TW202321238A - Map4k1抑制劑 - Google Patents
Map4k1抑制劑 Download PDFInfo
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- TW202321238A TW202321238A TW111126410A TW111126410A TW202321238A TW 202321238 A TW202321238 A TW 202321238A TW 111126410 A TW111126410 A TW 111126410A TW 111126410 A TW111126410 A TW 111126410A TW 202321238 A TW202321238 A TW 202321238A
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- TW
- Taiwan
- Prior art keywords
- compound
- pharmaceutically acceptable
- alkyl
- chloro
- acceptable salt
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
本發明之一個實施例為由式I表示之化合物或其醫藥學上可接受之鹽。式I中之變數在本文中定義。
Description
本申請案係關於MAP4K1抑制劑及其使用方法,諸如用於控制個體之MAP4K1的活性。
MAP4K1,亦稱為造血祖細胞激酶1 (HPKl),最初自造血祖細胞選殖(Hu, M.C.等人, Genes Dev, 1996. 10(18): 第2251-64頁)。MAP4K1作為目標備受關注,因為其主要在造血細胞,諸如T細胞、B細胞、巨噬細胞、樹突狀細胞、嗜中性白血球及肥大細胞中表現(Hu, M.C.等人, Genes Dev, 1996. 10(18): 第2251-64頁; Kiefer, F.等人, EMBO J, 1996. 15(24): 第7013-25頁)。MAP4K1激酶活性已被證明在活化T細胞受體(TCR) (Liou, J.等人, Immunity, 2000. 12(4):第399-408頁)、B細胞受體(BCR) (Liou, J.等人, Immunity, 2000. 12(4):第399-408頁)、轉形生長因子受體(TGF- R) (Wang, W.等人, J Biol Chem, 1997. 272(36):第22771-5頁; Zhou, G.等人, J Biol Chem, 1999. 274(19):第13133-8頁)或G
s偶合之PGE
2受體(EP2及EP4) (Ikegami, R等人, J Immunol, 2001. 166(7):第4689-96頁)時被誘導。因此,MAP4K1調節各種免疫細胞之多種多樣的功能。
MAP4K1在調節各種免疫細胞之功能方面至關重要且其已涉及自體免疫疾病及抗腫瘤免疫(Shui, J.W.等人, Nat Immunol, 2007. 8(1):第84-91頁; Wang, X.等人, J Biol Chem, 2012. 287(14):第11037-48頁)。此等觀測結果表明,MAP4K1活性減弱可有助於患者之自體免疫。此外,MAP4K1亦可經由T細胞依賴性機制控制抗腫瘤免疫性。在產生PGE2的路易斯(Lewis)肺癌腫瘤模型中,相較於野生型小鼠,腫瘤在MAP4K1基因剔除小鼠中發展得更緩慢(參見US 2007/0087988)。另外,已展示,MAP4K1缺失型T細胞的授受性轉移比野生型T細胞更有效地控制腫瘤生長及癌轉移(Alzabin, S.等人, Cancer Immunol Immunother, 2010. 59(3):第419-29頁)。類似地,MAP4K1基因剔除小鼠之骨髓衍生之樹突狀細胞(BMDC)相比於野生型BMDC更有效地發起T細胞反應以根除路易斯肺癌(Alzabin, S.等人, J Immunol, 2009. 182(10):第6187-94頁)。自MAP4K1激酶死亡小鼠獲得的資料證實,MAP4K1激酶活性在賦予MAP4K1在包括CD4+、CD8+、DC、NK至T調節細胞(Treg)之廣泛範圍的免疫細胞中之遏制功能方面至關重要,且激酶域之不活化足以引起強健的抗腫瘤免疫反應。Liu等人,
PLoS ONE 14(3):e0212670 https://doi.org/10.1371/jourNal.pone.0212670。此外,MAP4K1激酶功能的喪失遏制了臨床前腫瘤模型中的腫瘤生長,並且MAP4K1激酶及PD-L1的治療性聯合阻斷(co-blockade)增強了抗腫瘤反應。Hernandez S.等人,
Cell Reports 2018 25:第80-94頁。近來所呈現之結果展示了在使用小分子MAP4K1抑制劑之CT-26同基因型小鼠模型中之腫瘤生長抑制(Seungmook, L., Cancer research.AACR Journal, 2019, 摘要 4150)。此等資料已證實MAP4K1作為用於增強抗腫瘤免疫性之新穎藥物目標。
因此,需要調節MAP4K1活性的新穎化合物治療MAP4K1依賴性疾病或病症(諸如癌症、病毒感染及其他疾病及病症)。尤其重要的是需要選擇性調節MAP4K1活性之新穎化合物。
本文提供抑制MAP4K1從而增強個體之免疫反應的化合物或其醫藥學上可接受之鹽及組合物。舉例而言,表3中所提供之抑制MAP4K1之IC
50值表明此等化合物為MAP4K1之強效抑制劑。亦揭示使用本文所描述之化合物及組合物治療癌症及病毒感染之方法。
本發明之第一實施例為由式I表示之化合物:
,
或其醫藥學上可接受之鹽,其中:
A
1係選自N及CH;
A
2係選自CH及N;
X係選自C
1 - 3烷基、OR
3、NHR
4及鹵素;
B係選自CR
5及N,Y為CR
6,或
Y與B結合在一起形成5至7員雜環或C
5 - 6環烷基,其中該雜環或該環烷基視情況經1-6個R
7取代;
R
1及R
2各自獨立地選自氫、C
1 - 6烷基、C
1 - 6鹵烷基、經OR
8取代之C
1 - 6烷基、苯基、C
3 - 6環烷基及4至6員雜環,或
R
1及R
2與其所連接之原子一起形成C
3 - 6環烷基或4至6員雜環;
R
3係選自C
1 - 3烷基、C
3 - 6環烷基及4至6員雜環,其中該烷基、該環烷基及該雜環視情況經1-3個R
9取代;
R
4係選自氫、C
1 - 3烷基、C
3 - 5環烷基及4至6員雜環,其中該烷基、該環烷基及該雜環視情況經1-3個R
10取代;
R
5係選自氫、COOH、CN、鹵素及C
1 - 3烷氧基;
R
6係選自C
1 - 5烷基、C
4 - 6環烷基、3至6員雜環、NHR
11、NR
12R
13及OR
14,其中該烷基、該環烷基或該雜環視情況經OH、NH
2、1-4個鹵素或R
15取代;
各R
7獨立地選自C
1 - 3烷基、鹵素及OH,其中該烷基視情況經1-3個鹵素取代,或
連接至同一碳之兩個R
7形成側氧基,或
連接至同一碳原子之兩個R
7與其所連接之碳原子一起形成C
3 - 5環烷基;
R
8為H或C
1 - 3烷基;
各R
9獨立地選自C
1 - 3烷基、經鹵素取代之C
3 - 6環烷基、鹵素、C(O)Me、SO
2Me、C(O)NR
16R
17、C
1 - 3烷氧基及OH;
各R
10獨立地選自C
1 - 3烷基、經鹵素取代之C
3 - 6環烷基、鹵素、SO
2Me、C(O)NR
16R
17、C
1 - 3烷氧基及OH;
R
11係選自C
1 - 6烷基及C
3 - 6環烷基,其中該烷基或該環烷基視情況經1-3個R
18取代;
R
12及R
13各自獨立地選自C
1 - 6烷基及C
3 - 6環烷基,其中該烷基或該環烷基視情況經1-3個R
18取代;
R
14係選自C
1 - 6烷基及C
3 - 6環烷基,其中該烷基或該環烷基視情況經1-3個R
18取代;
R
15為OH、C
1-3烷基或C
3-5環烷基;
R
16及R
17各自獨立地選自C
1 - 6烷基及C
3 - 6環烷基,其中該烷基或該環烷基視情況經1-3個R
19取代;
各R
18獨立地為鹵素;及
各R
19獨立地為鹵素。
本發明之另一實施例為一種醫藥組合物,其包含醫藥學上可接受之載劑或賦形劑及本文所揭示之化合物或其醫藥學上可接受之鹽。
本發明之另一實施例為一種抑制有需要個體之MAP4K1之方法,其包含使MAP4K1與有效量的本文所揭示之化合物或其醫藥學上可接受之鹽或包含本文所揭示之化合物或其醫藥學上可接受之鹽的醫藥組合物接觸。
本發明之另一實施例為用於增強有需要之個體之免疫反應的方法,其包含向該個體投與有效量之本文所揭示之化合物或其醫藥學上可接受之鹽,或包含本文所揭示之化合物或其醫藥學上可接受之鹽的醫藥組合物。
本發明之另一實施例為一種治療有需要之個體之MAP4K1依賴性病症或疾病(例如,治療癌症)的方法,其包含向個體投與有效量的本文所揭示之化合物或其醫藥學上可接受之鹽或包含該(等)化合物之醫藥組合物。
本發明之另一實施例為本文所揭示之化合物或其醫藥學上可接受之鹽或包含該(等)化合物之醫藥組合物的用途,其用於製備供治療有需要之個體之MAP4K1依賴性病症或疾病(例如,治療癌症)用的藥劑。
本發明之另一實施例為本文所揭示之化合物或其醫藥學上可接受之鹽或包含該(等)化合物之醫藥組合物,其用於治療有需要之個體之MAP4K1依賴性病症或疾病(例如,治療癌症)。
相關申請案
本申請案主張2021年7月15日申請之美國臨時申請案第63/222341號之權益,其全部教示內容以引用之方式併入本文中。
所揭示之化合物或其醫藥學上可接受之鹽為MAP4K1抑制劑,其可用於治療MAP4K1依賴性病症或疾病。此類疾病或病症包括癌症及病毒感染。
第五實施例:由式V表示之化合物:
,
或其醫藥學上可接受之鹽,其中Y與B結合在一起形成5至7員雜環或C
5 - 6環烷基,且該雜環或該環烷基視情況經1-6個R
7取代。上文在第一實施例中描述式V中之變數。
第六實施例:由式VI表示之化合物:
,
或其醫藥學上可接受之鹽,其中:各R
7獨立地選自C
1 - 3烷基、鹵素及OH,其中該烷基視情況經1-3個鹵素取代,或連接至同一碳原子之兩個R
7與其所連接之碳原子一起形成C
3 - 5環烷基;n為0、1、2、3、4、5或6;且m為0、1或2。上文在第一實施例中描述式VI中之其餘變數。
第八實施例:由式I、II、III、IV(A)、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,其中X為NHR
4,且R
4為CH
3或環丙基。上文在第一、第五、第六及/或第七實施例中描述式I、II、III、IV(A)、IV(B)、V、VI及VII中之其餘變數。
第九實施例:由式I、II、III、IV(A)、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,其中X為OR
3。上文在第一、第五、第六及/或第七實施例中描述式I、II、III、IV(A)、IV(B)、V、VI及VII中之其餘變數。
第十實施例:由式I、II、III、IV(A)、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,其中:R
1及R
2各自獨立地選自氫、C
1 - 2烷基、C
1 - 2鹵烷基、經OR
8取代之C
1 - 3烷基、苯基及C
3 - 4環烷基,或R
1及R
2與其所連接之原子一起形成4至6員雜環;且R
8為C
1 - 2烷基。上文在第一、第五、第六、第七、第八及/或第九實施例中描述式I、II、III、IV(A)、IV(B)、V、VI及VII中之其餘變數。
第十一實施例:由式I、II、III、IV(A)、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,其中:R
1及R
2各自獨立地選自氫、CH
3、CH
2CH
3、CH
2OCH
3、CHF
2、CF
3、環丁基、環丙基及苯基,或R
1及R
2與其所連接之原子一起形成四氫哌喃。上文在第一、第五、第六、第七、第八及/或第九實施例中描述式I、II、III、IV(A)、IV(B)、V、VI及VII中之其餘變數。
第十二實施例:由式I、II、III、IV(A)、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,R
1及R
2各自獨立地選自氫、CH
3、CH
2CH
3、CH
2OCH
3、CHF
2、CF
3、環丁基、環丙基及苯基,或
R
1及R
2與其所連接之原子一起形成
。上文在第一、第五、第六、第七、第八及/或第九實施例中描述式I、II、III、IV(A)、IV(B)、V、VI及VII中之其餘變數。
第十三實施例:由式I、II、III、IV(A)、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,其中:R
3係選自C
1 - 3烷基、C
3 - 4環烷基及4員雜環;其中該烷基、該環烷基及該雜環視情況經1-3個R
9取代;且各R
9獨立地選自C
1 - 3烷基、鹵素、C(O)Me及SO
2Me。上文在第一、第五、第六、第七、第九、第十、第十一及/或第十二實施例中描述式I、II、III、IV(A)、IV(B)、V、VI及VII中之其餘變數。
第十四實施例:由式I、II、III、IV(A)、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,其中:R
3為含有氮之4員雜環;R
9為C(O)Me;且該4員雜環之環氮結合至⸾-C(O)Me。上文在第一、第五、第六、第七、第九、第十、第十一及/或第十二實施例中描述式I、II、III、IV(A)、IV(B)、V、VI及VII中之其餘變數。
第十五實施例:由式I、II、III、IV(A)、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,其中:R
3係選自CH
3、CH
2CH
3、CH
2CH
2CH
3、環丙基、環丁基、氮雜環丁烷基,其各自視情況經1-3個R
9取代;且各R
9獨立地選自CH
3、F、C(O)Me及SO
2Me。上文在第一、第五、第六、第七、第九、第十、第十一及/或第十二實施例中描述式I、II、III、IV(A)、IV(B)、V、VI及VII中之其餘變數。
第十六實施例:由式I、II、III、IV(A)、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,其中R
3係選自CH
3、CH
2CH
3、CH
2CHF
2、CH
2CF
3、CH
2CH
2CH
3、環丙基、
。上文在第一、第五、第六、第七、第九、第十、第十一及/或第十二實施例中描述式I、II、III、IV(A)、IV(B)、V、VI及VII中之其餘變數。
第十七實施例:由式I、II、III或IV(B)表示之化合物或其醫藥學上可接受之鹽,其中R
5為CN。上文在第一、第八、第九、第十、第十一、第十二、第十三、第十四、第十五及/或第十六實施例中描述式I、II、III及IV(B)中之其餘變數。
第十八實施例:由式I、II、III、IV(A)或IV(B)表示之化合物或其醫藥學上可接受之鹽,其中:R
6係選自C
1 - 4烷基及4至5員雜環,其中該烷基或該雜環視情況經1-4個鹵素或R
15取代;且R
15為C
1 - 2烷基。上文在第一、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六及/或第十七實施例中描述式I、II、III、IV(A)及IV(B)中之其餘變數。
第十九實施例:由式I、II、III、IV(A)或IV(B)表示之化合物或其醫藥學上可接受之鹽,其中R
6係選自CH(CH
3)
2、CF(CH
3)
2、C(CH
3)
3、
。上文在第一、第八、第九、第十、第十一、第十二、第十三、第十四、第十五、第十六及/或第十七實施例中描述式I、II、III、IV(A)及IV(B)中之其餘變數。
第二十實施例:由式I、II、III、IV(B)、V、VI或VII表示之化合物或其醫藥學上可接受之鹽,其中:各R
7獨立地為CH
3,或連接至同一個碳之兩個R
7形成側氧基,或連接至同一個碳原子之兩個R
7與其所連接之碳原子一起形成環丙基。上文在第一、第五、第六、第七、第八、第九、第十、第十一、第十二、第十三、第十四、第十五及/或第十六實施例中描述式I、II、III、IV(B)、V、VI及VII中之其餘變數。
第二十一實施例:由式I、II、III、IV(B)或V表示之化合物或其醫藥學上可接受之鹽,其中Y與B結合在一起形成:
,
其中⸾―表示連至A
2之鍵,且―⁎表示連至N之鍵。上文在第一、第八、第九、第十、第十一、第十二、第十三、第十四、第十五及/或第十六實施例中描述式I、II、III、IV(B)、V、VI及VII中之其餘變數。
在一個實施例中,本發明不包括表4中之化合物71-74及其醫藥學上可接受之鹽。
本發明亦包括表1中所描繪且在範例中以其中性形式及醫藥學上可接受之鹽形式製備的化合物。用於製備表1中之化合物的合成方案列於表1之最後一行中且各合成方案之完整細節描述於通用合成方法及中間物章節之流程1中。
表 1
化合物編號 | 結構 | LCMS (M+1) | NMR | 合成方案 及中間物 |
1 | 358 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.36 (d, J=0.8 Hz, 1H), 8.83 (s, 1H), 8.42 (d, J=6.0 Hz, 1H), 8.20 (s, 1H), 7.23 (d, J=6.0 Hz, 1H), 5.40 (q, J=6.4 Hz, 1H), 4.15 (s, 3H), 1.88 (s, 3H), 1.82 (s, 3H), 1.64 (d, J=6.4 Hz, 3H)。 | 流程1, 中間物14及中間物20, 藉由手性SFC之第1溶離異構體 管柱: Daicel Chiralcel OJ-H (250 mm×30 mm,5 μm); 移動相: [0.1% NH3H 2O MEOH];B%:20%-20%) | |
2 | 358 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.34 (d, J=0.8 Hz, 1H), 8.82 (s, 1H), 8.41 (d, J=6.0 Hz, 1H), 8.19 (s, 1H), 7.22 (d, J=6.0 Hz, 1H), 5.39 (q, J=6.4 Hz, 1H), 4.14 (s, 3H), 1.88 (s, 3H), 1.82 (s, 3H), 1.64 (d, J=6.4 Hz, 3H)。 | 流程1, 中間物14及中間物20, 藉由手性SFC之第2溶離異構體 管柱: Daicel Chiralcel OJ-H (250 mm×30 mm,5 μm); 移動相: [0.1% NH3H 2O MEOH];B%:20%-20%) | |
3 | 367 | 1H NMR (400 MHz, CD3OD):δ ppm 9.21 (s, 1H), 8.58 (s, 1H), 8.31 (d, J = 6.0 Hz, 1H), 8.00 (s, 1H), 7.47 (d, J = 6.0 Hz, 1H), 3.05 (s, 3H), 1.75 (s, 6H), 1.43 (s, 9H)。 | 流程1, 中間物21及2-(三級丁基)嘧啶-4-胺 | |
4 | 368 | 1H NMR (400 MHz, CD3OD):δ ppm 9.36 (s, 1H), 8.76 (s, 1H), 8.31 (d, J = 6.0 Hz, 1H), 8.14 (s, 1H), 7.40 (d, J = 6.0 Hz, 1H), 4.12 (s, 3H), 1.79 (s, 6H), 1.45 (s, 9H)。 | 流程1, 中間物22及2-(三級丁基)嘧啶-4-胺 | |
5 | 371 | 1H-NMR (400MHz, MeOD) δppm 9.41 (s, 1H), 9.02 (s, 1H), 8.34 (d, 1H, J= 6.0 Hz), 7.76 (d, 1H, J= 8.0 Hz), 7.33 (d, 1H, J= 6.0 Hz), 6.84 (d, 1H, J= 8.4 Hz), 4.05 (s, 3H), 1.84 (t, 12H, J= 9.2 Hz)。 | 流程1, 中間物14及中間物29, 反應條件: XPhosPre-catG2 Cs 2CO 3二㗁烷,120℃,12 h | |
6 | 372 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.35 (s, 1H), 9.05 (s, 1H), 8.37 (d, J= 6.0 Hz, 1H), 8.16 (s, 1H), 7.33 (d, J= 6.0 Hz, 1H), 4.12 (s, 3H), 1.84 (s, 3H), 1.79 (s, 9H)。 | 流程1, 中間物14及中間物22 | |
7 | 379 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.38 (s, 1H), 9.07 (s, 1H), 8.65 (s, 1H), 8.17 (s, 1H), 4.13 (s, 3H), 3.50-3.41 (m, 1H), 1.80 (s, 6H), 1.45 (d, J= 6.8 Hz, 6H)。 | 流程1, 中間物15及中間物22 | |
8 | 381 | 流程1, 中間物6及中間物22 | ||
9 | 381 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.32 (s, 1H), 8.83 (s, 1H), 8.12 (s, 1H), 7.96 (d, J= 5.6 Hz, 1H), 6.66 (d, J= 6.0 Hz, 1H), 4.60-4.52 (m, 1H), 4.24-4.16 (m, 1H), 4.12 (s, 3H), 4.10-4.02 (m, 1H), 2.59-2.46 (m, 1H), 2.04-1.90 (m, 1H), 1.76 (d, J= 1.6 Hz, 6H), 1.51 (d, J= 6.4 Hz, 3H)。 | 流程1, 中間物18及中間物22 | |
10 | 395 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.33 (s, 1H), 8.87 (s, 1H), 8.11 (s, 1H), 7.97 (d, J= 6.0 Hz, 1H), 6.59 (d, J= 5.2 Hz, 1H), 4.46-4.36 (m, 1H), 4.12 (s, 3H), 3.82-3.75 (m, 1H), 3.68-3.57 (m, 1H), 2.18-2.07 (m, 2H), 2.05-1.96 (m, 1H), 1.77 (s, 6H), 1.24 (d, J= 6.0 Hz, 3H)。 | 流程1, 中間物17及中間物22 | |
11 | 408 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.37 (s, 1H), 9.17 (s, 1H), 8.37 (d, J= 4.0 Hz, 1H), 8.18 (s, 1H), 7.26 (d, J= 8.0 Hz, 1H), 6.49-6.07 (m, 1H), 4.14 (s, 3H), 1.84 (d, J= 4.0 Hz, 6H), 1.79 (s, 3H)。 | 流程1, 中間物14及中間物23, 來自手性SFC之第1溶離異構體 管柱: Daicel Chiralpak AD (250 mm×30 mm,10 μm); 移動相: [0.1% NH3H 2O IPA];B%:40%-40%) | |
12 | 408 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.37 (s, 1H), 9.17 (s, 1H), 8.37 (d, J= 4.0 Hz, 1H), 8.18 (s, 1H), 7.26 (d, J= 8.0 Hz, 1H), 6.42-6.11 (m, 1H), 4.14 (s, 3H), 1.84 (d, J= 4.0 Hz, 6H), 1.79 (s, 3H)。 | 流程1, 中間物14及中間物23, 來自手性SFC之第2溶離異構體 管柱: Daicel Chiralpak AD (250 mm×30 mm,10 μm); 移動相: [0.1% NH3H 2O IPA];B%: 40%-40%) | |
13 | 420 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.34 (s, 1H), 8.80 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 4.81-4.78 (m, 1H), 4.12 (s, 3H), 4.08-3.99 (m, 1H), 3.85-3.76 (m, 1H), 2.24-2.11 (m, 2H), 2.08-1.99 (m, 1H), 1.82-1.77 (m, 1H), 1.75 (s, 6H), 1.29 (d, J= 6.4 Hz, 3H)。 | 流程1, 中間物16及中間物22 | |
14 | 423 | 1H NMR (400 MHz, 6 d-DMSO):δ ppm 10.72 (s, 1H), 9.30 (s, 1H), 8.93 (s, 1H), 8.07 (d, J= 8.0 Hz, 2H), 7.32 (d, J= 8.8 Hz, 1H), 5.32 (d, J= 4.0 Hz, 1H), 4.95-4.91 (m, 1H), 4.06 (s, 3H), 3.17-3.15 (m, 1H), 1.90-1.70 (m, 2H), 1.44-1.35 (m, 9H), 9.25 (t, J= 7.2 Hz, 3H)。 | 流程1, 中間物3及中間物24, 來自手性SFC之第1溶離異構體 管柱: Daicel Chiralpak AD (250 mm×50 mm,10 μm); 移動相: [0.1% NH3H 2O MEOH];B%:30%-30%) | |
15 | 423 | 1H NMR (400 MHz, 6 d-DMSO):δ ppm 10.72 (s, 1H), 9.30 (s, 1H), 8.93 (s, 1H), 8.07 (d, J= 8.0 Hz, 2H), 7.32 (d, J= 8.8 Hz, 1H), 5.32 (d, J= 4.0 Hz, 1H), 4.95 (m, 1H), 4.06 (s, 3H), 3.13-3.11 (m, 1H), 1.90-1.79 (m, 2H), 1.44-1.35 (m, 9H), 0.92 (t, J= 7.2 Hz, 3H)。 | 流程1, 中間物3及中間物24, 來自手性SFC之第2溶離異構體 管柱: Daicel Chiralpak AD (250 mm×50 mm,10 μm); 移動相: [0.1% NH3H 2O MEOH];B%:30%-30%) | |
16 | 437 | 1H-NMR (400 MHz, CD 3OD):δ ppm 9.23 (d, J= 5.2 Hz, 2H), 8.07 (s, 1H), 8.01 (d, J= 8.8 Hz, 1H), 7.13 (d, J= 8.8 Hz, 1H), 4.03 (s, 3H), 2.96 (d, J= 7.2 Hz, 1H), 2.20-2.04 (m, 2H), 1.69 (s, 3H), 1.42 (s, 3H), 1.35 (s, 3H), 1.30 (d, J= 7.2 Hz, 3H), 0.72 (d, J= 7.6 Hz, 3H) | 流程1, 中間物3及中間物25, 來自手性SFC之第1溶離異構體 管柱: Daicel Chiralpak OD (250 mm×30 mm,10 μm); 移動相: [0.1% NH3H 2O ETOH];B%:35%-35%) | |
17 | 437 | 1H-NMR (400 MHz, CD 3OD):δ ppm 9.28 (s, 1H), 9.21 (s, 1H), 8.06 (s, 1H), 8.01 (d, J= 8.8 Hz, 1H), 7.12 (d, J= 8.8 Hz, 1H), 4.03 (s, 3H), 3.03-2.95 (m, 1H), 2.21-2.04 (m, 2H), 1.68 (s, 3H), 1.42 (s, 3H), 1.36 (s, 3H), 1.29 (d, J= 7.2 Hz, 3H), 0.75-0.68 (m, 3H) | 流程1, 中間物3及中間物25, 來自手性SFC之第2溶離異構體 管柱: Daicel Chiralpak OD (250 mm×30 mm,10 μm); 移動相: [0.1% NH3H 2O ETOH];B%:35%-35%) | |
18 | 439 | 1H NMR (400 MHz, CD3OD):δ ppm 9.32 (s, 1H), 9.00 (s, 1H), 8.16 (s, 1H), 8.12 (d, J= 8.4Hz, 1H), 7.21 (d, J= 8.4Hz, 1H), 5.35-5.30 (m, 1H), 4.13 (s, 3H), 3.78-3.75 (m, 1H), 3.73-3.65 (m, 1H), 3.43 (s, 3H), 3.20-3.15 (m, 1H), 1.55-1.40 (m, 9H)。 | 流程1, 中間物3及中間物26, 來自手性SFC之第1溶離異構體 管柱: Daicel Chiralpak IG (250 mm×50 mm,10 μm); 移動相:[0.1% NH3H 2O MEOH];B%:50%-50%) | |
19 | 439 | 1H NMR (400 MHz, CD3OD):δ ppm 9.32 (s, 1H), 8.94 (s, 1H), 8.16 (s, 1H), 8.12 (d, J= 8.4Hz, 1H), 7.21 (d, J=8.4Hz, 1H), 5.38-5.30 (m, 1H), 4.13 (s, 3H), 3.78-3.75 (m, 1H), 3.70-3.63 (m, 1H), 3.41 (s, 3H), 3.25-3.15 (m, 1H), 1.55-1.40 (m, 9H)。 | 流程1, 中間物3及中間物26, 來自手性SFC之第2溶離異構體 管柱: Daicel Chiralpak IG (250 mm×50 mm,10 μm); 移動相:[0.1%NH3H 2O MEOH];B%:50%-50%) | |
20 | 448 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.22 (s, 1H), 9.05 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 8.05 (s, 1H), 7.33 (d, J= 8.8 Hz, 1H), 4.67-4.57 (m, 1H), 3.06-2.96 (m, 1H), 2.87-2.78 (m, 1H), 2.21-2.13 (m, 2H), 1.75 (s, 3H), 1.50 (d, J= 3.8 Hz, 3H), 1.46 (d, J= 6.4 Hz, 3H), 0.92-0.86 (m, 2H), 0.82 (t, J= 7.4 Hz, 3H), 0.69-0.64 (m, 2H)。 | 流程1, 中間物1及中間物27 | |
21 | 448 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.21 (s, 1H), 9.08 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.31 (d, J= 8.8 Hz, 1H), 4.68-4.56 (m, 1H), 3.09-2.99 (m, 1H), 2.87-2.78 (m, 1H), 2.32-2.09 (m, 2H), 1.75 (s, 3H), 1.48 (t, J= 6.8 Hz, 3H), 0.92-0.85 (m, 2H), 0.81 (t, J= 7.4 Hz, 3H), 0.70-0.63 (m, 2H)。 | 流程1, 中間物1及中間物27 | |
22 | 449 | 1H-NMR (400 MHz, CD 3OD):δ ppm 9.36 (s, 1H), 9.13 (s, 1H), 8.08 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 4.36-4.33 (m, 1H), 3.16-3.15 (m, 2H), 2.22-2.18 (m, 2H), 1.74 (s, 6H), 1.32 (s, 6H), 0.80-0.76 (m, 4H)。 | 流程1, 中間物11及中間物30 | |
23 | 451 | 1H-NMR (400MHz, CD 3OD):9.37 (s, 1H), 9.33 (s, 1H), 8.17 (s, 1H), 8.13 (d, J= 8.8 Hz, 1H), 7.25 (d, J= 8.4 Hz, 1H), 4.63-4.53 (m, 2H), 3.12-3.03 (m, 1H), 2.30-2.14 (m, 2H), 1.80 (s, 3H), 1.58-1.50 (m, 6H), 1.47 (s, 3H), 1.45-1.39 (m, 3H), 0.84 (t, J= 7.2 Hz, 3H)。 | 流程1, 中間物3及中間物31 | |
24 | 451 | 1H-NMR (400MHz, CD 3OD):9.40 (s, 1H), 9.37 (s, 1H), 8.15 (s, 1H), 8.13 (d, J= 8.4 Hz, 1H), 7.24 (d, J= 8.8 Hz, 1H), 4.62-4.55 (m, 2H), 3.17-3.07 (m, 1H), 2.36-2.16 (m, 2H), 1.80 (s, 3H), 1.57-1.51 (m, 6H), 1.48 (s, 3H), 1.41 (d, J= 7.2 Hz, 3H), 0.83 (t, J= 7.2 Hz, 3H)。 | 流程1, 中間物3及中間物32 | |
25 | 461 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.30 (s, 1H), 9.24 (s, 1H), 8.36 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.30 (d, J= 8.8 Hz, 1H), 4.64-4.55 (m, 1H), 4.48-4.42 (m, 1H), 3.11-3.02 (m, 1H), 1.75 (s, 3H), 1.64-1.57 (m, 1H), 1.51-1.45 (m, 6H), 0.93-0.84 (m, 4H), 0.71-0.62 (m, 1H), 0.60-0.48 (m, 3H)。 | 流程1, 中間物1及中間物33, 來自手性SFC之第1溶離異構體 管柱: Daicel Chiralpak OJ-H (250 mm×30 mm,5 μm); 移動相:[0.1% NH3H 2O MEOH];B%:30%-30%) | |
26 | 461 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.27 (s, 1H), 9.26 (s, 1H), 8.34 (s, 1H), 8.14 (d, J= 8.8 Hz, 1H), 7.34 (d, J= 8.4 Hz, 1H), 4.65-4.56 (m, 1H), 4.50-4.42 (m, 1H), 3.08-2.97 (m, 1H), 1.72 (s, 3H), 1.68-1.58 (m, 1H), 1.54-1.45 (m, 6H), 0.94-0.87 (m, 4H), 0.69-0.62 (m, 1H), 0.60-0.49 (m, 3H)。 | 流程1, 中間物1及中間物33, 來自手性SFC之第2溶離異構體 管柱: Daicel Chiralpak OJ-H (250 mm×30 mm,5 μm); 移動相:[0.1% NH3H 2O MEOH];B%:30%-30%) | |
27 | 461 | 1H NMR (400 MHz, CD3OD):δ ppm 9.25 (s, 1 H), 8.72 (s, 1 H), 8.16-8.10 (m, 2 H), 7.39 (d, J= 8.8 Hz, 1 H), 4.64-4.57 (m, 1 H), 4.49-4.42 (m, 1 H), 2.24-2.09 (m, 2 H), 1.82-1.77 (m, 1 H), 1.75 (s, 3 H), 1.58-1.50 (m, 1 H), 1.37 (d, J= 6.4 Hz, 3 H), 1.23-1.14 (m, 2 H), 0.89 (s, 4 H), 0.84-0.79 (m, 3 H)。 | 流程1, 中間物8及中間物35 | |
28 | 462 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.22 (d, J= 2.0 Hz, 2H), 8.11 (d, J= 8.8 Hz, 1H), 8.05 (s, 1H) 7.24 (d, J= 8.4 Hz, 1H), 3.09-3.02 (m, 1H), 2.88-2.80 (m, 1H), 2.24-2.13 (m, 2H), 1.76 (s, 3H), 1.51 (s, 3H), 1.45 (s, 3H), 1.39 (d, J= 7.2 Hz, 3H), 0.94-0.88 (m, 2H), 0.83 (t, J= 7.4 Hz, 3H), 0.71-0.66 (m, 2H)。 | 流程1, 中間物3及中間物27 | |
29 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.29 (s, 1H), 9.22 (s, 1H), 8.10 (d, J= 8.8 Hz, 1H), 8.04 (s, 1H), 7.22 (d, J= 8.4 Hz, 1H), 3.14-3.04 (m, 1H), 2.87-2.77 (m, 1H), 2.32-2.11 (m, 2H), 1.76 (s, 3H), 1.52 (s, 3H), 1.45 (s, 1H), 1.38 (d, J= 7.2 Hz, 3H), 0.95-0.86 (m, 2H), 0.82 (t, J= 7.4 Hz, 3H), 0.71-0.64 (m, 2H)。 | 流程1, 中間物3及中間物28 | ||
30 | 463 | 1H NMR (400 MHz, CDCl 3):δ ppm 9.29 (s, 1H), 9.11 (s, 1H), 8.25-8.19 (m, 2H), 7.96 (s, 1H), 7.17 (d, J= 8.8 Hz, 1H), 4.55-4.49 (m, 1H), 3.04-2.07 (m, 1H), 2.27- 2.11 (m, 2H), 1.90 (s, 1H), 1.80 (s, 3H), 1.49 (d, J= 2.0 Hz, 6H), 1.44 (d, J= 6.8 Hz, 3H), 0.95-0.86 (m, 7H) | 流程1, 中間物3及中間物34 | |
31 | 463 | 1H-NMR (400 MHz, CDCl 3):δ ppm 9.29 (s, 1H), 9.15 (s, 1H), 8.24-8.18 (m, 2H), 7.96 (s, 1H), 7.15 (d, J= 8.8 Hz, 1H), 4.55-4.48 (m, 1H), 3.06-2.97 (m, 1H), 2.23-2.14 (m, 2H), 1.92 (s, 1H), 1.80 (s, 3H), 1.49 (d, J= 3.6 Hz, 6H), 1.43 (d, J= 7.2 Hz, 3H), 0.95-0.90 (m, 4H), 0.87 (t, J= 7.2 Hz, 3H) | 流程1, 中間物3及中間物35 | |
32 | 463 | 1H-NMR (400MHz, CD 3OD):9.45 (s, 1H), 9.36 (s, 1H), 8.35 (s, 1H), 8.13 (d, J= 8.8 Hz, 1H), 7.27 (d, J= 8.8 Hz, 1H), 4.58 (q, J= 7.2 Hz, 2H), 3.21-3.09 (m, 1H), 1.78 (s, 3H), 1.68-1.59 (m, 1H), 1.56-1.51 (m, 6H), 1.49 (s, 3H), 1.39 (d, J= 7.2 Hz, 3H), 0.74-0.65 (m, 1H), 0.64-0.48 (m, 3H) | 流程1, 中間物3及中間物37 | |
33 | 463 | 1H-NMR (400MHz, CD 3OD):9.41 (s, 1H), 9.36 (s, 1H), 8.31 (s, 1H), 8.13 (d, J= 8.4 Hz, 1H), 7.29 (d, J= 8.8 Hz, 1H), 4.58 (q, J= 7.2 Hz, 2H), 3.09 (q, J= 7.2 Hz, 1H), 1.75 (s, 3H), 1.71-1.62 (m, 1H), 1.57-1.51 (m, 6H), 1.47 (s, 3H), 1.42 (d, J= 6.8 Hz, 3H), 0.71-0.44 (m, 4H) | 流程1, 中間物3及中間物36 | |
34 | 463 | 1H NMR (400 MHz, CD3OD):δ ppm 9.26 (s, 1 H), 8.88 (s, 1 H), 8.15-8.10 (m, 2 H), 7.42 (d, J= 8.8 Hz, 1 H), 4.60-4.52 (m, 1 H), 4.51-4.38 (m, 1 H), 2.31-2.09 (m, 2 H), 1.75 (s, 3 H), 1.53 (s, 3 H), 1.45 (d, J= 6.4 Hz, 3 H), 1.31 (s, 3 H), 0.94-0.86 (m, 4 H), 0.84-0.78 (m, 3 H)。 | 流程1, 中間物12及中間物35 | |
35 | 465 | 1H NMR (400 MHz, CDCl3):δ ppm 9.29 (s, 1H), 9.03 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.15 (s, 1H), 7.81 (s, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.57-4.43 (m, 2H), 4.06 (d, J=9.2 Hz, 1H), 3.62 (d, J=9.2 Hz, 1H), 3.48 (s, 3H), 3.06 - 2.96 (m, 2H), 1.74 (s, 3H), 1.55-1.50 (m, 6H), 0.94-0.86 (m, 4H)。 | 流程1, 中間物1及中間物39 | |
36 | 465 | 1H NMR (400 MHz, CDCl3):δ ppm 9.29 (s, 1H), 8.96 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.25 (d, J=8.8 Hz, 1H), 4.57-4.43 (m, 2H), 4.04 (d, J=9.2 Hz, 1H), 3.62 (d, J=9.2 Hz, 1H), 3.48 (s, 3H), 3.06-2.96 (m, 2H), 1.74 (s, 3H), 1.55-1.50 (m, 6H), 0.94-0.86 (m, 4H)。 | 流程1, 中間物1及中間物38 | |
37 | 467 | 1H-NMR (400 MHz, MeOD):δ ppm 9.40 (s, 1H), 9.26 (s, 1H), 8.15-8.13 (m, 2H), 7.31 (d, J= 8.8 Hz, 1H), 4.84 (s, 2H), 4.63-4.60 (m, 1H), 3.09-3.02 (m, 1H), 1.81 (d, J= 3.6 Hz, 6H), 1.53-1.47 (m, 6H), 1.23-1.16 (m, 2H), 0.96 (d, J= 7.2 Hz, 2H) | 流程1, 中間物1及中間物40 | |
38 | 475 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.46 (s, 1H), 9.24 (s, 1H), 8.37 (s, 1H), 8.11 (d, J= 8.8 Hz, 1H), 7.24 (d, J= 8.8 Hz, 1H), 4.49-4.42 (m, 1H), 3.18-3.07 (m, 1H), 1.77 (s, 3H), 1.67-1.58 (m, 1H), 1.51 (s, 3H), 1.46 (s, 3H), 1.37 (d, J= 7.2 Hz, 3H), 0.93-0.85 (m, 4H), 0.72-0.64 (m, 1H), 0.62-0.47 (m, 3H)。 | 流程1, 中間物3及中間物33, 來自手性SFC之第1溶離異構體 管柱: Daicel Chiralpak IC (250 mm×30 mm,10 μm); 移動相:[0.1% NH3H 2O MEOH];B%:60%-60%) | |
39 | 475 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.42 (s, 1H), 9.25 (s, 1H), 8.33 (s, 1H), 8.11 (d, J= 8.8 Hz, 1H), 7.26 (d, J= 8.4 Hz, 1H), 4.49-4.42 (m, 1H), 3.12-3.01 (m, 1H), 1.74 (s, 3H), 1.70-1.62 (m, 1H), 1.50 (s, 3H), 1.45 (s, 3H), 1.41 (d, J= 7.2 Hz, 3H), 0.93-0.85 (m, 4H), 0.68-0.62 (m, 1H), 0.61-0.46 (m, 3H)。 | 流程1, 中間物3及中間物33, 來自手性SFC之第2溶離異構體 管柱: Daicel Chiralpak IC (250 mm×30 mm,10 μm); 移動相:[0.1% NH3H 2O MEOH];B%:60%-60%) | |
40 | 475 | 1H NMR (400 MHz, CD 3Cl):δ ppm 9.30 (s, 1H), 8.71 (s, 1H), 8.24 (d, J= 8.8 Hz, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.21 (d, J= 8.4 Hz, 1H), 4.55-4.50 (m, 1H), 2.18-2.14 (m, 2H), 1.93 (s, 1H), 1.79 (s, 3H), 1.67-1.63 (m, 2H), 1.43 (s, 6H), 1.19-1.18 (m, 2H), 0.94-0.88 (m, 7H)。 | 流程1, 中間物10及中間物35 | |
41 | 475 | 1H NMR (400 MHz, CD 3Cl):δ ppm 9.22 (s, 1H), 8.61 (s, 1H), 8.16 (d, J= 8.4 Hz, 1H), 8.06 (s, 1H), 7.66 (s, 1H), 7.12 (d, J= 8.8 Hz, 1H), 4.45-4.42 (m, 1H), 2.09-2.06 (m, 2H), 1.76 (s, 1H), 1.70 (s, 3H), 1.60-1.52 (m, 2H), 1.34 (s, 6H), 1.09 (s, 2H), 0.85-0.79 (m, 7H)。 | 流程1, 中間物10及中間物34 | |
42 | 477 | 流程1, 中間物5及中間物60 | ||
43 | 489 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.41 (s, 1H), 9.23 (s, 1H), 8.20 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.22 (d, J= 8.8 Hz, 1H), 4.48-4.41 (m, 1H), 3.40-3.34 (m, 1H), 3.16-3.06 (m, 1H), 2.37-2.24 (m, 1H), 2.12-2.02 (m, 1H), 2.01-1.91 (m, 1H), 1.88-1.79 (m, 1H), 1.70 (s, 3H), 1.68-1.61 (m, 1H), 1.52 (s, 3H), 1.46 (s, 3H), 1.43 (d, J= 7.2 Hz, 3H), 0.92-0.86 (m, 4H)。 | 流程1, 中間物3及中間物41 | |
44 | 489 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.45 (s, 1H), 9.23 (s, 1H), 8.21 (s, 1H), 8.12 (d, J= 8.8 Hz, 1H), 7.23 (d, J= 8.4 Hz, 1H), 4.48-4.42 (m, 1H), 3.42-3.36 (m, 1H), 3.12-3.05 (m, 1H), 2.34-2.22 (m, 1H), 2.13-2.02 (m, 1H),1.97-1.90 (m, 1H), 1.85-1.77 (m, 1H), 1.70 (s, 3H), 1.67-1.61 (m, 1H), 1.53 (s, 3H), 1.47 (s, 3H), 1.42 (d, J= 7.2 Hz, 3H), 0.93-0.86 (m, 4H)。 | 流程1, 中間物 3及中間物42 | |
45 | 492 | 1H NMR (400 MHz, CD 3OD) δ ppm 9.42 (d, J= 3.2 Hz, 1H), 9.29 (d, J= 3.2 Hz, 1H), 8.16 (s, 1H), 8.14 (d, J= 8.8 Hz, 1H), 7.33 (d, J= 8.8 Hz, 1H), 5.63 (s, 1H), 4.77-4.69 (m, 1H), 4.62 (t, J= 6.8 Hz, 1H), 4.53-4.45 (m, 1H), 4.42-4.33 (m, 1H), 4.19-4.09 (m, 1H), 3.07 (t, J= 6.4 Hz, 1H), 1.96 (s, 3H), 1.83 (d, J= 3.6 Hz, 6H), 1.54 (d, J= 7.2 Hz, 3H), 1.50 (d, J= 6.4 Hz, 3H)。 | 流程1, 中間物1及中間物43 | |
46 | 流程1, 中間物5及中間物59 | |||
47 | 499 | 流程1, 中間物3及中間物44 | ||
48 | 499 | 流程1, 中間物3及中間物44, 藉由手性SFC之第1溶離異構體 管柱: ChiralPak IC-H 21 x 250 mm; 移動相: 30%甲醇 + 0.25%含二乙胺之CO 2) | ||
49 | 499 | 流程1, 中間物3及中間物44, 藉由手性SFC之第2溶離異構體 管柱: ChiralPak IC-H 21 x 250 mm; 移動相: 30%甲醇 + 0.25%含二乙胺之CO 2 | ||
50 | 503 | 1H-NMR (400 MHz, CDCl 3):δ ppm 9.29 (s, 1H), 9.18 (s, 1H), 8.29 (s, 1H), 8.21 (d, J= 8.4 Hz, 1H), 7.90 (s, 1H), 7.18 (d, J= 8.4 Hz, 1H), 4.58-4.51 (m, 1H), 3.05-2.97 (m, 1H), 2.83-2.65 (m, 1H), 2.05 (s, 3H), 1.48 (d, J= 3.6 Hz, 6H), 1.43 (d, J= 7.2 Hz, 3H), 0.97-0.91 (m, 4H) | 流程1, 中間物3及中間物45 | |
51 | 503 | 1H-NMR (400 MHz, CDCl 3):δ ppm 9.30 (s, 1H), 9.13 (s, 1H), 8.29 (s, 1H), 8.22 (d, J= 8.8 Hz, 1H), 7.82 (s, 1H), 7.20 (d, J= 8.8 Hz, 1H), 4.58-4.52 (m, 1H), 3.05-2.97 (m, 1H), 2.68-2.62 (m, 1H), 2.04 (s, 3H), 1.48 (s, 6H), 1.42 (d, J= 7.2 Hz, 3H), 0.96-0.90 (m, 4H) | 流程1, 中間物3及中間物46 | |
52 | 505 | 1H-NMR (400 MHz, CD 3OD):9.42 (s, 1 H), 9.36 (s, 1 H), 8.22 (s, 1 H), 8.15 (d, J= 8.8 Hz, 1 H), 7.25 (d, J= 8.8 Hz, 1 H), 5.11 (q, J= 24 Hz, 2 H), 3.09 (d, J= 7.2 Hz, 1 H), 2.27-2.19 (m, 2 H), 1.82 (s, 3 H), 1.54 (s, 3 H), 1.48 (s, 3 H), 1.40 (d, J= 7.2 Hz, 1 H), 0.85 (d, t= 14.8 Hz, 1 H)。 | 流程1, 中間物3及中間物47 | |
53 | 505 | 1H-NMR (400 MHz, CD 3OD):9.49 (s, 1 H), 9.36 (s, 1 H), 8.21 (s, 1 H), 8.14 (d, J= 8.8 Hz, 1 H), 7.24 (d, J= 8.8 Hz, 1 H), 5.11 (q, J= 24 Hz, 2 H), 3.12 (d, J= 7.2 Hz, 1 H), 2.30-2.20 (m, 2 H), 1.81 (s, 3 H), 1.55 (s, 3 H), 1.48 (s, 3 H), 1.41 (d, J= 7.2 Hz, 1 H), 0.84 (d, t= 14.8 Hz, 1 H)。 | 流程1, 中間物3及中間物48 | |
54 | 517 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.43 (s, 1 H), 9.31 (s, 1 H), 8.39 (s, 1 H), 8.22 (d, J= 8.8 Hz, 1 H), 7.27 (d, J= 8.8 Hz, 1 H), 5.15-5.09 (m, 2 H), 3.23-3.18 (m, 1 H), 1.72 (s, 3 H), 1.65-1.58 (m, 1 H), 1.51 (s, 3 H), 1.48 (s, 3 H), 1.45 (d, J= 7.2 Hz, 3 H), 0.65-0.51 (m, 4 H)。 | 流程1, 中間物3及中間物49 | |
55 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.53-9.49 (m, 1 H), 9.34 (s, 1 H), 8.38-8.33 (m, 1 H), 8.21 (d, J= 8.4 Hz, 1 H), 7.28-7.24 (m, 1 H), 5.13-5.06 (m, 2 H), 3.18-3.04 (m, 1 H), 1.76 (d, J= 11.2 Hz, 3 H), 1.68-1.57 (m, 1 H), 1.51 (s, 3 H), 1.46 (d, J= 7.2 Hz, 3 H), 1.42-1.35 (m, 3 H), 0.70-0.48 (m, 4 H)。 | 流程1, 中間物3及中間物50 | ||
56 | 527 | 1H NMR (400 MHz, 6 d-DMSO):δ ppm 10.68 (s, 1H), 9.32 (s, 1H), 9.29 (s, 1H), 8.09-8.07 (m, 2H), 7.36 (d, J= 8.8 Hz, 1H), 5.40-5.32 (m, 1H), 5.22 (s, 1H), 4.61-4.54 (m, 1H), 3.88-3.79 (m, 1H), 3.01-2.96 (m, 1H), 2.94 (s, 3H), 2.89-2.82 (m, 2H), 2.07 (s, 1H), 1.69 (s, 6H), 1.45 (d, J= 7.2 Hz, 3H), 1.38 (d, J= 6.8 Hz, 3H)。 | 流程1, 中間物1及中間物51 | |
57 | 528 | 1H NMR (400 MHz, CD 3OD)δ ppm 9.40 (s, 1H), 9.27 (s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 7.32 (d, J= 8.8 Hz, 1H), 5.60 (s, 1H), 4.70-4.56 (m, 1H), 4.44 (t, J= 7.8 Hz, 2H), 4.28-4.11 (m, 2H), 3.33 (s, 6H), 3.05 (s, 4H), 1.82 (s, 6H), 1.57-1.45 (m, 6H)。 | 流程1, 中間物1及中間物54 | |
58 | 528 | 1H NMR (400 MHz, CD 3OD):δ ppm 10.76 (s, 1H), 9.41 (s, 1H), 8.88 (s, 1H), 8.10 (d, J= 8.8 Hz, 1H), 8.05 (s, 1H), 7.33 (d, J= 8.4 Hz, 1H), 5.62-5.52 (m, 1H), 5.40-5.30 (m, 1H), 5.00-4.90 (m, 1H), 4.60-4.50 (m, 2H), 4.45-4.32 (m, 2H), 4.30-4.20 (m, 2H), 3.15 (s, 3H), 3.15-3.05 (m, 1H), 1.90-1.80 (m, 9H), 1.49 (d, J= 7.2 Hz, 3H), 1.44 (d, J= 6.4 Hz, 3H), 0.95-0.85 (m, 3H) | 流程1, 中間物1及中間物55 | |
59 | 528 | 1H NMR (400 MHz, CD 3OD):δ ppm 10.77 (s, 1H), 9.42 (s, 1H), 8.85 (s, 1H), 8.11 (d, J= 8.8 Hz, 1H), 8.07 (s, 1H), 7.33 (d, J= 8.4 Hz, 1H), 5.62-5.52 (m, 1H), 5.40-5.30 (m, 1H), 5.00-4.90 (m, 1H), 4.60-4.50 (m, 2H), 4.45-4.32 (m, 2H), 4.30-4.20 (m, 2H), 3.15 (s, 3H), 3.15-3.05 (m, 1H), 1.90-1.80 (m, 9H), 1.49 (d, J= 7.2 Hz, 3H), 1.44 (d, J= 6.4 Hz, 3H), 0.95-0.85 (m, 3H)。 | 流程1, 中間物1及中間物56 | |
60 | 541 | 1H NMR (400 MHz, 6 d-DMSO):δ ppm 10.72 (s, 1H), 9.38 (s, 1H), 9.32 (s, 1H), 8.11 (s, 1H), 8.06 (d, J= 8.8 Hz, 1H), 7.31 (d, J= 8.8 Hz, 1H), 5.40-5.33 (m, 1H), 5.21 (s, 1H), 3.86-3.81 (m, 1H), 3.03-2.98 (m, 1H), 2.94 (s, 3H), 2.89-2.82 (m, 2H), 2.07 (s, 1H), 1.71 (s, 6H), 1.39 (d, J= 13.6 Hz, 6H), 1.33 (d, J= 7.2 Hz, 3H)。 | 流程1, 中間物3及中間物51 | |
61 | 541 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.36 (s, 1H), 9.22 (s, 1H), 8.14 (d, J= 8.4, 1H), 8.13 (s, 1H), 7.30 (d, J= 8.4 Hz, 1H), 5.49 - 5.39 (m, 1H), 4.68 - 4.54 (m, 2H), 3.88 - 3.74 (m, 1H), 3.02 - 2.96 (m, 2H), 2.93 (s, 3H), 2.75 - 2.64 (m, 2H), 2.28 - 2.12 (m, 2H), 1.77 (s, 3H), 1.51 (d, J= 7.2 Hz, 3H), 1.47 (d, J= 6.8 Hz, 3H), 0.80 (t, J= 7.6 Hz, 3H)。 | 流程1, 中間物1及中間物53 | |
62 | 541 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.36 (s, 1H), 9.19 (s, 1H), 8.14 (s, 1H), 8.13 (d, J= 8.8 Hz, 1H), 7.30 (d, J= 8.8 Hz, 1H), 5.48-5.39 (m, 1H), 3.88 - 3.76 (m, 1H), 3.02 - 2.95 (m, 2H), 2.93 (s, 3H), 2.74 - 2.63 (m, 2H), 2.25 - 2.12 (m, 2H), 1.77 (s, 3H), 1.51 (d, J= 7.2 Hz, 3H), 1.47 (d, J= 6.8 Hz, 3H), 0.81 (t, J= 7.2 Hz, 3H)。 | 流程1, 中間物1及中間物52 | |
63 | 542 | 1H NMR (400 MHz, CD 3OD):δ ppm 10.77 (s, 1H), 9.41 (s, 1H), 8.91 (s, 1H), 8.09 (d, J= 8.8 Hz, 1H), 8.06 (s, 1H), 7.32 (d, J= 8.8 Hz, 1H), 5.62-5.55 (m, 1H), 5.50-5.30 (m, 1H), 5.00-4.90 (m, 1H), 4.50-4.40 (m, 2H), 4.20-4.10 (m, 2H), 3.20-3.05 (m, 4H), 1.90-1.80 (m, 2H), 1.60-1.30 (m, 9H), 1.00-0.85 (m, 3H) | 流程1, 中間物3及中間物56 | |
64 | 542 | 1H NMR (400 MHz, CD 3OD):δ ppm 10.78 (s, 1H), 9.42 (s, 1H), 8.96 (s, 1H), 8.09 (d, J= 8.8 Hz, 1H), 8.04(s, 1H), 7.33 (d, J= 8.8 Hz, 1H), 5.62-5.55 (m, 1H), 5.50-5.30 (m, 1H), 5.00-4.90 (m, 1H), 4.50-4.40 (m, 2H), 4.20-4.10 (m, 2H), 3.20-3.05 (m, 4H), 1.90-1.80 (m, 2H), 1.60-1.30 (m, 9H), 1.00-0.85 (m, 3H) | 流程1, 中間物3及中間物55 | |
65 | 555 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.39 (s, 1H), 9.34 (s, 1H), 8.13 (s, 1H), 8.11 (d, J= 8.4 Hz, 1H), 7.21 (d, J= 8.8 Hz, 1H), 5.48 - 5.38 (m, 1H), 3.88 - 3.77 (m, 1H), 3.12 - 3.04 (m, 1H), 3.02 - 2.95 (m, 2H), 2.93 (s, 3H), 2.74 - 2.64 (m, 2H), 2.32 - 2.12 (m, 2H), 1.77 (s, 3H), 1.52 (s, 3H), 1.45 (s, 3H), 1.38 (d, J= 7.2 Hz, 3H), 0.81 (t, J= 7.6 Hz, 3H)。 | 流程1, 中間物1及中間物53 | |
66 | 555 | 1H NMR (400 MHz, CD 3OD):δ ppm 9.35 (s, 1H), 9.33 (s, 1H), 8.15 (s, 1H), 8.11 (d, J= 8.8 Hz, 1H), 7.22 (d, J= 8.8 Hz, 1H), 5.49 - 5.38 (m, 1H), 3.88 - 3.77 (m, 1H), 3.08 - 3.04 (m, 1H), 3.01 - 2.95 (m, 2H), 2.93 (s, 3H), 2.74 - 2.62 (m, 2H), 2.20 (m, 2H), 1.78 (s, 3H), 1.52 (s, 3H), 1.45 (s, 3H), 1.40 (d, J= 7.2 Hz, 3H), 0.82 (t, J= 7.6 Hz, 3H)。 | 流程1, 中間物1及中間物52 | |
67 | 557 | 1H NMR (400 MHz, CD3OD):δ ppm 9.35 (s, 1 H), 9.17 (s, 1 H), 8.24-8.05 (m, 2 H), 7.30 (d, J= 8.4 Hz, 1 H), 5.76-5.60 (m, 1 H), 4.72-4.49 (m, 1 H), 3.42-3.34 (m, 1 H), 3.07-2.98 (m, 1 H), 2.94 (s, 3 H), 2.48-2.36 (m, 1 H), 2.26-2.07 (m, 3 H), 1.77 (s, 3 H), 1.53-1.45 (m, 12 H), 0.87-0.75 (m, 3 H)。 | 流程1, 中間物1及中間物57 | |
68 | 557 | 1H NMR (400 MHz, CD3OD):δ ppm 9.35 (s, 1 H), 9.21 (s, 1 H), 8.25-8.05 (m, 2 H), 7.29 (d, J= 8.8 Hz, 1 H), 5.80-5.59 (m, 1 H), 4.66-4.58 (m, 1 H), 3.43-3.34 (m, 1 H), 3.10-3.00 (m, 1 H), 2.94 (s, 3 H), 2.46-2.37 (m, 1 H), 2.29-2.07 (m, 3 H), 1.76 (s, 3 H), 1.52-1.45 (m, 12 H), 0.85-0.74 (m, 3 H)。 | 流程1, 中間物1及中間物58 | |
69 | 571 | 1H NMR (400 MHz, CD3OD):δ ppm 9.34 (d, J= 6.4 Hz, 2 H), 8.17 (s, 1 H), 8.11 (d, J= 8.8 Hz, 1 H), 7.22 (d, J= 8.8 Hz, 1 H), 5.77-5.54 (m, 1 H), 3.42-3.34 (m, 1 H), 3.10-3.02 (m, 1 H), 2.93 (s, 3 H), 2.47-2.37 (m, 1 H), 2.29-2.08 (m, 3 H), 1.78 (s, 3 H), 1.53-1.48 (m, 9 H), 1.45 (s, 3 H), 1.40 (d, J= 7.2 Hz, 3 H), 0.87-0.78 (m, 3 H)。 | 流程1, 中間物3及中間物57 | |
70 | 571 | 1H NMR (400 MHz, CD3OD):δ ppm 9.41 (s, 1 H), 9.34 (s, 1 H), 8.15 (s, 1 H), 8.11 (d, J= 8.8 Hz, 1 H), 7.21 (d, J= 8.8 Hz, 1 H), 5.84-5.59 (m, 1 H), 3.44-3.34 (m, 1 H),3.13-3.04 (m, 1 H), 2.94 (s, 3 H), 2.46-2.38 (m, 1 H), 2.34-2.03 (m, 3 H), 1.78 (s, 3 H), 1.53-1.48 (m, 9 H), 1.46 (s, 3 H),1.38 (d, J= 7.2 Hz, 3 H), 0.85-0.77 (m, 3 H)。 | 流程1, 中間物3及中間物58 |
本發明教示內容包括本文所揭示之化合物(包括表1中所揭示之化合物1-70及範例)的醫藥學上可接受之鹽以及對應的電荷中性形式,例如游離鹼。
本發明之另一實施例為一種本文所揭示之化合物,其包括式I、II、III、IV(A)、IV(B)、V、VI或VII之化合物,或表1中或範例中之化合物,或前述任一者之醫藥學上可接受之鹽,其中一或多個氫原子經氘置換。氫已由氘置換之位點中之任一者處的氘富集為至少50%、75%、85%、90%、95%、98%或99%。氘富集為莫耳百分比且藉由將富集位點處具有氘富集之化合物的數目除以富集位點處具有氫或氘之化合物的數目獲得。
定義如本文所用,術語「醫藥學上可接受之鹽」係指合理醫學判斷範疇內適用於與人類及低等動物之組織接觸使用而無異常毒性、刺激及過敏反應且與合理益處/風險比相稱的醫藥鹽。醫藥學上可接受之鹽在此項技術中為吾人所熟知。舉例而言,S. M. Berge等人在
J. Pharm. Sci.(1977) 66:1-19中描述了藥理學上可接受之鹽。具有鹼基的本發明教示之化合物可與醫藥學上可接受之酸一起形成醫藥學上可接受之鹽。本文中描述之化合物的適合醫藥學上可接受之酸加成鹽包括無機酸(諸如鹽酸、氫溴酸、磷酸、硝酸及硫酸)之鹽及有機酸(諸如乙酸、苯磺酸、苯甲酸、甲磺酸及對甲苯磺酸)之鹽。具有酸基的本發明教示之化合物可與醫藥學上可接受之鹼一起形成醫藥學上可接受之鹽。適合的醫藥學上可接受之鹼性鹽包括銨鹽、鹼金屬鹽(諸如鈉鹽及鉀鹽)及鹼土金屬鹽(諸如鎂鹽及鈣鹽)。
單獨或作為較大部分之一部分使用的術語「烷基」,諸如「烷氧基」、「羥基烷基」及其類似物意謂飽和脂族直鏈或分支鏈單價烴基。除非另外規定,否則烷基通常具有1至6個碳原子(C
1-6烷基),(亦即,1、2、3、4、5或6個),替代地,1至3個碳原子(C
1-3烷基) (亦即,1、2或3個)。「C
1-6烷基」意謂具有呈直鏈或分支鏈排列之1至6個碳原子的基團,諸如甲基、乙基、丙基、異丙基、丁基、異丁基、三級丁基及其類似基團。
除非另外規定,否則術語「伸烷基」意謂二價烷基,例如C
1-C
6烷基係其中n為1至6的基團‒(CH
2)n‒,C
1-C
3烷基係其中n為1至3的基團‒(CH
2)n‒。
「環烷基」意謂飽和脂族環烴環基。除非另外規定,否則環烷基具有3至8個環碳原子(C
3-8環烷基) (亦即3、4、5、6、7或8個),替代地,3至6個環碳原子(C
3-6環烷基) (亦即3、4、5或6個),替代地,3至5個碳原子(C
3-5環烷基) (亦即3、4或5個)。「C
3-6環烷基」意謂具有以單環排列之3至6個碳原子的基團。C
3-6環烷基包括環丙基、環丁基、環戊基及環己基。C
3-5環烷基包括環丙基、環丁基及環戊基。術語「環烷基」亦意謂包括與芳族基稠合之飽和脂族環烴,諸如在式(I)中「Y與B結合在一起形成C
5 - 6環烷基」的情況。
術語「鹵素」或「鹵基」意謂氟或氟基(
F)、氯或氯基(Cl)、溴或溴基(Br)或碘或碘基(
I)。
除非另外規定,否則術語「雜環」係指含有選自碳原子及1或2個雜原子之3至8個環原子(亦即「3員、4員、5員、6員、7員或8員」)的單環非芳環基團。各雜原子係獨立地選自氮、四級氮、氧化氮(例如,NO);氧;及硫,包括亞碸及碸。舉例而言,含有氮之4-6員雜環係指含有2-5個碳原子及1或2個氮原子之單環非芳環基團;含有氧原子之4-6員雜環係指含有2-5個碳原子及1或2個氧之單環非芳環基團。代表性雜環包括氮雜環丁烷基、嗎啉基、硫嗎啉基、吡咯啶酮基、吡咯啶基、哌啶基、哌𠯤基、內醯脲基、戊內醯胺基、環氧乙烷基、氧雜環丁烷基、四氫呋喃基、四氫哌喃基、四氫吡啶基、四氫嘧啶基、四氫噻吩基、四氫硫哌喃基及其類似基團。
術語「羥基(hydroxyl/hydroxy)」係指基團OH。
術語「經取代」無論之前是否有術語「視情況」,均係指既有結構中之氫取代基經非氫取代基置換。因此,舉例而言,經取代之烷基為至少一個非氫取代基代替該烷基上之氫取代基的烷基。舉例說明,單氟烷基為經一個氟取代基取代之烷基,且二氟烷基為經兩個氟取代基取代之烷基。應認知,若取代基上存在超過一個取代,則各非氫取代基可相同或不同(除非另外陳述)。
若將基團描述為「視情況經取代」,則該基團可(1)未經取代或(2)經取代。
若將基團描述為視情況經多至特定數目非氫取代基取代,則彼基團可(1)未經取代;或(2)經多至特定數目非氫取代基或多至取代基上可取代位置之最大數目(以較少者為準)取代。因此,舉例而言,若將基團描述為視情況經多達3個非氫取代基取代之環烷基,則具有小於3個可取代位置的任何環烷基將視情況經僅多達與環烷基所具有可取代位置一樣多的非氫取代基取代。
術語「碸」係指基團-S(O)
2-。
具有一或多個手性中心之化合物可以各種立體異構形式存在,亦即各手性中心可具有
R或
S組態或可為兩者之混合物。立體異構體為僅在其空間排列不同的化合物。立體異構體包括化合物之所有非對映異構及對映異構形式。對映異構體為彼此不重疊鏡像之立體異構體。非對映異構體為具有兩個或更多個手性中心之彼此不同且不為鏡像之立體異構體。
當具有一或多個手性中心之化合物中之一個手性中心的立體化學組態藉由其化學名稱(例如化學名稱中由「
R」或「
S」指示組態)或結構(例如由「楔形」鍵指示組態)描繪時,所指示組態相對於相反組態之富集大於50%、60%、70%、80%、90%、99%或99.9%(除了當指定「rac」或「外消旋體」隨附該結構或名稱時,如下文兩個段落中所闡述)。「所指示組態相對於相反組態之富集」為莫耳百分比且係藉由將混合物中手性中心具有所指示立體化學組態之化合物的數目除以具有相同或相反立體化學組態之所有化合物的總數目來測定。
當化合物中之手性中心處的立體化學組態藉由其化學名稱(例如,其中名稱中由「
R」或「
S」指示組態)或結構(例如,由「楔形」鍵來指示組態)描繪且名稱「rac」或「外消旋體」隨附結構或以化學名稱表示時,意欲為外消旋混合物。
當兩個或更多個立體異構體藉由其化學名稱或結構描繪且化學名稱或結構藉由「或」連接時,意欲存在兩個或更多個立體異構體中之一者或另一者,但並非兩者。一種立體異構體相對於另一者之富集係如上文所指示。
當具有手性中心之所揭示化合物由在該手性中心處未展現出組態之結構描繪時,該結構意欲涵蓋在該手性中心處具有
S組態之化合物、在該手性中心處具有
R組態之化合物或在該手性中心處具有
R及
S組態之混合物的化合物。當具有手性中心之所揭示化合物由在該手性中心處未展現出組態「
S」或「
R」之化學名稱描繪時,該名稱意欲涵蓋在該手性中心處具有
S組態之化合物、在該手性中心處具有
R組態之化合物或在該手性中心處具有
R及
S組態之混合物的化合物。
外消旋混合物意謂50%為一種對映異構體且50%為其對應對映異構體之混合物。本發明教示包涵本文所述之化合物的所有對映異構性純、對映異構性富集、非對映異構性純、非對映異構性富集及外消旋混合物及非對映異構混合物。
藉由熟知方法,諸如手性氣相層析法、手性相高效液相層析法,使化合物結晶成手性鹽複合物,或在手性溶劑中使化合物結晶,對映異構及非對映異構混合物可分解為其組分對映異構體或立體異構體。藉由熟知不對稱合成方法,對映異構體及非對映異構體亦可自非對映異構性或對映異構性純中間物、試劑及催化劑獲得。
實驗章節中之「峰1」或「第一溶離異構體」係指自層析分離/純化獲得的預定反應產物化合物,其相比於來自相同前述反應之第二預定反應產物化合物更早溶離。第二預定產物化合物稱為「峰2」或「第二溶離異構體」。
當藉由指示單一對映異構體之名稱或結構表示化合物時,除非另外指示,否則化合物為至少60%、70%、80%、90%、99%或99.9%光學純(亦稱為「對映異構性純」)。光學純度為所命名或描繪之對映異構體之混合物的重量除以兩種對映異構體之混合物的總重量。
當藉由結構命名或描繪所揭示化合物之立體化學,且經命名或經描繪結構涵蓋超過一個立體異構體(例如,作為非對映異構對)時,應理解,除非另外指示,否則包括所涵蓋立體異構體或所涵蓋立體異構體之任何混合物中之一者。進一步理解經命名或描繪立體異構體之立體異構純度至少60重量%、70重量%、80重量%、90重量%、99重量%或99.9重量%。藉由將該名稱或結構涵蓋之立體異構體之混合物的總重量除以所有立體異構體之混合物的總重量來測定在此狀況下之立體異構純度。
用途實施例本發明之化合物為MAP4K1抑制劑。使用字組「抑制劑」意謂化合物或其醫藥學上可接受之鹽抑制MAP4K1活性。本文之「抑制」意謂與不存在抑制劑之情況下的酶活性相比目標酶之活性降低。在一些替代方案中,術語「抑制」意謂MAP4K1活性降低至少5%、至少10%、至少20%、至少50%、至少60%、至少79%、至少80%、至少90%或至少95%。在其他替代方案中,抑制意謂MAP4K1活性降低5%至25%、25%至50%、50%至70%、75%至100%。在一些實施例中,抑制意謂MAP4K1活性降低約95%至100%,例如活性降低95%、96%、97%、98%、99%或100%。此類降低可使用熟習此項技術者可識別的多種技術量測,包括活體外激酶分析法。
本發明之化合物為選擇性MAP4K1抑制劑。如本文所用,「選擇性MAP4K1抑制劑」係指相對於其他目標能夠選擇性地抑制MAP4K1激酶的化合物或其醫藥學上可接受之鹽。更特定言之,選擇性MAP4K1抑制劑具有相對於另一激酶選擇性抑制MAP4K1之能力。選擇性MAP4K1抑制劑具有經由與目標直接或間接相互作用相對於偏離目標信號傳導活性選擇性地降低目標信號傳導活性之能力。能夠用化合物或醫藥學上可接受之鹽選擇性地靶向MAP4K1相較於非選擇性化合物或鹽在提高效能、降低脫靶活性及增加臨床成功機率方面提供優勢。
選擇性地抑制MAP4K1之MAP4K1抑制劑可具有相對於另一種激酶至少2倍的活性(例如至少10倍;至少15倍;至少20倍;至少30倍;至少40倍選擇性;至少50倍;至少60倍;至少70倍;至少80倍;至少90倍;至少100倍;至少125倍;至少150倍;至少175倍;或至少200倍。在一些替代方案中,選擇性MAP4K1抑制劑相對於另一種激酶(例如LCK及MAP4K家族成員(MAP4K4 (HGK)及MAP4K3 (GLK))展現出至少15倍選擇性。在一些替代方案中,選擇性MAP4K1抑制劑相對於EGFR及L858R/T790M EGFR具有選擇性。在一些替代方案中,本發明之選擇性MAP4K1抑制劑相對於BTK具有選擇性。在一些替代方案中,本發明之選擇性MAP4K1抑制劑相對於JNK具有選擇性。
本發明提供調節(例如抑制)有需要之個體之MAP4K1活性之方法,該方法包含向該個體投與本文所提供之化合物或其醫藥學上可接受之鹽。在某些實施例中,本發明化合物或其醫藥學上可接受之鹽適用於在有需要之個體中,例如在癌症患者或病毒感染患者中治療性投與以增強、刺激及/或增加免疫性。在一些情況下,本發明化合物或其醫藥學上可接受之鹽減少、抑制或以其他方式削弱pSLP76。
在一些情況下,本發明化合物或其醫藥學上可接受之鹽適用於治療性投與以相對於投與前增強T細胞之活化、激活、遷移、增殖、存活及細胞溶解活性中之至少一者。在某些態樣中,T細胞活化之特徵在於相對於投與化合物或其醫藥學上可接受之鹽之前,T細胞生產之IL-2、IFN-γ或顆粒酶B含量提高。在一些情況下,本發明化合物或其醫藥學上可接受之鹽適用於治療性投與,以誘導細胞週期或細胞存活率之變化。
在一些情況下,本發明化合物或其醫藥學上可接受之鹽適用於改進T效應細胞之功能。在一些情況下,本發明化合物或其醫藥學上可接受之鹽適用於抑制T調節細胞之遏制作用或改善對包括腺苷及PGE2之免疫抑制因子的T細胞反應。在一些情況下,本發明化合物或其醫藥學上可接受之鹽適用於增加CD8+腫瘤浸潤性淋巴細胞(TILS)之頻率。在一些情況下,本發明化合物或其醫藥學上可接受之鹽適用於提高CD3+/Treg比率。
在一些情況下,本發明化合物或其醫藥學上可接受之鹽適用於增強細胞介素。在一些情況下,本發明化合物或其醫藥學上可接受之鹽適用於增強細胞介素而對IL-6無影響。在一些情況下,本發明化合物或其醫藥學上可接受之鹽間接地抑制癌細胞生長。在一些情況下,本發明化合物或其醫藥學上可接受之鹽適用於激活對腫瘤或病毒之免疫反應(亦即疫苗)以啟動或產生抗病毒/抗腫瘤免疫。在一個實例中,本發明化合物或其醫藥學上可接受之鹽用於增強或增加對疫苗(諸如癌症疫苗或個人化癌症疫苗(PCV))或CAR-T細胞療法之反應。
治療MAP4K1依賴性疾病或病症之方法可包括向有需要之個體投與治療有效量之本文所提供之化合物或其醫藥學上可接受之鹽。舉例而言,MAP4K1依賴性疾病或病症為癌症。術語「癌症」涵蓋所有形式之癌症,包括但不限於所有形式之癌瘤、黑色素瘤、母細胞瘤、肉瘤、淋巴瘤及白血病。在一些實施例中,癌症包括轉移性形式。另外,本發明包括可使用本發明化合物抑制生長之難治性或復發性惡性病。對於本文所述之用途,本發明之化合物中之任一者或其醫藥學上可接受之鹽可單獨或與其他治療劑組合使用。
在一些實施例中,在停止治療之後,治療引起個體之持續反應。「持續反應」係指在停止治療之後,對降低腫瘤生長之持續作用。舉例而言,與投藥階段開始時之尺寸相比,腫瘤尺寸可保持相同或減小。在一些實施例中,持續反應之持續時間長度至少與治療持續時間相同、為治療持續時間之至少1.5倍、2.0倍、2.5倍或3.0倍。
本文所揭示之治療方法可引起部分或完全反應。如本文所用,「完全反應」或「CR」係指所有目標病變消失;「部分反應」或「PR」係指目標病變之最長直徑的總和(SLD)減小至少30%,以基線SLD作為參考;及「穩定疾病」或「SD」係指目標病變既未充分收縮具有PR資格,亦未充分增加到具有PD資格,以治療開始時之最小SLD作為參考。如本文所用,「全部反應率」(overall response rate,ORR)係指完全反應(CR)率與部分反應(PR)率之總和。
本文所揭示之治療方法可引起投與選擇性MAP4K1抑制劑之個體的無進展存活期及總存活期增加。如本文所用,「無進展存活期」(progression free survival,PFS)係指治療期間及治療後之時間長度,其間所治療之疾病(例如,癌症)未惡化。無進展存活期可包括個體經歷完全反應或部分反應之時間量,以及個體經歷穩定疾病之時間量。
如本文所用,「總存活期」(OS)係指可能在特定持續時間之後存活之組中個體的百分比。
在一些實施例中,可用本發明化合物或其醫藥學上可接受之鹽治療之癌症包括大腸癌、胰臟癌、乳癌、前列腺癌、肺癌、卵巢癌、子宮頸癌、腎癌、膀胱癌、胃癌、肝癌、胃癌、頭頸癌、淋巴瘤、白血病、尿道上皮癌、梅克爾細胞癌(merkel cell carcinoma)、胃食道接合部癌、食道鱗狀細胞癌、皮膚鱗狀細胞癌及黑色素瘤。
在一些實施例中,可用本發明化合物或其醫藥學上可接受之鹽治療之癌症包括大腸癌、胰臟癌、乳癌、前列腺癌、肺癌、卵巢癌、子宮頸癌、腎癌、膀胱癌、胃癌、肝癌、頭頸癌、淋巴瘤、白血病及黑色素瘤。
在一些實施例中,可使用本發明化合物或其醫藥學上可接受之鹽治療之癌症包括但不限於實體腫瘤,包括前列腺癌、大腸癌、食道癌、子宮內膜癌、卵巢癌、子宮癌、腎癌、肝癌、胰臟癌、胃癌、乳癌、肺癌、頭頸癌、甲狀腺癌、腦癌及膀胱癌;及血液癌,包括淋巴瘤、白血病(慢性及急性形式),諸如ALL、AML、CLL、CML、DLBCL、套細胞淋巴瘤、非霍奇金氏淋巴瘤(Non-Hodgkin's lymphoma,NHL) (包括復發性或難治性NHL及復發性濾泡)、霍奇金氏淋巴瘤及多發性骨髓瘤;及骨髓增生性疾病。
在一些實施例中,可使用本發明化合物或其醫藥學上可接受之鹽治療的疾病及適應症包括但不限於血液癌、肉瘤、呼吸道癌、胃腸癌、泌尿生殖道癌、肝癌、骨癌、神經系統癌、婦科癌症及皮膚癌。
例示性血液癌包括例如淋巴瘤及白血病,諸如ALL、AML、急性骨髓性白血病(APL)、CLL、CML、DLBCL、套細胞淋巴瘤、非霍奇金淋巴瘤(NHL),包括原發性縱隔B細胞淋巴瘤(PMBCL)、復發性或難治性NHL、復發性濾泡及原發性CNS淋巴瘤、霍奇金氏淋巴瘤、骨髓增生疾病,其包括原發性骨髓纖維化(PMF)、真性紅血球增多症(PV)、原發性血小板增多症(ET)、骨髓發育不良症候群(MDS)、T細胞急性淋巴母細胞淋巴瘤(T-ALL)、多發性骨髓瘤、皮膚T細胞淋巴瘤、瓦爾登斯特倫氏巨球蛋白血症(Waldenstrom's Macroglubulinemia)、毛細胞淋巴瘤、慢性骨髓樣淋巴瘤及勃氏淋巴瘤(Burkitt's lymphoma)。
例示性肉瘤包括例如軟骨肉瘤、尤文氏肉瘤、卡堡氏肉瘤、骨肉瘤、橫紋肌肉瘤、血管肉瘤、纖維肉瘤、脂肪肉瘤、黏液瘤、橫紋肌瘤、橫紋肌肉瘤、纖維瘤、脂肪瘤、錯構瘤、軟組織肉瘤及畸胎瘤。
例示性呼吸道癌包括例如肺癌,諸如非小細胞肺癌(NSCLC)、小細胞肺癌、表皮樣癌、支氣管癌(包括鱗狀細胞、未分化小細胞、未分化大細胞)、腺癌、肺泡(細支氣管)癌瘤、支氣管腺瘤、軟骨瘤狀錯構瘤、間皮瘤及胸膜肺母細胞瘤。
例示性胃腸癌包括例如食道之癌症,包括鱗狀細胞癌、腺癌、平滑肌肉瘤及淋巴瘤;胃之癌症,包括癌瘤、淋巴瘤及平滑肌肉瘤;胰臟之癌症,包括導管腺癌、胰島素瘤、升糖素瘤、胃泌素瘤、類癌及血管活性腸肽瘤;小腸之癌症,包括腺癌、淋巴瘤、類癌、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神經纖維瘤及纖維瘤;大腸之癌症,包括腺癌、管狀腺瘤、絨毛狀腺瘤、錯構瘤及平滑肌瘤;大腸之癌症;及膽囊之癌症,包括腺癌;以及腸型及彌漫型胃腺癌、直腸癌、常見腺瘤性息肉癌瘤及遺傳性非息肉大腸直腸癌。
例示性泌尿生殖道癌症包括例如腎臟之癌症,包括腺癌、威爾姆斯瘤(Wilm's tumor) [腎母細胞瘤]、腎細胞癌、尿道上皮癌、近腎小球細胞腫瘤(腎素瘤)、血管肌瘤、腎嗜酸性腺瘤、貝里尼導管癌(Bellinio duct carcinoma)、腎臟透明細胞肉瘤及中胚層性腎瘤;腎上腺之癌症;腎盂之癌症;膀胱之癌症,包括移行細胞癌、鱗狀細胞癌、腺癌、肉瘤及小細胞癌;尿道之癌症,包括鱗狀細胞癌、移行細胞癌及腺癌;前列腺之癌症,包括腺癌、肉瘤及癌瘤;睪丸之癌症,包括精原細胞瘤、畸胎瘤、胚胎性癌、畸胎癌、絨毛膜癌、肉瘤、間質細胞癌、纖維瘤、纖維腺瘤、腺瘤樣腫瘤及脂肪瘤;陽莖之癌症;及胰臟之癌症。
例示性肝癌包括例如肝癌,包括肝細胞癌、膽管癌、肝母細胞瘤、血管肉瘤、肝細胞腺瘤、膽道癌及血管瘤。
例示性骨癌包括例如成骨肉瘤、纖維肉瘤、惡性纖維組織細胞瘤、軟骨肉瘤、尤文氏肉瘤、惡性淋巴瘤(包括網狀細胞肉瘤、多發性骨髓瘤、惡性巨細胞瘤脊索瘤)、骨軟骨瘤(包括骨軟骨外生骨疣、良性軟骨瘤、軟骨母細胞瘤、軟骨黏液性纖維瘤)、骨樣骨瘤及巨細胞腫瘤
例示性神經系統癌包括例如頭骨之癌症,包括骨瘤、血管瘤、肉芽腫、黃瘤及變形性骨炎;腦膜之癌症,包括脊膜瘤、脊膜肉瘤及神經膠質過多;大腦之癌症,包括星形細胞瘤、髓母細胞瘤、神經膠質瘤、室管膜瘤、胚細胞瘤(松果體瘤)、神經外胚層腫瘤、神經膠母細胞瘤、多形性神經膠母細胞瘤、少突神經膠質瘤、神經鞘瘤、視網膜母細胞瘤、先天性腫瘤、腦幹及下丘腦神經膠質瘤;及脊髓之癌症,包括神經纖維瘤、腦膜瘤、神經膠質瘤及肉瘤;以及神經母細胞瘤及小腦發育不良性節細胞瘤(Lhermitte-Duclos disease)。
例示性婦科癌症包括例如子宮之癌症,包括子宮內膜癌;子宮頸之癌症,包括子宮頸癌、腫瘤前子宮頸發育不良、鱗狀細胞癌、腺癌、腺鱗癌、小細胞癌、神經內分泌腫瘤、玻璃樣細胞癌及乳頭狀腺癌;卵巢之癌症,包括卵巢癌(漿液性囊腺癌、黏液性囊腺癌、未分類癌瘤、子宮內膜腫瘤、高惡性度漿細胞癌)、濾泡膜細胞瘤、支持間質細胞瘤(Sertoli-Leydig cell tumor)、無性細胞瘤、惡性畸胎瘤及卵巢男胚瘤;外陰之癌症(鱗狀細胞癌、上皮內癌瘤、腺癌、纖維肉瘤及黑色素瘤;陰道之癌症,包括透明細胞癌、鱗狀細胞癌及葡萄樣肉瘤(胚胎性橫紋肌肉瘤);陰唇之癌症;及輸卵管之癌症。
例示性皮膚癌包括黑色素瘤、皮脂腺癌瘤、基底細胞癌、鱗狀細胞癌、卡波西氏肉瘤、梅克爾細胞皮膚癌、發育不良痣、脂肪瘤、血管瘤、皮膚纖維瘤及瘢痕瘤。
乳癌之實例包括例如ER+/HER2-乳癌、三陰性乳癌(TNBC)、侵襲性乳腺管癌、侵襲性小葉癌、乳腺管原位癌及小葉原位癌。
例示性頭頸癌包括例如神經膠母細胞瘤、黑色素瘤、橫紋肌肉瘤、淋巴肉瘤、骨肉瘤、鱗狀細胞癌、腺癌、口腔癌、咽喉癌,包括口咽癌、喉癌、鼻咽癌、鼻癌及鼻竇癌、唾液腺癌、口腔癌、眼癌、聽神經瘤、垂體腺瘤、咽喉及甲狀腺癌(髓及乳頭狀)及副甲狀腺癌。
其他癌症包括例如汗腺癌、脊軸腫瘤、胸癌、鐮狀細胞貧血及環境誘導之癌症,包括由石棉誘導之彼等癌症。
在一些實施例中,本發明化合物或其醫藥學上可接受之鹽用於治療晚期黑色素瘤、晚期NSCLC或晚期頭頸部鱗狀細胞癌,包括個體難以用免疫檢查點抑制劑療法治療或對其具有部分反應之情況。
在一些情況下,MAP4K1依賴性疾病或病症為病毒感染,諸如由B型肝炎病毒(HBV)、C型肝炎病毒(HCV)、人類乳頭狀瘤病毒(HPV)、巨細胞病毒(CMV)、單純疱疹病毒(HSV)、埃-巴二氏病毒(EBV)、水痘帶狀疱疹病毒、科沙奇病毒(coxsackie virus)及人類免疫缺乏病毒(HIV)引起之感染。
組合療法本發明化合物或其醫藥學上可接受之鹽可作為唯一醫藥劑或與一或多種用於治療癌症之其他抗癌劑組合投與,其中該組合不會引起不可接受之不良影響。在一些實施例中,其他抗癌劑為免疫-腫瘤學藥劑、作為酶/蛋白質/受體抑制劑之抗癌劑、輻射或化學療法。
本發明化合物或其醫藥學上可接受之鹽可與免疫腫瘤學藥劑共調配。免疫腫瘤學藥劑包括例如小分子藥物、抗體或其他生物製劑或小分子。生物免疫-腫瘤學藥劑之實例包括但不限於癌症疫苗、抗體及細胞激素。在一個態樣中,抗體係單株抗體。在另一態樣中,單株抗體為人類化抗體或人類抗體。在另一態樣中,抗體為雙特異性抗體。
在一個態樣中,免疫腫瘤學藥劑為(i)刺激(包括協同刺激)受體之促效劑或(ii)抑制(包括共抑制) T細胞上之信號之拮抗劑,其兩者均引起抗原特異性T細胞反應擴大(通常稱為免疫檢查點調節因子,在一些情況下稱為免疫檢查點抑制劑)。
某些刺激及抑制分子為免疫球蛋白超家族(IgSF)成員。結合至協同刺激或共抑制受體之膜結合配位體的一個重要家族為B7家族,其包括B7-1、B7-2、B7-H1 (PD-L1)、B7-DC (PD-L2)、B7-H2 (ICOS-L)、B7-H3、B7-H4、B7-H5 (VISTA)及B7-H6。結合至協同刺激或共抑制受體之另一膜結合配位體家族為結合至同源TNF受體家族成員之分子之TNF家族,其包括CD40及CD40L、OX-40、OX-40L、CD70、CD27L、CD30、CD30L、4-1BBL、CD137 (4-1BB)、TRAIL/Apo2-L、TRAILR1/DR4、TRAILR2/DR5、TRAILR3、TRAILR4、OPG、RANK、RANKL、TWEAKR/Fnl4、TWEAK、BAFFR、EDAR、XEDAR、TACI、APRIL、BCMA、LTfiR、LIGHT、DcR3、HVEM、VEGI/TL1A、TRAMP/DR3、EDAR、EDA1、XEDAR、EDA2、TNFRl、淋巴毒素α/ΤΝΡβ、TNFR2、TNF a、LT R、淋巴毒素α 1β2、FAS、FASL、RELT、DR6、TROY、NGFR。
在一個態樣中,可藉由本發明化合物與以下中之一或多者之組合來刺激T細胞反應:(i)抑制T細胞活化之蛋白質的拮抗劑(例如免疫檢查點抑制劑),該蛋白質為諸如CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、TIM-3、半乳糖凝集素9、CEACAM-1、BTLA、CD69、半乳糖凝集素-1、TIGIT、CD113、GPR56、VISTA、2B4、CD48、GARP、PD1H、LAIR1、TIM-1及TIM-4;及(ii)刺激T細胞活化之蛋白質的促效劑,該蛋白質為諸如B7-1、B7-2、CD28、4-1BB (CD137)、4-1BBL、ICOS、ICOS-L、OX40、OX40L、GITR、GITRL、CD70、CD27、CD40、DR3及CD28H。
在一個態樣中,本發明化合物或其醫藥學上可接受之鹽可與至少一種其他免疫檢查點抑制劑組合投與。在其他態樣中,可投與本發明化合物或其醫藥學上可接受之鹽以用於治療耐免疫檢查點抑制劑之NSCLC,包括個體難以用鉑及/或太平洋紫杉醇及/或多烯紫杉醇療法治療或對其具有部分反應之情況。視情況,本發明化合物或其醫藥學上可接受之鹽可與至少一種其他抗癌劑組合投與,該其他抗癌劑為諸如太平洋紫杉醇、多烯紫杉醇或鉑抗癌療法。可投與本發明化合物或其醫藥學上可接受之鹽以用於表現高PD-LI (≥50%腫瘤比例評分(TPS)、野生型EGFR或野生型ALK的NSCLC的一線治療。
其他可與本發明化合物組合用於治療癌症之藥劑包括抑制NK細胞上之受體之拮抗劑或活化NK細胞上之受體之促效劑。舉例而言,本發明化合物可與KIR之拮抗劑,諸如利瑞路單抗(lirilumab)組合。
用於組合療法之其他藥劑包括抑制或耗盡巨噬細胞或單核球之藥劑,其包括但不限於CSF-1R拮抗劑,諸如包括RG7155或FPA-008之CSF-1R拮抗性抗體。
在另一態樣中,本發明化合物或其醫藥學上可接受之鹽可與以下中之一或多者一起使用:接合陽性協同刺激受體的促效劑;經由抑制受體減弱信號傳導的阻斷劑;拮抗劑;及一或多種全身性增加抗腫瘤T細胞之頻率的藥劑;克服腫瘤微環境內不同免疫抑制路徑(例如阻斷抑制性受體接合(例如PD-Ll/PD-1相互作用)、耗盡或抑制Treg (例如使用抗CD25單株抗體(例如達利珠單抗(daclizumab))或藉由離體抗CD25珠粒耗盡)、抑制諸如IDO之代謝酶或逆轉/防止T細胞失能或衰竭)的藥劑及在腫瘤部位處觸發先天性免疫活化及/或發炎之藥劑。
在一些實施例中,免疫-腫瘤學藥劑為CTLA-4拮抗劑,諸如拮抗CTLA-4抗體。適合的CTLA-4抗體包括例如YERVOY (伊匹單抗(ipilimumab))或曲美木單抗(tremelimumab)。在另一態樣中,免疫腫瘤學藥劑為PD-1拮抗劑,諸如拮抗PD-1抗體。適合之PD-1抗體包括例如OPDIVO (納武利尤單抗(nivolumab))、KEYTRUDA (派立珠單抗(pembrolizumab))或MEDI-0680 (AMP-514;WO2012/145493)。免疫腫瘤學藥劑亦可包括皮立珠單抗(pidilizumab) (CT-011),儘管其對PD-1結合之特異性已受到質疑。靶向PD-1受體之另一方法為由PD-L2 (B7-DC)之胞外域與IgGl之Fc部分融合而構成之重組蛋白,稱作AMP-224。
在另一態樣中,免疫腫瘤學藥劑為PD-L1拮抗劑,諸如拮抗PD-L1抗體。適合的PD-L1抗體包括例如TECENTRIQ (阿特珠單抗(atezolizumab)) (RG7446;WO2010/077634)、德瓦魯單抗(durvalumab) (MEDI4736)、BMS-936559 (WO2007/005874)及MSB0010718C (WO2013/79174)。
在另一態樣中,免疫-腫瘤學藥劑為LAG-3拮抗劑,諸如拮抗LAG-3抗體。適合之LAG3抗體包括例如BMS-986016 (WO10/19570、WO14/08218)或IMP-731或IMP-321 (WO08/132601、WO09/44273)。
在另一態樣中,免疫腫瘤學藥劑為CD137 (4-1BB)促效劑,諸如促效CD137抗體。適合之CD137抗體包括例如優瑞路單抗(urelumab)及PF-05082566 (W012/32433)。
在另一態樣中,免疫-腫瘤學藥劑為GITR促效劑,諸如促效GITR抗體。適合之GITR抗體包括例如BMS-986153、BMS-986156、TRX-518 (WO06/105021、WO09/009116)及MK-4166 (WOl 1/028683)。
在另一態樣中,免疫-腫瘤學藥劑為IDO拮抗劑。適合之IDO拮抗劑包括例如INCB-024360 (WO2006/122150、WO07/75598、WO08/36653、WO08/36642)、因多莫得(indoximod)或NLG-919 (WO09/73620、WO09/1156652、WOl1/56652、W012/142237)。
在另一態樣中,免疫-腫瘤學藥劑為OX40促效劑,諸如促效OX40抗體。適合之OX40抗體包括例如MEDI-6383或MEDI-6469。在另一態樣中,免疫腫瘤學藥劑為OX40L拮抗劑,諸如拮抗性OX40抗體。適合的OX40L拮抗劑包括例如RG-7888 (WO06/029879)。
在另一態樣中,免疫-腫瘤學藥劑為CD40促效劑,諸如促效CD40抗體。在又另一個實施例中,免疫腫瘤學藥劑為CD40拮抗劑,諸如拮抗CD40抗體。適合的CD40抗體包括例如魯卡木單抗(lucatumumab)或達西珠單抗(dacetuzumab)。
在另一態樣中,免疫-腫瘤學藥劑為CD27促效劑,諸如促效CD27抗體。適合之CD27抗體包括例如瓦里木單抗(varlilumab)。
在另一態樣中,免疫-腫瘤學藥劑為MGA271 (針對B7H3) (WOl 1/109400)。
本發明化合物或其醫藥學上可接受之鹽可與抗癌劑組合使用,該等抗癌劑為酶/蛋白質/受體抑制劑,其在目標中調節目標之活性以治療此類病況時展現不同的偏好。靶向超過一種信號傳導路徑(或超過一種涉及指定信號傳導路徑之生物分子)可降低細胞群體中產生之耐藥性的可能性,及/或降低治療之毒性。
本發明化合物或其醫藥學上可接受之鹽可與一或多種用於治療癌症之其他酶/蛋白質/受體抑制劑組合使用。舉例而言,本發明化合物可與一或多種用於治療癌症之以下激酶的抑制劑組合:Aktl、Akt2、Akt3、TGF-βΡν、PKA、PKG、PKC、CaM激酶、磷酸酶激酶、MEKK、ERK、MAPK、mTOR、EGFR、HER2、HER3、HER4、INS-R、IGF-1R、IR-R、PDGFotR、PDGFpR、CSFIR、KIT、FLK-II、KDR/FLK-1、FLK-4、flt-1、FGFR1、FGFR2、FGFR3、FGFR4、c-Met、Ron、Sea、TRKA、TRKB、TRKC、FLT3、VEGFR/Flt2、Flt4、EphAl、EphA2、EphA3、EphB2、EphB4、Tie2、Src、Fyn、Lck、Fgr、Btk、Fak、SYK、FRK、JAK、ABL、ALK及B-Raf。
在一些實施例中,本發明化合物或其醫藥學上可接受之鹽可與用於治療癌症之以下抑制劑中之一或多者組合。可與本發明化合物或其醫藥學上可接受之鹽組合用於治療癌症的抑制劑之非限制性實例包括FGFR抑制劑(FGFR1、FGFR2、FGFR3或FGFR4,例如非索替尼(fisogatinib)、AZD4547、BAY 1187982、ARQ087、BGJ398、BIBF1120、TKI258、德立替尼(lucitanib)、多韋替尼(dovitinib)、TAS-120、J J-42756493、Debiol347、INCB54828、INCB62079及INCB63904)、JAK抑制劑(JAK1及/或JAK2,例如魯索利替尼(ruxolitinib)、巴瑞替尼(baricitinib)或伊他替尼(itacitinib) (INCB39110))、IDO抑制劑(例如艾卡哚司他(epacadostat)及NLG919)、LSD1抑制劑(例如GSK2979552、INCB59872及INCB60003)、TDO抑制劑、PI3K-δ抑制劑(例如INCB50797及INCB50465)、PI3K-γ抑制劑(諸如PI3K-選擇性抑制劑(依格列西布(eganelisib))或雙重PI3K-δ/選擇性抑制劑(杜韋利西布(duvelisib)))、CSF1R抑制劑(例如PLX3397及LY3022855)、TAM受體酪胺酸激酶(Tyro-3、Axl及Mer)、血管生成抑制劑(諸如Avastin(貝伐單抗(bevacizumab)))、介白素受體抑制劑、溴及超末端家庭成員抑制劑(例如溴結構域抑制劑或BET抑制劑,諸如OTX015、CPI-0610、INCB54329及INCB57643)及腺苷受體拮抗劑或其組合。HDAC之抑制劑,諸如帕比司他(panobinostat)及伏立諾他(vorinostat),可與本發明化合物組合。c-Met之抑制劑,諸如奧妥珠單抗(onartumzumab)、替伐尼布(tivantnib)及卡馬替尼(capmatinib) (INC-280),可與本發明化合物組合。BTK抑制劑,諸如依魯替尼(ibrutinib)可與本發明之化合物組合。mTOR之抑制劑(諸如雷帕黴素(rapamycin)、西羅莫司(sirolimus)、替西羅莫司(temsirolimus)及依維莫司(everolimus))可與本發明之化合物組合。Raf抑制劑,諸如維羅非尼及達拉非尼可與本發明之化合物組合。MEK之抑制劑,諸如曲美替尼、司美替尼及GDC-0973可與本發明之化合物組合。KIT之抑制劑,包括阿伐替尼(avapritinib)、BLU-263、伊馬替尼(imatinib)、舒尼替尼(sunitinib)、瑞戈非尼、瑞普替尼(ripritinib) (DCC2618)、PLX9486、PLX3397、克萊拉尼(crenolanib)、CDX-0158、CDX-0159。RET之抑制劑包括普拉替尼(pralsetinib)、塞爾帕替尼(selperctinib)、阿來替尼(alectinib)、樂伐替尼(levatinib)、卡博替尼(cabozantinib)、BOS172738 (DS-5010)、SL-1001、TPX-0046、斯特替尼(sitravatinib) (MGCD516)及RXDX-105。Hsp90 (例如坦螺旋黴素(tanespimycin))、週期素依賴性激酶(例如帕泊昔布(palbociclib))、PARP (例如奧拉帕尼(olaparib))及Pim激酶(LGH447、INCB053914及SGI-1776)之抑制劑亦可與本發明之化合物組合。
本發明化合物或其醫藥學上可接受之鹽可與一或多種用於治療癌症之藥劑組合使用。在一些實施例中,藥劑為烷化劑、蛋白酶體抑制劑、皮質類固醇或免疫調節劑。烷化劑之實例包括苯達莫司汀(bendamustine)、氮芥、伸乙基亞胺衍生物、磺酸烷基酯、亞硝基脲及三氮烯、尿嘧啶氮芥、氮芥、環磷醯胺(CYTOXAN)、異環磷醯胺、美法侖(melphalan)、氯芥苯丁酸、哌泊溴烷、三伸乙基三聚氰胺、三伸乙基硫代磷胺、白消安、卡莫司汀(carmustine)、洛莫司汀(lomustine)、鏈脲佐菌素、達卡巴嗪(dacarbazine)及替莫唑胺(temozolomide)。在一些實施例中,蛋白酶體抑制劑為卡非佐米(carfilzomib)。在一些實施例中,皮質類固醇為地塞米松(dexamethasone) (DEX)。
本發明化合物或其醫藥學上可接受之鹽可與一或多種抗癌藥物,諸如化學治療劑組合投與。例示性化學治療劑包括以下之任一者:阿巴瑞克(abarelix)、阿比特龍(abiraterone)、阿法替尼(afatinib)、阿柏西普(aflibercept)、阿地白介素(aldesleukin)、阿侖單抗(alemtuzumab)、阿利維A酸(alitretinoin)、安樂普利諾(allopurinol)、六甲蜜胺、阿那曲唑、三氧化二砷、天冬醯胺酶、阿西替尼(axitinib)、氮胞苷、貝伐單抗、貝沙羅汀(bexarotene)、巴瑞替尼、比卡魯胺(bicalutamide)、博萊黴素(bleomycin)、硼替佐米(bortezombi)、硼替佐米(bortezomib)、布立尼布(brivanib)、布帕昔布(buparlisib)、靜脈內白消安、口服白消安、卡魯睾酮、卡培他濱(capecitabine)、卡莫司汀、西地尼布(cediranib)、西妥昔單抗(cetuximab)、氯芥苯丁酸、克拉屈濱(cladribine)、氯法拉濱(clofarabine)、克卓替尼(crizotinib)、環磷醯胺、阿糖胞苷、達卡巴嗪、達可替尼(dacomitinib)、放線菌素、達肝素鈉(dalteparin sodium)、達沙替尼(dasatinib)、放線菌素、道諾黴素(daunorubicin)、地西他濱(decitabine)、地加瑞克(degarelix)、地尼白介素(denileukin)、地尼介白素迪夫托斯(denileukin diftitox)、去氧助間型黴素、右雷佐生(dexrazoxane)、多烯紫杉醇、小紅莓(doxorubicin)、屈洛昔芬(droloxafine)、丙酸屈他雄酮(dromostanolone propionate)、艾庫組單抗(eculizumab)、恩雜魯胺(enzalutamide)、表鬼臼毒素(epidophyllotoxin)、表柔比星(epirubicin)、埃羅替尼(erlotinib)、雌氮芥、磷酸依託泊苷、依託泊苷(etoposide)、依西美坦(exemestane)、檸檬酸芬太尼(fentanyl citrate)、非格司亭(filgrastim)、氟尿苷(floxuridine)、氟達拉濱(fludarabine)、氟尿嘧啶、氟他胺(flutamide)、氟維司群(fulvestrant)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥單抗(gemtuzumab)、奧佐米星(ozogamicin)、乙酸戈舍瑞林(goserelin acetate)、乙酸組胺瑞林(histrelin acetate)、替伊莫單抗(ibritumomab tiuxetan)、艾達黴素(idarubicin)、艾德昔布(idelalisib)、異環磷醯胺(ifosfamide)、甲磺酸伊馬替尼、干擾素α2a、伊立替康(irinotecan)、二甲苯磺酸拉帕替尼(lapatinib ditosylate)、來那度胺(lenalidomide)、來曲唑(letrozole)、甲醯四氫葉酸、乙酸亮丙瑞林(leuprolide acetate)、左旋咪唑(levamisole)、洛莫司汀、氮芥、乙酸甲地孕酮、美法侖、巰基嘌呤、甲胺喋呤、甲氧沙林(methoxsalen)、光神黴素(mithramycin)、絲裂黴素C、米托坦(mitotane)、米托蒽醌(mitoxantrone)、苯丙酸諾龍(Nandrolone phenpropionate)、去甲長春花鹼(navelbene)、耐昔妥珠單抗(necitumumab)、奈拉濱(nelarabine)、來那替尼(neratinib)、尼羅替尼(nilotinib)、尼魯胺(nilutamide)、諾非妥莫單抗(nofetumomab)、奧舍瑞林(oserelin)、太平洋紫杉醇、帕米膦酸鹽、帕尼單抗(panitumumab)、帕唑帕尼(pazopanib)、培門冬酶、派非格司亭(pegfilgrastim)、培美曲塞二鈉(pemetrexed disodium)、噴司他汀(pentostatin)、皮拉力絲(pilaralisib)、哌泊溴烷、普卡黴素(plicamycin)、順鉑、卡鉑、奧沙利鉑(oxaliplatin)、普納替尼(ponatinib)、普賴松(prednisone)、丙卡巴肼(procarbazine)、奎納克林(quinacrine)、拉布立酶(rasburicase)、瑞戈非尼(regorafenib)、瑞洛薩芬(reloxafine)、利妥昔單抗(rituximab)、魯索利替尼(ruxolitinib)、索拉非尼(sorafenib)、鏈脲佐菌素、舒尼替尼、順丁烯二酸舒尼替尼、他莫昔芬(tamoxifen)、喃氟啶(tegafur)、替莫唑胺(temozolomide)、替尼泊苷(teniposide)、睪內酯、沙立度胺(thalidomide)、硫鳥嘌呤、塞替派(thiotepa)、拓樸替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲妥珠單抗(trastuzumab)、視網酸、曲普瑞林(triptorelin)、尿嘧啶氮芥、戊柔比星(valrubicin)、凡德他尼(vandetanib)、長春鹼、長春新鹼、長春瑞濱(vinorelbine)、伏立諾他(vorinostat)及唑來膦酸鹽。
其他抗癌劑包括抗體療法,諸如曲妥珠單抗。
本發明化合物或其醫藥學上可接受之鹽可作為唯一醫藥劑或與一或多種抗病毒劑組合投與以用於治療慢性病毒感染,其中該組合不會引起不可接受之不良影響。慢性病毒感染包括但不限於由以下引起之疾病:C型肝炎病毒(HCV)、人類乳頭狀瘤病毒(HPV)、巨細胞病毒(CMV)、單純疱疹病毒(HSV)、埃-巴二氏病毒(EBV)、水痘帶狀疱疹病毒、科沙奇病毒、人類免疫缺乏病毒(HIV)。寄生蟲感染(例如瘧疾)亦可藉由上文方法來治療,其中視情況添加已知治療寄生蟲病況之化合物來代替抗病毒劑。
預期與本發明化合物或其醫藥學上可接受之鹽組合使用的適合抗病毒劑可包含核苷及核苷酸逆轉錄酶抑制劑(NRTI)、非核苷逆轉錄酶抑制劑(NRTI)、蛋白酶抑制劑及其他抗病毒藥物。
適合之NRTI的實例包括齊多夫定(zidovudine) (AZT);地達諾新(didanosine) (ddl);紮西他濱(zalcitabine) (ddC);司他夫定(stavudine) (d4T);拉米夫定(lamivudine) (3TC);阿巴卡韋(abacavir) (1592U89);阿德福韋二吡呋酯(adefovir dipivoxil) [雙(POM)-PMEA];洛布卡韋(lobucavir) (BMS-180194);BCH
-I0652;艾米特賓(emitricitabine) [(-)-FTC];β-L-FD4 (亦稱作β-L-D4C且命名為β-L-2',3'-二脫氧-5-氟-胞嘧啶核苷);DAPD ((-)-β-D-2,6-二胺-嘌呤二氧雜環戊烷);及洛德諾新(lodenosine) (FddA)。典型的適合NNRTI包括奈韋拉平(nevirapine) (BI-RG-587);地拉韋啶(delaviradine) (BHAP,U-90152);依法韋侖(efavirenz) (DMP-266);PNU-142721;AG-1549;MKC-442 (l-(乙氧基-甲基)-5-(l-甲基乙基)-6-(苯基甲基)-(2,4(lH,3H)-嘧啶二酮);及(+)-四環香豆素A (NSC-675451)及B。典型的適合之蛋白酶抑制劑包括沙奎那韋(saquinavir) (Ro 31-8959);利托那韋(ritonavir) (ABT-538);茚地那韋(indinavir) (MK-639);奈非那韋(nelfnavir) (AG-1343);安普那韋(amprenavir) (141W94);拉西那韋(lasinavir) (BMS-234475);DMP-450;BMS-2322623;ABT-378;及AG-1549。其他抗病毒劑包括羥基脲、病毒唑(ribavirin)、IL-2、IL-12、潘它夫西地(pentafuside)及Yissum項目第11607號。
當向個體投與超過一種醫藥劑時,其可同時、分開、依序或以組合形式投與(例如對於超過兩種藥劑而言)。舉例而言,當與額外抗癌劑或抗病毒劑一起投與時,所揭示之化合物或其醫藥學上可接受之鹽可在同一醫藥調配物中同時或在各別醫藥調配物中同時投與。替代地,當與額外抗癌劑或抗病毒劑一起投與時,所揭示之化合物或其醫藥學上可接受之鹽可在不同時間投與,此視額外抗癌劑或抗病毒劑之給藥要求而定。
所揭示的醫藥組合物包括一或多種本文所提供之化合物(諸如式I、II、III、IV(A)、IV(B)、V、VI及VII之化合物),及通常至少一種額外物質,諸如賦形劑、除本發明治療劑以外的已知治療劑及其組合。在一些實施例中,所揭示之化合物或其醫藥學上可接受之鹽可與已知具有有益活性之靶向上文所列之疾病或病症的其他藥劑組合使用。舉例而言,所揭示之化合物或其醫藥學上可接受之鹽可單獨或與一或多種抗癌劑或抗病毒劑組合投與。
如本文所使用之術語「投與(administer)」、「投與(administering)」、「投與(administration)」及其類似術語係指可用於使組合物能夠遞送至所需生物作用部位之方法。此等方法包括但不限於關節內(於關節中)、靜脈內、肌肉內、腫瘤內、皮內、腹膜內、皮下、口服、局部、鞘內、吸入、經皮、經直腸及其類似方法。可與本文描述之藥劑及方法一起採用的投與技術見於例如:Goodman及Gilman,
The Pharmacological Basis of Therapeutics, 當前版;Pergamon; 及Remington之
Pharmaceutical Sciences(當前版), Mack Publishing Co., Easton, Pa。
「個體」為哺乳動物,較佳為人類,但亦可為需要獸醫治療之動物,例如伴侶動物(例如,狗、貓及其類似動物)、農畜(例如,牛、羊、豬、馬及其類似動物)及實驗室動物(例如,大鼠、小鼠、天竺鼠及其類似動物)。
提供個體「有效量」的所投與化合物或其醫藥學上可接受之鹽的精確量將視投與模式、疾病或病況之類型及嚴重程度以及個體特徵,諸如一般健康狀況、年齡、性別、體重及對藥物之耐受性而定。熟習此項技術者將能夠根據此等及其他因素確定適當的劑量。當與其他治療劑組合投與時,例如當與抗癌劑或抗病毒劑組合投與時,任何額外治療劑之「有效量」將取決於所用藥物之類型。經批准之治療劑的適合劑量為已知的,且熟習此項技術者可遵循(例如)文獻中報導及《醫師手冊(Physician's Desk Reference)》(第57版,2003)中推薦之劑量,根據個體之病況、所治療病況之類型及所用之本發明化合物或其醫藥學上可接受之鹽的量來調節該等劑量。
術語「有效量」意謂當向個體投與時產生有利或所需結果,包括臨床結果,例如相比於對照,抑制、遏制或減輕個體所治療之病況之症狀的量。舉例而言,治療有效量可以單位劑型(例如0.1 mg至約50 g/天,或者1 mg至約5公克/天;且在另一替代方案中為10 mg至1公克/天)給出。
考慮案例之細節(例如,個體、疾病、所涉及之疾病況態、具體治療及治療是否為預防性的),主治臨床醫師將選擇特定投與模式及給藥方案。治療可涉及在幾天至數月或甚至數年之時段內每日或多日或少於每日(諸如每週或每月等)給藥。
本發明之醫藥組合物經調配成與其預期投與途徑相容。在一實施例中,組合物係根據常規程序調配為適合於靜脈內、皮下、肌肉內、經口、鼻內或局部向人類投與之醫藥組合物。在較佳實施例中,醫藥組合物經調配為以供靜脈內投與。
「醫藥學上可接受之賦形劑」及「醫藥學上可接受之載劑」係指有助於活性劑之調配及/或向個體投與及/或由個體吸收且可包括於本發明之組合物中而不對個體造成顯著不良毒理學影響之物質。醫藥學上可接受之賦形劑之非限制性實例包括水、NaCl、標準生理鹽水溶液、乳酸林格氏液(lactated Ringer's)、標準蔗糖、標準葡萄糖、黏合劑、填充劑、崩解劑、潤滑劑、包衣、甜味劑、調味劑、鹽溶液(諸如林格氏溶液)、醇、油、明膠、諸如乳糖之碳水化合物、直鏈澱粉或澱粉、脂肪酸酯、羥甲基纖維素、聚乙烯基吡咯啶及色素以及其類似者。此類製劑可為滅菌的且必要時與輔助劑(諸如潤滑劑、防腐劑、穩定劑、濕潤劑、乳化劑、影響滲透壓之鹽、緩衝劑、著色劑及/或芳族物質及其類似物)混合,該等助劑與本文所提供之化合物不產生有害反應或干擾本文所提供化合物的活性。所屬領域中具通常知識者將認識到,其他醫藥賦形劑適合於與所揭示化合物一起使用。
通用合成方法及中間物流程1展示用於製備式iii化合物之合成方案。
範例 縮寫ACN 乙腈(「MeCN」)
ATP 三磷酸腺苷
BOP 六氟磷酸苯并三唑-1-基氧基參(二甲胺基)鏻
BrettPhos 二環己基(2',4',6'-三異丙基-3,6-二甲氧基-[1,1'-聯苯]-2-基)膦
C 攝氏度
DAST 三氟化二乙基胺基硫
DBU 二氮雜雙環[5.4.0]十一-7-烯
DCM 二氯甲烷
DIAD 偶氮二甲酸二異丙酯
DIPEA 二異丙基乙胺
DMBNH
22,4-二甲氧基苯甲基胺
DME 二甲氧基乙烷
DMF 二甲基甲醯胺
DMSO 二甲亞碸
dppf [1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)
DTT 二硫蘇糖醇
eq 當量
EA 乙酸乙酯
EDTA 伸乙基二胺四乙酸
Et
3N 三乙胺
FA 甲酸
h 小時
HEPES 4-(2-羥乙基)-1-哌𠯤乙磺酸
HPLC 高效液相層析
IBX 2-碘氧基苯甲酸
IC50 50%抑制濃度
IPA 異丙醇
LiHMDS 雙(三甲基矽烷基)醯胺鋰
mCPBA 間氯過氧苯甲酸
Me
2S 二甲硫
MeMgBr 甲基溴化鎂
min 分鐘
MTBE 甲基三級丁基醚
MeOH 甲醇
2-MeTHF 2-甲基四氫呋喃
MsCl 甲磺醯氯
NBS N-溴丁二醯亞胺
NMO N-甲基𠰌啉N-氧化物
NMP N-甲基-2-吡咯啶酮
Oxone® 過氧單硫酸鉀
PE 石油醚
SFC 超臨界流體層析
TBAB 溴化四丁銨
TBAF 氟化四丁銨
TEA 三甲胺
THF 四氫呋喃
TFA 三氟乙酸
TfOH 三氟甲磺酸
TMSCF
3三氟甲基三甲基矽烷
用於製備本發明化合物之方法可在熟習有機合成技術者容易選擇的適合溶劑中進行。適合的溶劑實質上可在進行反應之溫度,例如可在溶劑冷凍溫度至溶劑沸騰溫度範圍內之溫度下,不與起始物質(反應物)、中間物或產物反應。指定反應可在一種溶劑或超過一種溶劑之混合物中進行。視特定反應步驟而定,適用於特定反應步驟之溶劑可藉由熟習此項技術者選擇。
本發明之化合物的製備可涉及各種化學基團之保護及保護基去除。是否需要保護及脫除保護,及選擇適當保護基可由熟習此項技術者容易地確定。保護基之化學作用可見於例如Wuts及Greene,《有機合成中的保護基(Protective Groups in Organic Synthesis)》, 第5版, John Wiley & Sons: New Jersey,(2014),其以全文引用之方式併入本文中。
反應可根據此項技術中已知的任何適合方法來進行監測。舉例而言,產物形成可藉由光譜手段(諸如核磁共振(NMR)光譜法(例如
1H或
13C)、紅外(IR)光譜法、分光光度法(例如UV-可見)、質譜(MS)或藉由層析方法(諸如高效液相層析(HPLC)或薄層層析(TLC)來加以監測。用於化合物表徵之分析儀器及方法:
LC-MS:除非另外指示,否則所有液相層析質譜(LC-MS)資料(分析樣品之純度及身分)使用Agilent模型6120質譜儀在22.4攝氏度下利用配備有Agilent Poroshel 120 (EC-C18,2.7 µm粒度,3.0×50 mm尺寸)逆相管柱之ES-API電離的Agilent模型-1260 LC系統獲得。移動相由溶劑0.1% FA於水中及0.1% FA於乙腈中之混合物組成。在4分鐘過程內利用95%水性/5%有機至5%水性/95%有機移動相之恆定梯度。流動速率恆定在1 mL/min。
製備型 LC-MS:在22.4攝氏度下對配備有LuNa 5u C18(2) 100A、AXIA封裝、250×21.2 mm逆相管柱之Shimadzu Discovery VP®製備系統進行製備型HPLC。移動相由溶劑0.1% FA於水中及0.1% FA於ACN中之混合物組成。在25分鐘過程內利用95%水性/5%有機至5%水性/95%有機移動相之恆定梯度。流動速率恆定在20 mL/min。在微波中進行之反應在Biotage Initiator微波裝置中進行。
矽膠層析:在Teledyne Isco CombiFlash® Rf單元或Biotage® Isolera Four單元上進行矽膠層析。
質子 NMR:除非另外指示,否則所有
1H NMR譜使用Varian 400MHz Unity Inova 400 MHz NMR儀器得到(獲取時間=3.5秒,1秒延緩;16至64次掃描)。在表徵下,所有質子相對於殘餘DMSO (2.50 ppm)以百萬分率(ppm)形式報導於DMSO-
d6溶劑中。
一般熟習此項技術者將認識到梯度、管柱長度及流動速率之修改為可能的,並且一些條件可能比其他條件更適合用於化合物表徵,此視所分析之化學物質而定。
實例 1 :芳基胺中間物之合成 實例 1a 中間物 1 及 2 :(7
S,8
R)-2-胺基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(中間物1)及(7
R,8
S)-2-胺基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(中間物2)
其中之各者由以下展示之結構表示:
(中間物1之前驅體I)及
(中間物2之前驅體I)。
其中之各者由以下展示之結構表示:
(中間物1之前驅體II)及
(中間物2之前驅體II)。
其中之各者由以下展示之結構表示:
(中間物1)及
(中間物2)。
步驟 1:(
E)
-2-(丁-2-烯-2-基)-6-甲氧基菸鹼酸甲酯
將K
3PO
4(120 g,565 mmol,3.00當量)及Pd(dppf)Cl
2-CH
2Cl
2(7.70 g,9.42 mmol,0.05當量)添加至2-氯-6-甲氧基菸鹼酸甲酯(38.0 g,188 mmol,1.00當量)及(
Z)
-2-(丁-2-烯-2-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼雜環戊烷(44.6 g,245 mmol,1.30當量)於THF (320 mL)及H
2O (80.0 mL)中之溶液中。在N
2下在70℃下攪拌反應混合物2小時。反應混合物用水(300 mL)稀釋且用EA (250 mL×3)萃取。合併有機層且經硫酸鈉乾燥,隨後過濾且真空濃縮,得到殘餘物。殘餘物藉由製備型HPLC (具有0.1% TFA添加劑之ACN-H
2O梯度)純化。使用固體碳酸鈉將含產物之溶離份調節至pH=8-9且用EA (300 mL×3)萃取混合物。合併之有機層用鹽水(500 mL)洗滌,經Na
2SO
4乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(37.0 g,167 mmol,88.7%產率)。
步驟 2 :2-甲氧基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
在80℃下攪拌(
E)
-2-(丁-2-烯-2-基)-6-甲氧基菸鹼酸甲酯(37.0 g,167 mmol,1.00當量)於TfOH (171 g,1.15 mol,101 mL,6.85當量)中之溶液0.5小時。隨後將混合物冷卻至環境溫度,倒入飽和NaHCO
3水溶液(1000 mL)中且用EA (300 mL×5)萃取。有機層經硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,1%至25% EA-PE)純化,得到呈黃色油狀之標題化合物(30.0 g,144 mmol,86.6%產率)。
步驟 3:2-羥基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
在150℃下攪拌2-甲氧基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(30.0 g,144 mmol,1.00當量)及吡啶-鹽酸鹽(41.8 g,361 mmol,2.50當量)之混合物0.5小時。反應混合物直接藉由矽膠急驟管柱層析(梯度溶離,2%至10% MeOH
-DCM)純化,得到呈黃色固體狀之標題化合物(26.0 g,134 mmol,92.9%產率)。
步驟 4 :外消旋-(7
S,8
S)-2-羥基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮及外消旋-(7
S,8
R)-2-羥基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
將DBU (60.8 mL,403 mmol,3.00當量)添加至2-羥基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(26.0 g,134 mmol,1.00當量)於甲苯(290 mL)中之溶液中。在100℃下攪拌反應混合物12小時,隨後冷卻至環境溫度且真空濃縮。殘餘物藉由矽膠急驟管柱層析(梯度溶離,1%至10% MeOH
-DCM)純化,得到呈異構體混合物形式之標題化合物,其未經進一步純化即用於下一步驟中。
步驟 5 :外消旋-(7
S,8
S)-2-氯-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮及外消旋-(7
S,8
R)-2-氯-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
在100℃下攪拌外消旋-(7
S,8
S)-2-羥基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮及外消旋-(7
S,8
R)-2-羥基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(26.0 g,134 mmol,1當量)於POCl
3(150 mL,1.61 mol,11.9當量)中之混合物1小時。隨後使反應混合物冷卻至環境溫度且在0-10℃下倒入飽和NaHCO
3水溶液(2 L)中。經淬滅之混合物用EA (300 mL×3)萃取,且合併之有機層用鹽水洗滌,經硫酸鈉乾燥,過濾,且濃縮。藉由製備型HPLC (管柱:Phenomenex LuNa C18 250×50 mm×10 µm;移動相:[水(0.1%TFA)-ACN];B%:35% ACN-55% CAN,經20分鐘)分離順式及反式外消旋異構體。外消旋-(7
S,8
S)-2-氯-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮為第一個溶離之化合物且以白色固體形式獲得。MS (ES+) C
10H
10ClNO
2需值:211,實驗值:212[M+H]
+。
1H NMR: 400 MHz, CDCl
3δ 8.29 (d,
J= 8.2 Hz, 1H), 7.39 (d,
J= 8.2 Hz, 1H), 4.83 (dq,
J= 3.2, 6.6 Hz, 1H), 3.09 (dq,
J= 3.2, 7.2 Hz, 1H), 1.49 (d,
J= 6.5 Hz, 3H), 1.30 (d,
J= 7.2 Hz, 3H)。外消旋-(7
S,8
R)-2-氯-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮為第二個溶離之化合物且以白色固體形式獲得。MS (ES+) C
10H
10ClNO
2需值:211,實驗值:212[M+H]
+。
1H NMR: 400 MHz, CDCl
3δ 8.28 (d,
J= 8.2 Hz, 1H), 7.38 (d,
J= 8.2 Hz, 1H), 4.58 - 4.43 (m, 1H), 3.05 (quin,
J= 7.2 Hz, 1H), 1.56 - 1.40 (m, 6H)。
步驟 6 :(7
S,8
R)-2-氯-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮及(7
R,8
S)-2-氯-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
外消旋-(7
S,8
R)-2-氯-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮藉由SFC (管柱:DAICEL CHIRALPAK AD (250 mm×50 mm,10 µm);移動相:MeOH/CO
2)分離,得到呈白色固體狀之第一溶離異構體(峰1)及呈白色固體狀之第二溶離異構體(峰2)。
步驟 7 :(7
S,8
R)-2-((2,4-二甲氧基苯甲基)胺基)-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
將DIPEA (7.48 g,57.8 mmol,10.1 mL,2.50當量)及DMBNH
2(5.03 g,30.1 mmol,4.53 mL,1.30當量)添加至(7
S,8
R)-2-氯-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(來自上文步驟6的第1溶離異構體(峰1)) (4.90 g,23.1 mmol,1.00當量)於NMP (50.0 mL)中之溶液中。在100℃下攪拌反應混合物1小時,隨後倒入水(500 mL)中且用EA (100 mL×3)萃取。合併之有機層用鹽水(200 mL)洗滌,經硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(7.93 g,粗物質),其直接用於下一步驟中。MS (ES+) C
19H
11N
2O
4需值:342,實驗值:343[M+H]
+。
步驟 8 :(7
S,8
R)-2-胺基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
在70℃下攪拌(7
S,8
R)-2-((2,4-二甲氧基苯甲基)胺基)-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(7.93 g,23.1 mmol,1.00當量)於HCl/二㗁烷(4.00 M,50.0 mL,8.64當量)中之溶液1小時。隨後將反應混合物濃縮且分配於飽和碳酸氫鈉水溶液(100 mL)之間且用DCM (100 mL×3)萃取。合併之有機層用鹽水(200 mL)洗滌,經硫酸鈉乾燥,過濾且濃縮。於MTBE (50 mL)中濕磨殘餘物10分鐘且過濾,得到黃色固體。在真空下乾燥黃色固體,得到標題化合物中間物1 (3.23 g,16.4 mmol,71.2%產率,98.1%純度)。MS (ES+) C
10H
12N
2O
2需值:192,實驗值:193[M+H]
+。
1H NMR: 400 MHz, DMSO-
d6 δ 7.77 (d,
J= 8.6 Hz, 1H), 6.97 (s, 2H), 6.40 (d,
J= 8.6 Hz, 1H), 4.43 - 4.21 (m, 1H), 2.88 - 2.65 (m, 1H), 1.35 (d,
J= 6.4 Hz, 3H), 1.25 (d,
J= 7.0 Hz, 3H)。中間物1之絕對立體化學藉由X射線晶體結構確定。
步驟 9 及 10 :(7
R,8
S)-2-胺基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
標題化合物(中間物2)使用與中間物2之步驟7及8中所描述相同的兩步驟程序,由(7
R,8
S)-2-氯-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(步驟6之第二溶離異構體(峰2))分開製備。MS (ES+) C
10H
12N
2O
2需值:192,實驗值:193[M+H]
+。
1H NMR: 400 MHz, DMSO-
d 6δ 7.77 (d,
J= 8.6 Hz, 1H), 6.97 (s, 2H), 6.40 (d,
J= 8.6 Hz, 1H), 4.43 - 4.21 (m, 1H), 2.88 - 2.65 (m, 1H), 1.35 (d,
J= 6.4 Hz, 3H), 1.25 (d,
J= 7.0 Hz, 3H)。
實例 1b 中間物 3 及 4 :(
R)
-2-胺基-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮及(
S)
-2-胺基-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
其中之各者由以下展示之結構表示:
(中間物3之前驅體)及
(中間物4之前驅體)。
其中之各者由以下展示之結構表示:
(中間物3)及
(中間物4)。
步驟 1-5 :外消旋2-((2,4-二甲氧基苯甲基)胺基)-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
標題化合物使用與上文中間物1之步驟1-3及5-7中所描述類似的程序,由2-氯-6-甲氧基菸鹼酸甲酯及4,4,5,5-四甲基-2-(3-甲基丁-2-烯-2-基)-1,3,2-二氧雜硼雜環戊烷製備。
步驟 6 :(
R)
-2-((2,4-二甲氧基苯甲基)胺基)-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮及(
S)
-2-((2,4-二甲氧基苯甲基)胺基)-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
外消旋2-((2,4-二甲氧基苯甲基)胺基)-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮藉由SFC (管柱:DAICEL CHIRALPAK AS-H (250 mm×30 mm,5 µm);移動相:[0.1% NH
4OH MeOH於CO
2中])分離,得到(
R)
-2-((2,4-二甲氧基苯甲基)胺基)-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(第1溶離異構體(中間物3之前驅體),0.55 g,79%產率)及(
S)
-2-((2,4-二甲氧基苯甲基)胺基)-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(第2溶離異構體(中間物4之前驅體),0.55 g,79%產率)。各中間物經分離,呈黃色油狀。
步驟 7 及 8 :(
R)
-2-胺基-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮及(
S)
-2-胺基-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
標題化合物(中間物3及4)使用與中間物1之步驟8中所描述相同的程序,分別由第1及第2溶離異構體,亦即(
R)
-2-((2,4-二甲氧基苯甲基)胺基)-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮及(
S)
-2-((2,4-二甲氧基苯甲基)胺基)-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮製備。中間物3,即(
R)
-2-胺基-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮,以黃色固體形式獲得。MS (ES+) C
11H
14N
2O
2需值:206,實驗值:207[M+H]
+。
1H-NMR (400 MHz, CD
3OD): δ ppm 7.89 (d,
J= 8.8 Hz, 1H), 6.50 (d,
J= 8.8 Hz, 1H), 2.85-2.80 (m, 1H), 1.41 (s, 6H), 1.27 (d,
J= 7.2 Hz, 3H)。中間物4,即(
S)
-2-胺基-7,7,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮,以黃色固體形式獲得。MS (ES+) C
11H
14N
2O
2需值:206,實驗值:207[M+H]
+。
1H-NMR (400 MHz, CD
3OD): δ ppm 7.89 (d,
J= 8.8 Hz, 1H), 6.50 (d,
J= 8.8 Hz, 1H), 2.85-2.80 (m, 1H), 1.41 (s, 6H), 1.27 (d,
J= 7.2 Hz, 3H)。中間物3之立體化學在化合物16之情形下使用X射線晶體結構確定。
步驟 1 :7,7-二甲基-1,5,7,8-四氫-2
H-哌喃并[4,3
-b]吡啶-2-酮
在145℃下使用迪安-斯塔克分離器(Dean-Stark)將2,2-二甲基四氫-4
H-哌喃-4-酮(500 g,3.90 mol,1.00當量)及吡咯啶(391 mL,4.68 mol,1.20當量)於甲苯(4.00 L)中之混合物加熱2小時。自迪安-斯塔克分離器(Dean-Stark trap)移除水層(約16 mL)且將反應混合物冷卻至15℃。冷卻後,添加丙-2-基醯胺(539 g,7.80 mol,2.00當量)且將反應混合物加熱至150℃。在150℃下加熱反應混合物10小時,隨後冷卻至環境溫度。過濾經冷卻之反應混合物,且減壓濃縮濾液,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(10%甲醇-二氯甲烷)純化,得到呈黃色固體狀之標題化合物(560 g,62%產率)。
步驟 2 :2-氯-7,7-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶
將7,7-二甲基-1,5,7,8-四氫-2
H-哌喃并[4,3
-b]吡啶-2-酮(500 g,2.23 mol,1當量)於POCl
3(350 mL,3.77 mol,9.64當量)中之溶液加熱至100℃持續6小時。隨後使反應混合物冷卻至環境溫度且真空濃縮。將殘餘物倒入冰水(1.00 L)上。用EA (750 mL×2)萃取混合物。合併之有機層經Na
2SO
4乾燥,過濾且真空濃縮,得到呈棕色油狀之標題化合物(363 g,82.2%產率)。
步驟 3 :2-氯-7,7-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
向NaIO
4(487 g,2.28 mol,3.00當量)於水(1.20 L)中之溶液中添加2-氯-7,7-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶(150 g,759 mmol,1.00當量)於MeCN (50.0 mL)及CCl4 (2.70 L)中之混合物。使混合物冷卻至0℃,且隨後添加RuCl
3(11.0 g,53.1 mmol,0.07當量)。在0℃下攪拌反應混合物0.5小時,隨後升溫至20℃持續11.5小時。添加飽和亞硫酸鈉水溶液(1.00 L),且過濾混合物。用EA (500 mL×3)萃取濾液,且合併有機層。合併之有機層用鹽水(1.00 L)洗滌,經Na
2SO
4乾燥,過濾且濃縮,得到呈黃色固體狀之標題化合物(132 g,624 mmol,82.1%產率)。
步驟 4 :2-((2,4-二甲氧基苯甲基)胺基)-7,7-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
在環境溫度下,將(2,4-二甲氧基苯基)甲胺(160 g,957 mmol,1.50當量)添加至2-氯-7,7-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(135 g,638 mmol,1.00當量)及DIPEA (222 mL,1.28 mol,2.00當量)於NMP (1.08 L)中之溶液中。將反應混合物加熱至140℃持續2小時,且接著冷卻至環境溫度。隨後將反應混合物分配於水(700 mL)與EA之間。分離各層,且用EA (500 mL×3)進一步萃取水層。合併之有機層且用鹽水(400 mL×3)洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色固體狀之標題化合物(160 g)。粗產物直接用於下一步驟中。
步驟 5 :2-胺基-7,7-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
在20℃下,將HCl (4.0 M於二㗁烷中,1.20 L,11.0當量)添加至:2-((2,4-二甲氧基苯甲基)胺基)-7,7-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(150 g,438 mmol,1.00當量)。將反應混合物加熱至60℃持續2小時,接著冷卻至環境溫度且真空濃縮。將殘餘物倒入飽和NaHCO
3水溶液(1.00 L)中且用EA (500 mL×4)萃取。合併之有機層用鹽水(500×2)洗滌,經Na
2SO
4乾燥,過濾且濃縮。將殘餘物溶解於EA (300 mL)中且逐滴添加石油醚(150 mL),得到黃色漿液。過濾固體且收集,得到呈黃色固體狀之標題化合物(52.0 g,60.9%產率)。MS (ES+) C
10H
12N
2O
2需值:192,實驗值:193[M+H]
+。
1H NMR (400 MHz, DMSO-
d6) δ 7.76 (d,
J= 8.4 Hz, 1H), 6.98 (s, 2H), 6.39 (d,
J= 8.8 Hz, 1H), 2.89 (s, 2H), 1.37 (s, 6H)。
步驟 1 :2-胺基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
使用與針對中間物5之步驟1-5中所描述相同的五步驟程序,由四氫-4
H-哌喃-4-酮製備標題化合物。MS (ES+) C
8H
8N
2O
2需值:164,實驗值:165[M+H]
+。
1H NMR, 400 MHz, DMSO-
d6, δ = 7.77 (d,
J= 8.8 Hz, 1H), 7.01 (s, 2H), 6.41 (d,
J= 8.8 Hz, 1H), 4.44 - 4.41 (m, 2H), 2.88 - 2.85 (m, 2H)。
步驟 1 :2-(3-溴-6-氯吡啶-2-基)乙酸甲酯
在25℃下在氮氣下,將LiHMDS (1 M,388 mL)添加至3-溴-6-氯-2-甲基吡啶(20.0 g,96.9 mmol)於THF (300 mL)中之溶液中。2.5小時之後,向混合物中添加碳酸二甲酯(14.0 g,155 mmol)且在25℃下攪拌13.5小時。隨後將反應混合物添加至飽和NH
4Cl水溶液(1000 mL)中且用EA (60 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,0%至10% EA-石油醚)純化,得到呈黃色油狀之標題化合物(18.0 g,70%產率)。
1H NMR (400 MHz, CDCl3): δ ppm 7.81 (d,
J= 8.4 Hz, 1H), 7.16 (d,
J= 8.0 Hz, 1H), 4.03 9s, 2H), 3.74 (s, 3H)。
步驟 2 :1-(3-溴-6-氯吡啶-2-基)環丙烷-1-甲酸甲酯
在25℃下,將溴化四丁基銨(2.44 g,7.56 mmol)及NaOH (50 mL,50重量%於水中)添加至1,2-二溴乙烷(10.7 g,56.7 mmol)及2-(3-溴-6-氯吡啶-2-基)乙酸甲酯(10.0 g,37.8 mmol)於甲苯(50 mL)中之溶液中。在25℃下攪拌反應混合物16小時,隨後用水(300 mL)稀釋且用EA (200 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,0%至10% EA-石油醚)純化,得到呈黃色固體狀之標題化合物(6.10 g,56%產率)。
1H NMR (400 MHz, CDCl
3): δ ppm 7.81 (d,
J= 8.4 Hz, 1H), 7.15 (d,
J= 8.0 Hz, 1H), 3.66 (s, 3H), 1.81-1.75 (m, 2H), 1.46-1.41 (m, 2H)。
步驟 3 :(1-(3-溴-6-氯吡啶-2-基)環丙基)甲醇
在-78℃下在氮氣下,將氫化二異丁基鋁(1 M,56 mL)添加至1-(3-溴-6-氯吡啶-2-基)環丙烷-1-甲酸甲酯(5.40 g,18.6 mmol)於DCM (80 mL)中之溶液中。在-78℃下,將反應混合物攪拌0.5小時,隨後藉由添加飽和NH
4Cl水溶液(50 mL)淬滅,用水(200 mL)稀釋且用EA (200 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色固體狀之粗標題化合物(5.00 g,粗物質),其未經進一步純化即用於下一步驟中。
步驟 4 :5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-甲酸甲酯
在氮氣氛圍下,將三乙胺(2.31 g,22.9 mmol)及Pd(dppf)Cl
2(557 mg,762 µmol)添加至(1-(3-溴-6-氯吡啶-2-基)環丙基)甲醇於MeOH (25 mL)及DMF (25 mL)中之溶液中。懸浮液在真空中脫氣且用一氧化碳吹掃若干次。將混合物在一氧化碳(50 psi)下在80℃下攪拌16小時。隨後濃縮反應混合物以移除甲醇,用水(100 mL)稀釋且用EA (60 mL×3)萃取。合併之有機層用鹽水(100 mL×3)洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。獲得呈黃色固體狀之標題化合物(1.8 g,粗物質)且不經進一步純化即用於下一步驟中。MS (ES+) C
10H
10N
2O
2需值:233,實驗值:234[M+H]
+。
步驟 5 :5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-甲酸
將氫氧化鋰(555 mg,23.2 mmol)添加至5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-甲酸甲酯(1.80 g,7.72 mmol)於甲醇(30 mL)及水(10 mL)中之溶液中。在25℃下攪拌反應混合物0.5小時,接著濃縮以移除甲醇。用水(60 mL)稀釋混合物且用EA (50 mL×3)萃取。藉由添加鹽酸水溶液(6 M,5 mL)酸化水層,隨後用EA (50 mL×3)萃取混合物。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈棕色固體狀之標題化合物(1.20 g,71%產率),其不經進一步純化即使用。
步驟 6 :(5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-基)胺基甲酸三級丁酯
將三乙胺(831 mg,8.21 mmol)及疊氮磷酸二苯酯(2.26 g,8.21 mmol)添加至5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-甲酸(1.20 g,5.47 mmol)於三級丁醇(20 mL)中之溶液中。在100℃下攪拌反應混合物1小時,隨後冷卻至環境溫度,用水(60 mL)稀釋,且用EA (50 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,0%至50% EA-石油醚)純化,得到呈黃色固體狀之標題化合物(330 mg,19%產率)及呈黃色油狀之2'-胺基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-5'-酮(420 mg,28%產率)。
步驟 7 :2'-胺基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-5'-酮
在25℃下,將含HCl之二㗁烷(4.0 M,0.5 mL)添加至(5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-基)胺基甲酸三級丁酯(100 mg,344 µmol)於二㗁烷(1.5 mL)中之溶液中。攪拌反應混合物10分鐘,接著濃縮。將DCM (2 mL)及TFA (1 mL,13.5 mmol)添加至殘餘物中,且在25℃下攪拌反應混合物30分鐘。隨後濃縮反應混合物且向殘餘物中添加EA (5 mL)。藉由添加飽和NaHCO
3水溶液(20 mL)中和混合物且用EA (15 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(60.0 mg,92%產率),其不經進一步純化即用於下一步驟中。MS (ES+) C
12H
11NO
4需值:190,實驗值:191[M+H]
+。
實例 1f 中間物 8 及 9 :(
R)
-2'-胺基-7'-甲基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-5'-酮及(
S)
-2'-胺基-7'-甲基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-5'-酮
其中之各者由下文所示之結構中之一者表示:
其由下文所示之結構中之一者表示:
步驟 1 :1-(3-溴-6-氯吡啶-2-基)環丙烷-1-甲醛
將IBX (6.50 g,10.7 mmol,46%純度)添加至(1-(3-溴-6-氯吡啶-2-基)環丙基)甲醇(2.65 g,10.1 mmol)於EA (80 mL)中之溶液中。在80℃下攪拌反應混合物1小時,隨後再添加IBX (2.00 g,3.29 mmol,46%純度)。在80℃下攪拌反應混合物0.5小時,接著過濾且濃縮,得到呈黃色固體狀之標題化合物(2.60 g,粗物質),其不經進一步純化即使用。MS (ES+) C
9H
7BrClNO需值:261,實驗值:262 [M+H]
+。
步驟 2 :1-(1-(3-溴-6-氯吡啶-2-基)環丙基)乙-1-醇
在0℃下,將溴化甲基鎂(3 M,17 mL)添加至1-(3-溴-6-氯吡啶-2-基)環丙烷-1-甲醛(2.60 g,9.98 mmol)於THF (80 mL)中之溶液中。攪拌反應混合物10分鐘,隨後藉由添加飽和NH
4Cl水溶液(80 mL)淬滅,用水(40 mL)稀釋且用EA (80 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(2.70 g,粗物質),其不經進一步純化即使用。MS (ES+) C
10H
11N
2O
2需值:277,實驗值:278 [M+H]
+。
步驟 3-5 :(7'-甲基-5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-基)胺基甲酸三級丁酯
標題化合物使用與上文中間物7之步驟4-6中所描述類似的程序,由1-(1-(3-溴-6-氯吡啶-2-基)環丙基)乙-1-醇製備。
1H NMR (400 MHz, CDCl
3): δ ppm 8.29 (d,
J= 8.8 Hz, 1H), 7.90 (d,
J= 8.8 Hz, 1H), 7.31 (s, 1H), 4.63-4.53 (m, 1H), 1.61 (s, 3H), 1.53 (s, 9H), 1.38-1.35 (m,1 H), 1.09-1.00 (m, 2H)。
步驟 6 :(
R)
-(7'-甲基-5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-基)胺基甲酸三級丁酯及(
S)
-(7'-甲基-5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-基)胺基甲酸三級丁酯
(7'-甲基-5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-基)胺基甲酸三級丁酯(400 mg)藉由SFC (管柱:REGIS (s,s) WHELK-O1 (250 mm×50 mm,10 µm),具有0.1% NH
4OH的CO
2中之EtOH梯度)分離,得到兩個單獨峰。獲得呈黃色固體狀之第一溶離異構體(100 mg,24%產率)及第二溶離異構體(140 mg,34%產率)。
步驟 7 :(
R或
S)-2'-胺基-7'-甲基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-5'-酮中之一者
將TFA (2.31 g,20.3 mmol)添加至(R或S)-(7'-甲基-5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-基)胺基甲酸三級丁酯中之一者(來自步驟6之第一溶離異構體,100 mg)於DCM (6 mL)中之溶液中。在25℃下攪拌反應混合物30分鐘,接著用飽和NaHCO
3水溶液(30 mL)淬滅且用DCM (20 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(中間物8,70 mg,粗物質),其不經進一步純化即使用。MS (ES+) C
11H
12N
2O
2需值:204,實驗值:205[M+H]
+。
步驟 8 :(
R或
S)-2'-胺基-7'-甲基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-5'-酮中之剩餘一者
標題化合物(中間物9)使用與中間物8之步驟7中所描述相同的程序,由(R或S)-(7'-甲基-5'-側氧基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-2'-基)胺基甲酸三級丁酯中之一者(來自步驟6之第二溶離異構體)製備。MS (ES+) C
11H
12N
2O
2需值:204,實驗值:205[M+H]
+。
步驟 1 :2-(1-(3-溴-6-氯吡啶-2-基)環丙基)丙-2-醇
在25℃下,向1-(3-溴-6-氯吡啶-2-基)環丙烷-1-甲酸甲酯(1.3 g,4.47 mmol)於THF (10 mL)中之溶液中添加MeMgBr (3 M,14.9 mL)。在25℃下攪拌反應混合物10分鐘,隨後倒入水(20 mL)中且用EA (50 mL×3)萃取。將有機層合併且經硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO
2,PE/EA=1/0至50/1)純化,得到呈無色油狀之標題化合物(500 mg,38%產率)。
步驟 2-5 :2'-胺基-7',7'-二甲基-5'
H,7'
H-螺[環丙烷-1,8'-哌喃并[4,3
-b]吡啶]-5'-酮
標題化合物使用與上文中間物7之步驟4-6及中間物8之步驟7中所描述類似的程序,由2-(1-(3-溴-6-氯吡啶-2-基)環丙基)丙-2-醇製備。
1H NMR (400 MHz, CDCl
3): δ ppm 8.05 (d,
J= 8.4 Hz, 1H), 6.36 (d,
J= 8.8 Hz, 1H), 4.85 (s, 2H), 1.42-1.32 (m, 8H), 1.06-1.03 (m, 2H)。
步驟 1 :(
E)
-3-(6-((三級丁氧基羰基)胺基)吡啶-2-基)丙烯酸甲酯
將Pd(OAc)
2(1.23 g,5.49 mmol)、P(鄰甲苯基)
3(2.51 g,8.24 mmol)及二異丙基乙基胺(71.0 g,549 mmol,95.7 mL)添加至(6-溴吡啶-2-基)胺基甲酸三級丁酯(15.0 g,54.9 mmol)及丙烯酸甲酯(18.9 g,220 mmol,19.8 mL)於
N , N-二甲基甲醯胺(150 mL)中之溶液中。在100℃下攪拌反應混合物1小時,隨後用EA (200 mL)稀釋且用鹽水(200 mL×3)洗滌。有機層經硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,10%至33% EA-石油醚)純化,得到呈黃色固體狀之標題化合物(7.00 g,39%產率)。
步驟 2 :3-(6-((三級丁氧基羰基)胺基)吡啶-2-基)丙酸甲酯
將Pd/C (100 mg,10%純度)添加至(
E)
-3-(6-((三級丁氧基羰基)胺基)吡啶-2-基)丙烯酸甲酯(7.00 g,25.2 mmol)於甲醇(100 mL)中之溶液中。在25℃下在氫氣下攪拌混合物12小時,接著過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,10%至33% EA-石油醚)純化,得到呈黃色固體狀之標題化合物(6.00 g,18.6 mmol,74%產率)。
步驟 3 :(6-(3-羥基-3-甲基丁基)吡啶-2-基)胺基甲酸三級丁酯
在0℃下,將溴化甲基鎂(3 M,35.7 mL)添加至3-(6-((三級丁氧基羰基)胺基)吡啶-2-基)丙酸甲酯(6.00 g,21.4 mmol)於四氫呋喃(100 mL)中之溶液中。在25℃下攪拌反應混合物0.5小時,隨後倒入水(200 mL)中且用EA (50 mL×3)萃取。合併之有機層經硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,15%至50% EA-石油醚)純化,得到呈黃色固體狀之標題化合物(5.00 g,15.9 mmol,74%產率)。
步驟 4 :(5-溴-6-(3-羥基-3-甲基丁基)吡啶-2-基)胺基甲酸三級丁酯
在0℃下,將含N-溴丁二醯亞胺(3.17 g,17.8 mmol)之乙腈(50 mL)添加至(6-(3-羥基-3-甲基丁基)吡啶-2-基)胺基甲酸三級丁酯(5.00 g,17.8 mmol)於乙腈(50 mL)中之溶液中。在25℃下攪拌反應混合物1小時,隨後倒入水(200 mL)中且用EA (50 mL×3)萃取。合併之有機層經硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,10%至33% EA-石油醚)純化,得到呈黃色固體狀之標題化合物(4.00 g,62%產率)。
1H-NMR (400 MHz, CDCl
3): δ ppm 7.72 (d,
J= 8.4 Hz, 1H), 7.65 (d,
J= 8.8 Hz, 1H), 7.39 (S, 1H), 2.99-2.93 (m, 2H), 1.87-1.78 (m, 2H), 1.49 (s, 9H), 1.27 (s, 6H)。
步驟 5 :6-((三級丁氧基羰基)胺基)-2-(3-羥基-3-甲基丁基)菸鹼酸
在-78℃下,將正丁基鋰(2.5 M,11.1 mL)添加至(5-溴-6-(3-羥基-3-甲基丁基)吡啶-2-基)胺基甲酸三級丁酯(2.00 g,5.57 mmol)於四氫呋喃(50 mL)中之溶液中。在-78℃下攪拌反應混合物10分鐘,隨後添加二氧化碳,且在-78℃下攪拌混合物20分鐘。隨後將反應混合物倒入水(100 mL)中且用乙酸乙酯(30 mL×3)萃取。丟棄有機層,且將氯化銨水溶液添加至水層中以調節pH<7。用EA (30 mL×5)萃取混合物,且合併之有機層經硫酸鈉乾燥,過濾且濃縮,得到呈黃色固體狀之標題化合物(200 mg,粗物質)。
步驟 6 :(7,7-二甲基-5-側氧基-5,7,8,9-四氫氧呯并[4,3
-b]吡啶-2-基)胺基甲酸三級丁酯
將二環己基碳化二亞胺(229 mg,1.11 mmol,225 μL)添加至6-((三級丁氧基羰基)胺基)-2-(3-羥基-3-甲基丁基)菸鹼酸(180 mg,粗物質)及4
-N,N-二甲基胺基吡啶(33.9 mg,277 μmol)於二氯甲烷(20 mL)中之溶液中。在25℃下攪拌反應混合物12小時,接著濃縮,得到殘餘物。殘餘物藉由矽膠製備型TLC (33% EA-石油醚)純化,得到呈黃色固體狀之標題化合物(30.0 mg,粗物質)。
步驟 7 :2-胺基-7,7-二甲基-8,9-二氫氧呯并[4,3
-b]吡啶-5(7
H)-酮
標題化合物使用與中間物8之步驟7中所述的類似程序,由(7,7-二甲基-5-側氧基-5,7,8,9-四氫氧呯并[4,3
-b]吡啶-2-基)胺基甲酸三級丁酯製備。
1H-NMR (400 MHz, CDCl
3): δ ppm 7.92 (d,
J= 8.8 Hz, 1H), 6.36 (d,
J= 8.8 Hz, 1H), 5.17 (s, 2H), 2.96-2.92 (m, 2H), 2.11-2.09 (m, 2H), 1.33 (s, 6H)。
實例 1i 中間物 12 及 13 :(
R)
-2-胺基-7,8,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮或(
S)
-2-胺基-7,8,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
步驟 1 :2-(3-溴-6-氯吡啶-2-基)-2-甲基丙酸甲酯
在0℃下,將氫化鈉(2.91 g,72.8 mmol,60%純度)添加至2-(3-溴-6-氯吡啶-2-基)乙酸甲酯(5.50 g,20.8 mmol)於四氫呋喃(20 mL)中之溶液中。在0℃下攪拌反應混合物15分鐘,隨後添加碘甲烷(7.38 g,51.9 mmol)。使反應混合物升溫至25℃且攪拌45分鐘,隨後用水(30 mL)淬滅且用EA (30 mL×2)萃取。濃縮合併之有機層,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,0%至10% EA-石油醚)純化,得到呈黃色油狀之標題化合物(5.5 g,90%產率)。
1H NMR (400 MHz, CD
3OD): δ ppm 7.97 (d,
J= 8.4 Hz, 1H), 7.20 (d,
J= 8.4 Hz, 1H), 3.95 (s, 2H), 1.50 (s, 6H)。
步驟 2 :2-(3-溴-6-氯吡啶-2-基)-2-甲基丙-1-醇
標題化合物使用與中間物7之步驟3中所描述類似的程序,由2-(3-溴-6-氯吡啶-2-基)-2-甲基丙酸甲酯製備
步驟 3-7 :(外消旋)-2-胺基-7,8,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
標題化合物使用與中間物8之步驟1-5中所描述類似的程序,由2-(3-溴-6-氯吡啶-2-基)-2-甲基丙-1-醇製備。C
11H
14N
2O
2需值:206,實驗值:207 [M+H]
+。
步驟 8 :(
R)
-2-胺基-7,8,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮或(
S)
-2-胺基-7,8,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
(外消旋)-2-胺基-7,8,8-三甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(120 mg)藉由SFC (管柱:REGIS (s,s) WHELK-O1 (250 mm×50 mm,10 um),具有0.1% NH
4OH的CO
2中之MeOH梯度)分離,分別得到兩個峰。獲得呈黃色固體狀之第一溶離異構體(中間物12,60 mg,50%產率)及第二溶離異構體(中間物13,60 mg,50%產率)。
步驟 1:4-胺基嘧啶-2-甲酸乙酯
在0℃下,將三乙胺(285 g,2.81 mol,2.00當量)逐滴添加至2-胺基-2-亞胺基乙酸乙酯鹽酸鹽(215 g,1.41 mol,1.00當量)及2-氯丙-2-烯腈(112 mL,1.41 mol,1.00當量)於EtOH (1.8 L)中之溶液中。使混合物升溫至25℃且在25℃下攪拌6小時。濃縮反應混合物,且將殘餘物分配於水(10.0 L)與EA (5.0 L)之間。分離各層,且用EA (5.0 L×2)萃取水層。合併有機層且經Na
2SO
4乾燥。過濾經乾燥溶液,且濃縮濾液,得到呈深棕色固體狀之標題化合物(270 g,粗物質)。
步驟 2:2-(4-胺基嘧啶-2-基)丙-2-醇
在-20℃,將溴化甲基鎂(900 mL,3.0 M,5.0當量)添加至4-胺基嘧啶-2-甲酸乙酯(90.0 g,538 mmol,1.00當量)於2-MeTHF (1.00 L)中之溶液中。使反應混合物升溫至0℃且在該溫度攪拌1小時。用飽和氯化銨水溶液(10.0 L)稀釋反應混合物,且用EA (3.0 L×4)萃取水層。合併有機層且經Na
2SO
4乾燥,且過濾經乾燥溶液。濃縮濾液,得到呈深棕色固體之標題化合物(50 g,粗物質)。
步驟3:2-(2-氟丙-2-基)嘧啶-4-胺
在0℃,將DAST (414 mL,3.13 mol,10.0當量)添加至2-(4-胺基嘧啶-2-基)丙-2-醇(48.0 g,313 mmol,1.00當量)於DCM (1.30 L)中之溶液中。在0℃攪拌反應混合物0.5小時,且接著用水(4.50 L)稀釋。用氫氧化鈉水溶液(0.50 L)及碳酸鈉溶液(200 mL)將反應混合物調節至pH=7~8,接著用EA (2.00 L×3)萃取。合併有機層且經Na
2SO
4乾燥,且過濾經乾燥溶液且濃縮。殘餘物藉由rp-HPLC (中性條件)純化,得到呈白色固體之標題化合物(13.0 g)。
1H NMR (400MHz DMSO-
d6) δ 8.05 - 8.07 (d,
J= 5.6Hz), 6.93 (s, 1H), 6.32 - 6.33 (d,
J= 5.6Hz, 1H), 1.63 (s, 3H), 1.58 (s, 3H)。
步驟 1:5-胺基-3-(丙-1-烯-2-基)吡𠯤-2-甲腈
將5-胺基-3-氯吡𠯤-2-甲腈(50.0 g,324 mmol,1.00當量)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧雜硼雜環戊烷(dioxaborolane) (81.54 g,485.3 mmol,1.50當量)、K
2CO
3(89.42 g,647.0 mmol,2.00當量)及Pd(PPh
3)
4(18.69 g,16.18 mmol,0.05當量)於二㗁烷(250 mL)及H
2O (50 mL)中之混合物在100℃在N
2下攪拌20小時。隨後將反應混合物冷卻至環境溫度且用EA (800 mL)及H
2O (300 mL)稀釋。隨後經由矽藻土過濾兩相混合物,隨後分配。有機層用鹽水(500 mL×4)洗,且隨後有機層經Na
2SO
4乾燥,過濾且真空濃縮。殘餘物藉由矽膠急驟管柱層析(梯度溶離,10%至33% EA-石油醚)純化,得到呈淡黃色固體之標題化合物(41.0 g,39.0%產率)。
步驟 2:5-胺基-3-異丙基吡𠯤-2-甲腈
將Pd/C (10重量%,10.0 g)添加至5-胺基-3-(丙-1-烯-2-基)吡𠯤-2-甲腈(45.0 g,281 mmol,1.00當量)於MeOH (800 mL)中之溶液中。使懸浮液真空脫氣且用H
2吹掃三次。在H
2(15 psi)下在25℃下攪拌反應混合物16小時。經由矽藻土過濾混合物且真空濃縮濾液。殘餘物用石油醚/EA (110 mL,10:1)處理且在25℃下攪拌10分鐘,隨後過濾。在真空下乾燥濾餅,得到呈淡黃色固體狀之標題化合物(39.5 g,85.6%產率)。MS (ES+) C
8H
10N
4需值:162,實驗值:163[M+H]
+。
1H NMR: 400 MHz CDCl
3δ: 7.83 (s, 1H), 5.07 (br s, 2H), 3.43-3.33 (m, 1H), 1.28 (s, 3H), 1.26 (s, 3H)。
步驟 1:(
S)
-5-胺基-3-(2-甲基吡咯啶-1-基)吡𠯤-2-甲腈
將N,N-二異丙基乙胺(0.237 mL,1.36 mmol,3.00當量)添加至5-胺基-3-氯吡𠯤-2-甲腈(70.0 mg,453 umol,1.00當量)及(
S)
-2-甲基吡咯啶(HCl鹽,71.6 mg,589 umol,1.30當量)於2-甲基-2-丁醇(2 mL)中之混合物中。在100℃下攪拌反應混合物3小時,隨後倒入20 mL水中且用EA (15 mL×3)萃取。有機層藉由無水硫酸鈉乾燥,過濾且減壓濃縮,得到呈黃色固體狀之標題化合物(90.0 mg,粗產物),其未經進一步純化即使用。MS (ES+) C
10H
13N
5需值:203,實驗值:204[M+H]
+。
步驟 1 :(
S)
-2-(2-甲基吡咯啶-1-基)嘧啶-4-胺
在密封小瓶中將2-氯嘧啶-4-胺(1.0 g,7.72 mmol)、(2S)-2-甲基吡咯啶鹽酸鹽(1.03 g,8.49 mmol)及DIPEA (2.02 mL,11.6 mmol)於IPA (15 mL)中之混合物加熱至95℃。在95℃下攪拌反應混合物16小時,接著濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(0至10% MeOH
-DCM)純化,得到呈白色固體狀之標題化合物。MS (ES+) C
9H
14N
4需值:178,實驗值:179[M+H]
+。
步驟 1 :(
S)
-2-(2-甲基氮雜環丁烷-1-基)嘧啶-4-胺
標題化合物使用與上文針對中間物18所描述類似的程序,由2-氯嘧啶-4-胺及(
S)
-2-甲基氮雜環丁烷鹽酸鹽製備。MS (ES+) C
8H
12N
4需值:164,實驗值:165[M+H]
+。
步驟 1 :4-溴-6-氯-2,7-㖠啶-1(2
H)-酮
將NBS (70.9 g,398 mmol,1.20當量)添加至6-氯-2,7-㖠啶-1(2H)-酮(60.0 g,332 mmol,1.00當量)於DMF (600 mL)中之溶液中。在20℃下攪拌反應混合物2小時,隨後倒入水(1 L)中且過濾。在真空下乾燥濾餅,得到呈棕色固體狀之4-溴-6-氯-2,7-㖠啶-1(2H)-酮(90.8 g,粗物質)。MS (ES+) C
8H
4BrClN
2O需值:260,實驗值:261[M+H]
+。
步驟 2 :4-溴-1,6-二氯-2,7-㖠啶
在25℃下,將4-溴-6-氯-2,7-㖠啶-1(2H)-酮(70.8 g,272 mmol,1.00當量)逐份添加至POCl
3(484 g,3.16 mol,293 mL,11.5當量)。隨後在110℃下攪拌反應混合物3小時。隨後真空濃縮反應混合物,且在25℃下用飽和Na
2CO
3水溶液將殘餘物調節至pH=8。混合物用DCM (500 mL×3)萃取,用鹽水(500 mL)洗滌,經Na
2SO
4乾燥,過濾且真空濃縮,得到呈黃色固體狀之標題化合物(75.0 g,269 mmol,98.9%產率)。MS (ES+) C
8H
3BrCl
2N
2需值:278,實驗值:279[M+H]
+。
步驟 1 :4-溴-6-氯-1-甲氧基-2,7-㖠啶
在25℃下攪拌4-溴-1,6-二氯-2,7-㖠啶(75.0 g,269 mmol,1.00當量)、K
2CO
3(111 g,809 mmol,3.00當量)於MeOH (3 L)中之懸浮液16小時。隨後真空濃縮反應混合物,且將殘餘物溶解於H
2O (300 mL)中且用DCM (100 mL×2)萃取。真空濃縮合併之有機層,得到殘餘物。殘餘物在PE/EA (40 mL 20:1)中濕磨且過濾。在真空下乾燥濾餅,得到呈黃色固體狀之標題化合物(47.0 g,171 mmol,63.6%產率)。
步驟 2 :6-氯-4-(1-乙氧基乙烯基)-1-甲氧基-2,7-㖠啶
在80℃下在N
2下攪拌4-溴-6-氯-1-甲氧基-2,7-㖠啶(47.0 g,171 mmol,1.00當量)、三丁基(1-乙氧基乙烯基)錫烷(74.4 g,206 mmol,69.6 mL,1.20當量)及Pd(PPh
3)
4(19.8 g,17.1 mmol,0.10當量)於甲苯(500 mL)中之溶液16小時。隨後使反應混合物冷卻至20℃且倒入飽和KF水溶液(500 mL)中且攪拌1小時。用EA (300 mL×3)萃取水性混合物,且合併有機層。真空濃縮合併之有機層,得到呈黃色油狀之標題化合物(64.0 g,粗產物)。MS (ES+) C
13H
13ClN
2O
2需值:264,實驗值:265[M+H]
+。
步驟 3 :1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)乙-1-酮
將HCl水溶液(1.50 M,20.1 mL,0.10當量)添加至6-氯-4-(1-乙氧基乙烯基)-1-甲氧基-2,7-㖠啶(80.0 g,302 mmol,1.00當量)於THF (480 mL)及H
2O (80 mL)中之溶液中。在25℃下攪拌反應混合物1小時。隨後將反應混合物倒入飽和NaHCO
3水溶液(500 mL)中且用EA (300 mL×2)萃取。合併有機層且真空濃縮。殘餘物藉由矽膠急驟管柱層析(梯度溶離,5%至50% EA-PE)純化,得到呈白色固體狀之標題化合物(28.0 g,118 mmol,39.1%產率)。MS (ES+) C
11H
9ClN
2O
2需值:236,實驗值:237[M+H]
+。
步驟 4 :1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)乙-1-醇
向1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)乙-1-酮(500 mg,2.11 mmol)於MeOH (10 mL)中之溶液中添加NaBH
4(120 mg,3.17 mmol)。在25℃下攪拌混合物10分鐘,隨後藉由添加水(5 mL)來淬滅且用EA (5 mL×3)萃取。濃縮合併之有機層,得到殘餘物。殘餘物藉由管柱層析(SiO
2,PE/EA=10/1至1:1)純化,得到呈灰白色固體狀之標題化合物(400 mg,79%產率)。
步驟 1 :4-溴-6-氯
-N-甲基-2,7-㖠啶-1-胺
向4-溴-6-氯-2,7-㖠啶-1(2H)-酮(600 mg,2.31 mmol)於DMF (15 mL)中之溶液中添加DBU (528 mg,3.47 mmol,523 uL)及BOP (1.53 g,3.47 mmol),接著向反應混合物中添加甲胺(2 M,3.04 g)且在25℃下攪拌1小時。隨後用水(10 mL)稀釋反應混合物,過濾且乾燥濾餅,得到呈黃色固體狀之標題化合物(440 mg,70%產率),其不經進一步純化即使用。MS (ES+) C
9H
7BrClN
3需值:271,實驗值:272[M+H]
+。
步驟 2-3 :1-(6-氯-1-(甲基胺基)-2,7-㖠啶-4-基)乙-1-酮
標題化合物使用與中間物20之步驟2-3中所描述類似的程序,由4-溴-6-氯
-N-甲基-2,7-㖠啶-1-胺製備。
步驟 4 :2-(6-氯-1-(甲基胺基)-2,7-㖠啶-4-基)丙-2-醇
在0℃下,向1-(6-氯-1-(甲基胺基)-2,7-㖠啶-4-基)乙-1-酮(100 mg,424 umol)於THF (8 mL)中之溶液中添加MeMgBr (3 M,424 uL)。在0℃下攪拌反應混合物0.5小時,隨後藉由添加水(17 mL)來淬滅且用EA (15 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由製備型TLC (矽膠,PE:EA=1:1)純化,得到呈黃色固體狀之標題化合物(50.0 mg,47%產率)。MS (ES+) C
12H
14ClN
3O需值:251,實驗值:252[M+H]
+。
步驟 1 :2-(6-氯-1-甲氧基-2,7-㖠啶-4-基)丙-2-醇
在0℃下,向1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)乙-1-酮(220 mg,930 umol)於THF (10 mL)中之溶液中添加MeMgBr (3 M,930 uL)。在0℃下攪拌反應混合物0.5小時,隨後藉由添加水(17 mL)淬滅,用EA (15 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色固體狀之標題化合物(200 mg,85%產率),其不經進一步純化即用於下一步驟中。MS (ES+) C
12H
13ClN
2O
2需值:252,實驗值:253[M+H]
+。
步驟 1 :2-(6-氯-1-甲氧基-2,7-㖠啶-4-基)-1,1-二氟丙-2-醇
向1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)乙-1-酮(100 mg,423 umol)及二氟甲基(三甲基)矽烷(105 mg,845 umol)於DME (3 mL)中之溶液添加18-冠-6 (78.2 mg,296 umol)及CsF (44.9 mg,296 umol)。在25℃下攪拌反應混合物12小時,接著過濾且濃縮,得到殘餘物。殘餘物藉由製備型TLC (PE:EA=5:1)純化,得到呈黃色固體狀之標題化合物(70.0 mg,57%產率)。MS (ES+) C
12H
11ClF
2N
2O
2需值:288,實驗值:289[M+H]
+。
步驟 1 :6-氯-1-甲氧基-4-乙烯基-2,7-㖠啶
在80℃下攪拌4-溴-6-氯-1-甲氧基-2,7-㖠啶(23.5 g,85.9 mmol)、三氟(乙烯基)硼酸鉀(15.0 g,112 mmol)、Et
3N (17.4 g,172 mmol)及Pd(dppf)Cl
2(6.29 g,8.59 mmol)於H
2O (48 mL)及EtOH (480 mL)中之混合物12小時。隨後用EA (300 mL)及鹽水(100 mL)稀釋反應混合物。將有機層經Na
2SO
4乾燥,過濾並濃縮。殘餘物藉由矽膠管柱層析(PE/EA=10/1)純化,得到呈白色固體狀之標題化合物(10 g,粗物質),其不經進一步純化即使用。
步驟 2 :6-氯-1-甲氧基-2,7-㖠啶-4-甲醛
將6-氯-1-甲氧基-4-乙烯基-2,7-㖠啶(800 mg,3.63 mmol)於DCM (6 mL)及MeOH (1 mL)中之溶液冷卻至-78℃,接著將臭氧鼓泡至反應混合物中。10分鐘後,用氮氣吹掃反應混合物,且隨後添加Me
2S (4.45 g,71.6)且使混合物升溫至25℃。在25℃下攪拌50分鐘後,將反應混合物倒入水(20 mL)中且用EA (20 mL×3)萃取。合併之有機層用水(20 mL×3)洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟層析(PE/EA=10:1至1:1)純化,得到呈黃色固體狀之標題化合物(400 mg,50%產率)。
步驟 3 :1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)丙-1-醇
在20℃下一次性向6-氯-1-甲氧基-2,7-㖠啶-4-甲醛(100 mg,284 umol)於THF (2 mL)中之溶液中添加EtMgBr (5.65 g,39.8 mmol)。在20℃下攪拌反應混合物1小時,隨後用水(20 mL)淬滅且用EA (20 mL×3)萃取。合併之有機層用水(20 mL×3)洗滌,經硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(50 mg,48%產率)。
1H NMR (400MHz, CDCl
3) δ ppm 9.41 (s, 1H), 8.20 (s, 1H), 8.03 (s, 1H), 5.00-4.96 (m, 1H), 4.17 (s, 3H), 2.01-1.94 (m, 2H), 1.00 (t,
J= 7.6 Hz, 3H)。
步驟 1 :2-(6-氯-1-甲氧基-2,7-㖠啶-4-基)丁-2-醇
在0℃下,向1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)乙-1-酮(1 g,4.23 mmol)於THF (20 mL)中之溶液中添加EtMgBr (3 M,4.23 mL)。移除冷卻浴,且在25℃下攪拌反應混合物0.5小時。隨後將反應混合物分配於EA (60 mL)與飽和氯化銨水溶液(40 mL)之間。有機層用飽和氯化鈉水溶液(40 mL×3)洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO
2,PE/EA=100/1至2/1)純化,得到呈白色固體狀之標題化合物(400 mg,28%產率)。MS (ES+) C
13H
15ClN
2O
2需值:266,實驗值:267[M+H]
+。
1H-NMR (400 MHz, CD
3OD): δ ppm 9.36 (s, 1H), 8.67 (s, 1H), 8.20 (s, 1H), 4.16 (s, 3H), 2.08-2.04 (m, 2H), 1.70 (s, 3H), 0.81 (d,
J= 7.6 Hz, 3H)。
步驟 1 :1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)乙烷-1,2-二醇
一次性向6-氯-1-甲氧基-4-乙烯基-2,7-㖠啶(15 g,68.0 mmol)及NMO (15.9 g,136 mmol,14.4 mL)於丙酮(300 mL)及H
2O (75 mL)中之混合物中添加OsO
4(173 mg,680 umol)。在25℃下攪拌反應混合物12小時,接著用飽和Na
2SO
3水溶液(100 mL)淬滅。過濾混合物,且濃縮濾液以移除有機溶劑。水層用EA (3×200 mL)萃取。合併之有機層經Na
2SO
4乾燥,過濾且濃縮,得到呈黃色固體狀之標題化合物(9.8 g,粗物質),其不經進一步純化即用於下一步驟中。
步驟 2 :1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)-2-甲氧基乙-1-醇
向1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)乙烷-1,2-二醇(1 g,3.93 mmol)及TBAB (127 mg,393 umol)於H
2O (4 mL)及THF (20 mL)中之溶液中添加NaOH (471 mg,11.8 mmol)於H
2O (4 mL)中之溶液,接著添加Me
2SO
4(594 mg,4.71 mmol)。在25℃下攪拌反應混合物4小時,且隨後添加更多Me
2SO
4(594 mg,4.71 mmol)。在25℃下再攪拌反應混合物12小時,隨後將混合物分配於EA (150 mL)與H
2O (50 mL)之間。將有機層經Na
2SO
4乾燥,過濾並濃縮。殘餘物藉由矽膠管柱(PE/EA=1:2)純化,接著藉由製備型HPLC (管柱:Waters Xbridge C18 150×50 mm×10 um;移動相:[水(0.05%氫氧化氨v/v)-ACN];B%:18%-48%,11分鐘)純化,得到標題化合物,其為具有區位異構體之1:1混合物。混合物藉由手性SFC (管柱:Daicel Chiralpak AD (250 mm×30 mm,10 um);移動相:[0.1%NH3H
2O ETOH];B%:25%-25%)分離,得到標題化合物作為第二溶離峰。MS (ES+) C
12H
13ClN
2O
3需值:268,實驗值:269[M+H]
+。
1H NMR (400 MHz, CD
3Cl): δ ppm 9.43 (s, 1H), 8.19 (s, 1H), 8.00 (s, 1H), 4.72-4.65 (m, 1H), 4.18 (s, 3H), 3.95-3.85 (m, 1H), 3.76-3.70 (m, 1H), 3.37 (s, 3H), 2.36-2.30 (m, 1H)。
步驟 1 :4-溴-6-氯
-N-環丙基-2,7-㖠啶-1-胺
在80℃下攪拌4-溴-1,6-二氯-2,7-㖠啶(2.00 g,7.20 mmol)、環丙胺(493 mg,8.64 mmol)及DIPEA (2.79 g,21.6 mmol)於NMP (20 mL)中之溶液2小時。隨後將反應混合物倒入水(200 mL)中且過濾。濾餅經乾燥,得到呈黃色固體狀之標題化合物(2.50 g,粗物質),其不經進一步純化即用於下一步驟中。MS (ES+) C
11H
9BrClN
3需值:297,實驗值:298[M+H]
+。
步驟 2-3 :1-(6-氯-1-(環丙基胺基)-2,7-㖠啶-4-基)乙-1-酮
標題化合物使用與中間物20之步驟2-3中所描述類似的程序,由4-溴-6-氯
-N-環丙基-2,7-㖠啶-1-胺製備。
步驟 4 :(
R)
-2-(6-氯-1-(環丙基胺基)-2,7-㖠啶-4-基)丁-2-醇及(
S)
-2-(6-氯-1-(環丙基胺基)-2,7-㖠啶-4-基)丁-2-醇
向1-(6-氯-1-(環丙基胺基)-2,7-㖠啶-4-基)乙-1-酮(850 mg,3.25 mmol)於THF (170 mL)中之溶液中添加EtMgBr (3 M,3 mL)。反應混合物在15℃下攪拌0.5小時,接著藉由添加飽和氯化銨溶液(200 mL)淬滅且用EA (200 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠層析(PE:EA=1:0至1:1)純化,得到呈黃色固體狀之標題化合物之外消旋混合物(360 mg,37%產率)。外消旋體藉由手性SFC (管柱:Daicel Chiralpak IC (250mm×30mm,10um);移動相:[0.1%NH
3H
2O MEOH];B%:40%-40%)分離,得到呈黃色固體狀之(
R)
-2-(6-氯-1-(環丙基胺基)-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-(環丙基胺基)-2,7-㖠啶-4-基)丁-2-醇中之第一者(峰1,中間物27,120 mg,33 %產率)及呈黃色固體狀之(
R)
-2-(6-氯-1-(環丙基胺基)-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-(環丙基胺基)-2,7-㖠啶-4-基)丁-2-醇中之第二者(峰2,中間物28,120 mg,33%)。MS (ES+) C
15H
18ClN
3O需值:291,實驗值:292[M+H]
+。
步驟 1:N-(5-溴-2-甲氧基苯甲基)-2,2-二乙氧基乙醯亞胺醯胺
在N
2氛圍下,將2,2-二乙氧基乙亞胺酸甲酯(8.9 g,55.5 mmol)添加至(5-溴-2-甲氧基-苯基)甲胺(10 g,46.3 mmol)於MeOH (100 mL)中之溶液中。在25℃攪拌混合物12小時。LCMS顯示偵測到所需質量。將反應混合物過濾且減壓濃縮,得到殘餘物。殘餘物用H
2O (50 mL)稀釋且用DCM 200 mL (50 mL×4)萃取。合併之有機層用飽和NaCl水溶液(50 mL)洗滌,經Na
2SO
4乾燥,過濾且減壓濃縮,得到呈白色固體狀之標題化合物(12 g,粗物質),其未經進一步純化即用於下一步驟中。
步驟 2 :5-溴-8-甲氧基異喹啉-3-胺
在0℃下,將N-(5-溴-2-甲氧基苯甲基)-2,2-二乙氧基乙醯亞胺醯胺(11 g,31.9 mmol)添加至H
2SO
4(111.61 g,1.1 mol,60.6 mL,98%純度)中,且隨後在25℃下在N
2氛圍下攪拌混合物3小時。在0℃下反應混合物藉由添加含NaOH (120 g)之H
2O (5 L)淬滅且用2-MeTHF (1 L×2)萃取。合併之有機層用飽和NaCl水溶液(1 L)洗滌,經Na
2SO
4乾燥,過濾且減壓濃縮,得到殘餘物。殘餘物藉由逆相製備型HPLC純化,得到呈黃色固體狀之標題化合物(3 g,11.8 mmol,37%產率)。
步驟 3 :5-(1-乙氧基乙烯基)-8-甲氧基異喹啉-3-胺
在N
2氛圍下,將Pd(PPh
3)
4(1.02 g,884.8 µmol)及三丁基(1-乙氧基乙烯基)錫烷(6.79 g,18.8 mmol,6.3 mL)添加至5-溴-8-甲氧基異喹啉-3-胺(2.8 g,11.1 mmol)於甲苯(30 mL)中之溶液中。在100℃下,在N
2氛圍下,攪拌混合物4小時。在0℃下反應混合物藉由添加CsF水溶液(60 mL)淬滅且用EA (40 mL×3)萃取。合併之有機層用飽和NaCl水溶液(50 mL)洗滌,經Na
2SO
4乾燥,過濾且減壓濃縮,得到呈棕色油狀之標題化合物(2.7 g,粗物質),其未經進一步純化即用於下一步驟中。
步驟 4 :1-(3-胺基-8-甲氧基異喹啉-5-基)乙-1-酮
在25℃下在N
2氛圍下攪拌5-(1-乙氧基乙烯基)-8-甲氧基異喹啉-3-胺(2.7 g,11.1 mmol)於THF (20 mL)及HCl (1M,11 mL)中之混合物30分鐘。過濾反應混合物,得到呈黃色固體狀之標題化合物(1.1 g,粗物質),其未經進一步純化即用於下一步驟中。
步驟 5 :1-(3-氯-8-甲氧基異喹啉-5-基)乙-1-酮
在N
2氛圍下,將吡啶鹽酸鹽(1.03 g,8.9 mmol)、CuCl (25.2 mg,254.3 umol,6.08 uL)及NaNO
2(614.2 mg,8.9 mmol)添加至1-(3-胺基-8-甲氧基異喹啉-5-基)乙-1-酮(550 mg,2.5 mmol)於DCM (5 mL)中之溶液中。隨後在-10℃下,將HCl (37.6 mg,381.5 umol,36.9 uL,37%純度)添加至反應混合物,且在0℃下攪拌混合物30分鐘。在N
2氛圍下在25℃攪拌混合物1小時。將反應混合物過濾且減壓濃縮,得到殘餘物。殘餘物藉由急驟管柱層析純化,得到呈白色固體狀之標題化合物(530 mg,44%產率)。
步驟 6 :2-(3-氯-8-甲氧基異喹啉-5-基)丙-2-醇
在N
2氛圍下,將MeMgBr (3M/THF,1.41 mL)添加至1-(3-氯-8-甲氧基異喹啉-5-基)乙-1-酮(200 mg,848.7 umol)於THF (2 mL)中之溶液中,且在25℃下在N
2氛圍下攪拌反應混合物1小時。在0℃下藉由添加H
2O (10 mL)淬滅反應混合物。將反應混合物過濾且減壓濃縮,得到殘餘物。殘餘物藉由急驟管柱層析純化,得到呈黃色固體狀之標題化合物(580 mg,90.5%產率)。
步驟 1:4-溴-6-氯-1-環丙氧基-2,7-㖠啶
向4-溴-1,6-二氯-2,7-㖠啶(10.5 g,37.78 mmol)及環丙醇(4.39 g,75.6 mmol)於ACN (100 mL)中之溶液中添加K
2CO
3(15.7 g,113 mmol)。在60℃下攪拌反應混合物16小時,接著向反應混合物中添加額外的環丙醇(4.39 g,75.6 mmol)且將其再加熱至70℃持續3小時。接著濃縮反應混合物,得到殘餘物。用水(200 mL)稀釋殘餘物,過濾且乾燥濾餅,得到呈黃色固體狀之標題化合物(11.3 g,99%產率)。
步驟 2-3:1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)乙-1-酮
標題化合物使用與中間物20之步驟2-3中所描述類似的程序,由4-溴-6-氯-1-環丙氧基-2,7-㖠啶製備。
步驟 4 :2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)丙-2-醇
標題化合物使用與中間物22之步驟1中所描述類似的程序,由1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)乙-1-酮製備。MS (ES+) C
14H
15ClN
2O
2需值:278,實驗值:279[M+H]
+。
步驟 1 :4-溴-6-氯-1-乙氧基-2,7-㖠啶
在50℃攪拌4-溴-1,6-二氯-2,7-㖠啶(3.00 g,10.7 mmol)及K
2CO
3(4.48 g,32.3 mmol)於EtOH (30 mL)中之混合物16小時,接著濃縮,得到殘餘物。用水(100 mL)處理殘餘物,過濾,且乾燥濾餅,得到呈白色固體狀之標題化合物(3.00 g,97%產率)。MS (ES+) C
10H
8BrClN
2O需值:288,實驗值:289[M+H]
+。
步驟 2-3 :1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)乙-1-酮
標題化合物使用與中間物20之步驟2-3中所描述類似的程序,由4-溴-6-氯-1-乙氧基-2,7-㖠啶製備。
步驟 4 :(
R)
-2-(6-氯-1-乙氧基-2,7-㖠啶-4-基)丁-2-醇及(
S)
-2-(6-氯-1-乙氧基-2,7-㖠啶-4-基)丁-2-醇
標題化合物之外消旋體使用與中間物27之步驟4中所描述類似的程序,由1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)乙-1-酮製備。混合物藉由手性SFC (管柱:Daicel Chiralpak AD (250mm×30mm,10um);移動相:[0.1%NH
3H
2O ETOH];B%:20%-20%)分離,得到呈黃色油狀之(
R)
-2-(6-氯-1-乙氧基-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-乙氧基-2,7-㖠啶-4-基)丁-2-醇中之第一者(峰1,中間物31,50.0 mg,50%產率)及呈黃色油狀之(
R)
-2-(6-氯-1-乙氧基-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-乙氧基-2,7-㖠啶-4-基)丁-2-醇中之第二者(峰2,中間物32,50.0 mg,50%產率)。
步驟 1:1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-環丙基乙-1-醇
在15℃下,向1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)乙-1-酮(500 mg,1.90 mmol)於MTBE (8 mL)中之溶液中添加溴化環丙基鎂(3 M,3.17 mL)。將混合物加熱至60℃持續1小時,接著藉由添加飽和氯化銨水溶液(20 mL)淬滅且用水(20 mL)稀釋。所得混合物用EA (30 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由急驟矽膠層析(溶離劑為0~65% EA/PE)純化,得到呈白色固體狀之標題化合物(460 mg,72%產率)。MS (ES+) C
16H
17ClN
2O
2需值:304,實驗值:305[M+H]
+。
步驟 1 :(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)丁-2-醇及(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)丁-2-醇
在0℃下,向1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)乙-1-酮(300 mg,1.14 mmol)於MTBE (10 mL)中之溶液中添加EtMgBr (3 M,1.14 mL)。在0℃下攪拌反應混合物15分鐘,隨後用飽和氯化銨水溶液(20 mL)淬滅且用EA (25 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO
2,PE:EA=10:1至3:1)純化,得到呈黃色固體狀之標題化合物之外消旋混合物(300 mg,84%產率)。
1H-NMR (400 MHz, CDCl
3): δ ppm 9.31 (s, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 4.55-4.47 (m, 1H), 2.13-2.05 (m, 2H), 1.75 (s, 3H), 0.94-0.91 (m, 4H), 0.90-0.85 (m, 3H)。混合物藉由手性SFC (管柱:Daicel Chiralpak IG (250mm×30mm,10 um);移動相:[0.1% NH
3H
2O MeOH];B%:30%-30%)分離,得到呈黃色固體狀之(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)丁-2-醇中之第一者(峰1,中間物34,90.0 mg,60%產率)及呈黃色固體狀之(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)丁-2-醇中之第二者(峰2,中間物35,105 mg,70%產率)。
實例 2n 中間物 36 及 37 :(
R)
-1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)-1-環丙基乙-1-醇及(
S)
-1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)-1-環丙基乙-1-醇
步驟 1 :(
R)
-1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)-1-環丙基乙-1-醇及(
S)
-1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)-1-環丙基乙-1-醇
向1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)乙-1-酮(300 mg,1.20 mmol)於MTBE (20 mL)中之溶液中添加溴化環丙基鎂(0.5 M,11.9 mL)。在60℃下攪拌混合物0.5小時,隨後藉由添加飽和氯化銨水溶液(30 mL)淬滅且用EA (2×30 mL)萃取。合併之有機層經硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由製備型TLC (PE/EA=1/1)純化,得到呈黃色油狀之標題化合物之外消旋混合物(80.0 mg,23%產率)。混合物藉由手性SFC (管柱:Daicel Chiralpak IG (250mm×30mm,10um);移動相:[0.1%NH
3H
2O MEOH];B%:30%-30%) 4分鐘)分離,得到呈黃色固體狀之(
R)
-1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)-1-環丙基乙-1-醇或(
S)
-1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)-1-環丙基乙-1-醇中之第一者(峰1,中間物36,40.0 mg,50%產率)及呈黃色固體狀之(
R)
-1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)-1-環丙基乙-1-醇或(
S)
-1-(6-氯-1-乙氧基-2,7-㖠啶-4-基)-1-環丙基乙-1-醇中之第二者(峰2,中間物37,40.0 mg,50%產率)。
實例 2o 中間物 38 及 39 :(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-甲氧基丙-2-醇及(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-甲氧基丙-2-醇
步驟 1 :6-氯-1-環丙氧基-4-(丙-1-烯-2-基)-2,7-㖠啶
在80℃攪拌4-溴-6-氯-1-環丙氧基-2,7-㖠啶(8 g,26.7 mmol)、4,4,5,5-四甲基-2-(丙-1-烯-2-基)-1,3,2-二氧雜硼雜環戊烷(4.71 g,28.0 mmol)、Pd(dppf)Cl
2(1.95 g,2.67 mmol)及K
2CO
3(11.1 g,80.1 mmol)於二㗁烷(150 mL)及H
2O (30 mL)中之混合物2小時。隨後反應混合物用EA (100 mL)萃取,且有機層用鹽水(100 mL)洗滌,經Na
2SO
4乾燥,過濾且濃縮。殘餘物藉由矽膠管柱層析(PE/EA=10/1)純化,得到呈無色油狀之標題化合物(5.7 g,78%產率)。
步驟 2 :6-氯-1-環丙氧基-4-(2-甲基環氧乙烷-2-基)-2,7-㖠啶
向6-氯-1-環丙氧基-4-(丙-1-烯-2-基)-2,7-㖠啶(5.7 g,21.9 mmol)於DCM (80 mL)中之溶液逐份添加mCPBA (7.07 g,32.8 mmol,80%純度)。在25℃下攪拌反應混合物2小時,接著用飽和Na
2SO
3水溶液(100 mL)淬滅且用EA (100 mL)萃取。將有機層經Na
2SO
4乾燥,過濾並濃縮。殘餘物藉由矽膠管柱層析(PE/EA=4/1)純化,得到呈白色固體狀之標題化合物(2.2 g,28%產率)。MS (ES+) C
14H
13ClN
2O
2需值:276,實驗值:277[M+H]
+。
步驟 3 :2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)丙烷-1,2-二醇
在25℃下,向6-氯-1-環丙氧基-4-(2-甲基環氧乙烷-2-基)-2,7-㖠啶(2.2 g,7.95 mmol)於THF (16 mL)中之溶液中逐滴添加H
2SO
4(780 mg,7.95 mmol)於H
2O (4 mL)中之溶液。在60℃下攪拌反應混合物0.5小時,隨後倒入飽和NaHCO
3水溶液(50 mL)中且用EA (100 mL)萃取。有機層經Na
2SO
4乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(2.1 g,70%產率),其不經進一步純化即用於下一步驟中。MS (ES+) C
14H
15ClN
2O
3需值:294,實驗值:295[M+H]
+。
步驟 4 :(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-甲氧基丙-2-醇及(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-甲氧基丙-2-醇
在25℃下,向2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)丙烷-1,2-二醇(500 mg,1.33 mmol)於THF (10 mL)中之溶液中添加NaH (133 mg,3.33 mmol,60%純度)。在25℃下攪拌反應混合物0.5小時,且隨後添加CH
3I (198 mg,1.40 mmol)。在25℃下攪拌反應混合物4小時,接著過濾且濃縮。殘餘物藉由製備型HPLC (管柱:Phenomenex luna C18 150×40 mm×15 um;移動相:[水(0.225% FA) - ACN];B%:35%-65%,10分鐘)純化,得到呈黃色油狀之標題化合物之外消旋混合物(100 mg,23%產率)。MS (ES+) C
15H
17ClN
2O
3需值:308,實驗值:309[M+H]
+。混合物藉由手性SFC (管柱:Daicel Chiralpak IG (250 mm×30 mm,10 um);移動相:[0.1% NH
3H
2O-MEOH];B%:25%-25%)分離,得到呈黃色固體狀之(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-甲氧基丙-2-醇或(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-甲氧基丙-2-醇中之第一者(峰1,中間物38,135 mg,34%產率)及(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-甲氧基丙-2-醇或(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-甲氧基丙-2-醇中之第二者(峰2,中間物39,25 mg,25%產率)。
步驟 1 :4-溴-6-氯-1-((1-氟環丙基)甲氧基)-2,7-㖠啶
向4-溴-1,6-二氯-2,7-㖠啶-1 (771 mg,2.77 mmol)及(1-氟環丙基)甲醇(500 mg,5.55 mmol)於ACN (15 mL)中之溶液中添加K
2CO
3(1.15 g,8.32 mmol)及CsF (422 mg,2.77 mmol)。在60℃下攪拌反應混合物12小時,接著濃縮。殘餘物藉由矽膠管柱層析[PE:EA=10:1]純化,得到呈無色油狀之標題化合物(800 mg,87%產率)。
步驟 2-3 :1-(6-氯-1-((1-氟環丙基)甲氧基)-2,7-㖠啶-4-基)乙-1-酮
標題化合物使用與中間物20之步驟2-3中所描述類似的程序,由4-溴-6-氯-1-((1-氟環丙基)甲氧基)-2,7-㖠啶製備。
步驟 4 :2-(6-氯-1-((1-氟環丙基)甲氧基)-2,7-㖠啶-4-基)丙-2-醇
向1-(6-氯-1-((1-氟環丙基)甲氧基)-2,7-㖠啶-4-基)乙-1-酮(310 mg,1.05 mmol)於MBTE (4.00 mL)中之溶液中添加MeMgBr (3 mol,1.75 mL)。在25℃下攪拌反應混合物0.5小時,隨後倒入飽和氯化銨水溶液(20 mL)中且用EA (40 mL×3)萃取。合併之有機層用水、鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮。殘餘物藉由矽膠管柱層析[PE:EA=20:1至2:1]純化,得到呈黃色油狀之標題化合物(440 mg,粗物質)。
實例 2q 中間物 41 及 42 :(
S)
-1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-環丁基乙-1-醇及(
R)
-1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-環丁基乙-1-醇
步驟 1 :(
S)
-1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-環丁基乙-1-醇(
R)
-1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-環丁基乙-1-醇
在70℃下,向1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)乙-1-酮(300 mg,1.14 mmol)於MTBE (20 mL)中之溶液中添加溴化環丁基鎂(0.5 M,7 mL)。在70℃下攪拌反應混合物1小時,接著藉由在20℃下添加水(30 mL)淬滅。混合物用EA (30 mL×2)萃取,且合併之有機層用水(30 mL)洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由製備型HPLC (管柱:Phenomenex luna C18 150×40 mm×15 um;移動相:[水(0.1% TFA)-ACN];B%:47%-77%,11分鐘)純化,得到呈黃色油狀之標題化合物之外消旋混合物(110 mg,27%產率)。混合物藉由手性SFC (管柱:Daicel Chiralpak IG (250 mm×30 mm,10 um);移動相:[0.1% NH
3H
2O MEOH];B%:30%-30%)分離,得到呈黃色固體狀之(
S)
-1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-環丁基乙-1-醇或(
R)
-1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-環丁基乙-1-醇中之第一者(峰1,中間物41,30.0 mg,27%產率)及呈黃色固體狀之(
S)
-1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-環丁基乙-1-醇或(
R)
-1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-環丁基乙-1-醇中之第二者(峰2,中間物42,30.0 mg,27%產率)。
步驟 1 :1-(3-((4-溴-6-氯-2,7-㖠啶-1-基)氧基)氮雜環丁烷-1-基)乙-1-酮
在0℃下,將氫化鈉(2.15 g,53.8 mmol,60重量%)添加至1-(3-羥基氮雜環丁烷-1-基)乙-1-酮(Combi-Blocks #ST-8959) (5.16 g,44.8 mmol)於THF (200 mL)中之溶液中。移除冷卻浴,攪拌反應混合物0.5小時,且接著添加4-溴-1,6-二氯-2,7-㖠啶(12.4 g,44.8 mmol)。在25℃下在MeOH中攪拌反應混合物1小時,接著藉由添加水(70 mL)淬滅。經淬滅之反應混合物用EA萃取,經硫酸鈉乾燥,過濾且濃縮,得到標題化合物(10.0 g,63%產率)。
步驟 2 :1-(3-((6-氯-4-(1-乙氧基乙烯基)-2,7-㖠啶-1-基)氧基)氮雜環丁烷-1-基)乙-1-酮
將化合物三丁基(1-乙氧基乙烯基)錫烷(9.14 g,25.3 mmol1-(3-((4-溴-6-氯-2,7-㖠啶-1-基)氧基)氮雜環丁烷-1-基)乙-1-酮(8.20 g,23.0 mmol)及Pd(PPh
3)
4(2.66 g,2.30 mmol)於甲苯(150 mL)中之混合物脫氣且用氮氣吹掃3次,且隨後在100℃下攪拌混合物16小時。使反應混合物冷卻至環境溫度,藉由添加飽和KF水溶液(300 mL)淬滅,用水(100 mL)稀釋且用EA (200 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析純化,得到呈黃色固體狀之標題化合物(7.50 g,94%產率)。
步驟 3 :1-(3-((4-乙醯基-6-氯-2,7-㖠啶-1-基)氧基)氮雜環丁烷-1-基)乙-1-酮
在20℃下,將鹽酸水溶液(6 M,0.5 mL)添加至1-(3-((6-氯-4-(1-乙氧基乙烯基)-2,7-㖠啶-1-基)氧基)氮雜環丁烷-1-基)乙-1-酮(6.90 g,19.8 mmol)於THF (105 mL)及水(35 mL)中之溶液中。在20℃下攪拌反應混合物1小時,隨後用水(300 mL)稀釋且用EA (200 mL×3)萃取。用硫酸鈉乾燥合併之有機層,將其過濾且濃縮。殘餘物藉由矽膠急驟管柱層析(梯度溶離,0%至100% EA-PE)純化,得到呈黃色固體狀之標題化合物(5.00 g,79%產率)。
步驟 4 及 5 :1-(3-((6-氯-4-(2-羥基丙-2-基)-2,7-㖠啶-1-基)氧基)氮雜環丁烷-1-基)乙-1-酮
在0℃下,將溴化甲基鎂(3 M於二乙醚中,14 mL)添加至1-(3-((4-乙醯基-6-氯-2,7-㖠啶-1-基)氧基)氮雜環丁烷-1-基)乙-1-酮(4.50 g,14.1 mmol)於THF (200 mL)中之溶液中。在0℃下攪拌反應混合物15分鐘,隨後用水(200 mL)淬滅且用EA (150 mL×3)萃取。合併之有機層經硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之1-(3-((6-氯-4-(2-羥基丙-2-基)-2,7-㖠啶-1-基)氧基)氮雜環丁烷-1-基)乙-1-酮及2-(1-(氮雜環丁烷-3-基氧基)-6-氯-2,7-㖠啶-4-基)丙-2-醇(4.10 g,99%產率)之混合物。將混合物溶解於DCM (50 mL)中且添加TEA (3.53 g,34.9 mmol)及乙酸酐(2.14 g,20.9 mmol)。在25℃下攪拌反應混合物1小時,隨後用水(200 mL)稀釋且用DCM (150 mL×3)萃取。合併之有機層經硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠急驟管柱層析(梯度溶離,50%至100% EA-PE,接著5%至10% MeOH
-EA)純化,得到呈黃色油狀之標題化合物(4.10 g,87%產率)。
步驟 1 :4-溴-6-氯-1-(2,2-二氟乙氧基)-2,7-㖠啶
在0℃下,將NaH (60重量%,0.863 g,21.6 mmol)添加至2,2-二氟乙-1-醇(1.624 g,19.79 mmol)於DMF (36 mL)中之溶液中。在0℃攪拌反應混合物30分鐘,接著一次性添加4-溴-1,6-二氯-2,7-㖠啶(5.0 g,18 mmol)。自冷卻浴移出反應混合物且在25℃下攪拌3小時。反應混合物接著用EA稀釋且用飽和碳酸氫鈉水溶液、鹽水洗滌,經硫酸鈉乾燥,過濾且濃縮。殘餘物藉由矽膠急驟管柱層析(20-100% EA-己烷)純化,得到呈黃色固體狀之標題化合物(2.1 g,36%產率)。
步驟 2-3 :1-(6-氯-1-(2,2-二氟乙氧基)-2,7-㖠啶-4-基)乙-1-酮
標題化合物使用與中間物20之步驟2-3中所描述類似的程序,由4-溴-6-氯-1-(2,2-二氟乙氧基)-2,7-㖠啶製備。
步驟 4 :1-(6-氯-1-(2,2-二氟乙氧基)-2,7-㖠啶-4-基)-1-環丙基乙-1-醇
在25℃下,將溴化環丙基鎂(0.5 M,3.49 mL,1.74 mmol)添加至1-(6-氯-1-(2,2-二氟乙氧基)-2,7-㖠啶-4-基)乙-1-酮(0.25 g,0.87 mmol)之溶液中。反應混合物在25℃下攪拌30分鐘,隨後用EA稀釋且用飽和碳酸氫鈉水溶液、鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮。殘餘物藉由矽膠急驟管柱層析(20-100% EA:己烷)純化,得到標題化合物(106 mg,37.0%產率)。MS (ES+) C
15H
15ClF
2N
2O
2需值:328,實驗值:329[M+H]
+。
實例 2t 中間物 45 及 46 :(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1,1,1-三氟丙-2-醇及(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1,1,1-三氟丙-2-醇
步驟 1 :(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1,1,1-三氟丙-2-醇及(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1,1,1-三氟丙-2-醇
向1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)乙-1-酮(300 mg,1.14 mmol)及TMSCF
3(244 mg,1.71 mmol)於THF (20 mL)中之溶液中添加TBAF (1 M,228 uL)。在20℃下攪拌反應混合物15分鐘,隨後藉由添加水(30 mL)來淬滅且用EA (30 mL×2)萃取。合併之有機層用水(30 mL)洗滌,經無水硫酸鈉乾燥,過濾且濃縮。殘餘物藉由製備型HPLC (管柱:Waters Xbridge 150×25 mm×5 um;移動相:[水(0.05%氫氧化銨v/v)-ACN];B%:41%-61%,10分鐘)純化,得到呈黃色固體狀之標題化合物之外消旋混合物(250 mg,65%產率)。
1H-NMR (400 MHz, CDCl
3): δ ppm 9.24 (s, 1H), 8.52 (s, 1H), 8.26 (s, 1H), 4.50-4.45(m, 1H), 2.88(s, 1H), 1.93(s, 3H), 0.86(d,
J= 5.2 Hz, 4H)。混合物藉由手性SFC (管柱:Daicel Chiralpak OJ-H (250 mm×30 mm,5 um);移動相:[0.1%NH
3H
2O IPA];B%:15%-15%)分離,得到呈黃色固體狀之(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1,1,1-三氟丙-2-醇或(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1,1,1-三氟丙-2-醇中之第一者(峰1,中間物45,100 mg,83%產率)及(
R)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1,1,1-三氟丙-2-醇或(
S)
-2-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1,1,1-三氟丙-2-醇中之第二者(峰2,中間物46,110 mg,92%產率)。
實例 2u 中間物 47 及 48 :(
R)
-2-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)丁-2-醇及(
S)
-2-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)丁-2-醇
步驟 1-3 :1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)乙-1-酮
標題化合物使用與中間物44之步驟1及中間物20之步驟2-3中所描述類似的程序,由4-溴-1,6-二氯-2,7-㖠啶及2,2,2-三氟乙-1-醇製備。
步驟 4 :(
R)
-2-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)丁-2-醇及(
S)
-2-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)丁-2-醇
在40℃下,向1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)乙-1-酮(300 mg,984 umol)於MTBE (10 mL)中之溶液中添加EtMgBr (3 M,1.64 mL)。在40℃下攪拌反應混合物0.5小時,隨後藉由添加飽和氯化銨水溶液(30 mL)淬滅且用EA (3×30 mL)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由製備型HPLC管柱(Phenomenex Gemini-NX C18 75×30mm×3um;移動相:[水(0.1%TFA)-ACN];B%:55%-65%,7分鐘)純化,得到呈黃色固體狀之標題化合物之外消旋混合物(50.0 mg,15%產率)。混合物藉由手性SFC (管柱:Chiralpak AD-3 50×4.6mm I.D.,3um;移動相:相A針對CO
2,且相B針對EtOH (0.05%DEA);溶離梯度:B/A 5%至40%)分離,得到呈黃色油狀之(
R)
-2-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)丁-2-醇中之第一者(峰1,中間物47,25 mg,50%產率)及呈黃色油狀之(
R)
-2-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)丁-2-醇中之第二者(峰2,中間物48,25 mg,50%產率)。
實例 2v 中間物 49 及 50 :(
S)
-1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)-1-環丙基乙-1-醇及(
R)
-1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)-1-環丙基乙-1-醇
步驟 1 :(
S)
-1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)-1-環丙基乙-1-醇及(
R)
-1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)-1-環丙基乙-1-醇
將1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)乙-1-酮(200 mg,656 μmol)於MTBE (5 mL)中之混合物脫氣且用氮氣吹掃3次,且接著添加溴化環丙基鎂(0.5 M,2.63 mL)。在60℃下攪拌反應混合物0.5小時,隨後藉由在25℃下添加飽和氯化銨水溶液(30 mL)淬滅且用EA (30 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO
2,PE/EA=1/0至5/1)純化,得到呈黃色固體狀之標題化合物之外消旋混合物(90.0 mg,40%產率)。MS (ES+) C
15H
14ClF
3N
2O
2需值:346,實驗值:347[M+H]
+。外消旋混合物藉由手性SFC (管柱:Daicel Chiralpak AD-H (250mm×30mm,5um);移動相:[0.1%NH
3H
2O IPA];B%:20%-20%)分離,得到呈白色油狀之(
S)
-1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)-1-環丙基乙-1-醇或(
R)
-1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)-1-環丙基乙-1-醇中之第一者(峰1,中間物49,35.0 mg,39%產率)及呈白色油狀之(
S)
-1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)-1-環丙基乙-1-醇或(
R)
-1-(6-氯-1-(2,2,2-三氟乙氧基)-2,7-㖠啶-4-基)-1-環丙基乙-1-醇中之第二者(峰2,中間物50,45.0 mg,50%產率)。MS (ES+) C
15H
14ClF
3N
2O
2需值:346,實驗值:347[M+H]
+。
步驟 1 :1-(6-氯-1-羥基-2,7-㖠啶-4-基)乙-1-酮
向1-(6-氯-1-甲氧基-2,7-㖠啶-4-基)乙-1-酮(3.00 g,12.7 mmol)於THF (30 mL)中之溶液中添加HCl水溶液(6 M,20 mL)。在25℃下攪拌反應混合物16小時,隨後用水(80 mL)稀釋且用EA (60 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈白色固體狀之標題化合物(2.80 g,99%產率),其不經進一步純化即用於下一步驟中。
1H NMR (400 MHz, 6
d-DMSO): δ ppm 12.45 (s, 1H), 9.16 (s, 1H), 8.80 (s, 1H), 8.45 (d,
J= 3.2 Hz, 1H), 2.53 (s, 3H)。
步驟 2 :1-(1,6-二氯-2,7-㖠啶-4-基)乙-1-酮
將1-(6-氯-1-羥基-2,7-㖠啶-4-基)乙-1-酮(1.00 g,4.49 mmol)添加至POCl
3(10 mL)中,且在100℃下攪拌反應混合物且攪拌2小時。隨後將反應混合物冷卻至23℃且緩慢倒入飽和碳酸氫鈉水溶液(500 mL)中。用EA (200 mL×3)萃取混合物。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮。殘餘物藉由矽膠管柱層析(PE:EA=1:0至3:1)純化,得到呈白色固體狀之標題化合物(660 mg,58%產率)。
1H NMR (400 MHz, CDCl
3): δ ppm 9.62 (s, 1H), 9.01 (s, 1H), 8.95 (s, 1H), 2.78 (s, 3H)。
步驟 3 :1-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)乙-1-酮
在0℃下,向順-3-(甲磺醯基)環丁-1-醇(685 mg,4.56 mmol)於THF (10 mL)中之溶液中添加NaH (199 mg,4.98 mmol,60%純度)。在25℃下攪拌反應混合物0.5小時,隨後添加1-(1,6-二氯-2,7-㖠啶-4-基)乙-1-酮(1.00 g,4.15 mmol)且在25℃下攪拌混合物0.5小時。隨後用飽和氯化鈉水溶液(50 mL)稀釋反應混合物且用EA (50 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO
2,PE/EA=1:0至1:4)純化,得到呈黃色固體狀之標題化合物(1.05 g,2.96 mmol,71%產率)。MS (ES+) C
15H
15ClN
2O
4S需值:354,實驗值:355[M+H]
+。
步驟 4 :2-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)丙-2-醇
在25℃下,向1-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)乙-1-酮(350 mg,986 μmol)於THF (10 mL)中之溶液中添加MeMgBr (3 M,1.64 mL)。在25℃下攪拌反應混合物30分鐘,接著用飽和氯化銨水溶液(25 mL)稀釋且用EA (25 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO
2,PE/EA=0:1至1:3)純化,得到呈黃色固體狀之標題化合物(170 mg,46%產率)。MS (ES+) C
16H
19ClN
2O
4S需值:370,實驗值:371[M+H]
+。
實例 2x 中間物 52 及 53 :(
R)
-2-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)丁-2-醇及(
S)
-2-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)丁-2-醇
步驟 1 :(
R)
-2-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)丁-2-醇及(
S)
-2-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)丁-2-醇
在0℃下,向1-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)乙-1-酮(650 mg,1.83 mmol,1當量)於THF (10 mL)中之溶液中添加EtMgBr (3 M,1.83 mL,3當量)。移除冷卻浴,且在25℃下攪拌反應混合物15分鐘。藉由添加水(50 mL)淬滅反應混合物且用EA (50 mL×3)萃取。有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO
2,PE/EA = 1/0至0/1),接著製備型HPLC (管柱:Phenomenex Gemini-NX C18 75×30mm×3um;移動相:[水(0.225%FA) -ACN];B%:28%-58%,7分鐘)純化,得到呈黃色固體狀之標題化合物之外消旋混合物(110 mg,15.6%產率)。混合物藉由手性SFC (管柱:Chiralpak IG-3 50×4.6mm I.D.,3um移動相:相A針對CO
2,且相B針對MeOH (0.05%DEA);溶離梯度:40% MeOH (0.05% DEA)於CO
2中)分離,得到呈黃色固體狀之(
R)
-2-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)丁-2-醇中之第一者(峰1,中間物52,40 mg)及呈黃色固體狀之(
R)
-2-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-(順-3-(甲磺醯基)環丁氧基)-2,7-㖠啶-4-基)丁-2-醇中之第二者(峰2,中間物53,40 mg)。MS (ES+) C
17H
21ClN
2O
4S需值:384,實驗值:385[M+H]
+。
步驟 1 :2-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-2-醇
向2-(1-(氮雜環丁烷-3-基氧基)-6-氯-2,7-㖠啶-4-基)丙-2-醇(50 mg,170 umol)及Et
3N (51.7 mg,511 umol,71.1 uL)於DCM (5 mL)中之溶液中添加MsCl (14.5 uL,187 umol)。在25℃下攪拌反應混合物2小時,隨後藉由添加水(20 mL)來淬滅且用EA (20 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由製備型TLC (PE:EA=0:1)純化,得到呈白色固體狀之標題化合物(40 mg,61%產率)。
實例 2z 中間物 55 及 56 :(
S)
-1-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-1-醇及(
R)
-1-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-1-醇
步驟 1 :1-(氮雜環丁烷-3-基氧基)-4-溴-6-氯-2,7-㖠啶
在20℃下,向TFA (16.5 g,145 mmol)於DCM (11 mL)中之溶液中添加3-((4-溴-6-氯-2,7-㖠啶-1-基)氧基)氮雜環丁烷-1-甲酸三級丁酯(3.00 g,7.23 mmol)。在20℃下攪拌反應混合物30分鐘,接著濃縮,得到呈黃色油狀之標題化合物(3.10 g,TFA,粗物質),其不經進一步純化即使用。
步驟 2 :4-溴-6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶
在0℃下,向1-(氮雜環丁烷-3-基氧基)-4-溴-6-氯-2,7-㖠啶(3.10 g,7.23 mmol,TFA)於DCM (30 mL)中之溶液中添加Et
3N (1.83 g,18.1 mmol),接著添加MsCl (911 mg,7.96 mmol)於DCM (2 mL)中之溶液。在0℃下攪拌反應物混合物1小時,接著用水(10 mL)淬滅且用DCM (20 ml×3)萃取。合併之有機層用水(20 mL)洗滌,經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由急驟矽膠層析(溶離劑為0~50% EA/PE)純化,得到呈灰白色固體狀之標題化合物(2.00 g,67%產率)。
步驟 3 :6-氯-4-(2-甲基丙-1-烯-1-基)-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶
在80℃攪拌4-溴-6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶(2.00 g,5.09 mmol)、4,4,5,5-四甲基-2-(2-甲基丙-1-烯-1-基)-1,3,2-二氧雜硼雜環戊烷(974 mg,5.35 mmol)、Pd(dppf)Cl
2(373 mg,509 μmol)及K
2CO
3(1.41 g,10.2 mmol)於二㗁烷(40 mL)及水(1 mL)中之混合物16小時。隨後濃縮反應混合物,且藉由急驟矽膠層析(溶離劑為0~30% EA/DCM)純化殘餘物,得到呈灰白色固體狀之標題化合物(1.40 g,75%產率)。
步驟 4 :6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-甲醛
將6-氯-4-(2-甲基丙-1-烯-1-基)-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶(1.20 g,3.26 mmol)於MeOH (1.2 mL)及DCM (36 ml)中之溶液冷卻至-78℃。在15 psi下,將臭氧鼓泡至反應混合物5分鐘。隨後用N
2吹掃反應混合物,且隨後將Me
2S (2.03 g,32.6 mmol)添加至反應混合物中。使反應混合物升溫至25℃且攪拌2小時,接著濃縮,得到呈白色固體狀之標題化合物(1.10 g,粗物質)。MS (ES+) C
13H
12ClN
3O
4S需值:341,實驗值:342[M+H]
+。
步驟 5 :(
S)
-1-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-1-醇及®-1-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-1-醇
在20℃下一次性向6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-甲醛(500 mg,1.46 mmol)於THF (6 ml)中之溶液中添加EtMgBr (3 M,1.46 ml)。在20℃下攪拌反應混合物10分鐘,接著用鹽水(1 mL)淬滅且濃縮,得到殘餘物。殘餘物藉由急驟矽膠層析(溶離劑為0~50% EA/PE)純化,得到呈白色固體狀之標題化合物之外消旋混合物(400 mg,70%產率)。
1H NMR:
(400 MHz, CD
3OD): δ ppm 9.45 (s, 1H), 8.15 (s, 1H), 7.90-8.15 (m, 1H), 5.60-5.40 (m, 1H), 5.10-4.90 (m, 1H), 4.50-4.40 (m, 2H), 4.30-4.10 (m, 2H), 2.95 (s, 3H), 2.00-1.90 (m, 2H), 1.10-0.90 (m, 3H)。混合物藉由手性SFC (管柱:Daicel Chiralpak IG (250mm×30mm,10μm);移動相:[Neu-MeOH];B%:60%-60%)分離,得到(
S)
-1-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-1-醇或®-1-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-1-醇中之第一者(峰1,中間物55,170 mg,42%產率),且獲得呈白色固體狀之(
S)
-1-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-1-醇或®-1-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-1-醇中之第二者(峰2,中間物56,170 mg,42%產率)。
實例 2aa 中間物 57 及 58 :(
R)
-2-(6-氯-1-(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)-2,7-㖠啶-4-基)丁-2-醇及(
S)
-2-(6-氯-1-(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)-2,7-㖠啶-4-基)丁-2-醇
步驟 1 :(2
R,4
R)-4-((三級丁基二甲基矽烷基)氧基)戊-2-醇
在0℃下,向(2
R,4
R)-戊烷-2,4-二醇(3.80 g,36.5 mmol)於THF (120 mL)中之溶液中添加NaH (1.75 g,43.8 mmol,60%純度)。攪拌反應混合物30分鐘,隨後添加三級丁基二甲基氯矽烷(6.05 g,40.1 mmol)且在25℃下攪拌反應混合物1.5小時。隨後將反應混合物添加至水(200 mL)中且用EA (150 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠管柱層析(PE/EA=1:0至5:1)純化,得到呈無色油狀之標題化合物(7.80 g,98%產率)。
步驟 2 :4-硝基苯甲酸(2
S,4
R)-4-((三級丁基二甲基矽烷基)氧基)戊-2-基酯
在0℃下,向(2
R,4
R)-4-((三級丁基二甲基矽烷基)氧基)戊-2-醇(1.00 g,4.58 mmol)、化合物4-硝基苯甲酸(1.53 g,9.16 mmol)及三苯基膦(3.60 g,13.7 mmol)於THF (34 mL)中之溶液中添加DIAD (2.78 g,13.74 mmol)。在0℃下攪拌反應混合物30分鐘,隨後在25℃下攪拌15.5小時,用水(50 mL)稀釋且用EA (40 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠管柱層析(PE/EA=1:0至10:1)純化,得到呈黃色油狀之標題化合物(1.50 g,78%產率)。
步驟 3 :(2
S,4
R)-4-((三級丁基二甲基矽烷基)氧基)戊-2-醇
向4-硝基苯甲酸(2
S,4
R)-4-((三級丁基二甲基矽烷基)氧基)戊-2-基酯(1.50 g,4.08 mmol)於THF (12 mL)及水(4 mL)中之溶液中添加LiOH•H
2O (977 mg,40.8 mmol)。在60℃下攪拌反應混合物1小時,隨後用水(50 mL)稀釋且用EA (40 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(890 mg,100%產率),其不經進一步純化即用於下一步驟中。
步驟 4 :甲烷磺酸(2
S,4
R)-4-((三級丁基二甲基矽烷基)氧基)戊-2-基酯
在0℃下,向(2
S,4
R)-4-((三級丁基二甲基矽烷基)氧基)戊-2-醇(890 mg,4.07 mmol)於DCM (15 mL)中之溶液中添加TEA (1.24 g,12.2 mmol)及MsCl (934 mg,8.15 mmol)。攪拌反應混合物1小時,接著用水(100 mL)稀釋且用DCM (80 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(1.20 g,99%產率),其不經進一步純化即用於下一步驟中。
步驟 5 :三級丁基二甲基(((2
R,4
R)-4-(甲基硫基)戊-2-基)氧基)矽烷
向化合物甲烷磺酸(2
S,4
R)-4-((三級丁基二甲基矽烷基)氧基)戊-2-基酯(1.20 g,4.05 mmol)於DMF (30 mL)中之溶液中添加甲硫醇鈉(709 mg,10.1 mmol)。在25℃下攪拌反應混合物0.5小時,隨後用水(80 mL)稀釋且用EA (60 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(1.00 g,99%產率),其不經進一步純化即用於下一步驟中。
步驟 6 :三級丁基二甲基(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)矽烷
向三級丁基二甲基(((2
R,4
R)-4-(甲基硫基)戊-2-基)氧基)矽烷(1.00 g,4.02 mmol)於THF (14 mL)及水(7 mL)中之溶液中添加Oxone® (4.95 g,8.05 mmol)。在25℃下攪拌反應混合物0.5小時,隨後藉由添加飽和亞硫酸鈉水溶液(30 mL)淬滅且用EA (20 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到呈黃色油狀之標題化合物(1.10 g,97%產率),其不經進一步純化即使用。
步驟 7 :(2
R,4
R)-4-(甲磺醯基)戊-2-醇
向三級丁基二甲基(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)矽烷(1.10 g,3.92 mmol)於THF (8 mL)中之溶液中添加HCl水溶液(6 M,2 mL)。在25℃下攪拌反應混合物0.5小時,隨後用水(50 mL)稀釋且用EA (40 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由矽膠管柱層析(PE/EA=1:0至0:1)純化,得到呈黃色油狀之標題化合物(230 mg,35%產率)。
步驟 8 :2-(1,6-二氯-2,7-㖠啶-4-基)丁-2-醇
在25℃下,向1-(1,6-二氯-2,7-㖠啶-4-基)乙-1-酮(540 mg,2.24 mmol)於MTBE (216 mL)中之溶液中添加EtMgBr (3 M,2.24 mL)。在25℃下攪拌反應混合物0.5小時,隨後藉由添加飽和氯化銨水溶液(20 mL)淬滅,用水(10 mL)稀釋且用EA (40 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由急驟矽膠層析(溶離劑為0~40% EA/PE)純化,得到呈黃色固體狀之標題化合物(320 mg,50%產率)。
步驟 9 :(
R)
-2-(6-氯-1-(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)-2,7-㖠啶-4-基)丁-2-醇及(
S)
-2-(6-氯-1-(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)-2,7-㖠啶-4-基)丁-2-醇
在0℃下,向(2
R,4
R)-4-(甲磺醯基)戊-2-醇(290 mg,1.07 mmol)於THF (12 mL)中之溶液中添加NaH (51.3 mg,1.28 mmol,60%純度)。移除冷卻浴,且在25℃下攪拌反應混合物0.5小時,隨後添加2-(1,6-二氯-2,7-㖠啶-4-基)丁-2-醇(267 mg,1.60 mmol)。在25℃下攪拌反應混合物0.5小時,隨後用H
2O (30 mL)淬滅且用EA (40 mL×3)萃取。合併之有機層經無水硫酸鈉乾燥,過濾且濃縮,得到殘餘物。殘餘物藉由管柱層析(SiO
2,PE/EA=1/0至1/1)純化,得到呈黃色油狀之標題化合物之混合物(320 mg,74%產率)。MS (ES+) C
18H
25ClN
2O
4S需值:400,實驗值:401[M+H]
+。混合物藉由手性SFC (管柱:Daicel Chiralpak AD-H (250mm×30mm,5μm);移動相:[0.1%NH
3H
2O EtOH];B%:30%-30%)分離,得到呈白色油狀之(
R)
-2-(6-氯-1-(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)-2,7-㖠啶-4-基)丁-2-醇中之第一者(峰1,中間物57,130 mg,41%產率)及呈白色油狀之(
R)
-2-(6-氯-1-(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)-2,7-㖠啶-4-基)丁-2-醇或(
S)
-2-(6-氯-1-(((2
R,4
R)-4-(甲磺醯基)戊-2-基)氧基)-2,7-㖠啶-4-基)丁-2-醇中之第二者(峰2,中間物58,130 mg,41%產率)。
步驟 1 :1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)-1-苯基乙-1-醇
在23℃下在THF (5.71 ml)中攪拌1-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)乙-1-酮(0.15 g,0.571 mmol)且添加苯基溴化鎂(1.0 M,0.685 ml,0.685 mmol)。反應混合物在23℃下攪拌30分鐘,接著用EA稀釋,用飽和碳酸氫鈉水溶液、鹽水洗滌,經無水硫酸鈉乾燥,過濾且濃縮。殘餘物藉由矽膠急驟管柱層析(20-100% EA:己烷)純化,得到標題化合物(65 mg,33%)。MS (ES+) C
19H
17ClN
2O
2需值:340,實驗值:341[M+H]
+。
步驟 1 :-(6-氯-1-環丙氧基-2,7-㖠啶-4-基)四氫-2
H-哌喃-4-醇
在-78℃下,將正丁基鋰(421 µl,1.052 mmol)逐滴添加至4-溴-6-氯-1-環丙氧基-2,7-㖠啶(300 mg,1.001 mmol)於THF (7 mL)中之溶液中。在-78℃下攪拌反應混合物30分鐘,隨後逐滴添加四氫-4
H-哌喃-4-酮(111 µl,1.202 mmol)。在-78℃下攪拌反應混合物40分鐘,接著藉由添加飽和氯化銨水溶液(4 mL)淬滅。移除冷卻浴,且反應混合物用水稀釋且用EA萃取。有機層經硫酸鈉乾燥,過濾且濃縮。殘餘物藉由矽膠急驟管柱層析(0-90% EA/己烷)純化,得到標題化合物(108 mg,33.6%產率)。
實例 3a :合成方法 1 (7
S,8
R)-2-((5-(2-羥基丙-2-基)-8-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-3-基)胺基)-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(化合物57)
步驟 1 :(7
S,8
R)-2-((5-(2-羥基丙-2-基)-8-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-3-基)胺基)-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮
向2-(6-氯-1-((1-(甲磺醯基)氮雜環丁烷-3-基)氧基)-2,7-㖠啶-4-基)丙-2-醇(30 mg,80.7 umol)及(7
S,8
R)-2-胺基-7,8-二甲基-7,8-二氫-5
H-哌喃并[4,3
-b]吡啶-5-酮(17.1 mg,88.8 umol)於二㗁烷(2 mL)中之溶液中添加BrettPhos (Pd, G4) (7.43 mg,8.07 umol)、BrettPhos (4.33 mg,8.07 umol)及乙酸鉀(23.8 mg,242 umol)。在80℃下,在氮氣下,攪拌混合物1小時。隨後將反應混合物過濾且減壓濃縮,得到殘餘物。反應混合物藉由製備型HPLC (管柱:Phenomenex Synergi C18 150×25×10um;移動相:[水(0.225%FA)-ACN];B%:29%-59%,10分鐘)純化,得到呈淡黃色固體狀之標題化合物(15.4 mg,30%產率)。MS (ES+) C
25H
29N
5O
6S需值:527,實驗值:528[M+H]
+。
1H NMR (400 MHz, CD
3OD)δ ppm 9.40 (s, 1H), 9.27 (s, 1H), 8.15 (s, 1H), 8.13 (s, 1H), 7.32 (d,
J= 8.8 Hz, 1H), 5.60 (s, 1H), 4.70-4.56 (m, 1H), 4.44 (t,
J= 7.8 Hz, 2H), 4.28-4.11 (m, 2H), 3.33 (s, 6H), 3.05 (s, 4H), 1.82 (s, 6H), 1.57-1.45 (m, 6H)。
實例 4 : 抑制 MAP4K1 生物化學酶活性使用Perkin Elmer電泳移動率變動技術平台-EZReader 2監測MAP4K1 (HPK1)及相關偏離目標酶活性。在激酶及ATP存在下且在所給藥化合物存在下培育經螢光標記受質肽,使得化合物之各劑量產生反映將要磷酸化之肽的比例。在激酶的酶反應之線性穩定狀態階段內,使磷酸化(產物)及非磷酸化(受質)肽之混合池在所施加電位差下穿過PerkinElmer EZ Reader 2之微流體系統。產物肽上之磷酸酯基的存在提供受質肽之質量與電荷之間的差異,使得樣品中之受質與產物池分離(Perrin等人2010)。隨著產物及受質肽混合物穿過儀器內之雷射,偵測此等池(λ
ex =488 nm,λ
em =568 nm)且解析為單獨峰。此等峰之間的比率反映化合物在彼等條件下在彼濃度下(在彼孔中)之活性。
酶活性抑制分析方案:將抑制劑以10 mm之儲備濃度溶解於100% DMSO中。在100% DMSO中手動地或在Hamilton STAR液體處置器上對各抑制劑進行100X、10點、4倍連續稀釋,以相關濃度(通常1 mM)開始。使用TTPLabtech Mosquito奈升級施配器一式兩份地將各濃度之0.130 µL的體積轉移至384孔盤(Greiner 781 201)之相關孔中。使用Multidrop Combi向130 nL所給藥化合物中如下添加激酶反應物之其餘組分(關於最終反應細節,參見下表):
在ATP的
APPK
M或1 mM ATP下之酶活性分析:在384孔盤之各孔中,將0.1-15 nM未處理酶與1.5 µM螢光肽及20-1000 µM ATP在25℃下在存在或不存在化合物的所給藥濃度系列(1% DMSO最終濃度)下在總共13 µL緩衝液(100 mM HEPES pH 7.5,0.015% Brij 35,10 mM MgCl2,1mM DTT)中培育60至180分鐘。藉由添加70 µl終止緩衝液(100 mM HEPES pH 7.5,0.015% Brij 35,35 mM EDTA及0.2%塗佈試劑3 (Caliper Lifesciences))來中止激酶反應。在上文所述之Caliper EZReader 2上讀取盤。
表 2 激酶反應條件
S6K2tide;CarNa Biosciences (5-FAM-專用序列-CONH2)
FL4tide;Perkin Elmer (5-FAM-EGIYGVLFKKK (SEQ ID NO: 1)-CONH
2)
FL25tide;Perkin Elmer (5-FAM-VDGKEIYNTIRRK (SEQ ID NO: 2)-CONH
2)
PKAtide;ANaspec Peptide Co.(5-FAM-GRTGRRNSI (SEQ ID NO: 3)-CONH
2)
Perrin D, Frémaux C, Shutes A. Capillary microfluidic electrophoretic mobility shift assays: application to enzymatic assays in drug discovery. Expert Opin Drug Discov. 2010,
5(1):51-63。
酶( 來源) | 酶濃度 | ATP 濃度 | 受質肽及濃度 | 激酶反應時間 |
HPK1 (Invitrogen) | 0.5 nM | 26 µM | S6K2tide,1.5 µM | 120 min. |
HPK1 (Invitrogen) | 0.25 nM | 1000 µM | S6K2tide,1.5 µM | 120 min. |
LCK (Invitrogen) | 12 nM | 26 µM | FL4tide,1.5 µM | 60 min. |
HGK (Invitrogen) | 0.1 nM | 50 µM | FL25tide,1.5 µM | 60 min. |
GLK (SigNalChem) | 15 nM | 20 µM | PKAtide,2 µM | 180 min. |
根據實例製備之化合物的此等實驗中獲得的結果概述於下表3中。
表 3
化合物編號 | MAP4K1 IC50 (nM) | IL-2初級T細胞EC50 (nM) |
1 | 121.00 | |
2 | 64.30 | |
3 | 23.10 | |
4 | 2.34 | |
5 | 18.40 | |
6 | 9.23 | |
7 | 17.50 | |
8 | 4.73 | |
9 | 1.63 | |
10 | 1.19 | |
11 | 15.30 | |
12 | 46.50 | |
13 | 6.36 | |
14 | 0.25 | |
15 | 3.06 | |
16 | 0.61 | |
17 | 0.30 | 10 |
18 | 1.65 | |
19 | 14.30 | |
20 | 3.48 | |
21 | 1.98 | |
22 | 23.60 | |
23 | 3.34 | |
24 | 0.39 | |
25 | 27.00 | |
26 | 1.06 | |
27 | 1.70 | 42 |
28 | 3.03 | |
29 | 1.43 | |
30 | 2.38 | |
31 | 0.42 | 47 |
32 | 15.50 | |
33 | 0.56 | |
34 | 2.53 | 132 |
35 | 67.30 | |
36 | 3.86 | |
37 | 2.01 | |
38 | 11.10 | 273 |
39 | 0.46 | 47 |
40 | 2.09 | 169 |
41 | 6.55 | |
42 | 3.38 | |
43 | 6.72 | |
44 | 1.53 | |
45 | 1.91 | |
46 | 31.90 | |
47 | 1.57 | |
48 | 39.50 | |
49 | 0.53 | |
50 | 4.51 | |
51 | 12.30 | |
52 | 23.20 | |
53 | 3.75 | |
54 | 16.90 | |
55 | 15.90 | |
56 | 0.45 | |
57 | 0.20 | |
58 | 2.52 | |
59 | 12.90 | |
60 | 0.29 | 65 |
61 | 0.39 | 23 |
62 | 1.66 | |
63 | 2.94 | |
64 | 0.67 | |
65 | 0.39 | |
66 | 1.74 | |
67 | 0.66 | |
68 | 0.41 | |
69 | 0.89 | |
70 | 0.49 |
亦在實例4之MAP4K1 (HPK1)酶分析中測試屬於式(I)範疇內之額外化合物71-74,參見下表4,且所有此等化合物具有大於10微莫耳濃度之抑制活性。
表 4
化合物編號 | 結構 |
71 | |
72 | |
73 | |
74 |
實例 5 : 細胞介素之 T 細胞增強自全血分離及擴增T細胞
根據製造商的方案,藉由免疫磁性陰性選擇自健康供體之全血分離出T細胞(StemCell Technologies,人類T細胞分離套組)。藉由流動式細胞測量術評定經分離細胞之純度且得到95-98% CD3
+T細胞。為了擴增T細胞,將1×10
6個細胞/孔接種於含有30U重組人類IL2 (R&D)之無血清細胞擴增培養基(ThermoFisher)中且在24孔盤中用25 ul CD3/CD28珠粒(Invitrogen)刺激3-4天。T細胞隨後在175 cm燒瓶中擴增,且藉由每2-3天添加2/3新鮮培養基,將細胞密度維持在1至2.5×10
6個細胞/毫升天下。在10至14天之後,將細胞冷凍於BamBanker冷凍培養基(Thermo)中且儲存於液氮中。藉由流動式細胞測量術對經擴增T細胞進行表型分析,常規地顯示在冷凍時60%細胞為CD8+ T細胞。
細胞介素量測
為了IL2量測,使經擴增CD3
+T細胞以100K個細胞/孔分配(在X-VIVO 10無血清培養基中培養),且在各種濃度的媒劑或本發明之化合物存在下用盤結合的抗CD3及可溶性抗CD28刺激24小時。如製造商的方案(Cisbio)中所概述,將16 µL改良性培養基轉移至白色384孔低容量盤。在與抗IL2抗體一起培育24小時之後,量測均質時間解析螢光(HTRF)。
實例 6 : 在同基因型小鼠模型中抑制抗腫瘤活性產生MCA205同基因型異種移植抗腫瘤功效研究
使六至八週齡雌性C57BL/6小鼠(Jackson Labs,Bar Harbor,ME)在左側腹皮下植入1×10
6個MCA205細胞/小鼠。在腫瘤平均體積達到50 mm
3之後,將小鼠隨機分至各處理組中,每組10隻小鼠,腫瘤尺寸範圍為30-70 mm
3。將本發明之化合物10-30 mg/kg、抗小鼠PD-L1 mAb (B7 H1,純系# 10F.9G2 Bio-X-細胞,Lebanon,NH)及媒劑單獨或以不同組合形式投與負載腫瘤的小鼠。量測腫瘤體積隨時間推移之減少[mm
3]。
等效物在申請專利範圍中,除非相反地指示或另外自上下文顯而易見,否則諸如「一(a/an)」及「該」之冠詞可意謂一或超過一。除非相反地指示或以其他方式自上下文顯而易見,否則若一個、超過一個或所有群成員存在於給定產物或方法中、用於給定產物或方法中或以其他方式與給定產物或方法相關,則在該群的一或多個成員之間包括「或」的申請專利範圍或描述視為滿足。本發明包括其中恰好群組之一個成員存在於給定產物或方法中、用於給定產物或方法中或以其他方式與給定產物或方法相關之實施例。本發明包括其中超過一個或所有群組成員存在於、用於給定產物或方法中或以其他方式與給定產物或方法相關之實施例。
此外,本發明涵蓋所有變化、組合及排列,其中將來自所列的申請專利範圍中之一或多者之一或多個限制、要素、條款及描述性術語引入另一申請專利範圍中。舉例而言,依附於另一技術方案之任何請求項可經修改以包括在依附於同一基本技術方案之任何其他技術方案中可見的一或多個限制。在要素如所列,例如呈馬庫什(Markush)組格式呈現之情況下,亦揭示要素之各子組,且可自該組移除任何要素。應理解,一般而言,當本發明或本發明之態樣稱為包含特定要素及/或特徵時,本發明之某些實施例或本發明之態樣由此類要素及/或特徵組成或基本上由其組成。出於簡單之目的,彼等實施例尚未具體地以詞語闡述在本文中。在給出範圍的情況下,包括端點。此外,除非另外指示或以其他方式自上下文及一般熟習此項技術者的理解顯而易見,否則表示為範圍之值可在本發明之不同實施例中採用所述範圍內之任何特定值或子範圍,除非上下文另外明確規定,否則達到該範圍下限之單位的十分之一。
熟習此項技術者將認識到或能夠僅使用常規實驗即可確定本文所述及主張之本發明之特定實施例的許多等效物。該等等效物欲由隨附申請專利範圍所涵蓋。
TW202321238A_111126410_SEQL.xml
Claims (33)
- 一種式I化合物, , 或其醫藥學上可接受之鹽, 其中: A 1係選自N及CH; A 2係選自CH及N; X係選自C 1 - 3烷基、OR 3、NHR 4及鹵素; B係選自CR 5及N,Y為CR 6,或 Y與B一起形成5至7員雜環或C 5 - 6環烷基,其中該雜環或環烷基視情況經1-6個R 7取代; R 1及R 2各自獨立地選自氫、C 1 - 6烷基、C 1 - 6鹵烷基、經OR 8取代之C 1 - 6烷基、苯基、C 3 - 6環烷基及4至6員雜環,或 R 1及R 2與其所連接之原子一起形成C 3 - 6環烷基或4至6員雜環; R 3係選自C 1 - 3烷基、C 3 - 6環烷基及4至6員雜環,其中該烷基、環烷基及雜環視情況經1-3個R 9取代; R 4係選自氫、C 1 - 3烷基、C 3 - 5環烷基及4至6員雜環,其中該烷基、環烷基及雜環視情況經1-3個R 10取代; R 5係選自氫、COOH、CN、鹵素及C 1 - 3烷氧基; R 6係選自C 1 - 5烷基、C 4 - 6環烷基、3至6員雜環、NHR 11、NR 12R 13及OR 14,其中該烷基、環烷基或雜環視情況經OH、NH 2、1-4個鹵素或R 15取代; 各R 7獨立地選自C 1 - 3烷基、鹵素及OH,其中該烷基視情況經1-3個鹵素取代,或 連接至同一碳之兩個R 7形成側氧基(oxo),或 連接至同一碳原子之兩個R 7與其所連接之碳原子一起形成C 3 - 5環烷基; R 8為H或C 1 - 3烷基; 各R 9獨立地選自C 1 - 3烷基、經鹵素取代之C 3 - 6環烷基、鹵素、C(O)Me、SO 2Me、C(O)NR 16R 17、C 1 - 3烷氧基及OH; 各R 10獨立地選自C 1 - 3烷基、經鹵素取代之C 3 - 6環烷基、鹵素、SO 2Me、C(O)NR 16R 17、C 1 - 3烷氧基及OH; R 11係選自C 1 - 6烷基及C 3 - 6環烷基,其中該烷基或環烷基視情況經1-3個R 18取代; R 12及R 13各自獨立地選自C 1 - 6烷基及C 3 - 6環烷基,其中該烷基或環烷基視情況經1-3個R 18取代; R 14係選自C 1 - 6烷基及C 3 - 6環烷基,其中該烷基或環烷基視情況經1-3個R 18取代; R 15為OH、C 1-3烷基或C 3-5環烷基; R 16及R 17各自獨立地選自C 1 - 6烷基及C 3 - 6環烷基,其中該烷基或環烷基視情況經1-3個R 19取代; 各R 18獨立地為鹵素;及 各R 19獨立地為鹵素。
- 如請求項1至7中任一項之化合物或其醫藥學上可接受之鹽,其中: X為NHR 4;及 R 4為CH 3或環丙基。
- 如請求項1至7中任一項之化合物或其醫藥學上可接受之鹽,其中X為OR 3。
- 如請求項1至9中任一項之化合物或其醫藥學上可接受之鹽,其中: R 1及R 2各自獨立地選自氫、C 1 - 2烷基、C 1 - 2鹵烷基、經OR 8取代之C 1 - 3烷基、苯基及C 3 - 4環烷基,或 R 1及R 2與其所連接之原子一起形成4至6員雜環;及 R 8為C 1 - 2烷基。
- 如請求項1至9中任一項之化合物或其醫藥學上可接受之鹽,其中: R 1及R 2各自獨立地選自氫、CH 3、CH 2CH 3、CH 2OCH 3、CHF 2、CF 3、環丁基、環丙基及苯基,或 R 1及R 2與其所連接之原子一起形成四氫哌喃。
- 如請求項1至7及9至12中任一項之化合物或其醫藥學上可接受之鹽,其中: R 3係選自C 1 - 3烷基、C 3 - 4環烷基及4員雜環;其中該烷基、環烷基及雜環視情況經1-3個R 9取代;及 各R 9獨立地選自C 1 - 3烷基、鹵素、C(O)Me及SO 2Me。
- 如請求項1至7及9至12中任一項之化合物或其醫藥學上可接受之鹽,其中: R 3為含有氮之4員雜環; R 9為C(O)Me;及 該4員雜環之環氮結合至⸾-C(O)Me。
- 如請求項1至7及9至12中任一項之化合物或其醫藥學上可接受之鹽,其中: R 3係選自CH 3、CH 2CH 3、CH 2CH 2CH 3、環丙基、環丁基、氮雜環丁烷基,各自視情況經1-3個R 9取代;及 各R 9獨立地選自CH 3、F、C(O)Me及SO 2Me。
- 如請求項1至4及8至15中任一項之化合物或其醫藥學上可接受之鹽,其中R 5為CN。
- 如請求項1至4及8至16中任一項之化合物或其醫藥學上可接受之鹽,其中: R 6係選自C 1 - 4烷基及4至5員雜環,其中該烷基或雜環視情況經1-4個鹵素或R 15取代;及 R 15為C 1 - 2烷基。
- 如請求項1至16中任一項之化合物或其醫藥學上可接受之鹽,其中: 各R 7獨立地為CH 3,或 連接至同一碳之兩個R 7形成側氧基,或 連接至同一碳原子之兩個R 7與其所連接之碳原子一起形成環丙基。
- 一種表1之化合物或其醫藥學上可接受之鹽。
- 一種醫藥組合物,其包含如請求項1至22中任一項之化合物或其醫藥學上可接受之鹽及醫藥學上可接受之載劑或賦形劑。
- 一種抑制有需要之個體之MAP4K1的方法,其包含使MAP4K1與有效量之如請求項1至22中任一項之化合物或其醫藥學上可接受之鹽;或如請求項23之醫藥組合物接觸。
- 一種用於增強有需要之個體之免疫反應的方法,其包含向該個體投與有效量之如請求項1至22中任一項之化合物或其醫藥學上可接受之鹽;或如請求項23之醫藥組合物。
- 一種用於治療有需要之個體之MAP4K1依賴性病症或疾病的方法,其包含向該個體投與有效量的如請求項1至22中任一項之化合物或其醫藥學上可接受之鹽;或如請求項23之醫藥組合物。
- 如請求項26之方法,其中該MAP4K1依賴性疾病或病症為癌症。
- 如請求項27之方法,其中該癌症包含至少一種選自由以下組成之群的癌症:大腸癌、胰臟癌、乳癌、前列腺癌、肺癌、卵巢癌、子宮頸癌、腎癌、膀胱癌、胃癌、肝癌、頭頸癌、淋巴瘤、白血病及黑色素瘤。
- 如請求項26或27之方法,其中該方法進一步包含向該個體投與另外抗癌劑。
- 如請求項26之方法,其中該MAP4K1依賴性病症或疾病為病毒感染。
- 如請求項1至22中任一項之化合物或其醫藥學上可接受之鹽,其用於治療MAP4K1依賴性疾病或病症。
- 如請求項31之化合物,其中該MAP4K1依賴性疾病或病症為癌症。
- 一種如請求項1至22中任一項之化合物或其醫藥學上可接受之鹽之用途,其用於製備治療MAP4K1依賴性疾病或病症之藥劑。
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KR101607288B1 (ko) | 2005-07-01 | 2016-04-05 | 이. 알. 스퀴부 앤드 선즈, 엘.엘.씨. | 예정 사멸 리간드 1 (피디-엘1)에 대한 인간 모노클로날 항체 |
US20070087988A1 (en) | 2005-09-30 | 2007-04-19 | New York University | Hematopoietic progenitor kinase 1 for modulation of an immune response |
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US20080125470A1 (en) | 2006-09-19 | 2008-05-29 | Incyte Corporation | N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
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