3.64), 1.184 (3.76), 1.201 (10.20), 1.229 (7.56), 1.590 (5.08), 1.608 (5.11), 1.662 (7.62), 1.694 (7.63), 2.181 (0.58), 2.199 (0.79), 2.204 (0.67), 2.217 (0.64), 2.222 (0.80), 2.240 (0.52), 2.331 (0.95), 2.336 (0.44), 2.409 (16.00), 2.518 (5.18), 2.523 (3.37), 2.673 (0.93), 2.678 (0.42), 5.335 (8.16), 5.774 (0.83), 5.792 (1.28), 5.810 (0.81), 7.202 (0.81), 7.221 (1.91), 7.240 (1.27), 7.296 (0.76), 7.300 (0.87), 7.317 (1.23), 7.333 (0.59), 7.606 (0.69), 7.622 (1.23), 7.638 (0.64), 8.955 (1.97), 8.970 (1.96), 9.085 (4.85), 9.329 (1.47), 9.347 (1.37)。 LC-MS (方法2): R t= 1.06 min;MS (ESIpos): m/z = 496 [M+H]⁺ 實例70 20.0 mg (95%純度,9%產率) Rt (分析方法) = 2.03 min;de 99% |
72 | 1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}-2-甲基丙-2-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.902 (3.43), 0.920 (3.48), 0.942 (3.53), 0.960 (3.46), 1.142 (3.45), 1.160 (3.61), 1.182 (3.94), 1.199 (8.10), 1.222 (6.94), 1.589 (4.96), 1.607 (4.95), 1.653 (7.38), 1.685 (7.32), 2.192 (0.53), 2.210 (0.77), 2.216 (0.65), 2.228 (0.59), 2.233 (0.76), 2.252 (0.56), 2.331 (1.07), 2.336 (0.47), 2.413 (16.00), 2.518 (5.52), 2.523 (3.69), 2.673 (1.05), 2.678 (0.48), 5.333 (7.65), 5.770 (0.81), 5.788 (1.25), 5.805 (0.78), 7.214 (0.76), 7.233 (1.85), 7.252 (1.22), 7.299 (0.73), 7.303 (0.85), 7.320 (1.14), 7.336 (0.55), 7.622 (0.66), 7.638 (1.14), 7.654 (0.58), 8.938 (1.90), 8.952 (1.90), 9.084 (4.68), 9.305 (1.38), 9.323 (1.32)。 LC-MS (方法2): R t= 1.05 min;MS (ESIpos): m/z = 496 [M+H]⁺ 實例70 20.0 mg (95%純度,9%產率) Rt (分析方法) = 2.50 min;de 98% |
73 | (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體之混合物) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (1.06), 0.948 (1.21), 0.953 (2.61), 0.968 (2.63), 0.972 (1.38), 0.978 (1.18), 0.987 (1.28), 0.992 (1.33), 0.997 (2.65), 1.011 (2.55), 1.016 (1.29), 1.030 (1.07), 1.131 (3.89), 1.148 (3.90), 1.601 (4.35), 1.619 (4.36), 1.655 (4.08), 1.663 (4.27), 1.688 (4.01), 1.696 (4.10), 1.962 (0.52), 1.972 (0.95), 1.978 (0.69), 1.981 (0.75), 1.991 (1.23), 1.997 (0.75), 2.000 (0.79), 2.009 (1.02), 2.019 (0.56), 2.023 (0.56), 2.028 (0.62), 2.413 (16.00), 2.518 (2.18), 2.523 (1.60), 4.194 (0.41), 4.210 (0.42), 5.579 (2.69), 5.595 (2.63), 5.749 (0.49), 5.756 (0.54), 5.767 (0.77), 5.774 (0.78), 5.785 (0.52), 5.791 (0.47), 7.223 (0.50), 7.229 (0.51), 7.242 (1.15), 7.249 (1.13), 7.261 (0.70), 7.268 (0.68), 7.357 (0.71), 7.374 (1.15), 7.392 (0.52), 7.641 (0.70), 8.945 (1.02), 8.956 (1.26), 8.959 (1.20), 8.970 (1.03), 9.086 (4.67), 9.294 (0.73), 9.311 (1.31), 9.328 (0.69)。 LC-MS (方法2): R t= 0.95 min;MS (ESIpos): m/z = 468 [M+H]⁺ 中間物221 142 mg (95%純度,65%產率) |
實例73之非對映異構體係根據下列方法分離。 分析方法: 儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SB 3 µ,100x4.6;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:70%A+30%B;流量:1.4 ml/min;溫度:25℃;UV:280 nm; 製備方法: 儀器:PrepCon Labomatic HPLC-3;管柱:YMC Cellulose SB 10 µ,250x50;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:70%A+30%B;流量:120 mL/min;溫度:25℃;UV:280 nm; | |
74 | (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (1.86), 0.953 (4.55), 0.972 (2.21), 0.977 (2.07), 0.996 (4.42), 1.016 (1.99), 1.133 (4.29), 1.149 (4.32), 1.232 (1.33), 1.352 (0.63), 1.602 (4.85), 1.619 (4.88), 1.663 (7.45), 1.696 (7.38), 1.953 (0.40), 1.962 (0.76), 1.972 (1.17), 1.981 (0.84), 1.991 (1.60), 2.004 (0.91), 2.010 (1.06), 2.023 (0.79), 2.332 (0.81), 2.413 (16.00), 2.518 (4.50), 2.523 (2.95), 2.673 (0.82), 4.209 (0.41), 5.578 (3.24), 5.594 (3.13), 5.756 (0.80), 5.774 (1.21), 5.791 (0.77), 7.223 (0.87), 7.242 (2.00), 7.261 (1.18), 7.354 (0.64), 7.357 (0.73), 7.374 (1.10), 7.390 (0.53), 7.623 (0.61), 7.641 (1.08), 7.656 (0.54), 8.955 (1.84), 8.969 (1.82), 8.971 (1.78), 9.086 (4.37), 9.310 (1.32), 9.328 (1.24)。 LC-MS (方法2): R t= 0.95 min;MS (ESIpos): m/z = 468 [M+H]⁺ 實例73 48.9 mg (99%純度,23%產率) Rt (分析方法) = 3.57 min;de >99% |
75 | (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.948 (1.90), 0.967 (4.31), 0.987 (2.15), 0.992 (2.04), 1.011 (4.42), 1.030 (2.01), 1.130 (4.44), 1.146 (4.50), 1.232 (0.94), 1.600 (5.04), 1.617 (5.04), 1.655 (7.22), 1.688 (7.24), 1.971 (0.86), 1.978 (0.98), 1.990 (1.08), 1.997 (1.16), 2.009 (1.11), 2.019 (0.88), 2.028 (0.83), 2.414 (16.00), 2.518 (4.27), 2.522 (2.88), 4.195 (0.41), 4.210 (0.42), 5.580 (3.25), 5.595 (3.15), 5.749 (0.80), 5.767 (1.25), 5.784 (0.79), 7.229 (0.89), 7.249 (2.04), 7.268 (1.22), 7.359 (0.76), 7.376 (1.17), 7.392 (0.55), 7.632 (0.64), 7.649 (1.14), 7.666 (0.57), 8.945 (1.90), 8.959 (1.88), 9.085 (4.53), 9.293 (1.35), 9.312 (1.32)。 LC-MS (方法2): R t= 0.95 min;MS (ESIpos): m/z = 468 [M+H]⁺ 實例73 42.2 mg (99%純度,20%產率) Rt (分析方法) = 4.46 min;de 97.5% |
76 | (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體之混合物) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.933 (1.07), 0.944 (1.17), 0.952 (2.49), 0.964 (2.34), 0.971 (1.40), 0.976 (1.35), 0.983 (1.38), 0.988 (1.30), 0.996 (2.49), 1.007 (2.31), 1.015 (1.21), 1.026 (1.01), 1.143 (4.61), 1.159 (4.54), 1.600 (4.69), 1.617 (4.65), 1.658 (4.08), 1.664 (4.40), 1.691 (4.03), 1.697 (4.33), 1.963 (0.60), 1.973 (0.93), 1.977 (0.83), 1.981 (0.82), 1.992 (1.21), 1.997 (0.95), 2.005 (0.83), 2.009 (0.96), 2.017 (0.63), 2.024 (0.63), 2.028 (0.63), 2.069 (0.51), 2.441 (16.00), 4.175 (0.46), 5.587 (0.53), 5.796 (0.51), 5.804 (0.59), 5.814 (0.79), 5.822 (0.81), 5.832 (0.55), 5.839 (0.50), 7.231 (0.62), 7.235 (0.60), 7.250 (1.36), 7.254 (1.29), 7.270 (0.84), 7.273 (0.78), 7.364 (0.84), 7.381 (1.28), 7.397 (0.61), 7.400 (0.56), 7.644 (0.59), 7.648 (0.54), 7.661 (0.99), 7.674 (0.48), 7.679 (0.51), 8.132 (1.44), 8.957 (1.01), 8.968 (1.33), 8.971 (1.26), 8.982 (1.04), 9.086 (4.52), 9.386 (0.48), 9.403 (0.80), 9.420 (0.48)。 LC-MS (方法2): R t= 0.95 min;MS (ESIpos): m/z = 468 [M+H]⁺ 中間物220 61.0 mg (95%純度,31%產率) |
實例76之非對映異構體係根據下列方法分離。 分析方法: 儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SB 3 µ,100x4.6;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:90%A+10%B;流量:1.4 ml/min;溫度:25℃;UV:280 nm 製備方法: 儀器:PrepCon Labomatic HPLC-3;管柱:YMC Cellulose SB 10 µ,250x50;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:90%A+10%B;流量:100 mL/min;溫度:25℃;UV:280 nm | |
77 | (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體3) LC-MS (方法2): R t= 0.96 min;MS (ESIpos): m/z = 468 [M+H]⁺ 中間物 15.0 mg (95%純度,8%產率) Rt (分析方法) = 6.05 min;de >99% |
78 | (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體4) LC-MS (方法2): R t= 0.95 min;MS (ESIpos): m/z = 468 [M+H]⁺ 中間物 17.0 mg (95%純度,9%產率) Rt (分析方法) = 7.76 min;de 98% |
79 | (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體之混合物) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.892 (2.49), 0.904 (2.78), 0.910 (2.81), 0.922 (2.67), 0.932 (2.64), 0.944 (2.76), 0.950 (2.74), 0.962 (2.48), 1.131 (4.24), 1.143 (8.70), 1.161 (5.10), 1.183 (4.88), 1.201 (4.81), 1.601 (5.44), 1.619 (5.42), 1.650 (5.69), 1.659 (5.82), 1.683 (5.71), 1.691 (5.75), 2.180 (0.43), 2.198 (0.70), 2.204 (0.53), 2.212 (0.65), 2.217 (0.76), 2.221 (0.68), 2.230 (0.49), 2.236 (0.68), 2.254 (0.46), 2.332 (0.62), 2.413 (16.00), 2.518 (3.00), 2.523 (2.21), 2.673 (0.61), 4.173 (0.42), 4.194 (0.54), 4.210 (0.56), 5.578 (2.81), 5.581 (2.82), 5.594 (2.77), 5.597 (2.69), 5.747 (0.68), 5.753 (0.72), 5.765 (1.05), 5.770 (1.05), 5.782 (0.71), 5.787 (0.66), 7.221 (0.65), 7.231 (0.71), 7.240 (1.50), 7.251 (1.51), 7.259 (0.95), 7.270 (0.88), 7.355 (0.96), 7.373 (1.54), 7.392 (0.72), 7.620 (0.47), 7.634 (1.12), 7.651 (1.07), 7.667 (0.42), 8.931 (1.35), 8.946 (2.60), 8.960 (1.34), 9.082 (6.42), 9.307 (0.92), 9.328 (1.22), 9.347 (0.87)。 LC-MS (方法2): R t= 1.02 min;MS (ESIpos): m/z = 481.6 [M+H] +中間物223 140 mg (95%純度,62%產率) |
實例79之非對映異構體係根據下列方法分離。 分析方法: 儀器:Waters Acquity UPC2 QDA;管柱:Chiral Art Amylose-SA 3 μ 100x4.6 mm;溶析液A:CO 2;溶析液B:2-丙醇+ 0.4體積%二乙胺;等度:10%B;梯度:無;流量:4 ml/min;溫度:40.0℃;BPR:1800 psi;UV:220 nm 製備方法: 儀器:Sepiatec:Prep SFC100;管柱:Chiral Art Amylose-SA 5 μ 250x30 mm;溶析液A:CO 2;溶析液B:2-丙醇+ 0.4體積%二乙胺;等度:10%B;梯度:無;流量:100 ml/min;溫度:40℃;BPR:150 bar;UV:215 nm | |
80 | (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體1) LC-MS (方法2): R t= 1.01 min;MS (ESIpos): m/z = 482 [M+H]⁺ 實例79 23.0 mg (95%純度) Rt (分析方法) = 2.41 min;de 98% |
81 | (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體2) 實例79 25.1 mg (95%純度) Rt (分析方法) = 3.07 min;de 95% |
82 | (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.889 (2.10), 0.895 (2.05), 0.907 (2.20), 0.913 (2.06), 0.930 (2.16), 0.936 (2.10), 0.948 (2.18), 0.953 (2.00), 1.135 (3.61), 1.143 (4.61), 1.153 (4.63), 1.159 (4.71), 1.175 (3.29), 1.192 (3.18), 1.601 (4.54), 1.619 (4.48), 1.652 (4.21), 1.658 (4.79), 1.684 (4.23), 1.690 (4.72), 2.071 (1.36), 2.193 (0.58), 2.198 (0.44), 2.205 (0.49), 2.211 (0.64), 2.216 (0.54), 2.230 (0.54), 2.441 (16.00), 3.458 (0.60), 4.176 (0.42), 5.583 (0.52), 5.796 (0.46), 5.805 (0.55), 5.813 (0.73), 5.822 (0.79), 5.831 (0.52), 5.839 (0.49), 7.230 (0.55), 7.237 (0.53), 7.249 (1.28), 7.256 (1.15), 7.269 (0.79), 7.275 (0.70), 7.359 (0.73), 7.362 (0.84), 7.380 (1.30), 7.396 (0.62), 7.400 (0.58), 7.639 (0.42), 7.655 (0.80), 7.668 (0.72), 8.134 (3.43), 8.947 (0.96), 8.962 (1.96), 8.977 (1.06), 9.086 (5.10), 9.421 (0.61), 9.440 (0.42)。 LC-MS (方法2): R t= 1.00 min;MS (ESIpos): m/z = 482 [M+H]⁺ 中間物222 69.0 mg (95%純度,34%產率) |
實例82之非對映異構體係根據下列方法分離。 分析方法: 儀器:Waters Acquity UPC2 QDA;管柱:Chiral Art Amylose-SA 3 µ 100x4.6 mm;溶析液A:CO2;溶析液B:2-丙醇+ 0.4體積%二乙胺;等度:10%B;梯度:無;流量:4 ml/min;溫度:40.0℃;BPR:1800 psi;UV:220 nm 製備方法: 儀器:Sepiatec:Prep SFC100;管柱:Chiral Art Amylose-SA 5 µ 250x30 mm;溶析液A:CO2;溶析液B:2-丙醇+ 0.4體積%二乙胺;等度:10%B;梯度:無;流量:100 ml/min;溫度:40℃;BPR:150 bar;UV:215 nm | |
83 | (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體3) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (3.20), 0.911 (3.21), 0.934 (3.27), 0.952 (3.21), 1.027 (2.57), 1.042 (2.66), 1.094 (0.52), 1.112 (1.03), 1.131 (0.67), 1.144 (6.29), 1.161 (7.38), 1.183 (3.30), 1.201 (3.27), 1.596 (4.68), 1.614 (4.62), 1.659 (7.38), 1.691 (7.35), 1.906 (0.50), 2.181 (0.45), 2.198 (0.70), 2.204 (0.58), 2.217 (0.52), 2.222 (0.67), 2.240 (0.44), 2.332 (2.08), 2.336 (0.87), 2.434 (16.00), 2.518 (9.68), 2.523 (6.99), 2.678 (0.84), 5.563 (3.11), 5.578 (2.95), 5.798 (0.74), 5.816 (1.12), 5.833 (0.72), 7.231 (0.83), 7.250 (1.92), 7.270 (1.15), 7.361 (0.72), 7.378 (1.07), 7.395 (0.51), 7.637 (0.60), 7.653 (1.04), 7.670 (0.54), 8.947 (1.72), 8.961 (1.67), 9.087 (4.34), 9.089 (4.33), 9.312 (1.25), 9.331 (1.19)。 LC-MS (方法2): R t= 1.01 min;MS (ESIpos): m/z = 482 [M+H]⁺ 實例82 24.0 mg (95%純度,12%產率) Rt (分析方法) = 1.92 min;de 98% |
84 | (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體4) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.904 (3.41), 0.922 (3.49), 0.945 (3.38), 0.962 (3.39), 1.027 (6.87), 1.042 (7.04), 1.079 (0.77), 1.097 (1.59), 1.115 (0.84), 1.143 (7.54), 1.161 (6.59), 1.183 (3.52), 1.201 (3.50), 1.594 (4.81), 1.612 (4.80), 1.650 (7.53), 1.683 (7.56), 2.197 (0.52), 2.214 (0.73), 2.220 (0.60), 2.232 (0.53), 2.238 (0.72), 2.256 (0.46), 2.336 (0.63), 2.435 (16.00), 2.518 (6.66), 2.523 (5.10), 2.679 (0.62), 4.343 (0.81), 4.354 (0.72), 5.561 (2.83), 5.576 (2.74), 5.791 (0.75), 5.808 (1.17), 5.826 (0.74), 7.240 (0.87), 7.259 (1.93), 7.278 (1.16), 7.362 (0.74), 7.380 (1.12), 7.396 (0.52), 7.649 (0.64), 7.666 (1.05), 7.684 (0.53), 8.933 (1.72), 8.947 (1.79), 9.087 (4.64), 9.291 (1.29), 9.309 (1.20)。 LC-MS (方法2): R t= 1.00 min;MS (ESIpos): m/z = 482 [M+H]⁺ 實例82 22.0 mg (95%純度,11%產率) Rt (分析方法) = 2.49 min;de 96% |
85 | 1-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-2,5-二氫-1H-1λ 5-磷雜環戊烯-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.154 (0.48), 1.172 (1.03), 1.190 (0.79), 1.205 (6.19), 1.230 (6.40), 1.592 (4.70), 1.610 (4.72), 1.987 (1.42), 2.415 (16.00), 2.518 (3.30), 2.523 (2.38), 2.562 (0.75), 2.604 (1.18), 2.646 (1.03), 2.880 (1.03), 2.889 (0.99), 2.925 (0.73), 2.934 (0.76), 5.336 (7.64), 5.759 (0.91), 5.779 (0.76), 5.796 (1.18), 5.814 (0.75), 6.008 (2.47), 6.081 (2.48), 7.204 (0.74), 7.223 (1.77), 7.243 (1.13), 7.300 (0.66), 7.304 (0.78), 7.321 (1.08), 7.336 (0.52), 7.341 (0.47), 7.613 (0.61), 7.629 (1.05), 7.645 (0.55), 9.069 (1.94), 9.082 (7.89), 9.312 (1.28), 9.330 (1.23)。 LC-MS (方法2): R t= 1.02 min;MS (ESIpos): m/z = 492 [M+H]⁺ 中間物224 88.0 mg (95%純度,49%產率) |
86 | (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丙-2-醇 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.146 (4.82), 1.162 (4.81), 1.594 (5.34), 1.611 (5.34), 1.688 (7.55), 1.693 (7.82), 1.722 (7.69), 1.727 (7.64), 2.436 (16.00), 2.518 (5.63), 2.523 (3.58), 4.167 (0.45), 4.183 (0.46), 5.568 (2.56), 5.584 (2.49), 5.758 (0.45), 5.800 (0.87), 5.818 (1.32), 5.836 (0.85), 7.234 (0.94), 7.253 (2.14), 7.272 (1.30), 7.363 (0.83), 7.380 (1.29), 7.397 (0.62), 7.641 (0.72), 7.659 (1.29), 7.676 (0.67), 8.958 (2.01), 8.974 (2.00), 9.092 (4.83), 9.272 (1.07), 9.290 (1.05)。 LC-MS (方法2): R t= 0.93 min;MS (ESIneg): m/z = 451 [M-H]⁻ 中間物225 42.0 mg (95%純度,50%產率) |
87 | (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.851 (4.84), 0.868 (5.03), 0.912 (5.48), 0.929 (5.67), 1.596 (5.03), 1.614 (5.03), 1.691 (9.50), 1.724 (9.67), 1.739 (0.75), 1.749 (0.63), 1.756 (0.72), 1.766 (0.70), 1.773 (0.52), 1.783 (0.48), 2.405 (16.00), 2.518 (4.24), 2.523 (2.97), 3.895 (0.40), 5.547 (2.82), 5.565 (2.75), 5.742 (0.81), 5.760 (1.26), 5.777 (0.80), 7.220 (0.97), 7.240 (2.14), 7.258 (1.26), 7.387 (0.74), 7.404 (1.20), 7.420 (0.60), 7.610 (0.66), 7.627 (1.19), 7.644 (0.62), 8.958 (1.94), 8.975 (1.98), 9.089 (4.67), 9.290 (1.41), 9.308 (1.36)。 LC-MS (方法2): R t= 1.03 min;MS (ESIpos): m/z = 481 [M+H]⁺ 中間物177 19.0 mg (100%純度,43%產率) |
89 | (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丁-2-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.899 (2.58), 0.918 (6.07), 0.937 (2.99), 1.342 (0.40), 1.359 (0.51), 1.367 (0.45), 1.377 (0.45), 1.384 (0.52), 1.511 (0.44), 1.517 (0.48), 1.529 (0.55), 1.535 (0.55), 1.545 (0.46), 1.597 (5.07), 1.615 (5.12), 1.691 (9.06), 1.724 (9.11), 2.408 (16.00), 2.518 (3.82), 2.523 (2.70), 3.903 (0.42), 5.577 (2.69), 5.595 (2.65), 5.744 (0.83), 5.762 (1.29), 5.780 (0.83), 7.218 (0.93), 7.237 (2.10), 7.256 (1.29), 7.351 (0.79), 7.369 (1.23), 7.384 (0.60), 7.615 (0.67), 7.633 (1.20), 7.649 (0.63), 8.956 (1.95), 8.972 (2.01), 9.087 (4.71), 9.288 (1.42), 9.306 (1.37)。 LC-MS (方法2): R t= 0.97 min;MS (ESIpos): m/z = 468 [M+H]⁺ 中間物179 20.0 mg (100%純度,45%產率) |
表8中顯示之實例係根據一般程序1自各別鹵芳基衍生物及各別氧化膦製備。
實例表
8
實例 | 結構;IUPAC名稱;分析資料;起始材料;產率 |
90 | (2R*)-1-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.912 (1.79), 0.931 (4.64), 0.948 (4.96), 0.953 (2.30), 0.967 (2.45), 0.973 (4.95), 0.990 (4.97), 1.009 (1.95), 1.130 (4.04), 1.145 (4.08), 1.603 (4.59), 1.620 (4.57), 1.952 (0.46), 1.962 (1.08), 1.971 (1.29), 1.981 (1.84), 1.990 (1.83), 1.997 (1.26), 2.000 (1.62), 2.005 (1.54), 2.009 (1.56), 2.024 (1.25), 2.031 (0.96), 2.041 (0.43), 2.332 (0.44), 2.413 (16.00), 2.518 (2.20), 2.523 (1.56), 5.588 (0.85), 5.599 (0.88), 5.749 (0.74), 5.767 (1.15), 5.785 (0.73), 7.228 (0.84), 7.247 (1.91), 7.267 (1.16), 7.358 (0.70), 7.375 (1.06), 7.391 (0.51), 7.395 (0.48), 7.634 (0.58), 7.651 (1.02), 7.667 (0.52), 8.936 (1.76), 8.950 (1.74), 9.086 (4.33), 9.325 (1.25), 9.342 (1.19)。 LC-MS (方法1): R t= 0.89 min;MS (ESIpos): m/z = 481 [M+H]⁺ 中間物45 62.7 mg (95%純度,56%產率) |
91 | 4-[2,8-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 LC-MS (方法2): R t= 1.50 min;MS (ESIpos): m/z = 578 [M+H]⁺ 中間物140 201 mg (153%產率) |
92 | 6-(二乙基磷醯基)-N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.911 (1.80), 0.930 (5.37), 0.948 (5.63), 0.953 (2.38), 0.967 (2.59), 0.972 (5.44), 0.990 (5.65), 1.009 (1.95), 1.106 (4.58), 1.143 (0.48), 1.230 (0.76), 1.613 (4.88), 1.631 (4.86), 1.951 (0.45), 1.961 (1.20), 1.970 (1.23), 1.980 (1.98), 1.988 (1.76), 2.000 (1.78), 2.007 (1.99), 2.011 (1.21), 2.021 (1.10), 2.026 (1.24), 2.031 (0.95), 2.426 (16.00), 2.518 (2.23), 2.522 (1.44), 5.779 (0.74), 5.797 (1.14), 5.815 (0.72), 7.105 (1.14), 7.241 (2.41), 7.289 (0.81), 7.308 (1.78), 7.327 (1.02), 7.377 (1.00), 7.495 (0.59), 7.512 (1.00), 7.528 (0.51), 7.700 (0.55), 7.717 (1.00), 7.735 (0.49), 8.087 (0.49), 8.936 (1.74), 8.950 (1.76), 8.952 (1.71), 9.091 (4.19), 9.326 (1.17), 9.344 (1.13)。 LC-MS (方法2): R t= 1.13 min;MS (ESIneg): m/z = 435 [M-H]⁻ 中間物165 53.1 mg (90%純度,90%產率) |
93 | 1-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.602 (4.89), 1.616 (4.95), 1.799 (0.41), 1.816 (0.59), 1.827 (0.75), 1.843 (0.64), 1.858 (0.47), 1.967 (0.51), 1.981 (0.70), 2.003 (0.75), 2.017 (0.88), 2.035 (0.77), 2.051 (0.76), 2.065 (0.53), 2.073 (0.43), 2.099 (0.61), 2.118 (0.75), 2.132 (0.68), 2.144 (0.50), 2.365 (0.81), 2.422 (16.00), 2.514 (3.33), 2.518 (3.29), 2.522 (2.58), 3.957 (1.12), 3.986 (2.16), 4.014 (0.99), 5.765 (0.79), 5.778 (1.20), 5.793 (0.76), 7.253 (0.88), 7.269 (1.95), 7.284 (1.08), 7.422 (0.62), 7.435 (1.04), 7.449 (0.52), 7.667 (0.56), 7.681 (1.00), 7.694 (0.52), 9.011 (1.69), 9.022 (1.68), 9.095 (4.00), 9.317 (1.27), 9.331 (1.20)。 LC-MS (方法2): R t= 1.13 min;MS (ESIpos): m/z = 479 [M+H]⁺ 中間物172 42.8 mg (95%純度,77%產率) |
94 | N-{(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.603 (3.58), 1.618 (3.54), 1.692 (4.65), 1.695 (4.76), 1.719 (4.74), 1.722 (4.66), 2.421 (11.48), 2.514 (1.30), 2.518 (1.29), 2.522 (1.00), 3.333 (16.00), 3.957 (0.80), 3.986 (1.55), 4.014 (0.69), 5.765 (0.56), 5.778 (0.85), 5.793 (0.55), 7.257 (0.64), 7.273 (1.39), 7.289 (0.77), 7.424 (0.45), 7.438 (0.75), 7.682 (0.72), 8.957 (1.22), 8.969 (1.23), 9.090 (2.87), 9.288 (0.89), 9.303 (0.85)。 LC-MS (方法2): R t= 1.04 min;MS (ESIpos): m/z = 453 [M+H]⁺ 中間物172 44.4 mg (95%純度,71%產率) |
95 | 1-[4-({(1R)-1-[3-胺基-5-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.549 (6.34), 1.567 (6.32), 1.790 (0.64), 1.807 (0.90), 1.825 (1.05), 1.860 (0.70), 1.956 (0.78), 1.974 (1.22), 1.991 (1.51), 2.009 (1.53), 2.031 (1.37), 2.049 (1.21), 2.065 (0.85), 2.088 (1.21), 2.106 (1.14), 2.125 (1.24), 2.141 (1.02), 2.158 (0.60), 2.475 (16.00), 2.518 (3.00), 2.523 (2.09), 5.515 (0.98), 5.534 (1.51), 5.553 (1.55), 5.566 (3.69), 6.700 (3.11), 6.853 (2.86), 6.908 (3.15), 8.977 (2.27), 8.992 (2.23), 9.092 (4.34), 9.201 (1.47), 9.220 (1.41)。 LC-MS (方法1): R t= 0.90 min;MS (ESIpos): m/z = 450 [M+H]⁺ 中間物241 119 mg (95%純度,72%產率) |
96 | 6-(二乙基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.911 (1.25), 0.927 (1.57), 0.931 (3.06), 0.946 (3.36), 0.950 (1.83), 0.953 (1.55), 0.965 (2.05), 0.969 (1.83), 0.972 (3.27), 0.988 (3.28), 0.991 (1.66), 1.007 (1.34), 1.107 (16.00), 1.230 (0.52), 1.570 (3.29), 1.588 (3.31), 1.959 (0.74), 1.970 (0.79), 1.974 (0.86), 1.978 (1.24), 1.989 (1.05), 1.992 (0.88), 1.997 (1.00), 2.002 (1.33), 2.005 (0.95), 2.008 (1.03), 2.021 (1.15), 2.027 (0.71), 2.415 (10.76), 2.518 (1.99), 2.523 (1.32), 2.632 (3.96), 4.189 (1.17), 5.704 (0.50), 5.722 (0.77), 5.739 (0.49), 7.352 (0.45), 7.371 (0.99), 7.390 (0.57), 7.540 (1.08), 7.558 (0.85), 7.808 (0.94), 7.827 (0.85), 8.087 (0.40), 8.934 (1.19), 8.936 (1.23), 8.949 (1.19), 8.951 (1.18), 9.071 (2.90), 9.412 (0.80), 9.430 (0.78)。 LC-MS (方法2): R t= 1.28 min;MS (ESIneg): m/z = 449 [M-H]⁻ 中間物117 44.1 mg (99%純度,82%產率) |
97 | N-{(1R)-1-[3-胺基-5-(三氟甲基)苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.552 (4.76), 1.570 (4.79), 1.683 (6.10), 1.689 (6.28), 1.716 (6.20), 1.723 (6.12), 2.475 (16.00), 2.518 (2.58), 2.523 (1.80), 5.519 (0.71), 5.537 (1.10), 5.556 (1.08), 5.568 (3.76), 5.759 (2.22), 6.703 (2.24), 6.856 (2.06), 6.910 (2.28), 8.920 (1.77), 8.922 (1.80), 8.936 (1.78), 8.938 (1.72), 9.088 (4.14), 9.169 (1.28), 9.188 (1.23)。 LC-MS (方法2): R t= 0.99 min;MS (ESIpos): m/z = 424 [M+H]⁺ 中間物241 27.0 mg (95%純度,14%產率) |
98 | 6-[二(丙-2-基)磷醯基]-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.920 (3.58), 0.926 (3.57), 0.937 (3.77), 0.944 (3.68), 0.958 (3.68), 0.965 (3.64), 0.976 (3.68), 0.982 (3.53), 1.105 (3.25), 1.116 (3.61), 1.123 (3.73), 1.134 (3.57), 1.142 (3.48), 1.154 (3.66), 1.160 (3.60), 1.172 (3.28), 1.573 (4.99), 1.590 (4.92), 2.413 (16.00), 2.439 (1.02), 2.447 (1.14), 2.465 (2.09), 2.518 (9.24), 2.523 (6.80), 2.636 (6.09), 2.678 (0.84), 5.700 (0.77), 5.718 (1.18), 5.735 (0.76), 7.355 (0.71), 7.374 (1.52), 7.393 (0.89), 7.539 (1.67), 7.557 (1.31), 7.807 (1.48), 7.827 (1.32), 8.895 (1.86), 8.907 (1.82), 9.066 (4.30), 9.068 (4.32), 9.451 (1.26), 9.468 (1.22)。 LC-MS (方法2): R t= 1.39 min;MS (ESIneg): m/z = 477 [M-H]⁻ 中間物117 26.0 mg (95%純度,22%產率) |
99 | 1-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.567 (5.03), 1.584 (5.07), 1.793 (0.42), 1.809 (0.60), 1.829 (0.77), 1.842 (0.63), 1.863 (0.48), 1.960 (0.50), 1.977 (0.78), 1.993 (0.99), 2.010 (1.12), 2.033 (0.92), 2.051 (0.85), 2.067 (0.64), 2.087 (0.98), 2.101 (0.79), 2.119 (0.74), 2.125 (0.73), 2.136 (0.64), 2.154 (0.44), 2.331 (0.83), 2.417 (16.00), 2.518 (4.43), 2.523 (3.13), 2.626 (6.06), 2.673 (0.84), 5.705 (0.77), 5.722 (1.21), 5.739 (0.75), 7.342 (0.69), 7.361 (1.51), 7.381 (0.87), 7.538 (1.63), 7.556 (1.31), 7.796 (1.45), 7.815 (1.31), 9.007 (1.79), 9.009 (1.84), 9.022 (1.80), 9.024 (1.81), 9.078 (3.98), 9.402 (1.24), 9.420 (1.20)。 LC-MS (方法2): R t= 1.27 min;MS (ESIpos): m/z = 449 [M+H]⁺ 中間物117 80.0 mg (95%純度,72%產率) |
100 | 1-[2,7-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.576 (4.85), 1.593 (4.82), 1.805 (0.53), 1.830 (0.61), 1.847 (0.57), 1.855 (0.58), 1.873 (0.40), 1.975 (0.65), 2.014 (1.02), 2.052 (0.59), 2.069 (0.53), 2.337 (0.63), 2.366 (16.00), 2.418 (0.57), 2.436 (0.48), 2.518 (7.74), 2.523 (5.54), 2.612 (5.77), 2.678 (0.61), 2.816 (12.58), 5.708 (0.72), 5.725 (1.13), 5.743 (0.73), 7.343 (0.65), 7.362 (1.43), 7.383 (0.84), 7.543 (1.62), 7.561 (1.34), 7.749 (1.39), 7.769 (1.26), 8.906 (2.01), 8.938 (1.95), 9.026 (1.22), 9.042 (1.16)。 LC-MS (方法2): R t= 1.15 min;MS (ESIpos): m/z = 463 [M+H]⁺ 中間物18 50.0 mg (95%純度,45%產率) |
101 | 6-(二甲基磷醯基)-7-甲氧基-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.530 (3.90), 1.548 (3.93), 1.698 (6.62), 1.733 (6.52), 2.332 (0.92), 2.337 (0.52), 2.349 (13.88), 2.518 (4.84), 2.523 (3.40), 2.618 (4.73), 2.673 (0.83), 4.008 (16.00), 5.688 (0.60), 5.706 (0.93), 5.723 (0.60), 7.336 (0.54), 7.356 (1.20), 7.376 (0.70), 7.528 (1.30), 7.546 (1.04), 7.801 (1.14), 7.820 (1.03), 9.139 (2.24), 9.156 (1.07), 9.171 (2.77)。 LC-MS (方法2): R t= 1.13 min;MS (ESIpos): m/z = 453 [M+H]⁺ 中間物35 43.0 mg (95%純度,41%產率) |
102 | 6-[二(丙-2-基)磷醯基]-2,7-二甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.877 (0.98), 0.895 (1.97), 0.913 (1.26), 0.917 (1.28), 0.934 (1.96), 0.953 (1.04), 1.165 (0.99), 1.185 (1.41), 1.203 (1.97), 1.222 (1.48), 1.240 (1.16), 1.580 (1.70), 1.598 (1.71), 2.337 (1.24), 2.362 (5.93), 2.518 (16.00), 2.523 (11.18), 2.564 (0.43), 2.609 (2.12), 2.674 (2.90), 2.679 (1.30), 2.819 (3.80), 7.366 (0.52), 7.540 (0.57), 7.559 (0.47), 7.723 (0.49), 7.744 (0.43), 8.832 (0.42), 8.860 (0.42)。 LC-MS (方法2): R t= 1.24 min;MS (ESIneg): m/z = 491 [M-H]⁻ 中間物18 7.00 mg (95%純度,6%產率) |
103 | 1-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[2,3-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.943 (1.87), 0.952 (2.00), 0.962 (4.51), 0.971 (4.36), 0.981 (2.35), 0.986 (2.39), 0.990 (2.44), 0.995 (2.23), 1.004 (4.41), 1.014 (4.47), 1.023 (2.05), 1.033 (1.96), 1.200 (6.32), 1.226 (6.50), 1.591 (4.69), 1.609 (4.67), 1.998 (0.52), 2.007 (0.58), 2.017 (0.82), 2.026 (0.92), 2.032 (0.74), 2.036 (0.86), 2.041 (1.16), 2.045 (1.06), 2.051 (0.99), 2.061 (1.37), 2.066 (1.07), 2.070 (0.92), 2.079 (1.19), 2.085 (0.96), 2.092 (0.86), 2.098 (1.17), 2.104 (0.63), 2.111 (0.82), 2.117 (1.04), 2.123 (0.40), 2.130 (0.55), 2.135 (0.58), 2.395 (16.00), 2.518 (2.34), 2.523 (1.61), 5.340 (2.52), 5.776 (0.76), 5.794 (1.16), 5.812 (0.73), 7.208 (0.75), 7.228 (1.80), 7.247 (1.16), 7.301 (0.69), 7.305 (0.80), 7.322 (1.10), 7.338 (0.52), 7.342 (0.46), 7.609 (0.61), 7.626 (1.07), 7.641 (0.55), 9.118 (1.48), 9.123 (1.79), 9.127 (1.64), 9.132 (1.56), 9.179 (1.30), 9.197 (1.24), 9.215 (1.36), 9.220 (1.25), 9.242 (1.33), 9.247 (1.19)。 LC-MS (方法2): R t= 0.98 min;MS (ESIpos): m/z = 496 [M+H]⁺ 中間物17 33.0 mg (95%純度,40%產率) |
104 | 1-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.571 (4.98), 1.588 (5.03), 1.857 (0.43), 1.872 (0.58), 1.893 (0.78), 1.912 (0.78), 1.928 (1.05), 1.946 (0.81), 1.970 (0.63), 2.017 (0.55), 2.033 (0.71), 2.050 (0.81), 2.063 (0.99), 2.086 (1.34), 2.102 (0.92), 2.124 (0.60), 2.331 (0.90), 2.336 (0.46), 2.357 (16.00), 2.518 (3.88), 2.523 (2.60), 2.635 (6.07), 2.673 (0.85), 5.720 (0.76), 5.737 (1.17), 5.755 (0.75), 7.332 (0.70), 7.351 (1.51), 7.371 (0.86), 7.526 (1.64), 7.543 (1.31), 7.645 (1.33), 7.652 (1.33), 7.667 (1.54), 7.673 (1.51), 7.809 (1.44), 7.829 (1.33), 7.880 (0.87), 7.884 (0.90), 7.905 (1.49), 7.908 (1.03), 7.926 (0.72), 7.929 (0.76), 8.819 (1.23), 8.822 (1.24), 8.850 (1.25), 8.853 (1.22), 9.009 (1.25), 9.026 (1.20)。 LC-MS (方法2): R t= 1.23 min;MS (ESIneg): m/z = 446 [M-H]⁻ 中間物182 53.0 mg (95%純度,48%產率) |
105 | 1-苄基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.798 (0.78), 0.814 (0.87), 0.821 (0.84), 0.840 (0.41), 0.886 (0.42), 0.904 (0.90), 0.923 (0.50), 0.951 (0.50), 1.035 (1.10), 1.052 (2.48), 1.070 (1.41), 1.154 (5.91), 1.172 (12.30), 1.190 (6.08), 1.218 (0.47), 1.236 (1.07), 1.253 (0.48), 1.579 (8.04), 1.597 (8.01), 1.751 (1.80), 1.907 (3.01), 1.927 (0.84), 1.964 (1.55), 2.003 (0.92), 2.323 (3.18), 2.327 (4.27), 2.331 (3.51), 2.336 (2.34), 2.364 (16.00), 2.518 (12.96), 2.523 (8.33), 2.631 (11.72), 2.660 (1.42), 2.665 (2.70), 2.669 (3.56), 2.673 (2.62), 2.783 (1.77), 2.812 (1.87), 2.841 (0.88), 2.884 (1.19), 2.941 (1.19), 3.065 (0.93), 3.084 (2.76), 3.096 (2.81), 3.102 (2.81), 3.114 (2.58), 3.133 (0.83), 3.423 (0.46), 3.435 (0.48), 3.452 (0.42), 3.576 (0.47), 3.652 (7.00), 5.722 (1.14), 5.739 (1.68), 5.756 (1.11), 7.277 (1.58), 7.291 (1.52), 7.298 (1.30), 7.311 (1.35), 7.358 (9.04), 7.365 (12.01), 7.380 (2.43), 7.535 (3.03), 7.553 (2.50), 7.659 (1.62), 7.664 (1.68), 7.679 (1.84), 7.685 (1.78), 7.774 (2.73), 7.795 (2.45), 8.036 (0.76), 8.058 (1.31), 8.080 (0.69), 8.816 (1.51), 8.846 (1.55), 8.969 (0.48)。 LC-MS (方法2): R t= 1.37 min;MS (ESIpos): m/z = 554 [M+H]⁺ 中間物182 144 mg (95%純度,81%產率) |
106 | 6-(二甲基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}喹唑啉-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.570 (4.80), 1.587 (4.73), 1.723 (15.57), 1.756 (16.00), 2.323 (0.50), 2.327 (0.70), 2.331 (0.52), 2.356 (15.45), 2.518 (2.15), 2.523 (1.46), 2.635 (5.71), 2.665 (0.52), 2.669 (0.68), 2.673 (0.47), 5.720 (0.72), 5.737 (1.11), 5.755 (0.71), 7.336 (0.66), 7.356 (1.42), 7.375 (0.82), 7.528 (1.54), 7.546 (1.23), 7.631 (1.30), 7.637 (1.30), 7.652 (1.46), 7.659 (1.42), 7.805 (1.36), 7.824 (1.23), 7.973 (0.86), 7.976 (0.88), 7.993 (0.86), 7.997 (1.65), 8.001 (0.96), 8.018 (0.75), 8.023 (0.75), 8.806 (1.20), 8.809 (1.18), 8.838 (1.20), 8.841 (1.16), 8.934 (1.18), 8.952 (1.15)。 LC-MS (方法2): R t= 1.17 min;MS (ESIneg): m/z = 420 [M-H]⁻ 中間物182 47.0 mg (95%純度,45%產率) |
107 | 1-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.609 (4.96), 1.627 (4.90), 1.791 (0.40), 1.812 (0.55), 1.831 (0.72), 1.843 (0.60), 1.864 (0.46), 1.961 (0.51), 1.978 (0.79), 1.994 (1.02), 2.012 (1.06), 2.019 (0.93), 2.035 (0.91), 2.053 (0.82), 2.068 (0.59), 2.090 (0.94), 2.103 (0.76), 2.120 (0.76), 2.132 (0.67), 2.138 (0.67), 2.150 (0.50), 2.156 (0.44), 2.331 (0.41), 2.428 (16.00), 2.518 (2.21), 2.523 (1.54), 2.673 (0.41), 2.727 (3.08), 2.729 (2.92), 2.888 (3.75), 5.759 (0.73), 5.783 (0.75), 5.801 (1.15), 5.819 (0.74), 7.104 (1.17), 7.240 (2.39), 7.280 (0.84), 7.299 (1.82), 7.319 (1.04), 7.376 (1.02), 7.493 (0.61), 7.510 (1.04), 7.527 (0.50), 7.690 (0.56), 7.708 (1.03), 7.726 (0.51), 7.950 (0.44), 9.009 (1.70), 9.011 (1.76), 9.025 (1.74), 9.027 (1.73), 9.097 (4.09), 9.315 (1.20), 9.333 (1.16)。 LC-MS (方法2): R t= 1.12 min;MS (ESIpos): m/z = 435 [M+H]⁺ 中間物165 76.0 mg (95%純度,68%產率) |
108 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[二(丙-2-基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.920 (3.14), 0.932 (3.45), 0.938 (3.59), 0.950 (3.39), 0.959 (3.36), 0.971 (3.51), 0.977 (3.55), 0.989 (3.16), 1.103 (3.07), 1.120 (5.80), 1.138 (4.35), 1.158 (5.85), 1.175 (3.12), 1.615 (4.82), 1.633 (4.77), 2.154 (0.53), 2.423 (16.00), 2.437 (1.00), 2.445 (0.80), 2.450 (0.86), 2.455 (1.01), 2.463 (1.30), 2.468 (1.52), 2.518 (4.58), 2.523 (3.26), 5.775 (0.75), 5.793 (1.15), 5.810 (0.73), 7.106 (1.16), 7.242 (2.35), 7.291 (0.83), 7.310 (1.80), 7.329 (1.03), 7.377 (1.01), 7.493 (0.60), 7.511 (1.01), 7.529 (0.49), 7.695 (0.55), 7.713 (1.01), 7.731 (0.50), 8.893 (1.72), 8.895 (1.74), 8.908 (1.76), 8.910 (1.72), 9.085 (4.40), 9.087 (4.30), 9.364 (1.21), 9.382 (1.16)。 LC-MS (方法2): R t= 1.25 min;MS (ESIneg): m/z = 463 [M-H]⁻ 中間物165 28.0 mg (95%純度,24%產率) |
109 | 1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-酮 LC-MS (方法2): R t= 1.17 min;MS (ESIpos): m/z = 479.6 [M+H]⁺ 中間物85 246 mg (96%產率) |
110 | 1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-酮 LC-MS (方法2): R t= 1.23 min;MS (ESIpos): m/z = 493 [M+H]⁺ 中間物63 142 mg (95%純度,63%產率) |
111 | 1-(4-{[(1R)-1-{3-[(2R*)-1,1-二氟-2-羥丙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ 5-磷雜環戊烷-1-酮(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.146 (4.48), 1.163 (4.52), 1.231 (0.42), 1.592 (5.06), 1.610 (5.04), 1.792 (0.51), 1.811 (0.68), 1.830 (0.84), 1.844 (0.72), 1.865 (0.57), 1.961 (0.61), 1.978 (0.94), 1.995 (1.18), 2.013 (1.23), 2.036 (1.06), 2.054 (0.94), 2.069 (0.66), 2.091 (1.02), 2.102 (0.96), 2.119 (1.08), 2.137 (1.04), 2.155 (0.72), 2.332 (0.90), 2.336 (0.40), 2.437 (16.00), 2.518 (4.97), 2.523 (3.26), 4.183 (0.41), 5.566 (1.93), 5.582 (1.91), 5.758 (6.16), 5.800 (0.80), 5.817 (1.24), 5.834 (0.79), 7.229 (0.90), 7.248 (2.03), 7.268 (1.23), 7.361 (0.77), 7.378 (1.18), 7.394 (0.56), 7.640 (0.65), 7.656 (1.15), 7.674 (0.59), 9.011 (1.88), 9.025 (1.86), 9.096 (4.56), 9.296 (1.39), 9.314 (1.32)。 LC-MS (方法2): R t= 1.02 min;MS (ESIneg): m/z = 477 [M-H]⁻ 中間物44 22.0 mg (95%純度,25%產率) |
112 | 1-(4-{[(1R)-1-{3-[(2R*)-1,1-二氟-2-羥丙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ 5-磷雜環戊烷-1-酮(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.133 (4.42), 1.149 (4.48), 1.228 (0.58), 1.598 (5.01), 1.616 (4.97), 1.793 (0.51), 1.811 (0.69), 1.831 (0.85), 1.844 (0.72), 1.865 (0.59), 1.961 (0.59), 1.977 (0.92), 1.995 (1.17), 2.013 (1.26), 2.036 (1.06), 2.053 (0.95), 2.069 (0.68), 2.084 (0.84), 2.090 (1.07), 2.102 (0.93), 2.119 (1.00), 2.137 (0.91), 2.153 (0.62), 2.415 (16.00), 2.435 (0.48), 2.518 (1.78), 2.523 (1.22), 4.194 (0.41), 4.211 (0.41), 5.580 (1.76), 5.595 (1.69), 5.758 (6.77), 5.772 (1.25), 5.789 (0.79), 7.219 (0.90), 7.238 (2.05), 7.257 (1.24), 7.355 (0.76), 7.373 (1.19), 7.388 (0.57), 7.623 (0.64), 7.641 (1.15), 7.657 (0.60), 9.010 (1.93), 9.025 (1.88), 9.091 (4.57), 9.312 (1.37), 9.330 (1.30)。 LC-MS (方法2): R t= 1.01 min;MS (ESIpos): m/z = 479 [M+H]⁺ 中間物45 6.20 mg (95%純度,7%產率) |
113 | (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.134 (5.25), 1.150 (5.30), 1.602 (5.83), 1.620 (5.82), 1.690 (9.02), 1.693 (9.26), 1.724 (9.16), 1.727 (9.08), 2.331 (0.72), 2.420 (16.00), 2.441 (0.55), 2.518 (4.62), 2.523 (2.99), 2.673 (0.70), 4.208 (0.46), 5.581 (0.93), 5.596 (0.90), 5.758 (1.24), 5.778 (1.42), 5.796 (0.91), 7.227 (1.02), 7.246 (2.35), 7.265 (1.42), 7.361 (0.90), 7.378 (1.42), 7.395 (0.68), 7.627 (0.79), 7.644 (1.40), 7.660 (0.76), 8.964 (2.14), 8.980 (2.12), 9.092 (5.14), 9.340 (0.52)。 LC-MS (方法2): R t= 0.92 min;MS (ESIneg): m/z = 451 [M-H]⁻ 中間物45 23.3 mg (95%純度,28%產率) |
114 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (1.22), 0.905 (2.54), 0.910 (1.54), 0.923 (2.43), 0.932 (1.35), 0.946 (2.59), 0.950 (1.54), 0.964 (2.41), 1.144 (3.41), 1.161 (3.52), 1.183 (3.41), 1.201 (3.37), 1.610 (3.95), 1.627 (4.01), 1.648 (5.47), 1.657 (2.97), 1.681 (5.42), 1.689 (2.90), 2.198 (0.60), 2.216 (0.68), 2.222 (0.66), 2.235 (0.46), 2.240 (0.65), 2.425 (16.00), 2.518 (1.82), 2.523 (1.29), 5.775 (0.57), 5.793 (0.88), 5.800 (0.55), 5.811 (0.58), 7.106 (0.92), 7.242 (1.91), 7.291 (0.61), 7.301 (0.73), 7.310 (1.31), 7.321 (0.44), 7.329 (0.75), 7.378 (0.82), 7.494 (0.61), 7.511 (1.05), 7.528 (0.51), 7.703 (0.52), 7.716 (0.78), 8.933 (1.24), 8.934 (1.27), 8.948 (1.63), 8.950 (1.36), 8.960 (0.67), 8.962 (0.65), 9.088 (4.55), 9.311 (0.86), 9.329 (1.01), 9.350 (0.44)。 LC-MS (方法2): R t= 1.12 min;MS (ESIpos): m/z = 438 [M+H]⁺ 中間物165 12.0 mg (95%純度,7%產率) |
實例114之非對映異構體係根據下列方法分離。 分析方法: 儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SB 3 µ,100x4.6;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:90%A+10%B;流量:1.4 ml/min;溫度:25℃;UV:280 nm; 製備方法: 儀器:PrepCon Labomatic HPLC-2;管柱:YMC Cellulose SB 10 µ,250x50;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:90%A+10%B;流量:70 ml/min;溫度:25℃;UV:280 nm; | |
115 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體1) LC-MS (方法2): R t= 1.12 min;MS (ESIpos): m/z = 438 [M+H]⁺ 實例114 20.0 mg (95%純度) Rt (分析方法) = 3.40 min (de = >99%) |
116 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.906 (2.00), 0.924 (2.04), 0.946 (2.03), 0.964 (1.99), 1.144 (1.97), 1.162 (2.12), 1.184 (2.08), 1.202 (2.08), 1.232 (1.07), 1.352 (4.07), 1.609 (2.94), 1.627 (3.02), 1.648 (4.31), 1.681 (4.24), 2.181 (0.60), 2.217 (0.44), 2.241 (0.44), 2.336 (0.66), 2.426 (9.21), 2.518 (16.00), 2.522 (10.76), 2.678 (0.66), 5.775 (0.46), 5.793 (0.70), 5.810 (0.47), 7.106 (0.69), 7.242 (1.39), 7.292 (0.48), 7.311 (1.08), 7.331 (0.65), 7.378 (0.60), 7.512 (0.64), 7.716 (0.67), 8.934 (1.07), 8.950 (1.07), 9.090 (2.46), 9.312 (0.72), 9.330 (0.73)。 LC-MS (方法2): R t= 1.11 min;MS (ESIneg): m/z = 435 [M-H]⁻ 實例114 24.0 mg (95%純度) Rt (分析方法) = 4.90 min (de = 97%) |
117 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (0.99), 0.950 (1.15), 0.954 (2.52), 0.969 (2.24), 0.973 (1.39), 0.978 (1.16), 0.989 (1.04), 0.994 (1.24), 0.997 (2.58), 1.013 (2.27), 1.016 (1.32), 1.032 (0.92), 1.612 (3.71), 1.630 (3.71), 1.654 (3.47), 1.662 (4.13), 1.687 (3.40), 1.694 (4.16), 1.963 (0.46), 1.973 (0.97), 1.978 (0.59), 1.982 (0.65), 1.991 (1.25), 1.997 (0.62), 2.003 (0.76), 2.010 (0.94), 2.023 (0.61), 2.029 (0.55), 2.427 (16.00), 2.518 (3.53), 2.523 (2.45), 5.786 (0.50), 5.796 (0.63), 5.803 (0.72), 5.814 (0.43), 5.821 (0.44), 7.105 (0.92), 7.241 (1.87), 7.284 (0.49), 7.289 (0.44), 7.303 (1.08), 7.308 (0.93), 7.322 (0.62), 7.328 (0.52), 7.377 (0.84), 7.495 (0.59), 7.512 (1.00), 7.530 (0.49), 7.694 (0.42), 7.711 (0.76), 8.945 (0.84), 8.947 (0.87), 8.954 (1.06), 8.956 (1.08), 8.960 (0.93), 8.969 (1.00), 8.971 (0.95), 9.092 (4.04), 9.300 (0.58), 9.316 (1.11), 9.333 (0.65)。 LC-MS (方法2): R t= 1.06 min;MS (ESIpos): m/z = 424 [M+H]⁺ 中間物165 58.0 mg (95%純度,36%產率) |
實例117之非對映異構體係根據下列方法分離。 分析方法: 儀器:Thermo Fisher UltiMate 3000;管柱:YMC Cellulose SB 3 µ,100x4.6;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:90%A+10%B;流量:1.4 ml/min;溫度:25℃;UV:280 nm; 製備方法: 儀器:PrepCon Labomatic HPLC-2;管柱:YMC Cellulose SB 10 µ,250x50;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:90%A+10%B;流量:70 ml/min;溫度:25℃;UV:280 nm; | |
118 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (1.96), 0.953 (4.50), 0.972 (2.19), 0.977 (2.12), 0.997 (4.54), 1.016 (2.13), 1.232 (1.15), 1.613 (5.29), 1.631 (5.38), 1.661 (7.54), 1.694 (7.56), 1.963 (0.78), 1.973 (1.21), 1.981 (0.88), 1.991 (1.65), 2.004 (0.98), 2.010 (1.13), 2.023 (0.84), 2.336 (0.58), 2.427 (16.00), 2.522 (11.51), 2.659 (0.65), 5.786 (0.82), 5.803 (1.28), 5.820 (0.83), 7.104 (1.21), 7.240 (2.50), 7.284 (0.88), 7.303 (1.96), 7.322 (1.16), 7.376 (1.07), 7.495 (0.66), 7.512 (1.17), 7.530 (0.60), 7.691 (0.62), 7.709 (1.16), 7.727 (0.61), 8.955 (1.89), 8.969 (1.94), 9.092 (4.43), 9.315 (1.32), 9.333 (1.28)。 LC-MS (方法2): R t= 1.07 min;MS (ESIneg): m/z = 421 [M-H]⁻ 實例117 21.0 mg (95%純度) Rt (分析方法) = 4.69 min (de = 99%) |
119 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.850 (0.40), 0.950 (1.88), 0.969 (4.42), 0.988 (2.20), 0.993 (2.16), 1.013 (4.28), 1.032 (2.07), 1.231 (1.31), 1.610 (5.20), 1.628 (5.29), 1.654 (7.19), 1.687 (7.19), 1.972 (0.88), 1.978 (0.99), 1.991 (1.12), 1.997 (1.12), 2.002 (1.08), 2.009 (1.16), 2.021 (0.90), 2.028 (0.90), 2.074 (5.04), 2.427 (16.00), 2.522 (7.40), 5.777 (0.79), 5.795 (1.23), 5.814 (0.80), 7.106 (1.17), 7.242 (2.40), 7.289 (0.85), 7.309 (1.87), 7.328 (1.12), 7.377 (1.05), 7.497 (0.64), 7.514 (1.15), 7.531 (0.59), 7.698 (0.61), 7.716 (1.15), 7.735 (0.60), 8.946 (1.81), 8.960 (1.84), 9.092 (4.20), 9.299 (1.24), 9.317 (1.28)。 LC-MS (方法2): R t= 1.06 min;MS (ESIneg): m/z = 421 [M-H]⁻ 實例117 13.0 mg (95%純度) Rt (分析方法) = 6.09 min (de = 95%) |
120 | N-{(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.229 (0.53), 1.593 (5.52), 1.610 (5.49), 1.622 (0.56), 1.693 (6.41), 1.699 (6.47), 1.727 (6.62), 1.733 (6.46), 2.327 (1.27), 2.331 (0.90), 2.337 (0.41), 2.385 (16.00), 2.518 (5.28), 2.523 (3.67), 2.669 (1.28), 2.673 (0.89), 3.159 (2.38), 3.171 (2.40), 4.099 (0.42), 5.758 (0.51), 5.872 (0.85), 5.890 (1.31), 5.907 (0.83), 7.495 (0.84), 7.514 (1.83), 7.534 (1.07), 7.728 (1.46), 7.731 (1.62), 7.748 (1.31), 7.751 (1.27), 7.862 (1.37), 7.865 (1.37), 7.882 (1.25), 8.984 (1.85), 8.998 (1.84), 9.000 (1.82), 9.095 (4.21), 9.413 (1.29), 9.430 (1.25)。 LC-MS (方法2): R t= 1.16 min;MS (ESIpos): m/z = 444 [M+H]⁺ 中間物168 15.0 mg (95%純度,17%產率) |
121 | N-{(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.251 (7.88), 1.259 (8.21), 1.588 (5.18), 1.605 (5.21), 1.692 (8.85), 1.724 (8.78), 2.406 (16.00), 2.518 (3.58), 2.523 (2.37), 3.174 (15.82), 5.758 (4.86), 5.775 (1.29), 5.793 (0.81), 7.205 (0.76), 7.224 (1.86), 7.243 (1.26), 7.287 (0.75), 7.292 (0.88), 7.308 (1.18), 7.324 (0.55), 7.329 (0.50), 7.617 (0.65), 7.633 (1.15), 7.648 (0.60), 8.965 (1.96), 8.981 (1.98), 9.088 (4.73), 9.285 (1.37), 9.303 (1.32)。 LC-MS (方法2): R t= 1.15 min;MS (ESIpos): m/z = 481 [M+H]⁺ 中間物67 42.4 mg (95%純度,68%產率) |
122 | 1-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (0.96), 1.251 (8.36), 1.259 (8.52), 1.586 (5.16), 1.603 (5.17), 1.795 (0.56), 1.812 (0.74), 1.832 (0.90), 1.846 (0.74), 1.867 (0.62), 1.907 (0.40), 1.960 (0.59), 1.978 (0.93), 1.995 (1.18), 2.014 (1.27), 2.036 (1.07), 2.054 (0.95), 2.070 (0.69), 2.091 (1.08), 2.104 (0.91), 2.119 (0.96), 2.137 (0.88), 2.154 (0.60), 2.407 (16.00), 2.518 (4.46), 2.523 (2.97), 3.174 (15.82), 5.758 (4.37), 5.775 (1.29), 5.793 (0.81), 7.200 (0.77), 7.219 (1.87), 7.239 (1.25), 7.285 (0.73), 7.289 (0.86), 7.306 (1.19), 7.322 (0.55), 7.326 (0.51), 7.615 (0.66), 7.631 (1.16), 7.647 (0.61), 9.019 (1.94), 9.034 (1.94), 9.093 (4.74), 9.313 (1.38), 9.331 (1.33)。 LC-MS (方法2): R t= 1.23 min;MS (ESIpos): m/z = 507 [M+H]⁺ 中間物67 44.3 mg (95%純度,80%產率) |
123 | 1-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.913 (2.00), 0.928 (2.69), 0.932 (4.85), 0.948 (5.09), 0.951 (3.05), 0.955 (2.60), 0.967 (2.80), 0.970 (3.03), 0.974 (4.81), 0.989 (4.86), 0.993 (2.59), 1.008 (2.02), 1.199 (7.13), 1.225 (7.50), 1.591 (5.20), 1.609 (5.13), 1.947 (0.46), 1.965 (1.18), 1.973 (1.69), 1.977 (1.56), 1.983 (1.85), 1.992 (2.40), 2.005 (2.33), 2.012 (2.15), 2.024 (1.86), 2.031 (1.20), 2.043 (0.63), 2.327 (1.10), 2.331 (0.78), 2.411 (16.00), 2.518 (3.45), 2.523 (2.27), 2.669 (1.09), 2.674 (0.77), 5.334 (7.02), 5.759 (6.85), 5.772 (0.88), 5.791 (1.32), 5.808 (0.84), 7.210 (0.83), 7.229 (1.95), 7.248 (1.26), 7.299 (0.78), 7.303 (0.90), 7.320 (1.24), 7.336 (0.59), 7.339 (0.53), 7.621 (0.70), 7.638 (1.23), 7.653 (0.64), 8.943 (2.03), 8.957 (2.01), 9.088 (4.80), 9.321 (1.47), 9.339 (1.39)。 LC-MS (方法2): R t= 1.07 min;MS (ESIneg): m/z = 493 [M-H]⁻ 中間物70 33.0 mg (95%純度,40%產率) |
124 | 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2,8-二甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.595 (4.71), 1.613 (4.66), 1.668 (6.38), 1.672 (6.60), 1.702 (6.60), 1.707 (6.49), 2.075 (0.56), 2.440 (16.00), 2.518 (2.80), 2.523 (2.04), 2.775 (13.05), 3.891 (0.49), 3.906 (0.55), 3.927 (0.98), 3.943 (1.03), 3.963 (0.48), 3.979 (0.48), 5.703 (0.88), 5.719 (2.03), 5.735 (0.85), 5.775 (0.75), 5.793 (1.14), 5.810 (0.73), 7.238 (0.85), 7.257 (1.90), 7.277 (1.10), 7.402 (0.67), 7.419 (1.06), 7.435 (0.52), 7.646 (0.58), 7.663 (1.03), 7.679 (0.52), 8.784 (1.83), 8.801 (1.82), 9.160 (1.26), 9.178 (1.22)。 LC-MS (方法1): R t= 0.87 min;MS (ESIpos): m/z = 453 [M+H]⁺ 中間物142 65.2 mg (95%純度,62%產率) |
125 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺 ¹H-NMR (600 MHz, DMSO-d6) δ [ppm]: 1.637 (1.64), 1.649 (1.66), 1.870 (1.75), 1.892 (1.75), 2.441 (4.75), 3.317 (5.26), 7.237 (0.65), 7.304 (0.62), 8.310 (16.00), 9.467 (0.53), 9.488 (0.52)。 LC-MS (方法2): R t= 1.10 min;MS (ESIpos): m/z = 477 [M+H]⁺ 中間物180 5.00 mg (95%純度,7%產率) |
126 | 1-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2,7-二甲基吡啶并[2,3-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.232 (0.81), 1.625 (4.85), 1.643 (4.83), 1.801 (0.51), 1.825 (0.57), 1.841 (0.53), 1.850 (0.56), 1.949 (0.49), 1.969 (0.69), 1.986 (0.79), 2.012 (1.03), 2.049 (0.54), 2.064 (0.49), 2.332 (1.20), 2.336 (0.52), 2.378 (16.00), 2.421 (0.40), 2.518 (6.56), 2.522 (4.55), 2.673 (1.24), 2.678 (0.54), 2.828 (12.47), 5.759 (1.50), 5.790 (0.72), 5.808 (1.11), 5.825 (0.70), 7.107 (1.08), 7.243 (2.35), 7.280 (0.80), 7.299 (1.74), 7.318 (0.98), 7.378 (0.95), 7.497 (0.58), 7.514 (0.97), 7.532 (0.48), 7.663 (0.53), 7.682 (0.97), 7.700 (0.48), 8.908 (2.00), 8.940 (2.52), 8.961 (1.16)。 LC-MS (方法2): R t= 1.01 min;MS (ESIpos): m/z = 449 [M+H]⁺ 中間物19 37.0 mg (95%純度,33%產率) |
127 | 1-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基喹唑啉-6-基]-1λ 5-磷雜環戊烷-1-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.616 (4.97), 1.633 (4.94), 1.857 (0.40), 1.874 (0.54), 1.895 (0.73), 1.905 (0.75), 1.913 (0.69), 1.928 (1.03), 1.936 (0.95), 1.949 (0.72), 1.954 (0.71), 1.976 (0.65), 1.993 (0.52), 2.017 (0.60), 2.034 (0.69), 2.057 (0.75), 2.073 (0.96), 2.088 (1.19), 2.110 (0.84), 2.129 (0.60), 2.332 (0.65), 2.367 (16.00), 2.518 (2.63), 2.523 (1.92), 5.759 (6.49), 5.812 (0.76), 5.829 (1.16), 5.847 (0.73), 7.105 (1.17), 7.241 (2.40), 7.271 (0.84), 7.290 (1.82), 7.309 (1.04), 7.376 (1.01), 7.480 (0.63), 7.497 (1.02), 7.514 (0.48), 7.666 (1.31), 7.672 (1.33), 7.687 (2.07), 7.693 (1.70), 7.706 (1.02), 7.723 (0.50), 7.901 (0.92), 7.905 (0.89), 7.922 (0.91), 7.925 (1.46), 7.929 (0.95), 7.946 (0.74), 7.950 (0.74), 8.813 (1.22), 8.817 (1.20), 8.844 (1.21), 8.848 (1.17), 8.915 (1.23), 8.933 (1.17)。 LC-MS (方法2): R t= 1.09 min;MS (ESIpos): m/z = 434 [M+H]⁺ 中間物181 37.0 mg (95%純度,44%產率) |
128 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基喹唑啉-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.923 (0.41), 1.614 (4.93), 1.632 (4.90), 1.724 (15.61), 1.758 (15.54), 2.332 (1.08), 2.336 (0.50), 2.366 (16.00), 2.518 (4.91), 2.522 (3.39), 2.673 (1.09), 2.678 (0.48), 5.808 (0.73), 5.825 (1.14), 5.843 (0.72), 7.105 (1.15), 7.241 (2.36), 7.275 (0.81), 7.294 (1.77), 7.314 (1.02), 7.377 (1.00), 7.483 (0.59), 7.500 (1.01), 7.517 (0.49), 7.651 (1.32), 7.657 (1.32), 7.672 (1.50), 7.679 (1.50), 7.687 (0.58), 7.705 (1.00), 7.723 (0.50), 7.988 (0.90), 7.992 (0.92), 8.009 (0.86), 8.013 (1.66), 8.017 (0.96), 8.034 (0.74), 8.038 (0.78), 8.806 (1.20), 8.808 (1.18), 8.837 (2.27), 8.856 (1.15)。 LC-MS (方法2): R t= 1.02 min;MS (ESIpos): m/z = 408 [M+H]⁺ 中間物181 36.0 mg (90%純度,44%產率) |
129 | N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[二(丙-2-基)磷醯基]-2,7-二甲基吡啶并[2,3-d]嘧啶-4-胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.887 (2.33), 0.892 (2.40), 0.905 (2.45), 0.910 (2.43), 0.927 (2.38), 0.932 (2.40), 0.945 (2.40), 0.950 (2.28), 1.168 (2.06), 1.180 (2.47), 1.185 (2.49), 1.198 (2.32), 1.205 (2.28), 1.218 (2.54), 1.222 (2.60), 1.235 (2.41), 1.625 (3.64), 1.643 (3.56), 2.332 (2.97), 2.336 (1.35), 2.356 (1.22), 2.370 (12.34), 2.518 (16.00), 2.522 (11.33), 2.569 (0.81), 2.586 (1.41), 2.673 (3.03), 2.678 (1.31), 2.829 (7.84), 5.759 (0.99), 5.774 (0.62), 5.792 (0.91), 5.810 (0.57), 7.098 (0.90), 7.234 (1.86), 7.283 (0.70), 7.302 (1.38), 7.321 (0.79), 7.370 (0.81), 7.493 (0.46), 7.508 (0.77), 7.628 (0.42), 7.646 (0.77), 7.665 (0.42), 8.835 (0.84), 8.863 (0.85), 8.996 (0.69), 9.014 (0.68)。 LC-MS (方法2): R t= 1.11 min;MS (ESIneg): m/z = 477 [M-H]⁻ 中間物19 9.00 mg (95%純度,8%產率) |
130 | 2-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙-1-醇(非對映異構體之混合物) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (0.91), 0.949 (1.18), 0.953 (2.33), 0.969 (2.44), 0.972 (1.25), 0.977 (1.04), 0.988 (1.19), 0.993 (1.28), 0.997 (2.31), 1.012 (2.50), 1.016 (1.17), 1.031 (1.05), 1.603 (3.92), 1.620 (3.94), 1.655 (3.87), 1.663 (3.72), 1.688 (3.92), 1.696 (3.72), 1.962 (0.44), 1.972 (0.93), 1.978 (0.64), 1.982 (0.66), 1.991 (1.20), 1.997 (0.68), 2.002 (0.77), 2.010 (0.96), 2.021 (0.58), 2.028 (0.57), 2.431 (16.00), 2.518 (1.97), 2.523 (1.49), 3.377 (0.40), 3.891 (0.54), 3.907 (0.60), 3.927 (1.07), 3.943 (1.12), 3.963 (0.51), 3.979 (0.51), 5.708 (1.12), 5.724 (2.71), 5.741 (1.08), 5.774 (0.46), 5.780 (0.47), 5.792 (0.72), 5.799 (0.68), 5.810 (0.48), 5.816 (0.42), 7.244 (0.47), 7.249 (0.50), 7.263 (1.05), 7.268 (1.09), 7.282 (0.62), 7.287 (0.63), 7.406 (0.64), 7.424 (1.06), 7.441 (0.50), 7.658 (0.42), 7.675 (0.73), 8.942 (0.98), 8.952 (1.02), 8.956 (1.06), 8.958 (1.01), 8.965 (0.89), 9.087 (4.31), 9.285 (0.69), 9.303 (1.20), 9.320 (0.62)。 LC-MS (方法1): R t= 0.80 min;MS (ESIpos): m/z = 454 [M+H]⁺ 中間物141 133 mg (95%純度,59%產率) |
實例130之非對映異構體係根據下列方法分離。 製備方法: 儀器:PrepCon Labomatic HPLC-2;管柱:YMC Cellulose SB 5 µ,250x30;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:80%A+20%B;流量:30 ml/min;溫度:25℃;UV:280 nm; 分析方法: 儀器:Thermo Fisher UltiMate 3000;YMC Cellulose SB 3 µ,100x4.6;溶析液A:甲基三級丁基醚+ 0.1體積%二乙胺;溶析液B:乙腈;等度:80%A+20%B;流量:1.4 ml/min;溫度:25℃;UV:280 nm; | |
131 | 2-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙-1-醇(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.935 (1.78), 0.954 (4.33), 0.973 (2.10), 0.978 (1.99), 0.997 (4.14), 1.016 (1.90), 1.231 (0.58), 1.604 (4.79), 1.622 (4.77), 1.663 (6.99), 1.696 (7.12), 1.954 (0.40), 1.963 (0.76), 1.973 (1.16), 1.981 (0.86), 1.991 (1.57), 2.003 (0.94), 2.010 (1.03), 2.023 (0.80), 2.331 (0.51), 2.432 (16.00), 2.518 (2.67), 2.523 (1.82), 2.673 (0.51), 3.892 (0.56), 3.908 (0.61), 3.927 (1.10), 3.944 (1.17), 3.963 (0.53), 3.980 (0.52), 5.704 (1.16), 5.720 (2.77), 5.736 (1.11), 5.782 (0.75), 5.801 (1.16), 5.819 (0.73), 7.244 (0.88), 7.263 (1.91), 7.282 (1.12), 7.407 (0.69), 7.424 (1.08), 7.440 (0.53), 7.655 (0.60), 7.672 (1.06), 7.690 (0.53), 8.953 (1.75), 8.955 (1.75), 8.969 (1.77), 9.089 (4.30), 9.305 (1.28), 9.323 (1.22)。 LC-MS (方法1): R t= 0.81 min;MS (ESIpos): m/z = 454 [M+H]⁺ 實例130 28.0 mg (95%純度,12%產率) Rt (分析方法) = 3.28 min (de = >99%) |
132 | 2-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙-1-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.950 (1.81), 0.969 (4.47), 0.988 (2.08), 0.993 (2.12), 1.013 (4.32), 1.032 (1.93), 1.137 (0.45), 1.232 (0.51), 1.602 (4.68), 1.619 (4.68), 1.655 (6.94), 1.688 (6.79), 1.972 (0.81), 1.978 (0.93), 1.990 (1.03), 1.998 (1.05), 2.001 (1.00), 2.009 (1.06), 2.020 (0.81), 2.029 (0.78), 2.336 (0.44), 2.432 (16.00), 2.518 (5.33), 2.523 (3.70), 2.678 (0.44), 3.892 (0.54), 3.908 (0.58), 3.929 (1.04), 3.944 (1.10), 3.963 (0.51), 3.980 (0.50), 5.703 (1.16), 5.718 (2.72), 5.735 (1.12), 5.776 (0.74), 5.794 (1.15), 5.812 (0.72), 7.250 (0.84), 7.269 (1.88), 7.289 (1.09), 7.409 (0.68), 7.427 (1.05), 7.442 (0.52), 7.664 (0.58), 7.681 (1.02), 7.697 (0.52), 8.943 (1.70), 8.945 (1.70), 8.959 (1.70), 9.089 (4.17), 9.288 (1.21), 9.306 (1.16)。 LC-MS (方法1): R t= 0.80 min;MS (ESIpos): m/z = 454 [M+H]⁺ 實例130 33.0 mg (95%純度,15%產率) Rt (分析方法) = 4.07 min (de = 97%) |
133 | 2,2-二氟-2-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}乙-1-醇(非對映異構體之混合物) LC-MS (方法1): R t= 0.85 min;MS (ESIpos): m/z = 467.6 [M+H]⁺ 中間物141 68.0 mg (31%產率) |
實例133之非對映異構體係根據下列方法分離。 分析方法: 儀器:Waters Acquity UPC2 QDA;管柱:Chiral Art Amylose-SA 3 µ 100x4.6 mm;溶析液A:CO2;溶析液B:2-丙醇+ 0.4體積%二乙胺;等度:10%B;梯度:無;流量:4 ml/min;溫度:40.0℃;BPR:100 bar;UV:215 nm 製備方法: 儀器:Sepiatec:Prep SFC100;管柱:Chiral Art Amylose -SA 5 µ 250x30 mm;溶析液A:CO2;溶析液B:2-丙醇+ 0.4體積%二乙胺;等度:10%B;梯度:無;流量:100 ml/min;溫度:40℃;BPR:150 bar;UV:215 nm | |
134 | 2,2-二氟-2-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}乙-1-醇(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.893 (3.44), 0.910 (3.53), 0.933 (3.41), 0.951 (3.43), 1.144 (3.47), 1.161 (3.59), 1.183 (3.60), 1.201 (3.51), 1.605 (5.17), 1.622 (5.18), 1.659 (7.63), 1.691 (7.64), 2.075 (0.44), 2.181 (0.54), 2.198 (0.76), 2.204 (0.64), 2.217 (0.61), 2.222 (0.78), 2.240 (0.50), 2.337 (0.47), 2.430 (16.00), 2.518 (5.69), 2.523 (4.04), 2.673 (1.08), 2.678 (0.47), 3.891 (0.62), 3.906 (0.68), 3.927 (1.23), 3.943 (1.31), 3.962 (0.60), 3.979 (0.60), 5.701 (1.24), 5.717 (3.03), 5.734 (1.22), 5.779 (0.84), 5.797 (1.29), 5.815 (0.82), 7.243 (0.90), 7.262 (2.06), 7.282 (1.24), 7.405 (0.77), 7.423 (1.24), 7.439 (0.60), 7.652 (0.64), 7.669 (1.17), 7.686 (0.63), 8.945 (1.92), 8.960 (1.86), 9.087 (4.45), 9.323 (1.38), 9.340 (1.32)。 LC-MS (方法1): R t= 0.85 min;MS (ESIpos): m/z = 468 [M+H]⁺ 實例133 55.6 mg (95%純度,24%產率) Rt (分析方法) = 2.37 min (de = >99%) |
135 | 2,2-二氟-2-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}乙-1-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.905 (3.95), 0.922 (3.96), 0.945 (4.03), 0.963 (3.96), 1.038 (0.44), 1.058 (0.41), 1.075 (0.43), 1.144 (3.95), 1.162 (4.36), 1.184 (4.25), 1.202 (4.12), 1.603 (5.81), 1.621 (5.82), 1.650 (8.59), 1.683 (8.60), 2.197 (0.59), 2.215 (0.86), 2.221 (0.72), 2.233 (0.67), 2.238 (0.86), 2.257 (0.56), 2.336 (0.58), 2.435 (16.00), 2.518 (6.98), 2.523 (4.90), 2.679 (0.55), 3.893 (0.59), 3.905 (0.63), 3.929 (1.12), 3.943 (1.16), 3.964 (0.58), 3.978 (0.56), 5.701 (0.61), 5.717 (1.19), 5.733 (0.61), 5.776 (0.90), 5.794 (1.39), 5.812 (0.90), 7.254 (1.02), 7.273 (2.31), 7.292 (1.36), 7.409 (0.85), 7.426 (1.37), 7.443 (0.66), 7.665 (0.75), 7.681 (1.30), 7.698 (0.68), 8.935 (1.94), 8.950 (1.99), 9.089 (5.00), 9.333 (0.52)。 LC-MS (方法1): R t= 0.83 min;MS (ESIpos): m/z = 468 [M+H]⁺ 實例133 33.5 mg (95%純度,14%產率) Rt (分析方法) = 2.95 min (de = 97%) |
136 | (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-醇(非對映異構體1) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.929 (16.00), 1.588 (3.55), 1.605 (3.54), 1.692 (7.77), 1.725 (7.69), 2.448 (11.77), 2.518 (0.87), 2.523 (0.63), 5.541 (1.39), 5.560 (1.37), 5.803 (0.56), 5.821 (0.85), 5.839 (0.54), 7.222 (0.68), 7.242 (1.49), 7.261 (0.87), 7.380 (0.51), 7.397 (0.82), 7.628 (0.45), 7.645 (0.81), 7.661 (0.40), 8.969 (1.30), 8.984 (1.30), 9.092 (3.30), 9.261 (0.96), 9.280 (0.92)。 中間物60 65.0 mg (95%純度,62%產率) |
137 | (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-醇(非對映異構體2) ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.934 (16.00), 1.600 (3.60), 1.618 (3.59), 1.691 (7.97), 1.724 (7.93), 2.421 (12.38), 2.518 (1.69), 2.523 (1.28), 5.573 (1.86), 5.592 (1.82), 5.774 (0.57), 5.792 (0.88), 5.810 (0.56), 7.207 (0.70), 7.226 (1.52), 7.245 (0.90), 7.376 (0.50), 7.393 (0.83), 7.602 (0.45), 7.620 (0.80), 7.636 (0.41), 8.961 (1.36), 8.976 (1.36), 8.978 (1.34), 9.088 (3.30), 9.267 (0.98), 9.286 (0.94)。 中間物61 70.0 mg (95%純度,67%產率) |
表9中顯示之實例的製備係根據一般程序3,接著藉由一般程序7自各別受N-Boc保護之衍生物直接轉化粗中間物。
實例表
9
實例 | 結構;IUPAC名稱;分析資料;起始材料;產率 |
138 | 1-乙醯基-4-(2-甲基-4-{[(1S)-1-[2-甲基-3-(三氟甲基)苯基]( 2H 4)乙基]胺基}吡啶并[3,4-d]嘧啶-6-基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.929 (0.41), 0.946 (0.42), 1.541 (0.72), 2.055 (0.41), 2.116 (16.00), 2.254 (0.44), 2.275 (0.44), 2.332 (0.58), 2.382 (0.42), 2.422 (14.00), 2.518 (3.35), 2.523 (2.25), 2.622 (6.56), 2.673 (0.61), 3.320 (0.82), 3.848 (0.41), 3.860 (0.60), 3.873 (0.58), 3.886 (0.49), 3.918 (0.43), 7.348 (0.77), 7.368 (1.69), 7.388 (0.97), 7.543 (1.74), 7.561 (1.39), 7.785 (1.57), 7.805 (1.41), 9.006 (1.80), 9.023 (1.78), 9.094 (4.93), 9.096 (4.61), 9.371 (1.95)。 LC-MS (方法2): R t= 1.10 min;MS (ESIpos): m/z = 510 [M+H]⁺ 中間物184 60.6 mg (95%純度,64%產率) |
139 | 1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.609 (0.48), 1.627 (0.48), 2.118 (1.77), 2.425 (1.27), 3.332 (2.08), 3.341 (16.00), 9.112 (0.46)。 LC-MS (方法2): R t= 1.01 min;MS (ESIpos): m/z = 536 [M+H]⁺ 中間物186 68.4 mg (95%純度,55%產率) |
140 | 1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.251 (6.79), 1.258 (7.05), 1.596 (4.28), 1.614 (4.27), 2.118 (16.00), 2.318 (0.67), 2.387 (0.40), 2.413 (12.45), 2.518 (7.52), 2.523 (5.16), 3.175 (13.87), 3.865 (0.66), 3.899 (0.46), 5.757 (0.52), 5.775 (0.78), 5.791 (0.51), 7.208 (0.66), 7.227 (1.60), 7.247 (1.08), 7.296 (0.73), 7.313 (1.02), 7.329 (0.47), 7.612 (0.57), 7.629 (0.99), 7.646 (0.51), 9.022 (1.56), 9.039 (1.55), 9.113 (4.13), 9.279 (1.02), 9.297 (0.99)。 LC-MS (方法1): R t= 1.01 min;MS (ESIpos): m/z = 564 [M+H]⁺ 中間物191 21.6 mg (95%純度,14%產率) |
141 | 1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟乙基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.615 (4.89), 1.632 (4.93), 1.911 (4.08), 1.958 (7.61), 2.005 (3.52), 2.055 (0.40), 2.082 (0.72), 2.113 (16.00), 2.473 (14.64), 2.518 (0.70), 2.523 (0.50), 3.842 (0.50), 3.853 (0.64), 3.866 (0.49), 3.881 (0.45), 3.891 (0.46), 5.635 (0.69), 5.653 (1.03), 5.672 (0.68), 7.436 (3.94), 7.452 (1.80), 7.471 (0.48), 7.578 (1.10), 7.591 (0.71), 7.595 (1.02), 7.691 (2.04), 8.969 (1.59), 8.985 (1.58), 9.101 (4.33), 9.217 (1.09), 9.236 (1.05)。 LC-MS (): R t= min;MS (): m/z = 中間物190 54.2 mg (95%純度,47%產率) |
142 | 1-乙醯基-4-[4-({(1R)-1-[2-氟-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.635 (4.58), 1.653 (4.55), 2.057 (0.42), 2.118 (16.00), 2.256 (0.44), 2.277 (0.43), 2.318 (0.44), 2.323 (0.78), 2.327 (1.01), 2.331 (0.72), 2.415 (11.01), 2.518 (3.31), 2.523 (2.16), 2.665 (0.69), 2.669 (0.96), 2.673 (0.67), 3.851 (0.43), 3.861 (0.59), 3.873 (0.61), 3.887 (0.52), 3.917 (0.42), 5.744 (0.54), 5.762 (0.81), 5.779 (0.52), 7.351 (0.73), 7.370 (1.55), 7.390 (0.86), 7.643 (0.64), 7.661 (1.11), 7.679 (0.55), 7.819 (0.60), 7.837 (1.07), 7.855 (0.54), 9.012 (1.62), 9.028 (1.60), 9.118 (3.89), 9.327 (1.12), 9.344 (1.09)。 LC-MS (方法2): R t= 1.09 min;MS (ESIpos): m/z = 510 [M+H]⁺ 中間物189 53.0 mg (95%純度,56%產率) |
143 | 1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.615 (5.17), 1.633 (5.15), 1.902 (0.42), 2.052 (0.45), 2.114 (16.00), 2.253 (0.44), 2.265 (0.45), 2.276 (0.44), 2.378 (0.44), 2.389 (0.43), 2.402 (0.42), 2.472 (15.05), 2.518 (2.87), 2.523 (1.93), 3.287 (15.25), 3.697 (0.42), 3.736 (0.43), 3.821 (0.40), 3.830 (0.44), 3.853 (2.59), 3.887 (4.23), 3.922 (1.87), 4.028 (0.41), 5.634 (0.76), 5.652 (1.14), 5.670 (0.75), 7.399 (0.89), 7.419 (1.89), 7.442 (1.38), 7.461 (2.00), 7.481 (0.82), 7.599 (1.46), 7.618 (1.16), 7.667 (2.29), 8.973 (1.71), 8.990 (1.71), 9.107 (4.63), 9.225 (1.23), 9.245 (1.19)。 LC-MS (方法2): R t= 0.99 min;MS (ESIpos): m/z = 518 [M+H]⁺ 中間物192 73.9 mg (99%純度,64%產率) |
144 | 1-乙醯基-4-[7-甲氧基-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.542 (4.32), 1.560 (4.36), 1.978 (0.44), 2.124 (16.00), 2.318 (0.73), 2.323 (1.38), 2.327 (1.94), 2.332 (1.56), 2.337 (0.97), 2.356 (7.41), 2.432 (0.44), 2.455 (0.47), 2.518 (6.12), 2.523 (4.35), 2.611 (5.59), 2.660 (0.47), 2.665 (1.11), 2.669 (1.57), 2.673 (1.06), 2.679 (0.46), 3.974 (15.38), 5.697 (0.41), 5.706 (0.57), 5.715 (0.56), 7.343 (0.63), 7.362 (1.36), 7.381 (0.80), 7.535 (1.41), 7.554 (1.15), 7.779 (1.23), 7.799 (1.11), 9.128 (0.87), 9.136 (0.91), 9.161 (1.06), 9.169 (1.04)。 LC-MS (方法1): R t= 0.90 min;MS (ESIpos): m/z = 536 [M+H]⁺ 中間物199 52.0 mg (95%純度,38%產率) |
145 | 1-乙醯基-4-[2,7-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.296 (1.94), 1.313 (1.97), 1.572 (2.56), 1.577 (2.70), 1.590 (2.66), 1.595 (2.60), 1.816 (5.50), 2.100 (16.00), 2.164 (0.43), 2.300 (0.41), 2.318 (0.87), 2.323 (1.51), 2.327 (2.07), 2.331 (1.67), 2.336 (1.14), 2.365 (9.16), 2.367 (9.34), 2.404 (2.00), 2.407 (1.95), 2.444 (0.43), 2.518 (5.63), 2.523 (4.06), 2.608 (5.56), 2.660 (0.44), 2.665 (1.01), 2.669 (1.41), 2.673 (0.98), 2.678 (0.43), 2.866 (10.77), 3.391 (0.56), 3.421 (0.53), 3.754 (0.41), 5.713 (0.42), 5.723 (0.61), 5.730 (0.60), 5.740 (0.42), 7.348 (0.62), 7.367 (1.41), 7.388 (0.90), 7.546 (1.49), 7.566 (1.24), 7.607 (0.41), 7.738 (0.72), 7.747 (0.73), 7.758 (0.66), 7.766 (0.64), 8.790 (0.87), 8.796 (0.87), 8.822 (0.88), 8.829 (0.84), 9.010 (0.68), 9.017 (0.73), 9.026 (0.73), 9.034 (0.65)。 LC-MS (方法2): R t= 1.06 min;MS (ESIneg): m/z = 518 [M-H]⁻ 中間物200 35.9 mg (90%純度,45%產率) |
146 | (R)-1-(4-(2,8-二甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d]嘧啶-6-基)-4-氧離子基-1,4-氮雜磷雜環己烷-1-基)乙-1-酮 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.84 Hz, 3 H) 1.78 - 2.09 (m, 2 H) 2.12 (s, 3 H) 2.20 - 2.40 (m, 2 H) 2.43 (s, 3 H) 2.62 (s, 3 H) 2.77 (s, 3 H) 3.62 - 4.11 (m, 4 H) 5.58 - 5.80 (m, 1 H) 7.29 - 7.44 (m, 1 H) 7.51 - 7.61 (m, 1 H) 7.71 - 7.83 (m, 1 H) 8.77 - 8.88 (m, 1 H) 9.18 - 9.31 (m, 1 H)。 中間物201 74.3 mg (95%純度,62%產率) |
147 | 1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.574 (4.94), 1.591 (4.90), 2.000 (0.44), 2.117 (16.00), 2.318 (0.74), 2.323 (1.11), 2.327 (1.44), 2.331 (1.07), 2.337 (0.57), 2.403 (15.42), 2.518 (4.85), 2.523 (3.44), 2.620 (6.24), 2.660 (0.41), 2.665 (0.88), 2.669 (1.21), 2.673 (0.83), 3.471 (0.51), 3.500 (0.51), 3.751 (0.47), 3.782 (0.52), 5.714 (0.77), 5.731 (1.19), 5.749 (0.76), 7.349 (0.64), 7.369 (1.41), 7.388 (0.81), 7.547 (1.68), 7.566 (1.36), 7.771 (1.28), 7.790 (1.16), 9.226 (0.80), 9.232 (0.92), 9.239 (1.72), 9.244 (2.62), 9.250 (2.13), 9.255 (2.02), 9.260 (1.33), 9.291 (1.08)。 LC-MS (方法2): R t= 1.06 min;MS (ESIpos): m/z = 506 [M+H]⁺ 中間物203 52.2 mg (95%純度,69%產率) |
表10中顯示之實例係根據一般程序8自各別胺衍生物製備。
實例表
10
實例 | 結構;IUPAC名稱;分析資料;起始材料;產率 |
149 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2S)-2-甲氧基丙醯基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.253 (10.99), 1.266 (10.60), 1.626 (7.20), 1.640 (7.17), 1.957 (0.65), 2.040 (0.56), 2.361 (1.54), 2.447 (16.00), 2.514 (3.86), 2.518 (3.22), 2.522 (2.38), 2.635 (1.27), 3.252 (9.56), 3.258 (8.52), 3.888 (0.91), 3.913 (0.85), 4.301 (0.80), 4.314 (2.84), 4.327 (2.71), 4.340 (0.77), 5.796 (1.04), 5.811 (1.55), 5.825 (1.00), 7.133 (1.62), 7.241 (3.34), 7.297 (1.37), 7.312 (2.87), 7.328 (1.62), 7.350 (1.44), 7.509 (1.01), 7.521 (1.77), 7.536 (0.92), 7.700 (0.91), 7.713 (1.62), 7.729 (0.86), 9.036 (1.48), 9.048 (1.50), 9.115 (2.34), 9.121 (2.21)。 LC-MS (方法2): R t= 1.05 min;MS (ESIpos): m/z = 537 [M+H]⁺ 實例9 52.0 mg (95%純度,44%產率) |
150 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2R)-2-羥基丙醯基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.226 (5.79), 1.242 (5.81), 1.303 (0.46), 1.369 (0.44), 1.619 (5.36), 1.636 (5.37), 1.931 (0.42), 1.957 (0.41), 2.318 (0.52), 2.323 (0.89), 2.327 (1.19), 2.331 (0.91), 2.336 (0.53), 2.401 (0.54), 2.432 (16.00), 2.518 (4.76), 2.523 (3.14), 2.665 (0.75), 2.669 (1.05), 2.673 (0.74), 3.875 (0.44), 3.897 (0.57), 3.930 (0.44), 4.492 (0.56), 4.508 (0.83), 4.524 (0.54), 5.194 (0.75), 5.211 (0.79), 5.227 (0.68), 5.244 (0.58), 5.782 (0.88), 5.800 (1.34), 5.817 (0.86), 7.106 (1.39), 7.241 (2.92), 7.287 (1.03), 7.306 (2.24), 7.325 (1.27), 7.377 (1.22), 7.499 (0.80), 7.516 (1.36), 7.533 (0.67), 7.690 (0.75), 7.709 (1.35), 7.726 (0.68), 9.020 (1.62), 9.036 (1.63), 9.114 (4.32), 9.276 (0.47), 9.295 (0.57), 9.306 (0.68), 9.324 (0.55)。 LC-MS (方法2): R t= 1.00 min;MS (ESIpos): m/z = 523 [M+H]⁺ 實例9 47.0 mg (95%純度,41%產率) |
151 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(1-氟環丙烷-1-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.237 (2.53), 1.260 (2.47), 1.289 (1.22), 1.300 (1.82), 1.324 (0.72), 1.337 (0.96), 1.351 (1.66), 1.629 (7.89), 1.646 (7.90), 2.074 (1.67), 2.318 (0.94), 2.392 (0.95), 2.457 (16.00), 2.518 (11.56), 2.523 (7.58), 2.659 (0.82), 4.165 (0.93), 5.801 (1.15), 5.819 (1.76), 5.836 (1.11), 7.107 (2.01), 7.243 (4.22), 7.297 (1.42), 7.316 (3.11), 7.336 (1.78), 7.378 (1.76), 7.509 (1.10), 7.526 (2.04), 7.545 (1.15), 7.565 (0.45), 7.595 (0.54), 7.612 (0.43), 7.621 (0.54), 7.624 (0.52), 7.700 (1.01), 7.718 (1.85), 7.736 (0.91), 9.054 (2.20), 9.070 (2.21), 9.137 (6.40)。 LC-MS (方法2): R t= 1.13 min;MS (ESIpos): m/z = 537 [M+H]⁺ 實例6 38.0 mg (90%純度,31%產率) |
152 | 1-{4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羰基}環丙烷-1-甲腈 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.586 (2.87), 1.632 (8.32), 1.650 (11.20), 2.074 (2.14), 2.142 (0.52), 2.318 (0.65), 2.359 (0.41), 2.461 (16.00), 2.518 (8.22), 2.523 (5.56), 2.659 (0.61), 2.888 (0.45), 3.696 (0.48), 3.707 (0.80), 3.710 (0.65), 3.715 (0.45), 4.116 (0.52), 5.805 (1.11), 5.823 (1.71), 5.840 (1.10), 7.108 (1.92), 7.244 (3.96), 7.299 (1.35), 7.319 (2.95), 7.338 (1.69), 7.379 (1.70), 7.512 (1.04), 7.529 (1.86), 7.547 (1.07), 7.704 (0.97), 7.721 (1.75), 7.740 (0.90), 8.132 (0.51), 9.060 (2.13), 9.076 (2.14), 9.143 (6.29)。 LC-MS (方法2): R t= 1.09 min;MS (ESIpos): m/z = 544 [M+H]⁺ 實例9 34.0 mg (90%純度,27%產率) |
153 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(2-甲基丙醯基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.033 (5.86), 1.049 (9.78), 1.063 (5.90), 1.626 (7.85), 1.643 (7.88), 1.928 (0.59), 1.976 (0.49), 2.028 (0.60), 2.074 (0.53), 2.275 (0.57), 2.318 (1.09), 2.354 (0.61), 2.451 (16.00), 2.518 (11.60), 2.523 (7.61), 2.678 (0.85), 2.941 (0.66), 2.958 (1.68), 2.974 (2.29), 2.991 (1.65), 3.008 (0.64), 3.730 (0.55), 3.760 (0.56), 3.901 (0.52), 3.926 (0.59), 3.961 (0.65), 4.009 (0.90), 4.051 (0.72), 5.796 (1.05), 5.813 (1.60), 5.831 (1.03), 7.106 (1.96), 7.242 (4.14), 7.294 (1.39), 7.313 (3.03), 7.333 (1.73), 7.377 (1.73), 7.507 (1.06), 7.525 (1.81), 7.542 (0.95), 7.565 (0.41), 7.595 (0.47), 7.621 (0.49), 7.624 (0.45), 7.696 (0.96), 7.714 (1.75), 7.733 (0.87), 9.038 (2.27), 9.054 (2.25), 9.123 (6.54)。 LC-MS (方法2): R t= 1.10 min;MS (ESIpos): m/z = 521 [M+H]⁺ 實例9 26.0 mg (90%純度,22%產率) |
154 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(甲氧基乙醯基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.624 (2.71), 1.638 (2.67), 2.441 (6.19), 2.515 (1.08), 2.518 (1.07), 2.522 (0.84), 3.325 (16.00), 3.339 (3.58), 4.197 (2.60), 4.201 (2.62), 5.806 (0.51), 7.133 (0.61), 7.241 (1.24), 7.294 (0.48), 7.310 (1.04), 7.325 (0.57), 7.350 (0.54), 7.520 (0.57), 7.711 (0.56), 9.023 (0.80), 9.036 (0.79), 9.117 (2.10)。 LC-MS (方法2): R t= 1.02 min;MS (ESIpos): m/z = 523 [M+H]⁺ 實例9 35.0 mg (95%純度,31%產率) |
155 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2R)-2-甲氧基丙醯基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.251 (13.31), 1.268 (13.27), 1.624 (6.91), 1.642 (6.91), 1.957 (0.66), 1.997 (0.63), 2.037 (0.55), 2.074 (0.41), 2.284 (0.43), 2.318 (0.87), 2.322 (1.50), 2.327 (1.97), 2.331 (1.49), 2.336 (0.85), 2.381 (0.45), 2.445 (13.85), 2.518 (6.96), 2.523 (4.62), 2.659 (0.55), 2.665 (1.18), 2.669 (1.69), 2.673 (1.23), 2.678 (0.55), 3.255 (16.00), 3.882 (0.97), 3.925 (1.10), 3.940 (0.96), 3.992 (0.56), 4.296 (0.89), 4.313 (3.45), 4.329 (3.38), 4.346 (0.85), 5.791 (0.93), 5.808 (1.43), 5.826 (0.92), 7.106 (1.92), 7.242 (3.96), 7.292 (1.29), 7.311 (2.83), 7.331 (1.62), 7.377 (1.67), 7.504 (1.04), 7.521 (1.72), 7.539 (0.84), 7.693 (0.94), 7.712 (1.72), 7.730 (0.85), 9.033 (2.33), 9.050 (2.31), 9.116 (3.04)。 LC-MS (方法2): R t= 1.04 min;MS (ESIpos): m/z = 537 [M+H]⁺ 實例9 44.0 mg (95%純度,37%產率) |
156 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(1-羥基環丙烷-1-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.795 (0.96), 0.809 (2.86), 0.814 (2.99), 0.826 (1.33), 0.975 (3.60), 0.982 (3.08), 1.226 (0.66), 1.616 (5.77), 1.633 (5.72), 2.003 (0.51), 2.396 (0.60), 2.429 (16.00), 2.518 (4.04), 5.779 (0.95), 5.797 (1.46), 5.815 (0.93), 6.532 (5.95), 7.102 (1.30), 7.238 (2.69), 7.283 (1.04), 7.303 (2.26), 7.322 (1.30), 7.374 (1.17), 7.495 (0.85), 7.511 (1.42), 7.530 (0.70), 7.688 (0.78), 7.707 (1.42), 7.725 (0.72), 9.018 (2.04), 9.034 (2.02), 9.114 (5.09), 9.296 (1.59), 9.314 (1.53)。 LC-MS (方法2): R t= 1.03 min;MS (ESIpos): m/z = 535 [M+H]⁺ 實例9 34.0 mg (95%純度,29%產率) |
157 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2S)-2-羥基丙醯基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.226 (6.07), 1.242 (6.02), 1.619 (5.29), 1.636 (5.26), 1.931 (0.43), 2.318 (0.75), 2.323 (1.36), 2.327 (1.89), 2.331 (1.41), 2.336 (0.76), 2.401 (0.59), 2.404 (0.59), 2.432 (16.00), 2.518 (7.12), 2.523 (4.77), 2.659 (0.55), 2.665 (1.21), 2.669 (1.72), 2.673 (1.21), 2.678 (0.54), 3.623 (0.43), 3.896 (0.58), 3.931 (0.45), 4.493 (0.55), 4.508 (0.79), 4.522 (0.53), 5.196 (0.54), 5.211 (0.63), 5.227 (0.57), 5.244 (0.45), 5.782 (0.86), 5.800 (1.32), 5.817 (0.85), 7.106 (1.42), 7.241 (2.98), 7.287 (1.04), 7.306 (2.25), 7.325 (1.29), 7.377 (1.25), 7.499 (0.79), 7.516 (1.36), 7.535 (0.66), 7.690 (0.75), 7.709 (1.33), 7.726 (0.66), 9.020 (1.60), 9.036 (1.59), 9.114 (4.11), 9.278 (0.47), 9.295 (0.57), 9.307 (0.69), 9.325 (0.56)。 LC-MS (方法2): R t= 0.99 min;MS (ESIpos): m/z = 523 [M+H]⁺ 實例9 35.0 mg (95%純度,31%產率) |
158 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(氧雜環丁烷-3-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.617 (6.38), 1.635 (6.38), 1.963 (0.73), 2.002 (0.83), 2.118 (0.54), 2.318 (2.06), 2.323 (3.26), 2.327 (4.33), 2.331 (3.32), 2.336 (1.87), 2.432 (16.00), 2.518 (14.87), 2.523 (9.79), 2.659 (1.08), 2.665 (2.47), 2.669 (3.50), 2.673 (2.50), 2.678 (1.13), 3.592 (0.85), 3.638 (0.88), 3.805 (0.50), 3.836 (0.50), 4.039 (0.49), 4.231 (0.80), 4.236 (0.89), 4.253 (1.63), 4.271 (0.95), 4.274 (1.04), 4.292 (0.45), 4.670 (0.92), 4.683 (3.32), 4.695 (4.78), 4.700 (3.24), 4.708 (1.63), 4.715 (5.30), 4.729 (2.24), 4.737 (2.40), 4.752 (1.08), 5.782 (0.76), 5.799 (1.14), 5.813 (0.73), 7.105 (1.64), 7.241 (3.51), 7.286 (1.22), 7.306 (2.66), 7.325 (1.55), 7.377 (1.45), 7.500 (0.92), 7.517 (1.55), 7.535 (0.77), 7.685 (0.83), 7.704 (1.52), 7.721 (0.76), 9.005 (2.21), 9.022 (2.24), 9.107 (5.91), 9.269 (1.48), 9.286 (1.48)。 LC-MS (方法2): R t= 0.98 min;MS (ESIpos): m/z = 534 [M+H]⁺ 實例9 18.0 mg (95%純度,15%產率) |
159 | 1-[1-(二氟甲基)環丙烷-1-羰基]-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.101 (8.69), 1.633 (11.90), 1.647 (11.75), 2.050 (1.58), 2.074 (12.49), 2.354 (2.99), 2.358 (4.72), 2.361 (5.85), 2.365 (4.43), 2.463 (16.00), 2.515 (13.36), 2.518 (13.47), 2.522 (10.65), 2.628 (1.48), 2.631 (3.14), 2.635 (4.51), 2.639 (3.26), 2.642 (1.47), 2.687 (0.61), 2.729 (0.49), 2.888 (0.65), 3.927 (1.05), 4.099 (1.47), 5.809 (1.48), 5.823 (2.25), 5.837 (1.50), 5.867 (2.51), 5.979 (4.89), 6.091 (2.20), 7.134 (3.13), 7.242 (6.31), 7.303 (2.14), 7.319 (4.49), 7.334 (2.54), 7.351 (2.71), 7.515 (1.58), 7.529 (2.74), 7.540 (2.01), 7.549 (2.00), 7.556 (1.63), 7.560 (0.99), 7.564 (1.84), 7.570 (1.71), 7.596 (1.65), 7.600 (2.35), 7.614 (2.06), 7.617 (1.91), 7.621 (2.12), 7.623 (2.12), 7.627 (1.91), 7.631 (1.28), 7.637 (1.45), 7.705 (1.55), 7.719 (2.83), 7.735 (1.41), 8.132 (1.89), 9.054 (2.46), 9.066 (2.45), 9.139 (7.71)。 LC-MS (方法2): R t= 1.11 min;MS (ESIpos): m/z = 569 [M+H]⁺ 實例9 47.0 mg (90%純度,36%產率) |
160 | 1-(3,3-二氟環丁烷-1-羰基)-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.619 (7.28), 1.637 (7.28), 1.988 (0.65), 2.002 (0.68), 2.041 (0.74), 2.081 (0.43), 2.299 (0.61), 2.323 (2.16), 2.327 (2.74), 2.331 (2.25), 2.336 (1.51), 2.357 (0.86), 2.396 (0.45), 2.434 (16.00), 2.518 (8.79), 2.523 (5.89), 2.660 (0.68), 2.665 (1.52), 2.669 (2.10), 2.673 (1.51), 2.678 (0.67), 2.769 (0.72), 2.796 (1.70), 2.819 (2.10), 2.830 (1.91), 2.836 (2.29), 2.858 (2.09), 2.881 (0.81), 3.352 (1.05), 3.359 (0.92), 3.374 (1.12), 3.380 (1.11), 3.395 (0.69), 3.402 (0.66), 3.799 (0.89), 3.816 (1.69), 3.828 (1.39), 3.841 (1.36), 3.856 (1.64), 3.870 (1.05), 3.990 (0.54), 5.783 (0.80), 5.801 (1.19), 5.815 (0.79), 7.106 (1.74), 7.241 (3.70), 7.287 (1.28), 7.306 (2.79), 7.326 (1.61), 7.377 (1.52), 7.500 (0.95), 7.517 (1.62), 7.535 (0.80), 7.687 (0.86), 7.705 (1.58), 7.724 (0.79), 9.012 (2.47), 9.028 (2.46), 9.111 (6.36), 9.268 (1.74), 9.286 (1.68)。 LC-MS (方法2): R t= 1.14 min;MS (ESIpos): m/z = 569 [M+H]⁺ 實例9 32.0 mg (95%純度,26%產率) |
161 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-4-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.627 (4.20), 1.641 (4.10), 2.045 (0.64), 2.074 (0.70), 2.357 (1.22), 2.361 (1.64), 2.365 (1.39), 2.368 (0.83), 2.382 (0.68), 2.392 (0.65), 2.449 (8.07), 2.514 (3.96), 2.518 (3.85), 2.522 (3.06), 2.631 (0.93), 2.634 (1.29), 2.638 (0.93), 2.642 (0.43), 3.867 (16.00), 4.170 (0.58), 5.798 (0.60), 5.812 (0.91), 5.827 (0.57), 7.133 (0.95), 7.242 (1.99), 7.297 (0.74), 7.313 (1.57), 7.329 (0.88), 7.350 (0.84), 7.509 (0.54), 7.522 (0.90), 7.537 (0.46), 7.700 (0.50), 7.714 (0.92), 7.730 (0.50), 7.743 (4.22), 7.744 (4.12), 8.159 (4.00), 9.048 (1.08), 9.061 (1.05), 9.128 (3.23)。 LC-MS (方法2): R t= 1.01 min;MS (ESIpos): m/z = 559 [M+H]⁺ 實例9 56.0 mg (95%純度,46%產率) |
162 | 3-{4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-基}-3-側氧基丙腈 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.052 (0.43), 1.156 (1.28), 1.174 (2.77), 1.192 (1.30), 1.231 (0.62), 1.241 (1.34), 1.256 (1.75), 1.272 (0.90), 1.576 (6.27), 1.593 (6.27), 1.973 (0.53), 2.130 (0.64), 2.171 (0.40), 2.306 (0.62), 2.318 (0.99), 2.323 (1.63), 2.327 (2.17), 2.331 (1.76), 2.424 (16.00), 2.518 (7.34), 2.523 (5.11), 2.624 (8.68), 2.660 (0.62), 2.665 (1.29), 2.669 (1.76), 2.673 (1.27), 2.678 (0.58), 3.079 (0.60), 3.091 (0.62), 3.097 (0.62), 3.109 (0.61), 3.760 (0.90), 3.776 (1.55), 3.789 (1.24), 3.801 (1.21), 3.816 (1.69), 4.018 (0.50), 4.155 (0.68), 4.202 (4.67), 4.217 (4.92), 4.265 (0.77), 5.711 (0.70), 5.724 (1.01), 5.729 (1.02), 5.741 (0.69), 5.759 (1.53), 7.350 (0.95), 7.369 (2.08), 7.389 (1.21), 7.545 (2.32), 7.564 (1.87), 7.787 (2.06), 7.806 (1.87), 9.016 (2.18), 9.033 (2.16), 9.095 (6.08), 9.380 (0.98), 9.396 (0.97)。 LC-MS (方法2): R t= 1.16 min;MS (ESIpos): m/z = 532 [M+H]⁺ 實例6 25.0 mg (90%純度,25%產率) |
163 | 1-(環丙烷羰基)-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.754 (1.18), 0.761 (3.20), 0.781 (5.35), 0.794 (3.17), 1.623 (6.70), 1.641 (6.71), 1.913 (0.46), 2.036 (0.47), 2.069 (0.65), 2.074 (0.71), 2.081 (1.04), 2.088 (1.02), 2.100 (1.47), 2.113 (0.78), 2.119 (0.74), 2.284 (0.49), 2.318 (0.67), 2.445 (16.00), 2.518 (6.48), 2.523 (4.44), 3.719 (0.42), 3.745 (0.42), 4.071 (0.70), 4.229 (0.42), 5.791 (0.95), 5.808 (1.46), 5.826 (0.94), 7.106 (1.64), 7.242 (3.43), 7.291 (1.16), 7.311 (2.49), 7.330 (1.45), 7.378 (1.43), 7.504 (0.91), 7.521 (1.50), 7.536 (0.86), 7.547 (0.44), 7.565 (0.41), 7.595 (0.48), 7.621 (0.48), 7.624 (0.46), 7.693 (0.80), 7.712 (1.45), 7.731 (0.72), 9.034 (2.10), 9.050 (2.08), 9.127 (5.66)。 LC-MS (方法2): R t= 1.07 min;MS (ESIpos): m/z = 519 [M+H]⁺ 實例9 55.0 mg (90%純度,46%產率) |
164 | 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(氧雜環丁烷-3-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.852 (0.50), 1.232 (1.55), 1.353 (0.50), 1.573 (5.95), 1.591 (5.89), 2.000 (0.96), 2.117 (0.52), 2.292 (0.99), 2.318 (1.83), 2.323 (3.04), 2.327 (4.02), 2.331 (3.00), 2.391 (0.42), 2.421 (16.00), 2.518 (11.39), 2.523 (7.56), 2.622 (8.69), 2.660 (1.12), 2.665 (2.39), 2.669 (3.23), 2.673 (2.30), 2.678 (1.02), 3.599 (0.95), 3.640 (1.11), 3.796 (0.50), 3.818 (0.51), 4.057 (0.50), 4.235 (0.83), 4.252 (1.51), 4.274 (0.92), 4.291 (0.40), 4.670 (0.86), 4.684 (2.98), 4.693 (4.75), 4.702 (2.68), 4.715 (4.11), 4.729 (1.85), 4.738 (2.31), 4.752 (1.08), 5.708 (0.73), 5.725 (1.02), 5.738 (0.68), 7.349 (0.91), 7.368 (2.00), 7.388 (1.16), 7.545 (2.32), 7.563 (1.85), 7.783 (2.01), 7.802 (1.81), 9.003 (1.84), 9.019 (1.85), 9.087 (5.62), 9.362 (1.12), 9.375 (1.13)。 LC-MS (方法2): R t= 1.14 min;MS (ESIpos): m/z = 548 [M+H]⁺ 實例6 27.0 mg (95%純度,31%產率) |
165 | 1-[(2S)-2-羥基丙醯基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.225 (6.98), 1.242 (7.04), 1.282 (0.46), 1.303 (0.72), 1.320 (0.54), 1.353 (0.93), 1.369 (0.78), 1.575 (5.61), 1.593 (5.62), 1.960 (0.46), 2.336 (1.16), 2.421 (16.00), 2.518 (11.20), 2.523 (7.48), 2.625 (8.10), 2.673 (2.32), 2.678 (1.05), 3.891 (0.52), 4.492 (0.57), 4.509 (0.83), 4.524 (0.55), 5.190 (0.90), 5.208 (0.91), 5.228 (0.74), 5.245 (0.67), 5.708 (0.90), 5.725 (1.39), 5.743 (0.90), 7.350 (0.89), 7.370 (1.87), 7.389 (1.08), 7.545 (2.15), 7.564 (1.72), 7.788 (1.86), 7.808 (1.65), 9.017 (1.48), 9.033 (1.48), 9.095 (4.51), 9.361 (0.50), 9.378 (0.57), 9.394 (0.72), 9.410 (0.60)。 LC-MS (方法2): R t= 1.13 min;MS (ESIpos): m/z = 536 [M+H]⁺ 實例6 39.0 mg (95%純度,46%產率) |
166 | 1-[(2R)-2-羥基丙醯基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.225 (6.94), 1.241 (6.84), 1.574 (5.34), 1.592 (5.37), 1.956 (0.43), 2.074 (0.55), 2.323 (0.99), 2.327 (1.32), 2.331 (1.00), 2.336 (0.54), 2.421 (16.00), 2.518 (4.47), 2.523 (2.66), 2.624 (7.58), 2.660 (0.41), 2.665 (0.84), 2.669 (1.16), 2.673 (0.84), 3.305 (0.52), 3.863 (0.42), 3.889 (0.53), 3.918 (0.41), 4.491 (0.56), 4.507 (0.80), 4.522 (0.53), 5.193 (0.61), 5.210 (0.66), 5.230 (0.57), 5.247 (0.47), 5.706 (0.86), 5.724 (1.30), 5.741 (0.84), 7.350 (0.82), 7.369 (1.77), 7.389 (1.02), 7.544 (2.01), 7.563 (1.62), 7.789 (1.75), 7.808 (1.57), 9.017 (1.54), 9.034 (1.55), 9.094 (4.38), 9.366 (0.48), 9.383 (0.56), 9.397 (0.68), 9.414 (0.56)。 LC-MS (方法2): R t= 1.13 min;MS (ESIpos): m/z = 536 [M+H]⁺ 實例6 38.0 mg (95%純度,45%產率) |
167 | 1-{4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羰基}環丙烷-1-甲腈 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.578 (6.84), 1.596 (6.13), 1.648 (2.52), 2.331 (1.07), 2.336 (0.55), 2.427 (16.00), 2.518 (5.21), 2.523 (3.39), 2.626 (6.94), 2.673 (1.01), 5.713 (0.84), 5.730 (1.28), 5.748 (0.82), 7.353 (0.80), 7.372 (1.69), 7.391 (0.99), 7.547 (1.87), 7.566 (1.51), 7.791 (1.64), 7.811 (1.48), 9.033 (1.89), 9.049 (1.85), 9.108 (4.92), 9.376 (1.39), 9.393 (1.34)。 LC-MS (方法2): R t= 1.23 min;MS (ESIpos): m/z = 557 [M+H]⁺ 實例6 45.0 mg (95%純度,52%產率) |
168 | 1-(1-氟環丙烷-1-羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.236 (1.74), 1.259 (1.65), 1.286 (0.84), 1.298 (1.23), 1.335 (0.62), 1.351 (1.13), 1.576 (5.35), 1.593 (5.36), 2.074 (0.92), 2.327 (1.88), 2.331 (1.45), 2.392 (0.80), 2.424 (16.00), 2.518 (8.02), 2.523 (4.80), 2.625 (7.36), 2.673 (1.29), 4.172 (0.66), 5.709 (0.86), 5.727 (1.32), 5.744 (0.84), 7.351 (0.80), 7.370 (1.76), 7.390 (1.01), 7.545 (1.93), 7.564 (1.55), 7.790 (1.71), 7.809 (1.55), 9.028 (1.93), 9.044 (1.93), 9.102 (4.90), 9.385 (1.31), 9.402 (1.28)。 LC-MS (方法2): R t= 1.26 min;MS (ESIpos): m/z = 550 [M+H]⁺ 實例6 57.0 mg (95%純度,66%產率) |
169 | 1-[1-(二氟甲基)環丙烷-1-羰基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.101 (4.81), 1.576 (5.75), 1.593 (5.73), 2.040 (0.88), 2.323 (2.02), 2.327 (2.49), 2.331 (2.11), 2.391 (0.55), 2.424 (16.00), 2.522 (4.97), 2.624 (8.21), 2.665 (1.21), 2.669 (1.59), 2.673 (1.20), 3.929 (0.60), 4.111 (0.82), 5.709 (0.95), 5.726 (1.43), 5.744 (0.94), 5.842 (1.12), 5.981 (2.20), 6.121 (0.98), 7.350 (0.90), 7.370 (1.91), 7.389 (1.14), 7.545 (2.13), 7.564 (1.72), 7.787 (1.92), 7.807 (1.72), 9.020 (2.10), 9.036 (2.07), 9.101 (5.20), 9.366 (1.58), 9.383 (1.51)。 LC-MS (方法2): R t= 1.24 min;MS (ESIpos): m/z = 582 [M+H]⁺ 實例6 39.0 mg (95%純度,43%產率) |
170 | 1-(3,3-二氟環丁烷-1-羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.575 (6.73), 1.592 (6.62), 1.983 (0.66), 1.999 (0.64), 2.037 (0.72), 2.074 (1.21), 2.294 (0.61), 2.323 (1.54), 2.327 (1.89), 2.331 (1.58), 2.349 (0.85), 2.368 (0.60), 2.390 (0.59), 2.422 (16.00), 2.518 (4.27), 2.523 (2.66), 2.623 (9.30), 2.665 (0.88), 2.669 (1.20), 2.673 (0.87), 2.768 (0.73), 2.793 (1.62), 2.814 (1.96), 2.819 (2.04), 2.836 (2.19), 2.858 (1.98), 2.881 (0.82), 3.351 (1.09), 3.358 (0.92), 3.373 (1.11), 3.379 (1.08), 3.395 (0.67), 3.402 (0.63), 3.820 (1.68), 3.833 (1.33), 3.851 (1.35), 3.861 (1.42), 4.006 (0.54), 5.710 (0.75), 5.723 (1.06), 5.727 (1.09), 5.740 (0.72), 7.350 (1.03), 7.369 (2.25), 7.389 (1.30), 7.545 (2.41), 7.564 (1.97), 7.784 (2.21), 7.803 (1.97), 9.009 (2.17), 9.025 (2.15), 9.090 (6.36), 9.359 (1.28), 9.371 (1.23)。 LC-MS (方法2): R t= 1.27 min;MS (ESIpos): m/z = 582 [M+H]⁺ 實例6 55.0 mg (95%純度,60%產率) |
171 | 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(2-甲基丙醯基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.033 (3.78), 1.047 (6.22), 1.062 (3.74), 1.574 (5.24), 1.591 (5.31), 2.322 (0.53), 2.327 (0.69), 2.332 (0.58), 2.336 (0.40), 2.354 (0.40), 2.420 (16.00), 2.518 (1.51), 2.523 (1.01), 2.622 (6.71), 2.669 (0.50), 2.955 (1.08), 2.973 (1.43), 2.989 (1.04), 4.016 (0.56), 4.059 (0.43), 5.705 (0.70), 5.723 (1.07), 5.741 (0.69), 5.758 (5.72), 7.348 (0.79), 7.367 (1.69), 7.387 (0.97), 7.543 (1.82), 7.561 (1.46), 7.786 (1.61), 7.806 (1.45), 9.015 (1.85), 9.031 (1.81), 9.089 (4.93), 9.370 (1.18), 9.387 (1.13)。 LC-MS (方法2): R t= 1.23 min;MS (ESIpos): m/z = 534 [M+H]⁺ 實例6 25.0 mg (95%純度,30%產率) |
172 | 1-(環丙烷羰基)-4-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.754 (0.86), 0.762 (2.22), 0.781 (3.76), 0.794 (2.27), 1.203 (6.04), 1.227 (6.25), 1.596 (4.30), 1.614 (4.27), 2.068 (0.45), 2.081 (0.72), 2.088 (0.72), 2.100 (0.99), 2.112 (0.53), 2.119 (0.51), 2.419 (13.10), 2.518 (4.88), 2.523 (3.28), 4.072 (0.56), 5.340 (6.30), 5.758 (16.00), 5.775 (0.69), 5.793 (1.04), 5.811 (0.65), 7.207 (0.69), 7.226 (1.63), 7.245 (1.05), 7.306 (0.73), 7.323 (1.06), 7.339 (0.49), 7.609 (0.58), 7.625 (1.04), 7.641 (0.53), 9.031 (1.64), 9.047 (1.62), 9.116 (4.28), 9.283 (1.24), 9.301 (1.18)。 LC-MS (方法2): R t= 1.02 min;MS (ESIpos): m/z = 576 [M+H]⁺ 中間物228 40.6 mg (95%純度,55%產率) |
173 | 1-(1-羥基環丙烷-1-羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.799 (0.78), 0.812 (2.21), 0.818 (2.32), 0.830 (1.06), 0.979 (2.99), 0.986 (2.43), 1.576 (4.90), 1.593 (4.91), 2.318 (0.68), 2.323 (1.31), 2.327 (1.79), 2.331 (1.35), 2.336 (0.72), 2.423 (16.00), 2.518 (5.21), 2.523 (3.52), 2.625 (6.24), 2.660 (0.52), 2.665 (1.16), 2.669 (1.60), 2.673 (1.12), 2.678 (0.50), 5.708 (0.78), 5.725 (1.19), 5.743 (0.77), 6.532 (7.20), 7.351 (0.71), 7.370 (1.57), 7.390 (0.91), 7.545 (1.71), 7.563 (1.37), 7.792 (1.50), 7.811 (1.35), 9.018 (1.72), 9.034 (1.69), 9.098 (4.63), 9.382 (1.29), 9.399 (1.24)。 LC-MS (方法2): R t= 1.17 min;MS (ESIpos): m/z = 548 [M+H]⁺ 實例6 35.0 mg (95%純度,35%產率) |
174 | 1-(環丙烷羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.761 (2.91), 0.780 (4.77), 0.792 (2.97), 1.575 (5.54), 1.593 (5.51), 1.908 (0.47), 2.029 (0.48), 2.067 (0.62), 2.080 (0.91), 2.086 (0.91), 2.099 (1.23), 2.111 (0.72), 2.118 (0.66), 2.262 (0.52), 2.331 (0.92), 2.423 (16.00), 2.625 (7.76), 2.673 (0.80), 3.706 (0.42), 4.058 (0.69), 4.092 (0.63), 4.233 (0.44), 5.708 (0.85), 5.725 (1.28), 5.743 (0.83), 7.350 (0.87), 7.369 (1.84), 7.388 (1.08), 7.544 (2.01), 7.564 (1.64), 7.788 (1.81), 7.808 (1.66), 9.020 (2.07), 9.036 (2.05), 9.100 (4.96), 9.379 (1.46), 9.396 (1.39)。 LC-MS (方法2): R t= 1.21 min;MS (ESIpos): m/z = 532 [M+H]⁺ 實例6 55.0 mg (95%純度,56%產率) |
175 | 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-4-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.575 (4.07), 1.593 (4.10), 2.037 (0.65), 2.331 (0.86), 2.337 (0.54), 2.370 (0.70), 2.394 (0.68), 2.422 (13.30), 2.518 (3.48), 2.523 (2.32), 2.625 (5.33), 2.673 (0.74), 3.866 (16.00), 4.137 (0.41), 4.183 (0.58), 5.708 (0.65), 5.725 (1.01), 5.743 (0.64), 7.350 (0.61), 7.369 (1.31), 7.389 (0.76), 7.545 (1.45), 7.563 (1.15), 7.742 (4.56), 7.744 (4.61), 7.789 (1.28), 7.809 (1.15), 8.160 (3.97), 9.028 (1.48), 9.043 (1.43), 9.097 (3.95), 9.382 (1.08), 9.399 (1.03)。 LC-MS (方法2): R t= 1.15 min;MS (ESIpos): m/z = 572 [M+H]⁺ 實例6 58.0 mg (95%純度,55%產率) |
176 | 1-[(2S)-2-甲氧基丙醯基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.250 (7.71), 1.267 (7.67), 1.574 (4.82), 1.592 (4.75), 2.318 (0.49), 2.323 (0.89), 2.327 (1.18), 2.331 (0.88), 2.336 (0.48), 2.421 (16.00), 2.518 (4.09), 2.523 (2.88), 2.624 (6.38), 2.665 (0.78), 2.669 (1.07), 2.673 (0.75), 3.250 (6.35), 3.257 (5.68), 3.882 (0.50), 3.905 (0.55), 3.935 (0.59), 4.295 (0.53), 4.311 (1.95), 4.327 (1.92), 4.344 (0.50), 5.706 (0.72), 5.724 (1.12), 5.741 (0.72), 7.350 (0.73), 7.369 (1.55), 7.389 (0.89), 7.544 (1.72), 7.562 (1.38), 7.787 (1.40), 7.807 (1.26), 9.017 (1.21), 9.033 (1.19), 9.085 (1.80), 9.092 (1.62), 9.359 (0.46), 9.376 (0.55), 9.387 (0.61), 9.404 (0.50)。 LC-MS (方法2): R t= 1.14 min;MS (ESIpos): m/z = 550 [M+H]⁺ 實例6 31.9 mg (95%純度,51%產率) |
177 | 1-(甲氧基乙醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.574 (3.04), 1.591 (3.06), 2.318 (0.43), 2.322 (0.67), 2.327 (0.85), 2.331 (0.67), 2.421 (8.96), 2.522 (4.84), 2.623 (4.17), 2.664 (0.55), 2.669 (0.74), 2.673 (0.57), 3.299 (0.42), 3.305 (0.62), 3.313 (1.62), 3.324 (16.00), 3.370 (1.32), 3.377 (0.68), 3.810 (0.41), 3.823 (0.41), 4.198 (3.69), 5.705 (0.42), 5.723 (0.63), 5.740 (0.43), 7.349 (0.47), 7.368 (1.01), 7.388 (0.60), 7.543 (1.10), 7.562 (0.90), 7.785 (0.99), 7.805 (0.90), 9.009 (1.04), 9.026 (1.04), 9.090 (2.81), 9.370 (0.72), 9.387 (0.72)。 LC-MS (方法2): R t= 1.11 min;MS (ESIpos): m/z = 545 [M+H]⁺ 實例6 29.6 mg (95%純度,49%產率) |
178 | 1-[1-(羥甲基)環丙烷-1-羰基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.716 (2.83), 0.807 (2.14), 1.575 (4.95), 1.593 (4.95), 2.011 (0.57), 2.323 (1.25), 2.327 (1.55), 2.332 (1.23), 2.336 (0.84), 2.422 (16.00), 2.518 (3.60), 2.523 (2.63), 2.623 (6.36), 2.665 (0.71), 2.669 (1.00), 2.673 (0.68), 3.304 (0.40), 3.310 (0.58), 3.365 (0.41), 3.476 (1.99), 3.490 (1.99), 4.110 (0.42), 4.958 (1.16), 4.972 (2.72), 4.987 (1.13), 5.707 (0.78), 5.725 (1.19), 5.742 (0.77), 7.349 (0.75), 7.369 (1.59), 7.388 (0.92), 7.544 (1.73), 7.562 (1.39), 7.787 (1.54), 7.806 (1.38), 9.011 (1.73), 9.026 (1.69), 9.095 (4.86), 9.097 (4.50), 9.361 (1.32), 9.378 (1.26)。 LC-MS (方法2): R t= 1.09 min;MS (ESIpos): m/z = 562 [M+H]⁺ 實例6 41.9 mg (95%純度,66%產率) |
179 | N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)甲磺醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.754 (0.61), 0.761 (1.59), 0.781 (2.68), 0.794 (1.59), 1.107 (16.00), 1.609 (3.16), 1.626 (3.18), 2.081 (0.51), 2.088 (0.50), 2.100 (0.72), 2.119 (0.42), 2.442 (10.30), 2.518 (4.01), 2.523 (2.63), 2.830 (11.35), 3.729 (0.49), 3.747 (0.56), 3.770 (0.75), 3.786 (0.70), 4.191 (1.48), 5.785 (0.49), 5.803 (0.75), 5.820 (0.48), 7.272 (0.62), 7.291 (1.36), 7.311 (0.79), 7.429 (0.48), 7.445 (0.78), 7.679 (0.42), 7.696 (0.75), 7.766 (0.49), 7.783 (1.06), 7.800 (0.47), 9.025 (1.17), 9.041 (1.14), 9.120 (3.17), 9.276 (0.91), 9.294 (0.86)。 LC-MS (): R t= min;MS (): m/z = 中間物232 41.4 mg (95%純度,62%產率) |
180 | N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)乙醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.753 (0.47), 0.761 (1.26), 0.781 (2.08), 0.793 (1.24), 1.106 (16.00), 1.607 (2.46), 1.625 (2.47), 1.791 (9.04), 2.100 (0.55), 2.327 (0.46), 2.441 (7.35), 2.518 (1.41), 2.523 (1.04), 2.669 (0.40), 4.192 (1.69), 5.800 (0.58), 7.239 (0.46), 7.258 (1.01), 7.277 (0.60), 7.400 (0.61), 7.667 (0.58), 8.344 (0.76), 9.024 (0.92), 9.040 (0.91), 9.118 (2.38), 9.269 (0.70), 9.287 (0.67)。 LC-MS (): R t= min;MS (): m/z = 中間物233 42.8 mg (95%純度,52%產率) |
181 | N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基甲磺醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.761 (1.00), 0.781 (1.67), 0.794 (1.01), 1.106 (16.00), 1.602 (2.01), 1.620 (2.02), 2.100 (0.45), 2.431 (6.17), 2.518 (1.02), 2.523 (0.63), 2.857 (10.46), 4.191 (1.54), 5.784 (0.48), 7.287 (0.86), 7.307 (0.50), 7.454 (0.49), 7.686 (0.47), 9.030 (0.75), 9.047 (0.74), 9.119 (2.02), 9.276 (0.58), 9.294 (0.55)。 LC-MS (): R t= min;MS (): m/z = 中間物234 60.6 mg (95%純度,67%產率) |
182 | N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基乙醯胺 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.763 (0.56), 0.778 (0.66), 0.793 (0.50), 1.107 (16.00), 1.607 (0.73), 1.616 (0.71), 1.621 (0.79), 1.630 (0.63), 1.917 (1.72), 1.926 (2.44), 2.429 (1.94), 2.434 (2.17), 2.515 (0.53), 2.518 (0.53), 2.522 (0.42), 2.841 (1.25), 3.022 (1.64), 4.189 (1.60), 9.033 (0.45), 9.046 (0.45), 9.119 (0.65), 9.122 (0.57)。 LC-MS (): R t= min;MS (): m/z = 中間物235 43.7 mg (95%純度,63%產率) |
表11中顯示之實例係根據一般程序9自各別胺衍生物及各別異氰酸酯製備。
實例表
11
實例 | 結構;IUPAC名稱;分析資料;起始材料;產率 |
183 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.932 (0.90), 0.948 (0.85), 1.616 (5.09), 1.634 (5.11), 1.791 (0.47), 1.831 (0.87), 1.871 (0.46), 2.290 (0.79), 2.322 (2.72), 2.327 (3.49), 2.331 (2.68), 2.336 (1.40), 2.430 (14.52), 2.518 (16.00), 2.522 (9.74), 2.660 (1.01), 2.665 (2.19), 2.669 (3.10), 2.673 (2.28), 2.678 (1.08), 3.630 (0.80), 3.664 (0.86), 3.692 (0.42), 3.833 (0.54), 3.879 (0.75), 5.779 (0.80), 5.797 (1.26), 5.814 (0.78), 6.242 (3.60), 7.105 (1.19), 7.241 (2.46), 7.285 (0.91), 7.305 (1.99), 7.324 (1.16), 7.377 (1.04), 7.498 (0.70), 7.514 (1.16), 7.532 (0.58), 7.687 (0.64), 7.705 (1.18), 7.724 (0.61), 8.996 (1.71), 9.012 (1.68), 9.121 (4.35), 9.284 (1.28), 9.302 (1.26)。 LC-MS (方法2): R t= 0.96 min;MS (ESIpos): m/z = 494 [M+H]⁺ 中間物226 57.0 mg (95%純度,53%產率) |
184 | N-環丙基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.391 (0.72), 0.403 (2.11), 0.408 (2.20), 0.412 (2.31), 0.418 (2.58), 0.429 (0.96), 0.551 (0.94), 0.561 (2.13), 0.568 (2.63), 0.579 (2.78), 0.585 (1.85), 0.597 (0.74), 1.571 (5.00), 1.588 (5.02), 1.831 (0.82), 1.870 (0.45), 2.218 (0.40), 2.242 (0.83), 2.258 (0.70), 2.265 (0.77), 2.327 (0.95), 2.332 (0.67), 2.419 (16.00), 2.518 (3.62), 2.523 (2.72), 2.563 (1.05), 2.572 (1.03), 2.580 (0.79), 2.589 (0.49), 2.621 (6.41), 2.669 (0.98), 2.673 (0.68), 3.636 (0.76), 3.644 (0.72), 3.668 (0.79), 3.697 (0.42), 3.816 (0.52), 3.862 (0.75), 5.703 (0.80), 5.720 (1.23), 5.738 (0.78), 6.846 (1.80), 6.853 (1.77), 7.346 (0.73), 7.365 (1.61), 7.385 (0.93), 7.542 (1.74), 7.559 (1.41), 7.784 (1.55), 7.803 (1.40), 8.990 (1.77), 9.005 (1.76), 9.089 (4.72), 9.366 (1.37), 9.383 (1.32)。 LC-MS (方法2): R t= 1.17 min;MS (ESIpos): m/z = 547 [M+H]⁺ 實例6 46.7 mg (95%純度,69%產率) |
185 | N-(2,2-二氟乙基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.573 (4.76), 1.590 (4.75), 1.883 (0.74), 1.921 (0.41), 2.273 (0.77), 2.296 (0.69), 2.318 (0.80), 2.322 (1.44), 2.327 (1.84), 2.332 (1.38), 2.336 (0.60), 2.420 (16.00), 2.518 (6.29), 2.523 (4.45), 2.622 (5.98), 2.660 (0.52), 2.664 (1.13), 2.669 (1.65), 2.673 (1.17), 2.678 (0.51), 3.420 (0.56), 3.433 (0.44), 3.447 (0.78), 3.461 (1.07), 3.471 (0.79), 3.486 (0.41), 3.498 (0.53), 3.715 (0.66), 3.724 (0.65), 3.749 (0.68), 3.776 (0.40), 3.855 (0.48), 3.898 (0.72), 5.706 (0.75), 5.723 (1.16), 5.740 (0.74), 5.866 (0.62), 5.997 (0.55), 6.006 (1.28), 6.017 (0.59), 6.148 (0.56), 7.204 (0.70), 7.218 (1.46), 7.232 (0.68), 7.348 (0.70), 7.367 (1.51), 7.386 (0.87), 7.543 (1.64), 7.561 (1.32), 7.785 (1.46), 7.804 (1.32), 9.000 (1.69), 9.015 (1.64), 9.091 (4.53), 9.093 (4.44), 9.366 (1.28), 9.384 (1.23)。 LC-MS (方法2): R t= 1.19 min;MS (ESIpos): m/z = 571 [M+H]⁺ 實例6 44.9 mg (95%純度,64%產率) |
186 | 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.572 (5.07), 1.590 (5.03), 1.829 (0.79), 1.866 (0.44), 2.258 (0.47), 2.282 (0.77), 2.304 (0.76), 2.318 (0.91), 2.323 (1.29), 2.327 (1.64), 2.331 (1.19), 2.336 (0.69), 2.418 (16.00), 2.518 (4.69), 2.523 (3.24), 2.622 (6.60), 2.660 (0.43), 2.665 (0.90), 2.669 (1.25), 2.673 (0.84), 3.297 (0.58), 3.627 (0.75), 3.659 (0.79), 3.842 (0.55), 3.877 (0.68), 3.889 (0.72), 3.927 (0.42), 5.703 (0.80), 5.720 (1.23), 5.738 (0.78), 6.242 (3.45), 7.347 (0.77), 7.367 (1.65), 7.386 (0.94), 7.542 (1.79), 7.561 (1.45), 7.786 (1.57), 7.805 (1.41), 8.993 (1.64), 9.008 (1.64), 9.098 (4.88), 9.372 (1.30), 9.389 (1.19)。 LC-MS (方法2): R t= 1.05 min;MS (ESIpos): m/z = 507 [M+H]⁺ 實例6 39.5 mg (95%純度,69%產率) |
表12中顯示之實例係根據一般程序10自各別胺衍生物及各別異氰酸酯製備。
實例表
12
實例 | 結構;IUPAC名稱;分析資料;起始材料;產率 |
187 | 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸乙酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.203 (5.63), 1.220 (12.70), 1.238 (6.01), 1.616 (5.37), 1.633 (5.40), 1.916 (0.40), 1.956 (0.84), 1.995 (0.48), 2.293 (0.82), 2.318 (0.99), 2.323 (1.23), 2.327 (1.36), 2.331 (1.03), 2.336 (0.69), 2.432 (16.00), 2.518 (3.02), 2.523 (2.03), 2.665 (0.53), 2.669 (0.76), 2.673 (0.52), 3.742 (0.62), 3.898 (0.57), 3.945 (0.80), 3.980 (0.42), 4.085 (0.63), 4.103 (1.64), 4.120 (1.58), 4.136 (0.58), 5.779 (0.79), 5.797 (1.20), 5.815 (0.77), 7.105 (1.29), 7.240 (2.67), 7.284 (0.97), 7.304 (2.10), 7.323 (1.21), 7.376 (1.14), 7.498 (0.72), 7.514 (1.23), 7.533 (0.72), 7.547 (0.45), 7.565 (0.50), 7.573 (0.44), 7.595 (0.65), 7.612 (0.54), 7.621 (0.63), 7.624 (0.63), 7.687 (0.66), 7.705 (1.21), 7.724 (0.60), 9.012 (1.87), 9.028 (1.84), 9.112 (4.63), 9.290 (1.33), 9.307 (1.28)。 LC-MS (方法2): R t= 1.14 min;MS (ESIpos): m/z = 523 [M+H]⁺ 中間物226 73.0 mg (95%純度,64%產率) |
188 | N,N-二甲基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 LC-MS (方法2): R t= 1.19 min;MS (ESIpos): m/z = 535 [M+H]⁺ 實例6 22.4 mg (95%純度,34%產率) |
189 | 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸乙酯 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.202 (5.63), 1.220 (12.21), 1.237 (5.81), 1.571 (5.27), 1.589 (5.24), 1.918 (0.41), 1.952 (0.85), 1.990 (0.49), 2.263 (0.48), 2.286 (0.96), 2.298 (0.74), 2.309 (0.88), 2.323 (1.17), 2.327 (1.25), 2.331 (0.98), 2.420 (16.00), 2.518 (3.51), 2.523 (2.33), 2.622 (6.92), 2.665 (0.63), 2.669 (0.87), 2.673 (0.62), 3.159 (4.56), 3.171 (4.80), 3.737 (0.63), 3.908 (0.61), 3.922 (0.48), 3.943 (0.80), 3.956 (0.85), 3.992 (0.44), 4.086 (1.02), 4.099 (2.55), 4.112 (1.88), 4.118 (1.60), 4.136 (0.58), 5.703 (0.83), 5.720 (1.27), 5.738 (0.81), 7.346 (0.78), 7.366 (1.70), 7.386 (0.98), 7.542 (1.86), 7.561 (1.50), 7.784 (1.66), 7.804 (1.49), 9.007 (1.94), 9.024 (1.90), 9.092 (4.86), 9.373 (1.44), 9.390 (1.37)。 LC-MS (方法2): R t= 1.28 min;MS (ESIpos): m/z = 536 [M+H]⁺ 實例9 35.9 mg (95%純度,54%產率) |
表13中顯示之實例係根據一般程序7自各別胺衍生物製備。
實例表
13
實例 | 結構;IUPAC名稱;分析資料;起始材料;產率 |
190 | 1-乙醯基-4-[4-({(1R)-1-[3-(二氟甲基)-2-甲基苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.559 (5.62), 1.573 (5.64), 1.907 (0.43), 2.056 (0.46), 2.115 (15.60), 2.259 (0.47), 2.278 (0.44), 2.358 (0.57), 2.361 (0.77), 2.365 (0.64), 2.389 (0.45), 2.402 (0.44), 2.441 (16.00), 2.515 (1.73), 2.518 (1.77), 2.522 (1.43), 2.631 (0.44), 2.635 (0.63), 2.639 (0.43), 3.703 (0.43), 3.729 (0.44), 3.829 (0.41), 3.836 (0.41), 3.848 (0.43), 3.859 (0.57), 3.876 (0.58), 3.884 (0.52), 3.906 (0.47), 4.031 (0.41), 4.040 (0.43), 5.742 (0.59), 5.756 (0.87), 5.767 (0.57), 7.109 (1.01), 7.219 (2.16), 7.289 (0.88), 7.305 (2.03), 7.320 (1.28), 7.329 (0.89), 7.391 (1.91), 7.406 (1.37), 7.674 (1.60), 7.690 (1.44), 9.012 (1.89), 9.025 (1.84), 9.092 (4.70), 9.326 (0.99), 9.337 (0.96)。 LC-MS (方法2): R t= 1.03 min;MS (ESIpos): m/z = 489 [M+H]⁺ 中間物227 91.0 mg (95%純度,41%產率) |
191 | 1-乙醯基-4-[4-({(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.600 (4.69), 1.618 (4.68), 2.121 (16.00), 2.280 (0.40), 2.323 (0.47), 2.327 (0.64), 2.332 (0.44), 2.389 (10.08), 2.409 (0.40), 2.518 (2.12), 2.523 (1.55), 2.665 (0.40), 2.669 (0.57), 3.868 (0.47), 3.891 (0.44), 5.866 (0.46), 5.870 (0.48), 5.883 (0.70), 5.887 (0.70), 5.900 (0.47), 5.904 (0.45), 7.495 (0.75), 7.514 (1.62), 7.533 (0.92), 7.733 (1.35), 7.750 (1.10), 7.855 (1.23), 7.874 (1.12), 9.038 (1.58), 9.054 (1.55), 9.117 (4.10), 9.407 (1.18), 9.423 (1.12)。 LC-MS (方法2): R t= 1.12 min;MS (ESIpos): m/z = 526 [M+H]⁺ 中間物237 63.8 mg (95%純度,67%產率) |
192 | 1-乙醯基-4-[2-甲基-4-({(1R)-1-[3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.627 (4.94), 1.644 (4.99), 2.116 (16.00), 2.273 (0.40), 2.464 (14.00), 2.475 (0.97), 2.518 (3.73), 2.523 (2.64), 3.309 (0.58), 3.856 (0.52), 3.869 (0.53), 3.881 (0.46), 5.645 (0.68), 5.663 (1.04), 5.681 (0.67), 7.555 (0.49), 7.575 (1.53), 7.593 (1.88), 7.601 (1.99), 7.621 (0.55), 7.766 (1.28), 7.784 (1.01), 7.850 (2.04), 8.963 (1.57), 8.979 (1.55), 9.112 (4.23), 9.235 (0.99), 9.254 (0.95)。 LC-MS (方法2): R t= 1.06 min;MS (ESIpos): m/z = 492 [M+H]⁺ 中間物238 56.8 mg (95%純度,60%產率) |
193 | (R)-1-(4-(4-((1-(3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基)乙基)胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)-4-氧離子基-1,4-氮雜磷雜環己烷-1-基)乙-1-酮 1H NMR (400 MHz, DMSO-d6) δ ppm 1.21 (d, J=9.89 Hz, 6 H) 1.60 (d, J=7.10 Hz, 3 H) 1.79 - 2.10 (m, 2 H) 2.12 (s, 3 H) 2.19 - 2.31 (m, 1 H) 2.42 (s, 3 H) 3.60 - 4.14 (m, 4 H) 5.34 (s, 1 H) 5.67 - 5.89 (m, 1 H) 7.14 - 7.27 (m, 1 H) 7.29 - 7.38 (m, 1 H) 7.58 - 7.67 (m, 1 H) 8.99 - 9.07 (m, 1 H) 9.09 - 9.15 (m, 1 H) 9.22 - 9.35 (m, 1 H)。 LC-MS (方法2): R t= 0.94 min;MS (ESIpos): m/z = 550.5 [M+H]⁺ 中間物228 36.7 mg (95%純度,51%產率) |
194 | 1-乙醯基-4-[4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)-2-(三氟甲基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.618 (4.76), 1.636 (4.71), 1.953 (0.40), 1.962 (0.40), 2.124 (16.00), 2.273 (0.49), 2.287 (0.65), 2.297 (0.44), 2.406 (0.51), 2.429 (0.48), 2.518 (0.51), 2.594 (6.44), 3.892 (0.62), 3.906 (0.51), 3.918 (0.41), 3.934 (0.44), 5.662 (0.56), 5.679 (0.82), 5.694 (0.55), 7.340 (0.74), 7.359 (1.60), 7.379 (0.92), 7.536 (1.72), 7.555 (1.39), 7.764 (1.56), 7.783 (1.40), 9.176 (1.72), 9.193 (1.70), 9.333 (4.61), 10.065 (0.92), 10.078 (0.89)。 LC-MS (方法1): R t= 1.26 min;MS (ESIpos): m/z = 561 [M+H]⁺ 中間物229 260 mg (100%純度,63%產率) |
195 | 1-乙醯基-4-[2-(二氟甲基)-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 LC-MS (方法1): R t= 1.18 min;MS (ESIpos): m/z = 543 [M+H]⁺ 中間物230 110 mg (100%純度,58%產率) |
196 | 1-乙醯基-4-[2-氯-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.592 (5.09), 1.609 (5.10), 1.920 (0.42), 2.074 (0.67), 2.118 (16.00), 2.242 (0.46), 2.266 (0.42), 2.331 (0.84), 2.337 (0.47), 2.373 (0.46), 2.397 (0.44), 2.518 (4.05), 2.523 (2.80), 2.600 (6.71), 2.673 (0.75), 3.702 (0.40), 3.735 (0.41), 3.853 (0.41), 3.865 (0.50), 3.889 (0.60), 3.900 (0.48), 3.929 (0.44), 4.062 (0.41), 5.634 (0.63), 5.651 (0.94), 5.667 (0.62), 7.379 (0.77), 7.399 (1.69), 7.419 (0.98), 7.578 (1.82), 7.596 (1.46), 7.776 (1.63), 7.795 (1.46), 9.083 (1.85), 9.100 (1.86), 9.134 (5.00), 9.934 (0.98), 9.949 (0.94)。 LC-MS (方法2): R t= 1.18 min;MS (ESIpos): m/z = 526 [M+H]⁺ 中間物231 31.0 mg (98%純度,21%產率) |
197 | 1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.576 (5.53), 1.594 (5.58), 1.953 (0.60), 1.996 (0.52), 2.040 (0.53), 2.115 (15.75), 2.258 (0.46), 2.273 (0.51), 2.283 (0.42), 2.337 (0.68), 2.358 (16.00), 2.386 (0.55), 2.399 (0.57), 2.411 (0.49), 2.518 (7.58), 2.523 (5.24), 2.630 (6.98), 2.673 (1.24), 2.678 (0.56), 3.299 (0.57), 3.307 (0.76), 3.311 (1.00), 3.379 (1.62), 3.386 (1.06), 3.393 (0.68), 3.398 (0.50), 3.461 (0.62), 3.487 (0.58), 3.742 (0.52), 3.773 (0.60), 5.719 (0.85), 5.736 (1.31), 5.754 (0.84), 7.337 (0.71), 7.357 (1.55), 7.376 (0.90), 7.531 (1.86), 7.549 (1.50), 7.659 (1.49), 7.666 (1.51), 7.681 (1.67), 7.687 (1.60), 7.787 (1.46), 7.806 (1.32), 8.044 (0.84), 8.047 (0.85), 8.069 (1.61), 8.090 (0.74), 8.094 (0.75), 8.829 (1.31), 8.860 (1.32), 8.957 (0.78), 8.965 (0.91), 8.974 (0.87), 8.983 (0.78)。 LC-MS (方法2): R t= 1.13 min;MS (ESIneg): m/z = 503 [M-H]⁻ 中間物239 34.8 mg (95%純度,76%產率) |
198 | N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)甲磺醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.106 (16.00), 1.608 (3.19), 1.626 (3.24), 2.118 (12.03), 2.441 (8.61), 2.518 (3.37), 2.523 (2.01), 2.830 (10.92), 3.742 (0.59), 3.771 (0.73), 3.785 (0.60), 3.826 (0.42), 3.850 (0.41), 3.865 (0.55), 4.192 (1.55), 5.803 (0.58), 7.272 (0.65), 7.291 (1.41), 7.310 (0.83), 7.428 (0.49), 7.445 (0.80), 7.677 (0.43), 7.695 (0.78), 7.783 (0.79), 9.015 (1.23), 9.032 (1.21), 9.116 (3.24), 9.267 (0.93), 9.286 (0.89)。 LC-MS (): R t= min;MS (): m/z = 中間物232 36.8 mg (95%純度,57%產率) |
199 | N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)乙醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.106 (16.00), 1.607 (3.49), 1.624 (3.50), 1.790 (13.84), 2.117 (13.05), 2.322 (0.56), 2.327 (0.76), 2.331 (0.54), 2.440 (9.20), 2.518 (3.19), 2.523 (2.07), 2.665 (0.48), 2.669 (0.70), 2.673 (0.50), 3.837 (0.48), 3.848 (0.60), 3.864 (0.72), 3.877 (0.72), 3.885 (0.65), 3.894 (0.62), 3.920 (0.60), 3.934 (0.41), 4.192 (1.47), 5.782 (0.41), 5.799 (0.61), 5.814 (0.41), 7.239 (0.68), 7.258 (1.49), 7.277 (0.89), 7.383 (0.53), 7.400 (0.86), 7.417 (0.40), 7.648 (0.45), 7.666 (0.81), 7.683 (0.42), 8.328 (0.52), 8.344 (1.08), 8.360 (0.50), 9.015 (1.33), 9.030 (1.32), 9.114 (3.56), 9.260 (0.96), 9.278 (0.93)。 LC-MS (): R t= min;MS (): m/z = 中間物205 53.9 mg (95%純度,68%產率) |
200 | N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基甲磺醯胺 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.107 (16.00), 1.604 (1.73), 1.618 (1.75), 2.118 (6.31), 2.431 (4.17), 2.515 (0.59), 2.518 (0.58), 2.522 (0.46), 2.856 (8.31), 3.872 (0.40), 4.190 (1.42), 7.288 (0.73), 7.303 (0.41), 9.023 (0.61), 9.036 (0.61), 9.117 (1.55), 9.268 (0.48), 9.282 (0.45)。 LC-MS (): R t= min;MS (): m/z = 中間物234 59.0 mg (95%純度,68%產率) |
201 | N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基乙醯胺 ¹H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.107 (16.00), 1.607 (1.14), 1.616 (1.08), 1.621 (1.23), 1.630 (0.96), 1.916 (2.72), 1.926 (3.90), 2.118 (6.15), 2.428 (2.50), 2.434 (2.79), 2.515 (1.12), 2.518 (1.09), 2.522 (0.86), 2.840 (1.96), 3.021 (2.50), 4.191 (0.57), 7.249 (0.45), 9.024 (0.71), 9.037 (0.70), 9.116 (1.00), 9.119 (0.87)。 LC-MS (): R t= min;MS (): m/z = 中間物 41.2 mg (95%純度,62%產率) |
202 | N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)-N-環丙基乙醯胺 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.735 (3.46), 0.748 (3.38), 0.798 (0.46), 0.834 (0.46), 0.851 (0.80), 1.035 (0.86), 1.052 (1.68), 1.070 (0.85), 1.232 (6.50), 1.616 (5.24), 1.634 (5.31), 1.883 (3.02), 1.956 (0.58), 2.022 (11.62), 2.075 (0.53), 2.116 (16.00), 2.292 (0.50), 2.323 (2.67), 2.327 (3.49), 2.331 (2.74), 2.357 (0.45), 2.415 (14.98), 2.522 (11.64), 2.665 (2.21), 2.669 (3.02), 2.673 (2.24), 3.452 (0.46), 3.492 (0.63), 3.518 (0.61), 3.756 (0.59), 3.787 (0.65), 3.925 (0.47), 3.969 (0.47), 4.004 (0.76), 4.040 (0.81), 4.185 (0.55), 4.221 (1.08), 4.257 (1.03), 5.784 (0.85), 5.801 (1.31), 5.819 (0.83), 7.240 (0.72), 7.258 (1.57), 7.279 (0.96), 7.409 (0.71), 7.426 (1.18), 7.444 (0.63), 7.636 (0.61), 7.655 (1.05), 7.672 (0.59), 9.119 (1.18), 9.137 (1.18), 9.255 (1.33), 9.260 (2.13), 9.266 (1.78), 9.271 (2.37), 9.307 (1.23)。 LC-MS (): R t= min;MS (): m/z = 中間物156 6.20 mg (95%純度,94%產率) |
表14中顯示之實例係自各別胺衍生物根據一般程序11製備。
實例表
14
實例 | 結構;IUPAC名稱;分析資料;起始材料;產率 |
203 | 1-(二氟乙醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.231 (0.87), 1.576 (5.67), 1.593 (5.73), 2.043 (0.49), 2.085 (0.52), 2.120 (0.52), 2.318 (1.14), 2.323 (2.35), 2.327 (3.17), 2.331 (2.49), 2.336 (1.40), 2.357 (0.51), 2.424 (16.00), 2.518 (9.40), 2.523 (6.29), 2.624 (7.56), 2.660 (0.93), 2.665 (2.02), 2.669 (2.85), 2.673 (1.98), 2.678 (0.87), 3.807 (0.47), 3.841 (0.47), 3.908 (0.43), 3.942 (0.55), 3.968 (0.69), 4.009 (0.48), 4.122 (0.46), 5.710 (0.67), 5.728 (1.00), 5.742 (0.68), 6.720 (1.31), 6.851 (2.86), 6.982 (1.11), 7.350 (0.88), 7.370 (1.90), 7.389 (1.08), 7.546 (2.08), 7.564 (1.64), 7.787 (1.82), 7.807 (1.63), 9.027 (2.03), 9.044 (1.99), 9.099 (5.47), 9.385 (1.20), 9.402 (1.15)。 LC-MS (方法2): R t= 1.22 min;MS (ESIpos): m/z = 542 [M+H]⁺ 中間物231 19.0 mg (95%純度,23%產率) |
204 | 4-[4-({(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(二氟乙醯基)-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.601 (7.23), 1.619 (7.32), 2.051 (0.59), 2.089 (0.62), 2.129 (0.62), 2.323 (1.29), 2.327 (1.72), 2.332 (1.37), 2.336 (1.02), 2.349 (0.62), 2.361 (0.63), 2.391 (16.00), 2.454 (0.94), 2.459 (0.91), 2.518 (6.68), 2.523 (4.38), 2.665 (0.98), 2.669 (1.37), 2.673 (0.97), 3.297 (0.45), 3.812 (0.58), 3.848 (0.63), 3.876 (0.41), 3.914 (0.55), 3.924 (0.53), 3.948 (0.67), 3.962 (0.58), 3.975 (0.83), 4.020 (0.61), 4.128 (0.56), 5.872 (0.84), 5.886 (1.24), 5.903 (0.84), 6.724 (1.52), 6.855 (3.20), 6.986 (1.28), 7.496 (1.22), 7.515 (2.63), 7.535 (1.50), 7.735 (2.31), 7.751 (1.86), 7.855 (2.07), 7.874 (1.88), 9.053 (2.53), 9.070 (2.50), 9.120 (6.44), 9.418 (1.90), 9.435 (1.84)。 LC-MS (方法1): R t= 1.14 min;MS (ESIpos): m/z = 562 [M+H]⁺ 中間物237 51.7 mg (95%純度,51%產率) |
205 | 1-(二氟乙醯基)-4-[2-甲基-4-({(1R)-1-[3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.627 (5.59), 1.645 (5.62), 2.041 (0.43), 2.080 (0.46), 2.118 (0.45), 2.318 (0.59), 2.323 (0.89), 2.327 (1.31), 2.332 (1.01), 2.336 (0.63), 2.352 (0.42), 2.444 (0.58), 2.465 (16.00), 2.518 (4.14), 2.523 (2.82), 2.665 (0.67), 2.669 (0.93), 2.673 (0.66), 3.806 (0.42), 3.840 (0.44), 3.938 (0.50), 3.950 (0.48), 3.964 (0.62), 4.006 (0.46), 4.117 (0.40), 5.647 (0.74), 5.665 (1.13), 5.683 (0.74), 6.717 (1.15), 6.849 (2.37), 6.980 (0.98), 7.556 (0.56), 7.575 (1.73), 7.594 (2.14), 7.602 (2.31), 7.622 (0.66), 7.766 (1.49), 7.784 (1.20), 7.851 (2.46), 8.978 (1.70), 8.995 (1.68), 9.114 (4.83), 9.248 (1.14), 9.266 (1.12)。 LC-MS (方法1): R t= 1.04 min;MS (ESIpos): m/z = 528 [M+H]⁺ 中間物238 56.2 mg (95%純度,55%產率) |
206 | 1-(二氟乙醯基)-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.233 (0.66), 1.620 (6.16), 1.637 (6.13), 2.044 (0.49), 2.085 (0.53), 2.123 (0.48), 2.337 (1.36), 2.436 (16.00), 2.518 (10.02), 2.523 (6.74), 2.674 (2.08), 2.679 (0.91), 3.812 (0.48), 3.848 (0.49), 3.910 (0.46), 3.945 (0.68), 4.004 (0.51), 4.104 (0.44), 5.784 (0.79), 5.801 (1.18), 5.819 (0.80), 6.720 (1.40), 6.851 (3.00), 6.982 (1.20), 7.106 (1.52), 7.242 (3.30), 7.288 (1.14), 7.307 (2.49), 7.326 (1.40), 7.377 (1.34), 7.501 (0.82), 7.517 (1.38), 7.535 (0.68), 7.689 (0.76), 7.706 (1.38), 7.726 (0.69), 9.029 (2.18), 9.046 (2.14), 9.119 (5.76), 9.294 (1.51), 9.311 (1.45)。 LC-MS (方法2): R t= 1.09 min;MS (ESIneg): m/z = 526 [M-H]⁻ 中間物226 15.0 mg (95%純度,81%產率) |
207 | 1-(二氟乙醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 ¹H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.576 (6.11), 1.594 (6.08), 2.060 (0.70), 2.066 (0.67), 2.074 (1.12), 2.095 (0.74), 2.337 (0.72), 2.361 (16.00), 2.389 (0.62), 2.401 (0.65), 2.415 (0.64), 2.430 (0.70), 2.443 (0.73), 2.518 (5.95), 2.523 (4.12), 2.630 (7.76), 2.678 (0.47), 3.579 (0.65), 3.608 (0.65), 3.650 (0.58), 3.812 (0.51), 3.843 (0.59), 4.014 (0.41), 5.720 (0.90), 5.737 (1.37), 5.755 (0.88), 6.686 (0.85), 6.817 (1.73), 6.949 (0.80), 7.336 (0.84), 7.356 (2.17), 7.364 (1.02), 7.376 (1.04), 7.531 (2.10), 7.550 (1.68), 7.666 (1.53), 7.673 (1.67), 7.688 (1.71), 7.695 (1.62), 7.790 (1.53), 7.811 (1.28), 8.057 (0.82), 8.079 (1.43), 8.101 (0.72), 8.139 (2.01), 8.851 (1.37), 8.883 (1.37), 8.986 (1.16), 9.003 (1.13)。 LC-MS (方法1): R t= 0.98 min;MS (ESIpos): m/z = 541 [M+H]⁺ 實例6 68.5 mg (95%純度,70%產率) |
實驗部分-生物分析
實例係於選定生物分析中測試一或多次。當測試多於一次時,資料係以平均值或以中值報導,其中
平均值(亦稱為算術平均值)表示獲得值之總和除以測試次數,及
中值表示按昇冪或降冪排列時該組值之中間數。若數據組中值數量為奇數,則該中值係中間值。若該數據組中值數量為偶數,則該中值係兩個中間值之算術平均值。
將實例合成一或多次。當合成超過一次時,來自生物分析之數據表示利用獲自一或多個合成批次之測試之數據組計算之平均值或中值。
生物化學分析:hK-RasG12C與hSOS1之相互作用分析
此分析定量人類SOS1 (SOS1)與人類K-Ras
G12C(K-RasG12C)之平衡相互作用。藉由量測自與GST-K-RasG12C結合之抗GST-銪(FRET供體)至與His標記之hSOS1 (FRET受體)結合之抗6His-XL665之均質時間分辨螢光共振能量轉移(HTRF)達成對該相互作用之偵測。
分析緩衝液含有5 mM HEPES pH 7.4 (Applichem)、150 mM NaCl (Sigma)、10 mM EDTA (Promega)、1 mM DTT (Thermofisher)、0.05% BSA溶離份V,pH 7.0,(ICN Biomedicals)、0.0025% (v/v) Igepal (Sigma)及100 mM KF (FLUKA)。
N端GST標記之人類K-RasG12C (稱為GST-hK-RasG12C)及N端His標記之人類SOS1 (稱為His10-hSOS1)之表現及純化描述於WO 2019/201848,第220頁第12至34行及第222頁第13至25行(表現)及第222頁第26行至第223頁第17行(純化)中。所使用蛋白質批次之濃度係經最佳化以於HTRF信號之線性範圍內。於通常含有10 nM GST-hK-RasG12C及2 nM抗GST-Eu(K) (Cisbio, France)之分析緩衝液中製備Ras工作溶液。於含有通常20 nM His-hSOS1及10 nM抗6His-XL665 (Cisbio, France)之分析緩衝液中製備SOS1工作溶液。於含有10 nM抗6His-XL665而無SOS1之分析緩衝液中製備抑制劑對照溶液。
將測試化合物於DMSO中之50 nl 100倍濃縮溶液轉移至黑色微量滴定測試盤(384或1536,Greiner Bio-One, Germany)內。針對此,使用蜂鳥(Hummingbird)液體處理器(Digilab, MA, USA)或Echo聲學系統(Labcyte, CA, USA)。
分析之所有步驟均在20℃下進行。使用Multidrop分配器(Thermo Labsystems)將2.5 µl體積之Ras工作溶液添加至測試盤之所有孔。在2 min預培養後,將2.5 µl SOS1工作溶液添加至除彼等該測試盤側面之孔外之所有孔,該等側面之孔隨後用2.5 µl抑制劑對照溶液填充。在60 min培養後,以Pherastar (BMG, Germany)使用HTRF模組(激發337 nm,發射1:620 nm,發射2:665 nm)量測螢光。
比例數據(發射2除以發射1)係使用對照(DMSO = 0%抑制,具有抑制劑對照溶液之抑制對照孔= 100%抑制)標準化。以多達11種濃度(為20 µm、5.7 µm、1.6 µm、0.47 µm、0.13 µm、38 nm、11 nm、3.1 nm、0.89 nm、0.25 nM及0.073 nM)一式兩份測試化合物。藉由4參數擬合使用商業套裝軟體(Genedata Screener, Switzerland)計算IC50值。
實例 | K-RasG12C - SOS相互作用分析 IC 50- [mol/l] (平均值) | 實例 | K-RasG12C - SOS相互作用分析 IC 50- [mol/l] (平均值) |
1 | 2.06E-8 | 106 | 1.61 E-8 |
2 | 5.08E-8 | 107 | 2.05 E-8 |
3 | 1.91E-8 | 108 | 1.53 E-7 |
4 | 1.28E-8 | 109 | 3.33 E-8 |
5 | 2.61E-7 | 110 | 5.68 E-8 |
6 | n.d. | 111 | 2.15 E-8 |
7 | 6.24E-9 | 112 | 1.12 E-8 |
8 | 9.40E-8 | 113 | 7.85 E-9 |
9 | 2.23E-8 | 114 | 6.65 E-8 |
10 | 7.80E-9 | 115 | 8.03 E-8 |
11 | 5.29E-8 | 116 | 5.76 E-8 |
12 | 5.94E-8 | 117 | 5.69 E-8 |
13 | 1.63E-8 | 118 | 5.65 E-8 |
14 | 9.78E-9 | 119 | 4.29 E-8 |
15 | 4.71E-8 | 120 | 3.67 E-8 |
16 | 1.06E-8 | 121 | 8.71 E-8 |
17 | 1.06E-8 | 122 | 6.26 E-8 |
18 | 2.77E-8 | 123 | 5.90 E-8 |
19 | 1.43E-8 | 124 | 1.67 E-8 |
20 | 7.21E-9 | 125 | 4.43 E-8 |
21 | 1.21E-7 | 126 | 9.24 E-9 |
22 | 1.87E-8 | 127 | 2.34 E-8 |
23 | 1.24 E-8 | 128 | 2.09 E-8 |
24 | ! 2.00 E-5 | 129 | 1.32 E-7 |
25 | 4.85 E-6 | 130 | 1.61 E-8 |
26 | 9.18 E-9 | 131 | 1.15 E-8 |
30 | 1.36 E-6 | 132 | 1.17 E-8 |
31 | 6.37 E-9 | 134 | 2.52 E-8 |
32 | 1.22 E-8 | 135 | 1.70 E-8 |
33 | 7.06 E-9 | 136 | 3.89 E-8 |
34 | 7.28 E-8 | 137 | 4.04 E-9 |
35 | 2.15 E-8 | 138 | 6.01 E-9 |
36 | 1.67 E-8 | 139 | 5.40 E-9 |
37 | 9.69 E-9 | 140 | 1.14 E-8 |
38 | 1.07 E-8 | 141 | 1.28 E-8 |
39 | 1.11 E-8 | 142 | 6.30 E-9 |
40 | 1.83 E-8 | 143 | 1.26 E-8 |
41 | 1.74 E-7 | 144 | 1.97 E-9 |
42 | 4.87 E-9 | 145 | 4.35 E-9 |
43 | 3.75 E-7 | 146 | 8.10 E-8 |
44 | 1.59 E-8 | 147 | 4.51 E-9 |
45 | 1.70 E-8 | 149 | 1.80 E-8 |
46 | 6.10 E-9 | 150 | 4.76 E-9 |
47 | 1.38 E-8 | 151 | 1.22 E-8 |
48 | 2.93 E-8 | 152 | 1.27 E-8 |
49 | 8.75 E-8 | 153 | 7.40 E-9 |
50 | 1.56 E-7 | 154 | 6.15 E-9 |
51 | 8.63 E-8 | 155 | 1.11 E-8 |
52 | 3.55 E-8 | 156 | 1.14 E-8 |
53 | 6.54 E-8 | 157 | 5.04 E-9 |
54 | 2.25 E-8 | 158 | 7.89 E-9 |
55 | 2.62 E-8 | 159 | 1.27 E-8 |
56 | 7.41 E-8 | 160 | 7.87 E-9 |
57 | 1.93 E-8 | 161 | 1.34 E-8 |
58 | 6.33 E-9 | 162 | 2.72 E-7 |
59 | 7.06 E-9 | 163 | 4.77 E-9 |
60 | 1.35 E-8 | 164 | 7.01 E-9 |
61 | 9.82 E-9 | 165 | 4.37 E-9 |
62 | 1.35 E-8 | 166 | 4.83 E-9 |
63 | 1.01 E-8 | 167 | 1.27 E-8 |
64 | 1.78 E-8 | 168 | 1.20 E-8 |
65 | 1.05 E-8 | 169 | 9.55 E-9 |
66 | 2.51 E-8 | 170 | 1.13 E-8 |
67 | 6.69 E-8 | 171 | 6.76 E-9 |
68 | 2.82 E-8 | 172 | 4.78 E-9 |
69 | 1.95 E-8 | 173 | 5.62 E-9 |
70 | 2.76 E-8 | 174 | 3.89 E-9 |
71 | 3.54 E-8 | 175 | 9.07 E-9 |
72 | 2.43 E-8 | 176 | 6.82 E-9 |
73 | 1.13 E-8 | 177 | 5.01 E-9 |
74 | 2.46 E-8 | 178 | 7.94 E-9 |
75 | 1.53 E-8 | 179 | 3.68 E-9 |
76 | 2.13 E-8 | 180 | 4.60 E-9 |
77 | 1.78 E-8 | 181 | 2.95 E-9 |
78 | 2.18 E-8 | 182 | 3.95 E-9 |
79 | 1.23 E-8 | 183 | 8.38 E-9 |
80 | 5.88 E-9 | 184 | 5.62 E-9 |
81 | 1.02 E-8 | 185 | 3.86 E-9 |
82 | 2.45 E-8 | 186 | 4.71 E-9 |
83 | 3.10 E-8 | 187 | 1.20 E-8 |
84 | 2.41 E-8 | 188 | 6.34 E-9 |
85 | 1.20 E-8 | 189 | 2.06 E-8 |
86 | 3.66 E-8 | 190 | 5.90 E-9 |
87 | 2.86 E-9 | 191 | 8.09 E-9 |
89 | 6.06 E-9 | 192 | 1.17 E-8 |
90 | 2.66 E-8 | 193 | 4.10 E-9 |
91 | 2.86 E-7 | 194 | 1.21 E-8 |
92 | 7.72 E-8 | 195 | 6.56 E-9 |
93 | 3.70 E-8 | 196 | 2.38 E-9 |
94 | 4.65 E-8 | 197 | 7.40 E-9 |
95 | 2.39 E-8 | 198 | 4.61 E-9 |
96 | 5.02 E-8 | 199 | 4.61 E-9 |
97 | 1.36 E-8 | 200 | 3.95 E-9 |
98 | 1.39 E-7 | 201 | 5.81 E-9 |
99 | 3.21 E-8 | 202 | 3.89 E-9 |
100 | 4.89 E-9 | 203 | 5.65 E-9 |
101 | 1.75 E-8 | 204 | 5.96 E-9 |
102 | 8.02 E-8 | 205 | 9.64 E-9 |
103 | 1.42 E-8 | 206 | 3.77 E-9 |
104 | 1.88 E-8 | 207 | 6.84 E-9 |
105 | 1.17 E-7 |
Claims (23)
- 一種通式(I)化合物, (I) 其中 X 1表示CH或N; X 2表示CR a或N X 3表示CR a或N X 4表示CH或N Y表示O或S; R 1、R 2係彼此獨立地選自C 1-4烷基、OR b或NR cR d;或 R 1、R 2連同其等結合之磷原子一起形成4至7員雜環烷基,其中一或多個碳原子可經-O-、-NR e-、-S-、-S(O)-、S(O) 2-或-S(O)NR f-置換;且其中各殘餘碳原子可視需要經一或兩個CH 3或經一個-CH 2-CH 3取代, R 3係選自-H、-OH、-OMe、-CN、-NR pR q,或視需要經OH、OMe、CN或鹵素取代之C 1-2-烷基, R 4係選自-F、-Cl、-Br、-OH、-NH 2、-N(CH 3)H、-CH 3或-CF 2H; R 5表示-A-B-E,其中 A表示-CR jR k-或不存在,及 B表示-CR lR m-或不存在,及 E表示-H、-F、-OH、-OCH 3、-NH 2、-NH-CH 3、-N(CH 3) 2、-N(CH 3)-OCH 3、-CN、-SO 2-CH 3、-NH-SO 2-CH 3、-N(CH 3)-SO 2-CH 3、-NH-C(O)-CH 3、-N(CH 3)-C(O)-CH 3、-S(=NH)(=O)-CH 3、-S(=N-CH 3)(=O)-CH 3、-C(O)-NH 2、-C(O)-NH(CH 3)、-C(O)-N(CH 3) 2,或 R 5表示-SO 2-NR nR o, R 6係選自-H、鹵素或-CH 3; R a係選自-H、鹵素、-OH、-OCH 3、-CN、環丙基、-NH 2、-NH(CH 3)、-N(CH 3) 2,或視需要經鹵素、-OH或-OCH 3、-CH 3、-CF 3、-NH 2、-NH(CH 3)、-N(CH 3) 2或-CN取代一或多次之C 1-2烷基, R b係選自-H (在以下條件下:若R 1及R 2兩者均為OR b,則僅一個R b可為H)、-CH 3、-CH 2-CH 3、-CH(CH 3) 2或環丙基, R c係選自-CH 3、-CH 2-CH 3、-CH(CH 3) 2或環丙基, R d係選自-H、-CH 3、-CH 2-CH 3、-CH(CH 3) 2或環丙基, R e係選自H、視需要經一或多個F取代之C1-C3-烷基、環丙基、-C(O)-R g、-SO 2-CH 3或視需要經-CH 3、鹵素、-CF 3或-CF 2H取代之5員雜芳基, R f係選自H、-CH 3或-CH 2-CH 3, R g係選自視需要經-OH、-OCH 3、-CH 3、鹵素取代之C 1-4烷基;或 係選自視需要經-CH 3、CH 2CH 3、CF 2H、CF 3或鹵素取代之5員雜芳基;或 係選自NR hR i; R h係選自H或-CH 3,及 R i係選自視需要經鹵素取代之C 1-3烷基或選自環丙基, R j及R k係彼此獨立地選自H、F或-CH 3,或連同其等結合之碳原子一起形成環丙基; R l及R m係彼此獨立地選自H、氘或-CH 3、-CH 2-CH 3、環丙基; 或連同其等結合之碳原子一起形成環丙基;或 R n及R o係獨立地選自H或視需要經-OH、-OCH 3取代之C 1-4烷基,或 R n及R o連同其等結合之氮一起形成4至7員雜環烷基,其視需要含有其他選自N或O之雜原子,其中此雜環烷基之碳原子可視需要經H或C 1-4烷基取代且其中此C 1-4烷基可再次經鹵素、=O、-OH、-OCH 3、-NH 2、-NH-CH 3或-N(CH 3) 2取代,且其中此雜環烷基之氮原子可視需要經-C(O)-環丙基或-C(O)-C 1-4-烷基取代,兩者均視需要經F取代一或多次; R p及R q係獨立地選自H、-CH 3或-CH 2-CH 3; 或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1之通式(Ia)化合物, (Ia) 其中 X 1表示CH; X 2表示CR a或N X 3表示CR a或N X 4表示CH或N Y表示O; R 1、R 2係彼此獨立地選自-CH 3、-CH 2-CH 3或-CH(CH 3) 2;或 R 1、R 2連同其等結合之磷原子一起形成 ; 或 ; R 3係選自-CH 3、-CHF 2、-CF 3或-Cl; R 4係選自-H、-NH 2或-CH 3; R 5係選自-Br、-CF 2-H、-CF 2-F、-CF 2-CH 3、-CF 2-CH 2-OH、-CF 2-CD 2-OH、-CF 2-CH 2-OCH 3、-CF 2-CH(CH 3)-OH、-CF 2-CH(CH 2-CH 3)-OH、-CF 2-C(CH 3) 2-OH、CF 2-C(CH 3) 2-OCH 3、-CF 2-CH(CH(CH 3) 2)-OH、-CF 2-CH(C(CH 3) 3)-OH、-CF 2-C(CH 3)(CH 2-CH 2-CH 2-CH 3)-OH、-CF 2-C(=O)-CH(CH 3) 2、-CF 2-C(=O)-C(CH 3) 3、-CF 2-C(=O)-OH、-CF 2-C(=O)-NH 2、-CF 2-C(=O)-N(CH 3) 2、-CF 2-C(=O)-NH-CH 3、-CF 2-C(=O)-NH-CH 2-CH 3、-CF 2-C(=O)-NH-環丙基、-CF 2-CH 2-NH-SO 2-CH 3、-CF 2-CH 2-N(CH 3)-SO 2-CH 3、-CF 2-CH 2-NH-C(=O)-CH 3或-CF 2-CH 2-N(CH 3); R 6係選自-H、-CH 3、-Fl或-Cl; R a係選自-H、-CH 3、-CH 2-CH 3、-CF 3、-CHF 2、-CH 2-OH、-CH 2-O-CH 3、-OH、-OCH 3或環丙基, R r係選自-H、-CH 3、-CH(CH 3) 2、-CH 2-苯基、-C(=O)-H、-C(=O)-CH 3、-C(=O)-CH 2F、-C(=O)-CH(CH 3) 2、-C(=O)-CH(CH 3)-OH、-C(=O)-CH(CH 3)-O-CH 3、 、 、 、 、 、 、 、 、 、-C(=O)-CH 2-CN、-C(=O)-CH 2-O-CH 3、-C(=O)-O-C(CH 3) 3、-C(=O)-O-CH 2-CH 3、-C(=O)-NH 2、-C(=O)-N(CH 3) 2、-C(=O)-CH 2-CHF 2、-C(=O)-NH-環丙基、-C(=S)-CH 3、-SO 2-CH 3、 或 ; R s係選自-CH 3或-CD 3; R t係選自-H或D; 或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中X 1、X 2、X 3或X 4中之僅一者係N,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中Y表示O,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中R 1及R 2係選自C 1-4烷基,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中R 3係選自視需要經1至3個F取代之C 1-2-烷基,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中R 6係選自-F、-Cl、-H或-CH 3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中R a係選自-H、-Cl、-CH 3、-CF 3或-CF 2H,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1之化合物,其中R j及R k連同其等結合之碳原子一起形成環丙基或選自兩個-F、兩個-CH 3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中兩個R 1及R 2均為-CH 3,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中R 5係-CF 3且R 6係-F,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中X 2係N且X 3係CH,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1之化合物,其中R n及R o連同其等結合之氮一起形成嗎啉或N-乙醯基哌嗪,兩者均視需要經1或2個-CH 3、-CF 3或-CF 2H取代,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1或2之化合物,其中請求項3至14之任何取代基可與來自請求項3至14中一或多項之任何其他一或多個取代基組合,或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1之化合物,其選自由以下組成之群: 6-(二甲基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺 N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 1-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 1-苄基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-苄基-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2,8-二甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 1-{3-[(1R)-1-({6-[二(丙-2-基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 6-(二甲基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺 1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[2,3-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 1-{3-[(1R)-1-({6-[二(丙-2-基)磷醯基]-2-甲基吡啶并[2,3-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 1-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[2,3-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 6-(二甲基磷醯基)-2,7-二甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺 N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2,7-二甲基吡啶并[2,3-d]嘧啶-4-胺 1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2,7-二甲基吡啶并[2,3-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 1-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2,7-二甲基吡啶并[2,3-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 1-{3-[(1R)-1-({6-[二(丙-2-基)磷醯基]-2,7-二甲基吡啶并[2,3-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 6-(二甲基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺 (2RS)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基己-2-醇(非對映異構體之混合物) 6-(二甲基磷醯基)-2-甲基-N-{1-[2-(三氟甲基)吡啶-4-基]乙基}吡啶并[3,4-d]嘧啶-4-胺(對映異構體1) 6-(二甲基磷醯基)-2-甲基-N-{1-[2-(三氟甲基)吡啶-4-基]乙基}吡啶并[3,4-d]嘧啶-4-胺(對映異構體2) 4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-8-醇 1-乙醯基-4-[8-羥基-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醛 1-硫代乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基喹唑啉-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇 1-乙醯基-4-[8-(羥甲基)-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[8-環丙基-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[8-(二氟甲基)-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[8-(甲氧基甲基)-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 (2RS)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-8-乙基-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丁-2-醇(非對映異構體之混合物) 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-4-基)-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-3-基)-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(甲磺醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 {3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}(二氟)乙酸 2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-N-環丙基-2,2-二氟乙醯胺 2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N,N-二甲基乙醯胺 2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙醯胺 2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N-甲基乙醯胺 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙醯胺 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-N-乙基-2,2-二氟乙醯胺 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N,N-二甲基乙醯胺 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟-N-甲基乙醯胺 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-甲基-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(丙-2-基)-1,4λ 5-氮雜磷雜環己烷-4-酮 1-苄基-4-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 6-(二甲基磷醯基)-N-{(1R)-1-[2-氟-3-(三氟甲基)苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 N-[(1R)-1-(3-溴-2-氟苯基)乙基]-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 1-乙醯基-4-[4-({(1R)-1-[3-(二氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[4-({(1R)-1-[2,5-二甲基-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-[4-({(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-2,5-二氫-1H-1λ 5-磷雜環戊烯-1-酮 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟( 2H 2)乙-1-醇 1-(4-{[(1R)-1-{3-[1,1-二氟-2-羥基( 2H 2)乙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ 5-磷雜環戊烷-1-酮 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇 1-[4-({(1R)-1-[3-(1,1-二氟-2-羥乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 2-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇 (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丁-2-醇(非對映異構體1) (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-醇(非對映異構體1) 1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇(非對映異構體之混合物) 1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇(非對映異構體1) 1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇(非對映異構體2) 1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}-2-甲基丙-2-醇(非對映異構體之混合物) 1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}-2-甲基丙-2-醇(非對映異構體1) 1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}-2-甲基丙-2-醇(非對映異構體2) (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體之混合物) (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體1) (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體2) (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體之混合物) (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體3) (2R*)-1-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體4) (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體之混合物) (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體1) (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體2) (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇 (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體3) (2R*)-1,1-二氟-1-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}丙-2-醇(非對映異構體4) 1-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-2,5-二氫-1H-1λ 5-磷雜環戊烯-1-酮 (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丙-2-醇 (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-醇(非對映異構體2) (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丁-2-醇(非對映異構體2) (2R*)-1-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體2) 4-[2,8-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸三級丁酯 6-(二乙基磷醯基)-N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基吡啶并[3,4-d]嘧啶-4-胺 1-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 N-{(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 1-[4-({(1R)-1-[3-胺基-5-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 6-(二乙基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺 N-{(1R)-1-[3-胺基-5-(三氟甲基)苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 6-[二(丙-2-基)磷醯基]-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[3,4-d]嘧啶-4-胺 1-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 1-[2,7-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 6-(二甲基磷醯基)-7-甲氧基-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺 6-[二(丙-2-基)磷醯基]-2,7-二甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}吡啶并[2,3-d]嘧啶-4-胺 1-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[2,3-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 1-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1λ 5-磷雜環戊烷-1-酮 1-苄基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 6-(二甲基磷醯基)-2-甲基-N-{(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}喹唑啉-4-胺 1-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[二(丙-2-基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺 1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3-甲基丁-2-酮 1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-酮 1-(4-{[(1R)-1-{3-[(2R*)-1,1-二氟-2-羥丙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ 5-磷雜環戊烷-1-酮(非對映異構體1) 1-(4-{[(1R)-1-{3-[(2R*)-1,1-二氟-2-羥丙基]-2-氟苯基}乙基]胺基}-2-甲基吡啶并[3,4-d]嘧啶-6-基)-1λ 5-磷雜環戊烷-1-酮(非對映異構體2) (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟丙-2-醇(非對映異構體2) N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物) N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體1) N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-胺(非對映異構體2) N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體之混合物) N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體1) N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-胺(非對映異構體2) N-{(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 N-{(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-胺 1-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 1-{3-[(1R)-1-{[6-(二乙基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-2-甲基丙-2-醇 2-{3-[(1R)-1-{[6-(二甲基磷醯基)-2,8-二甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙-1-醇 N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基-7-(三氟甲基)吡啶并[2,3-d]嘧啶-4-胺 1-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2,7-二甲基吡啶并[2,3-d]嘧啶-6-基]-1λ 5-磷雜環戊烷-1-酮 1-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基喹唑啉-6-基]-1λ 5-磷雜環戊烷-1-酮 N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-(二甲基磷醯基)-2-甲基喹唑啉-4-胺 N-{(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}-6-[二(丙-2-基)磷醯基]-2,7-二甲基吡啶并[2,3-d]嘧啶-4-胺 2-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙-1-醇(非對映異構體之混合物) 2-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙-1-醇(非對映異構體1) 2-{3-[(1R)-1-({6-[乙基(甲基)磷醯基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙-1-醇(非對映異構體2) 2,2-二氟-2-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}乙-1-醇(非對映異構體之混合物) 2,2-二氟-2-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}乙-1-醇(非對映異構體1) 2,2-二氟-2-{2-氟-3-[(1R)-1-({2-甲基-6-[甲基(丙-2-基)磷醯基]吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]苯基}乙-1-醇(非對映異構體2) (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-醇(非對映異構體1) (2R*)-1-{3-[(1R)-1-{[6-(二甲基磷醯基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-1,1-二氟-3,3-二甲基丁-2-醇(非對映異構體2) 1-乙醯基-4-(2-甲基-4-{[(1S)-1-[2-甲基-3-(三氟甲基)苯基]( 2H 4)乙基]胺基}吡啶并[3,4-d]嘧啶-6-基)-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟乙基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[4-({(1R)-1-[2-氟-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[4-({(1R)-1-[3-(1,1-二氟-2-甲氧基乙基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[7-甲氧基-2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[2,7-二甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 (R)-1-(4-(2,8-二甲基-4-((1-(2-甲基-3-(三氟甲基)苯基)乙基)胺基)吡啶并[3,4-d]嘧啶-6-基)-4-氧離子基-1,4-氮雜磷雜環己烷-1-基)乙-1-酮 1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[2,3-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2S)-2-甲氧基丙醯基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2R)-2-羥基丙醯基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(1-氟環丙烷-1-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 1-{4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羰基}環丙烷-1-甲腈 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(2-甲基丙醯基)-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(甲氧基乙醯基)-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2R)-2-甲氧基丙醯基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(1-羥基環丙烷-1-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-[(2S)-2-羥基丙醯基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(氧雜環丁烷-3-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 1-[1-(二氟甲基)環丙烷-1-羰基]-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(3,3-二氟環丁烷-1-羰基)-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-4-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 3-{4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-基}-3-側氧基丙腈 1-(環丙烷羰基)-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(氧雜環丁烷-3-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 1-[(2S)-2-羥基丙醯基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-[(2R)-2-羥基丙醯基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-{4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羰基}環丙烷-1-甲腈 1-(1-氟環丙烷-1-羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-[1-(二氟甲基)環丙烷-1-羰基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(3,3-二氟環丁烷-1-羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(2-甲基丙醯基)-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(環丙烷羰基)-4-[4-({(1R)-1-[3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(1-羥基環丙烷-1-羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(環丙烷羰基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1-(1-甲基-1H-吡唑-4-羰基)-1,4λ 5-氮雜磷雜環己烷-4-酮 1-[(2S)-2-甲氧基丙醯基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(甲氧基乙醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-[1-(羥甲基)環丙烷-1-羰基]-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)甲磺醯胺 N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)乙醯胺 N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基甲磺醯胺 N-(2-{3-[(1R)-1-({6-[1-(環丙烷羰基)-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基]-2-甲基吡啶并[3,4-d]嘧啶-4-基}胺基)乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基乙醯胺 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 N-環丙基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 N-(2,2-二氟乙基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸乙酯 N,N-二甲基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-甲醯胺 4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-4-側氧基-1,4λ 5-氮雜磷雜環己烷-1-羧酸乙酯 1-乙醯基-4-[4-({(1R)-1-[3-(二氟甲基)-2-甲基苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[4-({(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[2-甲基-4-({(1R)-1-[3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 (R)-1-(4-(4-((1-(3-(1,1-二氟-2-羥基-2-甲基丙基)-2-氟苯基)乙基)胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基)-4-氧離子基-1,4-氮雜磷雜環己烷-1-基)乙-1-酮 1-乙醯基-4-[4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)-2-(三氟甲基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[2-(二氟甲基)-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[2-氯-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-乙醯基-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)甲磺醯胺 N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)乙醯胺 N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基甲磺醯胺 N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)-N-甲基乙醯胺 N-(2-{3-[(1R)-1-{[6-(1-乙醯基-4-側氧基-1,4λ 5-氮雜磷雜環己烷-4-基)-2-甲基吡啶并[3,4-d]嘧啶-4-基]胺基}乙基]-2-氟苯基}-2,2-二氟乙基)-N-環丙基乙醯胺 1-(二氟乙醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 4-[4-({(1R)-1-[2-氯-3-(三氟甲基)苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1-(二氟乙醯基)-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(二氟乙醯基)-4-[2-甲基-4-({(1R)-1-[3-(三氟甲基)苯基]乙基}胺基)吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(二氟乙醯基)-4-[4-({(1R)-1-[3-(二氟甲基)-2-氟苯基]乙基}胺基)-2-甲基吡啶并[3,4-d]嘧啶-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮 1-(二氟乙醯基)-4-[2-甲基-4-({(1R)-1-[2-甲基-3-(三氟甲基)苯基]乙基}胺基)喹唑啉-6-基]-1,4λ 5-氮雜磷雜環己烷-4-酮, 或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或鹽,或其混合物。
- 如請求項1至16中任一項之通式(I)化合物,其用以治療或預防疾病。
- 一種醫藥組合物,其包含如請求項1至16中任一項之通式(I)化合物及一或多種醫藥上可接受之賦形劑。
- 一種醫藥組合,其包含: 一或多種第一活性成分,特別是如請求項1至16中任一項之通式(I)化合物,及 一或多種其他活性成分,特別是:131I-chTNT、阿巴瑞克(abarelix)、阿貝西利(abemaciclib)、阿比特龍(abiraterone)、阿卡替尼(acalabrutinib)、阿柔比星(aclarubicin)、阿達木單抗(adalimumab)、阿多曲妥珠單抗-恩他新(ado-trastuzumab emtansine)、阿法替尼(afatinib)、阿柏西普(aflibercept)、阿地白介素(aldesleukin)、艾樂替尼(alectinib)、阿崙單抗(alemtuzumab)、阿崙膦酸(alendronic acid)、阿曲諾英(alitretinoin)、阿爾法拉丁(alpharadin)、六甲蜜胺(altretamine)、胺磷汀(amifostine)、胺麩精(aminoglutethimide)、胺基乙醯丙酸己酯(hexyl aminolevulinate)、氨柔比星(amrubicin)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、安塞司亭(ancestim)、茴香腦二硫雜環戊二烯硫酮(anethole dithiolethione)、雷星-阿奈妥單抗(anetumab ravtansine)、血管收縮素II (angiotensin II)、抗凝血酶III (antithrombin III)、阿帕魯胺(apalutamide)、阿瑞匹坦(aprepitant)、阿西莫單抗(arcitumomab)、阿格拉賓(arglabin)、三氧化二砷(arsenic trioxide)、天冬醯胺酸酶(asparaginase)、阿特珠單抗(atezolizumab)、阿維魯單抗(avelumab)、阿基侖賽(axicabtagene ciloleucel)、阿西替尼(axitinib)、阿紮胞苷(azacitidine)、巴厘昔單抗(basiliximab)、貝洛替康(belotecan)、苯達莫司汀(bendamustine)、貝西索單抗(besilesomab)、貝利司他(belinostat)、貝伐單抗(bevacizumab)、貝沙羅汀(bexarotene)、比卡魯胺(bicalutamide)、比生群(bisantrene)、博來黴素(bleomycin)、博納吐單抗(blinatumomab)、硼替佐米(bortezomib)、博舒替尼(bosutinib)、布舍瑞林(buserelin)、貝倫妥單抗維多汀(brentuximab vedotin)、布加替尼(brigatinib)、白消安(busulfan)、卡巴他賽(cabazitaxel)、卡博替尼(cabozantinib)、降鈣素(calcitonine)、亞葉酸鈣(calcium folinate)、左亞葉酸鈣(calcium levofolinate)、卡培他濱(capecitabine)、卡羅單抗(capromab)、卡馬西平卡鉑(carbamazepine carboplatin)、卡波醌(carboquone)、卡非佐米(carfilzomib)、卡莫氟(carmofur)、卡莫司汀(carmustine)、卡妥索單抗(catumaxomab)、塞來昔布(celecoxib)、西莫白介素(celmoleukin)、西米普利單抗(cemiplimab)、色瑞替尼(ceritinib)、西妥昔單抗(cetuximab)、氮芥苯丁酸(chlorambucil)、氯地孕酮(chlormadinone)、氮芥(chlormethine)、西多福韋(cidofovir)、西那卡塞(cinacalcet)、順鉑(cisplatin)、克拉屈濱(cladribine)、氯膦酸(clodronic acid)、氯法拉濱(clofarabine)、考比替尼(cobimetinib)、庫潘尼西(copanlisib)、克立他酶(crisantaspase)、克唑替尼(crizotinib)、環磷醯胺(cyclophosphamide)、環丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、達卡巴嗪(dacarbazine)、更生黴素(dactinomycin)、達雷木單抗(daratumumab)、阿法達貝泊汀(darbepoetin alfa)、達拉非尼(dabrafenib)、達洛魯胺(darolutamide)、達沙替尼(dasatinib)、道諾黴素(daunorubicin)、地西他濱(decitabine)、地加瑞克(degarelix)、地尼白介素迪夫托斯(denileukin diftitox)、地諾單抗(denosumab)、地普奧肽(depreotide)、德舍瑞林(deslorelin)、雙脫水半乳糖醇(dianhydrogalactitol)、右雷佐生(dexrazoxane)、二溴螺氯銨(dibrospidium chloride)、雙脫水半乳糖醇、雙氯芬酸(diclofenac)、地努妥昔單抗(dinutuximab)、多西他賽(docetaxel)、朵拉司瓊(dolasetron)、去氧氟尿苷(doxifluridine)、阿黴素(doxorubicin)、阿黴素+雌酮(doxorubicin + estrone)、屈大麻酚(dronabinol)、杜瓦魯單抗(durvalumab)、依庫珠單抗(eculizumab)、依決洛單抗(edrecolomab)、依利醋銨(elliptinium acetate)、埃羅妥珠單抗(elotuzumab)、艾曲波帕(eltrombopag)、恩西地平(enasidenib)、內皮抑素(endostatin)、依諾西他濱(enocitabine)、恩雜魯胺(enzalutamide)、表柔比星(epirubicin)、環硫雄醇(epitiostanol)、阿法依伯汀(epoetin alfa)、倍他依泊汀(epoetin beta)、仄他依泊汀(epoetin zeta)、依鉑(eptaplatin)、艾日布林(eribulin)、埃羅替尼(erlotinib)、埃索美拉唑(esomeprazole)、雌二醇(estradiol)、雌莫司汀(estramustine)、炔雌醇(ethinylestradiol)、依託泊苷(etoposide)、依維莫司(everolimus)、依西美坦(exemestane)、法曲唑(fadrozole)、芬太尼(fentanyl)、非格司亭(filgrastim)、氟甲睪酮(fluoxymesterone)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟尿嘧啶(fluorouracil)、氟他胺(flutamide)、亞葉酸(folinic acid)、福美坦(formestane)、福沙匹坦(fosaprepitant)、福莫司汀(fotemustine)、氟維司群(fulvestrant)、釓布醇(gadobutrol)、釓特醇(gadoteridol)、釓特酸葡甲胺(gadoteric acid meglumine)、釓弗塞胺(gadoversetamide)、釓塞酸(gadoxetic acid)、硝酸鎵(gallium nitrate)、加尼瑞克(ganirelix)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥珠單抗(gemtuzumab)、穀卡匹酶(Glucarpidase)、氧化型麩胱甘肽(glutoxim)、GM-CSF、戈舍瑞林(goserelin)、格拉司瓊(granisetron)、顆粒性白血球群落刺激因子(granulocyte colony stimulating factor)、組胺二鹽酸鹽(histamine dihydrochloride)、組胺瑞林(histrelin)、羥基脲(hydroxycarbamide)、I-125核種、蘭索拉唑(lansoprazole)、伊班膦酸(ibandronic acid)、替伊莫單抗(ibritumomab tiuxetan)、依魯替尼(ibrutinib)、伊達比星(idarubicin)、異環磷醯胺(ifosfamide)、伊馬替尼(imatinib)、咪喹莫特(imiquimod)、英丙舒凡(improsulfan)、吲地司瓊(indisetron)、英卡膦酸(incadronic acid)、巨大戟醇甲基丁烯酸酯(ingenol mebutate)、奧英妥珠單抗(inotuzumab ozogamicin)、干擾素α (interferon alfa)、干擾素β (interferon beta)、干擾素γ (interferon gamma)、碘比醇(iobitridol)、碘苄胍(iobenguane) (123I)、碘美普爾(iomeprol)、伊匹單抗(ipilimumab)、伊立替康(irinotecan)、伊曲康唑(Itraconazole)、伊沙匹隆(ixabepilone)、艾沙佐米(ixazomib)、蘭瑞肽(lanreotide)、蘭索拉唑、拉帕替尼(lapatinib)、阿索氯林(Iasocholine)、來那度胺(lenalidomide)、樂伐替尼(lenvatinib)、來格司亭(lenograstim)、香菇多醣(lentinan)、來曲唑(letrozole)、亮丙瑞林(leuprorelin)、左旋咪唑(levamisole)、左炔諾孕酮(levonorgestrel)、左甲狀腺素鈉(levothyroxine sodium)、麥角乙脲(lisuride)、洛鉑(lobaplatin)、洛莫司汀(lomustine)、氯尼達明(lonidamine)、多他酸鑥Lu 177 (lutetium Lu 177 dotatate)、馬索羅酚(masoprocol)、甲羥孕酮(medroxyprogesterone)、甲地孕酮(megestrol)、美拉胂醇(melarsoprol)、美法侖(melphalan)、美雄烷(mepitiostane)、巰基嘌呤(mercaptopurine)、美司鈉(mesna)、美沙酮(methadone)、胺甲喋呤(methotrexate)、甲氧沙林(methoxsalen)、甲胺基乙醯丙酸鹽(methylaminolevulinate)、甲基普賴蘇濃(methylprednisolone)、甲基睪固酮(methyltestosterone)、甲酪胺酸(metirosine)、米哚妥林(midostaurin)、米伐木肽(mifamurtide)、米替福新(miltefosine)、米鉑(miriplatin)、二溴甘露醇(mitobronitol)、米托胍腙(mitoguazone)、二溴衛矛醇(mitolactol)、絲裂黴素(mitomycin)、米托坦(mitotane)、米托蒽醌(mitoxantrone)、莫加木單抗(mogamulizumab)、莫格莫司亭(molgramostim)、莫匹達莫(mopidamol)、鹽酸嗎啡(morphine hydrochloride)、硫酸嗎啡(morphine sulfate)、姆瓦西(mvasi)、大麻隆(nabilone)、納比西莫(nabiximols)、那法瑞林(nafarelin)、納洛酮+噴他佐辛(naloxone + pentazocine)、納曲酮(naltrexone)、那托司亭(nartograstim)、耐昔妥珠單抗(necitumumab)、奈達鉑(nedaplatin)、奈拉濱(nelarabine)、來那替尼(neratinib)、奈立膦酸(neridronic acid)、奈妥吡坦(netupitant)/帕洛諾司瓊(palonosetron)、納武單抗(nivolumab)、噴曲肽(pentetreotide)、尼羅替尼(nilotinib)、尼魯米特(nilutamide)、尼莫唑(nimorazole)、尼妥珠單抗(nimotuzumab)、尼莫司汀(nimustine)、尼達尼布(nintedanib)、尼拉帕尼(niraparib)、二胺硝吖啶(nitracrine)、納武單抗、奧比妥珠單抗(obinutuzumab)、奧曲肽(octreotide)、奧法木單抗(ofatumumab)、奧拉帕尼(olaparib)、奧拉木單抗(olaratumab)、美琥他辛(omacetaxine mepesuccinate)、奧美拉唑(omeprazole)、昂丹司瓊(ondansetron)、奧普瑞白介素(oprelvekin)、奧古蛋白(orgotein)、奧瑞莫德(orilotimod)、奧希替尼(osimertinib)、奧沙利鉑(oxaliplatin)、羥考酮(oxycodone)、羥甲烯龍(oxymetholone)、奧佐米辛(ozogamicine)、p53基因療法、紫杉醇(paclitaxel)、帕博西尼(palbociclib)、帕利夫明(palifermin)、鈀-103核種、帕洛諾司瓊、帕米膦酸(pamidronic acid)、帕尼單抗(panitumumab)、帕比司他(panobinostat)、泮托拉唑(pantoprazole)、培唑帕尼(pazopanib)、培門冬酶(pegaspargase)、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、派姆單抗(pembrolizumab)、聚乙二醇化非格司亭(pegfilgrastim)、聚乙二醇干擾素α-2b (peginterferon alfa-2b)、派姆單抗、培美曲塞(pemetrexed)、噴他佐辛(pentazocine)、噴司他丁(pentostatin)、佩洛黴素(peplomycin)、全氟丁烷(Perflubutane)、培磷醯胺(perfosfamide)、帕妥珠單抗(Pertuzumab)、畢西巴尼(picibanil)、匹魯卡品(pilocarpine)、吡柔比星(pirarubicin)、匹杉瓊(pixantrone)、普樂沙福(plerixafor)、普卡黴素(plicamycin)、聚胺葡糖(poliglusam)、聚雌二醇磷酸酯(polyestradiol phosphate)、聚乙烯吡咯啶酮+玻尿酸鈉(sodium hyaluronate)、多醣-K、泊馬度胺(pomalidomide)、普納替尼(ponatinib)、卟吩姆鈉(porfimer sodium)、普拉曲沙(pralatrexate)、潑尼莫司汀(prednimustine)、強體松(prednisone)、丙卡巴肼(procarbazine)、丙考達唑(procodazole)、普萘洛爾(propranolol)、喹高利特(quinagolide)、雷貝拉唑(rabeprazole)、雷妥莫單抗(racotumomab)、氯化鐳-223 (radium-223 chloride)、雷多替尼(radotinib)、雷洛昔芬(raloxifene)、雷替曲塞(raltitrexed)、雷莫司瓊(ramosetron)、雷莫蘆單抗(ramucirumab)、雷尼莫司汀(ranimustine)、拉布裡酶(rasburicase)、雷佐生(razoxane)、瑞法替尼(refametinib)、瑞戈非尼(regorafenib)、瑞博西尼(ribociclib)、利塞膦酸(risedronic acid)、依替膦酸錸-186 (rhenium-186 etidronate)、利妥昔單抗(rituximab)、羅拉吡坦(rolapitant)、羅米地辛(romidepsin)、羅米司亭(romiplostim)、羅莫肽(romurtide)、魯卡帕尼(rucaparib)、來克西德南釤(153Sm) (samarium (153Sm) lexidronam)、沙格司亭(sargramostim)、沙利魯單抗(sarilumab)、沙妥莫單抗(satumomab)、胰泌素(secretin)、司妥昔單抗(siltuximab)、普列威(sipuleucel-T)、西佐喃(sizofiran)、索布佐生(sobuzoxane)、甘胺雙唑鈉(sodium glycididazole)、索尼德吉(sonidegib)、索拉非尼(sorafenib)、司坦唑醇(stanozolol)、鏈脲佐菌素(streptozocin)、舒尼替尼(sunitinib)、他拉泊芬(talaporfin)、拉赫他利莫近(talimogene laherparepvec)、他米巴羅汀(tamibarotene)、他莫昔芬(tamoxifen)、他噴他多(tapentadol)、他索納明(tasonermin)、替西白介素(teceleukin)、諾非妥莫單抗鍀(99mTc) (technetium (99mTc) nofetumomab merpentan)、99mTc-HYNIC-[Tyr3]-奧曲肽、替加氟(tegafur)、替加氟+吉美西(gimeracil) +奧替西林(oteracil)、替莫泊芬(temoporfin)、替莫唑胺(temozolomide)、替西羅莫司(temsirolimus)、替尼泊苷(teniposide)、睪固酮、替曲磷(tetrofosmin)、沙利度胺(thalidomide)、噻替哌(thiotepa)、胸腺法新(thymalfasin)、促甲狀腺素α (thyrotropin alfa)、硫鳥嘌呤(tioguanine)、替沙侖賽(tisagenlecleucel)、替雷利珠單抗(tislelizumab)、托珠單抗(tocilizumab)、拓撲替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲貝替定(trabectedin)、曲美替尼(trametinib)、曲馬多(tramadol)、曲妥珠單抗(trastuzumab)、曲妥珠單抗恩他新(trastuzumab emtansine)、曲奧舒凡(treosulfan)、視網酸(tretinoin)、曲氟尿苷(trifluridine) +替吡嘧啶(tipiracil)、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、曲美替尼、曲磷胺(trofosfamide)、血小板生成素、色胺酸、烏苯美司(ubenimex)、瓦拉替尼(valatinib)、戊柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽(vapreotide)、威羅非尼(vemurafenib)、長春花鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、長春氟寧(vinflunine)、長春瑞濱(vinorelbine)、維莫德吉(vismodegib)、伏立諾他(vorinostat)、伏氯唑(vorozole)、釔-90玻璃微球體、淨司他丁(zinostatin)、淨司他丁斯酯(zinostatin stimalamer)、唑來膦酸(zoledronic acid)、佐柔比星(zorubicin)。
- 一種如請求項1至16中任一項之通式(I)化合物之用途,其用於治療或預防疾病。
- 一種如請求項1至16中任一項之通式(I)化合物之用途,其用於製備治療或預防疾病之藥劑。
- 如請求項17、20或21之用途,其中該疾病係過度增生性疾患,舉例而言,諸如特定疾患。
- 一種用於在人類及動物中控制疾病之方法,其藉由投與抗過度增生性有效量之至少一種如請求項1至16中任一項之化合物,或如請求項17至21中任一項定義之藥劑。
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WO2019173182A1 (en) | 2018-03-05 | 2019-09-12 | Bristol-Myers Squibb Company | Phenylpyrrolidinone formyl peptide 2 receptor agonists |
CN109776607B (zh) | 2019-02-21 | 2021-06-04 | 青岛海洋生物医药研究院 | 芳基磷氧类和芳基磷硫类化合物及其制备方法和应用 |
SG11202109036WA (en) | 2019-03-01 | 2021-09-29 | Revolution Medicines Inc | Bicyclic heteroaryl compounds and uses thereof |
MX2021010323A (es) | 2019-03-01 | 2021-12-10 | Revolution Medicines Inc | Compuestos bicíclicos de heterociclilo y usos de este. |
CN115461342A (zh) | 2020-05-09 | 2022-12-09 | 正大天晴药业集团股份有限公司 | 含磷的sos1抑制剂 |
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2021
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- 2022-04-13 EP EP22722729.5A patent/EP4322962A1/en active Pending
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- 2022-04-13 CA CA3216503A patent/CA3216503A1/en active Pending
- 2022-04-13 KR KR1020237038673A patent/KR20230170032A/ko unknown
- 2022-04-13 PE PE2023002853A patent/PE20240022A1/es unknown
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ECSP23077322A (es) | 2023-11-30 |
DOP2023000218A (es) | 2023-11-15 |
JP2024513595A (ja) | 2024-03-26 |
CR20230485A (es) | 2023-12-12 |
KR20230170032A (ko) | 2023-12-18 |
AU2022258751A1 (en) | 2023-10-05 |
CL2023003045A1 (es) | 2024-03-22 |
EP4074317A1 (en) | 2022-10-19 |
CO2023013469A2 (es) | 2024-04-29 |
WO2022219035A1 (en) | 2022-10-20 |
PE20240022A1 (es) | 2024-01-04 |
BR112023019030A2 (pt) | 2023-10-24 |
CA3216503A1 (en) | 2022-10-20 |
CN117500507A (zh) | 2024-02-02 |
AR125672A1 (es) | 2023-08-02 |
EP4322962A1 (en) | 2024-02-21 |
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